Endocrine Clark

ELSEVIER
SAUNDERS
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TEXTBOOK OF ENDOCRINE SURGERY
ISBN 0-7216-0139-1
Copyright 2005, 1997 Elsevier Inc.
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Libraryof CongressCataloging-in-Publication Data
NOTICE
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or
appropriate. Readers are advised to check the most current information provided (i) on procedures
featured or (ii) by the manufacturer of each product to be administered, to verify the recommended
dose or formula, the method and duration of administration, and contraindications. It is the
responsibility of the practitioner, relying on their own experience and knowledge of the patient, to
make diagnoses, to determine dosages and the best treatment for each individual patient, and to
take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the
EditorslAuthors assumes any liability for any injury and/or damage to persons or property arising
out or related to any use of the material contained in this book.
Textbook of endocrine surgery / [edited by] Orlo H. Clark, Quan-Yang Duh,

Electron Kebebew. - 2nd ed.
p. . crn.
Includes bibliographical references and index.
ISBN 0-7216-0139-1
I. Endocrine glands-Surgery. 2. Endocrine glands-Diseases. I. Clark, Orlo H. II. Duh,
Quan-Yang. III. Kebebew, Electron.
[DNLM: 1. Endocrine System Diseases-surgery. 2. Endocrine Glands-surgery. WK
140 T355 2006]
RD599.T492006
2005042824
617.4' 4-dc22
Acquisitions Editor: Judith Fletcher

Publishing Services Manager: Tina Rebane
Project Manager: Norm Stellander
Design Manager: Gene Harris
Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
We would like to dedicate this book to our wives, Carol, Ann, and Tida, and families, and to
Ms. Kate Poole. Their wonderful support helped to make this book possible.
Claudette Abela-Forman EK, MD

Assistant Professor, Department of Ophthalmology,
Medical University of Vienna; Senior Resident, General
Hospital of Vienna, Vienna, Austria
Metabolic Complications of Primary Hyperparathyroidism
Bo Ahren, MD, PhD
Professor, Department of Medicine, Lund University,
Lund, Sweden
Pancreatic Endocrine Physiology
Goran Akerstrom, MD, PhD
Professor of Surgery, Uppsala University; Professor of
Surgery and Chief of Endocrine Surgery, Department of
Surgical Sciences, University Hospital, Uppsala, Sweden
Natural History of Untreated Primary
Hyperparathyroidism
Maha AI-Fehaily, MD
Associate Consultant, Breast and Endocrine Surgery,
King Faisal Specialist Hospital and Research Centre,
Department of Surgery, Riyadh, Saudi Arabia
Sporadic Nontoxic Goiter
Saif AI-Sobhi, MD, FRCS (Glas), ABIS
Chairman, Department of Surgery, King Faisal Specialist
Hospital and Research Centre, Riyadh, Saudi Arabia
Parathyroid Hyperplasia: Parathyroidectomy
Ahmad Assalia, MD
Deputy Director, Department of Surgery, Rambam Medical
Center, Haifa, Israel
Laparoscopic Adrenalectomy
Jon Armstrong, MD
Clinical Instructor, University of Perth, Royal Perth
Hospital; Senior Surgeon, General and Endocrine
Surgery, Royal Perth Hospital, Perth, Western Australia,
Australia
Adrenocortical Carcinoma: Nonfunctioning and
Functioning
Sylvia L. Asa, MD, PhD
Professor, Department of Laboratory Medicine and
Pathobiology, University of Toronto, Toronto;
Pathologist-in-Chief, University Health Network, and
Medical Director, Toronto Medical Laboratories,
Toronto, Ontario, Canada
Anaplastic Carcinoma of the Thyroid Gland
Anders O. J. Bergenfelz, MD, PhD

Associate Professor, Lund University; Consultant Surgeon,
Department of Surgery, University Hospital,
Lund, Sweden
Surgical Approach to Primary Hyperparathyroidism
(Unilateral Approach)
Piero Berti, MD
Professor of Surgery, University of Pisa; Assistant,
S. Chiara Hospital, Pisa, Italy
Minimally Invasive Parathyroid Surgery
Michael Sean Boger, MD, PharmD
House Officer, Department of Internal Medicine,
Wake Forest University Baptist Medical Center,
Winston-Salem, North Carolina
Graves' and Plummer's Diseases: Medical and Surgical
Management
H. Jaap Bonjer, MD, PhD
Professor of Surgery, Dalhousie University; Director of
Minimally Invasive Surgery, Queen Elizabeth II Health
Sciences Center, Halifax, Nova Scotia, Canada
Technique of Parathyroidectomy
Bert A. Bonsing, MD, PhD
Staff Surgeon, Department of Surgery, Leiden University
Medical Center, Leiden, Germany
Occurrence and Prevention of Complications in Thyroid
Surgery
Michael Brauckhoff, MD
Department of General, Visceral, and Vascular Surgery,
University of Halle, Halle, Germany
Surgical Management ofAdvanced Thyroid Cancer
Invading the Aerodigestive Tract
James D. Brierley, MB BS, MRCP, FRCP, FRCP (C)
Associate Professor, Department of Radiation Oncology,
University of Toronto, Toronto; Staff Radiation
Oncologist, Princess Margaret Hospital, University
Health Network, Toronto, Ontario, Canada
Hajo A. Bruining, MD, PhD
Emeritus Professor of Surgery, Erasmus University,
Rotterdam, The Netherlands
vi - - Contributors
Laurent Brunaud, MD, PhD
Professor of Surgery, University of Nancy; Staff Surgeon,
Department of General and Endocrine Surgery,
Chu Nancy-Brabois, Nancy, France
Comparative Genomic Hybridization in Thyroid
Neoplasms; Neuroendocrine Tumors
Blake Cady, MD
Professor of Surgery, Brown Medical School; Interim
Director, Comprehensive Breast Center,
Rhode Island Hospital, Providence, Rhode Island
Predictors of Thyroid Tumor Aggressiveness
Denise M. Carneiro-Pia, MD
Fellow, Department of Endocrine Surgery, University of
Miami/Jackson Memorial Center, Miami, Florida
Intraoperative Parathyroid Hormone Assay as a Surgical
Adjunct in Patients with Sporadic Primary
Hyperparathyroidism
Herbert Chen, MD, FACS
Chief of Endocrine Surgery, and Assistant Professor of
Surgery, University of Wisconsin, Madison, Wisconsin
Hiirthle Cell Adenoma and Carcinoma
Polly S-Y Cheung, MB BS (HK)
Consultant Surgeon, Hong Kong Sanatorium and Hospital,
Happy Valley, Hong Kong
Medical and Surgical Treatment of Endemic Goiter
Orlo H. Clark, MD
Professor of Surgery, Department of Surgery, University of
California, San Francisco, School of Medicine,
San Francisco, California
Sporadic Nontoxic Goiter; Thyroiditis; Papillary Thyroid
Carcinoma: Rationale for Total Thyroidectomy;
Potentially New Therapies in Thyroid Cancer; Diagnosis
of Primary Hyperparathyroidism and Indications for
Parathyroidectomy; Parathyroid Hyperplasia:
Parathyroidectomy
Roderick Clifton-Bligh, MBBS, PhD, FRACP
Honorary Senior Lecturer in Medicine, University of
Sydney; Staff Specialist in Endocrinology, Royal North
Shore Hospital, Sydney, New South Wales, Australia
Thyroid Physiology
Alan P. B. Dackiw, MD, PhD
Assistant Professor of Surgery, Johns Hopkins University,
Baltimore, Maryland
Transplantation of Endocrine Cells and Tissues
Leigh Delbridge, MD, FRACS
Professor of Surgery, University of Sydney; Head,
Department of Surgery, Royal North Shore Hospital,
Sydney, New South Wales, Australia
Thyroid Physiology
Michael J. Demeure, MD
Chief, Section of General Surgery, Professor of Surgery,
Arizona Health Sciences Center, Tucson, Arizona
Mechanisms and Regulation of Invasion in Thyroid Cancer
Gerard M. Doherty, MD
M. W. Thompson Professor of Surgery, University of
Michigan, Ann Arbor, Michigan
Follicular Neoplasms of the Thyroid
Henning Dralle MD
Head, Department of General, Visceral, and Vascular
Surgery, University of Halle, Halle, Germany
Quan-Yang Duh, MD
Professor of Surgery, University of California,
San Francisco, School of Medicine, San Francisco,
California
Potentially New Therapies in Thyroid Cancer;
Surgical Approach to Primary Hyperparathyroidism
(Bilateral Approach)
Erol Duren, MD
Professor Emeritus, Department of Surgery, University of
Istanbul, Cerrahpasa Medical School;
Medical Director and Chief of Surgery, Istanbul German
Hospital, Istanbul, Turkey
Recurrent Thyroid Cancer
Mete Duren, MD
Professor, Department of Surgery, University of Istanbul,
Cerrahpasa Medical School, Istanbul, Turkey
Kathryn L. Edmiston, MD
Assistant Professor of Medicine, Associate Director,
Breast Center, University of Massachusetts Medical
Center, Boston, Massachusetts
Chemotherapy for Unresectable Endcorine Neoplasms
E. Christopher Ellison, MD
Professor and Chair, Department of Surgery, The Ohio
State University College of Medicine and Public Health,
Columbus, Ohio
Multiple Endocrine Neoplasia Type 2B
Gennaro Favia, MD
Professor of Surgery and Head, Endocrine Surgery Unit,
Department of Surgical and Gastroenterological
Sciences, University of Padua, School of Medicine,
Padova, Italy
Cushing's Syndrome
Contributors - - vii
Volker Fendrich, MD
Resident in Surgery, Philipps University; Resident in the
Department of Visceral, Thoracic, and Vascular Surgery,
Klinikum Der Philipps-Universitat, Marburg, Germany
Localization of Endocrine Pancreatic Tumors
Oliver Gimm, MD
Martin Luther University of Halle-Wittenberg, Halle,
Germany
Douglas L. Fraker, MD
Jonathan Rhoads Associate Professor of Surgery;
Vice Chairman, Clinical Affairs, and Director, General
Surgery, University of Pennsylvania, Philadelphia,
Pennsylvania
Factors That Predispose to Thyroid Neoplasia
Victor Gorelev, MD
Professor of Surgery, Heinrich Heine University,
DUsseldorf, Germany
Oncogenes in Thyroid Tumors
John R. Frandon, BSc, MD, FRCSt

Formerly Professor of Surgery, University of Bristol,
United Kingdom
Surgical Embryology and Anatomy of the Adrenal Glands
Yoshihide Fujimoto, MD, PhD
Former Professor of Surgery, Department of Endocrine
Surgery, Tokyo Women's Medical University, Tokyo;
Adviser of the Hospital and Director, Division of
Thyroid-Endocrine Surgery, Cancer Institute Hospital,
Tokyo, Japan
Papillary Thyroid Carcinoma: Rationale for
Hemithyroidectomy
Shuji Fukata, MD
Chief of Internal Medicine, Kuma Hospital, Kobe, Japan
Hypothyroidism
Michel Gagner, MD, FRCS, FACS
Professor of Surgery, Weill Medical College of Cornell
University; Chief, Laparoscopy and Bariatric Surgery,
Department of Surgery, New York-Presbyterian Hospital,
New York, New York
Armando Gamboa-Dominguez, MD, PhD
Associate Professor of Pathology, Facultad de Medicina,
Universidad Nacional Aut6noma de Mexico;
Senior Pathologist, Instituto Nacional de Ciencias
Medicas y Nutrici6n Salvador Zubiran, Mexico City,
Mexico
Parathyroid Embryology, Anatomy, and Pathology
Helene Gilbelin, MD
Consultant Surgeon, Endocrine Surgery, Jean Bernard
Hospital, Poitiers, France
Familial Hyperparathyroidism in Multiple Endocrine
Neoplasia Syndromes
Glenn Gibson, BA
Senior Scientist, Pfizer Global Research and Development,
Ann Arbor; Michigan
Cryopreservation of Parathyroid Tissue
tDeceased
Peter E. Goretzki, MD
DUsseldorf, Germany
Clive S. Grant, MD
Professor of Surgery, Mayo Clinic, Rochester, Minnesota
Pheochromocytoma
Staffan Grandal, MD, PhD
Associate Professor of Surgery, Karolinska Institutet;
Consultant, Department of Surgery, Danderyds Hospital,
Stockholm, Sweden
Adrenal Physiology
Bertil Hamberger, MD, PhD
Professor of Surgery, Department of Surgical Sciences,
Karolinska Institutet; Consultant; Department of
Surgery, Karolinska Hospital, Stockholm, Sweden
Adrenal Physiology
J. F. Hamming, MD, PhD
Surgeon, St. Elisabeth Hospital, Tilburg; The Netherlands
Management of Regional Lymph Nodes in Papillary,
Follicular, and Medullary Thyroid Cancer
Jay K. Harness, MD
Medical Director, St. Joseph Hospital Comprehensive
Breast Center, Orange, California
Childhood Thyroid Carcinoma
Susannah E. Harte, MD, MRCPI
University College, Dublin, Ireland
Use and Abuse of Thyroid-Stimulating Hormone
Suppressive Therapy in Patients with Nodular Goiter
and Benign or Malignant Thyroid Neoplasms
Nils-Erik Heldin, PhD
Associate Professor in Experimental Pathology, University,
Hospital, Uppsala, Sweden
Growth Factor, Thyroid Hyperplasia, and Neoplasia
Jean-Francois Henry, MD
Professor of Surgery, University of Marseilles; Chief,
Department of General and Endocrine Surgery,
University Hospital La Timone, Marseilles, France
Surgical Anatomy and Embryology of the Thyroid and
Parathyroid Glands and Recurrent and External
Laryngeal Nerves; Endoscopic Parathyroidectomy
viii - - Contributors
Miguel F. Herrera, MD, PhD

Associate Professor of Surgery, Facultad de Medicina,
Universidad Veracruzana; Staff Surgeon, Instituto
Nacional de Ciencias Medicas y Nutrici6n Salvador
Zubiran, Mexico City, Mexico
Parathyroid Embryology, Anatomy, and Pathology
Shih-ming Huang, MD
Professor, Department of Surgery, Buddhist Tzu-Chi
University; Professor and Consultant Surgeon, Buddhist
Tzu-Chi General Hospital, Hualien, Taiwan
Familial Hyperparathyroidism
Electron Kebebew, MD
Assistant Professor of Surgery, University of California,
San Francisco/Mt, Zion Medical Center, San Francisco,
California
Thyroid Oncogenesis
Rachel R. Kelz, MD
Assistant Professor of Clinical Surgery, University of
Pennsylvania, Philadelphia, Pennsylvania
Factors that Predispose to Thyroid Neoplasia
Maurizio Iacobone, MD
Assistant Professor, Clinical Research, University of
Padua, School of Medicine; Endocrine Surgery Unit,
Department of General and Gastroenterological
Sciences, University of Padua, Italy
Cushing's Syndrome
Job Kievit, MD, PhD

Professor of Clinical Decision Analysis and Associate
Professor of Surgery, Leiden University Medical Center;
Chief, Section of EndocrinelHead and Neck Surgery,
Department of Surgery, Leiden University Medical
Center, Leiden, Germany
Occurrence and Prevention of Complications in
Thyroid Surgery
Masatoshi Iihara, MD
Assistant Professor, Department of Endocrine Surgery,
Tokyo Women's Medical University; Assistant Professor,
Department of Endocrine Surgery, Tokyo Women's
Medical University Hospital, Shinjuku-ku, Tokyo, Japan
Hyperaldosteronism
Barbara K. Kinder, MD
William H. Carmalt Professor of Surgery, Yale University,
School of Medicine; Attending Surgeon, Yale-New
Haven Hospital, New Haven, Connecticut
Endocrine Emergencies: Hypoglycemic and
Hyperglycemic Crises
Silvio E. Inzucchi, MD
Professor of Medicine, Section of Endocrinology,
Yale University School of Medicine; Director,
Yale Diabetes Center, Yale-New Haven Hospital,
New Haven, Connecticut
Endocrine Emergencies: Hypoglycemic and
Jean-Louis Kraimps, MD
Professor, Poitiers University Medical School; Professor of
General Surgery, Jean Bernard Hospital, Poitiers, France
Neoplasia Syndromes
George L. Irvin III, MD

Professor of Surgery, University of Miami School of
Medicine, Miami, Florida
Intraoperative Parathyroid Hormone Assay as a Surgical
Adjunct in Patients with Sporadic Primary
Hyperparathyroidism
Yukio Ito, MD
Associate Professor, Department of Endocrine Surgery,
Tokyo Women's Medical University; Associate
Professor, Department of Endocrine Surgery, Tokyo
Women's Medical University Hospital, Shinjuku-ku,
Tokyo, Japan
Hyperaldosteronism
Suzanne Jan de Beur, MD
Director, Division of Endocrinology, Johns Hopkins
Bayview Medical Center, Baltimore, Maryland
Hypoparathyroidism and Pseudohypoparathyroidism
Edwin L. Kaplan, MD
Professor of Surgery, The University of Chicago, Pritzker
School of Medicine; Attending Physician, The
University of Chicago Hospitals, Chicago, Illinois
Insulinomas
Kanji Kuma, MD
Honorary Director, Kuma Hospital, Kobe, Japan
Hypothyroidism
Geeta Lal, MD, MSc, FRCS(C)
Assistant Professor of Surgery, University of Iowa; Staff
Surgeon, Department of Surgery, University of Iowa
Hospitals and Clinics, Iowa City, Iowa
Thyroiditis; Diagnosis of Primary Hyperparathyroidism
and Indications for Parathyroidectomy
Anne C. Larkin, MD
Director of Undergraduate Surgical Education, Department
of Surgery, University of Massachusetts Medical School,
Worcester, Massachusetts
Chemotherapy for Unresectable Endocrine Neoplasms
Chen-Hsen Lee, MD
Professor of Surgery, National Yang-Ming University; Team
Leader of Endocrine Surgery and Vice Superintendent,
Taipei Veterans General Hospital, Taipei, Taiwan
Thyroid Emergencies: Thyroid Storm and Myxedema Coma
Sten Lennquist, MD, PhD
Professor Emeritus, University of Linkoping; Former
Chairman, Department of Surgery, University Hospital,
Linkoping, Sweden
Thyroidectomy
Contributors - - ix
Hong-Da Lin, MD
Clinical Professor, Taipei Medical University, School of
Medicine; Chief, Division of Endocrinology and
Metabolism, Taipei Veterans General Hospital,
Taipei, Taiwan
Thyroid Emergencies: Thyroid Storm and Myxedema Coma
Christopher R. McHenry, MD
Professor of Surgery, Case Western Reserve University
School of Medicine; Vice Chairman, Department of
Surgery, and Director, Division of General Surgery,
MetroHealth Medical Center, Cleveland, Ohio
Anatomy and Embryology of the Pancreas
Dimitrios A. Linos, MD
Associate Professor of Surgery, Athens Medical School,
and Director of First Surgical Clinic, Hygeia Hospital
Athens, Greece; Lecturer in Surgery, Harvard Medical
School, and Consultant in Surgery, Massachusetts
General Hospital, Boston, Massachusetts
Clinically Inapparent Adrenal Mass (Incidentaloma or
Adrenaloma)
Paolo Miccoli, MD
Professor of Surgery, and Chairman, Department of
Surgery, Universita Studi di Pisa, Pisa, Italy
Papillary and Follicular Carcinoma: Surgical and
Radioiodine Treatment of Distant Metastases; Minimally
Invasive Parathyroid Surgery
Chung Yau Lo, MB BS(HK), MS(HK),

FRCS(Edin), FACS
Associate Professor, Faculty of Medicine, The University
of Hong Kong, Queen Mary Hospital; Associate
Professor and Chief of Endocrine Surgery, Department
of Surgery, University of Hong Kong Medical Center,
Queen Mary Hospital, Hong Kong
Parathyroid Reoperations
Franco Lumachi, MD
Assistant Professor, Clinical Research, University of
Padua, School of Medicine; Endocrine Surgery Unit,
Department of Surgical and Gastroenterological
Sciences, University of Padua, School of Medicine,
Padova, Italy
Cushing's Syndrome
Ewa Lundgren, MD, PhD
Associate Professor, Uppsala University, Medical Faculty;
Consultant and Head of the Surgery Department,
Institution of Surgical Sciences, University Hospital,
Uppsala, Sweden
Natural History of Untreated Primary
Hyperparathyroidism
Andreas Machens, MD
University of Halle, Halle, Germany
Lloyd A. Mack, MD, FRCSC
Assistant Professor, Department of Surgery and Oncology,
Division of General Surgery, University of Calgary
Faculty of Medicine, Calgary, Alberta, Canada
Unusual Thyroid Cancers, Lymphoma, and Metastases to
the Thyroid
Paul R. Maddox, BSc, MCh, FRCS(Ed),
FRCS(Eng)
Consultant Surgeon, Royal United Hospital, Bath,
England, United Kingdom
Approach to Thyroid Nodules
Raducu Mihai, MD, PhD, MRCS

Lecturer in Surgery, University of Bristol; Specialist
Registrar in Endocrine Surgery, Bristol Royal Infirmary,
Bristol, United Kingdom
Surgical Embryology and Anatomy of the Adrenal Glands
Craig A. Miller, MD
Director of Vascular Services, St. Joseph Hospital,
Kokomo, Indiana
Multiple Endocrine Neoplasia Type 2B
Daishu Miura, MD
Staff, Department of Endocrine Surgery, Toranomon
Hospital, Tokyo, Japan
Comparative Genomic Hybridization in Thyroid
Neoplasms
Jeffery F. Moley, MD
Associate Professor of Surgery, Washington University
School of Medicine; Associate Chief of Surgery,
St. Louis Veterans Administration Medical Center,
St. Louis, Missouri
Medullary Thyroid Carcinoma
Jack M. Monchik; MD, FACS
Clinical Professor of Surgery, Brown University School of
Medicine, Chief, Endocrine Surgery, Rhode Island
Hospital, Providence, Rhode Island
Normocalcemic Hyperparathyroidism
Bruno Niederle, MD
Professor of Surgery, Section of Endocrine Surgery,
Division of General Surgery, Department of Surgery,
Medical University of Vienna; Chief, Endocrine Surgery,
General Hospital of Vienna, Vienna, Austria
Ronald H. Nishiyama, MD
Chief Emeritus, Department of Pathology, Maine Medical
Center, Portland, Maine
Pathology of Tumors of the Thyroid Gland
Shiro Noguchi, MD, PhD, FJCS, FACE
Chief Executive Officer, Noguchi Thyroid Clinic and
Hospital Foundation, Beppu, Oita, Japan
Localization Tests in Patients with Thyroid Cancer
x - - Contributors
Jeffrey A. Norton, MD
Professor of Surgery, Stanford University Medical Center;
Chief of Surgical Oncology, Stanford University,
Department of Surgery, Stanford, California
Somatostatinoma and Rare Pancreatic Endocrine Tumors
Patricia J. Numann, MD
The Lloyd S. Rogers Professor of Surgery, SUNY
Distinguished Teaching Professor, and SUNY
Distinguished Service Professor, State University of
New York, Upstate Medical University; Medical
Director, University Hospital, Syracuse, New York
Addison's Disease and Acute Adrenal Hemorrhage
Takao Obara, MD, PhD
Professor and Chief, Department of Endocrine Surgery,
Tokyo Women's Medical University, Tokyo; Director,
Institute of Clinical Endocrinology, Tokyo Women's
Medical University Hospital, Tokyo, Japan
Hemithyroidectomy; Hyperaldosteronism
Niall O'Higgins, MCh, FRCSI, FRCS(Edin),
FRCS(Eng)
Professor and Head, Department of Surgery, University
College, Dublin; Professor of Surgery, St. Vincent's
University Hospital, Dublin, Ireland
Takahiro Okamoto, MD, PhD
Assistant Professor, Department of Endocrine Surgery,
Tokyo Women's Medical University, Tokyo, Japan
Hemithyroidectomy
Furio Pacini, MD
Professor of Endocrinology, Universita di Siena, Siena
Italy
Papillary and Follicular Carcinoma: Surgical and
Radioiodine Treatment of Distant Metastases
Kevin Packman, MD
Department of Surgery, Froedtert Memorial Lutheran
Hospital and Medical College of Wisconsin, Milwaukee,
Wisconsin
P. Parrilla, MD
Professor of Surgery, Department of Surgery, School of
Medicine, University of Murcia; Chairman, Department
of General Surgery, Virgen de la Arrixaca University
Hospital, Murcia, Spain
Localization Studies in Persistent or Recurrent
Hyperparathyroidism
Jin-Woo Park, MD, PhD
Associate Professor, College of Medicine, Chungbuk
National University, Cheongju, Korea
Potentially New Therapies in Thyroid Cancer
Janice L. Pasieka, MD
Clinical Professor of Surgery and Oncology, Faculty of
Medicine, Department of Surgery, University of
Calgary; Regional Division Chief, Division of General
Surgery, Calgary Health Region and University of
Calgary, Foothills Medical Center, Calgary, Alberta,
Canada
Unusual Thyroid Cancers, Lymphoma, and Metastases to
the Thyroid; Asymptomatic Primary
Hyperparathyroidism
Fran~ois
N. Pattou, MD
Associate Professor of Surgery, Medical School of Lille;
Senior Surgeon, Department of General and Endocrine
Surgery, Lille University Hospital-Huriez, Lille,
France
Advenocortical Carcinoma: Nonfunctioning and
Functioning
Nilima A. Patwardhan, MD
Professor of Surgery, University of Massachusetts
Medical Center, Worcester, Massachusetts
Chemotherapy for Unresectable Endocrine Neoplasms
Nancy Dugal Perrier, MD FACS
Associate Professor of Surgery, Department of Surgical
Oncology, University of Texas M.D. Anderson Cancer
Center, Houston, Texas
Graves' and Plummer's Diseases: Medical and Surgical
Management
Gerhard Prager, MD
Assistant Professor, Section of Endocrine Surgery, Division
of General Surgery, Department of Surgery, Medical
University of Vienna; Senior Resident, General Hospital
of Vienna, Vienna, Australia
Richard A. Prinz, MD
Helen Shedd Keith Professor and Chairman, Department of
General Surgery, Rush University; Chairman,
Department of General Surgery, Rush University
Medical Center, Chicago, Illinois
Open Operative Approaches to the Adrenal Gland
Charles A. G. Proye, MD
Professor and Chairman of Surgery, Medical School of
Lille; Head of the Department of General and Endocrine
Surgery, Lille University Hospital-Huriez, Lille, France
Adenocortical Carcinoma: Nonfunctioning and Functioning
Roderick M. Quiros, MD
General Surgery Resident, Rush University Medical
Center, Chicago, Illinois
Jonas Rastad, MD, PhD
Associate Professor, Department of Surgery,
Uppsala University Hospital, Uppsala, Sweden
Parathyroid Hormone: Regulation of Secretion and
Laboratory Determination
Contributors - - xi
Peter Ridefelt, MD, PhD

Associate Professor, Department of Surgery, Uppsala
University Hospital, Uppsala, Sweden
Andrew Saxe, MD
Associate Program Director, Michigan State University,
East Lansing; Director, Surgical Education, McLaren
Regional Medical Center, Flint, Michigan
Cryopreservation of Parathyroid Tissue
Jose M. Rodriguez, MD
Professor of Surgery, Department of Surgery, School of
Medicine, University of Murcia; Endocrine Surgery
Unit, Department of Surgery, Virgen de la Arrixaca,
II University Hospital, Murcia, Spain
Localization Studies in Persistent or Recurrent
Hyperparathyroidism
Frederic Sebag, MD
Medical School, Mediterranean University; Attending
Surgeon in Endocrine Surgery, Department of Endocrine
Surgery, University Hospitalla Timone, Marseilles,
France
Endoscopic Parathyroidectomy
Hans-Dietrich Roeher, MD
Dusseldorf, Germany
Oncogenes in Thyroid Tumors; Neuroendocrine Tumors
Wen T. Shen, MD
Fellow, Endocrine Surgical Oncology Program,
Department of Surgery, University of California,
San Francisco, San Francisco, California
Irving B. Rosen, MD, FRCS(C)

Professor, Department of Surgery, University of Toronto,
Toronto; Attending Surgeon, Mt. Sinai Hospital,
Toronto, Ontario, Canada
Nina Shervin, MD
Resident in Surgery, Harvard Combined Orthopaedic
Residency Program, Massachusetts General Hospital,
Boston, Massachusetts
Matthias Rothmund, MD
Professor of Surgery, Philipps University; Professor of
Surgery and Chairman of the Department of Visceral,
Thoracic, and Vascular Surgery, Klinikum der
Philipps-Universitat, Marburg, Germany
Adrenal Imaging Procedures; Localization of Endocrine
Pancreatic Tumors
Mauricio Sierra, MD
Fellow in Endocrine Surgery, Jean Bernard Hospital,
Poitiers, France
Neoplasia Syndromes
J. A. Roukema, MD, PhD

Surgeon, St. Elisabeth Hospital, Tilburg, The Netherlands
Management of Regional Lymph Nodes in Papillary,
Follicular, and Medullary Thyroid Cancer
Dietmar Simon, MD
Dusseldorf, Germany
Neuroendocrine Tumors; Oncogenes in Thyroid Tumors
Mary Ruppe, MD
Senior Fellow, Division of Endocrinology, Johns Hopkins
Bayview Medical Center, Baltimore, Maryland
Hypoparathyroidism and Pseudohypoparathyroidism
Antonio Sitges-Serra, MD
Professor of Surgery, Universedad Aut6noma de
Barcelona; Head, Department of Surgery, Hospital del
Mar, Barcelona, Spain
Surgical Management of Recurrent and Intrathoracic
Goiters; Metabolic Complications of Secondary
Hyperparathyroidism; Surgical Approach to Secondary
Hyperparathyroidism
David E. Sahar, MD
Resident, University of California San Francisco-East Bay
Program, San Francisco, California
Juan J. Sancho, MD
Associate Professor, Universidad Aut6noma de Barcelona;
Staff Surgeon; Hospital del Mar, Barcelona, Spain
Surgical Management ofRecurrent and Intrathoracic
Goiters; Metabolic Complications of Secondary
Hyperparathyroidism; Surgical Approach to Secondary
Hyperparathyroidism
Kerstin Sandelin, MD, PhD
Associate Professor of Surgery, Department of Surgical
Sciences, Korolinska Institutet, Stockholm; Senior Staff
Surgeon, Karolinska University Hospital, Solna,
Stockholm, Sweden
Parathyroid Carcinoma
Allan E. Siperstein, MD
Professor of Surgery and Section Head, Endocrine Surgery,
The Cleveland Clinic Foundation, Cleveland, Ohio
Signal Transduction in Thyroid Neoplasms
Staffan Smeds, MD, PhD
Professor of Surgery, University Hospital, Linkoping,
Sweden
Growth Factor, Thyroid Hyperplasia, and Neoplasia
Ilfet Songun, MD, PhD
Surgeon, University Hospital, Maastricht,
The Netherlands
Thyroid Surgery
xii - - Contributors
Maria Sorhede-Winzell, PhD

Department of Medicine, Lund University, Lund, Sweden
Pancreatic Endocrine Physiology
Gordon J. Strewler, MD
Professor of Medicine, Harvard Medical School; Vice
Chairman, Department of Medicine, Brigham and
Women's Hospital; Chief of Medical Service, Brockton/
West Roxburg, Veterans Administration Medical Center,
Boston, Massachusetts
Hypercalcemia of Malignancy and Parathyroid
Hormone-Related Protein
Masahiro Sugawara, MD
Professor of Medicine, University of California, Los Angeles,
School of Medicine; Staff Physician, Greater Los Angeles
VA Medical Center, Los Angeles, California
Hypothyroidism
Hiroshi Takami, MD
Professor of Surgery, Teiko University School of Medicine,
Tokyo,Japan
Hypercalcemic Crisis
Serdar T. Tezelman, MD
Professor of Surgery, Department of Surgery, Istanbul
Faculty of Medicine, Istanbul University; Attending
Surgeon, International Hospital, Istanbul, Turkey
Signal Transduction in Thyroid Neoplasms
Geoffrey B. Thompson, MD
Professor of Surgery, Mayo Graduate School; Consultant,
Department of Surgery, Division of Gastroenterologic
and General Surgery, Mayo Clinic, Saint Mary's and
Rochester Methodist Hospitals, Rochester, Minnesota
Multiple Endocrine Neoplasia Type 1
Norman W. Thompson, MD
Emeritus Professor of Surgery, University of Michigan,
Ann Arbor, Michigan
Pancreatic Surgery for Endocrine Tumors
Sten A. G. Tibblin, MD, PhDt
Formerly Associate Professor and Consultant Surgeon,
Department of Surgery, University Hospital, Lund, Sweden
Surgical Approach to Primary Hyperthyroidism
Lars-Erik Tisell, MD, PhD
Retired Chief of Endocrine Surgery, Department of Surgery,
Sahlgrenska University Hospital, Sahlgrenska, Sweden
Natural History of Treated Primary Hyperparathyroidism
Robert Udelsman, MD, MBA, FACS
Lampman Professor of Surgery and Oncology, and
Chairman, Department of Surgery, Yale University
School of Medicine; Chief of Surgery,
Yale New Haven Hospital, New Haven, Connecticut
Hiirthle Cell Adenoma and Carcinoma
tDeceased
John A. van Heerden, MB, ChB, MS(Surg) (Minn),

FRCS (C), FACS, Hon FCM(SA), Hon FRCS(Edin),
FRCPS (Glasg)
Fred C. Anderson Professor of Surgery, Mayo Graduate
School; Consultant in General Surgery, Mayo Clinic,
Rochester, Minnesota
Cornelis J. H. van de Velde, MD, PhD
Professor of Surgery, Leiden University Medical Center,
Leiden, Germany
Thyroid Surgery
Nobuyuki Wada, MD, PhD
Assistant Professor, Department of Surgery, Yokohama City
University School of Medicine, Yokohama City, Japan
Comparative Genomic Hybridization in Thyroid Neoplasms
Jeffrey D. Wayne, MD
Assistant Professor of Surgery, Northwestern University,
Feinberg School of Medicine; Attending Physician,
Northwestern Memorial Hospital, Chicago, Illinois
Insulinomas
Malcolm H. Wheeler, MD, FRCS
Professor of Surgery, University Hospital of Wales,
Cardiff, Wales, United Kingdom
Scott M. Wilhelm, MD
Assistant Professor of Surgery, University Hospital of
Cleveland, Case Western Reserve University; Staff
Surgeon, University Hospitals of Cleveland, Cleveland,
Ohio
Stuart D. Wilson, MD
Professor and Chief, Division of
PancreatobiliarylEndocrine Surgery, Medical College of
Wisconsin; Senior Attending Surgeon, Froedtert
Memorial Lutheran Hospital, Milwaukee, Wisconsin
Gastrinoma
Michael W. Yeh, MD
Fellow, University of California, San Francisco,
San Francisco, California; Endocrine Surgical Unit,
Royal North Shore Hospital, St. Leonards,
New South Wales, Australia
William F. Young, Jr, MD, MSc
Professor of Medicine, Mayo Clinic College of Medicine;
Consultant, Division of Endocrinology and Metabolism,
Mayo Clinic, Rochester, Minnesota
Multiple Endocrine Neoplasia Type 1
Rasa Zarnegar, MS
Surgical Resident, Case Western Reserve University
Cleveland, Ohio
Sodium-Iodide Symporter and Radioactive Iodine Therapy
Contributors - - xiii
Andrew P. Zbar, MB, BS

University of the West Indies, Queen Elizabeth Hospital,
St. Michael, Barbados
Martha A. Zeiger, MD
Associate Professor of Surgery, Division of Endocrine and
Oncologic Surgery, Johns Hopkins Medical Institutions,
Baltimore, Maryland
Hypoparathyroidism and Pseudohypoparathyroidism;
Transplantation of Endocrine Cells and Tissues
Andreas Zielke, MD
Department of Surgery, Endocrine Research Group,
Philipps University, Marburg, Germany
Adrenal Imaging Procedures
Since the first edition of the Textbook of Endocrine Surgery

there have been considerable changes in the clinical management of patients with endocrine surgical problems, as
well as advances in basic science regarding endocrine
neoplasms. Many colleagues have asked Drs. Duh and Clark
whether another edition will be published because of numerous recent changes in endocrine surgery. Major changes
have occurred regarding the indications for parathyroidectomy in patients with primary hyperparathyroidism based on
the natural history of the disease. The surgical approach for
patients with primary hyperparathyroidism has also changed
as more surgeonsare now recommending a selective approach
rather than a bilateral approach. Much of this change is due to
better preoperative localization studies and the use of intraoperative parathyroid hormone assays to determine when all
abnormal parathyroid tissue has been removed. Some
experts are also recommending a minimally invasive
approach via small == 2.S-cm incisions or by using an endoscopic approach with I.S-cm incisions for patients with
primary hyperparathyroidism.
Substantial changes have also occurred regarding indications for adrenalectomy for patients with incidentally discovered adrenal neoplasms. More accurate localization studies
and improved testing have made the diagnosis easier and
tumor identification more precise. Most endocrine surgeons
are now recommending laparoscopic removal of non-malignant-appearing adrenal tumors under 6 em in maximal
diameter. Such treatment has dramatically reduced the duration of hospitalization and has also increased the referral of
such patients to endocrine surgical units that are proficient
in laparoscopic operations.
There have been numerous other advances in using
genetic testing to diagnose patients with multiple endocrine
neoplasia types I and II. Children who are ret oncogene positive usually receive prophylactic thyroidectomy before age
6 and before they develop medullary thyroid cancer. More
information is also available regarding genotype-phenotype
relationships in predicting tumor behavior. Familial nonmedullary thyroid cancer with or without other syndromes
has recently become a recognized clinical syndrome, and
the thyroid cancers in these patients are somewhat more
aggressive than are sporadic thyroid cancers. Papillary thyroid cancer in children and after radiation are frequently
associated with ret/PTC rearrangements and other papillary

thyroid cancers with BRAF mutations, whereas follicular
cancers are more often associated with PAX-S/PPARy and
ras mutations.
Since the Chemobyl nuclear accident in 1986, considerably
more information has become available relating to the
association of radiation exposure and thyroid cancer. Many
other advances or consensus of opinion have also become
available regarding the diagnosis, localization, and treatment of endocrine neoplasms, including endocrine tumors
of the pancreas.
New or revised areas in the second edition of Textbook
of Endocrine Surgery include: (l) recent advances in the
etiology and molecular biology of endocrine neoplasms;
(2) methods used to diagnose patients with sporadic and
familial thyroid cancers and the risks and benefits of prophylactic operations; (3) the association of low-dose therapeutic
radiation, RET/PTC rearrangements, and surgical management of thyroid tumors; (4) current information regarding the
adverse effects of primary hyperparathyroidism and related
symptoms, associated conditions, and survival, as well as
the indications for parathyroidectomy (this will include the
usefulness of the follow-up information regarding the NIH
consensus criteria and newer studies regarding quality of life
improvement after parathyroidectomy); (5) the changing
selective surgical approach for patients with primary hyperparathyroidism based on preoperative localization tests and
intraoperative PTH testing; (6) the indications for operations
for patients with incidentally discovered adrenal neoplasms;
and (7) the use of laparoscopic adrenalectomy to remove
most adrenal tumors under 6 em in maximal diameter.
In summary, during the past several years there have
been improved methods for diagnosing and treating patients
with endocrine neoplasms, including screening for familial
disease, more precise diagnostic tests, better preoperative
localization studies, and new surgical instrumentation, as
well as a better understanding of the natural history of many
of these disorders.
Orlo H. Clark, MD
Quan- Yang Duh, MD

xv
Table of Contents
1
Thyroid physiology
Surgical anatomy and embryology of the thyroid and parathyroid

glands and recurrent and external laryngeal nerves
Medical and surgical treatment of endemic goiter
16
Sporadic nontoxic goiter
24
Thyroiditis
34
Hypothyroidism
44
Graves' and Plummer's diseases : medical and surgical management
54
Use and abuse of thyroid-stimulating hormone suppressive therapy in

patients with nodular goiter and benign or malignant thyroid
68
neoplasms
Approach to thyroid nodules
85
10
Childhood thyroid carcinoma
93
11
Papillary thyroid carcinoma : rationale for hemithyroidectomy
102
12
Papillary thyroid carcinoma : rationale for total thyroidectomy
110
13
Follicular neoplasms of the thyroid
115
14
Hurthle cell adenoma and carcinoma
123
15
Medullary thyroid carcinoma
129
16
Localization tests in patients with thyroid cancer
142
17
Papillary and follicular carcinoma : surgical and radioiodine treatment

152
of distant metastases
18
Anaplastic carcinoma of the thyroid gland
159
19
Unusual thyroid cancers, lymphoma, and metastases to the thyroid
168
20
Recurrent thyroid cancer
181
21
Thyroidectomy
188
22
Management of regional lymph nodes in papillary, follicular, and

medullary thyroid cancer
195
23
Occurrence and prevention of complications in thyroid surgery
207
24
Thyroid emergencies : thyroid storm and myxedema coma
216
25
Pathology of tumors of the thyroid gland
223
26
Factors that predispose to thyroid neoplasia
240
27
Predictors of thyroid tumor aggressiveness
248
28
Growth factor, thyroid hyperplasia, and neoplasia
256
29
Signal transduction in thyroid neoplasms
265
30
Oncogenes in thyroid tumors
280
31
Thyroid oncogenesis
288
32
Mechanisms and regulation of invasion in thyroid cancer
295
33
Surgical management of recurrent and intrathoracic goiters
304
34
Surgical management of advanced thyroid cancer invading the

aerodigestive tract
318
35
Potentially new therapies in thyroid cancer
334
36
Comparative genomic hybridization in thyroid neoplasms
344
37
Sodium-iodide symporter and radioactive iodine therapy
355
38
Parathyroid embryology, anatomy, and pathology
365
39
Parathyroid hormone : regulation of secretion and laboratory

determination
372
40
Diagnosis of primary hyperparathyroidism and indications for

parathyroidectomy
384
41
Natural history of untreated primary hyperparathyroidism
393
42
Metabolic complications of primary hyperparathyroidism
402
43
Natural history of treated primary hyperparathyroidism
413
44
Asymptomatic primary hyperparathyroidism
419
45
Normocalcemic hyperparathyroidism
424
46
Localization studies in persistent or recurrent hyperparathyroidism
430
47
Technique of parathyroidectomy
439
48
Surgical approach to primary hyperparathyroidism (bilateral

approach)
449
49
Surgical approach to primary hyperparathyroidism (unilateral

approach)
456
50
Minimally invasive parathyroid surgery
462
51
Endoscopic parathyroidectomy
467
52
Intraoperative parathyroid hormone assay as a surgical adjunct in

patients with sporadic primary hyperparathyroidism
472
53
Parathyroid hyperplasia : parathyroidectomy
481
54
Familial hyperparathyroidism in multiple endocrine neoplasia

syndromes
489
55
Familial hyperparathyroidism
493
56
Metabolic complications of secondary hyperparathyroidism
502
57
Surgical approach to secondary hyperparathyroidism
510
58
Parathyroid reoperations
518
59
Hypoparathyroidism and pseudohypoparathyroidism
527
60
Cryopreservation of parathyroid tissue
530
61
Hypercalcemia of malignancy and parathyroid hormone-related

protein
536
62
Hypercalcemic crisis
543
63
Parathyroid carcinoma
549
64
Surgical embryology and anatomy of the adrenal glands
557
65
Adrenal physiology
571
66
Adrenal imaging procedures
576
67
Clinically inapparent adrenal mass (incidentaloma or adrenaloma)
586
68
Hyperaldosteronism
595
69
Adrenocortical carcinoma : nonfunctioning and functioning
604
70
Cushing's syndrome
612
71
Pheochromocytoma
621
72
Addison's disease and acute adrenal hemorrhage
634
73
Open operative approaches to the adrenal gland
641
74
Laparoscopic adrenalectomy
647
75
Anatomy and embryology of the pancreas
665
76
Multiple endocrine neoplasia type 1
673
77
Transplantation of endocrine cells and tissues
691
78
Pancreatic endocrine physiology
701
79
Insulinomas
715
80
Localization of endocrine pancreatic tumors
730
81
Pancreatic surgery for endocrine tumors
737
82
Gastrinoma
745
83
Multiple endocrine neoplasia type 2B
757
84
Somatostatinoma and rare pancreatic endocrine tumors
764
85
Non-multiple endocrine neoplasia endocrine syndromes
773
86
Neuroendocrine tumors
780
87
Endocrine emergencies : hypoglycemic and hyperglycemic crises
789
88
Chemotherapy for unresectable endocrine neoplasms
800
Thyroid Physiology
Roderick Clifton-Bligh, MB, BS, PhD Leigh Delbridge, MD, FRCS
The thyroid gland contains two separate physiologic

endocrine systems: one responsible for the production of the
thyroid hormones thyroxine (T4 ) and triiodothyronine (T3) ,
and the other responsible for the production of the hormone
calcitonin.
The functional unit for thyroid hormone production is
the thyroid follicle. This is composed of a single layer of
cuboidal follicular cells surrounding a central space filled
with colloid. The average size of a follicle varies from 100
to 300 urn, each of which is surrounded by a network of
capillaries. The primary function of the thyroid follicle is
to make and store thyroid hormones.
Calcitonin is produced by C cells within the thyroid.
These cells, of neural crest origin, lie in a parafollicular position in direct contact with the follicular basement membrane.
Thyroid Embryogenesis
Thyroid primordial cells develop from pharyngeal ectoderm,
forming a visible medial anlage by human gestational days
16 to 17.1 The thyroid diverticulum then migrates caudally to
reach its final position in the thyroid primordial body anterior
to the cricoid cartilage (Fig. 1-1). Subsequently, these cells
begin to express markers of mature thyrocyte differentiation,
including proteins that are intrinsic to thyroid secretory
function (thyroglobulin, thyroperoxidase, and the sodiumiodide symporter [NIS]), and the thyroid-stimulating hormone (TSH) receptor that controls both thyroid growth and
secretory function. The foramen caecum, at the junction
between the anterior two thirds and posterior third of the
tongue base, remains as an embryologic reminder of thyroid
origin. Thyrocytes form thyroid follicles, while intervening
cells derived from the ultimobranchial body within the
fourth pharyngeal pouch develop into calcitonin-secreting C
cells (see Fig. 1-1). The parathyroid glands develop from the
third and fourth pharyngeal pouches and migrate to the posterior surface of the thyroid gland. The thyroid gland begins
to trap iodide between gestational weeks 10 and 12.1
Several transcription factors involved in the development
of the thyroid gland have been identified. Three such factors-thyroid transcription factors (TTFs)-1 23 and _24 and
the paired homeodomain factor Pax-85.6-were identified
and isolated by their binding to specific regulatory elements
within the promoters of thyroid-specific genes (e.g., thyroperoxidase and thyroglobulin). Mutation of any of these
transcription factors leads to thyroid dysgenesis, together
with other phenotypic features specific to each transcription
factor (TTF-l, pulmonary disease; Pax-8, renal hemiagenesis;
TTF-2, cleft palate).7-9
The transcription factor GATA3 has been shown to be
important in parathyroid gland development since mutations
in this gene are associated with HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal aplasia).'? Failure
of parathyroid gland development is also a feature of
DiGeorge syndrome, in which parathyroid and thymic aplasia are variably accompanied by cardiac defects and facial
malformations owing to microdeletion or rearrangement of
the short arm of chromosome 22. 11 Several transcription
factors involved in the development of the parathyroid
glands in mouse models have been identified," including
Gcm2 and Hoxa3.
Thyroid Hormone Physiology

Iodide Metabolism and Uptake
Iodine usually enters the body as the result of dietary and water
uptake, but it can also be found in various drugs, such as cough
medicines, and in diagnostic agents. Dietary iodine intake
varies widely throughout various parts of the world. The relationship between iodine intake and thyroid disease was first
demonstrated by Chatin in 1852, but the practice of iodine supplementation of food and water, which he recommended, fell
into disrepute and was not revived until the large-scale experiments of Marine and Kimball in Ohio in 1917.14 Even in areas
where endemic goiter is not a problem, iodine intake and
excretion vary considerably with urinary excretion, ranging
from as little as 40 ug/day up to 400 ug/day." Iodine deficiency is associated with nodular goiter, hypothyroidism,
and cretinism" as well as the development of follicular
thyroid carcinoma.!? In areas of the world where iodine
deficiency is still a problem, a variety of measures are being
introduced to increase iodine intake, such as iodination of
salt, bread, and water to treat entire population groups and
injections of iodized oil for target groups such as pregnant
women.P Iodine excess, on the other hand, is associated
4 - - Thyroid Gland
FIGURE 1-1. Thyroid embryogenesis. Left, Coronal section through the pharyngeal arch region in a late-somite embryo. The thyroid
diverticulum forms from a thickening in the midline of the anterior pharyngeal floor. The two lateral anlagen (ultimobranchialbodies) are
derived from the fourth or fifth pharyngeal pouch; the thymus and inferior parathyroids are derived from the third pouch, whereas the
superior parathyroid glands form from the fourth pharyngeal pouch (not shown). Right, Ventral view of the pharyngeal organ derivatives
following migration toward their ultimate positions.The thyroid diverticulumhas caudally migrated anterior to the cricoid cartilage, where
it is infiltrated by cells from the ultimobranchial bodies that will form parafollicular C cells. The superior and inferior parathyroid glands
are positioned on the posterolateral surface of the thyroid gland. The two thymic primordia will fuse to become a single gland anterior
to the trachea. (Adapted from Manley NR, Capecchi MR. The role of Hoxa-3 in mouse thymus and thyroid development. Development
1995;12l:l989.)
with an increased incidence of autoimmune thyroid disease

such as Graves' disease and Hashimoto's thyroiditis'S" as
well as papillary thyroid carcinoma. I?
Iodine, in the form of inorganic iodide, is rapidly and
efficiently absorbed from the gastrointestinal tract and
enters the extracellular iodide pool, where it is joined by
iodide derived from the breakdown of previously formed
thyroid hormone. Less than 10% of total body iodide is contained in the extracellular pool; the remaining 90% is stored
in the thyroid gland as either preformed thyroid hormone or
iodinated amino acids.'?
Iodide is taken up from the extracellular space into the
follicular cells by an active transport process. The major
source of loss of iodide from the extracellular space, in addition to uptake by the thyroid gland, is renal excretion. Small
quantities of iodide are also lost through the skin, through
the saliva, or in expired air. The active transport of iodide
into the cells results in a significant intrathyroidal iodide
gradient. The NIS is part of a family of membrane-associated
transport glycoproteins that probably contain 12 membranespanning domains. 2o21 Iodide is actively transported using
energy from the coupled inward sodium transport.
Mutations in the NIS gene are associated with goitrous congenital hypothyroidism.P Iodide transport into the follicular
cells is influenced by TSH levels as well as by the glandular
content of iodide.
Synthesis of Thyroid Hormone

After uptake into the follicular cells through the basal
membrane (Fig. 1-2), inorganic iodide is rapidly oxidized.
Thyroid hormones are then synthesized by the combination
of iodine with tyrosyl residues within the protein thyroglobulin. This reaction is catalyzed by thyroperoxidase in two
principal steps. In the first reaction, iodide reacts with
FIGURE 1-2. Uptake of iodide into the follicular cell by active

transport, with subsequent iodide oxidation, tyrosine iodination,
and iodotyrosine coupling occurring at the apical membrane,
catalyzed by thyroid peroxidase. DIT = diiodotyrosine; MIT =
monoiodotyrosine; T3 = triiodothyronine; T4 = thyroxine.
Thyroid Physiology - -
tyrosyl residues in thyroglobulin to form monoiodotyrosine

(MIT) and diiodotyrosine (DIT). In the second reaction,
MIT and DIT condense to form 3,5,3'-triiodothyronine (T 3)
or the inactive 3,3',5'-triiodothyronine (rT3) , whereas two
molecules of DIT condense to form T 4 T 3 and rT 3 are also
formed by intrathyroidal deiodination of thyroxine, catalyzed
by deiodinase enzymes.P In conditions of iodine-sufficient
intake, the predominant iodothyronine synthesized by the
thyroid gland is T 4 24 Once formed, the thyroid hormones,
covalently bound to thyroglobulin, are stored in colloid
within the center of the follicle. The thyroid gland contains a
very large store of thyroid hormone, which lasts for several
weeks in the absence of the formation of new hormone. 19
Thyroid peroxidase (TPO) is a membrane-bound glycoprotein that is localized to the apical membrane of the follicular cell; the peroxidase reactions occur at the cell-colloid
interface.f TPO has now been cloned and has been shown to
have a hydrophobic signal peptide at its aminoterminus and a
hydrophobic region with the characteristics of a transmembrane domain near the carboxylterminus.P This structure is
consistent with TPO being a membrane-associated protein.
The synthesis of thyroglobulin occurs exclusively in the thyroid gland, where homodimers are formed in the endoplasmic
reticulum before being transported into the apical lumen of
thyroid follicles.P Defects in thyroglobulin synthesis usually
cause moderate to severe hypothyroidism in association
with low circulating thyroglobulin levels." A partial organification defect and goiter (with or without overt hypothyroidism) is associated with sensorineural deafness in
Pendred's syndrome. Mutations in a putative sulfate transporter gene (PDS) have recently been associated with this
disorder," Although the precise mechanisms by which
the pendrin protein causes the phenotype is unclear, it is proposed that defective sulfation of thyroglobulin impairs its
subsequent iodination."
Release of thyroid hormone into the peripheral blood
occurs as the result of lysosomal hydrolysis within the follicular cells (Fig. 1-3). Pseudopodia form at the apical membrane
of the thyroid cell, and multiple vesicles containing thyroglobulin are incorporated into the follicular cell by endocytosis. Lysosomal hydrolysis of the thyroglobulin, with
reduction of disulfide bonds, leads to release of both T3 and
T 4 through the basement membrane into the circulation. The
ratio of the levels of these two hormones released into the
peripheral blood approximates their levels in stored thyroglobulin (T3:T4 is "" 1:13). Very little thyroglobulin reaches the
peripheral circulation; however, when sensitive immunoassay
procedures are used, small quantities can be detected in normal
individuals.P Iodotyrosines released from thyroglobulin
undergo deiodination and are recycled, with the iodide so
released available for new thyroid hormone synthesis.
Peripheral Transport and Metabolism of

Thyroid Hormones
More than 99% of circulating thyroid hormones are bound
to serum proteins, including thyroxine-binding globulin
(TBG), transthyretin, and albumin." TBG is a glycoprotein
that contains only one binding site per molecule. TBG is
responsible for the transport of more than three fourths of
thyroid hormone in the blood, and its levels are significantly
increased by elevated levels of estrogens, as occurs in pregnancy. Dissociation of the free hormone from its binding
proteins is rapid and efficient. Thyroid hormones are
lipophilic and are capable of passive diffusion into cells,
although specific transporters may also regulate intracellular
thyroid hormone content."
T 3 synthesized directly by the thyroid forms a relatively
small proportion of the effective T 3 concentration in tissues,
which is mainly derived from peripheral deiodination of T4 .
This reaction is catalyzed by two deiodinases with characteristic tissue distributions. Type I deiodinase (5'DI) is predominant in liver, kidney, and thyroid, whereas type II
deiodinase (5'DII) is present in the central nervous system,
pituitary, placenta, brown adipose tissue, cardiac and skeletal muscle, and thyroid.'? A third deiodinase (5'DIII) catalyzes deiodination of T 4 to rT 3 or T 3 to diiodothyronine (T 2)
and is found in the placenta and central nervous system."
These differences in distribution and regulation may explain
some tissue-specific variation in thyroid hormone action.
Peripheral conversion of T 4 to T 3 may be impaired in a
number of situations, including systemic illness, malnutrition, and trauma or by various drugs.
The thyroid hormones generally have slow turnover
times in the peripheral circulation. In adults, the half-life of
T 4 is about 7 days, presumably because of the high degree
of binding of T4 to its carrier proteins, whereas the half-life
of T, is approximately 8 to 12 hours.
Peripheral Action of Thyroid Hormones
FIGURE 1-3. Lysosomal hydrolysis of pinocytotic vesicles containing

stored colloid, with subsequent release of thyroid hormone into the
peripheral circulation. T 3 = triiodothyronine; T4 = thyroxine.
The major effects of thyroid hormone action occur through

the intranuclear action of Tj, with T4 being largely a prohormone." It remains controversial as to whether T 4 might also
regulate non-nuclear biologic responses in some contexts,
for instance, the activation of certain mitochondrial or cellmembrane enzymes." In the 1960s, Tata and associates
observed that T3 treatment resulted in the rapid synthesis of
nuclear RNA, which preceded increases in protein synthesis
6 - - Thyroid Gland
and mitochondrial oxygen consumption." Subsequently, subcellular fractionation demonstrated specific nuclear binding
sites for T 3 and identified the anterior pituitary, liver, brain,
and heart as having high binding capacity for T 3.3! Thus, the
current concept of thyroid hormone action is that its nuclear
receptor binds to specific regulatory regions in target genes
and regulates gene transcription in response to T 3.32-34
Thyroid hormone receptors (TRs) are members of the
steroid hormone receptor superfamily. There are two TR
genes, a and ~, located on chromosomes 17 and 3, respectively, and differential splicing of both these genes yields
a total of four isoforms, denoted as TRal, TRa2, TRf3I, and
TRf32 (Fig. 1_4).32 The expression of the various TR isoforms is both developmentally regulated and tissue specific,
such that TRa is widely expressed at all stages of development, preceding the appearance of endogenous thyroid hormone, whereas TR~ begins to be expressed as thyroid
hormone-dependent processes occur," An aminoterminal
is specifically
splice variant of the TR~ receptor, TR~2
expressed in the hypothalamus and pituitary and may therefore be the critical subtype involved in negative-feedback
effects of T 3.32 In the adult, TRal may be the predominant
isoform in myocardium, skeletal muscle, and fat, whereas
TR~l
and TR~2 predominate in the pituitary and liver."
TRa2 does not bind ligand and its function is poorly understood, although it may function as an inhibitor of thyroid
hormone action in some contexts.F
TRs bind to specific regulatory DNA sequences usually
within gene promoters.P A consensus regulatory binding
site, termed the thyroid hormone response element (TRE),
consists of a pair of hexanucleotide half-sites. Natural TREs
present in gene promoters are commonly degenerate variations of these consensus sequences. Biochemical evidence
suggests that on many TREs, the receptor complex is most
active when bound to DNA as a heterodimer with the
retinoid X receptor."
FIGURE 1-4. Multiple human thyroid hormone receptor (TR) isoforms, TRa and TR~ receptors are transcribed from different genes
on chromosomes 17 and 3, respectively. Different isofonns are
then generated from differential splicing of the primary messenger
RNA transcripts in each case, such that TRal and TRa2 isofonns
and TR~2 isofonns
differ in their carboxytennini, whereas TR~I
differ in their aminotermini, as shown. (Adapted from Lazar MA.
Thyroid hormone receptors: Multiple forms, multiple possibilities.
Endocr Rev 1993;14:184.)
The clinical manifestations of thyroid hormone action

are the net result of the actions of the products of the various genes whose expression is regulated by T 3. For example,
thyroid hormones affect cardiac contractility by affecting
the transcription of, and subsequent relative proportions of,
the various myosin heavy chains in cardiac muscle.P'" In the
pituitary, T 3 regulates the transcription of the genes for both
ex and ~ subunits of TSH, thus affecting the level of TSH
secretion.'?
Thyroid Hormone Regulation

Thyroid hormone production and release are under the control of the hypothalamic-pituitary-thyroid axis (Fig. 1-5),
acting in a negative-feedback cycle. TSH is the major regulator of thyroid gland activity. Increased levels of TSH lead
to hypertrophy and increased vascularity of the gland,
whereas decreased levels of TSH lead to gland atrophy.
A glycoprotein secreted by the anterior pituitary, TSH is
composed of an a subunit and a ~ subunit. The ex subunit is
common to a family of glycoprotein hormones, including
FIGURE 1-5. Negative-feedback regulation of thyroid hormone

production. TRH = thyrotropin-releasing hormone; TSH = thyroidstimulating hormone; T 3 = triiodothyronine; T 4 = thyroxine.
Thyroid Physiology - - 7
follicle-stimulating hormone, luteinizing hormone, and

human chorionic gonadotropin (hCG).
TSH binds to a specific receptor on the surface of the thyroid cell. The TSH receptor is a G protein-coupled receptor.
After activation by TSH, the receptor interacts with a guanine nucleotide-binding protein (G protein), which induces
the production of cyclic adenosine monophosphate (cAMP).4o
This cAMP then stimulates the synthesis and secretion of
thyroid hormones. Receptors that are linked to G proteins
are characterized by the presence of seven transmembranespanning domains linked by cytoplasmic and extracellular
loops. The first cytoplasmic loop, as well as the carboxylterrninal residues in the second and third cytoplasmic loops, are
important in mediating a TSH-dependent increase in intracellular cAMP production." The TSH receptor has been cloned.f
and specific mutations have been identified in association with
hyperfunctioning follicular thyroid neoplasms.tv"
TSH is secreted from the anterior pituitary in response
to thyrotropin-releasing hormone (TRH) and to reduced
pituitary levels of T; TRH acts to directly stimulate the thyrotropic cells to increase both the synthesis and the release of
TSH. TRH is a tripeptide synthesized in the paraventricular
nucleus of the hypothalamus, and, after synthesis, it passes
to the median eminence and down the pituitary stalk in the
hypophysial portal system. It is thought that the principal
function of TRH is to set the ambient level of regulatory control whereby thyroid hormone levels are mediated by negative
feedback. TRH secretion itself is also under negative-feedback
control in response to peripheral thyroid hormone levels.
T 3, on the other hand, derived principally from the local
deiodination of peripheral T 4 in the pituitary, directly
inhibits the release and synthesis of TSH. It is also thought
that peripheral thyroid hormone levels may regulate TRH
receptor numbers on the surface of the pituitary thyrotropic
cells, thus decreasing their responsiveness to TRH.
A number of other factors affect thyroid hormone synthesis in addition to the hypothalamic-pituitary feedback cycle.
Other hormones can have a direct effect on the thyroid
gland. Catecholamines are thought to have a direct stimulatory effect on thyroid hormone release. hCG also stimulates
thyroid hormone production, with free levels of thyroid
hormone increasing during pregnancy and in the presence of
hydatidiform moles." Glucocorticoids, on the other hand,
act to reduce thyroid hormone production by suppressing
pituitary TSH secretion. The thyroid also obtains direct
adrenergic innervation, and there is some evidence that sympathetic stimulation can increase thyroid hormone synthesis.
Other external factors that can affect thyroid regulation
include nonthyroidal illness, starvation, and temperature
changes. A variety of disorders, especially severe illness,
lead to reduced levels of peripheral thyroid hormone in the
absence of a compensatory rise in TSH (the so-called sick
euthyroid syndrome). Starvation also leads to markedly
reduced levels of both T 4 and T 3 , as does exposure to high
temperatures.
Autoregulatory Mechanisms
The thyroid can also control its own stores of thyroid hormone by intrinsic autoregulatory mechanisms. These mechanisms are principally seen in response to alterations in
iodide availability. For example, an excess of dietary iodide

leads to autoregulated inhibition of iodide uptake into the follicular cells, whereas iodide deficiency results in increased
iodide transport and uptake. Large doses of iodide have more
complex effects, including an initial increase followed by a
decrease in organification, the so-called Wolff-Chaikoff
effect." Excess iodide also inhibits, at least initially, the
release of stored thyroid hormone from the thyroid follicle.
Calcitonin Physiology
Calcitonin Secretion
Calcitonin is secreted by the parafollicular C cells located in
the lateral lobes of the thyroid. This hormone is a 32-amino
acid polypeptide with an NH-terminal 7-member disulfide
ring."? Calcitonin acts to lower serum calcium concentration, principally by inhibition of bone resorption. Secretion
of the hormone is increased in the presence of elevated levels
of serum calcium. In the clinical context, calcitonin secretion
can be stimulated by a number of techniques, including calcium infusion, pentagastrin infusion, and alcohol.t''
Peripheral Action of Calcitonin

Calcitonin acts via specific cell surface receptors located
predominantly on the surface of osteoclasts." These receptors have also been found in renal tubular epithelium, neural
tissue, and lymphocytes.t" The predominant action of calcitonin is to inhibit osteoclast action, although in the physiologic situation calcitonin does not actually cause a lowering
of s~rum calcium levels. Indeed, in patients with medullary
carcinoma of the thyroid, in which calcitonin levels may be
many thousands of times the normal level, hypocalcemia is
not seen. Similarly, patients who have had a total thyroidectomy, with removal of all known C cells, maintain normal
calcium metabolism.
Summary
In summary, the thyroid gland contains two separate functioning units. The follicular cells produce T 4 and T 3, which
regulate growth and metabolism, whereas the parafollicular
cells produce the antihypercalcemia hormone calcitonin.
Iodine is required for the synthesis of thyroid hormone, and
iodine deficiency can result in endemic goiter and cretinism.
Circulating levels of thyroid hormone depend on a negative
feedback between T 3 and T 4 and TSH secretion as well as a
positive action of TSH. Thus, medications and other factors
can influence ambient thyroid hormone levels and, consequently, the metabolic state.
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Surgical Anatomy and

Embryology of the Thyroid
and Parathyroid Glands
and Recurrent and External
Laryngeal Nerves
Jean-Francois Henry, MD
The surgical anatomy of the thyroid, parathyroid glands, and

recurrent and external laryngeal nerves should be considered as a whole. A thorough knowledge of the anatomy and
an understanding of the embryonic development of the
thyroid and parathyroid glands are the keys to successful
surgery.
Thyroid Embryology and

Developmental Abnormalities
The thyroid gland has a double origin from the primitive
pharynx and the neural crest. The main body of the thyroid
gland is derived from epithelial cells of the endoderm of the
primitive pharynx. These cells will form the greater portion
of the follicular elements of the thyroid tissue. They arise
as a diverticulum from the midline of the pharyngeal floor.
It soon develops as a bilobed, encapsulated structure that
descends in the midline of the neck. With further development, this diverticulum remains attached to the buccal cavity
by a narrow tract-the thyroglossal duct. Its distal end may
become the pyramidal lobe.
The neural crest is the source of the parafollicular cells,
or C cells, which secrete calcitonin. 1,2 These C cells migrate
from the neural crest of the ultimobranchial bodies of the
fourth branchial pouch (P IV) and the fifth branchial pouch.
The incorporation of the fifth pouch with the P IV leads
to the formation of the caudal-pharyngeal complex, which
includes not only the ultimobranchial bodies (lateral thyroids) but also the parathyroid glands arising from the endoderm of the P IV. Eventually, C cells populate the thyroid
tissue by way of its lateral lobes, which join the main body
on each side (Fig. 2-1).
The normal adult thyroid gland is composed of two lateral lobes connected by an isthmus. Anomalies of embryonic development of the two lobes result in a large variety
of shapes and sizes. Rarely, in fewer than 0.1 % of cases, the
isthmus or one lobe may not develop.
The thyroglossal duct may persist or may differentiate
into thyroid tissue at any level. Normally, the epithelium of
the thyroglossal duct disappears. Occasionally, the epithelium and the duct may form thyroglossal cysts or fistulas,
which usually present above the hyoid bone but may occur
at any site along the duct between the base of the tongue and
the suprasternal notch. These are essentially midline structures. Because the duct passes through or anterior or posterior to the hyoid bone, excision of the midsection of the
hyoid bone is necessary for complete excision of the entire
cyst and thyroglossal duct up to the foramen cecum.
Midline ectopic thyroid rests are the result of the failure
of or incomplete descent of the thyroglossal duct and of
abnormal development of its epithelium. The most common
example is the pyramidal lobe, which extends upward from
the isthmus or from either lateral lobe in about 30% of
patients. It may be considerably enlarged in patients with
endemic goiters and in Graves' disease. In the latter case,
if overlooked, it may be responsible for recurrent hyperthyroidism. Complete failure of descent of the thyroglossal
duct results in a lingual thyroid, located at the base of the
tongue. A lingual thyroid may be the only functioning
tissue and may be responsible for lingual goiter; symptoms
depend on its size. Other midline ectopic thyroid rests
of the thyroglossal duct may be found below or above
the hyoid bone. Usually asymptomatic, they are demonstrated on radioiodine scanning after total thyroidectomy.
Carcinomas may rarely arise in median ectopic thyroid tissue.
10 - -
Thyroid Gland
FIGURE 2-1. Schematic view of embryonic migrations of parafolIicular andparathyroid tissues. At the 13- to l4-mm stage, the P III
and P IV migrate together with the thymus and ultimobranchial
bodies, respectively.
About I % of thyroglossal cysts contain papillary thyroid

cancers.
Aberrant thyroid tissue has also been identified lateral or
inferior to the main body of the thyroid gland and in the
superior anterior mediastinum. When aberrant thyroid tissue
is situated lateral to the jugular vein and is unassociated with
lymph node tissue, it may rarely be a developmental anomaly deriving from the fourth pouch. Ectopic intrathoracic
thyroid tissue may also be found in the periaortic region
and the pericardium. It is the result of the displacement of
thyroid rests into the mediastinum by the descent of the
heart and great vessels. Because their blood supply is from
intrathoracic vessels, tumors arising from these thyroid
remnants usually cannot be removed by cervicotomy and
require a sternum-splitting incision.
In contrast with the former rare situations, what appears
on histologic examination to be normal thyroid tissue within
lymph nodes lateral to the jugular vein in fact represents
metastatic papillary thyroid carcinoma. On the other hand,
on rare occasions, a few follicles of normal thyroid tissue are
observed within the capsule of medially located lymph nodes.
They do not necessarily represent metastases, provided that
the follicular cells appear normal and the follicles are limited
to the periphery of the lymph node. It has been demonstrated
that in these rare cases, the thyroid gland is entirely normal
at meticulous histologic examination.' Thyroid tissue may
also rarely be found in ovarian teratomas. In rare instances,
when thyroid tissue is the main component, struma ovarii
may arise and be responsible for thyrotoxicosis or malignancy
with peritoneal metastases.
it as the origin of the thymus IV (rudimentary thymus IV),

which rapidly undergoes involution. The fatty lobules sometimes found at the site of the upper parathyroid (P IV) may
well constitute the vestigial remnants of this thymus IV.
At the 13- to 14-mm stage, the P III and P IV migrate
together with the thymus and ultimobranchial bodies,
respectively. The P III-thymus complex separates from the
pharyngeal wall and moves toward the caudal and medial
regions. Because of the extension of the cervical spine and
the descent of the heart and great vessels, the thymus and
the P III are drawn toward the superior mediastinum. At the
20-mm stage, the cephalic regression of the thymus brings
about its separation from the P III, which are thus abandoned at the level of the anterior or posterolateral region
of the inferior poles of the thyroid lobes or at the level of
thyrothymic ligaments, vestigial structures indicative of
their former connections. This embryologic migration
results in an extensive area of dispersal of the normal P III.
In 61% of cases, they are situated at the level of the inferior
poles of the thyroid lobes on the posterior, lateral, or anterior aspects. In 26% of cases, they are situated in the thyrothymic ligaments or on the upper cervical portion of the
thymus. More rarely, in 7% of cases, they are situated higher
up, at the level of the middle third of the posterior aspect
of the thyroid lobes, and may then be confused with P IV
(Fig. 2-2).
The P IV follow the thyroid migration of the ultimobranchial bodies, which travel toward the lateral part of the
main median thyroid rudiment. Their descent in the neck is
thus relatively limited. They remain in contact with the posterior part of the middle third of the thyroid lobes. The short
course of embryonic migration of P IV explains why they
remain relatively stable in their topography when they are
not pathologic. Thus, in 85% of cases, they are grouped at
the posterior aspect of the thyroid lobes, in an area 2 em in
diameter, whose center is situated about 1 em above the
Parathyroid Embryology and

Developmental Abnormalities
The inferior parathyroid glands arise from the dorsal part of
the P III. The thymus arises from the ventral portion of the
same pouch. This common origin justifies labeling P III and
thymus as parathymus. The dorsal part of the P IV gives rise
to the superior parathyroids. The fate of the ventral portion of
the P IV is little understood in humans. Gilmour" regarded
FIGURE 2-2. The embryonic migration of the third branchial
pouch (P III)-thymus complex results in an extensive area of the

normal P III from the angleof the mandible to pericardium.
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - -
FIGURE 2-3. The short course of embryonic migration of the

fourth branchial pouches explains why they remain relatively
stable in the topography when they are not pathologic. In 85% of
cases, they are grouped at the junction of the middle and superior
thirds of the posterior aspect of the thyroid lobe.
crossing of the inferior thyroid artery and the recurrent nerve

(Fig. 2_3).4.6 Thus, the P IV are crossed by the P III during
the descent of the parathymus. This embryonic crossing of
P III and P IV explains why their grouping at the level of
the inferior thyroid artery, at the junction of the middle and
inferior thirds of the thyroid lobe, is more or less close,
depending on the migration of P III.
Because the area of dispersal of the P IV is limited by
their short migratory course, a congenital ectopic position of
P IV is unusual. In 12% to 13% of cases, the glands are on
the posterior aspect of the superior pole of the thyroid lobe
in a laterocricoid, lateropharyngeal, or intercricothyroid
position, and, exceptionally, in less than 1% of cases, they
are above the upper pole of the lobe. In 1% to 4% of cases,
they are frankly posterior behind the pharynx or esophagus.
Because the embryonic descent of the thymus extends
from the angle of the mandible to the pericardium, anomalies of migration of the parathymus, whether excessive or
defective, are responsible for high or low ectopias of P III.
The incidence of high ectopias, along the carotid sheath,
from the angle of the mandible to the lower pole of the thyroid, does not seem to exceed 1% to 2%.5.8 Conversely, if
their separation from the thymus is delayed, the P III may be
dragged down into the anterior mediastinum to a varying
degree. They are then usually in the thymus, at the posterior
aspect of its capsule, or still in contact with the great mediastinal vessels. These low ectopias are found in 3.9% to 5%
of cases.v" Parathyroid glands found in the posterosuperior
mediastinum are usually tumoral P IV that have migrated
subsequently because of gravity."
The strictly intrathyroid localization of some parathyroids is explicable only on embryologic grounds. According
to Wang,1O the P IV may become included within the thyroid
at the time of fusion of the ultimobranchial bodies with the
median thyroid rudiment. Although the P III do not arise
from the P IV, undeniable cases of a normal or pathologic
P III included in the lower poles of the thyroid lobes have
been reported.t'! According to Gilmour," intrathyroid
inclusion of parathyroid tissue may be found with the same
incidence as inclusions of thymic tissue. Overall, the incidence of intrathyroid ectopias that seem to involve both P III
and P IV is between 0.5% and 3.5%.4,8-11
Other embryologic cervical or mediastinal ectopic glands
are more rare and usually related to supernumerary
glands. 13, 14 These develop from accessory parathyroid debris
11
arising from fragmentation of the pharyngotracheal duct

when the pharyngeal pouches separate from the pharynx.
The incidence of these supernumerary glands is relatively
high at 13%.5 Akerstrom and colleagues' distinguish
between accessory parathyroid glands containing simple
tissue debris and weighing less than 5 mg, found very close
to the main glands, and true supernumerary glands weighing
more than 5 mg (average weight, 24 mg) situated apart from
the other glands.
Ectopic or supernumerary parathyroids may also be situated in quite exceptional positions. They are then revealed
by tumoral formations developing from them and are
responsible for hyperparathyroidism: in the middle mediastinum (0.3%) at the level of the aortopulmonary window,"
lateral to the jugulocarotid axis." The migration of pathologic parathyroid tissue seems highly improbable in such
cases. In both cases, the embryologic hypotheses suggest a
precocious fragmentation of P Iy' 15.16
Parathyroid tissue'? and parathyroid adenomas" have
also been described within the vagus nerve. In the latter
case, it has been hypothesized that parathyroid tissue arises
from the P III, which is closely related to the vagus nerve
during embryogenesis.'? A case of a parathyroid located in
the mucosa of the piriform sinus has even been reported. 19
Surgical Anatomy of the

Thyroid and Parathyroid Glands
The normal adult thyroid gland weighs about 17 g. It is
wrapped around the anterolateral portion of the upper tracheal rings and larynx. Each lobe occupies a bed between
the trachea and the esophagus medially; the carotid sheath
posteriorly; and the sternocleidomastoid, the sternohyoid,
and the sternothyroid muscles laterally and anteriorly. If the
sternothyroid and sternohyoid muscles are to be divided
transversely, they must be transected high, at the cricoid
level, to preserve their motor nerve, the ansa hypoglossi.
Section of the strap muscles has no clinical functional
consequence.
The normal thyroid is soft, dark wine-red in color, and
covered with a thin capsule. It is loosely attached to neighboring structures. The variations in fixation of the gland may
arouse suspicion of pathologic change, particularly when
the history suggests acute thyroiditis or cancer. Normally,
the gland adheres only to the cricoid cartilage and the upper
tracheal rings. This is the posterior suspensory, or Berry's,
ligament.
The superior and inferior thyroid arteries are derived
from the external carotid arteries and the thyrocervical
trunks, respectively. Occasionally, a branch from the innominate artery or aorta, the arteria thyroidea ima, may be present. It passes directly upward in front of the trachea to enter
the lower border of the isthmus. Its frequency of occurrence
has been greatly overemphasized.
The superior thyroid artery is the first branch of the external carotid artery. It arises just above the thyroid cartilage. It
gives off the superior laryngeal artery and then descends on
the surface of the inferior constrictor of the pharynx, deep to
the sternothyroid muscle. It enters the upper pole of the thyroid on its anterosuperior surface. It gives off a relatively
12 - -
Thyroid Gland
FIGURE 2-4. Relation between the external branchof the superior

laryngeal nerve and the thyroid artery. The nerve may run partly to
or around the artery or its branches.
large branch to the pyramidal lobe and isthmus. The superior

thyroid artery, via its posterior branch, feeds the superior
parathyroid or P IV. There is an extremely close relationship
between the superior thyroid artery and the external branch
of the superior laryngeal nerve (Fig. 2_4).20.2\ This nerve is
the motor nerve to the cricothyroid muscle, which produces
tension of the vocal cord and makes possible the production
of high-pitched voice sounds. Injuries to the nerve, in particular bilateral injuries, are easily overlooked at postoperative
laryngoscopy. In 6% to 18% of cases, the external branch of
the superior laryngeal nerve runs with or around the superior
thyroid artery or its branches. Therefore, the nerve is highly
vulnerable during ligation of the superior thyroid artery.
Nevertheless, routine identification of the nerve during thyroid surgery is usually not advocated. Indeed, in 20% of
cases, the nerve is not located in the surgically accessible
area around the superior thyroid pole. It cannot be identified
without dissection into or through the fibers of the pharyngeal constrictor muscle.
To avoid nerve injury when ligating the superior thyroid
vascular pedicle, one may recommend first identifying the
branches of the artery to avoid ligation of its main trunk.
This identification is particularly recommended during excision of pathologically enlarged thyroid glands. The superior
thyroid arteries should be ligated as low as possible on
the thyroid gland. Second, it is advisable to dissect the superior thyroid vessels away from the nerve by opening up a
space between the cricothyroid muscle and the upper pole of
the thyroid. This dissection requires strong downward and
outward traction on the upper pole of the gland. During this
traction, the nerve should be sought more or less transversely between the superior thyroid vessels and the pharyngeal constrictor muscle or the cricothyroid muscle. Finally,
the dissection must be performed from medial to lateral.
Moreover, small vessels run from the superior thyroid artery
into the pharyngeal constrictor and the cricothyroid muscles. As the nerve slips under these muscles, there is a risk
of heat injury to the nerve during cauterization of these little
muscular vascular branches.
The inferior thyroid artery arises from the thyrocervical
trunk. It runs upward behind the carotid sheath to about the
level of the cricoid cartilage, loops medially and downward

to a level above the inferior pole of the thyroid, crossing the
sympathetic trunk or its branches, and then runs upward
again to reach the gland at its midportion. For the surgeon,
the inferior thyroid artery appears from beneath the carotid
artery only when the thyroid gland is retracted medially and
the jugular vein laterally. This maneuver puts tension on the
artery and makes it easier to identify. Before entering the thyroid, the artery usually divides into three branches: inferior,
posterior, and internal. One branch or sometimes the trunk
itself supplies the inferior parathyroid or P III.
The inferior thyroid artery and its terminal branches are
intimately associated with the recurrent laryngeal nerve at
about the level of the junctions of the lower and middle
thirds of the thyroid gland (Fig. 2-5). The left recurrent
laryngeal nerve ascends at the depth of the tracheoesophageal groove or just lateral to it at the lower pole of the
thyroid. Usually it crosses deep to the inferior thyroid artery,
sometimes between the terminal branches of the artery,
rarely superficially. The right recurrent laryngeal nerve
courses more obliquely, being somewhat more lateral in
position caudally. It rarely crosses deep to the artery, usually
between its terminal branches. Innumerable variations have
been described.F This is one of the most vulnerable areas
for injury to the recurrent laryngeal nerve.
From a practical point of view, it is safer to search for the
nerve below the artery. Identification of the inferior thyroid
artery and careful ligation of its branches close to the gland
is an excellent means of preserving the nerve and the inferior parathyroid. The recurrent nerve may be mistaken for
one branch of the artery and especially for the inferior laryngeal artery. The nerve is somewhat less regular, rounded,
and elastic than the artery. A small, red, sinuous vessel, a
vasa nervorum, is always observed on it. The tortuousity of
this small vessel is reduced when retraction of the thyroid
puts the nerve under tension. Rarely, the nerve branches
below the inferior thyroid artery. In any case, the surgeon
must consider each extralaryngeal branch of the recurrent
nerve as the possible motor branch and make every attempt
to preserve them all.
FIGURE 2-5. Recurrent laryngeal nerve and its relationship to the
inferior thyroid arteryandto Berry's ligament. The nerve is embedded in the posterior portion of Berry's ligament. It is accompanied
by the inferiorlaryngeal artery, whichgivesoff a small branch that
crosses the nerve internally.
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - -
The recurrent laryngeal nerve continues upward and

medially at the posterolateral aspect of the middle third of
the thyroid gland. It is extremely close to the capsule of the
gland. In a few cases, particularly in pathologically enlarged
glands, it may appear to penetrate or may actually penetrate
the thyroid gland itself before entering the larynx. At the two
upper tracheal rings, the nerve is embedded in the posterior
portion of Berry's ligament (see Fig. 2-5). This ligament
extends posteriorly behind the recurrent nerve and loosely
attaches the thyroid to the esophagus. Vessels and connective tissue are more condensed anteriorly at the level of the
tracheal rings. The nerve commonly divides before the point
at which it enters the larynx, posterior to the cricothyroid
muscle. The nerve is accompanied by the inferior laryngeal
artery. At the site of Berry's ligament, this artery, usually
just posterior to the recurrent nerve, gives off a small branch
that crosses the nerve to enter the thyroid glands. Therefore,
bleeding vessels in this portion of the ligament should never
be clamped until the nerve has been identified. It is in this
area that the recurrent nerve is most vulnerable to injury.
Medial retraction on the thyroid lobe makes the nerve more
vulnerable to injury during lobectomy. Indeed, this maneuver puts tension on the inferior thyroid artery and its
branches and on Berry's ligament; consequently, the nerve
is displaced anteriorly on the lateral aspect of the trachea.
Moreover, the posterior fibers of Berry's ligament press the
nerve against the lateral aspect of the tracheal rings, increasing the difficulties of dissection. Instead of medial retraction, it is preferable to retract the lobe upward after complete
dissection of its lower pole. With this maneuver, it is easier
to follow the nerve until its entry in the larynx at the level of
the cricoid cartilage.
The recurrent laryngeal nerve is the motor nerve to the
intrinsic muscles of the larynx." Injury to the motor trunk
causes paralysis of the vocal cord on the ipsilateral side. The
other extralaryngeal branches are sensory.
On rare occasions (0.63%), the right inferior laryngeal
nerve does not recur'" On the left side, this anomaly is quite
exceptional (0.04%). As a rule, the origin of the nonrecurrent laryngeal nerve is cervical. Depending on its level of
origin, the nerve runs more or less down along the vagus
nerve and more or less across the jugulocarotid groove,
making a downward curve. It always passes behind the
common carotid artery. In one third of cases, it is in close
contact with the trunk or the branches of the inferior thyroid
artery; it enters the larynx at the usual level. Nonrecurrence
of the inferior laryngeal nerve results from a vascular anomaly during embryonic development of the aortic arches: no
innominate artery, but an aberrant subclavian artery (arteria
lusoria). Nerve anomaly on the left side requires, in addition, a right aortic arch associated with situs inversus viscerum. A nonrecurrent laryngeal nerve has been also
reported in association with an ipsilateral recurrent laryngeal nerve.25-28 Curiously, in some cases, no vascular anomaly has been demonstrated." The supposed coexistence of a
recurrent and a nonrecurrent laryngeal nerve is questionable.
First, an enlarged anastomotic branch between the cervical
sympathetic system and the recurrent laryngeal nerve
may be mistaken for nonrecurrent laryngeal nerve."
Second, in the reported cases, it has never been demonstrated
that the recurrent branch originated from the vagus nerve.
13
The nervous branch has only been described running in the

usual pathway of a recurrent laryngeal nerve and having a
small caliber. Whether this branch really originates from the
vagus nerve and not from the sympathetic system, for example, the stellate ganglion, has not been proved."
During thyroid lobectomy, if the nerve is not found at its
usual place, before it crosses the inferior thyroid artery, it
should be sought more or less transversely between the laterally retracted carotid sheath and the medially retracted
thyroid in a plane that, in the case of nerve anomaly, cannot
be cleaved as easily as usual, because the nonrecurrent inferior laryngeal nerve links the two structures.
Other aberrant pathways for the recurrent laryngeal nerve
are observed only with pathologically enlarged thyroids and
particularly with large posterior nodules and in substernal
multinodular goiters. In these cases, if it is not possible to
search for the nerve at its usual place, below the inferior
thyroid artery, it should be located superiorly near to where
it enters the larynx at the level of the cricoid cartilage. This
maneuver requires previous dissection of the upper pole of
the gland, or an "inside-out" approach, after section of the
isthmus. Then the nerve should be dissected in a downward
direction.
The venous drainage is more variable than the arterial
supply. The capsular veins vary in size and may be enormous in pathologic glands. These are thin-walled structures
that intercommunicate freely among themselves, forming
a characteristic capsular network. The vessels within the
gland itself are relatively small. Consequently, hemorrhage
from capsular vessels may be important, but, provided that
the vessels are clamped, subtotal resection of a lobe is a
relatively bloodless procedure. The capsular network is
schematically drained by three pedicles. The superior thyroid veins, just anterior and lateral to the superior thyroid
artery, empty directly or indirectly into the internal jugular
vein. The lateral or middle veins vary greatly in number.
They pass directly from the anterolateral border of the lobe
into the internal jugular vein. Careful lateral retraction of the
carotid sheath facilitates their identification and their ligation, especially in enlarged glands where they may be mistaken for capsular veins. The inferior thyroid veins leave the
lower pole and the isthmus in several trunks, frequently
forming a plexus. They empty into the internal jugular vein
and directly into the innominate vein. Ligation of the most
lateral inferior thyroid veins requires previous identification
of the recurrent nerve. The nerve may be anterior and, particularly when the thyroid lobe is medially retracted, could
be mistaken for a vein. Follicular carcinomas, because of
their high tendency for vascular invasion, may spread
directly through veins into the internal jugular veins and
sometimes downward into the innominate vein. In such
cases, previous distal control of these veins is mandatory
before thyroidectomy.
Lymphatic drainage of the thyroid is extensive and may
flow practically in all directions. Capsular lymph channels,
draining the intraglandular capillaries, may even crosscommunicate with the isthmus and opposite lobe. Therefore,
it is technically impossible to remove all the potential lymph
node metastases in thyroid cancers.
Nevertheless, and from a practical point of view, the surgeon must consider two zones of lymphatic drainage for the
14 - -
Thyroid Gland
FIGURE 2-6. The two sites of lymphatic drainage of the thyroid.

The first site is the visceral compartment of the neck. The second
site is the lateral cervical region. The boundary between the two
sites is the carotid sheath.
thyroid (Fig. 2-6). The first site is the paraglandular space or

middle or visceral compartment of the neck. The second site is
the lateralcervical region. The boundary between the two sites
is the carotid sheath. In the visceral compartment, there are
two groups: (l) the prelaryngeal and pretracheal and (2) the
paratracheoesophageal. The prelaryngeallymphatic vessels
lie anterior to and above the isthmus and merge superiorly
and laterally with the lymphatic vessels of the superior pole
of the thyroid along the superior thyroid vessels to drain into
the nodes of the lateral neck. The pretracheal lymphatic
vessels lie below the isthmus and merge inferiorly with the
lymphatic vessels of the anterior and superior mediastinum.
The anterior boundary of the visceral compartment is the
posterior surface of the prethyroid muscles, but sometimes
node metastases may be found very anteriorly in the midline, particularly just above the isthmus (Delphian lymph
nodes). The paratracheoesophageal lymphatic vessels lie
along the lateral and posterior aspects of the thyroid gland
and along the course of the recurrent laryngeal nerves. They
communicate laterally with the lymphatic vessels in the
supraclavicular triangles and posteriorly with those around
and behind the trachea, the larynx, the pharynx, and the
esophagus. Lymphatic drainage of the isthmus flows down
into the mediastinal nodes and upward into the paralaryngeal nodes. The normal flow direction from the central and
lower parts of the lateral lobes is toward the tracheoesophageal nodes. Only lymphatic drainage of the superior
poles of the lobes may flow directly into the lateral neck
nodes. This may explain why papillary thyroid carcinomas
revealed by metastatic laterocervical lymph nodes are
located in the upper pole of thyroid lobes in nearly two thirds
of cases.'? Therefore, the central neck area is the primary
zone of lymphatic drainage for all thyroid cancers except
those located in upper poles of the glands. Lateral neck areas
(internaljugular chains and posterior triangles) are secondary
zones of lymphatic drainage. Some of the involvement probably is brought about by retrograde extension resulting from
obstruction of the lymph flow route in the central neck area."
Because the visceral or central compartment of the neck
is the primary zone of involvement, many surgeons advocate
prophylactic neck dissection in this area in cases of papillary
and medullary thyroid carcinomas. Indeed, even if metastatic nodal recurrences are rare, reoperations in the central
neck area are difficult and increase the risk of injury to the
recurrent laryngeal nerve and parathyroid glands.
Just as embryology helps the surgeon understand where
the parathyroid glands are positioned, their gross appearance makes it possible to identify them and to differentiate
them from other structures. The parathyroid glands vary in
shape but remain compact in 94% to 98% of cases.' Their
color depends on their adipocyte content and vascularization: light brown or coffee colored when the gland is very
fatty, and darker, buff, or reddish brown when the gland is
more cellular or has a richer blood supply. They are soft and
supple and retain their original shape during dissection. If
flattened by the development of a thyroid nodule, they can
become rounded again when detached from its surface.
Their average size varies from 5.25 x 3 x 1.28 mm to 5 x
3 x 1 mm, as reported by Gilmour and Martin'? and Wang,6
respectively. The average weight of a normal gland is 40 mg
(range, 10 to 78 mg). They are encapsulated and have sharp
outlines and a smooth, glistening surface. Parathyroid
glands have a particular affinity for fat and are often found
completely or partially embedded in a fatty globule. They
often have a fatty capsule over their surface like the crest of
a helmet. Characteristically, they can be separated easily
from the adjacent fatty structures.
Whatever their size, shape, or color, the parathyroid
glands always share an encapsulated appearance, which
gives them a proper shape, an ocher tint, and a soft elastic
consistency. Fat is softer, paler, and straw colored, with no
definite shape. Thyroid tissue is firmer, less homogeneous,
darker wine-red in color with bluish-gray tints, and often
embedded in "padding." Lymph nodes are firmer, more
rounded, less homogeneous, and white, dirty gray, or putty
colored, with black dots. Nodes are separated from the adjacent fat with greater difficulty. Lymph nodes are usually
multiple. Thymic tissue is paler, grayish yellow or grayish
pink, granular, and adherent to the fat.
The arterial supply of the parathyroid glands is terminal in
type; the artery is solitary in two thirds of cases. The length
of the artery varies (l to 40 mm), but in cases of thyroidectomy, even if the parathyroid is pedicled, its preservation
depends primarily on the distance between the origin of its
artery and the thyroid capsule. The vascularization of P III
depends primarily on the inferior thyroid artery. The P IV
are supplied by the inferior thyroid artery, by the posterior
branch of the superior thyroid artery, or by the posterior
marginal arch of Evans. Both P III and P IV may be entirely
dependent on the inferior thyroid artery. Therefore, during
thyroid lobectomy, the inferior thyroid artery must never be
ligated at the level of its main trunk. Similarly, the preservation of P IV requires separate ligation of the branches of
the superior thyroid artery so as to preserve the posterior
branch. At the lower poles of the thyroid lobes, the preservation of P III is ensured by the technique of ultraligation
Surgical Anatomy and Embryology of the Thyroid and Parathyroid Glands - - 15
advised by Halsted and Evans." When the lower parathyroid glands (P III) are situated in the thyrothymic ligaments
or in the upper poles of the thymus, they are supplied by the
inferior thyroid artery.
Venous drainage occurs by three methods: (1) by the
capsular network of the thyroid, (2) by the venous pedicles
of the thyroid body, or (3) by a combination. Thyroid lobectomy may render the ipsilateral parathyroid glands
ischemic. Hemostasis of a parathyroid vein generally should
be avoided because of the risk of glandular infarction.
Parathyroid ischemia is often evidenced by progressive
darkening of the gland. Incision of the capsule and superficial parenchyma may prevent venous stasis and allow the
gland to recover its normal color.
Summary
The thyroid gland is made up of follicular and parafollicular
cells of endoderm and neural crest origin, respectively. The
lower parathyroid glands and thymus arise from the dorsal
part of the P III, and the upper parathyroid glands arise from
the P IV. The lower parathyroid glands are usually situated
caudal to where the inferior thyroid artery and recurrent
laryngeal nerve cross. If not situated here, they are usually
in the thymus. The upper parathyroid glands are more dorsal
or posterior, more consistent in position at the level of the
cricoid cartilage. When not situated here, they may descend
along the esophagus into the posterior mediastinum. An
understanding of the embryonic formation of the thyroid
and parathyroid glands as well as experience helps the surgeon recognize not only the normal relationship of the thyroid and parathyroid glands with the adjacent structures but
also the aberrant development or position of these glands.
This knowledge is of paramount importance for successful
operations.
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I. Le Douarin N, Le Lievre c. Embryologie experimentale: Demonstration
de I'origine neurale des cellules a calcitonine du corps uItimobranchial
chez I'embryon de poulet. Comptes rendus de l'Academie des Sciences
1970;270:2857.
2. Pearse AGE, Cavalheira AE Cytochemical evidence for an ultimobranchial origin of rodent thyroid C cells. Nature 1967;214:929.
3. Meyer JS, Steinberg LS. Microscopically benign thyroid follicles
in cervical lymph nodes. Cancer 1969;24:302.
4. Gilmour JR. The gross anatomy of the parathyroid glands. J Pathol Bact
1938;46:133.
5. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human
parathyroid glands. Surgery 1984;95:14.
6. Wang CA. The anatomic basis of parathyroid surgery. Ann Surg 1976;
183:271.
7. Fraker DL, Doppman JL, Shawker TH, et al. Undescended parathyroid
adenoma: An important etiology for failed operations for primary hyperparathyroidism. World J Surg 1990;14:342.
8. Henry JF, Denizot A. Anatomic and embryologic aspects of primary

hyperparathyroidism. In: Barbier J, Henry JF (eds), Primary
Hyperparathyroidism. Paris, Springer-Verlag, 1992, p 5.
9. Thompson NW. Surgical anatomy of hyperparathyroidism. In:
Rothmund M, Wells SA Jr (eds), Parathyroid Surgery. Basel,
Switzerland, Karger, 1986, p 59.
10. Wang CA. Hyperfunctioning intra-thyroid parathyroid gland: A
potential cause of failure in parathyroid surgery. J R Soc Med
1981;74:49.
I I. Wheeler MH, Williams ED, Wade JSH. The hyperfunctioning intrathyroid parathyroid gland: A potential pitfall in parathyroid surgery. World
J Surg 1987;11:110.
12. Gilmour JR. The embryology of the parathyroid glands, the thymus,
and certain associated rudiments. J Pathol Bact 1937;45:507.
13. Numano M, Tominaga Y, Uchida K, et al. Surgical significance of
supernumerary parathyroid glands in renal hyperparathyroidism,
World J Surg 1998;22:1098.
14. Pattou NF, Pelissier LC, Noel C, et al. Supernumerary parathyroid
glands: Frequency and surgical significance in treatment of renal hyperparathyroidism. World J Surg 2000;24: I330.
15. Curley IR, Wheeler MH, Thompson NW, Grant CS. The challenge of
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of the lateral triangle of the neck: Report of two cases. Surgery
1987;101:114.
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vagus nerve. Arch Pathol Lab Med 1988;112:304.
18. Raffaelli M, Defechereux T, Lubrano D, et al. Intravagal ectopic
parathyroid gland. Ann Chir 2000;125:961.
19. Joseph MP, Nadol JB, Goodman ML. Ectopic parathyroid tissue in the
hypopharyngeal mucosa (pyriform sinus). Head Neck Surg 1982;5:70.
20. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in thyroid surgery. Surgery 1987;102:999.
21. Cernea CR, Ferraz AR, Cordeiro AC. Surgical anatomy of the superior
laryngeal nerve. In: Randolf GW (ed), Surgery of the Thyroid and
Parathyroid Glands. Philadelphia, WB Saunders, 2003, p 293.
22. Reed AE Relations of inferior laryngeal nerve to inferior thyroid
artery. Anat Rec 1943;85:17.
23. Randolf WR. Surgical anatomy of the recurrent laryngeal nerve. In:
Randolf GW (ed), Surgery of the Thyroid and Parathyroid Glands.
Philadelphia, WB Saunders, 2003, p 300.
24. Henry JF, Audiffret J, Denizot A. The nonrecurrent inferior laryngeal
nerve: Review of 33 cases, including two on the left side. Surgery
1988;104:977.
25. Katz AD, Nemiroff P. Anastomoses and bifurcations of the recurrent
laryngeal nerve: Report of II 77 nerves visualized. Am Surg 1993;
59:188.
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1988;104:983.
27. Proye CAG, Carnaille BM, Goropoulos A. Nonrecurrent and recurrent
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Am J Surg 1991;162:495.
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nerves and their association with a recurrent branch. Am J Surg
1983;146:501.
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supply and preservation. Ann Surg 1907;46:489.
Medical and Surgical

Treatment of Endemic Goiter
Polly S-Y Cheung, MBBS(HK)
Endemic goiter is a preventable disease caused by iodine

deficiency. According to statistics from the World Health
Organization (WHO) in 1999, a total of 740 million
people-about 13% of the world's population-are affected
by endemic goiter alone. '
Clinically, the individual with endemic goiter may present
with a diffuse to multinodular goiter. Biochemically, the
urinary iodine excretion level is low, and the serum thyroxine
(T4) level may be low or normal with an elevated thyroidstimulating hormone (TSH) level. Long-standing goiters may
become autonomous in function and produce toxicity.
Mechanical obstruction to the trachea and the thoracic inlet and
malignant changes are possible sequelae of endemic goiters.
The occurrence of endemic goiter is preventable by an
adequate supply of iodine in the diet. Universal salt iodination is the goal of WHO in an attempt to eliminate the disease
by the year 2000. Data from WHO in 1999 showed that 68%
of the total population in countries affected by iodine deficiency disorders (IDDs) have access to iodized salt. Existing
endemic goiters are currently treated with iodine supplementation to reverse hypothyroidism and to reduce the size of the
goiters. For long-standing goiters, the treatment is the same
as that for sporadic goiter: T4 therapy and thyroidectomy are
used for treatment; radioiodine therapy is used selectively.
Goiter, an enlargement of the thyroid gland, is conventionally called an endemic goiter when it occurs in more
than 10% of the population in a defined geographic area; the
area is called an endemic area? A total goiter rate of 5% or
higher is now recommended as the cut-off point to indicate
a public health problem, following a decision made by the
WHOlUnited Nations International Children's Emergency
Fund (UNICEF)/lnternational Council for the Control of
Iodine Deficiency Disorders (ICCIDD) Consultation on
IDD Prevalence in November 1992.3 This recommendation
is based on the observation that goiter prevalence rates
between 5% and 10% may be associated with a range of
abnormalities, including inadequate urinary iodine excretion
or subnormal levels of T4 among adults, children, and
neonates. Epidemiologic studies are usually carried out in
school-age children (6 to 12 years of age) because of their
high physiologic vulnerability and their accessibility
16
through school for studies on baseline health parameters and

results of public health programs.
Endemic goiter is the chief consequence of iodine deficiency, resulting from either low iodine intake or ingestion
of goitrogens. The effects of iodine deficiency on human
growth and development are denoted collectively as IDDs
(Table 3-1). 4 It affects all stages of development from fetus
and neonate to infant, child, and adolescent. Severe iodine
deficiency affects the developing central nervous system.
In the fetus, it causes abortion, stillbirth, congenital anomalies, or cretinism. In children and adolescents, it produces
problems ranging from mild intellectual impairment to
mental retardation to full-blown endemic cretinism. It is
well recognized that a marginal iodine intake is associated
with some degree of motor deficit or developmental delays,
such as poor hand-eye coordination and impaired intellectual
performance exemplified by a reduction in IQ scores by as
much as 10 to 15 points in tests of mental development.'
Prevalence
According to a global review in 1999, more than 2 billion
people are at risk for iodine deficiency, this number
representing 38% of the world's population. Approximately
741 million people from 130 countries have endemic goiter,
representing 13% of the world population (Table 3-2).'
Most of the world's natural supply of iodine exists in
the ocean as iodide. In high, mountainous areas and inland
waters, the soil becomes leached of iodine by snow water
and glaciation. Lowlands with heavy rainfall or flooding can
also become iodine deficient. The most important goitrous
areas historically include the northern and southern slopes
of the Himalayas, the Andean region of South America, the
European Alps, and the mountainous areas of China. Goiters
also occur in lowlands far from the oceans, such as the
central part of Africa and, to a lesser extent, in the coastal
areas of Europe."
The global prevalence of goiter has hardly increased at
the global level from 1990 to 1998 (Table 3-3),1 This figure
was thought to reflect the vigorous efforts in survey and
Medical and Surgical Treatment of Endemic Goiter - - 17
increased data, especially in countries in the Eastern

Mediterranean, Africa, and Europe, where the total goiter
rate is high. The Eastern Mediterranean region has the
highest goiter prevalence rate, with 74% of the population at
risk for iodine deficiency. On the other hand, IDD prevalence
has decreased slightly in the Americas, Southeast Asia, and
the Western Pacific, reflecting the impact of IDD control
programs, especially salt iodization, on the population.
Southeast Asia and the Western Pacific (including China)
together account for more than 50% of the world's total
population at risk for IDD (Fig. 3-1). Countries in this
region, including India, Pakistan, Bangladesh, Nepal,
Myanmar (Burma), Vietnam, and Thailand, share a large
rate of prevalence of IDD; 599 million people are at risk and
172 million are goitrous. China alone has 300 million people
at risk of IDD because of the extensive mountainous areas in
that country, with 109 million suffering from goiter.8
Iodine deficiency persists mostly in developing countries
despite the established benefits of iodine supplementation in
the prevention of endemic goiter. In decreasing order of
magnitude, the number of people at risk of IDD is largest in
the Eastern Mediterranean, followed by Africa, Southeast
Asia, Europe, Western Pacific, and the Americas (see
Table 3-2).
18 - - Thyroid Gland
FIGURE 3-1. Prevalence of iodine deficiency disorders (IDDs)-global distribution. TGR = total goiter rate. (From WHOIUNICEFI
International Council for the Control of Iodine Deficiency Disorders. Global Prevalence of Iodine Deficiency Disorders. Geneva,
Switzerland, World Health Organization, 1996.)
Mild to moderate iodine deficiency still persists in a

number of European regions, namely Italy, Spain, Germany,
Greece, Romania, Hungary, Poland, and the former
Yugoslavia." Continuous measures to provide iodine are
required to overcome the socioeconomic and cultural limitations in different regions.
The prevalence of endemic goiter is influenced by age
and gender. In severely iodine-deficient areas, goiter appears
at an early age, and the prevalence increases markedly
during childhood and attains its peak during puberty. From
the age of 10 years, the prevalence is higher in girls than in
boys, probably because of the difference in metabolism of
iodine during adolescent growth. In both sexes, goiter prevalence decreases during adulthood, but the decline is sharper
in men than in women. 10
Etiology of Iodine Deficiency

Iodine is an essential substrate in the synthesis of the thyroid
hormones i.-thyroxine (T4) and t-triiodothyronine (T 3) .
The normal human thyroid gland releases about 65 ug of
hormonal iodine to the circulation per day, which represents
the minimum daily requirement of iodine. Iodine requirements increase during puberty, pregnancy, and lactation.
Iodine intake is considered adequate when it is between

100 and 200 ug/day (Table 3-4). The principal source of
iodine intake is from diet or pharmaceuticals. I I
The highest amounts of iodine in food are found in fish,
seafood, and seaweed. Iodine is also found to a lesser extent in
milk, eggs, and meat from animals whose diet contained sufficient amounts of iodine. Fruits and vegetables, except spinach,
generally have very low iodine contents. The iodine content of
drinking water is too low to serve as a consistent contributor to
iodine supply.12 In an iodine-deficient environment, the locally
grown food will also have a low iodine content. Some foods,
beverages, and drugs, such as multivitamins, minerals, and
antacids, have coating or coloring agents that contain iodine.

Low supply of dietary iodine is the main cause of development of endemic goiter. Because it is difficult to measure
the iodine content of foods, the adequacy of dietary iodine is
usually determined by the measurement of urinary excretion
of iodine. This measurement represents the ratio between
concentrations of iodine and creatinine in casual urine
samples. 13 Two or more casual urine samples from the same
individual taken on consecutive days are recommended to
allow for variation in creatinine content." Experience has
shown that the iodine concentration in early-morning urine
specimens adequately reflects an individual's iodine status.
In addition, iodine concentration per liter of urine bears a 1:I
relationship with iodine per gram of creatinine and is now
adopted as the standard in field studies by WHO.3 Measuring
iodine concentration per liter of urine helps avoid the cumbersome measurement and calculation of the iodinecreatinine ratio. In nonendemic areas, the urinary iodine
measurement is at least 100 ug/L. Severe iodine deficiency is
considered to occur with a daily iodine excretion of less than
20 IlgIL; moderate deficiency, 20 to 49 IlglL; and mild deficiency, 50 to 99 IlgIL.15.16 The prevalence of endemic goiter
varies with the severity of iodine deficiency (Table 3-5).
Increasing iodine consumption in endemic areas has
resulted in a reduction in goiter prevalence. The persistence of
goiter in some areas with adequate iodine prophylaxis and the
unequal geographic distribution of goiter in iodine-deficient
areas suggest the existence of other goitrogenic factors.
Natural goitrogens were first found in vegetables of the
Brassica family, including cabbage, turnips, and rutabagas.
Their antithyroid action is related to the presence of thioglucosides, which, after digestion, release thiocyanate and
isothiocyanate. These compounds have goitrogenic actions
by inhibiting iodide transport in the thyroid gland. A particular
thioglucoside, goitrin, is also found in the weeds growing in
pastures in Finland and Tasmania. 17
Cyanoglucosides are another important group of naturally
?ccurring goitrogens found in several staple foods in the tropICS, namely cassava, maize, bamboo shoots, and sweet potatoes. They are converted to the goitrogen thiocyanate after
digestion. Flavonoids from millet, a staple food in Sudan, are
also known to have antithyroid activity. IS The consumption of
millet in Sudan and cassava in Zaire was found to aggravate
the severity of the goiter endemism in these places.'?
Protein malnutrition coexists frequently with endemic
goiter. Studies of malnourished individuals in endemic areas
show alterations in thyroid morphology and functions, suggesting that malnutrition has a goitrogenic effect.P
Pathophysiology of Endemic
Goiter
Endemic goiter is the end result of the physiologic and morphologic changes in the thyroid gland as an adaptation to
an insufficient supply of dietary iodine. When iodine intake
is low, thyroid hormone synthesis is impaired. This impairment leads to an increased thyroidal clearance of iodide
from the plasma and decreased urinary excretion of iodide,
an adaptation toward iodine conservation.
T3, being three to four times more potent than T 4 but
containing only three fourths as much iodine as T 4, is
preferentially synthesized over T 4 . There is also increased
peripheral conversion of T 4 to T321
Clinical euthyroidism is thus maintained, but biochemically the pattern of low serum T4, elevated TSH, and normal
or supranormal T 3 is often found. 22 . 24 In severe thyroid failure,
such as that in endemic cretinism, serum T3and T 4 concentrations are low and serum TSH concentration is markedly
elevated. In less severe thyroid endemism, serum T3 and
T 4 concentrations may remain normal. The serum TSH level
may also be normal or moderately elevated, and there may be
an exaggerated TSH response to thyrotropin-releasing hormone (TRH) simulation, implying an increase in the pituitary
reserve of TSH and subclinical hypothyroidism.
Such changes are thought to be mediated through an
elevation in the serum TSH level. However, a wide variation
in the level of TSH has been observed in normal and
goitrous individuals in endemic areas.P Such dissociation
between goiter size and biochemical findings suggests the
po~sible
role of circulating thyroid growth factors, such as
epidermal growth factors, or an autoimmune process in the
pathogenesis of goiter." Activity of thyroid growth-promoting
i~unoglo~ulin
(TGI) has been demonstrated in patients
With sporadic and endemic goiter.'? However, conflicting
results were obtained, and the methods of detection of such
activity have been criticized, with this uncertainty leaving an
unsettled role of TGI in goitrogenesis.P-"
Morphologic Changes in
Endemic Goiter
An increase in thyroid gland mass often accompanies the
physiologic changes in response to iodine deficiency.
Generalized epithelial hyperplasia occurs, with cellular
hypertrophy and reduction in follicular spaces. In chronic
iodine deficiency, the follicles become inactive and distended with colloid accumulation. These changes persist
into adult life, and focal nodular hyperplasia may develop,
leading to nodule formation." Some nodules retain the ability to secrete thyroid hormone and form hot nodules. Others
do not retain this ability, become inactive, and form cold
nodules. Necrosis and scarring result in fibrous septa, which
contribute to the formation of multinodular goiter.
Clinical Presentation and

Diagnosis
Goiter is classified according to the size of the thyroid gland
on inspection and palpation, and the following grading
system was proposed by WHO in 196032 :
Stage 0: no goiter
Stage Ia: goiter detectable only by palpation and not
visible even when the neck is fully extended
Stabe Ib: goiter palpable but visible only when the neck
is fully extended
Stage II: goiter visible with the neck in the normal
position; palpation is not needed for diagnosis
FIGURE 3-2. Classification of goiter size. 1, Stage Ia: goiter palpable but not visible. 2, Stage Ib: goiter visible when neck
extended. 3, Stage II: goiter visible in normal neck extension.
4, Stage III: goiter visible at a distance. (From Perez C, Scrimshaw
NS, Munoz JA. Technique of endemic goitre surveys. In: Endemic
Goiter, Monograph Series No. 44. Geneva, Switzerland, World
Health Organization, 1960, p 369.)
Stage III: very large goiter that can be recognized at a

considerable distance (Fig. 3-2)
Because of observer variation in the measurement of
goiter by inspection and palpation, the WHOIUNICEFI
ICCIDD Consultation on IDD indicators in November 1992
recommended a simplified classification of goiter by combining the previous stages la and Ib into a single grade
(grade 1) and combining stages II and III into grade 2. 3 The
sum of grades 1 and 2 is taken as the total goiter rate. The
simplicity of this assessment allows for easy training of field
staff in public health surveys.
Grade 0: no palpable or visible goiter
Grade 1: a mass in the neck that is consistent with an
enlarged thyroid that is palpable but not visible when
the neck is in the neutral position; it also moves upward
in the neck as the subject swallows
Grade 2: a swelling in the neck that is visible when the
neck is in a neutral position and is consistent with an
enlarged thyroid when the neck is palpated
In areas of mild endemicity where the goiter rate is low
and goiters are generally small (i.e., grade 1 or bordering on
either grade 0 or 2), interobserver variations can be as high
as 40%. Ultrasonography is therefore recommended by WHO
as a safe, noninvasive method for providing a more precise
and objective measurement of thyroid volume than inspection and palpation."
The most common form of goiter in children is a diffuse
thyroid enlargement. Nodularity may occur at a young age,
and the finding of a small, solitary, palpable nodule in adolescence is common. Some diffuse goiters persist into adulthood, or the main bulk of the goiter may be replaced by
multiple nodules that form a multinodular goiter, simulating
a bag of marbles on palpation.
Functionally, the individual often remains clinically
euthyroid despite biochemical evidence of hypothyroidism,
with low or normal serum T4 concentrations and minimally
elevated serum TSH levels. Scintigraphy of the thyroid in
endemic areas may show marked heterogeneity in the uptake
of radioiodine and formation of hot or cold nodules.
Autonomous function of the nodules leads to failure of 1311
or 1231 suppression with T 3 and absence of TSH response to
TRH. Hyperthyroidism in older patients with endemic goiter
may be precipitated by iodination and cause Jodbasedow
hyperthyroidism.>'
Endemic cretinism is a sequela of severe iodine deficiency in which intrauterine growth is affected by deficiencies of maternal T4 and dietary iodine. The infant is born
with mental retardation and either (1) a predominantly neurologic syndrome of hearing and speech defects and varying
degrees of characteristic stance and gait disorders or (2) predominant hypothyroidism and stunted growth. These
changes are preventable with iodine prophylaxis but are not
curable once they have occurred.
Mechanical problems often arise in patients with huge goiters that cause tracheal deviation and compression. Large, substernal, or retrosternal goiter can cause venous congestion and
the development of collateral venous circulation on the chest
wall (Fig. 3-3). Surgical treatment is indicated in such patients.
The presence of hard nodules suggests possible malignant disease, although an increase in the number of thyroid
cancers in endemic goiter remains controversial.v-"
Medical and SurgicalTreatment of Endemic Goiter - - 21
FIGURE 3-3. Large goiter with thoracic inlet obstruction. (From
DeSmetMP. Pathological anatomy of endemic goiter. In: Endemic

Goiter, Monograph Series No. 44. Geneva, Switzerland, World
Health Organization, 1960, p 338.)
Follicular and anaplastic carcinoma are more common in areas

of endemic goiter. The diagnosis is often delayed in such
patients because goiters are so common in iodine-deficient
areas. Fine-needle aspiration biopsy helps select patients for
thyroidectomy.'?
Treatment and Prophylaxis

The occurrence of endemic goiter can be prevented by
supplying an adequate amount of iodine in the diet and
eliminating goitrogens and malnutrition.
Iodination of salt is the preferred method of prophylaxis
because salt consumption is consistent and universal, the
technology of iodination is simple, and its production is easy
to regulate. It was first successfully introduced in Switzerland
and in the state of Michigan in 1921.38 Iodine in the form of
potassium iodide is added to table salt in varying amounts
ranging from 1 to 10,000 parts of salt to 1 to 200,000 depending on local factors such as customary consumption of salt.
Potassium iodate is preferred in humans because of its
increased stability." Epidemiologic surveys have confirmed
that there is a dramatic reduction in the prevalence of goiter
and progressive disappearance of endemic cretinism within
several years after introduction of salt iodination programs."
Countries such as the United States, the United Kingdom,

New Zealand, Australia, the Netherlands, Norway, and
Sweden have completely eliminated IDDs.41 Difficulties in
implementation occur in countries where locally inexpensive
noniodized salt is available and government programs to
increase iodine consumption are lacking.
Iodination of vegetable oil is the principal alternative
used in developing countries and in areas where salt is not
customarily used, such as the New Guinea highlands.f It is
also used as a short-term intervention while an iodized-salt
program is being established. One intramuscular injection
containing 480 mg of iodine provides adequate amounts of
iodine for up to 3 years. Oral administration of iodized oil
has the advantage of avoiding injections, but its duration of
action is shorter and more variable, depending on absorption
of iodine through the gastrointestinal tract." An oral dose
of 1 mL (containing 480 mg of iodine) provides adequate
iodine for 1 to 2 years after a single administration.
An increased incidence of thyrotoxicosis occurs after
increased iodine consumption. This increase was observed
in Tasmania after bread iodination in 1966 and was most
evident in older people." The thyrotoxicosis was attributed
to the presence of autonomous nodules or underlying hyperthyroidism in persons with long-standing endemic goiters.
Overall, however, the long-term correction of iodine deficiency not only abolishes endemic goiter but also reduces
the incidence of toxic nodular goiters. Therefore, the occurrence of thyrotoxicosis does not outweigh the enormous
benefits of iodine prophylaxis in endemic regions. However,
iodination does have some risk in individuals older than
45 years with goiter, because hyperthyroidism may develop.
At the World Summit for Children in 1990, which was
attended by 71 heads of state and government, WHO,
UNICEF, and ICCIDD established the target of virtual
elimination of IDDs by the year 2000 and universal salt
iodination in affected countries by the end of 1995.45
Efforts have been made to reduce the cost of salt iodination by reducing the price of potassium iodate and the
manufacturing cost of the spray-mixing equipment for salt
iodination. At present, the cost of salt iodination is approximately $0.05 per person per year. Campaigns have been
launched in affected countries to analyze the existence
and the severity of the problem and to convince governments, salt producers, and other relevant bodies of the costeffectiveness and benefits of salt iodination. Funds have
been raised to help developing countries start programs of
salt iodination.i"
A 1998 global survey by WHO reported that 85% of
the total number of countries affected by IDD have either
formed legislation on salt iodization to start implementing
national plans for iodination of all salt and introducing legislation to prohibit the sale of uniodized salt'? or have plans
of action for controlling IDD. Data also showed that of the
5 billion people living in countries with IDD, 68% have
access to iodized salt and 65% of these countries have laboratory facilities to monitor urinary iodine status and salt
iodine levels. America is the region that is closest to virtual
elimination of IDD, with more than 90% of the total population consuming iodized salt.
For the patient with hypothyroidism and endemic goiter,
the functional and neurologic changes are irreversible.
Iodine supplementation during the first 6 months of life,
however, has been shown to prevent some of the neurologic
problems and also to cause regression in the size of endemic
goiter in young children and adolescents.f
In adults with large, diffuse, or nodular goiters, T4 therapy
suppresses TSH secretion and in 50% to 87% of patients
causes involution of the hyperplastic tissue and a 20%
decrease in goiter size."
Surgical treatment is indicated in diffuse or nodular goiters in the following situations: (1) large size or increase in
size while the individual is receiving TSH suppression treatment; (2) mechanical obstruction to the trachea, esophagus,
or thoracic inlet, such as in retrostemal or intrathoracic
goiter; (3) toxic change; (4) suspected or proven malignant
change; and (5) cosmetic reasons. Subtotal thyroidectomy,
near-total, and total thyroidectomy are acceptable operations, and the indications are the same as those for patients
with sporadic goiters.P
Radioiodine therapy has been used to reduce the size of
euthyroid goiters and to control toxicity in the presence of
autonomously functioning tissue in multinodular goiters.5152
However, large doses of radioiodine are usually required
because of the low levels of uptake in these large multinodular
goiters, which are also more radioresistant than diffuse toxic
goiters." Surgical treatment is preferred for most patients
because it eliminates the bulk of the goiter, corrects the functional abnormality, removes possible malignant neoplasms,
and avoids long-term complications of radioiodine therapy.
Conclusion
In conclusion, endemic goiter is preventable and is a public
health problem worldwide, affecting 13% of the world's
population. Iodination is cost-effective, and although it
results in a transient increase in hyperthyroidism, overall the
benefits greatly outweigh the risks. Significant progress has
been achieved in a global effort in eliminating IDD in the
last decade, with 68% of the 5 billion people living in countries with IDD having access to iodized salt. The global rates
of goiter, mental retardation, and cretinism are falling.
For established goiters, treatment with thyroid hormone
is helpful in some patients in stabilizing or decreasing goiter
size. Thyroidectomy becomes indicated for mechanical and
cosmetic reasons or because of possible or documented
malignancy.
Acknowledgment
The author is grateful to Mrs. Pat Soong for providing technical assistance
in the preparation of the chapter and Ms. Veronica Chan for typing the
manuscript.
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24. Bachtarzi H, Benmiloud M. TSH regulation and goitrogenesis in
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on intelligence, thyroid status, and somatic growth in school-aged
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treatment with levothyroxine or iodine on thyroid size and thyroid
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Bockisch A, Jamitzky T, Derwanz R, et al. Optimized dose planning
of radioiodine therapy of benign thyroidal disease. J Nucl Med
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Nygaard B, Hegedus L, Gervil M, et al. Radioiodine treatment of
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Shapiro B. Optimization of radioiodine therapy of thyrotoxicosis:
What have we learned after 50 years? J Nucl Med 1993;34: 1638.
Sporadic Nontoxic Goiter

Maha AI-Fehaily, MD Orlo H. Clark, MD
The term goiter (L. guttur, throat) refers to an enlarged

thyroid gland, but what constitutes "enlargement" is often
not clearly defined.' Goiters can be classified according to
prevalence of the disease, thyroid function, location of the
thyroid (neck or mediastinum), morphology, or underlying
etiology (Table 4-1).
Sporadic nontoxic goiter (SNG) may be diffuse or nodular, is associated with normal thyroid function, develops
in subjects living in an iodine-sufficient area, and does
not result from an inflammatory or neoplastic process.'
Endemic goiter is present when more than 10% of the population living in a specific geographic area have a goiter. The
term sporadic goiter is used in regions with normal iodine
intake and a lower prevalence of goiter. Worldwide, endemic
goiter is the most common endocrine disorder, occurring in
more than 850 million people, or 7% of the world population. It occurs almost exclusively in the iodine-deficient
areas. Sporadic goiter affects about 5% of the adult population in the United States.'
Sporadic nodular goiter is a common clinical entity.
Patients often present with small, diffuse, or nodular goiters
or have a solitary palpable nodule. In addition, recent studies using high-resolution ultrasonography and previous
autopsy studies document that up to 50% of the general population have thyroid nodules, even when the thyroid gland is
normal to palpation. In addition, about 50% of individuals
with a solitary thyroid nodule to palpation have other
smaller thyroid nodules by ultrasound examination."
There are numerous unresolved issues regarding the etiology, natural history, evaluation, and optimal management
of persons with goiter' Goiter represents an impairment of
the thyroid gland's function, growth, and size. The problems
that arise in patients with goiter include the following:
Growth of the gland causing compressive symptoms or
cosmetic problems (Fig. 4-1)
Development of subclinical or overt thyrotoxicosis or
hypothyroidism
Risk of malignancy in nodular goiter
Cretinism or congenital hypothyroidism, as occurs in
as many as 10% of infants born in areas of severe
iodine deficiency'
24
Causes of Goiter
Several mechanisms, including the interplay of intrinsic and
extrinsic factors in the thyroid, cause goiter. The goitrogenic
process involves genetic, environmental, dietary, endocrine,
and other factors. The most common worldwide cause of
endemic nontoxic goiter, as mentioned earlier, is iodine deficiency. In patients with sporadic goiter, the cause is usually
unknown. Sporadic goiter is a result of environmental or
genetic factors that do not affect the general population. The
various types of goiter are listed in Table 4-1.
Genetic Factors
The thyroid gland contains a series of enzymes that are
essential for the biosynthesis and secretion of thyroid hormones. A defect in any of these hormones can result in
diminished hormone synthesis and a condition of goiter formation known as dyshormonogenesis. Because the defects
are inherited disorders, dyshormonogenesis is also known
as familial goiter. These enzyme defects may be partial or
complete. Patients with a more severe enzymatic defect
may develop goiter and cretinism early in life. When the
defect is partial or less severe, goiter often develops during
adolescence or later in life, and these individuals are usually
euthyroid. Although familial clustering of goiter is well
recognized, no simple mode of inheritance has been recognized. Familial euthyroid goiter has recently been linked to
a multinodular nontoxic goiter (MNG1) locus on chromosome 14q.6,7 Concordance rates for simple goiter in female
monozygotic twins have been reported higher than in female
dizygotic twins (42% and 13%, respectively)." The ageadjusted cumulative risk for simple goiter from birth to age
43 years was 0.53 for female monozygotic twins and 0.18
for female dizygotic twins." These facts provide evidence of
a genetic component of the etiology of goiter.
Tissue refractoriness to thyroid hormones due to a
thyroid-stimulating hormone receptor (TSHR) defect is a
rare cause of familial goiter. A germline mutation on codon
727 of the TSHR gene on chromosome 14q31 is specifically
Sporadic Nontoxic Goiter - -
associated with toxic multinodular goiter.1O11 Similar somatic

cell mutations may activatean intrinsic growth control system
leading to goiter.
Environmentally Induced Goiter

IODINE DEFICIENCY
Endemic goiter is discussed in Chapter 3. An inadequate

adaptive mechanism of the thyroid to protect from severe
iodine deficiency results in the development of goiter. These
adaptive mechanisms include increased iodide clearance,
increased production of triiodothyronine (T3) relative to
thyroxine (T4 ) , and increased mass of thyroid follicular
cells. I Pregnancy increases the need for iodine and T4,
which results from significant transfer of thyroid hormone
from the mother to the fetus and also increased iodide loss
in the urine. 12 Iodine-deficient thyroid tissue is more growth
responsive to thyroid-stimulating hormone (TSH) than is
iodine-replete thyroid tissue." Thyroid cellular growth is
also influenced by the higher human chorionic gonadotropin
serum concentrations that occur during pregnancy.14
ENVIRONMENTAL AND OTHER FACTORS
The development of sporadic goiter is influenced by many

factors. Thiocyanate is a well-known goitrogen produced
from cigarette smoke and vegetable foods such as cassava
and cabbage. These goitrogens, however, seem to be of clinical importance only in areas of iodine deficiency.
The intake of an excessive amount of iodine inhibits

thyroid peroxidase and results in the Wolff-Chaikoff effect.
The normal gland is usually able to escape from this effect
by inhibition of iodide uptake so that the intrathyroidal
iodide level falls and organification resumes. However, in
some patients with underlying thyroid disorders, the thyroid
is unable to adapt to iodide excess and goiter and hypothyroidism ensue (iodide-induced myxedema). Patients at risk
of goiter and or hypothyroidism due to failure to escape
from iodine inhibition of thyroid hormonogenesis are those
with Hashimoto's thyroiditis or those with reduced or
damaged thyroid tissue after thyroidectomy or after radiation exposure to the neck. 1516 Excess iodine intake in
contrast media may also cause goiter with hyperthyroidism
(Jodbasedow hyperthyroidism). Numerous medications
also have antithyroid and goitrogenic effects. Amiodarone,
which is rich in iodine (37%), has been associated with
induction of hypothyroidism and hyperthyroidism. Lithium
causes hypothyroidism by inhibiting (1) colloid formation
stimulated by cyclic adenosine monophosphate and (2) the
release of thyroid hormone from the gland. Contrast media
used for imaging are rich in iodine and may cause transient
hypothyroidism but not goiter. Ionizing radiation, either
externally or with therapeutic doses of radioactive iodine
(1 311), usually destroy thyroid tissue, causing hypothyroidism,
but smaller doses (200 to 1500 rad) increase the risk of developing nodular goiter, thyroiditis, or thyroid cancer. I
Pathogenesis
Goiter Growth
Goiters result from focal follicular cell hyperplasia at one
or multiple sites within the thyroid gland. Iodine deficiency
works synergistically with other causes of goiter but does
not appear to change the basic mechanisms of goitrogenesis.
There is a positive correlation between the total DNA content of the goiter and goiter weight. The increased amount of
interstitial tissue and colloid formation usually contributes
little to the total goiter growth. An intrinsically abnormal
growth pattern of some thyroid cells is usually the driving
force behind goiter growth. Heterogeneous subpopulations
of thyrocytes proliferate at different rates. Both extrathyroidal and intrathyroidal growth factors modulate goiter
formation. Under physiologic in vivo conditions, TSH is the
most important stimulator of thyroid growth and function. A
decrease in iodine intake leads to decreased synthesis and
FIGURE 4-1. Frontal (A) and side

(B) views of a 45-year-old man
with long-standing multinodular
goiter in an endemic area.
25
secretion of thyroid hormones. As a result, the serum TSH
level increases, stimulating thyroid growth.'? The increase
must be relatively short lived and intermittent because most
patients have normal serum TSH levels. Other growth factors are obviously involved since the sizes of various nodules
vary considerably in the same patient. Furthermore, goiters
may grow despite administration of T 4 in doses that reduce
the serum TSH level to a subnormal level or in patients with
toxic nodular goiter. Thus, thyroid growth-modulating
factors in addition to TSH are involved in thyroid growth.
Some growth factors (e.g., insulin-like growth factor 1, epidermal growth factor, and fibroblast growth factor) have a
growth-promoting effect, whereas others (e.g., transforming
growth factor [TGF]-~
and activin A) inhibit growth.l"
Increased expression of ras and other protooncogenes may
also contribute to goiter growth.'?
Nodule Formation
With increasing age, most thyroid glands and goiters
become nodular. Initially, many goiters are diffuse; however,
with intermittent stimulation, some diffuse goiters outgrow
their blood supply and become nodular (Fig. 4_2).20,21 Some
thyroid cells are more sensitive to growth factors and
become larger nodules. If these nodules trap and organify
iodine, the nodule may be "hot" or autonomous rather
than "cold." Hot nodules are associated with TSHR and gsp
mutations.
In general, formation of thyroid nodules can be explained
by the following mechanisms.
Heterogeneous Subpopulation of Thyrocytes with

Different Proliferation Rates that Cause Focal
Hyperplasia or Nodular Transformation Time. Derwahl
and Studer investigated the pathogenesis of this heterogeneity and suggested that multinodular goiters are "true" benign
neoplasms due to intrinsically higher growth rates of some
thyrocytes.Pr" However, most, but not all, nodules in a
multinodular goiter are polyclonal when compared to true
neoplasms." Kopp and associates have also documented
that both monoclonal and polyclonal nodules can be present
within the same multinodular thyroid gland."
Somatic Mutations and Clonality of the Thyroid

Nodules. Different somatic mutations of the TSHR have
been identified." Mutations in oncogenes such as ras appear
to be early mutations because they are present in both

benign and malignant thyroid nodules.
Scarring, Necrosis, and Hemorrhage. For thyroid
nodules to grow, angiogenesis and new vessel formation are
required. These newly formed capillary vessels are often
fragile and are sometimes unable to adequately supply the
growing thyroid tissue, This may result in areas of ischemic
necrosis and hemorrhage within the goiter. Inflammation
and granulation tissue replace the necrotic areas, ultimately
resulting in fibrosis, scarring, and calcification. The resulting network of inelastic fibrous bands' connective tissue
leads to nodularity because it interferes with smooth growth
of thyroid parenchyma. 1
Autonomy
Thyroid nodules that. function in the presence of a suppressed blood TSH level are referred to as autonomous or
hot nodules. Autonomous function and autonomous growth
mayor may not be related. Thus, cold nodules and hot
nodules within a nodular goiter may have exactly the same
growth potential and may respond or be refractory to TSHsuppressive T 4 treatment." Some thyroid follicular cells
take up and organify iodine in the absence of TSH, causing
hot or autonomous nodules. As previously mentioned, these
nodules usually have either TSHR mutations or, less commonly, gsp mutations. When these nodules reach a certain
size and secrete increased amounts of thyroid hormone, the
patient develops subclinical and then overt hyperthyroidism.
This may occur either spontaneously or after exposure to an
excessive amount of iodine (Jodbasedow hyperthyroidismj.F
Natural History
The natural history of nontoxic goiter varies. Children in
endemic areas generally have diffuse goiters, whereas
sporadic goiters tend to develop at an older age and tend to
be nodular. Patients with multinodular goiter are usually
older and have larger goiters than do patients with diffuse or
uninodular goiters. The growth rate of thyroid nodules is
usually slow, but some goiters increase up to 20% yearly."
Rapid growth of a nodule is usually caused by hemorrhage
or cyst formation. One must also be concerned about
malignant tumors such as a thyroid lymphoma or a poorly
differentiated or anaplastic cancer. Patients with goiters
appear to have a slightly higher risk of thyroid malignancy
(discussed later). Patients with multinodular goiters and
suppressed TSH levels are generally older and have a higher
plasma-free T 4 level and larger goiters than those with
multinodular goiters and a normal TSH. Up to 10% of
patients with euthyroid nodular goiter eventually develop
hyperthyroidism.P-'?
Intervention Versus Observation

FIGURE 4-2. Nodular goiter can involve either one or both lobes
of the thyroid gland.
Clear indications for operation (whether the patient is symptomatic or potentially symptomatic) include the following:
1. Large goiter with obstructive symptoms such as shortness of breath and dysphagia
Sporadic Nontoxic Goiter - - 27

2. Substernal goiter, especially with abnormal flow-loop
study
3. Large nodule (>4 em), because patients with large
solitary or dominant nodules are more likely to be
symptomatic and have an increased risk of cancer"
4. Disfigurement
5. Family history of thyroid cancer or exposure to lowdose therapeutic radiation
Patients with a family history of thyroid cancer are much
more likely to develop thyroid cancer. Familial medullary
thyroid cancer, with or without multiple endocrine neoplasia, should always be excluded. Familial non-medullary
thyroid cancer, with or without Cowden's syndrome (multiple
hamartomas, breast cancer, colon cancer, and nodular goiter),
Gardner's syndrome,familial polyposis coli, or Carney's syndrome (schwannomas, myxomas, adrenal tumors, pigmented
skin lesions), should also be considered.
Exposure to low or moderate doses of therapeutic radiation also dramatically increases the risk of thyroid cancer."
Previous investigations document that exposure to as little
as 6 cGy radiation increases the risk of thyroid cancer sixfold.33 The risk increases as the dose of radiation increases
to 2000 cGy. Higher doses of radiation, such as 5000 to
6000 cGy, result in hypothyroidism, but thyroid cancer does
not appear to increase appreciably, probably because the
thyroid cells are destroyed." Younger children who receive
radiation are most likely to develop thyroid cancer. A genetic
predisposition to developing thyroid cancer after exposure to
low-dose therapeutic radiation or radiation fallout may be
present.34,35
Other factors that increase the risk of thyroid cancer
include rapid enlargement of the thyroid nodule, presence of
a dominant firm or hard nodule, ipsilateral vocal cord paralysis, fixation to adjacent structures, ipsilateral enlarged
lymph nodes, and development of new thyroids nodule in
young 20-year-old) or older (>60-year-old) individuals.
When two of these factors suggest a possible cancer, the
likelihood of thyroid malignancy approaches 100%.36 Fineneedle aspiration (FNA) biopsy for cytology often confirms
the diagnosis but should be done only when it will alter
therapy. Computed tomography (CT) scanning should be used
selectively in patients with very large, fixed, or substernal
goiters when the limits cannot be determined clinically.
CT scanning is also indicated in patients with dysphagia,
dyspnea, or hemoptysis.
In patients with small to moderate-sized nodular goiters
without other risk factors for malignancy, an ultrasound of
the thyroid gland may be helpful for subsequent comparison
regarding growth, but CT or magnetic resonance imaging
(MRI) scanning is not neccessary."
Although the risk of malignancy in unselected patients
with multinodular goiter has been considered to be about
I % to 3%, there are several studies that suggest thyroid nodules within a multinodular goiter harbor malignancy at a rate
similar to those with solitary thyroid nodule (5% to 10%).38-40
These figures, however, include small papillary carcinomas
of questionable clinical significance. Evidence suggests that
clinically important thyroid carcinoma occurs in fewer than
I% of patients, given the high prevalence of multinodular
goiter and the very low incidence of clinical thyroid
carcinoma."
Studies indicated that about 4% of the population in the

United States has multinodular goiters and that 4% of these
patients harbor thyroid cancer; therefore, the estimated
prevalence would be around 1.6 per 1000. However, the
estimated incidence of clinical thyroid cancer is only 0.025
to 0.05 cases per 1000, suggesting that less than I of 30
histologic microcarcinomas leads to clinically relevant disease each year."
In other investigations, occult thyroid cancers have been
found at autopsy in up to 36% of patients.v" The clinical
significance of latent cancers (autopsy studies) and incidental occult cancers I em in diameter) found by histologic
examination after removal of benign thyroid tissues has
been questioned" The incidence of clinical thyroid cancer
(>10 mm) obtained in mass screening is about 0.2%, and in
some investigations, only about 2% or 3% of these thyroid
microcancers 10 mm) ever develop into clinical thyroid
cancer." Thus, occult thyroid cancers do not represent an
appreciable risk to an individual when found incidentally
and confined to the thyroid gland. Recent clinical studies
document that about 4% to 6% of nonpalpable nodules biopsied under ultrasound guidance are malignant.Fv' To date,
there are, to our knowledge, no longitudinal studies that document any clinical benefit to performing a biopsy of nonpalpable nodules less than I em in diameter; however, occult
thyroid tumors are presumably of more concern in high-risk
individuals with a family history of thyroid cancer or individuals with a history of exposure to low-dose therapeutic
radiation.P
How Patients with Sporadic Nontoxic

Goiter Should be Managed
Ultrasound examination is helpful for establishing the
presence of multiple, nonpalpable, and cystic nodules and
provides a baseline for subsequent comparison regarding
nodule growth. Certain ultrasonic features in nodular goiter
may suggest malignancy. Several groupS54.56,57 have recommend performing an ultrasound-guided FNA biopsy of any
nodule that is I em or larger, hypoechoic, or solid or has
microcalcifications, irregular borders, central blood flow, or
an absent halo. Some clinicians suggest performing a biopsy
on the dominant nodule. Papini and colleagues'? have
documented invasive cancers (T4) in nodules smaller than
I em; thus, the size cutoff may not be accurate in predicting
the malignant potential of all nodules, and suspicious nodules on ultrasound examination should be considered for
biopsy. A selective approach seems to be indicated; that is,
most occult nodules can be followed by ultrasound examination, but biopsy should be performed in suspicious occult
nodules or nodules in high-risk patients.
Clinical Evaluation
History
Patients with nontoxic goiter are usually asymptomatic and
seek medical advice because of a thyroid mass. Goiters are
more common in women than men (,.,4:1). Sporadic goiters
from dyshormonogenesis and endemic goiter due to iodine
deficiency are usually first noted during childhood and
continue to grow with age. Other causes of sporadic goiter

rarely occur before puberty and do not have a peak age of
occurrence. Thyroid nodules increase in incidence with age.
The natural history of nontoxic goiter is characterized by
slow, often progressive or intermittent growth, with many
patients eventually becoming symptomatic.
Although most goiters are present for years, sudden,
rapid growth of a discrete nodule or thyroid lobe, as previously mentioned, should suggest possible hemorrhage into a
nodule or dedifferentiation to a poorly differentiated thyroid
carcinoma, anaplastic carcinoma, or possible lymphoma.
Benign goiters are rarely painful or grow quickly unless
recent hemorrhage into a nodule has occurred. Some goiters,
especially in patients with chronic lymphocytic thyroiditis,
may cause a choking sensation or pain radiating to the ear.
Symptoms may be caused by compression of structures
in the neck and superior mediastinum. Obstructive symptoms are more likely to occur in patients with a substernal
goiter. As the substernal goiter continues to grow, the thoracic inlet may become occluded, a phenomenon known as
the thyroid cork. This is because substernal goiter is confined between the sternum and the vertebral bodies and may
displace or impinge on the trachea, esophagus, recurrent
laryngeal nerve, and, rarely, the superior vena cava or the
cervical sympathetic chain. Tracheal compression is generally asymptomatic until critical narrowing has occurred
(""75% of cross-sectional area) to about 4 mm. Nocturnal or
positional dyspnea and dyspnea with exertion suggest that
they are caused by substernal goiter. Anxiety when raising
one's arm above one's head with a reddened face and distended neck veins (positive Pemberton sign) suggests
superior mediastinal obstruction. Upper respiratory tract
infection or hemorrhage into a nodule or cyst may exacerbate upper airway obstruction and result in acute respiratory
distress. Dysphagia occurs in about 20% of patients with
substernal goiters. Ischemia and stretching of the recurrent
laryngeal nerve with vocal cord dysfunction may cause
hoarseness in about 4% of patients with benign substernal
goiters, but cancer is more likely in these patients.
Compression of the venous outflow through the thoracic
inlet and sympathetic chain, causing Homer's syndrome,
may rarely occur.58.59
Review of the possible causative factors of goiter and the
differential diagnosis of nontoxic goiter include family history of benign or malignant thyroid disorder, a history of
living in an endemic goiter area or of intake of goitrogens,
a history of radiation exposure or, rarely, metastases from
other organs to the thyroid gland. The last one occurs most
often in patients with lung cancer, breast cancer, hypernephroma, and melanoma.
Physical Examination
In general, the size of a smaller goiter is overestimated,
whereas the size of larger goiters is underestimated. Thyroid
enlargement is often best observed when the patient swallows. A visible goiter has usually reached a size of 30 to
40 mL (""1.5- to 2-fold increase in the size of a normal thyroid gland). One should determine whether the thyroid gland
is symmetrical or a solitary nodule, a multinodular goiter, or
a dominant nodule in a multinodular goiter. Does the goiter
move with swallowing, or is the goiter fixed? Are the nodules hard, firm, or soft? Is there associated lymphadenopathy?
One should also determine whether there is any tracheal
deviation. As previously mentioned, one can document
whether there is venous obstruction by having the patient
elevate his or her arms above the head. If the neck veins
become prominent or the face become flushed, this is a positive Pemberton sign. 60.61
One should also evaluate the patients for signs of
hypothyroidism, hyperthyroidism, or possible other medical
disorders. Features that suggest malignancy include vocal
cord paralysis, fixed firm nodules, or associated lymphadenopathy.F Occasionally, a patient with recurrent
laryngeal nerve palsy can have a benign nodule.P
Diagnosis
The differential diagnosis of a patient with nodular goiter
includes benign nodular goiter, Hashimoto's thyroiditis,
follicular adenoma, and carcinoma.
The laboratory evaluation of a patient with a thyroid
nodule or a nodular goiter should begin with a TSH measurement to determine whether the patient is euthyroid,
hypothyroid, or hyperthyroid. The degree of thyroid dysfunction is often mild or subclinical, with only an isolated
TSH abnormality. The diagnosis of thyrotoxicosis should
be considered in all, but particularly in elderly, patients with
long-standing nodular goiter and/or atrial fibrillation. In
some, usually elderly, patients, the diagnosis of hyperthyroidism is not clinically apparent (apathetic hyperthyroidism). TSH is suppressed to a variable degree, and
characteristically the plasma T 3 level is elevated, whereas
the plasma T4level is normal (T 3 thyrotoxicosis).
When the thyroid gland is only moderately enlarged and
firm, Hashimoto's thyroiditis should be considered. A blood
test documenting increased levels of antithyroid peroxidase
antibodies or thyroglobulin antibodies helps confirm the
diagnosis. Ultrasound often reveals a heterogeneous thyroid
gland. FNA is helpful when there is a discrete nodule within
the firm thyroid gland. Some clinicians recommend evaluating calcitonin levels in patients with nodular goiter, but most
believe it is not cost-effective.v'
A chest radiograph often brings attention to cervical or
substernal goiter due to tracheal deviation. Occasionally,
fine calcifications in a nodular goiter suggest the presence of
a papillary carcinoma.
Ultrasound, as previously mentioned, is particularly
helpful in patients who are to be followed to assess and
monitor the size of a nodule or the goiter. Some clinicians
recommend treating patients with small or moderate-sized
euthyroid goiter with thyroid hormone. In about 25% of
these patients, the goiter decreases in size, and in others, the
growth rate may decrease (see Chapter 8). CT or MRI scanning of the neck and superior mediastinum in patients with
substernal or fixed goiters may reveal tracheal deviation or
compression (Fig. 4_3).65.66 Thyroid scintigraphy is not indicated for the assessment of nodular goiter unless the patient
has a suppressed TSH or treatment with 1311 is being considered. Euthyroid patients with large goiters usually have low
iodine uptake so that a large dose of radioiodine is required.
Sporadic Nontoxic Goiter - - 29
FIGURE 4-3. CT scan of a patient with a large goiter. Note the

evidence of severe tracheal compression and deviation to the right
side (arrow),
Such treatment is only rarely indicated but has recently been

reported to be more effective than TSH suppression."
Evidence of airway obstruction can be obtained by a flowvolume loop tracing. A barium swallow is rarely indicated
unless other causes of dysphagia are considered.
The role of FNA has previously been discussed. We recommend FNA for selected patients with multinodular goiter
who have a dominant nodule within a multinodular goiter, a
large (>4 ern) nodule, nodules with ultrasonic features suggestive of malignancy, a rapidly enlarging nodule, and suspicious complex thyroid nodules (biopsy the solid component).
Treatment
The available treatment options are thyroidectomy, treatment with T4, and radioiodine (Table 4_2).68,69 The treatment
goals for a patient with a nodular goiter include relief of
local compressive symptoms or cosmetic deformity,
prevention of progressive thyroid enlargement, and removal
of possible but uncommon coexistent thyroid cancer,
Asymptomatic euthyroid patients with moderate-sized
goiters can be safely observed. When there is any concern
about malignancy, patients should have an FNA.
T4 therapy is effective in reducing the size of goiters in
patients with iodine deficiency or those with subclinical
hypothyroidism. About half of the clinicians in the United
States and Europe use TSH suppression therapy in patients
with euthyroid goiters. The benefits of such therapy are
disputed.P?' T4 therapy seems to be more efficacious in
patients with small goiters." T4 therapy carries the risk of
inducing thyrotoxicosis, especially when there is autonomy of
the thyroid gland. In addition, T4 administration to the elderly
may predispose to cardiac arrhythmias and cardiovascular
insufficiency.P"? Long-term T4 therapy with hyperthyroidism
is also associated with reduction in bone density, especially

in postmenopausal women. 78-81 This does not appear to be a
problem in euthyroid patients with low-normal or minimally
suppressed TSH levels.
Radioiodine therapy of nontoxic goiters is used primarily
in Europe. It is not standard practice in the United States
unless a patient is a poor surgical risk or has chemical evidence of thyrotoxicosis. Radioiodine therapy does, however,
result in goiter reduction, producing a 40% to 60% decrease in
volume within 2 years. Such studies have led to an increased
use of 1311 in euthyroid or hyperthyroid elderly patients with
multinodular goiter, to both decrease the size and, in the
latter, to treat the hyperthyroidism.P:" Prior administration
of human recombinant TSH may reduce the dose of radioactive iodine required for successful therapy. 1311therapy may be
particularly helpful in selected patients (see Table 4_2).84-86
Side effects of radioiodine therapy include the following:
1. Hypothyroidism (20% to 30% at 5 years)"
2. Radiation thyroiditis-the symptoms are usually mild
and transient but may be devastating due to acute thyroid
swelling in patients with large substernal goiters83,87
3. Induction of Graves' disease in about 5% of patients,
presumably due to release of antigens stimulating an
autoimmune responsev"
4. Temporary thyrotoxicosis-to avoid this possibly catastrophic complication in poor-risk patients, antithyroid
drugs should be administered to patients with hyperthyroidism several weeks before the administration of
1311and/or treatment with ~-adrenergic
blocking agents
after 1311 administration
The potential risk of radiation-associated thyroid cancer
is low when 1311 therapy is used in elderly patients. Recent
evidence suggests that radioiodine therapy in patients with
hyperthyroidism slightly increases the risk of thyroid cancer.
Unfortunately, these thyroid cancers appear to be more
aggresslve.v" Younger patients with large goiters should be
treated surgically because this provides definitive therapy
and rapid resolution of the problem.
We recommend radioiodine ablation therapy only in
selected patients with nodular goiter such as those who are
poor surgical risks.A prospective trial comparing the results of
surgery and 1311therapy in elderly patients would be of interest.
Thyroidectomy offers a rapid reduction in goiter and resolution of the problem with minimal risk when the operation
is done by an experienced thyroid surgeon. Thyroidectomy
also provides tissue for histologic examination and radiation
exposure is not necessary. The procedure is the preferred
treatment for patients with substernal goiter because goiter
may swell after 1311 therapy, and there appears to be a higher
risk of cancer in substernal goiters; such goiters are generally not accessible for FNA. 65,93,94
The indications of thyroidectomy in patients with goiter
are listed in Table 4-2.
Extent of Surgery
The extent of thyroidectomy depends on the type of goiter.
For patients with unilateral goiter, lobectomy-isthmectomy
is sufficient. When the goiter is bilateral, we recommend
total lobectomy on the side with the largest mass and subtotal, near-total, or total lobectomy of the contralateral side.
The reason for this recommendation is that 10% to 20% of

patients develop recurrent goiter.95,96 However, when the
surgeon is not completely happy about the status of the
parathyroid glands and/or recurrent laryngeal nerve on
the initial side, less than total thyroidectomy is recommended on the contralateral side.
Total thyroidectomy has been suggested to be as safe as
subtotal thyroidectomy when the operation is performed by
an experienced thyroid surgeon, with a 1% to 2% incidence
of injury to the recurrent laryngeal nerve and 0.5% to 5%
of hypoparathyroidism. Surgical morbidity is highest in
patients with very large goiters, those with invasive cancers
with extensive lymphadenopathy, those with substernal
goiter, and those who undergo reoperation because of recurrent goiter,97-100
Proponents of subtotal thyroidectomy believe that leaving
about 2 to 4 g of thyroid tissue results in little risk of
recurrence.'?' Proponents of total thyroidectomy suggest that
there is a low morbidity rate of total thyroidectomy, that there
is no risk of recurrence, and that patients after total or neartotal thyroidectomy should take thyroid hormone. 102-104
We believe that total lobectomy on one side and subtotal
resection on the other side, leaving a small ("'4- to 5-g)
remnant of thyroid tissue posteriorly (Hartley-Dunhill
operation) is the preferred operation. If recurrence were to
occur after the Hartley-Dunhill operation. reoperation
would be required only on one side.
The administration of iodide in sporadic multinodular
goiter is not recommended and may result in thyrotoxicosis
(Jodbasedow phenomenon). 105
Summary
Sporadic nontoxic goiter is a relatively common problem.
Iodine deficiency is the most common cause of goiter
worldwide. Sporadic goiter due to environmental or genetic
factors is also relatively common. Nontoxic goiter can be
SporadicNontoxic Goiter - - 31
caused by iodine excess, goitrogens, genetic defects, and
other unknown factors. Determination of the serum TSH level
is essential in all patients with thyroid enlargement. Imaging
of the thyroid gland by ultrasonography to document baseline characteristic for future comparison is helpful and FNA
is recommended selectively. CT or MRI scanning is recommended only for substernal goiters or fixed lesions. Patients
with a family history of thyroid cancer, those with a history
of radiation exposure, and patients with large clinically suspicious nodules suggesting cancer may be treated surgically
without further investigation. Patients with clinically important compressive symptoms or cosmetic concern should be
managed by surgery. Radioiodine can be helpful in poor-risk
patients and those with toxic nodular goiter. Asymptomatic
low-risk patients should be observed. We recommend doing
total lobectomy on one side and subtotal lobectomy on the
other side (Hartley-Dunhill operation) to minimize complications, yet avoid recurrent goiter.
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1998;83:202.
33
105. Vagenakis AG, Wang CA, Burger A, et aJ. Iodide-induced thyrotoxicosis in Boston. N Engl J Med 1972;287:523.
106. Robbins J, Schneider AB. Thyroid cancer following exposure to
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therapy in Sweden. Thyroid 1997;7:205.
Thyroiditis
Geeta Lal, MD Orlo H. Clark, MD
Thyroiditis is defined as an inflammatory disorder of the

thyroid gland. It may result from a myriad of etiologies and
is usually classified into acute, subacute, and chronic forms
(Table 5-1). Each of these is associated with a distinct clinical presentation and histology. Medical therapy remains the
mainstay of management of thyroiditis, but surgical treatment is warranted in certain specific circumstances.
Eikenella corrodens, and Corynebacterium species have also

been cultured. Rare other implicated organisms include
Mycobacteria, Salmonella, Aspergillus, and Actinomycoses
species. J In general, (X- and p-hemolytic Streptococcus and
anaerobes account for about 70% of cases. Pneumocystis
carinii has been identified as the causative organism in
patients with AIDS.
HISTOLOGIC FEATURES
Acute (Suppurative) Thyroiditis

Acute thyroiditis was first described by Bauchet in 1857
and accounted for approximately 0.1 % of thyroid surgeries
before the advent of antibiotic therapy. J
ETIOLOGY AND PATHOGENESIS
The thyroid gland has an innate resistance to infection due

to its extensive blood and lymphatic supply, high iodide
content, and fibrous capsule.' Despite these protective mechanisms, acute thyroiditis may be caused by infectious agents
that seed the thyroid gland (1) by the hematogenous or lymphatic route, (2) by direct spread from persistent pyriform
sinus fistulas or thyroglossal duct cysts, or (3) as a result of
penetrating trauma to the thyroid gland.'
Takai and associates first demonstrated that acute suppurative thyroiditiscan result from persistent pyriform sinus fistulas."
Since then, several investigators have demonstrated that pyriform sinus fistulas are responsible for a large proportion of
cases of recurrent acute thyroiditis. These fistulas are commonly believed to be fourth branchial pouch remnants and
originate at the apex of the pyriform fossa.t The tract courses
in an anteroinferior direction to end blindly in the perithyroidal
space or the thyroid parenchyma-? as shown in Figure 5-1.
As a result, infection may lead to acute thyroiditis or soft
tissue abscesses, which can secondarily extend to the thyroid.
Immunosuppression may be another risk factor for the
disease and acute suppurative thyroid infections and necrosis
have been described in patients with acquired immunodeficiency syndrome (AIDS)8 and those undergoing aggressive
chemotherapy for hematologic malignancies."
Oral cavity bacteria such as Staphylococcus and
Streptococcus species and anaerobes are the most common
causative organisms. Other bacteria such as Escherichia
coli, Pseudomonas aeruginosa, Haemophilus influenzae,
34
Acute thyroiditis usually arises in a normal thyroid gland,

although occurrence in a multinodular gland is not uncommon.'? Histologically, the gland demonstrates an intense
inflammatory response with numerous polymorphonuclear
leukocytes and lymphocytes. II Necrosis of the thyroid gland
and abscess formation often ensue.
CLINICAL PRESENTATION
Acute suppurative thyroiditis is more common in children

and young adults and occurs equally in both sexes. The
disease is often preceded by an upper respiratory tract infection or otitis media. It is characterized by severe neck pain
radiating to the jaws or ear, fever, chills, odynophagia,
and dysphonia. Infants may present with respiratory distress
and stridor secondary to tracheal compression caused by a
thyroid abscess.'? Rarely, acute suppurative thyroiditis may
cause transient vocal cord palsy.'?
On physical examination, erythematous skin usually overlies an extremely tender thyroid gland. The patient holds the
neck in a flexed position to avoid stretching the overlying
strap muscles. Fluctuance indicates an underlying abscess.
These findings are more frequent on the left side and reflect
the left-sided predominance of pyriform sinus fistulas.'?
This is thought to be due to embryologic asymmetry of
the transformation of the fourth branchial arch to form the
aortic and innominate arteries or to poor development of the
ultimobranchial body on the right side of the embryo.i-"
Acute suppurative thyroiditis can be complicated by
systemic sepsis, tracheal or esophageal rupture, jugular vein
thrombosis, laryngeal chondritis and perichondritis, or sympathetic trunk paralysis.!'
DIFFERENTIAL DIAGNOSIS
Several other conditions that must be considered in the

differential diagnosis include subacute painful thyroiditis,
Thyroiditis - -
Hashimoto's thyroiditis, suppurative lymphadenitis, thyroid

carcinoma, thyroglossal duct or branchial cleft cyst,
Ludwig's angina, and dissecting retropharyngeal abscess.
Laryngeal and esophageal carcinomas have also been
reported to present as acute thyroiditis.P'P
These disorders can often be distinguished by clinical
history, physical examination, and various diagnostic tests
described in the following section. Lin and colleagues studied
the clinical features that may help distinguish acute thyroiditis from aggressive malignant thyroid tumors and concluded
that patients with malignancy were older and more likely to
have a history of dysphonia, right thyroid lobe involvement,
larger lesions, anemia, and sterile thyroid aspirates."
DIAGNOSTIC TESTS
Blood tests reveal leukocytosis and an elevated erythrocyte

sedimentation rate (ESR). Blood cultures are useful to identify
35
the causative organisms. Thyroid function tests are usually

normal, although transient elevations of triiodothyronine (T3)
and thyroxine (T4 ) may occur as a result of release of preformed hormone from the inflamed gland.'? Radioactive
iodine uptake (RAIU) scans are usually normal, or there is
decreased uptake due to suppression of thyroid-stimulating
hormone (TSH) by the release of thyroid hormones. However,
if a thyroid abscess is present, an area of decreased uptake
will be seen on the scan. Ultrasound is helpful to distinguish
solid from cystic lesions. Fine-needle aspiration (FNA)
biopsy for Gram stain, culture, and cytology confirms the
diagnosis and helps guide antibiotic therapy and diagnose
underlying malignancy. Computed tomography scans not
only aid in the diagnosis of acute thyroiditis but also help
delineate the extent of infection. 18.19
If a persistent pyriform sinus fistula is suspected, a barium
swallow demonstrates the anomalous tract with 80% sensitivity. False-negative results are usually due to edema around
the tract orifice during acute infection. Hence, contrast studies should be performed after antibiotic therapy during the
quiescent phase.P Direct laryngoscopy is also helpful in
identifying the tract.
TREATMENT
Patients should be treated with parenteral antibiotics based

on the results of the Gram stain and culture. Abscesses are
treated by drainage, either by aspiration with a wide-bore
needle or open surgical drainage. In patients with pyriform
sinus fistulas, complete resection of the sinus tract,
including the area of the thyroid where the tract ends, is
recommended. Miyauchi and coworkers have demonstrated
that complete fistulectomy is essential for cure.? Methylene
blue infiltration via a Fogarty catheter is sometimes used
to cannulate the tract and facilitate its identification and
dissection.P
Subacute Thyroiditis
Painful (de Quervain's) Thyroiditis
Painful thyroiditis is a transient inflammatory thyroid disorder
that was first described by de Quervain in 19042 1 and is
the most common cause of a painful thyroid gland. Other
eponyms for this condition include granulomatous thyroiditis.
subacute granulomatous thyroiditis. or pseudogranulomatous
thyroiditis.
FIGURE 5-1. Gastrografin swallow showing a fistula originating

in the left pyriform sinus. The arrows indicate the fistula.
Painful thyroiditis is thought to be viral in origin or result

from a post-viral inflammatory response. This theory is
supported by the following observations:
1. The disorder is frequently preceded by a respiratory
infection, is usually self-limiting, and has a seasonal
distribution (summer and fall).
2. It is often associated with specific viral infection
outbreaks such as coxsackievirus, mumps, measles,
adenovirus, and infectious mononucleosis.
3. Cytopathic viruses have been cultured from thyroid
tissue.
4. Viral antibodies have been detected in the sera of
patients with the disease.F
36 - -
Thyroid Gland
There is also evidence for a genetic predisposition,

manifested by its strong association with the HLA-B35
haplotype." A model of pathogenesis suggests that antigens
(either directly from viruses or from damaged thyroid
tissue) are presented by macrophages in the context of
HLA-B35 and stimulate cytotoxic T lymphocytes. These
lymphocytes proceed to damage thyroid follicular cells. This
autoimmune process, however, is self-limiting. Antibodies
directed against the TSH receptor have also been described,
but they seem to be related to the inflammatory process and
are not believed to cause the disease.
HISTOLOGIC FEATURES
The inflammatory process may involve the entire gland or

a single lobe. On cut section, the involved areas are firm
and yellow-white. Microscopically, the changes vary with
the stage of the disease and may overlap. Microabscesses,
which result from neutrophil replacement of disrupted
follicles, are commonly seen during the early inflammatory
stage. Later, lymphocytes, histiocytes, and plasma cells are
seen to accumulate around damaged follicles. Colloid (or
fragments thereof) are surrounded by multinucleated giant
cells, giving this disorder the designation of granulomatous
thyroiditis, as shown in Figure 5-2. 11
high fever, tOXICIty, and pronounced edema leading to

obstructive symptoms.
The disorder classically progresses through four stages."
The initial hyperthyroid phase, due to release of thyroid
hormone, lasts 3 to 6 weeks and may be accompanied by
symptoms such as tremors, sweating, palpitations, and heat
intolerance in 50% to 70% of patients. Patients then
progress to the second or euthyroid phase. Hypothyroidism,
which is the hallmark of the third phase, occurs in about
20% to 30% of patients and lasts from weeks to months. The
last phase is characterized by resolution of the disease and
returns to the euthyroid state in more than 90% of patients.
Of note, some patients may progress directly from the hyperthyroid phase to the recovery phase, without the intervening
hypothyroid phase. A few patients develop recurrent disease.
Disorders that mimic the presentation of subacute thyroiditis include hemorrhage into a thyroid nodule or cyst,
acute suppurative thyroiditis, painful Hashimoto's thyroiditis, infected thyroglossal duct or branchial cleft cyst, and
pseudothyroiditis." The last entity is produced by rapid
growth of anaplastic or poorly differentiated thyroid
malignancies.
DIAGNOSTIC STUDIES
Painful thyroiditis occurs more commonly in women (malefemale ratio of 1:3 to I :6) between 30 and 40 years of age.
It is characterized by the sudden or gradual onset of unilateral or bilateral pain in the neck, which may radiate toward
the mandible or ear and is exacerbated by swallowing or
neck movement. Many patients report a preceding upper
respiratory tract infection with low-grade fever, neck pain,
dysphagia, and flu-like symptoms with malaise and myalgias.
Physical examination reveals an enlarged, exquisitely
tender thyroid gland that is firm, particularly in the acute
phase. The overlying skin may be erythematous if the
inflammation is severe. Rarely, patients may present with
In the early stages of the disease, TSH is decreased, and

thyroglobulin, T 4, and T 3 levels are elevated due to the
release of preformed thyroid hormone and colloid from
destroyed follicles. In contrast with Graves' disease, T 4 and
T 3 are elevated in proportions reflecting their intrathyroidal content." Thyroid antibody titers (antithyroglobulin,
antimicrosomal, and TSH receptor antibody) are also elevated in 10% to 20% of patients, although they bear no
relationship to the state of thyroid function. The most characteristic abnormality is an elevation of the ESR greater than
100 mm/hr. In fact, a normal ESR rules out active subacute
thyroiditis.F RAID is also decreased 2% at 24 hours) even
in euthyroid patients due to the destruction of the thyroid
parenchyma and iodine-trapping mechanism and release of
thyroid hormones with TSH suppression. RAID returns to
normal as the process resolves. FNA biopsy may be useful
in equivocal cases or to rule out malignancy or acute
thyroiditis. Thyroid ultrasound shows areas of hypoechogenicity that disappear as the disease process resolves-"
as demonstrated in Figure 5-3, and thyroid ultrasound has
demonstrated usefulness in predicting autoimmune thyroid
disease in a multicenter study. 29
TREATMENT
FIGURE 5-2. Histologic features of subacute granulomatous

thyroiditis. The thyroidparenchyma contains a chronic inflammatoryinfiltrate with a multinucleate giantcell (upper left corner) and
a colloid follicle (lower right corner). (From Cotran R, KumarY,
Collins T, RobbinsSL reds], Robbins Pathologic Basis of Disease,
6th ed. Philadelphia, WB Saunders, 1999, p 1135.)
Painful thyroiditis is self-limited and usually resolves within

a few months without specific therapy. Therefore, treatment
is primarily symptomatic. Aspirin and other nonsteroidal
anti-inflammatory drugs are often the initial medications of
choice for pain relief. However, prednisone (40 mg/day)
may be indicated for early relief of pain and swelling in
more severe cases." These drugs suppress the inflammatory
response but do not alter the underlying disease process.
The dose is usually tapered after a week and then discontinued
within 2 to 4 weeks. If pain and swelling recur during
the taper or after withdrawal, the treatment is restarted.
Thyroiditis - - 37
FIGURE 5-3. Thyroid ultrasound (transverse) showing normal thyroid echogenicity (A) and subacute thyroiditis (B). In B, the thyroid is
enlarged and shows reduced echogenicity, similar to surrounding strap muscles. Arrows indicate the thyroid surface. M = muscle;
T = thyroid parenchyma; C = common carotid artery; TR = trachea; VC = vertebral column. (A and B, From Pedersen OM, Aardal NP,
Larssen TH, et al. The value of ultrasonography in predicting autoimmune thyroid disease. Thyroid 2000; 10:251.)
Hyperthyroidism may rarely require treatment with Pblockers. Thyroid replacement may be needed in the hypothyroid
phase, if patients are symptomatic. Therapy should be withdrawn and the patient re-evaluated after 6 months. Externalbeam radiation therapy was used to treat subacute thyroiditis in
the past. However, this modality as been abandoned due to a
slower and less predictable response than steroids, an approximately 25% failure rate, and the risk of thyroid cancer formation." Thyroidectomy is reserved for the rare patient who has
a prolonged course not responsive to medical measures.
titers are typically higher than in patients with the sporadic

variant. Postpartum thyroiditis is more likely to occur in
successive pregnancies. Familial clustering of cases has also
been reported," and a positive family history for postpartum
thyroiditis can be elicited in up to 50% of patients.t''
Silent thyroiditis can also develop after exposure of
the thyroid gland to therapeutic doses of external-beam
radiation" or drugs such as interferon IX used in the management of chronic hepatitis."
Painless Thyroiditis
Painless thyroiditis is also known as lymphocytic thyroiditis with spontaneously resolving hyperthyroidism, subacute
lymphocytic thyroiditis, painless lymphocytic thyroiditis,
painless thyroiditis, or silent thyroiditis. Painless thyroiditis
may occur sporadically or in the postpartum period.
The thyroid gland may be asymmetrically enlarged on gross

inspection. Microscopic examination reveals a multifocal
inflammatory infiltrate, consisting chiefly of smalllymphocytes. Scattered areas of disrupted and collapsed thyroid
follicles are also present. Unlike Hashimoto's thyroiditis,
plasma cells and germinal centers are not conspicuous, and
this feature is helpful in distinguishing the two conditions."
Both variations of subacute painless thyroiditis are considered

to be autoimmune in origin. Like Hashimoto's thyroiditis,
patients with painless thyroiditis have a high prevalence of
anti-thyroid peroxidase (anti-TPO or antimicrosomal) antibodies and lymphocytic infiltration of the thyroid gland. 3D
Furthermore, painless thyroiditis is also associated with other
autoimmune conditions such as Sjogren's syndrome,"
autoimmune Addison's disease.F Graves' disease." and
Hashimoto's thyroiditis." There is also evidence for a genetic
predisposition with an association with HLA-DR3, -DR4,
and -DR5 haplotypes.Y"
The evidence supporting an autoimmune origin for postpartum thyroiditis is much stronger. This variant typically
occurs at about 6 weeks' postpartum in women with
high TPO antibody titers in early pregnancy. This timing is
thought to coincide with a decrease in the normal immune
tolerance of pregnancy and consequent rebound elevation of
antibody titers.'? TPO antibodies mediate thyrocyte destruction via complement activation.t" Furthermore, the antibody
Painless thyroiditis is also more common in women (malefemale ratio, 1:1.5 to 3) and occurs between 30 and 60 years
of age. The clinical course parallels painful thyroiditis and
is characterized by four stages-thyrotoxic (occurs 1 to
3 months' postpartum), euthyroid, hypothyroid (occurs at
3 to 6 months' postpartum), and euthyroid again (occurs by
1 year). However, only about 30% of all patients follow this
classic sequence of events. Thyrotoxicosis or hypothyroidism alone is the presenting features in about 35% and
40% of patients, respectively." When hyperthyroid symptoms occur, they are transient and characterized by tachycardia, palpitations, heat intolerance, nervousness, and weight
loss. The hypothyroid phase is more pronounced in terms
of symptoms. Physical examination demonstrates a normalsized or slightly enlarged, slightly firm, nontender gland.
HISTOLOGIC FEATURES
DIAGNOSTIC TESTS
The results of thyroid function studies correlate with the

clinical stage of disease. In the early phases, TSH is
38 - -
Thyroid Gland
suppressed and T 4 and T 3 levels are elevated, similar

to painful thyroiditis. In contrast with subacute painful
thyroiditis, the ESR is normal or only mildly elevated
(usually <40 mm/hr) and the leukocyte counts are
normal. Titers of thyroid autoantibodies, particularly TPO
antibodies, are often elevated. RAID is typically low or suppressed. Approximately 45% of patients with postpartum
thyroiditis also demonstrate increased hypoechogenicity
of the thyroid gland on thyroid ultrasound at 4 to 8 weeks,
and this finding increases to 86% at 15 to 25 weeks'
postpartum."
Graves' disease, factitious hyperthyroidism, granulomatous

thyroiditis, and struma ovarii are some of the conditions
that should be considered in the differential diagnosis of
painless thyroiditis. Most of these disorders can be
distinguished based on careful history, physical examination, laboratory evaluations, and RAIU scans, as outlined
earlier.
TREATMENT
Specific treatment is sometimes required in patients with severe

symptoms. ~ blockers are useful in controlling symptoms
of hyperthyroidism. Antithyroid drugs are not necessary
since there is no increase in thyroid hormone synthesis.
Corticosteroids have been used to shorten the hyperthyroidism
phase but are generally not helpful." Thyroid hormone
replacement is indicated in patients with hypothyroidism.
Thyroidectomy is indicated only for the rare patients with
recurrent, disabling episodes of thyroidiris." RAI ablation of
the thyroid may also be used in these rare cases."
CLINICAL COURSE
Despite similarities in clinical presentation, painless

thyroiditis and postpartum thyroiditis differ with respect to
outcomes. In a long-term study, only 2.5% of patients with
subacute thyroiditis had a goiter, but 48% of patients with
postpartum thyroiditis had residual thyroid abnormalities
(goiter, positive TPO, or hypothyroidism) at the conclusion
of follow-up." Up to 23% of patients with postpartum
thyroiditis have been reported to develop permanent
hypothyroidism at long-term follow-up.fv'? Women with
high TPO antibody titers, hypothyroid-phase presentation,
and thyroid hypoechogenicity on ultrasound are more likely
to develop permanent hypothyroidism. 50 Furthermore,
patients with postpartum thyroiditis are more likely to have
recurrent episodes of thyroiditis, as seen in Figure 5-4.
As such, patients with a history of postpartum thyroiditis
should be screened periodically for the development of permanent hypothyroidism.
The presence of TPO antibodies and antithyroglobulin
antibodies in pregnancy have been suggested as possible
markers to predict the development of postpartum thyroiditis.
However, Kuijpens and associates have shown that the
TPO antibody has a positive predictive value of only 33%.51
Other markers such as soluble CD4 (a product of CD4+
T lymphocytes) may be more promising. Lack of a
physiologic decrease in the levels of these markers in
the third trimester was predictive of recurrent postpartum
thyroiditis in women with a previous history of the disease.S
FIGURE 5-4. Incidence of postpartum thyroiditis in three groups
of women: With a history of postpartum thyroiditis in a previous

pregnancy (A); with a prior history of type 1 diabetes mellitus (B);
and those who were antibody positive in a prior pregnancybut did
not develop postpartum thyroiditis (C). (From Stagnaro-Green A.
Recognizing, understanding, and treating postpartum thyroiditis.
Endocrinol Metab Clin North Am 2000;29:417.)
Atypical Subacute Thyroiditis

Variants of subacute thyroiditis, designated atypical subacute thyroiditis, have also been described. Patients may
present with features of painful thyroiditis but lack the
HLA-B35 haplotype" or present with painless thyroiditis
without evidence of thyroid autoimmunity. 54 Further studies
are needed to characterize this variant adequately.
Chronic Thyroiditis
Lymphocytic (Hashimoto's) Thyroiditis
Lymphocytic thyroiditis was first described in four female
patients by Hashimoto in 1912 as struma lymphomatosaa transformation of thyroid tissue to lymphoid tissue.f
Subsequently, Roitt and colleagues demonstrated thyroid
autoantibodies in patients with this disease.56 Chronic
autoimmune thyroiditis has two different clinical manifestations: an atrophic form and a goitrous form. The latter is
also known as Hashimoto's thyroiditisi' and is the most
common inflammatory disease of the thyroid. Prevalence
rates of chronic autoimmune thyroiditis vary depending on
the criteria used for diagnosis. Autopsy studies demonstrate
that 40% to 45% of women and 20% of men in the
United States and United Kingdom have focal thyroiditis.P-"
Most autopsy and thyroid antibody studies document
Hashimoto's thyroiditis in approximately 17% of women in
the United States and Japan.r'' However, a recent review of
population-based studies with strict criteria for the diagnosis
of Hashimoto's thyroiditis reported a prevalence of 0.79% in
adults with an incidence of 22 per 100,000 inhabitants."!
T Cells, Autoantibodies, and Apoptosis. The autoimmune process is thought to be initiated by the activation of
CD4+ T (helper) lymphocytes with specificity for thyroid
antigens.v' However, the mechanism of activation of these
cells is not completely understood. One hypothesis centers
on molecular mimicry and postulates that viral or bacterial
infection with proteins similar to thyroid proteins leads to
the activation of thyroid-specific lymphocytes. In fact, serologic evidence of such infection has been documented in
patients with chronic autoimmune thyroiditis,63.64 but the
cumulative evidence is not convincing.P
Thyroiditis - - 39
The other more widely accepted hypothesis suggests that

thyroid cells themselves present intracellular proteins to
helper T cells. This theory is supported by the observation
that, unlike normal thyrocytes, thyroid cells of patients with
autoimmune thyroiditis express the major histocompatibility
complex (MHC) class II proteins (HLA-DR, HLA-DP,
and HLA-DQ),66 which are required for antigen presentation
to CD4+ helper cells. Activated T cells release the cytokine
interferon y,67 which further promotes the expression of
these MHC molecules and thus perpetuates the autoimmune
process.f
Once activated, T cells can recruit cytotoxic CD8+
T cells to the thyroid. Hypothyroidism is believed to result
mainly from the destruction of thyrocytes by these cells.
T-helper cells also recruit self-reactive B cells to the thyroid
and stimulate them to secrete autoantibodies. These antibodies are directed against three main antigens: thyroglobulin,
TPO (microsomal antigen), and the thyrotropin receptor."
Antibodies to the sodium-iodine symporter (NIS) have also
been reported in patients with Hashimoto's thyroiditis.s?
although more recent studies indicate that they are not as
important as previously thought." Autoantibodies can also
cause hypothyroidism via blockage of their ligands, fixation
of complement, and antibody-mediated cytotoxicity (natural
killer cells). However, the relative contributions of these mechanisms to thyrocyte destruction in vivo remain unresolved."
Apoptosis (programmed cell death) has also been implicated in the pathogenesis of Hashimoto's thyroiditis.
Thyrocytes from patients with this disease consistently show
increased expression of death receptors such as FasL and
decreased levels of the anti-apoptotic molecule Bcl2 when
compared to cells from patients with Graves' disease."
Environmental Factors. The prevalence of chronic
autoimmune thyroiditis parallels that of iodine intake."
Supplementation in iodine-deficient areas increases thyroid
lymphocytic infiltration and prevalence of thyroid antibodies. 73,74 Supplementation in iodine-replete regions leads to
reversible hypothyroidism by inhibition of the biosynthesis
and release of thyroid hormone. Various drugs have
also been implicated in the etiology of chronic thyroiditis.
Amiodarone has a long half-life and a high iodine content
and can mediate iodine-induced hyporhyroidism." Transient
hypothyroidism has also been associated with lithium therapy." The effects of these medications are more pronounced
in patients with thyroid antibodies than in those without
antibodies. Treatment with interferon a,76 interleukin 2,77 or
granulocyte-macrophage colony-stimulating factor" may
also lead to reversible formation of thyroid autoantibodies,
hypothyroidism, or Graves' disease. An iodine-rich diet has
been shown to produce thyroiditis in chickens 79 and beagle
dogs."
Genetic Predisposition. Evidence for an inherited susceptibility for chronic autoimmune thyroiditis is derived
from both experimental and spontaneously occurring animal
models of autoimmune thyroiditis and human studies."
Human family studies suggest an increased incidence of
thyroid autoantibodies (up to 46%) in first-degree relatives
of patients with Hashimoto's thyroiditis compared to only
15% of controls.P Segregation analyses indicate that this
susceptibility is inherited in a mendelian dominant fashion
with high penetrance." However, Hashimoto's thyroiditis
does not exhibit classic mendelian inheritance, and genetic

predisposition appears to be complex, possibly caused
by many disease-associated alleles located at different
genetic loci."
Further support for genetic susceptibility for Hashimoto's
thyroiditis is shown by the occurrence of the autoantibodies
and hypothyroidism in patients with specific chromosomal
abnormalities such as Turner's'" and Down syndromes.f
Available evidence suggest that at least a part of the genetic
susceptibility to Hashimoto's thyroiditis may reside on the
chromosomes X and 21 (which are respectively involved in
these disorders). Associations with HLA-B8, -DR3, and -DR5
haplotypes of the major histocompatibility complex have also
been described.f':" although the HLA locus is not believed
to be a major etiologic factor.s?
HISTOLOGIC FEATURES
The thyroid gland is generally mildly enlarged throughout

and has a pale, grayish tan cut surface that is firm and slightly
nodular. On microscopic examination, the gland is diffusely
infiltrated by mononuclear cells (small lymphocytes and
plasma cells) and occasionally shows well-developed
germinal centers. Thyroid follicles are smaller than normal
with reduced amounts of colloid. The follicles are lined
by Hiirthle or Askanazy cells, which are characterized by
abundant eosinophilic, granular cytoplasm as shown in
Figure 5-5. In addition, the amount of interstitial connective
tissue is increased and manifests itself as fibrosis. In contrast
to Riedel's thyroiditis, the fibrosis does not extend beyond
the gland itself. 1I
In atrophic chronic thyroiditis, the fibrosis is more
pronounced. Of note, existing evidence does not support the
progression of the goitrous form to the atrophic form. 90,91
Like other autoimmune diseases, Hashimoto's thyroiditis is

also more common in women (male-female ratio, 1:10 to
20) between the ages of 30 and 50 years. The most common
FIGURE 5-5. Histologic features of Hashimoto's thyroiditis. The

thyroid parenchyma contains a dense lymphocytic infiltrate with
germinal centers. Residual thyroid follicles lined by deeply
eosinophilic Hurthle cells are also seen. (From Cotran R, Kumar V,
Collins T, Robbins SL reds], Robbins Pathologic Basis of Disease,
6th ed. Philadelphia, WB Saunders, 1999, p 1135.)
presentation is that of a relatively small, firm, and granular
gland discovered on routine physical examination or the
awareness of a painless anterior neck mass. In unusual
cases, the thyroid gland may enlarge rapidly, causing
compressive symptoms and dysphonia. Pain, especially
radiating to the ear, is a rare manifestation. Approximately
20% of patients present with hypothyroidism.F whereas 5%
present with hyperthyroidism (hashitoxicosisj.P In classic
goitrous Hashimoto's thyroiditis, physical examination
reveals a diffusely enlarged, firm gland that is also
lobulated. An enlarged pyramidal lobe is usually palpable.
The goiter may be asymmetrical, and, rarely, nodules and
enlarged lymph nodes may be palpated. Thyroid-associated
ophthalmopathy occurs rarely in patients with chronic
autoimmune thyroiditis.
DIAGNOSTIC STUDIES
When Hashimoto's thyroiditis is suspected clinically, an

elevated TSH level and thyroid autoantibodies confirm
the diagnosis. About 95% of patients have increased antirnicrosomal antibody titers, whereas antithyroglobulin antibodies are positive in about 60% of patients." The microsomal
antigen has been identified as TPO (the rate-limiting enzyme
in thyroid biosynthesis)." Anti-TPO antibodies measured
by radioimmunoassay are a more sensitive indicator of
Hashimoto's thyroiditis than are antimicrosomal antibodies
detected by hemagglutination studies." Antibodies to the
TSH receptor are present in up to 60%,96 and antibodies to
NIS can be found in 25% of patients."?
RAID is variable and may mimic Graves' disease, multinodular goiter, or a hot or cold nodule/" However, the RAIU
is usually normal or elevated, even in hypothyroid patients,
and thus allows differentiation from subacute thyroiditis.
FNA biopsy is indicated in patients who present with a solitary suspicious nodule or rapidly enlarging goiter. Most
patients with thyroid lymphoma have underlying Hashimoto's
thyroiditis. Patients with multiple endocrine neoplasia (MEN)
type 2, POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, M protein, and skin changes), Addison's
disease and, as mentioned earlier, Down and Turner's syndromes, have a higher than baseline incidence of chronic
autoimmune thyroid disease. As such, these patients should
undergo periodic TSH measurements. 57
The differential diagnosis of Hashimoto's thyroiditis includes

nontoxic multinodular goiter and thyroid lymphoma. In the
former, patients are usually euthyroid, the thyroid gland has
more distinct nodules, and thyroid antibody levels are lower
than in Hashimoto's thyroiditis. As mentioned earlier, patients
with Hashimoto's thyroiditis are predisposed to thyroid lymphoma and often have a short history of a rapidly enlarging
gland. About 30% of these patients present with significant
compressive symptoms.
CLINICAL COURSE
Some patients with subclinical hypothyroidism can progress

to overt hypothyroidism. A 20-year follow-up study of
patients, initially reported in the Whickham survey, with
elevated TSH and positive antibodies but normal thyroxine
levels (subclinical hypothyroidism), documented that 55%
Q)
0.95
U
OJ C/l
> .'t::
0.80
t:
iii
~~
o~
~E C/l
._
0.50
o... J:.
>- 0.10
a..
-----
Antibody-positive
(fitted model)
='0
.0
._
III 0
.0'"
(5
~
:::c 0.02
0.2
0.5
Observed data
(smoothed)
Antibody-negative
(fitted model)
10
20
50
Thyrotropin (mU per liter)
FIGURE 5-6. Probability of developing overt hypothyroidism in

women within 20 years of initial measurement of serum thyrotropin
(follow-up of the Whickham survey). (From Vanderpump MP,
Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham
Survey. Clin Endocrinol [Oxf] 1995;43:55.)
of female patients became hypothyroid (a progression of

4.3% per year)."? The probability of developing overt
hypothyroidism in these patients is shown in Figure 5-6.
Male patients and those with higher initial TSH levels had
an even higher rate of progression. However, patients who
had slightly elevated TSH levels but no antibodies did not
progress to hypothyroidism.
Rarely, patients may develop Graves' disease'!" or lymphoma. Thyroid lymphoma is a well-recognized, ominous
complication of chronic autoimmune thyroiditis and has a
prevalence 80 times higher than the expected frequency in
this population than in a control population without thyroiditis. Most thyroid lymphomas are of the non-Hodgkin's
B cell type and tend to occur in older female patients.l'"
TREATMENT
Thyroid hormone replacement therapy is indicated in

overtly hypothyroid patients with a goal of normal TSH
levels. The management of patients with subclinical
hypothyroidism (normal T 4 and elevated TSH) is controversial. Since these patients do progress to overt disease,
treatment is generally recommended, especially for male
patients and those with TSH higher than 10 mUlL. 57
Treatment is also indicated in euthyroid patients to shrink
large goiters.P? Surgery is occasionally indicated for suspicion of malignancy or for goiters causing compressive
symptoms or cosmetic deformity.
Riedel's Thyroiditis
Riedel's thyroiditis is a rare variant of thyroiditis that was
initially described in two patients by Riedel in 1896 and
subsequently in a third patient in 1897. 103104 It is also known
as Riedel's struma or invasive fibrous thyroiditis and leads to
a wood-like thyroid gland. A review of the Mayo Clinic
experience disclosed 37 cases in 56,700 thyroidectomies
over a 64-year period. ros
Thyroiditis - -
Riedel's thyroiditis is characterized by the replacement of

thyroid parenchyma by fibrous tissue, which also invades
into adjacent tissues. The etiology of this disorder is controversial and has not been resolved. This disorder has been
reported to occur in patients with other autoimmune
diseases such as pernicious anemia and Graves' disease.
This association, coupled with the presence of lymphoid
infiltration and response to steroid therapy, led some investigators to suggest a primary autoimmune etiology.l06,107
Riedel's thyroiditis is also associated with other focal sclerosing syndromes, including mediastinal, retroperitoneal, periorbital, and retro-orbital fibrosis and sclerosing cholangitis,108
suggesting that it may be a primary fibrotic disorder.
HISTOLOGIC FEATURES
The histologic criteria for the diagnosis of Riedel's thyroiditis

were first described by Woolner and coworkers in 1957. The
thyroid is typically involved with a fibrotic process consisting
of fibroblasts and collagen. The chief light microscopic
features that enable this entity to be distinguished from
Hashimoto's thyroiditis are (1) extension of the fibrotic
~rocess
through the strap muscles and other surrounding
tissue, (2) phlebitis with luminal distention by fibrous or
lymphoid tissue, and (3) relatively normal remnant thyroid
tissue.P? Tissue eosinophil infiltration is also a characteristic
finding in fibrous thyroiditis.!'?
CLINICAL FEATURES
The disease occurs predominantly in women (male-female

ratio, I :3) between the ages of 30 and 60 years. It typically
presents as a painless, hard anterior neck mass that progresses
over weeks to years to produce symptoms of compression
including dysphagia, dyspnea, choking, and hoarseness.
Patients may present with symptoms of hypothyroidism as
the gland is replaced by fibrous tissue. Extension of the
process can also l~ad
to hypoparathyroidism and, rarely,
vocal cord paralysis.U'{'? Physical examination reveals a
~ard,
"woo~y"
thyroid gland with fixation to surrounding
tIs~ues.
TYPI~ally,
the thyroid is diffusely involved, although
unilobular disease has been described.
The. differential diagnosis includes lymphoma, poorly or

undifferentiated thyroid cancer, chronic thyroiditis, and
granulomatous thyroiditis.
DIAGNOSTIC STUDIES
An. elevate? TSH and hypocalcemia may be present in

patIent~
WIth hypothyroidism and hypoparathyroidism,
respectively, Antithyroid antibodies and a mild eosinophilia
~e diagnosis needs to be confirmed by open
may ~e p~esent.
thyroid bIOpSY, WhICh also helps exclude carcinoma. The firm
and fibrous nature of the gland renders FNA inadequate. I 13
TREATMENT
~urgery
is ~e mainstay of the treatment of Riedel's thyroiditis. The chief goal of operation is to decompress the trachea
by wedge excision of the thyroid isthmus and to make a
tissue diagnosis. More extensive resections are not advised
41
owing to the infiltrative nature of the fibrotic process that

obscures usual landmarks and structures (recurrent laryngeal nerves, parathyroids, carotid arteries). Hypothyroid
patients are treated with thyroid hormone replacement.
External-beam radiation therapy is not usually effective. 114
Some patients remain symptomatic even after these
treatment modalities. These patients have been reported
to experience dramatic improvement after treatment with
corticosteroids.l" In another study, these patients experienced subjective and objective relief of symptoms after
several weeks of treatment with the antiestrogen medication
tamoxifen (20 mg twice a dayj.!" Although estrogen receptors have been identified in normal and neoplastic thyroid
tissue,'!" tumors from these patients were not positive for
estrogen, and the mechanism underlying the response to
tamoxifen has been postulated to be related to transforming
growth factor (TGF)-~I'
TGF-~I
is a potent growth inhibitor
of immature fibroblasts and epithelial cells!" and has been
shown to be upregulated by tamoxifen.I'v!"
Summary
Surgeons are rarely in the frontline of the diagnosis and
management of patients with the different variants of
thyroiditis. However, an understanding of these disorders is
an important component of the endocrine surgeon's armamentarium in the unusual situations when surgical invention
is required for localized symptoms and diagnosis. FNA
biopsy for cytology and culture is helpful for diagnosis in
many patients, as is careful analyses of laboratory tests.
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89. Roman SH, Greenberg D, Rubinstein P, et al. Genetics of autoimmune
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91. Vickery AL, Hamblin EJ. Struma Iymphomatosa (Hashimotos's
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thyroid peroxidase and its identification as the microsomal
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95. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase
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43
96. Cho BY, Kim WB, Chung JH, et al. High prevalence and little change
in TSH receptor-blocking antibody titres with thyroxine and antithyroid drug therapy in patients with nongoitrous autoimmune thyroiditis. Clin Endocrinol (Oxf) 1995;43:465.
97. Ajjan RA, Kemp EH, Waterman EA, et al. Detection of binding and
blocking autoantibodies to the human sodium-iodide symporter in
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98. Ramtoola S, Maisey MN, Clarke SE, Fogelman I. The thyroid scan in
Hashimoto's thyroiditis: The great mimic. Nucl Med Commun
1988;9:639.
99. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of
thyroid disorders in the community: A twenty-year follow-up of the
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100. Kurihara H, Sasaki J, Takamatsu M. Twenty cases with Hashimoto
disease changing to Graves' disease. In: Nagataki S, Mori T,
Torizuka K (eds), Eighty Years of Hashimoto Disease. Amsterdam,
Elsevier Science, 1993, p 249.
101. Matsuzuka F, Miyauchi A, Katayama S, et al. Clinical aspects of primary thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 1993;3:93.
102. Hegedus L, Hansen JM, Feldt-Rasmussen U, et al. Influence of thyroxine treatment on thyroid size and antithyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf) 1991;35:235.
103. Riedel BMCL. Die chronische, zur Bildung eisenharter Tumoren
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105. Hay ill. Thyroiditis: A clinical update. Mayo Clin Proc 1985;60:836.
106. Heufelder AE, Hay ill. Evidence for autoimmune mechanisms in the
evolution of invasive fibrous thyroiditis (Riedel's struma). Clin Invest
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107. Zimmermann-Belsing T, Feldt-Rasmussen U. Riedel's thyroiditis: An
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108. Dehner LP, Coffin CM. Idiopathic fibrosclerotic disorders and other
inflammatory pseudotumors. Semin Diagn Pathol 1998;15:161.
109. Harach HR, Williams ED. Fibrous thyroiditis-an immunopathological study. Histopathology 1983;7:739.
110. Heufelder AE, Goellner JR, Bahn RS, et al. Tissue eosinophilia and
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Ill. McRorie ER, Chalmers J, Campbell IW. Riedel's thyroiditis complicated by hypoparathyroidism and hypothyroidism. Scott Med J 1993;
38:27.
112. Yasmeen T, Khan S, Patel SG, et al. Riedel's thyroiditis: Report of a
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113. Tseleni-Balafouta S, Kyroudi-Voulgari A, Paizi-Biza P,
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115. Bagnasco M, Passalacqua G, Pronzato C, et al. Fibrous invasive
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treatment. Cancer Res 1992;52:4261.
Hypothyroidism
Kanji Kuma, MD Shuji Fukata, MD Masahiro Sugawara, MD
Hypothyroidism is the state of decreased thyroid hormone

action at the target tissue. There are two types of hypothyroidism, on the basis of thyroid function tests: (1) clinical
or overt and (2) subclinical. Patients with the former show
elevated serum thyroid-stimulating hormone (TSH) and
reduced serum thyroid hormone levels, which are the characteristic laboratory findings of primary hypothyroidism.
The latter disorder is characterized by a mildly elevated serum
TSH concentration and normal serum thyroid hormone
levels. Subclinical hypothyroidism is the most common
thyroid dysfunction nationwide, with a marked increase
in prevalence in the elderly population.l-' Hypothyroidism,
including subclinical hypothyroidism, can cause cardiovascular problems, lipid disorders, cognitive dysfunction,
neurologic abnormalities, and a high rate of abortion. An
extreme case of untreated hypothyroidism is myxedema coma.
The timely detection of hypothyroidism and appropriate
therapy with thyroid hormone are beneficial for patients and
reduce perioperative morbidity as well as mortality.
Prevalence and Subclinical

Forms
The prevalence rates of overt hypothyroidism and subclinical hypothyroidism in the general population are 0.4% and
9%, respectively, based on the Colorado Thyroid Disease
Prevalence Study.' The National Health and Nutrition
Examination Survey (NHANES) III in the United States
showed overt hypothyroidism of 0.3% and subclinical
hypothyroidism of 4.3% in the general population in all ages.?
Thus, subclinical hypothyroidism is 16 to 20 times more
common than overt hypothyroidism. The prevalence of
subclinical hypothyroidism increases with age and is more
common in women than in men. In groups older than
70 years of age, a steep increase in prevalence of subclinical
hypothyroidism is apparent; it reaches to 14% in the white
population and 5% in the black population.? Subclinical
hypothyroidism, therefore, should always be suspected
whenever elderly patients undergo surgical procedures. Most
patients with subclinical hypothyroidism have either mild
symptoms of hypothyroidism or nonspecific symptoms.
Before making the diagnosis of subclinical hypothyroidism,
it is important to exclude other causes of elevated serum
TSH concentration, such as the recovery stage from a
nonthyroidal illness (serum TSH concentration can be
44
mildly elevated during the recovery stage), intermittent

thyroid hormone ingestion for treatment of hypothyroidism,
TSH-secreting tumor, and thyroid hormone resistance.' The
causes of subclinical hypothyroidism are the same as those
for overt hypothyroidism listed in a later section. Patients
with subclinical hypothyroidism previously were considered
as having a mild form of hypothyroidism, and no clear treatment has been established. Chu and Crapo claimed that thyroid hormone treatment is seldom needed unless the serum
TSH concentration exceeds 10 mU/mL,4 but these patients
have more chance of myocardial infarction,' hyperlipidemia,"
and hyperhomocysteinemia.? The trend is to treat patients
with subclinical hypothyroidism to reduce these complications; in fact, most members of the American Thyroid
Association choose thyroid hormone treatment for patients
with subclinical hypothyroidism."
Causes and Clinical Features

Hashimoto's Thyroiditis
Hashimoto's thyroiditis, known as an autoimmune or chronic
lymphocytic thyroiditis, is the leading cause of hypothyroidism. The pathogenesis of hypothyroidism is complex.
Three mechanisms have been proposed: (1) thyroid cell
damage by the thyroid antibody-mediated complement attachment; (2) T-cell-mediated cytotoxicity; and (3) enhanced
apoptosis (programmed cell death). The initial event is the
formation of antibody in response to self-antigen such as thyroid peroxidase (TPO) and thyroglobulin; this event does not
normally happen. If self-antigen is falsely recognized by the
immune system, antibody formation takes place to the specific
self-antigen, creating organ-specific autoimmunity. This leads
to immune complex deposition in the basement membrane
of follicular cells and complement activation, as suggested
in 1977.9 Weetman and associates confirmed the presence of
terminal complement complexes around thyroid follicles.'?
Thyrocytes attacked by complement through antibodies
were shown to release cytokines interleukin (lL)-l and
IL-6," which may promote infiltration and autoactivation
of lymphocytes, subsequently leading to cell destruction.
However, anti-TPO titers do not always correlate with the
degree of thyroid cell destruction. Thus, thyroid antibodies
should not be the sole cause of cell destruction. T-cellmediated cytotoxicity then came to attention. T lymphocytes
originating from the bone marrow are differentiated in the
Hypothyroidism - -
thymus and become T cells (thymus-derived lymphocytes).

One population of T cells expresses the surface molecule
CD8, called cytotoxic T cells, and recognizes antigen that is
associated with class I major histocompatibility complex
(MHC) molecules. These class I MHC molecules are present in all cells and permit the CD8 cells to recognize and
destroy foreign tissues, infected cells, or tumor cells. There
are two pathways to destroy thyroid cells by cytotoxic
T cells. One mechanism is to release lytic granules that
contain perforin and granzyme.F'" These molecules enter
the target cells and activate apoptosis pathways (caspase
or cytochrome c release from the mitochondria). The other
mechanism is an involvement of binding of Fas ligand
(CD 178, expressed on the surface of T cells and thyrocytes)
to the Fas death receptor (CD95/APO) of thyrocytes. This
binding (dimerization of Fas and Fas ligand) triggers activation of the intracellular apoptosis pathway using adapter
protein (Fas-associated protein death domain), Whatever the
initial events are, the final immune reaction is cell destruction.
In 1997, Giordano and colleagues first described the presence of Fas (CD95) in thyrocytes of Hashimoto's thyroiditis
and not in normal thyroid gland,!" raising the possibility
of Fas-mediated apoptosis in Hashimoto's thyroiditis. Since
then, cell destruction by apoptosis has been studied intensely.
Details of apoptosis in Hashimoto's thyroiditis have been
reviewed by Baker" and Stassi and De Maria.16 The apoptosis
in Hashimoto's thyroiditis involves complex linkages among
thyrocytes, cytokines, CD4 cell, and death receptors/ligand.
The interactions of these factors lead to either cell death or
cell survival. Cytokines-biochemical signals that help
coordinate immune responses-playa particularly central role
in autoimmune diseases. The most important final event is
activation of cytosolic cell lysis by expression of either Fas
receptor-Fas ligand and/or tumor necrosis factor (TNF)-a
and the TNF-related apoptosis-inducing ligand in thyrocytes.!? How does it happen? T-helper (TH) cells expressing
CD4 playa critical role in cell death and survival in autoimmune diseases. CD4 T cells recognize antigen present on the
surface of antigen-presenting cells (APCs) in association
with class II MHC molecules. Unlike class I MHC molecules, class II MHC molecules are expressed only on APCs
such as macrophages, B cells, and dendritic cells. There are
two functionally distinct subsets of TH cells based on
cytokine production: Tw land T w2. Twi cells secrete interferon (INF)-y and other cytokines that are associated with
inflammation and cell-mediated immune responses. Tw2
cells promote humoral immune responses and inhibit Twi
cell-mediated responses by the release of IL-4, IL-5, and
IL_1O.18,19 TH-l cells are predominant in Hashimoto's thyroiditis, whereas Tw2 cells are prevalent in Graves' disease,
Cytokines from Twi cells, such as INF-y and to a lesser
extent IL-l~,
stimulate the appearance of Fas death receptor
in thyrocytes.'? Thus, cytokine-mediated reactions in
Hashimoto's thyroiditis favor cell death by overcoming cell
survival signals of cytokines from TH-2 cells and antiapoptotic proteins, Clinical features of Hashimoto's thyroiditis
include the presence of goiter and variable thyroid functional status, Most patients with Hashimoto's thyroiditis
have a small goiter. On palpation, the goiter can be felt as
lobulated or multinodular; the consistency varies from rubbery to firm to stony hard. The surface of the Hashimoto's
45
thyroid gland is often described as bosselated. Thyroid function can be euthyroid, hypothyroid, or hyperthyroid depending on the stage of Hashimoto's thyroiditis and its associated
conditions, For instance, at the beginning of this disease, most
patients are euthyroid. As the disease progresses, patients
become hypothyroid. If silent thyroiditis occurs in the thyroid gland of patients with Hashimoto's thyroiditis, patients
may have transient hyperthyroidism due to thyroid cell
destruction. Also, true hyperthyroidism can occur if Graves'
disease and Hashimoto's thyroiditis coexist. The presence of
antithyroid antibodies is the hallmark of this disorder; antirnicrosomal antibodies or anti-TPO antibodies are positive in
more than 95% of cases. 19 Therefore, the presence of thyroid
antibodies is used exclusively as the diagnostic test of
Hashimoto's thyroiditis. Antibodies against thyroglobulin,
sodium-iodide symporter, and TSH receptor may be
detected. Also, ultrasound findings of hypoechogenicity of
the thyroid gland should assist in the diagnosis of
Hashimoto's thyroidiris-" and thyroid dysfunction." The clinical conditions described in the following sections need
special attention in patients with Hashimoto's thyroiditis,
Pregnancy. All pregnant women should have thyroid
function tests and a TPO antibody test. If pregnant women
have Hashimoto's thyroiditis, postpartum thyroid dysfunction is expected in 5% to 70%.22,23 This disorder can cause
a transient hypothyroidism or hyperthyroidism in the postpartum period. If hypothyroidism or subclinical hypothyroidism is discovered during pregnancy, thyroid hormone
treatment must be started as soon as possible. This is because
of a high spontaneous abortion rate of 60% to 70%24 and
adverse effects of hypothyroidism on the neuropsychological
development of children, including IQ score." Also, thyroid
hormone deficiency during early fetal life (first 12 weeks of
pregnancy) leads to psychomotor development abnormality
in infancy/"; the fetus is dependent on maternal thyroid hormone until 12 weeks' gestation.
Smoking. Smoking is a risk factor for hypothyroidism in
patients with Hashimoto's thyroiditis. Fukata and coworkers
showed an increased prevalence of subclinical hypothyroidism in patients with Hashimoto's thyroiditis who smoke
cigarettes because of an increased serum level of thiocyanate
from smoking.?" This relationship between hypothyroidism
and smoking has also been described by others.28.29 In addition
to hypothyroidism, smoking is associated with the development of Graves' disease, Graves' ophthalmopathy, nodular
goiter, and antithyroid antibodies.P
Iodine. Iodine is needed for thyroid hormone formation.
However, patients with Hashimoto's thyroiditis are known
to have increased sensitivity to excessive iodine causing
reversible hypothyroidism.v-" although the exact mechanism
is unclear.
Amiodarone. One of the common sources of excessive
iodine is arniodarone; this antiarrhythmic drug contains 75 mg
of iodine in a 200-mg tablet. Therefore, iodine-induced
hypothyroidism is a possible side effect of this medication,
particularly in patients with Hashimoto's thyroiditis.'? Also,
amiodarone can cause destructive hyperthyroidism followed
by transient hypothyroidism.>' An elevated serum level of
IL-6 is a marker of amiodarone-induced thyroditis."
Lithium. This medication is used for the treatment of
bipolar disorder. Lithium has multiple actions in the thyroid
gland, including inhibition of thyroid hormone secretion."
thyroid hormone formation," and activation of the protein
kinase C pathway.'? If the thyroid gland has marginal
function (i.e., Hashimoto's thyroiditis), lithium treatment
can cause hypothyroidism. In fact, lithium-induced hypothyroidism is more commonly seen in patients with Hashimoto's
thyroiditis than in people without underlying thyroid disease." suggesting that the effect of lithium on the normal
thyroid gland is subtle.
Cytokines. INF-a and IL-2 treatment for malignant disease or hepatitis C can cause hypothyroidism in patients
with Hashimoto's thyroiditis. The mechanism of induction
of hypothyroidism by cytokines is still unclear, and addition
of ribavirin, an antiviral therapeutic agent, to INF increases
the chance of hypothyroidism.'? The development of thyroid
dysfunction does not appear to be dependent on the dose of
INF.40 Also, INF-a treatment can induce anti-TPO antibodies
in some patients during hepatitis C treatment." The outcome
of hypothyroidism in these patients seems to be partly
dependent on the persistence or disappearance of anti-TPO
antibodies. If anti-TPO antibodies disappear at the end of
INF-a treatment, patients' thyroid status also improves."
Association with Other Autoimmune Endocrine

Disorders. A small number of patients with Hashimoto's
thyroiditis may have autoantibodies to other endocrine

organs, such as the pancreas, adrenal gland, and ovary, causing diabetes mellitus, adrenal insufficiency, or premature
ovarian failure, respectively (polyglandular autoimmune
syndrome). The association of Hashimoto's thyroiditis with
adrenal insufficiency has been previously referred to as
Schmidt's syndrome.
Thyroid Lymphoma. Thyroid lymphoma accounts for
2% to 5% of malignant thyroid tumors and occurs exclusively in the thyroid gland of Hashimoto's thyroiditis. 42,43
When a goiter develops rapidly in an elderly patient with
Hashimoto's thyroiditis, thyroid lymphoma should be suspected. This is a potentially curable malignant tumor as long
as it is discovered at an early stage."
Hypothyroidism Caused by Iodine Therapy

Radioactive iodine (l3II) is one of the common methods of
treating patients with Graves' disease. This treatment leads
to the development of hypothyroidism in most patients. The
dose of l311 administered affects the onset of hypothyroidism. Of patients who receive 370 MBq (10 mCi) or more
(>5.55 MBq/g of thyroid tissue), about 50% of patients
become hypothyroid 1 year after treatment and about 70%
of patients are hypothyroid 10 years after treatment.v-"
Euthyroidism can initially be attained by treatment with a
low dose of radioactive iodine (l.48 to 2.59 MBq/g of thyroid tissue delivered); however, most patients subsequently
develop hypothyroidism by 10 years or later,"
Hypothyroidism Caused by External

Radiation to the Neck
External radiation to the neck is known to cause thyroid
disorders, including hypothyroidism.f? Radiation doses of
4500 cGy or more cause hypothyroidism by 20 years in
approximately 50% of patients of all ages," and more cases
occur thereafter. The effect of radiation therapy on the

development of hypothyroidism is dose and duration
dependent. The higher the dose and the longer the observation period, the higher the incidence of hypothyroidism. The
timing of development of hypothyroidism after the initial
radiation therapy can be 4 months to years, depending on
the dose and duration received." Ionized radiation releases
reactive oxygen species from the water molecule. 50 This
appears to be the mechanism of radiation-induced hypothyroidism. In addition to hypothyroidism, radiation therapy to
the neck also predisposes to hyperthyroidism, thyroid cancer,
Hashimoto's thyroiditis, and benign thyroid nodules.tv" Lifelong observation is needed in patients who received external
radiation therapy to the neck.
Hypothyroidism after Subtotal or Total

Thyroidectomy
Subtotal thyroidectomy is still an excellent form of treatment for patients with Graves' disease, particularly when
antithyroid drugs and 131 1 therapy are not suitable." Surgical
approach has three advantages over radioactive iodine therapy.
First, the incidence of overt hypothyroidism is considerably
less than after radioactive iodine therapy. Second, the incidence of hypothyroidism does not increase as much in later
years. Third, patients with Graves' ophthalmopathy are less
likely to develop progression than after radioactive iodine
therapy. Kuma and associates characterized the type of
postoperative hypothyroidism after surgery in patients with
Graves' disease who underwent subtotal thyroidectomy. 52
Nearly 40% to 50% of patients experienced subclinical
hypothyroidism during the first 4 years after surgery, and the
incidence correlates inversely with the size of the thyroid
remnant. Palit and colleagues reviewed 35 published papers
regarding subtotal thyroidectomy for Graves' disease
and found a 25.6% prevalence of postoperative hypothyroidism." The most important aspect of the outcome of
surgery is the remnant size of thyroid tissue. The average
weight of remnant tissue is 6.1 g, and the increment of each
gram of thyroid tissue decreases the prevalence of hypothyroidism by 8.9% but increases the risk of recurrent hyperthyroidism." Other factors, such as the degree of lymphocyte
infiltration, iodine deficiency, and medications, may affect
the outcome of thyroid surgery and thyroid function.
Iodine Deficiency
Iodine deficiency is a serious worldwide problem, particularly
in Africa, China, southern Asia, and Europe. It is estimated that
about 1 billion people are iodine deficient. About 20 million
people have endemic goiter and 2 million people have
endemic cretinism. 53 To form adequate amounts of thyroid
hormone, 100 to 150 ug/day of iodine is needed.P If iodine
intake is less than 100 ug/day, endemic goiter may develop.
Further decrease in iodine intake of less than 25 Ilg/day may
cause endemic cretinism.P Most patients with endemic goiter
have normal thyroid function; however, hypothyroidism
develops when iodine deficiency is severe. Endemic cretinism
is divided into two types: neurogenic and myxedematous. 54
The former is more common than the myxedematous type
and is characterized by irreversible neurologic deficits such
Hypothyroidism - -
as deafness, gait abnormality, squint, and spasticity.

Curiously, neurogenic cretins are euthyroid, despite severe
iodine deficiency. Myxedematous cretinism is relatively rare
and is limited to parts of central Africa, Nepal, and western
provinces of China. The clinical manifestation of myxedematous cretinism is attributed to hypothyroidism.
Iodide-Induced Hypothyroidism
Hypothyroidism caused by excessive iodine intake has also
been observed in patients having the following conditions or
underlying diseases: history of postpartum thyroiditis, after a
previous episode of subacute thyroiditis, and recombinant
INF-a treatment.P The hypothyroidism is transient, and
thyroid function returns to normal 2 to 3 weeks after iodide
withdrawal; however, long-term follow-up is needed for
these patients because some subsequently develop permanent
primary hypothyroidism/"
Central Hypothyroidism
Abnormalities of the pituitary gland, such as pituitary tumor,
ischemic lesion (Sheehan's syndrome), and iatrogenic events
(surgical removal or radiation therapy), can cause central
hypothyroidism with decreased pituitary TSH secretion. Other
rare causes of pituitary lesions include tuberculosis, syphilis,
hemochromatosis, sarcoidosis, histiocytosis, and aneurysms
of the internal carotid artery.
Hypothalamic lesions, such as suprasellar extension of
pituitary tumors or craniopharyngioma, meningioma, glioma,
and metastatic tumors, can damage the hypothalamus and
decrease thyrotropin-releasing hormone (TRH) secretion.
This event leads to decreased TSH secretion and subsequent
hypothyroidism. Chronic head trauma (e.g., in boxers) can
also be the cause of hypothalamic dysfunction.
Bexarotene, a retinoid X receptor-selective ligand used for
treatment of T-cell lymphoma, has been shown to suppress
TSH secretion and cause reversible central hypothyroidism."
Hereditary central hypothyroidism is rare, and two types
have been described: (1) isolated cases caused by alteration of
TSH-~
and TRH receptors and (2) combined pituitary hormone deficiency caused by inactivating mutations of different
pituitary transcription factors." It is important to diagnose
central hypothyroidism and start treatment at an early stage.
Congenital Hypothyroidism
Congenital hypothyroidism is a rare cause of hypothyroidism. There are three different etiologies: (1) athyreosis
(absent thyroid); (2) dysgenesis (hypoplastic or lingual
thyroid); and (3) dyshormonogenesis (congenital defect in
the steps of thyroid hormone synthesis). The importance of
identifying the etiology for treatment and follow-up planning
has been described previously. 58
Generalized Thyroid Hormone Resistance

Hypothyroidism resulting from generalized thyroid hormone
resistance is a rare familial disorder. This is caused by a
mutation of thyroid hormone receptor ~. Because the thyroid
47
hormone receptor does not function normally, tissues do not

get messages of thyroid hormone. Thus, clinical features of
hypothyroidism appear in the presence of elevated serum
thyroid hormone levels.
Increased Thyroid Hormone Destruction

as a Cause of Hypothyroidism
Huang and coworkers first reported an infant with hepatic
hemangioma who had severe hypothyroidism despite vigorous thyroid hormone treatment. The study revealed increased
type 3 deiodinase activity in the liver, causing degradation of
thyroid hormone by increased deiodination."
Symptoms and Signs

Symptoms of hypothyroidism are listed in Table 6-1.
Figure 6-1 shows the characteristic facial expression of
primary hypothyroidism and secondary hypothyroidism
(Sheehan's syndrome). Prominent periorbital edema is seen
in patients with primary hypothyroidism, and this sign is usually absent or minimal in patients with secondary hypothyroidism. Patients with the latter disorder present with a pale
face, increased wrinkles, and loss of eyebrow, particularly the
lateral portions. In general, patients with overt hypothyroidism
have more symptoms than those with subclinical hypothyroidism. Also, the number of symptoms and hypothyroid
signs increase as they progress from subclinical hypothyroidism to overt hypothyroidism. In 1969, Billewicz and
associates described a scoring system of hypothyroid symptoms and signs to assist in diagnosing hypothyroidism,
because no TSH assay was available at that time/" This scoring system was re-evaluated by analyzing symptoms and signs
based on modem thyroid function tests in 1997. 61 Delayed
relaxation of ankle reflex is the most prominent sign
of hypothyroidism with the highest specificity" ; this is
Primary hypothyroidism
Secondary hypothyroidism
FIGURE 6-1. Characteristic facial expression in primary hypothyroidism (A) and central (secondary) hypothyroidism (B).
consistent with the finding of the Billewicz group.

Periorbital puffiness, slow movements, and hearing loss
should be sought as hypothyroid signs because of the specificity of these signs in hypothyroidism.w-" Some patients
have only mild symptoms and signs of hypothyroidism
despite profound biochemical hypothyroidism, and some
patients have marked symptoms despite only mild thyroid
dysfunction. The discrepancy between symptoms and thyroid function tests indicates that tissue responsiveness and
not serum TSH levels determines the symptoms and signs
of hypothyroidism." In addition, hypothyroid patients may
have many atypical clinical signs and manifestations such
as sleep apnea, galactorrhea, respiratory failure, pericardial
effusion, pleural effusion, dementia, depression, psychosis,
adynamic ileus, and anemia. Therefore, judicious judgment
is required when patients show atypical symptoms or signs
of hypothyroidism. Even though these symptoms and signs
suggest hypothyroidism, the final diagnosis should be made
based on laboratory tests.
single test, but the accuracy of the test eventually turns out to
be more cost-effective because it avoids frequent repeat testing.
In summary, if thyroid status is to be screened as a routine test
without clinical signs of thyroid dysfunction, serum TSH alone
is acceptable. If one suspects thyroid dysfunction, both TSH
and Ff4 testing should be done. Radioactive iodine uptake or
thyroid scan is not needed for diagnosing hypothyroidism.
Nonthyroidal Illness as a
Diagnostic Dilemma
Nonthyroidal illness is an alteration of serum thyroid hormone levels due to the presence of medical illness or fasting
or after surgery. The nature of this disorder and a practical
approach to this disorder have been well described.F'''?
Initially, these patients present with low serum triiodothyronine (T 3) levels due to decreased deiodinase 1 activity that
converts T 4 to T 3 As the disease progresses, total T 4 concentrations are reduced. When Ff4 was measured by equilibrium dialysis, FT 4 levels were usually normal/" whereas
FT 4 measured by the analog method is low.68 The analog
method is used in automated thyroid testing in most clinical
laboratories and is significantly altered by high or low serum
protein levels." Serum TSH levels vary depending on the
stage of nonthyroidal illness. During the recovery stage of
illness, serum TSH levels tend to be elevated. This causes
difficulty in determining whether patients are hypothyroid.
History of medical illness, careful physical examination,
and selection of the right laboratory tests can be helpful. For
instance, the presence of goiter, positive TPO antibody, and
a long history of hypothyroid symptoms favor a diagnosis of
hypothyroidism. Also, the level of serum TSH is known to be
helpful. When serum TSH levels are higher than 20 IlIU/mL,
primary hypothyroidism is likely, with a few exceptions.s?
Laboratory Testing for

Detection of Hypothyroidism
Thyroid Hormone Treatment
The diagnosis of hypothyroidism is now focused on a single

or most cost-effective test. A single TSH test was advocated
for screening of thyroid dysfunction in 1993. 62 Serum TSH
measurements use highly sensitive second- and thirdgeneration assays, based on lower limits of detection of 0.1
and O.OlIlU/mL, respectively. The TSH test accurately measures thyroid function and helps provide accurate thyroid
hormone treatment. The limitation of the single TSH test is
missing central hypothyroidism, since serum TSH concentrations in most patients with central hypothyroidism are
normalP In addition, some patients have elevated serum
TSH concentrations (immunologically active and biologically
inactive TSH) despite the presence of central hypothyroidism.P Using serum free thyroxine (Ff4) alone as a diagnostic test of hypothyroidism detects hypothyroidism and
monitors rapidly changing function better, but it cannot detect
subclinical hypothyroidism. Also, low Ff4 alone is not sufficient to make the diagnosis of central or primary hypothyroidism. The combination of serum TSH and Ff4 is the most
accurate test for detecting central as well as primary hypothyroidism/" Addition of serum Ff4 to TSH costs more than the
There are three thyroid hormone preparations: L-thyroxine

(T 4) , T 3 , and combined T 4 and T 3 (desiccated thyroid
[Thyrolar]). Synthetic levothyroxine (L-T4 ) is used most
often and has distinct advantages: long half-life of 7 days and
efficient conversion to T 3 Thus, this medication is given
once a day, and missing a dose for 1 to 2 days is not harmful.
L-T4 also generates T 3 in the liver, the kidney, the brain
and other tissues, providing tissue T 3 . The dose of L-T4 of
1.7 ug/kg (0.075 to 0.15 mg/day) should normalize the serum
TSH level in most patients with hypothyroidism."? The daily
requirement of T4 is 100 to 150 ug for adults, 50 to lOOllg
for children, and 50 ug for infants. These are commonly used
doses; the dose may need to be adjusted for some patients
depending on body weight and severity of hypothyroidism.
Patients with myocardial ischemia or cardiac arrhythmia,
such as atrial fibrillation, should be treated using a small
starting dose of thyroxine (0.0125 to 0.025 mg once a day)."
Because of the long half-life of T 4 , once-a-week dosing is
also recommended for patients who are not compliant." If
L-T4 is to be given once a week, the weekly dose should be
slightly higher than seven times the usual daily dose.
Hypothyroidism - -
Is additional T 3 to L-T4 beneficial? The study by

Bunevicius and coworkers showed improvement in
neuropsychological behavior and mood by combined T 4 and
T 3 treatment in hypothyroid patients." In animal models of
thyroidectomized rats, the addition of T3 to T 4 normalized
plasma and tissue levels of thyroid hormone; T 4 treatment
alone did not achieve such normal levels." However, the
addition of T, may cause palpitations and worsening angina,
particularly in elderly patients. Therefore, T 3 treatment
should be used carefully if it is to be employed.
Follow-up of patients who are receiving thyroid hormone
replacement is critically important. It is now known that
about 60% of patients receive an appropriate amount of thyroid hormone and the remaining 40% of patients take too little
or too much, based on serum TSH levels in the Colorado
Thyroid Disease Prevalence Study. 1 This finding is probably
relevant to other geographic areas. It is now known that subclinical hyperthyroidism and subclinical hypothyroidism are
risk factors for cardiovascular complications and that strictly
controlling thyroid status is beneficial. To achieve normal
thyroid status, serum TSH levels should be measured periodically and the thyroid hormone dose should be adjusted
accordingly. The only exception is central hypothyroidism,
in which a serum TSH level is not helpful; serum Ff4 and
Ff3 should be used to determine the thyroid status. Ordering
serum Ff3 is important because Ff4 level alone is not sufficient to determine the adequacy of thyroid hormone dose,
and normalization of serum FT3 level is also needed in
patients with central hypothyroidism." A biologic marker
of thyroid hormone action should also be useful when
serum TSH levels do not accurately determine thyroid
status. Resting energy expenditure has been reported to be a
sensitive marker of thyroid hormone replacement." Clinical
use of this method seems to be of interest.
Conditions that Affect the Maintenance

Dose of T4
Several conditions require increasing the dose of T 4 .
Pregnancy is the most important because more T 4 is needed
during pregnancy in patients with hypothyroidism based on
serial serum TSH measurements." Similarly, patients with
hypothyroidism who take estrogen require more thyroid
hormone due to increased thyroid-binding protein by estrogen and subsequent decrease in available FT 4.78 Medications
to decrease T4 absorption include cholestyramine, sucralfate, ferrous sulfate, aluminum hydroxide, and calcium
carbonate.Ys? Increased thyroid hormone replacement
should be considered if patients are on these medications. Patients should also take these medications at a
different time than when they take their thyroid hormone.
Measurement of serum TSH levels is an excellent method
to determine the appropriate T4 dose in patients with primary hypothyroidism. In contrast, some conditions require
decreased thyroid hormone dose. Androgen therapy
decreases T 4-binding globulin and increases Ff4 hormone."
Delayed degradation of thyroid hormone can be expected
in elderly patients. Thus, patients with androgen therapy for
breast cancer and elderly patients (>65 years of age) may
need less thyroid hormone.
49
Adverse Effects of T4 and Bone

Mineral Density
Sodium levothyroxine is not recognized as a foreign antigen;
thus, allergic reactions to levothyroxine should not occur.
However, an allergic reaction to the coloring agents of
levothyroxine has been reported.F In this situation, taking a
noncolored tablet prevents an allergic reaction.
Thyroid hormone is known to increase osteoclastic
activity.83 It is documented that patients with untreated Graves'
disease will develop bone 10ss.84 This is because of persistently
high levels of circulating thyroid hormone levels for prolonged
periods. There is controversy regarding how patients who have
had thyroidectomy for thyroid cancer should be managed. In
general, TSH suppression with high-normal T3and T 4 levels is
recommended. There are conflicting opinions about the risks
and benefits when patients' serum TSH levels are chronically
suppressed.v-" Recently, Quan and associates analyzed
the effect of thyroid hormone on bone mineral density in
11 studies that also describe confounding factors relevant to
bone loss." They concluded that thyroid hormone suppression
treatment does not affect bone mineral density in premenopausal women and in men. However, the effect of TSH
suppression in postmenopausal women remains controversial.
Surgery in Patients with

Hypothyroidism
Surgery in patients with undiagnosed hypothyroidism may
cause a catastrophic outcome. It is essential for surgeons to
know the precise approach and management of patients with
hypothyroidism who may have to undergo surgery in the
hypothyroid state. In this section, we describe a practical
approach as well as potential problems that may occur
during surgery in patients with untreated hypothyroidism.
Approach
The following considerations should be taken into account:
1. Does your patient have hypothyroidism or nonthyroidal illness?
2. Does your patient require urgent or elective surgery?
3. Is your patient's cardiac condition stable?
4. Are there any significant complications of hypothyroidism that may cause problems during surgery
(anemia, hyponatremia, respiratory failure, signs of
adrenal insufficiency)?
The first step is to make sure that patients are actually
hypothyroid and not in the category of nonthyroidal illness.
Patients who undergo surgery often have a picture similar to
nonthyroidal illness, which is sometimes difficult to distinguish from primary hypothyroidism. The diagnosis of
hypothyroidism should be established as outlined earlier in this
chapter by laboratory testing. After the diagnosis is made, one
needs to determine whether patients need elective or
emergency surgery. If elective surgery is indicated, patients
should be treated with thyroid hormone to restore the euthyroid state. This eliminates some of the hypothyroid-related
surgical complications. However, difficulty arises if patients
50 - -
Thyroid Gland
have to undergo emergency surgery in the hypothyroid state.

At present, there is a general consensus that emergency surgery
can be done in patients with mild to moderate hypothyroidism
as long as potential perioperative problems and complications
are appreciated (Table 6-2). In particular, cardiopulmonary
complications (hypotension, respiratory failure, heart failure),
hypothermia, hyponatremia, bleeding tendency, and adrenal
insufficiency should be the main concerns during and after surgery." Chronic thyroid hormone deficiency affects cardiac
function by prolonging systolic and diastolic function, as seen
by echocardiography.'" Even patients with subclinical hypothyroidism have an increased risk of myocardial infarction.?"
hyperlipidemia," and byperhomocysteinernia,? Therefore,
patients' cardiac status needs to be carefully evaluated before
surgery. Because of these complications, thoughtful planning
for surgery and special preoperative and postoperative management of these patients become critically important.
There are three control studies in which surgery was performed on patients in the hypothyroid state. 88.91,92 Problems
and complications during and after surgery were then compared with those of euthyroid patients. On the basis of these
studies, we have established guidelines for the care of
patients in a hypothyroid state who may have to undergo
surgery (Table 6-3). Before surgery, all surgical patients in a
hypothyroid state should have glucocorticoid administered
because hypothyroidism can be of central origin, and even
primary hypothyroid patients may experience adrenal insufficiency during surgery.92.93 It is appropriate to administer
50 to 100 mg hydrocortisone every 8 hours during the
preoperative period. The normal adrenal gland produces
as much as 300 mg hydrocortisone a day; thus, 100 mg
of hydrocortisone given every 8 hours should be sufficient
to cover all surgical stress. The dose of preoperative medications, such as sedatives, should be reduced or avoided.
During intubation, one may encounter difficulty controlling
the airway because of a goiter or vocal cord edema. Deep
anesthesia should be avoided by adjusting the amount of
anesthetic agents administered. During the operation, blood
pressure and cardiac function should be monitored carefully.
It is highly advisable that inotropic agents and vasopressors
be ready for use should these complications arise. One
should be aware that patients with severe hypothyroidism
may be refractory to the administration of cathecolamines.?"
After surgery, extubation may be delayed because of a combination of respiratory failure from hypothyroidism and respiratory depression caused by anesthetic agents. Therefore,
monitoring of arterial blood levels is essential.
During the postoperative period, the dose of postoperative

sedatives should be reduced. Complete blood count, electrolytes, and cardiopulmonary status need to be routinely
checked. Infection may be more difficult to diagnose because
some patients with hypothyroidism fail to become febrile.
The most difficult case for physicians involves the patient
with untreated or profound hypothyroidism who needs emergency surgery. The question is whether such patients should
be treated with intravenous T 4 before and during surgery.
To our knowledge, no comprehensive study is available in
regard to the outcome of surgery with and without T4 therapy.
However, surgical procedures are a precipitating cause of
myxedema coma, so that patients with severe hypothyroidism
should receive intravenous T 4 before surgery (i.e., 200 to
500 ug L-T4 used for myxedema coma). An electrocardiogram
should be obtained prior to T 4 treatment.
What should be done in patients with ischemic heart
disease and profound hypothyroidism who need surgery?
If elective surgery is possible, patients should be treated
slowly, starting with a low dose of thyroid hormone to restore
a near-euthyroid state before surgery. If emergency surgery is
required in such patients, 100 to 200 ug of t,- T 4 intravenously
is needed, depending on the patient's condition.
Coronary Bypass Surgery

Coronary artery bypass graft surgery (CABO) is one of the
conditions in which intravenous T 3 may be beneficial and has
potential application. CABO can produce a picture of nonthyroidal illness with low serum T 3.95 It is speculated that this
low T 3 state may have significant hemodynamic consequences
Hypothyroidism - -
similar to those seen with chronic hypothyroidism. In fact,

diminished cardiac contractility altered gene expression similar to that seen in hypothyroidism developed in animals."
Also, T 3 treatment increased left ventricular function in
patients with congestive heart failure who also exhibited the
picture of nonthyroidal illness.9798 There have been several
investigations showing the beneficial effects of T3 treatment
given before and after CABG in adults and children by
demonstrating increased cardiac outpUt. 99- 103 Administration
of T3 had no adverse effects in most studies99IOO,102 and even
lowered the incidence of atrial fibrillation after cardiac
surgery.l'" The dose of T3 administered intravenously by
Klemperer and colleagues was 1.4 ug/kg of body weight
over a period of 6 hours (average total dose of 110 ug) starting immediately after surgery.103 If hypothyroid patients need
bypass surgery, the same strategy of intravenous T 3 treatment
should be considered, but such management remains controversial. In fact, one investigation failed to find any change in
outcome when Tj-treated bypass patients were compared to
those receiving dopamine and to placebo groups."
Prevention
Neonatal screening must be done for all infants because
mental retardation and growth abnormality caused by
hypothyroidism can be prevented by thyroid hormone treatment. Because serum TSH levels in normal newborns are
elevated immediately after birth, blood samples should be
obtained 4 to 6 days after birth. Neonatal screening is generally performed by spotting blood from the heel onto filter
paper. Measurement of T, and TSH is done in the eluate from
the filter paper. T4 therapy should be started immediately
after the diagnosis of hypothyroidism is established. For
newborn infants, the dosage is 25 to 50 ug/day: for infants 6
to 12 months old, 50 to 75 ug/day is commonly used. T4
should be crushed and mixed with milk for administration.
Early treatment of infants in whom hypothyroidism was
discovered 3 to 6 days after birth was associated with a
normal IQ and normal growth. !04
Iodine Deficiency
Iodine is an important precursor of thyroid hormone. Thus,
iodine deficiency leads to impaired production of thyroid
hormones that are essential for prenatal and postnatal brain
development for normal cognitive and neurologic function.
The importance of iodine deficiency was addressed by the
Rome Conference on Nutrition and the 1990 World Summit
for Children, which called for the virtual elimination of
iodine deficiency by the year 2000,105 There are three
methods of iodine prophylaxis: iodinated salt, iodized oil,
and iodinated water. Iodinated salt is the most inexpensive
and most suitable for the general population. Iodinated salt is
designed to provide more than 100 ug of iodine per day,
assuming that daily intake of salt is 2 to 5 g. However, iodine
content in salt varies in each country. Iodized oil is a longacting iodine and can be given orally or intramuscularly.
One dose of 1 mL of iodized oil contains 480 mg of iodine.
If given intramuscularly, it provides enough iodine for 2 to
3 years in children and 7 years in adults. Duration of oral
51
iodized oil is 1 to 2 years. Iodination of drinking water is not

widely practiced except in Italy. Iodine prophylaxis is an
important project to be carried out nationwide to save many
children and adults from endemic goiter and cretinism.
Prevention of Hypothyroidism after

Subtotal Thyroidectomy
Approximately 25% of patients develop hypothyroidism
after subtotal thyroidectomy for Graves' disease."
Prevention of postoperative hypothyroidism has been
attempted by changing the size of remnant tissues.
Increasing remnant tissue size decreases the incidence of
hypothyroidism,' 1 but recurrent Graves' disease is a problem. S2.106 Shimizu and coworkers tried autotransplantation
of cryopreserved thyroid tissues in four patients who developed postoperative hypothyroidism after subtotal thyroidectomy for Graves' disease.P? About 2.5 to 3.5 g of
cryopreserved thyroid tissues at -80C were autotransplanted into the muscle of the forearm, and three of the four
patients were able to discontinue thyroid hormone medications.I'" This interesting technique may be applicable for the
prevention of postoperative hypothyroidism in some cases.
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Graves' and Plummer's

Diseases: Medical and
Surgical Management
Michael Sean Boger, MD, PharmD Nancy Dugal Perrier, MD
Historical Aspects
The striking clinical malady of exophthalmic goiter, with its
distinctive protruding eyes, tachycardia, nervousness, and
enlarged thyroid, has been known for more than 150 years.
Thyrotoxicosis was first described in 1786 by Parry, a physician in England, but was not reported until after his death
in 1825. It was also noted by von Basedow and a handful of
others. I To this day, on the continent of Europe, it is known
as Basedow's disease. In the English-speaking world it is
named for Robert James Graves because of a lucid monograph he wrote on the subject. As with many medical
eponyms, however, he was not the first to describe the
condition.' It was during the next century that Dr. Henry
Plummer first described toxic nodular goiter, which came to
be known as Plummer's disease. Both of these physicians
made everlasting contributions to the field of endocrinology.
Robert James Graves (1796-1853)

Robert James Graves (Fig. 7-1) was a descendant of a colonel
in Cromwell's army. He was described as a brilliant student,
highly cultured, handsome, and charming. In Dublin, Ireland,
where he was born and trained in medicine, he received the
highest educational award, the Golden Medal, for organizing
medical education.' He introduced "clinical teaching,"
which has evolved into bedside teaching today, encouraging
students to actually examine patients, present them to the
professor, and write clinical histories-a novel idea at the
time. 1,4 He insisted that his students attend autopsies to correlate findings there with the patient's state prior to death.'
This was met with great opposition by the then current
tradition that students have extensive book knowledge and
little practical experience. I
Dr. Graves' clinical lectures were the talk of the town,
where he introduced many novel concepts including the pinhole pupil after pontine hemorrhage, timing the pulse by
watch, and abandoning the practice of bleeding and starving
54
patients with pyrexia. i.as His book, Clinical Lectures on the

Practice ofMedicine, is regarded as a medical masterpiece.'
He was a pioneer in proper nutritional therapy for the sick
and requested that his epitaph read: "He Fed the Fevers."!
In 1835, he published his famous monograph, "A Newly
Observed Affection of the Thyroid Gland in Females."
Three cases of violent and long continued palpitations in each of which the same peculiarity presented
itself (with) enlargement ofthe thyroid gland ... the
eyes assumed a singular appearance for the eye balls
were apparently enlarged, so that when she slept or
tried to shut her eyes, the lids were incapable of closing. When the eyes were open, the white sclerotic
could be seen, to a breadth of several lines, all around
the cornea. .. .The enlargement of the thyroid ... seems
... essentially different from goiter, in not attaining a
size at all equal to that observed in the latter disease.6
Henry Plummer (1874-1937)

The death rate in the United States from hyperthyroidism
around 1908 was 25%. The extremely high mortality in
goiter surgery was underscored by Samuel Gross, who
stated the following:
Can the thyroid gland, when in a state of enlargement,

be removed with a reasonable hope of saving the
patient? Experience emphatically answers no... no
sensible man will. ... Every stroke of a knife will be
followed by a torrent of blood, and lucky will it be for
him if his victim lives long enough to enable him to
finish his horrid butchery/
By 1918, Charlie Mayo had performed his 5000th
thyroidectomy. He had a personal death rate of 3%, a number
touched by no one on the continent, in part due to Dr. Henry
Plummer (Fig. 7-2).2 From Minnesota, Dr. Plummer was first
consultant to Drs. Will and Charlie Mayo.? He developed a
Graves' and Plummer's Diseases: Medical and Surgical Management - -
55
clinical one. He was a pioneer in the development of radiographic diagnosis and therapy," His other achievements
include designing the tube system for transporting patient
records and the complex medical record system still in use
at Mayo today." He later developed the first intercom system
and irrigation system in the United States.'
By 1922, Dr. Plummer was elaborating a theory about
goiter disease. He led weekly "goiter lunches" to share his
expertise.l When thyroxine (T4) proved to be 65% iodine, he
posed the hypothesis that the extra toxic substance he postulated to be the cause of crises in exophthalmic goiter was a
noniodinated molecule of T4, a compound discovered at the
Mayo Clinic by Dr. Edward Kendall.s? He reasoned that a
(then unknown) stimulus causes the thyroid gland to work
too fast and if not enough iodine was readily available in
the blood, the gland would tum out a half-finished product,
a molecule of T4 with the essential iodine missing. At once,
he believed that iodine should be tried on his goiter service
at St. Mary's Hospital, and the results were miraculous.'
FIGURE 7-1. Dr. Robert James Graves. (From Jay V. Dr. Robert
James Graves. Arch Pathol Lab Med 1999;123:284.)
special interest in the thyroid gland through his neighbor,

Mr. Strain, the first goiter patient to be operated on by the
Mayo brothers.' In 1913, Dr. Plummer first distinguished
toxic adenomatous goiter from exophthalmic goiter. Until the
availability of radioactive iodine, which made scintigraphy
possible in the mid-1940s, this disease was an entirely
Against all tradition, every professor of medicine,

every textbook ... following his own understanding of
the function of the thyroid, [he] saved the life of a
woman by injecting 5.0 mg of thyroxine intravenously/'
At the Association of American Physicians in May 1923,
he presented his results that administration of iodine preoperatively and postoperatively would prevent the crises that
caused death after symptomatic treatment of exophthalmic
goiter. He found that iodine in both nonoperative cases and as
preoperative treatment significantly reduced mortality." His
work turned the most treacherous operation known to surgery
into one of the safest in the hands of any competent operator.
It was hailed as one of medicine's greatest gifts to surgery and
the Germans coined the fitting word for it-Plummerung. 2
Graves'Disease
Epidemiology
There are several subtle but distinct differences among
patients with hyperthyroidism from Graves' and Plummer's
diseases, as outlined in Table 7-1. 10-13 Graves' disease is the
most prevalent autoimmune disorder in the United States
and the most common cause of hyperthyroidism. The chief
risk factor for Graves' disease is female gender, in part due
to modulation of the autoimmune response by estrogen.
Other potential precipitants of the autoimmune process
FIGURE 7-2. Dr. Henry Plummer. (From Clapesattle H. The

Doctors Mayo. Rochester, MN, Mayo Foundation for Medical
Education and Research, 1990.)
FIGURE 7-3. A, Pathogenesis of Graves' hyper-
Propylthiouracil X Beta-blockers X
Potassium iodide
Potassium perchlorata
Methimazole ~
Glucocorticoids { } Calcium channel blockers
thyroidism.IO18.48,S3 Inflammatory cells infiltrate the thyroid, producing inflammatory mediators including
various interleukins and tumor necrosis factor (TNF)-a.
Such inflammatory mediators increase the production
of stimulatory antibodies to the thyroglobulin receptor,
leading to an increased production of cyclic adenosine
monophosphate (cAMP) and, thus, thyroid hormones.
They also bind to other receptors on thyroid follicular
cells, including HLA class I, further increasing their
production, and antithyroglobulin antibodies, producing
a vicious cycle. B, Thyroid hormone synthesis. IO,18,48.53
The production of thyroid hormones involves (A) active
transport of iodide into the follicular cell mediated by a
sodium-iodide transporter in the basement membrane of
the follicular cell and secretion across the apical membrane into colloid; (B) uptake of amino acids, which are
then synthesized into thyroglobulin (TG) via the endoplasmic reticulum (ER), which is modified by the Golgi
apparatus and secreted via exocytosis of secretory vesicles into colloid; (C) oxidation and organification of
iodide into iodine via thyroperoxidase (TPO) and
hydrogen peroxide; (D) iodination of TG via TPO to
attach iodine to tyrosyl residues in the TG molecule to
form monoiodotyrosine (MIT) and diiodotyrosine (DIT);
(E) coupling of two iodotyrosine residues via TPO produces thyroid hormones thyroxine (T4) and triiodothyronine (T3) that are incorporated in the TG molecule for
storage in colloid; (F) endocytosis of colloid from the
lumen back into the follicular cell; (G) TG proteolysis
via lysozymes into T4, MIT, and DIT; (H) deiodination
of MIT and DIT into iodide; and (I) deiodination of T4
into T3, which occurs, to a lesser extent, in the thyroid
gland and, predominantly, in the periphery. C, Effects of
antithyroidal therapies. l3,48.S1 Propylthiouracil (PTU)
and methimazole (MTM) inhibit synthesis of T 3 and T4
by serving as preferential substrates for TPO, becoming
iodinated and diverting oxidized iodine away from
potential iodination sites in TG. They are actively
trapped by the thyroid gland against a concentration
gradient. They may also inhibit the oxidation and organification of iodine and the coupling reaction. PTU, but
not MTM, inhibits deiodinase in both the thyroid gland
and in peripheral tissues. Both agents appear to have
direct effects on the disordered immunity in Graves' disease. ~ Blockers (BB) and calcium-channel blockers
(CCB) reduce the vascularity of the gland; BBs
control the peripheral manifestations of hyperthyroidism. Glucocorticoids in stress doses may help stabilize the vascular bed and block conversion of
T4 to T3. Potassium iodide decreases iodine transport,
iodine organification, TG proteolysis, and thyroid
hormone secretion. It may also inhibit the ability of
thyroid-stimulating hormone and cAMP to stimulate
colloid endocytosis. Potassium perchlorate inhibits the
iodine-trapping mechanism.
Graves' and Plummer's Diseases: Medical and Surgical Management - - 57
include infection, particularly Yersinia enterocolitica, stress,

and iodine exposure. Smoking is weakly associated but
strongly associated with the development of ophthalmopathy. There is no evidence that infection affects the susceptibility to Graves' hyperthyroidism or directly induces it. No
single gene is known to cause the disease or to be necessary
for its development, although there is a well-established association with certain human leukocyte antigen (HLA) alleles
that vary among racial groups. Prevalence is similar among
whites and Asians and lower in blacks. 14
Pathogenesis
Graves' hyperthyroidism is caused by thyroid-stimulating
antibodies that bind to and activate the thyrotropin receptor
on thyroid follicular cells, stimulating the synthesis of cyclic
adenosine monophosphate (cAMP) and, in tum, thyroid
hormones (Fig. 7_3A).13.15-18 Inflammatory cells infiltrate the
thyroid gland and produce inflammatory mediators including various interleukins and tumor necrosis factor (TNF)-a.
These inflammatory mediators stimulate the production of
stimulating antibodies to the thyrotropin receptor, leading
to an increased production of cAMP and, thus, thyroid hormones. These inflammatory mediators bind to and stimulate
various other receptors on the follicular cells of the thyroid,
including HLA class I, causing a further increase in their
production and a further increase in antithyrotropin antibodies, leading to a vicious cycle.
Antibodies are also produced against thyroid peroxidase
and thyroglobulin. This leads to abnormalities in most
organ systems, including the cardiovascular and central
nervous systems. The thyroid-stimulating antibodies not
only cause thyroid hypersecretion but also hypertrophy and
hyperplasia of the thyroid follicles, which have a columnar
and folded epithelium and little colloid. The result is the
characteristic goiter (Fig. 7-4A and B). This is due to
the emergence of autoreactivity of T and B cells to the
thyrotropin receptor. The exact mechanisms involved are
unknown.
As illustrated in Figure 7-3A, there are high circulating
levels of various cytokines produced by lymphocytes in the
thyroid gland. There is no direct correlation between serum
concentrations of thyroid-stimulating antibodies and serum
thyroid hormone. There is diffuse columnar epithelial hyperplasia and colloid excess. 14 Lymphocytic infiltration is often
present, occasionally resulting in the formation of germinal
centers.Iv'? These intrathyroidal lymphocytes are a major
source of autoantibodies, with contributions from the cervical
lymph nodes and bone marrow. 14
Clinical Manifestations
The manifestations of Graves' disease can be marked or
subtle, with periods of exacerbation or remission. It is now
recognized as a multisystem disease characterized by diffuse
goiter (see Fig. 7-4B), thyrotoxicosis, infiltrative ophthalmopathy and, occasionally, by infiltrative dermopathy?" The
symptoms can be functional as a result of increased
circulating levels of thyroid hormones or systemic as a result
of autoantibodies directed against thyroid and extrathyroid
organs such as the eye or skin. In an individual patient, these
features may occur singly or in varying combinations, such

that the full syndrome may never develop.
The most common symptoms are nervousness, fatigue,
irritability, palpitations or rapid heartbeat, heat intolerance,
weight loss, tremor, and decreased menstrual periods in
women. These symptoms are present in more than half of all
patients with the disease. With myxedema, the skin is warm
and moist and has a silky texture. Patients may have graying
of the hair, vitiligo, or onycholysis. The hair becomes thinner,
and alopecia may develop.v"
The classic goiter is one of the most consistent features
of Graves' disease. Approximately 90% of patients younger
than 50 years of age have a firm, diffuse goiter compared to
75% in older patients." It is usually symmetrical, smooth,
firm, and rubbery and a bruit or thrill may be present in the
gland. Graves' disease can also occur in normal-sized
glands, especially in the elderly."
Clinically evident ophthalmopathy occurs in 50% of
patients, in 75% of whom the eye signs appear within a year
before or after diagnosis of hyperthyroidism. There is an
inflammatory infiltrate composed predominately of activated
T cells in the extraocular muscles and orbital connective
tissue. This infiltrate may localize in the orbit via recognition
by T cells of an orbital antigen that cross-reacts with thyroid
antigen, such as the thyrotropin receptor expressed in
preadipocyte fibroblasts. Cytokines stimulate the production
of glycosarninoglycans, leading to edema and fibrosis.Pv"
These changes displace the eyeball forward due to increased
volume of tissue within the orbit and may interfere with
extraocular eye muscle function.P Patients may have photophobia, eye irritation, diplopia, and change in visual acuity.
Most frequently, this presents as eyelid retraction or lag and
periorbital edema. Proptosis (exophthalmos) occurs in up to
one third of patients (Fig. 7-5A and B). Eyelid erythema,
conjunctival injection, chemosis, swelling, and eyelid
edema may occur. 13.20
Dermopathy occurs in 1% to 2% of patients, almost
always in the presence of severe ophthalmopathy. In fact,
there are close histologic similarities between the orbital
connective tissue in Graves' ophthalmopathy and the pretibial connective tissue in pretibial dermopathy (Fig. 7-5C).22
Infiltrative skin manifestations are associated with eye
changes in most cases. 13.20 It is most frequent over the
anterolateral aspects of the shin but can occur in other
sites.'? Pretibial myxedema presents as scaly, thickened,
indurated skin, often with an orange-peel texture. 19.22
Diagnosis
Features for the diagnosis of Graves' disease are shown in
Table 7_2.13.20.23 The clinical triad of palpitations, weight
loss, and heat intolerance plus diffuse bilateral goiter usually
secures the diagnosis, but one must rule out subacute
thyroiditis, thyrotoxicosis factitia, and other conditions.
Radioactive iodine uptake studies can demonstrate a diffuse
goiter (see Fig. 7-4C). Patients with increased thyroid
hormone secretion have high uptake, whereas those with
low uptake indicate suppression of thyroid-stimulating hormone (TSH) levels without increased thyroid-stimulating
antibodies.P A radionuclide scan is essential if subacute thyroiditis is suspected to differentiate it from Graves' disease."
FIGURE 7-4. The characteristic diffuse goiter in Graves' disease.

A, Patient with a symmetrically diffusely enlarged thyroid gland.
B, Surgical specimen reveals diffuse hypertrophy and hyperplasia
with a smooth, rubbery yet lobular consistency. C, Homogeneous
increased technetium (99mTc) uptake on radionuclide scan.
(A, Courtesy of Ken Greer, MD, Charlottesville, VA.)
c
Patients with low uptake do not need treatment, because
low-uptake hyperthyroidism usually implies thyroiditis,
which generally resolves spontaneously. Some argue for
routine testing of antibodies, whereas others note that
Graves' disease can nearly always be inferred correctly on
the basis of clinical findings."
Therapy
The ideal therapeutic agent for Graves' disease would offer

(I) prompt control of disease manifestations, (2) return to
and maintenance of euthyroidism, (3) minimal morbidity
and mortality, and (4) reasonable COSt,20 The current therapeutic armamentarium remains empirical with antithyroid
medications, radioactive iodine ablation, and subtotal or
near-total thyroidectomy. Each option has advantages, disadvantages, and complications. Factors to consider when
deciding on a treatment plan for thyrotoxicosis include
patient age, associated ophthalmopathy, thyroid size, presence of compressive symptoms, substernal thyroid extension, contraindications to the use of radioiodine, intolerance
to antithyroid drugs, presence of a dominant nodule,
response to previous therapy, and patient preference. 12
Subtotal thyroidectomy was the standard of treatment in

the early part of the 20th century. The goal was to eliminate
the underlying pathology while leaving a tiny thyroid remnant to achieve a euthyroid state without causing recurrent
hyperthyroidism. Eastern countries such as Japan continue
to use surgery as first-line therapy today. In 1946, Hertz and
Roberts described radioactive iodine therapy for hyperthyroidism, which has since gradually replaced surgery as firstline therapy because of the belief that it was safer and more
effective. It is inexpensive and safer for debilitated patients
who may be poor surgical candidates. However, since the
introduction of radioactive iodine, surgery has improved with
preoperativedrug treatment and modem operative techniques.
There is a worldwide variation in the use of therapy.
A recent questionnaire from the American Thyroid
Association demonstrated what many believe-using a
selective surgical approach is an underused treatment modality in the United States when an experienced surgeon is available. Radioactive iodine is widely used in North America,
whereas antithyroid medications and surgery are more
commonly used in Europe, China, and Japan. Radioactive
iodine is used by most clinicians for patients with recurrent
or persistent hyperthyroidism," A similar survey was
59
FIGURE 7-5. Systemic manifestations of Graves' disease.

Graves' ophthalmopathy with characteristic wide, staring gaze,
lid lag, significant periorbital edema (A), and proptosis (B).
Dermopathy (C) presenting as pretibial myxedema with nonpitting edema over the shins, scaly thickening, and skin induration,
creating the characteristic orange-peel texture. (Courtesy of Ken
Greer, MD, Charlottesville, VA.)
c
conducted by Soloman and associates in the United States
using hypothetical cases of Graves' disease." Radioiodine
therapy was chosen 70% of the time, with antithyroid drug
therapy as the alternative. Surgery represented only 2% of the
total options selected.
ANTITHYROID MEDICATIONS
Indications of a favorable response to medical therapy include

a small thyroid gland, reduction in goiter size with medical
therapy, biochemical euthyroidism with normalization of
TSH, and decreased antibody titers." Antithyroid medications interfere with one or more steps in the biosynthesis
and secretion of thyroid hormone, as illustrated in Figure 7-3B

and C.13.16-18.27.28 Initial doses are methimazole 10 to 40 mg
three times daily and propylthiouracil (PTU) 100 to 300 mg
three times daily and subsequently decreased to oncedaily dosing once the patient is rendered euthyroid. The
rapidity of response is influenced by the severity of the
underlying disease, the size of the gland reflecting hormonal
stress, and the dose and frequency of the agent used. Patients
generally become euthyroid within 6 to 12 weeks after
starting therapy.
Methimazole has the advantage of once-daily dosing and
improves compliance and side effects, particularly hepatotoxicity. Side effects are less common when used in low
dose compared with PTU, where side effects are not dose
dependent. PTU is preferred in pregnancy and lactation due
to higher protein binding. Methimazole may cause aplasia
cutis, a scalp defect, in newborns. PTU is also preferred in
thyroid storm when rapid normalization of serum thyroid
hormone levels is critical because it inhibits peripheral
conversion of T4 to triiodothyronine (T3) . However, it may
cause agranulocytosis."
Potassium perchlorate is used with iodine-induced hyperthyroidism related to amiodarone exposure. Pretreatment
with antithyroid medications before radioactive iodine
therapy reduces radiation-induced thyroiditis that could
transiently exacerbate hyperthyroidism but also reduces the
effectiveness of radiation therapy. Propranolol, 5 to 40 mg
four times daily, can be given to control the catecholamine
response of hyperthyroidism. Two drops of saturated solution of potassium iodide (SSKl, Lugol's solution) three
times a day (48 ug/drop) can be added 10 to 14 days
prior to surgery to decrease the vascularity of the gland"
Although it rapidly decreases serum thyroid hormone levels,
most patients treated with SSKI have a rapid "escape"
within 1 to 2 weeks back to hyperthyroidism. Antithyroid
medications are used for 12 to 24 months and should be
slowly tapered.??
Because of the high failure rate, medical therapy with
curative intent is primarily indicated in adults with small,
nontoxic goiter 40 g), those with mildly elevated thyroid
hormone levels, and those who exhibit rapid remission with
reduction of gland size. Long-term therapy may lead to
remission, but approximately 40% of patients fail a 2-year
course." The recurrence rate of disease is 60% after 6 months
of therapy, with a latent period of 2 to 6 weeks.'?
The disadvantages of these agents are that multiple daily
dosing requires strong patient compliance, and they often
fail to produce a lasting remission. Predictors of poor
response to oral medications are large goiter size and high
thyroid hormone output. The disadvantages of the major
treatment modalities for Graves' disease are outlined in
Table 7_3. 21,27 For methimazole and PTU, the latent period
is 2 to 6 weeks due to initial stores of hormone, and after
2 years of therapy, up to 69% have a recurrence." Side
effects occur in up to 7% of patients; the most serious is
agranulocytosis, occurring in approximately 0.3% of cases.
Hypothyroidism develops in 15% of cases. For these
reasons, antithyroid therapy is most useful in patients with
mild disease, in those with small goiters, and in children and
adolescents.?"
RADIOACTIVE IODINE
Advantages of radioactive iodine therapy are avoidance of

daily medications and symptoms of hyperthyroidism. The
lifetime risk of early or late hypothyroidism with radioactive
iodine necessitating, lifelong replacement therapy, is 3%
per year. Euthyroidism may take 4 to 6 months to achieve,

and multiple doses may be required. Hyperparathyroidism
may develop from radiation exposure. It is contraindicated
in pregnancy, which should be avoided for a year, and in
breastfeeding mothers. Factors to consider in therapy with
radioactive iodine include increased risk of benign thyroid
tumors, malignant transformation in young patients, thyroid
cancers that develop are more aggressive, and ophthalmopathy is more likely compared with surgery.29,30
The effect of therapy for Graves' hyperthyroidism on
the course of ophthalmopathy is controversial. A recent
prospective, randomized study evaluated the effects of
radioactive iodine versus antithyroid medications and the
effects of glucocorticoids in patients with or without
Graves' ophthalmopathy." Among those treated with
radioactive iodine, ophthalmopathy developed or worsened
in 15% of patients 2 to 6 months after therapy. None of
the patients with baseline ophthalmopathy in this group had
improved eye disease. Among patients treated with a combination of radioactive iodine and prednisone, 67% of patients
with ophthalmopathy at baseline had improvement and no
patients had progression. In the methimazole group, 92%
of patients with baseline ophthalmopathy had improved eye
disease, 3% had worsening of disease, and the remainder
had no change.
Since treatment with antithyroid medications such as
methimazole is not often followed by development or progression of ophthalmopathy, it might be argued that patients
with Graves' disease who have ophthalmopathy should be
treated with these agents. However, antithyroid therapy may
not give satisfactory control of hyperthyroidism and, more
important, hyperthyroidism can recur after withdrawal of
therapy. Therefore, it is best to achieve permanent control
of hyperthyroidism in patients with ophthalmopathy, which
can occur only with surgery. Total thyroidectomy has been
recommended for patients with severe or progressive
ophthalmopathy to completely remove the abnormal thyroid
antigens serving as the stimulus for damage to the extraocular muscles and optic nerve. 12
If radioactive iodine is used, the best chance for preventing ophthalmopathy is with use of steroids, although their
use also comes with significant side effects. There is an
unexplained increased mortality as compared to the general

population. In a study evaluating the mortality in a cohort of
7209 patients with hyperthyroidism treated with radioactive
iodine, mortality from all causes and mortality due to cardiovascular and cerebrovascular diseases and fracture was
increased. For cerebrovascular disease, mortality was most
marked in the first year and was confined to patients aged
50 years and 01der. 32 This may reflect diastolic hypertension
or atrial fibrillation, and there appeared to be a relationship
between the severity of hyperthyroidism and risk of cerebrovascular disease."
Therefore, the role of radioactive iodine in the treatment
of Graves' disease is controversial. Radioactive iodine is a
good choice for patients with recurrence after surgery, since
reoperation is more technically difficult"
SURGERY
Surgery for Graves' disease is underused in the United

States. The advantages are that treatment is rapid and stops
hyperthyroidism, avoids the possible long-term risks of
radioactive iodine, and provides tissue for histologic examination. The complication rate is low in experienced hands.
The disadvantages are that hyperthyroidism may persist or
recur if insufficient tissue is removed and hypothyroidism
usually develops after near-total thyroidectomy.
The absolute and relative indications for thyroidectomy
are summarized in Table 7_4. 20,24 Five percent of patients
with Graves' disease develop nodules, 20% of which are
malignant. Thyroidectomy is useful in patients having serious allergic reactions during medical therapy. In pregnancy,
surgery is usually performed during the second trimester.
Surgery is not more technically difficult in patients who
have been treated medically. There is a higher chance of
hypothyroidism after radioactive iodine ablation than after
subtotal thyroidectomy. Radioactive iodine therapy has a
6-week to 6-month latency of onset, during which patients
need to be placed on antithyroid medications, whereas surgery results in rapid remission. Total or near-total thyroidectomy appears to stabilize or improve eye manifestations,
whereas radioactive iodine tends to aggravate Graves'
ophthalmopathy unless given with steroids." For substernal
goiters, even in the absence of symptoms, surgery is always
recommended, because most patients will likely develop
61
symptoms in the future as the gland enlarges, including

acute respiratory distress.s'
Surgery is particularly advantageous in juvenile Graves'
disease, which primarily affects female children between
11 to 15 years of age. It is the leading cause of hyperthyroidism in childhood.v' Most children present with
emotional lability, hyperactivity, nervousness, and learning
disabilities. In this population, medical therapy has a failure
rate approaching 60% to 80% due to poor compliance, side
effects, and disease aggressiveness at this age.35 When
compared to surgery, radioactive iodine has a higher incidence of recurrence, hypothyroidism, and subsequent hyperparathyroidism." Additionally, the risk of cancer in patients
treated with radioactive iodine is greater than in the general
population and is inversely related to age. Children treated
with radioactive iodine are also more likely to experience
hyperparathyroidism than adults. The recommendation is to
leave one remnant less than 4 g on one side as relapse is
more likely.34
The anatomy of the thyroid gland and surrounding arteries and nerves must be carefully considered during surgery
(Fig. 7-6). While dissecting the upper pole of the gland,
carefully avoid the external branch of the superior laryngeal
nerve and superior thyroid artery. An approach via the avascular space between the cricothyroid muscle and the upper
pole of the gland allows a medial approach to the superior
pole vessels and early ligation of the vessels directly on
the thyroid capsule." The external branch of the superior
thyroid a,
Inferior
thyroid a.
Recurrent
laryngeal n.
Ligament
of Berry
FIGURE 7-6. Important anatomic considerations during thyroid

surgery. The recurrent laryngeal nerve is at greatest risk for injury
at three key locations: at the ligament of Berry, during ligation
of branches of the inferior thyroid artery, and at the thoracic inlet.
The external branch of the superior laryngeal nerve is at greatest
risk when dissecting the superior pole of the gland, whereas the
internal branch would theoretically be damaged at the level of the
thyrohyoid membrane,
laryngeal nerve is motor to the cricothyroid muscles, and the
internal branch is purely sensory, innervating the mucosal
lining of the supraglottic larynx. The external branch is intimately associated with the superior thyroid artery, and the
relationship of these two structures is extremely variable. In
up to 20% of normal individuals and in up to 56% of patients
with large goiters, it crosses the avascular space below the
tip of the superior pole of the thyroid.
Damage to the external branch leads to an inability to
reach high pitches or project the voice or to easy vocal
fatigue during prolonged speech. Although this may be
subtle in everyday conversation, such a disability is significant in patients whose voice is key to their career (e.g.,
singers). Damage to this nerve may be reduced by beginning
dissection in the avascular cricothyroid space and proceeding cephalad. Ligating and dividing the vessels near the
capsule reduces the chance of injury to the external branch
when it is adherent to or passing between the branches of the
superior thyroid artery, which occurs in approximately 15%
of cases. 37,38 Damage to the internal branch leads to anesthesia of the superior laryngeal mucosa and loss of the protective mechanism for foreign bodies in the larynx. The reported
incidence of permanent damage to the external branch of the
superior laryngeal nerve after surgery is approximately 1%
and of the recurrent laryngeal nerve is 0 to 4%.28
There are also many variations in the relationship of the
recurrent laryngeal nerve (inferior laryngeal nerve) to the
inferior thyroidal artery-it may pass superficial, deep to
(most common), or within the terminal branches of the
artery. Thus, it is extremely important to properly identify
the branches of the inferior thyroid artery in relation to the
end-arteries supplying the parathyroid glands and delineate
their relationship to the recurrent laryngeal nerve." Passing
superiorly and medially to enter the larynx along the posterior portion of the cricothyroid muscle, it is intimately
related to the capsule of the thyroid and may be invisible.
The most common regions where the recurrent laryngeal
nerve is at risk of injury are near the inferior thyroid artery,
near the ligament of Berry, and at the inferior pole of the
gland (see Fig. 7-6).
All of the intrinsic laryngeal muscles are supplied by
the recurrent laryngeal nerve-the posterior cricoarytenoid
muscle that abducts the vocal fold, the lateral cricoarytenoid
muscle that adducts the vocal fold, the thyroarytenoid that
relaxes the vocal fold, the transverse and oblique arytenoid
muscles that close the intercartilaginous portion of the rima
glottidis, and the vocalis muscles that relax the posterior
vocal ligament and tense the anterior vocal ligament.
Therefore, damage to the recurrent laryngeal nerve can lead
to significant pathology. Unilateral recurrent nerve damage
causes the vocal cord to be adducted toward the midline
causing hoarseness, temporary aphonia, and laryngospasm.
Bilateral damage may lead to respiratory distress, necessitating intubation." It is not unusual for the tubercle of
Zuckerkandl to extend laterally over this nerve."
Hypoparathyroidism after surgery may be temporary or
permanent. It is most frequent with bilateral thyroid lobectomies. Once the superior pole is mobilized, the inferior
pole vessels can be carefully mobilized with preservation of
the lower parathyroids, which often lie in or near the thyrothymic ligament. The parathyroids are also at risk when
dissecting cervical lymph nodes. The incidence of permanent hypoparathyroidism after thyroid surgery should be
less than 2%. Hematoma is a rare complication after thyroidectomy but has devastating consequences. An expanding hematoma can severely compromise the airway and
become a medical emergency."
The extent of thyroidectomy performed depends on
several factors. A total thyroidectomy is indicated in patients
with a coexisting malignancy such as thyroid cancer or
multiple endocrine neoplasia, in those with severe ophthalmopathy, or in patients unwilling to undergo reoperation or
radioactive iodine therapy. Subtotal thyroidectomy is useful
for most patients. Factors associated with hypothyroidism
after subtotal thyroidectomy include remnant size and
autoimmune activity. If a euthyroid patient is the goal, some
functioning thyroid tissue must be preserved. A 4- to 7-g
remnant is the most appropriate size. The classic report by
Mitchie illustrated that, in the range of 2 to 8 g, increasing
the remnant size by 1 g decreases the rate of postoperative
hypothyroidism by about 10%.38 Increasing the remnant
size above 109 does not, however, lead to further appreciable decreases in hypothyroidism but, rather, leads to more
recurrences. Remnants that are 8 g or larger decrease the
risk of hypothyroidism but increase the incidence of persistent or recurrent disease. Three-gram remnants are suggested
for children, a population that has a higher incidence of
disease recurrence.A"
Witte and colleagues performed a prospective, randomized trial to further examine the effects of total versus
subtotal thyroidectomy." Patients were randomized to
one of three interventions: bilateral subtotal thyroidectomy
with less than 4-g remnant, unilateral hemithyroidectomy
and contralateral subtotal thyroidectomy with less than
4-g remnant, and total thyroidectomy. Ophthalmopathy
improved in 72% of all patients. The TSH receptor antibody
level showed no difference in any group. Hypoparathyroidism
was most common in total thyroidectomy (28% vs. 12%,
P < 0.002). If the removal of thyroid tissue could reduce the
antigenic load, one would expect total thyroidectomy to be
more effective than subtotal thyroidectomy in preventing
eye disease. Unfortunately, total thyroidectomy may be
more likely than subtotal thyroidectomy to have operative
complications and postoperative hypothyroidism. Therefore,
given the lack of difference in postoperative outcome and
increased chance of hypoparathyroidism, total thyroidectomy is not advocated. The upper limit of 4-g total thyroid
remnant size was chosen in that study because of the higher
incidence of recurrent Graves' disease in patients with larger
thyroid remnants.
Abe and coworkers assessed the influence of subtotal
thyroidectomy compared to radioactive iodine therapy on
the outcome of Graves' ophthalmopathy.t? Over a 5-year
period, 287 cases were studied prospectively. All patients
were treated initially with antithyroid medications to maintain euthyroidism, and those having a high titer of TSH
receptor antibody were considered for thyroidectomy or
radioactive iodine. Among patients who did not have proptosis at baseline, the incidence of eye disease occurrence
was 7.1% in the surgically treated group, 9.2% in the medically treated group, and 11.9% in the radiation-treated
group. In patients treated with surgery, ophthalmopathy
progressed in 5.6% and was alleviated in 16.7% compared

with 10.4% and 3.0%, respectively, with radioactive iodine.
Eye disease improved in 75% of patients treated with
surgery, in 61.5% of patients treated medically, and in only
25% of patients treated with radioactive iodine. This study
further supports that surgery is a better treatment than
radioactive iodine in patients with Graves' disease with eye
involvement.
Gupta and associates examined the effect of 1311 therapy
on Graves' ophthalmopathy in 20 newly diagnosed patients
with Graves' hyperthyroidism.f Patients were followed
with ophthalmologic evaluations and magnetic resonance
imaging at baseline, 2, and 6 months and with examination
alone at 6 years. At baseline, 50% of patients showed
evidence of mild Graves' ophthalmopathy. There was no
significant risk for radioiodine-induced initiation or progression of mild Graves' ophthalmopathy. However, this study
did not assess patients with moderate to severe Graves'
ophthalmopathy in whom radioiodine may have a more
detrimental effect.
Recent clinical studies of thyroidectomy for Graves' disease may not reflect outcomes accurately because of small
sample size, especially when estimating ideal remnant size.
A meta-analysis was performed by Palit and colleagues
on studies in which patients underwent total or subtotal
thyroidectomy.f The purpose of the study was to determine
the overall efficacy and complication rates for both procedures in Graves' disease. There were 35 studies comprising
7241 patients with a median follow-up of 5.6 years. Overall,
persistent or recurrent hyperthyroidism occurred in 7.2%
of patients, and successful treatment of hyperthyroidism
occurred in 92%. Hypothyroidism occurred in all patients
receiving a total thyroidectomy. Subtotal thyroidectomy
produced a euthyroid state in more than 60% of cases, with
an 8% rate of persistent or recurrent hyperthyroidism. There
was no statistical difference in complication rates of the two
procedures, including permanent recurrent laryngeal nerve
injury or permanent hypoparathyroidism.
Andaker and coworkers examined the effects of two
types of subtotal thyroidectomy: (1) bilateral subtotal with
2 g of remnant tissue left on both sides and (2) the HartleyDunhill procedure with a total lobectomy and isthmectomy
on one side and a 4-g remnant on the other side, as
illustrated in Figure 7_7.43 They found no differences in
the results but preferred the Hartley-Dunhill procedure. A
bigger remnant on one side allows dissection not to be carried far enough laterally to encounter the recurrent laryngeal
nerves or parathyroid glands, thereby minimizing the risk of
complications. If disease were to recur, only one side of the
neck would need to be re-explored.
The operation is more difficult than operating on patients
with nontoxic goiter or thyroid neoplasms because of the
extensive vascularity of the gland in Graves' disease.
However, complication rates are still low. Patients should be
rendered euthyroid before thyroidectomy to prevent thyroid
storm. Preoperative iodine for patients with Graves' disease
is useful in reducing intraoperative bleeding, allowing better
visualization and preservation of the surrounding nerves,
vasculature, and parathyroid glands. 12
Thyroid storm is a medical emergency and presents as central nervous system agitation or depression, cardiovascular
B
FIGURE 7-7. Types of subtotal thyroidectomy. A, Bilateral subtotal,
with remnant tissue left on both sides. B, Hartley-Dunhill procedure,
with total lobectomy and isthmectomy on one side and remnant on
other side.
dysfunction, fever, and hyperthyroidism. It is precipitated by

surgery, trauma, infection, and administration of an iodine
load as occurs with amiodarone or after radioactive iodine
treatment. Signs and symptoms resemble severe thyrotoxicosis, with profound tachycardia, fever, and confusion.
Disorientation may occur from dehydration, vomiting,
diarrhea, and fever, and in extreme cases overt mania or
coma may occur as a late sequela."
The best management of thyroid storm is prophylaxis
by rendering patients euthyroid prior to surgery. It should
be treated immediately with hemodynamic support and
oxygen. Oral Lugol's solution (potassium iodide, SSKI),
5 drops three or four times daily, or intravenous iodinated
radiographic contrast agents such as sodium ipodate block
iodine uptake and the secretion of thyroid hormones
(see Fig. 7-3). Antithyroid therapy should be started at least
1 hour prior to SSKI to prevent eventual worsening of
hyperthyroidism. PTU blocks the peripheral conversion of
L-T4 to T 3, for rapid resolution of symptoms. Fever should
be controlled with nonaspirin compounds and rapid cooling
with ice or cooling blankets. Aspirin should be avoided
because it increases free thyroid hormone levels. ~ Blockers
in high doses, such as propranolol 480 mg/day in divided
doses or a 2- to 5-mg/hr infusion, control adrenergic manifestations. Calcium channel blockers are useful in patients
intolerant to ~ blockers. Glucocorticoids in stress doses help
stabilize the vascular bed, block peripheral conversion of T,
to T3 , and prevent adrenal exhaustion." Dialysis may be
necessary in some cases, such as thyroid storm induced by
amiodarone. Sedation may be necessary in cases of agitation
with hyperactivity."
Plummer's Disease (Toxic

Multinodular Adenomatous
Goiter)
Toxic multinodular goiter was first described in 1913 by
Dr. Henry Plummer (see Fig. 7-2), who believed that
practically all adenomatous goiters would eventually
become toxic given enough time. He noted that the average
interval from first detection of the goiter to subsequent
development of symptoms was 15 years.45.46
Pathogenesis
Nodular goiters (Fig. 7-8A) occur when hyperplasia of a small
subset of follicular cells with abnormal growth potential
occurs at multiple sites in the thyroid gland." In contrast

with Graves' disease, where the thyroid follicular cells are
hyperfunctional due to an external factor, IgG, which binds
to and stimulates the TSH receptor, autonomous thyroid
nodules develop hyperfunction through alterations in the
cell biology of the follicular cell, possibly via a somatic
mutation constitutively activating cAMP.47 The development of toxic multinodular goiter is a gradual process, as
Plummer noted that goiters were present an average of
17 years before becoming toxic. 45.46 Plummer's disease
occurs when one or more thyroid nodules become
autonomous, trap and organify more iodine, and secrete
more thyroid hormone independently of control by TSH
stimulation." In the remainder of the gland, the normal
feedback mechanism is operative. 11 As the adenomatous
areas grow, their contribution to thyroid secretion increases
and TSH secretion, therefore, decreases. This decrease in
TSH results in decreased activity of the extranodular tissue.
One or more follicles in a diffuse goiter has greater intrinsic
growth and functional capability than the others and
continues to grow and function despite declining TSH secretion, causing initially a nontoxic multinodular goiter and,
ultimately, a toxic multinodular goiter." There is a gradual
evolution of a sporadic diffuse goiter to a toxic one.
A multinodular goiter occurs due to recurrent episodes of
hyperplasia and involution and is considered toxic if it
FIGURE 7-8. Toxic multinodular goiter (Plummer's disease).

A, Patient with a multilobulated, asymmetrically enlarged thyroid
gland. B, The gland is inhomogeneous and coarsely nodular with
areas of fibrosis and cystic change. C, Focal regions of increased
99mTc uptake on radionuclide scan revealing multiple functioning
thyroid nodules with suppressed uptake in surrounding tissue.
(B from Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid.
In: Manual of Endocrine Surgery, 2nd ed. New York,
Springer-Verlag, 1984.)
induces thyrotoxicosis. These multinodular goiters produce

the most extreme enlargement of the thyroid, up to 2 kg,
and are multilobulated and asymmetrically enlarged.'? Most
"hot" or "autonomous" nodules have either TSH receptor
mutations (most often) or gsp (less common) mutations."
There is no correlation between morphology and function of
the nodules.'? In contrast to the thyroid in Graves' disease,
which is soft and resembles muscle, the thyroid in
Plummer's disease on cut section has irregular nodules
containing brown, gelatinous colloid.'? It most commonly
occurs in areas of endemic goiter."
Plummer's disease is more common than Graves' disease in
elderly patients. It accounts for 15% of cases of hyperthyroidism in nonendemic goiter regions.'? The hyperthyroidism may be caused by multiple hyperfunctioning nodules
or, less frequently, a single hyperfunctioning nodule. It is
differentiated from Graves' disease in that extrathyroidal
manifestations and thyroid autoantibodies are not present,20,44 Approximately 80% of patients with multinodular
goiter are chemically euthyroid at initial presentation.'?
Patients are more likely to have a prolonged course with
weight loss, depression, atrial fibrillation, and muscle wasting than with Graves' disease and thyrotoxicosis is often less
obvious and easily missed.P When it presents in the young,
thyrotoxicosis is seen as weight loss, anxiety, tremor, insomnia, and heat intolerance, similar to Graves' disease." Atrial
fibrillation in the setting of an enlarged goiter is often the
only finding in the elderly." Symptoms of dysphagia,
hoarseness, dyspnea, stridor, and cough may indicate a retrosternal or intrathoracic multinodular goiter.'? It is important to monitor T 3 carefully because these patients are more
likely to have T 3 toxicosis, with high serum free T 3 and
normal free T4 concentrations. This may be due to limited
ability of the nodules to oxidize iodide or may be due to
their preponderance in areas of relatively low iodine intake.
On examination, the goiter has one or more palpable
nodules. Compressive symptoms such as dysphagia or dyspnea may be present. Thyrotoxicosis may be exacerbated
following iodine-containing contrast media, leading to the
Jodbasedow phenomenon." Toxic multinodular goiter
accounts for less than 5% of cases of thyrotoxicosis in
iodine-sufficient areas but nearly half of cases in relatively
iodine-deficient areas. Many patients have subclinical
thyrotoxicosis with few, if any, symptoms and signs of thyrotoxicosis and normal thyroid hormone levels, but others
have overt thyrotoxicosis. The incidence of thyroid cancer
coexisting with multinodular goiter approaches 10%, similar to that in patients with a solitary thyroid nodule.
Coexistent cancer is more common with nonfunctioning
nodules and in men. 10
Diagnosis
Patients with toxic multinodular goiter present with increased
T 3 but a normal T 4 and free T4 index (T 3 thyrotoxicosis).
A thyroid scintiscan (Fig. 7-8B) classically reveals one or more
areas of increased uptake and suppressed areas in between.
The hot nodules are identified as areas concentrating
radioactive iodine to a greater degree than the surrounding

thyroid tissue. Technetium pertechnetate is preferred over
radioiodide scanning and is useful in the differentiation
of toxic nodular goiter from Graves' disease or to evaluate
compressive symptoms.'? However, iodine is the preferred
imaging agent for a toxic goiter with a substernal component due to its higher energy photons."
Autonomous function of the nodules can be demonstrated by administering suppressive doses of T 3, which does
not affect the function of the nodule but decreases the uptake
of the extranodular tissue. Administration of TSH increases
or restores the radionuclide uptake in the quiescent tissue."
In contrast with Graves' disease, administration of exogenous T 3 or T 4 does not suppress the function of autonomous
nodules because their secretory activity is, by definition,
independent of stimulation with pituitary TSH. In addition,
the secretions of the autonomous nodules suppress pituitary
TSH, causing variable reduction of the function of the
extrathyroidal tissue.
Therapy
Similar to treatment of Graves' disease, there are three major
classes of therapy: antithyroid medications, radioactive
iodine ablation, and subtotal or near-total thyroidectomy.
Antithyroid medications have not been widely accepted in
the treatment of Plummer's disease because they are less
effective and lifetime therapy would be necessary since,
unlike the usual spontaneous remission of Graves' disease,
the hyperthyroidism of toxic multinodular goiter continues
indeflnitely.Pr" Their use is recommended only as adjunctive
when needed for the initial control of hyperthyroidism. 10
As with Graves' disease, prior to surgery, patients should be
rendered euthyroid with p blockers and thionarnides."
Lugol's solution, in contrast with Graves' disease, should be
avoided in pretreatment of Plummer's disease because it
may significantly worsen thyrotoxicosis."
Radioactive iodine therapy is inferior to its role in
Graves' disease because the toxic multinodular goiter often
persists after therapy.r' The goal of radiation therapy in
Plummer's disease is destruction of autonomous tissue and
restoration of euthyroidism.t? Erickson and associates
evaluated medical records of 253 patients treated for toxic
multinodular goiter between 1975 and 1993. 50 Of those
treated with radioactive iodine, 20% required a second treatment, compared to zero patients treated with surgery.
A latency of several months occurs before treatment is
effective. In the report by Erickson and associates, half of
surgically treated patients had achieved success within
3 days for surgical treatment versus 3 months for radioactive
iodine treatment" Similar results were found in a report
by Jensen and colleagues, who evaluated the records of
446 patients treated between 1950 and 1974. 51
The dose of radioactive iodine is variable, and several
doses may be needed. Uptake is often relatively low, necessitating high doses to almost twice those given to Graves'
patients for successful treatment. Uptake is localized to the
autonomous toxic nodules and the remaining thyroid tissue
is suppressed.r' The thyroid tissue adjacent to the thyroid
nodule receives about 2000 rads, which is in the carcinogenic
range for the surrounding normal tissue, enough to induce
subsequent thyroid cancer. Radioactive iodine therapy in
large multinodular goiters extending substernally puts
patients at risk for radiation-induced thyroiditis that can,
although rare, cause acute thyroid enlargement and airway
compression."
A follow-up study assessed solitary autonomous thyroid
nodules treated with iodine.P In this study of 23 patients,
54% of nodules were still palpable, 9% had increased in
size, and 36% were hypothyroid. Goldstein and Hart concluded that iodine does not eradicate the nodule. The incidence of hypothyroidism in that study was not related to
gland size, thyroid function, or total dose of radiation.
Radioactive iodine is an effective therapy for hyperthyroidism caused by a single hot nodule, since the suppressed
normal extranodular tissue should be protected via its inability to concentrate radioactive iodine. It is also suitable for
patients with mild hyperthyroidism or those considered at
high risk for surgical management"
A recent study suggests that patients treated with high
doses of 1311, such as those needed for Plummer's disease,
may have xerostomia and xerophthalmia that persist for
several years after therapy.53 Seventy-nine patients were
treated between 1990 and 1995 with a dose ranging from
25 to 100 mCi. The numbers of patients who reported xerostomia 1, 2, and 3 years after therapy were 33%, 20%, and
15%, respectively. The most common symptoms were dry
mouth and abnormal taste; oral ulcers and sialadenitis were
also reported. One explanation is that salivary glands and
lacrimal tissue have sodium-iodide transporters. Induction
of an autoimmune lacrimal gland dysfunction, similar to that
in Sjogren's syndrome, may also occur.
For these reasons, surgery is the treatment of choice in
Plummer's disease, particularly if patients have obstructive
symptoms or if there is concern of carcinoma in the goiter.
Surgery is immediate and certain, there is a low recurrence
rate, and the patient is freed from the large goiter volume
and its associated cardiac manifestations. The surgical
approach varies depending on the type of nodule." For
solitary nodules, nodulectomy or thyroid lobectomy is the
treatment of choice because cancer is rare. For toxic multinodular goiter, lobectomy on one side and subtotal lobectomy
on the other side is recommended in most cases to prevent
the need for bilateral reoperation in cases of recurrence.>'
The approach and precautions are similar to the surgical
management of Graves' disease.
Conclusions
There is a key role for both the endocrinologist and
endocrine surgeon in the management of hyperthyroidism
due to Graves' and Plummer's diseases, and therapy
involves a team approach. The three basic treatment modalities-antithyroid therapy, radioactive iodine therapy, and
surgery-each have their advantages and disadvantages.
Surgery is an excellent therapy for both diseases because
there is no mortality, and there are few complications or
recurrences. It allows a rapid and consistent method of
achieving euthyroidism and avoids the long-term risks of
radioactive iodine. However, experience is important. The
Hartley-Dunhill procedure is the treatment of choice.
Patients should be rendered euthyroid before operation.

It can be technically difficult because of gland vascularity.
Radioactive iodine ablation should be considered for disease
recurrence after surgery.
Acknowledgments
The authors owe many thanks to the following individuals, without whom
preparation of this chapter would not have been possible:
Gloria Graham, MD, Associate Professor, Department of Dermatology,
Wake Forest University School of Medicine, Winston-Salem, North
Carolina, for her expert guidance on the dermatologic manifestations of
thyroid diseases
Kenneth Greer, MD, Associate Professor, Department of Dermatology,
University of Virginia Health Systems, Charlottesville, Virginia, for generously providing prize photographs of the systemic manifestations of
Graves' disease
Nat Watson, Jr, MD, Associate Professor, Radiological SciencesRadiology, Wake Forest University School of Medicine, for his indispensable
guidance on nuclear medicine and graciously providing radiologic images
Paige Clark, MD, Associate Professor, Radiological Sciences-Radiology,
Wake Forest University School of Medicine, for providing technetium 99m
radionuclide scans
Phyllis Easter, Secretarial Assistant, Department of Surgery, Wake Forest
University School of Medicine, for her endless devotion in assisting with
the preparation of this chapter
Andrea Hassell, Secretarial Assistant, Division of Surgery, Wake Forest
University School of Medicine, for her wonderful assistance
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5. Whitehead RW. Robert James Graves, physician, educator, scientist.
Circulation 1969;39:719.
6. Graves RJ. Clinical lectures. Lond Med Surg J 1835;7:516.
7. McConahey WM, Pady DS. Henry Stanley Plummer. Endocrinology
1991;129:2271.
8. Anonymous. Henry Stanley Plummer, MD, 1874-1937. Int Surg
1977;62:635.
9. Keys TE. Dr. Henry Stanley Plummer, 1874-1937. Minn Med
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10. Hurley DL, Gharib H. Evaluation and management of multinodular
goiter. Otolaryngol Clin North Am 1996;29:527.
II. Weiner JD. Plummer's disease: Localized thyroid autonomy.
J Endocrinol Invest 1987; 10:207.
12. Mittendorf EA, McHenry CR. Thyroidectomy for selected patients
with thyrotoxicosis. Arch Otolaryngol Head Neck Surg 2001;127:61.
13. Weetman AP. Graves' disease. N Engl J Med 2000;343: 1236.
14. McIver BM, Morris IC. The pathogenesis of Graves' disease.
15. Felz MW. Stein PP. The many "faces" of Graves' disease: I. Postgrad
Med 1999;106:57.
16. Carrasco N. Thyroid hormone synthesis. In: Braverman LE, Utiger RD
(eds), Werner and Inghar's The Thyroid. Philadelphia, Lippincott
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LJ, Iameson JL (eds), Endocrinology. Philadelphia, WB Saunders,
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18. Stevens A, Lowe I. Endocrine system. In: Human Histology, 2nd ed.
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19. Cotran R, Kumar S, Collins T: The endocrine system. In: Robbins
Pathologic Basis of Disease. Philadelphia, WB Saunders, 1999, p 1121.
20. AIsanea 0, Clark O. Treatment of Graves' disease: The advantages of
surgery. Endocrinol Metab Clin North Am 2000;29:321.
21. Felz MW, Stein PP. The many "faces" of Graves' disease: II. Postgrad
Med 1999;106:45.

22. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy.
N Engl J Med 1993;329:469.
23. Dabon-Almirante CLM, Surks MI. Clinical and laboratory diagnosis of
thyrotoxicosis. Endocrinol Metab Clin North Am 1998;27:25.
24. Alsanea 0, Clark OH. Benign disorders of the thyroid gland. World J
Surg. In press.
25. Olinoer D, Hesch D, Lagasse R, et al. The management of
hyperthyroidism due to Graves' disease in Europe in 1986: Results of
an international survey. Acta Endocrinol Suppl 1987;285:3.
26. Soloman B, Glinoer D, Lagasse R, et al. Current trends in the management of Graves' disease. J Endocrinol Metab 1990;70:1518.
27. Cooper DS. Antithyroid drugs for the treatment of hyperthyroidism
caused by Graves' disease. Endocrinol Metab Clin North Am
1998;27:225.
28. Udelsman R. Thyroid gland. In: Greenfield LJ, Mulholland MW,
Oldham KT, et al (OOs), Surgery: Scientific Principles and Practice.
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29. Tezelman S, Grossman RF, Siperstein AE, et al. Radioiodine-associated
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30. Wood LC, Ingbar SH. Hypothyroidism as a late sequelae in patients
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31. Bartalena L, Marocci C, Bogazzi F, et al. Relation between therapy for
hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J
Med 1998;338:73.
32. Franklyn JA, Maisonneuve P, Sheppard MC, et al. Mortality after the
treatment of hyperthyroidism with radioactive iodine. N Engl J Med
1998;338:712.
33. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip
fracture in white women. N Engl J Med 1995;332:767.
34. Bergman P, Auldist AW, Cameron F. Review of the outcome of
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35. Witte J, Goretzki PE, Roher HD. Surgery for Graves' disease in
childhood and adolescence. Exp Clin Endocrinol Diabetes 1997;105
(SuppI4):58.
36. Cheetham TD, Wraight P, Hughes lA, et al. Radioiodine treatment of
Graves' disease in young people. Hormone Res 1998;49:258.
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1998;22:714.
Gupta MK, Perl J, Beham R, et al. Effect of 13l-iodine therapy on the
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Thyroid 2001; 11:959.
Palit TK, Miller CC, Miltenburg DM. The efficacy of thyroidectomy
for Graves' disease: A meta-analysis. J Surg Res 2000;90:161.
Andaker L, Johansson K, Smeds S, et al. Surgery for hyperthyroidism:
Hemithyroidectomy plus contralateral resection or bilateral resection?
A prospective randomized study of postoperative complications and
long-term results. World J Surg 1992;16:765.
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Plummer HS. The clinical and pathological relationship of simple and
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multinodular goiter. Endocrinol Metabol Clin North Am 1988; 27:151.
Corvilain B, Dumont JE, Vassart G. Toxic adenoma and toxic multinodular goiter. In: Braverman LE, Utiger RD (eds), Werner and Inghar's
The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 564.
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Erickson D, Gharib H, Li H, et al. Treatment of patients with toxic
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Use and Abuse of

Thyroid-Stimulating Hormone
Suppressive Therapy in
Patients with Nodular Goiter
and Benign or Malignant
Thyroid Neoplasms
Niall O'Higgins, MCh Andrew P. Zbar, MB Susannah E. Harte, MD
Nodular disease of the thyroid gland is common. The

medical suppressive treatment of goiter relies heavily on the
ability to distinguish benign from malignant disease, largely
through the use of high-resolution thyroid ultrasonography
and fine-needle aspiration cytology of solitary and dominant
thyroid masses.
Thyroid nodules occur in approximately 0.8% of adult
men and in as many as 5% of adult women in iodine-replete
areas; there is a steady increase in detectable incidence
after 45 years of age. 1 The prevalence of thyroid nodules
is population dependent and is markedly higher in areas of
endemic iodine deficiency? Exposure to low-dose ionizing
radiation early in life increases the incidence of both benign
and malignant nodules.v' Thyroid cancer is the most
common endocrine malignancy, with an annual incidence of
10,000 new cases in the United States." Thyroid glands that
are normal by palpation frequently have one or more nodules demonstrable at autopsy, and as many as 4% of patients
at autopsy harbor microscopic, so-called occult, carcinomas
of the thyroid.v?
Ultrasonography in high-risk cases has produced a further
dilemma in management with the discovery of impalpable
nodules as small as 1 mm. The natural history and significance of these subclinical masses are unknown."
Nodular goiter, on the other hand, is probably the most
common endocrine "problem" in the world, and delineation
of the value of thyroid suppression therapy in patients at low
risk for carcinoma has significant implications for global
health care costs.v'? The use of thyroid-stimulating hormone
(TSH; thyrotropin) suppressive therapy after thyroidectomy
68
for benign and malignant disease remains controversial

largely because of the heterogeneity of disorders for which
it has been advocated and because the natural history of
malignant disease is long.
Unfortunately, few randomized, controlled clinical trials
exist for specific disorders such as solitary nodular disease,
multinodular goiter, and differentiated carcinoma to support
unequivocally the value of long-term suppressive therapy.
The failure to monitor adequately the suppression of TSH
in patients, to establish the compliance with suppression
medication, and to evaluate nodular size objectively have
also contributed to difficulties in interpreting the results in
patients receiving suppressive therapy. It is clear, however,
that despite an overall increase in the detectable incidence of
differentiated thyroid cancer over the last 30 years, there has
been a steady decrease in mortality, and this may be explained
by both earlier diagnosis and more widespread use of TSH
suppressive treatment. I1,12
The introduction of highly sensitive thyrotropin immunoenzymometric assays has led to a standardization of
TSH suppression and permitted closer monitoring of both
the efficacy of and problems with thyroxine (T4 ) treatment.
However, these assays, although sufficiently sensitive to
allow more accurate quantification of subnormal values, are
still not routinely used in certain parts of the United States."
Measurement of serum TSH permits precise levothyroxine
dosage in both replacement therapy and TSH suppressive
therapy when supraphysiologic doses of levothyroxine are
given to maintain TSH levels below normal. Evidence of
the delayed complications of overzealous and minimally
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - -
monitored T4 replacement in both overt and subclinical

hypothyroidism, most notably in inducing bone demineralization, altering serum lipid profiles, and contributing to cardiac
morbidity, particularly in elderly patients, has raised
concerns about the dangers of T4 therapy when used in the
long term in supraphysiologic doses to suppress TSH in both
benign and malignant disease." Decreased bone mineral
density and an accelerated rate of bone loss have been
reported in the literature in both pre- and postmenopausal
women who are receiving doses of levothyroxine sufficient
to produce subnormal serum TSH levels.P:" A better understanding of growth factors that affect normal thyrocyte function and that may explain TSH independence of autonomous
nodules, as well as a more selective individual approach to
suppressive therapy of tumors in patients deemed to have
a poor prognosis, will be of value in limiting the number
of patients receiving long-term suppression. Excessive
levothyroxine therapy, either intentional or inadvertent, is
not as innocuous as once was supposed, and studies have
shown that as many as 50% of patients treated with
levothyroxine therapy, who were clinically euthyroid, were
overtreated based on their serum TSH concentration. 19.20
Physiology and Pharmacology

Levothyroxine treatment relies on a negative feedback on
pituitary thyrotropin production. In euthyroid humans, 20%
of circulating 3,5,3'-triiodothyronine (T3) is produced in
the thyroid gland and 80% is formed extrathyroidally by
monodeiodination of Tz, largely in the liver and kidney under
the action of a selenium-dependent type I deiodinase, a
selenoprotein." The presence of selenocysteine renders the
conversion of T4 to T3 sensitive to dietary selenium levels.P
T 3 is the principal functioning thyroid hormone binding to a
nuclear receptor (T3 receptor) and regulating transcription of
thyroid hormone-responsive genes.P
Pituitary and cerebral cortical T 3 is, however, produced
predominantly by local deiodinase II action, and thus central
nervous system levels of active thyroid hormone depend on
both circulating T 3 and T4. Conversion of T4 to T 3 in these
tissues contributes equally to or even as much as 80% to
levels of nuclear bound T3. Therefore, although most peripheral tissues depend primarily on circulating T 3 levels, the
central nervous system is sensitive to both circulating T3and
T4.24-26 In thyrotropin suppression treatment, the aim is not
principally the physiologic replacement of T 4 (and T 3) as in
hypothyroidism (although this may well be necessary in
patients rendered hypothyroid after total or near-total thyroidectomy), but the use of T4 is to induce a particular level
of TSH suppression by supraphysiologic dosing without
rendering the patient clinically hyperthyroid. In this setting,
the benefit-risk equation for TSH suppression therapy must
be assessed for each patient on the basis of the likely hazards
of untreated thyroid disease in benign cases or the
likelihood of local or systemic recurrence in carcinoma as
balanced against the potential complications of prolonged T4
overdosage.
Precise feedback relations between circulating thyroid
hormones and pituitary TSH secretion, along with exact
measurement of serum TSH concentration, are essential in
69
the management of patients receiving suppressive levothyroxine therapy." Thyroid function and T 4 dosing can be
monitored most accurately by new and highly sensitive
immunometric assays for TSH that are sensitive for levels as
low as 0.01 mUlL. The normal circulating TSH concentration
is 0.5 to 3.5 mUlL, and the newer assays are at least 10 times
more sensitive than the original TSH radioimmunoassays.P:"
Basal TSH levels are directly proportional to the TSH
response to thyrotropin-releasing hormone (TRH) stimulation, rendering this test virtually obsolete." Debate regarding the use of suppressive therapy centers on the role ofTSH
as the principal growth-stimulating factor in benign and
malignant disease and on the degree of TSH suppression
needed.
Thyroid suppression therapy has a very long history. It
has been used as a treatment for goiter since the 12th century"
and historically has had better clinical success in diffuse as
opposed to nodular goiter." Its use was expanded by Crile
to the treatment of patients with thyroid cancer using thyroid
extract and desiccated animal thyroid.F Today, the principal
TSH suppression agents used are levothyroxine and liothyronine. Levothyroxine is one of the most commonly prescribed
medications; more than 15 million prescriptions are filled
annually in the United States alone.P It is synthetically produced and is identical to T 4 secreted by the thyroid. It is the
more frequently used agent and has a half-life of about 7 days.
It is a more standardized preparation than Iiothyronine, being
dose encoded by high-performance liquid chromatography,"
and its regular administration and compliance result in
more stable serum levels ofT3.35 Gastrointestinal absorption
is approximately 80%,36 with peak levels attained at between
2 and 4 hours, remaining above basal level for up to 6 hours.'?
Liothyronine has a more powerful peripheral and central
action and has a half-life of about 24 hours. It is used in
emergency situations and when cessation of therapy should
be limited, such as in the assessment of brittle-boned
patients with thyroid cancer undergoing follow-up thyroid
scanning. There is, however, considerable variation in T 4
dosing in patients during replacement and suppression"
Combination preparations such as liotrix (T 4 plus T 3) and
animal-derived products such as thyroid extract or thyroglobulin are rarely used today. These agents are less standardized and may lead to unwanted supraphysiologic rises
in T 3, with clinically troublesome side effects for relatively
low serum T 4 levels. The advantage of levothyroxine is a
more controlled T 3 conversion in extrathyroidal sites, which
is of value in fasting states and illness when peripheral
generation of T3 is normally decreased, partly on the basis
of variable absorption and bioavailability.v-"
Several states, such as pregnancy, malabsorption, and
caloric deprivation, and certain drugs alter levothyroxine
needs, and these are of particular importance when supraphysiologic dosing is required (Table 8-1). During pregnancy,
serum TSH levels increase largely as a result of an increase in
T 4-binding globulins, with a consequent fall in circulating free
T 4 and free T3. This is offset by a natural amelioration of such
diseases as chronic autoimmune thyroiditis but, in general, T4
requirements tend to be greater. 39.40 Certain drugs may block
T 4 absorption (e.g., cholestyramine." sucralfate," aluminum
hydroxide," ferrous sulfate"), increase nondeiodinative T 4
clearance by pathways not leading to T 3 generation, such as
sulfation and glucuronidation (e.g., rifampin.f carbamazepine." phenytoin [Dilantin]47), or inhibit the peripheral
conversion of T, to T3 (e.g., amiodarone'v" and essential selenium deficiency'"), Conversely, levothyroxine dosage needs to
be diminished in elderly persons in part because of a lower
general requirement." The serum TSH levels should be monitored more often in these circumstances, with adjustment in
levothyroxine dosage to maintain an appropriate therapeutic
serum TSH level in those receiving suppressive therapy.
Much of the concern about TSH suppressive therapy
and supraphysiologic levothyroxine dosing has arisen from
reports about the long-term complications of replacement
therapy for primary and subclinical hypothyroidism.52 Does
it matter whether thyrotropin levels are reduced below
0.1 mUlL in an otherwise healthy person with no clinical
features of hyperthyroidism?
There is increasing evidence that excessive levothyroxine
administration, resulting in suppressed serum TSH levels, is
associated with physiologic alterations in peripheral tissue.
In several studies, as many as 50% of patients requiring
levothyroxine replacement alone who were clinically judged
to be euthyroid were actually deemed overtreated on the
basis of TSH concentration.P Some evidence implicates
overtreatment with harmful effects, particularly in elderly
patients, most notably a sustained increase in nocturnal heart
rate, a reduction in systolic ejection time, an increase in
urinary sodium excretion, an increase in hepatic and muscular
enzyme activity as well as serum ferritin level, and
potentially hazardous alterations in blood lipid profile.
In short, these are the metabolic effects of subclinical
hyperthyroidism.54-56
It is becoming increasingly clear, however, that bone
resorption is a significant problem in prolonged levothyroxine
usage, as indicated by an increase in serum and urinary

calcium, a decrease in parathyroid hormone level, a rise in
urinary excretion of pyridinium cross-links (specific markers
for bone resorption), and a rise in serum osteocalcin
(a peripheral marker for bone formation). These effects are
not confined to postmenopausal women and are exaggerated
when suppressive as opposed to replacement therapy is
used,57-60 Premenopausal women treated with excess
levothyroxine show a predominantly cortical bone loss,
measured in wrist and hip, as opposed to trabecular bone
loss, measured in the spine. 15-17 Postmenopausal women, on
the other hand, show reductions in both cortical and trabecular bone mineral density.!"!? The risk is appreciably higher
in patients who are already at risk for osteoporosis (heavy
smokers and patients with inadequate calcium intake,
steroid dependence, alcoholism, or prior hyperthyroidism),
although this subclinical form of hyperthyroidism has not
been associated with a clinical rise in symptomatic fractures."
The development of osteopenia during TSH suppressive
therapy is of increased concern because up to 70% of
patients with nodular thyroid disease or thyroid cancer are
female and have been receiving supraphysiologic suppressive
treatment for decades.
Conversely, undertreated patients (hormone replacement
cases after thyroidectomy or iodine 131 therapy) suffer
from subclinical hypothyroidism. Debate exists about the
relative risks of this condition if left untreated, although
on a background of impaired left ventricular function, the
consequences are likely to be deleterious.f Overzealous
TSH suppressive therapy may have major effects on lipid
metabolism and cardiac function.
Thyroxine and Lipid

Metabolism
There is an overall increase in hyperlipidemia in overt
hypothyroidism, and there have been claims of higher
mortality from ischemic heart disease in undertreated
patients. 63.64 In subclinical hypothyroidism the biologic
efficacy of thyroid hormone replacement has been confirmed
with observed changes in serum lipoprotein concentration,
improvement in cognitive performance and indices of
cardiac function, and reduction of subjective symptoms. The
majority of patients show no fundamental changes in lipid
profile during levothyroxine treatment for TSH suppression.f
but occasional reports of deleterious changes in relative
high-density lipoprotein (HDL)-low-density lipoprotein
(LDL) cholesterol concentration have been documented.w'"
Franklyn and colleagues''? have argued that supraphysiologic
levothyroxine may be distinctly beneficial because of its
effects on LDL cholesterol in reducing the number of cardiac
events in those so treated, but it may not be possible to
extrapolate the effects on lipid profile from replacement
to suppressive therapy; this study was confined to women
and showed a beneficial effect only in patients older
than 35 years. The total cholesteroVHDL and LDL/HDL
ratios, which are correlated with increased cardiovascular
disease risk, have been shown to decrease with TSH suppressive therapy.70-72 That beneficial effects on lipids may be
achievable only by inducing subclinical hyperthyroidism

implies that the advantages of such deliberate treatment
must be offset in each case against the expected delayed
cardiac morbidity and the known consequences for bone
metabolism.P
Thyroxine and Ischemic

Heart Disease
Clearly, T4 replacement is necessary to prevent the development of overt hypothyroidism in postsurgical patients. There
is also an annual conversion rate of 3% from subclinical to
clinical hypothyroidism after 131 1 therapy and slightly less
than 1% per year after thyroidectomy. Post-thyroidectomy
hypothyroidism is more likely in elderly patients and in those
who have circulating thyroid auroantibodies.V"
Myocardial infarction and angina are both recognized
complications of levothyroxine therapy in hypothyroid
patients, even in dosages as small as 25 ug/day. Forty percent of patients with a history of angina are unable to tolerate fully suppressive doses of T4 . 76 Patients with known
cardiac disease who are older than 65 years should, therefore, be treated with caution.
Substantial increases in both heart rate and left ventricular
contractility tend to increase myocardial oxygen consumption,
although slight reductions in ventricular afterload may offset
this effect." It is likely that only a small percentage of
patients will experience new-onset angina with TSH suppressive therapy; about 33% of patients will have significant
improvement in preexisting angina, 50% will remain stable,
and about 16% will worsen. Cardiac function was observed
in a randomized l-year trial of levothyroxine therapy (mean
dose 71 ug/day) in patients with subclinical hypothyroidism.
There was no demonstrable difference in systolic time intervals between treatment and placebo groups. Abnormal
values however, were restored to normal in the five patients
with the most abnormal baseline values."? Other studies
have shown improved cardiac contractility of up to a 10%
mean increase in left ventricular ejection fraction with
maximal exertion by the patient.??
Levothyroxine in such patients should be initiated at
50 ug, with 25-/lg increments at 3-month intervals until TSH
is suppressed to one tenth of normal. In clinical practice, the
vigor with which TSH suppression is undertaken is related
more to the underlying condition for which it is prescribed
than to the likelihood of worsening preexisting cardiovascular
disease. Whether evidence exists for justification of suppressive therapy still remains unclear.
In suppressive therapy, there remains a need (despite
logistic difficulties in its conduct) for a longitudinal study to
assess the effects of levothyroxine on bone metabolism in
defined groups of patients. The theoretical advantages of a
possible reduction in morbidity from cardiac disease must
be balanced against the effects on a susceptible population
of levothyroxine-induced osteopenia.
However, there appears to be no difference in
overall morbidity between the patients with normal TSH
levels and those with mildly suppressed TSH levels."
Clearly, although lessons can be learned from patients
71
treated with replacement T4 for hypothyroidism, the metabolic and systemic effects may not be readily extrapolated to
patients in whom it is used for deliberate TSH suppression.
In patients treated with T4 suppression, clinical judgment
alone is insufficient to monitor cases."
Suppression and the Solitary
Thyroid Nodule
Studies in this area are confusing in that they include a
heterogeneous collection of goiters (such as nodules with
functional autonomy or cystic degeneration), are frequently
uncontrolled and poorly randomized, fail to establish compliance or consistent TSH suppression, and do not objectively
evaluate nodule size and treatment response. Inclusion in a
suppressive treatment arm relies on the absolute ability to
distinguish a benign from a malignant nodule largely on the
basis of accurate fine-needle aspiration cytology.82-86 TSH
suppressive therapy is of unproven benefit in the solitary
nodule. The reported incidence of reduction in thyroid
nodule size varies from 9% to 68%,87.88 although disappearance of the nodule is rare. Several controlled, randomized,
double-blind trials have failed to show significant reduction
in nodular size on the basis of volumetric calculation by
high-resolution ultrasonography, although most studies have
shown a marked reduction in contralateral thyroid lobar
volume during T4 therapy provided it is carried on for periods
exceeding 6 months. 78,87-91.93-99 In three prospective randomized studies involving a total of 167 patients with mean
treatment periods ranging from 6 months to 18 months,
levothyroxine was shown to be no more effective than
placebo in reducing nodule size. 93.97, l oo However, in other
studies, nodule size decreased more than 50% in 56% of
levothyroxine-treated patients with serum TSH suppression.f
Both these studies lacked placebo control groups for comparison but still recorded a decrease in nodule size during
levothyroxine therapy greater than the natural 15% to 30%
observed spontaneous regression rate (Table 8-2).
Further, some of these studies have confirmed that there
is a natural tendency for up to one third of solitary nodules
to regress spontaneously during follow-up beyond 1 year. In
some, this is explained by hormonally insensitive events such
as cystic degeneration, resorption of colloid, or necrosis of
follicular epithelia, and in others, it is explained by regression
of surrounding normal, hormonally responsive thyroid.
Treatment of the solitary nodule medically in this way
should be undertaken with caution; it must be remembered
that fine-needle aspiration cytology has a false-negative
rate of 5% and that up to 15% of solitary nodules continue
to grow with adequate TSH suppressive treatment.101.I02
Studies suggest that the response of a nodule to T4 is independent of age, duration of nodule, pretreatment nodular size,
TRH-TSH amplitudes, initial technetium uptake, and
pretreatment thyroglobulin level. The large or complex
nodule should not be medically treated because it is less
likely on average to respond and because cytologic sampling
error is always possible.
Recommendations for the Use

of Thyroxine in the Solitary
Thyroid Nodule
Given that the expected nodule response rate slightly
exceeds the reported natural regression rate, suppression
therapy may be considered to be of slight benefit. If it is to
be used (perhaps in the context of an institutional trial), it
must be for the proven solitary nodule that has unequivocally
negativecytology,is homogeneously solid on ultrasonography,
and has normal or reduced uptake on technetium 99m
pertechnetate scanning (Fig. 8-1).
These nodules ideally should be associated with a normal
thyroid profile and negative thyroglobulin and thyroid
peroxidase autoantibody status. Patients with a large nodule,
particularly if it possesses echogenic heterogeneity or has
been present for longer than 2 years, or in whom there is a
history of head and neck irradiation, should not be treated in
this manner. One may aim for a TSH suppression level of
0.05 to 0.10 mUlL in premenopausal patients without cardiac
risk factors and for a level of 0.1 to 0.3 mUlL in postmenopausal women, particularly those with a known history
of osteoporosis, and in men older than 65 years with a
recognized cardiac history.
Treatment is continued for 6 months to 1 year with
clinical and ultrasonographically calculated nodular volume
based on anteroposterior length and width, assuming the
nodule to be a spherical ellipsoid. This is complemented by
assessment of the contralateral thyroid lobar volume to
gauge response to suppression.l'" Ultrasonography is essential in the follow-up of these patients because of its greater
accuracy in nodule assessment and because it eliminates
patients' and clinicians' bias.l'" If the nodule regresses,
treatment may be stopped after 6 to 12 months of therapy
and reinstituted if it remains stable or gradually enlarges
after 6 months of therapy cessation. If the nodule actually
enlarges with compliant therapy, repeated fine-needle aspiration cytology or thyroidectomy is mandatory to exclude
Clinical
solitary nodule
~High-resolution
Ultrasonography
confirjmed solitary-
i:
TSH
Thyroglobulin
autoantibodies
/FNA
Negative
TSH suppression
>
Premenopausal
----.
Postmenopausal
<60 years of age
Prior cardiac disease
TSH = 0.05-0.1 mUll
TSH
<,
= 0.1-0.3 mUll
Follow-up sensitive
TSH assay
Contralateral thyroid volume and nodule volume assessed
by ultrasonography
Serum thyroglobulin measurement
Nodule enlarges
FNA repeat
FIGURE 8-1. An algorithm for the use of thyroxine (T4 ) in a solitary

thyroid nodule. FNA =fine-needle aspiration; T 3 =triiodothyronine;
TSH = thyroid-stimulating hormone.
the possibility of malignant degeneration. This phenomenon,

however, although well recognized, is relatively infrequent.
In treating such patients with thyroid hormone, more
questions are raised than are answered. Most notably, what
are the desired endpoints in the treatment of patients with a
benign thyroid nodule? Is mere regression acceptable, or is
complete nodular disappearance required? What is the
mechanism behind spontaneous nodule regression? Is the
treatment cost-effective? Is there a nodule limiting size?
Finally, how does TSH suppressive therapy work if it
works at all?
Suppressive Therapy and
Nodular Goiter
Apart from the solitary nodule and thyroid carcinoma, TSH
suppression therapy may be used for a range of thyroid
diseases, most notably nontoxic multinodular goiter, diffuse
goiter (including chronic autoimmune thyroiditis), functionally autonomous nodules, neonatal goiter, and postpartum
goiter. It also has specific use in the patient who has a known
history of irradiation to the thyroid area and in the prevention
of recurrent nodular disease after partial thyroidectomy.
Nontoxic Multinodular Goiter:

Theories of Pathogenesis and
Thyrocyte Regulation
The pathogenesis and hence the treatment of multinodular
goiter are debatable. If a goiter were simply induced by
uninhibited TSH stimulation, one might expect it to be a
diffuse goiter. Early studies by Taylor suggested a "natural"
progression from diffuse toward multinodular.l'" Indeed,
TSH levels are in general not elevated in sporadic goiters.
Studer and Ramelli 105 suggested that newly generated follicles involve thyrocyte clones that may retain the ability to
concentrate iodine (hot nodules) or that have lost that ability
(cold nodules). This phenomenon, coupled with an impairment of blood supply during growth, may lead to areas of
fibrotic regression and dystrophic calcification indicative of
a degenerate multinodular goiter. 105
Changes in follicular function are probably due to environmental factors, such as the local iodine supply.l'" failing
blood supply to an active goiter.I'" and the relative aging of
cellular components, which has been shown in the aging
mouse thyroid as a transformation of normally functioning
follicles into irreversibly cold follicles. 108
Genetically separable thyrocyte clones probably also
generate nodular heterogeneity. This in itself does not
explain all the features of a multinodular goiter, in particular
the natural tendency toward autonomous nodule formation
or the variability of metabolic function such as TSH-inducible
adenosine monophosphate activity within the goiter. I 09 JIO
Moreover, multinodular goiters have unique growth
patterns with variable iodine turnover and demonstrate
growth that is discordant with radioscintigraphic function,
which separates their behavior from that of other types
73
of goiter. The cells from human multinodular goiters in tissue

culture have variable TSH dependence, with cells with
equivalent growth potential clustering near one another.
Presumably, the clones with inherent growth potential
respond to strong extrathyroidal stimuli (such as TSH or
epidermal growth factor) and differ from the clones with
low mitotic activity that respond to weak stimuli (such as
endemic iodine fluctuation or the activity of local goitrogens)
over very prolonged periods.
Further evidence, although controversial, has implicated
a putative set of thyroid growth-stimulating immunoglobulins
(TSIs) in multinodular goiter development, which are
thought to act independently of the TSH but through the
TSH receptor. 101,I I J- 113 We believe most evidence suggests
that TSIs work through the TSH receptor.The newly generated
follicles are then integrated into the growing goiter by cellular adherence to the dominant follicle, by papillary protrusion
into the follicular lumen, and by the formation of daughter
follicles. All of these processes incorporate cellular groups
with widely differing iodinating capacities and TSH
responsiveness 114 but with individual follicular similarity
in terms of ultrastructure, metabolic activity, and receptor
expression.l'<!"
It is believed that in addition to differences in follicular
activity, variable interregional DNA concentration per unit
volume of goiter weight may reflect variability in stromal
content. Factors affecting the elastic connective tissue framework of the goiter may alter the capacity of the developing
capillary network to keep pace with the metabolic requirements of expanding follicular cohorts. This effect ultimately
changes the shape of the enlarging goiter as well as its overall
function and level of degeneracy.U":' 18
Suppressive Treatment of
the Multinodular Goiter
Sporadic, nontoxic multinodular goiters are pathologically
diverse with cystic, colloid, hemorrhagic, fibrotic, and calcific
components. Their natural history is characterized by unpredictable periods of stability in size and function and occasionally by rather sudden enlargement.
There is considerable debate about the efficacy of
levothyroxine suppressive treatment of the nonendemic,
nontoxic multinodular goiter, and the results are even less
satisfying in many cases than those for solitary nodular
disease because of the greater amount of pathologic thyroid
tissue that is likely to be hormonally insensitive, the variability of TSH dependence given the likelihood of multiple
other thyroid growth factors, and the difficulty in objectively
evaluating the response of dominant nodules. This should be
coupled with the fact that up to 10% of dominant masses
within multinodular goiters may actually spontaneously
regress during follow-up.'!" A randomized study of
115 patients showed a total reduction in thyroid volume of
more than 13% (by ultrasonographic measurement) in 58%
of patients receiving TSH suppressive doses of levothyroxine
for an average of 9 months. The thyroid volume was also
shown to increase on cessation of levothyroxine therapy. I 19
Evidence for the routine use of suppressive levothyroxine

in multinodular goiter is varied. Two controlled clinical
trials to assess this question demonstrated benefit in reduction
in overall goiter size in about 50% of cases (Table 8_3).119.120
Accurate and consistent assessment of dominant nodules
within an abnormal gland, along with a concern that malignancy may coexist in a small percentage of cases, makes the
routine use of TSH suppressive therapy for this condition
inappropriate except in patients for whom surgery is
contraindicated.98,121
No clear response association exists with patient's age,
duration of goiter, family history of thyroid disease, pretreatment thyroid volume, or preliminary radioactive iodine
uptake.99.122-125 The mechanism in the patients who respond
is unknown, but T4 has been shown to influence thyrocyte
growth synergistically in the presence of other growthstimulating factors.!" Many questions remain concerning
this type of treatment. What constitutes response? Is complete regres-sion necessary, and is uniform regression ever
possible? Considering that a significant proportion of
patients are never submitted for surgery, what is the true
underlying incidence of carcinoma?
point in continuing treatment if an effect is not observed

within this time.
It should also be noted that after surgery for nodular
nontoxic goiter, only 15% of patients experience recurrence;
hence, potentially lifelong treatment is unnecessary in 85%.
One randomized trial comparing levothyroxine therapy
versus no therapy after thyroid lobectomy showed no difference in thyroid size after a follow-up of 1 year when the thyroid remnant size was recorded ultrasonographically.F'
Several large retrospective studies, including a total of
656 patients and mean follow-up of 5 to 8 years, showed that
postoperative levothyroxine therapy did not decrease the
frequency of goiter recurrence, which on average was 10%
at 8 years. 128 In many patients older than 50 years, dominant
nodules never change in size after discovery. Because of the
logistic difficulty in assessing response to suppressive treatment in multinodular goiter, we do not recommend its use,
although other clinicians do.
Recommendations for the Use

of Thyroxine in the Nontoxic
Multinodular Goiter
Diffuse nontoxic goiter can be sporadic or endemic. Iodine

treatment is clearly the treatment of choice over T4 therapy
in endemic cases, as shown by Hintze and colleagues!" in a
1989 multicenter trial.
The most common cause of adult diffuse nontoxic goiter
in nonendemic areas is chronic autoimmune thyroiditis.
Both microsomal cytoplasmic and thyroid peroxidase
autoantibodies are evident in 10.3% of adult women and
2.7% of adult men in clinical surveys of sporadic goiter.
Conversely, about one third of patients with detectable antibodies have clinical goiters. 1
Chronic autoimmune thyroiditis is also the most common
cause of sporadic childhood and adolescent goiter, of which
there is a spectrum of illness ranging from focal thyroiditis to
Hashimoto's thyroiditis. Such patients typically have high
titers of antimicrosomal antibodies and are often hypothyroid,
either clinically or subclinically. Levothyroxine is given to
both euthyroid and hypothyroid patients with chronic goitrous
thyroiditis of this type and has been shown to be associated
with a mean reduction in palpable thyroid volume.!"
This type of treatment must be balanced against a small
chance of spontaneous regression of active Hashimoto's
In practical terms, if TSH suppressive treatment is to be tried,

it would be logical to give enough levothyroxine to reduce
the TSH consistently to 0.5 mUlL. If the goiter decreases in
overall size or remains static (both clinically and by ultrasonography), treatment may be continued indefinitely in a
low dose (perhaps in patients younger than 60 years), with
periodic monitoring of TSH and thyroglobulin levels to
assess the patient for the likelihood of functional anatomy.
If the goiter clinically enlarges, further evaluation for
underlying carcinoma is necessary. If the serum TSH
concentration is low in the clinically euthyroid case to begin
with, levothyroxine is contraindicated because of the likelihood of subclinical incipient functional autonomy. The
natural history of these glands is toward hyperthyroidism
over a 15- to 25-year period of goiter follow-up.
Goiters that respond usually do so within a period of
6 months of commencement of therapy, so there is little
Thyroxine Suppressive Therapy

and Diffuse Goiter
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - - 75
disease in a subgroup of patients with detectable thyrotropinblocking antibodies, which inhibit the peripheral action
of TSH.13J.l32
The natural history of autoimmune thyroiditis, however,
is in general toward inexorable hypothyroidism at a rate
of roughly 5% per year, especially in patients with very
elevated antibody titers.73.133134 Few trials of levothyroxine
suppressive therapy in diffuse goiter have been conducted
(Table 8_4).135-137 These suggest a reasonable response rate
for adequately suppressive therapy over a 3- to 6-month
period, although the level of TSH suppression required
is not known. Clearly, if the gland is unresponsive after
6 months of compliant therapy, levothyroxine should usually
be withdrawn. One study observed that a return to normal
of the serum TSH resulted in a mean decrease of 32% in
thyroid volume, with almost 50% attaining normal thyroid
size after 2 years of therapy.138
Suppression and the
Post-Thyroidectomy Patient
Levothyroxine may prevent clinical hypothyroidism after
bilateral or subtotal thyroidectomy and occasionally after
unilateral Iobectomy.P? In three randomized, controlled
trials comparing levothyroxine with placebo, there was
no demonstrable difference in nodular recurrence after a
range of thyroid operations in the TSH-suppressed
patients.14o-142 Miccoli and colleagues'< demonstrated an
advantage for suppressive as opposed to substitutive T4
dosing on echographic follow-up at 3 years, but this was
in an area of endemic goiter in northern Italy, where the
rate of nodular recurrence postoperatively is normally
relatively high. The particularly high early recurrence of
echographically demonstrable postoperative recurrence
after thyroidectomy in the latter article (78% on substitutive
T4 therapy) may not be indicative of the general Western
experience.
Large, uncontrolled, retrospective series, however, with
prolonged follow-up over periods ranging from 5 to 8 years,
have failed to demonstrate an advantage for patients treated
with levothyroxine after surgery.122,143,144 The role of T4 therapy in patients with normal serum TSH concentration who
have had thyroid lobectomy only is debatable. Its use has
mainly been advocated in cases in which preoperative autoantibody titers are high and postoperative hypothyroidism
is anticipated rather than for prevention of recurrence,
although antibody titers do not clearly discriminate in

untreated cases for the development of either overt or
subclinical hypothyroidism. 145
After subtotal thyroidectomy, it is clearly recognized
that with extended follow-up moderate hypothyroidism
develops in about 20% of cases. This depends largely on
the size of the thyroid remnant.!" the degree of lymphocytic infiltration of the gland,"? the preoperative level,
if present, of complement-fixing thyroid antibody.l" and
the original condition for which thyroidectomy was
performed. 149
There is evidenceI43.150-154 from Westermark and colleagues that T4 dosage needs to be higher in the patients
treated with subtotal thyroidectomy than in those treated
by unilateral lobectomy to reduce TRH stimulation of TSH
secretion, implying that pituitary TRH responsiveness needs
a longer period of recovery after supraphysiologic T4dosing
than basal TSH production.l" Because of the variability of
goiter growth, both de novo and postoperatively, and the fact
that a certain percentage of patients exhibit flat TRH-TSH
responsiveness preoperatively, other mechanisms apart from
the TSH receptor must be invoked, most notably the presence of TSIs. Because of the expression by thyroid tissue of
human leukocyte antigen DR, it has been postulated that
a secondary autoimmune process may be induced as part
of the goitrous phenomenon.l"
On balance, there is little evidence for the routine use
of suppressive as opposed to replacement therapy after
lobectomy or subtotal thyroidectomy. This must be weighed
against the known hazards of secondary surgery to the thyroid in terms of recurrent laryngeal nerve injury and serious
sustained hypoparathyroidism should reoperation be needed
for recurrent goiter,157,158
Suppression and Miscellaneous
Benign Goiters
Levothyroxine has been advocated for a variety of benign
goitrous conditions, most notably in the follow-up of patients
who have experienced irradiation to the head and neck in
some cases of functionally autonomous nodules and in postpartum and neonatal goiter.
Irradiation during childhood or adolescence for a range
of benign conditions (tinea capitis, tonsillar and thymic
enlargement, acne vulgaris, or head and neck vascular malformations) has been associated with a substantial increase
in both benign and malignant nodules of the thyroid as well
as an increase in parathyroid adenomas.159-162
Controversy exists in regard to the optimal management
of patients both with and without palpable thyroid nodules
who have been exposed to low-dose irradiation to the thyroid
area. Evidence suggests that thyroid suppressive therapy
is as likely to be successful in this group of patients as in
those with sporadic multinodular goiter, but the main
difficulty seems to be in the delineation of underlying
malignancy.95.163.164 Shimaoka and coworkers'P were the first
to conduct a double-blind study of suppressive treatment using
T3, desiccated thyroid, or both, in irradiated patients with
measurable thyroid nodules. In 1500 patients exposed with
a 34% incidence of nodules and an average interval between
radiation exposure and nodule detection of 27 years, TSH
suppression of nodules was possible in 18% of patients over
6 months of therapy. This approach was uncontrolled, however, and made no attempt to assess the efficacy of suppression
in a heterogeneous group of patients.
Clearly, there is a risk of underlying malignancy in this
group on the order of 5% of those without clinical nodules
and 40% of those with clinical nodules. Thus, and in the
presence of a clinical nodule, because of this possibility
as well as the potential for cytologic sampling error, total
thyroidectomy is generally advocated. A question remains,
however, regarding the role of suppressive therapy in
patients without either clinical or subclinical nodules. The
rationale for treating the latter group of patients is that an
intact pituitary thyroid axis is needed for the production of
thyroid tumors that are likely to be TSH sensitive, as has
been demonstrated in rats by the protective effect of
hypophysectomy on the irradiated thyroid.165.166
In a study by Fogelfeld and associates.P' 511 patients
exposed were monitored for up to 40 years after irradiation
following initial surgery for benign thyroid nodules, with an
overall nodular recurrence rate of 19.5%. Thyroid hormone
supplementation reduced the incidence of recurrent nodules
from 35.8% in the untreated group to 8.4% in the treated
group. TSH suppressive therapy, however, had no effect on
the rate of underlying malignancy, which was 19.2%.151 The
implication is that recurrent nodules of this type, which
develop during TSH suppressive therapy, are much more
likely to be malignant. Such a study should, however, be
viewed with caution because of its lack of randomization, its
failure to substantiate effective TSH suppression in many
cases, and the nonstandardization of T4 dosage.
Given that there is an increased incidence of hypothyroidism and thyroid nodules in children exposed to head and
neck irradiation for such conditions as Hodgkin's disease, neuroblastoma, Wilms' tumor, and leukemia, as well as in adults
irradiated for breast cancer and lymphoma, the role of TSH
suppressive therapy in an expanding population of patients
needs to be defined.167.168 The question remains whether
patients who have been exposed should have suppressive treatment in the absence of nodules as well as the correct management of ultrasonographically demonstrable impalpable
nodules. It should also be recognized that the rate of falsenegative fine-needle aspiration cytology is significantly higher
in the irradiated gland. 169 What is also unknown is the role of
TSH suppressive treatment during the time of neck irradiation.
Autonomously functioning nodules represent about 5%

of all solitary or dominant nodules in the thyroid gland.
Toxicity is more a feature of nodule size, with nodules
smaller than 2.5 em in diameter rarely causing clinical
hyperactivity. Young patients with functionally autonomous
nodules with low TSH levels are more likely to experience
clinical toxicity and have a slightly higher incidence of
malignancy. 170
Functional status of such nodules with low TSH concentration is best assessed by both technetium 99m and iodine
123 scanning because the discordant nodule (hot on 99mTc,
cold on 1231) is more likely to represent a carcinoma.
Although the growth and function of many of these nodules
appear to be TSH independent, the true incidence of hyperthyroidism over prolonged follow-up is only about 10%.171
These nodules may also be characterized by a relative
increase in the T 3ff4 ratio (T 3 toxicosis). Furthermore, there
is a moderate rate of spontaneous regression of these
autonomous nodules with time, and their development
may represent one part of the spectrum of multinodular
goiter. 104
Because autonomous thyroid nodules are uncommon and
because patients with these nodules are treated with either
radioiodine or surgery, their true natural history remains
unknown. The demonstration of a responsive TSH receptor
mechanism in these cases, as evidenced by an intact TSH
adenylate cyclase system in tissue culture.F? and the fact
that exogenous T4 has been shown to reduce the radioiodine
uptake and size in certain nodulesI73.174 imply that there is at
best only partial autonomy from TSH influence. These more
"dependent" cases are on average smaller with preserved
and unsuppressed surrounding parenchyma and over time
tend to involute or undergo degenerative change. However,
the role of TSH suppression in such cases is quite unclear
because there is a risk of rendering patients subclinically
hyperthyroid if treatment is based merely on the presence
of a low preliminary TSH concentration or if the nodule
inadvertently undergoes spontaneous degeneration during
suppressive treatment.!" It is likely that these so-called
autonomous nodules represent a heterogeneous mix of thyroid tissues, with some follicles predisposed toward hyperfunction, autonomy, and TSH independence and others
toward autonomous growth or function, or both, exhibiting
some initial T 4 responsiveness but later undergoing degeneration and hypofunction. Because these features are essentially unpredictable, TSH suppressive therapy is usually not
recommended.
T 4 may also be of value in the treatment of transient
goitrous hypothyroidism in infants exposed to the transplacental passage of thyrotropin receptor antibodies in maternal
chronic autoimmune thyroiditis. Changes in T 4-binding
globulins and relative subclinical reductions in circulating
free T4 and T3 during pregnancy are not compensated for by
increased thyroid hormone secretion by the gland because
of lack of functioning thyroid tissue. Such patients, with
Hashimoto's disease during pregnancy, tend to suffer from
repeated episodes of transient postpartum thyroid dysfunction, which may require suppressive treatment in its own right
and ultimately replacement therapy because of the small risk
of clinical hypothyroidism in multiparous cases.l?"
TSH Suppressive Therapy in Patients with Nodular Goiter and Benign or Malignant Thyroid Neoplasms - - 77
Suppression and Thyroid
Cancer
Controversy exists in thyroid cancer management about the
extent of surgery, the use of 131 1 ablation therapy, the place
of thyroglobulin assay in follow-up, and the role and level of
TSH suppressant treatment. Further, there is debate about
the degree of TSH dependence of differentiated thyroid carcinomas and the importance of other thyroid growth factors.
Thyroid Growth Factors and

Thyroid Carcinoma
Thyroid tumors vary markedly in prognosis, and the natural
history of differentiated tumors is long. The control of thyroid
cell growth is complex and is influenced by many hormones
and growth factors operating through distinctly different cell
signal transduction systems. Classically, TSH is considered the
major thyroid growth hormone, and, although there is no dispute about its role in stimulating thyroid gland function, its
effects on thyroid growth and particularly abnormal growth are
in question. TSH stimulates "differentiated" thyroid functions,
most notably iodine uptake and organification as well as thyroglobulin synthesis, by activating a membrane-bound adenylate cyclase system and increasing intracellular cyclic
adenosine monophosphate; this results in cytoplasmic protein
phosphorylation and increased nuclear transcription. I?? In general, follicular thyroid neoplasms have enhanced adenylate
cyclase activity in response to TSH stimulation and tend to
have an inverse correlation with the state of aggressiveness of
the tumor.!" It is also evident that TSH functions through the
phosphatidyl inositol phosphokinase C-intracellular calcium
system because it is known that high dietary calcium, particularly in areas of endemic iodine deficiency, promotes goiter
formation. I?9,180 Elevated levels of TSH promote thyroid
tumors in rats, and these tumors can be prevented by treating
with thyroid hormone (TSH suppressionj.l'"
TSH is generally considered a relatively weak factor for
human thyroid cell growth in tissue culture. 182 The cells tend
to be very heterogeneous in their response, 183 and transplanted
human thyroid tumors ultimately demonstrate TSH independence in vitro. 165 The fact remains that thyroid tumor
tissue has demonstrable TSH receptor sites, although the
importance of these sites clinically is another matter.P'
The list of known thyroid growth factors is quite long
(Table 8-5) and includes 'I'Sls, epidermal growth factor,
epidermal growth factor receptor (EGFr), insulin-like growth
factors, and prostaglandin E2. Inhibitors of thyroid growth in
vitro include transforming growth factor ~, somatostatin,
and vitamin A 185-187
EGF functions as a powerful thyroid growth stimulant,
possibly more active than TSH and perhaps acting synergistically with TSH, promoting cell growth but inhibiting cellular
differentiated functions.188.189 Further, EGFr expression has
been shown to be associated with reduced disease-free survival
in differentiated tumors. 190.J91
Thyroid cell proliferation is further affected by growthpromoting oncogenes and inhibited by tumor suppressor genes.
Their protein products presumably replace known specific

growth regulators, growth factor receptors, and signal
transducers. TSIs and fibroblast growth factor function as
circulating growth factors. The protooncogene c-erb B2
(HER-2/neu) is a plasma membrane receptor and the ras
oncogene a signal transducer for thyroid growth. 192 c-erb B2
is a surface growth receptor that has been shown to be frequently overexpressed in a proportion of breast and ovarian
cancers and to correlate with poor prognosis. 193
Oncogenes, whether natural (protooncogenes) or viral,
encode protein products, which act in either the nucleus or
cytoplasm. Both ras and c-myc oncogenes are overexpressed
in about 60% of differentiated thyroid neoplasms; prognosis
is worse in the cases in which c-myc is heavily encoded. 194,195
Frauman, Lemoine, Wyllie, and Clarkl96-2oo and their colleagues have discussed the subject in great depth. Both the
tumor suppressor gene p53, which has been heavily implicated in the tumorigenesis of colorectal carcinoma, and
platelet-derived growth factor have been found to be overexpressed in anaplastic tumors. 201,202 It is evident then that
TSH suppression in thyroid cancer is likely to have only a
partial role in tumor control, perhaps similar to that of tamoxifen therapy in women with breast cancer.
Thyroid-Stimulating Hormone Suppressive

Therapy in Thyroid Cancer
TSH suppressive therapy was first advocated for thyroid
carcinoma by Dunhill in 1937 203 and was used extensively
in the treatment of disseminated differentiated thyroid
cancer by Crile. 204 The rationale for its use has subsequently
been the demonstration of TSH receptors in malignant tissue
from differentiated thyroid cancers of follicular cell origin
and the noted increase in adenylate cyclase activity in
response to TSH stimulation in vitro. 205,2o6 Thyroid tumors,
however, that already have increased basal TSH adenylate
cyclase activity are unlikely to be particularly responsive to
TSH suppression.P?
It is clear that 80% of patients with papillary thyroid
cancer and many cases of follicular thyroid cancer do well
almost regardless of how they are treated.208.209 TSH suppression has been shown to date to have no proven benefit in
patients with medullary thyroid carcinoma.
The use of TSH suppressive therapy has to show survival
advantage over prolonged follow-up for the patients deemed
to have poor prognoses and, in view of the potential side
effects of long-term suppressive treatment, it seems sensible
to individualize its use on the basis of expected likelihood
of local or systemic recurrence. Factors associated with a
particularly poor prognosis in differentiated thyroid cancer
include poor 1311 uptake (such as Htirthle cell variantsj.i'?
decreased adenylate cyclase response to TSH,178 DNA
aneuploidy,"! the expression of EGFr,191 and the extent of initial surgical treatment. 212 This has been complemented by the
AGES classification devised by Hay and colleagues to classify
patients as high risk and low risk on the basis of age, histologic
grade, extent of primary tumor, and primary size.213 Notably,
patients older than 40 years at diagnosis with tumors larger
than 4 em with marked DNA aneuploidy have been shown to
have markedly worse disease-free and overall survival.i"
In this sense, it is advocated that TSH suppressive therapy
should be adjusted to individual prognostic factors to avoid
unnecessary radical surgery, radiation exposure, and the
costs associated with monitoring patients at minimal risk for
recurrent disease.
The use of TSH suppression is very much aligned with
the view that differentiated thyroid carcinoma should be
treated by total thyroidectomy. The advantage of total thyroidectomy in such cases is to permit both diagnostic and,
where appropriate, ablative radioactive 131 1 to be administered
without the problem of a competing thyroid lobe as well as
to diminish the likelihood of troublesome recurrence in the
central neck, which is difficult to treat and whose surgical
therapy is fraught with considerable morbidity.215216 Other
advantages of total thyroidectomy in this setting include
the removal of the contralateral lobe, which has as much
as an 80% chance of containing a microscopic focus of
carcinoma,"? as well as the elimination of the very small
risk of a differentiated tumor dedifferentiating into an anaplastic cancer.t" Total thyroidectomy permits better potential
ablation of metastatic disease and allows serum thyroglobulin
levels to be more reflective of recurrence.
The evidence for T 4 treatment actually improving survival
in differentiated carcinoma is at best uncontrolled.
Mazzaferri 219,220 and Massin-" and their coworkers showed
the best long-term survival in the patients treated by total
thyroidectomy, ablative radioiodine, and deliberate TSH
suppression. A beneficial effect has been reported in both
papillary and follicular cancer,222 in papillary cancer
alone,22o and in neither.F' The most convincing evidence
comes from Mazzaferri, who was able to show a cumulative
recurrence rate for papillary carcinoma of 17% for patients
receiving T 4 compared with 34% when no T 4 was used over
a lO-year follow-up period.P' This retrospective series was
neither controlled nor randomized. However, another large
study failed to show any improvement in survival with thyroid
hormone therapy.-"
T 4 is probably tumor static and not tumoricidal. The dose
requirements and level of required TSH suppression are
simply not known.F" No study has documented conclusively the optimal degree ofTSH suppression, and patients'
compliance is an issue that remains largely unexplored.
Because of the heterogeneity of thyroid cancers, their
variable prognostic indicators, the required length of follow-up
needed to demonstrate survival advantage, and a general failure to record uniformly both the presence and extent of TSH
suppression, it seems unlikely that such a controlled, randomized, prospective trial assessing the value of levothyroxine,
particularly in carcinoma subgroups, will ever be conducted.F'
Suppression of TSH to less than 0.1 mUlL is recommended. The average daily dose of T 4 to achieve this level
of suppression is usually 2.2 to 2.5 ug/kg. Because low-risk
cases represent about 75% of all patients-" and the incidence
of local recurrence is greatest within the first 5 years after
thyroidectomy.-" it is recommended that high-level TSH
suppression be used for this initial period, allowing the TSH
concentration to rise to between 0.1 and 0.3 mUlL if no
recurrences are demonstrable at 5 years.
Recommendations for the

Use of Levothyroxine in
Thyroid Cancer
The consensus recommendation currently is that TSH
suppressive therapy should be given postoperatively to
all patients with differentiated thyroid cancer. The exact
definition of appropriate TSH suppression to suppress tumor
growth adequately remains unclear. Studies with very large
numbers and follow-up would be required to detect significant differences. The true efficacy of ablative 131 1 has never
been established in a controlled clinical setting. 228,229 In the
postoperative setting in the cases believed to be high risk
(the older male patient with a tumor larger than 4 em with
either capsular or angioinvasion if follicular or extensive
lymphadenopathy if papillary), T 4 replacement therapy is
avoided for 4 to 6 weeks. This allows maximal TSH stimulation to occur and permits a valuable assessment of postoperative thyroglobulin levels (because thyroglobulin levels
increase as serum TSH levels increase in patients with remnant normal thyroid tissue or metastatic thyroid cancer after
thyroidectomyj.P" In some patients with rapidly growing
metastases, it may be critical to minimize TSH stimulation
of the tumor after thyroidectomy or 1311scanning or ablation,
and this is best achieved by the use of T3, which, because of
its shorter half-life, needs to be discontinued for only about
2 weeks to stimulate TSH for diagnostic or therapeutic
purposes.P'
It can be seen that radioiodine scanning and ablation
are not trivial undertakings. The need to stop replacement
therapy and to render the patient at least subclinically hypothyroid, along with the precautions necessary in the use of
radiopharmaceuticals, must be coordinated by a nuclear
medicine physician with a specific interest and experience
in thyroid tumor treatment. The timing of the first scan, the
indications for remnant removal or ablation, and the interval
between scanning are all matters of controversy.
Serum thyroglobulin determination is also comparable
to or more sensitive than 131 1 scanning in the follow-up of
patients with differentiated carcinoma. Thyroglobulin is a

large glycoprotein synthesized by thyroid follicular cells
and stored in colloid, providing the tyrosyl groups for iodination and coupling to form both T 3 and T 4. TSH stimulates
thyroglobulin release, and thus serum thyroglobulin is
elevated in any disease associated with an increased mass
or activity of the gland. As a result, it is elevated in endemic
and sporadic goiter, thyroiditis, and benign and malignant
thyroid neoplasms.P? Its use in the assessment of patients
after total thyroidectomy is roughly equivalent to that of
radioiodine scanning. 233 -238 In 8% to 22% of cases of differentiated thyroid carcinoma, thyroglobulin measurement is
difficult, however, because of circulating antithyroglobulin
antibodies leading to spuriously high levels.P? although the
newer use of monoclonal antibodies to thyroglobulin and
immunometric assays will lessen this problem.s'" A serum
concentration suppressed according to a second-generation
assay with a TSH of less than 0.1 mUlL may be readily
detectable by a third-generation assay with a limit of
0.01 mUlL. The term "undetectable" then becomes obsolete
when assessing TSH suppression and is relative to the
assay used.
Equally, in a small group of patients with nonfunctioning
but differentiated metastases (particularly elderly patients
with invasive Hiirthle cell tumors), both thyroglobulin measurement and sestamibi or thallium scanning or technetium
pyrophosphate bone scanning, or a combination, are superior
to diagnostic 1311 scans. 24 1,242
TSH suppression has been shown to reduce recorded
levels of thyroglobulin in patients with proven functional
metastases, and thus thyroglobulin levels are best assessed
with the patient not receiving replacement thyroid hormone. 243 ,244 An elevated thyroglobulin concentration with
a normal 1311 diagnostic scan without thyroid hormone
should alert the clinician to the possibility of nonfunctioning
osseous or pulmonary metastases and result in careful clinical
assessment with standard radiologic methods for detecting
metastatic disease, such as computed tomography scanning,
skeletal surveys, and magnetic resonance imaging. When
treated with therapeutic doses of 1311, some of these patients
have their thyroglobulin levels decrease to below 3 ng/mL,
and metastatic tumor is seen on a follow-up scan (approximately 5 days after treatment). The value of thyroglobulin
measurement after simple lobectomy in thyroid cancer is
clearly debatable, but if it is elevated after such surgery in
patients receiving levothyroxine suppression (i.e., above
the normal range for an intact thyroid lobe), a search for
metastatic disease should be initiated. 232,245 An algorithm for
the use of TSH suppression therapy, based on data from
Schlumberger and colleagues.s" is shown in Figure 8-2.
Conclusion
Treatment by supraphysiologic dosing of levothyroxine is
done to create adequate suppression of TSH without inducing clinical evidence of hyperthyroidism. The rationale is
that TSH is one of the principal stimulants of thyroid
growth.
Its use is recommended in patients after a total thyroidectomy for differentiated carcinoma of the thyroid, particularly
79
After total thyroidectomy (wait 4-6 weeks off T4 or 2 weeks off T3)
131 1 total
body scan
T4, TSH, TG, pregnancy test, if female
AntiTG antibody status
TG < 2.5
Annual clinical examination

Every 5 years
131)
TG > 5
Annual clinical examination
scan
131 1 scan
TG
TG
Chest x-ray film
Chest x-ray film
Low TG off T4
High TG off T4
Ablative
131 1
""T"
Ablative 131 1
CT scan of neck and chest

Bone scan
Thallium-201 scan
FIGURE 8-2. An algorithm for the use of thyroid-stimulating

hormone (TSH) suppression in the follow-up of thyroid carcinoma.
CT =computed tomography; 1311 =iodine 131; TG =thyroglobulin;
T3 = triiodothyronine; T4 = thyroxine. (Data from Schlumberger M,
Travagli JP, Fragu P, et al. Follow-up of patients with differentiated
thyroid carcinoma: Experience at Institute Gustave-Roussy,
Villejuif. Eur J Cancer Clin Oncol 1988;24:345.)
in the first 5 years after surgery when there are prognostic

factors that imply a worse overall prognosis for the tumor.
Suppressive therapy is not recommended in patients with
multinodular goiter after thyroid resection for benign disease because of the difficulty in assessing dominant masses
within an abnormal gland. Replacement therapy to avoid
hypothyroidism may be useful. Suppression treatment must
be stopped before diagnostic scanning and thyroglobulin
assessment in malignant disease. Treatment with T4 to suppress TSH must be monitored closely because of the risks
of subclinical hyperthyroidism and T4-induced osteopenia
and cardiac dysfunction, particularly in elderly persons.
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Paul R. Maddox, MCh, FRCS Malcolm H. Wheeler, MD
Thyroid nodules are the most common thyroid disorder, and

their incidence increases with advancing age. 1 The prevalence of palpable thyroid nodules in adult Americans has
been estimated to be 4% to 7%2; about 9 million adults
harbor a thyroid nodule.' and new nodules appear at a rate
of 0.08% per year," However, the true prevalence of thyroid
nodules has been shown to be far greater," Autopsy studies
reveal that 50% of adults had nodules, most of which were
impalpable.t'' In agreement with these data, Horlocker and
colleagues have shown, using high-resolution ultrasonography, that 50% of patients have thyroid nodules by the age of
50 years."
Most thyroid nodules are benign, and thyroid cancer is
comparatively rare, with an incidence of approximately
4 per 100,000 individuals per year." constituting only 1% of
all malignancies' and 0.5% of all cancer-related deaths."
Postmortem data, however, have demonstrated that occult
thyroid cancer, which is mostly papillary, has a prevalence
ranging from 6% to 28%.10,11 Although the natural history of
thyroid carcinoma usually involves a slow, indolent course,
with a death rate of only 6 per 1 million, it is equally true
that small, seemingly innocuous tumors with a diameter
smaller than 1 ern have been known to develop into progressive metastatic disease and cause death. 12
It is the anxiety induced by the fear of malignancy within
the solitary thyroid nodule against a background of common
benign nodular disease that generates the diagnostic
dilemma for the clinician. Consequently, the management of
thyroid nodules has been controversial.P:!" with the ironic
stance of some physicians advocating aggressive surgery"
and many surgeons continuing to advise a more conservative
approach." Clearly, the truth must lie in the gray area
between these two extremes, and the approach to thyroid
nodule management must be a selective one, embracing the
appropriate use of continually improving diagnostic techniques, thereby identifying those patients with malignancy
who require surgery and avoiding thyroidectomy in most
patients with benign lesions.
Clinical Evaluation
Careful clinical assessment with particular attention to
clinical risk factors (Table 9-1) gives important indicators
for the diagnosis and requirements for surgery, Most thyroid

nodules are asymptomatic, presenting as a chance finding
by the patient or during a medical examination. Pain is
uncommon, but a malignant lesion may occasionally cause
discomfort in the neck. With respect to single and multiple
nodules, current evidence suggests that when a dominant
nodule appears in a multinodular gland, the risks of malignancy are probably the same as those in a true solitary
nodule. I? The development of a new single nodule (Fig. 9-1)
or the rapid growth of an existing dominant nodule (Fig. 9-2)
may suggest malignancy, but a malignant nodule can also
be extremely slow growing, present for many years before
a diagnosis is made. However, the sudden presentation of
a painful swelling in the thyroid is almost pathognomonic
of hemorrhage into a colloid nodule. This is important to
recognize because spontaneous resolution will occur within
a few weeks, obviating any need for medical intervention.
Children younger than 14 years of age who present with
a solitary nodule have a 50% chance of malignancy.P:'? but
some evidence suggests that this increased risk may be a
consequence of exposure to ionizing radiation" Previous
thyroid irradiation confers a risk of malignartcy in a palpable nodule of 20% to 50%21-23; therefore, a history of neck
irradiation clearly influences surgical management, lending
support toward a more aggressive approach.
Geographic factors may play a role in papillary cancer,
which has been found to have an increased incidence in
iodine-rich regions.s' The incidence of follicular cancer is
increased in iodine-deficient endemic goitrous areas."
Although thyroid nodules are more frequently found in
women, a solitary nodule in a male conveys a greater risk
of malignancy. A family history of endocrine disease should
suggest the diagnosis of medullary thyroid carcinoma. This
rare tumor constitutes 7% of all thyroid malignancies but
may be familial in more than 20% of cases as multiple
endocrine neoplasia (MEN) type 2A or 2B syndrome or
rarely as a non-MEN familial syndrome. Coexistent
endocrine disease, particularly pheochromocytoma, must
clearly be sought and adequately treated before any thyroid
surgical intervention. Papillary carcinoma is also occasionally
familial" and has been described with familial adenosis polyposis (Gardner's syndromej" and ataxia-telangiectasia"
The patient with a thyroid nodule is usually euthyroid,
but features of thyroid dysfunction may help establish
85
the diagnosis. For example, hyperthyroidism in a patient presenting with a solitary nodule suggests a toxic autonomous
nodule, whereas associated hypothyroidism may indicate
nodular Hashimoto's disease or possibly lymphomatous
change within a Hashimoto's goiter. Palpation determines
whether the thyroid lesion is a true solitary nodule or a dominant nodule within a multinodulargoiter,but in approximately
50% of cases a clinically solitary nodule is found to be part
of a multinodular gland." This distinction has been given
inappropriate attention in the past, and current evidence
suggests similar malignancy rates in the two types of
glands.v-" This fact is particularly relevant in the multinodular goiter with a dominant nodule increasing rapidly in
size, which clearly should be treated as a true solitary
nodule. A hard, fixed nodule is likely to be malignant,
but some papillary carcinomas present as cystic lesions,
and follicular carcinoma can be hemorrhagic and soft.
Conversely, a benign colloid nodule can be hard with
dystrophic calcification; therefore, consistency is not a
reliable feature. However, associated lymphadenopathy is
strongly suggestive of malignancy, and the so-called lateral
aberrant thyroid with cystic change within a cervical lymph
node involved with papillary carcinoma can occasionally be
mistaken for a branchial cyst.
Presentation with a recurrent laryngeal nerve palsy in the
absence of respiratory disease or previous thyroid surgery is
a strong indicator of malignancy with direct nerve invasion.
Occasionally, nerve palsy can occur as a result of local
pressure symptoms of benign colloid nodular disease.
FIGURE 9-2. Dominant nodule within a multinodular goiter.
These coexistent pressure symptoms on the esophagus or

trachea will independently be indications for surgery despite
any consideration of potential malignant disease.
Diagnostic Procedures
Thyroid dysfunction is assessed by measurement of free
thyroxine (T4 ) , thyroid-stimulating hormone (TSH), and
free triiodothyronine (T3) , but, as previously stated, most
patients with a thyroid nodule are euthyroid. A malignant
nodule may occasionally be found in association with
thyroiditis or Graves' disease, but it is rare for a malignant
nodule to actually be the cause of hyperthyroidism. Thyroid
antibody titers and thyroglobulin measurement add little
to the clinical assessment. Retrostemal extension may be
further assessed with radiographs of the chest and neck,
but magnetic resonance imaging (MRI) and computed
tomography (CT) are currently the best modalities to assess
intrathoracic extension. When there is a positive family
history suggestive of MEN 2 syndrome, serum calcitonin
should be measured as an aid to diagnosis but has most
usefulness in serial monitoring of the patient after surgery
for medullary thyroid cancer.
Thyroid Scintigraphy
FIGURE 9-1. Solitary thyroid nodule.
Isotope scanning of the thyroid has been used to classify

nodules into those that are nonfunctioning ("cold"), normally
functioning ("warm"), and hyperfunctioning ("hot") as a
result of their ability to take up the commonly used isotopes
iodine 123 and technetium Tc 99m pertechnetate. The finding of a hot nodule is usually consistent with benignity, and,
because of the limitations of the procedure, the few cases of
malignancy associated with hot nodules 32,33 are probably a
consequence of a cold focus of cancer being adjacent to the
hot lesion, leading to incorrect interpretation. More than
80% of nodules are cold (Fig. 9-3), but fewer than 20% of
these are malignant. 34,35 About 10% are warm, and 10% of
these are malignant. Only 5% of scans have hot nodules,
with fewer than 5% being malignant." Furthermore, it is
well recognized that there may be a discrepancy in imaging
between 1231 and 99mTc scintigraphy." In summary, isotope
Approach to Thyroid Nodules - - 87
FIGURE 9-4. Small tumor seen within a cyst cavity with high-
resolution ultrasound scan.
FIGURE 9-3. Thyroid isotope scan of a cold nodule.
scanning is extremely poor in differentiating between

benign and malignant lesions, and its practical role is
actually now limited to the identification of autonomously
functioning thyroid tissue.
Ultrasonographic Scanning
Ultrasonography is an operator-dependent modality but is
capable of identifying impalpable nodules as small as 0.3 mm
in diameter." Ultrasonography discriminates cystic from
solid lesions but, disappointingly, does not aid in the overall
diagnosis of malignancy. Originally, it was thought that the
hypoechoic lesion, as with breast carcinoma, was more
likely to be malignant," but overlap of sonographic findings
has led to a low specificity.'? Recently, the association of
sonographically detected thyroid calcifications with malignant dominant nodules has been found to increase diagnostic accuracy." It is difficult to assess mixed lesions on
ultrasonography because, although they may usually represent colloid disease with associated hemorrhage in degeneration, they may also be indicative of a tumor within a cyst wall
(Fig. 9-4). We consider that conventional ultrasonography has
limited routine practical value in the assessment of thyroid
nodules.
Needle Biopsy and Aspiration Cytology

Needle core biopsy is a reliable diagnostic technique for differentiating benign from malignant nodules with conventional
histology" and particularly in the assessment of dominant
nodules with coexistent long-standing Hashimoto's disease,
where cytologic interpretation of possible lymphoma may be
difficult. It suffers, however, from inherent disadvantages in
that it is a painful procedure and has poor patient compliance. Complications range from hematoma and hemorrhage
to tracheal puncture and recurrent laryngeal nerve damage.

The theoretical fear of seeding of malignancy along the
needle tract appears to have been greatly exaggerated,
and Miller4 2 did not see this complication in more than
3000 biopsies, with a false-negative rate of only I%.
However, lesions smaller than 3 em may not be amenable to
this technique.
Fine-needle aspiration cytology (FNAC) is an alternative
and more acceptable method that is now commonly used
(Fig. 9-5). Pioneering work in Scandinaviav" subsequently
led to almost universal acceptance of FNAC as the procedure of choice in diagnostic assessment of thyroid nodules.
Cytologic assessment may use a wet fixed specimen
(Papanicolaou stain) or an air-dried preparation (MayGriinwald-Giemsa). In our own center, we have modified
the FNAC technique to use the cell block method, in which
the thyroid architecture is preserved to facilitate a diagnosis.
Immunocytochemical studies and special stains can also be
performed. At least six passes of the needle are used in each
case. FNAC has good patient compliance with few complications, and it is easy to repeat the sampling if required.
FNAC can confidently identify colloid nodule; thyroiditis,
papillary medullary, and anaplastic cancer; lymphoma; and
even secondary cancer (Fig. 9-6). The major limitation of
FNAC is in the evaluation of the follicular nodule: histology
is required for distinguishing between the benign follicular
adenoma and follicular carcinoma, the diagnosis of which
rests on the presence of capsular and vascular invasion. Core
biopsy for these follicular lesions diagnosed on FNAC may
add further useful information, but any follicular neoplasm
diagnosed by cytology should be regarded as potentially
malignant and should be selected for formal surgical excision. The finding that DNA aneuploidy often occurs in
follicular adenomas as well as in carcinomas'<" lends
further support for the view that follicular neoplasia should
be regarded and treated as a single entity.
FIGURE 9-5. Fine-needle aspiration cytology performed with the
use of a syringe holder with a 23-gauge needle, with the patient

supine and the lesion fixed between two fingers. In this situation,
glovesand appropriate infection control barriers would be used.
Obviously, there must be a low false-negative rate and
false-positive rate for a surgeon to rely on FNAC in overall
assessment and selection for surgery. Two large studies
using FNAC before surgery have demonstrated a false-positive
rate of 0% with an acceptable low false-negative rate of

2.2% (falling later to 0%)45 and 0.7%, respectively." It is
concluded that FNAC is a safe, reliable, accurate means
of differentiating benign from malignant thyroid nodules.
Henry and associates'? demonstrated that using an immunocytochemical technique for detection of thyroperoxidase
(TPO) (with the monoclonal antibody termed MOAB 47)
may be a useful adjunct to FNAC in the preoperative
diagnosis of malignancy, with reported sensitivity, specificity, and overall accuracy of 100%, 86.7%, and 89%,
respectively.
An FNAC that is reported as suspicious presents a difficult
dilemma, but it is better to err on the side of caution, leading
to increased false-positive results but an increased sensitivity
for the method. Grant and colleagues'" reported 23% of suspicious lesions to be malignant, with similar findings documented by other workers. 45,50 Inadequate samples should
not be regarded as negative but as an indication for repeat
aspiration, perhaps with an ultrasound-guided technique."
The implementation of FNAC in the diagnostic assessment has led to an increasing incidence of malignancy in
several series of patients undergoing surgery, from 10% to
31 % up to 50%,4,52,53 and to improved selection, with the
total number of cases coming to thyroid surgery drastically
reduced, with favorable cost implications.w-" FNAC has
been deemed so valuable that some authors have recommended that no patient with a goiter be denied the diagnostic
technique. 56
In 1994, Delbridge and coworkers'? showed that proton
magnetic resonance spectroscopy (PMRS) analysis of
FNAC specimens may further enhance diagnostic evaluation
and help avoid unnecessary surgery for benign follicular
neoplasms.
FIGURE 9-6. The cytologic features of thyroid nodules. A, Colloid nodule; B, Hashimoto's thyroiditis; C, papillary carcinoma;
D, follicular neoplasm; E, anaplastic carcinoma; F, secondary deposit melanoma.
Approach to Thyroid Nodules - -
Current research on galectin-3 shows great potential to

improve the differential diagnosis on cytology. The galectins
are a family of ~-galactoside
binding lectins and galectin-3
has been shown to be overexpressed in malignant thyroid
tissue58-6 1 compared to a normal background, and also in
comparison to follicular adenoma or hyperplastic thyroid
tissue (Fig. 9-7). Work is now currently under way in
Newcastle, United Kingdom/? to assess galectin-3 expression in preoperative FNAC and determine its potential role
as a marker of well-differentiated thyroid cancer. We await
further confirmatory reports of these new advances, and
perhaps the use of all four modalities (FNAC, TPO, PMRS,
and galectin-3) may maximize overall accuracy, sensitivity,
and specificity.
In conclusion, FNAC is a highly accurate and cost-effective
diagnostic technique of low morbidity, providing a valuable
89
adjunct to the clinical assessment in the overall selection of

patients with thyroid nodules for surgery.
Thyroid Cysts
FNAC serves as a diagnostic and therapeutic tool for the
management of simple thyroid cysts. Simple cyst aspiration
eliminates many small lesions, but surgical excision may
still be required in about 6% when there is a residual
nodule.P Certainly, negative cytology does not exclude a
neoplasm, and if there is a residual palpable lesion after
aspiration, surgery is recommended. After cyst aspiration,
tissue adjacent to the cyst wall should be sampled by reaspiration. It seems reasonable to reaspirate recurrent cysts for
up to three times if necessary, but if this persists, surgery
is indicated. Cysts larger than 4 em in diameter should
be resected in view of the increased risk of malignancy.-v"
A sudden painful presentation of an acute hemorrhagic
colloid nodule produces a blood-stained aspirate, and the
lesion will resolve spontaneously; otherwise, blood in the
aspirate should be regarded with suspicion of malignancy
and surgery is advised.
Spontaneous Resolution
The natural history of benign thyroid nodules has received

scant attention in the past and is important to predict outcome and determine appropriate management. A long-term
follow-up (6.1 years) study by Grant and associates" of
FNAC in 641 patients focused on the demonstration of a
low false-negative rate of 0.7% but did not document exact
changes in the untreated benign thyroid nodules, suffering
from the inherent weakness of review by telephone, correspondence, or referring physician letter. However, the fate of
putatively benign solitary thyroid nodules by clinical reexamination after 10 to 30 years has been studied by Kuma
and colleagues.v who demonstrated that most nodules reduce
in size and nearly 36% disappear. There was, however,
a malignancy rate of 26.3% in enlarging nodules. A more
recent study by the same group'< has used physical
re-examination (by the same two clinicians) and clinical and
ultrasound-guided FNAC to assess the nature of nodules of
9 to 11 years' duration. This study again demonstrated that
99% of benign nodules remained benign; most decrease in
size or disappear during this follow-up period. An increase
in nodule size remains a worrying clinical feature (occurring
in 21% to 23%), with a malignancy rate of 4.5%; clearly,
there should be a high index of clinical suspicion for such
enlarging lesions.
Medical Treatment
FIGURE 9-7. A, Galectin-3 expression in thyroid follicular carcinoma tissue. Invasion of the capsule by strongly positive follicular
carcinoma cells (brown cytoplasmic stain for galectin-3) is demonstrated (x40). B, Galectin-3 expression in papillary carcinoma cells
(brown cytoplasmic stain to the right of the photograph) in comparison to the negative-staining normal thyroid cells on the left (x40).
(A and B, Courtesy of Drs. Pallavi Mehrotra and Tom Lennard.)
Although thyroid hormone administration may be beneficial

"suppressive therapy" for diffuse colloid goiter, once nodule
formation has developed, patients are unlikely to benefit. 67.68
TSH suppression with exogenous T4 may also reduce the
size of some malignant nodules.s? This clearly underscores
the problem of potential misdiagnosis for the unwary when
to diagnosis, clinical assessment remains the fundamental
basis for selection for surgery and may lead the surgeon
to operate irrespective of cytologic findings. In an endemic
goitrous area, patients are selected for surgery because of
coincidental pressure symptoms (e.g., dyspnea, dysphagia,
or choking sensation) associated with a progressive expansion
in nodular disease. Assessment with flow-loop respiratory
function tests and CT or MRI of the neck can be helpful in
such cases. In a consecutive series of 100 patients undergoing
surgery for histologically proven benign solitary nodules at
the University Hospital of Wales, Cardiff, 50% had significant
pressure symptoms warranting surgery.
using this therapy as a nonoperative management of thyroid

nodular disease.
Toxic nodular goiter (Plummer's disease) may identify a
toxic nodule (or at least ascertain the side of activity) with
radioiodine scanning and surgery is usually recommended if
the nodule is greater than 3 em diameter or symptomatic.
Radioiodine treatment for toxic multinodular goiter usually
requires higher or repeated doses than for Graves' disease,
but toxic solitary nodule (toxic adenoma) is usually well
controlled by a single treatment, although radioiodine may
not diminish nodule size. One follow-up study has demonstrated that 50% remain unchanged and 10% actually
increased in size." Where the patient has symptomatic pressure symptoms and the goiter is relatively large, radioiodine
does not relieve local symptoms and surgery is indicated,
almost certainly if the nodule is larger than 3 em in diameter.
However, radioiodine may be indicated for elderly patients
or those with a significant risk of general anesthesia.
Thyroid Surgery for Nodular

Disease
Thyroid and other endocrine surgery requires a multidisciplinary team approach with, in particular, an anesthesiologist
and surgeon both skilled in this particular field. At open
operation, the ipsilateral side is initially examined together
with the nodule, its characteristics are assessed, and any
lymphadenopathy is noted. The contralateral lobe is palpated
through the strap muscles to determine whether any nodularity is present that may not have been clinically evident.
Indications for Surgery

The overall assessment of clinical risk factors coupled with
the findings of FNAC constitute the fundamental basis of
selection for surgery. Although cytology is an invaluable aid
1------
1 Solitary ThyroidNodule
Hyperthyroid
!
FNAC
!
123-1 scan
!
>3cm
diameter
surgery
Suspicious
!
<3cm
diameter
131-1
>4 cm diameter
Blood
Recurrence
RepeatFNACin
6 months-Benign
I DiSCh:rge I
~--I
I
Recurrence
SUrg:ry
FIGURE 9-8. Scheme of management for solitary thyroid nodule. FNAC = fine-needle aspiration cytology. (Adapted from Famdon JR.
Endocrine Surgery: A Companion to Specialist Surgical Practice, 2nd ed. Philadelphia, WB Saunders, 2001.)
Approach to Thyroid Nodules - -
If the nodule is truly unilateral, a total thyroid lobectomy

(removing isthmus and pyramidal lobe en bloc) is indicated,
preserving both parathyroid glands, the external branch of
superior laryngeal nerve, and the recurrent laryngeal nerve.
This approach is advocated because it enables a full histologic examination of the lesion without any risk of tumor
spillage into the operative field. It is a safe procedure with
low morbidity when performed in experienced hands.
Unilateral subtotal lobectomy should not be used because it
makes a possible reoperation on this side quite difficult and
is associated with a higher risk of complications.
Frozen section histology may confirm preoperative diagnosis and can aid decision making for definitive surgery. If
benign disease is identified, no further resection is required
unless there is significant contralateral multinodular disease,
when a subtotal unilateral lobectomy or, as some authors may
prefer, a complete, total thyroidectomy is recommended."
If the report is one of papillary or medullary tumor, then one
should proceed to carry out a formal total thyroidectomy
and appropriate lymph node clearance. There is little
evidence to support the use of a formal en bloc dissection
technique for these nodes. The difficulty occurs with the
follicular lesion where frozen section may be unreliable and
paraffin section histology is required to be certain of frank
capsule invasion. If this fails to be seen on frozen section
analysis or there is discordance between FNAC and frozen
section interpretation, it is a simple matter to await the final
histology and reoperate a few days later to perform a definitive, complete, total thyroidectomy, removing the contralateral
thyroid lobe in safe virgin territory. A minimally invasive
follicular carcinoma is adequately treated by unilateral lobectomy alone. By adopting this conservative approach, the risk
of underoperation has been found to be small, amounting to
fewer than 6% of cases with thyroid nodules," and thereby
avoids the hazards of unnecessary extensive surgery.
A summary of the management of the patient with a solitary thyroid nodule is shown in Figure 9-8.
Summary
Nodular disease of the thyroid is common, whereas malignancy is rare. The differentiation of a malignant nodule from
a benign nodule hinges on fundamental clinical assessment
coupled with FNAC. This approach provides a safe, reliable,
and cost-effective method of selecting patients for surgery
who truly need it and avoids an unnecessary operation in the
remainder who do not already have mechanical and pressure
symptoms resulting from an enlarging goiter.
Acknowledgments
The authors express their gratitude to Pallavi Mehrotra, BAES Research
Fellow, and Tom Lennard, Professor Breast and Endocrine Surgery, Head
of The School of Surgical and Reproductive Sciences, and Consultant
Surgeon, The Medical School University of Newcastle-upon-Tyne, for their
help in supplying Figure 9-7.
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Jay K. Harness, MD David E. Sahar, MD
Historical Aspects
Carcinoma of the thyroid was first described in a child in
1902. 1 It was not until 1951 that medullary carcinoma was
described by Hom. 2 Nonmedullary, differentiated thyroid
carcinoma (DTC) in children and adolescents is an uncommon
disease with a high incidence of cervical metastasis and a
favorable prognosis. DTC is the most frequent malignant
endocrine tumor of childhood. The association of thyroid
carcinoma with the use of external low-dose irradiation to the
head and neck during childhood has been well documented.'
The rapid increase in reports on children with DTC began in
1935 and peaked in 1955. Winship and Rosvoll observed a
mean latency period of 8 years between irradiation exposure
and detection of thyroid carcinoma.' Although radiation
treatment of various benign conditions has been abandoned,
cases of childhood DTC continue to be identified. Worldwide,
the most dramatic increase in thyroid carcinoma in children
has occurred in Belarus and Ukraine after the 1986 Chernobyl
nuclear power plant accident in northern Ukraine.
The initial clinical presentation of childhood DTC, as
reported in one of the largest U.S. series, has changed considerably in those diagnosed since 1971.4 Before 1971, most
patients seen with childhood DTC had a history of head
and neck irradiation, presented with advanced cervical
lymphadenopathy, had more locally infiltrative tumors,
and had nearly a 20% incidence of pulmonary metastasis.
Since 1971, childhood DTC has often been less locally
advanced, and fewer patients have been presenting with
distant metastasis.
For years, controversy has continued over the extent of
thyroid surgery for DTC in adults. The lack of a unified
approach in adults quite naturally leads to an intensified
debate as to the appropriate surgical therapy in children
and adolescents. Total thyroidectomy may be viewed as
overtreatment that is associated with increased morbidity.
On the other hand, total thyroidectomy with low morbidity
can be seen as the most acceptable form of therapy because
it may provide a lower incidence of local regional disease,

enhance the efficacy of therapeutic radioactive iodine ( 1311),
and improve mortality. These and other issues require
further review to determine whether a unified treatment
regimen for childhood DTC can be proposed.
Incidence and Etiology

Carcinoma of the thyroid gland affects approximately
11,000 people in the United States each year, with a femaleto-male ratio of nearly 3: 1. It accounts for 90% of all
endocrine malignancies and kills approximately 1300 people
annually.'
In the United States, childhood thyroid carcinoma constitutes approximately 3% of all childhood cancers. Its incidence rate is three to five cases per million per year.67
Childhood DTC is so uncommon that even the largest
referral centers in the United States may see only two or three
cases per year. It may take 35 to 50 years to develop a series
of only 100 patients. Childhood thyroid cancer constitutes
3% to 4.8% of all thyroid cancers in the general population
but a much larger proportion of radiation-related thyroid
carcinomas.S? In 1950, Duffy and Fitzgerald reported a 32%
incidence of low-dose head and neck irradiation in children
with thyroid carcinoma, and a series reported by Winship
and Rosvoll in 1970 demonstrated an 80% incidence.v'?
Such exposure contributed substantially to the peak in the
number of patients seen from 1950 to 1965, whereas its
abandonment was largely responsible for the decrease in
patients by 1970. Figure 10-1 shows this referral pattern at a
university medical center. The increased number of new
patients seen since 1970 appears to be related to established
referral patterns and not necessarily to an increase in the
incidence of childhood DTC. Several series of thyroid
carcinoma in children and adolescents published since 1970
reported an incidence of radiation exposure ranging from
3% to 57% (mean, 21%).4.11-14
93
10-1. Patients with

childhood differentiated thyroid
carcinoma treated at the
University of Michigan Medical
Center, 1935-2000.
FIGURE
A child's thyroid is more susceptible than an adult's to

the tumorigenic effect of radiation. This has been seen in the
results of studies carried out on Marshall Islanders and on
residents of Hiroshima and Nagasaki and from the longterm outcome study by the University of Illinois College of
Medicine, the Michael Reese Hospital (Chicago) study.P"?
It has been noted from these last reports that the typical
latency period from exposure to irradiation and the appearance of thyroid cancer ranges from 8 to 11 years. However,
latency periods as short as 3 years have been found in both
the Michael Reese Hospital series and in reports after the
Chernobyl accident.l":"
The Chernobyl nuclear power plant accident on April 26,
1986, led to widespread contamination. About 70% of the
most contaminated territory of the former Soviet Union was
located in the republic of Belarus. The entire spectrum of
radioactive products of nuclear fuel decay also contaminated
major populations of Ukraine. Iodine radionuclides entered
the body through inhalation or by mouth, which in tum
resulted in large radiation doses to the thyroid glands. The total
dose of thyroid exposure was caused primarily by 1311 and 1331.
Additional external gamma radiation exposure and internal
exposure were attributed to cesium and other radionuclides.
Children younger than 7 years of age living in the resettlement zone around the power plant received the maximal
thyroid exposure. The average dose in these children ranged
from 2.1 to 4.7 Gy, depending on the district in which they
lived. 19 The effects of radioactive iodine took place against
a background of endemic goiter, which is characteristic of
many Belarus regions. A large-scale screening program was
started in 1990. A total of 10,000 children were examined8000 from contaminated territories and 2000 from control
areas. The incidence of thyroid carcinoma was 6.2 per 1000 in
contaminated areas and none in control areas.'? This largescale survey found that children of the republic of Belarus had
a significant increase in thyroid nodule disease, including
adenoma, nodular goiter, and especially carcinoma. 19
Thyroid carcinoma has been reported to be increased in
endemic goiter areas, in Graves' disease, in autonomous
nodules, in Hashimoto's thyroiditis, after therapeutic use of
131
1, and after radiation therapy for Hodgkin's lymphoma.P'"
Medullary thyroid carcinoma, inherited in an autosomal
dominant fashion in 30% of cases, occurs in the syndromes
of familiar medullary carcinoma and multiple endocrine
neoplasia (MEN) types 2A and 28. These entities are
described in detail in Chapter 76. Although not as clearly
described, heredity also plays a role in familial papillary
carcinoma syndrome and other genetic disorders. Three-andone-half to 6% of patients with papillary carcinoma have an
affectedrelative." Papillary carcinoma may occur in association
with autosomal dominantly inherited Gardner's syndrome and
familial polyposis.F-"
In comparison with medullary carcinoma, cytogenetic
and molecular genetic studies of papillary and follicular
carcinomas have been relatively less common. Advances in
cytogenetic and molecular biology have led to a better understanding of the biology of thyroid carcinoma at the genome
level. Analysis of cytogenetic studies show chromosome
lOq abnormalities to be more common in papillary tumors,
whereas chromosome 3 abnormalities are associated with
follicular cancer. A tumor suppressor gene in the short arm
of chromosome 3 may be important in the development and
progression of follicular carcinoma." In 1987, the role of a
thyroid-specific oncogene retlPTC was described in papillary
thyroid carcinoma (PTC). Mutational rearrangement of novel
upstream regulators leads to increased expression of the
Childhood Thyroid Carcinoma - -
95
ret/PTC chimeric gene and unregulated ret tyrosine kinase

activity." This mutation is found in spontaneous as well as
radiation-induced (Chernobyl accident) PTC.3l It is more
common in children than in adults. A report by Nikiforov
and associates found rearrangements of the ret oncogene in
71% of sporadic PTC in children from the United States and
87% in children from the radiation-contaminated areas of
Belarus.F Differential expression of ret/PTC type (ret/PTC1,
retIPTC2, retIPTC3) has been reported in spontaneous and
radiation-induced groups."
Increase in telomerase expression has also been shown in
thyroid tumors, which has been thought to confer immortal
status to thyroid cancer cells." Mutation in the ras oncogene
has also been described in PTC, although less frequently
in children compared to adults." This mutation has been
described as a prognostic factor in papillary carcinoma.P
Finally, growth factors have been shown to be important in
promoting growth and recurrence in PTe. Vascular endothelial growth factor (VEGF), VEGF receptor (FIt-I) and hepatocyte growth factor/scatter factor, and hepatocyte growth
factor/scatter factor receptor (cMET) play an important role
in the clinical outcome of thyroid carcinoma. VEGF expression appears to be increased in large tumors and in those
destined to recur. Furthermore, these growth factors are
increased in children with PTC compared with adults."
Hepatocyte growth factor/scatter factor and cMET overexpressions are found in tumors with high recurrence."
Ongoing molecular and genetic research is providing
greater insight into the pathogenesis and outcomes of
childhood PTe. Such insights will hopefully lead to more
uniformed therapeutic interventions.
Pathology
Papillary carcinoma is the most common malignant tumor
of the thyroid in both adults and those 18 years of age and
younger. However, differences do exist between adult and
childhood PTe. Thyroid cancers in children have a higher
incidence of lymph node metastasis, extension outside the
thyroid capsule, and distant metastasis, especially lung, than
do those in adults.4.8.l0-l4,38.39 Despite the more aggressive
clinical and biologic behavior of childhood thyroid cancers,
the mortality rate in children is much less than in adults."
Papillary carcinoma appears as a firm, nonencapsulated or
partially encapsulated lesion. It may be small and intrathyroidal or extrathyroidal. Calcifications and cysts may
be present. Microscopically, papillary carcinomas contain
predominant or focal papillary areas as well as follicles.
Psammoma bodies are found in 40% to 50% of papillary
carcinomas. The nuclei have classically been described as
pale, clear, ground-glass, empty, or "Orphan Annie eyed."
Papillary carcinoma typically shows areas of sclerosis either
centrally or at the peripheral invasive margins." Papillary
carcinoma invades lymphatic spaces, giving rise to multifocal
lesions through intraglandular spread. Lymphatic invasion
also accounts for the high incidence of regional nodal
metastases.f
The follicular variant of papillary carcinoma is an important subtype in children. These tumors may appear grossly
and microscopically encapsulated. A follicular pattern of
FIGURE 10-2. Tissue section showing tightly packed, small follicles containing colloid. Note the nuclear chromatin clearing and
irregular, thickened, and occasionally cleft nuclear membranes,
classically seen in papillary thyroid carcinoma (hematoxylin-eosin).
growth is seen that includes ground-glass nuclei, psammoma bodies, desmoplastic reaction, and papilla in nodal
metastases." Figure 10-2 shows pathologic features representative of the follicular variant of papillary carcinoma. Some
authors believe there is a great propensity for vascular invasion in metastases beyond regional lymph nodes with this
subtype. 42.44 In contemporary series, the follicular variant
constitutes 21% to 25% of pediatric thyroid carcinomas.w"
The diffuse sclerosis variant of papillary carcinoma often
presents as goitrous enlargement with replacement of both
lobes by firm and calcified tumor." This subtype tends to be
a tumor affecting children, teenagers, and young adults. It
appears to be an aggressive form of papillary carcinoma;
one series reported a 100% incidence of regional nodal
metastasis at the time of diagnosis and a subsequent 25%
incidence oflung metastasis.f'These tumors have numerous
psammoma bodies, causing the gland to feel stony hard on
palpation. Plain radiographs of the neck can show diffuse
calcification of the thyroid.
The solid variant form of papillary carcinoma is
considered to be a poorly differentiated papillary cancer.'?
Microscopically, the tumor grows with nests without papilla
or follicle formation. This is an unusual variant about which
there is no uniformity of morphologic definition. Its prognostic implications are unknown.50
Pure follicular carcinoma of the thyroid occurs somewhat
less frequently in patients 18 years of age and younger. In
several large series of childhood thyroid carcinoma in which
detailed histologic analyses were included, pure follicular
carcinoma constituted 2.7% to 7% of total cases. 4.12.51 It is
certainly possible that some tumors classified as follicular carcinoma were, in fact, the follicular variant of papillary
carcinoma. If this were true, then the incidence of childhood follicular carcinoma is even lower than in reported
series.
Hiirthle cell tumors and thyroid sarcomas are unusual
tumors seen in childhood and may develop more frequently
in persons exposed to radiation.P-"
Clinical Presentation
The clinical presentation of childhood thyroid carcinoma
has changed in several ways over the past several decades.
The 1992 report on the University of Michigan experience
demonstrated important changes in history and clinical
presentation." The study compared patients treated from 1936
to 1970 with those treated from 1971 to 1990. The Michigan
surgeons found that 50% of the former group reported a
history of head and neck irradiation compared with only 3% in
the latter group. Similarly, the incidence of palpable cervical
adenopathy at initial presentation decreased from 63% to
36%; the rate of local infiltration of the primary cancer fell
from 31% to 6%; and the rate of initial pulmonary metastases
decreased from 19% to 6%. Alternatively, the incidence of
finding a palpable mass or thyroid nodule on presentation
increased from 37% to 73%.4 This meaningful change in
presentation may reflect an increased awareness by pediatricians of the importance of routine examination of the thyroid.
It appears that, at least in the Michigan experience, patients
were being diagnosed at an earlier stage of their disease.
A palpable thyroid nodule in a child or adolescent,
especially a male, is thyroid cancer until proved otherwise.
Thyroid carcinoma has been found in 22% to 50% of childhood thyroid nodules brought to surgical exploration. 54-56
All reports suggest that carcinoma is roughly twice as likely
to be found in children with thyroid nodules as in adults.
Persistent lymphadenopathy must be of concern because
it is a common presenting finding in childhood thyroid
carcinoma." Most thyroid cancers in children are asymptomatic. A careful history should be taken to determine whether
dysphasia, hoarseness, or a change in the voice is present.
These are often findings suggestive of a more locally
advanced stage. Pulmonary metastases are usually asymptomatic. Initial pulmonary metastases are not uncommon in
childhood thyroid carcinoma and should be screened for
by initial chest radiograph, computed tomography (CT) scan
of the chest, serum thyroglobulin determination, and
postoperative 1311 whole-body scanning. Table 10-1 summarizes the initial extent of disease reported in several large
series. Cervical lymph node metastases in these reports were
confirmed by pathologic examination. Pulmonary and distant
metastases were diagnosed by radiograph or 1311 scanning
or both.
Diagnostic fine-needle aspiration (FNA) biopsy is a

useful procedure, especially when it is positive for carcinoma. FNA can be performed on either the primary thyroid
nodule and/or a palpable enlarged cervical lymph node.
Ultrasound guidance of diagnostic FNA biopsies provides
increased assurance of the proper location of the needle
tip in a target lesion. When adequate samples are taken,
ultrasound-guided FNAs have fewer false-negative results/"
Diagnostic excision lymph node biopsy is occasionally
useful if there is no palpable thyroid nodule or if an FNA of
the node is negative. If all diagnostic efforts fail, then a child
with a palpable thyroid nodule should undergo total lobectomy
of the involved side. Nucleation of a nodule is unacceptable,
and the diagnostic resection should be nothing less than a total
thyroid lobectomy.
Treatment
Surgical
The debate over the most effective or appropriate extent of
surgical resection in adults for DTC has continued for years;
little wonder, then, that there is no uniformity of opinion
about the treatment of childhood thyroid cancer. The ideal
therapy would (1) eliminate the primary disease, (2) reduce
local and distant recurrence, (3) facilitate the treatment of
metastases, (4) have the lowest possible morbidity, and
(5) achieve the highest cure rate.
The two major treatment "camps" are the total thyroidectomists and the less than total thyroidectomists. Those who
argue against total thyroidectomy do so because they believe
that this procedure does not afford a survival advantage and
is associated with the possibility of the significant morbidity
of permanent hypoparathyroidism and recurrent laryngeal
nerve injury.
Those who argue in favor of total thyroidectomy do so
because (1) papillary carcinoma and its subtypes are typically multifocal; (2) there is a reduced incidence of local and
distant recurrence; (3) it facilitates the use of 131 1; and (4) it
allows the use of serum thyroglobulin to detect recurrence.
To determine a survival advantage of any form of therapy
in childhood thyroid carcinoma is difficult because the number
of cases is relatively small and the current reported mortality is
about 8%. If survival benefit is difficult to determine, then
analyzing local and distant recurrences may be a better

measure of the adequacy of initial treatment, including the
role of total thyroidectomy.
The extent of cervical lymph node dissection in childhood thyroid carcinoma is an important issue because of the
consistently high incidence of nodal metastasis. Most series
report a 71% to 90% incidence of cervical and upper anterior
mediastinal metastases.4.II-14,61 Typically, carcinomas of the
upper one third of the thyroid gland metastasize to the middle
and upper jugular chain. Carcinomas in the lower two thirds
may spread to the middle and lower jugular chain, the central
compartment nodes (pretracheal and peritracheal nodes
between the jugular veins), or the anterosuperior mediastinal
nodes.
To establish cervical metastasis, it is important to explore
and sample lymph nodes in areas of likely spread. If
involved nodes are found in the central compartment region,
a complete ipsilateral central neck dissection from the level
of the thyroid notch (Delphian node) to and including the
anterior superior mediastinum should be performed. If jugular nodes are affected, the entire jugular chain should be
explored, including the region of the lower spinal accessory
nerve. All clinically involved nodes should be resected,
including bilateral exploration and resection if indicated by
the extent of the disease. What is typical in children is
multinodal involvement,4,14,40,61 A classic radical neck dissection is virtually never indicated in childhood with DTC
of follicular cell origin,
Experience has shown that subsequent regional lymph
node recurrence is related to the extent of initial disease as
well as the scope of initial node dissection.' Patients who
experience cervical lymph node recurrence within a year
of thyroidectomy should probably be considered to have
persistent or "missed" disease as a result of an inadequate
exploration and resection, Frankenthaler and coworkers
observed that DTC in young patients can involve any of
the cervical and upper mediastinal nodal groups except
the submental, submaxillary, and upper and lower
97
spinal accessory?' Schlumberger and colleagues found anterosuperior mediastinal involvement only in patients with involvement of the recurrent laryngeal nerve chain (peritracheal).14
Complications
The increased incidence of complications associated with
total thyroidectomy has been an argument against this
procedure, especially if it does not improve survival. The two
most feared complications of total thyroidectomy are permanent recurrent laryngeal nerve paralysis and permanent
hypoparathyroidism. The incidence of these complications
has been disturbingly high in several reports on childhood
thyroid carcinoma. LaQuaglia and coworkers found that the
probability of a major complication varied inversely with
age. Children 6 years of age and younger had greater than a
60% chance of a major complication. Total or subtotal
thyroidectomy in their series was associated with an 80%
chance of a major complication in the same age group."
Table 10-2 shows complication rates for total or
near-total thyroidectomy in nine large series of patients with
childhood thyroid carcinoma. Overall, the average rates
were 12% for hypoparathyroidism and 6% for recurrent
laryngeal nerve palsy. In contrast, the Michigan surgical
group reported a zero incidence for these two complications
in the 33 patients treated from 1971 to 1990. For the past
35 years, the University of Michigan's Department of Surgery
has decided to treat all cases of DTC (whether in adults or
children) uniformly with total thyroidectomy. Since 1971,
nearly all thyroidectomies have been performed by members
of Michigan's Division of Endocrine Surgery. This has
resulted not only in a consistent approach but also in an
excellent operative safety record. Other centers should be
able to obtain the same results with a significant complication rate of about 2%.
Total thyroidectomy should reduce the rate of recurrence
in the thyroid bed to zero. Regional lymph node recurrence
is related to the extent of initial disease and the scope of
98 - -
Thyroid Gland
lymph node dissection. Pulmonary-distant recurrence is

probably related to the biology and extent of disease at
presentation and perhaps also to the extent of initial surgical
therapy and the use of adjunctive 1311. Table 10-3 compares
the use of total or near-total thyroidectomy and postoperative
131
1 with cervical, thyroid bed, and pulmonary-distant recurrences. The University of Michigan report by Harness and
colleagues had the highest combined rate of total thyroidectomies (91%) and utilization of 1311 (73%) of the series
shown in Table 10-3. The second highest combined use of
total thyroidectomy (74%) and 1311 therapy (64%) was from
Jarzab and associates." This group had the lowest incidence
of recurrent cervical metastasis (6%) and the second lowest
rate of distant pulmonary recurrence (6%). The University
of Michigan group had zero recurrence in the thyroid bed."
Similar results were reported by Mazzaferri and Jhiang in
their report on the long-term impact of initial surgical and
medical therapy in 1355 patients (primarily adults) with
DTC. 62 Median follow-up was 15.7 years; 42% of patients
were observed for 20 years and 14% for 30 years. They
reported that patients with tumors 1.5 em or larger or with
tumors that were multicentric, metastatic, or locally invasive
disease had significantly improved long-term outcome-in
terms of recurrence and cancer death-when initial therapy
combines near-total or total thyroidectomy and 1311 remnant
ablation or 1311 therapy for a residual local tumor. 62
ll-year-old boy with bronchiectasis and diffuse macronodularpulmonary metastasis, Figure 10-4 shows the 1311scintiscan
of the lungs 6 weeks after total thyroidectomy. Uptake over
the lungs was 17.4% at 24 hours. This patient eventually
died 7 years later from progressive pulmonary metastasis
despite aggressive 1311 therapy.
The ability to "cure" patients of their pulmonary
metastases is dependent on the initial extent of metastases.
Schlumberger and colleagues, in their study of 283 patients
(29 patients ranging in age from 4 to 19 years) treated with
131
1 for distant metastasis, found that complete remissions
occurred in 64% of patients with normal radiographic examinations at discovery of metastasis and in only 8% of
patients with initially abnormal radiographs." It is important
to detect and treat distant metastasis early rather than late.
Radioiodine
There is considerable experience with the use of 1311 as an
adjunct to surgery in adult DTC. By comparison, there is
less experience with this agent in children. Children are
probably three times more sensitive to radiation than adults
and are at higher risk for cancer over a longer projected life
expectancy after 1311 therapy.v Yet, to date, only one case of
a second cancer (hepatocellular cancer) has been reported in
series reporting their long-term follow-up of children receiving
131
1 therapy. 55 In children, doses as high as 650 mCi have
been used in an effort to eradicate pulmonary metastases/"
In most series, the total dose of 1311 averages a little more
than 200 mCi. 64
Pulmonary metastasis occurs with increased frequency in
children. 4 .64 ,65 Figure 10-3 is a radiograph of the chest of an
FIGURE 10-3. Chest radiograph of ll-year-old boy with diffuse

pulmonary metastasis and bronchiectasis.
99
to 100%.4,11-14,40.64,65 Most deaths occur in children II years

of age or younger at initial diagnosis. Late recurrences of
childhood DTC have been reported up to 20 years after initial treatment." As a result, childhood DTC requires lifelong follow-up.
Summary
FIGURE 10-4. Iodine 131 scintiscan of lungs of the l l-year-old

boy shown in Figure 10-3.
The best results for postoperative whole-body 131 1

scintigraphy are obtained after 4 to 6 weeks of hypothyroid
status to achieve adequate endogenous thyroid-stimulating
hormone (TSH) stimulation or through the use of recombinant human TSH (rhTSH). Initial trials with rhTSH in
euthyroid patients have documented equivalent results with
hypothyroid scans, and in some instances rhTSH scans have
detected additional sites of 131 1 uptake not seen with
hypothyroid scans." Selectivity in the use of 131 1has become
more common over the last 30 years. Ablation of uptake in
the thyroid bed only is not typically performed. Radioiodine
can be used to treat residual microscopic disease, such as
that around recurrent laryngeal nerves and in nonpalpable
lymph nodes as well as pulmonary metastases.
Not only does total thyroidectomy facilitate the detection
and treatment of metastasis with 131 1 but also it allows the use
of serum thyroglobulin as a sensitive indicator of recurrence.
Normal thyroglobulin levels range from 0 to 60 ng/mL.
Patients who have undergone total thyroidectomy and have
no residual disease should have a thyroglobulin level of
5 ng/mL or less. The usefulness of this approach in childhood
DTC was confirmed in a 1992 report.68 The patients in
whom there is no evidence of focal uptake on diagnostic 131 1
scans, but who have increased serum thyroglobulin levels,
may still be candidates for 131 1 therapy.
Long-Term Survival
No single microscopic or ultrastructural feature of childhood
DTC has emerged as a reliable means of predicting a fatal
outcome. Adolescent and adult patients with DTC often have
long periods observed from the time of initial diagnosis and
treatment to the time of eventual recurrence and death. 69.7o
Series reporting only 10- to 15-year follow-up periods are less
meaningful because there have been documented instances of
recurrence 15 to 25 years after initial treatment, and death
may occur as long as 30 years after initial therapy."
Despite presenting with initially more advanced disease, children with DTC have very good long-term
survival. Survival rates vary in the literature from 86%
DTC in children and adolescents is an uncommon disease

with a generally favorable prognosis, a high incidence of
cervical metastasis, and an increased rate of pulmonary
metastasis when compared with that in adults. Although the
treatment ofDTC in children and adults remains controversial,
total thyroidectomy is the best management option. It is safe
when performed by a skilled and experienced endocrine
surgeon. When used with appropriate cervical lymph node
dissection, total thyroidectomy is essential not only for controlling cancer in the neck but for allowing 131 1 ablation
therapy of microscopic regional and distant metastases.
Children with thyroid carcinoma (differentiated or
medullary) should be referred to centers with skilled and
experienced endocrine surgeons. Thyroidectomies and neck
dissections in children should not be performed in community
hospitals or by surgeons who perform such procedures
infrequently. To do so subjects these young patients to
unnecessarily high rates of complications.
Total thyroidectomy, appropriate neck dissection, selective
use of postoperative 131 1, monitoring of serum thyroglobulin,
and thyroid hormone replacement offer children and adolescents the best opportunity for recurrence-free long-term
survival.
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60. Harness JK, Czako PE Ultrasound of the thyroid and parathyroid glands.
In: Harness JK, Wisher DB (eds), Ultrasound in Surgical Practice:
Basic Principles and Clinical Applications. New York, Wiley-Liss,
2001, p 237.
61. Frankenthaler RA, Sellin RV, Cangir A, Goepfert H. Lymph node
metastasis from papillary-follicular thyroid carcinoma in young
patients. Am J Surg 1990;160:341.
62. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and
medical therapy on papillary and follicular thyroid cancer. Am J Med
1944;97:418.
63. National Council on Radiation Protection. Induction of thyroid cancer
by ionizing radiation (NCRP Report No. 80). Bethesda, MD, National
Council on Radiation Protection, 1985.
64. Becker DV, Zawzonico PB. Radioiodine therapy in children. In:
Robbins J (ed), Treatment of Thyroid Cancer in Childhood. Bethesda,
MD, National Institutes of Health, 1994, p 117.
65. Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al. Pulmonary metastases in children and young adults with differentiated thyroid cancer.
Cancer 1993;71:1348.
Childhood Thyroid Carcinoma - 66. Schlumberger M, Tubiana M, DeVathare F, et al. Long-term results of
treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960.
67. Meier CA, Braverman LE, Ebner SA, et al. Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase III!
study). J Clin Endocrinol Metab 1994;78:188.
68. Kirk JMW, Mort C, Grant DB, et al. The usefulness of serum
thyroglobulin in the follow-up of differentiated thyroid carcinoma in
children. Med Pediatr Oncol 1992;20:201.
101
69. Tollefsen HR, DeCosse 11, Hunter RVP. Papillary carcinoma of the
thyroid: A clinical and pathological study of 70 fatal cases. Cancer
1964;17:1035.
70. Tollefsen HR, Shah JP, Huvos AG. Follicular carcinoma of the thyroid.
Am J Surg 1973;126:523.
71. Harness JK, McLeod MK, Thompson NW, et al. Deaths due to
differentiated thyroid cancer: A 46-year perspective. World J Surg
1988;12:623.
Papillary Thyroid Carcinoma:

Rationale for
Hemithyroidectomy
Yoshihide Fujimoto, MD, PhD Takao Obara, MD, PhD
Takahiro Okamoto, MD, PhD
Current Considerations
Papillary thyroid carcinoma is a rather common disease, at
least in iodine-sufficient areas. Surgical treatment of this
disease has remained controversial concerning the extent of
thyroidectomy and the need for prophylactic lymph node neck
dissection. The controversies persist because of the surgical
complications associated with total or near-total thyroidectomy, which depend on the skill of the surgeon. On the other
hand, because of the increased risk of recurrence and possibly
cancer-related death after conservative surgery, there is a
general consensus that postoperative thyroid-stimulating hormone (TSH) suppression therapy should be routinely given to
all patients with papillary thyroid carcinoma.
Attempts to determine prognostic factors, based on large
retrospective studies of patients who underwent thyroidectomy for differentiated thyroid cancers, have been carried
out at many institutions in North America,"? Japan.v" and
Europe.r-" In 1979 15 and 1988,1 Cady and associates at the
Lahey Clinic proposed a simple scoring system, AMES
(age, distant metastasis, extrathyroid invasion, and size of
the primary lesion), to predict the outcome of patients with
differentiated thyroid carcinoma at the time of initial surgery.
Hay and colleagues at the Mayo Clinic proposed another
prognostic scoring system, AGES (age, histologic grade,
extrathyroid invasion and distant metastasis, and size) in
1987. 16 In 1979, Byar and the European Organization for
Research on Treatment of Cancer Thyroid Cancer Cooperative
Group'? published yet another staging system, taking into
account the following variables: age, sex, principal cell type,
extrathyroidal invasion, and the presence of distant metastases. The International Union Against Cancer introduced
the TNM staging system in 1987,18 and it was endorsed as
the standard international staging system by the American
Joint Committee on Cancer in 1988. 19 Statistically significant
prognostic factors that are common to all these scoring
systems are the presence of distant metastases and
102
extrathyroid invasion. As for age, most patients with high-risk

papillary thyroid carcinoma are late middle-aged or elderly
persons at the time of initial diagnosis: 41 years or older for
males and 51 years or older for females. There are, however,
patients in all age groups who have low-risk papillary thyroid
carcinoma, as demonstrated in our cohort at Tokyo Women's
Medical University Hospital (Table 11-1). In our series from
1981 to 1989, distant metastases and local extrathyroid invasion were the important prognostic factors for high-risk
papillary thyroid carcinoma, regardless of the patient's age.
Many studies using these scoring or staging systems have
shown that there are two distinctly different risk groups for
patients with papillary thyroid carcinoma.P:" Hay" wrote an
excellent review of all those prognostic scoring systems and
compared them with each other. He reported that both the
AGES and AMES systems allow the best discrimination
between low-risk and high-risk papillary thyroid carcinoma.
The mortality rate in the low-risk cancer group was 1%
at 20 years following surgery, whereas it was 40% in the highrisk cancer group. This excellent outcome for low-risk patients
demonstrates that low-risk papillary thyroid carcinoma is associated with an extremely low risk of cancer death. In iodinesufficient areas, low-risk cancers make up 85% to 90% of all
papillary thyroid carcinomas. In our series at Tokyo Women's
Medical University Hospital, the ratio of the low-risk to the
high-risk groups is 92:8, and at an average 12-year follow-up
the cancer-related death rates in the low-risk and high-risk
groups were 0.5% and 35.1 %, respectively (Table 11-2).
Because many of the results of retrospective, long-term
follow-up studies reveal that low-risk papillary thyroid carcinomas are associated with a low cancer-mortality rate and that
high-risk papillary thyroid carcinomas are associated with a
high cancer morality rate,1,8,16,20-22 it seems rational to treat
these two risk groups differently. Generally, even for patients
with low-risk papillary thyroid carcinoma, curative resection
is most important to prevent local recurrence. If the judgment
of "low-risk cancer" at the initial operation is definite, then
Papillary Thyroid Carcinoma: Rationale for Hemithyroidectomy - -
we determine whether the papillary cancer lesion in a given

patient localizes in one lobe or extends to the contralateral
lobe. Only for the former, we choose hemithyroidectomy to
prevent postoperative cancer recurrence .in the rernn~t
thyroid. The differentiation between the umlateral and bilateral
lesions may be possible by preoperative ultrasonography and
intraoperative careful observation by surgeons. If we perform
total thyroidectomy for all those patients, the procedure may
carry increased surgical complications.
.
Concerning the need for TSH suppression therapy, there
are two views. Most experts routinely administer thyroid hormone to patients for the rest of their lives to suppress pituitary
'~1_
25
TSH secretion.P Others, such as our group, 24 'THUI..
ai,
an d
Boley and associates." do not use th~roid
ho~one
for TS~
suppression therapy in euthyroid patle~ts.
Thl~
approach ,IS
acceptable in patients who have low-risk papillary thyroid
carcinoma that is macroscopically localized in only one lobe,
but in most other patients TSH suppression therapy appears to
be indicated.2.2327 For high-risk patients with papillary thyroid
carcinoma, surgeons should select a more aggressive surgical
approach. This subject is discussed in more detail later.
It is generally recognized that in iodine-rich areas like the
United States and Japan, papillary thyroid carcinoma accounts
for 80% or more of all thyroid cancers,28.29 and the ratio of
low-risk to high-risk carcinoma is close to 9: 1,1.16 whereas in
iodine-deficient areas papillary carcinoma constitutes 60%
or less and the ratio of low-risk to high-risk carcinomas
103
appears to be much higher. 30.31 Thus, the amou?t of i?dine

intake may be a factor in the development of l?w-nsk papill~
thyroid carcinoma.30,32,33 There are three kinds of areas III
terms of the amount of daily iodine intake, which is measured
daily
by urinary iodine excretion. Areas in which the a~erage
urinary iodine excretion is 50 ug or le~s are c?ns.ldered t~ be
iodine deficient." In most of the previously iodine-deficient
areas of Europe, iodide has been added to table salt. Urinary
iodine excretion has increased to 100 to 200 ug daily." The
average daily iodine excretion in the United States is 500 to
700 Ilg 36 and that in Japan is as high as 1000 to 1500 Ilg.37 In
most Western countries, supplemented iodine has been added
to the water or diet so that some populations are in a transition
from iodine-deficient to iodine-sufficient states. It appears that
iodine deficiency should be a consideration when we treat
patients with papillary thyroid carcinoma.
.
TSH suppression therapy has long been applied postoperatively as an effective modality to prevent recurrence or to
prevent regrowth of unresected cancer t~ss?es.left
?ehind at
~eas,
the initial operation.P However, at least III IOd~ne-nch
large, long-term, retrospective follow-up studies of patients
who underwent surgery for papillary thyroid carcinoma by
Cady and others, 1,38 Vickery and colleagues." and our gr~up40
showed that TSH suppression therapy was not associated
with improved survival in patients with low-risk carcinomas,
probably because these patients have an exceedingly favorable
prognosis even without TSH suppression.
Definition, Advantages, and

Disadvantages of
Hemithyroidectomy
Hemithyroidectomy can be used in a patient with low-risk
papillary thyroid carcinoma that is macroscopically l.ocalized
in one thyroid lobe. In this procedure, the whole involved
lobe, the isthmus, and occasionally the medial portion of the
contralateral lobe are resected. When the medial third of the
contralateral lobe is included in the resection, the thyroid operation is referred to as subtotal thyroidectomy in the United
States" and in Japan. 8.24 We include patients who had subtotal
thyroidectomy in our group of hemithyroidectomy patients.
We have performed subtotal thyroidectomy and lobectomy
(removal of one lobe without resection of the isthmus) in 71 %
and 13%, respectively, among our group of 408 patients with
low-risk papillary thyroid carcinoma (Table 11-3).
The advantages of this surgical approach are that, when
compared with total thyroidectomy, surgical complications
including permanent hypoparathyroidism and bilateral
recurrent laryngeal nerve palsy are lower, even when an
inexperienced surgeon perforrns the operation. In patients
treated in this manner, only one of the two recurrent nerves
and two or three of the four parathyroid glands are at risk.
Most patients are also euthyroid postoperatively, so that lifelong thyroid hormone replacement therapy is unnecess~ry.
When we recently examined thyroid function by measunng
serum thyroxine (T 4 ) , triiodothyronine (T 3), and TSH concentrations in 150 patients who had hemithyroidectomy,
95 (63%) of all patients examined were euthyroid, 31 (21 %)
had subclinical hypothyroid (low T 4 and normal T 3 with
abnormally high TSH), and 24 (16%) were hypothyroid.
104 - -
Thyroid Gland
indicator of persistent or recurrent disease because of the

presence of a thyroid remnant and (2) distant metastases are
often not detected by postoperative radioiodine scanning
because of the presence of a thyroid remnant.
Rationale and Indications for

Hemithyroidectomy
Although there are only a few long-term retrospective studies of patients with low-risk papillary thyroid carcinoma who
had hemithyroidectomy as compared to patients who had total
or near-total thyroidectomy,' tumor recurrence may occur at
significantly higher rates after hemithyroidectomy than after
near-total or total thyroidectomy.W? Russell.f Katoh,44 and
their coworkers reported that thyroid carcinoma disseminates
from the primary tumor site to all parts of the gland through
intrathyroidal lymphatics in 87.5% and 78.1%, respectively.
Despite this observation, the incidence of actual tumor recurrence in the contralateral lobe after hemithyroidectomy is
surprisingly low (4.7% to 24%, mean recurrence about 7%).45
When hemithyroidectomy is carried out with strict indications,
the recurrence rate is much lower only in those patients in
whom preoperative ultrasonography does not demonstrate
minute cancer lesions in the contralateral lobe and enlarged
lymph nodes in the contralateral jugular chain, as demonstrated in our series. Only 2 (0.6%) of our 348 patients experienced recurrences in the thyroid remnant when these patients
were monitored for an average of 12 years (Table 11-4).
Two additional disadvantages of hemithyroidectomy are that
(1) determination of serum thyroglobulin as a tumor marker
in the postoperative follow-up period is not as sensitive an
Before 1945, thyroid cancers were more aggressive tumors in

most other parts of the world except Japan. This is probably
because in Japan there was high iodine intake as a result of
the consumption of seaweed and seafood. In the United States,
the addition of iodine to table salt, bread, and water was begun
in the 1920s and 1930s, and in European countries it was
added after the end of World War II. Currently, most
of the Western countries have become iodine sufficient,
and some even iodine rich, such as the United States. Whereas
the biologic characteristics of thyroid cancers have remained
virtually unchanged in Japan, there have been considerable
changes in clinical and survival patterns in patients with thyroid cancers in the United States. 26,46 In iodine-rich areas,
approximately 90% of all differentiated thyroid cancers of
follicular cell origin are papillary thyroid carcinomas, and of
these, approximately 90% are low-risk cancers."
Using Cady's AMES scoring system, it is usually easy to
determine whether a patient should be included in a low-risk
or a high-risk category at the time of initial operation. I Hay
and associates? in 1993 proposed a new prognostic scoring
system, MACIS (metastases, age, completeness of resection,
invasion, and size), which is applicable at the time of surgery
by excluding histologic grade from the previous AGES classification system.
The introduction of fine-needle aspiration biopsy has
greatly facilitated the accurate preoperative diagnosis of
papillary thyroid carcinoma. Therefore, surgeons should
usually be able to determine whether a patient is at high or
low risk at the time of the initial surgery based on either
AMES, MACIS, or any other classifying system. Since this
high- or low-risk information is 97% to 99% accurate, it
should be useful in selecting the extent of thyroidectomy
that will result in the best prognosis with the least risk of
complications.
Papillary Thyroid Carcinoma: Rationale for Hernithyroideetomy - -
Hemithyroidectomy should be performed for low-risk

papillary thyroid carcinoma that is macroscopically localized to one lobe to decrease the risk of local recurrence. We
believe that even when a patient is in the low-risk papillary
thyroid carcinoma group, total thyroidectomy or near-total
thyroidectomy is preferable to hemithyroidectomy when the
patient has (l) multicentric occurrence of cancer in both
lobes or (2) markedly invasive cancer in both lobes, including
the diffuse sclerosing variant of papillary carcinoma that
occurs in young individuals.f
Whether these cancers can be diagnosed at the time of
hemithyroidectomy is controversial. Using preoperative or
intraoperative ultrasonography and careful palpation of the
105
thyroid gland, experienced surgeons can usually know at

the time of operation whether there is significant bilateral
involvement. Lesions as small as 2 mm can be detected in
the otherwise normal thyroid tissue by these methods. In
Japan, preoperative ultrasonography has been widely used
in many institutions.
After a hemithyroidectomy is carried out, the resected
thyroid specimen is longitudinally cut on the operating table
as a routine procedure and the cut surface is macroscopically examined. Hemithyroidectomy is usually indicated
when papillary thyroid carcinoma on the cut surface shows
a well-circumscribed lesion without any associated satellite
lesions (Fig. Il-lA) or with a small number of minute
FIGURE 11-1. Macroscopic views of the cut surfaces of surgical specimens obtained by hemithyroidectomy (A, B) or total thyroidectomy
(C), showing various modes of intrathyroid papillary cancer spread. A, A sharply marginated primary lesion, measuring 3 x 2 em, is located
in the left thyroid lobe and accompanied by four proven metastatic jugular chain nodes and one peritracheal node. The patient is a 43-yearold woman who is currently alive, well, and euthyroid without thyroid-stimulating hormone (TSH) suppression 10 years postoperatively.
B, A 3 x 2-cm lesion was found in the right lobe with intrathyroid satellite lesions (arrowheads) associated with proved metastatic lesions
in two jugular nodes and one peritracheal node. The patient was a 43-year-old woman who is alive, well, and euthyroid without TSH suppression 9 years after surgery. C, A diffusely infiltrating, whitish papillary carcinoma was found in the right lobe, and many tiny intrathyroid metastatic foci were found in the left lobe. Miliary lung metastases were noted on a chest radiograph at the time of operation. Total
thyroidectomy and bilateral neck dissection followed by 1311 therapy were performed on the patient, a 30-year-old woman who is alive with
disease 9 years after surgery, under TSH suppression therapy.

lesions only in areas close to the main lesion (Fig. 11-1B),
and the contralateral lobe is normal to palpation.
Intrathyroidal deposits of cancer are seen as whitish spots.
When we have observed that papillary thyroid cancer tissue is
known preoperatively to contain psammoma bodies, as in the
case of the diffuse sclerosing variant, psammomatous shadows
on a soft tissue roentgenogram of a resected specimen indicate intrathyroidal cancer spread." When intrathyroidal
metastatic lesions are in close proximity to the surgical
margin (Fig. 11-2), the remaining contralateral lobe should
be removed.
Previously, we occasionally failed to detect pulmonary
metastases in young patients with papillary thyroid carcinoma because of normal chest radiographs at the time
of the initial operation. Those patients subsequently experienced miliary lung metastases. They usually have diffusely
invasive growth of cancer in the thyroid gland (see Fig. 11-1C )
and often have multiple lymph node metastases. Today,
we recommend preoperative computed tomography scanning of the chest in such patients to detect lung metastases
preoperatively. Those patients are then classified as
high risk and are treated by total thyroidectomy. In our
follow-up study, we also noted the postoperative development of lung metastasis in elderly patients, most of whom
had a large primary tumor at the initial surgery. This result
indicates the importance of tumor size as one of the criteria
for classifying a high-risk patient who is elderly. Because
of these observations, we currently perform more total
thyroidectomies than in the past, although most lung
metastases in elderly patients did not actually take up
radioiodine.
In our series at the Tokyo Women's Medical University
Hospital, 408 patients with low-risk papillary thyroid
carcinoma were treated from 1981 through 1989, a
total thyroidectomy was done in 60 (15%), hemithyroidectomy including partial resection of the contralateral
lobe in 343 (84%), and partial lobectomy in 5 (1%) (see
Table 11-3). An average 12-year follow-up study in
these patients was completed through August 15,2002, and
these results are shown in Table 11-4. Of the 343 hemithyroidectomy patients, only 2 patients (0.5%) died of thyroid
cancer. Two patients (0.5%) had recurrence in the remaining contralateral thyroid lobe. Local recurrence in the
thyroidectomy bed and at the scar of open biopsy carried
out elsewhere occurred in 5 patients and 1 patient, respectively. Cancer recurrence in lymph nodes was noted in
a total of 31 patients (8.8%) who had undergone modified
radical neck dissection and in 2 who had not undergone
neck lymph node dissection. Lung metastasis was detected
in 15 patients: 5 (8.5%) of 59 patients who had total
thyroidectomy and 10 (2.9%) of 343 patients who
had hemithyroidectomy. All 5 patients who had total
thyroidectomy failed to have radioiodine uptake in the
lung metastases. The 4 patients treated with hemithyroidectomy underwent completion total thyroidectomy,
and only 1 of them was successfully treated with 1311. The
other 3 patients did not have radioiodine uptake in the lung
metastases. In the remaining 6 patients, a completion
total thyroidectomy was not performed because of the
patients' age, associated diseases, and/or concomitant
recurrences.
FIGURE 11-2. Soft tissue roentgenogram of a thyroid specimen

resected by subtotal thyroidectomy in a female patient with the diffuse sclerosing variant of papillary carcinoma. Note the presence
of many psammomatous calcifications throughout the whole specimen, including the surgical cut end (arrow), which definitely indicates cancer remaining in the rest of the thyroid lobe.
Additional Considerations and

the Need for Combined Lymph
Node Neck Dissection
Some papillary thyroid carcinomas invade the intrathyroidal
lymphatic channels and spread intrathyroidally via the richly
distributed lymphatic vessels.43,44 When Lipiodol Ultrafluid
(2 mL of radiopaque material used for lymphography) is
injected into the thyroid lobe, the material quickly enters the
lymphatic network in the thyroid gland. The flow is directed
upward to the upper pole of the thyroid lobe and within
30 minutes goes through the lymphatic vessels along the
superior thyroid artery to the nodes located at the site where
the internal and external carotid arteries originate from the
common carotid artery (Fig. 11-3). These studies document
that the whole thyroid gland has a very rich network of lymphatic vessels and that the lymphatic drainage is upward.'?
The intrathyroidal lymphatics, draining lymphatics, and
regional lymph nodes represent a thyroid-lymphatic organ
unit. This is best demonstrated by two specific variants of
papillary thyroid carcinoma. One of them is the diffuse sclerosing variant of papillary carcinoma, in which even a tiny primary lesion may cause involvement of a whole thyroid gland
and bilateral jugular node metastases through intrathyroidal
and extrathyroidal lymphatic vessels (Fig. 11-4) without any
distant metastasis." The other example is a small papillary
thyroid carcinoma located in the upper pole of the thyroid
Papillary Thyroid Carcinoma: Rationale for Hernithyroidectomy - -
107
FIGURE 11-3. Thyroid lymphogram of a patient with simple
goiter taken 30 minutes after percutaneous injection of Lipiodol

Ultrafluid, showing an abundant network of intrathyroid lymphatic
channels and a rapid upward flow of the lymph from belowin the
lobe. The contrast materialhas reachedthe upperand middlejugular nodes. (Courtesy of Nobukatsu Kasai, MD, Cancer Institute
Hospital, Tokyo.)
lobe, which often causes metastatic lymph node enlargement
in the upper jugular chain (Fig. 11-5). Papillary thyroid cancer
cells from the upper pole lesion easily enter the lymphatic vessels and spread to the regional lymph nodes. In most of these
patients, the initial clinical finding is nodal enlargement in the
submandibular region, and the primary lesion in the thyroid
may be barely palpable or not palpable. We consider it necessary to remove regional cervical nodal metastases if one wants
to perform an en bloc procedure.
Although the presence of regional node metastases has
only a small effect on the life expectancy of patients with
low-risk papillary thyroid carcinoma, especially in iodinesufficient areas such as the United States and Japan,3,6,20,39,46
most endocrine surgeons recommend ipsilateral, or occasionally bilateral, modified radical neck dissection along
with a central neck dissection in patients with clinically recognizable lymph node metastases.
Prophylactic lymph node neck dissection is generally not
recommended, except in children,5o,51 in Western countries.
Although 80% to 90% of patients with papillary thyroid
carcinoma have microscopic metastases in the regional
nodes, the subsequent clinical appearance of lymph node
metastases occurs in only about 7% to 15% of patients who
have had no lymph node dissection. 20,46,52-54 Furthermore, if
dissection is delayed, the survival rate is not decreased.'
In Japan, previously, many patients presented with
marked lymph node metastasis preoperatively, and most
FIGURE 11-4. Simple soft tissue roentgenogram of a thyroid
specimenresected from a patientwith the diffuse sclerosing variant

of papillary carcinoma, showing a network of intrathyroid
lymphatics, which was eventually constructed of numerous psammoma bodiespresentin cancer tissue growing in intrathyroid lymphatic vessels.
postoperative local recurrences were due to cervical lymph
node metastases. To decrease recurrences, in most Japanese
institutions, modified neck dissection had been carried out
almost routinely for patients with papillary thyroid carcinomas 1.5 em or larger.55 Today, the number of patients with
incidentally found small papillary carcinoma without palpable lymph node metastases has increased because of the
increased use of annual health examinations. We have found
that, even with modified neck dissection, many patients
complain of postoperative neck discomfort. Therefore, prophylactic lymph node dissection is less likely to be done in
these patients than before.
Postoperative Adjuvant Therapy

Because of the excellent prognosis of most patients with
low-risk papillary thyroid carcinoma, it has been difficult to
demonstrate any benefit from adjuvant therapy in the form
of radioiodine or TSH suppression therapy. Vickery;'?
Cady,I,38 and their associates concluded that the usual course
of low-risk papillary carcinoma treated by conservative
surgery is generally so benign that further beneficial effects
of radioiodine, thyroid suppressive treatment, or total
thyroidectomy have never been convincingly shown. In a
report from the Mayo Clinic.j" where postoperative radioiodine ablation therapy has been used since 1976, Hay
Treatment of High-Risk
Papillary Thyroid Carcinoma
FIGURE 11-5. Cut surfaces of a surgically resected right thyroid
lobe and the right jugular chain nodes taken from a 52-year-old
woman who had been aware of the enlarged lymph nodes for
4 years. At the operation, the node measured 4.5 em (curved
arrow), and the primary lesion (straight arrow) in the upper pole
of the right thyroid lobe measured 1.5 x I cm. The patient is currently alive andwell 12years after the operation, and she is euthyroid without thyroid-stimulating hormone suppression.
presented his own disappointing results in terms of prevention of tumor recurrence and mortality and also reviewed
historic trends of this procedure, including published
critical opinions against its effectiveness. Once TSH suppression therapy begins, patients must take the hormone
daily for the rest of their lives. Such life-long therapy is not
easy for either physician or patient, especially in developing countries.
Hernithyroidectomy, leaving enough thyroid tissue to
maintain normal thyroid function postoperatively, is easier
for patients, unless TSH suppression therapy is required.
Approximately 35% of our patients who underwent
hemithyroidectomy have an elevated TSH level and have
consequently been treated with L-thyroxine (25 to 150 ug
daily) to normalize the serum TSH concentration.
Although we adopted TSH suppression therapy in the
1950s and 1960s, when accurate determination of serum
TSH concentration first became available in 1970, we were
surprised to find poor drug compliance. We also noted
no difference in the postoperative tumor recurrence rate
or in the cancer mortality rate in patients with a suppressed
serum TSH level and those with nonsuppressed TSH
levels. 56,57 Since then, many institutions in Japan have
used hernithyroidectomy to preserve the normal thyroid
function after surgery, and if the patients are euthyroid, no
thyroid hormone therapy is given. We adopted this strategy
in 1970, and so far we have had satisfactory follow-up
results,
Patients with high-risk papillary thyroid carcinomas may

have local extrathyroid invasion and distant metastases. The
cancer-related mortality rate is about 40% at 20 years after
surgery." The main causes of death are either locally progressive cervical disease or distant metastases.
Most experts from the United States and from European
countries advocate total thyroidectomy followed by 1311wholebody scan and ablation with TSH suppression therapy more
for high-risk than for low-risk patients. 12,16,4 J,52,S8 If the cancer
invades into the adjacent structures and it is not possible to
resect the tumor with negative margins, radioiodine treatment
should be given. When there is no or inadequate uptake or progression of disease, external irradiation is used.20,52
Older patients with high-risk papillary thyroid carcinoma
appear to be much less sensitive to both TSH suppression
therapy and radioactive iodine therapy than younger patients
with low-risk cancers. We, therefore, believe that high-risk
patients should be treated more aggressively with total or
near-total thyroidectomy and radical or modified ipsilateral
neck dissection, including partial or sleeve resection of the
trachea, if it is invaded. This therapy appears to increase
patients' quality of life and may be curative. 59 -62
Summary
We recommend a selective approach to the treatment of
patients with papillary thyroid carcinoma. We include
patients with direct extrathyroid invasion and distant metastases in our high-risk group, regardless of age. For low-risk
patients, if a cancer is macroscopically localized in one lobe,
we recommend hemithyroidectomy and, for those with
clinical lymph node metastases, ipsilateral modified radical
neck dissection with no postoperative radioiodine therapy or
TSH suppression unless the patient is hypothyroid. For
high-risk patients we recommend total thyroidectomy,
resection of adjacent structures if invaded by cancer, and
ipsilateral radical or modified neck dissection with postoperative TSH suppressive therapy,
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Papillary Thyroid Carcinoma:

Rationale for Total
Thyroidectomy
Orlo H. Clark, MD
Considerable controversy continues about whether all or

part of the thyroid gland should be removed for patients with
differentiatedthyroid cancer of follicular cell origin (papillary,
mixed papillaryfollicular,follicular,and Hiirthle cell), because
there are no controlled, prospective studies comparing the
results of different methods of treatment (lobectomy, neartotal thyroidectomy, or total thyroidectomy). Patients with
these thyroid cancers also generally have a good prognosis,
with an overall mortality of about 20%, so that studies comparing survival must include large numbers of patients who
are monitored for a long period. The rate of thyroidectomy
complications, including vocal cord paralysis resulting from
recurrent laryngeal nerve injury and hypoparathyroidism,
should be low but ranges from less than 1% to more than
10%.1-4 Complications are reported to increase in patients
having more extensive thyroid operations, especially when
thyroidectomy is associated with central and modified radical
neck dissection.v'
Most surgeons and endocrinologists recommend thyroid
lobectomy for patients with occult papillary thyroid cancers
1 em) and for patients with minimally invasive follicular
thyroid cancer, because these patients have little risk of
dying from these tumors. Lobectomy with isthmectomy is
also the treatment of choice for noncompliant patients who
will not take thyroid hormone and for patients who do not
have access to thyroid hormone. Other surgeons recommend
a similar approach for patients determined to be at low risk
by the AGES (age, grade, extent, size) (Table 12-1) or AMES
(age, metastases, extent, size) classification, and more
extensive resection (near-total or total) is recommended for
high-risk patients and for patients with bilateral tumors
(Table 12-2).6,7
Other surgeons recommend total thyroidectomy for all but
very low risk patients with papillary and follicular cancers, as
described previously, when this operation can be done safely
2% complication rate of recurrent laryngeal nerve injury or
permanent hypoparathyroidisml.s'P A near-total thyroidectomy rather than a total thyroidectomy is recommended when
110
the surgeon believes that the viability of the parathyroid

glands or recurrent laryngeal nerve might be compromised;
therefore, a little thyroid tissue is preserved to avoid injury
to the parathyroid glands and recurrent nerve on the contralateral side of the cancer. The remnant tissue in these
patients can subsequently be ablated with iodine 131. The
smaller the remnant, the less radioiodine is required to
ablate it. 13 It is difficult for me to understand, however, why
one would recommend a near-total rather than total thyroidectomy when both recurrent laryngeal nerves have been
clearly identified and the parathyroid glands are situated off
the thyroid gland or have already been dissected off the thyroid
gland. The advantage of total thyroidectomy over near-total
thyroidectomy is that it eliminates the need to give an ablative
dose of 1311 to destroy this remnant thyroid tissue, because
all thyroid tissue has been removed. The 1311 that is given
should therefore be effective in detecting or destroying possible metastatic disease. In my analysis of radioiodine therapy
in 400 patients with thyroid cancer of follicular cell origin,
about 65% of the patients' tumors took up enough 1311
for this treatment to be effective. Similar results have been
reported by Schlumberger and associates." Recent investigations suggest that redifferentiation of some papillary
thyroid cancers may improve the effectiveness of radioiodine therapy.P:"
The purpose of this chapter is to describe the rationale for
total thyroidectomy based on the pathophysiology of differentiated thyroid cancer and the short- and long-term results
as well as the complication rate. Some surgeons also recommend total thyroidectomy for patients with benign thyroid
problems such as Graves' disease and bilateral multinodular
goiters because it eliminates the risk of recurrent disease.I':"
Total thyroidectomy is also recommended by some surgeons
for patients with thyroid nodules and a history of exposure
to low-dose therapeutic radiation and for patients with
familial papillary thyroid cancer, because these tumors are
often multifocal with both benign and malignant tumors in
the same thyroid gland.':":"
Papillary Thyroid Carcinoma: Rationale for Total Thyroidectomy - -
Papillary thyroid cancer, including mixed papillary

follicular thyroid cancer and follicular variants of thyroid
cancer, is the most common thyroid cancer (""80%); luckily,
patients with this tumor have the best prognosis.Ui'? It is
somewhat surprising that patients with this tumor, and
especially young patients, do so well, because papillary
thyroid cancers are often (:5:88.5%) multifocal within the
thyroid gland and regional cervical lymph nodes are
involved, at least microscopically, in up to 80% of these
patienrs.P-" Some patients have poorly differentiated papillary thyroid cancers, including tall cell and columnar cell
tumors, and these patients have a worse prognosis.F'"
Follicular thyroid cancers account for about 10% of all thyroid cancers and are more common in patients from iodinedeficient areas (i.e., areas of endemic goiten." Follicular
thyroid cancers are usually solitary tumors within the thyroid gland, and only about 10% are multifocal or involve the
cervical lymph nodes. 12,25 Medullary thyroid cancers
account for about 5% of all thyroid cancers; about 70%
occur sporadically, and 30% are familial. These tumors are
bilateral in most patients with familial medullary thyroid
cancer and in patients with multiple endocrine neoplasia
types 2A and 2B. Regional lymph nodes are present in 60%
of patients with primary medullary thyroid tumors larger
than 2 em."
Htirthle cell thyroid cancers are included with follicular
thyroid cancers in the World Health Organization classification. I believe, however, that they should be classified
separately. Although they are of follicular origin and usually
secrete thyroglobulin-like follicular cancers, Htirthle cell
111
carcinomas, in contrast to follicular carcinomas, usually

do not trap radioiodine (only 10%), whereas most follicular
carcinomas do. Also, about 30% are multifocal, whereas follicular cancers are usually solitary. In addition, they involve
regional lymph nodules (30%), whereas follicular cancers
usual~y
do not (6%),27,28 A Hurthle cell variant of papillary
thyroid cancer has also been identified.
The remaining thyroid tumors, including anaplastic
cancer, thyroid lymphoma, teratomas, squamous cell cancers, and carcinosarcomas, account for 1% to 2% of all thyroid cancers. These are aggressive tumors (see Chapter 44).
About 80% of the anaplastic thyroid cancers also contain a
differentiated thyroid cancer, suggesting a possible progression from differentiated to undifferentiated tumors." Recent
experimental findings support this clinical observarion.l"
Luckily, this occurs in only about I% of patients with
differentiated tumors.'!
. As mentioned, patients can be separated into low- and highnsk groups on the basis of patient age, grade of tumor, extent,
and size of the tumor (AGES)7,32 or on age, metastases, extent,
and size (AMES).6,33 Other factors also predict the behavior
of a thyroid cancer, including (1) surgical resectability."
(2) ploidy of the tumor.i-" (3) adenylate cyclase response
to thyroid-stimulating hormone (TSH),36 (4) radioiodine
uptake." and (5) epidermal growth factor (EGF) receptor
leveJ.38,39 Other factors also include the presence of specific
oncogenes or tumor suppressor genes such as gsp, ras, ret,
and 'p'53 as w~ll as whether the patient has nonmedullary
familial thyroid cancer. 40.43 Patients whose tumors cannot
be completely resected.t' those with aneuploid DNA,35
those with a low adenylate cyclase response to TSH,36 those
with a low or absent radioiodine uptake.'? and those whose
tumors have more EGF binding have a worse prognosis.V-"
Unfortunately, many of these factors or conditions, such
as invasion, distant metastases, and resectability, are determined only postoperatively. Thus, the AGES and AMES
classifications, as well as the TNM, MACIS (distant metastasis, patient age, completeness of resection, local invasion,
tumor size) or European Organization for the Research
and Treatment of Cancer (EORTC) classifications, which are
used to separate patients into low- and high-risk groups, are
postoperative, rather than preoperative, classifications.r' These
classifications, however, do help predict tumor behavior,
because the risk of death from thyroid cancer in low-risk
patients is about 5%, whereas in the high-risk patients it is
about 40%. Fortunately, most patients (""70%) are in the
low-risk group.
Despite the excellent outcome among most patients with
thyroid cancer, I believe that if one can decrease the death
rate from 5% to 2% or 3% and the rate of complications is
less than 2%, one should perform a total thyroidectomy
because not only is this operation associated with fewer
recurrences but also several studies report improved survival.
Grant and associates" reported that bilateral thyroid procedures decreased recurrence in both low-risk and high-risk
patients and death and recurrence rates in high-risk patients.
Cady and colleagues," who are advocates of lobectomy for
low-ris~
patients with papillary thyroid cancer, reported
that, usmg the AMES classification, 11% of their low-risk
patients experienced recurrent tumors and 33% of these
patients subsequently died of thyroid cancer.
112 - -
Thyroid Gland
Although some studies suggest that the survival rate

is comparable in patients with thyroid cancer treated by
either lobectomy or total thyroidectomy.f'" other studies,
including those of Massin" Schlumberger," Defrroot," I
Mazzaferri,s2,s3 Loh,s4 and their colleagues, document not
only decreased recurrence but also improved survival when
patients were treated by total or near-total thyroidectomy
and postoperative 131 1 therapy, The benefits are similar to
those obtained by not smoking or by coronary artery surgery
for patients with three-vessel occluding coronary artery
disease. ss-s7
The benefits of total thyroidectomy, in order of importance,
are as follows:
1. Thyroid tissue is removed so that postoperative 131 1
scanning and ablative therapy can be effective.
2. Serum thyroglobulin levels are rendered more sensitive
for detecting recurrent or persistent disease,
3, Intrathyroid cancer that is present in more than 50% of
patients is removed.
4. The small risk of a differentiated thyroid cancer becoming
an undifferentiated thyroid cancer is decreased.
I also recommend completion total thyroidectomy, except
for patients who have occult papillary or minimally invasive
follicular thyroid cancers. When the initial thyroid operation
was a total lobectomy, this completion thyroidectomy should
not be associated with any higher risk of complications, as my
colleagues and IS8 and others" have reported. The best time to
perform a total thyroidectomy is also at the initial operation,
when it can be done safely and there is less scarring.
Some experts question whether a total thyroidectomy can
be done because most patients have some uptake of radioiodine after total thyroidectomy. Among my own patients,
about 25% have no uptake above background, and in most
of the others the uptake is less than 1%. Higher uptake
usually occurs in patients with residual disease. As reported
by Leung,'? Park,60 and their coworkers, it is easier and takes
less 131 1 to destroy small thyroid remnants than to destroy
larger thyroid remnants.
Recent studies support the use of ultrasonography prior
to the initial operation or reoperation. Such studies frequently
document multifocal or bilateral papillary thyroid cancers as
well as regional lymph node metastases."
The technique of total thyroidectomy that I use is similar
to that described by Thompson and associates' and Perzik. 64
The side of the dominant or suspicious nodule is mobilized
by (1) dividing the middle thyroid veins laterally;
(2) dividing the inferior thyroid veins on the trachea in
the midline as well as dividing the thyrothymic ligaments;
(3) looking for a Delphian node and pyramidal lobe and
dividing the fascia just superior to the thyroid isthmus;
(4) mobilizing the tissues laterally and then medially along
the upper portion of the thyroid; (5) dividing and ligating the
superior thyroid vessels individually relatively low on the
thyroid gland to avoid injuring the external laryngeal nerve;
(6) sweeping the tissues laterally from the thyroid gland
with blunt dissection, and dividing any remaining middle
thyroid vein or veins; and (7) identifying the recurrent laryngeal nerve and upper parathyroid gland at the level of the
cricoid cartilage where the nerve enters posterior to the
cricothyroid muscle. The upper parathyroid glands are more
consistent in position and more dorsal or posterior than the
lower parathyroid glands, and they are usually the easiest

parathyroid glands to dissect from the thyroid on a vascular
pedicle. The lower parathyroid glands are almost always situated anterior to the recurrent laryngeal nerves. Once the recurrent nerve has been identified, the dissection may proceed
more quickly. No tissue that might be the recurrent nerve
should be divided until the recurrent nerve has been definitively identified. When bleeding occurs in the region of the
recurrent laryngeal nerve, it should be controlled by gentle
pressure until one is sure that the nerve is not at risk. A similar
technique is used on the other side after mobilization of the
first lobe and after the thyroid mobilization across the midline
of the trachea. All enlarged or abnormal lymph nodes adjacent
to the thyroid should be removed, and a functional lateral neck
dissection should be done when palpable nodes are present.
After total thyroidectomy, the removed thyroid gland is
inspected to be sure that it does not contain a parathyroid
gland. If a parathyroid gland has been removed, it should be
dissected off the removed thyroid, a small biopsy taken for
frozen section confirmation, and the remnant kept in iced
saline. If this proves to be a parathyroid gland, it should be
autotransplanted in l-mm pieces in separate muscular pockets
within the sternocleidomastoid muscle and marked with a
suture or clip.
Postoperatively, a sterile pressure dressing is applied and
the patient is placed in a low Fowler's position (back and head
elevated 20 degrees). Medications are ordered for nausea.
In 300 consecutive patients having total thyroidectomy,
my colleagues and I had no cases of unplanned permanent
recurrent laryngeal nerve injury, and two patients 1 %) had
permanent hypoparathyroidism.' Most of our patients after
total or other thyroid operations are discharged on the first
postoperative day.
Summary
Surgeons performing thyroid surgery must learn how to
perform a safe total thyroidectomy by training with an experienced thyroid surgeon. Numerous surgeons have demonstrated that total thyroidectomy can be done with minimal
morbidity.I,8-10,17,63 The complication rate is higher in
patients with extensive invasive tumors, marked lymphadenopathy, and in those requiring reoperation. When
total thyroidectomy can be done safely, it is the treatment of
choice for most patients with thyroid cancer because
persistent or recurrent disease can be detected earlier by
determining increased serum thyroglobulin levels and by
scanning with radioiodine. When metastatic thyroid cancer
is detected early, it can often be ablated with 1311.14,64,6S
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human thyroid cancers. Cancer Res 1988;48:4459.
42. Santoro M, Dathan NA, Berlingieri MT, et al. Molecular characterization of RETIPTC3, a novel rearranged version of the RET
protooncogene in a human thyroid papillary carcinoma. Oncogene
1994;9:509.
43. Grossman RF, Tu SH, Duh QY, Siperstein AE, et al. Familial nonmedullary thyroid cancer. An emerging entity that warrants aggressive
treatment. Arch Surg 1995;130:892.
44. Hay If), Thompson GB, Grant CS, et al. Papillary thyroid carcinoma
managed at the Mayo Clinic during six decades (1940-1999):
Temporal trends in initial therapy and long-term outcome in 2,444
consecutively treated patients. World J Surgery 2002;26:879.
45. Grant CS, Hay Il), Gough IR, et al. Local recurrence in papillary
1988;104:954.
46. Cady B, Sedgwick CE, Meissner WA, et al. Risk factor analysis in
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47. Wanebo Hl, Andrews W, Kaiser DL. Thyroid cancer: Some basic
considerations. CA Cancer J Clin 1983;33:87.
48. Farrar WB, Cooperman M, lames AG. Surgical management of
papillary and follicular carcinoma of the thyroid. Ann Surg 1980;
192:701.
49. Schroder DM, Chambors A, France Cl. Operative strategy for thyroid
cancer: Is total thyroidectomy worth the price? Cancer 1986;58:2320.
50. Massin JP, Savoie lC, Garnier H, et al. Pulmonary metastases in
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for the primary tumor treatment. Cancer 1984;53:982.
51. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history,
treatment, and course of papillary thyroid carcinoma. 1 Clin Endocrinol
Metab 1990;71:414.
52. Mazzaferri EL, Young RL. Papillary thyroid carcinoma: A 10 year
follow-up report of the impact of therapy in 576 patients. Am 1 Med
1981;70:511.
53. Mazzaferri EL, lhiang SM. Long-term impact of initial surgical and
medical therapy on papillary and follicular thyroid cancer. Am 1 Med
1994;97:418.
54. Loh KC, Greenspan F, Gee L, et al. Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas.
55. Wong JB, Kaplan MM, Meyer KB, Pauker SG. Ablative radioactive
iodine therapy for apparently localized thyroid carcinoma: A decision
analytic perspective. Endocrinol Metab Clin North Am 1990;19:741.
56. Kebebew E, Clark OH: Differentiated thyroid cancer: "Complete"
rational approach. World J Surg 2000;24:942.
57. Esnaola NF, Cantor SB, Sherman SI, et al: Optimal treatment strategy
in patients with papillary thyroid cancer: a decision analysis. Surgery
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Surgery 1992;111:604.
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of thirty-three cases. Surgery 1990;108:1014.
60. Park HM, Perkins OW, Edmondson lW, et al. Influence of diagnostic
radioiodines on the uptake of ablative dose of iodine 131. Thyroid
1994;4:49.

61. Kebebew E, Duh QY, Clark OH. Total thyroidectomy or thyroid lobectomy in patients with low-risk differentiated thyroid cancer: Surgical
decision analysis of a controversy using a mathematical model. World
Surg 2000;24:1295-1302.
62. Perzik S. The place of total thyroidectomy in the management of 909
patients with thyroid disease. Am J Surg 1976; 132:480.
63. Lennquist S. Surgical strategy in thyroid carcinoma: A clinical review.
Acta Chir Scand 1986; 152:321.
64. Pacini F, Cetani F, Miccoli P, et al. Outcome of 309 patients with

metastatic differentiated thyroid carcinoma treated with radioiodine.
65. Casara D, Rubello D, Saladini G, et aI. Different features of pulmonary
metastases in differentiated thyroid cancer: Natural history and multivariate statistical analysis of prognostic variables. J Nucl Med 1993;34:1626.
Follicular Neoplasms
of the Thyroid
Gerard M. Doherty, MD
In the normal thyroid gland, the basic functional unit is the

follicle. Follicles are single-layer spheres of follicular cells
surrounding a lake of viscous colloid that primarily stores
thyroglobulin. Other cell types that are present in the thyroid
gland are interposed between these follicular spheres. These
cells include perifollicular cells, also called C cells, which
secrete calcitonin, as well as some supportive fibrous tissue,
vascular structures, and nerves. The most common tumors
of the thyroid gland arise from the follicular cells, including both papillary tumors and follicular tumors. Papillary
tumors are discussed elsewhere in this text; however,
follicular cancers are probably best described in the ways
in which they differ from papillary tumors. Papillary tumors
consist of single layers of thyroid cells arranged around
vascular stocks, forming papillations. A substantial minority
of papillary tumors (-40%) also include laminated calcified
spheres called psammoma bodies. Follicular tumors include
neither of these characteristics. The tumor cells surround
persistent spherical follicles that frequently contain a small
amount of colloid compared with normal. The follicular
cells are often bland in their cytologic appearance, although
more aggressive lesions can have more abnormal-appearing
cells. Notably, the tumors that are purely follicular do not
have any of the papillations or psammoma bodies that
are typical of papillary tumors. Tumors that have a mainly
follicular appearance but also contain some papillations
or psammoma bodies are classified as follicular variants
of papillary cancer; their biologic behavior supports their
inclusion as papillary cancers.
Incidence and Prevalence

There are approximately 22,000 new cases of thyroid
cancer, and 1400 people who die of thyroid cancer, in the
United States each year.' Of these, approximately 15% to
20% are follicular neoplasms. Because of the difficulties in
distinguishing follicular from papillary neoplasms in some
marginal cases and because of changes in the definitions of
follicular neoplasms over the past 20 years, exact proportions are difficult to determine. Of all follicular neoplasms
demonstrated by needle aspiration or biopsy, approximately

15% are cancers. Thus, 85% percent of the follicular lesions
diagnosed in the United States each year are benign
follicular adenomas. In Sweden, where reliable cancer statistics can be generated because of a fairly comprehensive
national cancer registry, the incidence of follicular carcinoma of the thyroid appeared relatively stable between 1958
and 1981, at about I case per 100,000 women per year and
0.4 cases per 100,000 men per year.' This study also demonstrated the substantially increased risk of follicular thyroid
cancer in areas with high frequency of an iodine-deficient diet.
In addition, in the same review, there is a gradual increase in
the overall incidence of thyroid cancer over time; almost all
of this increase is accounted for by changes in the annual
incidence of papillary thyroid cancer. The changes in thyroid
cancer incidence over time is complex, however, as shown
by a study in Tasmania that demonstrated an increasing incidence of papillary thyroid cancer and decreasing proportion
of thyroid cancers that are follicular tumors over a 20-year
interval coincident with the discontinuation of universal
iodine supplements.'
Autopsy studies have demonstrated the prevalence of
unrecognized follicular thyroid neoplasms. In a detailed
evaluation of 300 whole thyroid glands from people with no
known thyroid disease, 13 had follicular adenomas (4.3%
overall, 5% of men and 3% of women)." Follicular carcinoma was found in four thyroids (1.3% overall, 0.5% of
men and 3% of women). In a separate study that evaluated
only grossly evident lesions in 625 thyroid glands, only two
follicular carcinomas, both in men, were identified (0.3%
overall)." The difference between these studies probably lies
in the thoroughness of evaluation of each thyroid gland;
unsuspected follicular cancer probably exists in approximately 1% of the population.
The spectrum of clinical follicular thyroid neoplasms
includes follicular adenomas of various histologic types
as well as follicular carcinomas. This chapter describes the
differences between the follicular adenomas and carcinomas
as well as the implications of those differences and presents
a scheme for the management of follicular nodules of the
thyroid.
115
116 - -
Thyroid Gland
Follicular Adenoma
Pathologic Features of Follicular Adenoma
Follicular adenomas are benign tumors of the thyroid gland
that grow in glandular or follicular patterns. They can occur
in any portion of the thyroid and in any age group; they are
more common in young adults. Adenomas are usually solitary and less than 3 em in size, although significant numbers
of exceptions to these rules exist." The lesions tend to grow
slowly within a capsule of surrounding compressed thyroid
glandular tissue. Over time, they develop a dense capsule
surrounding the lesion. Because of this they are more firm
than the surrounding tissue. They become palpable when
they reach 5 to 10 mm in size. On cut section, they vary from
a soft grayish white tissue that bulges out above the cut
surface to brown gelatinous tissue. On histologic examination, the follicular adenoma demonstrates the presence of
follicles (Fig. 13-1). There can be marked variability in the
follicles produced in one follicular adenoma compared with
another. Some follicular tumors can be composed of nearly
solid cords of tumor cells with rudimentary acinar formation. These are also sometimes called embryonal adenomas.
Some follicular adenomas form extremely large dilated
glandular structures with a large amount of colloid and only
a very scant stroma. These follicular adenomas are sometimes
called colloid nodules. Other patterns that are sometimes
recognized include a variant with small well-formed acini
very similar to normal thyroid tissue but with a large amount
of hyalin collagenous fibrous tissue separating the follicles
(fetal adenomas). Finally, adenomas with well-formed follicles but follicular cells that are considerably larger and more
variable in size than usual thyroid follicular cells and that
contain an abundant granular pink cytoplasm are called
Hiirthle cell adenomas.' Hiirthle cell tumors are discussed in
more detail in a separate chapter in this book.
The origin of follicular adenomas and the stimuli that
maintain them are as yet not clear. Investigations have supported the idea that most, if not all, follicular adenomas are
of a monoclonal origin and represent true neoplasms. The
evidence suggesting that follicular adenomas are monoclonal
FIGURE 13-1. Follicular adenoma of the thyroid. Note the

well-formed acini and the intact tumor capsule. Original
magnification x160.
neoplasms comes from cytogenetic or restriction fragment

length polymorphism (RFLP) analysis.?"" Studies have
focused on the growth advantages conferred by these molecular changes. These include activating mutations of the thyroidstimulating hormone (TSH) receptor.!':"
Clinical Features of Follicular Adenoma

Adenomas tend to grow slowly, be unchanged for years at
a time, and become symptomatic only late and rarely. They
are typically discovered by palpation by the patient or physician on directed physical examination. If they are very
inconveniently placed or are allowed to grow to a large size,
the tumors can occasionally cause local symptoms such as
dysphasia, voice changes, stridor, or pain. These symptoms
may be brought on by bleeding or necrosis of the center
portion of the lesion that causes a sudden increase in size. In
that situation, the symptoms may be temporary and a portion of the lesion may become cystic.
The vast majority of follicular adenomas are hypofunctional on radioiodine scan. If imaged in this fashion, they
are seen as "cold" or "warm" (the same as normal thyroid)
nodules. A small proportion of these nodules may be hyperfunctional, concentrating iodine avidly, which may suppress
function in the remainder of the thyroid. They may occasionally produce thyrotoxicosis (toxic adenoma).
Interestingly, once the neoplasm has differentiated as
a follicular adenoma, it appears only rarely if ever to degenerate to carcinoma. There is little evidence in humans to
suggest that adenomas transform into invasive carcinomas.
Changes from hyperplasia to adenoma to invasive carcinoma
are seen rarely in some people who have congenital goitrous
hypothyroidism. This does not appear to be the typical
course in most adults.
The indications for removing a follicular adenoma are
(1) evaluation for possible carcinoma, (2) treatment of toxic
adenoma, and (3) resolution of local compressive symptoms.
Follicular Carcinoma
Pathologic Features of Follicular Carcinoma
Follicular carcinomas are the malignant counterparts to follicular adenoma. Follicular carcinomas come in two anatomic
forms. The less aggressive but more difficult to diagnose
variety is also called the angioinvasive encapsulated carcinoma or minimally invasive follicular carcinoma. These are
usually small and seemingly encapsulated neoplasms of the
thyroid gland that are grossly indistinguishable from follicular adenomas. Microscopically, however, they demonstrate
invasive features that reveal them as carcinomas; with
only minimal invasion, these tumors can have an excellent
prognosis." The second variety is the follicular cancers,
which are much larger and clearly grossly invasive; they
may replace the entire thyroid lobe or extend outside the
thyroid into adjacent soft tissues.
Histologically, these tumors are adenocarcinomas with
substantial range in the size and differentiation of the acinar
follicles. Some carcinomas have only small incomplete
gland formation with very little colloid evident. These
resemble the embryonal pattern of follicular adenoma.
Follicular Neoplasms of the Thyroid - -
FIGURE 13-2. Follicular thyroid cancer with capsular invasion.

This specimen demonstrates a broad tongue of tumor extending
through the tumor capsule and abutting normal thyroid tissue.
Large arrows, tumor capsule. Small arrows, normal thyroid
follicles. Original magnification x160.
Others produce very well defined glands or follicles

containing colloid. Occasionally, the differentiation of these
tumors from normal thyroid architecture is difficult. This
well-differentiated variety of follicular carcinoma has been
misdiagnosed as lateral aberrant thyroid tissue in cervical
lymph nodes (also known as benign metastasizing struma).
The degree of invasiveness of the lesions is also variable. As
noted, the microinvasive variety can be nearly indistinguishable from follicular adenoma. The salient characteristics are
invasion of blood vessels in the tumor or invasion of the
complete thickness of the tumor capsule (Figs. 13-2 and
13-3). In the more anatomically aggressive types of follicular cancer, this invasion can be grossly obvious and the
diagnosis much more clear in spite of a benign histologic
appearance of the follicles themselves.
The follicular variant of papillary cancer is important
to distinguish it from pure follicular cancer (Fig. 13-4).
These tumors may be almost completely follicular; however,
FIGURE 13-3. Follicular thyroid cancer with vascular invasion. This

tumor has areas of differentiated follicles along with the demonstrated tumor invasion into blood vessels. Large arrow, intravascular
tumor. Small arrows, follicles. Original magnification x 300.
117
B
FIGURE 13-4. Follicular variant of papillary thyroid cancer.
A, Low-power view of lesion shows an encapsulated follicular
neoplasm that could be mistaken for a follicular adenoma. Original
magnification x160. B, In a higher power view of the same lesion,
the presence of several optically clear nuclei (Orphan Annie nuclei,
arrow) defines the lesion as the follicular variant of papillary
carcinoma. Original magnification x600.
if they contain any papillary structures, psammoma bodies,

or optically clear nuclei (Orphan Annie nuclei), they should
be classified as the follicular variant of papillary cancer.
These tumors behave similarly to papillary carcinoma of
the thyroid." The follicular variant of papillary cancer has
frequently been misclassified in the past; thus, pathologic
review is an important component of any retrospective series
of follicular cancer," Another follicular variant contains
cells that are large and have an abundant acidophilic cytoplasm with small pyknotic central nuclei; these are called
Hiirthle cell carcinomas.!? They are discussed in a separate
chapter of this text. Some pathologists have identified a
subgroup of follicular tumors that contain an insular
component.t-" This insular component is a near-solid portion of the tumor with nests of cells separated by capillaries.
There is a small amount of follicular formation within the
nests. Some tumors are composed of small amounts of insular
component, whereas others are formed predominately of
insular-type histology. The presence of this insular component
correlates with a more aggressive clinical behavior, consistent
with that of other widely invasive follicular thyroid cancers."
118 - -
Thyroid Gland
These features of follicular cancer-the often cytologically

benign cells and the sometimes minimal capsular or vascular
invasion-usually make follicular cancer demonstrable only on
permanent histologic sections. Fine-needle aspiration (FNA)
cytology is limited because it assesses only small groups of
cells and depends mainly on abnormalities of the individual
cells (Fig. 13-5).Some criteria have been developed to improve
the diagnostic accuracy of FNA for follicular lesions,such as
the presence of microfollicles, necrotic debris, nuclear size,
and the presence of nucleoli.22-24 In addition, immunocytologic
techniques are being evaluated that may be useful.25 26 In spite
of these advances, there are still many indeterminate follicular
neoplasms by FNA. Frozen section analysis has limitations
for follicular tumors because the diagnosis of follicular cancer
may rest on local capsular invasion, which can be difficult and
time-consuming to assess on limited frozen section."
demonstrate a relatively benign-appearing follicular tumor;

however, by its behavior it has defined itself as an invasive
malignant variety. Thus, follicular cancers typically arise as a
slowly growing solitary thyroid mass in a middle-aged to older
person. About 25% of patients have extrathyroidal invasion at
the time of presentation. Between 10% and 33% of patients
have distant metastasis at the time of initial diagnosis.
Most follicular cancers are nonfunctional ("cold") by
radioiodine thyroid scan. Occasionally, a follicular cancer
retains the ability to concentrate iodine to a degree similar to
that of adjacent thyroid tissue ("warm") or even to a greater
degree than the normal thyroid ("hot"). The rare "functional"
thyroid cancer is nearly always a follicular carcinoma rather
than a papillary tumor.
Clinical Features of Follicular Carcinoma
The prognosis of follicular carcinoma of the thyroid overall

is slightly worse than that of papillary carcinoma of
the thyroid. 29 -3 1 Some representative series are presented in
Table 13-1. The overall survival for patients presenting with
follicular carcinoma of the thyroid depends on the stage
of the patient at presentation. In the series in Table 13-1,
overall survival ranges from 43% at 10 years to 95%, with
a mean lO-year follow-up. However, substantial differences
exist in the proportion of patients who had demonstrable
metastatic disease at presentation among the various series,
and this can explain at least a large part of the variability in
overall survival. Each of these series recognizes certain
important prognostic factors that can be easily clinically
defined. The presence of metastases at initial diagnosis was
associated with a very poor 5-year survival. Although these
patients can be treated or palliated by radioiodine therapy
with some benefit, the overall survival and outcome for
patients with distant metastases are grim. The cause of death
is typically progression of distant metastases.v-"
Age at the time of initial diagnosis appears to be a very
important prognostic factor that was recognized in each of
the series noted in Table 13-1. Although the exact age cutoff
varied from series to series, as would be expected when assigning an abrupt cutoff to retrospective analysis of a continuous
variable, somewhere between 40 and 60 years of age appeared
to be a substantial transition point for patients presenting with
this tumor. Overall, older patients have a worse prognosis with
follicular carcinoma. Besides age and the presence of metastases, important prognostic factors appeared to be the degree of
invasion (microinvasive versus widely invasive) and in one
series the degree of tumor cell differentiation.
Using this information about the risk of death from follicular thyroid cancer in various clinical situations, one can
develop a system for identifying those at substantial risk. In
such a system, age and the degree of invasion present in the
tumor appear to be the important variables for patients with
localized tumor at presentation. Thus, for young patients
with minimally invasive tumors, one can be relatively reassuring about their good outcome in spite of the occasional
exception. On the other hand, an elderly patient with evidence
of a widely invasive follicular carcinoma of the thyroid
would have a much more guarded outlook and in fact would
have a predicted 8% survival after 10 years of follow-up,
according to the data from the Mayo Clinic.
Although follicular thyroid cancers can occur in any age

group, the median age of groups with follicular cancers is
typically higher than that of groups with papillary cancers.
Typically, the median age at presentation is in the sixth
decade of life. As with papillary cancer, the female-male
ratio is between 2: I and 5: 1.
The typical presentation of a patient with follicular carcinoma of the thyroid is similar to that of a patient with
follicular adenoma. Most patients present with a solitary
thyroid nodule. In contrast to patients with follicular
adenoma, patients with follicular thyroid cancers are more
likely to have local symptoms. These can include difficulty
swallowing, dysphonia, stridor, or pain. Patients can also
present with evidence of distant metastases, most typically
metastases in the bone, lung, brain, or liver. Apparently
because of their propensity for vascular invasion, follicular
tumors often metastasize by hematogenous pathways and
only rarely by cervical lymph nodes, as would be more typical of papillary cancer," Biopsy at these distant sites may
FIGURE 13-5. Fine-needle aspiration specimen from a follicular

thyroid neoplasm. Note the bland and uniform cytologic appearance of the cells. Defining features for follicular cancer, such as
vascular or capsular invasion, can, of course, not be assessed in this
type of specimen. Original magnification x600.
Prognosis of Follicular Carcinoma
Follicular Neoplasms of the Thyroid - - 119
Treatment of Follicular Carcinoma: Surgery

Substantial controversy surrounds the selection of therapy
for patients with follicular carcinoma of the thyroid. Some
authors have recommended unilateral operations, typically
lobectomy and isthmusectomy, for patients who are in good
prognostic groupS.34,35 This would include lesions that are
confined to the thyroid, smaller in size, and in younger
patients. Others have contended that it is important to
remove all or nearly all of the thyroid tissue in order
to achieve certain desirable goalS. 35-37 First, although most
patients who fall into the good prognostic groups do well, a
few do poorly, and at this point the disease course cannot be
predicted, There are data to suggest that a more complete
removal of the thyroid improves overall prognosis even for
the patients who are in the low-risk groups if their tumor
is over I em in size.38,39 Further, more complete removal of
the thyroid tissue allows ablation of the remaining normal
thyroid tissue more easily using 131 1 and may allow better
therapeutic use of 1311. This in tum decreases recurrence
and may also decrease the death rate from tumor.39,40 More
complete removal of the thyroid improves the value of
postablation l3l1 whole-body scanning and also allows the
clinician to follow serum thyroglobulin levels as a tumor
marker.'? Finally, all patients with well-differentiated thyroid
cancer should be treated with thyroxine replacement for life
regardless of the extent of their surgery, and there is no functional physiologic value to leaving a contralateral thyroid
lobe in place." Total or near-total thyroidectomy at the
initial operation is a very safe procedure in the hands of an

experienced thyroid surgeon.i' For all of these reasons,
many respected thyroid surgeons and endocrinologists
prefer a more extensive operation, even for patients in good
prognostic groups with follicular carcinoma of the thyroid.
The role of reoperation to remove remaining thyroid
tissue in a patient who has had less than total thyroidectomy
(completion thyroidectomy) for follicular cancer is controversial.36,42,43 The frequency with which this issue arises
should be minimized by careful initial surgery and gross
intraoperative evaluation, As previously mentioned, patients
can have a very benign histologic appearance of the follicular cancer in the thyroid gland. However, if the patient has
metastasis to lymph nodes near the thyroid or has evidence
of local soft tissue invasion outside the thyroid glands, the
patient should clearly have a total or near-total thyroidectomy. Frozen section analysis of the thyroid gland itself
is not often helpful in making this decision; the utility of
frozen section analysis of follicular thyroid lesions has
been assessed by a randomized clinical trial." However,
careful gross evaluation, attention to the clinical situation,
and judicious use of frozen section analysis of abnormalities
away from the primary tumor may make the need for total
thyroidectomy apparent at the initial operation."
The most common indication for completion thyroidectomy is a frozen section analysis of a thyroid lesion that is
interpreted as benign follicular adenoma. On subsequent
permanent pathology, areas of invasion are identified and
the diagnosis is changed to follicular carcinoma. In this
120 - -
Thyroid Gland
situation, the surgeon is faced with the decision of whether

to go back and remove the contralateral thyroid gland for
completion of the thyroidectomy or to leave the contralateral
gland in place. Studies have demonstrated that completion
thyroidectomy can be done safely by experienced surgeons
and that cancer can be found in the contralateral thyroid in
a significant proportion of these patients. 36,42 There are no
data to demonstrate that the completion thyroidectomy has
an effect on recurrence or survival because no one has studied this topic prospectively. In my opinion, the decision
should be individualized. If the patient is in a very good prognostic group, such as a 35-year-old woman with a l-cm follicular tumor that has minimal invasion of the capsule only, it is
reasonable to maintain the patient with thyroxine suppression
and not perform completion thyroidectomy. If, however, the
patient has any risk factors that might indicate a more significant risk for tumor recurrence and mortality, I would suggest
reoperation for completion of the thyroidectomy.
For the patients in the worse prognostic groups and for
those with previous neck irradiation, complete removal of the
thyroid gland is more clearly indicated. Radiation exposure
increases the risk of multicentric disease, and patients with
follicular tumors after radiation exposure are at a particularly
increased risk for recurrence.f Complete removal of the
thyroid gland removes gross or occult contralateral disease
and allows the therapeutic use of 1311, which can treat local,
regional, and distant follicular carcinoma. Most surgeons
avoid procedures that might alter function for the patient in the
presence of a well-differentiated follicular tumor. For example,
radical neck dissection or laryngectomy would rarely be indicated given the efficacy of 1311 therapy for disease that is not
resectable by less mutilating means.
In patients with metastases, therapy should begin with
thyroidectomy. This is the quickest way to make the patient
hypothyroid and allow total-body 1311 scanning. Patients who
have a single demonstrable resectable metastasis should have
resection, as this may lead to cure or prolonged survival.
Multiple metastases are best treated by radioactive iodine
therapy and occasionally adjuvant chemotherapy or external
beam irradiation. Local therapies to relieve symptoms from
bone metastases are palliative."
Treatment of Follicular Carcinoma:

Adjuvant Therapy
Suppression of pituitary TSH release with exogenous thyroid
hormone replacement is an important therapy for follicular
thyroid cancer." Because TSH acts as a growth factor for some
thyroid cancers, it appears to be reasonable to manage all
patients having follicular carcinoma of the thyroid with oral
thyroxine replacement for life, although the demonstration of
efficacy for all groups is lacking.'? The use of thyroxine
to suppress TSH to very low levels can be accompanied by
osteoporosis or evidence of thyrotoxicosis, including cardiac
arrhythmias. Because of this potential toxicity, patients
for whom thyroxine replacement is used in an adjuvant
setting should have their TSH suppressed to a level of 0.2 to
0.4 mU/mL. Patients who have demonstrable metastatic
cancer should be treated with higher doses to suppress TSH to
an undetectable level as long as this is not associated with
adverse side effects, such as cardiac effects.
Therapy of follicular carcinoma of the thyroid with radioiodine is currently recommended for most patients.P''" Only
those with the very best prognosis, such as patients younger
than 30 with very small lesions, unless they have had radiation
exposure, are excluded from treatment. Radioiodine treatment
is used in an adjuvant setting in all other patients who can have
their disease completely resected and as a treatment modality
in patients with metastatic disease.
Patients are managed with suppressive hormone therapy
immediately after thyroidectomy. It is most convenient to
use liothyronine (T 3) in this setting because of its shorter
half-life than thyroxine. After the patient has recovered from
surgery, the liothyronine is discontinued for at least 7 days
and the TSH level measured. Once the TSH level has
achieved the supraphysiologic range (>25 units/ml.), maximal stimulation of any residual thyroid tissue or thyroid
cancer can be assumed. Patients are given a small dose
of 1311 and a total-body scan performed to survey for areas
of uptake. A substantial proportion of patients have residual
uptake in the cervical region in spite of total anatomic thyroidectomy. This residual uptake in what is usually normal
thyroid tissue can be subsequently ablated with an appropriate dose of 1311. After this dose (typically -30 mCi) has been
administered, the patient can be started on thyroxine
replacement. If there were no demonstrable extracervical
metastatic lesions on the initial scan, the patient should be
rescanned in 6 months to 1 year. If, however, the patient has
had metastatic disease defined on the initial radioiodine
scan, the patient should be treated with a substantial dose
of radioiodine, typically 75 to 250 mCi. This cycle of
radioiodine scanning and treatment for metastatic lesions
can be repeated every 6 to 9 months as appropriate given the
patient's physiologic status and tumor response.
The efficacy of radioiodine in an adjuvant setting is variable. A study from Young and colleagues demonstrated clear
improvement in the overall recurrence rate in patients with
disease initially confined to the neck who were treated
with surgery, radioiodine, and hormonal therapy compared
with patients treated with only surgery and hormonal
therapy." Overall, survival was improved; however, there
may be subgroups that are at very low risk that do not
benefit from radioiodine ablation. One of these groups was
evaluated retrospectively in a study from the University of
British Columbia. In 71 patients with follicular thyroid
cancers and minimal invasion, this group saw no difference
in survival or disease-free survival between the 46 patients
who underwent hormonal suppression only and the 17 patients
who had radioiodine ablation and hormonal suppression."
With the data currently available, radioiodine ablation
should be recommended for most patients with follicular
carcinoma of the thyroid; however, there may be low-risk
groups who will be more clearly defined in future studies as
not benefitting from such treatment.
Management of Follicular
Neoplasms
A scheme for the management of patients with follicular
neoplasms is presented in Figure 13-6. The typical euthyroid patient with a solitary nodule should be evaluated with
Follicular Neoplasms of the Thyroid - -
Solitary
No Evidence
of
Euthyroid
Thyroid'
Nodule
Metastases
Fineneedle
aspiration
High Risk
Size>3 em
Age> 60 yr
History of neck radiation
Suspicious cytology
Thyroxine
suppression
Foilowsize
each6 months
'--1
I No Growth I
~
Operation
Thyroidlobectomy
and isthmusectomy
FIGURE 13-6. Management scheme for patients with follicular

neoplasms.
FNA of the nodule. Cytology cannot usually distinguish

between follicular adenoma and follicular carcinoma
because the diagnosis of carcinoma depends upon histologic
features (vascular or capsular invasion) that are not demonstrable by FNA. The diagnosis then is follicular neoplasm.
Patients who are at low risk for having thyroid carcinoma
rather than adenoma, as well as low risk for a poor outcome
if they do have carcinoma, can be managed conservatively.
Conservative management consists ofTSH suppression with
exogenous thyroxine to decrease the growth stimulus for
the neoplasm. The value of suppression as a technique for
distinguishing between carcinoma and adenoma has been
questioned, and the potential downside of oversuppression
(osteoporosis in particular) has been recognized. However,
it seems reasonable to suppress TSH to a moderately low
level (0.3 to 0.6 mU/mL) while patients are being observed
conservatively. This is done not to decide that lesions that
shrink are not cancers, as 2 of 19 follicular cancers shrank
with suppression therapy in the University of California
series," but to remove growth stimulation during the prolonged follow-up. If the lesion does grow during follow-up,
the patient should have a thyroid lobectomy and isthmusectomy. Patients with thyroid nodules should be observed
indefinitely for evidence of growth.
Intermediate-risk patients include those whose lesions
are I to 3 em in size and those who are older than 40 years.
The patients should have a functional (1 231 or 99mTc04) scan
to assess the nature of the nodule. Patients with functional
nodules are unlikely to harbor cancer in that lesion; they can
join the low-risk follow-up group with thyroxine suppression. Patients who have nonfunctioning nodules should have
thyroid lobectomy and isthmusectomy for diagnosis, not
only because they are at higher risk of having follicular
121
cancer but also because they are at higher risk of having an

aggressive tumor if they do have thyroid cancer. Low-risk
patients who are averse to the inherent risk of delaying treatment of a cancer, which is possible in the more conservative
plan of follow-up, can be included with this group and
assessed with a functional scan.
The high-risk group includes patients who are older than
60 years and those with nodules greater than 3 em in size.
These patients are at higher risk of having cancer in the nodule
and of having an aggressive cancer. In addition, patients who
have a history of neck irradiation, or whose cytology is suspicious for cancer (because of atypia or necrosis, for example),
have a higher risk of cancer. These patients should have a diagnostic thyroid lobectomy and isthmusectomy without further
evaluation because of their higher risk.
The scheme outlined here is one of several possible designs
for managing patients with follicular thyroid neoplasms. More
important than the algorithm itself are the data that underlie it.
If the clinician understands these data, individual algorithms
can be constructed for each patient and new information
incorporated into future plans.
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Obstet 1985;160:409.
Hurthle Cell Adenoma

and Carcinoma
Herbert Chen, MD, FACS Robert Udelsman, MD, MBA, FACS
Few topics in endocrine surgery have been as controversial

as Hiirthle cell neoplasms of the thyroid. Hiirthle cell
neoplasms (adenomas and carcinomas) are "solitary masses
in the thyroid comprised of Hiirthle cells exclusively, or
at least over 50% so comprised, and confined by a capsule
found in a gland not otherwise overcome by chronic
thyroiditis.'" They comprise 3% to 10% of all epithelial
thyroid tumors and have been reported to account for 15%
to 20% and 2% to 8% of all follicular and papillary cancers,
respectively.' Hurthle cell tumors are well differentiated and
tend to be more aggressive than routine follicular thyroid
cancers but less so than sporadic medullary thyroid cancers.
Since their initial description, there has been debate about
their origin, clinical behavior, classification, diagnosis,
surgical management, and prognosis. Part of the difficulty in
characterizing the behavior of these tumors is due to the
relative low incidence of malignant Hiirthle cell lesions;
therefore, experience obtained in any single institution is
limited. In this chapter, we discuss the controversy surrounding
Hiirthle cell neoplasms and outline our current management.
Historical Background
The term Hiirthle cell tumor is a misnomer. In 1894, Hiirthle
described intrafollicular cells of the thyroid in a normal dog
that actually were parafollicular C cells.' True Hiirthle cells
were first described in 1898 in a patient with thyrotoxicosis
by Askanazy." In 1907, Langhans reported the first Hiirthle
cell tumor, and Ewing, in 1919, described a true Hiirthle cell
tumor and miscredited Hiirthle as the original discoverer.'
Therefore, these tumors are occasionally referred to as
Askanazy cell tumors or Langhans tumors; however, they
are most commonly referred to as Hiirthle cell neoplasms.
Origin and Classification

Controversy exists regarding the presumed origin of Hiirthle
cells. Most believe that they originate from thyroid follicular cells. This conclusion is supported by the following:
(1) histology from a single thyroid gland can show the
transition from follicular cells to Hiirthle cells; (2) Hiirthle

cells can secrete thyroglobulin similar to thyroid follicular
cells; (3) a high concentration of Hiirthle cells is seen in
inflammatory diseases of the thyroid; and (4) a functional
thyroid-stimulating hormone (TSH) receptor-adenylate
cyclase system is present in Hiirthle cell neoplasms." There
are some investigators, however, who suggest that Hiirthle
cells are of parafollicular origin. This is based on the fact
that Hiirthle cell cancers more often metastasize to lymph
nodes, are less likely to trap radioactive iodine, and have a
distinct oncogene expression profile as compared to follicular
cancers.'
The confusion surrounding the description of Hiirthle cell
tumors continues today. The nomenclature is not standardized;
Hi.irthle cell tumors (adenomas and carcinomas) are also referred
to as oncocytomas, oxyphilic tumors, Askanazy cell tumors,
Langhans tumors, and follicular Hiirthle cell tumors. In
1988, the World Health Organization formally classified
Hiirthle cell carcinoma as an oxyphilic variant of follicular
carcinoma. However, since then, several investigators have
presented convincing evidence that these tumors should be
classified separately as Hiirth1ecell carcinomas.
Clinical Characteristics
Histology
Hiirth1e cells are large polygonal, eosinophilic cells with
pleomorphic, hyperchromatic nuclei and fine granular,
acidophilic cytoplasm, representing an abundance of
mitochondria (Fig. 14-1). The individual cells are 10 to 15 urn
in diameter and can vary in shape and size from small dumbbells to bizarre giant cells. Hiirthle cell neoplasms are
encapsulated collections of Hiirthle cells (Fig. 14-2).
Therefore, the presence of nonencapsulated Hiirth1e cells
does not signify a neoplastic process, because they are commonly associated with Hashimoto's thyroiditis, Graves' disease, and nodular goiters as well as with well-differentiated
thyroid cancers.
Hiirthle cell tumors continue to be classified as variants
of follicular neoplasms. However, Hiirthle cell carcinomas
123
124 - -
Thyroid Gland
Risk Factors
Up to 39% of patients with Htirthle cell neoplasms in one
study reported previous childhood head and neck radiation. II
Previous radiation exposure has also been correlated with an
increase in bilaterality and multicentricity of Htirthle cell
tumors, as well as an increased incidence of contralateral
non-Htirthle cell malignant thyroid lesions. No genetic syndromes have been reported to be associated with Htirthle cell
tumors. Other than radiation exposure and age, no other risk
factors have been associated with Htirthle cell neoplasms.
Presentation
FIGURE 14-1. Fine-needle aspiration of a thyroid nodule showing

an abundance of polygonal-shaped Hiirthle cells. Note the
pleomorphic hyperchromatic nuclei and granular cytoplasm.
generally behave in a more aggressive manner, metastasizing

more frequently, and are less likely to respond to radioactive
iodine." In addition, Htirthle cell variants of papillary thyroid
cancer have been reported with increasing frequency." These
tumors behave in a manner more similar to Htirthle cell
carcinomas, metastasizing and recurring more frequently
than papillary carcinomas. Therefore, most believe that
Htirthle cell tumors should be classified as a distinct category,
with subgroups of follicular and papillary variants.
Demographics
Htirthle cells neoplasms have a peak incidence in the fifth
to sixth decades. With advancing age there is an increased
chance of a malignancy. 10 There is a female preponderance,
with reported ratios ranging from 2:1 to 10:1. However,
male patients with Htirthle cell neoplasms have a higher
relative incidence of carcinoma.
FIGURE 14-2. A Htirthle cell adenoma (A). Note the presence of

a thin capsule (C) without any signs of capsular invasion. Most of
this neoplasm is composed of Htirthle cells.
Most patients with Htirthle cell neoplasms present with a

solitary thyroid nodule. Approximately 80% of these lesions
are nonfunctioning and are therefore "cold" on nuclear
scans. Approximately 5% to 60% (in most series, 10% to
35%) of Htirthle cell neoplasms are carcinomas. In patients
presenting with malignant lesions, 70% to 80% are confined
to the gland, 11% have lymph node metastasis, and 15%
have distant metastasis, most commonly to bone or lung.
Patients may also present with advanced local disease
manifested by esophageal or airway obstructive symptoms.
Diagnosis
Histopathology
In 1974, Thompson and colleagues reported a series of
25 patients with Htirthle cell neoplasms in which 75% of
these whose lesions were initially described as benign (i.e.
adenomas) subsequently died of Htirthle cell carcinoma."
This led to the suggestion that gross and histopathologic
examination of Htirthle cell neoplasms could not reliably predict clinical behavior and that all lesions should be treated as
malignant or potentially malignant. Since then, however, several studies have shown that histologic criteria can reliably
differentiate between Htirthle cell adenomas and carcinomas.
Grant and colleagues in 1988 reviewed 272 surgically
resected Htirthle cell neoplasms at the Mayo Clinic that
were deemed to be histologically benign and found that only
1 had an incorrect diagnosis manifested by tumor recurrence,
with a mean follow-up of 4 years.13 The criteria currently used
to diagnose Htirthle cell carcinoma are capsular or vascular
invasion, invasion of adjacent structures, lymph node
metastases, and distant metastases. Moreover, Carcangiu and
associates found similar results in reviewing 153 cases of
Htirthle cell neoplasms." In their study, patients were
grouped into three categories: benign (90), indeterminate (35),
and malignant (28). Malignant lesions had to demonstrate fullthickness capsular invasion, vascular invasion, or invasion into
adjacent tissue. Indeterminate lesions had minimal capsular
invasion, solid versus follicular growth pattern, marked
nuclear atypia, and extensive necrosis. With up to 22 years
of follow-up, no tumor recurrences or cause-specific death
was seen in the benign or indeterminate groups. From these
and other studies.v-" one can conclude that histologic
examination can differentiate benign from malignant
Htirthle cell neoplasms and that the sine qua non of Htirthle
cell carcinoma is full-thickness capsular and/or vascular
invasion (Figs. 14-3 and 14-4).
Htirthle Cell Adenoma and Carcinoma - - 125
>.
80%
c:
ctl
c: 60%
.Ql
(ij
E 40%
'0
Q)
Cl
c: 20%
ctl
s:
0%
1 em
or less
>1 em and
<4 em
4em or
greater
Tumor size
FIGURE 14-3. A Hurthle cell carcinoma invading through fullthickness capsule(C).The tumor(T) is presenton both sides of the
capsule and extends almostbeyondthe thyroidcapsule.
Fine-Needle Aspiration
Fine-needle aspiration (FNA) can reliably detect Hiirthle
cell neoplasms (see Fig. 14_1).16.18 FNA can also be helpful
in differentiating Hiirthle cell neoplasms from non-neoplastic
lesions with Hiirthle cells present. Hiirthle cell tumors are
associated with a high percentage of Hiirthle cells; nests of
Hiirthle cells; cellular dyshesion; large nucleoli; nuclear
pleomorphism; significant nuclear enlargement; and the
absence of macrophages, plasma cells, or lymphocytes. 19
Although reliable histologic criteria for malignancy exist,
FNA cannot accurately distinguish Hiirthle cell adenomas
from carcinomas.W' Since FNA cannot determine the
presence of full-thickness capsular and/or vascular invasion,
several studies have focused on determining if any cellular
features seen on FNA are associated with malignancy.
Unfortunately, cellular atypia, including nuclear size, nuclear
mitoses, cellular pleomorphism, necrosis, and percentage of
Hiirthle cells, does not have a relationship to malignancy. 10
Molecular profiling for expression of ras, p53, mdm-Z, p21,
cyclin DI, Bcl-2, and other markers associated with
Number of
patients (n)
=6
= 34
= 17
FIGURE 14-5. Tumor size is predictive of malignancy. With

increasing size, the chanceof malignancy increases. (FromChenH,
Nicol TL, Zeiger MA, et al: Hiirthle cell neoplasms of the thyroid:
Are there factors predictive of malignancy? Ann Surg 1998;
227:542.)
malignancy have failed to show any correlation with Hiirthle

cell carcinomas,?,22,23 DNA aneuploidy has been associated
with increased recurrence and distant metastasis in patients
with Hiirthle cell carcinoma; however, Hiirthle cell adenomas
are also often aneuploid.P Finally, size of a Hiirthle cell
neoplasm has been shown to correlate with malignant potential (Fig. 14-5). In a series of 57 consecutive Hiirthle cell
neoplasms, tumors 1 cm or less were found to be malignant
in 17% of cases." However, 65% of tumors at least 4 em in
diameter proved to be malignant. Thus, other than size, no
cytologic characteristics can reliably predict malignancy.
Therefore, the cornerstone of diagnostic studies remains
careful histologic evaluation.
Frozen Section Evaluation

Intraoperative frozen section evaluation has traditionally been
used to assess indeterminate thyroid lesions. There have been
no studies specifically addressing the use of frozen section
evaluation in the management of Hiirthle cell neoplasms.
However, because follicular thyroid carcinomas and Hiirthle
cell carcinomas both are diagnosed solely by the presence of
capsular and/or vascular invasion, studies addressing follicular lesions appear applicable. In a review of 125 consecutive
patients with follicular thyroid lesions, including a small
number of Hiirthle cell neoplasms.. who underwent surgical
exploration, frozen section evaluation was of minimal value,
rendering no additional diagnostic information 87% of the
time." Although providing diagnostic information in 13% of
patients, in only 3.3% did frozen section correctly modify the
surgical procedure. Notably, in 5% of patients, the frozen section was incorrect and potentially led to misguided interventions. Therefore, frozen section evaluation should play only a
minor role in the management of Hiirthle cell neoplasms.
Management
FIGURE 14-4. Vascular invasion by Htirthle cell carcinoma (H).
An endothelial-lined blood vessel (V) structure is completely
occluded by tumor cells (T).
Patients presenting with Hiirthle cell neoplasms usually

have had a solitary thyroid nodule evaluated by FNA. In our

experience, 35% of these lesion ultimately prove to be
malignant, although in some series, up to 60% have been
reported to be cancers.t-" Accordingly, we recommend surgical exploration for patients in whom the FNA demonstrates a
Hiirthle cell neoplasm.
Surgical Procedure
A careful exploration is always undertaken to detect the
presence of obvious malignant disease-i.e., tumor invasion
into adjacent structures, metastatic nodal disease-as well
as contralateral nodular thyroid disease. We advocate onestage total or near-total thyroidectomy if obvious malignant
disease or contralateral nodular disease is present or if the
patient has a history of childhood head and neck irradiation.
This is based on the fact that there is an increased incidence
of multifocal disease as well a 50% chance of a concomitant
papillary cancer associated with previous head and neck
irradiation. II Furthermore, Carcangiu and associates have
shown that local recurrence of Hurthle cell carcinoma is
correlated with the extent of surgery, with recurrence rates
for nodulectomy, thyroid lobectomy, and total thyroidectomy
of 75%, 40%, and 15%, respectively.'? In addition, some
patients, understanding the 35% risk of carcinoma, may
elect to have an initial total thyroidectomy rather than
having a completion thyroidectomy should cancer be found.
For the routine patient with a single dominant nodule,
surgical management should consist of an ipsilateral
lobectomy and isthmusectomy. Surgical procedures involving less than a lobectomy, in our opinion, have no role in the
management of neoplastic lesions. Some surgeons advocate

intraoperative frozen section evaluation to assess capsular
and/or vascular invasion." If frozen section reveals a benign
process such as thyroiditis or goiter, or a Hiirthle cell neoplasm
lacking capsular or vascular invasion, the surgery is
terminated. If capsular or vascular invasion is present, then
total or near-total thyroidectomy is performed. Although this is
theoretically an acceptable approach, because frozen section is
inherently unreliable in detecting capsular/vascular invasion,"
one can argue for omitting frozen section evaluation.
Although some recommend random lymph node sampling
in all cases." we typically do not excise lymph nodes unless
they are enlarged. If disease is found outside the thyroid-i.e.
soft tissue invasion or lymph node metastasis-resection of
all gross/microscopic disease is performed. Because surgical
resection is usually the only curative treatment option for
Hiirthle cell carcinoma, every effort should be made to resect
all disease. This includes a modified radical neck dissection
for positive cervical lymph node metastasis. We occasionally advocate more radical surgery for advanced Hurthle cell
carcinoma, including resection of the larynx, trachea, skin,
soft tissue, cervical lymph nodes, and esophagus (Fig. 14-6).
In patients who underwent an initial lobectomy/isthmusectomy whose final pathology was diagnostic of carcinoma,
we generally perform a completion thyroidectomy as soon
as possible after the initial surgery. In patients with only partial capsular invasion, the decision is not as clear. Several
studies, however, have illustrated that these lesions do not
behave in a malignant manner.v!':" This has also been
our experience. Although some advocate completion
FIGURE 14-6. A patient with very

aggressive Htirthle cell carcinoma. A,
MRI demonstrates a large thyroid mass.
B, CT scan of the neck depicts almost
complete airway obstruction by tumor.
C, A barium swallow study illustrates
esophageal deviation and obstruction
secondary to the mass. This patient's
operative management included total
thyroidectomy, total laryngectomy,
bilateral modified radical lymph node
dissections, esophagectomy, and gastric
pull-up reconstruction.
Hurthle Cell Adenoma and Carcinoma - - 127
thyroidectomy in this case, we would favor close clinical

follow-up and life-long thyroid suppression. In patients with
the diagnosis of Hiirthle cell adenoma, no further operative
intervention is warranted. However, close clinical follow-up
is recommended. There have been reports of recurrence with
Hiirthle cell adenomas.P but this is a rare occurrence.
Radioactive Iodine and Other Modalities

Hiirthle cell carcinomas generally fail to concentrate 131 1
and, therefore, in most patients, radioablation does not offer
a therapeutic benefit. As a result, the only curative treatment
for Hiirthle cell carcinoma is surgical resection. However,
there have been case reports of metastatic tumors that have
131 I uptake. In 4 of 7 patients with pulmonary metastases
from Hiirthle cell carcinoma, 131 1 uptake by the metastatic
tumors was present." Although there have also been reports
of resolution of pulmonary metastases with 131 1 treatment, it
is important to note that uptake does not always correlate
with tumor responsiveness. However, because results from
other modalities of treatment for metastatic disease have been
dismal, each patient's case must be individually considered in
evaluating the role for 1311. In most patients, it is unlikely that
BII has a therapeutic benefit. In another series, two patients,
who had pulmonary metastases responsive to 131 1 treatment,
also had extraordinarily elevated serum thyroglobulin
levels.'? Others have also reported regression of Hiirthle cell
carcinoma metastases with 131 1 in tumors that apparently
secreted thyroglobulin." Hiirthle cell adenomas and carcinomas are known to be able to secrete thyroglobulin. We
have also had two patients with pulmonary and hilar lymph
node metastases, respectively, who responded to 131 1 therapy." Based on these reports, some advocate 131 1 scans in
patients with elevated thyroglobulin levels 4 to 6 weeks after
total thyroidectomy, and treatment if positive. Other
modalities of treatment have no efficacy in the primary treatment of Hiirthle cell carcinoma. These tumors are not
responsive to various regimens of chemotherapy. Extemalbeam radiation to the soft tissue in the neck has shown no
effect of survival." However, it does have a role for palliation
of bony metastasis.
Postoperative Follow-Up
Our philosophy is based on the belief that total or neartotal thyroidectomy is the treatment of choice for welldifferentiated thyroid cancers including Hiirthle cell carcinomas. After thyroidectomy, we advocate 131 1 ablation if any
residual uptake is present. This offers the advantage of
screening for recurrence by thyroglobulin levels. After ablation, thyroglobulin levels should be checked at 6-month intervals initially. If thyroglobulin levels are elevated, the patients
should be withdrawn from thyroid hormone and a scan
performed. If positive, the patient should be treated with
therapeutic doses of 1311. If the 131 1 scan is negative, then we
use other modes of imaging, including neck ultrasound,
computed tomography scan or magnetic resonance imaging
of the neck and chest, and positron-emission tomography
(PET) scans. In a recent meta-analysis for the detection of
Hiirthle cell carcinoma by PET, the reported sensitivity,
specificity, positive predictive value, negative predictive
value, and accuracy were 92%,80%,92%,80%, and 89%,

respectively.F Another emerging method to detect Hiirthle
cell carcinoma recurrence is octreotide scintiscanning.
Gorges and associates recently reported their experience
with 29 patients with recurrent Hiirthle cell cancers.P They
found that in patients with thyroglobulin greater than
10 ng/ml., 95 % had positive IIIIn-octreotide scans. If any of
these studies localize recurrent disease, surgical resection is
considered.
Prognosis
The lO-year survival rates for the classes of well-differentiated
thyroid cancers are papillary, 95%; follicular, 85%; and
Hiirthle cell, 70%. The cause-specific 20-year mortality for
Hiirthle cell carcinomas has been reported to range from
20% to 35%.34Prognosis generally depends on extent of disease at the initial diagnosis and the possibility of resection.
The most favorable prognosis is associated with disease
confined to the thyroid gland itself. A strong correlation has
been demonstrated between tumor DNA aneuploidy and
decreased survival in Hiirthle cell carcinomas." However,
adenomas often have an aneuploid DNA status and do not
recur or metastasize. Therefore, aneuploidy is not an
unfavorable prognostic factor. Studies that have focused
strictly on Hiirthle cell cancers have failed to identify useful
prognostic factors such as age at diagnosis, tumor size, histologic grade, and tumor growth pattern. 10 None of these factors
have been found to be associated with survival advantage.
There is universal agreement, however, that adequate surgical
resection (at least total lobectomy) is the treatment of choice of
all Hiirthle cell carcinomas.
Summary
Hiirthle cell tumors comprise 3% to 10% of thyroid tumors,
whereas Hiirthle cell cancer makes up I % to 3% of all thyroid
cancers. They hematogenously metastasize to bone, lung,
brain, and lymph nodes. FNA can reliably diagnose Hiirthle
cell neoplasms, but it cannot determine malignancy, which
occurs in 35% of patients. Frozen section analysis is rarely
useful. Treatment is primarily surgical consisting of total or
near-total thyroidectomy. Ablation with 131 1 plays a limited
role. The 10-year survival rate for patients with Hiirthle cell
cancer is 70%.
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of DNA content in Hiirthle cell adenomas and carcinomas of the thyroid.
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2. Hundahl SA, Cady B, Cunningham MP, et at. Initial results from a
prospective cohort study of 5583 cases of thyroid carcinoma treated in
the united states during 1996: U.S. and German Thyroid Cancer Study
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Patient Care Evaluation Study. Cancer 2000;89:202.
3. Hiirthle K. Beitrage sur kenntnis des sekretionsvorganges in der
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4. Askanazy M. Pathologish-anatomische bitrage zur kenntnis des morbus
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128 - -
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5. Langhans T. Uber die epithelialan formen der malignen struma.

Virchows Arch 1907;189:69.
6. Clark OH, Gerend PL. Thyrotropin receptor-adenylate cyclase system
in Hiirthle cell neoplasms. 1 Clin Endocrinol Metab 1985;61:773-778.
7. Hoos A, Stojadinovic A, Singh B, et al. Clinical significance
of molecular expression profiles of Hiirthle cell tumors of the
thyroid gland analyzed via tissue microassays. Am 1 Pathol 2002;
160:175.
8. Chen H, Nicol TL, Zeiger MA, et al. Hurthle cell neoplasms of the
thyroid: Are there factors predictive of malignancy? Ann Surg
1998;227:542.
9. Herrera MF, Hay ID, Wu PS, et al. Hiirthle cell (oxyphilic) papillary
thyroid carcinoma: A variant with more aggressive biologic behavior.
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10. Carcangiu ML, Bianchi S, Savino D, et al. Follicular Hiirthle cell
tumors of the thyroid gland. Cancer 1991;68:1944.
II. Arganini M, Behar R, Wu TC, et al. Hiirthle cell tumors: A
twenty-five-year experience. Surgery 1986;100:1108.
12. Thompson NW, Dunn EL, Batsakis lG, Nishiyama RH. Hiirthle cell
lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555.
13. Grant CS, Barr D, Goellner lR, Hay ID. Benign Hiirthle cell tumors of
the thyroid: A diagnosis to be trusted? World 1 Surg 1988;12:488.
14. Bronner MP, LiVolsi VA. Oxyphilic (Askanazy/Hiirthle cell) tumors
of the thyroid: Microscopic features predict biologic behavior. Surg
Pathol 1988;1: 137.
15. Stojadinovic A, Hoos A, Ghossein RA, et al. Hiirthle cell carcinoma: A
60-year experience. Ann Surg Oncol 2002;9: 197.
16. Mclvor NP, Freeman Jl., Rosen I, Bedard yc. Value of fine-needle aspiration in the diagnosis of Hurthle cell neoplasms. Head Neck 1993;15:335.
17. McHenry CR, Rosen IB, Walfish PG, Bedard Y. Influence of
fine-needle aspiration biopsy and frozen section examination on the
management of thyroid cancer. Am 1 Surg 1993;166:353.
18. Udelsman R, Chen H. The current management of thyroid cancer. Adv
Surg 1999;33: I.
19. Gonzalez Jl., Wang HH, Ducatman BS. Fine-needle aspiration of
Hiirthle cell lesions: A cytomorphologic approach to diagnosis. Am 1
Clin Pathol 1993; 100:231.
20. Kini SR, Miller 1M, Hamburger JI. Cytopathology of Hiirthle cell
lesions of the thyroid gland by fine-needle aspiration. Acta Cytol
1981;25:647.
21. Chen H, Udelsman R. Follicular, Hiirthle cell, and anaplastic thyroid

cancer. In: Bland K (ed), The Practice of General Surgery.
22. Johnson TL, Lloyd RV, Burney RE, Thompson NW. Hiirthle
cell thyroid tumors: An immunohistochemical study. Cancer
1987;59:107.
23. Flint A, Davenport RD, Lloyd RV,et al. Cytophotometric measurements
of Hiirthle cell tumors of the thyroid gland: Correlation with pathologic features and clinical behavior. Cancer 1988;61:110.
24. Chen H, Nicol TL, Udelsman R. Follicular lesions of the thyroid: Does
frozen section evaluation alter operative management? Ann Surg
1995;222: 101.
25. Cooper DS, Schneyer CR. Follicular and Hiirthle cell carcinoma of the
thyroid. Endocrinol Metab Clin North Am 1990;19:577.
26. McLeod MK, Thompson NW. Hiirthle cell neoplasms of the thyroid.
Otolaryngol Clin North Am 1990;23:441.
27. Rosen IB, Luk S, Katz 1. Hiirthle cell tumor behavior: Dilemma and
resolution. Surgery 1985;98:777.
28. Sugino K, Ito K, Mimura T, et al. Hiirthle cell tumor of the thyroid:
Analysis of 188 cases. World 1 Surg 2001;25:1160.
29. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary
metastasis of differentiated thyroid carcinoma: Treatment results in
101 patients. 1 Clin Endocrinol Metab 1985;60:376.
30. Bondeson L, Bondeson AG, Ljungberg O. Treatment of Hiirthle cell
neoplasms of the thyroid. Arch Surg 1983;118: 1453.
31. Caplan RH, Abellera RM, Kisken WA. Hiirthle cell neoplasms of
the thyroid gland: Reassessment of functional capacity. Thyroid
1994;4:243.
32. Plotkin M, Hautzel H, Krause Bl, et al. Implication of 2-18fluor-2deoxyglucose positron-emission tomography in the follow-up of
Hiirthle cell thyroid cancer. Thyroid 2002;12:155.
33. Gorges R, Kahaly G, Muller-Brand 1, et al. Radionuclide-Iabeled
somatostatin analogues for diagnostic and therapeutic purposes in nonmedullary thyroid cancer. Thyroid 2001;11:647.
34. Hay ID, Klee GG. Thyroid cancer diagnosis and management. Clin
Lab Med 1993; 13:725.
35. Erickson LA, lin L, Goellner lR, et al. Pathologic features, proliferative activity, and cyclin D[ expression in Hiirthle cell neoplasms of the
thyroid. Mod Pathol 2000;13: 186.

Jeffrey F. Maley, MD Nina Shervin, MD
Background
Medullary thyroid carcinoma (MTC) occurs in sporadic and
hereditary clinical settings and displays a variety of clinical
behaviors ranging from moderately aggressive to extremely
indolent. The discovery of the gene responsible for hereditary
MTC has shed light on the biologic basis for this range
of clinical presentations. MTC was described in 1959
by Hazard, Hawk, and Crile. 1 MTC is a tumor of the thyroid
C cells, also known as the parafollicular cells (Fig. 15-1).
These cells are of neural crest derivation. Other neural
crest-derived tumors include melanomas, pheochromocytomas, and neuroblastomas. C cells are dispersed throughout
the thyroid gland, with the highest concentration in the
upper poles. C cells secrete calcitonin, a hormone involved
in calcium metabolism. Calcitonin is a sensitive and specific
marker for the presence of MTC. It has been invaluable in
the screening of individuals predisposed to the hereditary
forms of the disease and in the follow-up of patients who
have been treated. MTC cells have been noted to express
and secrete a variety of substances in addition to calcitonin.
Some of these are carcinoembryonic antigen (CEA), histaminase, neuron-specific enolase, calcitonin gene-related
peptide, somatostatin, thyroglobulin, thyrotropin-stimulating
hormone, adrenocortical releasing hormone, gastrin-related
peptide, serotonin, chromogranin, substance P, and propriomelanocortin. MTC is often associated with a proliferative
lesion, C-cell hyperplasia. It is likely that C-cell hyperplasia
is a precursor of MTC.
MTC constitutes approximately 5% to 10% of all thyroid
cancers. MTC occurs as unifocal or multifocal clonal populations of tumor cells. Regional lymphatic spread occurs to
perithyroidal lymph nodes, paratracheallymph nodes, nodes
of the jugular chain, and upper mediastinal nodes.' Nodal
metastases are often found along the recurrent laryngeal
nerves in the paratracheal regions and may be present where
these nerves branch and insert into the larynx. Nodes may be
in close association with the parathyroid glands. MTC may
remain confined to the neck for long periods of time. In more
advanced stages, metastases are found in liver, lungs, bone,
and sometimes brain and subcutaneous tissues (Fig. 15-2).
Histologic features of aggressiveness include vascular invasion, lymphatic invasion, invasion of the thyroid capsule,
and extranodal spread of tumor in lymph node metastases.
The disease can be locally aggressive, and local structures

may be invaded by the primary tumor or by tumor in nodal
metastases. In the neck, the structures most commonly
invaded include the trachea, recurrent laryngeal nerve,
and strap muscles. Invasion of the trachea in the neck or
mediastinum can cause death.
MTC may be sporadic or familial. In sporadic MTC, tumors
are usually single and unilateral. There is no family history
and no other endocrinopathies are present. Sporadic MTC
arises as a mass in the neck, and metastases to lymph nodes
in the neck are usually present at the time of diagnosis.
Familial forms of MTC are the multiple endocrine neoplasia
(MEN) type 2A and 2B syndromes and the related disorder of
familial non-MEN MTC (FMTC) (Table 15-1, Fig. 15-3).3-5
In these autosomal dominant inherited disorders, the tumor
is multifocal, bilateral, and there is an early age of onset.
In MEN 2A, patients develop multifocal, bilateral MTC
associated with C-cell hyperplasia. Approximately 42% of
affected patients develop pheochromocytomas, which may
also be multifocal and bilateral; these tumors occur in
the setting of diffuse adrenal medullary hyperplasia.
Hyperparathyroidism develops in 10% to 35% of patients
and is due to hyperplasia, which may be asymmetrical, with
one or more glands becoming enlarged." Cutaneous lichen
amyloidosis has been described in some patients with
MEN 2A7 and Hirschsprung's disease is infrequently associated with MEN 2A.8-IO
In MEN 2B, 40% to 50% of patients develop pheochromocytomas, and all individuals develop neural gangliomas,
particularly in the mucosa of the digestive tract, conjunctiva,
lips, and tongue.t'! MEN 2B patients also have megacolon,
skeletal abnormalities, and markedly enlarged peripheral
nerves. MEN 2B patients do not have hyperparathyroidism.
MTC develops in all patients at a very young age (infancy)
and appears to be the most aggressive form of hereditary
MTC, although its aggressiveness may be related more to
the extremely early age of onset than the biologic virulence
of the tumor. MTC in MEN 2B is rarely cured.
FMTC is characterized by the development of MTC
without any other endocrinopathies. 12 MTC in these patients
129
130 - -
Thyroid Gland
FIGURE 15-1. Photomicrograph of a focus of medullary thyroid
carcinoma surrounded by normal thyroidfollicles in a patient with

multiple endocrine neoplasia type 2A.
has a later age of onset and a more indolent clinical course

than MTC in patients with MEN 2A and MEN 2B.
Occasional patients with FMTC live to their seventh and
eighth decades without clinical evidence of MTC (symptoms
or a lump in the neck), although biochemical testing and histologic evaluation of the thyroid always demonstrate MTC.
In families affected by hereditary forms of MTC, biochemical and genetic screening of at-risk family members
have resulted in the routine detection of MTC before a mass
is palpable in the neck. In those cases, metastases are rarely
detectable at the time of thyroidectomy. 13,14 MTC, however,
is a common cause of death in patients who are not diagnosed early. The pattern of spread and metastasis is similar
in hereditary and sporadic forms of MTC.
Individuals at risk for MEN 2A, MEN 2B, and FMTC
may be screened for MTC by measurement of calcitonin
levels. IS Pheochromocytomas may be detected by measurement of plasma metanephrines. Alternatively, 24-hour urine
collection for catecholamines, metanephrines, and vanillylmandelic acid may be done. Hyperparathyroidism is detected
by measurement of serum calcium and parathyroid hormone
levels. Now that the gene responsible for hereditary forms of
MTC is known (the RET protooncogene), accurate genetic
testing allows early identification of mutant gene carriers,
FIGURE 15-2. Distant metastatic disease in patients with
medullary thyroid carcinoma. Top left, Lymphangitic pulmonary

spread in childwithmultiple endocrine neoplasia type 2B (MEN 2B)
and medullary thyroid carcinoma (MTC). Bottom left, Solitary
brainmetastasis in patientwithMEN 2A and MTC. Right, Multiple
skeletal metastases in patientwith sporadic MTC. (FromMoley IF,
Lairmore TC, Phay IE, et al. Hereditary endocrinopathies, Curr
Probl Surg 1999;36:653.)
which obviates the need to continue biochemical testing
of family members who have not inherited the mutation
(Table 15-2). Control of MTC in those found to have inherited
the mutation is more effective because surgical intervention
is carried out before there is clinical or biochemical evidence
of tumor.
In patients who present with a mass in the neck, the diagnosis of MTC is made by fine-needle aspiration cytology
and measurement of serum calcitonin. If a patient is found
to have MTC, careful physical examination should be
performed to look for signs of MEN 2B. Patients should
be questioned about family history of thyroid, adrenal, or
Medullary Thyroid Carcinoma - -
131
FIGURE 15-3. Featuresof patients

with hereditary medullary thyroid
carcinoma (MTC). A, Bisected
thyroid gland from a patient with
multiple endocrine neoplasia
type 2A (MEN 2A) showing
multicentric, bilateral foci of
MTC. B. Adrenalectomy specimen
from patient with MEN 2B demonstrating pheochromocytoma. C,
Megacolon in patient with MEN
2B. D. Midface and tongue of
patient with MEN 2B showing
characteristic tongue notching
secondary to plexiform neuromas.
(A, Courtesy of S.A. Wells, MD.
B. C, and D, Courtesy of R.
Thompson, MD.)
c
parathyroid disease as well as Hirschsprung's disease. A
family history of hypertension and sudden unexplained
deaths may indicate the presence of undiagnosed pheochromocytomas. Symptoms of hoarseness, dysphagia, stridor,
and hemoptysis indicate a locally invasive tumor. Physical
examination should attempt to delineate the size and location
of the mass, fixation to local structures, unilaterality versus
bilaterality, and presence of regional nodal metastases. All
patients with a preoperative diagnosis of MTC, whether
detected by screening or finding of a palpable mass, should
D
undergo measurement of CEA and plasma calcitonin levels.
Screening for hyperparathyroidism and pheochromocytoma
is important, even in those who are thought to have sporadic
MTC. Sizemore and colleagues found that 19% of patients
thought to have sporadic MTC were eventually found to be
index cases of MEN 2A.16 Genetic testing for mutations
in the RET protooncogene should be done in all patients
with a diagnosis of MTC. 14 17.18 At-risk family members
should also be screened by genetic testing or by stimulated
calcitonin testing.
132 - -
Thyroid Gland
Blood levels of calcitonin may be measured in the basal

state or after the administration of the secretagogues calcium
and pentagastrin." After basal levels have been obtained,
intravenous calcium (2 mg/kg/min) is infused, followed
immediately by pentagastrin (0.5 ug/kg per 5 seconds), and
then blood is drawn for measurement of plasma calcitonin
levels at 1,3, and 5 minutes. Recently, pentagastrin has not
been made in the United States; however, European-made
pentagastrin has been obtained and approved for use at
Washington University in St. Louis (investigational new
drug number 61,205) and at Duke University.
Factors Influencing Prognosis

As discussed in the previous section, the age of onset and
clinical course of MTC are different in FMTC, MEN 2A,
and MEN 2B. As is the case in most cancers, nodal status and
tumor stage are associated with outcome.19-21 MTC often has
an indolent clinical course, with approximately 75% lO-year
overall survival and 50% 15-year overall surviva1. 22.23
Patients with high levels of calcitonin secondary to MTC
may experience symptoms of flushing and diarrhea. The
presence of such symptoms is associated with a poor
prognosis.e' Other features that may correlate with clinical
outcome include plasma calcitonin levels, CEA levels, DNA
ploidy, and calcitonin and somatostatin immunohistochemistry. In a study of 94 patients, a high preoperative stimulated
calcitonin level (> 10,000 pg/mL) was associated with a
worse outcome." Those who presented with lower calcitonin
levels were less likely to have nodal metastatic disease at
operation than patients with high levels. CEA is elevated in
more than 50% of patients with MTC.26 Elevated levels of
CEA have been reported to be associated with the presence
of metastatic disease, although this is not always the case.27,28
Surgical Treatment-Palpable
Disease
In this section, the surgical approach to the patient with a
palpable tumor is addressed. A later section addresses the
surgical approach to patients identified as RET mutation
carriers by genetic screening. The surgical treatment of
MTC is influenced by several factors. First, the biology
and behavior of MTC are very different from those of
differentiated thyroid cancer. MTC cells do not take up

iodine, and radioactive iodine therapy is ineffective. Unlike
differentiated thyroid cancer, MTC does not respond to
thyroid suppression. Surgery is the only effective therapeutic modality for MTC. Second, MTC is multicentric in 90%
of patients with hereditary forms of the disease and in 20%
of patients with the sporadic form. Fourth, nodal metastases
are present in more than 70% of patients with palpable
disease (Tables 15-3 and 15_4).29,21.30 Lastly, the ability to
measure postoperative stimulated calcitonin levels allows the
adequacy of surgical extirpation to be assessed.
Total thyroidectomy is the appropriate treatment of the
primary tumor, accompanied by a central node dissection in
patients with a palpable thyroid tumor. In this operation, all
thyroid tissue and all nodal tissue from the level of the hyoid
bone superiorly to the innominate vessels inferiorly are
removed. After the parathyroid glands are identified, central
nodal tissue on the anterior surface of the trachea is
removed, exposing the superior surface of the innominate
vein behind the sternal notch. Fatty and nodal tissue
between the carotid sheaths and the trachea is removed,
including paratracheal nodes along the recurrent nerves. On
the right, the junction of the innominate and right carotid
arteries is exposed, and on the left, nodal tissue is removed
to a comparable level behind the head of the left clavicle. A
systematic approach to the removal of all nodal tissue in the
central neck has been reported to improve recurrence and
survival rates when compared retrospectively with procedures in which only grossly involved nodes were removed."
Management of the Parathyroids

Controversy exists over the optimal management of the
parathyroid glands in operations for MTC. Some surgeons
prefer to leave the parathyroid glands in situ, ensuring that
the vascular pedicle is preserved. 18,32-36 Our approach, in
patients with established palpable MTC, is to remove the
parathyroids and transplant them because complete thyroidectomy and central node dissection invariably cause
devascularization of the glands." The blood supply to the
parathyroids is intimately associated with the posterior capsule of the thyroid and with the central perithyroidal lymph
nodes. Attempts to leave the parathyroids in place result in
either leaving thyroid tissue and central nodes in the neck
or leaving devascularized parathyroids. Furthermore, if the
need for reoperation in the central compartment arises,
the risk of subsequent hypoparathyroidism is negligible if

the patient has a functioning autograft. Finding and preserving parathyroids in a scarred, previously operated neck are
difficult, and the risk of hypoparathyroidism after such
procedures is significant. Therefore, we advocate parathyroidectomy with autotransplantation as part of total thyroidectomy for established, palpable MTC (we do not recommend
routine parathyroidectomy with autotransplantation for
young MEN 2 patients having preventative thyroidectomy
after genetic testing, as will be discussed later).'?
Parathyroid glands to be autotransplanted are removed
and placed in cold saline. The glands are sliced into 1- by
3-mm fragments and autotransplanted into individual
muscle pockets (two fragments per pocket-approximately
15 pockets). We use the sternocleidomastoid muscle in
patients with sporadic MTC, FMTC, and MEN 2B and the
nondominant forearm in patients with MEN 2A (because
they may develop graft-dependent hyperparathyroidismlocalization of the source of hyperparathyroidism and surgical
removal of the hyperfunctional tissue are greatly simplified if
the grafts are in the forearm). In patients with MEN 2A who
have hyperparathyroidism at the time of operation, at least
100 mg of parathyroid tissue should be transplanted, and
residual tissue should be viably frozen." The autografts generally function well within 4 to 6 weeks, at which time
calcium supplementation of patients can be stopped.
133
(see Table 15-3). In patients with bilateral intrathyroidal

tumors, nodal metastases were present in 78% of central
level VI nodal groups, in 71% of level II through V nodes
ipsilateral to the largest intrathyroidal tumor, and in 49% of
level II through V nodes contralateral to the largest intrathyroidal tumor (see Table 15-4). This is an alarmingly high
incidence of nodal involvement.
In this series, intraoperative palpation of nodes was not
an accurate predictor of the presence or absence of metastases. The sensitivity of intraoperative assessment by the
surgeon was only 64%, and the specificity was 71%.40
Therefore, reliance on intraoperative assessment would miss
involved nodes 36% of the time. The strategy of resecting
only "clinically involved nodes" may be effective in differentiated thyroid cancer, for which effective adjuvant therapy
is available; however, no effective adjuvant treatments for
MTC are available. On the basis of the results, our recommendation for patients who present with palpable MTC is
total thyroidectomy, parathyroidectomy with autotransplantation, central neck dissection, and unilateral or bilateral
dissection of level II through V nodes (Fig. 15-4).
Management of Regional Nodes

Regional node metastases are present in the majority of
patients with palpable MTC. Because these tumors do not
take up iodine, nodal metastases cannot be ablated with
radioactive iodine. Surgical node clearance is the only effective strategy for eliminating these deposits. 2 1.3 1,39 In a report
in 1999, we evaluated the incidence and pattern of nodal
metastatic spread in patients with palpable MTC (see
Tables 15-3 and 15-4).40 In this series, 73 patients with palpable MTC underwent thyroidectomy with concurrent or
delayed central and bilateral cervical node dissection. The
number and location of lymph node metastases in the central
(levels VI and VII) and bilateral (levels II through V) nodal
groups were noted and were correlated with the size and location of the primary thyroid tumor. In patients with unilateral
intrathyroidal tumors, nodal metastases were present in 81%
in central level VI, in 81% in ipsilateral levels II through V,
and in 44% in contralateral levels II through V nodal groups
FIGURE 15-4. Total thyroidectomy and central (levels VI and VII)

and bilateral level II through V node dissections from a thin young
male with multiple endocrine neoplasia type 2B and bilateral
palpable thyroid masses (parathyroids not shown). Microscopic
metastases were present in all nodal groups. (From Moley IF,
Lairmore TC, Phay JE, et al. Hereditary endocrinopathies. CUff
Probl Surg 1999;36:653.)
134 - -
Thyroid Gland
As with any specialized procedure undertaken for an

unusual clinical problem, these operations should be performed by surgeons familiar with the disease and with
expertise in the techniques described.
Genetic Testing
for Hereditary MTC
Germline defects in the RET protooncogene are responsible for MEN 2A, MEN 2B, and FMTC. 4 1-43 RET encodes
a transmembrane growth neurotrophic receptor with tyrosine kinase activity. In MEN 2A and FMTC, gain-offunction mutations within codons specifying cysteine residues
in the extracellular ligand-binding domain of the RET gene
product are most commonly found (see Table 15-2). In
MEN 2B, a mutation is found in the intracellular tyrosine
kinase domain. Changes in protein structure and function
that result from these mutations predispose to neoplasia by
a dominant oncogenic mechanism." Loss-of-function
mutations in different regions of the same gene have been
found in patients with Hirschsprung's disease. A small
percentage of patients with MEN 2A have Hirschsprung's
disease.v '? All patients with MEN 2B have megacolon and
constiparion.v'<!'
Discovery of the genetic alterations underlying hereditary
forms of MTC has allowed detection of disease gene
carriers before calcitonin levels become elevated. Reliance
upon a calcitonin test for clinical screening of kindred
members at risk for MTC has certain drawbacks. First, a
positive basal or stimulated calcitonin test indicates that
cancer has probably already developed. A few of these
patients develop distant metastatic disease, even after
thyroidectomy with removal of tiny (l-mm) primary tumors.
These patients would benefit from earlier thyroidectomy.
Second, because the disease is inherited in an autosomal
dominant fashion, 50% of at-risk patients never develop
disease and are spared the expense and inconvenience of
routine scheduled testing if a definitive genetic test is
applied. Third, the provocative calcitonin test is unpleasant
and uncomfortable, and some patients do not keep scheduled testing appointments because of this. In principle,
genetic testing, which requires the drawing of blood
for extraction of lymphocyte DNA, needs to be performed
only once in an at-risk individual's lifetime. Stimulated
calcitonin testing remains an important modality in
monitoring patients for recurrent or residual disease after
thyroidectomy.
To test a patient for the presence of a mutation in RET,
peripheral blood is drawn and the lymphocyte pellet is
separated. Lymphocytes have nuclei, as opposed to red
blood cells, and DNA is extracted by proteinase digestion
and phenol extraction. Regions of the RET protooncogene
are amplified by polymerase chain reaction, and mutations
are detected by one of several techniques. These include
direct DNA sequencing, analysis of restriction sites
introduced or deleted by a mutation, and gel shift analysis
(denaturing gradient gel electrophoresis or single-strand
conformation polymorphism analysis).
Preventive Surgery for Multiple

Endocrine Neoplasia Type 2
Gene Carriers
Individuals with MEN 2A, 2B and FMTC are virtually certain to acquire MTC at some point in their lives (usually
before age 30 years). Therefore, at-risk family members
who are found to have inherited the RET gene mutation are
candidates for thyroidectomy regardless of their calcitonin levels. It has been shown in several series that RET
mutation carriers often harbor foci of MTC in the
thyroid gland even when stimulated calcitonin levels are
normal. I4 , IS,33,34,45-47
In a series from Washington University in St. Louis
reported in 1994, Wells and coauthors described the performance of preventive surgery in asymptomatic RET mutation
carriers." Families of patients with MEN 2A were screened
with genetic and biochemical testing. Thirteen children
found to be asymptomatic RET mutation carriers were
treated with total thyroidectomy, central lymph node dissection, and parathyroid autotransplantation (six with normal
plasma calcitonin levels and seven with elevated levels).
After surgery, patients received thyroid, calcium, and
vitamin D supplementation. Approximately 8 weeks after
the operation, the oral calcium and vitamin D were stopped.
1\\'0 weeks later the serum calcium concentration was
within the normal range in each patient. All patients had
microscopic foci of MTC or C-cell hyperplasia. In 1996,
Wells and colleagues reported an updated series including
49 patients with similar results.f Lips and colleagues, in
a series from the Netherlands reported in 1994, identified
14 young members of families affected by MEN 2A who
had normal calcitonin testing but who were found to be
MEN 2A gene carriers by DNA testing. IS Thyroidectomy
was performed on 8 of these 14, and foci of MTC were
identified in all 8.
At Washington University in St. Louis, we have performed
85 such procedures to date. All patients had central neck
node dissection and parathyroidectomy with autotransplantation. Two patients were found to have nodal metastases
(one despite a normal stimulated calcitonin level), and
calcitonin levels remain elevated in two. Three patients
continue to receive calcium supplementation. There were no
recurrent laryngeal nerve injuries. Follow-up testing is being
carried out in all of these patients to determine the long-term
outcome of such procedures.
The finding of carcinoma in the glands of many young
patients with normal stimulated calcitonin testing indicates
that the operation is often therapeutic, not prophylactic.
There is some urgency, therefore, to apply this genetic test
to other at-risk individuals and to perform thyroidectomy
on those who test positive genetically. The ideal age for
performance of thyroidectomy in patients found to be genetically positive has not been determined unequivocally. We
believe that 6 years of age is a reasonable time to perform
surgery in patients with MEN 2A and FMTC. Patients with
MEN 2B should undergo thyroidectomy during infancy
because of the aggressiveness and earlier age of onset of
MTC in these patients. Follow-up over the next decades
Medullary Thyroid Carcinoma - - 135

will determine whether there is a significant rate of recurrence after preventive thyroidectomy. At present, it is advisable to observe these patients with stimulated plasma
calcitonin levels every 1 to 2 years. These patients must also
continue to be observed for the development of pheochromocytomas and hyperparathyroidism.
Nonsurgical Treatment
of the Patient with Persistent
or Recurrent Medullary
Thyroid Carcinoma
Radiation Therapy
Persistent or Recurrent
Hypercalcitoninemia
After primary surgery for MTC, persistent or recurrent elevation of the basal or stimulated calcitonin levels indicates
the presence of residual or recurrent tumor. Although longer
follow-upof reported series is needed, it is likely that thyroidectomy is curative in children with MEN 2A and FMTC in
whom the diagnosis of MTC is made by genetic testing or
by detection of an elevated calcitonin level after previous
negative yearly testing.lv" Patients in whom the diagnosis
of hereditary MTC is made at an older age, however, when
calcitonin levels are already high or a palpable tumor is
present, are more likely to have residual disease after
thyroidectomy. In one series, approximately 50% of these
patients had persistent elevations of calcitonin levels
postoperatively." In patients who present with a mass in the
neck (this includes virtually all patients with sporadic
MTC), lymph node metastases are present in more than
50%, and persistent elevation of calcitonin levels occurs in
50% to 100%.50,51 In one study of patients who presented
with palpable tumors, 15 of 18 patients (83%) with hereditary disease and 11 of 20 patients (55%) with sporadic
tumors had persistent disease as indicated by elevated
calcitonin levels postoperatively. 50
The clinical course of patients with MTC who have positive
nodes has been addressed in several studies. MTC can be a
very indolent disease. Many patients with persistently high
levels of calcitonin after thyroidectomy and node dissection
continue to do well without evidence of disease for many
years. In a study of 18 patients, 16 of whom had persistently
elevated calcitonin levels after "adequate surgery," Block
and coworkers found that calcitonin levels remained stable
for up to 6 years and recommended observation in the
absence of overt clinical disease. 52 These observations and
this approach have been supported by other groups.v-"
Other studies have indicated a poorer outcome in these
patients. In a Norwegian study of 84 cases of MTC, it was
noted that more than 50% of patients who presented with
cervical node metastases eventually died of the disease.'?
In a series of 139 patients operated on for MTC at Mayo
Clinic, it was found that 59% of the patients with positive
cervical lymph nodes experienced progression of disease.v
In a subsequent report from Mayo Clinic, 66% of nodepositive patients with hereditary MTC died, and none of the
patients with positive nodes had normal calcitonin levels
after a median follow-up of 15.7 years." The variable outcome of patients with positive lymph nodes is explained by
differences in the biologic virulence of the tumor, the extent
of spread at the time of treatment, and the adequacy of surgical extirpation.
The thyroid C cells do not concentrate iodine, and reports

of radioactive iodine treatment of metastatic MTC have
indicated a lack of significant effect." Several reports have
advocated the use of external beam radiation therapy for
MTC.55-58 These retrospective studies involved small numbers of patients, and it is difficult to determine whether
or not radiation treatment had a significant effect. Other
studies have not supported the use of radiation therapy
in MTC.23.24.59 In the report by Samaan and colleagues,
202 patients were studied retrospectively. Even though the
authors believed that the characteristics of the two groups
were comparable, it was found that the patients who
received external beam radiation therapy had a worse outcome those who did not." A study from France in 1992
reported a series of 59 patients with MTC, all of whom
received external beam radiation therapy to the neck and upper
mediastinum after surgery.'" Of these 59 patients, 44 had
positive nodes and 11 had residual tumor after surgery. After
radiation therapy to a mean dose of 54 Gy, 18 patients (30%)
experienced clinically evident local recurrences. Thirty-five
patients were still alive (median follow-up, 65 months),
and 24 had no clinical evidence of disease, although
calcitonin levels were not available for all patients. These
data indicate a high rate of clinically significant local
recurrence, and without post-treatment calcitonin levels it
is impossible to determine the actual response rate.
Postradiation scarring, fibrosis, and vasculitis make further
surgery for removal of metastatic deposits much more
difficult and dangerous in the radiated patient. Further
studies are needed to define the role of radiation therapy in
this disease.
Chemotherapy
In patients with advanced or metastatic MTC, chemotherapeutic regimens have not been extensively studied because
of the relative rarity of the disease. Existing reports, however,
have not shown any consistent benefit from either singleagent or combination chemotherapy regimens. Doxorubicin
(Adriamycin) as a single agent was not noted to alter the
progression ofMTC. 61A study of combination chemotherapy,
using doxorubicin, cisplatin, and vindesine, resulted in one
partial remission and three minor responses of 20 patients
treated/? Another study used a combination of dacarbazine
(dimethyl triazeno imidazole carboxamide, DTIC) and
5-fluorouracil (5_FU).61 In the five patients treated, there
were three partial responses that lasted less than a year.63 In
a study by Schlumberger and coworkers, combinations of
5-FU and streptozocin and 5-FU and dacarbazine were
given alternately to 20 patients with metastatic MTC. Three
partial responses and 11 long-term stabilizations were
observed.P"
136 - -
Thyroid Gland
The use of low-dose interferon-a was reported in two

patients with MTC. 64,65 Both of these patients showed
improvement in symptoms and in calcitonin level after
treatment, Neither had a complete response,
Juweid and colleagues reported the results of a phase I
clinical trial in which 12 patients were treated with highdose 1311-MN-14F(abh anti-CEA monoclonal antibody
combined with autologous hematopoietic stem cell rescue
(AHSCR).66 Toxicity was acceptable, and one partial
response was reported. Schott and coauthors reported treatment of seven patients with MTC by immunotherapy with
calcitonin-pulsed dendritic cells."? One significant response
was seen in this preliminary study. Chemoembolization of
liver metastases from patients with MTC has been effective
in reducing the size of lesions and in ameliorating symptoms
(author, unpublished data).
Studies with tyrosine kinase inhibitors have shown in
vitro activity, and clinical trials to test these agents are
under way.68-70
Localization of Persistent
or Recurrent Medullary
Thyroid Carcinoma
Computed Tomography
and Ultrasonography
A number of methods have been used to localize residual or
recurrent disease in patients with persistent or recurrent
calcitonin elevation after surgery for MTC. Careful physical
examination may reveal adenopathy in the jugular and paratracheal regions. Patients with advanced metastatic disease
may acquire subcutaneous tumors of the trunk and extremities.
Imaging studies that have been reported to be successful
in localization include ultrasonography with fine-needle
biopsy, computed tomography (CT) scanning, magnetic resonance imaging (MRI), selective venous catheterization
(SVC), and nuclear imaging studies. Van Heerden and
colleagues reported on high-resolution (lO-MHz) ultrasonography with ultrasound-guided fine-needle aspiration
biopsy in patients with a negative clinical examination.P In
a study of 47 patients with elevated calcitonin levels after
primary surgery for MTC, Raue and associates evaluated
ultrasonographic examination of the neck as well as
physical examination, CT scan, SVC, fine-needle biopsy, and
combinations of these modalities in localization of metastatic
MTC.71 After reoperation in 14 patients, calcitonin levels
were normalized in 2 patients. In a subsequent study they
reported that SVC correctly localized tumor tissue in 89%
of patients compared with 38% with CT scan and only 28%
with ultrasonography."
Selective Venous Catheterization

SVC facilitates detection of occult foci of metastatic MTC
by determining basal or stimulated calcitonin levels in
samples of venous blood drawn from sites in the neck, chest,
and abdomen. This technique was used successfully by
Norton and coworkers in seven patients." They reported that
SVC correctly localized tumor to a surgically resectable
area of the neck in every case. In a study by Mrad and

colleagues," localized disease in the neck was identified by
SVC in six patients. In two patients the calcitonin levels
were normal after operation guided by SVC data."
In a study from France in 1994, SVC was performed in
19 patients, and calcitonin elevations suggestive of distant
metastases were found in 5 patients." All five eventually
acquired clinically apparent distant disease, recommending
the usefulness of this technique in identifying distant metastases. In another series from Norway, elevated hepatic vein
stimulated calcitonin levels were believed to indicate the
presence of hepatic metastases. In this series, however, only
three patients were demonstrated to have hepatic metastases
by other means, and the significance of this finding is
unclear,"
In our series, eight patients with hepatic vein calcitonin
gradients were not found to have evidence of liver metastases by CT scanning and laparoscopy with liver biopsy."
These patients underwent resection of metastatic MTC in
the neck and two of the eight had subsequent normalization
of stimulated calcitonin levels, indicating that the hepatic
vein elevations may have been spurious. We no longer routinely use SVC in patients with occult MTC. The technique
of SVC varies depending on the institution. At our institution, catheters are simultaneously placed in the right and left
jugular veins and also in the left innominate vein and in a
hepatic vein. Peripheral blood is drawn from a femoral
catheter. After obtaining baseline values from these locations, a standard injection of calcium and pentagastrin is
performed. Samples for calcitonin levels are drawn at I, 3,
and 5 minutes from each of these locations. Values obtained
are compared with simultaneously obtained baseline and
stimulated peripheral values. Other authors do not use calciumpentagastrin stimulation during SVC but rather use sample
basal levels from multiple sites in the neck, chest, and
abdomen and determine gradients by comparing these with
peripheral levels."
Nuclear Imaging Studies

A number of different radiopharmaceuticals have been
described to localize metastatic MTC. Thallium 201 (l0ITl)
chloride and technetium 99m dimercaptosuccinic acid
(99mTc DMSA) have been shown to be useful in evaluating
hypercalcitoninemic patients. 78-8o Iodine 131 metaiodobenzylguanidine (MIBG) scintigraphy can be used to image
MTC but is not consistent.v-" Octreotide scans with indium
III CII In) have been used to localize metastatic disease, but
these scans do not detect small liver metastases.Pv"
Monoclonal anti-CEA antibodies labeled with iodine 131
( 1311) or iodine 123 C231), 1111n, and 991l1Tc have been evaluated for localization of MTC. 85,86 Juweid and colleagues
reported the largest series with 26 patients, but only 9 of
those were identified as patients with occult disease.f'"
Single-photon emission CT (SPECT) with labeled monoclonal anti-CEA antibodies was compared with ultrasonographic examination and CT scan, and in four of nine
patients imaged metastatic foci were confirmed by operative
results.f" The value of monoclonal antibodies in localization of occult MTC remains to be proved. Anticalcitonin
monoclonal antibodies have also been evaluated in a small
number of cases but have never gained broad attention."
In addition, studies have examined the imaging of cholecystokinin B receptors, which have been demonstrated in a high
percentage of MTCs in vitro in patients with MTC. 90,91
Radioimmunoguided surgery is a technique designed to
facilitate the intraoperative detection of metastases. After
systemic administration of tumor-specific radiolabeled
monoclonal antibodies, a hand-held gamma counter is used
to scan the operative field. Areas of increased activity are
explored, and soft tissue and nodes from these areas are
resected. In five patients in whom immunoscintigraphy
using an anti-CEA monoclonal antibody was applied, all
previously identified metastases could be visualized.
According to the authors, the technique detected tumor foci
missed by intraoperative inspection and palpation in three of
five patients. Radioimmunoguided surgery did not identify
two small (10 mm x 10 rom) lesions that were resected and
found to contain microscopic cancer." In a case report,
intraoperative scanning after III In pentetreotide administration was used to localize metastatic sites. Plasma calcitonin
levels fell remarkably after surgery but were not reduced
to normal values.f Although these results are promising,
surgical cures were not noted, and a compartment-oriented
resection or observation may also be considered in asymptomatic patients."
Fluorodeoxyglucose (FDG) positron emission tomography
(PET) has been evaluated by our group in the staging of
MTC. From January to December 1996, 10 consecutively
treated patients (7 men and 3 women) with elevated serum
calcitonin levels after primary operative treatment for MTC
were included in the study. FDG-PET images were compared with CT and MRI images, and suspected metastatic
foci were assessed by correlation with intraoperative
and histopathologic findings.?" FDG-PET imaging proved
to be more sensitive but less specific in detecting cervicomediastinal metastatic lesions compared with CT or MRI,
respectively. Two patients with liver metastases detected by
laparoscopy only, however, had no evidence of abnormal
liver FDG uptake on PET imaging."
Diagnostic Laparoscopy
MTC metastatic to the liver often has a miliary appearance,
with multiple small (1 to 3 mm), white, raised nodules on
the liver surface, which are easy to see with the laparoscope
but may not be detected by CT scan, MRI, or other imaging
techniques. We have routinely used diagnostic laparoscopy
to look for liver metastases in patients with elevated calcitonin levels after primary surgery for MTC (Fig. 15-5).77 In
a series of 41 patients, liver metastases were demonstrated
in 8 patients, 7 of whom had negative CT imaging. In an
update of this series, 136 patients had direct inspection of
the liver by laparoscopy (126) or open procedure (10). Liver
metastases were identified in 29 patients (21.3%).77
Surgical Treatment of Recurrent

or Persistent Medullary
Thyroid Cancer
Because of the lack of success reported for other modalities
in the treatment of persistent or recurrent MTC, surgical
137
B
FIGURE 15-5. A, Computed tomography (CT) of liver from
patient with multiple endocrine neoplasia type 2A, recurrent
medullary thyroid carcinoma (MTC), and elevated calcitonin
levels. There is no evidence of liver metastases on the scan.
B, Laparoscopic view of liver from the same patient showing
multiple small raised whitish lesions on andjust beneath the surface
of the liver, confirmed to be metastatic MTC by biopsy. These
small, multiple metastases are often not seen with routine CT
scanning or other imaging modalities, including nuclear scanning.
(From Tung WS, Veseley TM, Moley IF. Laparoscopic detection of
hepatic metastases in patients with residual or recurrent medullary
thyroid cancer. Surgery 1995;118:1024.)
reintervention has been used by several groups to attempt to

control the disease. MTC is often indolent and remains in
the neck for long periods of time. It is possible that removal
of residual or recurrent disease in the neck will result in cure
in some cases and arrest the course of the disease in others.
Several groups have reported their experience with reoperation for persistent or recurrent MTC in the neck.29.73.95.96
A significant reduction in stimulated calcitonin levels after
reoperation was reported in many patients, and normalization of calcitonin levels was noted in some. In 1986, Tisell
and colleagues reported a series of 11 MTC patients with
persistent hypercalcitoninemia after previous apparently
adequate surgery.97 Tisell performed what he called a
"microdissection." This involves a meticulous dissection of
all lymph node and fatty tissue of the central and lateral
zones of the neck, including the thyroid bed, both recurrent
nerves, and nodes in the lateral neck, extending from the
level of the mastoid process down to the innominate vein
and subclavian arteries and out laterally to the level of the
138 - -
Thyroid Gland
spinal accessory nerve. In several cases, a median sternotomy

and resection of upper mediastinal nodes were also performed. In this series, the calcitonin levels were normalized
in four patients and significantly lowered in three.
We reported two series of cervical reoperations for MTC:
from 1990 to 1993 98 and from 1993 to 1996. 99 In the first
series, 37 operations were done in 32 patients. The patients
had previously undergone total thyroidectomy and most
of the patients also had previous lymph node dissections.
All patients had elevated stimulated calcitonin levels.
Localization studies, including selected venous catheterization, CT scanning, and physical examination, were successful in localizing tumor in half the cases. Operative morbidity
was low and there were no deaths. In 28 of the 35 operations, discharge from the hospital occurred 2 to 5 days postoperatively. In nine cases (group 1), calcitonin was reduced
to undetectable levels following reoperation. In 13 cases
(group 2), postoperative calcitonin levels were decreased by
40% or more. In 10 cases (group 3), postoperative calcitonin
levels were not improved. Patients' sex, disease, number of
nodes previously resected, preoperative calcitonin levels,
and preoperative localization study results were not significantly different among the three groups and therefore
unlikely to predict outcome for reoperation. Previously
resected tumors from patients in group 3, however, were
more likely to have demonstrated invasive features (invasion
of adjacent structures, extranodal or extracapsular spread)
than tumors from patients in groups 1 and 2 (P < .05,
Fisher's exact test)."
In this series, reoperation resulted in normalization of
calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The
results also suggested that determination of the degree of
invasiveness of the primary tumor may help in selecting
patients likely to benefit from reoperative surgery for recurrent
medullary thyroid cancer.
In the second series, we sought to improve our results
through better selection of patients likely to benefit from
reoperation.?? This was achieved by obtaining a systematic

metastatic work-up including routine staging laparoscopy,
described earlier. One hundred and fifteen patients with persistent elevation of calcitonin after primary surgery for MTC
were evaluated. After metastatic work-up, which revealed
distant disease in 25% of these patients, and discussion of
the options (including observation in patients without gross
cervical disease), 52 patients elected to undergo cervical
reoperation. Seven patients had paIliative procedures and
45 patients had cervical re-exploration with curative intent.
In the seven patients who had paIliative cervical operations,
one patient had persistent postoperative hypocalcemia.
There were no other complications in that group. In the
45 patients who underwent reoperation with curative intent,
there were no postoperative deaths and no transfusions were
required. Complications included thoracic duct leak in four
patients (8.9%) and hypocalcemia (2 patients [4%] at
follow-up of 3 months and 2 years). Careful identification
and exposure of the recurrent laryngeal nerves (RLNs) were
done through a previously undissected area by the lateral,
backdoor, or anterior approach. There were no permanent
recurrent nerve injures."?
In the 45 patients who had reoperation with curative
intent, the mean decrease in postoperative stimulated
calcitonin level was 73.1% (see Fig. 15-4). In 22 of 45 patients
(48%), the postoperative stimulated calcitonin level dropped
more than 90% compared with the preoperative value
(Fig. 15-6). Seventeen (38%) had postoperative stimulated
calcitonin levels that were within the normal range (group 1),
and six (13%) had no significant decrease in stimulated
calcitonin levels (group 3). The remaining patients had a
greater than 35% reduction in stimulated calcitonin levels
(group 2). As in our earlier series, tumor invasiveness was
the only parameter correlated with failure to reduce postoperative calcitonin levels to the normal range (P < .05,
Fisher's exact test)."
These results indicate an improvement in outcome after
reoperation for persistent or recurrent MTC. In the second
100
90 -+-11 - - - - - - - - - - - - - - - - - - - - 80
c: 70
'c
.9
'0 60
til
o 50
c.
0
S! 40
c.
~
0
-t-.......-.t. . . . . . . . .t - - . . . - - - - - - - - - - - - - - - - - - - . - - - . - - - .
30
20
10
0
3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45
Patients
FIGURE 15-6. Postoperative change in

peak stimulated calcitonin levels. The
shaded bars indicate the postoperative
stimulated calcitonin levels of the
45 patients who underwent curative
cervical reexploration and dissection.
The postoperative calcitonin level is
expressed as a percentage of the preoperative calcitonin level. One hundred
percent indicates no change in calcitonin level, and 10% indicates that the
stimulated calcitonin level fell by 90%.
'Postoperative levels were higher than
preoperative levels. (From Moley JF,
DeBenedetti MK. Patterns of nodal
metastases in palpable medullary
thyroid carcinoma: Recommendations
for extent of node dissection. Ann Surg
1999;229:880.)
series (1992 to 1996),38% (17 of 45) of patients had normal

postoperative stimulated calcitonin levels, compared with
28% (9 0["32) in the first series. Only 13% (6 of 45) of
patients had no decrease in calcitonin levels following
reoperation, compared with 31% (10 of 32) in the first series
(P = .07, Fisher's exact test). This improvement occurred
through better preoperative selection of patients and the
institution of routine laparoscopic liver examination preoperatively, which identified metastases in 10 patients, 9 of
whom had normal CT or MR imaging of the liver and who
would otherwise have undergone neck reoperation with
curative intent.
In this series of 115 patients, 24 decided not to have
surgical intervention."? If a patient with elevated calcitonin
levels has had an adequate previous operation and results
of imaging studies are negative, an expectant approach with
routine yearly screening is appropriate in many cases.P We
do, however, believe that it is important to observe these
patients closely with routine CT or MRI of the neck and
chest. If central recurrence develops, resection prevents
death from airway or great vessel invasion in some patients.
Tumor debulking may afford some patients relief from
symptoms caused by local disease in the neck or from
tumor-induced flushing and diarrhea. We treated six patients
with severe, disabling diarrhea who had preoperative stimulated calcitonin levels greater than 25 ng/mL, in whom
surgery reduced calcitonin levels and abolished the diarrhea
(author, unpublished results).
These reports support the use of reoperation in patients
with persistently elevated calcitonin levels after surgery for
MTC. Although patients with highly invasive tumors are not
as likely to benefit from this approach, these operations can
be done safely in the majority of cases and may result in
long-term survival benefit and prevention of recurrence
complications in the neck. Long-term follow-up of these
patients is needed to confirm the presumed benefit derived
from these operations.
Summary and Conclusions

MTC is a tumor of the thyroid C cells that occurs in sporadic
and hereditary clinical settings. Measurement of plasma
calcitonin is a sensitive marker for the presence of this
tumor. Hereditary forms of MTC, including MEN 2A,
MEN 2B, and FMTC, are associated with mutations in the
RET protooncogene. Genetic testing can identify mutant
gene carriers, and preventive thyroidectomy should be done
in patients found to have inherited a mutant gene. Surgical
treatment for palpable MTC is total thyroidectomy with central and lateral functional neck dissection. Recurrent or
residual MTC may be localized by ultrasonography, CT
scanning, MRI, nuclear scanning, or SVc. Reoperation with
systematic node dissection in patients with localized or
occult MTC and no evidence of distant metastases has
resulted in normalization of calcitonin levels in a significant
number of patients. Radiation and chemotherapy have not
been shown to be consistently effective in the treatment of
MTC, and the treatment of patients with widely metastatic
disease is unsatisfactory. Clinical trials of newer chemotherapeutic agents may identify more effective regimens.
139
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Localization Tests in Patients

with Thyroid Cancer
Shiro Noguchi, MD, PhD, FJCS, FACE
Differentiated Thyroid Cancer

of Follicular Cell Origin
The minimal test for determining the diagnosis of a thyroid
nodule is fine-needle aspiration cytology with or without
ultrasonography. Use of these two tests enables one to discriminate benign from malignant thyroid tumors in about 85%
of patients. The remaining 15% of thyroid malignancies are
follicular cancer, Htirthle cell cancer, and some follicular
variants of papillary thyroid cancer. Various imaging techniques are used for detecting regional and/or distant metastasis
and identifying local invasion of adjacent structures.
Ultrasonography for Papillary Cancer

Since the advent of high-resolution ultrasonography, it is
sometimes possible to establish the diagnosis of papillary
cancer with only ultrasonography, and fine-needle aspiration
cytology is used to confirm the diagnosis.!:" Papillary cancer
is most frequently thyroid cancer (""80%). The presence of
calcification, irregular shape, absence of a halo and hypoechogenicity, and local invasion suggest it is a malignant
nodule. Calcification is identified as multiple, small hyperecho genic spots in a hypoechogenic area (Figs. 16-1 and
16-2). They are usually due to superimposed psammoma
bodies. Larger papillary thyroid cancers often degenerate,
and complex cyst formation is common. These partially
cystic areas are usually located at the peripheral part of the
tumor (Fig. 16-3). A protrusion of solid tumor into the cyst
can frequently be seen. Lymph node metastases or recurrence
in lymph nodes is also identified with ultrasonography.
Lymph nodes greater than 9 mm in diameter, those with
a longitudinal-transverse diameter ratio of less than 2.0, and
those with a round configuration are likely to contain metastatic cancer (Fig. 16-4).5.7 When one or more suspicious nodes
are identified by ultrasonography, fine-needle aspiration
cytology is usually recommended for confirmation of diagnosis. Ultrasonography is an accurate and sensitive localization
test for diagnosing cervical metastases, but unfortunately it is
142
not useful for identifying metastases in the retroclavicular

area and mediastinum. Thus, when serum thyroglobulin
levels are increased, other localization tests are necessary,
such as magnetic resonance imaging (MRI) or radioiodine
whole-body scanning (WBS), the latter for the patient who
has previously had a total or near-total thyroidectomy. The
search for enlarged lymph node metastases in the neck has
become easier because of ultrasonography; however, microscopic metastases are also present in about 80% of patients
with papillary thyroid cancer who have no evident cervical
metastases on clinical examination.f-? These small metastases mayor may not be visualized with ultrasonography."
In patients with papillary thyroid cancer, the importance of
nodal metastasis on survival is controversial. Some studies
suggest that the presence of clinically evident lymph node
metastases in patients with papillary and follicular cancer
has an adverse effect on survival. 1116 Extracapsular invasion
of nodal metastases of thyroid cancer is associated with a
poorer survival rate in patients with papillary microcarcinoma." Other studies suggest that lymph node metastases
are associated with increased recurrence rate, but survival is
not affected.":" Since cervical lymph node is the most frequent site for recurrent tumor, ultrasonography of the neck is
helpful for the management of patients with papillary thyroid
cancer.
Radioiodine Scintigraphy
Iodine 131 ( 1311) is a favored scanning agent for following
patients after total or near-total thyroidectomy for thyroid
cancer of follicular cell origin because 1311 can be used therapeutically. Many studies have examined the sensitivity and
specificity of a low dose (370 MBq, or lower) and high dose
of 131 1 (2.9 GBq, 80 mCi, or more) for the detection of
disease. 22. 34 The sensitivity ranges from 40% to 84%
depending on the dose of 1311, the age of the patient, tumor
differentiation, and tumor location. The specificity is high
and the range is narrow, from 90% to 100% (Fig. 16-5). The
sensitivity for detecting lung metastases is reported to vary
from 42% to 60%, and for bone metastasis it varies from
Localization Tests in Patients with Thyroid Cancer - -
143
ultrasonography, 18F-2-fluoro-2-deoxY-D-glucose positronemission tomography (FDG-PET), or Tc 99m sestamibi are

often used alone or in combination to document the presence
and site of persistent or recurrent disease.
1231 is a pure lower energy (l59-keV) gamma emitter,
whereas 131 1 is a high-energy (364-keV) gamma and beta
emitter. 1231has better resolution imaging properties than 131 I
because 1231 does not emit beta particles; therefore, a larger
dose of 1231 can be administered with a lower risk of stunning, which reduces subsequent therapeutic efficacy."
Image quality after radioiodine administration is good in
terms of resolution and low background at 24 hours. The
recommended dose of 1231 is 56 MBq; there is little incremental advantage of sensitivity after scanning using larger
doses. The concordance with 131 1 is almost identical with
post-therapy scan.37.38 The overall sensitivity of 1231 is 93%
when compared with 1311.
Scintigraphy with Alternative Nucleotides

THALLIUM 201 CHLORIDE
B
FIGURE 16-1. Papillary cancer. A and B, Many small hyperechoic
spots are seen in the hypoechoic region.
54% to 60%.26,35 The sensitivity for detecting lymph node

metastasis is only about 22%26; luckily, ultrasonography,
computed tomography (CT), MRI, Tc 99m sestamibi, and
thallium can usually detect cervical lymph node metastases.
The sensitivity may change depending on the definition of
tumor presence. Serum thyroglobulin levels, 20lTI scan, neck
Thallium 201 eOIT!) was first used in the early 1980s for
detecting metastases from both well-differentiated thyroid
cancer and recurrent medullary cancer in 1980s.39. 44 It accumulates in the tumor and gives a positive image by contrasting with the negative image by radioiodine and remains in
the tumor longer than it does in normal thyroid (Fig. 16-6).
Tc 99m sestamibi became available around 1987, and many
investigators compared the results of 20lTI scintigraphy to
Tc 99m sestamibi. Although these two imaging isotopes
gave comparable results, Tc 99m sestamibi results were
slightly better and clearer than those with 20lTI in patients
with differentiated thyroid cancer.45,46 For patients with
medullary cancer 99mTc(V)-dimercaptosuccinic acid (Tc 99m
DMSA) appeared to be somewhat more accurate than 20lTI
for routine clinical use." 20lTI imaging is most useful after
total or near-total thyroidectomy and 131 1 ablative therapy in
patients with rising or elevated serum thyroglobulin levels.
In addition, about 10% of hypothyroid patients with verified
thyroid cancer and positive 20lTI scan have a low serum
thyroglobulin leve1. 48,49 20lTI imaging has an additional
advantage in that it can be done in the patients who are
FIGURE 16-2. Papillary cancer.

Arrow I, right carotid artery;
arrow 2, primary tumor; arrow
3, trachea; arrow 4, esophagus;
and arrow 5, left carotid artery.
144 - -
Thyroid Gland
negative 131 1 scan in a patient with an elevated serum

thyroglobulin level. 28,49
20lTI scanning is helpful for detecting cervicomediastinal
nodal metastases but is not accurate for detecting a normal
thyroid remnant or pulmonary metastasis. Overall, 20lTI is
the most commonly used radioactive pharmaceuticals for
patients with thyroid cancer, other than 1311.
TECHNETIUM 99M SESTAMIBI
FIGURE 16-3. Papillary thyroid cancer with cystic degeneration.
receivmg thyroid hormone. Discontinuation of thyroid

hormone medication stimulates increased thyroid-stimulating
hormone (TSH) secretion, which can stimulate thyroid
tumor uptake of radioiodine and tumor growth. Imaging
with 20lTI also requires only one visit, in contrast with scanning with 131 1 using human recombinant TSH, which
requires several visits. The sensitivities reported for 20lTI
vary depending on the dose of 20lTI and the timing of imaging after injection of the isotope. When imaging is done
15 to 20 minutes after injection, sensitivities ranging from
74% to 94% have been reported.23.27.50 Reported specificities
range from 84% to 97%.27,49
In a large retrospective series including 326 patients, 20lTI
scintigraphy demonstrated abnormal findings in 39 patients
who had negative 131 1 studies." Among these patients,
26 were confirmed histologically and 5 radiologically, and
8 had no definite confirmation. The sensitivity was 94%
and the specificity was 98%. There is a large discordance
between 20lTI and 131 1 studies in patients with remaining
normal thyroid tissue, because the sensitivity oeolTI is poor
when normal thyroid remains, whereas 131 1 uptake is high in
this tissue.t' After ablation with 1311, 20lTI has a sensitivity of
94% and a specificity of 96%.23 The sensitivity of 20lTI is
equivalent or superior to low-dose 131 1 but less sensitive than
high-dose 1311. 20lTI is particularly useful in the setting of a
Scanning with Tc 99m sestamibi in thyroid cancer patients

has been compared to radioiodine." with 201TI,45 with
Tc 99m terrofosmin, and with MRI.52 Tc 99m sestamibi,
like 20ITI, does not require discontinuing thyroid hormone
and requires only one visit. This is an advantage of Tc 99m
sestamibi over 1311. Imaging with non iodine radiopharmaceuticals is independent of TSH stimulation, but TSH
stimulation improve the quality of images.
Contemporary gamma cameras are optimized for imaging at the emission energy of 99mTc (140 keY) rather than
much higher emission energies of 1311 (364 keY) or the
lower emission energy of 20lTI (69 to 81 keY). Tc 99m
sestamibi has the advantage of the availability of a kit-based
radiopharmaceutical with same-day imaging. The other
advantage ofTc 99m sestamibi over 20lTI is a short physical
half-life of 6 hours, whereas 20lTI has a physical half-life of
73 hours. Therefore, Tc 99m sestamibi can be administered
in a larger dose (20 to 25 mCi), resulting in better images
and lower radiation exposure to the patient.
Invasion of Papillary Cancer to

Adjacent Organs
Involvement of the recurrent laryngeal nerve by tumor
cannot be determined preoperatively unless vocal cord palsy
is evident on direct laryngoscopy. However, the size and
position of the primary tumor provide some information.
Among our 3148 patients with papillary thyroid cancer
larger than 10 mm in maximum dimension, there was a
direct correlation between adhesion/invasion of the recurrent laryngeal nerve. Thus, involvement occurred in 9.2% of
tumors 10 to 14 mm, 17.3% of tumors 15 to 24 mm, and
33.0% of tumor more than 25 mm in maximum diameter.
Using the same size criteria, as determined by frozen
section, invasion/adhesion occurred within the esophagus in
2.7%,9.2%, and 21.4%. respectively. CT, MR!, conventional
esophagography, and esophagoscopy may help predict the
FIGURE 16-4. Lymph node metastasis
with calcification (A) and with cystic

degeneration (B).
Localization Tests in Patients with Thyroid Cancer - - 145
FIGURE 16-5. Lung metastases. A, With conventional chest

radiograph, no metastases were seen. B, With high-dose 1311
scintigraphy, extensive metastases were shown. C, With helical

CT,multiple small shadows of metastases wereseen in one patient.
presence of invasion of thyroid cancer into the esophagus;

however, these modalities are insufficient for a precise diagnosis and determination of exact depth of invasion.
Recently, endoscopic ultrasonography was reported to be
superior to MRI and esophogography in terms of accuracy
and specificity regarding esophageal invasion." Invasion of
the trachea is also difficult to determine preoperatively.
Using the same size criteria, adhesion/invasion to the
trachea was observed in 17%, 29%, and 40%, respectively;
however, when the tumor was close to Berry's ligament, it
was hard to differentiate. These figures therefore could be an

overestimation. Tumor size is a well-known predictor of
tumor behavior. 5455 MRI helps determine extent of tracheal
invasion. Characteristic findings include a soft tissue signal
in the tracheal cartilage, intraluminal mass, and degree
of tumor circumference around the trachea abutting
180 degrees or more.>' An anterior part of the trachea is
most likely to be invaded by thyroid cancer in primary
cases; however, in cases of recurrence, invasion can occur
in any part of the trachea. Endoscopic documentation of
FIGURE 16-6. Thallium scan, showing early image (A) and delayed image (B). The arrow in B indicates tumor localization.
laryngotracheal invasion was recently reported. The major

findings included mucous membrane swelling, dilated
capillaries, localized reddening, localized swelling, edema,
and erosion (Fig. 16-7). Intraluminal tumor is rare." When
these findings are present, resection of a part of the trachea
followed by end-to-end anastomosis or partial resection
with preservation of the recurrent laryngeal nerve is recommended rather than shaving the tumor off the surface of the
trachea.T"
Follow-Up of Patients Who Lost

Differentiation Markers
Although the serum thyroglobulin level is the most sensitive
and useful marker for follow-up of patients with differentiated thyroid cancer, especially in patients after total thyroidectomy, in some patients serum basal thyroglobulin
levels are not increased and fail to increase when TSH levels
are increased. Thyroglobulin in this small group does not
FIGURE 16-7. A, Stage I thyroid cancer that

extended through the capsule of the thyroid
gland and abutted the external perichondrium.
B, Stage 2 thyroid cancer that invaded between
the rings of cartilage or destroyed the cartilage.
C, Stage 3 thyroid cancer that extended through
the cartilage or between the cartilaginous plates
into the lamina propria of the tracheal mucosa.
D, Stage 4 thyroid cancer that extended through
the entire thickness of and expanded the tracheal
mucosa.

serve as a useful marker for recurrence. Some thyroid
cancers also dedifferentiate, particularly with advanced
disease and age. 131 1 ablation is less effective in these
patients. 7,45,48,52,59-61 Since the most common site of recurrence is in the neck lymph nodes, ultrasonography would be
selected first for local disease and 20lTI or Tc 99m sestamibi
for WBS. For lung metastases with small miliary foci, helical CT is better than WBS. External-beam radiation can be
helpful for treatment of high-risk patients with persistent or
recurrent disease. Redifferentiation with retinoic acid and
other agents may be helpful.F
Image Diagnosis
of Medullary Cancer
All patients with a preoperative diagnosis of medullary
cancer of the thyroid should be tested for a ret protooncogene germline point mutation and also be screened for
pheochromocytoma and hyperparathyroidism (see other
chapters regarding medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism). Medullary cancer
secretes calcitonin and carcinoembryonic antigen (CEA)
and occasionally neuron-specific enolase, serotonin,
chromogranin, gastrin-releasing peptide, substance P,
pro-opiomelanocortin-derived products, and somatostatin.
Among them, calcitonin and CEA are used as tumor markers for following patients for persistent disease or recurrent
disease. Calcitonin is the most sensitive biochemical marker
for predicting the presence of tumor. A steep slope with
rapidly rising CEA levels indicates that the patients have
rapidly progressive tumor. A normal CEA level or a flat
slope indicates that patients may be cured or they have only
slowly progressive disease.63,64 Decrease of the calcitonin/CEA
ratio indicates dedifferentiation of medullary thyroid cancer.
Ultrasonography
Medullary cancer is a considerably rare disease, constituting
only 4% to 9% of all thyroid cancers. Ultrasonography is the
most recommended helpful modality for detecting primary
tumor as well as localizing cervical metastases in the central
or lateral neck nodes, particularly those associated with
multiple endocrine neoplasia (MEN) type 2A. Ultrasonography is superior to radionucleotide scanning for detecting
cancer foci within the thyroid or in the cervical lymph

nodes. One can identify primary tumors as small as 3 mm
by high-resolution ultrasonography. Lymph node metastases
are common in patients with MEN 2A and familial
medullary cancer. Pathologic examinations of the lymph
nodes during primary staging revealed cervical lymph node
involvement in 31% to 33% of the p'I'I cases,65.66 in 53% of
the pT2 cases." and in 100% of the pT3 and pT4 patients.
Ultrasonographic features include hypoechoic nodules with
disseminated or focal echogenic calcifications that may cast
an acoustic shadow and smooth or irregular delimited
nodules with pseudopod-like projections (Fig. 16-8). These
features are found both in primary tumors as well as in
lymph node metastases. Since these ultrasonographic findings are nonspecific and may be present in adenomatous
nodular goiters, one should interpret the ultrasonographic
findings with the serum calcitonin levels.67,68 Serum calcitonin
levels are highly specific for medullary thyroid cancer and
are helpful for both preoperative planning and postoperative
evaluation. Most patients with mild increases in calcitonin
have metastatic tumors only in the cervical lymph nodes.
Some of these metastatic nodes are too small to detect by
palpation but may be detected by ultrasound scanning.
Ultrasonography therefore is the first choice as a localization test. It is inexpensive and there is no radiation hazard.
An experienced ultrasonographer, however, is essential for
good results.
MmG
Three years after the advent of 1321-metaiodobenzylguanidine (MIBG) as an imaging agent for pheochromocytomata.v? it was noted that some medullary thyroid cancers
also could be identified by MIBG scanning. This is also true
for metastases.?? From these observations it was expected
that MIBG might be a helpful therapeutic agent."
Unfortunately, due to the poor sensitivity of MIBG scintigraphy in medullary thyroid cancer, this agent is not suitable
for initial diagnosis but can be used when internal radiation
therapy with 1311-MIBG is planned. 1311-MIBG has been
used for treatment of pheochromocytoma, paraganglioma,
and medullary cancer when MIBG scanning is positive.
Symptomatic control was achieved in all patients treated
with 1311-MIBG alone, including hormonal improvement
and tumor regression or stabilization in patients with
FIGURE 16-8. Calcification of medullary

thyroid cancer (A) and of part of a multinodular goiter (B).
148 - -
Thyroid Gland
metastatic tumors with minimal adverse effects." Also,

in many other articles, no important adverse effect is
mentioned.Y" However, in one article, a patient with
metastatic pheochromocytoma to the lung, liver, and
paraaortic lymph node was treated with 3.7 GBq (100 mCi)
of 1311_MIBG. The metastatic nodes in the lung and liver
disappeared, and the secretion of catecholamine levels
decreased to normal. Major but temporary untoward
responses were hypertension and hyperglycemia."
Anti-CEA Monoclonal Antibody

Medullary cancer contains and secretes CEA as well as
calcitonin. 1311-labeled or 1llln-labeled CEA unfortunately
detects only relatively large metastases (> 10 mrn'') as
occurred in 5 of II patients with medullary thyroid cancer.s"
Initially, radiolabeled CEA monoclonal antibodies were
reported to be specific but not very sensitive. Subsequent
investigation demonstrated nonspecific uptake of radiolabeled CEA in the spleen, kidneys, bone marrow, and liver,
presumably due to the poor specificity of the antibody that
was used." Hoefnagel," Zanin.t' and their associates
suggested that 1311-labeled monoclonal antibody might be
used therapeutically in patients with medullary thyroid cancer.
In 1997, Juweid and colleagues'" reported that anti-CEA
monoclonal antibodies were excellent agents for imaging
recurrent, residual, or metastatic medullary thyroid cancer. The
high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents
ideal for staging patients, monitoring disease preoperatively
or postoperatively, and especially for evaluating patients
with recurrent or persistent elevated calcitonin or CEA
levels after primary surgery." Sensitivity of anti-CEA
radiolabeled antibody technique seems to be dependent on
the quality of monoclonal antibody.P Combined therapy
using 1311-labeled CEA with conventional chemotherapy of
medullary thyroid cancer has been reported in animals.f"
Behr and coworkers reported that 30 patients with smallvolume metastatic colorectal cancers have been treated with
13 'Llabeled anti-CEA as an adjuvant setting."
99mTc(V)-Dimercaptosuccinic Acid
and Somatostatin Analog
Ohta and associates first reported the use of DMSA for
imaging medullary cancer of the thyroid in 1984. 88 Four
patients with medullary cancer showed clear and specific
tumor uptake in primary and/or metastatic foci. DMSA
uptake was subsequently noted in the nasopharynx, axial
skeleton, breast, liver, spleen, heart, kidney, urinary bladder,
great vessels, and skeletal muscles." There was no DMSA
uptake in the male breast. Positive uptake was seen in
only one of three subjects younger than 15 years of age, in
16 of 23 patients (70%) between 15 and 50, and in 7 of 25
(28%) older than 50. 90 The overall sensitivity of DMSA
ranged from 57% to 95%.91-96 The differences in sensitivity
may depend on the method of preparing pentavalent DMSA
since the pH of the mixture has to be high (7.5) for highest
activity. When the pH is low, trivalent DMSA is synthesized,
which makes DMSA sensitivity low.?? Unfortunately, most
subsequent studies have not found DMSA to be sensitive
enough to recommend it for routine use in patients with

medullary thyroid cancer. Kwekkeboom and colleagues'"
have reported tumor localization in 11 of 17 patients (65%)
with 1llln-octreotide with medullary thyroid cancer. They
reported that neither serum calcitonin nor CEA levels
differed significantly between patients whose tumor accumulated labeled octreotide in vivo and those tumors that did
not. Numerous authors have subsequently presented their
experience using octreotide scintigraphy for the localization
of recurrent medullary cancer.99-107 When somatostatin
scintigraphy was compared with MRI scanning in nine
patients, the same 17 lesions were seen by both methods;
however, 13 additional suspicious lesions were seen with
somatostatin scintigraphy. Histologic confirmation was
available from 19 metastases; MRI was positive in 13 (68%)
and somatostatin receptor scintigraphy was positive in
18 (95%).99.100 Comparison of 1llln-octreotide and DMSA
has also been done. Three papers concluded that octreotide
is superior; however, the sensitivity of DMSA is relatively
IOW. 91,1 02.108 Another investigation suggests that both 1111n
and DMSA are relatively that insensitive. 103
Imaging of Metastases
of Thyroid Cancer with Fluorine
18 Fluorodeoxyglucose
FDG is a o-glucose analog, which is converted in cells to
FDG-6-phosphate by hexokinase. FDG-6-phosphate is
metabolically trapped and accumulates in tissue where
glucose-6-phosphatase is lacking. Metabolic trapping
is the key factor responsible for the biodistribution of
18F-2-deoxyglucose.109 Because other enzymes that act on
glucose-6-phosphate have only a negligible affinity for
FDG-6-phosphate and membrane permeability is low, the
rate of accumulation of FDG-6-phosphate is proportional to
the phosphorylation rate of exogenous glucose and o-glucose
utilization of the tissue. 18F has a half-life of about
109 minutes, so that the patient is exposed to a tolerable
amount of radiation. 110
FDG-PET is primarily used to localize recurrent differentiated and poorly differentiated thyroid cancers, especially
in patients who are serum thyroglobulin positive and 131 1
WBS negative. Serum thyroglobulin determination and
diagnostic 131 1 WBS provide the diagnosis of recurrent
disease. Recurrent differentiated thyroid cancer mayor may
not take up radioiodine. III A patient whose recurrent tumor
is detected by radioiodine scanning has a significantly better
prognosis than does a patient whose tumor does not take
up 131I.ll2 FDG-PET can be positive in the same site as a
WBS-positive site or WBS-negative site, or both can be
present in the same patient. Grunwald and associates 113
reported that FDG-PET was particularly useful in WBSnegative patients, showing a high sensitivity of 85%.
Patients with poorly differentiated thyroid cancers were
more likely to be WBS negative and FDG-PET positive.
Those patients also have a worse prognosis-FDG-PET
helps stage the disease and guide treatment strategy. Possible
therapeutic strategies include surgery, external-beam
radiation, and redifferentiation therapy.Uv'!? Patients who

are WBS positive and FDG-PET negative usually respond
better to treatment with 1311. The result obtained from
FDG-PET scanning may influence therapy; for example, the
removal of mediastinum lymph node metastases usually
should be omitted when additional distant metastases are
detected by FDG-PET scan in 131 1 scan-negative patients. The
benefit of further radioiodine therapy in thyroglobulin-positive
1311 scan-negative patients is controversial.
Correlation between the grade of differentiation and the
rate of detectability with FDG-PET and MIBI or WBS
exists. Since glucose metabolism is increased particularly in
poorly differentiated tumors, a higher sensitivity of FDGPET can be expected in these tumors, in association with a
low sensitivity ofWBS.118-123 Metastases showing high FDG
uptake but low 131 1 uptake often grow more rapidly and are
generally more aggressive.l" A higher mortality rate in
patients who have a negative WBS (with or without elevated
thyroglobulin levels) in spite of proven metastases has also
been reported.l" Grunwald and coworkersl-" reported a
higher rate of positive FDG-PET scans in patients with highrisk patients by TNM staging. Thus, positive FDG-PET
scans were observed in 2 of 14 patients (14%) with pTl/pT2
tumor stage versus 8 of 17 patients (47%) with pT3/pT4
tumors. Higher tumor stage correlates with a poorer prognosis. Positive FDG-PET scans also occur in patients with
sarcoidosis.l" granulomas.I" parathyroid tumors.!" Hiirthle
cell adenomas.F' follicular adenomas, and adenomatous
goiters.F" FDG-PET scanning can detect metastases in
lymph nodes less than 1 em in diameter. 123 Small pulmonary
metastases I em), with or without radioiodine uptake,
were not detected by FDG-PET but were detected by spiral
CT scanning.123.124
Conclusion
Localization tests are helpful for documenting metastases
in patients with thyroid cancer. Ultrasonography is recommended for cervical nodal metastases, spiral CT for
pulmonary metastases, and FDG-PET scans for patients
with poorly differentiated thyroid cancers and for
thyroglobulin-positive, WBS-negative patients. Radioiodine
scans are positive in about 75% of patients with metastases.
Radioiodine scans require a previous total or near-total
thyroidectomy. 131} can be used for ablative therapy.
Sestamibi, thallium, DSMA, and octreotide scans are
occasionally helpful but are not sensitive enough to
be recommended for routine use in the follow-up of most
patients.
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management of well-differentiated thyroid carcinoma: A roundtable
discussion. J Endocrinol Invest 1999;22:35.
112. Coburn M, Teates D, Wanebo HI. Recurrent thyroid cancer: Role of
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113. Grunwald F, Briele B, Biersack HJ. Non-P'Lscintigraphy in the
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114. Lerch H, Schober 0, Kuwert T, Saur HB. Survival of differentiated
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115. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid
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1998;39:1903.
117. Grunwald F, Pakos E, Bender H, et al. Redifferentiation therapy with
retinoic acid in follicular thyroid cancer. J Nuel Med 1998;39: 1555.
118. Joensuu H, Ahonen A. Imaging of metastases of thyroid carcinoma
with fluorine-18 fluorodeoxyglucose. J Nuel Med 1987;28:910.
119. Sisson JC, Ackermann RJ, Meyer MA, Wahl RL. Uptake of
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diagnosis and therapy. J Clin Endocrinol Metab 1993;77:1090.
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125. Platz D, Lubeck M, Beyer W. Einsatz der [18F]-deoxyglukose-PET in
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127. Wiesner W, Engel H, von Schulthess GK, et al. FDG-PET-negative
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128. Adler LP, Bloom AD. Positron-emission tomography of thyroid
masses. Thyroid 1993;3:195.
Papillary and Follicular

Carcinoma: Surgical
and Radioiodine Treatment
of Distant Metastases
Paolo Miccoli, MD Furia Pacini, MD
Patients with distant metastases from differentiated thyroid

carcinoma present an important therapeutic challenge.
Among our nearly 3000 patients with thyroid cancer, 12.4%
had distant metastases. J Similar percentages have been
reported in other large series.>? Distant metastases, particularly in the bone, may be the presenting symptom of the
disease, but about two thirds of distant metastases are found
at the time of diagnosis or are identified by the postthyroidectomy iodine 131 scan. 1 Distant metastases may
also develop as long as 15 years after initial treatment.t"
Long-term follow-up of patients with differentiated thyroid
cancer is certainly recommended.
Location of Distant Metastases

The lungs are the most common site of distant metastases in
differentiated thyroid cancer, followed by the skeleton. Both
lung and bone metastases also occur in about one third of
patients with distant metastases. Other less common sites
of metastases are the brain, the liver, the skin, and, rarely, the
omentum and adrenal glands." These rare sites of metastatic
disease are found more frequently in patients with lung and
bone metastases.
The pattern of metastatic lung involvement may vary from
one or more macronodular (> 1 em in diameter) nodules to
a diffuse micronodular spread.l-v' The latter is usually not
detected by chest x-ray films and sometimes not even by
computed tomography (CT) scan but can be easily diagnosed
by an 131 1 whole-body scan (WBS). Enlarged mediastinal
lymph node metastases are relatively common in patients
with papillary thyroid cancer.s'?
Only 3.8% of our patients with differentiated thyroid
cancer had bone metastases. They usually occur in patients
with follicular cancer and in older patients. The vertebrae,
pelvis, and ribs are the most frequently affected sites,
but any bone may be involved. Single bone metastases are
152
present in one third of the patients. As shown in Table 17-1,

most metastases are detectable by both WBS and x-ray film,
but a significant proportion (25% in our series) were visible
only by WBS.2,11 The latter group is more likely to respond
to 131 1 therapy.
The identification of distant metastases from differentiated
thyroid cancer requires a complete evaluation because many
of the distant metastases are initially asymptomatic. Patients
with pulmonary metastases are usually asymptomatic unless
the metastases involve the pleura (21% in the series by
Schlumberger and colleagues-). Bone metastases are more
likely to cause pain or neurologic symptoms because of the
tumor itself or because of the associated pathologic fractures. As mentioned, some patients with bone metastases are
completely asymptomatic. After total thyroidectomy, postoperative 131 1 ablation of any thyroid remnant tissue, serum
thyroglobulin (Tg) measurement, and 131 1WBS are valuable
for detecting distant metastases.
Serum Thyroglobulin Measurement

Most patients (about 95%) with distant metastases have an
elevated serum Tg concentration when measured after withdrawal of thyroid-stimulating hormone (TSH) suppressive
therapy. While patients are receiving i.-thyroxine (L-T4),
their serum Tg concentrations are often relatively low, but
these levels are usually higher than in patients with nodal
metastases (Fig. 17_1).2,12 The best time to determine the
serum Tg level is when the patient is hypothyroid in preparation for a radioscan.
There is usually a good correlation between the serum
Tg levels and 131 1WBS uptake.13,14 Detectable serum Tg levels
are usually associated with a positive WBS, and undetectable
Papillary and Follicular Carcinoma: Surgical and Radioiodine Treatment of Distant Metastases - -
serum Tg levels are found in patients with a negative scan,

indicating that the patient is in complete remission.
However, serum Tg measurement results are more sensitive
than WBS in predicting the presence of metastases. About
95% of patients with persistent thyroid cancer after total
thyroidectomy have serum Tg levels above 3 mg/mL,
whereas only about 75% of patients with metastatic thyroid
cancer have uptake in the tumor. IS
Iodine 131 Whole-Body Scan

Because most primary and metastatic well-differentiated
thyroid cancers retain their ability to concentrate iodine,
131 1 is usually used to scan for and treat metastases.
105
NODES
METASTASES
BONE "c,'}d LUNG
:J
a::
en
10
nd
ON
OFF
ON
THERAPY
OFF
FIGURE 17-1. Behavior of serum thyroglobulin (Tg) levels in
patients with node metastases or distant metastases (bone and/or

lung) studied with and without levothyroxine (L-T4 ) therapy.
Note that when not receiving L-T4 , all patientshave elevatedserum
Tg levels;when patientsare receivingL-T4, the serumTg levelsare
still elevated, or at least detectable, in those with distant metastases
(with one exception) and are suppressed to undetectable values in
many of those with node metastases.
153
Radioiodine uptake by metastatic tumor increases as TSH

stimulation increases. To increase serum TSH levels, total
or near-total thyroidectomy is required before it is possible
to detect or ablate local or distant metastases. It is important to withdraw thyroid hormone therapy for a long
enough period of time to induce a state of hypothyroidism
sufficient to elicit high endogenous serum levels of
TSH.16.I7 The minimum level of serum TSH required for
adequate incorporation of 131 1 in neoplastic tissues is
about 30 ul.l/ml., a level that is usually achieved after 30
to 45 days without L-T4 and after 2 weeks without t-triiodothyronine (L-T 3). For effective 131 1 uptake, and thus
treatment, the patient must also avoid any iodine intake,
such as with intravenous contrast material during a CT
scan. We also recommend a low-iodine diet for at least
2 weeks before scanning. The most frequent causes of a
false-negative 131 1 WBS result are an insufficiently
increased TSH and an increased iodine intake. Several
centers, therefore, advocate checking the serum TSH
concentration and urinary iodine concentration before performing 131 1 WBS and 131 1 therapy.
WBS is performed 48 to 72 hours after the administration
of 131 1, with the use of either a rectilinear scanner or a
gamma camera. l3I1 doses of 2 to 5 mCi are usually used
for scanning; higher doses are not indicated because of
the possibility of producing a sublethal radiation effect in
the metastatic cells, thus preventing uptake of the subsequent therapeutic dose of 1311. 18
When there is no abnormal 131 1 uptake despite elevation
of serum Tg with the patient not receiving T 4, the search for
metastases should include chest x-ray film, CT scan (without contrast), bone scintigraphy, and liver and neck echography. If no localization is found, a WBS performed 5 to
7 days after the administration of 100 mCi of 131 1 often
allows the localization of small neoplastic foci not found by
the conventional WBS and has a therapeutic effect in most
patients. 19.20
The need to render the patient hypothyroid has been
avoided by using exogenous TSH stimulation by the injection of recombinant human TSH (rhTSH, Thyrogen,
Genzyme Therapeutics). Several large studies have shown
that preparation of the patient by hypothyroidism or rhTSH
is equally effective in eliciting sufficient uptake of radioiodine and Tg secretion by the tumor. 21 24
Whenever a metastasis has been identified by WBS, a
complete radiologic work-up should also be done. When a
single bone metastasis is identified, we recommend surgical removal followed by 131 1 ablative treatment because
such treatment is occasionally curative. 11.2S When pulmonary metastases are present, it is also extremely important to establish whether there is one or more macronodular
lesions or multiple micronodules, not visible on the chest
x-ray film but identified by the 131 1 scanning. Diffuse lung
metastases, not detectable by x-ray film but identifiable by
radioiodine scanning, such as those frequently encountered
in children, are highly responsive to treatment with 13IJ.26.28
About two thirds of patients who are radioiodine scan
positive and chest x-ray or CT scan negative can be rendered tumor free, whereas only about 8% of those with
metastases seen on x-ray film or CT scan can be rendered
tumor free. 16.26
Therapeutic Procedures
Surgery
The decision to treat distant metastases surgically in patients
with differentiated thyroid cancer depends on the overall
health of the patient, the extent and number of distant metastases, the ability of the metastases to concentrate radioiodine,
and the radiologic pattern.
Pulmonary micrometastases are frequently completely
ablated by radioiodine therapy. Surgical therapy is, therefore, useful in a minority of patients with a single or several
macronodular metastases with or without mediastinal lymph
node involvement, especially when these metastases do not
take up radioiodine. The presence of mediastinal lymph node
metastases supports a surgical approach.? These patients
must be carefully selected because often more pulmonary
metastases are present than expected. Operation generally
consists of enucleation of the metastases or lobectomy; a
pneumonectomy is rarely performed. Isolated metastases can
often be removed thoracoscopically. Too few patients have
been operated on for pulmonary metastases to know whether
this treatment improves survival; however, in some of our
patients, a long-term remission has been achieved, and in
patients with isolated metastases, even definitive cure has
been described."
For patients with bone metastases, a surgical approach is
gaining in popularity because of the relative insensitivity of
these tumors to radioiodine therapy.9,11.25 The resection
of bone metastases may be palliative or curative. Palliation
is required in case of pathologic fractures or to ameliorate
neurologic symptoms resulting from spinal cord compression by vertebral metastases. In these cases, the operation
generally consists of laminectomy and sometimes must be
performed emergently. Curative surgery is possible when
the metastasis is single and localized, but this situation is
uncommon. Large metastases are difficult to ablate with 131 1,
and the pelvis is a more favorable site of bone metastases
(Fig. 17-2). When the bones are large or are not totally
resectable, surgery may help reduce the tumor mass, making
subsequent treatment with radioiodine therapy more effective (Fig. 17-3). Among our patients with bone metastases,
surgery was performed in 14 patients: 3 patients underwent
laminectomy to ameliorate neurologic manifestations, 5 were
operated on for palliation of pathologic fractures, and
6 patients, with a single bone metastasis, underwent radical
resection; complete cure was achieved in 3 of these patients.
Brain metastases are rare, ranging from 0.15% to 1.3% in
different series. 30-33 When these metastases are present, the
prognosis is poor. Although these metastases usually take
up 131 1, the therapy of choice, whenever feasible, is surgical
resection because of severe neurologic symptoms. External
radiation is also sometimes required to treat pain and
prevent fracture. It, unfortunately, is usually palliative rather
than curative.
Radioiodine
The role of and indications for 131 1 therapy in the management of distant metastases from differentiated thyroid
FIGURE 17-2. Surgical specimen of a single bone metastasis (rib)

from follicular thyroid carcinoma treated with surgery. The patient
had no recurrence in the subsequent follow-up.
carcinoma are well established. The results are reproducible

in large series of patients and indicate complete responses
in 35% and 45% of patients. 1,2,4,5,28 As mentioned, pulmonary metastases have a better response than bone metastases. In adult patients, the treatment dosage is usually 100
to 150 mCi, repeated every 8 to 12 months. Lower doses
(empirically 1 mCi/kg body weight) should be used in children with lung metastases, particularly of the diffuse type,
to avoid the risk of acute pulmonary insufficiency or more
chronic radiation-induced pulmonary fibrosis. 25,34
In a review of 118 of our patients with distant metastases
treated with 131 1, 43 patients (36.4%) were cured (defined as
negative WBS and undetectable serum Tg in the absence of
L-T 4), 28 (23.7%) died of their disease, and the others have
persistent disease (Figs. 17-4 and 17-5).1 Of those who died,
10 had lung metastases, 8 had bone metastases, 9 had both,
and 1 had skin metastases. Interestingly, patients with
metastatic papillary cancers did better than patients with
follicular tumors. The risk of dying was higher if lung
metastases were macronodular and detectable by chest x-ray
films, if bone metastases were multiple, and if both lung and
bone metastases were present. The mean cumulative dosage
of 131 1 used in cured patients was 233 mCi, delivered in
2.2 treatment courses during 3.4 years. Loss of radioiodine
uptake was seen in four (5.2%) patients after a mean cumulative dose of 161 mCi 2.7 years from the beginning of treatment. Six patients with single bone metastases and one with
155
FIGURE 17-3. X-ray film and corresponding iodine 131 (1 311) whole-body scan (WBS) in a patient who had a partial response to
1311
therapy and a complete response after surgical resection of the iliac metastasis. Upper row, At the first diagnosis. Middle row,
X-ray film and WBS after 700 mCi of 1311. It is possible to note the reduction of 1311 uptake in the left iliac bone and the disappearance of
uptake in the middle area corresponding to L-3 (x-ray negative). Lower row, After resection of the left iliac lesion, no 1311 uptake was
detected in this area; serum Tg at this stage was undetectable. (From Marcocci C, Pacini F, Elisei R, et al. Clinical and biologic behavior
of bone metastases from differentiated thyroid carcinoma. Surgery 1989;106:960.)
156 - -
Thyroid Gland
80
[J papillary (n=77)
.follicular(n=41)
70
71
l:iIaU (n=118)
60
FIGURE 17-4. Effect of radioiodine therapy in patients

with distant metastases. Mean millicuries delivered,
mean number of doses, and mean years over which
iodine 131 was administered are shown at the bottom.
(From Pacini F, Cetani F, Miccoli P, er al. Outcome
of 309 patients with metastatic differentiated thyroid
carcinoma treated with radioiodine. World J Surg
1994;18:600.)
50
40
30
20
10
O~=
meen
cured
mel
233
2.2
3.4
n.do...
y_",
nouptake
continued disease
161
1.5
2.7
a macronodular lung metastasis were treated surgically. In

these patients, histology revealed that the metastatic tumor
was less well differentiated than the corresponding primary
tumor.
Among patients with elevated serum Tg levels but no
appreciable uptake, 13,14 the site of the metastatic deposits
was usually the lung or mediastinal lymph nodes.1314.19.26
About 20% of our patients with distant metastases were
included in this group. The administration of high doses of
131 1 has a therapeutic effect on metastatic deposits in patients
with low radioiodine uptake. Our data demonstrate that,
within a few days after the administration of 131 1 therapy,
there is a transient increase in serum Tg concentrations,
which, in our opinion, can be explained only by the release
of Tg into the circulation by radiation-damaged malignant cells. A progressive decrease of serum Tg levels and
normalization of the abnormal chest CT scan in
patients with radiographic evidence of micronodular lung
metastases" have been observed in some patients. 19.26
Overall, about one third of these patients appeared to receive
appreciable clinical benefits.f
536
4.7
4.3
Side Effects and Complications

of Radioiodine Therapy
Side effects after the administration oftherapeutic 131 1 doses
are frequent but usually transient and mild. The symptoms
usually include gastrointestinal symptoms, nausea, vomiting, and acute sialoadenitis. The last side effect, which is
potentially serious if it becomes chronic (after several
doses), may be reduced, in our experience, by hydration and
by giving low doses of corticosteroids for 2 to 3 days after
treatment.
More serious complications are those involving blood
and bone marrow. An increased risk of leukemia, on the
order of five cases per 1000 treated patients, has been
reported." The risk is increased by increasing cumulative
doses, by reducing the intervals between treatments, and by
giving total blood doses per treatment higher than 2 Gy.35
Pancytopenia has been reported in 4.4% of patients treated
with mean 1311 doses of 536 mCi by Schober and colleagues."
In the same study, anemia was found in about 25% of the
patients and thrombocytopenia in 33%.
FIGURE 17-5. Representative example of negative diagnostic whole-body scan (WBS) with 5-mCi tracer dose (A) and of post-therapy
(l00 mCi) WBS (B) showing diffuse uptake in the lung in the same patient.
Another complication of radioiodine therapy is radiationinduced pulmonary fibrosis, which may develop in patients
treated repeatedly for lung metastases, particularly of the
extensive diffuse type. Children seem to be particularly
susceptible to this complication. We observed a 22-year-old
woman who had been treated in another institution with
high doses of 131 1 since she was 10 years old for lung metastases, who died, apparently free from disease, from pulmonary fibrosis.'?
The occurrence of a second solid cancer after radioiodine
treatment has also been reported. Three extra cases of bladder carcinoma and three extra cases of breast carcinoma
among 258 patients treated for differentiated thyroid cancer
have been documented." All these patients were treated
with more than 900 mCi of 1311. The development of second
malignancies is controversial, but there may be a very slight
increased risk of developing other tumors.
Whether radioiodine treatment can promote the transformation of a well-differentiated thyroid cancer to an anaplastic
cancer is also controversial. Although a varying degree of
"dedifferentiation" is observed in almost all series of thyroid
cancer, the question is whether this is due to radioiodine
or whether it is an independent biologic event. Studies
of molecular biology38,39 have shown that anaplastic thyroid
carcinoma is strictly associated with the loss of expression
or function of the oncosuppressor gene p53, whereas
p53 mutations are rare in differentiated thyroid tumors. It is
possible, but not proved, that differentiated thyroid cancers,
through a radiation-induced second mutation in the p53
gene or for other reasons, shift toward the poorly differentiated or undifferentiated histotype. Mutations of the p53 gene
have not been detected in differentiated thyroid cancer
of Belarussian children exposed to radiation after the
Chernobyl accident.'"
We have also reported the presence of reversible and
nonreversible testicular damage, limited to the germinal
epithelium, in men treated with high levels of administered
activity of 131 1, particularly when they were treated for bone
metastases close to the testis."
Prognostic Factors
Successful treatment of patients with distant metastases
depends largely on the size, location, and number of
metastatic lesions and their ability to take up radioiodine.
Patients with micronodular diffuse lung metastases and, to a
lesser extent, small metastases in bone revealed by WBS in
the absence of radiographic abnormalities have the greatest
chance of cure. This is particularly true in children, who
often have this pattern of metastatic pulmonary spread and
yet do exceptionally well after treatment with radioiodine
therapy.27,42 Patients with macronodules in the lung and
large or multiple bone metastases have a poor prognosis, but
long-term palliation and occasional cure can be accomplished by resection of these tumors in selected patients.
Loss of radioiodine uptake by the metastatic tumor is also a
prognostic indicator of a poor outcome. These findings
emphasize the importance of early recognition and early
treatment of distant metastases. This is best accomplished
by total thyroidectomy or near-total thyroidectomy with
157
postoperative ablation of the remnant, and then serum Tg

determination and radioiodine scanning to detect micrometastases that can be successfully ablated with 1311.
Importance of L- Thyroxine
Suppressive Therapy
Both the function and the growth of some metastatic thyroid
tumors are under TSH control. It is a common observation
that bone or lung metastases increase in size and take up
radioiodine during periods of T, withdrawal, whereas a reduction in size and lack of uptake are observed during periods of
T4 therapy. Serum Tg, a marker of cell function, increases
dramatically during hypothyroidism (see Fig. 17-1), whereas
Tg levels return to low values during treatment with T4 In
the classic article by Mazzaferri.P thyroid hormone therapy
significantly influenced both recurrence rate and survival as
an independent variable. In this regard, suppression of
endogenous TSH to undetectable levels is to be regarded as
a true antineoplastic therapy and should never be omitted in
patients with active disease.
The drug of choice is T4 , and the effective dosage is
between 2.2 and 2.8 ug/kg body weight. Higher dosages are
usually required in children. In any patient, attempts should
be made to use the lowest dose necessary to suppress TSH
secretion. The adequacy of the therapy is monitored by
measurement of serum TSH, which should be undetectable
with an ultrasensitive assay, and serum free T 3, which
should be in the normal range to avoid iatrogenic thyrotoxicosis. When these guidelines are followed, T4 suppressive
therapy is safe and is devoid of long-term side effects on the
heart or bone."
Summary
Distant metastases were present in 12.4% of nearly
1000 patients with differentiated thyroid cancer. Pulmonary
metastases were most common, and bone metastases
occurred in 3.8% of patients. Patients with distant metastases,
in general, have a poor prognosis, but when these metastases
are small and take up radioiodine, curative treatment or complete remission with 1311 ablative therapy is still possible in
about 35% of patients. Children and young adults with pulmonary micrometastases identified by radiographic scanning,
but not seen on chest x-ray film, have the best prognosis.
These and other micrometastases are best detected when
patients are treated by total thyroidectomy. Serum Tg levels
and radioiodine scanning are the sensitive indicators of persistent disease. Our data and those in the literature support the
use of total thyroidectomy and postoperative serum Tg and
radioiodine scanning to detect and treat metastatic disease.
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Ceccareli C, Pacini F, Lippi F, et aJ. Thyroid cancer in children and
adolescents. Surgery 1988; I04: 1143.
Maxon HR, Smith HS. Radioiodine-I 3 I in the diagnosis and treatment
of metastatic well-differentiated thyroid cancer. Endocrinol Metab Clin
NorthAm 1990;19:685.
Proye CAG, Dromer DHR, Carnaille BM, et aJ. Is it still worthwhile to
treat bone metastases from differentiated thyroid carcinoma with
radioactive iodine? World J Surg 1992;16:640.
Mazzaferri EL. Papillary and follicular thyroid cancer: A selective
approach to diagnosis and treatment. Annu Rev Med 1981;32:73.
Parker LN, Wu SY, Kim DD, et aJ. Recurrence of papillary thyroid
carcinoma presenting as a focal neurological deficit. Arch Intern Med
1986; 146: 1985.
Hay ID. Brain metastases from papillary thyroid carcinoma. Arch
Intern Med 1987;147:607.
Venkatesh A, Leavens ME, Samaan NA. Brain metastases in patients
with well-differentiated thyroid carcinoma: Study of II cases. Eur J Surg
Oncol 1990; 16:448.
Rail JE, Alpers JB, Lewallen CG, et aJ. Radiation pneumonitis and
fibrosis: A complication of radioiodine treatment of pulmonary metastases from cancer of the thyroid. J Clin Endocrinol Metab
1957;17:1263.
Leeper R. Controversies in the treatment of thyroid cancer: The New
York Memorial Hospital approach. Thyroid Today 1982;5: 1.
Schober 0, Gunter HH, Schwarzrock R, et aJ. Hamatologische
Langzeitveranderungen bei der Schilddrusenkarzinoms. Strahlenther
OnkoI1987;163:464.
Edmonds CJ, Smith T. The long-term hazard of the treatment of
thyroid cancer with radioiodine. Br J RadioI1986;59:45.
Herrmann MA, Hay ID, Bartelt DH Jr, et aJ. Cytogenetic and molecular genetic studies of follicular and papillary thyroid cancers. J Clin
Invest. 1991 Nov;88(5):1596-604.
Pacini F, Pinchera A, Mancusi F, et aJ. Anaplastic thyroid carcinoma:
A retrospective clinical and immunohistochemical study. Oncol Rep
1994; I :921.
Fugazzola L, Pilotti S, Pinchera A, et aJ. Oncogenic rearrangements of
the RET proto-oncogene in papillary thyroid carcinomas from children
exposed to the Chernobyl nuclear accident. Cancer Res 1995;55:5617.
Pacini F, Gasperi M, Fugazzola L, et aJ. Testicular function in patients
with differentiated thyroid carcinoma treated with radioiodine. J Nucl
Med 1994;35: 1418.
Schlumberger M, De Vathaire F, Travagli JP, et aJ. Differentiated
thyroid carcinoma in childhood: Long-term follow-up of 72 patients.
J Clin Endocrinol Metab 1987;65: 1088.
Marcocci C, Golia F, Bruno-Bossio G, et aJ. Carefully monitored
levothyroxine suppressive therapy is not associated with bone loss in
premenopausal women. J Clin Endocrinol Metab 1994;78:818.
Anaplastic Carcinoma
of the Thyroid Gland
Irving B. Rosen, MD Sylvia L. Asa, MD, PhD James D. Brierley, BSc, MB
It is ironic that the thyroid gland harbors two polar variants

of cancer in regard to aggressiveness in behavior. At the
one pole is the common, unaggressive, infrequently lethal,
well-differentiated carcinoma, usually papillary, sometimes
follicular, which makes up 80% of all thyroid cancers. At
the other pole is anaplastic thyroid cancer (ATC), which is
invariably lethal and has until recently constituted 4% to
18% of thyroid cancer. Currently, ATC is showing a marked
decline throughout the world, but in the United States it still
constitutes 1.6% of thyroid cancers and accounts for more
than half of the deaths from thyroid cancer. The survival of
ATC cases is usually measured in months. Although there is
a paucity of cases, leading institutions throughout the world
nevertheless have reported their results of treatment in up
to 160 patients, usually after several decades of experience.
Authors agree that ATC is an infrequent cancer that is highly
lethal and is usually unresponsive to currently available
treatment such as surgery, radiation, and chemotherapy.
New treatments are therefore necessary and are being developed in the hope that they will lead to improved survival
in ATC patients."!"
Anaplastic cancer, unlike its well-differentiated counterpart,
presents a clinical picture that unarguably indicates the presence of an underlying cancer. Patients can be categorized
into four different groups': (1) patients whose previous
well-differentiated carcinoma had undergone treatment, has
been stable over a long period of time, and then changes
character; (2) patients who have been viewed and treated for
presumptive benign goiter over a long period of time who
then demonstrate a rapid growth and change in character of
goiter; (3) patients who present de novo and acutely with an
extensive thyroid mass; and (4) patients whose widespread
metastatic cancer may demonstrate evidence of anaplastic

change. The process of transformation, poorly understood,
should be appreciated. Two of our patients had undergone
incisional biopsies for adenoma elsewhere as a basis for
conservative nonsurgical management with the eventual
emergence of fatal anaplastic cancer years to a decade later.
Such patients demonstrate not only anaplastic transformation but also the fallibility of incisional biopsy results in
long-term prognostication.
In consideration of anaplastic transformation.P'P one
should recognize that there is a high incidence of p53 mutations in ATC,15 which is not the case for differentiated
cancer, even when the two are coexistent. Inactivating mutations of the tumor suppressor gene p53 are of importance
in the progression of differentiated to undifferentiated or
anaplastic cancer." The N-ras oncogene shows an inverse
correlation with thyroglobulin expression that is absent in
ATe. No N-ras mutations were seen in well-differentiated
thyroid cancer in some reports, whereas gene mutations
were present in ATC that usually did not secrete thyroglobulin." Other oncogenes have been identified in some ATC
cases, including c-myc and NM23,1O as well as other alterations in tumor suppressor genes. 15 RET/PTC rearrangements
are common in papillary thyroid cancer but uncommon in
poorly differentiated malignancy so that progression from
a well-differentiated to poorly differentiated malignancy is
questioned. 16 Mutations in ~-catenin.
a widely expressed cytoplasmic protein that has a crucial role both in E-cadherinmediated cell-cell adhesion and as a downstream signal
molecule, are common in ATC.I? ~-Catenins
activate transcription factors, supporting the idea that they act as an
oncogene that contributes to the highly aggressive behavior
of ATe. Investigations have shown that both adenomas and
follicular carcinomas have N-ras mutations but that p53
mutation is unique in occurring in poorly and undifferentiated thyroid cancer, supporting a multistep transformation
159
160 - -
Thyroid Gland
in such tumors." Studies have further demonstrated that

ATC frequently involves a loss of l6P as documented by
comparative genomic hybridization studies and associated
with transformation from well-differentiated thyroid cancer
to anaplastic tumor.'? ATC also often overexpresses the
protooncogene HGF (hepatocyte growth factor) and its
receptor HGF-R.
Clinical Features
Anaplastic cancer affects women and men in a ratio of
1.0:1.5.2 The peak incidence of this disease occurs in the
seventh decade of life (mean, 64 yearsj.l-' It is unusual for
patients younger than 40 years to be affected by this disease,
and when it occurs one should question the reliability of the
diagnosis.
Radiation exposure has been documented but does not
seem to have a critical role in pathogenesis. Patients usually
present with a rapidly enlarging, bulky, thyroid mass1,25 that
is firm to hard and frequently fixed. There may be a variation in the extent of anaplasia because some thyroid tumors
may show small areas of dedifferentiation, which would still
qualify them in the consideration of anaplastic cancer.
However, such cases usually do not pose the same problem
or have the dire outlook of the diffusely involved gland.
Anaplastic cancer may compress the trachea and infiltrate
the skin, causing overlying necrosis. Lymph node enlargement is frequent (84%) and early.l-' The tumor extends to
and becomes fixed to the larynx, esophagus, and carotid vessels. Vocal cord paralysis can occur because of tumor infiltration of the recurrent laryngeal nerve or vocal cord, and
glottic obstruction is of concern. Obstruction of the superior
vena cava can be seen in more extensive cancer, particularly
when there is a retrosternal component.
Symptoms such as dysphagia, dysphonia, and dyspnea are
common.P> Systemic metastases occur in 75% of patients
and usually involve lung (more than 80%) as well as bone
and brain (15%), adrenal glands (33%), and intra-abdominal
nodes (17%).1,2
Investigation can vary and depends on the circumstances
of the individual patient. Thyroid function tests are usually
normal, but with a rapidly growing tumor, evidence of at
least incipient compensated hypothyroidism can be seen by
virtue of an elevated thyroid-stimulating hormone serum
level by sensitive assay. Scintiscan of the thyroid gland
shows a classic cold area at the site of the tumor. Chest x-ray
film and computed tomography scan can demonstrate
extrathyroidal extension and invasion.
Diagnosis can be established by fine-needle aspiration
biopsy (FNAB).4.7 Scandinavian authors adamantly prefer
FNAB for tissue diagnosis because they view incisional
biopsy as associated with poor healing, delay of treatment,
and acceleration of tumor growth.t? The diagnosis of anaplastic cancer must be differentiated from that of lymphoma and
poorly differentiated medullary carcinoma, and appropriate
immunophenotyping and other marker examinations may
be required.
DNA cytometry of anaplastic cancer usually shows an
aneuploid picture indicative of a poor outlook. Other thyroid
investigational imaging procedures such as ultrasonography,
computed tomography scan, and magnetic resonance imaging

document the limits of the imaging of a mass and sometimes
extensive invasion but cannot establish the tumor histology.
Somatostatin scans are occasionally positive in ATC and in
other thyroid cancers. Positron emission tomography scans
are unreliable in ATCs but appear to be positive in patients
with poorly differentiated thyroid cancer that does not take
up radioiodine."
Pathology
Microscopically, three general patterns can be recognized.
The most common type is the giant cell variant, which
is composed mainly of large cells with marked cytologic
pleomorphism.P The plump tumor cells harbor bizarre, often
multiple hyperchromatic nuclei (Fig. 18-1) with abundant
amphophilic or eosinophilic granular cytoplasm and densely
acidophilic, intracytoplasmic, hyaline globules. These tumors
grow in solid sheets; artifactual tissue fragmentation may
create the appearance of an alveolar pattern. The squamoid
variant is composed of nests of large, moderately pleomorphic epithelial cells resembling squamous carcinoma, which
may form keratin pearls. Spindle cell anaplastic carcinomas
resemble sarcomas (Fig. 18-2); the fascicular architecture
and dense stromal collagen may resemble fibrosarcoma,
markedly atypical cells and inflammatory infiltrates may
suggest malignant fibrous histiocytoma, and prominent
vascularization may mimic hemangioendotheliorna.P>'
In all three variants, mitotic figures, including atypical
forms, are frequent. Vascularization is prominent, and extensive areas of necrosis surrounded by inflammation may occur
so that the only viable tumor is seen around blood vessels.
Reactive osteoclast-like giant cells of monocytic-histiocytic
lineage may be seen. 25,26 Malignant cells usually grow
between residual thyroid follicles, invading skeletal muscle,
adipose tissue, and other peri thyroidal structures. Blood
vessel invasion and thrombosis with or without tumor cell
involvement are frequent.
FIGURE 18-1. A giant cell anaplastic thyroid carcinoma is composed of large pleomorphic cells with abundant cytoplasm and
hyperchromatic, often multiple, nuclei. Mitoses are conspicuous
(arrows).
Anaplastic Carcinoma of the Thyroid Gland - -
FIGURE 18-2. A spindle cell anaplastic thyroid carcinoma h~s
fascicular architecture resembling that of a sarcoma. (Hematoxylin

and eosin stain.)
Anaplastic carcinomas do not usually show reactivity for

thyroglobulin, and the few that are positive show a weak or
focal reaction 26-3o that may be due to trapped nontumorous
follicles or isolated follicular cells and the known phenomenon of thyroglobulin diffusion into tumor cel.ls.23 T~e
epithelial nature of the malignant cells ca~ be ven~ed
w~th
stains for low-molecular-weight cytokeratms and vimentm,
and in squamoid areas there may be reactivity for highmolecular-weight cytokeratins and epithelial membrane
antigen as well. 26-28 Carcinoembryonic antigen (CEA) may
be localized in the center of squamoid nests. 26-28 Occasional
tumors have been reported to exhibit reactivity for calcitonin, but this finding should alter the diagnosis to that of
anaplastic medullary carcinoma.v-" It has been shown that
. anap Iast'IC carcmom
.
as 24-28.,
p53 mutations are frequent m
mutated forms of this putative tumor suppressor gene have
prolonged half-lives, permitting immunolocalization.P and
the application of this technique has yielded positive results
in ATCs (Fig. 18-3).34
161
By electron microscopy,25.27,29,35.36 ther~

may ?e evidence
of epithelial differentiation with the formation of mtercellular
junctions of the zona adherens type an~ the presence ~f
microvilli. The cells may form basal lammae focally. Their
large nuclei have clumped chromatin and prominent nucleoli; the abundant cytoplasm usually contains poorly developed endoplasmic reticulum, numerous free ribosomes,
lipid droplets, lysosomes, and mitochondria. Scattere~,
dense bodies may be seen, but the cells do not contam
secretory granules. Occasional intermediate filaments
probably represent keratin or vimentin; these may form
filamentous whorls that correspond to the acidophilic hyaline
globules seen by light microscopy.
.
Small cell carcinomas and lymphomas constItute a
source of diagnostic error, often being misclassified as
anaplastic carcinornas.P:" The former are now well r~cognized as neuroendocrine carcinomas, usually poorly differentiated medullary carcinomas that can mimic giant cell or
spindle cell anaplastic carcinomas. They can be recogni~ed
by immunohistochemical positivity for neuron-specific
enolase, chromogranin, calcitonin, calcitonin gene-related
peptide, and CEA and by the ultrastructural detection of
membrane-bound secretory granules. Lymphoma is usually
composed of relatively uniform, small, round cells that do
not exhibit the marked pleomorphism of anaplastic carcinoma but do stain for leukocyte common antigen and other
immunohistochemical markers of lymphoid cells, and have
features of lymphocytes by electron microscopy. Rarely,
primary intrathyroidal thymoma may be mistaken for
anaplastic carcinoma."
Even in tumors without immunohistochemical or ultrastructural markers of epithelial differentiation, the diagnosis
of anaplastic carcinoma should be favored for any thyroid
pleomorphic lesion occurring in an older patient.
Poorly differentiated or insular carcinoma is a tumor of
follicular cell differentiation with morphologic and biologic
attributes between those of differentiated and anaplastic
carcinomas of the thyroid 38.39 and is composed of large,
well-defined clusters or nests of neoplastic cells reminiscent
of neuroendocrine tumors (Fig. 18-4). The neoplastic cells
are moderate to small and uniform in size and shape, with
FIGURE 18-3. Many tumor cells in an anaplastic thyroid carci-
noma show nuclear reactivity for p53, indicating accumulation

of protein as a result of mutation. (Streptavidin-biotin peroxidase
method with hematoxylin counterstain.)
FIGURE 18-4. An insular thyroid carcinoma is composed of solid
nests of small, polygonal, follicular epithelial cells with individual

cell necrosis (arrows). (Hematoxylin and eosin stain.)
162 - -
Thyroid Gland
FIGURE 18-5. A focus of anaplastic thyroid carcinoma characterized by giant epithelial cells (arrow) is seen in a tumor that is predominantly well-differentiated papillary carcinoma (top left) but
also exhibits insular architecture (bottom right). (Hematoxylin and
eosin stain.)
little pleomorphism and no bizarre, giant, or multinucleated

cells. There is a variable degree of mitotic activity, and
single-cell necrosis is prominent. Tumor cells stain for lowmolecular-weight cytokeratins and are focally positive for
thyroglobulin. Insular carcinoma appears to be intermediate
in the spectrum from well-differentiated to anaplastic carcinoma and may represent a transition of the former into the
latter 39 .40 (Fig. 18-5) because of factors still to be defined.
Accumulation of genetic mutations underlying oncogene
activation or the loss of tumor suppressor gene activity
correlates with the stepwise progression from adenoma to
carcinoma in tissues," and a similar pattern of molecular
events has been suggested for thyroid." The expression of
various ras mutations in benign thyroid tumors and welldifferentiated carcinomas suggests that activation of this
oncogene is an early event.t'" The expression of p53 in
anaplastic carcinomas is consistent with a late event that
may account for the aggressive behavior of such tumors.
Treatment
The standard form of treatment of thyroid cancer has been
surgical ablation, but in anaplastic cancer this maneuver is
usually not feasible. In our experience, in only 2 of 20 patients
labeled initially as having anaplastic cancer could total
thyroidectomy be carried out; subsequently, it was demonstrated that these cases represented respectively lymphoma
and secondary thyroid cancer from a pancreatic primary
tumor. Nonetheless, there appears to be well-documented,
ongoing experiences with thyroidectomy. Venkatesh and
colleagues I reported that 47% of 100 patients underwent
total thyroidectomy, 8% underwent subtotal thyroidectomy,
and 30% had lobectomy. Only 25% underwent biopsy only.
Tann and colleagues also reported that 7 of 21 (33%) patients
had undergone a thyroidectomy.- Famebo and coworkers"
also viewed thyroid resection as a possibility after induction
chemotherapy.
Postoperative external radiation has been historically

used. Of 91 patients, in 30 of whom curative surgery had
been attempted, 86 underwent postoperative external beam
radiation, 18 with chemotherapy.f Overall survival reported
by Junor and associates" was 11% at 3 years (median survival, 21 months). Local recurrence occurred in 50 patients,
distant only in 20, demonstrating the inability of external
beam radiation to guarantee local control, which is highly
desirable to avoid an unpleasant death of the patient.
Attempting to improve on the historic radiation approach,
Simpson" gave hyperfractionated radiation to 32 patients
with unresectable disease (age range, 31 to 87 years). This
was done with a single 5-Gy fraction followed by hyperfractionated radiation, 1 Gy four times daily, with an interfraction period of 3 hours, for a total dose of 35 to 45 Gy.
Fourteen patients received doxorubicin every 3 weeks. This
gave a local control rate of 22% with a median survival of
6 months and 3-year survival of 18%. There were three
treatment deaths resulting from radiation-myelopathy
(two) and neutropenic sepsis (one)-and this protocol was
discontinued (Fig. 18-6).
Multimodality therapy was further pursued. Kim and
Leiper" reported a complete remission rate of 84% and
local control of 68% in 19 patients treated with hyperfractionated radiation and weekly doxorubicin (median
survival, 6 months; 3-year survival, 20%). Schlumberger
and coworkers," using low-dose hyperfractionated radiation
with doxorubicin, cisplatin, or mitomycin C, reported a complete response rate in 5 of 20 patients, although only
3 patients survived more than 20 months.
Tennvall and colleagues" gave combined radiation and
chemotherapy preoperatively and postoperatively by hyperfractionation using doxorubicin as a single agent replacing
1.0 . - - - - - - - - - - - - - - - ,
0.8
:0
0.6
Cll
.c
ea.
.~
0.4
::::l
(/)
0.2
0.0 +-----,--,-------,----,---r-----\
12
o
24
36
Months
FIGURE 18-6. Survival graph of 32 patients wirh anaplastic thyroid cancer treated by hyperfractionated radiotherapy (Princess
Margaret Hospital experience'"),
bleomycin, 5-fluorouracil (5-FU), and cyclophosphamide

because of reduced toxicity. In 33 such patients, debulking
surgery was possible in 23 (70%), achieving local control in
48% with death from local disease in 8 of 33 patients. Only
four patients lived for more than 2 years.
Chemotherapeutic agents such as doxorubicin, cisplatin,
and 5-FU have radiation-sensitizing activity and have been
given beyond termination of radiation in an attempt to
improve survival. Hoskin and Harmer f studied the use of
single and combination agents and found only partial
responses in three patients, or 17% of the series. Williams
and coworkers'? reported on a phase II study from the
Southeastern Cancer Study Group using combined doxorubicin and cisplatin in seven patients, with only one partial
response and considerable toxicity. Shimaoka and colleagues," in a randomized, controlled study through the
Eastern Cooperative Oncology Group, compared doxorubicin with doxorubicin and cisplatin in 39 patients with
anaplastic cancer. There was a 5% partial response rate to
doxorubicin but an 18% response to the combined regimen,
suggesting that combined drug therapy was superior to
single-agent therapy but bore the cost of increased toxicity.
Schlumberger and associates," who gave doxorubicin every
4 weeks for up to nine courses in addition to radiation,
achieved 15% survival at 20 months.
Radioiodine and external thyroid feeding appeared to have
no inhibiting influence on anaplastic thyroid carcinoma. The
role of chemotherapy alone in anaplastic cancer is limited.
At one of the University of Toronto's radiation centersthe Princess Margaret Hospital-hyperfractionated radiotherapy'" without chemotherapy (60 Gy in 40 fractions,
1.5-Gy fractions twice a day over 4 weeks) was prescribed
for the rare patient who had had a resection and for other
patients who had no evidence of metastatic disease and had
good performance status. Otherwise, palliative radiation was
given at 20 Gy in five 4-Gy fractions over 1 week. This was
repeated 4 weeks later if a good response had been achieved.
An expectant policy was pursued in elderly patients with
poor performance status or patients with distant metastatic
disease and relatively little in the way of local symptoms
(Fig. 18-7).
Although anaplastic cancer is a rare tumor, an increasing
number of patients have been reported in series in the literature. The role of surgery in management has been significantly supported with l-year survival rates of 73%, 60%,
and 21%, respectively, for patients with incidental and ordinary ATC who underwent surgery and those with ordinary
ATC who underwent no surgery.P These figures seem inordinately high and appear to be based on selection bias. They
document, however, that thyroidectomy, when feasible,
should be performed. The Mayo Clinic reported the results
of treatment in 134 patients. In 30%, complete resection
was possible with 9.7% I-year survival. Thirty patients were
treated with multimodal treatment consisting of debulking
procedures, postoperative radiation, and chemotherapy, and
only 23% survived more than 1 year. Overall survival did
not vary among these groups. They concluded that "ATC is
a lethal malignancy" that has "seen no improvement in outcome during 50 years."
The Thyroid Center at Padua General Hospital reported
on 39 consecutive ATC patients and noted that a combination
163
FIGURE 18-7. A 75-year-old patient with anaplastic thyroid
cancer 10 years after incisional biopsy of "benign adenoma" who

died within 2 months of diagnosis.
of therapy with radiation, total thyroidectomy, and chemotherapy provided apparent benefits and that preoperative
chemotherapy and radiotherapy may enhance surgical
resectability.P The Institute of Oncology in Ljubljana,
Slovenia, reported on 79 patients; their best results were
obtained in those who had the tumor surgically removed and
had primary chemotherapy and radiotherapy. 14 The Swedish
group has had a long-standing repeated program for the
management of patients with ATC that they have reported.
Their experience indicates that multimodality treatment
consisting of radiation, chemotherapy, and then surgery and
further radiation and chemotherapy provides the best
results.t-"!' Their current standardized strategy includes
radiation of 46 Gy in 29 fractions, namely 1.6 Gy twice a
day, with simultaneous doxorubicin at 20 mg intravenously
once weekly for 4 weeks and surgery between the fourth and
fifth weeks, consisting of total thyroidectomy when possible
as well as nodal resection. Currently, no patient has failed to
complete the protocol because of toxicity, and in only 25% of
cases was death attributed to local failure. Five patients or
9% of the group survived more than 2 years. 11
There have been ongoing attempts at accelerating radiation treatment aiming to improve local response. One such
program treated patients twice daily 5 days a week to a total
dose of 60.8 Gy in 32 fractions over 20 to 24 days. Although
the response rate was encouraging, the program was modified because toxicity was unacceptable.>'
Chemotherapy has also received attention. In a phase 2 trial,
the collaborativeAnaplastic Thyroid Health InterventionTrials
Group assessed paclitaxel." This agent failed to improve
survival in patients with ATC, suggesting other new agents
or combined agents are necessary. 55 Adding manumycin to
paclitaxel resulted in an enhanced cytotoxic effect and
increased apoptotic cell death in ATC cells in vitro and
in vivo.56 Activity of this combination was also deemed
effective, without significant toxicity. The combination of
gemcitabine and cisplatin in anaplastic thyroid cell lines
appeared to show promising cytostatic activity in an in vitro
study.57
164 - -
Thyroid Gland
Survival Figures
Survival figures vary and are based on a small number of
cases. They have been reported at 2 years as near 0%,5 14%,2
and 17%1; at more than 3 years as 12%7; and at 5 years as
10%.2 Assiduous attempts have been made to define prognostic factors. I Factors favoring prolonged survival included
younger age 45 years), disease confined to the neck, treatment characterized by total or subtotal thyroidectomy, and
treatment by radiotherapy or chemotherapy or both. There
appeared to be no significant survival advantage in the transformed group over the de novo anaplastic group. Analysis of
long-term survivors (>24 months) indicated that they were
significantly younger at diagnosis, had less disease, and
received more extensive surgery, although this had not
reached statistical significance. Ten of 12 long-term surviving
patients received combined radiotherapy and chemotherapy
postoperatively.' In the Roswell Park Memorial series,"
patients who were female, who had tumors smaller than 6 em
and who had undergone complete resection survived significantly longer.
One study from Latin America reported significantly longer
survival in (l) patients with differentiated carcinoma with
areas of anaplastic lesions limited to one lobe, (2) patients
receiving a complete chemotherapy regimen, (3) patients
with tumors smaller than 10 em, and (4) those with a symptom duration of less than 4 months-" A Japanese study
reported a I-year survival rate in 44 patients with ATC to be
16%. The presence of acute symptoms, large tumors (>5 em),
distant metastasis, and leukocytosis correlated with a poor
outcome. A prognostic index (PI) based on these four factors
was devised; patients with a PI less than or equal to 1 had
62% survival at 6 months, whereas no patients with a PI
greater than 3 survived longer than 6 months.59
Investigation
The dismal outcome of patients after treatment in ATC has
stimulated research investigation to improve outcome results.
Exogenous interleukin 6 has been used but unfortunately was
ineffective/" After gene transfection with wild-type p53,
three ATC cell lines became more sensitive to doxorubicin

(Adriamycin), suggesting that combining wild-type p53 and
chemotherapy might improve the results of therapy?' The
transfection of a human thyroperoxidase gene to restore
iodine trapping in non-iodide-concentrating tumor cells
seen in anaplastic cancer was not effective.f Bone morphogenetic protein (BMP-7) resulted in growth inhibition in
ATC cells by inhibiting cyclin-dependent kinase activity,
shifting the Rb protein to the hypophosphorylated state. 63
The compound 1,25-dihydroxyvitamin D 3 and several of its
non-calciomimetic analogs show dose-dependent inhibition
of cell growth in ATC cells in vitro'" and in vivo. 65 Growth
inhibition of anaplastic cancer cells was also demonstrated
by histone deacetylase inhibitors as a result of increased
apoptosis, with activation of the caspase cascade and the
induction of a cell cycle arrest through reduction of cyclindependent kinase activity/"
Bovine seminal ribonuclease has been reported to have
beneficial effects for treatment of aggressive thyroid cancer/"
An ElB 55-kDa gene-defective adenovirus (ONYX-015)
worked synergistically with two antineoplastic drugs
(doxorubicin and paclitaxel) to increase cell death in ATC.68
Apigenin, a flavonoid, showed promise by inhibiting the
signal transduction pathways regulating growth and survival
in human ATC cells.s? It has also been documented that
levels of (k)alpha 1 tubulin relative to thyroglobulin were
greatly increased in anaplastic cancer so that chemotherapy
targeted at microtubulin might prove to be useful for ATC
treatment."? Restoration of p53 expression in ATC inhibited
proliferation and restored differentiation in human ATC
cells as well as responsiveness to physiologic stimuli." It
has also been reported that CA4P, a tubulin-binding agent
derived from the African bush willow, may have antitumor
effects in ATC, thought to be due to a combination of primary
antineoplastic effects and impairment of tumor vascularity."
Although investigation into the biologic character of ATC
continues, therapeutic innovations are still relatively scanty.
Even as prospective trials continue to be limited, it has been
noted that ATC arising from papillary or follicular thyroid
malignancies have different genetic backgrounds and retain
some of the cytogenetic characteristics of the parent
problem.F BRAF mutations have been demonstrated to be
restricted to papillary cancer and poorly differentiated and

anaplastic cancer arrising from papillary malignancy, with
distinct properties that enable them to develop poorly differentiated and anaplastic cancer." Also, a panel of tumor suppressor genes has been studied that is associated with
thyroid neoplasia. The results demonstrate a pattern of
alloleic loss, so that the majority of cases showed mutations
in two distinct areas and substantial increases in mutation
rates in the anaplastic components of the transformed ATC
from preexisting well-differentiated malignancy?" PlO7 is
thought to play a constitutive role in the progression of
papillary cancer to anaplasia, showing a marked decrease in
the anaplastic component." Efforts have also been made to
investigate the expression of cytokeratin 20 (ck20) in differentiated and anaplastic cancer, and the resultant investigation has demonstrated that ck20-positive tumors have a poor
prognosis, reinforcing the need for adjuvant treatment in
such a selected group." Cytogenetic work has also shown
that different gene dosage copy sequence and balances are
important to pathways of transformation of follicular into
anaplastic cancers." The transcriptional factor E2Fl controls the RB-E2F signaling pathway, and there is enough
regulation of E2Fl in papillary cancer as compared with
ATC that may demonstrate a role in carcinogenesis." Gene
therapy of ATC has been investigated using the interleukin-l Z
gene in BALB/C (nulnu) mice, and initial results suggest a
clinical application may be considered." Other investigation
has demonstrated that the radiosensitivity of transformed
thyroid cells is due in part to the elevated basal activity in
the induction of the active form of nuclear transcription
factor kappa B, prompting investigators to theorize that inhibition of NF-kappa B could enhance radiation therapy of
ATC.8o Workers have also looked at imatineb mesylate
monotherapy in treatment of ATC only to find that future
clinical studies are futile and not to be encouraged." It has
also been demonstrated that experimental in vitro incorporation of gemcitabine into liposomes enhances the drug's
cytotoxic effect, indicating a more effective drug intake
inside the cell, which may permit lower dosage of this drug
in the treatment of ATC.82 Etiology and more complex treatment programs may be investigated, but surgical investigators are still left with the rather simplistic feeling that,
although there is no successful treatment for ATC, patients
who have undergone liberal surgery for thyroid neoplasia or
early surgery with complete resection of ATC have the best
chance of response and survival. 83
Conclusion
ATC is rare and lethal; fortunately, it appears to be decreasing in frequency" but is nevertheless still a persistent occurrence. The decrease in frequency appears to be associated
with improvement in socioeconomic status, more accurate
diagnosis, histologic definition and exclusion of medullary
cancer and lymphoma, and the elimination of iodine deficiency. It is apparent that the traditional approaches of surgery
and postoperative radiation are inadequate in ATC treatment
if one is to expect a curative outcome. Currently, the most
effective treatment, at least for the control of local disease,
is a multimodality treatment consisting of a combination of
165
initial simultaneous radiotherapy and chemotherapy, followed

by surgical resection of as much tumor as safely possible,
followed by combined chemoradiotherapy, u Obviously,
more research is required and deserves support so that a new
therapeutic regimen may evolve to produce improved and
more successful results. 55-83
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Unusual Thyroid Cancers,

Lymphoma, and Metastases
to the Thyroid
Janice L. Pasieka, MD, FRCSC, FACS Lloyd A. Mack, MD, FRCSC
Unusual Thyroid Cancers

Unusual thyroid cancers, including the intermediately differentiated carcinomas, account for only 10% to 15% of all
primary thyroid neoplasms (Table 19-1). This unique group
of neoplasms behaves differently than the more common
type-the well-differentiated thyroid cancers (WDTCs).
They therefore present a challenge to both the surgeon and
the endocrinologist-oncologist. Most of these cancers behave
in an aggressive fashion and, at times, present as a medical
emergency. Multimodality therapy is the mainstay of treatment for these tumors. As a result, it is important for the
endocrine surgeon to have a clear understanding of the nature
of these tumors and recognize when surgery is indicated.
Plasmacytoma
Primary extramedullary plasmacytomas are rare forms of
plasma cell tumors. Solitary extramedullary plasmacytomas
may develop in any organ, but they occur predominantly in
the upper respiratory tract. 14 The thyroid gland is one of the
rarer sites; approximately 50 cases of solitary lesions have
been reported in the literature.l It is not uncommon, however, for multiple myeloma to involve the thyroid gland.r"
The diagnosis of solitary extramedullary plasmacytoma
can be made only after the exclusion of skeletal multiple
myeloma on long-term follow-up.v'?
Clinical Features. Extramedullary plasmacytoma of
the thyroid usually presents with a painless diffuse or nodular goiter. In several cases, it was a rapidly enlarged goiter
that brought the patient to seek medical advice.5.8.9.11
Typically, the patient is euthyroid and presents in the sixth
decade of life. Extramedullary plasmacytoma predominantly affects females. II
On physical examination, the thyroid is a firm, nontender,
mobile, multilobulated goiter. There is usually no associated
168
cervical lymphadenopathy. Biochemically, antithyroid

antibodies may be elevated. Some authors have suggested
an association with autoimmune thyroiditis." However, the
thyroiditis may represent a nonspecific inflammatory reaction to the presence of the tumor and may not be linked to
the cause of the tumor.
Pathology. Grossly, the lesions have a fleshy, red-brown
neoplastic appearance. Histologically, the tumor demonstrates
a dense infiltration of mature plasma cell arranged in sheets
or clusters replacing the normal thyroid architecture. Cellular
atypia may be seen and mitotic figures can be numerous
(Fig. 19-1). 8 Immunohistochemical staining can demonstrate monoclonal plasma cells for both kappa or lambda
immunoglobulin chains."
Diagnosis and Treatment. The diagnosis of a solitary
extramedullary plasmacytoma of the thyroid is suspected
on the clinical presentation and the pathologic appearance
of the tumor. Fine-needle aspiration (FNA) cytology results
may be misinterpreted as medullary thyroid carcinoma.'?
Because of the rarity of these tumors, there are no reported
cases of the diagnosis being made on the basis of FNA.
As stated earlier, it is important to rule out disseminated
multiple myeloma by performing a bone marrow aspiration.
Up to 25% of patients with solitary plasmacytoma have
elevated levels of M proteins in their blood or urine. 13
The optimal treatment for this tumor consists of a total
thyroidectomy plus high-dose external-beam radiation to the
neck. Surgery or low-dose radiation therapy alone has been
associated with a high local recurrence rate. 13 Some institutions have treated these rare tumors with only high-dose
radiation (5000 to 6000 rad) and have had relative success.t'"
Local recurrence does not appear to alter survival, and most
reported cases have been controlled with further radiation
therapy. I I The overall 5-year survival using combined
treatment is 85%.9 However, long-term follow-up of these
patients is necessary because progression to multiple
myeloma has been reported.t
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - - 169
Paraganglioma
Paragangliomas are rare tumors derived from the extra-adrenal
paraganglia cells of the autonomic nervous system. Most paragangliomas occur in the retroperitoneum or the head and
neck region (carotid body tumor). Over the last few decades,
several authors have reported unique thyroid lesions that
have been categorized as paraganglioma of the thyroid.'>"
The presence of a primary paraganglioma in the thyroid is
difficult to explain embryologically. Some authors have suggested that these lesions may be a form of medullary thyroid
cancer. However, amyloid has not been identified in these
lesions, and none of the lesions have stained for calcitonin.l'v"
Several authors have described lesions that appear to
have a histologic appearance similar to paragangliomas on
light microscopy but demonstrated positive thyroglobulin
immunoreactivity and negative immunoreactivity for calcitonin and neurofilament.t-P These investigators concluded
that true paraganglioma of the thyroid has not been proven
to exist and that these lesions represent a variant of follicular adenomas, describing these lesions as "hyalinizing trabecular adenoma"23.24 or "paraganglioma-like adenoma.r'P
FIGURE 19-1. Plasmacytoma of the thyroid: two thyroid follicles

entrapped in a sea of plasma cells (hematoxylin-eosin stain).
Clinical Features. The patients usually present with a

solitary, nontender thyroid nodule. Patients' ages range from
27 to 67 years (mean age, 46 years). Paragangliomas occur
predominantly in women.P:'? Some of these lesions are
"hot" on thyroid scintigraphy.
Pathology. The cytologic features on FNA can resemble
those of medullary thyroid cancer. Negative staining for calcitonin of these cells can aid in the differential diagnosis preoperatively (Fig. 19-2A). Grossly, the lesions are solid and
well encapsulated. They are described as tan to pink-gray in
appearance and granular in texture. Histologically, the tumors
are composed of oval, elongated spindle cells arranged in a
trabecular fashion. The cytoplasm is eosinophilic and finely
granular (Fig. 19-2B). Immunohistochemically, the lesions
stain positive for thyroglobulin, neuron-specific enolase, and
S-IOO but negative for calcitonin and neurofilament.20-23
LaGuette and associates" suggest that an immunohistochemical panel is essential for making the correct diagnosis
of this rare tumor.
Diagnosis and Treatment. Whether these lesions represent a variant of follicular adenomas or are truly paragangliomas of the thyroid is debatable. However, these rare
lesions exhibit several microscopic characteristics that are
similar to those of medullary thyroid cancer and can be potentially misinterpreted if not initially recognized as such. Most
patients reported to date have been successfully treated with
surgical excision alone. 22.23 External-beam radiation was used
unsuccessfully in one report.'? The literature suggests that
most of these lesions can be treated in a similar fashion to a
follicular adenoma, that of an unilateral thyroid lobectomy,
and these patients have the same excellent prognosis. It is
unclear whether lesions demonstrating local invasion are arising from the thyroid or are extrathyroidal in origin, invading
into the thyroid.l'v'? Therefore, when local invasion is found,
complete en bloc excision of the paraganglioma is necessary.
Sarcoma
Throughout the medical literature there are many case reports
of sarcoma arising in the thyroid gland. This is to
be distinguished from anaplastic thyroid carcinoma that has
been shown to demonstrate a variety of growth patterns,
including those resembling sarcomas.P:" In the case reports
of primary thyroid sarcoma presented in the literature,
patients usually present with large, ill-defined masses of the
thyroid associated with rapid growth.P?' Gender predilection
appears to be equal. The question as to whether primary mesenchymal thyroid neoplasms exist continues to be debated
in the literature. There are, however, reports of hemangioendotheliomas of the thyroid that have confirmed the endothelial nature of the tumor with electron microscopy,
immunohistochemical staining, and lack of thyroglobulin
messenger RNA expression. 29,31-3S Liposarcomas, carcinosarcomas, dendritic cell sarcomas, and leiomyosarcomas
of the thyroid gland have also been reported. 26.30,36-39
Immunoreactivity of these tumors for actin, desmin, and
vimentin with negativity for thyroglobulin, cytokeratin, and
S-IOO protein supports the distinct identity of these rare
tumors. 30.38 All subgroups of these tumors generally have
a poor prognosis despite treatment attempts with surgery,
external-beam radiation, and/or chemotherapy.29,31,34,3S,38,39

squamous cell carcinoma of the thyroid is rare, having been
estimated to make up only 0.2% to 0.3% of all thyroid
cancers.v A unique group of spindle cell squamous carcinomas associated with tall cell papillary thyroid cancer (PTC)
has also been described.">? The patients tend to be women
in their seventh decade of life.53.55.56.58 Most patients have
advanced disease at presentation, with invasion into adjacent
structures and distant metastases being common. Few
patients survive more than 12 months. 53.55.57.58 Diagnosis is
usually made after pathologic examination of the surgical
specimen, although Mai and colleagues described diagnosis
based on FNA,59 Total excision of gross disease, when possible, may be curative when followed by external-beam radiation. 53,6o The clinical usefulness of chemotherapy is
uncertain, with no proven responses.w'" Useful palliation
may be achieved with combined surgical debulking and
radiation in selected patients. 53,6o
Intermediately Differentiated Carcinomas
B
FIGURE 19-2. A, Cytology of a thyroid paraganglioma. B,
Paraganglioma of the thyroid. Shown are oval, elongated spindle
cells arranged in a trabecular fashion (hematoxylin-eosin stain).
Teratoma
Teratomas are believed to arise from totipotential cells and,
therefore, commonly arise in the reproductive organs. The
exact site of origin in the thyroid is unclear. Teratomas of the
thyroid can be either benign or malignant.f? The benign teratomas are usually cystic and occur in children. 41,42 Teratomas
that develop in adults are more common in women, present
with progressively enlarging thyroid masses, and are usually
malignant.Pr'? In the adult, thyroid teratomas are characteristically large tumors with areas of hemorrhage and necrosis.
Microscopically, the tumors demonstrate an admixture of
immature tissues with features of the three germ cell layers.
These tumors are highly aggressive. To date, treatment consists of total thyroidectomy and neck dissection for diagnosis and potential locoregional control. External-beam
radiation has been used; however, in general, these tumors
tend to be resistant to chemotherapy and radiation therapy.43,47,49 There have been a few long-term survivors with
aggressive combination chemotherapy.s'-"
Squamous Cell Carcinoma

Primary squamous cell carcinoma of the thyroid has been
extensively described in the literature.v" The frequency of
A recent classification of thyroid cancer based on tumor

prognosis has been suggested by Fadda and LiVolsi. 61 This
classification includes a group of intermediate variants of
thyroid cancer, including insular, columnar, mucoepidermoid, and diffuse sclerosing PTC; tall cell carcinoma; and
the solid/trabecular variant of PTC.61.63 These tumors have
a biologic aggressiveness that is intermediate between that
seen in WDTC and that of lethal anaplastic thyroid cancer.
Although the intermediate variants make up only 10% to
15% of all thyroid cancers, they are important variants
for the endocrine surgeon to be aware of because in many
cases they require a multimodality therapy that differs from
that of WDTC.
INSULAR CARCINOMA
Insular carcinoma of the thyroid was first described by

Langhans in 1907,64 and several decades later, Carcangiu and
coworkers established diagnostic criteria for this tumor.s'
There are now more than 200 cases reported in the literature,
accounting for 2% to 6% of all thyroid cancers. 66,67
Clinical Features. Insular carcinoma is a highly aggressive form of thyroid cancer.f Most of the tumors are relatively large, with a mean size of 5.5 em (ranging from 5 to
10 cm).68 There is a 2: 1 female predominance; age of onset
ranges from 37 to 76 years, with the mean age of presentation being 56 years. Most patients are euthyroid and present
with a cold thyroid nodule. There is usually no history of
low-dose radiation to the head and neck region in these
patients." Most patients have cervical and mediastinallymphadenopathy on presentation. Locoregional and/or distant
metastases have been reported in up to 70% of patients."
Pathology. Macroscopically, insular carcinoma is a solid
pale or gray color, often with areas of necrosis or hemorrhage. Microscopically, the tumor is characterized by the
formation of a large, well-defined nest of monotonous round
and oval tumor cells with occasional small follicles. These
nest of tumor cells resembles the pattern seen with carcinoid
tumors-hence, the name insular. 65 ,69 The tumor cells are
uniform and lack prominent nucleoli. Many of the nuclei are
optically clear, resembling the ground-glass nuclei of PTC.
Mitotic figures are present in all tumors (Fig. 19-3).65
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - -
FIGURE 19-3. Insular carcinoma: well-defined nests (insulae) of
round oval cells.
There is increasing evidence to support the concept that

insular carcinoma represents an intermediate step in the
dedifferentiation of WDTC to anaplastic thyroid cancer.
First, the presence of WDTC in combination with insular
cancer is seen in up to 59% of reported cases.F" Second,
similar to WDTC, insular carcinomas stain positive for thyroglobulin and negative for calcitonin, chromogranin, and
carcinoembryonic antigen. 65. 72 Finally, up to 38% of insular
cancers stain positive for p53 mutations, which is a higher
rate than reported in WDTC and significantly lower than
that seen in anaplastic carcinoma."
Diagnosis and Treatment. The rarity of these tumors
has not allowed for a uniform approach to treatment. In the
series of 25 patients by Carcangiu and associates, most of
the patients with insular carcinoma underwent total or neartotal thyroidectomy. Some patients had neck dissections,
and others received external-beam radiation. The extent of
surgical excision did not seem to influence the local or distant recurrence rates. More than 85% of patients developed
local, regional, or distant metastases in the 8-year follow-up.
The mortality rate during this same period of follow-up was
56%.65 In a recent review of the literature, the mean rate of
local and/or distant metastasis for insular carcinoma was
calculated to be 64%.68 In one series, 75% of metastatic
insular tumors concentrated radioiodine." Therefore, the
current treatment for insular thyroid cancer remains aggressive
surgical intervention, with or without lymph node dissection,
adjuvant radioiodine treatment (although not prospectively
evaluated), plus the possibility of external-beam radiation
for incompletely excised tumors.
171
an aggressive behavior and an unfavorable prognosis.

However, in two small series, when the tumor was circumscribed and encapsulated, the prognosis was similar to that of
WDTC,79.82 Mean age at presentation is 44 years. 79.8l The
tumors tend to be large, with a mean tumor size of 5.3 cm. 68
Patients typically present with a cold thyroid nodule and may
have regional lymph node metastases. The overall rate of distant metastases is 32%, although no cases of distant metastases have been reported when the tumor was encapsulated.
Distant metastases when present are found predominantly in
lung, bone, and regional lymph nodes.68.79.81
Pathology. FNA cytology has been described for these
lesions." The cytologic features can be confused with PTC,
medullary carcinoma of the thyroid, and metastatic adenocarcinoma. Grossly, the thyroid tumor tends to be an irregular,
multinodular, tanned mass (Fig. 19-4A). Histologically, the
tumors may be encapsulated or diffusely invasive. 79,82 In
contrast to well-differentiated PTC, the epithelium consists
of tall, columnar tumor cells displaying a pronounced nuclear
stratification. Columnar cell carcinoma has scant cytoplasm
with no oxyphilic changes. Most tumors display a papillary
growth pattern with mitotic figures and immunohistochemically stain positive for thyroglobulin (Fig. 19-4B).
COLUMNAR CELL CARCINOMA
Evans 74 in 1986 described two cases of thyroid cancer with

a distinct histologic pattern that he termed columnar cell
carcinoma. Others have since reported similar cases, all
displaying aggressive clinical behavior and a universally
poor prognosis.25.75.78 Columnar cell carcinoma is rare,
accounting for only 0.15% of all PTCS.79.81
Clinical Features. Earlier reports suggested a higher
incidence in males; however, in a recent review of the reported
cases in the literature, there was a female predominance.f
Most of these columnar cell tumors are associated with
B
FIGURE 19-4. A, Columnar cell carcinoma of the thyroid: Gross
picture of a resected liver metastasis. The multilobulated, tanned
color of this tumor is characteristic of these tumors. B, Columnar
cell carcinoma of the thyroid. The tall columnar tumor cells display
pronounced nuclear stratification (hematoxylin-eosin stain).
172 - -
Thyroid Gland
Columnar cell carcinoma differs histologically from the tall

cell variant of PTC51,52,83 in that the degree of nuclear
stratification and height of the columnar cell are much more
excessive in columnar cell tumors.r'-" The exact proportion
of columnar cells displaying nuclear stratification required
to make the diagnosis of columnar cell variant has not been
defined. In the largest reported series, the diagnosis of
columnar cell variant required more than 70% of the tumor
demonstrating nuclear stratification."
Diagnosis and Treatment. Most patients have been
treated with total or near-total thyroidectomy, with or without
lymph node dissection. Until recently the prog~osis
of
columnar cell carcinoma was thought to be universally
poor.74.76 Encapsulated or minimally infiltrative lesions h~ve
a relatively good prognosis, with all reported cases remaming disease free at 5 years. In contrast, tumors with extrathyroidal spread have a high incidence of distant metastases, and
67% of the patients have died of the disease, with a mean
mortality of only 40 months. 68,79,81,82 Radioactive iodine has
been used in about 60% of cases without evidence of demonstrated improvement.Y" External-beam radiation should be
considered when residual disease is present or for palliation.
MUCOEPIDERMOID CARCINOMA
In 1977, Rhatigan and colleagues's first described primary

mucoepidermoid carcinoma of the thyroid. Fourteen years
later, Chan and coworkers described sclerosing mucoepidermoid thyroid carcinoma arising from a metaplastic follicle
in Hashimoto's thyroiditis.f" There have been several case
reports of this rare tumor, with significant debate in the
literature regarding its histogenesis.t"?' It is believed that
mucoepidermoid tumors of the thyroid arise from either
metaplasia of the follicular epithelium89,92,93 or as vestiges of
the ultimobranchial body.94-98
Clinical Features. Although these tumors were original
described as indolent or low-grade tumors,63,84 many case
series suggest a more aggressive behavior, with a high incidence of local invasion,85,86.9I,93 ability to metastasize distantly,87.88 and mortality.P?' The tumor presents as a painless
neck mass that is "cold" on thyroid scintigraphy. There is a
female predominance occurring most commonly in the fifth
to eighth decades of life.84,85,89
Pathology. Microscopically, neoplastic proliferation is

composed of squamous or epidermoid areas with intermingling mucous cells. The epidermoid cells have round or oval
nuclei, prominent nucleoli, and eosinophilic cytoplasm.
Mucocytes with abundant clear to foamy-appearing cytoplasm and peripheral hyperchromatic nuclei are present.
Sclerosing mucoepidermoid carcinoma with the eosinophilia
variant often has a background of thyroiditis and prominent
sclerohyaline stroma infiltrated with eosinophils.Pv"
Immunohistochemistry on these tumor is positive for mucin
'.c
. 63 '85 ,89
. stains
. but negative
and cytokeratin
lor ca lei
citorun.
Diagnosis and Treatment. FNA cytology has diagnosed
these tumors; however, more commonly the diagnosis is only
made after surgical excision."? An en bloc thyroidectomy is the
treatment of choice with potential for cure even in locally invasive disease.84,91,100 External-beam radiation and chemotherapy
have been used with minimal success at controlling locoregional disease.87,88,92,93 Information regarding this tumor's
usual clinical course is lacking because of its rare occurrence.
DIFFUSE SCLEROSING VARIANT OF PAPILLARY

THYROID CANCER
The simultaneous occurrence of thyroiditis and PTC was

first described in 1985 by Vickery and associates. 101 This
variant, termed diffuse sclerosing variant of PTe, was later
incorporated into the World Health Organization (WHO)
classification of thyroid tumors and today accounts for 2%
to 6% of all thyroid tumors. 102-105 To date, there have been
72 cases of diffuse sclerosing PTC reported in the adult
literature.P Diffuse sclerosing PTC has also been described
in the children affected by the Chernobyl disaster. 106,107
Clinical Features. Diffuse sclerosing PTC occurs predominantly in females, with the age of presentation being in
the third decade of life. Patients present with either localized
or diffuse thyroid enlargement that may be painfu1.68,108
Fifty to 70% of patients have measurable titers of antimicrosomal and antithyroglobulin antibodies, leading to the
mistaken diagnosis at presentation of subacute or chronic
thyroiditis in 28% to 40% of patients. 102,108 Cervical lymph
node metastases are found in 70% of patients, and distant
metastases can be found in up to 60%.68,102-104
Pathology. The FNA cytology of diffuse sclerosing PTC
demonstrates the usual nuclear features of PTC: nuclear
grooves, pseudoinclusions, and overlapping nuclei. !he
presence of relative nuclear enlargement and pleomorphism
may help distinguish this variant from the usual PTC.109
These tumors usually demonstrate a diffuse involvement of
the thyroid lobe, with a pale, fibrous appearance macroscopically. Histologically, diffuse sclerosing PTC is made up of
numerous papillae with squamous metaplasia. The tumors
tend to have interstitial fibrosis, psammoma bodies in a background of lymphocytic inflammatory infiltrate (Fig. 19-5).
Extrathyroidal extension is seen in 40% of patients. I 10
Diagnosis and Treatment. Diffuse sclerosing PTC
tends to have a higher propensity for locoregional metatatic
compared with that found in WDTC. Local recurrence rates
are reported to be as high as 50%, and distant metastatic
rates of 60% have been described. 102,103,108,110 In a recent
review of 65 reported adult cases of diffuse sclerosing PTC,
FIGURE 19-5. Diffuse sclerosing papillary thyroid cancer, This
low-power view demonstrates interstitial fibrosis, psammoma

bodies, and lymphocytic infiltrate.
173
the mean weighted local recurrence rate was only 13%,

and the mean weighted distant metastatic rate was
calculated to be only 19%.68 Tumor-related mortality for
this variant is excellent, with only one reported death in the
literature. 103
The treatment of diffuse sclerosing PTC begins with the
awareness of this tumor's ability to mimic subacute thyroiditis at the time of presentation. The treatment of this
tumor should involve an en bloc excision of the thyroid
gland and any of the infiltrated structures within the neck.
Given the high rate of lymph node metastases, a modified
neck dissection should also be included. Following surgery,
adjuvant radioactive iodine therapy should be used.
TALL CELL VARIANT OF PAPILLARY THYROID CANCER
The tall cell variant of thyroid cancer accounts for 3% to

12% of all PTCs of the thyroid, although this is believed to
be an underestimate of the disease because of the difficulty
the pathologist may have at making the diagnosis.!" Tall
cell cancer of the thyroid was first described by Hawk and
Hazard in 1976. 52 These tumors are characterized by having
a significant proportion of the tumor composed of cells
in which the cell height is at least twice its width. There is
variation in the literature regarding the percentage of tall
cells within the tumor required to make the diagnosis.
Most series have used a minimum of 30% of the tumor
composed of tall cells to classify the tumor as a tall cell
variant, whereas others have used percentages as high as
50% to 70%.111-114
Clinical Features. There have been more than 200

reported cases in the English literature of tall cell variant
thyroid cancer." Although some authors have described a
male predominance, 115. 11664% of the patients reported in the
literature were women, with the average age of presentation
being 51 years (range, 43% to 65%).68 The tumor tends to be
larger than WDTC, averaging a diameter greater than 3 cm. 117
Extrathyroid extension is common and is found on average
in 67% of the patients, in contrast with WDTC that demonstrates extrathyroid invasion in less than 20% of patients.
Regional lymph node metastases occur on average in 57%
of the patients (range, 40% to 83%). Distant metastases
typically appear in the lung and bone and are found on
average in 22% of the patients.v"
Pathology. The cytologic features of tall cell cancer are
similar to those seen in PTC, including nuclear pseudoinclusions, nuclear enlargement, and nuclear grooves. ll8,119
Feature that help the cytopathologist to differentiate this
variant from PTC include larger cell size, eccentric nucleus,
and increased nuclear pleomorphism. Macroscopically,
these tumors appear as pale, firm neoplasms. Multifocality
is commonly seen in 36% to 58%.116 The characteristic tall
cells have a height that is at least twice their width, with
abundant cytoplasm and basal positioning of the nucleus
(Fig. 19-6). These features are distinct from the columnar
cell variant of PTC, which has stratification of its nuclei and
less cellular cytoplasm (see Fig. 19-4B). Most tall cell
tumors stain positive for thyroglobulin, vimentin, and
kertin.'!" Tall cell tumors have been shown to have a significantly higher incidence of p53 mutations compared to welldifferentiated PTC (61% vs. 11%); however, p53 mutations
FIGURE 19-6. Tall cell variant of papillary thyroid cancer. The

height of the cells is greater than twice their width.
have not been demonstrated to be a predictor of worse

outcome. I12
Diagnosis and Treatment. Regardless of the patient's
age or the tumor size, the histologic diagnosis of tall cell
carcinoma has been demonstrated to be an independently
poor prognostic factor. 113,120 With the exception of Ozaki
and coworkers.!" who found no recurrence or mortality in
13 patients with tall cell cancer, most authors have reported
tumor-related mortality rates up to as high as 74%.lI1,I15.117
Locoregional recurrence rates are greater than those seen
in PTC, with the risk of recurrence being greater in
patients older than 50 years of age and in tumors larger
than 4 cm. 11 I,117
In the study of 18 patients by Taylor and associates, the
use of radioiodine therapy in 131I-avid tumors was shown
to reduce the progression of the tumor signiflcantly.V'
However, in another study, Ain found that only 13% of tall
cell tumors were 131I-avid, and half of these patients eventually lost radioiodine uptake in the metastases over time.P"
The aggressive nature of this tumor warrants aggressive
surgical intervention. Total thyroidectomy combined with
lymphadenectomy of cervical nodes and an en bloc resection of adjacent tissues should be done when there is
evidence of local invasion. Since radioiodine therapy has
been shown to be of benefit in some patients, it should be
used in all P'f-avid tumors. External-beam radiation should
be considered in all cases of tall cell carcinoma that have
demonstrated extrathyroidal extension, incomplete resection,
or positive lymph node involvement.
SOLIDITRABECULAR VARIANT OF PAPILLARY
THYROID CANCER
The presence of focal areas of solid or trabecular growth

patterns in WDTC is common. When the tumor demonstrates
exclusively or predominantly a solid or trabecular pattern,
the diagnosis of a solid/trabecular variant of PTC is made.
Between 12% and 16% of PTCs are the solid/trabecular
variants. 123.124 More recently, this variant has been identified
in 37% of the radiation-induced thyroid cancers seen in children exposed to the Chernobyl nuclear disaster.l'" This is a
174 - -
Thyroid Gland
significantly higher rate of occurrence than that seen in agematched nonradiation-induced PTC, in which the solid/
trabecular variant made up only 4% of the tumors. 125
Clinical Features. The solid/trabecular variant is seen
in both the adult and pediatric population. In adults, the
mean age of presentation is in the fifth decade of life, with a
strong female predominance.P' In contrast, the radiationinduced tumors in the pediatric population exposed in the
Chernobyl disaster affected both males and females
equally.I'" Most of these children presented with a thyroid
nodule averaging 2 em in size, with clinical lymphadenopathy found in 85%. In adults, cervical nodal disease occurs in
between 57% and 83% of cases, and distant metastases are
found in up to 21% of patients at presentation. 123,124
Pathology. Macroscopically, these tumors appear as
nonencapsulated, firm, whitish nodules with evidence of
local invasion present in 84% of the patients. 106
Microscopically, these tumors are made up of solid nests or
a cordiike trabecular arrangement of epithelial cells, as
shown in Figure 19-7. The solid variant has typical nuclear
features of PTC, including nuclear inclusions and nuclear
grooves. Most tumors stain positive for thyroglobulin, and a
high prevalence of ret/PTC3 rearrangement has been
demonstrated. 125
Diagnosis and Treatment. It is unclear in the literature
as to whether the solid/trabecular variant has a worse prognosis than that of WDTC. Mizukarni and colleagues reported
a lO-year survival rate of the only 72% in a series of
30 patients.!" In contrast, Carcangui and coworkers reported
no tumor mortality in their series of 28 patients followed
longer than 6 years.123 The follow-up of solid/trabecular variant tumors from the Chernobyl disaster is too brief to draw
any conclusions on the long-term prognosis of these children.
Total thyroidectomy and cervical lymph node dissection
should be the treatment of choice because of the high
propensity of the solid/trabecular variant to extend beyond
the thyroid and to metastasize to lymph nodes. The use of
radioactive iodine in these tumors has not been studied.
Given that the histologic features of these tumors resemble
those of PTC, it seems reasonable to use radioiodine therapy
following surgical intervention.
Lymphoma of the Thyroid

Primary lymphomas of the thyroid are rare, accounting for
only 1% to 2% of thyroid malignancies and less than 2% of
extranodal Iymphomas.P'P''!" Most thyroid lymphomas are
non-Hodgkin's lymphomas of B-cell origin, although
Hodgkin's disease of the thyroid has been described. 126.129 I~
a large proportion of cases, thyroid lymphomas are associated with Hashimoto's thyroiditis and histologically may be
difficult to distinguish from this chronic lymphocytic
disease.25,130 Follow-up studies have estimated the relative risk
of thyroid lymphoma in patients with chronic lymphocytic
thyroiditis to be 70 to 80 times higher than in controls. 131
The actual relationship between Hashimoto's thyroiditis and
thyroid lymphomas remains obscure. Whether the presence
of lymphocytes in the thyroid provides the tissue in which
the lymphoma can develop or whether the chronic stimulation of the lymphocytes predisposes the cells to develop
malignant clones has not been defined.
Clinically, primary lymphoma poses a diagnostic and
therapeutic challenge because it can present in a fashion
similar to that of small cell anaplastic carcinoma of the
thyroid. 132-135 As a result, it is essential to be able to distinguish these two diseases, because there are different therapeutic and prognostic implications for each.
Clinical Features
Most patients present with a several-week history of a rapidly enlarging goiter. 134,135 Thyroid lymphomas tend to present in women in their seventh decade of life who may have
had a long-standing history of Hashimoto's thyroiditis. It is
usually painless and often associated with hoarseness and
dysphagia. 26,130.135 Less frequently, the patients may present
with tracheal compression, dyspnea, and respiratory
obstruction.!" Most patients are euthyroid. On palpation,
the thyroid is firm, with either unilateral or bilateral involvement. The gland may be fixed to adjacent structures, and
enlarged regional lymph nodes are not unusual. Computed
tomography usually demonstrates a diffusely enlarged thyroid gland with evidence of invasion into adjacent structures
and lymphadenopathy (Fig. 19-8A).
PATHOLOGY
FIGURE 19-7. Solid/trabecular variant of papillary thyroid cancer.

This high-power view demonstrates a cordlike trabecular arrangement of the cells.
Thyroid lymphomas grossly appear as pale gray or light tan

fleshy tumors (Fig. 19-8B). Most thyroid lymphomas are
the non-Hodgkin's type. 134,135 Aozasa and colleagues!"
reported that most thyroid lymphomas appear to be exclusively B-cell-derived tumors. Histologically, primary thyroid
lymphomas can be of several subtypes, classified by the
Revised European-American Lymphoma study group
(REAL) and the WHO classifications.Pv'F Deringer and
coworkers'> described four main subtypes in their large
series: 38% diffuse large B-celilymphoma without marginal
zone lymphoma, 33% diffuse large B-cell lymphoma with
marginal zone B-celilymphoma, 28% marginal zone B-cell
lymphoma of mucosa-associated lymphoid tissue (MALT),
and fewer than I % follicle-center lymphoma. The percentage of MALT lymphoma varies in the literature from 23%
to 77%.134.135,138.140 Many authors suggest that large cell
175
FIGURE 19-8. A, CT scan of a thyroid lymphoma, showing diffuse enlargement with tracheal compression. B, Thyroid lymphoma: left
resected lobe of the thyroid, with fleshy appearance on the cut surface. C, Thyroid lymphoma demonstrating diffuse replacement of the
thyroid parenchyma by lymphoma. D, Thyroid lymphoma extending beyond the thyroid capsule to invade surrounding strap muscles
(C and D, hematoxylin-eosin stain).
lymphomas may also evolve from low-grade lymphomas

of MALT.140-143 In general, the tumor cells are noncohesive
and have a lymphoid monomorphoric appearance.i" Thyroid
lymphoma may form nodules or may present with a diffuse
infiltrative pattern. Mitotic figures can be numerous
(Fig. 19-8C). Extrathyroid extension of the neoplastic cells
helps the pathologist distinguish this as a neoplastic process
versus chronic inflammation. DNA flow cytology and
immunohistochemical staining for CD 19 and CD20 are helpful for demonstrating the B-cell nature of the lymphocytes,
and the restricted expression of immunoglobulin light
chains allows for the distinction from chronic lymphocytic
thyroiditis.25.128.134.144
Diagnosis and Treatment

Thyroid lymphoma can be confused clinically with an
anaplastic thyroid carcinoma. FNA has helped distinguish
these two conditions preoperatively and has decreased
the need for open biopsy.126.130.145 Up to 88% of thyroid
lymphomas in some series are diagnosed on FNA alone

without further invasive testing.145.146 The use of flow
cytometry, immunohistochemistry, and polymerase chain
reaction has improved diagnostic results. 138.147.148 However,
FNA is experience dependent, and there are difficulties in
distinguishing thyroid lymphoma from Hashimoto's thyroiditis. This difficulty can lead to the need for open
surgical biopsy to make the diagnosis. 149.150
Once the diagnosis has been established or is suspected,
the patient's disease must be staged, as follows:
Stage IE involves localized disease within the thyroid.
Stage lIE is disease confined to the thyroid and
regional lymph nodes.
Stage IIIE involves disease on both sides of the
diaphragm.
Stage IVE is disseminated disease.
The treatment of thyroid lymphoma remains controversial. Initially, surgery was used extensively for the treatment
of this disease. More recently, however, surgical removal has
been shown to have a limited benefit. 150.151 Not all investigators
176 - -
Thyroid Gland
have agreed with this; some have suggested that the addition
of surgical debulking is necessary because the amount of
residual disease in the neck correlated to the relapse rate for
stages IE and lIE disease. Rosen and associates'V demonstrated a longer overall and relapse-free survival with complete or near-complete resection. However, most of the
literature reports have failed to demonstrate the benefit of
aggressive surgical intervention compared with combined
radiation and chemotherapy. The Mayo Clinic achieved a
complete response with predominantly radiation therapy in
stages IE and lIE lymphomas in 88% of its patients. 151 Since
most patients present with disease beyond the thyroid, the
surgical role in advanced tumors is limited to open biopsy
when needed.135.150.15I
Thyroid lymphomas have been shown to be both
radiosensitive and chemosensitive; therefore, most current
recommendations are to treat these tumors with a combinedmodality therapy.127.150.153 Doria and colleagues, in their
large 1994 review, demonstrated that nearly 30% of patients
with localized stage IE or lIE disease have systemic relapse
when treated with local radiation alone or in combination
with surgical debulking.F' They suggested that combined
radiation and chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone with or
without the addition of methotrexate, doxorubicin, or both
may decrease the chance of distant relapse. Radiation alone,
however, has been successfully used in localized thyroid
lymphoma of the MALT variety. Similar to MALT lymphomas of other sites, radiation alone has resulted in a 96%
complete response, with only a 30% relapse rate. I39,154 Many
centers treat all thyroid lymphomas (localized or disseminated) with multimodality therapy, including radiation and
chemotherapy. 134,150
Advanced stage of the tumor, a size greater than 10 em,
mediastinal involvement, and the presence of dysphagia
have been shown to be poor prognostic factors in primary
thyroid lymphoma.P'T" Most recurrences develop within
the first 4 years. The overall survival of patients with thyroid
lymphoma ranges from 50% to 70%.150,151 The 5-year survival is 80% for stage IE, 50% for stage lIE, and less than
36% for stages IIIE and IVE. 151
renal cancer patients, 10% of lung cancer patients, and 10%

of patients with primary head and neck tumors.P" Case
reports and studies of metastases to the thyroid gland from
less common primary tumor sites have been published,
including colon, soft tissue, neuroendocrine, stomach, bladder, and gynecologic tumors.160-165
The incidence of clinically apparent metastases appears
to be lower than the incidence found in autopsy material.
According to Shimaoka and colleagues.P" the thyroid
metastases were clinically apparent in only 5% to 10% of
patients in their study. Renal cell carcinoma is the most
common secondary to the thyroid when defined by clinical
detection. ' 64,166-168 Usually, there is a latency period lasting
years between the diagnosis of the primary cancer and the
appearance of a thyroid mass. 159,166-171 This finding is especially true for breast and renal primary tumors. Less commonly, patients may present with metastatic disease in the
thyroid before a primary diagnosis of cancer. l7u n
Diagnosis and Treatment

The presentation of a cold thyroid nodule years after the
treatment of a primary cancer often poses a diagnostic
dilemma. FNA has allowed for the preoperative diagnosis of
a secondary tumor, thus changing the preoperative work-up
of such a patient (Fig. 19_9).168,172.173 Once the diagnosis of
metastatic disease has been confirmed on FNA, the patient
should undergo a metastatic work-up to rule out other distant metastases. Several authors have demonstrated that for
isolated thyroid metastasis, thyroidectomy has prolonged
survival. l 64,166.167,169-171 This is especially true for tumors that
Metastases to the Thyroid

The true incidence of metastases to the thyroid gland has not
been clearly established. Autopsy studies have reported an
incidence ranging from 2% to 25%.156-159 In the study by
Mortensen and colleagues, 4% of patients with metastatic
neoplasms had secondary tumors of the thyroid gland.P?
Silverberg and Vidone-? found the incidence to be much
higher. In their study, they meticulously examined the thyroid and found the incidence of metastatic disease to the
thyroid to be 24% in patients dying from metastatic cancer.
This study suggested that the incidence of microscopic disease in the thyroid is greater the more diligently it is looked
for. Shimaoka and coworkersl'" studied the occurrence of
thyroid metastases for a given primary neoplasm. In their
autopsy study of patients who died of metastatic cancer,
they found that metastases to the thyroid occurred in 39%
of melanoma patients, 21% of breast cancer patients, 12% of
FIGURE 19-9. Algorithm outlining the approach to a thyroid

nodule in the face of a history of primary cancer. FNA = fine-needle
aspiration.
Unusual Thyroid Cancers, Lymphoma, and Metastases to the Thyroid - - 177
present years after the treatment of the primary cancer and

for breast and renal carcinomas. 164.166.167.170.171
Summary
Unusual thyroid neoplasms, intermediate variants, primary
lymphomas, and metastases to the thyroid gland make up a
rare group of tumors. Although they are uncommon, it is
important for the endocrine surgeon and endocrine oncologist to be able to recognize and differentiate them from the
more common thyroid neoplasms. These tumors, on the
whole, tend to behave more aggressively and, in most cases,
the use of multimodality therapy is recommended.
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Erol Diiren, MD Mete Diiren, MD
The clinical course of patients with thyroid cancer is

unpredictable. Numerous studies, however,have documented
that patients can be classified into groups at low or high risk
for recurrence or death on the basis of age, gender, tumor
size, histology, and extent of local invasion as well as the
presence or absence of distant metastases. 1 Resectability and
extent of resection, with the adjuvant use of iodine 131 and
thyroid-stimulating hormone (TSH) suppression therapy,
also influence outcome.
The various scoring systems such as AGES (age, grade,
extent, and size), AMES (ages, metastases, extent, and size),
and TNM (tumor, node, metastasis) attempt to identify prognostic factors of tumor behavior for recurrence and survival.I
Goiter, or thyroid nodules, occur in 4% to 6% of women
and in 2% of men in North America; clinical thyroid cancer,
however, occurs only in about 40 persons per million.' A
selective approach, therefore, must be used to determine
who will benefit from thyroidectomy and who can be safely
observed or treated with thyroid hormone. If this selection
process is not judicious, there will be delays in diagnosis
and an adverse outcome. Earlier diagnosis of thyroid cancer,
in the much larger number of patients with goiter, has a
considerable impact on both the recurrence and the survival
rate of patients with thyroid cancer.
Recurrent thyroid cancer after treatment may be local,
regional, or distant. Local recurrence is related both to the
invasiveness of the cancer at presentation and to the surgical
procedure used for the eradication of the malignant tissue.
Extracapsular invasion and multicentricity of the tumor
are determinant factors that also need to be considered.
Unfortunately, these factors usually cannot be ascertained
preoperatively to determine the extent of the resection. In
high-risk patients, recurrence is common (-30%), and treatment of recurrence is less successful.v' Because one cannot
precisely predict tumor behavior, we favor total thyroidectomy for most patients with thyroid cancer when this
operation can be safely performed. Just as the expression
"no acid, no ulcer" is generally accepted in patients with peptic
ulcer disease, the notion that "no tissue left, no local recurrence" may also be valid. In patients with clinical thyroid
cancer, local recurrence may occur in the residual thyroid
tissue, in the thyroid bed, or in the immediately adjacent
area, excluding lymph nodes. An insufficient thyroidectomy,
failure to remove all the thyroid, and the cancer may be
responsible for some recurrences; microscopic extension

into the adjacent tissue accounts for the remainder.
The results of thyroidectomy are well documented in the
study of 963 papillary thyroid cancer patients at the Mayo
Clinic by Grant and associates.' The risk of cancer death with
a local recurrence located outside the thyroid remnant was
much greater than with a remnant recurrence alone.
Practically, however, the exact type of this kind of recurrence, whether in residual tissue or in thyroid bed and adjacent tissues, is often difficult to determine when the
recurrent tumor has reached appreciable size. Of concern also
is that even patients judged to be at low risk have about a
15% recurrence rate, and at least 33% of these patients die
from their thyroid cancer. 1,3
Efforts to Prevent Recurrence

Preoperative Recognition of the Malignancy
Efforts to prevent local recurrence should start with the
preoperative, or at least perioperative, recognition of the
malignancy. Once it is revealed, a total or near-total thyroidectomy is the procedure of choice. It is common practice
for our surgical group to perform a meticulous, complete
lobectomy on the tumor side, and, while preparing the other
lobe, confirm the diagnosis histologically by frozen section
examination, if it is not already known to be a cancer by
fine-needle aspiration (FNA) biopsy cytology. The contralateral lobe is then removed unless there is concern about the
viability of the parathyroid glands. In the latter patients, a
small amount ('"1 em) of thyroid tissue may be left to protect the contralateral upper parathyroid gland or recurrent
laryngeal nerve at the level of the cricoid cartilage at the
posteromedial limit of the thyroid. For patients who have
thyroid cancer diagnosed by FNA, we remove the entire
thyroid gland as one piece because we do not wish to violate
the thyroid capsule.
Extra care must be taken when performing a total
thyroidectomy, because permanent hypoparathyroidism
and recurrent laryngeal nerve injuries are serious complications. 3,6 Thyroid cancers should also not be fractured during
the thyroidectomy because of possible implantation in the
thyroid bed.
181

Total thyroidectomy is usually not necessary for patients
with occult papillary thyroid cancer or minimally invasive
follicular thyroid cancer (capsular invasion only). Reoperation
for minimally invasive follicular cancer or occult papillary
carcinomas is also usually unnecessary.' The prognosis in such
patients is usually excellent. The outcome of such patients,
when compared with similar patients with papillary thyroid
cancer who underwent total thyroidectomy during the same
period, was similar, suggesting that reoperation is usually
not necessary for patients with occult or minimally invasive
tumors who have undergone lobectomy. This compromise is
mainly due to the increasing morbidity of reintervention and
because the prognosis is good without reoperation.
Reoperative thyroidectomy is often associated with
increased complications, including recurrent laryngeal nerve
injury and hypoparathyroidism. Bearhs" reported that vocal
cord paralysis occurred in 12.1% and hypoparathyroidism in
11.2% of the patients having thyroid reoperations for malignant disease. A low incidence of vocal cord paralysis (2%)
and permanent hypoparathyroidism (4%) at reoperation
has been reported by Reeve," Levin,'? Attie, 1I and their colleagues. Reeve and coworkers' experience with 408 secondary thyroidectomies during a 20-year period appears to be
associated with an improved outcome." Levin and associates'?
reported that there should be no higher complication rate
if patients were initially treated by a thyroid lobectomy,
because the remaining parathyroid glands and recurrent nerve
are in unviolated territory. Nevertheless, preoperative or
intraoperative recognition of the malignancy is important in
limiting the number of patients requiring reoperation, and
the easiest time to perform a total thyroidectomy is at the
initial operation.
Total Thyroidectomy
Despite possible increased risks of complications, we recommend a completion total thyroidectomy in most patients
with thyroid cancer when a significant amount of normal
or neoplastic thyroid tissue remains. Most papillary thyroid
cancers are multifocal. Even though multifocality has only
a minor detrimental effect on outcome, the likelihood of
malignancy in the contralateral thyroid lobe is great."
Clark reviewed his personal experience with 82 consecutive
patients who underwent total thyroidectomy.P Evaluation
of the resected thyroid showed that if less than a total, or
"near-total," thyroidectomy were performed, 31 (61%) of the
51 patients with thyroid cancer would have had malignancy
remaining in the contralateral thyroid lobe.'? Despite this
observation, in most patients residual microscopic thyroid
cancer in the remaining thyroid lobe does not recur.
Tollefsen and colleagues 13 examined the thyroid glands of
the patients who had been treated by total thyroidectomy
despite clinical involvement of one lobe and found that
5 of the 17 patients (29%) had occult thyroid carcinoma in
the other lobe. Despite this observation, only 4.6% of the
patients who initially underwent one-sided total lobectomy
proceeded to develop clinical recurrence in the opposite lobe
within 15 years. This striking difference between the local
recurrence rate in the opposite lobe in the group of patients
undergoing lobectomy (4.6%) and the six times higher
frequency of minute cancer found in the contralateral lobe
of total thyroidectomized patients has been reported by

other groups.I? Obviously, most occult thyroid cancers do
not grow, but no one as yet has been able to predict the
course of a particular patient with residual disease. Similar
observations have also been made in patients with metastatic
cervical lymph nodes. Ozaki and coworkers!" studied the
extent of regional lymph node involvement in 586 patients.
Among the 78 patients judged as stage NO during the operation, histologic examination of the prophylactically removed
lymphatic tissue revealed micrometastases in 34 cases
(43.6%). Noguchi and associates'S reported that more than
80% of patients with papillary thyroid cancer who underwent prophylactic neck dissections had occult nodal metastases. Despite this observation, clinically evident nodal
metastases develop in only about 8% of similar patients who
do not have prophylactic neck dissections.' It also appears
that papillary thyroid cancer in lymph nodes rarely metastasize to distant sites. Follicular thyroid cancers account for
about 10% of thyroid cancers, are somewhat more aggressive than papillary thyroid cancers, and usually metastasize
by the hematogenous route rather than the lymphogenous
route." Simpson and colleagues'? analyzed 1074 patients
with papillary cancer and 504 with follicular cancer treated in
Canada. They demonstrated that, from a recurrence point of
view, prognostic factors of papillary and follicular cancers
differed. They recommended total thyroidectomy for
patients with follicular thyroid cancer to facilitate postoperative uptake of radioactive iodine by possible subclinical
metastases. It is also important to emphasize, however that
microscopic distant pulmonary metastases in patients with
papillary thyroid cancer can also be ablated with radioiodine." For this reason, we recommend total thyroidectomy
and postoperative l3 l I scanning and ablative therapy for
patients with papillary thyroid cancers larger than 1.5 em in
diameter or extending through the thyroid capsule and in
high-risk patients with thyroid cancer of follicular cell origin.
Tisell and coworkers'? reported that, in 32 patients with
medullary thyroid carcinoma (MTC) who had elevated stimulated plasma calcitonin (CT) levels after thyroidectomy,
completion total thyroidectomy and meticulous nodal dissection resulted in normalization of CT levels in 28% of
these patients and a decrease in CT levels by 40% or more
in another 42%. For patients whose primary MTC invaded
beyond the thyroid gland or into lymph nodes and for
patients with markedly elevated CT levels, repeat operations
are unlikely to be curative and CT levels usually remain elevated.P Van Heerden and associates'? reported satisfactory
long-term results with a "wait-and-see" policy in the management of patients with persistently elevated CT levels but
no patients were cured. These authors recommended reintervention only in those patients with radiologically or clinically demonstrable disease. We would agree that a
wait-and-see policy is indicated when patients have had
definitive surgery-that is, total thyroidectomy, bilateral
central, and lateral neck dissections.
Thyroid-Stimulating Hormone Suppression

Ozaki and colleagues" identified 19 patients with thyroid
cancer among 743 patients with Graves' disease. These
patients had markedly invasive tumors with lymph node
Recurrent Thyroid Cancer - - 183

metastases, even though the primary tumor was small.
The clinical course in these patients suggested that thyroidstimulating antibodies playa part in the progression of these
neoplasms and that these antibodies may promote thyroid
cancer growth and invasion in a manner similar to TSH.
Pellegriti-' and Belfiore-' and their coworkers made similar
observations, but many other groups have not drawn this
conclusion."
Considerable clinical and biologic data suggest that welldifferentiated thyroid cancer cells of follicular cell origin
often respond to TSH stimulation; TSH suppression with
oral thyroxine (T4) has been a standard practice in the management of patients with thyroid cancer. To benefit, patients
should receive enough thyroid hormone to suppress TSH
secretion. Clark stated that dosage of thyroid hormone is
critical to obtain adequate reduction of TSH.2.25 Mazzaferri
and Young" studied the impact of medical (TSH suppression), surgical, and radioiodine treatment in 576 patients
with papillary thyroid carcinoma. They documented a significantly lower recurrence rate in patients who received
enough thyroid hormone to suppress TSH secretion. There
was recurrence in 40% of patients who did not receive thyroid hormone but in only 13.1% of patients who received
thyroid hormone. Unfortunately, some patients eventually
escape from the suppressive effects of this treatment." Pujol
et aF7 more recently reported a longer tumor-free period and
improved survival among 141 patients whose TSH levels
were suppressed less than 0.1 IlU/mL. Cady and colleagues"
studied 761 patients who had operable, well-differentiated
thyroid cancer. Contrary to these and most other reports,
they did not find statistically significant improvement in
survival among patients receiving thyroid hormone.i" These
authors volunteered, however, that they did not know whether
their patients were compliant in taking their thyroid medication and that their observation should not alter current
recommendations for postoperative treatment with thyroid
hormone to suppress serum TSH levels.
Overall, it appears from clinical observations and laboratory studies that TSH suppression has a positive impact, at
least on prolongation of the disease-free interval between
surgery and recurrence, if not on survival rate, as mentioned
earlier.3.27,29.}0 Therefore, all patients with differentiated
thyroid cancer of follicular cell origin should be treated
postoperatively with suppressive doses of thyroid hormone
whether or not endogenous thyroid gland secretion is sufficient
to prevent hypothyroidism. Patients with MTC and anaplastic
thyroid cancer should receive enough thyroid hormone to
keep them euthyroid, but suppressive doses are unnecessary
because these tumors do not have TSH receptors.
Adjuvant Use of Iodine 131

A long follow-up period is required to determine the effectiveness of any treatment modality in patients with welldifferentiated thyroid cancer. Many, but certainly not all,
clinicians reserve the adjuvant use of 131 1 after total or neartotal thyroidectomy for moderate- to high-risk patients with
well-differentiated thyroid cancer (i.e., for those with invasive disease and less well-differentiated cancer, for tumors>
1.5 em, and for patients> 45 years of age)." Mazzaferri
and Young" noted that the recurrence rate in patients who
were judged to be free of disease after surgical treatment

was lower when the patients were treated with radioiodine
and TSH suppression when compared with patients receiving only thyroid hormone (6.4% vs. 13.1%, respectively). In
the subgroup of these patients with small primary tumors
1 em), the results of treatment with thyroid hormone only
were similar to those after treatment with both 131 1 and TSH
suppression.
A few well-differentiated thyroid carcinomas have been
documented to concentrate radioiodine in the presence of
functional normal thyroid tissue. However, in most patients,
removal or ablation of all normal thyroid tissue is necessary
before 131 1 is effective in ablating metastatic disease. Normal
thyroid tissue generally has a 100-fold greater avidity for
radioactive iodine than does differentiated thyroid cancer.'
Before scanning, TSH values should be greater than
30 mU/mL. This degree of hypothyroidism is usually reached
6 weeks after discontinuing T4 , 2 weeks after discontinuing
triiodothyronine (T3) , or after treatment with two doses of
recombinant TSH. We recommend waiting at least 6 weeks
after thyroidectomy and treatment with T 3 to avoid the
unpleasant symptoms of hypothyroidism and to allow the
operative wound to recover from the operative edema and
tissue ischemia that may influence the uptake of 131 1 by the
tumor. T 3 treatment is then discontinued for 2 weeks, during
which time the patient is given a low-iodine diet before
scanning to increase the endogenous serum TSH level.
A scanning dose of 131 1 or a treatment dose of 131 1 is then
given. Several days prior to scanning and treatment, a blood
test is obtained for thyroglobulin (Tg) and TSH and a pregnancy test for patients who could become pregnant. Since
TSH is the best provocative test for increasing the Tg level
in patients with residual thyroid cancer of follicular cell
origin, documenting the Tg level is most important. A longer
period of hypothyroidism prior to radioiodine treatment
may influence the amount of radioactive iodine taken up by
the tumor, but patients are uncomfortable." Recombinant
human TSH is an alternative method used for scanning and
avoids hypothyroidism.Y'" It is used for patients with brain
metastases when hypothyroidism might stimulate tumor
growth.
External Radiation Therapy

External irradiation offers effective treatment for some patients
with locally invasive, inoperable, or recurrent differentiated
or poorly differentiated thyroid cancers, as well as for patients
with undifferentiated thyroid cancer. External irradiation is
used when there is no appreciable uptake of radioiodine in
patients with known microscopic or macroscopic unresectable
cancer after thyroidectomy. Such treatment is thus used in
patients when other treatments have failed. These patients
obviously have the least favorable prognosis.
Tubiana" reported that in 15 patients with MTC who
received postoperative prophylactic radiation therapy, the
elevated CT levels decreased slowly. In many patients with
MTC, serum CT levels remain elevated for years despite
the absence of clinically recurrent tumor. Virtually all these
patients have micrometastases, usually in the liver. Currently,
most studies do not support the use of external radiation for
occult disease.P One must be sure that patients with MTC
184 - -
Thyroid Gland
Measurement of Serum Thyroglobulin
FIGURE 20-1. MRl of a 65-year-old woman with anaplastic

thyroid cancer that invades the surrounding tissues.
have received definitive treatment, which includes total

thyroidectomy and bilateral central neck and ipsilateral
(unilateral disease) or bilateral modified neck dissection.
Several studies document that meticulous surgery can return
serum CT levels to normal and presumably cure patients,
especially when the CT values are slightly elevated.'?
Anaplastic carcinomas of the thyroid are locally invasive
and often metastatic (Fig. 20-1). Although some tumors can
be completely resected, most cannot. Treatment therefore
usually includes radiation and chemotherapy. Thyroidectomy
is recommended as the initial treatment when complete
resection is possible, whereas radiation and chemotherapy
are recommended when it is not. Unfortunately, the long-term
outlook is dismal, even in patients with respectable tumors.
When resection is done first, the neck and mediastinum
should be subsequently irradiated as soon as wound healing
permits. Unfortunately, in patients with undifferentiated thyroid cancer, recurrence occurs commonly, even after surgery
and radiation therapy. Some clinicians recommend the
combined use of chemotherapy and radiation therapy first
for 4 weeks, followed 2 weeks later with removal of as much
as is safely possible, and then after 2 weeks completion of
the course of radiation and chemotherapy." This is the mode
of treatment we generally recommend.
Diagnosis of Recurrence
After thyroid resection in patients with thyroid cancer
some patients develop (l) local recurrence in the thyroid
bed, (2) recurrence in the regional lymph nodes, usually
ipsilateral, or (3) distant metastases.
Tumor markers, Tg for papillary, follicular, and their
Hurthle cell variations and calcitonin for MTC, are sensitive
methods for detecting tumor persistence and recurrence.
Because normal and abnormal thyroid tissue are the only

sources of Tg in the peripheral blood, patients who have
undergone total thyroidectomy should have no circulating
Tg except that produced by residual normal thyroid tissue
or local or metastatic thyroid cancer. Measuring serum
Tg levels is most useful and sensitive after total ablation of
the thyroid gland, either surgically or after thyroidectomy
and 1311 ablation. Tg is normally present in serum in low
concentrations 60 ng/mL). Most (",95%) thyroid cancers
of follicular cell origin are sufficiently differentiated to produce Tg. Even poorly differentiated thyroid cancers usually
retain the ability to make Tg, even though the ability for
these cancers to take up iodine has been lost. LoGerfo
and associates'? reported that Tg levels in 46 members of a
healthy control group ranged from 0 to 60 ng/mL, whereas
all 10 patients with recurrent thyroid cancer had increased
Tg levels of more than 90 ng/mL. Seven of 10 patients with
known active metastatic disease had Tg levels higher than
450 ng/ml., whereas the other 3 patients with known residual but clinically inactive disease had moderately raised
levels of 100 to 260 ng/mL. Duren." Schlurnberger.'? and
their colleagues suggested that Tg levels higher than 40 to
50 ng/mL after total thyroidectomy suggest distant metastases. Tg levels are currently the most sensitive indicator of
persistent or recurrent disease after total thyroidectomy, but
Tg levels can also be helpful for following patients after
treatment with less extensive procedures such as lobectomy,
especially when preoperative Tg values are available.'?
Measurement of Tg levels in patients receiving suppressive doses of T4 provides useful information about the presence of thyroid cancer but is not as sensitive as Tg levels
after recombinant TSH or after thyroid hormone withdrawal, resulting in hypothyroidism." Tg levels in patients
with residual thyroid cancer usually increase when serum
TSH levels increase (e.g., when the patient is not receiving
thyroid hormone in preparation for a radioiodine scan).
Elevated antithyroglobulin antibody levels can produce
inaccurate Tg levels in 8% to 22% of patients.f However,
measuring messenger RNA transcripts of Tg in peripheral
blood may solve this problem.f Tumor-associated glycoprotein antigen CA 50 has also been used as a marker for
patients with persistent thyroid cancer." For patients with
MTC, determining serum CT and carcinoembryonic antigen
levels helps determine tumor persistence or recurrence.
Radioactive Iodine Scintigraphy

Radioiodine can be given as soon as 6 weeks after total
or near-total thyroidectomy. The delay following total or
near-total thyroidectomy allows endogenous blood thyroid
hormone levels to decrease and subsequently blood TSH
levels to increase. Patients can receive T3 during the first
4 weeks to avoid hypothyroidism. T 3 is used rather than T4
because it has a much shorter half-life than T 4 (T 3 half-life '"
1 day vs. T4 haf-life '" 7 days). As previously mentioned, all
thyroid hormone is then discontinued for 2 weeks and a lowiodine diet is given before scanning and or ablation. Also, as
previously mentioned, thyroid cancer rarely concentrates
enough 1311 to be seen in the presence of remaining normal
Recurrent Thyroid Cancer - -
thyroid tissue. Therefore, when the thyroid operation is less

than near- total thyroidectomy, postoperative scanning with
131
1 identifies only the remnant normal thyroid tissue. This
tissue can be ablated with about 30 mCi of 1311, but completion thyroidectomy is generally recommended. A repeat
scan can be done again after at least 6 months to document
possible metastatic disease. Such treatment wastes 1311,
which might subsequently be necessary to ablate residual
cancer. 1311 whole-body scanning is more sensitive than radiography or computed tomography scanning for detecting
pulmonary or osseous metastases. However, some poorly
differentiated thyroid cancers may produce Tg but not take
up 1311. This is especially true in patients with poorly differentiated tumors. In such patients, Tg levels may be high (>60
ng/mL), but there is no uptake of 1311. 45 Serum Tg determination and radioiodine scanning should be considered to be
complementary.tv"
Kodama and coworkers" used immunohistochemical
staining for T 4, T 3, and Tg. Tumors that were positive for T 4,
T 3, and Tg were most likely to "take up" radioiodine. In the
absence of T4 and T 3 staining, however, no prediction could
be made. We recommend scanning after total thyroidectomy
in hypothyroid patients and a follow-up scan 1 year after 1311
ablation in patients who had evidence of radioiodine uptake
outside the thyroid bed. Subsequent scanning is probably
unnecessary in low-risk patients, unless they experience clinical abnormalities or an increase in serum Tg level or, as
mentioned, unless the previous radioiodine scan was positive. Ablative therapy with 1311 should rarely be used more
frequently than at 6-month intervals, and for most patients at
I-year intervals, because leukemia is reported to be more
likely with shorter periods.
Thallium 201 scintigraphy, computed tomography,
magnetic resonance imaging (MRI), and positron emission
tomography (PET) are also used for the detection of recurrent
or metastatic thyroid carcinoma." Ohnishi and associates'?
compared MRI with thallium 201 scintigraphy in the followup of 39 patients who had undergone thyroidectomy and
modified radical neck dissection for differentiated thyroid
carcinoma. Among 51 tumor sites, 39 sites of recurrence
were detected by MRI and 24 were detected by thallium 201
scintigraphy. According to the results obtained, MRI was
more sensitive than thallium 201 scintigraphy for the detection of recurrent tumors (especially for small metastatic
nodes). In Japan, most surgeons treat patients with papillary
thyroid cancer with lobectomy and ipsilateral neck dissection so that postoperative radioiodine scanning is usually not
useful. We recommend computed tomography (without contrast material) or MRI scanning, and sometimes sestamibi or
thallium scanning, for patients who are at high risk for
recurrence and have residual thyroid tissue or who have no
uptake on radioiodine scanning and for patients who have
elevated serum Tg levels and negative radioiodine scans.
Incidence of Various Kinds of

Recurrence and Management
Despite the satisfying results of treatment modalities and
favorable clinical course of most patients with differentiated
185
thyroid carcinomas, approximately one third of the patients

who develop recurrent thyroid cancer, including low-risk
patients, eventually die from the disease.v'? Among 74 patients
with recurrent differentiated thyroid cancer studied retrospectively by Coburn and colleagues.l" 53% of recurrences were
regional, 28% were local, 13% were in the form of distant
metastases, and 6% were combined locoregional metastases.
This anatomic distribution is consistent with other investigations.v-? The site of recurrence appears to influence the
prognosis. Thus, Rossi and coworkers" reported that treatment
was successful in 73% of patients with nodal recurrence but in
only 53% of patients with local recurrence and 25% of patients
with distant metastases. Coburn and associates'? reported
similar findings. All of their patients with recurrent disease
and distant metastases died, regardless of treatment. Kukkonen
and colleagues-' reported that 11 of 20 patients (55%) with
recurrent papillary thyroid cancer in the neck died and 8 of
11 patients (73%) with distant metastases died.
However, other studies reported long-term survival in
patients with recurrent metastatic well-differentiated thyroid
cancer, especially when the metastatic foci concentrated
1311. 6,54 Different survival rates have also been reported in
patients whose recurrence was detected scintigraphically
versus those diagnosed clinically. The mortality or persistence of the recurrence after treatment was significantly
higher in clinically diagnosed cases in contrast with scintigraphically detected cases." Obviously, when larger tumors
are present, they are more difficult to remove and probably
are more likely to have metastasized. Also, tumors that take
up radioiodine are better differentiated and, therefore, are
more likely to be less aggressive; most of these patients can
be successfully treated with radioiodine.
The site and predisposition for recurrence vary in different types of thyroid cancer. For example, of 168 of our patients
with differentiated thyroid cancer, 8 patients with papillary
cancer and 3 with follicular thyroid cancer experienced
recurrent cancer in the neck. In contrast, only 2 patients with
papillary cancer and 5 patients with follicular cancer experienced distant metastases."
Wu and coworkers'" also reported that patients with
papillary thyroid cancer are more likely to die of recurrent
central neck disease and those with follicular cancer from
distant metastases. Patients who develop recurrent cancer in
lateral cervical lymph nodes are easier to treat successfully
than those who develop recurrent cancer in the central neck,
because the operative field is in unviolated tissues.
Reoperative central dissections are often tedious and place
the parathyroid glands and recurrent laryngeal nerve at risk."
Lung metastases from differentiated thyroid cancers have
been shown to accumulate more radioactive iodine than bone
metastases, so that patients with lung metastases respond
better to radioiodine therapy than those with bone metastases. This is especially true for micrometastases in the lung.
For patients with isolated (Fig. 20-2) or only several bone
metastases, surgical resection followed by radioiodine treatment is recommended. If no uptake of 1311 occurs, external
radiation therapy usually relieves pain, decreases the risk of
fracture, and is occasionally curative.V-?
Schlumberger and associates.V as mentioned, also
documented that 1311 is more effective for treatment of pulmonary micrometastases than for palliation of macronodules.

micrometastases can frequently be ablated after total thyroidectomy with postoperative 1311 therapy, especially in
young patients. Resection of recurrent disease is most successful for nodal metastases, but cure and long-term palliation
can also be obtained by resection of central neck recurrence as
well as isolated distant metastases followed by 1311 ablation.
Palliative resection is also indicated to avoid progression of
central neck and mediastinal disease. In patients who have no
1311uptake in their tumors and who are Tg negative, a redifferentiation trial with retinoids has been proposed as a treatment
option by Simon and colleagues, but overall the effects have
unfortunately not proven to be very helpful.60
Summary
FIGURE 20-2. Radiograph of the right femur of a 60-year-old

woman with follicular cancer metastasis.
This finding supports the concept of detecting and treating

recurrent or persistent thyroid cancers before they become
clinicallyevident. Such tumors can only be detected in patients
who have been treated by total thyroidectomy and receive
radioiodine scans. Recurrent cancer in regional lymph nodes
is best detected by ultrasound examination and treated by
modified radical neck dissection. Local recurrence in the
central neck should be treated surgically and with postoperative 1311 ablation and TSH suppression therapy. External
radiation treatment is helpful when tumors cannot be completely removed. As mentioned, however, local recurrence
carries a poorer prognosis compared with regional lymph
node metastases. Reoperations in the form of total thyroidectomy for patients who have already had bilateral procedures
or debulking of the tumor masses are also associated with a
higher morbidity rate and subsequent recurrent disease. For
this reason, it is essential to perform a meticulous, complete
hemithyroidectomy for all unilateral nodules that might be
cancerous, with removal of any possible involved nodes in
the central neck. Close follow-up for recurrent disease is also
indicated because it is easier to cure patients and resect small
rather than large metastases.
Thus, initial treatment with total or near-total thyroidectomy, radioiodine scanning, and postoperative ablation
with 131 1 and TSH suppressive treatment appear to decrease
the incidence of recurrent thyroid cancer. 18,54 Distant
Despite the favorable clinical course of most patients with

differentiated thyroid carcinoma, nearly one third of the
patients who experience recurrent thyroid cancer eventually
die from this disease. Therefore, every effort should be made
to prevent recurrence, including (1) early diagnosis and treatment of the disease; (2) complete removal of the tumor at
the initial operation; (3) total thyroidectomy, ipsilateral
central neck dissection, and ipsilateral therapeutic modified
radical neck dissection when indicated and when this can be
done safely; (4) adjuvant use of 1311 therapy, particularly in
high-risk patients postoperatively; (5) TSH suppression
therapy; and (6) selective use of external radiation therapy
in patients with unresectable cancer. For patients with MTC,
bilateral central and lateral neck dissection are necessary.
Blood Tg and calcitonin level determinations are sensitive
techniques for detecting recurrent or persistent subclinical
disease in patients with tumors of follicular and parafollicular cell origin, respectively. 1311 scintigraphy, ultrasonography,
computed tomography, MRI, and PET are helpful, as are
regular and long-term follow-up physical examinations.
Early diagnosis and treatment of recurrent or persistent disease appear to improve survival; recurrence with definitive
surgery or other surgery improves survival.
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48. Lips P, Comans EF, Hoekstra OS, et al. Positron emission tomography
for the detection of metastases of differentiated thyroid carcinoma.
Neth J Med 2000;57: 150.
49. Ohnishi T, Noguchi S, Murakami N, et al. Detection of recurrent thyroid cancer: MR versus thallium-201 scintigraphy. Am J Neuroradiol
1993; 14:1051.
50. Coburn M, Teates D, Wanebo HJ. Recurrent thyroid cancer: Role of
surgery versus radioactive iodine (1-131). Ann Surg 1994;219:587.
51. Davies C. Surgery of thyroid cancer. In: Lynn J, Bloom SR (eds),
Surgical Endocrinology. Oxford, England, Butterworth/Heinemann,
1993, p 254.
52. Young RL, Mazzaferri EL, Rahe AJ, et al. Pure follicular thyroid carcinoma: Impact of therapy in 214 patients. J Nucl Med 1980;21:733.
53. Kukkonen ST, Reijo KH, Kaarle OF, et al. Papillary thyroid carcinoma:
The new, age-related TNM classification system in a retrospective
analysis of 199 patients. World J Surg 1990;14:837.
54. Grant MD, Hay MB, Gough IR, et al. Local recurrence in papillary
1988;104:954.
55. Diiren M, Ertem M, Biikey Y, et al. [Thyroid carcinoma: An analysis of
a personal series.] Ulusal Cerrahi Dergisi 1996;12:43.
56. Wu HS, Young MT, Ituarte PH, et al. Death from thyroid cancer of
follicular cell origin. J Am Coli Surg 2000; 191:600.
57. Hamming JF, van de Velde CJH, Fleuren GJ, et al. Differentiated
thyroid cancer: A stage-adapted approach to the treatment of regional
lymph node metastases. In: Hamming JF (ed), Differentiated Thyroid
Cancer: Current Considerations on Diagnosis and Surgical Treatment.
Leiden, Netherlands, Drukkerij Groen BV, 1988, P 65.
58. Schlumberger M, Tubiana M, de Vathaire F, et al. Long-term results of
59. Marocci C, Pacini F, Elisei R, et al. Clinical and biological behaviour
of bone metastases from differentiated thyroid carcinoma. Surgery
1989;106:960.
60. Simon D, Koehrle J, Reiners C, et al. Redifferentiation therapy with
retinoids: Therapeutic option for advanced follicular and papillary thyroid
carcinoma. World J Surg 1998;22:569.
Thyroidectomy
Sten Lennquist, MD, PhD
The Accurately Performed

Thyroidectomy: A Challenge
with a Bad Response
Thyroid surgery has been and always will be the most
common endocrine surgical operation. Some subspecialists in
endocrine surgery are performing only thyroid and parathyroid
operations. Even in specialized centers in which the rarer
endocrine tumors (adrenal and gastrointestinal) constitute an
appreciable part of the workload, thyroid gland operations
are still the most common procedures.
An accurately performed operation on the thyroid gland
requires both experience and technical ability. In my experience, including more than 20 years of highly specialized
endocrine surgery in a large university hospital, a good
thyroid operation presents a greater challenge and requires
more technical precision and skill than an adrenalectomy or
removal of any gastrointestinal endocrine tumor. Many other
experienced endocrine surgeons are of the same opinion.
The thyroid operation is considered by many to be at the zenith
of endocrine surgery; the surgeon who can perform a good
thyroidectomy can, with little additional training, handle
most of the other operations within this field, because the
technique required is much the same.
With this background it is astonishing that relatively little
effort is put into teaching the art of thyroid surgery. The main
reason for this may be that it is more glamorous to teach and
talk about rare endocrine tumors (that most general surgeons
will never see) than to teach "everyday routine work."
Teaching about proper surgical technique is essential if
we, as surgeons, are to avoid complications. When thyroid
operations are performed without sufficient interest, training, or experience, the incidence of preventable complications increases. In many reported series, the incidence of
complications is high: figures such as 5% for persistent
recurrent laryngeal nerve injuries after operations for benign
thyroid lesions have been reported, I whereas it has been documented repeatedly that the incidence of such complications
can be close to 0% or at least less than 1%.2-5 Figures for
188
persistent hypoparathyroidism of 20% or more after bilateral

operations have been reported," whereas it has also been
shown that with careful technique this figure should be less
than 1%.2-5,7 Of concern is that the figures in unreported
series are even higher," Both hypoparathyroidism and recurrent laryngeal nerve injury cause disability and suffering for
patients.
One of the greatest responsibilities for endocrine surgeons
today is to make these poor results a thing of the past by
designing appropriate training programs that establish uniform protocols for accurate reporting of results and uniform
guidelines and standards for performing these operations.
General Principles
The following principles apply to all thyroid operations:
1. Good exposure of the thyroid gland is essential for
good results.
2. No operation should be performed on the thyroid
gland without proper identification of the anatomic
structures.
3. Bleeding can and should be kept to a minimum.
4. Diathermy (even bipolar) should be avoided in the
area around the laryngeal nerves.
Optimal Access
As in all operations, optimal access to the entire operative
field is one of the keys to success. It is a misconception,
however, that good exposure means a long incision. Good
exposure can be achieved by a number of simple procedures,
which are described later. Time and effort spent learning
these techniques are repaid many times during the operation.
Identification of the Anatomic Structures

Another misconception is that operations in this area could
or even should be done without proper identification of the
anatomic structures. It is hoped that this way of operating
Thyroidectomy - - 189
has been abandoned today. As late as 1976, however,
published recommendations could be found that advocated
that "the dissection at no time should be directed at identification and uncovering of the recurrent laryngeal nerve," I and
identification of the parathyroid glands was described as "an
erroneous guesswork implying a risk of inducing hypoparathyroidism."} It is still possible to find surgeons who continue to follow these principles; this is difficult to understand
because the general principle in surgery is that it is "always
better to see what you are doing." It is generally considered
to be impossible to perform a safe, complete lobectomy
without identification of the anatomic structures.
The argument that time is saved by not identifying the
anatomic structures is also based on a false premise: a surgeon who can see what he or she is doing operates not only
more safely but also faster than a surgeon who does not
know precisely where the parathyroid glands or recurrent
nerves are positioned."
Minimal Bleeding
My recommendation is that suction should not be used
routinely during thyroid surgery. First, the surgeon who
does not use suction dissects gently and precisely, with
meticulous ligation of vessels. Second, frequent suctioning
may injure the parathyroid glands and the nerves.
Restricted Use of Diathermy

The true state of the art of thyroid surgery can best be judged
by the way in which the recurrent laryngeal nerves are
handled. This is where the truly skilled thyroid surgeon can
be separated from the others. The process of meticulous
dissection and ligation of the vessels in Berry's ligament
requires absolute precision. It is a good technical exercise
for the whole field of endocrine surgery and should be done
properly. This is the only safe way to avoid injuries to the
recurrent laryngeal nerve.
description of the additional maneuvers needed for a resection or total thyroidectomy.
Access to the Gland

Dressing of the operation field, lines of incision, and the
technique of freeing and mobilizing the thyroid gland are
shown in Figures 21-1, 21-2, and 21-3.
After these first steps, it is a matter of personal preference whether to start the free dissection of the lobe by the
lateral (starting at the recurrent laryngeal nerve and inferior
thyroid artery) or the cranial (starting with the superior thyroid artery) approach. Both are used by experienced thyroid
surgeons, but I prefer to start with the lateral approach,
which I also use when teaching. This approach provides
good mobilization of the thyroid lobe at an early stage of
the operation and, therefore, facilitates dissection of the
superior pole vessels. It also provides better exposure of
the external branch of the superior laryngeal nerve. When
the goiter or tumor is large, however, it can be difficult to
identify the inferior thyroid artery and recurrent laryngeal
nerve without first mobilizing and dividing the superior pole
vessels, so in these cases I start superiorly.
The Recurrent Laryngeal Nerve and the

Inferior Thyroid Artery
The best way to identify the recurrent laryngeal nerve is to
stand on the opposite side of the patient, with the patient
rotated toward you, and apply firm traction to the thyroid
lobe, pulling it upward and toward the midline, putting the
tissues lateral to the thyroid under tension. This traction is
best applied with a gauze sponge held in the surgeon's hand.
Passing grasping instruments or sutures through the thyroid
Resection or Complete
Lobectomy?
A complete thyroid lobectomy and isthmectomy should be
performed for all unilateral nodules, for several reasons.
First, if additional surgery is required, the field of a previous
operation should be avoided because it makes reoperation
more difficult and considerably increases the risk of complications. This can easily happen because neither fine-needle
aspiration cytology nor frozen section will always give the
correct histopathologic diagnosis. Second, if one accepts
the concept that operations on the thyroid gland should be
performed only with proper identification of the anatomic
structures, complete hemithyroidectomy is no more difficult
than resection and may be even simpler and more straightforward." In fact, it can be accomplished with less bleeding
and more precision. In most training programs in endocrine
surgery, the first step should be to learn how to perform a
complete lobectomy followed at a later stage by a resection.
The technique of hemithyroidectomy is described in the
following text in detail, step by step, followed by a short
FIGURE 21-1. The incision is made two fingerbreadths above the

clavicles and 3 to 3.5 cm on each side of the midline, which is
sufficient for full access to the thyroidgland. If there are metastatic

lymph nodes in the lateral compartment of the neck, the line of
incision should be somewhat extended, but vertical incisions
should be avoided. (From LennquistS. Surgical strategyin thyroid
carcinoma. Acta Chir Scand 1986; 152:321.)
190 - -
Thyroid Gland
FIGURE 21-2. A, The subcutaneous fat and platysma muscle are divided in the line of incision and dissected free from the underlying
investing fascia of the neck and the anterior jugular veins. To facilitate the later dissection in the midline, it is important that the free
dissection of the platysma is extended in a cephalad direction to well above the thyroid cartilage (B) and in a caudal direction to the substernal notch (C). (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand 1986;152:321.)
gland is less effective and may cause bleeding from the

thyroid capsule or possible spreading of malignant cells.
During this traction, the fascia between the thyroid gland
and the common carotid artery can be opened by a combination of sharp and gentle blunt dissection with a hemostatic forceps, starting laterally. The dissection should always
be parallel, rather than perpendicular, to the anticipated
course of the nerve. The neurovascular intersection (where
the inferior thyroid artery crosses the recurrent laryngeal
nerve) should be identified (Fig. 21-4), and a loop placed
around the trunk of the inferior thyroid artery. Slight tension
applied to this loop facilitates further gentle dissection around
the recurrent laryngeal nerve. This loop should be removed
when the dissection has been completed. The inferior thyroid
artery should be ligated not truncally but peripherally on the
capsule of the thyroid gland to preserve the vascular supply

to the parathyroid glands (see Fig. 21-4).
The Superior Laryngeal Nerve and the

Superior Thyroid Artery
As mentioned, the dissection around the superior thyroid
artery is made considerably easier by the procedure just
described: incision of the fascia in the midline as far as the
sternal border and previous lateral mobilization of the thyroid
lobe. After these procedures are completed, one can place
a finger behind the superior pole and rotate it upward.
Transverse division of the muscles is rarely necessary.
The most critical structure to keep in mind when dividing
the vessels of the superior pole is the external branch of the
FIGURE 21-3. A, After division of the investing fascia in the midline, the fascia covering the thyroid gland is carefully incised so that the
surface of the gland is clearly seen. It is most important to obtain the correct plane of cleavage. The thyroid lobe in most cases can easily
be mobilized and rotated medially and upward with a sweeping finger movement. B, During this mobilization, care must be taken not to
tear the medial thyroid vein, which is ligated and divided. (From Lennquist S. Surgical strategy in thyroid carcinoma. Acta Chir Scand
1986;152:321.)
Thyroidectomy - -
191
FIGURE 21-4. The first step after mobilization of the thyroid lobe
is to identify the recurrent laryngeal nerve (1) and the inferior thyroid artery. As soon as the nerve is identified, a thread is pulled
around the trunk of the inferior thyroid artery (2). Slight tension on
this thread facilitates further dissection to free the nerve. After free
dissection of the nerve, this thread should be removed and the
artery ligated, not truncally but peripherally. Otherwise, the vascular supply of the parathyroid glands (3) will be compromised.
(From Lennquist S. The thyroid nodule: Diagnosis and surgical
treatment. Surg Clin NorthAm 1987;67:221.)
superior laryngeal nerve. This nerve branch has been referred

to as the "neglected" nerve in thyroid surgery. Injuries to it
may easily be overlooked because they are difficult to diagnose at laryngoscopy and because the initial symptoms are
often minimal and regarded as "natural postoperative voice
disturbance without injury to the recurrent laryngeal nerve."
Jansson and Tisell lo performed electromyographic studies
in an unselected series of patients after thyroid surgery
and reported that more than 20% had persistent symptoms
(e.g., voice exhaustion and impaired ability to sing) that were
confirmed by electromyography as being caused by injury to
the external branch of the superior laryngeal nerve. These
symptoms can be especially troublesome to singers and
professional speakers. Preservation of this nerve deserves
proper attention.
In anatomic and clinical studies of the superior laryngeal
nerve, with special reference to its anatomic relations to the
pharyngeal constrictor muscle, we found that in 20% of cases
the distal part of the nerve was entirely covered by fibers of
that muscle. I I In these cases, the nerve could not be identified without intramuscular dissection, which probably does
more harm than good. On the other hand, 20% of the nerves
that passed lateral to the pharyngeal constrictor muscle took
a perilous course, partly lateral to the superior thyroid artery
and its branches.
I recommend that the tracheothyroid space always be
carefully dissected and that the superior thyroid artery and
its branches be skeletonized before division. When the superior laryngeal nerve is not identified during this procedure,
identification by dissection into the pharyngeal constrictor
muscle is not recommended. Our technique is shown in
Figure 21-5. This does not take long, and it lessens the risk
of injuring the external branch of the superior laryngeal nerve.
In this way, many patients can be spared the unnecessary
FIGURE 21-5. Technique for preservation of the external branch

of the superior laryngeal nerve. A, A hemostatic forceps is placed
on the thyroid part of the superior thyroid artery (4). B, During
traction on this forceps caudally and laterally, the cricothyroid
space is opened up with another forceps so that the external branch
of the superior laryngeal nerve (5) can be identified and dissected
free. C, The superior pole vessels can now be ligated easily without risk of injury to the nerve. (From Lennquist S. The thyroid
nodule: Diagnosis and surgical treatment. Surg Clin North Am
1987;67:222.)
192 - -
Thyroid Gland
inconvenience and discomfort of vocal disturbance and loss

of singing ability.
When the vessels of the superior pole have been ligated
and divided, the pole is mobilized, and the lobe can be
retracted medially and downward and inspected in its
entirety from the lateral side.
The Parathyroid Glands

Even though hypoparathyroidism does not occur after unilateral thyroid operations, one should treat every parathyroid
as if it were the last, because one never knows whether the
patient may require a thyroid operation on the other side.
This means that one should always attempt to identify both
parathyroid glands on both sides. Some parathyroid glands
are present in ectopic locations so that all parathyroid glands
will not be identified in all patients (see Chap. 38). The
lower gland, for example, is frequently situated in the thymus.
Routine exploration of the thymus to find such a gland is not
recommended because it might devascularize the parathyroid
glands. When neither parathyroid gland can be identified
during thyroid lobectomy, the thyroid capsule must be scrupulously examined to ensure that the missing gland is not
removed accidentally.
It has long been thought that the vascular supply of the
parathyroids comes only from the inferior or superior thyroid
artery, or both. This is not true. We used laser Doppler flowmetry to study the parathyroid circulation during thyroid
surgery" and found that an appreciable part of the vascular
supply to the parathyroid glands comes from the small vessels in the thyroid capsule, without apparent communication
with the superior or inferior thyroid arteries. Using meticulous technique, most of these vessels can be preserved by
dissecting them downward, even during complete removal
of the thyroid gland. Truncal ligation of the inferior thyroid
artery should be avoided and should be done only when
technical problems arise; otherwise, it should be divided
peripherally to the neucovascular intersection on the thyroid
capsule (see Fig. 21-7 A). The procedure for preservation of
the parathyroid glands is shown in Figure 21-6.
In some patients, it is impossible to dissect the parathyroid
gland free from the thyroid capsule with an adequate vascular supply. Such glands should be removed, cut into small
pieces with a microsurgical knife, confirmed histologically,
implanted into an adjacent muscle, and marked by a nonabsorbable suture. In the case of an aggressive tumor with
the potential for recurrence, the parathyroid gland should be
autotransplanted outside the operation field.
Final Dissection of the Recurrent

Laryngeal Nerve
As the thyroid lobe is rotated further medially, the recurrent
laryngeal nerve should be systematically and carefully dissected free from the thyroid gland (Fig. 21-7A to C). There
are many variations in the anatomic relationship among the
recurrent laryngeal nerve, the inferior thyroid artery and its
branches, and the thyroid gland. The nerve may run in front
of or behind the inferior thyroid artery and its branches, and
more than 30 variations have been described, sometimes differing on the two sides. In 40% to 80% of cases, the nerve
B
FIGURE 21-6. Technique for preservation of the parathyroid
gland. A, The upper parathyroid gland (3) is gently loosened from
the thyroid capsule and dissected downward, with preservation of

its vascularsupply. B, The figurealso illustrates the rather common
branching of the recurrent laryngeal nerve (I) immediately after
the neurovascular intersection where the nerve passes the inferior
thyroid artery (2). (From Lennquist S. Surgical strategy in thyroid
carcinoma. Acta Chir Scand 1986;152:321.)
may branch into two or more parts before it enters the larynx
(see Fig. 21-6). This branching may be below the level of
the thyroid, which further increases the number of possible
variations. In about 1% of patients, the recurrent laryngeal
nerve on the right side is nonrecurrent and runs directly
from the cervical vagus to the larynx. It may also be transposed among branches of the inferior thyroid artery, resulting in its transposition to a level anterior to the wall of the
trachea. Consequently, there is no "safe" level at which the
surgeon can maneuver without first identifying the recurrent nerve. It is clear that the recurrent laryngeal nerve must
be identified and dissected precisely (see Figs. 21-6 and
Fig. 21-7).
After the thyroid lobe has been separated from the tracheal wall, the isthmus is divided at the point where it
enters the opposite lobe, and the remaining thyroid tissue is
continuously sutured.
Thyroidectomy - - 193
Using intraoperative scintigraphy, we have shown that
one of the most common areas in which there is residual
uptake of iodine is the site of the pyramidal lobe. 13 This indicates that this structure is difficult to identify and remove
completely. Good access to the pyramidal lobe by extension
of the midline incision between the strap muscles is, therefore,
important. The pretracheal fascia (anterior superior suspensory
ligament) and all thyroid tissue associated with it should be
excised, together with the thyroid gland.' Care should be taken
to stay medial when mobilizing the pyramidal lobe and to
stay caudal to the cricothyroid muscle when dividing the
anterior superior suspensory ligament to avoid injury to the
external branch of the superior laryngeal nerve.
Closing the Wound

Using drains after thyroidectomy cannot replace good hemostasis and are of little or no use if severe postoperative bleeding occurs. To reduce or remove a small hematoma, however,
a drain can sometimes be useful. If a drain is used, it should
be a small silicone drain with a closed, passive evacuation
system. Active suction fails to increase the evacuation capacity and may injure the recurrent laryngeal nerve.
The strap muscles are reapproximated, as is the platysma,
with interrupted or continuous absorbable sutures. The skin
may be closed by subcuticular suture, or with the use of
special broad clips removed after the first or second day,
and Steri-Strips placed. Whichever technique is used, it
should be done carefully; scars in this area can and should
be almost invisible.
Resection of the Opposite Side

The only difference between thyroid lobectomy and thyroid
resection, if or when this is indicated, should be that the final
separation of the thyroid lobe from the wall of the trachea is
not done. Identification of the anatomic structures and the
thorough mobilization of the thyroid lobe are the same.'
Mobilization of the thyroid lobe by the technique just mentioned enables adjustment of the remnant to the optimal size
and makes a safe resection possible, with minimal risk or
complications.!':'"
C
FIGURE 21-7. Technique for final free dissection of the inferior
laryngeal nerve (I). A, The branches of the inferior thyroid artery
(2) are individually ligated with absorbable sutures and divided;
in this way, the lobe can be successively separatedfrom the nerve.

Before entering the laryngeal cartilage, the superior laryngeal
nerve temporarily diverges in a ventral direction and then turns
back toward its entrance. This "knee" of the nerve is one of the
most critical points of the dissection. In the final separation of the
thyroid lobe from the tracheal wall,the fine paratracheal vessels (6)
in the ligament of Berry have to be ligated before division. At this
closerangeto the nerve, diathermy shouldnotbe used. C, Afterdivision of the ligament of Berry, the thyroid gland can be separated
from the tracheal wall with a sharp knife. The thyroidcapsulenow
can be removed intact, and no residual tissue is left on the tracheal
wall (8) or at the nerve entrance (7). 9 = carotid artery; 10 = vagal
nerve; II = internal jugularvein. (FromLennquist S. Surgical strategy in thyroid carcinoma. ActaChir Scand 1986;152:321.)
B,
Total Thyroidectomy
Total thyroidectomy in reality is two hernithyroidectomies.P'" Because every surgeon who deals with the thyroid
gland should be able to perform a safe, complete lobectomy,
he or she should also be able to perform a safe complete
bilateral hemithyroidectomy or total thyroidectomy.'
When performing a total thyroidectomy, I recommend an
en bloc procedure, which means that the hemithyroidectomy
is continued on the opposite side without dividing the
isthmus, and the whole thyroid is removed as one piece
(together with the lymph nodes in the central compartment
of the neck if there are any lymph node metastases). This
technique has been described in detail elsewhere.t->!?
Dissection of the lymph nodes in the lateral compartment of
the neck and the management of invasive tumors are
described in Chapter 22.
194 - -
Thyroid Gland
Goiters or Thyroid Tumors in the

Mediastinum
It is possible to remove most intrathoracic goiters and
thyroid tumors through a cervical incision. If it is difficult
to mobilize the thyroid lobe from the mediastinum, several
procedures, discussed next, may help.
TRANSVERSE DMSION OF THE STRAP MUSCLES
When it is necessary to divide the sternohyoid or sternothyroid

muscles, or both, this should be done in the top of the wound
to avoid scar fixation and to denervate less muscle, because the
ansa hypoglossal nerve innervates these muscles inferiorly.
DMSION OF THE SUPERIOR THYROID ARTERY
One should divide the superior thyroid artery and veins

because this makes it easier to pull the lobe upward.
DMSION OF THE ISTHMUS
Division of the isthmus further facilitates the pulling of the

goiter upward from the mediastinum.
T INCISION
Although making an inferior T in the Kocher transverse

collar incision is rarely necessary, in some patients it avoids
a mediastinotomy and also increases the preparedness for a sternal split if excessive bleeding were to occur when mobilizing
the substernal mass.
If these procedures, done by an experienced surgeon, are
insufficient to mobilize the thyroid from the mediastinum, I
do not recommend dividing or morselizing the tissue to get
it up, as has been advocated by others. This is not good surgery, and in these patients a median sternotomy should be
done. The risks and discomforts of median sternotomy have
been exaggerated. The procedure is performed daily in
thousands of patients worldwide for cardiac operations and
can be done with minimal morbidity. 18
Some patients have pain after sternotomy because it is
not done properly. Some surgeons believe that performing a
partial split is less dangerous and causes less pain. This is
wrong. Partial sternotomy means breaking the sternocostal
cartilage when opening the chest. This causes considerable
postoperative pain. The technique for mediastinal exploration is described elsewhere."
Summary
Thyroid surgery requires experience and recogrution of
the anatomy, especially the parathyroid glands and recurrent,
and external laryngeal nerves. The risk of complications
during thyroid operations should not exceed 1% to 2%.

Complication rates higher than 5% suggest that the surgeon
does not have sufficient training or interest in thyroid
surgery and should improve his or her training or refer the
patients elsewhere.
REFERENCES
I. Perzik SL. The place of total thyroidectomy in the management of
patients with thyroid disease. Am J Surg 1976;132:480.
with differential thyroid cancer. Ann Surg 1982;196:361.
3. Smeds S, Madsen M, Lennquist S, et al. Evaluation of preoperative
diagnosis and surgical management of thyroid tumors Acta Chir Scand
1984;150:513.
4. Total thyroidectomy in the treatment of thyroid carcinoma. In:
Thompson NW, Vinik AU (eds), Endocrine Surgery Update. New York,
Grone & Stratton, 1983.
5. Thompson NW. The resection therapy of carcinoma of the thyroid.
Surg Rounds 1984;100.
6. Crile G Jr. Changing trends and results in patients with papillary carcinoma of the thyroid. Surg Gynecol Obstet 1971;131:460.
7. Andaker L, Johansson K, Lennquist S, Smeds S. Surgery for hyperthyroidism: Hemithytoidectomy plus contralateral resection or bilatera resection? A prospective randomized study with regard to
postoperative complications and long-term results. World J Surg
1992;16:765.
8. Scandinavian Surgical Society. Multicenter study on thyroid carcinoma. Proceedings of the Scandinavian Surgical Society, Division of
Endocrine Surgery, Stockholm, 1991.
9. Lennquist S. Total Thyroidectomy with Safe Preservation of the
Laryngeal Nerves and Parathyroid Glands. Chicago, American College
of Surgeons Film Library, 1991.
10. Jansson S, Tisell LE. Partial superior laryngeal nerve (SLN) lesions
before and after thyroid surgery. World J Surg 1988;12:526.
II. Lennquist S, Cahlin C, Smeds S. The superior laryngeal nerve in
thyroid surgery. Surgery 1987;102:999.
12. Ander S, Johansson K, Lennquist S, Smeds S. Human parathyroid
blood supply determined by laser Doppler flowmetry. World J Surg
1994;18:417.
13. Lennquist S, Persliden J, Smeds S. The value of intraoperative scintigraphy as a routine procedure in thyroid carcinoma. World J Surg
1988;12:586.
14. Lennquist S, Smeds S. The hypermetabolic syndrome hyperthyroidism. Surg EndocrinoI1991;9:127.
Acta Chir Scand 1986;152:321.
16. Lennquist S. The thyroid nodule: Diagnosis and surgical treatment.
Surg Clin North Am 1987;67:213.
17. Lennquist S. The laryngeal nerves in thyroid surgery. In: van
Heerden J (ed), Common Problems in Endocrine Surgery. Chicago,
Year Book, 1988, p 123.
18. Lennquist S, Andaker L, Lindvall B, Smeds S. Combined cervicothoracic approach in thymectomy. Acta Chir Scand 1990;156:53.
Management of Regional
Lymph Nodes in Papillary,
Follicular, and Medullary
Thyroid Cancer
J. F. Hamming, MD, PhD. J. A. Roukema, MD, PhD
The surgical management of patients with thyroid cancer

continues to be a challenge. Over the last 3 decades surgeons
have debated about the "best" management of patients with
this disease. Randomized trials concerning the surgical
treatment are nonexistent, because execution of such studies
is hampered by the low incidence of thyroid carcinoma and
the relatively indolent behavior. Treatment results are based
on retrospective analysis of mostly heterogeneous groups
of patients. The discussion section in publications almost
invariably leads to the statement that the proposed and presented treatment modalities are to be preferred, but in fact
only tentative conclusions can be drawn. Proponents of more
extensive surgery can find theoretical arguments, and proponents of more conservative management refer to the lack of
proven benefit of the aggressive approach. This is applicable
to the extent of thyroidectomy as well as the approach toward
the management of regional lymph nodes.' Nevertheless,
progress has been made, and there is a tendency toward more
selected management for the different types of thyroid cancer.
Differences in opinion toward the management of regional
lymph node metastases of thyroid cancer concern mainly papillary, follicular, and medullary thyroid cancer. The treatment
of lymph node metastases of other less frequently occurring
types of thyroid cancer is not discussed in this chapter.
Well-differentiated, papillary, and follicular adenocarcinomas arise from follicular cells and are the most common
types of thyroid cancer. Medullary carcinoma represents
about 7% of all thyroid cancers, but 15% of deaths due to
thyroid cancer. It is also considered to be a differentiated form
of thyroid carcinoma, but it originates from parafollicular, or
C, cells. Its biologic behavior is somewhat more aggressive
than papillary or follicular thyroid cancer.
The prognosis of patients with thyroid cancer correlates
with histologic type, extrathyroidal growth of the primary
tumor, and the presence of distant metastases at the time of
diagnosis. The prognosis of patients with intrathyroid

papillary cancer differs only slightly from the average life
expectancy. On the other hand, patients with distant metastases of medullary carcinoma have a short life expectancy.
Patient-related factors such as age and-to a lesser extentgender are also important in assessing prognosis in an individual patient with thyroid cancer.
The natural history of the three types of differentiated
thyroid carcinoma differs from each other. Papillary cancer
spreads predominantly to the regional lymph nodes. The
influence of regional lymph node metastases on prognosis
in patients with papillary cancer is questionable. Distant
metastases occur in about 10% of patients and predict an
unfavorable prognosis. Follicular cancer mostly spreads to
distant sites; lymph node metastases are far less common
than in papillary carcinoma and, when present, indicate a
worse outcome. Medullary cancer frequently metastasizes
to the regional lymph nodes and the presence of nodal
involvement predicts a worse prognosis. Distant metastases,
especially to the liver, are common.
Although total thyroidectomy in patients with medullary
cancer is widely accepted, the necessity of total thyroidectomy in all cases of papillary and follicular cancer remains
controversial. Radical neck dissection for lymph node
metastases in patients with differentiated thyroid cancer is
no longer considered necessary. Modified radical neck
dissection, also referred to as modified neck dissection, is
usually recommended for patients with regional lymph node
metastases due to papillary, follicular, and medullary cancer.
For most patients with medullary cancer, standard modified
neck dissection is advocated. Since the influence of regional
lymph node metastases on the prognosis of patients with
papillary cancer is debated, the benefit of prophylactic or
elective neck dissection in these patients has not been established. The "best" management of lymph node metastases
195
196 - -
Thyroid Gland
is based on retrospective series and tradition. In this chapter

we describe the rationale and technique of modified neck
dissection for papillary, follicular, and medullary thyroid
cancer. Although there are no major disagreements about the
technique of modified neck dissection, the rationale and
indications for prophylactic neck dissection remain controversial. To formulate a sensible approach for the treatment
of patients with thyroid cancer metastatic to cervical and
mediastinal lymph nodes, the lymphatic drainage and the
incidence and localization of nodal metastases at the time of
diagnosis must also be considered.
Lymphatic Drainage
of the Thyroid
The thyroid has an extensive lymphatic drainage, which may
flow in a variety of directions.P Thyroid follicles are
enveloped with lymphatic vessels. The intraglandular lymphatic connections are extensive and enable lymphatic
drainage from one lobe to the other through a complex of
intrathyroidal and pericapsular nodes." The major lymph
vessels running efferently follow the branches of the thyroid
arteries and veins in three main directions: superiorly, laterally, and inferiorly. The upper region of the thyroid is
drained along the superior thyroid vessels to the upper jugular lymph nodes. From the isthmus, the lymph vessels run
to the prelaryngeal, or Delphian, nodes, which are connected
to the upper jugular nodes. Lateral lymph vessels follow
the medial thyroid vein to the mid- and lower jugular nodes.
The lower lymphatic drainage is to the pretracheal and paratracheal nodes and the lower jugular chain. Connections to
the anterior mediastinal nodes and retropharyngeal nodes are
common, but drainage to the submandibular and suprahyoid
nodes is less common. Through the pericapsular, pretracheal,
and prelaryngeal nodes, contralateral nodal involvement
occurs.' The extensive intrathyroid and extrathyroid
lymphatic connections probably contribute to the high incidence of multifocal intraglandular thyroid carcinoma."
Initial lymph node metastases are most commonly observed in
the central neck compartment (medially to the carotid sheet)
in the pretracheal and paratracheal nodes and subsequently
spread to the lateral compartment in the deep inferior and
lateral cervical nodes.' In general, patients with larger primary
thyroid tumors and multifocal intraglandular tumors have
more extensive lymph node metastases," but patients may also
present with nodal metastases and an occult thyroid cancer.
Applied Surgical Anatomy

Anatomic subdivisions of the neck define its borders and are
important to recognize." Recently, the Committee for Head
and Neck Surgery and Oncology of the American Academy
of Otolaryngology-Head and Neck Surgery has proposed
an update of the neck dissection classification." The new
guidelines present some minor revisions but do not differ
substantially from the previous guideline. The sternocleidomastoid muscle is the most prominent landmark and covers
the major vessels of the neck: the carotid artery and the
internal jugular vein.
Six major nodal regions can be distinguished and are

expressed as levels in the classification. A superior or submandibular and submental triangle (level l) is bounded by
the mandible, the hyoid bone, and the posterior belly of the
digastric muscle. The anterior belly of the digastric muscle
divides the superior triangle in a submental part anteriorly
and a submandibular part posteriorly. The submandibular
gland is part of this region. Three jugular regions are anteriorly bound by the lateral margin of the sternohyoid muscle
and the posterior edge of the sternocleidomastoid muscle.
The upper jugular nodes (level 2) run down from the skull
base to the level of the horizontal border of the hyoid bone,
which forms the cranial limit of the midjugular region
(level 3). The inferior border of the cricoid cartilage bounds the
rnidjugular (level 3) from the lower jugular region (level 4); the
lower jugular nodes are located between the inferior border
of the cricoid cartilage and the clavicle. The superior boundary of the posterior triangle of the neck (level 5) is the apex
formed by the convergence of the sternocleidomastoid and
trapezius muscle. It is bounded anteriorly by the posterior
border of the sternocleidomastoid muscle, posteriorly by the
anterior margin of the trapezius muscle, and inferiorly by
the clavicle. The anterior neck compartment (level 6) runs
from the suprasternal notch to the hyoid bone and from the
trachea to the carotid sheath. This compartment harbors the
lymph nodes, which are most frequently involved in patients
with thyroid cancer, and includes the lymph nodes around
the thyroid, along the recurrent laryngeal nerve, the precricoid
(Delphian) nodes, and the pretracheal and paratracheallymph
nodes. The region from the lower neck, from the suprasternal
notch to the innominate vein, is considered the superior
mediastinum (level 7) and is considered separately from the
six levels" but is also frequently involved in patients with
thyroid cancer with metastatic nodes in the tracheoesophageal
groove. Level 6 and the superior mediastinum together form
the central neck compartment.
Starting dorsally in the neck at the anterior border of the
trapezius muscle, the deep layer or "floor" of the operating
field consists of the splenius muscle of the head and the
levator muscle of the scapula with the spinal accessory
nerve. Then the scalenus muscles follow with the brachial
plexus running between the anterior and middle scalenus
muscles. The phrenic nerve runs across the anterior scalenus
muscle. Anteriorly, one comes to the vagal nerve, the internal jugular vein, and the carotid sheath. The hypoglossal
nerve passes under the digastric muscle. Ventrally, the laryngeal muscles, esophagus, trachea, and thyroid are located and
in this area special attention has to be drawn to the superior
laryngeal nerve, recurrent laryngeal nerve, and parathyroid
glands. The surgical anatomy of the superior and recurrent
laryngeal nerve as well as the parathyroids are discussed
elsewhere (see Chapter 2).
Lymph nodes can usually be removed from the superior
mediastinum via the Kocher collar incision. The removal of
lymph nodes caudal to the innominate vein in the mediastinum usually requires a median sternotomy.
For lymph node dissections in patients with thyroid
cancer, the neck should be divided into a central and a
lateral neck compartment divided by the carotid sheath.'
The fatty tissue encompassing the lymph nodes in the
neck is situated between the first and third layers of deep
Management of Regional Lymph Nodes in Papillary, Follicular, and Medullary Thyroid Cancer - -
cervical fascia. The first layer of fascia is formed by the back

side fascia of the sternocleidomastoid muscle; it runs posteriorly to the trapezius muscle and anteriorly to the digastric
muscle and covers the strap muscles. The deep, or third, layer
of cervical fascia covers the trachea and esophagus and runs
laterally over the scalenus muscles, the levator muscle of the
scapula, and the splenius muscle of the head to join the superficial cervical fascia at the trapezius muscle. The second layer
of deep cervical fascia is also called the prethyroidalfascia. An
aponeurotic sheet, which originates from the carotid sheet,
runs sagitally to the fascia covering the strap muscles superficially and to the deep cervical fascia covering the scalenus
muscles posteriorly. This aponeurotic sheet with the carotid
artery as its predominant structure divides the fascia-covered
tissue in a central and a lateral compartment. Because separate
visceral compartments can be distinguished, the laterally
located nodes cannot be truly resected en bloc with the
thyroid."Consequently,the neck dissection is to be subdivided
into a central neck dissection and a lateral neck dissection.
In the central neck compartment, the thyroid is situated along
with the trachea, esophagus, thyroid, parathyroids, and
recurrent laryngeal nerves in one visceral space, which also
contains the strap muscles. Superiorly it extends as far as
the hyoid bone and inferiorly it runs into the superior mediastinum to the innominate vein. Laterally lies the carotid
sheath, which serves as a medial border for the separate
lateral compartment containing the lateral cervical lymph
nodes. A modified neck dissection usually includes resection
of the three jugular regions (levels 2 to 4) and the posterior
triangle (level 5) as described earlier. The superior triangle or
suprahyoid area harbors the submandibular and submental
lymph nodes. It is usually not included in the modified neck
dissection for thyroid cancer, because lymphatic spread to
this region is rare.
Incidence and Localization

of Lymph Node Metastases
As mentioned before, papillary and medullary thyroid carcinomas frequently spread to the regional lymph nodes. Nodal
involvement in follicular cancer is uncommon and when
present one should consider that the tumor is a follicular
variant of a papillary thyroid cancer. Although the presence
and extent of initial lymph node metastases in patients with
papillary thyroid cancer is correlated with tumor size,5.6,ID
lymph node metastases often occur at an early stage of the
disease.P'!' Even in patients with papillary carcinoma
smaller than I em, metastases to the regional lymph nodes
are not uncommon. I 1-13 Thus, lymphatic spread of papillary
thyroid cancer is not always a sign of advanced primary
disease. Lymph node metastases are sometimes the presenting symptom in patients without a palpable lesion in the
thyroid.!"!? When prophylactic neck dissections are done in
patients without clinical evidence of nodal involvement, 30%
to 80% of patients are found to have lymph node metastases. 5,18-21 With more thorough examination, up to 90% of
patients with papillary thyroid cancer have nodal involvement.5,18,19 Thus, most patients with papillary thyroid cancer
have either clinical or occult regional lymph node metastases
at the time of their primary treatment. Another interesting
197
phenomenon is the fact that the incidence of cervical lymph

node metastases is higher in young patients. 12.16, 17,22
In patients with intrathyroidal follicular cancer without
distant metastases, lymph node metastases occur in about
5% of patients. Nodal involvement in patients with follicular carcinoma is associated with extrathyroidal extension
of the primary tumor and is therefore a sign of advanced
disease.F
The presence of clinically enlarged lymph nodes in
medullary thyroid cancer varies between 25% and more
than 60%.23-27 More than half of the patients with medullary
thyroid tumors have nodal involvement, but surprisingly
about half the patients whose medullary thyroid cancers
were detected by family screening also had lymph node
metastases.24.26-28 Patients with hereditary medullary thyroid
carcinoma may have more nodal involvement than patients
with sporadic cancer.23,29 In familial disease the primary
tumor is located bilaterally and lymph node metastases are
also bilateral. Nodal involvement in patients with multiple
endocrine neoplasia (MEN) 2B familial medullary thyroid
carcinoma is more frequent than in the MEN 2A patients.'?
Calcitonin is a sensitive and highly specific marker in persistent disease in patients with medullary thyroid cancer,
especially after pentagastrin and/or calcium provocative
testing. 31-34
Most patients with papillary and medullary thyroid cancer
have unilateral lymph node metastases, but bilateral or contralateral spread occurs, especially in hereditary medullary
thyroid cancer.5,6,16.19,23,35-37 Central neck nodes adjacent
to the thyroid nodule are usually first involved.5,10,37-42
Metastases are found in the fatty tissue along the trachea,
along the recurrent laryngeal nerves, and in the tracheoesophageal groove reaching laterally to the carotid artery
(level 6). Metastatic nodes also occur in the pretracheal
region and along the superior thyroid vessels. The lateral
compartment along the jugular chain is usually not involved,
until at least occult lymph node metastases exist adjacent to
the thyroid gland.5.9,16,34,35 In the lateral compartment, the
nodes along the mid and lower parts of the internal jugular
vein (levels 3 and 4) are more frequently involved than those
along the upper third of the vein (level 2) and those in the
posterior triangle and supraclavicular region (level 5). Of all
patients with nodal involvement, 80% of the metastases are
found in the central neck compartment in level 6 and along
the mid and lower internal jugular vein (levels 3 and 4). Unless
there is extensive lymph node involvement, the submandibular and submental nodes (level I) in thyroid cancer are
seldom affected. 5,16.19,43 Although lymphatic pathways to the
retropharyngeal nodes are usually present.? lymph node
metastases are rare in this area. The superior mediastinum
is less frequently involved in patients with papillary
than in patients with medullary carcinoma, although
mediastinal nodal involvement is relatively common in both
conditions. 6,22,24,43.44 Bilateral metastases are often found
concomitantly with mediastinal nodes in patients with
medullary carcinoma. 27,29,45 Metastases to the superior
mediastinal lymph nodes occur most frequently when there
is involvement along the internal jugular vein contralaterally
to the primary tumor. 17,44,46 More distant mediastinal nodal
metastases are rare, except in patients with advanced locoregional disease."
Prognostic Significance
of Regional Lymph Node
Metastases
In epidermoid cancers of the head and neck, the presence of
regional lymph node metastases is associated with an unfavorable prognosis. In papillary thyroid cancer, nodal metastases appear to be a minor rather than a major risk factor.
The prognostic significance of lymph node metastases is
different for the three types of thyroid cancer. In general,
nodal involvement at the time of diagnosis in papillary
cancer increases the risk of recurrent cancer but has only a
minor influence on overall survival. Regional lymph nodes
are not commonly involved in patients with follicular thyroid cancer, but in these patients the tumor tends to behave
more aggressively. Lymph node metastases in patients with
medullary thyroid cancer adversely influence survival.
The most important determinants for survival in thyroid
cancer of follicular cell origin are tumor stage, age, histologic type, local invasiveness, and to a lesser extent
gender. 12,15,22,26,47-57 Some studies suggest that the presence
of clinically evident lymph node metastases in patients with
papillary and follicular carcinoma has an adverse effect on
survival.6,49,53,58-60 Other authors have reported that patients
with nodal metastases have an increased recurrence rate, but
survival is not adversely affected,15,48,51,56,61-63 Only patients
with stage tumor growth beyond the lymph node capsule
(pN3) have an impaired survival.>' Other studies suggest
that lymph node metastases in patients with papillary carcinoma have no adverse effect on survival or recurrence rate
in their patients. 12,17,47,50,55 In one study, even a slightly better
prognosis in these patients was suggested.P However, these
authors did not account for the fact that young patients are
more likely to have nodal metastases and that the prognosis is
more favorable in younger than older patients with papillary
thyroid cancer. 22.58,59 In one study, which contained a relatively high proportion of node-positive patients with papillary
thyroid cancer older than 45 years of age, nodal involvement
was a strong independent risk factor for survival. 6 The difference in frequency of lymph node metastases in younger
versus older patients with papillary thyroid cancer could
explain the varying influence of lymph node metastases on
prognosis. Other authors noticed that, when patients were
matched by age, the presence of positive lymph nodes did
have an adverse effect on the survival and recurrence rate."
However, in this study 12% of the patients with nodal
involvement had a follicular carcinoma and the lymph node
metastases in patients with this type of thyroid cancer are
known to have a more ominous effect on prognosis than in
patients with papillary carcinoma. 13,56,60,64 The prognostic
significance of lymph node metastases from papillary and
follicular carcinoma should therefore be considered separately. Also, other authors do not discriminate between
lymph node metastases from papillary or follicular carcinoma,14,36.53,59.65,66 which hampers comparative evaluation of
survival analyses and does not justify selecting one type
of neck dissection over another.
Although most patients with papillary thyroid carcinoma
have at least microscopic lymph node metastases, the recurrence rate in patients without macroscopic nodal involvement,
who are not treated with a prophylactic neck dissection,

is low and usually does not exceed 20%,10,13,15.21.36,48,51,67-70
Moreover, the presence of metastatic nodes in the central
neck makes nodal metastases in the lateral neck more likely,
but subsequent development of recurrent disease in the
lymph nodes in the jugular chain or lateral neck is relatively
uncommon." Apparently, most of these occult metastases
fail to grow and some may regress, The development of
lymph node recurrence after primary treatment of papillary
carcinoma seems to have an independent significant effect
on survival in older patients, whereas the effect in younger
patients is less evident. 71
As already mentioned, the presence of lymph node metastases in patients with medullary carcinoma is associated with
a poorer prognosis,23,24,26,27,72 especially when metastases are
found in the mediastinum.Pv' In fact, the presence of more
than three nodes and nodes larger than 1 em correlate with a
worse prognosis." Measurement of plasma calcitonin levels
after administration of calcium and/or pentagastrin is a
sensitive method of documenting when persistent disease is
present. 31-33 Elevated calcitonin and carcinoembryonic antigen (CEA) levels are associated with residual or recurrent
disease.
Choice of Neck Dissection

Operations used to remove cervical lymph nodes vary from
removing only grossly affected lymph nodes ("node picking") to the classic radical neck dissection. Crile in 1906
developed the classic radical neck dissection for local control of head and neck cancers.P Although this operation
became the standard operation for most head and neck
cancers, it is not used today for patients with thyroid cancer.
Radical .neck dissection is associated with disfiguring
cosmetic and functional results, and equally good local
control and cure can be obtained with less extensive
operations. 9.14,15,18.26,35.38,55,74,75 The modified neck dissection, which is called "functional" neck dissection by other
surgeons." allows for an en bloc dissection ofthe lymphatic
network of the neck, while preserving the functionally
important structures (muscles, vessels, and nerves). The
technique of modified neck dissection for thyroid carcinoma
has been described,9,18,74 and the operation can be performed
with minimal morbidity and favorable cosmetic results. 9,I0,36
During dissection of the central neck, it is essential to
preserve the recurrent laryngeal nerve and the blood supply
to the parathyroid glands. The dissection of the superior
mediastinum is part of the central neck compartment dissection, including removing nodes from around the thymus
gland. In patients with extensive invasive papillary and
follicular thyroid cancers and more commonly with
medullary cancer, it is sometimes necessary to perform a
median sternotomy and remove all fatty tissue, thymus, and
lymph nodes from the anterosuperior mediastinum."
A modified neck dissection can be done, because most
nodal metastases from thyroid carcinoma do not invade
adjacent anatomic structures. Lymph node metastases are
rarely found within the substance of the sternocleidomastoid
muscle, even when there is extensive nodal involvement.P-"
It is therefore unnecessary to sacrifice this muscle. In most
cases, it is possible to dissect the spinal accessory nerve free

from surrounding tissue. Deformity of the neck, shoulder,
and subsequently the back is reduced by the preserving the
spinal accessory nerve. The internal jugular vein can also
usually be preserved, but it is essential to dissect all nodes
along the vein, especially behind the lower end." During
bilateral modified neck dissection it is important to preserve
at least one internal jugular vein to avoid possible severe
facial swelling and edema. A modified or functional neck
dissection is the treatment of choice for patients with
metastatic thyroid cancer in the cervical nodes. It benefits
especially young women, which form the largest group of
patients with papillary, follicular, and medullary thyroid
cancer.
Sentinel lymph node dissection is now used to assess the
status of lymph nodes in patients with breast cancer and
melanoma and has changed the surgical management.
Intraoperative lymphatic mapping has also been investigated
in thyroid cancer.76-78 The technique has been carried out
with a vital dye technique and/or a radiotracer technique.
The sentinel node dissection seems feasible, although the
false-negative rate is difficult to establish since not all patients
undergo a central and modified neck dissection. As mentioned
previously, the influence of occult lymph node metastases on
prognosis of papillary cancer is the most questionable.
Therefore, the usefulness in papillary cancer is limited
because most surgeons would agree that systematic surgical
resection of lymph nodes should be limited to therapeutic
dissection in patients with enlarged lymph nodes. Sentinel
lymph node studies might be helpful in patients with
medullary cancer and small primary tumors since surgeons
advocate a standard lateral neck dissection in these patients.
The identification of a sentinel node in the lateral neck compartment in patients without central neck involvement might
provide arguments to perform a lateral neck dissection. Further
information should be obtained to clarify this issue.
Papillary and Follicular Thyroid Carcinoma

A prophylactic modified neck dissection is not generally
advocated. Only a few authors advocated prophylactic neck
dissections, 18.62 and most recommend a more disease-related
strategy. Systematic neck dissection in patients with nodal
involvement and papillary or follicular thyroid cancer
reduces regional tumor recurrence compared to limited
nodal excision ("node picking"), but the extent
of neck dissection has no proven influence on overall
surviva1. 55,66,68,75 Although in one study nodal involvement
of papillary carcinoma adversely influenced survival as well
as the recurrence rate, more aggressive treatment did not
appear to have any influence on prognosis."? Therefore, an
attempt to eradicate all lymph node tissue to eliminate tumor
in patients with papillary and follicular thyroid cancer seems
unjustified, and it increases the risk of morbidity. However,
evident metastatic disease should be resected when this can
be done with minimal increased morbidity.
Some surgeons6,18,62,80,8! have recommended routine
removal of cervical lymph nodes from the central neck
compartment concomitant with the total thyroidectomy,
Other surgeons 38,49,69,82 mention careful inspection of the
central neck with removal of suspicious nodes for frozen
199
section; if positive, the lymph nodes in the central neck compartment are removed. Most surgeons 1,9,14,39,41,48,52,58,62,69,82-84
use the latter strategy in patients with papillary and follicular carcinoma and reserve modified neck dissection for
patients with clinically evident lymph node metastases in
the lateral neck. In patients without nodal involvement in the
lateral neck, a therapeutic modified neck dissection can be
performed later, if recurrence occurs in the lateral neck,
A subsequent neck dissection is not difficult because this area
has not previously been explored. Some authorities on thyroid
cancer advocate mid- and lower jugular sampling in patients
without clinically evident nodal involvement to decide
whether a modified neck dissection is necessary.36,65,66,70,80
When these nodes are positive, a modified neck dissection is
performed. They argue that lymph node metastases are associated with more aggressive differentiated thyroid cancer
even though most studies using multivariate analysis fail to
show an adverse effect on prognosis. A few surgeons reserve
the modified neck dissection for patients with more extensive nodal involvement rather than for all patients with nodal
metastases and use a limited resection or node picking for
patients with limited nodal involvement. 39,47,73,81
MedUllary Thyroid Carcinoma

Medullary thyroid carcinoma is biologically more aggressive
than papillary or follicular thyroid carcinoma, and the presence of lymph node metastases correlates with a poorer prognosis. Medullary thyroid cancer in contrast with papillary
and follicular cancer usually does not concentrate radioactive
iodine,26,57,85 so this form of adjuvant therapy is usually ineffective to treat persistent or recurrent disease. Most medullary
thyroid cancers are also resistant to chemotherapy or external
irradiation. For these reasons, a more extensive surgical
approach is warranted than in patients with papillary or
follicular thyroid cancer. In patients with medullary thyroid
cancer, a bilateral central neck dissection concomitantly
with the total thyroidectomy is essential and uniformly
advocated by experts in the field. 25,28,29,34,35,45,57,63,65,86-92
There is a potential risk of recurrent disease in the central
neck in these patients, because micrometastases are frequently
present in clinically node-negative patients and secondary
surgery in the central neck area is associated with a high
complication rate."
Standard modified neck dissectionin patients with medullary
thyroid cancer is controversial. Some authors45,57,65 advocate
modified neck dissection directed by sampling of the lymph
nodes along the ipsilateral lower and middle parts of the internal jugular vein during primary surgery in all patients. Other
surgeons88,89 do not advocate jugular sampling and recommend an ipsilateral modified neck dissection when the primary
thyroid cancer is 1.5 em or larger. Most surgeons29,37,90 would
recommend at least ipsilateral modified neck dissection in
all patients with any nodal involvement in the central neck
compartment. In addition, standard ipsilateral or bilateral
lateral neck dissection is advocated by some authors in all
patients with medullary thyroid cancer.91,92 More evidence
is necessary to determine whether extensive cervical lymphadenectomy improves overall survival. However, a normal
basal and stimulated calcitonin level after completion of the
neck dissection suggests a better long-term outcome.

A common problem arises when the serum calcitonin
level remains elevated despite adequate surgery including
total thyroidectomy, and bilateral central and lateral neck
dissection including the upper mediastinum. Noninvasive
and invasive imaging studies as well as venous sampling of
calcitonin have been used to try and identify site or sites
of persistent disease. When the localization studies are
negative and the patient has had definitive surgery (total
thyroidectomy, central neck dissection and a modified neck
dissection), there is no consensus about how to best manage
these patients. Prophylactic re-explorations have only infrequently resulted in normalization of calcitonin levels in
patients who have already had appropriate dissections.W"
Nevertheless long-term survival is relatively good in this
group of patients without reoperations.t-P-" In medullary
thyroid carcinoma, a systematic microdissection of the neck
has been recommended. A thorough neck dissection using
microdissection techniques with the help of magnifying
glasses is performed to remove all identifiable metastatic
tissue from the neck. 28,29.34 Meticulous dissection of regional
lymph nodes in the central neck compartment including the
superior mediastinum as well as a bilateral modified neck
dissection has been shown to be superior compared to less
systematic procedures with regard to the normalization of
calcitonin levels and survival. 28,29,34 Some surgeons have
extended the operation with a dissection of the mediastinum
using median sternotomy when positive nodes were found
in the superior mediastinum, but this extension has not
improved their results." A longer follow-up period is necessary to confirm the merit of these procedures, but the results
are promising, with serum calcitonin levels becoming undetectable in about 25% of these patients. Microdissection of
the neck is time consuming, and meticulous dissection is
best performed at the primary procedure before adhesions
make dissections more difficult.P
Medullary thyroid cancer is a relatively rare tumor, and
patients with these tumors require the most experienced
thyroid surgeons for the best results.
Operative Technique
The lymph nodes in the central neck compartment are usually
resected in continuity with the thyroid itself. The strap muscles are retracted laterally during the dissection. When the
strap muscles inhibit exposure, they can be divided superiorly, since they are innervated from below. The technique of
the total thyroidectomy has been described in previous chapters. As mentioned earlier, the central neck dissection puts the
recurrent laryngeal nerve and the blood supply to the parathyroids at risk. The parathyroid glands are delicately dissected
away from the thyroid, preserving their vascular pedicles
during thyroidectomy. When they cannot be kept on a vascular pedicle, they should be removed, biopsied with frozen
section, and autotransplanted.All fatty tissue and lymph nodes
between the carotid sheath and the esophagus can be removed
from the recurrent laryngeal nerve along the trachea and from
the tracheoesophageal groove (Fig. 22-1).
The recurrent laryngeal nerves must be identified to
minimize the risk of injury and consequent paralysis of the
vocal cords. When lymph nodes are extensively involved,
the position of the recurrent laryngeal nerve can be displaced

and identification can be more difficult. In most patients
removal of nodes from the recurrent nerve can be done
safely. When there is extensive nodal involvement, it may be
difficult to preserve the lower parathyroid gland on this side.
The upper parathyroid gland is usually easier to preserve
because it is situated more dorsally. Positive identification
and preservation of the contralateral parathyroid glands are
essential. The central neck dissection is continued into the
superior mediastinum while dissecting along the recurrent
laryngeal nerves bilaterally. The superior mediastinum can
be dissected by removing the upper thymus with the fatty
tissue after determining its relation with the inferior parathyroid glands. When the inferior parathyroid glands have not
been found during thyroidectomy, they are probably embedded in the cranial portion of the thymus. Opening of the
capsule of the cranial part of the thymus usually uncovers the
intrathymic parathyroid gland. When another parathyroid
gland has not been positively identified, it is best to leave the
thymus in situ or to autotransplant the identified intrathymic
parathyroid gland. The dissection is extended toward the
innominate vein. Occasionally it is necessary to split the sternum (median sternotomy) for invasive or extensive tumors.
When a modified neck dissection is planned, the Kocher
transverse collar incision is extended laterally (MacFee
extension), which provides adequate exposure in most cases.
The cosmetic results of this extension are favorable. Good
exposure can also be achieved by a vertical extension toward
the angle of the jaw, but this extension is cosmetically less
favorable. A second horizontal incision high in the neck and
parallel to the initial incision is preferable cosmetically. The
dissection plane of the skin flaps continues just deep to the
platysma muscle and anterior to the external jugular vein.
Special attention must be given to the retraction of the cranial
skin flap: the mandibular marginal branch of the facial nerve
runs just below the mandibula and can be compressed by
retractors. This must be avoided because it results in drooling from the comer of the mouth. It is usually not necessary
to transect the sternocleidomastoid muscle. The neck dissection can be performed adequately by retracting the muscle
medially and laterally and working beneath it. This can be
done with retractors or a rubber cord. Alternatively,the muscle
can temporarily be disconnected just caudal to its insertion
to the clavicle and sternum. In this situation the muscle
is dissected and elevated toward the mastoid region. The
superficial cervical fascia covering the sternocleidomastoid
muscle is incised longitudinally over the whole length of the
muscle and dissected away. When possible the external
jugular vein and greater auricular nerve are preserved and
retracted posteriorly by a separate vessel loop. The anterior
part of the superficial fascia is dissected from the muscle
and is left in continuity with the fascia, which covers the
internal jugular vein and its contiguous chain of lymph
nodes. The dissection either commences medially at the
junction of the lower part of the internal jugular vein and the
clavicle or laterally at the junction of the anterior border of
the trapezius muscle and the clavicle. We prefer the medial
approach where the fatty tissue and embedded lymph nodes
are dissected from the internal jugular vein starting just
above the sternoclavicular joint. On the left side, one should
identify the thoracic duct just above the junction of the
201
FIGURE 22-1. Total thyroidectomy with dissection of central neck compartment and midjugular sampling.
innominate vein and the internal jugular and subclavian veins.

The duct can be distended by compression of the areolar
tissue near the bifurcation, which facilitates its identification. The thoracic duct must be divided and ligated when
injured or the patient may develop a chyle fistula. The internaljugular vein is dissected free from its surrounding lymph
node-bearing tissue, which contains the beginning of the
modified neck dissection. Special attention must be drawn
to the lower jugular nodes, which are located behind the
vein. The vein should be retracted either medially or laterally to obtain a good view of this area. This retraction should
be done gently to avoid tearing the vein, which might cause
air embolism. The dissection is continued by exposing the
carotid artery, sympathetic chain, and vagus nerve. The lymph

node containing fatty tissue is mobilized laterally and superiorly along the clavicle, creating the inferior border of the
lateral compartment dissection specimen. Care is taken to
avoid injury to the pleura. The specimen is gradually dissected
upward from the floor of the lateral compartment. The
phrenic nerve is identified running obliquely on the scalenus
anticus muscle, and the brachial plexus is identified between
the scalenus anticus and medius muscles (Fig. 22-2).
The anterior border of the trapezius muscle is dissected
and the spinal accessory nerve is identified approximately
1 em anteriorly from the margin of the muscle. The trapezius muscle represents the lateral border of the lateral
FIGURE 22-2. Modified dissection of central neckcompartment.
neck compartment. The spinal accessory nerve runs parallel

to the trapezius muscle over the levator muscle of the scapula.
The nerve itself is rarely invaded by tumor but is often
surrounded by lymph nodes. It should be carefully dissected
from the adjacent tissues upward to the cranial part of the
sternocleidomastoid muscle. The spinal accessory nerve is
in a superficial position in the posterior triangle of the neck. A
plexus of branches from the cervical sensory nerves is located
caudal and parallel to the spinal accessory nerve and the
phrenic nerve, and these nerves should be preserved when
possible. The greater auricular nerve turns toward the sternocleidomastoid muscle near this point. In this area, too, care
must be taken to preserve the branch of the occipital artery,
which vascularizes partly the sternocleidomastoid muscle.
The occipital artery represents the upper posterior limit of
the dissection of the lateral compartment. The dissection

continues to the prevertebral fascia. The tissue behind and
above the spinal accessory nerve is mobilized from the nerve
itself and is dissected upward from the levator muscle of the
scapula and splenius muscle of the head. The inferior, lateral,
and upper posterior parts of the dissection are completed, and
the specimen is passed underneath the sternocleidomastoid
muscle, which is now retracted laterally. The anterior part of
the specimen is freed from the carotid sheet and jugular vein,
and the dissection continues superiorly along the jugular
vein, mobilizing the mid- and upper jugular lymph nodes.
The hypoglossal nerve, which runs behind the facial vein, is
identified. Sometimes the facial vein has to be ligated and
transected to obtain an adequate exposure to the hypoglossal
nerve while removing the upper jugular lymph nodes.
203
Macroscopic
lymphadenopathy
FIGURE 22-3. Proposed strategy for management of

regional lymph nodes in papillary and follicular thyroid
carcinoma. Modified neck dissection includes a central
neck dissection. Central neck dissection includes
a dissection of the superior mediastinum. Middle and
lower jugular sampling is optional. See additional
considerations in the section "Therapeutic Strategy."
Modified neck
dissection
Central neck
dissection
(Positive jugular sampling)
The dissection is terminated at the posterior belly of the

digastric muscle. The lymph nodes in the submandibular
region are rarely involved in patients with thyroid cancer
and are therefore not removed unless there is extensive lymphadenopathy adjacent to this area. The digastric muscle
marks the upper border of the dissection. The specimen can
now be removed. Careful hemostasis is performed, and suction
drains are often used. The heads of the sternocleidomastoid
muscle, when previously divided, are reapproximated. The
platysma muscle is approximated and the skin is closed.
Complications of Neck
Dissection
More extensive neck dissections, especially in the central
neck compartment, are associated with a higher risk of
hypoparathyroidism and other complications.tv" With complete resection of all fatty and lymph node tissue from the
central neck, the recurrent laryngeal nerves and the vascular
supply to the parathyroid glands are at risk, especially when
combined with total thyroidectomy.14,47,62,69,94-96 Awareness of
these potential problems emphasizes the importance of meticulous dissection and positive identification of the recurrent
laryngeal nerves and parathyroid glands. Magnifying glasses
(x2.5) and bipolar coagulation are helpful. The patient should
not receive muscle relaxants. The recurrent laryngeal nerve
should be dissected over its complete length with special care
for the part caudal to the thyroid. Unilateral paralysis causes
hoarseness, which is inconvenient to the patient. Bilateral
injury is a life-threatening complication that may make an
emergency tracheostomy necessary. Resection of the trachea
and esophagus muscle wall is occasionally necessary in
patients with extensive extracapsular tumor growth.
The modified neck dissection is designed to remove all of
the metastatic lymph nodes in the lateral neck yet minimize
morbidity. In experienced surgical hands, modified neck dissection is a safe procedure with minimal morbidity. 10.36.94
Resection of the spinal accessory nerve results in paralysis
of the trapezius muscle with a shoulder drop and decreased
abduction of the arm. Besides loss of function, paralysis of
the trapezius muscle is disfiguring. The choice of the incision as well as the preservation of the sternocleidomastoid
muscle and the spinal accessory nerve is an important aspect

for a favorable cosmetic result of a modified neck dissection. Injury to the phrenic nerve can result in paralysis of the
diaphragm, whereas injury to the sympathic ganglion leads
to Homer's syndrome. Resection of branches of the cervical
sensory nerves can cause sensory loss of the shoulder. As
previously stated, the identification of the thoracic duct on the
left side can be difficult. When the duct is injured, chylous
fluid collection or cyst occurs. The duct should therefore be
ligated to prevent postoperative chylous fistula or chylothorax. When such a complication occurs, reoperation and
ligation of the duct are often necessary. Both modified neck
dissection and dissection of the superior mediastinum can
cause a pneumothorax. A postoperative chest radiograph is
recommended. When a pneumothorax is present, a chest
catheter is placed under water seal.
Bilateral neck dissection can cause significant postoperative edema, and a temporary tracheostomy is rarely necessary.
When one internal jugular vein is resected, the contralateral
neck dissection should be delayed for at least 6 weeks to
avoid this problem. Wound infections are uncommon
(Figs. 22-3 and 22-4).
Bilateral central neck dissection
FIGURE 22-4. Proposed strategy for management of regional

lymph nodes in medullary thyroid carcinoma. Ipsilateral neck dissection is advocated if central neck nodes are involved with tumor.
All patients with tumors larger than 2 cm should undergo standard
ipsilateral neck dissection. Central neck dissection includes dissection of the superior mediastinum. See additional considerations in
the section "Therapeutic Strategy."
Therapeutic Strategy
Papillary and Follicular Thyroid Carcinoma
Figure 22-3 shows our strategy for the management of the
regional lymph nodes in patients with papillary or follicular
thyroid carcinoma. The object is to remove fatty and lymphatic tissue with minimal risk of complications. As mentioned previously, prophylactic neck dissections for
probable microscopic nodal involvement do not appear to be
indicated, except possibly in older male patients with central
node involvement. While performing total thyroidectomy,
the central neck compartment is carefully examined. Enlarged
nodes are removed and sent for frozen section analysis. When
positive, a central neck dissection is performed, including
removing nodal tissue from the superior mediastinum. When
there are numerous lymph node metastases in the central
neck, the lateral lymph nodes are palpated, and, if present,
they are removed (levels 2 to 5). Modified neck dissection
can usually be performed with minimal associated morbidity. When there is nodal involvement in the lateral neck
compartment without evident involvement in the central
neck, a modified neck dissection as well as a central neck
dissection, including removing the lymph nodes from the
superior mediastinum, is performed. En bloc or compartment
dissections are preferable to limited dissections or node picking to decrease the likelihood of recurrent disease. Repeat
operations in previously explored areas are associated with
increased morbidity but can offer significant palliation.

Figure 22-4 shows the strategy for the management of the
regional lymph nodes in patients with medullary carcinoma.
Total thyroidectomy with bilateral central neck dissection,
including the dissection of the superior mediastinum, is
recommended. Microdissection is helpful for identifying all
lymph node-bearing tissue so that it can be removed from
the central neck compartment bilaterally. When nodes contain
medullary thyroid cancer in the central neck, a modified neck
dissection is performed on the involved side. Although we
formerly advocated jugular node sampling, we now recommend either leaving the lateral compartment alone or proceeding with a systematic modified neck dissection. Formation
of scar tissue after jugular sampling make a subsequent
dissection of levels 3 and 4 more difficult. Patients with
large tumors (> 1.5 ern) should have standard prophylactic
ipsilateral modified neck dissection, and this should be done
bilaterally in patients with familial disease or with bilateral
tumor involvement. When at the initial operation the central
neck nodes are not involved, the operation can be limited to the
central neck dissection. If a subsequent modified neck dissection is required, adhesions will not be a problem. Nevertheless,
elective modified neck dissection should be performed in a
secondary session, when central neck nodes are involved with
medullary thyroid cancer at final histology and the basal or
stimulated serum calcitonin level is elevated. Postoperatively,
patients should be followed cautiously by monitoring the
serum calcitonin and CEA levels. In patients with persistent
elevated basal or stimulated calcitonin levels, noninvasive
studies such as magnetic resonance imaging of the neck and
mediastinum should be performed. Selective venous sampling

for calcitonin'? or microdissection of nonpreviously explored
compartments of the neck is useful in selected patients.28.29.34
Microdissection by experienced surgeons has reduced serum
calcitonin levels to normal in about one third of the patients.
In patients with distant metastases, local control is important
and therapeutic but not prophylactic nodal resections are
recommended.
Treatment of Regional
Recurrences in the Neck
Recurrent thyroid cancer most commonly occurs in the
cervical lymph nodes.47.66.69 Recurrent disease in the lateral
neck should be treated by modified neck dissection. When
a recurrence occurs after neck dissection, a repeat neck dissection or local excision should be performed. Central neck
re-explorations are hazardous, and although excellent
results have been reported." the recurrent laryngeal nerve
and the parathyroid glands are at increased risk of injury in
secondary explorations. Recurrences in the central neck in
patients with papillary and follicular cancer can be treated
with surgical excision and/or radioactive iodine. If the recurrence is small I em) and located in the thyroid bed, the
tumor is often best controlled by radioactive iodine or external irradiation. Larger tumor deposits should be resected.
Follicular cancers appear to be more amenable to radioactive iodine treatment than papillary cancers.l.85.99 Medullary
cancer is usually insensitive to radioactive iodine therapy,
and patients with nonresectable cancer should be treated
with external radiation.v" Median sternotomy should be
done for patients with elevated serum calcitonin levels and a
mediastinal mass. Prophylactic median sternotomy is more
controversial.34 Esophageal or tracheal resection is indicated
in selected patients and can usually be accomplished with
minimal morbidity.
Summary and Conclusions

The extent of lymph node dissection must be based on individual tumor type and stage, extent of nodal involvement at
the time of operation, and patient-related factors such as age
and general condition. The surgeon's experience should also
be taken into account. As mentioned previously, more aggressive surgical procedures do not always influence overall
survival in patients with papillary and follicular thyroid cancer.
Most patients with well-differentiated thyroid cancer of follicular cell origin benefit from therapeutic nodal dissection,
but prophylactic node dissection is not necessary.
An extensive search for micrometastases also does not
seem warranted. Although most patients with papillary carcinoma have at least microscopic nodal involvement, the recurrence is low even in patients not treated with prophylactic neck
dissection. Compartment-related dissections appear to be
preferable to local excision of lymph nodes to minimize local
recurrence: central neck dissection in case of lymph node
metastases in the central neck medially to the carotid arteries (level 6 and the superior mediastinum) and modified
neck dissection of levels 2 to 5 for nodal involvement of the

lateral neck.
In patients with medullary thyroid carcinoma, a more
extensive surgical approach is warranted. Medullary carcinoma is more aggressive than papillary and follicular thyroid
cancer and ablative treatment with 1311 is generally not effective. A total thyroidectomy and bilateral central neck dissection are therefore recommended for most patients with
medullary thyroid cancer. Ipsilateral modified neck dissection of levels 2 to 5 is indicated in all patients with primary
tumors larger than 1.5 em and bilateral neck dissection in
patients with bilateral thyroid tumors and hereditary
medullary thyroid cancer. Postoperatively, patients should be
followed cautiously by monitoring the serum calcitonin and
CEA levels. Some patients without demonstrable tumor but
with elevated calcitonin levels benefit from repeat central
and bilateral modified neck dissection of renewed surgery
in the neck using microsurgical techniques if this has not
already been done.
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Occurrence and Prevention of

Complications in Thyroid
Surgery
Job Kievit, MD, PhD Bert A. Bonsing, MD, PhD Ilfet Songun, MD, PhD
Comelis J.H. van de Velde, MD, PhD
The first surgeon to receive the Nobel Prize in medicine was

Theodor Kocher (1841-1917) in 1909, a pioneer in thyroid
surgery. One of his accomplishments was to reduce the frequency of thyroid surgery complications. The refinements of
his surgical methods from his first important article on thyroidectomy (1878) led to a reduction in mortality from high
initial figures (50%) to less than 4.5%. Currently, the mortality
rate of thyroidectomy, as reported in several large series,
approaches zero. The morbidity of thyroidectomy, however,
continues to be a matter of concern. Meticulous attention to
operative technique is required, as is a flexible approach that
balances the requirements of resection to avoid recurrences
against the risk of complications. In 1989, in the United
Kingdom, surgical claims for thyroidectomy complications
accounted for 4% of general surgical claims, all of which
involved recurrent laryngeal nerve injury.' Claims underrepresent complications, and complications in routine care
may occur more frequently than in published series. Most
complications of thyroidectomy can be avoided by detailed
knowledge of the anatomy and careful surgical technique.
Although it is a surgical truism that volume generally improves
quality, recent research suggests that surgeons may differ in
their ability to perform this refined surgery with sufficient
care.' Regardless of the background of the surgeon (general
surgeon, head and neck surgeon, or endocrine surgeon), the
collaboration with an endocrinologist and broad experience
in thyroid surgery not only will improve quality but will give
confidence in any legal challenge and will help educate
future surgeons in proper surgical decision making and
technique.
Surgery for Thyroid Disease

In the foregoing chapters, the indications for thyroid surgery
for different pathologic entities have been discussed.
Naturally, benefits of surgical therapy must outweigh the
risks involved. About 1 in 10 solitary thyroid nodules is

malignant.' Therefore, a selective approach must be used to
determine who will benefit from thyroidectomy and who
can be safely observed. The same applies to the extent of
thyroid surgery (e.g., total vs. subtotal thyroidectomy) or
of surgery for lymph node metastases (node picking or radical
neck dissection).
Complications in Patients
Undergoing Thyroid Surgery
In this chapter, we discuss "complications," being defined
as unfavorable and unintended outcomes of care-in short,
adverse outcomes. Complications of thyroid surgery can be
divided into general or specific complications, the latter being
directly related to surgical technique, and the former being
more or less independent of the surgical technical procedure
itself. Examples of general complications are circulatory and
respiratory problems and urinary tract infections. Specific
complications include vocal cord dysfunction resulting
from injury to the recurrent or external laryngeal nerves,
hypoparathyroidism, bleeding, serous or lymphatic leakage,
and hypoparathyroidism (origination from damage or
ischemia to the parathyroid glands). The nerves at risk during
thyroid operations are the external branch of the superior
laryngeal nerve (EBSLN), the recurrent laryngeal nerve,
and, depending on the surgical approach chosen, the various
branches of the hypoglossal ansa. Other complications, such
as lesions of the esophagus, thoracic duct, jugular vein, and
carotid artery, are extremely rare and are likely to occur only
in patients with large, invasive tumors requiring more extensive surgery. In the next sections, we deal with most general
and specific complications, drawing both from literature data
and from a series of 752 patients undergoing thyroid surgery
at the Leiden University Medical Center (27% of them being
reoperations). Attention is paid especially to the local anatomy,
207

surgical techniques that can prevent damage to the structures
at risk, and handling of complications.
General Complications
The most frequent general complications involve the heart
and the lungs. In our series, benign cardiac arrhythmias
occurred in 0.4% of patients; however, one patient (0.1 %)
died because of a cardiac arrest. Pulmonary complications
involved bronchitis or pneumonia (0.5%); none of these
caused severe morbidity or mortality. Other general complications were cystitis (0.2%) and fever (0.2%).
Specific Complications
Edema
Facial, neck, or tracheal edema may be caused by decreased
venous or lymphatic drainage from the operating field. It may
interfere with inspiration and occurs especially if thyroidectomy is combined with bilateral lymphadenectomy, such as
may be required in patients with medullary cancer.t-' Severe
edema in the case of isolated thyroid surgery is rare; none
of our patients needed treatment for this complication. It is
more common in patients with neck dissections, and it can
be prevented or reduced by keeping the head elevated and
applying cortisone preparations.
Bleeding
Bleeding in the operating field may occur from superficial
arteries and veins in the neck, lying on the superficial cervical
fascia and from vessels around the thyroid. Such bleeding
occurred in nine patients (1.2%) in our series, half of them
requiring reoperation. Ligatures tied around the superficial
neck veins may come loose and cause subcutaneous bleeding
or hematoma. The rich vascular supply of the thyroid gland
contributes to its bleeding tendency and stresses the need
for meticulous hemostasis. Perioperative bleeding may be
decreased by having the patient in a reverse Trendelenburg
position, with the head elevated 20 degrees. To test for
possible bleeding at the conclusion of the thyroidectomy,
the head can be tilted down and the lungs hyperinflated
by the anesthetist to increase intrathoracic pressure as well
as blood pressure in the neck veins. After thyroid surgery,
patients should be kept in a low Fowler position with
the head and shoulders elevated 10 to 20 degrees to keep a
negative pressure in the veins; they should be observed in
the postanesthesia care unit for several hours because most
significant hemorrhages with evident tracheal compression
occur within hours after operation. In accordance with
recent research, we do not routinely use drains, but only if
bleeding during or at the end of surgery causes concem.v!" If
used at all, drains should be at least be 14 gauge. Drains are
certainly not a reason to decrease concern: clots may form and
prevent adequate drain function of the placed drains. Extensive
dressings may hide the complication and prevent inspection of
the contour of the neck and are, therefore, not advised. In the
case of symptomatic postoperative hematomas, a liberal attitude toward re-exploration is justified. Hematoma or seroma
occurring after several days is uncommon and generally can

be managed expectantly.
Wound Healing Disorders and Infection

A well-positioned collar incision, approximately 2 em
above the jugulum or 1 em below the cricoid cartilage,
extended laterally and closed by intracutaneous running
suture, gives the best cosmetic result. A lower incision is
more prone to keloid development. If this occurs, excision
of the scar after I year may reduce the size of the deformity.
Infections occur rarely in thyroid surgery, most often when
combined with lymph node dissection (3 patients [0.4%1
in our series, one of whom also had a tracheostomy). Apart
from normal surgical hygiene and disinfection and the
avoidance of operations in patients with acute sore throats,
no additional preventive measures are required. Infections
should be treated by opening the wound and evacuating
the pus. After adequate drainage, when granulation starts, the
wound can be excised and closed secondarily by intracutaneous suture, which gives the same excellent aesthetic result
as in uncomplicated primary closure. Seroma can be treated
by aspiration.
Vascular and Lymphatic Lesions

Other specific surgical complications, typical for thyroid
surgery, involve the thyroid vessels and the thoracic duct.
The vessels most easily damaged during thyroidectomy are
the middle and inferior thyroid veins, which may be severed
between their origin from the internal jugular vein and their
entrance into the lateral margin of the thyroid lobe. This is
especially the case when very large goiters obscure the
trajectory of these vessels. Bleeding is easily controlled by
ligation and has no adverse effects. Damage to the thyroid
arteries rarely occurs accidentally but generally occurs on
purpose to devascularize the thyroid lobe. Ligation of both
arteries, but more so of the inferior than of the superior thyroid artery, may cause parathyroid ischemia. Some authors
contend that ligation of the inferior thyroid artery causes
ischemia to both the inferior and the superior parathyroid
glands, especially if the artery is ligated far away from the
thyroid gland.
Lesions to the thoracic duct may occur when thyroid surgery is combined with lymph node dissection (Fig. 23-1).
The duct is most frequently damaged at its craniolateral
aspect, where lymphatic vessels from the neck enter into the
duct, resulting in leakage of clear or milky chylous fluid. If
the thoracic duct, or one of its branches, is injured intraoperatively, it should be ligated. Ligation is sometimes difficult
because it may be hard to identify the duct. In such cases,
suturing the surrounding middle or deep cervical fascia over
the duct leak is often possible. Alternatively, the investing
fascia of the anterior scalenus muscle may be mobilized in a
craniocaudal direction and used to cover the site of leakage.
In that case, extreme care should be paid to the phrenic
nerve, and its prescalenal trajectory may obviate usage of
the anterior scalenus fascia. After successful suture ligation
treatment of leakage, any coverage achieved should be reinforced with the use of fibrin sealant in combination with
collagen (e.g., Tissuecol).
Occurrence and Prevention of Complications in Thyroid Surgery - - 209
FIGURE 23-1. Extensive lymphatic branching of the thoracic duct

in a patient undergoing neck dissection for thyroid cancer.
If leakage of the thoracic duct is recognized postoperatively

(because of the production of clear or milky fluid from the
wound drain), it may be treated conservatively (by total
parenteral nutrition for several weeks) or surgically. Surgery
is the most effective treatment and involves reopening the
neck, identifying the lesion, and treating it as described
previously. In our series, we were able to obtain surgical
control of the duct in all cases in which leakage occurred
both intraoperatively (1.2% of our patient series) and postoperatively (0.4% of patients in our series).
Nerve Damage to the Recurrent

Laryngeal Nerve
The recurrent laryngeal nerve is involved in most claims concerning complications of thyroid surgery.' Morbidity related
to this injury ranges from minimal changes in voice quality to
recurrent tracheal aspiration and/or severe dyspnea requiring
tracheostomy. The incidence of injury to the recurrent laryngeal nerve(s) during thyroid surgery is influenced by many
factors. The risk is higher in more extended thyroid resections, in patients with malignant thyroid disease, in patients in
whom the recurrent laryngeal nerves could not be identified,
and in re-operations due to recurrent thyroid disease.'!"?
Although it is recognized that experience reduces complication rates in surgery in general and reoperations on thyroid
disease specifically, reports concerning this topic in primary
thyroid surgery are conflicting and emphasize the importance
of individual surgical skill and performance. I 1.12.14,16.18,19 Use
of a harmonic scalpel reduces operating time but was not
shown in small studies to be safer in avoiding recurrent laryngeal nerve injury than bipolar coagulation and ligatures. 20 -22
The same is true for use of minimally invasive video-assisted
procedures.P:"
At present, there are mainly three strategies that can
reduce the risk of recurrent laryngeal nerve injury. The first
and most frequently used method is visual control by complete dissection of the full extralaryngeal trajectory of the
recurrent laryngeal nerve. I I Second, intraoperative electrical
nerve stimulation of the surgical field in addition to visual
control can be used to delineate the presence, function, and
FIGURE 23-2. Right-sided non-recurrent recurrent laryngeal

nerve in a woman with tertiary hyperparathyroidism.
possibly the course of the recurrent laryngeal nerves by

observing contractions of the cricopharyngeus muscle. 27- 32
Third, uninterrupted monitoring of laryngeal electromyographic activity through electrodes placed against the
posterior cricoarytenoid muscles can be used. It reveals
changes in mechanical activation by manipulation of the
recurrent laryngeal nerves during dissection. 27,33-36 Either
way, detailed knowledge of the anatomy is of paramount
importance to avoid damage to the recurrent laryngeal nerve.
The anatomy of the recurrent laryngeal nerves can be
quite variable, especially in patients with large goiters, and
in cases of "redo" surgery for recurrent thyroid outgrowth.
Normally, the right laryngeal nerve arises anterior to the
right subclavian artery or brachiocephalic trunk, ascends in
the neck behind the common carotid artery, and then curves
medially and ventrally, running obliquely and superiorly
toward the cricoid cartilage and inferior constrictor. In less
than I % of patients, the right recurrent nerve is nonrecurrent and may enter the thyroid from a superior or
lateral direction. I I ,37-39 Combinations of recurrent and nonrecurrent branches do also occur (Figs. 23-2 to 23-4).11
FIGURE 23-3. Right-sided partially non-recurrent recurrent

laryngeal nerve in young woman with multiple endocrine
neoplasia type I hyperparathyroidism.
FIGURE 23-4. Right-sided partially non-recurrent recurrent laryngeal nerve in a young woman with severe Hashimoto's thyroiditis.
The left recurrent nerve arises from the nervus vagus on

the left side of the aortic arch and winds around the arch
behind the attachment of the ligamentum arteriosum. It then
ascends in the anterior mediastinum and neck in a more
medial position, running in the left tracheoesophageal groove.
Both nerves subsequently ascend in the neck and cross the
lower lateral border of the thyroid at the level of the inferior
thyroid artery. They then pass behind the thyroid lobe and
laterodorsally to Berry's ligament before they penetrate the
cricothyroid muscle to enter the larynx.4o42 Inside the larynx,
the nerve divides into two or three branches-a lateral and a
medial branch-that innervate different laryngeal muscles.
In addition to this normal rarnification pattern within the
larynx, the recurrent nerve may also give off branches in its
extralaryngeal ascent in the neck in 60% to 75% of the
patients." In the first place, the nerve may divide at any level
between its origin and its entry in the larynx, resulting in a
full or partial duplication of the nerve within the neck. These
branches then ascend in the neck in a parallel course until
their entry in the larynx. Besides duplication of the recurrent
laryngeal nerve itself, the nerve may give off branches that do
not enter the larynx but connect the nerve to other structures
within the neck. In the lower part of the neck, small branches
may divert from the lateral aspect of the nerve to reach the
sympathetic chain, where they connect to the cranial and
medial cardiac nerves. Other small branches separate from
the nerve medially to innervate the trachea, esophagus, and
larynx. Finally, the recurrent nerve may infrequently give off
a large lateral branch that runs in a cranial and lateral direction and connects with the superior laryngeal nerve: the
communicating branch of the recurrent laryngeal nerve. In
conclusion, the recurrent nerve is not always a single strand
that ascends in the neck to enter the larynx. It may exhibit
a relatively complicated pattern of branches.
The easiest site at which to identify the recurrent nerve is
near where the inferior thyroid artery (which can easily be
seen or palpated between the carotid artery and the lateral
aspect of the lower pole of the thyroid) crosses the lateral
border of the lower pole of the thyroid gland. The recurrent
nerve or one of its branches may pass behind, between, or
before the branches of the artery, with at least one nerve
branch passing before the artery in about 40% of cases.
An advantage of this approach is its relative ease; a slight
disadvantage is the risk that the nerve has already given off
one or more branches at a more caudal level that are missed.

A result of such variation may be that if only one of two or
more branches of the recurrent nerve is identified, it may
be falsely assumed that "the" recurrent nerve has been
found, and the other branches may inadvertently be severed.
Fortunately, this situation is quite uncommon.
There are four other ways of identifying the recurrent
nerve.
1. The nerve can be located most caudally where it
crosses behind the cranial and medial curves of the
common carotid artery. At this level, the nerve lies further dorsally than at more cranial levels, but it can
always be identified if dissection is performed along
the mediocranial surface of the artery, exploring from
a lateral to a medial and dorsal direction toward the
trachea and esophagus. An advantage of this approach
is that the nerve is larger because it has not given
off branches. A second advantage is that, in case of
reoperation, the neck at this level may be unviolated,
facilitating identification of the recurrent nerve with
a lower risk of injury. A minor disadvantage of this
procedure is its slightly more cumbersome nature,
necessitating dissection of the loose connective, fatty,
and lymphoid tissues caudally in the neck.
2. The recurrent nerve can be identified at the level of
Berry's ligament, just caudal to its level of entry
through the cricothyroid muscle into the larynx. The
advantage of this approach is that the location of the
nerve at this level is fairly fixed. An important disadvantage is that it is located behind the thyroid, which
makes access difficult. In addition, this area is hypervascular, and annoying bleeding may easily occur,
especially from a small branch of the inferior laryngeal artery, which runs on the cranial border of Berry's
ligament and bleeds in close approximation to the
entry of the recurrent laryngeal nerve. Bleeding
from this artery should be treated with fine (5-0 or
6-0 Prolene) sutures or a hemoclip, a technique that
is preferable in all cases of bleeding close to the
recurrent laryngeal nerve. Coagulation with bipolar
diathermy is acceptable at distances of at least 5 mm
from the nerve and is therefore not the preferred
method of hemostasis in this area.
3. The recurrent laryngeal nerve can be identified with
the use of palpation instead of visually guided dissection. By gently pressing the loose connective, fatty,
and lymphoid tissues below the lower thyroid pole
against the trachea and moving the finger slowly ventrally and dorsally and back and forth, the nerve can
often be felt as a string that moves on the surface of
the trachea and tends to "snap" from underneath the
palpating finger. Once this sensation has been felt,
the connective tissue can be separated carefully in the
direction of the nerve. Careful alternation between
palpation and dissection prevents injury to the nerve.
4. Finally, neuromonitoring such as described earlier can
be used to identify the recurrent laryngeal nerve and
its course. 27. 37,46 Especially in reoperations, this can be
helpful, as are alternative surgical approaches to the
thyroid using previously undissected surgical planes
(i.e., an approach around the lateral border of the
sternohyoid and sternothyroid muscles)."
Complications concerning the laryngeal nerve cause

considerable morbidity and occur in 0% to 5% of the
patients. 11,27.44-48 In our series involving 755 nerves at risk,
the overall risk of permanent injury was 0.5%.
Postoperative hoarseness may be caused by several mechanisms. If it occurs in the first 2 to 5 days postoperatively, it
is most likely caused by edema in the operating field as a selflimited, innocent process. Long-term hoarseness (~6 months)
may occur if the recurrent nerve has been kept intact, whereas
stretching it too forcefully has damaged its axons. This can be
avoided by handling the nerve gently in all stages of the operation. The nerve should be separated carefully from the thyroid gland before the gland is retracted medially or otherwise
manipulated. Vessel loops, put around the nerve for better
anatomic identification, should never be kept in hemostats or
otherwise fixated, because traction on the loop may cause
nerve damage. In the case of nerve stretching, new axon ends
need to grow into the axon sheath, a process that takes 1 day
to grow 1 mm. Inadvertent cutting or clamping the recurrent
laryngeal nerve may cause permanent hoarseness. If this is
observed perioperatively, reanastomosis can be performed
using the operating microscope and 10-0 Prolene sutures, but
the outcome is often unsatisfactory.f'?'
When lesions of both recurrent laryngeal nerves occur,
patients have dyspnea and difficulty in breathing. These
patients should be reintubated or should have a tracheostomy. Most recover some function, but if dysfunction
is permanent, a lateralization or laser treatment of the vocal
cords is mandatory. Preoperative direct or indirect laryngoscopy should be performed in all patients with a voice
change, with proven malignancy, or with a history of neck
exploration. In our opinion, postoperative laryngoscopy does
not need to be performed routinely but instead may be
reserved for patients with vocal cord dysfunction seen at
laryngoscopy during extubation and for patients with voice
change after thyroid surgery. When vocal cord dysfunction
continues for 1 year, it is most likely permanent. However,
in cases of nerve reanastomosis, improvement is still possible, even after 1 to 2 years, in our own experience.
artery, and divides into terminal branches. Some of these

branches may communicate with branches of the recurrent
laryngeal nerve, either within the larynx, or externally. The
internal branch provides sensory innervation of the pharyngeal and laryngeal mucosa, extending from the base of the
tongue to the glottis and subglottic region. Lesion of the
nerve causes loss of sensation of the ipsilateral mucosa. This
loss is manifested clinically by aspiration of food and drink
on swallowing, caused by the defective sensori motor coordination of the glottis. Treatment consists of specialized
physiotherapy, in which the patient is trained to exhale while
swallowing.
The EBSLN takes a more caudal course, running in close
proximity to the medial aspect of the superior thyroid artery.
Cranial to the superior pole of the thyroid lobe, it curves
medially to innervate the cricothyroid muscle, which regulates the tension in the ipsilateral vocal cord. Two aspects
of its anatomy are important determinants of the risk of it
being injured during surgery at the upper pole of the thyroid:
(1) the level at which it crosses the (vessels of) the upper
pole of the thyroid and (2) whether it runs superficial to, or
is covered by, the inferior constrictor of the pharynx.
Cernea and associates have provided a classification system
for the course of the EBSLN that is widely accepted.52-54
Cernea type 1 means that the nerve crosses medially into
the cricothyroid muscle more than 1 em cranially to the
upper pole of the thyroid lobe; it occurs in about two thirds
of cases. Cernea type 2 means that the EBSLN runs within
a distance less than 1 em from the upper pole of the thyroid
gland, or passes even more caudally, thereby being at risk
during surgery at or near the upper pole; it occurs in the
remaining one third of cases. Depending on how far caudally the nerve extends, Cernea type 2 is subdivided into
types 2a and 2b. In Cernea type 2a, the nerve remains cranial to the upper pole of the thyroid lobe. A nerve that in its
most caudal position comes to lie below the upper pole of
the thyroid lobe is considered Cernea type 2b (Figs. 23-5
and 23-6). This location has clear surgical importance
Nerve Damage to the External Branch of

the Superior Laryngeal Nerve
Damage to the EBSLN causes less severe symptoms than
damage of the recurrent laryngeal nerve and is therefore less
easily recognized and documented. Because the course of
this nerve varies even more than that of the recurrent nerve,
knowledge of its anatomy is vital. The superior laryngeal
nerve, like the recurrent laryngeal nerve, originates from the
vagus nerve, in this case close to the caudal end of the
nodose ganglion above the hyoid bone. The nerve subsequently descends in the neck in a caudal, medial, and
ventral direction, crossing behind the external carotid artery
or the carotid bifurcation, where it gives off branches to the
carotid body. At the level of the hyoid bone, it divides into
an internal (sensory) branch and an external (motor) branch.
The common trajectory of the superior laryngeal nerve
and its internal branch is positioned cephalad to the dissection area used during thyroidectomy and is therefore not
encountered in standard thyroid surgery. The internal branch
of the superior laryngeal nerve curves medially, perforates
the thyrohyoid membrane above the superior laryngeal
FIGURE 23-5. External branch of superior laryngeal nerve

(EBSLN) passing below the left upper pole in a case of enlarged
dysplastic thyroid (Cernea type 2b).
FIGURE 23-6. External branch of superior laryngeal nerve
(EBSLN) running on the mediodorsal surface of the left upperpole

in a patient operated on acutely for asphyxia caused by a grossly
enlarged thyroid (Cernea type 2b).
because of an increased risk of injury during the dissection

and ligation of the superior thyroid pedicle during thyroidectomy (so-called high-risk nervesj." It goes without
saying that, especially in cases of type 2 crossing, the nerve
is at risk for inadvertent damage if the superior thyroid
vessels are clamped en masse and divided before the nerve
is freed.
The technique of identification of the EBSLN has been
described by several authors. 55-62 Of course, one should first
of all have adequate cranial exposure of the upper pole of the
thyroid by an adequate skin incision and by a sufficiently
high division of the linea alba cervicalis. Subsequently, the
sternohyoid and sternothyroid muscles are carefully dissected free from the underlying thyroid and are retracted laterally. An excellent procedure for identifying the EBSLN is
Lennquists's stepwise method, using (1) a midline incision
between the strap muscles, (2) opening of the space between
the upper pole and the cricothyroid muscle by laterocaudal
traction of the thyroid, (3) careful dissection of the thyroid
vascular pedicle, and (4) careful inspection of the inferior
pharyngeal constrictor." Most essential is step 2, in which
the upper part of the sternothyroid muscle is retracted
laterally and cranially to free the upper pole of the thyroid.
While this traction is continued, the loose connective tissue
located medial to the superior thyroid vessels is opened,
and the entire medial border of the thyroid lobe is carefully
inspected from the thyroid isthmus to the upper pole. One
should keep in mind that, if there are no nerve branches
crossing from the thyroid surface medially to enter the
cricothyroid muscle, one should not fear an EBSLN
entering the thyroid vascular pedicle more cranially. For
that reason, we prefer freeing the cricothyroid space in a
mediocaudal to laterocranial direction. Dissection is continued up to 1 em cranially from the end of the upper pole, until
the EBSLN is either identified and freed, or the superior thyroid vessels are freed over a sufficiently long course to make
certain that an unidentified nerve is not included in the vascular pedicle. In cases in which sparing of the EBSLN is crucial (e.g., in professional singers), use of the nerve stimulator
should be considered, especially in those cases where
anatomic identification of the nerve fails. Effective prevention

of iatrogenic lesions during thyroidectomy by intraoperative
identification of the external branch with a nerve stimulator
is described by Cernea and colleagues'? and Eisele. 63
However, identifying the nerve is not sufficient as long as
other important principles are forgotten. Lennquist and
coworkers reported that inappropriate use of diathermy
close to the external branch can cause damage, which also
occurs to the recurrent laryngeal nerves, and should therefore be avoided, in favor of ligatures." In all cases in which
sparing the EBSLN is considered relevant, the vessels of the
upper pole should be dissected individually and be ligated as
caudally as possible on the surface of the thyroid. The use
of clamps should be avoided in favor of suture ligation
between thin (4-0 or 5-0) absorbable ligatures.
The variations just described must be kept in mind when
one performs this procedure. Another important finding
is considerable asymmetry of the left and right EBSLNs.
Iatrogenic lesions of the external branch during thyroidectomy are not infrequent because of the anatomic variations
in relation to the superior thyroid vessels. The importance of
preserving the external branch during thyroidectomy was
dramatically demonstrated in 1935, when the famous opera
soprano Amelita Galli-Curci sustained injury to a superior
laryngeal nerve during thyroidectomy for an enlarged toxic
goiter, which ended her career. In singers, injury to this
nerve is a serious problem, although for some patients
symptoms are minimal and are often overlooked. Some
patients complain of mild hoarseness, voice weakness or
fatigue, loss of voice range (especially upper singing
registers), and lower voice volume. When both left and
right superior laryngeal nerves are injured, patients experience swallowing disorders, which make them vulnerable to
pneumonias.
The most accurate test for postoperative assessment of
superior laryngeal nerve paralysis is laryngeal electromyography; evaluation by laryngoscopy can be quite difficult.
The vocal cord on the involved side is usually bowed and at
a lower level than the contralateral vocal cord. In addition,
the anterior larynx is slightly rotated to the contralateral side
because of the action of the intact contralateral cricothyroid
muscle.
Hypoparathyroidism
Most individuals have four parathyroid glands situated on
the posterolateral capsule of the thyroid. Anatomic studies
have demonstrated that 80% to 86% of upper parathyroid
arteries and 90% to 95% of lower parathyroid arteries originate from the inferior thyroid artery. Truncal ligation of the
inferior thyroid arteries during thyroidectomy, however,
does not cause more hypoparathyroidism compared with
ligation of the branches of these arteries at the resection
margin of the thyroid capsule.v' Becuase superior thyroid
arteries may contribute significantly to the parathyroid
blood supply, and sufficient parathyroid blood supply may
be ensured by collaterals between thyroid vessels and neighboring esophageal and tracheal arteries.
The upper parathyroid glands are usually located lateral to
the recurrent laryngeal nerve at the level of Berry's ligament
and are the glands that are usually the easiest to preserve
during thyroidectomy because of their more lateral and

posterior position. The lower parathyroid glands are almost
always situated anterior to the recurrent laryngeal nerves
and caudal to where the recurrent laryngeal nerve crosses
the inferior thyroid artery.
Permanent hypoparathyroidism occurs in less than 3% ~f
the patients, whereas transient postoperative hypocalcemia
is much more common. 65-69 Ischemia or removal of the
parathyroid glands results in temporary or per~anent
hypoparathyroidism and may be caused ~y ?ccIdental
coagulation by heat induction, by devascularization, or by
accidental removal of the parathyroid glands. For better
identification of the vascularization of the gland, magnifying glasses (x2.5) are helpful. The parathyroid glands
should not be mobilized extensively, or they may be devascularized during the dissection. When a parathyroid gland
cannot be safely dissected from the thyroid gland on a good
vascular pedicle, it should be removed and then autotransplanted into the sternocleidomastoid muscle or into t~e
brachioradial muscle of the nondominant arm. Parathyroid
glands should be inspected carefully with m~gnifying
glasses both during and at the end of the operatron. Any
gland that appears ischemic should be removed and aut.otransplanted because there is no reason to assume that Its
vascular supply will recover. Not doing so means unnecessarily running the risk of hypoparathyroidism. On the other
hand, there is no reason to perform biopsy of normalappearing parathyroid glands durin~.
thyroid. su.rgery
because this obviously subjects them to injury. Earlier III our
patient series, when parathyroid biopsy was regularly used,
symptomatic hypocalcemia requiring supplementation
occurred in about 10% of patients, and permanent hypocalcemia (6 weeks to 6 months after thyroid surgery) was seen
in 3.5%. In later years, we have more and more come to rely
on surgical identification of the parathyroids. The criteria ~e
use are (1) position; (2) mobility independent of the thyroid
gland; (3) brownish color; (4) smooth, finely granular surface;
(5) presence of vascular pedicle; (6) easy bleeding on
manipulation, in particular the rapid spread of a subcapsular
hematoma in case of manipulation with forceps; and (7) the
presence of a small "fatty hood." With these seven criteria,
we rarely need frozen section biopsy to identify parathyroids. Permanent hypoparathyroidism has thereby decreased
to below 2%.
Preoperative serum calcium levels should be checked
routinely in each patient undergoing bilateral thyroid
procedures. Postoperative hypocalcemia resulting from
hypoparathyroidism is seen after bilateral thyroidectomy but
almost never after unilateral thyroidectomy unless the
patient has had previous thyroid surgery. If there are clinical
symptoms, oral calcium should be given. Permanent
hypoparathyroidism is evident when, after 1 year: serum
calcium levels are below 2.25 mmol/L and the patIent has
symptoms and requires treatment with vitamin D and
calcium. Such patients also have high phosphate levels.
Permanent hypoparathyroidism results in lifetime disability.
Despite frequent testing and adjustments in therapy, fatigue,
paresthesias, and irritability are common. Cata~acts
h~ve
been reported in as many as 70% to 80% of patients WIth
permanent hypoparathyroidism, despite laboratory evidence
of normocalcemia.s?
Hypothyroidism
Hypothyroidism occurs after total or near-total thyroidectomy and increases in frequency after subtotal procedur~s
as
the size of the remnant decreases. Menegaux and associates
compared the outcome of surgical treatment for Graves' disease from 1966 to 1980 and from 1981 to 1988. 70 During the
second period, in which bilateral subtotal thyroidectomy
was abandoned for unilateral total lobectomy and a subtotal
lobectomy on the other side (Dunhill procedure), the rate of
permanent recurrent laryngeal nerve and recurrent hyperthyroidism decreased (from 1% to 0% and from 11% to 3.7%,
respectively), whereas the rate of permanent hypoparathyroidism and hypothyroidism increased (from 1% to 1.9%
and 13% to 48.7%, respectively).
Summary
During thyroid operations, it is important to achieve a balance between the benefits of extensive resection for cure and
the increased potential for complications. More extensive
thyroid resections, especially when combined with bilateral
and central neck and modified radical neck dissections, are
associated with more postoperative complications, as are
reoperations.":" However, the literature contains numerous
reports of total thyroidectomy and reintervention by experienced surgeons in which the prevalence of recurrent laryngeal nerve injury and permanent hypoparathyroidism is
2% or less, demonstrating that these operations can be done
with minimal morbidity." Total thyroidectomy has been
proposed for multinodular goiters involving the entire g~a.nd,
Graves' disease, and malignancies by a few authorities,
because total thyroidectomy eliminates the possibility of
recurrence. However, complications may occur, even in
experienced hands, and in the same surgeon's hands more
extensive thyroid operations are associated with more complications. To keep morbidity to a minimum, thyroid operations for patients with cancer or large goiters should be
performed by surgeons trained in endocrine surgery, with
extensive knowledge of the topographic anatomy and its
variations. To maintain surgical skills, we believe that individual surgeons bearing responsibility for surgical outcomes
should perform no fewer than 10 thyroidectomies annually.
If these principles are followed, thyroid surgery can be
performed in teaching hospitals such as ours with minimal
morbidity and almost zero mortality.18,74-76
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Thyroid Emergencies: Thyroid

Storm and Myxedema Coma
Chen-Hsen Lee, MD Hong-Da Lin, MD
Thyroid storm and myxedema coma are life-threatening

medical emergencies resulting from extreme hyperthyroidism or hypothyroidism with multiorgan dysfunction.
Although they are rare conditions, when they are not recognized and treated quickly, the outcome may be fatal. Today,
these conditions rarely occur after thyroid operations.
Nevertheless, it is important that surgeons understand the
clinical manifestations, pathophysiology, and effective treatment of these conditions because they may be precipitated
by trauma, and patients with untreated or inadequately
treated preexisting hyperthyroidism or hypothyroidism may
require urgent operations.
Thyroid Storm
Thyroid storm is a poorly defined clinical syndrome. The
synonyms include thyroid crisis, thyrotoxic storm, and
thyrotoxic crisis. Thyroid surgery, once the most common
pathogenesis of thyroid storm, has become a rare cause of
this disorder. Even senior surgeons have seen only a few
such patients. This is attributable to recognition of these
patients, to administration of appropriate antithyroid drugs,
and to the popularity of radioactive iodine therapy for treating
patients with thyrotoxicosis. Nonthyroid surgery, major
trauma, infection, and image studies with iodinated contrast
medium in patients with unrecognized thyrotoxicosis may
act as precipitating factors of thyroid storm. For unequivocal cases of thyroid storm at our medical center, pneumonia,
perforation of a peptic ulcer, iodinated contrast medium, and
coexistent hyperparathyroidism with extreme hypercalcemia (serum calcium> 15 mg/dL) were considered precipitants. Known precipitants of thyroid storm are listed in
Table 24-1.1. 3 Without early clinical recognition and initiation
of therapy, thyroid storm carries a 10% to 75% mortality in
hospitalized populations."
Thyroid storm is usually abrupt in onset, with clinical features of thyrotoxicosis. Hypermetabolism contributes to the
216
development of fever, with temperatures occasionally

exceeding 40 C, and is usually considered a major factor in
differentiating thyroid storm from nonstorm thyrotoxicosis.>
Without treatment, the fever may progressively increase to
lethal levels within 24 to 48 hours. Patients with thyroid
storm have warm skin and are flushed, with profuse
diaphoresis. A goiter as well as exophthalmos mayor may not
be evident. Tachycardia-s-often greater than 140 beats/minand atrial fibrillation are common, and tachypnea is frequently seen. Ventricular dysfunction and acute pulmonary
edema or congestive heart failure may develop. Tremor
and severe agitation are characteristic. Emotional lability,
restlessness, confusion, and delirium are common and may
progress to frank psychosis, stupor, and coma. Severe diarrhea is the most common gastrointestinal symptom, but
nausea, vomiting, and abdominal pain also occur and may
suggest an acute abdominal emergency. Hepatomegaly is
often present, and mild jaundice and abnormal liver function
tests suggestive of hepatocellular dysfunction are sometimes
present. Leukocytosis is present occasionally, especially in
patients with coexistent infections.
Diagnosis
Early diagnosis and treatment remain the most important
determinants in the successful management of patients with
thyroid storm. Any delay in establishing this diagnosis and
instituting treatment may increase the risk of a fatal outcome.
Laboratory examinations for serum triiodothyronine (T 3),
thyroxine (T4 ) , and free T 4 are usually nondiagnostic,
because these tests are similar in patients with storm and
nonstorm thyrotoxicosis." It is important to recognize that
this condition is a clinical diagnosis. Characteristic features
such as Bayley's symptom complex? of insomnia, anorexia,
vomiting, diarrhea, marked sweating, and great emotional
instability are reliable in predicting impending storm. A
temperature greater than 38 C, marked tachycardia, accentuated symptoms and signs of thyrotoxicosis, and central
nervous system (CNS), cardiovascular, or gastrointestinal
system dysfunction indicate storm.v" A score of 25 to 44
using the scale of Burch and Wartofsky" is suggestive of
Thyroid Emergencies: Thyroid Storm and Myxedema Coma - - 217
impending storm, and a score of 45 or higher is highly suggestive of storm (Table 24-2). One should be aware that patients
rarely have thyroid storm and apathetic thyrotoxicosis, coma,
cerebral infarction, status epilepticus, rhabdomyolysis, and
acute renal failure."
Pathophysiology
The mechanism underlying the pathogenesis of thyroid
storm is not completely known. A dramatic increase in serum
free T4 level is commonly observed and may precipitate the
onset of thyroid storm. Additional factors such as poor
nutrition and complicating medical, surgical, and emotional
effects on thyroid hormone binding, metabolic clearance,
general physiologic reserve, and increased catecholamines
are other important contributors." Besides, in our unique
experience with thyroid storm combined with primary
hyperparathyroidism, a markedly elevated serum calcium
level may augment the action of T4 via its role as a second
messenger. 10
Treatment
It is crucial that treatment be instituted promptly. One
should not wait for the results of measurements of serum
total and free T4 or T 3 concentrations to begin treatment.'
Therapy is directed at blocking thyroid hormone synthesis,
secretion, and action on peripheral tissues. Supporting treatment to reverse the ongoing or incipient decompensation of
normal homeostatic mechanisms, with elimination of any
known precipitating factor or concurrent illness, is imperative. Continuous monitoring and minute to minute titration
of therapy in an intensive care unit are mandatory.
ANTITHYROID THERAPY
The antithyroid drug propylthiouracil (PTU) is administered

by mouth to block new hormone synthesis and to decrease
the extrathyroidal conversion of T4 to T3 The effect of this
treatment begins within an hour of administration. Burch

and Wartofsky" advised a loading dose of 600 to 1000 mg
PTU followed by 200 to 250 mg every 4 hours. In our
experience, a loading dose of 200 mg followed by 200 mg
of PTU every 4 hours can be equally effective. Methimazole
(20 mg every 4 hours) is not recommended because, even
though it decreases thyroid hormone synthesis, unlike PTU
it does not affect extrathyroidal conversion of T4 or T3. In
patients with severe vomiting or in those who cannot take
anything orally, rectal administration can be an alternative. 1I
In the stuporous, comatose, or uncooperative patient, gavage
is advised via a nasogastric tube.
Inorganic iodide is given to inhibit iodine pump, colloid
proteolysis, and release of T4 and T3 from the thyroid gland.
218 - -
Thyroid Gland
Oral dosages from 0.2 to 2 g/day are recommended. It can

be given as Lugol's solution, 8 drops every 6 hours, or a saturated solution of potassium iodide,S drops every 6 hours.
Sodium iodide for intravenous use, such as the radiographic
contrast medium sodium ipodate, if available, should be
infused slowly in a dosage of 0.5 to 1 g every 12 hours.F It
is advised that iodine therapy not be started until an effective
blockade of new hormone synthesis has been established
with antithyroid therapy ('"1 hour), because iodine alone will
lead to a further fortification of the thyrotoxic state and
increase surgical risk owing to an enrichment of glandular
hormone store." Treatment with iodide blocks thyroid gland
secretion and, therefore, has a faster onset of effective therapy than PTU, which blocks synthesis in a thyroid gland that
has a large store of already formed hormone.
ADRENERGIC DEPLETION
The fact that the manifestations of thyrotoxicosis closely

resemble those of sympathetic, especially p-adrenergic,
overactivity provides the rationale for adrenergic depletion.
Reserpine and guanethidine, either alone or in combination
with other modes of therapy, have been successful in the
treatment of thyroid storm. However, owing to hypotension
and other untoward side effects, their use has been replaced
by a p-adrenergic receptor blocker as the agent of choice.
Propranolol is the most frequently used p blocker, which
also inhibits peripheral conversion of T, to T 3 . It is, however,
contraindicated in patients with bronchial asthma because of
precipitating bronchospasm. Propranolol also blocks the
symptoms of hypoglycemia so that patients with insulinrequiring diabetes mellitus may not experience warning
signs of this dangerous situation. It should also be used with
caution in patients with heart failure unless one is sure that
the cardiac embarrassment is not due to intrinsic heart disease. On the other hand, severe bradycardia in response to
propranolol may be treated with atropine, and bronchospasm
or left ventricular compromise may be treated with isoproterenol. The recommended dosage of propranolol varies
from 20 to 80 mg orally, every, 4 to 6 hours. For a more
rapid effect, propranolol may be given intravenously by
slow push at an initial dose of 0.5 to 1 mg, along with continuous electrocardiographic monitoring. Subsequent intravenous doses of 1 to 2 mg at IS-minute intervals are used to
titrate the patient's heart rate. The ultrashort p blocker
esmolol has been reported successful in the perioperative
management of thyroid storm. 13,14 A loading dose of 250 to
500 ug/kg followed by a continuous infusion rate of 50 to
100 ug/kg/min has been demonstrated.
TREATMENT OF SYSTEMIC DECOMPENSATION
Treatment of systemic decompensation includes reversal of

hyperthermia, dehydration, congestive heart failure, and
dysrhythmia and prevention of adrenal crisis. Hyperthermia
should be aggressively treated with antipyretics and peripheral cooling. Acetaminophen is preferred to salicylates for
this purpose because aspirin increases free hormone levels by
decreasing the binding to T4-binding globulin and potentially
could aggravate the thyroid storm." Alcohol sponges, ice
packs, and cooling blankets are frequently used for peripheral cooling. It is important to prevent or decrease shivering
during the rapid reduction in elevated body temperature with
small doses of chlorpromazine and meperidine; the latter is

used so as not to depress the state of mentation.? To replace
fluid loss, either gastrointestinal or insensible, a volume of
3 to 5 L/day may be required. A central venous pressure
catheter, pulmonary wedge pressure monitoring, or both,
is necessary to evaluate fluid replacement carefully.
Electrolytes, glucose, and vitamins, especially thiamine, are
essential to replace possible deficiency. Cardiovascular
complications, including atrial fibrillation and congestive
heart failure, are treated conventionally. Larger loading and
maintenance doses of digoxin may be required because of
the more rapid clearance in patients with marked hyperthyroidism. Serum digoxin levels should be closely monitored,
particularly as thyroid storm improves and metabolic rate is
lowered, to prevent digitalis intoxication. Intravenous
hydrocortisone, 300 mg initially followed by 100 mg every
8 hours, is administered to prevent adrenal crisis because of
relative adrenal insufficiency. Steroids also decrease the
extrathyroidal conversion of T4 to T 3'
TREATMENT OF COEXISTENT ILLNESS
AND DEFINITIVE TREATMENT
Because most patients in thyroid storm are febrile, with

leukocytosis, an inflammatory or infectious focus should
be sought and bacterial cultures obtained. Prophylactic antibiotic treatment is not recommended." Any coexistent hypoglycemia, hypercalcemia, or diabetic ketoacidosis should be
corrected, and standard treatment for stroke or pulmonary
embolism should be instituted simultaneously with the treatment of thyroid storm. In the stuporous, comatose patient
or one with poor communication abilities, a history may
be unavailable or inaccurate. As many as 25% to 43% of
patients with thyroid storm present with no known precipitating event.4.7 8 In most patients, clinical improvement is
observed within 24 hours, and complete recovery from
storm occurs within a few days to a week. These treatment
modalities should be withdrawn gradually to prevent recurrent
crisis, because the half-life of T, is approximately 1 week. For
patients requiring emergency operation and those who have
sustained significant trauma, surgical intervention should be
performed as soon as the patient is stabilized with such
measures as hydration, p blockade, intravenous sodium ipodate, hydrocortisone, PTU, and cooling. For definitive treatment of thyrotoxicosis, a subtotal thyroidectomy or other
therapy is performed when the patient is euthyroid and the
crisis situation has resolved. Unless contraindicated, p
blockade should be continued during the postoperative
period. Our patient with thyroid storm and hypercalcemic
crisis was successfully treated by urgent removal of a 3-g
parathyroid adenoma and simultaneous subtotal thyroidectomy after rapid preoperative treatment of the hypercalcemia
and storm were instituted (Fig. 24-1). The mortality rate has
fallen from nearly 100% to about 20% with a better understanding of appropriate management of patients with thyroid
storm, although the improvement may also be partly attributable to the relaxation of diagnostic criteria.I-?
Prevention
Given the significant mortality associated with thyroid
storm, it would be beneficial to prevent episodes completely
Thyroid Emergencies: Thyroid Storm and Myxedema Coma - -
219
Hydration, diuretics, and ATD
s
...J
Serum P
2
Serum creatinine
<,_--""][------r--------~
~ctl
E
(])
a:
-5
10
Hospital days
20
FIGURE 24-1. Clinical course of a 47-year-old woman with hyperthyroid and hyperparathyroid crisis. She was found irritable with fever,
abdominal pain, and previously unrecognized grade II goiter. The consciousness change progressed to stupor 5 days after disease onset and
the patient was therefore referred to this medical center. When myocardial ischemia, shortened QT interval, and hypercalcemia were
revealed on electrocardiogram (ECG) and SMAC examinations, radiographs of the hand were taken and showed subperiosteal resorption
suggestive of primary hyperparathyroidism. Elevated serum phosphate, amylase, and creatinine levels were also noted. The white blood
cell (WBC) count was within the normal limit. Hydration and diuretics were started at the emergency department. On admission to the hospital, 24-hour iodine 131 uptake was 53% and thyroid scan showed diffuse uptake. Antithyroid treatment with propranolol and propylthiouracil were administered before elevated serum triiodothyronine (T3) and thyroxine (T4) levels were available on the third day. At the
end of the first week, the vital signs were stabilized and a follow-up ECG showed normal sinus rhythm while the consciousness fluctuated
from drowsiness to stupor. A second measurement of T 3 and T 4 levels showed the patient to be euthyroid on the 10th day, and an urgent
neck exploration was done. A parathyroid adenoma weighing 3 g was removed, and a simultaneous bilateral subtotal thyroidectomy was
performed. The patient was discharged in a euthyroid and fully conscious state 20 days after admission with normal renal function and
eucalcemia. P =phosphorus; Ca =calcium; BT = body temperature; PTx = parathyroidectomy; Tx = thyroidectomy; ATD =antithyroid drug;
HR = heart rate; CCr =creatine clearance.
or at least recognize impending storm and treat it aggressively before significant decompensation occurs. As noted
previously, surgical storm has been virtually eliminated by
the preoperative treatment of thyrotoxic patients. Patients
with hyperthyroidism should be diagnosed early in their
course and treated aggressively to return them to a euthyroid
state as quickly as possible. The potential for an intercurrent
illness to precipitate storm in a thyrotoxic patient needs to
be recognized and communicated to the patient as well.
Elective surgery should be postponed. If surgery is urgent,
patients should be properly prepared and watched closely
for evidence of developing storm. Thionamides should not
be withdrawn in preparation for radioiodine until hyperthyroidism is controlled. IS
Myxedema Coma
Myxedema coma is another thyroid emergency. It is
the extreme clinical manifestation of severe thyroid
hormone deficiency. This syndrome is rare and is usually,

but not exclusively, encountered in elderly women during
the winter months. Most patients have long-standing
untreated hypothyroidism or have arbitrarily discontinued
thyroid hormone replacement. Although the prognosis for
myxedema coma is markedly improved by the introduction
of high-dose intravenous T4 treatment, it is still associated
with a mortality rate of about 20%.16
Before the development of myxedema coma, patients usually have some signs of hypothyroidism. In some cases it
develops spontaneously as a result of prolonged severe
hypothyroidism, but in most situations several factors, such
as infection, trauma, surgery, stroke, myocardial infarction,
cold exposure, and administration of certain drugs, predispose to its development (see Table 24_1).6.17-19 The pathogenesis of myxedema coma is not completely understood.
Major clinical features are progressive deterioration of

consciousness, hypothermia, hypoventilation, hyponatremia,
bradycardia, hypotension, and seizure. Because patients
often present in coma, it may be difficult to know whether
the patient has had a stroke, has myxedema coma, or both.
Decreased mental function is an important feature of
myxedema coma. Lethargy, stupor, confusion, and psychiatric symptoms may precede the coma. The causes of the
altered mental status and CNS decompensation in patients
with severe thyroid hormone deficiency include hyponatremia,
carbon dioxide (C0 2) narcosis, hypoglycemia, postictal
mental disorder, and coexistent sepsis or hypoadrenalism.
Administration of sedatives and tranquilizers may further
suppress the CNS because the clearance of drugs is
markedly retarded in hypothyroid patients.
Heat production by brown adipose cells is stimulated
by catecholamines through a-adrenergic receptors and modulated by thyroid hormone. Hypothermia is commonly
encountered in myxedema coma and may precede the development of coma. The body temperature may be as low as
24 to 34 C and often cannot be recorded by the usual thermometer. Hypothermia is due to severe hypometabolism,
adaptive peripheral vasoconstriction, and relatively unopstimulation.'? Underlying hypoglycemia
posed ~-adrenergic
contributes to, and concurrent infection may impede, the
development of hypothermia,
Profound hypoventilation is common in patients with
myxedema coma and requires mechanical ventilatory assistance to relieve CO 2 retention and hypoxia. Although hypercapnia and loss of hypoxic drive are the cardinal physiologic
mechanisms involved, other factors such as macroglossia,
edema of vocal cords and pharynx, bradycardia, reduced
stroke volume, anemia, pleural effusion, ascites, pericardial
effusion, weakness of respiratory muscles, superimposed
pulmonary infection, and administration of drugs that cause
CNS depression may further suppress or worsen the respiratory function.
Hyponatremia is common in severe thyroid hormone
deficiency because thyroid hormone has an effect on renal
tubule sodium reabsorption and water excretion. In addition,
an inappropriate plasma vasopressin level has been demonstrated in some patients with myxedema coma." Other
factors such as fluid overload, congestive heart failure, and
inadequate use of diuretics further contribute to a low serum
sodium concentration. Severe hyponatremia not only leads
to deterioration of the patient's consciousness level but is
also responsible for most seizures, which occur in about
25% of patients with myxedema coma.
Hypoglycemia is an uncommon finding and may indicate
coexistent adrenal insufficiency. A low blood glucose
concentration, however, may also result from impaired
glycogenolysis and gluconeogenesis, increased insulin
sensitivity, and malnutrition without hypoadrenalism.
Hypoglycemia is also responsible for seizures in some
patients with myxedema coma.
Diagnosis
The natural course and fatal outcome of myxedema coma
can be altered by a timely diagnosis and prompt and appropriate treatment. A high index of suspicion on the basis of
history and clinical features is important. Measurement of
serum thyroid-stimulating hormone (TSH) and thyroid

hormone concentrations confirms the diagnosis of hypothyroidism. However, just as in thyroid storm, the results of
serum thyroid function tests correlate poorly with the clinical
severity of myxedema coma, and many patients with
hypothyroidism without coma have equally abnormal (high
TSH and low T 3 and T4 ) thyroid function tests. In patients
with central or secondary hypothyroidism, serum TSH, T 3,
and T4 levels are low. Elevation of serum creatine kinase
(CK), lactate dehydrogenase, and transaminase levels in
severe hypothyroidism may help in the differential diagnosis.
The isoenzyme pattern of increased CK is predominantly
MM, consistent with skeletal muscle origin. In case of a
greatly elevated CK-MB fraction, concomitant myocardial
infarction is suggested, which may not be evident clinically."
It is important to document these tests and to obtain an electrocardiogram (ECG) before instituting treatment with thyroid
hormone in case chest pain develops with treatment. Pituitary
adenomas and craniopharyngiomas are the most frequent
causes of secondary hypothyroidism. Computed tomography
scanning of the head may demonstrate either a pituitary or
hypothalamic lesion in most cases of central hypothyroidism.
Although the symptoms and signs of myxedema coma
usually create a pathognomonic clinical picture, the rarity
of this condition sometimes causes the diagnosis to be overlooked. The insidious onset of symptoms further impedes
the early recognition of this syndrome. Myxedema coma
should be considered in the differential diagnosis of any
patient who presents with an altered mental status, profound
hypothermia, and unexplained CO 2 retention, either alone
or in combination. One should be particularly alert to any
hypothyroid patient who has received radioiodine therapy or
who has been treated with total or subtotal thyroidectomy
for Graves' disease.
Treatment
The strategies for the treatment of myxedema coma are
(1) maintenance of cardiopulmonary function, (2) institution
of thyroid hormone therapy, (3) treatment of metabolic complications, (4) elimination of precipitating factors or concurrent illnesses, and (5) provision of general supportive care.
PULMONARY AND CARDIOVASCULAR SYSTEMS
Death in patients with myxedema coma is frequently caused

by respiratory failure and cardiovascular collapse. Once the
diagnosis is made, prompt and close monitoring of cardiopulmonary function must be instituted. CO2 retention and
respiratory acidosis can be confirmed by arterial blood gas
analysis and rapidly relieved by intubation and mechanical
ventilatory support. These treatments are usually required,
especially when hypoventilation is aggravated by the administration of sedatives, tranquilizers, or narcotics.
Hypotension in myxedema coma is due to blood volume
depletion, intrinsic heart disease, or pericardial effusion.
Thyroid hormone therapy, whole-blood transfusion, and
administration of hydrocortisone may correct the hypovolemia. Pressor agents are seldom needed. If congestive
heart failure develops, the patient should be digitalized
and treated with diuretics or afterload-reducing agents.
Concomitant myocardial infarction indicates a poor outcome.
Thyroid Emergencies: Thyroid Storm and Myxedema Coma - -
THYROID HORMONE REPLACEMENT
Myxedema coma is due to thyroid hormone deficiency,

resulting in organ decompensation. Thyroid hormone
replacement is, therefore, essential in its management. The
initial dose of levothyroxine is 300 to 500 ug given intravenously. Because the patient with myxedema coma usually
has intestinal atony with poor intestinal absorption, thyroid
hormone and other medications are administered intravenously rather than orally. After the initial dose, serum T4
and T 3 levels gradually rise, and the patient should be subsequently maintained on 50 to 100 ug/day intravenously. As
soon as the patient regains consciousness, orallevothyroxine
is instituted.
Formerly, low-dose thyroid hormone replacement was
recommended because of concern of underlying cardiac
disease, but the mortality rate was as high as 80% with
low-dose thyroid hormone treatment.Pr" However, there has
been considerable progress in supportive medical care in the
past decades. Yamamoto and associates suggested that not
every patient requires a high dose of thyroid honnone. They
also found that a bolus of 500 Ilg of levothyroxine by mouth
or via nasogastric tube is effective and can be tolerated by
patients younger than 55 years of age." A survey
of hospitals in Germany (1993-1995) identified a group of
24 patients with myxedema coma, treated initially with
levothyroxine in doses ranging from 25 to 500 ug, that had
six deaths (mortality rate, 25%).25
Some authors believe that myxedema coma is partially
related to decreased 5'-deiodinase activity with impairment
in conversion of T4 to T3 in patients with nonthyroidal
illnesses.v-" They recommend using liothyronine (T3) hormone at an initial dosage of 25 ug every 8 hours intravenously
for 1 day followed by 12.5 ug every 8 hours the next day. As
soon as the patient's consciousness improves, T 3 is changed to
orallevothyroxine. Gastrointestinal absorption of T 3 is better
than levothyroxine, and because an injectable form is not
available, T3 is usually given orally. Careful monitoring of
cardiac function is required during T 3 replacement, because
treatment with T 3 is associated with more cardiac arrhythmias and a higher mortality rate.2328 A survey that collected
87 cases of myxedema coma published in English, French,
German, and Japanese since 1970 found that the incidence
of death was highest after treatment with T3 of 75 ug/day or
more with or without levothyroxine."
Wartofsky has suggested the combined use of levothyroxine and T 3 for patients with myxedema coma." An initial
dose of 200 to 300 ug levothyroxine is given intravenously,
followed by a dose of 100 ug 24 hours later. A maintenance
dosage of 50 ug/day is started on the third day. T 3 is initially
given daily with a dosage of 10 ug every 8 hours and discontinued when the patient can take oral feedings.
No matter what type of hormonal replacement is given,
continuous ECG monitoring is mandatory, and patients
should be continuously monitored in an intensive care unit.
In patients with cardiac arrhythmia or myocardial ischemia,
thyroid hormone replacement is discontinued or dramatically lowered.
TREATMENT OF METABOLIC COMPLICATIONS
Hypothermia usually improves after administration of thyroid

hormone. Generally, no specific therapy is needed except
221
blankets to prevent further heat loss. External rewarming

should be avoided because it can cause vasodilation, leading
to cardiovascular collapse. Because prolonged profound
hypothermia suggests a poor prognosis, active rewarming is
sometimes recommended, accompanied by whole-blood
transfusion in patients with a body temperature below
30 C.6 Mild to moderate hyponatremia is usually corrected
by fluid restriction and thyroid hormone therapy. Hypertonic
saline and glucose are only occasionally required to alleviate
severe hyponatremia (sodium < 110 mEqlL) and hypoglycemia. Seizures are prevented by correcting the hyponatremia, hypoglycemia, hypercapnia, and hypoxia. When
seizures occur, they are treated with anticonvulsants.
ELIMINATION OF PRECIPITATING FACTORS
AND CONCURRENT ILLNESS
Infection is probably the most common precipitating factor

of myxedema coma. Any delay in the diagnosis and treatment of bacterial infection is associated with a poor outcome.
One should vigorously search for any possible source of
infection and aggressively treat it with specific antibiotics,
because fever, sweating, tachycardia, and leukocytosis may
be totally absent in patients with myxedema coma and concurrent bacterial infection. Nicoloff and LoPresti 19 recommended broad-spectrum intravenous antibiotic coverage for
patients until all cultures return to negative. One should also
be alert to the presence of other concurrent diseases such as
cardiac and cerebrovascular diseases and gastrointestinal
bleeding.
GENERAL SUPPORTIVE CARE
A plan of general medical care, as applied to comatose

patients, such as frequent changes in position, prevention of
aspiration, and bowel and bladder care, should be undertaken.
Paralytic ileus is frequently found with myxedema coma
and should be differentiated from mechanical obstruction,
which usually requires surgical intervention. Ileus resulting
from myxedema coma improves with thyroid hormone
therapy. Both thyroid and adrenocortical failure may occur
in patients with panhypopituitarism and polyglandular
autoimmune syndrome. Treatment of such patients with
thyroid hormone without simultaneous administration of
cortisol results in adrenal crisis. Because institution of
thyroid hormone therapy in severe hypothyroidism might
induce adrenocortical insufficiency, most investigators recommend intravenous hydrocortisone, 100 mg every 8 hours
for the first few days, for all myxedema coma patients. 293o
The dose can be rapidly tapered or discontinued when the
random serum cortisol value is 18 ug/dl, or greater."
Summary
Thyroid storm and myxedema coma are uncommon important endocrine emergencies. Despite improvement in treatment, patients still die. It is better, therefore, to prevent
thyroid storm and myxedema coma than to face their consequences. Rapid diagnosis on the basis of clinical judgment,
history, and physical examination and institution of appropriate therapy are important. Since both conditions can be
precipitated by trauma and critical illness that brought the
222 - -
Thyroid Gland
patients to the emergency department or intensive care unit,

physicians in charge should be alert to their occurrence
during the management for patients' primary diseases.
Usually, these two conditions present with typical findings.
Patients with both thyroid storm and myxedema coma
should be managed in an intensive care unit with continuous
ECG, arterial blood gas, and central venous pressure monitoring. Bacterial infection should be sought both in patients
with thyroid storm and with myxedema coma. Delay in
instituting therapy and premature weaning from the ventilator are common pitfalls in the management of patients with
myxedema coma. In addition, adverse reactions can occur
with the administration of vasopressors, sedatives, or tranquilizers and with active rewarming for hypothermia in
patients with myxedema coma. Early recognition and proper
treatment may avoid the catastrophe. "When in doubt, treat"
is an advisable clinical axiom for the successful management of these patients with decompensated hyperthyroidism
or hypothyroidism."
REFERENCES
I. McDermott MT. Kidd GS, Dodson LE, et al. Radioiodine-induced
thyroid storm: Case report and literature review. Am J Med 1983;
75:353.
2. Shimura H, Takazawa K, Endo T, et al. T4 thyroid storm after CT scan
with iodinated contrast medium. J Endocrinol Invest 1990;13:73.
3. Thompson NW, Fry WJ. Thyroid crisis. Arch Surg 1964;89:512.
4. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: Thyroid
storm. Endocrinol Metab Clin North Am 1993;22:263.
5. Ingbar SH. Thyroid storm or crisis. In: Werner SC, Ingbar SH (eds),
The Thyroid, 4th ed. Hagerstown, MD, Harper & Row, 1978, p 800.
6. Nicoloff JT. Thyroid storm and myxedema coma. Med Clin North Am
1985;69:1005.
7. Bayley RH. Thyroid crisis. Surg Gynecol Obstet 1984;59:41.
8. Waldstein SS, Slodki SL, Kaganiec GI, et al. A clinical study ofthyroid
storm. Ann Intern Med 1959;52:626.
9. Mazzaferri EL, Skillman TG. Thyroid storm: A review of 22 episodes
with special emphasis on the use of guanethidine. Arch Intern Med
1969;124:684.
10. Bennett WR. Huston DP. Rhabdomyolysis in thyroid storm. Am J Med
1984;77:733.
II. Yeung S, Go R. Balasubramanyam A. Rectal administration of iodide and

propylthiouracil in the treatment of thyroid storm. Thyroid 1995;5:403.
12. Wu S-Y, Chopra 11, Solomon DH, et al. The effect of repeated administration of ipodate (Oragrafin) in hyperthyroidism. J Clin Endocrinol
Metab 1978;47:1358.
13. Isley L, Dahl S, Gibbs H. Use of esmolol in managing a thyrotoxic
patient needing emergency surgery. Am J Med 1990;89:122.
14. Brunette DD, Rothong e. Emergency department management of thyrotoxic crisis with esmolol. Am J Emerg Med 1991;9:232.
15. Tietgens ST, Leinung Me. Thyroid storm. Med Clin North Am
1995;79:169.
16. Jordan RM. Myxedema coma, pathophysiology, therapy and factors
affecting prognosis. Med Clin North Am 1995;79:185.
17. Myers L, Hays J. Myxedema coma. Crit Care Clin 1991;7:43.
18. Wartofsky L. Myxedema coma. In: Braverman LE, Utiger RD (eds),
The Thyroid. Philadelphia, Lippincott Williams & Wilkins, 2000, p 843.
19. Nicoloff JT, LoPresti JS. Myxedema coma, a form of decompensation
hypothyroidism. Endocrinol Metab Clin North Am 1993;22:279.
20. Iwasaki Y, Oisa Y, Yamandin K, et al. Osmoregulation of plasma vasopressin in myxedema. J Clin Endocrinol Metab 1990;70:534.
21. Hickman PE, Silvester W, Musk AA, et al. Cardiac enzyme changes in
myxedema coma. Clin Chern 1987;33:622.
22. Nickerson JF, Hill SR, McNeil JH Jr, Barker SB. Fatal myxedema with
or without coma. Ann Intern Med 1960;53:475.
23. Forester CF. Coma in myxedema: Report of a case and review of the
world literature. Arch Intern Med 1963; 111:100.
24. Yamamoto T, Fukuyama J, Fujiyoshi A. Factors with mortality of
myxedema coma: Report of eight cases and literature survey. Thyroid
1999;9:1167.
25. Reinhardt W, Mann K. Incidence, clinical picture, and treatment of
hypothyroid coma: Results of a survey. Med Klin 1997;92:521.
26. McCullach W, Price P,Hinds CJ, et al. Effects of low-dose oral triiodothyronine in myxedema coma. Intensive Care Med 1985; II :259.
27. Pereira VG, Haron ES, Lima-Neto N, et al. Management of myxedema
coma: Report on three successfully treated cases with nasogastric or
intravenous administration of triiodothyronine. J Endocrinol Invest
1982;5:331.
28. Hylander B, Pesenquist U. Treatment of myxedema coma: Factors
associated with fatal outcome. Acta EndocrinoI1985;108:65.
29. Ridgway ES, McCammor JA, Benotti J, et al. Acute metabolic
responses in myxedema to large doses of intravenous t-thyroxine. Ann
Intern Med 1972;77:549.
30. Iranmanesh A, Lizarraldo G, Johnson ML, et al. Dynamics of 24-hour
endogenous cortisol secretion and clearance in primary hypothyroidism assessed before and after partial thyroid hormone replacement.
31. Grinspan SR, Riller BMK. Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923.
Pathology of Tumors of
the Thyroid Gland
Ronald H. Nishiyama, MD
Tumors of the thyroid gland can be problems for endocrinologists, surgeons, and pathologists. Carcinomas of the
thyroid gland range from the innocuous occult papillary
carcinoma to the extremely lethal anaplastic form.
Approximately 12,000 new cases of thyroid cancers are discovered each year in the United States; however, fewer than
1% of deaths caused by cancers are due to thyroid cancers. I
Because only 9% of patients affected by the disease die from
it, malignant tumors of the thyroid gland are not a significant public health problem.
The treatment of carcinoma of the thyroid gland continues
to engender controversy. The extent of thyroidectomy in the
treatment of papillary and follicular carcinomas is controversial. The role of radioactive iodine in the postoperative
treatment of patients is still debated, and histologic criteria
for the pathologic diagnoses of certain thyroid tumors are
uncertain.
This chapter concentrates on the epithelial tumors of the
thyroid gland. The discussion centers on the pathology
and cytopathology of carcinomas of the thyroid gland.
Controversies involving criteria to determine histologic diagnoses and classification of thyroid tumors are described.
Descriptions of nonepithelial tumors are included when
appropriate. Nodular goiters, thyroiditis, hyperplastic changes
in the thyroid gland, and other non-neoplastic changes are
discussed in the context of the diagnosis and treatment of
thyroid neoplasms.
Adenoma
Adenomas are the most common benign tumors of the thyroid
gland. They are of follicular cell origin, encapsulated with
varying histology. They have been subdivided according to
their histology, but no additional information is gained by
this practice.
Thyroid adenomas are probably common because of
the inability of pathologists to separate consistently cellular
adenomatous nodules in nodular goiters from adenomas.
The majority of "adenomas" are most likely adenomatous
nodules.
The atypical adenoma is a troublesome Iesion.? It is a

lesion characterized by solid architecture with disorderly
arrangements of follicular components and is troublesome
when there is moderate or marked cellular atypia, typical
of "angioinvasive adenomas" or microangioinvasive welldifferentiated follicular carcinomas. Capsular invasion,
invasion of capsular blood vessels, or both identify the
malignant lesions. Otherwise, the tumors can be histologically identical. The problem is compounded by the inability
of any preoperative procedure to demonstrate consistently
evidence of invasive growth.
The cytologic smears of these lesions can be problems.
Cytologic reports are descriptive and often conclude by
suggesting the presence of a follicular neoplasm or follicular neoplasia, the connotation being that a malignant
tumor is not totally excluded. It is well recognized that
well-differentiated angioinvasive carcinomas cannot usually
be distinguished from atypical adenomas and cellular
adenomatous nodules by fine-needle aspiration. Such tumors
should be surgically removed and evaluated histologically
for evidence of invasive growth, and treatment is dictated by
the final histologic diagnoses.
The extent of thyroidectomies may be determined by
protocols developed for the treatment of well-differentiated
carcinomas of the thyroid gland at different institutions. The
surgical procedure may vary from lobectomy to subtotal or
total thyroidectomy. Frozen sections of the offending nodules may be requested when thyroidectomies are preceded
by lobectomies. The nodules are sent for frozen sections.
However, frozen sections are not useful in follicular and
also Htirthle cell neoplasms because capsular or vascular
invasion cannot be identified consistently with the small
number of sections taken for histologic examination.' An
opposing opinion states that frozen sections are cost effective.
However, a different procedure is used for frozen sections at
that medical center."
The histologic criteria to establish the diagnosis of an
adenoma are not well defined. Adenomas are solitary
nodules that are well encapsulated and histologically distinct from adjacent thyroid parenchyma. Goitrous or adenomatous nodules may satisfy these criteria, and when atypical
223

histologic features are present, they are difficult to separate
from minimally invasive follicular carcinomas.
The hyalinizing trabecular adenoma may present problems.!
These tumors are either single dominant nodules or
one nodule in a nodular goiter. They are usually small 2 em)
and are encapsulated or circumscribed with pseudofollicles,
trabecular or alveolar arrangements of cells, or both.
Hyalinization of stroma can be seen, which may be confused
with amyloid. Immunohistochemical stains for thyroglobulin
are positive and stains for calcitonin are negative. No cytoplasmic secretory granules are seen by electron microscopy.
Erroneous diagnoses of medullary carcinoma and papillary
carcinoma have been made by mistaking the hyalinized
stroma for amyloid and the papillae for those of papillary
carcinomas.
Papillary Carcinoma
Papillary carcinomas are the most common malignant neoplasms of the thyroid gland." They are rarely composed
solely of papillae, with the most common form containing
both follicles and papillae. Such tumors were classified as
mixed papillary and follicular carcinomas. Follow-up studies have convincingly demonstrated that mixed and purely
papillary tumors are associated with similar outcomes, so
the separation of mixed papillary and follicular from the
purely papillary form is not warranted.'
The description of other histologic variants of papillary
carcinomas, some allegedly characterized by poorer clinical
outcomes than usual papillary carcinomas, has complicated
the classification of papillary carcinomas. The present classification of papillary carcinomas may include the following
histologic forms:
Usual papillary carcinoma
Microcarcinoma
Follicular variant
Tall cell type
Columnar cell type
Diffuse sclerosing type
Macrofollicular type
Encapsulated type
The most common type is the usual papillary carcinoma,
identified by a solid, well-circumscribed, unencapsulated
tumor arising in the background of a normal thyroid gland.
The size is larger than 1 em."
Histologically, papillae are present that are formed by
fibrovascular cores covered by neoplastic cells. The nuclei
are piled on one another, may show "grooves" formed
by folds in nuclear membranes, and contain "optically
clear" nuclei created by clearing of nuclear chromatin.
Cytologically, intranuclear inclusions, formed by inclusions
of cytoplasm into the nuclei, can be seen. Psammoma
bodies, calcified and laminated structures, support the
diagnosis of papillary carcinoma (Figs. 25-1 and 25_2).9.11
Areas of fibrosis and solid and trabecular areas are commonly
present. The latter changes are not poorly differentiated areas
within papillary carcinomas and do not affect their biologic
behavior.l-?
The finding of neoplastic papillae is essential to establish the histologic diagnosis of usual papillary carcinoma.
FIGURE 25-1. Papillary carcinoma: fibrovascular papillae, optically

clear nuclei (arrowheads), and psammoma body (arrow).
However, non-neoplastic papillae, associated with adenomatous and hyperplastic nodules, can lead to the erroneous
diagnosis of papillary carcinoma. These papillae have fibrovascular cores, but the covering cells lack the nuclear
changes of cells characteristic of papillary carcinomas.
Other important morphologic findings are smaller papillary carcinomas found on the same side of the dominant
lesion or in the opposite lobe. The prevalence of bilateral
lesions has been reported to be as high as 78%.13 The
smaller foci were considered to be additional primary tumors;
however, morphologic evidence indicates that these are
intraglandular metastases.P The evidence consists of the
location of the neoplasms in interstitial tissue and within
lymphatic channels, the close relationship of the number of
lymph nodal metastases to the incidence of small neoplastic
foci in the parenchyma of the gland, and the more common
FIGURE 25-2. Papillary carcinoma, fine-needle aspirate: cells with

intranuclear inclusion (arrow) and nuclear groove (arrowhead).
Pathology of Tumors of the Thyroid Gland - - 225
occurrence of psammoma bodies, thought to originate from

intralymphatic tumor thrombi, in the primary tumors.
However, contrary evidence, the finding of different types of
RET/PTC rearrangements in the multiple foci of cancers,
favors the conclusion that they are additional primary
tumors."
Papillary microcarcinoma, also known as occult carcinoma, occult sclerosing carcinoma, minimal carcinoma, and
encapsulated sclerosing carcinoma, is a common variant. The
World Health Organization (WHO) definition of a microcarcinoma limits its size to 1 em or less." Clinicians object to
this definition because microcarcinomas can sometimes be
palpated in the thyroid gland and can arise as palpable lymph
nodes, containing metastases, in the neck.
The ubiquitous nature of microcarcinomas is a unique feature of these small cancers. 13 The rates of occurrence of microcarcinomas in normal individuals vary with the geographic
location, with the highest occurring in Japanese in Japan and
Hawaii and Finns in Finland. The rates in the United States are
relatively low, with the highest recorded at 13%.15
Papillary microcarcinomas are incidental findings under
two conditions:
Thyroid glands removed for other thyroid diseases
such as Graves' disease, hyperthyroidism, nodular
goiters and, rarely, autoimmune thyroiditis
Thyroid glands, included in radical neck operations for
malignancies, other than thyroid cancers.
They occur multifocally and bilaterally in such glands
and in those removed for treatment of primary thyroidal cancers. This may argue for total removal of the thyroid gland
in the treatment of papillary carcinomas. However, there is
no convincing proof that microcarcinomas consistently
develop into clinically significant neoplasms.
The histology of microcarcinomas includes the classic
lesion, formed by a central core of neoplastic cells with
papillae with the pertinent nuclear changes, which are not
encapsulated but show radiating strands of fibrous tissue that
contain neoplasm. Other tumors can consist of neoplastic
cells arranged as follicles with no encapsulation, with the
cells showing nuclear changes characteristic of papillary
carcinomas.
One clinical circumstance in which microcarcinomas
become significant is that of the patient who presents with a
palpable mass or masses in the neck, usually enlarged lymph
nodes. A biopsy reveals metastatic papillary carcinoma, but
there are no palpable abnormalities in the thyroid gland.
This usually results in a lobectomy on the side of the positive lymph nodes. The problem, then, is to find the primary
thyroid carcinoma. When the metastatic deposits are very
well differentiated, the problem of "lateral aberrant thyroid"
may arise when the primary lesion is not discovered."
However, the primary carcinoma is inevitably demonstrated
in all cases. A report of 535 patients with papillary microcarcinomas, treated surgically during a 50-year period, revealed
the following!":
Mean tumor size, 8 mm
Intrathyroidallocation, 98%
Nodal metastases, 32%
Tumor, nodes, and metastasis (TNM) stages I (91%),
III (9%), IV (one patient)
Bilateral lobar resection (91%)
Incomplete resection of tumor (three patients)

Postoperative radioiodine ablation (l 0%)
20-year recurrence rate (6%) in patients with positive
lymph nodes or unilateral lobectomy
Death from tumors (two patients)
Primary diagnoses were established at the time of thyroidectomies in 69% of patients. In 20%, the diagnosis was
confirmed by biopsies of cervical lymph nodes. Thirteen
percent of cases were considered to be incidental findings at
operations. The conclusions were that
Patients with microcarcinomas have excellent outcomes
when initially treated by bilateral lobar resection.
Postoperative radioiodine ablation is not indicated.
Microcarcinomas are not entirely innocuous. A few cases
have been associated with distant metastases and a rare
death.l":"
The follicular variant of papillary carcinoma is a pathologic paradox.'? A histologic diagnosis of papillary carcinoma is made in the absence of demonstrable papillae. The
statement has been made that in everyone of these lesions,
papillae can be demonstrated by careful examination of
the thyroid gland. Nonetheless, within the limitations of the
techniques employed, there are papillary tumors that are
identified purely from the nuclear changes seen in the neoplastic cells. They are composed of follicles usually containing
darkly eosinophilic colloid with serrated edges, which
mimic the changes in Graves' disease and in neoplastic cells
with nuclear changes peculiar to papillary carcinomas.
The follicular variant warrants recognition because of
the difference in biologic behavior between papillary and
follicular carcinomas. This lesion was first recognized in
1960, so it is not a new entity.'? Undue emphasis on this variant of papillary carcinoma may lead to erroneous designations
of follicular lesions as carcinomas. On the other hand, diagnosing some lesions as follicular carcinomas may not be as
grievous an error as the erroneous diagnosis of a benign lesion.
Tall cell variants of papillary carcinomas are defined as
papillary carcinomas composed of cells that are twice as tall
as they are wide." The definition now includes the requirement that at least 30% of the neoplasm be composed of tall
cells.F The criteria to establish a diagnosis now encompass
two parameters that are highly subjective and vulnerable to
significant interobserver errors.
The current consensus on the prognosis for patients with
tall cell cancers is that more suffer from poor outcomes than
those with usual papillary carcinomas.P:" Additional data
now indicate that tall cell cancers are histologically unique
forms of papillary carcinomas but are not more aggressive
than usual papillary carcinomas. 26
A comparison of a group of patients with tall cell cancers
with a large group of patients with usual papillary carcinomas
showed the following:
Tall cell cancers were larger.
Tall cell cancers had a higher rate of metastases.
Tall cell cancers had a higher rate of extrathyroidal
invasion.
Patients older than 50 years had poorer outcomes.
The only factor that affected prognoses in patients with tall
cell cancers was age. The effect of age on prognosis in
patients with usual papillary carcinomas is well established,
with the age of 50 years recognized as a clinical benchmark."

Paradoxically, two phenomena, allegedly identifying
more aggressive thyroid neoplasms, are associated with tall
cell cancers: the overexpression of p53 and the more efficient delivery of mitogenic signals by papillary carcinomas
with RET/PTC3 rearrangements.P'"
Overexpression of p53 has been demonstrated in tall cell
cancers. One conclusion is that localization of p53 immunohistochemically is a useful prognostic index of clinical
behavior in differentiated carcinomas of follicular derivation.
All of the cancers in that study showed extrathyroidal
invasion. Because the tumors were not staged further, it is
difficult to determine whether positivity for p53 was the sole
indicator of aggressive behavior. Another study demonstrated
that clinical stages of the tumors at time of presentation were
more significant in determining outcomes than the percentage of tumors staining positively for p53.
The RET tyrosine kinase rearrangements that recombine
RET with heterologous genes to generate RET/PTC oncogenes are the most frequent genetic alterations in papillary
thyroid cancers." The most prevalent oncogenes that result
are RET/PTC] and RET/PTC3. RET rearrangements were
found in 36% of tall cell thyroid cancers and were all of the
RET/PTC3 type." The cells derived from these neoplasms
delivered mitogenic signals more efficiently to thyroid cells
of rats, and this phenomenon is proposed to account for the
alleged aggressive behavior of tall cell cancers in humans.
In contrast, the conclusion has been drawn that all thyroid
carcinomas harboring RET rearrangements show a welldifferentiated phenotype and are not more aggressive than
less differentiated tumors." However, RET/PTC3 oncogenes
are more common in cancers that develop in irradiated
thyroid glands and in children.
Columnar cell thyroid carcinomas differ from tall cell
cancers because of the stratification of nuclei within the tall
cells." The initial cases behaved aggressively and were
followed by other reports concurring with the conclusion
that these cancers were more virulent forms of papillary
cancer.P Indolent encapsulated forms have been reported in
addition to tumors composed of tall cells and columnar
cells, suggesting that the two neoplasms are expressions
of one form of papillary carcinoma."
The conclusion that columnar cell carcinomas are more
aggressive than usual papillary thyroid carcinomas (PTCs)
is challenged by a report of a group of patients whose
outcomes were determined by the clinical stages at the
time of presentation, rather than the unusual histology of the
neoplasms." These tumors did not differ in their behavior
from usual papillary carcinomas when gender, age, tumor
size, and histology were considered. The most important
prognostic factor was extrathyroidal invasion. Biologic
behavior of columnar cell papillary carcinomas of thyroid
gland appears to be determined by the same factors that
affect the behavior of usual forms of papillary carcinomas.
The unusual histology of these tumors does not identify
tumors that are clinically more aggressive.
The diffuse sclerosing variant is recognized by diffuse,
bilateral involvement of the thyroid gland. 36-39 Microscopically, clusters of neoplastic cells with numerous psammoma
bodies are found in well-defined spaces, presumably lymphatic channels, all in a background resembling autoimmune
thyroiditis.
The patients are young, predominantly female, and

commonly present with metastases to lymph nodes in the
neck and lungs. In spite of the extensive involvement of the
thyroid gland, the propensity to metastasize early to lymph
nodes and lungs, and a high rate of persistent disease postoperatively, the prognosis appears to be good. 3638 However,
this conclusion is disputed. Others report that the prognosis
associated with these neoplasms may be poor. 12.39 The youth
of the patients may be the ultimate determining factor of
clinical outcomes. It is well recognized that among young
patients, papillary carcinomas with metastases to regional
lymph nodes and lungs are more common but, with proper
treatment, the outcomes are excellent.
The rare macrofollicular variant is of greater interest to
pathologists than surgeons because its morphology is such
that it can easily be misdiagnosed as an adenomatous
nodule. 40A 1 The prognoses for patients are no different from
those for usual papillary carcinomas.
The encapsulated form of papillary carcinoma is a slowgrowing tumor with excellent clinical outcomes. Twentyfive patients with tumors with an average size of 3.1 cm
showed no metastases or recurrences after long periods of
follow-up."
In summary, the histology of papillary carcinomas does
not appear to be a significant prognostic factor. Others
concur with this conclusion." Prognostic factors for causespecific deaths caused by papillary carcinomas in a group
of 685 patients were determined to be age, extrathyroidal
invasion. and the differentiation of the neoplasm-that is,
the grade of the neoplasm.f
Grading of neoplasm was initially included in the AGES
(age of a patient, grade of neoplasm, extrathyroidal invasion, size of tumor) system for predicting prognoses in
patients with papillary carcinomas at the Mayo Clinic."
However, with use, it became apparent that the grading of
papillary carcinomas was subject to significant interobserver variation. The system was modified to include distant
metastasis and completeness of excision and discarded the
grading of tumors, the only histologic variable of the system."
With the group of patients described previously, histology of the tumors (differentiation) was defined as the level
of differentiation within the nonpapillary areas. Tall cell,
columnar cell, or insular changes were not described. The
tumors were divided into well-differentiated, moderately
differentiated, and poorly differentiated types, with the latter
two types being worse. Three factors predictive of local,
nodal, or systemic recurrences were age, nodal involvement,
and the size of the tumors. Patients younger than 40 years
had a much better rate of survival than patients older than
50 years. Extrathyroidal invasion was defined as extension
of neoplasm into perithyroidal tissue.
Follicular Carcinomas
Follicular carcinomas are more common in iodine-deficient
areas and less prevalent in countries that are iodine
sufficient.v-" Unlike papillary carcinomas, follicular carcinomas have no histologic landmarks, such as papillae, psammoma bodies, or distinctive nuclear changes (Fig. 25-3).
FIGURE 25-3. Minimally invasive follicular carcinoma with

invasion of capsular vein (arrow).
Follicular carcinomas can be divided into minimally and

extensively invasive forms, encapsulated and invasive types,
or microangioinvasive and macroangioinvasive tumors. 7,47-53
Well-differentiated, minimally invasive carcinomas are difficult to identify. For tumors formed of follicles lined by
well-differentiated cells and enclosed within well-formed
capsules, invasion through the capsule, into capsular blood
vessels, or both, must be identified before a diagnosis of
malignancy is made.5 1.54 Capsular invasion is defined by
complete penetration of the capsule by neoplasm with
extension into adjacent parenchyma.
The significance of capsular invasion alone as a marker
for malignancy has been questioned. 55 Tumors with only
capsular invasion did not develop regional or distant metastases or cause cancer-related deaths among such patients.
The conclusion was that vascular invasion is the most
important criterion to establish the histologic diagnosis of
well-differentiated follicular carcinomas. The significance
of invasion of the capsules of follicular neoplasms was
previously questioned. 56
Vascular invasion is defined as growth of neoplasm into
a blood vessel, usually a vein, within the capsule of the
tumors. Neoplastic thrombi are found within capsular blood
vessels and covered by a thin layer of endothelium, visible
only microscopically. Because of this requirement, follicular
tumors with such changes have been designated as encapsulated, microangioinvasive, well-differentiated follicular
carcinomas.f'>'
Encapsulated, angioinvasive, follicular carcinomas

(angioinvasive adenomas) have atypical histologic features
with increased numbers of mitotic figures, and follow-up
of such tumors showed recurrences and metastases within
5 years after excision of the tumors. The histology of the
tumors was not as reliable an indicator of malignancy as
the finding of vascular invasion. Eighteen percent of patients
died as a result of the tumors, and 68% developed metastases or local recurrences in one report.>
Vascular invasion is difficult to detect, and much controversy exists over the changes that characterize invasion of a
blood vessel."
The extensively invasive or macroangioinvasive follicular
carcinomas are easier to identify. Experienced surgeons, at
times, can identify neoplasm within larger blood vessels and
satellite nodules within parenchyma adjacent to the tumor at
the time of thyroidectomy.
Grossly, minimally invasive follicular carcinomas are wellencapsulated nodules, usually in a background of nodular goiters. The extensively invasive carcinomas have visible nodules
outside the tumor capsule and are relatively easy to recognize.
Metastases to lymph nodes are uncommon, and distant metastases are usually found in the lungs, bone, or both.
Patients with minimally invasive follicular carcinomas
have good prognoses, whereas those with extensively invasive forms have graver outcomes. Factors that determined
cancer-specific deaths in a group of 253 patients with
follicular cancers included extrathyroidal invasion, metastases, size, and nodal involvement.f Extrathyroidal invasion
was a potent predictor of cause-specific deaths, and distant
metastasis was, predictably, another important factor. The
sizes of the tumor and nodal metastases, supposedly an
uncommon event in follicular carcinomas, were other
significant variables.
Distant metastases, age, postoperative status, nodal involvement, and the size of the primary tumors were
predictive of recurrences. The postoperative status of the
patients indicates the completeness of excision of the
primary tumor, as judged by the surgeons and pathologists.
The prevalence of follicular carcinomas in this country
has markedly decreased.F-" One major medical center
recorded only two cases of follicular carcinomas in I year,
a relative incidence of I %, during a 5-year period. 57 During
the same period, not a single case of follicular carcinoma
was identified by fine-needle aspiration biopsy. The two
cases of anatomically documented follicular carcinomas did
not have fine-needle aspirates.
Perusal of reports of follicular carcinomas from large
medical centers appears to confirm the lowered incidence of
follicular carcinomas in iodine-sufficient countries. 48-52.59
Eighteen cases were recorded during 10 years (1.8 cases a
year) at the MD Anderson Hospital, 100 patients in 24 years
(4 cases a year) at the Mayo Clinic, 37 cases in 20 years
(1.8 cases a year) at the University of Michigan, 65 patients
in 35 years (1.8 cases a year) at the University of California
at San Francisco, and 9 tumors in 6 years (1.5 cases a year)
at the Karolinska Hospital.
The incidence of follicular carcinomas is low. This phenomenon appears to be predominantly due to the introduction of iodine prophylaxis in the United States. It lowered
the incidence of nodular goiters, which in tum lowered the

number of follicular carcinomas. The association of follicular
carcinomas with nodular goiters in iodine-deficient areas
has been well documented."
Is it significant to have so few follicular carcinomas in
the United States? One untoward result may be an increase
in the number of unnecessary thyroidectomies.
Well-differentiated follicular carcinomas cannot be
consistently separated from adenomas or cellular goitrous
nodules.s? Because of this problem, clinicians have become
accustomed to the "risky" cytologic report, identified by reference to the presence of follicular neoplasia or a follicular
neoplasm.57 Such reports usually result in thyroidectomies.
The histologic diagnoses in the overwhelming majority in
such cases are of benign disorders, either follicular adenomas or cellular adenomatous nodules. At times, follicular
variants of papillary carcinomas are removed, but the
number of "true" follicular carcinomas is low. A large portion of our medical resources is then being used to detect
and treat a rare neoplasm, the well-differentiated follicular
carcinoma.
The solution to this dilemma may be either improved
interpretations of fine-needle aspirates or modifications in
the clinical approach to patients with such nodules. This may
require the resurrection of methods used to evaluate thyroid
nodules before the availability of fine-needle aspiration. The
age and sex of a patient and palpatory findings, including
sizes of the nodules, may need to be considered before
embarking on thyroidectomies. Another alternative may be
to inform patients regarding the risk of thyroid carcinomas
associated with risky cytologic reports.V
Follicular carcinomas are more likely to metastasize
hematogenously to the lungs and bone than to regional
lymph nodes, representing one of the major differences
between the biologic behavior of follicular carcinoma and that
of papillary carcinoma. Perhaps any "follicular carcinoma"
metastatic to lymph nodes should be re-evaluated for a
"follicular-like carcinoma," possibly a follicular variant of
papillary carcinoma.
Follicular carcinomas are considered as biologically distinct from papillary carcinomas because of their propensity
to metastasize hematogenously to lungs and bone as well as
lacking metastases to regional lymph nodes. The separation
of papillary thyroid carcinomas from follicular carcinomas
is advocated to emphasize these differences, especially
because it may affect treatment.
Another point of view is that the observed differences
between papillary and follicular carcinomas may be purely
academic, because differences in survival rates are more
closely related to factors other than the papillary and follicular histology of the tumors.436 1 Perhaps it is appropriate to
refer to these follicular cell neoplasms generically as welldifferentiated carcinomas of the thyroid gland.
Hurthle Cell (Oncocytic) Tumors

Hiirthle cell tumors are neoplasms composed of oncocytes
or Hiirthle cells. These cells contain numerous mitochondria
and have a distinctive granular microscopic appearance with
routine hematoxylin and eosin stains. Oncocytes are not
peculiar to the thyroid gland but can occur in salivary
glands, upper respiratory glands, and the kidneys.
Considerable controversy is associated with Hiirthle cell

neoplasms. The criteria for histologic diagnosis, their biologic
behavior and treatment, are subjects for debate.
Oncocytic papillary carcinomas occur, but contrary conclusions concerning their aggressiveness and treatment have
been stated. 62-64 Some behave like their usual counterparts,
whereas others result in poorer outcomes. The suggestion
has been made that oxyphilic variants of papillary carcinomas are more akin to follicular carcinomas than usual papillary carcinomas in their aggressiveness.
Hiirthle cell neoplasms can be divided into adenomas
and carcinomas by the same criteria used to distinguish
follicular adenomas from carcinomas. Similarly, there are
minimally invasive and extensively invasive forms, and
prognosis is determined by the extent of invasive growth.
A controversy concerning Hiirthle cell neoplasms is
whether benign lesions can be consistently differentiated
from malignant ones. A report, the center of this controversy,
concluded that all Hiirthle cell tumors are potentially malignant and should be treated as such.65 The impetus for the
statement was that benign tumors could not be consistently
separated from the malignant ones in that analysis. This may
have been a catalyst for other institutions to report their
experiences with Hiirthle cell tumors. 66-73
The present consensus is that Hiirthle cell adenomas can
be reliably differentiated from carcinomas, using the criteria
applied to follicular carcinomas. However, some doubt still
remains, demonstrated by a statement that Hiirthle cell
tumors larger than 4 cm are malignant." In addition, one
institution reported two patients with the histologic diagnoses of indeterminate for malignancy (i.e., the neoplasms
invaded into but not through the capsule) who developed
recurrences.s'' One carcinoma was found in 40 patients with
benign diagnoses. The percentage of patients included in
this and the original controversial report who ultimately
developed carcinomas when the histologic diagnoses were
indeterminate or benign is 12.9%,65.66 a small but not
insignificant number. However, in another report, the
percentage was 1%.69
Does the problem still persist? Is a cellular Hiirthle cell
nodule, composed entirely of a uniform population of oncocytes with no cytologic atypia and no evidence of invasive
growth, benign or malignant? Are all Hiirthle cell tumors
larger than 4 em malignant?
A group of poorly differentiated oxyphilic tumors have
been described that may account for most of the problems
associated with Hiirthle cell tumors." These tumors had
capsular or vascular invasion, or both, and were divided into
two groups: large cell and small cell types. Solid or trabecular histologic patterns predominated, with little development of follicles.
However, there were problems with the descriptions of
these tumors. Vascular invasion was described as minimal in
10 cases. However, minimal invasion of blood vessels was
not defined. Capsular invasion was present in 15 of 20 cases.
No details of the degree of invasive growth were given.
The small cell tumors were more aggressive, with a rate
of recurrences of 37%, and 30% of the patients were either
alive with residual neoplasm or had died of their tumors. In
contrast, only I of 40 patients with the large cell type died
of neoplasm.
The small cell type is most likely the type of Hiirthle cell
carcinoma that causes difficulties. However, large cellular
neoplasms, composed only of large Hiirthle cells, may also
present problems for the pathologists.
The treatment of Hiirthle cell carcinomas is modified
from that of follicular carcinomas because not all Hiirthle
cell carcinomas take up radioactive iodine, and so the use
of radioactive iodine is less effective. Under such circumstances, total surgical removal of the neoplasm is indicated
and external beam radiation may be considered for invasive
and incompletely resected neoplasms. Chemotherapy has
been ineffective.
A confounding factor is the presence of Hiirthle cell
nodules in benign diseases of the thyroid gland, notably
in nodular goiters and Hashimoto thyroiditis. Hurthle cell
metaplasia of follicular cells is common in nodular goiters
and is an integral part of autoimmune thyroiditis. Histologically, such nodules are usually not problematic. However,
extensive Hiirthle cell changes in a goitrous nodule can
suggest a Hiirthle cell neoplasm. A more troublesome lesion
is the solid nodule composed entirely of Hiirthle cells in
autoimmune thyroiditis. It may be encapsulated, and a
Hiirthle cell neoplasm becomes a serious consideration. To
determine definitively which of such lesions is malignant
can be pathologically difficult.
The aggressiveness of Hiirthle carcinoma is between that
of papillary carcinoma and that of anaplastic carcinoma.
They are tumors of moderate malignancy."
A description of polymerase chain reaction-based
microsatellite polymorphism analysis of Hiirthle cell tumors
suggests that the oncocytes of Hiirthle cell tumors differ
significantly from cells of follicular tumors." Could this
account for the aggressiveness of these tumors when
compared with ordinary follicular carcinomas?
Medullary Carcinoma
The C cell is the cell of origin for medullary carcinoma and
is at the basal portion of follicular epithelium adjacent to
the basement membrane. C cells are best demonstrated by
immunohistochemical stains for calcitonin and markers for
neuroendocrine cells, such as neuron-specific enolase, chromogranin, and synaptophysin. The clinical syndromes
encountered with C cells include
C-cell hyperplasia
C-cell adenomas
Familial medullary carcinoma
Nonfamilial or sporadic medullary carcinoma
Seventy-fivepercent of medullary carcinomas are sporadic
and the remaining 25% are familial.
The familial forms are77
Medullary thyroid carcinoma alone (familial MTC or
FMTC).
Multiple endocrine neoplasia type 2A (MEN 2A),
characterized by medullary carcinoma of the thyroid
gland, bilateral adrenal medullary hyperplasias or
pheochromocytomas, primary hyperparathyroidism
with parathyroid glandular hyperplasia, and congenital
colonic aganglionosis (Hirschsprung disease).
Multiple endocrine neoplasia type 2B (MEN 2B),

defined by medullary carcinoma, pheochromocytomas,
a marfanoid habitus with distinct facies, hyperextensibility of joints, hypertrophic corneal nerves, submucosal neuromas of the conjunctiva and tongue, and
submucosal colonic ganglioneuromatosis.
C-cell hyperplasia is recognized as the precursor for
MTCs in the familial forms." There are two types of hyperplasia, one associated with familial medullary carcinomas
(neoplasm associated) and the second (physiologic hyperplasia) found with conditions such as autoimmune thyroiditis,
occasionally with hypothyroidism, non-Hodgkin thyroidal
lymphomas, and nodular and diffuse goiters with or
without hyperthyroidism. Primary and secondary hyperparathyroidism has been associated with C-cell hyperplasia.
The pathogenetic mechanisms for physiologic hyperplasia
may be thyroid-stimulating hormone stimulation and
hypercalcemia.
C-cell hyperplasia has also been described adjacent to
thyroid tumors of follicular cell origin." No explanation for
this phenomenon is available. In a few cases, mild increases
in serum calcitonin have been demonstrated, and preoperative diagnoses of C-cell carcinomas have been considered.
In contrast to the familial forms of C-cell hyperplasia,
physiologic hyperplasia appears to have extremely low
potential for malignant change. Rare cases of small
medullary carcinomas, existing with C-cell hyperplasia,
have been reported in thyroid glands of patients with longstanding primary or secondary hyperparathyroidism and
rarely when medullary carcinomas are found in glands
affected by autoimmune thyroiditis.
Medullary carcinomas form discrete masses that are
usually solid and well demarcated. They vary in size from a
few millimeters to large masses that occupy an entire thyroid
lobe. The neoplasms can be associated with massive metastases to regional lymph nodes.
Microscopically, the neoplasms are composed of oval and
spindle cells, separated into organoid nodules by thin bands
of collagen, similar to the pattern seen in carcinoids and paragangliomas (Fig. 25-4). Amyloid is present in 75% to 80% of
the tumors." Amyloid stains pink with hematoxylin-eosin
stain, and its presence is confirmed by the green birefringence
FIGURE 25-4. Medullary carcinoma: nests of ovoid cells

surrounded by dense matrix (amyloid by Congo red stain) (arrow).

seen when examined by polarized light. The most dependable method for identifying C-cell carcinomas is an
immunohistochemical stain for calcitonin.
The tumors are unilateral in the sporadic forms, whereas
the familial tumors are usually bilateral and, when found
unilaterally, are also multifocal. Only 6% of familial tumors
occur unilaterally.F'" Spread to lymph nodes is usually to
the central and lateral compartments. In patients who present
with no palpable tumors in the neck, metastases to lymph
nodes are uncommon (10%). In contrast, patients with
palpable neck masses have high rates of involvement of
lymph nodes by metastases.F"?
Medullary carcinomas of all types represent approximately 7% of all thyroid carcinomas and, of these, 75% are
sporadic. In sporadic cases, patients are usually in their
fourth decade and present with unilateral lesions without
associated endocrinopathy. The remainder occur as familial
forms, inherited as autosomal dominant traits.
The most indolent and most difficult to detect is FMTC.
MEN 2A may not be clinically expressed in 30% of patients
by 70 years of age. Pheochromocytomas, usually bilateral,
occur in approximately 50% of patients and hyperparathyroidism in approximately 20%. In MEN 2A, the thyroid
carcinoma develops before the pheochromocytomas or
parathyroid hyperplasia. MEN 2A can be associated with cutaneous lichen amyloidosis, Hirschsprung disease, or both.
Patients with MEN 2B have a marfanoid habitus,
mucosal and intestinal neuromas, and medullary carcinoma.
The patients have distinctive facies, with thick lips showing
neuromas that also occur in the conjunctiva and tongue.
Pheochromocytomas develop in 50% of patients, but unlike
the situation in MEN 2A, parathyroid glandular hyperplasia
does not. Hirschsprung disease, primarily a sporadic disease,
has been described in patients with FMTC and MEN 2A
with heterogeneous germline mutations of RET in some of
the families.
Surgery, total thyroidectomy, is the preferred method of
treatment for all medullary carcinomas, with resection of all
affected lymph nodes in the central compartment. If the primary tumor is larger than 1.5 ern, the dissection is extended
to include the lateral neck with removal of all affected
lymph nodes. These tumors do not take up radioactive
iodine, and there are no effective chemotherapeutic agents.
Preventive surgery in patients with MEN 2A and MEN 2B
has become routine because of the ready availability
of screening methods for the RET protooncogene.I''?? In
patients with MEN 2A and FMTC, prophylactic surgery
at 6 years of age is favored, and in patients with MEN 2B,
thyroidectomies are recommended during infancy. The earlier operations in patients with MEN 2B are recommended
because of the early development and aggressiveness of the
carcinomas in these patients.
The clinical outcomes associated with the different forms
of medullary carcinoma are
All forms, 5-year survival rate, 78% to 91%; lO-year
rate, 61 % to 75%
Sporadic MTC, corrected for stage, similar to MEN 2A
FMTC, best survival rate
MEN 2A, midway between sporadic MTC and 2B
MEN 2B, worst survival rate
Tumors of C cells with cells in papillary and follicular
patterns have been reported, and metastases with similar
histologic patterns have been described. 80-82 The cell of origin

for such tumors has not been established. Their clinical
behavior is similar to that of the usual medullary carcinomas.
C-cell adenomas have been described but have not been
accepted as recognizable clinical entities.P
Poorly Differentiated, Small Cell,

and Anaplastic Carcinomas
Poorly differentiated carcinomas purportedly are carcinomas
that have clinical outcomes midway between those of welldifferentiated and anaplastic carcinomas.tv" Insular carcinomas and poorly differentiated carcinomas, as they occur in
papillary and follicular carcinomas, are the two major forms.
The category of poorly differentiated carcinomas is compromised by the inclusion of tall cell, columnar cell, and
mixed tall and columnar carcinoma variants of papillary
carcinomas. 33,87,88 As noted previously, these tumors can be
recognized as follicular cell tumors and so, in the traditional
sense, are not poorly differentiated.
Insular carcinomas are characterized by solid masses of
round and oval cells separated into islands by thin bands
of fibrous connective tissue. 84 ,89 Mitotic figures, areas of
necrosis, and invasive growth are common and some show
papillary or follicular differentiation.
A review of a large number of cases in the literature
showed that insular carcinomas were very aggressive, but
another study resulted in a contrary conclusion.i-'" Insular
carcinomas within papillary and follicular carcinomas do
not appear to affect the prognosis adversely.
Insular carcinomas, in the initial report of such cases,
were described as aggressive tumors that caused early
deaths in patients. However, a second observer, after examining a series of slides included in the initial report, commented that an array of histologic changes were represented
in the slides and only two cases possessed the histology
described by the authors."
Another histologic type of poorly differentiated carcinoma is described in "high-risk" groups of patients with
papillary and follicular carcinomas.s" The tumors consist
of poorly differentiated carcinoma characterized by solid,
trabecular, or scirrhous patterns of neoplastic follicular cells
within well-differentiated papillary and follicular carcinomas, The conclusion was that the poorly differentiated areas
in papillary and follicular carcinomas are associated with
poorer clinical outcomes than with well-differentiated carcinomas but better than with anaplastic carcinomas.
Poorly differentiated carcinoma, as defined before, is difficult to recognize because solid, trabecular, and desmoplastic histologic patterns are also found in well-differentiated
papillary and follicular carcinomas and do not portend
aggressiveness.V:'? Alternatively, tumors with areas of poor
differentiation could be designated as high-grade papillary
or follicular carcinomas instead of poorly differentiated
carcinornas.?'
Another report of patients with papillary and follicular
carcinomas with areas of poorly differentiated carcinomas,
as defined before, included two cases with insular changes
and one with columnar cells. The overwhelming number of
cases had well-differentiated thyroid carcinomas associated
Pathology of Tumors of the Thyroid Gland - -
with poorly differentiated carcinoma, so the analysis essentially recapitulates the previous data."
Age, distant metastases at diagnosis, differentiation, and
extrathyroidal invasion were the prognostic factors. Except
for the omission of size, the variables in the AGES system
are duplicated.
The results highlighted a group of tumors (diffuse, poorly
differentiated carcinomas) that were associated with local
invasion, large tumor size, and lymph nodal and distant
metastases that caused more frequent relapses and poorer outcomes. The conclusion was that diffuse, poorly differentiated
carcinoma is an important clinicopathologic entity, with
"diffuse" identifying differentiated carcinomas with poorly
differentiated areas forming greater than 10% of the neoplasm.
A flaw in the study was the selection of 10% as the cutoff
point between focal and diffuse, poorly differentiated carcinomas. Ten percent is a small number and subject to significant interobserver variations. The most important finding
was that, as with all well-differentiated carcinomas, the
stage of the neoplasm at the time of diagnosis appears to be
the most significant prognostic factor.
Solid-trabecular forms of PTCs in adults have been
reported as separate pathologic entities. 93,94 One study considers the possibility that the cells in the solid-trabecular
areas were reminiscent of fetal thyroid cells (primordial
cells). Tumors were divided into two groups: those with
"insular" components and those with predominantly solidtrabecular areas with minor insular components. The
conclusions were as follows:
No fatalities within 6 months
No differences in survival rates
More frequent recurrences and distant metastases with
the insular group
Tumors are aggressive but show slow clinical courses
with good response to therapy
The data do not show that the tumors with the solidtrabecular patterns of growth are more aggressive. Descriptions
to stage the neoplasms are absent except for sizes of the
tumors, the presence of metastases, and infiltration of
the mediastinum.
A second study concluded that solid variants of PTC
are associated with a higher risk of distant metastases and
slightly lower long-term survival.P The results are such that
separation of this histologic type of papillary carcinoma
from usual papillary carcinomas is probably not warranted.
In summary, a thyroid neoplasm that can be classified as
a poorly differentiated carcinoma has not been definitively
described. There is no denying that papillary and follicular
carcinomas with less differentiated areas occasionally cause
deaths. However, the best prognostic factors are those that
have been long identified: age, extrathyroidal invasion, completeness of excision, size, and distant metastases at the time
of diagnosis.
Anaplastic thyroid carcinomas constitute approximately
1.5% of all cases of thyroid carcinomas in the United States,
an extremely small number of approximately 300 cases
per year." The rarity of the tumors accounts for the lack of
adequate data and expertise to assess the clinical behavior
and treatment of these tumors.
They occur more frequently in iodine-deficient geographic
areas with a high prevalence of nodular goiters and follicular carcinornas.v-" Iodine sufficiency, attributed to iodine
231
prophylaxis, may account for the low prevalence in the

United States of nodular goiters and follicular carcinomas.
It may also have increased the number of papillary carcinomas. Follicular carcinomas occur more commonly in nodular goiters, and the rarity of follicular carcinomas in the
United States may account for the very low rate of anaplastic
carcinomas.
Anaplastic carcinomas are typically found in women, in
older patients (mean age, 57 to 67 years), and in patients
who present with rapidly enlarging masses in the neck.
Hoarseness and dyspnea are common. Nearly 80% of
patients have tumors greater than 5 ern in diameter. Cervical
lymphadenopathy (40%), metastases to regional lymph
nodes (50%), and distant metastases (50%) are common.
Distant metastases commonly involve the lung, followed by
metastases to bone and brain.
Microscopically, these tumors consist predominantly of
spindle and giant cells (Fig. 25-5). It has been convincingly
demonstrated that many, if not all, anaplastic tumors are
accompanied by papillary and follicular carcinomas.v-"
They are also associated with medullary carcinoma, although
this phenomenon is problematic.v-" Some consider all
anaplastic tumors as originating from preexisting medullary
carcinomas. However, this is not the prevailing opinion,
although anaplastic carcinomas do occur simultaneously
with medullary carcinomas.
The anaplastic areas can resemble soft tissue sarcomas
histologically." Histologic patterns that replicate osteogenic
sarcomas, chondrosarcomas, giant cell tumors of bone, and
fibrosarcomas have been documented. This phenomenon
makes the diagnosis of primary soft tissue malignancies of
the thyroid gland difficult to establish. An exception may
be the hemangioendothelioma, a soft tissue sarcoma in the
thyroid gland that has been reported nearly exclusively in
Europe.??
Immunohistochemical methods play an important role in
establishing the diagnosis of anaplastic thyroid cancer.95,97
The most consistent procedure is an immunohistochemical
stain for keratin, positive in a great number of these tumors,
Stains for thyroglobulin are inconsistent and unreliable.
FIGURE 25-5. Anaplastic carcinoma: spindle cells, giant cells,

and neoplastic follicle (follicular carcinoma).

There are two viewpoints concerning the genesis of these
tumors. 95.97 The prevailing consensus is that the association
with well-differentiated carcinomas is consistent; the contrary
opinion contends that anaplastic carcinomas arise de novo.
The evidence for the de novo origin of anaplastic carcinomas is based on cytophotometric analysis of anaplastic
tumors." Only a portion of the differentiated cancers associated with anaplastic cancers shared the aneuploidy of the
anaplastic components, demonstrating that anaplastic
tumors do originate de novo. However, a contrasting study
showed that both elements can be aneuploid, and aneuploidy
in differentiated tumors was predictive of anaplastic transformation. Aneuploidy is common in anaplastic cancers but
is not a reliable prognostic factor. Coexistent papillary and
follicular thyroid cancers in anaplastic carcinomas have
similar cytogenetic patterns by comparative genomic
hybridization, which suggests that anaplastic cancers may
have arisen from the differentiated thyroid cancers."
The genes and oncogenes associated with anaplastic
cancers include p53, c-myc, NM23, and Ras. 95 Activation
of ras results in the expression of human H-ras, a rare
phenomenon. Mutations of p53 have been found in most
anaplastic cancers as well as in well-differentiated tumors,
so the implication of their presence in thyroid tumors is
uncertain.
The clinical course of these patients is alarmingly short,
a mean survival of approximately 4 months. It is the rare
patient who survives beyond a year. Comments have been
made that the tumors of patients who survive for a long
period should be re-examined for small cell tumors.
Anaplastic cancers occur most commonly in elderly
people, but cases in patients younger than 40 years have been
described.P''" The youngest patient was 22 years of age.
The results of treatment of these tumors have been discouraging. The treatment modalities include surgery, external
radiation, and chemotherapy. Varying combinations have
been attempted, with poor results. Appropriate therapy for
these tumors is yet to be developed.
One drastic change in the second WHO classification of
thyroid tumors was the exclusion of anaplastic small cell
carcinomas of the thyroid gland," The rationale was that
tumors previously classified as small cell carcinomas had
been identified as malignant lymphomas.95-97.100.101 Small
cell carcinomas of epithelial origin in the thyroid gland
are either medullary carcinomas or neoplasms that resemble
oat cell carcinomas of lung. 102 The latter stain immunohistochemically like neuroendocrine tumors but do not contain
calcitonin. These tumors were clinically aggressive and
caused the deaths of the patients in a short time. These may
be carcinomas similar to those that occur in other organs that
are tumors of neuroendocrine cells, but are not medullary
carcinomas of the thyroid gland.
Malignant Lymphoma
Malignant lymphomas are rare in the thyroid gland.
Approximately 5% of thyroid malignancies are non-Hodgkin
lymphomas of large diffuse B-cell type.l'" Lymphomas of the
thyroid gland are lymphomas of mucosa-associated lymphoid
tissue (MALToma or MALT-type lymphoma) and have been
classified as extranodal marginal zone B-celllymphoma (lowgrade B-celllymphoma of MALT type). 103-106 For uniformity,
lymphomas of mucosa-associated lymphoid and extranodal
lymphomas are referred to as marginal zone lymphomas.
Isaacson and Wright introduced the concept of extranodal lymphomas of MALT. 107 Central to their idea was that
the morphologic characteristics and the behavior of lymphocytes in the marginal zones found in the spleen and Peyer's
patch of terminal ileum were duplicated by lymphomas
derived from them. A marginal zone is not found in normal
lymph nodes except in mesenteric lymph nodes, but analogous areas are found in lymph nodes involved in inflammatory processes. Marginal zone lymphocytes possess
distinctive morphologic characteristics, and so do the cells
of marginal zone lymphomas. The cells of marginal zone
lymphomas characteristically invade epithelial structures to
form lymphoepitheliallesions, which, when present, support
the histologic diagnosis of malignant lymphoma.
Marginal zone lymphomas can involve the stomach, salivary gland, thyroid gland, dura, lung, skin, ocular regions,
and breast. 108 The stomach and thyroid gland are normally
devoid of lymphoid tissue but acquire lymphoid tissue in
response to chronic antigenic stimulation by chronic infections or autoimmunity-that is, the stomach in response to
infections with Helicobacter pylori and the thyroid gland
to autoimmune thyroiditis.
Another characteristic of marginal zone lymphomas is
their "homing" property.I07.l08 The lymphocytes in MALT
are postulated to be cells from the marginal zone of normal
lymph nodes. These cells are thought to have tissue-specific
homing properties that may well be determined from
whence they came. Cells originating in lymph nodes
"home" to lymph nodes, and cells from mucosal follicles
migrate to the gut or other mucosa-lined organ. However,
considering that marginal zone lymphomas also arise in
kidneys, urinary bladder, and prostate gland, all organs
lined by epithelial cells, usually columnar in type, may
home to epithelium rather than mucosa. The cells can be
distinguished from other cells only by morphologic and
immunophenotypic features because there is no single
immunologic marker that identifies these cells.
Because there are similarities in morphology and other
characteristics among lymphomas that arise in extranodal
sites, the spleen, and lymph nodes, the term marginal zone
lymphoma identifies these lymphomas.P''?'
Marginal zone lymphomas of the thyroid gland are most
common in older women with autoimmune thyroiditis. 109, 110
The relative risk of lymphomas arising in patients with
autoimmune thyroiditis was 67 times greater than
anticipated.l'" In Japan, the risk was determined to be 80
times greater than expected.
Most malignant lymphomas of the thyroid gland are diffuse large B-cell types that probably evolved from marginal
zone lymphomas, suggesting a morphologic progression from
autoimmune thyroiditis to low-grade marginal zone lymphoma to high-grade diffuse B-celllymphoma (Fig. 25-6).108
Because only a few cases of marginal zone lymphoma of the
thyroid gland have been reported, meaningful clinical and
pathologic data are not available.
The clinical presentation probably mimics that of autoimmune thyroiditis-namely, female preponderance, goiter
FIGURE 25-6. Malignant lymphoma: large lymphoid cells of

diffuse B-celllymphoma, residual follicle (star).
with hypothyroidism, and perhaps symptoms related to the

enlarged gland.l'" They remain localized for some time and
therefore may be curable by localized therapy. In addition,
when relapses occur, they develop in epithelium-lined organs
and are associated with prolonged disease-free intervals.
There are no meaningful data for low-grade marginal
zone lymphomas of the thyroid gland on treatment and
the outcomes of treatment. However, because thyroid lymphomas are nearly all marginal zone lymphomas, which
may then develop into diffuse large B-cell lymphomas, the
tumors, diagnosed in the early stages, should respond well
to conservative, localized treatment, with good outcomes.
The reports of lymphomas of the thyroid gland, prior to the
introduction of the concept of low-grade lymphomas of
the MALT type, dealt with an array of malignant lymphomas
such as diffuse histiocytic (large cell), plasmacytoma,
lymphoma with plasmacytoid features, germinal center cell
(follicular and follicular and diffuse), immunoblastic, and
follicular center cell lymphomas. 1031 12
The adoption of the MALT concept and the designation
of such lymphomas as marginal zone lymphomas unify
malignant lymphomas of the thyroid gland into one diagnostic category and facilitate diagnosis and treatment.

The nuclear accident at Chernobyl in 1986 refocused interest on radiation as a factor in the development of thyroid
carcinorna.T'<" Prior to 1950, irradiation was frequently
used to treat acne, enlarged tonsils and adenoids, chronic
sinusitis, and other benign conditions.I" External radiation
was commonly used to irradiate enlarged thymuses in
infants and young children. The latent period, the interval
from exposure to the appearance of thyroid cancer, was
assumed to be 1 years and increased for at least 3 decades.
Childhood thyroid cancer appeared within 4 years after the
Chernobyl accident.
Thyroid carcinomas in children and adolescents are rare
and differ from adult carcinomas of the thyroid gland in the
following ways 113-118:

More advanced disease in children: a high rate of
extrathyroidal invasion, more frequent metastases to
regional lymph nodes and lungs, larger tumors but
a lower rate of nondiploid tumors
Low mortality rates in spite of what may be more
advanced disease; higher rates of recurrences in lymph
nodes and lungs
The histologic categories for the thyroid tumors found
in irradiated patients include I 13-121:
Papillary carcinoma, including diffuse sclerosing and
oxyphilic types
Follicular carcinoma
Medullary carcinoma
Solid-follicular type
The papillary and follicular carcinomas are identical to
those described in adults. Medullary carcinomas constituted
a significant part (17%) of one report.!" However, the frequency of these tumors increased with the passage of time,
with the highest number recorded in the last segment of one
survey; hence, the increase is attributed to the development
of screening programs.
The results of investigations of thyroid cancers occurring
after the Chernobyl accident led to the consideration of these
questions concerning postradiation cancers in children:
Does the age of a patient affect the development of
thyroid carcinomas after exposure?
Is there a unique histologic variant of thyroid cancer in
this group of children?
Do such thyroid carcinomas behave more aggressively?
Studies related to thyroid carcinomas associated with the
Chernobyl accident have demonstrated that the thyroid
glands of very young children are much more sensitive to
the carcinogenic effect of radiation from fallout than the thyroid glands in older children. 121 The relative risk of developing thyroid carcinomas in irradiated children younger than
I year was 44 times more than the relative risk in nonirradiated patients (237:6).
The histology of the tumors was identical to that in
postirradiated adults with the exception of a unique thyroid
carcinoma, the solid-follicular type. A previous analysis of
such tumors indicated that they may well be more aggressive than other histologic forms found in children. 122
Microscopic examination of the tumors found in children
exposed at Chemobyl showed a significant number of solidfollicular carcinomas, most prevalent in patients in whom
the tumors developed earliest after exposure. However, can
one conclude that these tumors are more aggressive than other
forms of well-differentiatedcarcinomas? One probably cannot,
and longer follow-up is necessary to answer this question.
Genes, Protooncogenes,
and Thyroid Cancers
This
section is limited to:

RET protooncogene and MTC
RET protooncogene and PTC
Thyroid carcinomas and familial adenomatous polyposis
(FAP)
Thyroid carcinoma and Cowden's disease

RET protooncogene encodes a transmembrane receptor
that is a member of the receptors of the tyrosine kinase
family and is found on chromosome 10 (lOql1.2).31,123 The
gene is expressed normally in thyroid gland, adrenal gland,
nerve tissue, and developing kidney and pathologically in
neuroendocrine tumors (MTC, pheochromocytomas) and
hyperplasia and neoplasia of parathyroid glands.
The RET gene derived its name from an experiment in
which it induced classic NIH 3T3 transformation, NIH 3T
being an NIH assay (rearranged during rransfection).!" The
gene encodes a transmembrane receptor, tyrosine kinase,
that acts as a link between the extracytoplasm and plasma
membrane and the nucleus of the cell by the transduction
of signals.
The RET receptor is part of a complex of proteins that
serve as coreceptors on the cell membrane. The coreceptors
increase the affinity of RET receptors for three ligands, of
which glial cell line-derived neurotrophic factor (GDNF) is
the most prominent. GDNF is associated in the pathogenesis
of Hirschsprung disease.31.123
The RET protooncogene has been conclusively identified
in the MEN 2A and 2B syndromes and FMTC The characteristics associated with medullary carcinoma and the MEN
syndromes can be summarized as followS31,123:
Germline mutations may be associated with specific

areas of the gene.
95% of patients with MEN 2A have mutations in exons
10 and l l on chromosome 10.
90% of patients with MEN 2B have changes in exon 16,
codon 918.
FMTC is associated with mutations in exons 10, 11, and
13, codons 768, 609, 611, 620, and 634.
Patients with MEN 2A who have changes in codon
63 with Cys 634 to Arg are at a greater risk for the
development of parathyroid disease.
The mutations that occur in RET are":
Missense germline mutations, found in 97% of patients
with MEN 2A and 86% of patients with FMTC (codon
609,611,620, or 634)
Mutations involving the tyrosine kinase domain,
nearly exclusively in FMTC (codon 768, 790, 804,
844, or 891)
Unique mutations in exon 13 or 14
Mutations involving the tk domain, codon 883 or 918,
in virtually all patients with MEN 2B
The data for sporadic MTC are
Missense mutations in exon 16, substitution of methionine for threonine in codon 918.
Other mutations at codon 768, exon 13; codon 883,
exon 15.
Mutations at exons 10 and 11 may not lead to development of MTC but may prime the C cells before
transformation occurs.
About 23% of patients with sporadic MTC have mutations affecting exon 16 and codon 918. Because identical
mutations are found in MEN 2B, familial and sporadic
MTCs may result from similar changes in the gene. One
report concluded that a mutation in codon 918 in the RET
protooncogene in sporadic MTC is associated with a poor
prognosis, with frequent distant metastases and recurrences.
The characteristics of pheochromocytomas with or

without MEN changes are:
Sporadic pheochromocytomas have mutations in
codon 768.
There are mutations in codon 634 (cysteine to arginine)
in MEN 2A families (with at least one member with
pheochromocytoma and parathyroid hyperplasia).
Mutations involve codon 609, 611, 618, or 620 in
families with parathyroid hyperplasia and FMTC
without pheochromocytoma.
There is a significant association of hyperparathyroidism
and pheochromocytoma with mutation at codon 634.
No specific mutation correlates with familial
pheochromocytoma.
Parathyroid hyperplasia in MEN 2A, pheochromocytomas in MEN 2A and 2B, and the other somatic lesions,
such as marfanoid habitus, intestinal ganglioneuromatosis,
skeletal abnormalities and, rarely, parathyroid hyperplasia,
reflect the presence of the RET protooncogene in their
respective normal counterparts.
RET mutations, missense and nonsense, in exons 2, 3, 5,
and 6 have been found in patients with Hirschsprung
disease. The mutations lead to inactivation of RET rather
than the activation found with medullary thyroid cancer. The
normal activity of RET, in reference to the nervous system,
is to develop the enteric autonomic nervous system. Its
absence leads to the neural defect of Hirschsprung disease
(absence of ganglion cells in colonic enteric plexuses)."
The clinical significance of mutations of the RET gene in
sporadic MTC is controversial. Such tumors appear to be
aggressive and result in poor outcomes because of frequent
development of distant metastases and recurrences. However,
these findings have not been firmly established.
The rate of de novo mutations in MEN 2A and FMTC
is approximately 10%, whereas the rate in MEN 2B is
approximately 50%.
The finding of RET protooncogene in familial forms of
medullary carcinoma syndromes has altered the screening
procedures for medullary carcinoma (MTC). Before the discovery of the association of MTC with RET protooncogene,
screening was accomplished using intravenous pentagastrin
and calcium, a procedure fraught with discomfort for the
patient and a small but significant number (approximately
15%) of false-negative and false-positive results. Biochemical
screening has now been largely replaced by genetic screening.
Blood levels of calcitonin, either basal or after provocation,
are now primarily used to observe patients for recurrent or
persistent MTC after thyroidectomies."
The associations of the RET gene with PTC are I4,31,123,124:
RET/PTC rearrangements are unique to human PTC
The rearrangements are oncogenes, formed by translocation of three different genes of the tyrosine domain
of the RET protooncogene.
Four forms are recognized, RET/PTC] to RET/PTC4.
There is loss of differentiated functions of the thyroid
gland: thyroglobulin, thyroperoxidase, and thyrotropin
receptor gene expression.
Thyrotropin-independent cell growth is promoted.
Frequency of RET/PTC activation in PTCs varies
from 2% to 60% but is significantly higher in the
Pathology of Tumors of the Thyroid Gland - -
4- to 30-year-old age group; this may account for the

contribution of age to the clinical features of PTe.
No connection of RET/PTC rearrangements to the
aggressiveness of papillary carcinomas has yet been
demonstrated.
All thyroid carcinomas with RET rearrangements show
a well-differentiated phenotype and do not progress to
aggressive, poorly differentiated forms.
RET/PTC] is dominant in sporadic tumors and both
RET/PTC] and RET/PTC3 are common in radiationinduced tumors.
RET/PTC arrangements are common in papillary
microcarcinomas, so they are early developments in
thyroid neoplasia.
The incidence of RET/PTC rearrangements in clinically
significant papillary carcinomas is not known, although a
frequency of 2.5% to 50% has been reported. 14
Immunohistochemical staining for RET/PTC rearrangements can now be employed to identify definitively papillary carcinomas that mimic follicular lesions. Follicular
variants of papillary carcinomas can now be more precisely
identified.
Eighty percent of papillary microcarcinomas have the
rearrangements, as well as 50% of clinically significant
tumors." Using RET/PTC rearrangements as markers for
papillary differentiation, Htirthle cell tumors can now be more
accurately subdivided into Htirthle cell adenomas, Htirthle
cell carcinomas, and Htirthle cell papillary carcinomas.
The association of FAP with thyroid carcinoma has been
well documented.F'v-? The extracolonic manifestations of
the syndrome include upper gastrointestinal adenomas,
congenital hypertrophic retinal pigment epithelial lesions,
desmoids, osteomas, epidermoid cysts of skin, and dental
abnormalities.
Relevant data concerning FAP-associated thyroid carcinomas can be summarized as follows:
Age: younger patients, mean age 25 to 34 years.
Sex: predominantly female (12:1).
Histopathology: unique papillary carcinoma with
papillary pattern plus cribriform and solid areas with
spindle cells, squamoid cells, and whorled spindle
cells; numerous multifocal and bilateral microcarcinomas; Hashimoto-like parenchymal changes.!"
Genetics: autosomal dominant; adenomatous polyposis
coli (APC) germline mutations on chromosome 5q21.
Coexisting RET/PTC rearrangements: RET/PTC] and
RET/PTC3 in 80% of PTCs.
Treatment: total thyroidectomy because of unilateral
and bilateral multifocallesions.
Prognosis: presumably good; carcinomas appear to be
variants of papillary carcinoma, and no genetic or other
findings suggest poor clinical outcomes.
The APC gene is a tumor suppressor gene and does not
participate in the progression of sporadic thyroid cancer.
Interactions between the RET/PTC] activation and APC mutations are postulated in the development of FAP-associated
thyroid carcinomas.
The age and sex in FAP-associated carcinomas are in
keeping with usual papillary carcinomas. Bilateral and multicentric tumors are analogous to pathologic findings in PTCs.
235
The cribriform and solid histology in these tumors may be

sufficiently distinctive for pathologists to suggest the presence of the APC gene in patients in whom thyroid cancers are
the initial manifestations (Fig. 25_7).126 However, the same
histopathologic pattern allegedly occurs in sporadic cases.P"
Thyroid cancers are not common in patients with APe.
Only 1% to 2% of patients develop thyroid carcinomas.
Cowden's syndrome, the multiple hamartoma syndrome,
is an autosomal dominant disorder characterized by multiple
benign and malignant neoplastic lesions found in many
organs, including the thyroid gland and breast. 131-134
The thyroidal lesions are multinodular goiters, follicular
adenomas, or carcinomas. The specific change in the follicular neoplasms is loss of heterozygosity on chromosome
arm 10q. A novel tumor suppressor gene, PTEN, mapped to
lOq23.3 is the susceptibility gene for Cowden's syndrome.
The thyroid lesions are the major extracutaneous manifestations of the syndrome and are papillary carcinomas
in adenomatous goiters, multicentric follicular adenomas,
adenomatous nodules, and follicular carcinomas. As with
B
FIGURE 25-7. Familial adenomatous polyposis (FAP)-associated
thyroid carcinoma.

FAP-associated tumors, it is postulated that the histologic
findings in the thyroid gland may be unique to Cowden's
disease and its presence can be suggested by the changes
in the thyroid gland. 133,134 The finding of multiple adenomatous goiters or multiple follicular adenomas, particularly
in children and adolescents, should alert physicians to the
possibility of an inherited trait, such as Cowden's disease.
Because the tumors can be multicentric and can progress,
total thyroidectomy is recommended, even though the tumors
are usually benign. Progression of an adenoma to carcinoma
is not inevitable because there are studies that suggest that
adenomas and carcinomas can develop along separate,
nonserial pathways.
Cytopathology
Fine-needle aspiration of thyroid lesions has made interpretation of the aspirates one of the more important diagnostic
steps in the treatment of benign and malignant diseases of
the thyroid gland. However, every clinician who treats thyroid diseases should be aware of the limitations of the
method. The difficulty encountered in differentiating benign
from malignant follicular tumors, as well as the separation
of benign Hiirthle cell lesions from their malignant counterparts, has been described. There is liberal use of descriptive
terminology, such as "follicular neoplasia cannot be
excluded," with the connotation that a well-differentiated
follicular carcinoma may very well be present. Such cytologic reports may have resulted in the excess expenditure of
resources in pursuit of uncommon follicular carcinomas.
Suggestions have been made to rectify this situation. The
same comments apply to Hiirthle cell lesions.
The interpretations of fine-needle aspirates are nearly
indispensable in the diagnosis and treatment of papillary
and medullary carcinomas of the thyroid gland. Cytologic
smears of papillary carcinomas are easily recognized by
the syncytia of large follicular cells with nuclear membrane
folds (grooves), intranuclear inclusions, and prominent
nuclei. The clear nuclei seen on histologic slides are absent,
being artifacts of formalin fixation.
Medullary carcinomas are usually easily recognized. In
addition, stains for calcitonin and carcinoembryonic antigen
can aid in the diagnosis.
The cytopathologic appearances of tall cell and columnar
cell carcinomas have been described. However, these lesions
are rare, and the recognition of a malignant tumor should
suffice without specifying the cell type.
Cytopathologic smears are extremely helpful in establishing the diagnosis of malignant lymphomas of the thyroid
gland. Marginal zone lymphomas, per se, have rarely been
reported in the thyroid gland. The usual lymphoma of the
thyroid gland is a diffuse, large B-cell lymphoma. These
lymphomas are characterized by large cells with cleaved or
noncleaved nuclei and prominent nucleoli. Flow cytometry,
immunohistochemicalstaining, and gene rearrangement studies on fresh tissue specimens are extremely helpful in establishing the proper diagnosis. The association of autoimmune
thyroiditis with lymphomas of the thyroid gland may make
the diagnosis difficult. The ancillary studies suggested are
very helpful in establishing the proper diagnosis.
Cytopathologic smears can also establish the diagnosis

of benign lesions, such as nodular goiters and autoimmune
thyroiditis. The nodules of a nodular goiter are often associated with syncytia of cells, as seen in papillary carcinomas;
however, none of the nuclear changes of papillary carcinoma are seen, and the nuclei appear bland and benign.
Collections of macrophages, some laden with hemosiderin,
can be numerous. Typically, sheets of cells, most often Hiirthle
cells, are surrounded by benign-appearing lymphocytes in
autoimmune thyroiditis.
Summary
Thyroid carcinomas are basically separated into the four
familiar forms: papillary, follicular, medullary, and anaplastic carcinomas. Hiirthle cell carcinoma may be separated
as a special type, with distinctive morphologic changes and
somewhat more aggressive behavior than the other welldifferentiated carcinomas.
The subdivision of papillary carcinomas into tall cell and
columnar cell types, considered to be more aggressive than
the usual papillary carcinoma by some experts, has not been
clinically relevant, nor has the addition of the category of
poorly differentiated carcinoma as an intermediate form
between well-differentiated carcinoma and anaplastic carcinoma, with outcomes intermediate between the two forms.
Malignant lymphomas of thyroid gland are MALT lymphomas that probably evolve into diffuse, large B-celllymphoma, currently the most common malignant lymphoma of
the thyroid gland. Marginal zone lymphomas tend to remain
localized and spread according to their homing properties.
They are low-grade lymphomas that can be treated locally,
with long periods of remission. Autoimmune thyroiditis is
commonly associated with them.
The association of point mutations in the RET protooncogene with medullary carcinoma and gene rearrangements
with papillary carcinoma has been firmly established.
The Chemobyl accident has reemphasized the association of radiation with thyroid cancer, especially in younger
children. RET/PTC3 and RET/PTC] are the primary gene
rearrangements that have been identified in these cancers.
The finding of a unique, solid-trabecular variant of papillary
carcinoma in these children suggests that the solid variant
and the presence of RET/PTC3 oncogene may be associated
with a more aggressive form of papillary carcinoma.
Specimens for cytologic examination, acquired by fineneedle aspiration, are extremely useful in establishing the
diagnoses of thyroid diseases. However, their interpretations
are not without hazard. Papillary carcinomas are easily
recognized, but follicular and Hiirthle cell carcinomas are
difficult to differentiate from their respective benign lesions.
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Factors That Predispose to

Thyroid Neoplasia
Rachel R. Kelz, MD Douglas L. Fraker, MD
Radiation exposure of the thyroid gland is the only welldocumented risk factor that increases the incidence of welldifferentiated thyroid cancer. 1.2 Thyroid exposure to radiation
can result from external sources or from internal exposure
by ingestion of radioisotopes of iodine, which concentrate in
the thyroid gland. External exposure to the thyroid is primarily
from medically administered radiation but can also occur
with environmental exposures related to nuclear weapons or,
more recently, nuclear power plant accidents. This association
of radiation exposure and thyroid cancer is well established
and well characterized but accounts for only a small portion
of the total annual cases of well-differentiated thyroid cancer. 3
Other potential contributing etiologic factors, including diet,
effects of steroid hormones, and other occupational exposures,
have been evaluated.l-"
Radiation Exposure
Historical Aspects
The association between radiation exposure and increased
risk of thyroid cancer was first recognized by investigators
studying the increasing clinical problem of childhood thyroid
cancer in the mid-20th century.V The number of cases of
thyroid cancer diagnosed and treated in children or adolescents was quite low; only 18 cases of childhood thyroid cancer
were reported in the medical literature before 1930
(Fig. 26-1).7 Duffy and Fitzgerald recognized an increased
incidence of this disease and reported 28 cases between
1932 and 1948 at Memorial Sloan Kettering in New York
City.' They evaluated this population with the stated goals of
highlighting this increasingly important clinical condition,
defining the disease and natural history of childhood thyroid
cancer, and discovering "possible etiologic factors ... from
analysis of environmental, familial, and other biologic
factors." In addition to analyzing the sex distribution of the
patients, age at diagnosis in relation to puberty, and regional
dietary factors for these children, Duffy and Fitzgerald
noted that 9 of the 28 patients received radiation in infancy
for an enlarged thymus. Because 19 of these patients were
240
not known to have prior radiation, Duffy and Fitzgerald

believed that no definite association between radiation exposure and thyroid cancer could be concluded from their data.
Five years later, Clark adopted a similar strategy in evaluating
in detail 13 cases of thyroid cancer diagnosed and treated in
patients younger than 15 years at the University of Chicago."
Contrary to Duffy and Fitzgerald, Clark found that all of his
patients had received some type of childhood radiation,
although only 3 of the 13 were treated for an enlarged thymus; others received radiation therapy for acne, tonsillitis, or
cervical adenitis.
Winship and Rosvoll further documented the relationship
between radiation and childhood thyroid cancer by compiling
a national registry to track the incidence of this disease." The
peak number of cases in the United States was reported from
1950 to 1960 (see Fig. 26-1). The subsequent drop in incidence reflects the elimination of widespread use of radiation
treatments for benign conditions of infancy and early childhood, which occurred during the end of the 1950s. Detailed
analysis of subjects treated with radiation in early childhood
documenting the development of thyroid disease over a long
period of time, as well as case-control studies looking at the
same factor, defined the true risk of radiation exposure. The
impact of other variables such as the age at exposure, the doseresponse effect, and the greater problem of thyroid cancer
diagnosed in adults who were exposed to radiation therapy
as children has been characterized."
Childhood Radiation Exposure

1\\'0 case-control studies with extensive follow-up of large
populations of patients irradiated in childhood have been
published.v'? Shore and colleagues studied 2650 children
irradiated between 1926 and 1957 in Rochester, New York,
for an enlarged thymus compared with 4800 sibling control
subjects." Thirty cancers and 59 benign thyroid nodules
were detected in the treated group compared with 1 thyroid
cancer and 8 benign nodules in the control group. The relative risk for this entire population was 45 for cancer and 15
for benign neoplasms.
Factors That Predispose to Thyroid Neoplasia - -
300
200
'0
!E
::I
100
1900
1910
1920
1930
1940
1950
1960
1970
Year
FIGURE 26-1. The incidence of pediatric thyroid cancer in the

UnitedStatesfrom 1900to 1970from a nationalregistrydeveloped
by Winship showing the peak incidence occurring during the
1950s. (Adapted from Winship T, Rosvoll RV. Thyroid carcinoma
in childhood: Final reporton a 20 year study. Clin Proc Child Hosp
1970;26:327.)
Ron and coworkers studied 10,834 patients treated for

tinea capitis with radiation therapy before age 16 years
between the years 1948 and 1960. 10 A nonirradiated control
population consisted of 5392 siblings and 10,834 subjects
from the same area in Israel. In this study, there were
43 malignant thyroid tumors and 55 benign tumors in the
irradiated subjects compared with 16 cancers and 41 benign
lesions in the control subjects. The relative risk from radiation in this large study was 4 for malignant disease and 2 for
benign thyroid disease.
The difference in the degree of risk in these two studies
is explained by the characteristics of the radiation exposure
and the age of the patients at exposure. The relative risk of
thyroid cancer after childhood radiation is inversely related
to age at exposure and directly proportional to exposure
dose in lower dose ranges." The ages of subjects in the tinea
capitis study by Ron and coworkers ranged from infancy to
15 years (mean age, 7.4 years),'? whereas in the study by
Shore and colleagues, radiation treatment for an enlarged
thymus was given only to infants." The effect of having
much younger subjects in the study by Shore and colleagues
is to increase the relative risk, and this relationship is further
documented by analysis of the treated subjects in the study
by Ron and colleagues, in which the relative risk is less for
patients irradiated at age 7 years and older. The mean dose
of radiation to the thyroid in the Shore study? was more than
lO-fold higher (120 rad) than the mean dose in the Ron
study of scalp irradiation (9 rad).'? For a given population, a
roughly linear relationship exists between exposure dose
and estimated increased risk such that Ron and coworkers
could calculate an excess relative risk (ERR) of thyroid
cancer of 0.3 per rad of childhood radiation exposure.!?
241
In a series of reports, Schneider and coworkers at the

University of Chicago extensively studied their institution's
population of more than 3000 patients who underwent childhood radiation between 1939 and 1962. 11- 13 Of 3042 patients,
1145 had thyroid nodules and 318 were confirmed to have
thyroid cancer. II The natural history of almost 300 thyroid
cancers related to childhood radiation was reported in 1986.
Almost 75% were identified as lesions smaller than 1.5 em
in maximal diameter, but more than 50% of the patients had
multifocal disease. Eighty-eight percent of cases were papillary or mixed histology, and approximately 33% had lymph
node involvement." A 1993 analysis of the age at exposure
and dose of radiation confirms the relationship between these
factors in terms of degree of relative risk defined by the
case-control studies. 12 The ERR was 0.030 per rad for thyroid
cancer and followed a linear relationship for the benign
and malignant nodules over an exposure dose range of 0 to
150 rad. The ERRs at various ages at exposure are shown in
Figure 26-2, demonstrating an increased relative risk with
radiation at a younger age. Although females have a higher
overall incidence of thyroid cancer, the ERR tended to be
greater in the irradiated male population, although this variable was not significant.
Other undefined genetic or environmental factors may
contribute to radiation-induced thyroid neoplasia. Perkel and
colleagues identified 286 radiated sib pairs (i.e., two
children from the same family, both of whom had childhood
radiation exposure ).13 There was a significant familial concordance for all thyroid neoplasms (P = .05) but only a trend
for the subgroup of patients in whom thyroid cancer developed (P = .18), indicating that for a given age and dose of
exposure there are other factors that tend to make children
from certain families more susceptible than others to eventual thyroid cancer.
There are two explanations for the relatively high proportion of irradiated subjects documented to have thyroid
cancer in the Schneider population (10.5% of the total subjects
observed). I 1 First, the length of follow-up in this population
0.04
0.03
a:a:~ 0.02
w
0.01
0.00
< 1 year
1-4 years
5-15 years
Age
FIGURE 26-2. The effect of age at the time of radiation exposure

on the development of thyroid cancer. The excess relative risk
(ERR) per rad of thyroid exposure is shown over different age
ranges. (Adaptedfrom SchneiderAB, Ron E, Lubin J, et al. Doseresponse relationships for radiation-induced thyroid cancer and
thyroid nodules. J Clin Endocrinol Metab 1993;77:362. The
EndocrineSociety.)

was very long; the majority of patients were monitored for
more than 30 to 40 years after receiving radiation. In the
subgroup of patients observed for at least 40 years after
exposure, 60% had thyroid nodules and 15% had thyroid
cancer.12 The data of Schneider and coworkers indicate that
the annual incidence for thyroid cancer after childhood irradiation does not reach a plateau even after a long period of
time from exposure, suggesting that subjects irradiated
between 1930 and 1950 who are now in their sixth and seventh decades of life continue to have an increased ERR.12
Second, there is possible selection bias because this is a
non-case-control study. The potential for overestimation of
thyroid disease was demonstrated in a study comparing the
impact of childhood irradiation using two methods of analysis:
a questionnaire versus clinical evaluation. The degree of
increased relative risk was sixfold higher when the same
population was studied by questionnaire as opposed to clinical
examination." This difference was believed to be due to the
increased attention paid to the potential development of thyroid nodules by patients who had received childhood radiation
exposure and by the physicians who took care of them because
of this well-defined risk factor. Although the data characterizing relationship to dose of exposure and age of exposure are
unaffected in single institutional reviews, the most accurate
analyses of true estimates of increased risk come from the
case-control studies, in which all patients undergo a clinical
evaluation by the same team of investigators.
Radiation Exposure from

Medical Therapy and Diagnosis
Recognition of the potential for causing eventual thyroid
cancer by administration of radiation treatments in childhood essentially eliminated this practice for treatment of
benign diseases of the thymus, scalp, cervical lymph nodes,
tonsils, and skin more than 30 years ago." Although administration of external beam radiation treatments for malignant
conditions affects a smaller number of patients-particularly those in the lower age ranges-patients receiving therapeutic and diagnostic radiation therapy currently represent
the largest population in which the thyroid is exposed to
potentially carcinogenic doses of radiation. Because younger
age of exposure and higher radiation doses increase the
relative risk, patients receiving significant radiation therapy
in early childhood are the subgroup with the greatest likelihood of developing thyroid cancer.
A 1991 study by Tucker and associates of 9570 pediatric
subjects who received radiation therapy for a variety of malignant diagnoses, predominantly Wilms' tumor, Hodgkin's
disease, neuroblastoma, and non-Hodgkin's lymphoma,
demonstrated a significant risk in this group of survivors of
childhood malignancies. IS Patients with neuroblastoma were
irradiated at a mean age of 2 years with an estimated thyroid
exposure of 600 rad-significantly greater than the usual
exposures for the benign childhood conditions-and had an
increased relative risk of thyroid cancer of 350. A similar
highly significant increased risk in patients with Wilms'
tumor of 132 indicates that a high therapeutic radiation dose
at a young age (younger than 4 years) places the long-term
survivors of this disease at a very high risk for developing a
secondary thyroid cancer. IS In this study, patients with lymphoma had a significantly greater radiation exposure (dose
range, 2000 to 3500 rad), but it was administered at an older
age, and the relative risk was 81 and 67 for non-Hodgkin's
lymphoma and Hodgkin's disease, respectively. IS
Another large study of Hodgkin's disease not restricted to
pediatric patients reported an increased relative risk in a group
of subjects treated at a mean age of 29 years. 16 Hancock and
colleagues identified six thyroid cancers in 1677 patients
treated with radiation alone or radiation plus chemotherapy
for Hodgkin's disease, which was 15.6 times the expected
risk. The population of patients with Hodgkin's disease makes
up a significant proportion of currently treated patients at risk
for second thyroid neoplasms, because there is a high cure rate
with this disease compared with other solid pediatric malignancies in which radiation treatment is administered. The
impact of age at exposure and dose of exposure on relative
risk can be seen from data extracted from several case-control
studies in which these variables were defined (Table 26-1).
Other medical radiation exposures may occur in smaller
amounts in older patients but still may significantly alter
the risk of thyroid neoplasia. A large study of more than
150,000 women treated with radiation therapy for cervical
cancer reported a relative risk of 2.35 for thyroid cancer with
an estimated exposure of only II rad.!? Finally, patients who
receive minimal exposure from diagnostic or medical x-ray
examinations with an estimated thyroid dose of less than
1 rad still showed a modest increase in relative risk, particularly female patients younger than 50 years. 18
Factors That Predispose to Thyroid Neoplasia - - 243
Another type of medical exposure is that to radioactive

iodine, particularly iodine 131, for diagnostic or therapeutic
purposes. A significant amount of ingested iodine is taken
up and remains within the thyroid, and this gamma ray emitter
over time exposes the thyroid tissue to a significant radiation
dose. Therapeutic use of 131 1 for ablation of the thyroid in
Graves' disease exposes the thyroid to a dose equivalent of
between 6000 and 10,000 rad of external beam exposure. 19,20
Despite this high dose, there is minimal apparent increased
risk of thyroid cancer. A study of more than 3000 patients
treated with high-dose UII identified only 4 cases of thyroid
cancer compared with 3.2 predicted cases." An update from
the same investigatorsof a larger population of 10,552 patients
evaluating all types of secondary malignancies after highdose 131 1 showed a 10-year standardized incidence ratio
(SIR) of 1.32 for thyroid cancer." This mildly increased risk
in this population was similar to the increased risk of stomach cancer in the same patients (SIR = 1.33) but was lower
than the increased risk of brain and renal cancers (SIRs =
1.63 and 1.51, respectivelyj." Although this high-exposure
dose is similar to that from external beam treatments administered for Hodgkin's disease, in which there is a much more
significant risk, the lower increased risk with 131 1 treatment
may reflect the ability of this type of exposure to ablate or
destroy the thyroid parenchyma.
A second more widely used dose range of 131 1 is that
administered for diagnostic thyroid scans, which corresponds
to approximately 50 rad of external beam exposure. A study
of more than 35,000 diagnostic 131 1 scans administered
between 1951 and 1969 showed a slight increase in thyroid
cancer, with 50 actual cases versus 39.4 cases predicted
(SIR = 1.27).22 Subgroup analysis showed that the risk was
more significantlyelevated in males (SIR =2.70) than females
(SIR = 1.12) receiving UII diagnostic scans (Fig. 26-3). One
deficiency in this case-control study is the reason why the
treated population ended up in the group that received a
thyroid scan. That is, by definition, patients who undergo
Total
Males
Females
Thyroid Functional
Nodules Disease
FIGURE 26-3. The risk of thyroid cancer after diagnostic iodine

131 thyroid scans giving an estimated dose of 50 rad. The standardized incremental risk is shown for the total population, for subgroups based on sex, and for subgroups based on the category of
thyroid disease for which they were being studied. (Adapted from
Holm LE, Wiklund KE, Lundell GE, et al. Thyroid cancer after
diagnostic doses of iodine 131: A retrospective cohort study. J Nat!
Cancer Inst 1988;80:1132.)
a thyroid scan must have some clinical indications for having

this test ordered and, therefore, may be predisposed to the
development of thyroid neoplasms on those grounds as
opposed to any increased risk from the administered
radioisotope. Subgroup analysis of the patients who had
a diagnostic scan for nodular thyroid disease compared
with functional thyroid disease confirms this selection bias.
Patients who underwent a thyroid scan for nodular disease
had a significantly higher risk for acquiring an eventual thyroid cancer (SIR = 2.77) compared with patients scanned for
functional reasons (SIR = 0.62).22
The overall analysis of these large studies indicates that
exposure doses of 131 1 in a low range (diagnostic scans) or
a high range (therapeutic ablation) do not have the same
relative risk as an equivalent dose of external beam radiation, as delineated previously. The reason for this difference
is probably the energy levels and time course of a radiation
exposure from ingested UII as opposed to a clearly defined
acute delivery of fractionated external beam radiation. Other
factors such as the impact of the iodine dose as well as the
ablative effects of 131 1 directly on the thyroid gland may
contribute to the fact that radiation from ingested medically
used isotopes is not as carcinogenic as the external beam
radiation therapy.P
Environmental Radiation
Exposure
As with the medical radiation exposure just described, environmental radiation exposure of the thyroid can be from
external sources as well as internal ingestion of radioisotopes of iodine. The populations exposed are geographically
related to discrete regional events involving either nuclear
weapons or nuclear power plant accidents.
The largest, best studied population exposed to acute
external radiation from an environmental source includes
survivors of the atomic bombs detonated at Hiroshima
and Nagasaki.P>' A cohort of more than 100,000 residents
of these cities with a variable exposure dose on the basis
of proximity to the sites of explosion has been identified and
monitored. Relative risk of thyroid cancer clearly increased
in this population on the basis of age at exposure and dose
of radiation received. Younger people and, in particular,
females younger than 30 years at the time of the blasts had
the most increased relative risk. The dose response is
particularly well documented in Nagasaki, and the estimated
relative risks are 1.28, 1.61,2.36, and 3.82 for estimated exposure doses of 25, 50, 100, and 200 rad, respectively.-' This
increased risk is pertinent only to gamma ray exposure but
does not correlate with neutron radiation exposure. Within
this population, studied after the atomic bomb explosions,
there have been 112 total cases of thyroid cancer: 62 from
Hiroshima and 50 from Nagasaki." Histologically, the vast
majority of this radiation-associated thyroid cancer has been
papillary. The long-term survival for radiation-associated
papillary thyroid cancer in Hiroshima is 82% compared with
85% for comparable cases not associated with radiation
exposure from that area." These equivalent survival data
suggest that radiation-induced thyroid cancer does not have
an altered or more aggressive natural history.
Although, on the basis of the Japanese studies, acute

gamma radiation exposure from a single event such as an
atomic explosion clearly increases the risk of thyroid cancer,
chronic gamma radiation exposure does not have the same
effect. 25 A long-term study of subjects in southern China,
where a high level of background radiation is present as a
result of radioactive sand, showed an increase in chromosome abnormalities of the thyroid gland but no increased
incidence of thyroid neoplasia. The estimated exposure over
40 years in this population was a total of 14 rad, which as an
acute exposure would increase the risk of thyroid cancer,
and the relative risk was 1.02 compared with control
subjects after this chronic exposure.P
Nuclear weapon explosions also produce radioisotopes of
iodine in fallout that can contaminate water and food supplies,
leading to ingestion by patients. Like medically administered iodine, these isotopes concentrate in the thyroid gland
and can deliver focal radiation to the gland. Whereas 1311 is
used medically, nuclear fallout contains a mixture of 1311
with short-lived radioisotopes such as 1291, 1321, 1331, 1341,
and l351.26.27 The best data concerning nuclear weapon fallout
exposure come from testing sites in the Marshall Islands and
Nevada. On March I, 1954, a 15-megaton bomb was detonated in the atmosphere over a test site on the uninhabited
Bikini atoll in the northern Marshall Islands." Unfortunately,
high-activity radiation fallout from this blast exposed 253
residents of the neighboring two islands, causing acute radiation sickness. Among the 86 subjects most exposed on the
closest atoll, thyroid nodules developed in 32% of the total
population and in 63% of children younger than 10 years at
exposure." One report demonstrated that 12 other Marshall
Island atolls thought initially to be unexposed to fallout had
an increased incidence of thyroid nodules inversely proportional to the distance from the test site. The estimated doseresponse relationship defined in this study is II excess cases
per rad per year per I million population."
A second study of nuclear fallout involved Nevada test
sites. The U.S. Atomic Energy Commission conducted more
than 100 aboveground nuclear detonations between 1951
and 1958 at these sites.F This exposure was not as precisely
defined in time and amount as the Marshall Islands incident,
but dosimetry of surrounding areas including soil, vegetation, and milk from cattle showed that areas of Utah, Nevada,
and Arizona were exposed. A cohort was identified including 4818 children who ranged in age from 0 to 7 years
in 1953, the estimated time of peak exposure from fallout.
An increased relative risk of 3.4 for the development of
thyroid nodules was shown in the group of children with
an estimated thyroid exposure greater than 40 rad? Again,
the short-lived radioisotopes of iodine were believed to be a
major factor in this exposure.
All of the environmental exposures described previously
occurred more than 40 years ago and have in large part
been studied retrospectively to provide a long-term database
for acute gamma radiation and nuclear fallout exposure.
In April 1986, the Chernobyl nuclear power plant explosion
released an estimated 50 million Ci of radioactive materials
into the atmosphere and exposed an estimated 1.5 million
people in southern Belarus and the northern Ukraine." The
fallout early in the disaster consisted of a large amount of 1311
together with short-lived isotopes 1291, 1321, l331, 1341, and 1351. 29
An early study completed 4.5 years after the event using

clinical examination and ultrasonographic studies showed no
significant increased incidence of thyroid nodules in exposed
populations versus control subjects." However, this study
was completed just as the latent period after this exposure was
ending. Cases of pediatric thyroid cancer in Belarus increased
sequentially from 1986 through 199328,29 (Fig. 26-4). By
1996, more than 500 cases had been diagnosed in children
younger than 15 years." The disease in the exposed children
initially showed an equal sex distribution; 83 of 84 cases
involved papillary thyroid cancer and 1 involved medullary
thyroid cancer." Histologically, lesions that occurred soon
after exposure were aggressive, with capsular invasion in
89% and lymph node metastases in 88%.
Later, in 1998, Farahati and colleagues examined the agespecific effects of radiation on disease severity in 483 children living in Belarus and younger than 8 years of age at the
time ofthe accident." They found that the frequency of thyroid carcinoma was highest among infants and children
younger than 3 years and decreased rapidly with the advancing age at the time of exposure. There was a higher incidence of differentiated thyroid cancer among females
compared with males (1.6). Follicular cancer represented
only 3.6% of the cases, which may be explained by a longer
latency period for this variant. Age at exposure was inversely
related to disease severity. The study confirmed that younger
patients had more extrathyroid disease, lymph node involvement, and distant metastasis. The latency period, however,
did not differ by age group. The inverse relationship between
disease severity and age at the time of exposure is postulated
to be due to the small volume of thyroid tissue in children
70
60
50
Ul
GI
Ul
III
CJ
40
'0
GI
.c
E
30
:l
20
10
1987
1988
1989
1990
1991
1992
1993
Year
FIGURE 26-4. The number of cases of pediatric thyroid cancer

in Belarus from 1986 to 1993 showing increased incidence since
the April 1986 Chemobyl disaster. (Adapted from Nikiforov Y,
Gnepp DR. Pediatric thyroid cancer after the Chemobyl disaster.
Cancer 1994;74:748. Copyright 1994, American Cancer Society.
Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John
Wiley & Sons, Inc.)
younger than 2. The small volume of tissue would lead

to a proportionately larger radiation dose at the same level
of exposure.
Data for the radioactive exposure by ingestion from the
Marshall Islands, Nevada test sites, and Chernobyl show a
clear increased risk of thyroid cancer; the important variables of age at exposure and dose of exposure contribute to
the risk. This increase in incidence contrasts with the data
presented previously regarding medically administered 1311,
which even at high doses has minimal effect. 2022 One difference is that, contrary to 1311, radioactive fallout has shortlived high-energy beta isotopes, which may cause more
injury over a short period of time to the thyroid parenchyma
than an equivalent exposure dose of only 13IJ.26 However,
Baverstock pointed out that the negative data concerning
medical 131 1 use and thyroid cancer come almost exclusively
from an adult population of patients.P Little information is
available regarding medical exposure in children, who are
rarely treated or scanned with 1311. As the data from Chernobyl
continue to mature, the characteristics of increased risk in
both younger and older populations exposed to this high dose
of fallout will become clearer.
Some investigators have suggested that the increased
incidence of pediatric thyroid cancer in and around
Chernobyl is due to increased surveillance.F A French study
of a population near a long-term nuclear power plant at
Chooz showed no increased incidence in terms of proximity
to this plant and the exposure from normal operations near
a nuclear plant." However, the situation at Chernobyl with
early, very aggressive lesions documented in exposed children
is incontrovertible and argues that this acute intense exposure has significantly increased thyroid cancer incidence,
which will probably continue over the next several decades.
Molecular Carcinogenesis
The pathogenesis of radiation-induced thyroid cancer has
not yet been elucidated. Gene rearrangements may play an
important role in the process. Nikiforova and associates
found that radiation-induced tumors had a 4% prevalence of
BRAF point mutations and a 58% prevalence of RET/PTC
rearrangements, and sporadic papillary thyroid cancers
demonstrated a 37% prevalence of BRAF point mutations
and only a 20% prevalence of RET/PTC rearrangements.r'
Similarly, RET/PTC3 rearrangement was found in aggressive
tumors that occurred less than 10 years after the Chernobyl
accident. 35 Elisei and coauthors also found a prevalence of
38% of RET/PTC rearrangements in adenomas found within
radiation-exposed glands, implying that this rearrangement
is not restricted to the malignant phenotype but may be a step
in the development of malignant transformation of radiationinduced thyroid tumors. 36
Other Factors
A summary of the characteristics of radiation exposure and
thyroid cancer is given in Table 26-2. Although a sizable body
of data clearly defines this risk factor, most patients currently
with thyroid cancer have no history of radiation exposure.'
A study from the Connecticut tumor registry showed that only

9% of thyroid cancers could be related in any way to radiation exposure. Other risk factors include dietary intake, sex
hormones, other environmental exposures, lifestyle factors,
and increased genetic susceptibility.
The epidemiologic data on well-differentiated thyroid
cancer may offer some clues to other etiologic factors. First,
females are affected more frequently than males. Second,
certain geographic regions have a significantly higher incidence, particularly Iceland, Switzerland, coastal Norway, and
Hawaii." Unfortunately, studies of these populations in regard
to dietary, hormonal, and environmental factors yielded very
inconsistent results. Some studies reported opposite results,
with some showing that certain factors increased the incidence of thyroid cancer, whereas other investigators showed
a decrease risk from the same factors (Table 26-3).
Dietary influences contributing to thyroid cancer have
been extensively studied, focusing particularly on goitrogens
and iodine-deficient or iodine-excessive diets. Animal models
document that increased thyroid-stimulating hormone (TSH)
levels result in thyroid neoplasia, and dietary factors may
exert their effects by increasing TSH in one of three ways."
Iodine deficiency leads to compensatory higher TSH levels;
high-goitrogen diets (e.g., vegetables from the cruciferous
family) may block iodine uptake and incorporation and
lead to thyroid hypertrophy under the influence of TSH or
to direct anterior pituitary effects that release TSH. Although
theoretically these dietary influences can increase the risk of
thyroid cancer, in reality the data are mixed. Both low-iodine
diets and high-iodine diets have been reported to increase
risk." Large intake of shellfish and other seafoods that are
quite high in iodine content occurs in areas of the highest
incidence of thyroid cancer such as Iceland, Norway, and
Hawaii. 39,40 However, studies from northern Italy show that
high intake of fish exerts a protective effect; increased risk
is associated with starchy foods such as potatoes, rice, pasta,
and bread." except in one study in which pasta was shown
to have a protective effect."
Lifestyle factors have been studied with regard to the
development of thyroid neoplasms. Although consumption
of alcohol can cause TSH release directly, it does not appear
to be associated with increased risk." In fact, one study
actually found a reduced risk among women who consumed
at least 12 drinks per year," Cigarette smoking has also been

evaluated as a potential carcinogen; however, the association
between cigarette smoking and thyroid cancer has either been
nonexistent or found to be protective against the development
of thyroid neoplasia. 42-45 The mechanisms of this finding have
not yet been elucidated. Caffeine-containing beverages have
also been examined without evidence for any association with
thyroid neoplasia. Finally, working in the wood-processing,
pulp, and paper-making industry has been shown to be associated with an elevated risk of thyroid cancer." Hydrocarbons
have been suggested to be the causative agent in this setting,
but this has not been adequately studied.
A second area of associated risk factors specific for
females is the influence of sex hormone status. Different
factors such as parity, early "artificial" menopause, oral contraceptive use, abortions, and late age at first birth have been
reported to be associated with an increased risk of thyroid
cancer.47,48 However, not all studies have come to the same
conclusions (see Table 26-3). For example, two large studies
from Norway showed different results in terms of parity.49.50
One study showed a proportional increased risk between
zero and four children born, whereas a second study showed
no association with parity. One consistent finding in several
studies related to hormonal status is body weight. 1\\10 investigators have reported that obese patients in both younger and
older age groups, and particularly females, have an increased
risk for thyroid neoplasia.v-" The precise mechanism of this
effect, whether dietary or hormonal, is unclear.
Finally, the presence of benign nodular thyroid disease is
clearly associated with thyroid cancer. I This finding may be
related to a screening or selection bias or may be related to
common factors that lead to both nontoxic nodular goiter
and thyroid cancer. If only this subgroup of goiter patients is
analyzed (nontoxic nodular), there is a reported incidence of
thyroid cancer as high as 17% in one study; others report the
development of thyroid cancer in 9% to 11% of this population. 52Associations between thyroid cancer and other malignancies suggest possible genetic influences. An association
with familial polyposis of the colon, as well as melanoma
and testicular and bladder cancers, has been reported.
Summary
The only clearly documented risk factor for thyroid neoplasia is radiation exposure; a majority of patients acquiring
this disease have no known risk factors. Major questions for
the future include the definition of other genetic or environmental risk factors. Progress in this epidemiologic area will
go hand in hand with increased understanding of the molecular biology of thyroid cancer (see Chapters 30 and 31).
In patients with radiation-related thyroid cancer, investigators must determine whether the large population exposed as
infants or children who are now in their sixth or seventh
decade of life will continue to have a higher incidence of thyroid cancer 40 to 60 years after exposure and, if so, whether
these radiation-induced thyroid cancers will have the same
more aggressive natural history as non-radiation-induced
cancers occurring in the elderly population of patients.
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Predictors of Thyroid Tumor

Aggressiveness
Blake Cady, MD
The antecedents of attempts to predict thyroid cancer behavior

date back to the 1930s, when the concept of "lateral aberrant
thyroid'v-' was established, because thyroid tissue appearing
in lymph nodes in the neck was known to be associated with
an innocent clinical behavior pattern in a vast majority of
cases. As a result, these cases were considered to be not
cancer but an arrested embryonic migration phenomenon,
until Crile convincingly demonstrated small primary papillary cancers in such cases.' That was also an era when 15%
to 20% of all thyroid cancers were of an anaplastic variety
that was almost uniformly and rapidly fatal"; median survival
associated with anaplastic cancers was only 3 or 4 months,
and all but a few patients were dead within 6 months. This
wide range of clinical behavior from cancers arising from
the same thyroid follicular cell was noteworthy, even then,
in displaying the extremes of tumor biologic behavior.
Currently, of course, we have several well worked-out
and easily clinically applicable indicators of risk group
assignment to predict accurately the biologic behavior of
cancers of the thyroid gland.>!" Arriving at these unique,
clinically discernible risk estimations is a simple process in
thyroid cancer, whereas clinical predictors of outcome are
much less accurate and effective in other human cancers,
particularly in defining a preponderance of patients at very
low risk. It is important for surgeons to recognize the striking differences in behavior of thyroid cancers originating
from an identical cell so that appropriate surgical techniques
can be applied to patients to minimize morbidity and to
restore and maintain normal life in the vast majority of
patients currently being treated for differentiated thyroid
carcinoma.
Epidemiology
A number of epidemiologic features in thyroid carcinoma
may have implications regarding thyroid cancer behavior.
Beginning in the 1950s, it became well established that there
was an increased incidence of differentiated thyroid carcinoma in patients who had received therapeutic radiation
as infants and children. IS Such therapeutic radiation in the
248
1930s and the 1940s was frequently given for thymic, adenoid, and tonsillar enlargement, facial acne, and even tinea
capitis. As many as 30% to 40% of such patients later operated
on for thyroid nodules were discovered to have differentiated thyroid carcinoma, usually papillary and often only
microscopic." When this etiologic association became
apparent, such low-dose radiation therapy disappeared from
clinical practice, and as a result few patients today are seen
with a history of radiation treatment. Thyroid gland abnormalities in survivors of the nuclear bomb explosions in
Japan and the Pacific atolls are well described. I? These
nodules were both benign and malignant, but in almost half
of the cases of cancer, the lesion was a microscopic or small
focus in thyroid tissue adjacent to a benign nodule.
In the geographic area downwind of the Chernobyl
nuclear accident, an appreciable number of children exposed
to radioactive fallout have acquired thyroid carcinoma. 18 It is
now evident that these cases represent a real increase in thyroid cancer (Fig. 27-1). A peculiar aspect of the Chernobyl
reports has been the very short latency period of only a few
years to the appearance of these cancers'? and iodine deficiency.20.21 The median time to appearance of thyroid carcinoma associated with childhood radiation therapy in
previous reports has been about 20 years, and it appears to
increase for at least 3 decades after exposure. No cases of
thyroid carcinoma have been reported from the Three Mile
Island nuclear accident in Pennsylvania. Although there are
vast differences in background cosmic radiation between sea
level and mountain communities and between house construction of brick or stone compared with wood frame, there
have never been adequate data indicating that increased
background cosmic radiation has been associated with an
increased incidence of human thyroid carcinoma. Although
widespread childhood radiation is no longer an issue in the
United States, childhood Hodgkin's disease is frequently
treated with a mantle radiation port that includes the thyroid
gland; these patients have an increased risk for the development of differentiated thyroid cancer." Radiation-associated
thyroid cancers appear to exhibit biologic behavior similar
to that found in patients with thyroid cancer who have not
received radiation.
Predictors of Thyroid Tumor Aggressiveness - - 249
radiation-induced thyroid cancer, has received much attention28-33 and continues to elicit genetic analysis and definitions.
100
90
iii
Q)
80
>- 70
Iii
o, 60
oo
Q)
50
00
III
40
30
Iii
o
III
Belorussia
Ukraine
Russian Federation
20
10
o~~~~~
1986 1987 1988 1989 1990 1991 1992 1993 1994
Year
FIGURE 27-1. Sharp increase. Childhood thyroid cancer is rising
in three republics most affected by Chemobyl. (Redrawn with
permission from Balter M. Chemobyl's thyroid cancer toll.
Science 1995;270:1758. Copyright 1995, American Association
for the Advancement of Science.)
The basic iodine content in the diet has been linked to

varying patterns and incidences of thyroid carcinoma. 20 ,23-25
In regions with low dietary iodine, there is an increased
proportion of follicular carcinoma and a high incidence of
anaplastic carcinoma compared with areas with adequate
dietary iodine, where papillary carcinoma predominates and
anaplastic carcinoma is uncommon. There seem to be other
subtle differences in the pattern of both differentiated and
undifferentiated thyroid carcinoma in iodine-rich areas
compared with iodine-poor areas. Historically, because of
the presence of large "goiter belts" in the United States, an
experiment was carried out in Akron, Ohio, in the 1920s in
which schoolgirls were given iodine supplements, which
produced a marked reduction in endemic goiter incidence.
By the mid-1930s, the United States had established routine
iodinization of household salt to control endemic goiter. As
a result, 70 years later we have had two generations of our
population growing up with adequate iodine in their diet.
During this time there has been an increasing preponderance
of papillary carcinoma of the thyroid in the United States
and the virtual disappearance of anaplastic carcinoma.v?
Conversion of long-standing or recurrent papillary carcinoma to anaplastic cancer of the thyroid with resultant death
was a well-recognized phenomenon in the 1930s and 1940s
but is now uncommon in patients born and raised in this
country with adequate dietary iodine. This phenomenon
of ensuring adequate dietary iodine represents a major
public health accomplishment in preventing goiter and is
undoubtedly a major cause of the changes in presentation
of thyroid carcinoma since 1930. Many immigrants to the
United States come from iodine-poor regions, however, and
may display a pattern of disease that mimics the American
experience of the 1930s. Other subtle environmental factors
in the epidemiology of differentiated thyroid carcinoma
may exist and have effects on outcome but have not been
defined adequately to be recognized as a problem.P-" The
role of genetic abnormalities in thyroid cancer, particularly
Pathology
Understanding the pathology of thyroid carcinoma is critical
to appreciating the biologic behavior of the various neoplasms arising from the thyroid follicle cell and allowing
predictions of aggressiveness. Papillary and follicular thyroid carcinomas are the most common thyroid cancers
worldwide. Differentiated thyroid carcinomas that have both
papillary and follicular thyroid elements are classified as
papillary carcinomas because they have the same biologic
behavior as that of papillary carcinoma.v' In our series,"
whether the carcinomas were pure papillary or mixed papillary and follicular with varying proportions of follicular
components, including follicular predominant forms, the
clinical behavior was identical. In contradistinction, follicular carcinoma should describe thyroid cancers of a pure follicular pattern. Follicular carcinoma of poor differentiation
has a poor prognosis but must be separated from anaplastic
carcinomas consisting of giant and spindle cells. Undifferentiated thyroid carcinoma is a uniquely aggressive form of
carcinoma consisting of spindle and giant cell anaplastic
lesions, as well as some cases of small cell carcinomas.'
Although the diagnosis of small cell undifferentiated carcinoma was used frequently in the 1930s, 1940s, and 1950 in
contemporary studies using histochemical staining, many of
these were either medullary carcinomas (first described in
1957) or lymphomas of the thyroid. Thus, the proportion of
undifferentiated thyroid cancers that are of the small cell
variety is quite small.
Lymphoma of the thyroid is a recognized presentation of
extranodal non-Hodgkin's lymphoma.P-" Patients with such
lesions should have extensive diagnostic evaluation to rule
out disseminated lymphoma with thyroid involvement.
Thyroid lymphomas arise more often in patients with
Hashimoto's thyroiditis and lymphoid hyperplasia. Histologic
differentiation between these entities may be difficult, may
cause diagnostic confusion, and may require sophisticated
histochemical staining and electromicroscopy for accurate
diagnosis. Patients with thyroid lymphoma can be treated
for cure using surgical resection, if possible, but primarily
through chemotherapy and radiation therapy." Rare types
of thyroid carcinoma, such as sarcoma and squamous cell
carcinoma, also occur. Melanoma and cancers of the lung,
breast, and kidney are the tumors that most often metastasize to the thyroid gland.
At present, in the United States, differentiated thyroid cancers make up about 95% of cases of thyroid malignancy, of
which at least 80% are papillary; anaplastic carcinoma makes
up less than 2%, and thyroid lymphoma makes up about 1%.
Medullary carcinoma of the thyroid arises from parafollicular C cells, rather than thyroid follicle cells, and makes up
less than 4% of all thyroid cancers.v'? Many reports in the
literature indicate higher proportions of medullary carcinoma
in a particular institution, but this represents the phenomenon
of selection by diagnosis of familial clusters in the inherited
form of the disease. Overall, medullary carcinoma represents
less than 4% of all thyroid gland carcinomas.
250 - -
Thyroid Gland
Differentiated Thyroid
Carcinoma
Follicular Carcinoma
Pure follicular carcinoma appears to be decreasing in frequency and now makes up about 10% of differentiated thyroid cancers. This proportion may be different in geographic
areas with insufficient dietary iodine or with different pathologic definitions.P'" Follicular cancers are diagnosed by the
invasion of the follicular cells into or through the veins or
tumor pseudocapsule or into metastatic sites. Minor tumor
pseudocapsular involvement or only minor vessel involvement within the tumor itself may define follicular carcinoma,
but such technically defined follicular adenocarcinomas have
little, if any, risk of recurrence, metastases, or death from disease, regardless of age or risk group. Such a follicular cancer
with minor capsular involvement may be found in retrospect
in a patient presenting with distant metastases, but this is
rare. Extensive data from the Mayo Clinic" and Lahey
Clinic 9,34 confirm the essential absence of risk of recurrence
or death in such patients. In the 1930s and 1940s, the phenomenon of "benign metastasizing follicular adenoma" was
described but represented inadequate sampling of the primary
thyroid tumor pseudocapsule to discern completely the
extent of capsular involvement in such metastatic cancers.
However, major tumor pseudocapsular involvement represents a far more aggressive type of follicular thyroid cancer.34
Thus, gross breaching of the thyroid tumor pseudocapsule,
particularly with extension outside the thyroid gland itself
into surrounding structures (strap muscle, esophagus, soft
tissues, laryngeal or tracheal wall), clearly represents a type
of follicular adenocarcinoma with a worse prognosis. Such
pathologic extension through the tumor pseudocapsule is a
phenomenon that is somewhat linked with size, so that large
follicular adenocarcinomas frequently have extension outside
the thyroid gland and into surrounding structures, and minor
tumor pseudocapsular involvement usually occurs in smaller
lesions that are intraglandular. However, on occasion, even
small follicular adenocarcinomas demonstrate gross involvement of the thyroid gland capsule and invasion of surrounding
tissues. Such follicular adenocarcinomas, with major tumor
pseudocapsular involvement and extraglandular extension,
have a poor prognosis regardless of size. This poor prognostic implication of extensive tumor pseudocapsular involvement by follicular carcinoma applies across all age ranges,
including a few patients who otherwise might be considered
at low risk, but in older patients is particularly ominous. Thus,
the mortality rate in the few younger patients is about 25%,
but in older patients, who are more frequently affected, it may
be as high as 75%. Overall, patients with follicular
carcinoma have the same prognosis as patients with papillary
carcinoma. 9,34042 We do not separate Htirthle cell cancer from
other follicular cancers." Whether patients with Hiirthle cell
cancer have a unique risk of recurrence or death is debatable."
Papillary Carcinoma
Mention was previously made of the concept of lateral aberrant thyroid, which represented a phenomenon with such an
innocent long-term outlook that for many years it was considered an embryonic abnormality rather than a cancer.'
This history represents one aspect of the difficulty of prognostication in thyroid cancer. It is important to realize that
occult papillary cancers are extremely common in autopsy
studies and in apparently normal thyroid tissue and have no
impact or risk of clinical cancer or death from cancer. These
occult lesions are seen in between 6% and 18% of American
patients and are even more common in other countries.r'
Now, of course, with rare exceptions, we recognize the
presence of even benign-appearing thyroid tissue in lymph
nodes of the neck as metastatic disease, frequently with an
occult primary in the thyroid gland. More than 75% of
young patients with papillary thyroid cancer have lymph
node metastases when node dissections are performed.
Twenty-five percent of young patients present because of a
palpable lymph node in the neck rather than because of a
tumor in the thyroid gland. 34045 Although the initial presentation with a palpable lymph node metastasis in all other head
and neck carcinomas represents a poor prognosis and the
presence of lymph node metastases in all other human cancers indicates a worse prognosis than cases that have negative nodes, the implication of nodal metastases is uniquely
different in young patients with low-risk papillary carcinoma
of the thyroid. Indeed, with some exceptions,704M7 reports of
multifactorial analysis of differentiated thyroid carcinoma
prognosis and risk groups fail to find lymph node metastases
as a significant factor, and none of the risk group scoring
systems include lymph node metastases. Many surgeons,
endocrinologists, and physicians, however, still have difficulty in accepting such a uniquely different implication of
nodal metastases.v"
Risk Groups in Differentiated

Thyroid Cancer
The phenomenon of a relationship between age and outcome
in differentiated thyroid carcinoma dates back to reports
from the 1940s and earlier," Clinically, it became obvious
that the outcome of patients younger than 45 years was distinctly different from that of patients in older age groups. It
is now apparent that there is a strong relationship between
increasing age and worsening prognosis with age greater
than 40, 45, or 50 years, variously defined in different
reports.lv" Thus, in our reports,"!' all patients older than
70 years had an extremely high risk of recurrence and death
(67%) from disease regardless of the individual features of
the cancer, such as size, extent of disease, pathologic type,
and extent of surgery. In all the multifactorial risk group designations published over the past 20 years, age has been one
of the major prognosticating features, if not the major one.
When other primary tumor features, such as extent of disease, size, grade, completeness of surgery, and flow cytometry," are included with age, uniquely effective separations of
the benign-behaving preponderance of low-risk cases from
higher risk groups, which represent a minority of cases, can
be established. Early attempts at such prognostication by
clinical phenomena were represented by the International
Union Against Cancer tumor, nodes, and metastases (TNM)
staging system" and the European Oncology Research for the
Treatment of Cancer staging system published in the 1970s. 7
Predictors of Thyroid Tumor Aggressiveness - -
In the late 1970s and early 1980s, two other systems of

clinical assessment of risk were published-AGES (age,
grade, extent, and size) by the Mayo Clinic 8 and AMES
(age, metastases, extent, and size) by the Lahey Clinicf--;
that illustrated uniquely simple and effective postoperative
prognostic scoring systems. The latter two systems demonstrated that the basic risk group assessment superseded
the prognostic effect of type of surgery, use of radioactive
iodine, use of external radiation therapy, presentation of
primary disease, presentation of recurrent or metastatic disease, and perhaps even use of thyroid-stimulating hormone
(TSH) suppression by thyroid hormone administration. The
addition of flow cytometry to the AMES category (DAMES) I I
was proposed as yet another sophisticated prognostication in
individual cases but was not routinely clinically applicable
at the time of surgery because of the need for a postoperative tumor analysis by flow cytometry. A major report by
Shah and colleagues'? at Memorial Hospital in New York
again confirmed all the basic features of the previously
published multifactorial risk groups (age, metastases,
extent, size).
Finally, a Mayo Clinic study published by Hay and coauthors 14 has incorporated completeness of surgical removal of
the primary thyroid cancer in the most recent iteration of
their multifactorial analysis: MACIS (metastases, age, completeness of surgery, invasion of cancer, and size). Of all
their MACIS patients with papillary cancer, 84% fall into a
low-risk group, which has only a 3% 10-year recurrence rate
and a 1% 20-year death rate. Such a low death rate is identical to that for an age-adjusted similar population without
thyroid carcinoma. Three further levels of risk group assignment in this MACIS system have progressively worse prognoses, culminating in the highest scoring patients, who have
a 75% risk of cause-specific mortality. The MACIS system
is the only one that includes surgical resection, but it is
important to understand that the operative features relate
only to completeness of cancer removal and do not in any
way demonstrate a difference in survival when total thyroidectomy and lesser procedures are compared.
The outcome after incomplete surgical resection is heavily dependent on age. We have noted that only 11% of young
or low-risk patients who had incomplete removal of the primary cancer died of disease when monitored for a minimum
of 15 years, whereas high-risk or older patients had a risk
of death of greater than 90% if the cancer was not grossly
completely resected." Thus, even the results after incomplete
surgical removal are heavily dependent on basic biologic
phenomena, principally age and basic risk group.
Surgical Therapy of the Primary Cancer

and Lymph Node Metastases
Most multifactorial studies.>!" as well as many other
reports,50-61 document that the extent of thyroid gland resection, the extent of lymph node resection, and the number of
lymph node metastases involved had no bearing on patients'
survival. There may be a higher risk of local recurrence in
patients treated by thyroid lobectomy," but a recurrence in
the remnant thyroid tissue never caused a death in the Mayo
Clinic report. 57 No other human cancer represents such a lack
of relationship between survival and lymph node metastases
251
or the presence of residual cancer at the conclusion of the

surgical procedure as in young, low-risk patients with thyroid carcinoma. Indeed, even distant metastatic disease in
differentiated carcinoma is not uniformly fatal in children or
young adults 49,61 and can be treated for cure in a high proportion (>50%) of low-risk patients with radioactive iodine
therapy.62-64 To have effective treatment in these patients, the
remnant thyroid tissue must be removed or ablated.
It should be noted that, regarding outcome and prognosis,
medullary carcinoma of the parafollicular C cells does not
display this unique lack of relationship between lymph node
metastases and outcome. Medullary carcinoma of the thyroid
does display some age association with prognosis but has
the usual relationship between increasing lymph node
involvement and poorer long-term survival." Thus, even
cancers arising from different cells within the same gland
display uniquely different biologic phenomena. This merely
reemphasizes the fact that lymph node metastases in almost
all human cancers are "indicators but not governors'P" of poor
outcome. In patients with differentiated thyroid carcinoma,
the indicator function is less precise, and the prognosis
either is not affected by or, in one report, is even better in
cases with lymph node metastases." Lymph node metastases are extremely common in papillary cancer, and two
thirds of recurrences in the low-risk cancer are lymph node
metastases." None of these presentations of lymph node
metastases (occult, palpable, multiple, or recurrent) have
deleterious effects on the prognosis of low-risk patients with
differentiated thyroid carcinoma. In high-risk thyroid cancer
patients, however, there may well be an association between
lymph node metastases and a worse prognosis.f the usual
relationship, again displaying the unique features of lowrisk patients.
Radioactive Iodine
Clearly, in the presence of unresectable local disease, recurrent local disease, and distant metastases to the lungs, bones,
or other sites, the potential curability of patients is almost
totally dependent on the success of radioactive iodine (RAI)
therapy.67.68
Not all differentiated carcinomas of the thyroid take up
RAI, but when they do, the nuclear dose of radiation therapy is extraordinarily high (20,000 to 30,000 cGy)
and, therefore, highly successful in ablating metastatic
deposits. When tumors cannot be induced to take up RAI,
however, therapeutic effectiveness is absent. In younger
patients (low risk) and in children with distant metastases,
metastases frequently take up RAI in therapeutically significant amounts,63.64 and long-term disease-free life can be
achieved. This represents the unique phenomenon of a
"homing" compound (iodine) carrying a lethal cellular
poison (radiation-emitting isotope) that can seek out and
destroy cancer cells throughout the body, even in disseminated metastases. Such an idealized cancer treatment
remains the model and the elusive goal of cancer therapy
and, to date, has seldom been duplicated in any other human
cancer on a regular basis.
Because the avidity of the normal thyroid gland for
iodine and its radioactive isotopes is many magnitudes
higher than that of even the most efficient iodine metabolism

of differentiated thyroid cancer, all normal thyroid tissue
has to be eliminated to attempt therapeutic utilization of RAI.
In patients with metastases or unresectable local disease,
the need for total thyroidectomy, either surgical or radiotherapeutic, is unquestioned. After total thyroidectomy, with
avoidance of removal or devascularization of the parathyroid glands, diagnostic RAI scans are used to detect residual
normal thyroid tissue, which can be eliminated with small
therapeutic doses of RAI (-30 mCi). After ablation of
normal remnant thyroid tissue, iodine 131 can be used in
hypothyroid patients with high serum TSH levels to ablate
metastatic deposits. The curability of patients with metastatic
thyroid carcinoma is related to their basic risk group,49.63.64
but all patients with distant metastases should receive treatment with RAI. In low-risk or young patients, the curability
of pulmonary metastases is extremely high after appropriate
RAI use, but in older or high-risk patients successful and
effective treatment of distant metastases by RAI seldom
results in a long-term disease-free state because other metastases develop or the original metastases regrow.
Despite the acknowledged value of RAI for treatment in
advanced, high-risk, recurrent, or metastatic cases of differentiated thyroid carcinoma, there is little evidence that
routine adjuvant use of RAI in low-risk patients is of any
benefit. 67.68 Hay and colleagues'" have questioned the routine adjuvant use of RAI in low-risk patients and found no
evidence of improved cause-specific survival with RAI.
Changing Presentation of Thyroid Cancer

The clinical presentation of thyroid carcinoma has changed
dramatically over the years. The median size of all differentiated thyroid carcinomas has declined progressively, so that
by 1980 and continuing currently only 10% of older and
6% of younger patients presented with lesions larger than
3 em in diameter, and almost 66% of the younger patients and
60% of the older patients presented with primary cancers
smaller than 2 em in diameter." Clearly, such earlier disease
presentation has improved the overall prognosis. Several
authors have reported a better overall prognosis beginning
about 195034 or 1960 5 1.62 for reasons that may be related to
earlier diagnosis and, therefore, better risk group definition
but are primarily related to the declining incidence of conversion of papillary to anaplastic carcinoma and the presence
of less aggressive cancers that occur in populations with
adequate dietary iodine. Thus, patients seen in the 1990s had
a far better prognosis overall but, when separately defined
by a multifactorial risk group, were seen to have a clinical
behavior similar to that in previous decades." The better
overall prognosis, then, is related to a higher proportion of
cancers that can be completely resected, the smaller cancers
diagnosed, the decreased frequency of extension outside the
thyroid gland, and a lower proportion of patients presenting
initially with distant metastases. In the 1930s, as many as 6%
of patients initially presented with distant metastases, usually
pulmonary, but the proportion is currently less than 1%.
A multifactorial risk group assessment is also applicable to
patients with large or advanced cancers from third-world
countries (R. S. Rao, personal communication, 1994). Lowrisk patients by the AMES multifactorial classification still
have an excellent prognosis.
Children
Although frequently presenting with relatively advanced
local, nodal, or metastatic disease, young children and
teenagers have an extremely good prognosis.sl'" In some
reports, more children die of pulmonary fibrosis secondary
to RAJ treatment of the pulmonary metastases than die of
thyroid carcinoma. Children younger than 7 years may have
a poorer prognosis. Pulmonary metastases in children usually take up RAI, and these children can usually be cured
with appropriate treatment.
Recurrence
The term recurrent thyroid carcinoma is expected to imply
some decrement in outcome and prognosis. However, if the
"recurrence" is actually a new primary tumor in residual
contralateral thyroid tissue.? the prognosis is no different
from that for a primary carcinoma in any other presentation
and risk group assignment. True recurrent carcinoma in the
bed of the previously resected thyroid gland may be a difficult pattern of disease to treat; most such true local recurrences are not readily surgically resectable, but resection
should be attempted. If RAI in therapeutic doses was not
used initially, its potential use should be investigated by
diagnostic scans and elimination of all residual normal
thyroid. Reoperation for the completion of a total thyroidectomy at this time in the few patients who display such local
tumor bed recurrence should be performed or the residual
thyroid gland ablated by RAI.
Occasionally, persistent disease in the wall of a trachea or
larynx, with progressive growth, may cause airway encroachment and require surgical therapy."? Resection of a small
segment of trachea is sometimes required and can be accomplished successfully. On rare occasions, laryngectomy for
recurrent disease with airway obstruction may be required.
Such extensive surgery should rarely be performed initially
because of the excellent therapeutic outcome achieved
with RAI, which can result in a good disease-free, long-term
survival in low-risk or young patients." Thus, although
recurrence is a poor prognostic sign in high-risk patients, it
is not invariably an indication of fatal outcome, and indeed
low-risk patients may do quite well." In our study, 80% of
low-risk patients with recurrent disease survived, whereas
80% of older high-risk patients died. This is a further example of the risk group assuming more importance than the
particular presentation of disease, type of recurrence, or type
of therapy. Shaha has given a contemporary summary of risk
group relationship to outcome."
Metastases
Distant metastatic disease usually appears after treatment of
a patient with an advanced primary cancer; it is rarely the
presenting complaint of patients with a small or an obscure
primary thyroid carcinoma, particularly older or high-risk
patients. Low-risk patients with pulmonary metastases have
better than 50% long-term disease-free survival after treatment with 131 1 and TSH suppression.49.63.64.72.73 As mentioned
earlier, pulmonary metastases are far less common todayy34.49
Whether earlier detection and treatment in a preclinical
Predictors of Thyroid TumorAggressiveness - - 253

stage by diagnostic scanning (which requires total thyroid
ablation) and treatment when detected later by chest radiography are equivalent in outcome after RAI therapy is a matter
of some debate." Patients with distant metastases other than
to the lung tend to have a very poor outcome over the long
term, although aggressive resection of isolated bone metastases with postresection RAI therapy is sometimes effective.
Long-term outcome in these patients is also influenced by
age and basic risk group.49,63.64,72,73 High-risk patients may
have prolonged disease courses, but eventually almost all
older patients with distant metastases die of disease.
Clinical Application of
Indicators of Thyroid Tumor
Aggressiveness
The ready application of a variety of risk group definitions
(AMES, AGES, MACIS) indicates that all patients should
be so characterized before initial surgery and again at completion of surgery. Age and tumor size can be determined
preoperatively, whereas local invasion, distant metastases,
resectability, and tumor histology or grade are usually determined postoperatively. By characterizing the risk group, the
surgeon can make an initial preoperative estimate of the
need for and extent of thyroid and regional lymph node
resection and, postoperatively, the need for RAI treatment.
When the risk of recurrence is only 3% and the risk of death
only I % in the low-risk MACIS, AMES, or AGES risk definition categories, it is impossible to prove the advantage of
total thyroidectomy with RAI in contrast to a more limited
or unilateral operation. Although no randomized trial has
been conducted because of the infrequency of thyroid carcinoma even in young patients, studies addressing the issue
of extent of surgical resection in low-risk patients find no
consistent evidence of improved prognosis in patients
undergoing total thyroid removal.P''" The critical need in
patients who are young and have little or no risk of death is
to have an operation that avoids, as much as possible, the
chances of morbidity.57.75,76 In low-risk patients, the use of
RAI scanning in surgical follow-up appears to be unnecessary because it contributes nothing to improvement in the
near-perfect outcome. 66,68 Indeed, even the value of thyroid hormone administration in such patients is now questioned,68,77 except, of course, in patients who initially
undergo total or near-total thyroidectomy. Because all studies of long-term medication indicate poor compliance by
patients after many years, one needs either to monitor such
patients closely throughout the rest of their lives by repeated
TSH testing to prevent subtle hypothyroidism or iatrogenic
hyperthyroidism or to leave enough thyroid tissue so that the
patient is euthyroid in the absence of thyroid hormone
administration.
In older or high-risk patients and in low-risk patients with
extensive or bilateral disease, strong consideration should be
given to performing a total thyroidectomy initially because
postoperative RAI therapy almost certainly should be
attempted and TSH suppression therapy used. Total thyroidectomy in these situations is used primarily to facilitate
the use of RAI.
Because lymph node metastases do not appear to influence patients' outcomes adversely and their cells do not
implant in surgical wounds, it seems illogical to focus too
greatly on maximizing the extent of lymph node resections,
and selected nodal removal is adequate. Good functional
and cosmetic results should be the principal goals. Reports
from Sweden documenting prolonged microscopic surgical
dissection of extensive regional lymph node areas in patients
with medullary thyroid cancers seem illogical. No biologic
rationale for such an endeavor in differentiated thyroid
carcinoma exists, and the results of such reports should be
critically evaluated.
A convenient clinical approach to regional lymph node
metastases in low-risk patients indicates that, for preoperatively palpable lymph node metastases in the neck, a
function-preserving modified neck dissection is adequate.
Such a functional neck dissection would include, at the very
least, preservation of the spinal accessory nerve and the submandibular area with the ramus mandibularis. In addition,
preservation of the sternocleidomastoid muscle and jugular
vein should be attempted because limited selective dissection of the lymph nodes themselves is adequate, The phenomenon of wound implantation with differentiated thyroid
carcinoma is rare. If lymph node metastases are not felt
preoperatively but are observed or are palpable at the time of
thyroid surgery, these nodes and the central compartment
containing fat and nodes should be removed without extending the thyroid incision. Limited lateral neck dissection
should be done to include palpable node metastases. Such
central compartment or restricted node removal can be
accomplished with minimal to no morbidity. As a corollary
to the generally good prognosis and lack of relationship of
lymph nodes to outcome, it should be noted that any functioning recurrent laryngeal nerve should be preserved at all
costs, even if it has to be carefully dissected out from surrounding conglomerate lymph node metastases. Finally, if
no obvious lymph node metastases are noted either before
or at surgery, no formal lymph node removal needs to be
performed.
It is worth commenting on the fact that any young person
presenting with a palpable lymph node in the neck should
have as the first diagnostic maneuver a needle aspiration, not
an excision, of the lymph node that is palpable. Well-trained
cytopathologists can uniformly make the diagnosis of thyroid carcinoma using needle aspiration cytology of lymph
node metastases. If the diagnosis is made by aspiration, even
though the primary thyroid cancer is not palpable, operative
strategy and treatment can be planned effectively with
avoidance of a separate node biopsy.
When an appropriate neck dissection has been performed,
recurrence of cervical node metastases is very uncommon.
Overall, most recurrences (two thirds) in low-risk patients
are in the form of palpable lymph node metastases in the
absence of previous neck dissection. Because lymph node
metastases have little bearing on prognosis, the surgical or
therapeutic RAI treatment of node metastases is associated
with an excellent outcome, in keeping with the basic risk
group definition. Although either surgical approaches or
RAI may be suitable, there are advantages in performing
a cosmetically acceptable and function-preserving neck
dissection because (1) not all of these tumors take up RAI,

(2) treatment with RAI is prolonged and complicated and
may require hospitalization and a previous total thyroidectomy, and (3) the results are not as good as with surgical
removal.
The use of serum thyroglobulin determination as a tumor
marker has been encouraged as a component of the postoperative management of thyroid carcinoma. It seems illogical
to perform expensive technologic tests for careful follow-up
in the low-risk patients because the 20-year mortality is only
I % and total thyroid ablation is required for the utilization
of thyroglobulin determinations. Repeated RAI diagnostic
scans require a hypothyroid state each time and should be
avoided in low-risk patients, in whom such repeated periods
of hypothyroidism are disabling. Thus, a simplified followup approach would avoid any kind of intensive technical
follow-up in the 85% to 90% of patients at low risk, as
judged by the MACIS or AMES scoring systems. In highrisk patients in whom more extensive surgery was used, the
use of thyroglobulin determination and RAI scanning postoperatively appears to be justified in an attempt to increase
long-term disease-free survival, but almost all distant metastases eventually prove fatal.
Finally, several attempts78-80 to define differentiated thyroid cancer aggressiveness further are too recent to evaluate
their feasibility for clinical use, particularly when such
efficient practical clinical risk groups exist.
Summary
Most patients with papillary and follicular thyroid cancer
can be classified into low-risk groups by the AGES, AMES,
TNM, or MACIS classifications. These low-risk patients
have an excellent prognosis, so that total thyroidectomy is
not required for patients with cancers confined to one lobe.
Lymph node metastases should be removed by a functional
neck dissection preserving the spinal accessory nerve, the
internal jugular vein, and the sternocleidomastoid muscle.
High-risk patients may benefit from total or near-total thyroidectomy as well as postoperative use of RAI adjuvant
treatment, serum thyroglobulin determination, and TSH
suppression therapy.
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4. Rossi R, Cady B, Meissner WA, et al. Prognosis of undifferentiated
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Growth Factor, Thyroid
Hyperplasia, and Neoplasia

Staffan Smeds, MD, PhD Nils-Erik Heldin, PhD
Thyroid tissue homeostasis is controlled at several levels:

directly or indirectly by thyroid-stimulating hormone
(TSH), by locally acting growth stimulatory substances (i.e.,
epidermal growth factor [EGF], transforming growth factor-a
[TGF-a], insulin-like growth factors [IGFs], fibroblast
growth factors [FGFs], hepatocyte growth factor [HGF],
platelet-derived growth factor [PDGF], and the growth
inhibitory TGF-~),
and also by apoptotic mechanisms regulating cell death. Variation of thyroid volume reflects either
the demand of the organism through TSH or a disturbance
of the intricate network interaction between the locally
acting growth regulatory substances and the expression of
their receptors. Many of the latter are related to identified
protooncogene products.
In nodular goiter, hyperplasia seems related to increased
growth propensity, inherited from mother to daughter cells
in a subpopulation of cells at multiple sites in the gland.
Nodules can, however, be monoclonal, as is characteristic
for early neoplastic lesions.
Genetic events (i.e., oncogene activation) seem to be
operational along both hyperplastic and neoplastic growth
deregulation lines. From this early "gray zone" event, further
degeneration seems linked to specific mutations that give the
neoplasias their characteristic phenotypic expression.
Deregulation of the cell cycle by ablation of p53 and Rb
gene expression seems to add a further malignant potential
to the neoplastic degeneration.
Growth regulation of the thyroid gland comprises an
intricate network of interaction between regulatory signals
and the genetic template for cell reactions. The regulatory
mechanisms include autocrine and paracrine signal loops
as well as varying oncogene and growth suppressor gene
expressions, which interfere with and can disrupt cell cycle
transition. Qualitative and quantitative changes of the signal
pattern alter the phenotypic expression of thyroid function
or growth, and a number of mutations give constitutive
genetic lesions that stepwise alter the phenotypic expression
of tissue integrity, growth, and function.
Integration of the thyroid gland in the homeostasis of the
organism is monitored by hormonal, neural, and immunologic
systems. In this first level of thyroid control, the TSH is the
most important factor for function and growth. On a second
256
level, tissue homeostasis seems controlled by a number of

locally acting signal substances, some of which are referred
to as growth regulatory factors. On a third level, cell to cell
adhesion and parenchyma integrity are controlled by a
number of factors, the loss of which results in deregulation
of thyroid growth control. 1 At the genetic level, new insights
into programmed cell death (apoptosis) add a fourth level of
control to the complex hierarchy of thyroid growth control. 2
Apart from fetal and adolescent increase in thyroid
volume, the thyroid gland normally does not grow. Each
follicle cell is assumed to pass five mitotic cycles during
adulthood, indicating small kinetic cell compartments
undergoing proliferation and apoptosis.' The rest of the
follicle cell population expresses their differentiated functions (i.e., secretion of thyroid hormones that inhibit secretion of pituitary thyrotrophs of TSH by the well-known
negative feedback mechanism). The follicle cells, however,
retain their capacity to grow (hypertrophy) and multiply
(hyperplasia) in response to stimuli. Thus, decreased thyroid
hormone secretion, as induced by iodine deficiency or
administration of goitrogen or antithyroid drugs, gives
increased TSH secretion, with concomitant stimulated thyroid function and growth. The latter shows that a follicle cell
is reversibly terminally differentiated.
Thyroid follicle cell proliferation is under the control of
several factors, including hormones, classic growth factors,
and different low-molecular-weight agents. Because both
stimulatory and inhibitory factors are described, the net
growth effect is a sum of all these stimuli. Most of the
knowledge of thyroid growth regulation is from in vitro experiments in different culture systems. In Table 28-1, we have
listed the major thyroid growth-promoting and growthinhibiting factors. As seen in Table 28-1, the factors involved
in thyroid growth regulation can be divided into three major
groups according to the intracellular signal pathway used.
Mitogenic Pathways
The pathways through which extracellular signals are transferred into the follicle cell are conveyed by three membraneassociated transducing systems (Fig. 28-1).
Growth Factor, Thyroid Hyperplasia, and Neoplasia - - 257
1. Activation of the guanosine triphosphate (GTP)-binding

protein Gsa in the adenylate cyclase (AC), which evokes
the cyclic adenosine monophosphate (cAMP) protein
kinase A (PKA) signal (the AC-cAMP-PKA pathway).
2. A cAMP-independent mechanism involving activation
of membrane-bound tyrosine kinase receptors (RTKs),
resulting in an activation of the ras mitogen-activated
protein kinase (MAPK) pathway for transduction of
the mitogenic signal.
3. Phospholipid-hydrolyzing mechanisms by which a
number of agonists act by interaction with phospholipase, which catalyzes the formation of diacylglycerol and inositol triphosphate (from membrane
phosphatidylinositol [PI] or polyphosphoinositides),
resulting in the mobilization of calcium, the activation
of protein kinase C, the release of arachidonic acid
(precursor for prostaglandins, thromboxanes, and
leukotrienes), and the formation of cyclic guanosine
monophosphate by activation of guanylate cyclase
(the PI-PKC-Ca 2+ pathway, or PI cascade).
The TSH receptor confers the physiologic signal from the
hypothalamic-pituitary system to the follicle epithelium primarily for regulation of a thyroid hormone secretion rate.
The membrane-bound RTK path may confer information
from locally produced factors and neighboring cells in
paracrine and autocrine loops, whereas agonist interacting
with the phospholipid-hydrolyzing system seems to form a
more general route for integration of thyroid function and
growth with other surveillance systems.
These pathways are usually mitogenic, because activation
induces cell replication. It is generally accepted that all pathways are mitogenic. There are, however, distinct species
variations, and results from experimental systems cannot be
generalized to the human thyroid without careful investigation
in well-controlled experimental systems.
Thyroid Growth-Regulating
Factors
Thyrotropin
TSH has traditionally been considered the major stimulator
of the thyroid function." TSH is a heterodimeric glycoprotein
consisting of noncovalentiy associated a and P chains and
has a total molecular weight of about 28 kd. Thyroid follicle
cells are stimulated by TSH binding to specific cell surface
receptor proteins, the TSH receptor (TSH-R). Activation of
the TSH-R results in an increase in the intracellular level of
cAMP as the major intracellular second messenger for most
of the TSH effects.' However, TSH through the TSH-R has
also been demonstrated to increase the PI turnover as a
second messenger system for the action of TSH. The
amount of TSH needed for stimulation of the PI pathway is
5- to lO-fold greater than that needed for TSH activation
of AC.5
TSH-R was shown, by molecular cloning, to belong to
the family of receptors with seven membrane-spanning
regions, similar to other G-protein-coupled receptors."
The general concept ofTSH as a trophic pituitary hormone
regulating both function and growth of the thyroid has been
questioned. The positive effect on the functional activity is
undisputed; however, the stimulatory effect ofTSH on thyroid
follicle cell growth is questioned. During the last decade,
numerous studies have revealed a more complex system of
thyroid growth regulation and cell proliferation. Nevertheless,
administration of TSH to rats results in an enlargement of
the thyroid as a result of both cell hypertrophy and cell
hyperplasia. A rapid increase in the TSH level before
increased thyroid growth has also been observed in goitrogentreated experimental animals." Propylthiouracil treatment of
rats resulted in a several-fold increase in the thyroid volume
IP3~
1",
PhospholipaseC
DAG~n
Ca'"
!
T
.....
kinase C
-,
.G
~inkinaseA
TSH
--
cAMP
Mitogenic
signal
~
~MA,PK
s
: ': : ;:{:~~S'~P
.I
\
\
~KK
/
<,
FIGURE 28-1. Mitogenic pathways in the regulation of thyroid

function and growth. Schematic drawing shows the major pathways involved in the regulation of thyroid function and growth.
(1) TheAC/cAMPIPKA pathway: The major stimulator of this pathway in thyrocytes is thyroid-stimulating hormone (TSH), which
interacts with the TSH-receptor (TSH-R). Stimulation of the TSH-R
leads to an activation of guanosine triphosphate (GTP)-binding
regulatory proteins; the Gsa in the plasma membrane activates
adenylate cyclase (AC), generating cyclic adenosine monophosphate (cAMP) that activates the protein kinase A (PKA), and the
G, linked to the phospholipase C (PLC), which stimulates the
phosphatidylinositol (PI) turnover. (2) PI-PKC-Ca2+ pathway:This
signal transduction cascade is activated by a number of different
receptors (Rn in figure) besides the TSH-R. An activation of the
TSH as well as other receptors leads to an increasedPLC activity,
resulting in the formation of inositol lA,5,-triphosphate (IP3) and
diacylglycerol (DAG) with a subsequentincrease in the intracellular levelof calcium (Ca2+) and PKC activity. Both the PKA and the
PKC are serine-threonine kinasesand phosphorylate severaldifferent proteins. (3) Tyrosine kinase receptors (RTK): Ligandbindingto
RTK leads to a phosphorylation on tyrosine residues in the receptor molecule. The activatedphosphorylated receptors are linked to
many different signaling pathways (all pathways are not included
in the figure) via direct binding of signaling proteins containing
a src homology 2 (SH2) domain. However, the major mitogenic
pathway of many RTKs involves activation of a chain of events
in the ras pathway (shown in figure). In short, the phosphorylated
RTKinteracts with an adaptorproteincalled Grb2. Grb2 associates
with a protein called Sos ("son of sevenless"), leading to the activationof ras. The activated ras GTP leads to an increased activity
of raf, followed by a sequential activation of the proteins in the
(mitogen-activated protein kinase [MAPK]) cascade of events that
ultimately leads to an increased transcriptional activity (MAPKK,
MAPK kinase). The negative influence of an organified form of
iodine (I-X)on the differentpathways is also shown. ATP = adenosine triphosphate.
as well as in the mitotic index of the thyroid epithelium."

Furthermore, TSH has also been observed to have a positive
effect on thyrocyte proliferation in human thyroid tissue
transplanted into nude mice." However, hemithyroidectomy
of dwarf mice (lacking TSH) resulted in a compensatory
growth of the remaining thyroid lobe, showing that factors

other than TSH can also stimulate thyroid growth. 10
Although TSH through the TSH-R seems to be the major
modulator of thyroid growth, it has been difficult to show a
direct mitogenic effect of TSH on thyrocyte proliferation.
A number of in vitro studies have been performed with contradictory results; a stimulatory effect of TSH was found in
cultures of normal dog," rat,IZ.13 sheep," and human" thyrocytes. In contrast, no effect of TSH was reported in bovine,"
sheep,'? porcine," and human'? thyroid cells, and even an
inhibitory effect of TSH has been observed in porcine
thyroid follicle cells." The growth stimulatory effect of
TSH observed appeared to be mediated by cAMP because
the effect of TSH was mimicked by other stimulators of
cAMP, such as forskolin and cholera toxin.I':"
A positive involvement of the cAMP-PKA pathway in
thyroid growth regulation is strengthened by several observations. First, activating somatic mutations of the TSH-R
in patients with hyperfunctioning thyroid adenomas were
found. A single point mutation in the third intracellular loop
or in the transmembrane (TM) domain VI of the TSH-R
gene in hyperfunctioning thyroid nodules resulted in a constitutively activated receptor," Second, activating mutations
in the GTP-binding protein, Gsa, oftheAC (denoted as the gsp
oncogene) have been identified in hyperfunctioning thyroid
adenomas and in constitutively activated differentiated thyroid
carcinomas.v-? Third, introduction of cAMP-elevating adenosine receptor under the control of a thyroglobulin promoter
in transgenic mice resulted in thyroid hyperplasia.i" Finally,
a recessive inactivating mutation of the TSH-R (the hyt
mutation; TM domain IV, amino acid 556 proline ~
leucine) has been observed in a hypothyroid mouse strain
(hyt/hyt) resulting in a small and hypoplastic thyroid
gland. zs.z6 Taken together, all these observations indicate a
growth-promoting effect of an increased cAMP level within
the thyroid cells. However, as mentioned, there is little
evidence for a direct mitogenic action by TSH.
Islerz7 showed the need for other factors besides TSH in
the regulation of thyroid growth because hypophysectomy
in rats abolished the mitogenic effect of injected TSH.
Furthermore, injection of TSH in dwarf mice (growth
hormone and TSH deficient) did not result in an increased
mitotic activity in the thyroid gland.i" Other investigators
document that TSH requires IGF-I (or insulin in high
concentrations) in culture medium for a full mitogenic
effect.
A synergistic effect between TSH and EGF on thyroid
follicle cell proliferation has been found in vitro; stimulation
of porcine thyroid follicle cells with TSH was found to
increase the number of high-affinity receptors for EGF as
well as the mitogenic response to EGF stimulation.Pv?
Thus, TSH may promote growth by facilitating the action of
other peptide growth factors.
Epidermal Growth Factor and

Transforming Growth Factor-a
EGF is a potent mitogen for a variety of cells. It has a molecular weight of 6 kd and stimulates cells through the EGF
receptor (EGF-R), a member of the tyrosine kinase superfamily of receptors. The EGF-R is known to bind not only
Growth Factor, Thyroid Hyperplasia, and Neoplasia - -
EGF but also TGF-a. EGF (or urogastrone, human EGF) is

produced in many different tissues, including the thyroid.
EGF stimulates the mitotic activity of thyroid follicle
cells in culture, as first demonstrated by Westermark and
Westermark'? in sheep thyrocytes. Subsequent studies documented that EGF is mitogenic for thyrocytes from other
species, including dog," porcine.F human.P and bovine"
cells in culture. The EGF-Rs have been shown to be localized
to the basolateral surface of the thyroid follicle cells,29 and a
specific binding of EGF has also been demonstrated to thyroid
follicle cells" or membrane preparations." As previously
mentioned, a synergistic effect between EGF and TSH has
been observed; TSH (through cAMP) increased both the
binding'V? and the mitogenic action of EGF in porcine
thyrocytes in culture.F Besides the mitogenic action of EGF,
an inhibitory effect on the differentiated functions of the
thyroid follicle cells has been observed.F
Overexpression of the EGF-R has been implicated in
the development of thyroid carcinomas. Several reports
have found increased binding of iodine 125-EGF to membranes from human thyroid carcinomas compared with
membranes from normal thyroid tissue.P-" The expression
of EGF-R seems to correlate with the prognosis of the
patient (an increased number of EGF-Rs in patients with poor
prognosis) and has been suggested as a prognostic factor for
thyroid carcinomas.W' However, no prognostic importance
of the level of EGF-R expression was found by Mizukami
and colleagues."
Autocrine mechanisms in thyroid tumors involving the
EGF-R have also been reported. Coexpression of the EGF-R
and TGF-a has been found in thyroid carcinomas, suggesting
an autocrine growth stimulation in tumor cell growth." A
several-fold increase in the expression of TGF-a was found
in papillary carcinomas and their lymph node metastases.'?
Insulin-Like Growth Factors

IGF-I and IGF-II are both implicated in growth regulation of
the thyroid epithelium. Thyroid follicle cells have been
shown to express high-affinity receptors for both IGF-I and
IGF_II.4o.42 There is cross-reactivity among the receptors in
the IGF family; IGF-I, IGF-II, and insulin have all been
shown to bind to and activate the IGF-I receptor (lGF-I-R),
a member of the tyrosine kinase family of receptors. The
IGF-I-R is believed to mediate most of the growth stimulatory
effects of IGFs in thyroid follicle cells. The IGF-II-R, or
mannose-6-phosphate receptor, is believed to be involved in
the targeting of lysosomal enzymes to lysosomes rather than
in thyroid growth stimulation.
A growth stimulatory effect of IGF-I, IGF-II, or insulin
(in high concentrations) on thyroid epithelial cells in culture
has been reported. 40,43 As mentioned, IGF-I (or insulin in
high concentrations) has also been found to act as a permissive
factor for the growth-promoting effect of TSH on cultured
thyrocytes.!' Withdrawal of insulin-IGF-I from the culture
medium results in a decreased mitogenic effect of TSH;
hence, IGF-I acts as a permissive factor for the growth stimulatory effects of TSH. TSH has been shown to increase the
activity of the IGF-I-Rs in porcine thyrocytes in culture
stimulated with IGF-I, indicating the possible opposite
situation with TSH facilitating the action of IGFs. 44
259
Normal and neoplastic thyroid epithelial cells have been

shown to produce both IGF-I and IGF_II.41,45-47 The simultaneous expression of IGF-I and IGF-I-Rs on human thyroid
follicular cells in primary cultures,"? thyroid adenoma
cells," and a papillary thyroid carcinoma cell line" has led
to speculations about an autocrine stimulatory role in thyroid
growth regulation. Furthermore, increased amounts ofIGF-I,82
IGF-I-R,49 and IGF-II-R,42 compared with normal thyroid
tissue, have been described from studies of human thyroid
neoplasms. The increased expression is believed to contribute
to the abnormal growth of the thyroid follicle cells.
Fibroblast Growth Factors

Currently, there are nine members of the FGF family
(FGF I to 9). FGFs are known to stimulate proliferation,
differentiation, and function of several different cell types
and play an important role in the regulation of angiogenesis.
The cellular responses to FGFs are mediated by four different
FGF receptors (FGF-R I to 4), all belonging to the RTK
family.
Thyroid epithelium has been found to express FGF-Rs50
and produces FGF stored at the basement membrane of the
follicle cells. 5o.52 Using in vitro systems of thyroid follicle
cells, a growth-promoting effect of FGF has been found. 52.55
The simultaneous expression of FGF-2 (basic FGF) and
FGF-R-I (jig) on rat thyroid follicle cells has implicated
FGF-2 as an autocrine stimulatory factor in thyroid growth
regulation.i? A paracrine role of the FGF produced by the
thyrocytes has also been suggested to be involved in the
neovascularization observed within the thyroid during goiter
development. Greil and colleagues" found an endothelial
cell growth stimulatory effect of the factor (suggested to be
FGF-2) purified from porcine thyrocytes (Fig. 28-2).
As with EGF, addition of FGF results in an inhibition of
thyroid function. Addition of FGF led to inhibition of cAMP
formation'" and attenuation of the TSH effects. 55 Moreover,
administration of FGF-I (acidic FGF) to rats led to the formation of colloid goiter, probably resulting from inhibition
of the TSH-induced transport of colloid from the follicle
lumen by FGF. 56
Neovascularization
Adhesion molecule
synthesis
~~~~.:%'It
FIGURE 28-2. Autocrine and paracrine signals. The figure shows

a number of identified growth-regulating signal substances that are
growth promoting (+) or inhibitory (-) on thyrocytes via corresponding receptors. The signal substances may also act on surrounding
stromal cells to give endothelial cell and fibroblast proliferation.
IGF = insulin-like growth factor; TGF = transforming growth
factor; EGF = epidermal growth factor; FGF = fibroblast growth
factor; PDGF = platelet-derived growth factor; R = receptor.
Hepatocyte Growth Factor

HGF/scatter factor is a potent mitogen for several different
cell types, primarily cells of epithelial origin. The receptor
for HGF (HGF-R) is encoded by the protooncogene c-met,
a member of the RTK family. HGF has been found to be one
of the most potent mitogens for canine thyrocytes in cell
culture.V In conformity with EGF, HGF has a dedifferentiating effect on thyrocytes in vitro." Expression of the HGF-R
messenger RNA (mRNA) and protein have been found in
both human normal thyroid tissue'" and thyroid carcinomas.59
Di Renzo and coworkers'? found a IOO-fold increase in the
expression of the HGF-R protein in 22 of 41 human carcinomas derived from the thyroid epithelium; overexpression
was found in papillary and follicular carcinomas but not in
the anaplastic carcinomas in the study.
density (Fig. 28-3). Follicles in hyperplastic tissue display a

heterogenic expression of both functional characteristics
(iodination, peroxidase activity, thyroglobulin synthesis, and
endocytosis) and proliferative potential.s? Surprisingly, this
variation is observed among thyrocytes in the same follicle in
both experimental animals and in human thyroid glands.P?'
Thyrocytes with a high replication rate stay adjacent to each
other in the follicle wall, indicating that increased growth
propensity is inherited from mother to surrounding daughter
cells.'? With time, the goitrous gland is composed of a large
population of thyrocytes with this abnormal growth pattern.
Platelet-Derived Growth Factor

PDGFs are homo- or heterodimers of the four PDGF chains
(PDGF A, PDGF B, PDGF C and PDGF D). These PDGF
molecules are known to bind with different affinities to two
RTKs-namely the PDGF receptor-a (PDGF-R-a) and the
PDGF-R-~.
PDGF-Rs have been found to be expressed in
three of the four human anaplastic carcinoma cell lines that
were studied. 60,61 The presence of PDGF receptors has so far
not been demonstrated on normal thyrocytes. However, a
growth stimulatory effect of PDGF on rat thyrocytes in vitro
has been reported.55 In 1993, Matsuo and associates'S found
the expression and production of a PDGF-B-like protein in
a human papillary carcinoma cell line.
Thyroid Growth-Inhibiting
Factors
The TGF-~
family consists of three members (TGF ~l to ~3),
and three different TGF-~
receptors (TGF-~-R
I to III) have
been identified. Normal and diseased thyroid tissues express
and produce TGF-~
protein (TGF-~l).63
The expression of
TGF-~
1 mRNA was increased in the hyperplastic thyroids
of goitrogen-treated rats'" as well as after iodide administration to thyrocytes in vitro. 65 Addition of TGF-~l
to thyroid
follicle cells has been shown to result in growth inhibition."
Grubeck-Loebenstein and colleagues's suggested that TGF-~
has a role in goiter formation because lower production of
TGF-~
was observed in thyroid follicle cells from patients
with nontoxic goiter than in normal follicle cells.
Hyperplasia
It is common knowledge that nodules develop in normal
thyroid glands with aging."? In growing thyroids, the development of the goiter is almost invariably accompanied by
the development of multiple nodules of varying size. 68 The
nodules are generally softer than normal tissue. The surface
of a sectioned hyperplastic gland appears granular, and the
histopathologic picture shows a dysplastic arrangement with
wide variation of follicle size and areas with increased cell
B
FIGURE 28-3. Thyroid gland hyperplasia. The cut surface of a
hyperplastic nodule (A) in a human thyroid gland shows the smooth
and gel-like appearance of the colloid-rich parenchyma. A section

of the corresponding tissue (B) reveals numerous large follicles and
areas with high cellular density (hematoxylin and eosin).
Growth Factor, Thyroid Hyperplasia, and Neoplasia - -
Three mechanisms have been proposed to explain nodule

formation in multinodular goiters'":
1. The aforementioned tendency of cells with higher
growth potential to stay adjacent to each other results
in the formation of multiple growth centers and uneven
proliferation in the gland, with subsequent nodule
formation in different parts of the thyroid gland.
2. A somatic mutation may confer an inheritable growth
advantage to a subset of thyrocytes. This mechanism
may be operative in clonal tumor formation.P?"
3. The presence of fibrous strands in most thyroid tissue
results from scarring, necrosis, and hemorrhage in growing goiters and, with time, disturbs the normal thyroid
architecture."
Growth stimulation can be caused by external growth
signals such as TSH during iodine deficiency, by growthstimulating immunoglobulins, or by any other growthpromoting factors.73-78 In patients with multinodular goiter,
serum TSH levels are usually normal. A possible growthpromoting effect of TSH may be due to an inherited subset
of thyroid cells that have increased sensitivity to TSH. An
increased growth propensity toward TSH (or other external
growth-promoting factors) may also be induced by mutations
that alter cell cycle intervals (i.e., shorten Goor decrease apoptosis, leading to an increased number of cell multiplication
cycles before cell death).
Somatic Mutations
Although somatic mutations can occur in normally replicating
cells, those with an increased proliferation rate have a higher
risk of acquiring somatic mutations (i.e., allelic deletions
of tumor suppressor genes and point mutations in oncogenes).68,74.79 By the introduction of specific X chromosome
probes, it has been shown that both nonendemic and
endemic multinodular goiters contain polyclonal and monoclonal nodules." The clonal analyses have thus shown that a
genetic mutation mechanism may play a major role in the
formation of nodules in multinodular goiter. Cells with
mutations that favor growth slowly clonally outgrow the
other thyroid cells (Fig. 28-4).
Neoplasia
Early neoplastic lesions are generally monoclonal and arise
from a single mutation (or several) in a cell," which results
in a greater propensity of these cells to multiply more rapidly or to die more slowly than surrounding cells. With the
new knowledge of the monoclonal origin of nodules in
hyperplastic disease, the dichotomy between hyperplastic
and neoplastic transformation has become less distinct. In a
hypothetical overlapping gray zone (Fig. 28-5), the growth
of both hyperplastic and neoplastic nodules may be dependent
on single lesions, in the hyperplastic case arising from cells
with inherited high intrinsic growth potential and in the
neoplastic case arising from a single normal precursor cell.
Both benign and malignant thyroid neoplasms have been
shown to have ras mutations.s" It has, therefore, been
261
Normal cells
Population of cells with high {
intrinsic growth potential
. . . ..
N~;i,~ ~)i
.... .. ....
.~'
Increasing number of genetic lesions
FIGURE 28-4. The "gray zone." Growth stimulation by increased

signal pressure from external sources, increased sensitivity toward
normal signal pressure, or autocrine-paracrine growth stimulation
gives rise to hyperplasia. Single or multiple genetic lesions give
different neoplastic transformations in a stepwise way with the
appearance of initial nonmetastasizing benign forms, The "gray
zone" indicates a possibility of genetic lesions that may change the
growth potential in hyperplastic nodules without obvious neoplastic
transformation, as well as early lesions in neoplastic tissue.
proposed that Ha-ras activation is an early or initiating event

in the development of thyroid oncogenesis. In fact, in vitro
transfection of mutant ras genes extended the proliferative
life span of cultured rat thyroid follicle cells from less than
3 to more than 15 doubling times." The transformed thyroid
cells spontaneously mutate and form tumorigenic new cell
lines with loss of growth factor dependence and differentiated functions. These ras-transfected tumorigenic cells lose
their responsiveness to the growth inhibitor TGF-~l
and
have increased nuclear levels of p53 protein.
Benign follicular adenomas appear as single tumors in
both normal and hyperplastic thyroid tissue. They form
well-delineated firm nodules surrounded by a pseudocapsule.
The homogeneous appearance of the epithelial arrangement
reflects the currently held opinion that they represent true
monoclonal tumors.
Further dedifferentiation to malignant neoplasms seems
correlated with specific mutational events. Progression toward
the follicular phenotype has been reported to correlate with
a loss of function of a gene in the llq 13 locus (follicular
adenomajf and further dedifferentiation in follicular carcinomas with loss of genetic material in chromosome 3p.
Activation of the ret oncogene appears to occur only in papillary thyroid carcinomas.f This protooncogene encodes a
transmembrane receptor of the tyrosine kinase family, which
fuses with a gene product (RGF) to form a novel chimeric
oncogene (retIPTC3).84 p53 mutations have been found
primarily in anaplastic thyroid cancers, but one study found
them in other thyroid cancers." Thus, loss or decreased
activity of this gene product, which appears to regulate
growth-inhibiting signals at the G,-S transition of the cell
cycle, seems to correlate with continued cell division despite
the presence of multiple unrepaired and tumorigenic gene
defects.
Mutations in the retinoblastoma gene Rb have been
observed in differentiated and anaplastic thyroid cancers."
The gene encodes a nuclear phosphoprotein that switches
Conclusion
In conclusion, new findings concerning thyroid oncogenes and
tumor suppressor genes, as well as studies of growth factors,
are starting to explain why patients acquire specific thyroid
tumors with different behaviors.
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FIGURE 28-5. Benign thyroid neoplasia. A, The cut surface of a
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Signal Transduction in
Thyroid Neoplasms
Serdar T. Tezelman, MD Allan E. Siperstein, MD
In vivo and in vitro cellular proliferation, differentiation,

and protein phosphorylation of thyroid cells are regulated
and influenced by many stimulatory and inhibitory hormones,
neurotransmitters, and growth factors through several signal
transduction systems, including the adenylate cyclase (AC)cyclic adenosine monophosphate (cAMP)-protein kinase A
(PKA) system, the phospholipase C (PLC)-protein kinase C
(PKC) system, and the growth factor-tyrosine kinase signal
transduction system. In the past decade, advances in molecular biology and biochemistry have improved our knowledge
and understanding of signal transduction systems. Multiple
endocrine, paracrine, and autocrine factors, including thyroidstimulating hormone (TSH), epidermal growth factor (EGF),
vasoactive intestinal polypeptide (VIP), somatostatin,
insulin, insulin-like growth factor I (IGF-I), and estrogen,
bind to a variety of cell surface-specific and intracellular
receptors on the thyrocyte and cause a specific second
messenger response or directly activate PKC, such as 12-0tetradecanoyl phorbol-13 acetate (TPA) (Table 29-1).
Multiple mutations or abnormalities in the regulation of thyroid cell growth are responsible for uncontrolled growth and
the formation of benign and malignant thyroid neoplasms.
Thyrotropin (TSH) is secreted by the anterior pituitary
hormone and is a major regulator of thyroid growth and
differentiated functions, including thyroid hormone synthesis,
formation, and degradation as well as secretion, iodide
uptake, iodide organification, thyroid peroxidase, thyroglobulin, and protein synthesis. 1,2 The expression of the thyroglobulin gene is mediated by a cAMP-dependent mechanism
and is under the positive control of TSH.3 TSH has a tissuespecific trophic effect on both normal and neoplastic tissue.
Although the effect of TSH on thyroid function is well understood, its role in regulating thyroid growth is controversial.
The suppression of TSH by thyroid hormone administration
is used clinically to decrease the size of benign tumors and
to prevent the development of new or recurrent tumors in
patients after thyroidectomy for thyroid cancer of follicular
origin.i-' A better understanding of signal transduction systems in benign and malignant thyroid tumors should provide
us with new diagnostic and therapeutic opportunities.
Signal Transduction Systems

It is well known that most eukaryotic cells have at least two
signal transduction systems activated by extracellular signals
such as hormones, neurotransmitters, and growth factors that
bind selectively to specific receptors. All signals are transformed from cell surface receptors through intracellular
systems into second messengers through protein phosphorylation. Protein phosphorylation by protein kinase in
response to hormone or growth factors is responsible for
regulation of cell function. Growth factor-induced protein
phosphorylation is a key factor in the signal transduction
leading to mitogenic responses. Once the receptor is activated, it leads to activation of at least two signal transduction systems linked through stimulatory guanyl-nucleotide
proteins (G s ) to the AC-PKA signaling system and through
a guanyl-nucleotide protein termed G; to the phospholipasePKC signaling systems. Activated second messengers
initiate an increase in the levels of protooncogene products,
which lead to cell proliferation.v? Protooncogenes are genes
present in normal cells that code for proteins responsible for
normal growth. Growth factors, growth factor receptors, and
nuclear proteins are products of protooncogenes that participate in the signal transduction systems.t'? Cell proliferation is regulated by growth-stimulating protooncogenes and
growth-inhibiting suppressor genes. Mutations in signal
transduction systems, including structural alteration or overexpression, cause protooncogenes to become oncogenes,
which results in unregulated cell growth. To date, six signal
proteins, including ras and gsp, ret, trk, RET/PTC, and TSHreceptor (TSH-R) oncogenes, and one inhibitory protein,
p53, have been identified in thyroid neoplasms." The ras,
gsp, and TSH-R oncogenes are found primarily in "hot"
(gsp and TSH-R) and "cold" (ras, gsp, and TSH-R) thyroid
neoplasms, whereas RET/PTC and trk are more common in
papillary thyroid carcinoma. The trk oncogene codes for
nerve growth factor. The ras, gsp, and TSH-R are activated
genes coding for signal transduction (see Chapter 30). The
p53 protein is primarily found in anaplastic thyroid cancers
and differentiated thyroid cancer cell lines,"
265
Signal Transduction in Thyroid Neoplasms - -
,- -~
1
~-GTP
@sp
f;;\~
l~
Gs
lrSIH-~
Q~~
_\21
__ ~
GTP
GTPase
~PA
P1P2
267
~
__ ~
- --
PIP2
GOP
5'~
GOP
3',5' cAMP
-,
POE
B
Phosphorylation of cellular proteins
Growth, differentiated thyroid function
FIGURE 29-1. Adenylate cyclase (AC) signal transduction system, phosphoinositide turnover system, and calcium-calmodulin (Ca/CaM)
kinase system. A stimulating hormone (Hs) (e.g., thyroid-stimulating hormone [TSH] or vasoactive intestinal polypeptide), binds to its
specific receptor (Rs) that interacts with G, and activates the cyclase enzyme (AC). An inhibitory hormone (Hi) (e.g., somatostatin) binds
to its receptor (Ri), which interacts with G, and inhibits the AC. The AC converts adenosine triphosphate (ATP) to cyclic adenosine
monophosphate (cAMP), which activates protein kinase A (PKA), which phosphorylates cytosolic proteins. cAMP is hydrolyzed by phosphodiesterase (POE) to 5'-AMP. A hormone such as TSH also binds to its specific receptor, which interacts with G, and activates the
phospholipase C (PLC)-beta. PLC-gamma is activated by growth factors such as epidermal growth factor (EGF). Both PLC-beta and PLCgamma catalyze phosphatidylinositol-4,5-biphosphate (PIP z) to 1,2-diacylglycerol (DG) and inositol-I,4,5,-triphosphate (lP 3) . DG binds to
and activates protein kinase C (PKC). PKC can also be activated directly by tumor-promoting phorbol ester, such as 12-0-tetradecanoyl-phorbol13-acetate (TPA), which is structurally similar to DG. PKC phosphorylates cytosolic proteins. One of the degradation products of DG is
arachidonic acid (Ara), which is a precursor of prostaglandin. IP 3 mobilizes intracellular calcium (Ca'") stores and increases the intracellular calcium level. Calcium binds to calmodulin, and the Ca/CaM complex activates the Ca/CaM-dependent protein kinase (Ca/CaM
kinase), which also phosphorylates cytosolic proteins. Outlined molecules (TSH receptor [TSH-R] and gsp) are two genes in signal transduction that are activated in thyroid tumors and have point mutations of their coding sequence. GOP = guanosine diphosphate; GTP =
guanosine triphosphate; GTPase = guanosine triphosphatase.
increasing the coupling between different growth receptors

and PLC. Both ras and gsp hydrolyze GTP and are linked
to extracellular signaling of AC,27
An increased amount of stimulatory G protein and perhaps a decreased amount of G, are mechanisms for increased
cAMP production in thyroid tumors." There was 3.3-fold
more G, protein in the thyroid neoplasms than in normal
thyroid tissue, with much greater cAMP production than in
normal thyroid tissue. The reason for this is either that there
is a normal amount of constitutively activated G, or there is
an increased amount of an otherwise normal G s.28
Gsa is also highly expressed in growth hormonesecreting pituitary tumors, insulinomas, pheochromocytomas,
corticotropin-producing islet cell tumors of the pancreas, and
corticotropin-producing thymic carcinoids.i? Point mutations in the stimulatory G protein called gsp mutations cause
the constitutive activation of the stimulatory G protein and
increase cAMP production.v-" Thus, all tumors with gsp
mutations have a higher basal AC activity and a smaller AC
increase after TSH stimulation. Although the gsp oncogenes
have been found to be constitutively activated in follicular or

papillary thyroid cancers." gsp mutations are more common
in autonomous, or "hot," thyroid nodules.P'"
TSH AND TSH-R
TSH acts by binding to specific TSH receptors with consequent stimulation of AC within the plasma membrane that
converts ATP to cAMP (see Fig. 29-1). cAMP acts as a
second messenger and activates PKA and other intracellular
processes including P13K, p70S6k, and ras-related small
G protein, Rap I, and modulates thyroid cell survival. 14,17,37-39
The TSH-R is a member of G protein-coupled receptors
with a seven-transmembrane region." The gene for the TSH
receptor is localized on the long arm of chromosome 14
(14q31).41 Ligands other than TSH such as human chorionic
gonadotropin (hCG) and thyroid growth-stimulating antibodies also activate the TSH-R. TSH-Rs have also been
found in parafollicular thyroid cells, which is surprising
because medullary thyroid cancers that originate from
parafollicular cells do not respond to TSH stimulation.f
relationship between the ratio of TSH stimulated-to-basal

AC activity and aggressiveness of thyroid neoplasms.!'
Patients with a high TSH stimulated-to-basal AC activity
ratio had either benign tumors or stage I (tumor confined to
the thyroid) or stage II (regional nodal involvement) thyroid
cancers, whereas stage III (tumors with local invasion into
soft tissue and muscle) or IV (tumors with distant metastases) patients had a low TSH stimulated-to-basal AC activity
ratio (Fig. 29-2). This demonstrates that the average cyclase
responsiveness was approximately 18-fold for benign
thyroid neoplasms and decreased by about half with
each progressive stage to reach a low of a 1.6-fold increase
for stages III and IV thyroid cancers (see Fig. 29-2).51 Despite
this observation, there does not appear to be any relationship
between AC responsiveness and thyroid cancer histologic
degree of differentiation." Abnormalities in the TSH-R-AC
system might be responsible for the aberrant growth of
thyroid neoplasm of follicular origin. The decreased AC
responsiveness in thyroid cancers with increasing stage may
explain why TSH suppression therapy does not influence
the growth pattern of some malignant thyroid tumors. Thus,
other growth factors, oncogenes, or signal transduction
systems rather than TSH-AC-PKA-cAMP must be involved
in the growth of these thyroid tumors.
Three adenylyl cyclases including AC-III, AC-VI, and
AC-IX are mainly expressed in human and dog thyrocytes.V
The different ACs are divided into four distinct subgroups.
The first group, including ACs I, III, and VIII, is characterized by a stimulation by the calcium-calmodulin (CaCaM)
complex. The second group, including ACs II, IV, and VII,
is activated by G beta and gamma subunits and modulated
by PKC. The third group, including ACs V and VI, is inhibited by low concentrations of calcium. The last, fourth, group
is characterized by insensitivity to calcium. All ACs besides
AC-IX are activated by forskolin. 52-54 Kosugi and colleagues
demonstrated that a mutation of TSH-R (alanine 623) eliminates TSH-PLC signals but maintains TSH-AC signals.P
TSH increases tritiated thymidine incorporation into

DNA as well as cell proliferation.tv" Cholera toxin,
dibutyryl cAMP, and forskolin can mimic this TSH effect.
Although human thyroid cells in primary culture appear to
grow in response to TSH, this growth is not stimulated by
dibutyryl CAMP.45 Increasing concentrations of TSH, dibutyryl cAMP, and forskolin failed to affect cell proliferation
in some studies." Some thyroid nodules also grow in
patients with suppressed TSH levels, documenting that
signal transduction systems other than the TSH-AC-cAMPPKA system must also be involved in thyroid cell growth. In
addition to PKA activation, another cAMP-dependent
mechanism is involved in TSH action, especially cAMPEpac (exchange nucleotide protein directly activated by
cAMP)-Rapl cascade in dog thyroid cells." Although TSH
and forskolin activate Rapl in a PKA-independent pathway,
activation of Rapl is not specific for TSH or CAMP.47 Epac
is strongly expressed in the thyroid. However, it has been
documented that the cAMP-Epac-Rapl signaling pathway
in the thyroid gland does not play a major role in the cold
thyroid follicular adenomas." TSH is mitogenic for most
animal thyroid cells." Increased serum TSH levels enhance
iodine uptake in most differentiated thyroid neoplasms of
follicular cell origin. When thyroid hormone is discontinued
in preparation for radionuclide scanning or for radioiodine
treatment in patients with metastatic thyroid tumor, they
sometimes grow or become symptomatic.'? High-affinity
TSH-Rs have been reported in benign thyroid tumors and
most differentiated thyroid cancers but not in undifferentiated thyroid tumors. 17,50
Thyroid neoplasms, in general, have higher TSHstimulated AC activity than normal thyroid tissue from the
same patient.37 The AC activity increases in both normal
and neoplastic thyroid tissue in response to TSH, and the
consequent increase in cAMP production is probably a key
factor responsible for the aberrant growth of some thyroid
neoplasms. 12,17,37,51 Of interest, however, is the inverse
RATIO OF TSH STIMULATED TO BASAL

CYCLASE ACTIVITY
25
~
's;
20
r-
U
til
MeanSEM
~ 15
til
'iii 10
lIJ
.L
til
en
I-
Normal
Benign
n =59
n=20
P< .0001
..L
CarcinomaStage 1
CarcinomaStage 2
n = 25
n=6
P< .006
P< .02
--
Carcinoma- Medullary
Stage 3,4 Carcinoma
n = 11
n=3
FIGURE 29-2. The adenylate cyclase

(AC) responsiveness to thyroidstimulating hormone (TSH) over
basal adenylate cyclase activity is
shown for each tissue type. Benign
lesions show a marked AC response,
and there is a progressive decline in
AC responsiveness with increasing
aggressiveness or stage of the neoplasms, Analysis of the variance
shows a significant trend (P < ,02).
Medullary carcinomas, which lack
TSH receptors, as expected, show no
response to TSH (TSH/basalcyclase =
1.05 0.04), (From Siperstein AE,
Zeng QH, Gum ET, et al. Adenylate
cyclase activity as a predictor of
thyroid tumor aggressiveness. World
J Surg 1988;12:528.)
Signal Transduction in Thyroid Neoplasms - - 269

Although in one study there were no mutations in the intracytoplasmic TSH-R mutation." mutations in the TSH-R
gene (aspartic acid at 619 to glycine and alanine at 623
to isoleucine) have been reported to be present in 3 of
11 thyroid hyperfunctioning follicular adenomas.57 These
somatic mutations were found in the carboxyterminal portion
of the third cytoplasmic loop of the TSH-R. Although they
caused constitutive activation of AC with high basal cAMP
levels, there were no appreciable changes in the basal accumulation of inositol phosphates, and the inositol response to
TSH stimulation was maintained. TSH-R mutations leading
to constitutive activation of the TSH-R would result in
autonomous thyroid growth and function. These are the
main molecular mechanisms leading to thyroid adenomas
and some cases of multinodular goiter/" The constitutively
activated TSH-R genes detected in thyroid carcinomas may
have an oncogenic role, participating in their development
through two pathways, including the cAMP signal transduction pathway and through Gsa and the Ras-dependent
mitogen-activated protein kinase (MAPK) pathway through
G~, y, and P13K.59TSH controls the subunits of PKA at the
transcriptional level and at the translational or posttranslational level. 60 Activating mutations affecting important
signal transduction pathway components such as TSH-R
and Gsa occur in the majority of autonomously functioning
thyroid nodules. However, PKA Go. mutations at the codons
investigated do not represent an oncogenic mechanism in
the development of thyroid neoplasms.P' TSH also stimulates phosphorylation of the transcription factor cyclic AMP
response elements binding protein (CREB) via a cAMPresponsive DNA-binding protein.f Phosphorylated CREB
regulates the expression of the oncoprotein C-fOS.63
Thyroid growth-promoting antibodies or thyroid growth
immunoglobulins (TGIs), as well as thyroid-stimulating
immunoglobulins (TSls), are monoclonal immunoglobulins
(lgGs) present in patients with Graves' disease. These antibodies are able to promote the growth of thyroid cells and
stimulate the AC-cAMP system by binding to the TSH-R
and increasing cAMP.64,65 The TSI or TGI activity can be
blocked by antibodies from patients with primary
myxedema, Hashimoto's thyroiditis, and Graves' disease.
These blocking antibodies also act by binding to TSH-R but
do not stimulate cell growth or function. IgGs from patients
with nontoxic goiter also have a slight stimulatory effect on
thyroid cell growth, but the concentration of IgGs is considerably lower than that found in patients with Graves' disease/"
It has been suggested by some that these IgGs may be
responsible for recurrent goiter in patients receiving TSH
suppression therapy.
The glycoprotein hormones, such as TSH, hCG, and
human luteinizing hormone (hLH) , have a common alpha
subunit and a unique hormone-specific beta subunit. Some
patients with molar pregnancy or choriocarcinoma experience goiter and hyperthyroidism as a result of hCG, and
women during normal early pregnancy have elevated free
thyroxine (T 4) and triiodothyronine (T3).67 hCG is another
hormone acting via crossover binding to the TSH-R,
increasing cAMP with subsequent increased iodide uptake
and thymidine incorporation in rat FRTL-5 thyroid cells. 68
hLH also binds to TSH-R and stimulates cAMP.69
Luteinizing hormone increases iodide uptake and stimulates
thymidine incorporation similarly to hCG in Chinese hamster ovary (CHO) cells transfected with functional human
TSH_R.69,70 hLH, however, is a more potent thyroid stimulator
of the human TSH-R than hCG in vitro."
OTHER RECEPTORS AND CYTOKINES
VIP released from nerve endings is one of the important
factors for local neuronal control of thyroid function and
increases thyroid blood flow." VIP also causes the release
of thyroid hormone from thyroid tissue or thyroid cells in
culture.P?" VIP exerts its action through a separate VIP
membrane receptor that is coupled, like TSH, to stimulatory
G proteins and activates AC. 75 VIP stimulates AC activity in
normal and neoplastic thyroid tissues in vitro but less than
TSH. 75
Although both prostaglandin E 1 and prostaglandin E 2
stimulate AC activity in animal thyroid homogenates, the
effect of prostaglandin on thyroid growth is controversial.V"
Most benign thyroid tumors as well as differentiated thyroid
cancers contain estrogen receptors in the cytosol and in
membrane particulate fraction." Neoplastic thyroid tissue
has more estrogen receptors than non-neoplastic thyroid
tissue. There was, however, no correlation between the
number of estrogen receptors and TSH-R in either normal or
neoplastic thyroid tissue. The presence of steroid receptors
for estrogen, androgen, progesterone, and glucocorticoids in
thyroid tumors suggests that endogenous and exogenous
steroids may have a direct or indirect effect on the development and growth of these tumors."
Somatostatin, a 14-amino acid polypeptide, and its longacting analog octreotide block TSH secretion from the pituitary. Somatostatin acts through an independent cell surface
receptor coupled to inhibitory guanylyl-nucleotide regulatory G, proteins (see Fig. 29-1). Activation of G, proteins
inhibits AC activity. Octreotide has been used to treat TSHsecreting pituitary adenomas.s" Somatostatin also inhibits
the thyroid cells. 81,82 Somatostatin inhibits basal and TSHstimulated AC activity in both normal and neoplastic human
thyroid tissue. Somatostatin and tamoxifen also inhibit the
growth of papillary and follicular cells in culture.f Although
somatostatin inhibits both basal and TSH-stimulated activity
in normal and neoplastic human thyroid tissue, studies with
specific antibodies to the alpha subunit of G j suggest that G,
has only a minimal effect on AC activity.f
Tumor necrosis factor (TNF) is a cytokine produced
by macrophages. TNF and interleukin (lL)-1 mediate
inflammatory processes. TNF binds to its receptor, activates
phospholipase A 2 mediated through G proteins, and releases
arachidonic acid from phosphatidylinositol (PI).85 Although
TNF did not affect either basal or TSH-stimulated cAMP
generation, TNF did blunt TSH-stimulated thyroglobulin
(Tg) secretion." FRTL-5 cells have TNF receptors and TSH
increases the number of TNF receptors." TNF and IL-l
administration in animals decreases circulating thyroid
hormones and reduces iodide uptake and thyroid hormone
response to TSH.88,89 TNF also decreases thyroid cell function such as radioactive iodine uptake and T 3 release as well
as the growth of FRTL-5 rat thyroid cells."? IL-l suppressed
c-myc protooncogene expression and inhibited the growth of
a thyroid papillary cancer cell line.?' However, it failed to
inhibit the growth of other thyroid cell lines.
PI Turnover-Phospholipase-PKC System
Binding of TSH or other agonist hormones, neurotransmitters, or circulating growth factors for specific receptors on
the thyroid plasma membrane stimulates PI turnover, activates
PKC, and increases intracellular calcium. The stimulated
receptor interacts with a specific guanine-nucleotide regulatory protein (Gp) that activates the enzyme phospholipase
(PLC). PI is a minor component of the cell membrane
located in the inner leaflet of the membrane phospholipid
bilayer. Three phosphoinositides-PI, phosphatidylinositol4-phosphate, and phosphatidylinositol-4,5-biphosphate
(PIPz)-are in dynamic equilibrium in the plasma membrane. PLC converts PIP z into two second messengers:
inositol-I-4,5-triphosphate (IP3) and 1,2-diacylglycerol(DAG)
(see Fig. 29-1). IP3 increases intracellular calcium concentrations. DAG and calcium activate PKC and mediate cellular
processes, including growth and differentiated thyroid
function.9z,93 Activated PKC moves from the cytosol to the
plasma membrane and phosphorylates both membrane-bound
and cytosolic proteins. IP3 is converted into inositol-1,3,4,
5-tetrakisphosphate, which stimulates calcium entry from
the cell exterior. Hydrolysis of inositol phospholipid by
PLC may increase and prolong the activation of PKC for
cell proliferation and differentiation."
Activation of the PLC-PKC signal transduction system
has stimulatory effects on the growth of certain tissues and
an inhibitory effect in others. The human colon cancer cell
line CaCo-2 has an increased PLC activity in response to
I,25-dihydroxyvitamin D3.95 In other cell systems, increased
PLC activity correlates with inhibition of growth."
The TSH-R activates PLC through o, in thyroid cells.9z.93,97
The activity ofPLC was increased in ras-transformed NIH3T3

cells or NRK cells.98 Antibody to PIPz inhibited oncogeneinduced mitogenesis.'? Bombesin and bradykinin stimulate
inositol phospholipid metabolism in H-ras-transformed cells
more than in untransformed cells.l'" Normal forms of p21
Ha-ras increase PLC activity in response to platelet growth
factor, whereas the mutated forms of p21 ras increase PLC
activity without this growth factor.'?'
TSH stimulation of PLC has been demonstrated in animal
and human thyroid tissue slices. IOZ,103 The activation of this
system is independent of the Ac. 81,103 When rat thyroid
glands were exposed to the goitrogen methylthiouracil, the
activity of PKC paralleled goiter growth.P' The activity of
PKC decreased to less than half of the original level, and
goiter regressed after treatment with T4 . Neoplastic thyroid
membranes have greater PLC activity than that found in
histologically normal thyroid membranes removed from the
same patients.l'" PLC responsiveness to TSH in normal,
hyperplastic, and neoplastic (papillary, follicular, Hiirthle
cell) thyroid membranes have been studied in 56 patients. 106
Although the TSH-PLC-PKC system is intact and PLC
activity increased in response to TSH in normal, benign, and
stages I and II thyroid cancers, some invasive (stage III) or
metastatic (stage IV) cancers failed to increase PLC activity
in response to TSH.106 Thus, PLC increase in response to
TSH ranged from 1.2-fold to 2-fold stimulation over basal
activity in most tissues, whereas there was no significant
difference between control and TSH-stimulated PLC activity in stage III or IV thyroid cancers (Fig. 29-3). PKC is also
activated by the tumor-promoting phorbol ester TPA. TPA
mimics the effects of DAG and activates PKC without phosphoinositide turnover (see Fig. 29-1).107 Both TPA and TSH
FIGURE 29-3. Phospholipase C (PLC) responsiveness to thyroid-stimulating hormone (TSH) in normal, hyperplastic, and neoplastic thyroid membranes. Control (basal) and TSH-stimulated PLC activity were assayed in 56 thyroid and 4 parathyroid adenoma specimens.
Patients were stratified into histologic categories (normal thyroid, multinodular goiter, follicular adenoma, carcinoma, and parathyroid adenoma), and carcinomas were stratified further by clinical stage (DeGroot classes I and 2 and classes 3 and 4). All carcinomas were either
papillary, follicular, or Hiirthle cell. The number of patients in each group is listed below each category. (From Shaver JK, Tezelman S,
Siperstein AE, et al. TSH activates phospholipase C in normal and neoplastic thyroid. Surgery 1993;114:1064.)
Signal Transduction in Thyroid Neoplasms - -
increase growth of thyroid cancer cell line. TSH, however,

stimulated invasion and growth in vitro by a PKC rather than
by a PKA mechanism. 108
TUMOR-PROMOTING PHORBOL ESTERS
The phorbol ester TPA is a potent promoter of thyroid proliferation and increases PKC activity. 109-1 11 TPA induced DNA
synthesis and proliferation of dog thyroid cells.I'? In dog
thyroid cells, TPA enhanced the accumulation of c-myc
messenger RNA (mRNA) after 3 and 6 hours. I13 TPA stimulated invasion and growth of follicular thyroid cancer cells
in vitro.l'" A similar finding has been described in animal
thyroid cells. I 14-116 TPA also stimulates tritiated thymidine
incorporation and cell proliferation. I 14
Mezerein, telecidin, and aplasia toxin are PKC activators."
Inhibitors of PKC are H7 (l-(5-isoquinoline sulfonyl-2-0methylglycerol), AMG-C 16 (I-O-hexadecyl-2-0-methylglycerol), 117 staurosporine, phospholipid-interacting drugs
such as chlorpromazine, dibucine, and trifluoperazine.
Exogenous PLC mimics the effects ofTPA on differentiated
thyroid function in vitro.'!" The PKC inhibitor H7 reverses
the effects of TPA and PLC.II? Staurosporine, a microbial
alkaloid, acts at the ATP-binding site on protein kinase and
is a potent inhibitor of PKC and other protein kinases.118.119
Staurosporine enhanced TSH-stimulated iodide organification.!'? In the presence of staurosporine, TPA did not inhibit
TSH-stimulated iodide organification. 117 Staurosporine also
inhibited growth and invasion of a follicular thyroid cancer
cell line in a dose-dependent manner and abolished the
effect of TSH.108
Calcium-Calmodulin-Dependent
Protein Kinase System
During phosphoinositide turnover, IP 3 increases intracellular
calcium by mobilizing intracellular calcium stores from the
endoplasmic reticulum. Calcium binds calmodulin. Increased
Ca-CaM levels activate a Ca-CaM-dependent protein kinase,
a third protein kinase, which results in phosphorylation of
cytosolic proteins (see Fig. 29-1). Both increased PKC activity and increased intracellular calcium activate the fos and
myc oncogenes in the cell nucleus. 120 Trifluoperazine inhibits
the Ca-CaM-dependent protein kinase.!" Although epidemiologically increased calcium consumption enhances the
incidence of goiter in areas of endemic goiter, it is unknown
whether increased intracellular calcium is responsible for
thyroid cell growth and differentiation." In calf thyroid
tissue slices, TSH stimulates increased intracellular calcium
levels, which increase iodine accumulation, glucose oxidation, hydrogen peroxide generation, and Tg transport as well
as organification.l" Calcium ionophores increase intracellular calcium levels and thereby stimulate Tg and thyroid
hormone secretion. Although clones for at least six different
AC types have been isolated and expressed in animal cells,
only types I and III AC are stimulated by calmodulin and
calcium. 123
Growth Factor-Tyrosine Kinase System

Thyroid growth is influenced by TSH and other hormones
as well as many growth factors. The polypeptide growth factors, including EGF, IGF-I, and transforming growth factor
271
(TGF)-a. act via tyrosine kinase (Fig. 29_4).124 Growth

factors bind to specific receptors on the thyrocyte.!"
Phosphorylation of the receptor causes accumulation of
signal transduction proteins, including PI -modulating
enzyme, IP 3, kinase, PKC, serine-threonine kinase RAF,
G'TPase-activating protein (GAP), MAP kinase kinase
(MAPKK), MAPK, extracellular signal-regulated kinase
(ERK)-l, and ERK_2.126-128 In general, growth factors activate their own receptors, leading to phosphorylation on specific tyrosine residues and creating specific binding sites for
src homology and to various proteins. I15.129,130 The p21 ras
then becomes activated, and MAPK is also stimulated on
both threonine and tyrosine.P? The ras protein hydrolyzes
the active bound GTP to GDP, the inactive form, and inorganic phosphate (see Fig. 29-4). Intracellular calcium can
modulate the MAPK cascade via activation of the monomeric
G protein p21 ras through calcium-dependent tyrosine
kinase and calmodulin. 128
Activation of GTP hydrolysis is regulated by GAPS.l27,131
The GTP-bound ras transmits signals in thyroid cells.
Activated ras, in tum, causes activation of raf-l, which then
phosphorylates and activates the specific activators of MKK
and MAPK (see Fig. 29_2).132,133 The activating phosphorylation of MAPK is an important process of both the phorbol
ester-PKC system and the growth factor-tyrosine kinase
system. This is, however, not involved in the mitogenic
cAMP pathway. EGF binds to its EGF receptor (EGF-R),
which has three domains, including extracellular receptor
domain, transmembrane domain, and intracellular tyrosine
dornain.F' Activation of tyrosine kinase phosphorylates
cellular proteins and autophosphorylates itself. Tyrosinespecific protein kinase is associated with oncogene products
of the retroviral src gene family. The intracellular domain
of EGF-R is also activated by PKC. In A431 cells, EGF
also activates the phosphoinositide turnover-PKC-calcium
system with an increase in DAG and calcium influx. 134
IGF-I also stimulates cell proliferation and DNA synthesis in rat FRTL-5 thyroid cells." IGF-I is also involved in the
growth of human thyroid cancer cells.45.135 TGF-a. is structurally related to EGF and binds to the EGF-R. TGF-a. is
another potent mitogen of follicular cells.l'" Expression of
TGF-a. at both mRNA and protein levels has been demonstrated in thyroid follicular cells, and TGF-a. has an
autocrine function in normal thyroid follicular cells.!" TGF-~,
in contrast, is a potent inhibitor of follicular cell proliferation. 138 TGF-~
stimulates endothelial secretion in thyroid
tissues as well as endothelial synthesis and binding in thyroid follicular cells.P? TGF-~
binds its receptor and keeps
the p105rb in an unphosphorylated stater'? by inhibiting
kinase or stimulating phosphatase. 141 Genistein, an
isoflavone, is a specific inhibitor of tyrosine kinase, including the EGF-R kinase, pp60-v-arc, and pp 11O-gag-fes.142
Genistein also inhibits the activity of serine- and threoninespecific kinases such as cAMP-dependent protein kinase,
PKC, and phosphorylase kinase. 142 Genistein decreased the
EGF-stimulated increase in tyrosine phosphorylation in
A431 cells. 142 Genistein also arrests cell cycle progression at
G TM.143
EPIDERMAL GROWTH FACTOR
EGF is a 53-amino acid polypeptide isolated from the male

mouse submaxillary gland. EGF binds to a specific EGF-R
Transcription factors:
CREB, fos/jun, myc, srf, E2F
FIGURE 29-4. Growth factor-tyrosine kinase (Tyr K) system. Growth factor (e.g., epidermal growth factor [EGF], transforming growth
factor [TGF]-alpha, insulin-like growth factor I, nerve growth factor) binds to its receptor, which has three domains: (1) an extracellular
receptor domain (R); (2) a transmembrane domain (T); and (3) an intracellular tyrosine kinase domain (K). The binding of a growth factor
to its receptor activates a Tyr K, which phosphorylates cellular protein and autophosphorylates. The intracellular domain is also phosphorylated by protein kinase C (PKC). PI3-K, PLC-gamma, and PKC are involved in the regulation of ras. Ras protein hydrolyzes the bound
guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Activation of GTP hydrolysis is regulated by GTP-activating proteins
(GAPs). Ras-GTP, active form, activates raf-I, PKC, mitogen-activated protein (MAP) kinase kinase (MAPKK), and MAP kinase
(MAPK). Raf-l, PKC, and MAPK phosphorylate transcription factors.
situated primarily on the basolateral membrane of the thyroid
cells.l" The autophosphorylated EGF-R increases tyrosine

kinase, which stimulates PI turnover. EGF-R is the product
of the erb B protooncogene.lv The intracellular domain of
EGF-R is also phosphorylated by PKC.
EGF acts in a paracrine or autocrine manner to stimulate
thyroid growth.v" Many organs, including the submaxillary
gland, thyroid, pancreas, duodenum, jejunum, and kidneys,
have high concentrations of EGE The thyroid gland contains
5 nglg of EGE147 EGF-Rs have been identified in animal
thyroid tissues and in human normal and neoplastic thyroid
tissues. 148,149 Both TSH-Rs and EGF-Rs have a basolateral
distribution in thyroid cells. EGF stimulates DNA synthesis
and cell proliferation in animal and human thyroid cells in
culture and inhibits TSH-induced differentiation, 144,150,151
EGF stimulates the PLC-PKC-calcium system.P" EGF-Rs
are present in most normal and neoplastic thyroid tissues,
and neoplastic thyroid tissues have more EGF-Rs than do
non-neoplastic human thyroid tissues.!" EGF binding is
also higher in neoplastic than in normal thyroid tissue.
Higher EGF binding occurs in tumors from patients with a
poorer prognosis. 149 There is a positive correlation between

EGF binding and TSH binding and between EGF binding
and TSH-stimulated Ac. 152 Thus, as suggested by Duh and
Westermark and their colleagues, TSH increases EGF-Rs by
increasing intracellular cAMP.152-154 Follicular tumors,
including adenomas and carcinomas, have higher EGF binding and TSH binding than other thyroid tissues.r" EGF
stimulates the expression of c-fos and c-myc oncogenes in
porcine thyroid cells.l'" Differentiated thyroid formation is
stimulated by TSH via cAMP, and it is inhibited by EGF and
TPA,124,156 EGF is mitogenic in sheep thyroid cells in
culture 157 but has no apparent mitogenic effect in cultured
bovine or rat thyroid tissue. EGF, in contrast with TSH,
not only stimulates thyroid growth but also enhances invasion of follicular and papillary thyroid cancers in vitro. 158
EGF also activates MAPK p42 mapk (ERK-2) and p44 mapk
(i.e., ERK_l).132135 MAPK mediates the activation of cytosolie enzymes and nuclear transcription factor.132 Activated
MAPKs are important in mitogenic signaling. In dog thyroid
epithelial cells, EGF and phorbol esters increase MAPK phosphorylation on tyrosine, threonine, and serine.130
Desensitization of Signal
Transduction
Continuous agonist stimulation of receptors usually leads to a
decrease in receptor-mediated AC activity and cAMP levels.
This process is termed desensitization. Desensitization, or
a decreased response to the same or repetitive stimuli, is an
important physiologic process and a well-described mechanism of receptor-signaling modulation that occurs in a variety
of cell systems. There are two types of desensitization: homologous and heterologous. Homologous desensitization is
agonist specific, whereas heterologous desensitization occurs
when stimulation of another receptor or postreceptor stimulator leads to desensitization of the receptor. Defective
desensitization could impair various steps in the signal transduction pathway, including receptor-G protein coupling,
G protein activation by GTP, and G protein-effector
interaction. 159 Receptor mutations could lead to enhanced or
reduced desensitization. 160.161 The reduction in cAMP generation observed during desensitization could be due to either
a less efficient coupling of receptor to G, or an enhanced
efficiency of coupling of receptor to G j.159,162
Three independent mechanisms are responsible for
desensitization: phosphorylation, sequestration, and downregulation. The first step in desensitization involves an
agonist-induced phosphorylation of the receptor, resulting in
the functional uncoupling of the receptors from the effectors
downstream in the signaling system. Thus, receptor phosphorylation is a primary mechanism leading to desensitization162-165 involving at least two kinases: phosphorylation by
cAMP-dependent PKA and phosphorylation by ~-adrenergic
receptor kinase.166-168 PKA-mediated phosphorylation is
cAMP dependent and plays a major role only in heterologous
receptor kinase-mediated
desensitization. 163 ~-Adrenergic
phosphorylation is cAMP independent and is responsible
for homologous desensitization.l''? Phosphorylation may
promote binding of other proteins to the receptor. These
proteins are termed arrestins because they arrest signal
transduction, perhaps by blocking G protein-receptor
coupling. 159,167 After exposure to an agonist, receptors are
sequestered in the plasma membrane within a few minutes.
Sequestration refers to rapid, agonist-induced translocation
of ~-adrenergic
receptor away from the plasma membrane to
a distinct compartment deficient in G; Downregulation is a
process biochemically distinct from sequestration and results
in degradation of the receptor. Heterologous desensitization
in lymphoma cells requires an increase in intracellular cAMP
level.170
Prior exposure of human normal thyroid tissue to TSH
either in vivo or in vitro causes desensitization of AC.I7I - 174
TSH-induced homologous desensitization has been described
in human and animal normal thyroid cells.172-1 80 After the
cloning of the human TSH_R,181-184 the stable expression of
TSH-R in nonthyroidal cells such as CHO cells has been
used in desensitization studies.l'" Although one study suggested that TSH stimulation failed to cause desensitization in
CHO cells transfected with human TSH_R,185 a subsequent
study did document that human TSH-R-transfected CHO
cells do desensitize.l'" The latter investigation is important
because it documents that no specific thyroid factors other
than increased levels of cAMP are required.l'" Primary differentiated thyroid cancers, in general, desensitize similar to
normal thyroid cells, whereas some metastatic tumors do
not (Fig. 29-5). Loss of the desensitization ability could be
responsible for the growth of thyroid cancers in TSH-suppressed patients and perhaps for metastatic disease.
Desensitization of TSH-Rs in neoplastic cells is caused by
increased levels of cAMP. 186.187 TPA itself had no direct
effect on cAMP levels in all thyroid cancer lines, but it did
cause desensitization of the AC response to subsequent stimulation by TSH.187 The activation of PKC appears to be
responsible for the heterologous desensitization because
staurosporine, a potent PKC inhibitor, abolished or inhibited
the effect ofTPA on desensitization. 187 Prolonged TPA treatment leads to PKC downregulation as a result of depletion
Incubation
First
4th
CON
Second
30 min
CON~""'""'i""""",,.:. >. :>J
121 LNM 1
EJ LNM 2
o Primary Tumor
TSH CON~~~~~
cAMP (pmol/well)
FIGURE 29-5. Homologous desensitization of cyclic adenosine

monophosphate (cAMP) to thyroid-stimulating hormone (TSH)
stimulation in neoplastic thyroid cells from six patients. Cells were
cultured in 24 well plates for 3 days and for the last 24 hours in
medium lacking TSH and fetal calf serum until 95% confluence.
These cells were preincubated for 4 hours in either control medium
without TSH (CON) or in medium supplemented with TSH
(10 mU/mL) and washed three times with phosphate-buffered saline,
pH 7.4. The cells were then incubated for 30 minutes in control
medium and in medium supplemented with TSH (10 mU/mL) and
I mM isobutylmethylxanthine. Intracellular cAMP was then measured by radioimmunoassay. Each bar represents the mean SD
of 18 experiments. Neoplastic thyroid cells (white bar) showed
desensitization after pretreatment with TSH for 4 hours, whereas
two of three metastatic cell lines (type I, hatched bar) had an
increased cAMP level in response to TSH stimulation, and both
failed to desensitize. The third metastatic cell line both failed to
increase cAMP level in response to TSH and failed to desensitize
(type II). P < .002. (Data courtesy of Tezelman S, Shaver JK,
Grossman RF, et al. Mechanism of homologous and heterologous
desensitization in human neoplastic thyroid cells. Unpublished
personal data, 1996.)

of phorbol ester-binding studies in many cell types.l" The
effects of PKC downregulation on TSH-stimulated iodide
organification have been demonstrated in porcine thyroid
cells. 189 Like TPA, EGF had no direct effect on cAMP levels,
but it did cause desensitization of cAMP production to subsequent TSH stimulation.'?" The EGF-induced desensitization
of TSH-AC signal transduction system was abolished by
coincubation with EGF-R antibody (EGF-R monoclonal antibody 528) and by genistein.l'" Desensitization apparatus,
phosphodiesterase expression, and CREB may be activated
in functioning thyroid adenomas.P"!"
Interaction (Cross-Talk) of the

Different Signal Transduction
Systems
Cellular responses to external stimuli involve an integration of
inputs from hormones, neurotransmitters, and growth factors.
This integration is able to interact with distinct second messengers. The effect of one signal transduction system may
alter the response of another, as already mentioned. This is
called cross-talk. Although TSH stimulates both the AC
system and the phosphoinositide turnover-calcium systems in
animal cell cultures and human neoplastic membranes,43.106
the response patterns of protein phosphorylation to TSH and
TPA are different and not reproduced by elevating cAMP by
IBMX. 194 TSH and TPA had no additive effect on the proliferation of dog thyroid cells. 195.196 TPA, however, reduced the
cAMP response to TSH when both agonists were incubated
in dog and pig thyroid cells.197-199 TSH decreased cAMPdependent PKA activity in dog thyroid cells,2oo but the simultaneous presence of TPA and TSH, in contrast, inhibited
TSH-induced downregulation of PKA 1.197 TPA had a biphasic effect on TSH-induced stimulation of cAMP production
in pig thyrocytes.l'" TPA potentiated the effect of TSH when
pig thyroid cells were exposed simultaneously to TSH and
TPA for 10 minutes, but after 20 minutes TPA inhibited the
cAMP response to TSH.198 TPA blocked the TSH effect and
prevented cAMP-dependent PKA activity.!"
Graves' disease IgG can increase PLC activity as well as
cAMP production in rat FRTL-5 thyroid cells. PKC modulates different signal transduction systems, leading to positive
or negative cross-talk with calmodulin kinase.P' Increased
activation of calmodulin kinase by PKC results from PKCmediated phosphorylation of calmodulin-binding proteins.i"
Studies demonstrated that when neoplastic thyroid cells are
coincubated with TPA and TSH for 4 hours or longer, TPA
decreased the cAMP response compared with that when
cells are stimulated with TSH alone.I" This effect of TPA is
abolished by coincubation with staurosporine.P?
Although EGF does not change the level of cAMP
directly, TSH increases cAMP levels, which then stimulates
the production of EGF-Rs.I53154 TSH induces proliferation
and differentiation expression in dog thyroid cells, whereas
EGF and TPA induce proliferation and dedifferentiation.
When dog thyrocytes were simultaneously exposed to both
TSH and EGF, the expression of protooncogenes, such as
c-myc, was lower than with exposure to either EGF or TSH
alone. 203 Pretreatment with TSH or forskolin increases the
response of pig thyroid cells to EGF, probably because of

increasing numbers of EGF receptors.'>' TSH increases
both thyroid cell growth and differentiation, whereas EGF
increases only thyroid cell growth and inhibits cell differentiation. EGF also inhibits TSH-mediated thyroglobulin
synthesis, morphologic differentiation, and iodide uptake, as
well as organification. I44204-206 In general the PKC- and
PTK-mediated pathways are triggered by TPA and EGF.207
Increased concentrations of intracellular cAMP block
activation of raf-; and MAPK in fibroblasts.l'" Thus, EGFdependent MAPK activation was blocked by forskolin or
IBMX. PKA probably phosphorylates and inactivates
MAPKs. Dibutyryl cAMP blocks DNA synthesis and also
signal transmission from ras by inhibiting raj activation. 132
The incubation of EGF and TSH together induced a significant decrease in cAMP response to TSH compared with the
cAMP response that resulted after stimulation with TSH
alone. 190 Thus, EGF inhibits TSH-stimulated cAMP production. The inhibition of cAMP was abolished when neoplastic thyroid cells were incubated with TSH, EGF, and
EGF-R-monoclonal antibody 528. 190
Natriuretic peptides (NPs) and their receptors (NP-R) have
been identified in thyroid gland. 208 Although atrial natriuretic
factor inhibits cAMP formation and thyroglobulin production
in primary thyrocyte cultures through subsequent activation
ofGi NAPs, binding to NP-R can activate AC.209
Summary
The growth pattern of thyroid cells is complex and is under
the control of various signal transduction systems, including the AC-cAMP-PKA system, the PLC-PKC-system, the
Ca-CaM-kinase system, and the growth factor-tyrosine
kinase system. Extracellular signals such as hormones, neurotransmitters, and growth factors bind to their specific
receptors and stimulate intracellular transduction systems
into second messengers. The TSH-AC signal transduction
system has been well investigated in benign and malignant
thyroid tumors. The TSH-PLC and EGF-tyrosine kinase
system, as well as other signal systems, has also been studied. Derangements in the signal transduction systems cause
abnormal growth and behavior of thyroid follicular cells.
The interactions or cross-talk between signaling systems
play an important role in the growth pattern of normal and
abnormal thyrocytes. A better understanding of the various
factors that influence the particular signal transduction
system and of specific alterations in signaling that correlate
with changes in behavior should lead to new therapies.
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Peter E. Goretzki, MD Victor Gorelev, MD
Dietmar Simon, MD Hans-Dietrich Roeher, MD
The knowledge that a variety of environmental conditions,

such as exposure to external radiation or chemicals, or
chronic inflammatory processes and viral infections can
induce neoplasms initiated studies seeking the explanation
for these associations. Cells can be infected with RNA- or
DNA-containing viruses, and the viral genome becomes
inserted into the genetic code of the host cell.' As the cells
divide, the viral DNA is transcribed and translated, producing a protein that may act as a growth factor, as a growth
factor receptor, in signal transduction, or in the transcription
of other genes. In the latter situation, it may interfere with
apoptosis. Tumor development after viral infection occurs as
a result of insertion and activation of viral oncogenes in host
cells. 1 Subsequent investigation documented that eukaryotic
cells harbor genes similar to viral oncogenes, which started
the hunt for additional protooncogenes.
Radiation and chemical toxins lead to tumor development
and malignancy by causing multiple genetic changes that
accumulate in affected cells (Fig. 30-1). These genetic
changes may be single base pair changes (i.e, point mutations), insertions, deletions, rearrangements, and translocations. These genetic modifications affect encoded protein
structure (i.e., mutations) or amplify certain genes (i.e.,
translocation), which then alter normal regulatory processes,
turning protooncogenes into oncogenes.'
Protooncogenes can be defined as genes involved in cell
growth and cell differentiation that gain oncogenic potential
and support tumor development and tumor propagation
when amplified or structurally modulated. Thyroid tumors of
follicular cell origin appear to develop by means of multiple
genetic changes in cells rather than by activation of a single
oncogene.v' Oncogene products can be divided into different
protein families with specific cellular functions (e.g., growth
factor, growth factor receptor, signal-transducing protein),
and they may act on cell surfaces, within the cell cytoplasm,
or within the nucleus-that is, inhibitors and activators of
transcription (Fig. 30_2).2.5
Some variations of these general rules are related to the
physiologic characteristics of specific tissues. Oncogenes can
be deduced from their similarity to viral genes and from genes
encoding proteins involved in the physiologic pathways of
cell stimulation.P" Constitutive activation by specific mutations was demonstrated in vitro for the thyroid-specific
growth factor receptor (i.e., thyrotropin or thyroid-stimulating
280
hormone [TSH] receptor) and the signal-transducing protein

(gsp) connected to this receptor (i.e., alpha subunit of the
Gs protein [Gs-a]).
The field of oncogene research focuses on genetics and
incorporates information from microbiology (e.g., viral
infectious diseases), embryology, physiology (e.g., proteins
important in growth and differentiation), epidemiology
(e.g., prevalence of thyroid cancer in Russia before and after
the Chernobyl catastrophe), toxicology, and radiology
(e.g., effect of radiation on oncogene structure and expression). In this chapter, we review the roles of oncogenes in
human thyroid tumors.
Oncogenes Connected to
Receptor Mutations
The idea that physiologic pathways may be constitutively
activated by genetic alterations of single components of these
pathways was compelling but hard to prove. For thyroid
tumors, the TSH receptor (TSH-R) had to be cloned before
studies of the structure and expression of this receptor could
be performed. Cloning of the human TSH-R by Parmentier
and colleagues in 1989 9 was an important breakthrough in
this field. The knowledge that all G protein-related receptors
develop from a common progenitor and demonstrate specific
protein structures (i.e., an intracellular carboxyterminal end, an
extracellular ligand-specific end, and a seven-transmembrane
loop region) made it possible to use experiences from
p-adrenergic receptor studies for TSH-R investigations.
Liggett'? and Hausdorff"! and their colleagues used sitespecific deletions of the p-adrenergic receptor. They were
able to modulate specifically hormone-stimulated cyclic
adenosine monophosphate (cAMP) production of transfected
cells with wild-type or deleted p-adrenergic receptors.F
Because various groups had demonstrated the growthstimulating effect of TSH in human tumors and had demonstrated an enhanced cAMP response to TSH in differentiated
thyroid tumors.P:" the question arose whether tumorspecific changes in the cAMP response were caused by
TSH-R mutations. Several groups screened human thyroid
Oncogenes in Thyroid Tumors - - 281
FIGURE 30-1. Multistep mutation
theoryof thyroidtumordevelopment.
Mutations A-M and N-W are mutations that lead to cell death or early
apoptosis (i.e., programmed cell
death). Mutation X provides growth
advantage but no immortalization
(i.e.,cooperative mutationsin benign
tumor development). Y-Z mutations
cooperate in tumor development,
including mutations that interfere
with apoptosis and may lead to
immortalization and to uncontrolled
malignant tumor growth.
UNCONTROLLED GROWTH
tumors for activating mutations in the TSH-R gene, and

Parma" and Paschke'? and their coworkers found somatic
mutations in the TSH-R gene from the DNA of
autonomously functioning thyroid adenomas. Kopp and
colleagues" demonstrated TSH-R mutations in a patient with
congenital hyperthyroidism and an autonomously functioning goiter; the mutated genes increased basal cAMP production when transfected into COS cells. Nonhyperfunctioning
thyroid adenomas and differentiated thyroid cancer, however, lacked the stimulating mutations of the TSH-R gene, as
demonstrated by Matsuo and associates.'? Activating TSH-R
mutations are restricted to some benign thyroid tumors with
functional hyperactivity.
FIGURE 30-2. Oncogenes in human thyroid tumors.
Oncogeneproducts may be divided into receptor proteins,

proteins for transducingsystems, and nuclear transcription
factors or inhibitors of transcription. Known protooncogenes for thyroid tumors activated by mutation,
translocation,or amplificationare the gene for the thyroidstimulating, hormone receptor (leading to benign hyperfunctioning adenomas); genes for receptors with tyrosine
kinase activity, such as egf-r, trk, ret, and neu (demonstrated in differentiated thyroid cancer [DTC] and
medullary thyroid cancer [MTC]; the PDGF-r gene
(demonstratedin anaplastic thyroid cancer); and genes for
proteins in transducing systems with guanosine triphosphatase activity, such as ras and gsp (demonstrated in
benign and malignant thyroid tumors). Intranuclear protooncogenes,such as c-myc, c-fos, and c-jun, are amplified
by external stimulation, but their primary importance in
the development and propagationof human thyroid tumors
has not been proved.
G Protein Mutations
Activating mutations of the alpha subunit of the G protein
that enhances cellular cAMP were first demonstrated in
growth hormone-secreting pituitary tumors by Vallar and
coworkers in 1987.20 Further investigations by Landis"
and Masters" and their colleagues biochemically identified
and characterized the effect of these stimulating mutations
that inhibit G protein-specific guanosine triphosphatase
(GTPase) activity. The mutated stimulating G protein
(Gs) has a much lower GTPase activity than wild-type Gs.
The reduced susceptibility of GTP to hydrolysis may increase
the period of Gs in the GTP-bound state. Because Gs-GTP
FUNCTION
ONCOGENE
TUMOR TYPE
RECEPTOR
tsh-r
egf-r; trk
ret; neu
pdgf-r
BENIGN
DTC;MTC
TRANSDUCING
SYSTEM
ras; gsp
BENIGN &
DTC.MTC
NUCLEAR
FACTOR
myc; fos; jun

second. effects
UNDIF.CA

1)
PRIMER
c201
236bp
BstZ1
2)
PRIMER
BstZ1
190bp
220bp
rt 201
rnut201
DNA AMPLIFICATION BY PCR
DIGESTION BY BstZ1
3)
PRIMER
106 bp PRIMER
AMPLIFICATION OF MUTANT DNA

mut201
wt201 ssDNA
wt201/mut201 nondigested 1.PCR product
FIGURE 30-3. Detection of gsp mutations at codon 201 by two-step restriction fragment length polymorphism-dependent polymerase
chain reaction (PCR). In the first step, PCR primers are used to amplify a part of the gsp gene, including codon 201, with a tota11ength of
236 base pairs (bp). This product demonstrates two restriction sites for the enzyme BstZ1, with one inside codon 201 at the 5' end and one
at the 3' end. In the second step, digesting the product with BstZl causes a new product of 190 bp in the case of wild-type (wt) gsp at codon
201 and a product of 220 bp in the case of mutated (mut) gsp at codon 201. However, parts of undigested wild-type gsp genes may still be
present, even in optimal reaction conditions. In the third step, a second PCR with the first 5' end primer and an inner 3' end primer amplifies only mutant gsp and uncut wild-type gsp, yielding a product of 106 bp. A second digestion with BstZl does not change the 106-bp
product in the case of the mutant gsp at codon 20 I, but it gives rise to an additional 60-bp product in the case of noncut wild-type gsp.
represents the biologically active protein, some Gs

mutations enhance the amount of biologically active Gs
protein.
In 1990, Lyons and coauthors-' demonstrated an activating
Gs protein mutation (i.e., mutation of the gsp gene) in an
autonomously functioning multinodular goiter, a finding
that was confirmed by Suarez and colleagues.s' Sullivan and
associates.P and our group.! Unlike pituitary tumors,
multinodular goiter and various benign and malignant thyroid tumors are polyclonalv-" and demonstrate a low level
of gsp.8 Specific techniques were applied to isolate and
amplify gsp mutations in thyroid tumors: mutation-specific
oligonucleotide hybridization of asymmetric polymerase
chain reaction products" and two-step restriction fragment
length polymorphism methods (Figs. 30-3 and 30_4).29
By correlating these results with subcloning techniques, we
demonstrated gsp mutations in 35% of all 86 investigated
differentiated thyroid cancers and C-cell carcinomas of the
thyroid (Table 30-1). The proportion of cells bearing gsp
varies between 3% and 43%.30
When sensitive molecular biologic technique's are
applied, gsp mutations can frequently be detected in differentiated thyroid tumors of patients from low-iodine areas.
Whether these results are different in tumors from patients
with sufficient iodine supplementation, as hypothesized by
us in 1992,8 awaits further investigation.
We demonstrated enhanced expression of Gs-a when the
gene is mutated (Table 30_2).30 This contrasts with the effect
of chronic external Gs stimulation. For example, cholera
toxin causes tachyphylaxis, and Gs-a expression decreases
with time." Activating mutations of the TSH-R and Gs-a
enhance basal cAMP production directly and enhance it
indirectly by the lack of downregulation and overexpression
of mutated gsp-encoded protein.
Low abundant mutation detectable

(Lane 9 and 11)
FIGURE 30-4. Two-step restnction fragment length polymorphism method. Seven thyroid tumor tissues were tested by electrophoresis before and after the second digestion of the polymerase
chain reaction (PCR)-amplified gsp gene, including codon 201.
Lane 7 shows the DNA ladder for checking the length of PCR
products. Lanes I, 3, 5, 8, 10, 12, and 14 demonstrate undigested
second PCR products of gsp with lengths of about 220 bp (upper
arrow). Lanes 2, 4, 6, 9, 11, 13, and 15 demonstrate DNA after the
second BstZI digestion, with partial digestion at lanes 2, 4, 6, 13,
and 15 but no digestion of the DNA product at lanes 9 and 11
(lower arrow). These two tissues (8/9 and 10111) harbor mutant
gsp at codon 201, but tissues 1/2,3/4,5/6, 12/13, and 14/15 do not.
The sensitivity of detecting gsp mutations at codon 201 was less
than 3% (controlled by subcloning).
Stimulating mutations of Gs-a, demonstrable in benign

(especially autonomous nodules) and malignant differentiated thyroid tumors, are important somatic mutations in
the development and propagation of thyroid tumors. The
mutations increase cAMP production and Gs-a expression,
which stimulates cellular growth.
ras Family Oncogenes

Activating point mutations in three human ras genes
(i.e., Harvey ras [H-ras] on chromosome 11, Kirsten ras
[K-ras] on chromosome 12, and N-ras on chromosome 1)
have been demonstrated in numerous tumors, including
thyroid tumors.Approximately 40% to 50% of colon cancers,
more than 80% of pancreatic cancers and cholangiocarcinomas, and 30% to 40% of lung cancers harbor specific ras
mutations.P'" Ras encodes a small protein, p21, of 21,000 D
that has no intrinsic GTPase activity. p21 forms a complex
with a GTPase-activating protein, GAP, that enhances the
GTPase activity of p21 more than 4000 times. This GAPinduced GTP hydrolysis is reduced by a factor of 1000 by
mutant ras-encoded proteins when the mutations occur at
codon 12, 13, or 61.
Although ras mutations in colon, pancreatic, and other
cancers are mainly restricted to one or two different ras
genes, some researchers dealing with thyroid tumors have
found all three ras genes (on three different chromosomes)
mutated at different sites (Table 30_3).8.35-40 Although some
groups mainly found H-ras mutations, others predominantly

demonstrated N-ras mutations (see Table 30-3). Some of
these differences may be explained by variations in methodology, with possible errors generated when only hybridization techniques were applied. Hybridization techniques can
yield false-positive and false-negative results, as demonstrated by Chen and Viola.41 Even in cases of comparable
technical procedures, results vary significantly between
groups. The prevalence of ras mutations in thyroid tumors
therefore remains questionable. Most studies have shown
that the prevalence of ras mutations was not significantly
different in benign and malignant thyroid tumors, nor was
it different in tissues from patients living in low- or highiodine areas (Table 30_4).8.30
Exposure to low-dose therapeutic radiation seems to
increase the K-ras mutations in histologically normal thyroid tissues and in tissues from thyroid tumors. Fogelfeld
and colleagues'? demonstrated an increase in K-ras mutations in thyroid tumor tissue from 0% (0 of 18 patients) to
62% (8 of 13 patients) after radiation therapy. Confirmation
of this interesting finding is pending. Nevertheless, some
of the differences in the prevalence of ras mutations in
thyroid tumors may be caused by regional differences in
environmental conditions.>' similar to aflatoxin-induced
hepatocellular carcinomas occurring in Asia but not in
Europe.
Oncogenes Acting as Growth

Hormone Receptors with
Tyrosine Kinase Activity
Thyrocyte-activating growth factors not related to the cAMP
system, such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), act by stimulating membrane
receptors with tyrosine kinase activity." These receptors by
themselves may acquire oncogenic potential through truncation of regulatory elements, producing secondary overactivity,44 or by protein overexpression after gene translocation
and rearrangement with other promoter regions. The latter
mechanism has been demonstrated for ret (ligand still
unknown) and trk products (i.e., nerve growth factor receptor) in human papillary thyroid cancer.45,46 Point mutations
of the kinase domain of ret also change this protooncogene
to an effective oncogene, causing C-cell carcinomas and
pheochromocytomas in multiple endocrine neoplasia

type 2A (MEN 2A), MEN 2B, and medullary thyroid
carcinoma (MTC).47
Epidermal Growth Factor Receptor

and Neu/HER2/Erb-B2 and coMet
EGF has been demonstrated to be one of the most efficient
growth factors for thyrocytes in vitro and in vivo in numerous experiments.w'" EGF-receptor (EGF-R) overexpression, compared with that in normal tissue from the same
patients, has been found in membrane fractions from thyroid
tumors.V-? No mutation-induced activation of EGF-R has
been demonstrated in thyroid tumors, questioning the role of
EGF-R in thyroid tumor development and propagation.
Further studies were initiated when an EGF-R-related
truncated receptor, Neu/HER2/Erb-B2, was discovered in
breast cancer patients and predicted early hematogenous
spread of tumor and a bad prognosis.P>' Few studies of neuencoded protein expression in human thyroid cancers exist,
and their results are controversial. Haugen and coworkers'"
found increased messenger RNA (mRNA) and overexpression of neu-encoded protein in 12 of 17 (71%) papillary
thyroid cancers but not in follicular adenomas (0 of 5) or

in follicular carcinomas (0 of 5). Simon and associates'?
demonstrated overexpression of neu-encoded protein in only
5 of 23 (22%) papillary tumors but in 6 of 17 (35%) follicular thyroid cancers. Studies of Lemoine" and Auguste'"
and their colleagues failed to demonstrate amplified mRNA
or overexpressed neu-encoded protein in 20 follicular thyroid cancers and 21 thyroid adenomas (Table 30-5). The
EGF-R-related oncogene neu/HER2/erb-B2 is therefore of
questionable importance in differentiated thyroid cancers.
Additional interest was generated by studies of the hepatocyte growth factor receptor (HGF-R), which is expressed
in liver tissue and in various other human tissues, including
the thyroid. The high levels of c-met mRNA in thyroid
tissues contrasts with low or undetectable HGF-R protein
expression. 59 The reason for this inhibited translation in
normal thyroid tissue is unknown. In papillary thyroid
carcinomas, HGF-R protein is expressed 100-fold more
than in normal thyroid tissue, making this protein and
its c-met gene a good candidate in the search for thyroid
oncogenes.Pv" Further studies with more tumor samples
and using thyrocyte transfection assays are needed to prove
this hypothesis.
ret and trk Oncogenes

Transfection experiments by Donghi'" and Grieco" and
their colleagues in 1989 and 1990 demonstrated a papillary
thyroid carcinoma-specific oncogene (pte) that transformed
fibroblasts (NIH 3T3 cells) into colony-forming cells. The
gene was cloned and identified as the ret protooncogene by
Takahashi and Cooper in 1985. 62 The gene was translocated
and rearranged on the same chromosome 10 to an unknown
5' sequence.P
The expression of the trk protooncogene, which codes for
the receptor for nerve growth factor, was detected in a few
thyroid carcinomas, but little other information is available.
About 30% of papillary thyroid carcinomas from patients in
Italy have a ret rearrangement, but no other thyroid tumors
from Italian patients and no nonthyroid tumors had ret
rearrangements.s'r'" Further studies of thyroid tissues from
the United States and Asia confirmed the almost complete
specificity of pte (i.e., ret rearrangement) to papillary thyroid
carcinomas, although with a prevalence of only 5% to 17%
and 0% to 3%, respectively (Table 30_6).67-69 Nevertheless,
the ret oncogene has oncogenetic potential proved by transfection assay and has tissue specificity to papillary thyroid
cancer. Whether the ret oncogene initiates the primary step
from normal thyrocyte to papillary thyroid carcinoma or
from highly differentiated papillary thyroid carcinoma to a
less differentiated tumor state is unknown.
The pte oncogene gained general interest when it was
mapped to the same region on chromosome 1Oq11-12 as the
MEN 2A gene. Studies of the tyrosine kinase domain of the
ret protooncogene by Mulligan and coworkersf'-" revealed
that specific germline mutations of ret led to MEN 2A,
MEN 2B, and familial MTC. Further investigations demonstrated somatic mutations of ret in sporadic MTC as well,
but these and the mutations in patients with MEN 2B were
located at sites of ret different from those of the mutations
identified in MEN 2A patients."
In 1994, Lips and associates.F using the same molecular
genetic techniques, documented that patients who have a ret
protooncogene mutation develop MTC and that ret-negative
patients are not at risk. Documentation of the presence or
absence of ret oncogenes is a more accurate method than
using stimulated calcitonin determinations for detecting this
disorder. It is the first molecular genetic test in thyroidology
with direct clinical importance (i.e., early thyroidectomy),
and it should save lives and money.
Intranuclear Oncogenes
Nuclear protooncogenes involved in thyroid growth are
c-myc, c-jun, and c-fos. They were characterized by their
similarity to viral oncogenes. Unlike most oncogenes
encoding cell surface receptors or signal-transducing proteins, nuclear protooncogenes function by means of gene
amplification.
Because external stimulation of cells by growth factors
activates cellular receptors, signal-transducing proteins,
second messengers, and nuclear protooncogenes by means
of increased gene expression, it is difficult to determine
whether alterations in nuclear protooncogenes are primary
or secondary cellular phenomena. For example, it is difficult
to know whether increased staining for c-mye in thyroid adenomas and thyroid carcinomas, as demonstrated by Auguste
and associates." is a primary or secondary phenomenon.
In general, c-mye and c-fos protooncogenes are expressed
after stimulation of the thyroid by TSH and cAMP, which
increase thyroid growth and differentiation. EGF and TPA
cause thyroid growth and dedifferentiation mainly by
enhancing c-jun protooncogene expression. C-fos and c-jun
expression can inhibit the thyroid hormone receptor. The
thyroid hormone receptor, however, may inhibit the induction of C-fOS 73,74 and thus play the role of an antagonist to
cell-specific protooncogenes. Understanding this direct regulatory loop of tissue-specific and growth-inhibiting intranuclear hormone receptors with intranuclear protooncogenes
may increase our knowledge of thyroid growth and tumor
development in low-iodine areas. In 1991, Heldin and
Westermark" demonstrated the loss of a specific tumor suppressor gene, which coded for a nuclear thyroid-specific transcription factor (TIFI), in anaplastic thyroid carcinomas.
Summary
Molecular biologic studies have gathered substantial information about the pathogenesis of thyroid neoplasia.
Activ~ting
mutations of the TSH-R and the signal-transducing
protem encoded by gsp have been identified in thyroid
neoplasms. These activating mutations enhance cellular
cAMP production, which stimulates thyrocyte growth.
TSH-R-activating mutations result in the development of
autonomously functioning thyroid adenomas, and activating
gsp mutations are found in benign and malignant thyroid

tumors. Activating mutations of other GTP-binding proteins,
such as the ras oncogene product p2I, have also been
detected in benign and malignant thyroid tumors. The prevalence and the distribution of H-ras, N-ras, and K-ras mutations vary considerably among studies. Different results
have also been obtained for growth factor receptors with
tyrosine kinase activity, such as EGF-R, neu (also called
erb-B2 or HER2) proteins, and HGF-R, which were found to
be overexpressed in some malignant thyroid tumors, but all
lacked any mutations or deletions that might have predicted
the altered receptors could result in thyroid neoplasia.
ret rearrangements contribute to the development of papillary thyroid cancer, and point mutations in ret cause the MEN
2A and MEN 2B syndromes and familial form of MTC.
Genetic testing is a simple and effective method for detecting
affected family members. Whether the interaction of the
nuclear thyroid hormone receptor and nuclear protooncogenes
can explain goiter development and thyroid tumors in iodinedeficient areas awaits further investigation. This exciting
research should lead to important advances in our understanding and treatment of patients with thyroid neoplasia.
Recently B type Raf kinase (BRAF) activating mutations
have been identified in papillary thyroid cancers. Raf kinase
is a key component of the Ras-+Raf--+MEK--+MAP/ERK
signaling pathway involved in cell growth and tumorigenesis. BRAF is the strongest activator of this signaling system
and is located on chromosome 7. The most frequent BRAF
mutation is a Tl796A transversion point mutation in exon
15 which causes a V599E aminoacid missense mutation
resulting in activation of BRAF kinase. 76 77 BRAF mutations
occur in approximately 35 to 70% of papillary thyroid cancers. It is not found in follicular thyroid cancer, Hurthle cell
cancer, or benign thyroid adenomas, and occurs in about
20% of anaplastic thyroid cancers.Y'? There does not
appear to be any overlap between BRAF, RETIPTC and ras
mutations in papillary thyroid cancers.
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Thyroid Oncogenesis
Genetic alterations are the cornerstone of carcinogenesis.

Genetic changes can be due to hereditary predisposition,
acquired from viral infections (viral oncogenes), and result
from environmental exposures to external or ionized radiation or even from chronic inflammatory conditions. The resulting genetic alterations ultimately lead to "transformation" of
the cell toward a state of uncontrolled cell growth, disrupted
normal cellular differentiation or apoptosis, and an invasive
and metastatic cellular phenotype.
The multistep hypothesis of carcinogenesis has been the
framework on which genetic alterations have been investigated. 1The accumulation of multiple genetic events results in
the developmentof cancer (Fig. 31-IA).1.2 These genetic modifications can be point mutations (single base pair changes),
insertions, deletions, rearrangements, or translocations. When
such genetic changes occur, they can lead to an oncogene,
which can function in a dominant or recessive manner. An
oncogene has the potential to induce or unsuccessfully suppress oncogenesis. A protooncogene is a gene that regulates
cellular growth and/or cell differentiation that, when altered
or amplified, leads to the development or progression
of a neoplasm ("dominant" or "gain of function" genetic
change). The functional products of protooncogenes have
been classified at the cellular level as (I) growth factors,
(2) membrane or intracellular receptors, (3) signal transduction system proteins, and (4) nuclear transcriptional activators
or inhibitors. In contrast to dominant or gain of function oncogenes, tumor suppressor genes function to control cellular
growth, but in a recessive fashion. The loss of function of the
tumor suppressor gene product leads to unregulated cellular
growth. Protooncogenes and tumor suppressor genes can
occur as germline or somatic genetic mutations.
The integrated study of molecular biology, epidemiology,
embryology, physiology, and clinical medicine has led to
significant advances in our understanding of oncogenesis.
Many investigators have helped provide insight into the
genetic mechanisms involved in thyroid tumorigenesis and its
potential for clinical application in determining the prognosis
of patients with thyroid cancer and in identifying individuals
at risk of developing thyroid cancer. A working oncogenesis
model has been proposed for thyroid cancers of follicular cell
288
origin (Fig. 31-lB).3 The main genetic abnormality (germline

RET protooncogene point mutations) that occurs in the less
common thyroid cancer of parafollicular cell origin

(medullary thyroid cancer) is well characterized and has led
to earlier screening and treatment of patients with hereditary
medullary thyroid cancer (see Chap. 15). This has translated
into improved patient outcome." This chapter discusses
our current knowledge of oncogenesis in follicular cells of
the thyroid, a working model for thyroid carcinogenesis, and
the potential clinical applications of these findings. The
important growth factors and signal transduction factors
that also influence the initiation or progression of thyroid
neoplasms are discussed in Chapters 28 and 29.
Oncogenesis in Thyroid Cancers

of Follicular Cell Origin
Oncogene Receptor Proteins
THYROID-STIMULATING HORMONE RECEPTOR
The thyroid-stimulating hormone (TSH) receptor is a

transmembrane glycoprotein that is G protein coupled. TSH,
acting through its receptor, is the main regulator of thyrocyte function and growth. Its function is mediated via
the adenylate cyclase and phospholipase C intracellular
pathways.' Constitutively activating mutations in the TSH
receptor occur in the transmembrane segment and intracytoplasmic loop in hot thyroid nodules (""30%) but are usually absent in cold thyroid nodules or thyroid cancers
(Table 31_1).5-10 Unfortunately, the frequency of TSH
receptor-activating mutations observed in hot thyroid
nodules has been variable, ranging from 3% to 82%.5-12 This
discrepancy is likely due to several factors such as small
sample size, screening of only part of the TSH receptor
gene, less sensitive screening techniques (single-strand
conformation polymorphism), inaccurate characterization
of thyroid nodule function, and the quality of DNA in tissue
samples studied.P In general, TSH receptor-activating
mutations lead to some benign hot nodules but not to malignant thyroid neoplasms or cold thyroid nodules. 13
Thyroid Oncogenesis - -
289
Mitosis, accumulation of genetic

alterations leading to unregulated
proliferation and differentiation
"
,,'
"
<Jl
c:
~
ell
o
~
c:
__
~--------------------;
..
///~
(])
.------
"
<!l
Progression from normal cell toward a dedifferentiated state and uncontrolled growth
-----
TSHR
gsp
raa
Normal
follicular
thyroid cell
PTEN
fos
........
..............."<:':..: .~
----~==:===::::--------
p53
PAX8/ PPARy
Anaplastic
thyroid cancer
~ ::::::
---
......
----------------
p53
Growth factors and signal transduction protein also influence the

initiation and/or progression of thyroid neoplasm
EGF
TGF~----.
IGF
B
FIGURE 31-1. A, General multistep theory of genetic alterations in carcinogenesis. B. The genetic events that occur in thyroid oncogenesis
(the main genetic events are in bold). The dashed lines for each histologic type of thyroid cancers indicate that an adenoma-to-carcinoma
progression is not necessarily always the sequence of progression in carcinogenesis. PTC = papillary thyroid carcinoma; FfC = follicular
thyroid carcinoma; HCC = Hiirthle cell carcinoma; EGF = epidermal growth factor; TGF~ = transforming growth factor beta; IGF =
insulin-like growth factor; TSH-R = thyroid-stimulating hormone receptor.
Tyrosine Kinase Receptors

Tyrosine kinase receptor proteins are a well-recognized
group of oncoproteins that are implicated i~ several hu~an
cancers and include almost 50 receptor protems. The tyrosme
kinase genes classically encode a transmembrane recep~or
~rotein. Ligand binding to the tyrosine kinase leads to actrvation,
dimerization of the receptors, and then transphosphorylation
of tyrosine kinase residues, with downstream activation of
the tyrosine kinase genes. Several tyrosine kinase gene alterations are implicated in thyroid carcinogenesis; RET/PTC,
TRK, c-erb-2 and met activate thyrocyte growth through a
cyclic adenosine monophosphate-independent system.
RETIPTC ONCOGENE
The RET/PTC protooncogene maps to chromosome 10qll.2,

and five activating chromosomal rearrangements have
been characterized.l-" The RET/PTC chimeric genes have
been designated RET/PTC] to RET/PTC5. 15 Permanent activation of the tyrosine kinase results from the 5' foreign genes."
The five foreign genes fused to the RET tyrosine kinase
domain occur almost exclusively in papillary thyroid cancer
(see Table 31-1). The frequency of RET/PTC activating
somatic mutations in sporadic papillary thyroid cancer is
variable, ranging from 2.5% to 85%.2.17-30 This wide ran~e
in the prevalence of the RET/PTC rearrangement genes m
papillary thyroid cancer may be due to geographic variation,
the age of patients studied, or the sensitivity of experimental
techniques employed or a consequence of ionized radiation
or external radiation exposures.P'" For example, in thyroid
neoplasms associated with the Chernobyl accident, 55% to
85% of the thyroid cancers had RET/PTC rearrangement
oncogenes, and only a few were observed in follicular
adenoma.19,21.23,26 RETIPTC3 was the most common rearrangement identified in association with radiation exposure. 16.23 The
reason for the difference in distribution of the RET/PTC
Thyroid Oncogenesis - - 291
chimeric subtype genes and its relation to radiation exposure

remains unclear. The RET/PTC rearrangement genes have
been identified in occult papillary thyroid cancer; therefore,
it is considered to be an early event in the formation of papillary thyroid cancer.'? Some investigators have found that
the presence of RET/PTC in patients with papillary thyroid
cancer is associated with young age, radiation exposure, and
lymph node metastasis but not distant metastasis. 17,26,28,29
TRK ONCOGENE
The TRK protooncogene is located on chromosome lq2l-22. 32

TRK encodes for the receptor for nerve growth factor and
results from chromosomal rearrangements.P> This chimeric
gene is ubiquitously expressed and results in a constitutively
activated tyrosine kinase protein. Four chimeric genes have
been identified: three intrachromosomal rearrangements
(TRK, TRK-Tl, and TRK-T2) and one interchromosomal
rearrangement (TRK-T3). The TRK protooncogene occurs
infrequently in papillary thyroid cancer (6% to 20%) and
has been detected in patients with and without radiationassociated papillary thyroid cancers (see Table 31_1).32-34
MET ONCOGENE
Hepatocyte growth factor (scatter factor) binds the MET

transmembrane tyrosine kinase receptor.P Activation of the
MET receptor promotes a mitogen response, cellular motility, and cellular mvasion.F-" In normal cells, MET activation is a ligand-dependent transient event, whereas in tumor
cells MET activity is often constitutively upregulated.A'"
MET is overexpressed in about 75% of papillary thyroid
cancers and poorly differentiated cancer and in only 22% of
follicular thyroid cancers. 38-40 MET overexpression may be
associated with tumor multicentricity and less tumor angiogenesis in papillary thyroid cancer. 39,4O In contrast, absent
or low MET expression in papillary thyroid cancer has been
associated with a higher risk of distant metastasis."
Although results are discrepant, it is possible that MET
plays a role in the progression of thyroid cancers to an
aggressive phenotype and probably occurs as a late event,
because MET is overexpressed in more aggressive thyroid
cancers. 38,41.42
c-erb-2 ONCOGENE
The c-erb-2 oncogene (also referred to as HER and neu)

encodes a transmembrane glycoprotein with tyrosine kinase
activity." This epidermal growth factor (EGF) receptorrelated protein is truncated and has been demonstrated to be
predictive of prognosis in several human cancers.tv"
Because EGF, acting through the EGF receptor, is an
important regulator of thyroid cell growth, several groups
have studied c-erb-2 oncoprotein expression in thyroid
cancers. 45-48 The role of c-erb-2 in thyroid tumorigenesis is controversial. Some investigators have found that
the c-erb-2 protein is overexpressed in papillary thyroid
cancer but not detected in follicular adenoma, follicular carcinoma, medullary carcinoma, and anaplastic carcinoma."
Overamplification or rearrangement of the c-erb-2 oncogene has not been demonstrated in either benign or malignant thyroid neoplasms.f-" Therefore, it remains to be
determined if the c-erb-2 oncoprotein is an important factor
in thyroid tumorigenesis.
Activating Oncogene G Proteins

ras Oncogene
The ras oncogene encodes a 21-kd protein (p21) that functions in signal transduction from receptor proteins belonging
to the tyrosine kinase family of receptors. Three ras proteins
(H, K, N) exist in an active state when they are anchored to
the inner membrane and bound to guanosine triphosphate
(GTP) and in a resting state when they are bound to guanosine diphosphate (GDP). Activating point mutations in the
ras oncogene commonly occur in codons 12 and 13 in the
GTP-binding domain and in codons 59 and 61 in the guanosine triphosphatase (GTPase) domain." Mutations in the ras
gene result in growth stimulation and the inhibition of differentiation in thyrocytes. The three ras oncogenes in thyroid
tumors are randomly distributed and have a similar frequency
(7% to 92%,30% overall) (see Table 31-1). Although the ras
oncogenes are the most common genetic alteration reported
in thyroid neoplasms, there have been some discrepancies in
the frequency of ras mutations observed in several different
studies.50-55.55.55b It has been suggested, but not established,
that the amount of iodine intake, external radiation exposure, experimental techniques used, and demographic differences might account for this discrepancy. Transversion point
mutations may be associated with radiation-associated thyroid tumors.50 Since most investigations suggest that ras
mutations occur in similar frequencies in benign thyroid
adenomas and thyroid cancers, it appears that they occur as
an early genetic event in thyroid carcinogenesis. Some
investigators have also suggested that ras mutations may be
associated with a poor prognosis in patients with papillary
thyroid cancer. 56
gsp Oncogene
The stimulatory GTP-binding protein (gsp) participates in
the TSH signal transduction pathway by mediating the stimulation of adenylate cyclase. Activating point mutations in
the stimulatory G protein gene (commonly in codons 201
and 227) result in the gsp oncogene. The gsp oncoprotein
has decreased GTPase activity and leads to a G protein that
is constitutively activated, which results in high adenylate
cyclase activity. Point mutations in the inhibitory G protein
gene also result in high adenylate cyclase activity.57 Similar
to TSH-activating mutations, the gsp oncogene has been
detected mostly in hot thyroid nodules (7% to 28%) and less
frequently in nonfunctioning thyroid adenomas and thyroid
cancers (see Table 31_1).8.10.12,13,58 The overall low prevalence
of the gsp oncogene in hot thyroid nodules suggests that other
genetic alterations such as TSH receptor mutations are
responsible for most hot thyroid nodules. 58. The simultaneous
occurrence of gsp and ras mutations may be associated with
more aggressive papillary and follicular thyroid cancers.P
Nuclear Oncogenes
Nuclear protooncogene proteins such as myc, jun, and
fos have also been evaluated in thyroid tumorigenesis.

Most investigators have found that c-myc and c-fos are

overexpressed in benign and malignant thyroid neoplasm.v-"
Although c-myc expression has been demonstrated to be a
marker of aggressiveness in certain human cancers, this has not
been consistently observed in thyroid cancer. 59-62 The N-myc
oncogene expression is highest in thyroid cancer cell lines and
in undifferentiated thyroid cancers. Most Hiirthle cell cancers (up to 100%) are positive for N-myc by immunohistochemistry, whereas only 17% of follicular thyroid cancers
are N-myc positive.F
Although the nuclear oncogenes are overexpressed in
thyroid neoplasms at the messenger RNA and protein levels,
no gene amplification of the c-myc and c-fos oncogenes has
been observed in benign or malignant thyroid tumors.r"
Therefore, it is unclear if increased nuclear protooncogene
expression occuts as a primary event or secondarily to external
stimuli activating cell receptors or signal transduction proteins upstream. Nonetheless, the c-myc and c-fos oncogenes
probably playa role in thyroid carcinogenesis.
PAXB-PPARy1
The PAX8-PPARyl oncogene results from chromosomal
translocation t(2;3)(q13;p25). This leads to fusion of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PAX8-PPARyl).63
This finding was recently reported and its expression characterized in thyroid tissues.P The fusion protein was
detected only in follicular thyroid cancers but not in papillary
thyroid cancer, follicular adenoma, or multinodular goiter.v'
This novel finding needs confirmation in a larger sample
size but corroborates the cytogenetic findings that suggest a
putative tumor suppressor gene on chromosome 3p was possibly specific to follicular thyroid cancer."
Tumor Suppressor Genes

p53
The p53 tumor suppressor gene is one of the most common
genetic alterations observed in human cancers. The p53
gene, located on chromosome 17p 13, encodes a 53-kd
nuclear phosphoprotein and functions as a key cell cycle
regulator. p53 mutations lead to altered protein conformations that are nonfunctional and accumulate in the cell
nucleus. A p53 mutation needs to occur in only one allele to
lead to deregulated cellular growth. Most p53 gene mutations (98%) occur in exons 5 through 8. 64a p53 mutations are
primarily present in poorly differentiated and undifferentiated thyroid cancers and in immortalized thyroid cancer cell
lines (see Table 31_1).55.65-68b Radiation exposure may result
in p53 point mutations.P" Increased p53 immunostaining
may be useful in predicting the aggressiveness of thyroid
Some investigators have observed mutant Rb alleles in

thyroid cancer (~55%),
but no Rb mutations have been
reported in benign thyroid tumors. 71-73 The role of the
Rb protein in thyroid oncogenesis remains unclear, and the
discrepant reports may be due to experimental techniques
employed.
APe
The tumor suppressor adenomatous polyposis coli (APC)
gene has been established as the predisposing gerrnline
mutation for familial adenomatous polyposis coli (FAP). It
has been speculated that the APC gene may play a role in
thyroid tumorigenesis because of the increased incidence of
thyroid cancer in patients with FAP (Gardner's syndrome)."
No mutation of the APC gene has been observed in benign,
malignant, or normal thyroid tissue. 74.75 The APC gene probably does not playa significant role in thyroid cancers of
follicular cell origin.
MTS-1 and MTS-2

The multiple tumor suppressor (MTS)-l (p161NK4A) and
MTS-2 (p15INK4B) genes regulate cell cycles. Loss of function of p15INK4b and p16INK4a results in impaired control
of the cell cycle and contributes to the transformation of several cell types." Although it has been commonly observed
in a variety of human cancers, altered p15INK4b and
p16INK4a genes in thyroid neoplasms primarily have been
found in immortalized thyroid cancer cell lines and not in
thyroid tumors.Y" Therefore, the p15INK4b and p 16INK4a
tumor suppressor genes do not appear to play a significant
role in thyroid oncogenesis or may represent a late event.
PTEN
PTEN (MMAC or TEPI) is a tyrosine phosphatase protein
located on chromosome lOq23.3 and has a tumor suppressor
effect by antagonizing tyrosine kinase activity."? PTEN is
responsible for Cowden's syndrome.t" Cowden's syndrome is
an autosomal dominant hereditary syndrome characterized by
formation of hamartomas in several organs and an increased
risk of thyroid and breast cancer," Because Cowden's syndrome is associated with an increased risk of thyroid cancer,
the PTEN tumor suppressor gene has been studied in thyroid
tumors. PTEN gene mutations have been identified mostly
in benign thyroid adenomas (26%) and infrequently in thyroid cancer of follicular cell origin (6%).81 This would suggest that the PTEN tumor suppressor gene does not play a
significant role in malignant thyroid tumor and questions the
progression of thyroid adenoma to thyroid cancer.
cancers."?
Summary
Rb
Our understanding of the genes and genetic changes involved

in the pathogenesis of thyroid neoplasms has increased
greatly in the last decade. Some of the genetic changes have
been consistently demonstrated and are specific to certain thyroid cancers. On the other hand, investigators have reported
discrepancies in the frequency of some of the protooncogenes
The retinoblastoma gene is located on chromosome 13q14

and encodes a 11O-kd nuclear phosphoprotein (Rb). The Rb
protein also regulates cell cycle progression. Rb mutations can
occur as germline or somatic mutations in various tumors.
Thyroid Oncogenesis - - 293
and tumor suppressor genes, most likely due to different

experimental techniques. The reported prognostic importance
of the many oncogenes studied to date needs to be confmned.
Molecular prognostication can lead to better selection of
patients with thyroid cancer who would benefit from postoperative radioactive iodine therapy or thyroid hormone suppression therapy.
It is well established that activating TSH receptor mutations
and gsp oncogenes leads to toxic thyroid nodules, but other
unidentified genes probably also playa role. The ras oncogene is an early event in thyroid tumorigenesis and could
be a predictor of tumor aggressiveness. The altered function
or deregulated expression of the tyrosine kinase receptors
(RETIPTC, TRK, c-erb-2, and met) in thyroid cancer may
provide a useful molecular therapeutic target gene for patients
who do not respond to conventional therapy (e.g., tyrosine
kinase inhibitors). It is certain that if the commitment and
breadth of the research effort continue in thyroid oncogenesis, a fruitful result in regard to more accurate prognostication, diagnosis (e.g., preoperative differentiation of thyroid
follicular adenoma from follicular carcinoma), and molecular
gene treatment targeting will result in even better outcomes
for patients with thyroid cancer of follicular cell origin.
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Cancer Res 1997;57:4710.
Mechanisms and Regulation of

Invasion in Thyroid Cancer
Michael W. Yeh, MD Michael J. Demeure, MD Kevin Packman, MD
The management of invasive and metastatic disease represents the single greatest challenge in the treatment of cancer
today. I Although most differentiated thyroid cancers are
adequately treated with surgical resection and radioiodine
therapy, poorly differentiated and undifferentiated cancers,
whose behavior is characterized by aggressive local invasion
and metastasis, are often lethal.' Furthermore, metastatic
foci of differentiated thyroid cancer frequently fail to take
up sufficient quantities of radioiodine to be successfully
ablated.' Because conventional chemotherapy and radiotherapy have yielded disappointing results in the treatment
of aggressive thyroid cancers.v' new strategies for inhibiting
tumor growth, invasion, and angiogenesis (itself an invasive
process) are needed.
Thyroid nodules are a common problem, affecting
roughly 4% of the U.S. population. Fine-needle aspiration,
which has emerged as the single most useful test in the evaluation of nodular thyroid disease, is useful in distinguishing
between benign and malignant growths in most cases,"
Difficulty arises in the work-up of follicular and Hiirthle cell
neoplasms, which can currently be diagnosed as malignant
only after permanent pathologic examination reveals capsular or vascular invasion, or both.? Similar issues arise in the
management of adrenal neoplasms and neuroendocrine
tumors of the gastrointestinal tract. s.s Because only about
15% offollicular thyroid neoplasms are eventually proved to
be malignant, many patients undergo surgery unnecessarily.
Thus, it is hoped that an increased understanding of the invasion process in follicular thyroid cancer (FTC) may allow
the development of reliable cytologic or molecular indicators of tumor behavior.
Histologically, invasion through the epithelial basement
membrane marks the progression from carcinoma in situ to
carcinoma. The invasion process is thought to involve at
least three major components: (1) adhesion to the extracellular matrix, (2) proteolysis of the collagen barrier, and
(3) migration into adjacent tissues (Fig. 32-1).9 These steps,
however, are interlinked and inseparable. A number of intracellular and extracellular signaling molecules have been
implicated in the positive and negative regulation of invasive
behavior. These molecules have also linked the regulators
and effectors of invasion to the related processes of inflammation and angiogenesis.P'F This chapter is intended to
describe some of the many cellular mechanisms that appear
to be associated with invasion in thyroid cancer and human
cancers as a whole.
Cytoskeleton: Structure
and Function
In many ways, the cytoskeleton is analogous to the skeleton
of the human body in that it provides form and shape to the
cell, but its function is much more complex. It is important
in cell movement, cell division, adhesion, and communication with other cells and extracellular matrix as well as the
regulation of many intracellular processes. The cytoskeleton
is composed of filamentous structures generally classified
according to size, including microtubules (22 nm), intermediate filaments (8 to 10 nm), and microfilaments (7 nm).
Microtubules
Microtubules are composed primarily of tubulin, a 55-kd
protein. In its polymerized form, tubulin forms a microtubular network radiating from the perinuclear region of the
cell. This network is important in regulating and maintaining the location of endoplasmic reticulum and Golgi apparatus within the cell. During cell division, microtubules are
rapidly organized as part of the mitotic spindle. During
the transition from metaphase to anaphase, duplicated
chromosomes are pulled apart by contracting spindle microtubules toward the centrosomes of each daughter cell.
Anticancer drugs such as vincristine and vinblastine inhibit
the formation of microtubules and are hence thought to be
antimitotic. One additional function of the microtubules is
that they are important in cellular distribution of intermediate filaments and cortical actin filaments. Disruption of the
microtubules of cultured cells by colchicine, however, does
not necessarily prevent cell locomotion, which seems more
dependent on the actin microfilaments.
295
FIGURE 32-1. Schematic depicting the multistep process of cancer

cell invasion through the basement membrane. Cells must separate
from their primary tumor mass and then degrade a basement membrane barrier to allow infiltration.
Intermediate Filaments
Intermediate filaments are composed of different types of
proteins, depending on the type of cell, that form relatively
stable polymers.P Cytokeratins are specific to epithelial cells,
whereas vimentin is found in mesenchymal cells, desmin in
muscle cells, and glial fibrillary acidic protein in neural
cells. Because specificity is maintained after transition to
malignancy, anaplastic-appearing tumor cells may often be
characterized by immunohistochemistry using antibodies
recognizing specific intermediate filament proteins. Closely
related to the microtubule system, intermediate filaments
form a delicate network surrounding the nucleus that extend
into the cytoplasm toward the cell periphery. In epithelial cells,
keratin intermediate filaments join with the cell membrane
at desmosomes, which are specialized junctions between
adjoining cells. As such, intermediate filaments are thought
to provide structural integrity and tensile strength to epithelial membranes. Experiments with mouse and rat tumor cell
lines suggest that enhanced expression of intermediate filaments may be related to the ability of tumor cells to invade
and merastasize.P:"
Actin Microfilaments
The actin cytoskeleton is important in determining and maintaining cell shape and polarity but is also known to be involved
in a diverse array of other cellular functions, including the
transmission of intracellular signals and protein synthesis
by the sorting of messenger RNA (mRNA)P The actin
cytoskeleton interacts with the cell surface membrane at multiple levels, including junctional complexes, apical microvilli,
cellular adhesion molecules, and integrins. Microfilaments
are composed primarily of actin. In a fully polymerized
state, actin forms stress fibers anchoring a cell to its matrix
through adhesion plaques. Cells interact with their matrix
through heterodimeric receptors, consisting of an a and a
~ subunit, known as integrins. The prototypic adhesion
plaque is composed of an a5~1 integrin (fibronectin receptor)
interacting with talin, vinculin, o-actinin, and capping proteins. This assembly forms the attachment point for one end
of an actin stress fiber. These focal contacts are sites of communication of the cell with its external environment.
The loss of actin stress fibers has been associated with oncogenic transformation and increased metastatic potential.
Abnormally low cellular levels of F-actin have been suggested
as a marker of transformation in human bladder tumors." A
disordered actin microfilament architecture has been associated
with increased metastatic potential in several tumor models,
including murine melanoma and fibrosarcoma models.P-" A
loss of order in the actin microfilament architecture has also
been observed as a late phenomenon in the progression of
human colonic polyps to cancer," Mutated forms of actin have
been shown to either increase or decrease metastatic potential.
Transfection of a mutated form of ~-actin
with the substitution
of a leucine for an arginine at position 28 reduces the metastatic potential of highly aggressive murine B16 melanoma
cells." These cells developed organized actin stress fibers,
were less motile in vitro, were less invasive in collagen gels,
and produced fewer lung metastases in mice after tail vein
inoculation. On the other hand, transformed HUT-14 human
fibroblasts, which express a mutant actin with a single amino
acid substitution at position 244, resulted in fewer actin filaments and enhanced invasiveness.P
The actin system is dynamic in locomotion and in transmitting cellular signals. Cells migrate by advancing a leading
edge. Motile cells have polarity, with a leading edge exhibiting
microspikes and lamellipodia, both of which are dependent on
actin filaments. Cell movement is associated with rearrangement of actin architecture at the advancing cell border by actin
polymerization and depolymerization.s' When two migrating
cells come in contact, advancement of the leading edge immediately stops. This inhibition of locomotion is thought to
be mediated by a rapid alteration in the actin-based cortical
cytoskeleton. The actin cytoskeleton has been linked to
chemotactic receptors associated with G proteins and cyclic
adenosine monophosphate (cAMP),25 and in response to a
chemotactic stimulus, increased cellular cAMP promotes
F-actin assembly.-"
Thyrotropin has been shown to induce stress fibers in
cultured thyroid cancer cells.'? Just how perturbations in
actin structure and function affect thyroid cancer growth
and behavior is not known but is an exciting area for investigation. Most work on thyroid-stimulating hormone (TSH)
effects has centered on its ability to induce thyrocyte growth.
Perturbation of cell growth control results in tumors, but
tumorigenicity is independent of metastatic phenotype."
Because not all tumors have the ability to invade and metastasize, it follows that the cellular characteristics related to
invasion such as matrix attachment, protease production, and
locomotion are under separate control from the cell properties
regulating growth.
Cell-Extracellular Matrix and

Cell-Cell Contacts
A prominent feature of carcinomas is the uncontrolled
growth of epithelial cells. Contact inhibition of growth and
replication of epithelial cells is dependent on anchorage to
Mechanisms and Regulation of Invasion in Thyroid Cancer - - 297
underlying substratum. The progression of tumors from a

benign to a malignant state is thought to be associated with
diminished cell-cell adhesion and a loss of contact inhibition
of growth.i? Normal epithelial cells are polarized and have a
limited ability to move because they are anchored to a basement membrane by integrins and to neighboring cells by
cadherins.'? Generally, cell locomotion is inversely related
to the number and extent of focal adhesion plaques." Invasion
and tumorigenicity also seem to be inversely related to the
number and integrity of adhesion contacts.
Integrins and Malignancy

There is extensive interest in the cellular receptors for key
matrix components because of the interaction of tumor cells
with the extracellular matrix. These extracellular matrix
receptors, which span the cellular membrane and interact with
the actin cytoskeleton, are known as integrins (Fig. 32-2).
Integrins make up a family of glycoproteins that generally
exist as heterodimers, consisting of an a and a ~ subunit.
The 18 a subunits and 8 ~ subunits that have been identified
can exist in a number of combinations, each with a different
binding specificity. Several studies have shown that malignant change is associated with significant alterations in the
quantity, distribution, and type of integrins expressed on the
cell surface.P This has perhaps been best demonstrated in
Actin microfilaments
a-Actinin
Cell membrane
FIGURE 32-2. Schematic depicting organization of an integrinmediated adhesion plaque. Association with the actin cytoskeleton
and tyrosine phosphorylation-signaling proteins is demonstrated.
Such adhesion plaques are thought to be activated by engagement
of the integrins with extracellular matrix.
melanoma, where the onset of <Xv~3 integrin expression on the

invasive front is closely correlated with vertical invasion and
increased metastatic potential.F Likewise, upregulation of the
laminin-specific Ut;~4
integrin correlates with progression
from a benign to malignant phenotype in several cell types,
including those of thyroid origin.P Transformed cells commonly express markedly diminished levels of a5~1
fibronectin receptor but may exhibit increased levels of the
a3~1
integrin, which under certain conditions may also function as a fibronectin receptor." This observation corresponds with the finding that increased expression of the
a5~1
integrin receptor resulting from a transferred gene
reduces cell migration.P In some cells transformed by ras or
tyrosine kinase oncogenes, there is diminished expression
of the a 5 integrin subunit (fibronectin receptor).34.36.37 Our
laboratory reported this type of derangement in cultured
human FTC cells. Highly invasive clones of the FTC cell
line exhibited diminished expression of the a5 subunit of
the integrin fibronectin receptor relative to a less invasive
clone. Fibronectin production, on the other hand, was not
diminished.Fr"
Focal adhesion kinase (FAK) is an intracellular tyrosine
kinase that becomes phosphorylated and activated in
response to integrin binding of extracellular matrix ligands.
FAK is thought to be one of the major mechanisms by which
integrins influence intracellular signaling pathways that
control cell motility, growth, and survival. Invasive and
metastatic tumors of the colon, breast, prostate, and thyroid
are known to overexpress FAK. 39,40 Unlike normal cells,
which depend on appropriate contact with the extracellular
matrix in order to survive and proliferate, neoplastic cells
are capable of growing under anchorage-independent conditions. FAK may confer this property upon neoplastic cells,
as evidenced by the fact that its overexpression can rescue
epithelial cells from apoptosis in an anchorage-independent
environment." Cells derived from FAK-null mice display
impaired migration and a decreased ability to remodel contacts with the extracellular matrix.f
Cadherins and Catenins

Cadherins make up another major group of adhesion molecules involved in cell-cell and cell-matrix interactions.
E-cadherin, a subtype associated with epithelial tissues,
forms contacts with cadherin molecules on nearby cells in a
calcium-dependent fashion that has been described as a cell
adhesion "zipper."43 This process is also dependent on a
series of interactions between E-cadherin and a family of
intracellular proteins called catenins (Fig. 32-3). Catenins,
which include n-catenin, ~-catenin,
y-catenin, and pl20ctn,
bind the intracellular domain of cadherins to the actin
cytoskeleton.r'
Several distinct lines of evidence suggest that loss of cadherin expression is a critical step in cancer development and
progression. It has long been thought that the disruption of
normal cell-cell adhesion in transformed cells is a major
contributor to the invasive phenotype. The observation that
E-cadherin expression was diminished or lost in many
human cancers led to studies suggesting that alterations in
cadherin or catenin function played a causative role in promoting invasion. Gerrnline mutations in CDR] (the gene

Cell membrane
==
E-cadherin~s~~~~
Catenins
FIGURE 32-3. Demonstration of the cell-cell adherens junction
mediated by E-cadherins. Interaction with the actin cytoskeleton is

mediated by a complex that includes catenins and other, as yet
uncharacterized proteins. a-Actinin serves as an actin cross-linking
protein.
encoding E-cadherin) confer a high risk for certain types of

gastric cancer," and somatic mutations in CDHI have been
detected in malignancies of the breast, ovary, endometrium,
and stomach. Both transcriptional repression of CDHI and
hypermethylation of the CDHI promoter have been found
in several tumor types, supporting the idea that loss of
E-cadherin expression contributes to malignant change.t"
Treatment of normal epithelial cells with anti-E-cadherin
antibodies has been shown to induce invasive behavior,
whereas transfection of wild-type E-cadherin into neoplastic
cells was seen to suppress invasion.f"
A few reports exist on the potential association of
E-cadherin expression in thyroid neoplasms. When studied
using immunohistochemistry and Northern blot analysis,
normal thyroid tissue and cells from benign thyroid disorders such as goiter or follicular adenomas exhibit high levels
of E-cadherins, whereas anaplastic thyroid cancers exhibit
very low or no E-cadherins. The expression of E-cadherins
in recurrent thyroid cancers or in tumors with known metastases, regardless of the histologic type, was found to be low
or negligible.t? Another more recent report corroborates these
findings in that patients with tumors expressing low levels
ofE-cadherin were more likely to acquire metastatic disease
than those whose tumors expressed normal levels of
E-cadherin. 5o Notably, hypermethylation of the CDHI promoter was found in more than 80% of papillary thyroid
cancer cell lines tested in one study. A significant portion
of follicular, Hiirthle cell, and poorly differentiated carcinomas were similarly affected."
~-Catenin
alterations in cancer have been extensively
studied as a result of their close association with colorectal
carcinogenesis. Highly penetrant germline mutations in the
adenomatous polyposis coli (APe) gene were found to
cluster at a region of the gene responsible for the binding
and degradation of ~-catenin.
52 As mentioned earlier,
catenins playa critical structural role in cells by linking cadherins with the actin cytoskeleton, allowing the formation of
stable and functional adherens junctions. This interaction is
regulated in part by tyrosine phosphorylation of ~-catenin,
which causes separation of the cadherin-catenin unit and an
increase in the quantity of free ~-catenin
in the cytosol.
Epithelial cell migration has been shown to be dependent on

this process, which has the general effect of decreasing cellcell adhesiveness." Activation of receptor tyrosine kinases
belonging to the erb-B family and others (discussed later) is
known to trigger ~-catenin
phosphorylation.
Because inactivating ~-catenin
mutations have not been
consistently found in human cancers, focus has turned to
post-transcriptional events affecting catenin function, particularly in regard to its important role in signal transduction.
The current body of evidence suggests that ~-catenin
exists
in two distinct pools, one involving cellular adhesion and
another involving gene transcription through the Wnt pathway, which plays a crucial role in normal embryonic development. Wnt binding at the cell surface results in an increase
in free ~-catenin,
which translocates to the nucleus and activates the lymphoid enhancer factorff-cell factor (LEFffCF)
family of DNA binding proteins. These, in tum, activate a
number of genes promoting cell growth and invasion, such
as c-MYC,54 cyclin Dl,55 matrix metalloproteinase-L'" and
a growing list of other candidates. As much of the data
regarding ~-catenin
signaling is quite recent, much about the
role of this pathway in cancer development and progression
remains poorly understood.
Some cross-talk between the two pools of ~-catenin
is
thought to occur. An excess of E-cadherin can interfere with
LEFffCF signaling by sequestering ~-catenin,57
and high
levels of Wnt activity can occupy sufficient quantities of
~-catenin
to remove it from its role in cellular adhesion."
This begs the question of whether the inactivation of
E-cadherin and loss of cell-cell adhesion, with resultant
increases in free cytosolic ~-catenin,
are sufficient to stimulate LEFffCF transcription. As it turns out, E-cadherin
loss is not sufficient to have such transcriptional effects.l?
suggesting that a degradative pathway exists to limit excess
~-catenin
accumulation.
Proteases in Tumor Invasion

Proteolysis of extracellular matrix components is thought to
be an essential component of tumor invasion. Derangements
in the expression and activity of proteases have been found
in almost every malignancy studied, strongly implicating
them as causative agents in malignant progression. Several
classes of proteases capable of degrading the collagens, glycoproteins, and proteoglycans that make up the extracellular
matrix have been identified, including matrix metalloproteinases, serine proteases, carboxyl proteases, and glycosidases. Research to date suggests that the former two classes
play the most significant role in carcinogenesis.
In humans, matrix metalloproteinases (MMPs) make up
a family of at least 21 zinc-dependent enzymes that, collectively, are capable of degrading all components of the basement membrane (Table 32-1). MMPs are generally released
in an inactive form and require cleavage in the extracellular
space in order to gain full activity. Upregulation of MMPs
has been widely found in human malignancies and correlates with advanced tumor stage, increased invasion and
metastasis, and poor prognosis." In animal studies, minimally invasive cells can acquire malignant characteristics
when MMP expression is elevated." Conversely, highly
invasive cells can be rendered more quiescent when MMP

expression is reduced or when endogenous inhibitors of
MMPs (tissue inhibitors of metalloproteinases, TlMPs) are
overexpressed.P MMP-2 and MMP-9 have received particular attention in the cancer literature because of their ability to
degrade type IV collagen, the principal component of the
extracellular matrix. Membrane type 1 MMP (MTl-MMP),
the first identified member of the membrane-associated
MMPs, is also of special interest because of its role in activating pro-MMP-2. Indeed, elevated levels of MMP-2 have
been found in thyroid cancer homogenates, as has a positive
correlation between MMP-2 activation and the presence of
lymph node metastases.P
MMPs and their cleavage products have been shown to
play important roles in the regulation of cell growth and survival, angiogenesis, and the immune response to cancer.
Small molecules released by proteolysis have been demonstrated to have potent biologic effects in both normal tissue
and the tumor tissue microenvironment. It is important to
note that products of MMP activity have sometimes been
found to have an antitumor effect and that elevated levels of
TIMPs in tumors or adjacent normal tissues have correlated
both positively and negatively with prognosis in different
studies." In other words, although the weight of evidence
suggests that excess MMP activity favors tumor growth and
invasion, to state merely that MMPs are "bad" in cancer
progression would be a gross oversimplification. Further

understanding of the functions of MMPs has revealed that
they collectively exert both positive and negative regulatory
effects on cancer progression. This fact may partially explain
why clinical trials of MMP inhibitors in cancer therapy have
generally not yielded positive results (discussed further later).
Among serine proteases, the enzyme most prominently
implicated in cancer progression has been urokinase plasminogen activator (uPA). uPA converts plasminogen to plasmin, a
broad-spectrum protease that is capable of degrading many
components of the extracellular matrix as well as activating
pro-MMPs.65 Invading tumor cells have been shown to express
a cell surface receptor for uPA (uPAR), which focuses proteolytic activity at the invasive front. As with the MMPs,
uPA activity is negatively controlled by the endogenous
inhibitors PAI-l and PAI-2. Elevated expression of uPA has
been reported in malignancies of the breast, colon and
rectum, stomach, urogenital tract, and other tissues.P" The
plasmin activation system is known to contribute to matrix
degradation by thyroid carcinoma cell lines.s? but little more
is known about its role in thyroid cancer.
Our laboratory has extensively studied the role of proteases and their inhibitors in thyroid cancer invasion in vitro.
It is well established that epidermal growth factor (EGF)
enhances invasion in thyroid cancer cell lines of papillary
and follicular origins.f We found that EGF upregulates

earlier, EGF is a potent stimulator of thyroid cancer cell
invasion. In some cases, in vitro invasion by EGF-stimulated
cells was found to be seven times greater than that of
cells studied in a growth factor-free environment. In previous reports from our group, TSH was also shown to enhance
c
0
"00
ctl
>
.5
E
CIl
l:
invasion."
CIl
a.
EGF
AG1478
GM-6001
Col-3 (llg/mL)
+
+
+
+
10
10
FIGURE 32-4. Epidermal growth factor (EGF) stimulates invasion

by thyroid cancer cells in vitro. Cells treated with EGF, AG 1478
(tyrosine kinase inhibitor), GM-6001 (peptidomimetic matrix metalloproteinase [MMPj inhibitor), and Col-3 (tetracycline MMP
inhibitor). EGF was administered at a dose of 10 ng/ml., AG 1478
at 10 11M, and GM-6001 at 100 j.lM. Col-3 was administered at 5
and 10 j.lg/mL, as indicated. Data expressed as mean 1 standard
deviation. Brackets indicate pairwise comparisons. **p < .0001 by
analysis of variance.
MMP-9 and MTl-MMP expression in these cells and

that MMP-2 activation in the extracellular space parallels
MTl-MMP expression.P" EGF-stimulated invasion in
thyroid cancer cell lines is antagonized by both synthetic
MMP inhibitors and EGF receptor tyrosine kinase inhibitors
(Fig. 32-4), but not by the serine protease inhibitor aprotinin.
Our findings suggest that EGF acts by altering MMP gene
transcription downstream of its receptor and that, at least in
our model, serine proteases do not contribute significantly to
invasion.
Regulators of Invasion
Several growth factors have been identified as important
paracrine regulators of cancer growth and spread. Chief
among these are those that bind receptor tyrosine kinases,
such as EGF, hepatocyte growth factor/scatter factor
(HGF/SF), transforming growth factors, and platelet-derived
growth factor. Elevated expression of EGF receptors
(EGFRs) and related Erb-B receptors has been found in many
human malignancies. In cancers of the breast, head and neck,
urogenital tract, and other tissues, Erb-B receptor overexpression is associated with poor prognosis." The Erb-B2
receptor, also known as Her-2/neu, is of particular interest
because of its ability to form cell surface heterodimers with
other Erb-B family receptors, thus augmenting receptor
tyrosine kinase signaling."
Our initial interest in studying the role of EGF in thyroid
cancer stemmed from the fact that EGF is highly expressed
in the normal human thyroid, at levels more than twice those
found in other major organs." Several groups, including
our own, have identified Erb-B receptors on the surface
of thyroid cancer cells, and we have found that thyroid
cancer cell lines overexpress both the EGFR and Erb-B2
when compared with normal thyrocytes. As mentioned
Both EGF and HGF/SF have been shown to increase protease expression and invasion in human cancers.V"
Furthermore, they are reported to induce the dismantling
of adherens junctions, possibly by disrupting the cadherincatenin linkage to the actin cytoskeleton." Similar paracrine
signals are known to regulate the epithelial-mesenchymal
transformation during normal embryonal development, which
mirrors the pathologic events of malignant progression in
many ways. Thus, proteins that maintain normal epithelial
cell architecture, such as E-cadherin and catenin, are now
being seen as invasion or metastasis suppressors.
Stromal cells have been recognized as having an active
role in both the progression and inhibition of malignant
invasion. Stromal cells secrete a variety of proteases, and
cancer cells may stimulate them to synthesize MMPs in a
paracrine fashion by releasing growth factors and human
extracellular matrix metalloproteinase inducer (EMMPRJN76).
Coculture with activated stromal cells can confer
a malignant phenotype on immortal cells that generally display benign behavior.T" On the other hand, tumor stroma
has in many cases been found to harbor large quantities of
protease inhibitors,"? suggesting that normal fibroblasts may
mount an adaptive "tumoristatic" response.
Molecular Cross-Talk in
Malignant Progression
As previously mentioned, although adhesion, proteolysis,
and migration can be considered individually, the three are
actually inseparable events in the process of invasion.
Likewise, research has shed light on a myriad of interlinkages between the processes of cancer growth, survival, invasion, and angiogenesis. What follows is a brief discussion of
molecular cross-talk between these systems, with particular
reference to the adhesion molecules and proteases mentioned previously.
Angiogenesis, a process central to tumor growth and
survival, is an MMP-dependent process. As cancer cells
employ MMPs to invade into adjacent normal tissues,
endothelial cells stimulated by proangiogenic tumor signals
require MMP activity to invade into the tumor substance.
Both endogenous and synthetic MMP inhibitors have been
shown to block angiogenesis by interfering with endothelial
cell attachment, proliferation, migration, and growth. Small
molecules released by proteolysis of the extracellular
matrix, including growth factors and angiostatin, act as both
positive and negative regulators of angiogenesis.t"
The activation of pro-MMPs is a critical step in the regulation of extracellular matrix proteolysis. MMP-2 activation
is known to take place on the cell surface, where MTl-MMP
cleaves pro-MMP-2 into its active form in the presence of
permissive concentrations of TIMP-2. Studies of cancer
cells and angiogenic endothelial cells suggest that aV~3 integrin binds the carboxyterrninal PEX domain of MMP-2 and
Mechanisms and Regulation of Invasion in Thyroid Cancer - -
301
that this interaction may localize proteolytic activity to the

invasive front of cells. 81,82 Treatment of cancer cells with
anti-integrin antibodies has been shown to increase MMP-2
secretion as well as cell invasiveness, and other studies suggest that signaling through FAK upregulates MMP_9. 83,84
Integrins and the uPAIuPAR system are known to interact
and exert reciprocal regulatory actions on one another, but
these processes are just beginning to be understood. As mentioned before, aV~3
integrin is expressed on activated
endothelial cells. Antagonists of aV~3 integrin are known to
disrupt blood vessel formation in the chick allantoic membrane and other bioassay systems. In vivo, Uv~3 integrin
antagonists block tumor angiogenesis and, in some cases,
can cause tumor regression.f
The role of cadherin-catenin signaling in promoting
tumor growth and MMP-7 expression has already been mentioned. E-cadherin is also a substrate for MMP-3 and MMP-7.
Cleavage of E-cadherin results in release of the soluble
extracellular E-cadherin fragment, which has been found to
promote tumor cell invasion by acting in a paracrine
manner.f" The soluble E-cadherin fragment is thought to
interfere with normal E-cadherin function in nearby cells
and possibly to activate other signaling pathways that
remain to be identified.
Trastuzumab (Herceptin), a humanized monoclonal antibody

directed against Erb-B2 (Her-2), has undergone several
phase II and phase III clinical trials that have demonstrated
a survival benefit in patients with Her-2-overexpressing
breast cancers." These studies have led to the licensing of
trastuzumab in many countries for use in combination with
paclitaxel. EGFR antagonists are also being aggressively
investigated. Cetuximab (IMC-225, Erbitux), a monoclonal
antibody that binds the extracellular domain of EGFR, has
been investigated in phase II and phase III trials in colorectal cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinomas of the head and neck. Early results
show good response rates and few toxicities.
ZD1839 (Iressa) is a synthetic inhibitor ofthe EGFR tyrosine kinase. It belongs to a growing list of small-molecule
receptor tyrosine kinase inhibitors that display high specificity for certain receptor tyrosine kinase subtypes. ZD 1839
has undergone phase I and II trials in the treatment of
NSCLC and glioblastoma multiforme. It is generally well
tolerated and appears to have some antitumor effect.
Imatinib mesylate (Gleevec), which inhibits the KIT tyrosine kinase, has been approved in the United States for the
treatment of chronic myeloid leukemia and stromal tumors
of the gastrointestinal tract.
Implications for Clinical

Therapeutics
Summary
Pharmacologic agents targeting specific mechanisms of

tumor growth, invasion, and angiogenesis represent an
emerging class of anticancer therapies. Although the vast
majority of such drugs are in the preclinical or early clinical
investigative stages, their great potential warrants pursuit
from clinicians and scientists. The cadherin-catenin system
has received the most attention in colorectal carcinoma, in
which nonsteroidal anti-inflammatory drugs have been
shown to exert an antineoplastic effect that may be mediated
by reductions in intracellular ~-catenin.87
Interest in integrin
antagonists has generally focused on their antiangiogenic
activity. Medi-522 (Vitaxin), a monoclonal antibody with
activity against aV~3 integrin, has entered phase IIII clinical
trials in patients with advanced solid tumors and lymphoma.
Proteases are an attractive potential target for cancer
chemotherapy because they lie at the crossroads of several
central processes in malignant progression. Antagonists of
the uPAIuPAR system, which include small-molecule serine
protease inhibitors and a truncated form ofuPAR, are undergoing early clinical trials. Synthetic MMP inhibitors, including marimastat, batimastat, BMS-275291, BAY 12-9566,
Col-3, and others, have received substantial interest and
were utilized in several phase III trials during the late 1990s.
Unfortunately, results of these studies have been largely disappointing, with several studies terminating early because
of adverse outcomes.f Such findings have highlighted the
complex actions of MMPs as both positive and negative regulators of cancer progression; further understanding of their
functions is needed at the basic science level.
Perhaps the greatest immediate potential for emerging
anticancer therapy lies with growth factor antagonists.
The process whereby malignant cancer cells invade and

metastasize is complex, but current studies are elucidating
the cellular mechanisms in each step of the involved pathways. Cancerous cells must detach from their primary
tumors, disrupt restraining basement membrane barriers,
and move into their surrounding matrix to enter the blood
and lymph channels, allowing distant spread. Each of the
mechanisms involved is a normal cellular property that has
been coopted to promote malignant progression. Research
has shed light on the complex and pleiotropic effects of
adhesion molecules, proteases, and growth factors in cancer.
Rational drug design has allowed clinicians and scientists
to make promising early inroads into novel therapies that
target tumor growth, angiogenesis, and invasion. Further
basic science and clinical research are required before viable
treatments for advanced malignancies become a reality.
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Surgical Management
of Recurrent and
Intrathoracic Goiters
Antonio Sitges-Serra, MD Juan J. Sancho, MD
Recurrent and intrathoracic goiters may pose considerable

problems to the surgeon. Surgery is often indicated because
local complications are common, and it requires thorough
knowledge of the potentially distorted anatomy found at
exploration. An appropriate preoperative assessment is essential because thyroid function may be abnormal, there may be
sequelae from previous surgery, and precise anatomic definition of the lesion is important for a safe and expeditious
operation. Symptoms may differ considerably from those
found in uncomplicated goiters and may include airway
compression, superior vena cava syndrome, and dysphonia,
simulating a thyroid malignancy. Finally, the highest rates of
postoperative vocal cord paralysis are reported after surgery
for recurrent and complex intrathoracic goiters, suggesting
that there is still room for improvement of surgical technique
in this area. In this chapter, the pathogenesis, clinical presentation, preoperative assessment, and surgical approach to
recurrent and intrathoracic goiters are discussed.
Recurrent Goiter
Prevalence
Palpable recurrence of nontoxic nodular goiter is seen in 2.5%
to 20% of patients who have had previous thyroid surgery for
the same condition; there seems to be a trend toward higher
recurrence rates and probably more clinically complicated
recurrences with longer follow-up. 1 Miccoli and colleaguesreported palpable recurrences in up to 25% to 30% of their
patients after 3 years of follow-up, and this figure increased
to 75% when strict echographic criteria were used for
detecting small nodules. Although these authors noted that
the aim of their surgical intervention was to "completely
remove the thyroid nodules detected in the preoperative
ultrasound," many surgeons would agree that such a high incidence of recurrent benign goiter was somehow related to an
excessively conservative initial operation. Cohen-Kerem and
coworkers- carefully observed 100 patients operated on for
304
multinodular goiter with a less than total thyroidectomy for

a mean of 93 months. The recurrence rate in this group was
21%, although only 4% of patients with a recurrence
required a reoperation within that period.
Causes of Goiter Recurrence

EXTENT OF THE INITIAL SURGICAL PROCEDURE
It has been known for a century that conservative surgery for

multinodular goiter is associated with goiter recurrence.
Kocher reported an 18% recurrence rate after enucleation of
thyroid nodules." For this reason, bilateral thyroid resection
had already been advocated by pioneers in thyroid surgery,
such as Johann Mikulicz, Donald Balfour, Charles Mayo,
George Crile, and Thomas Dunhill." From those times until
2 decades ago, subtotal thyroidectomy was considered the
standard surgical treatment for multinodular goiter and for
Graves' disease. Recurrences are still observed, however,
because either this time-honored principle is ignored or
goiter recurs in the contralateral lobe after total lobectomy
for apparently uninodular disease. Furthermore, prolonged
follow-up of large series of patients has shown that even bilateral subtotal thyroidectomy is associated with a substantial
recurrence rate.
Conservative initial operation can be incriminated as the
main cause of goiter recurrence. Inadequate resections, such
as isthmusectomy, nodule enucleation, subtotal lobectomy,
and bilateral resection preserving the upper pole of the thyroid
lobes, are still frequently found to have been the initial operations in patients with goiter recurrence. In the study by
Bistrup and associates,' a recurrence rate of 19% was probably related to the number of atypical surgical procedures
(six isthmusectomies and seven enucleations). In Anderson
and colleagues' report," 38 subtotal lobectomies were followed
by eight recurrences, independent of whether thyroxine (T 4 )
was administered postoperatively. These atypical surgical
procedures on the thyroid gland should be abandoned.
Recurrence after total lobectomy or appropriate subtotal
Surgical Management of Recurrent and Intrathoracic Goiters - -
bilateral thyroidectomy poses more conceptual questions.

Did lobectomy miss significant contralateral disease? If so,
should the extent of surgery be dictated by preoperative
ultrasonographic findings? Should the contralateral lobe be
thoroughly explored at the time of planned lobectomy? Do
the remnant size and location determine recurrence? Most
surgeons believe that when nodules are not palpable in the
contralateral lobe preoperatively, a lobectomy is all that is
required. Excessive reliance on lobectomy, however, may
predispose to recurrence as a result of untreated contralateral
disease-"; up to 45% of clinically solitary nodules show other
associated nodules on echography." The extent of surgery for
multinodular goiter is also questioned; subtotal bilateral, total
on one side and subtotal on the other, and total thyroidectomy
are currently practiced by experienced endocrine surgeons.
A very low (2.5%) recurrence rate (l % after lobectomy
and 3% after bilateral operation) was reported by Kraimps
and colleagues- after a selectively aggressive policy. These
authors carried out lobectomy only if the contralateral lobe
did not have palpable nodules during the operation. They
performed total lobectomy of the most affected lobe plus
subtotal resection of the contralateral lobe in multinodular
goiters. In their opinion, recurrence was almost always due
to growth of nodules left behind at the initial operation. If
we compare these results with the 10% recurrence rate
reported in the comprehensive study by Berglund and
coworkers," two facts deserve attention and may substantiate
the opinion of the French group: (1) the time for the recurrence to appear was double in French patients (8 versus
4 years after the initial thyroidectomy) and (2) more extensive surgery was carried out by the French team (45% lobectomy and 53% bilateral operation versus 76% lobectomy
and 24% bilateral operation, respectively). In a 7-year followup study after thyroidectomy," patients with recurrent goiter
were compared with those without goiter. Again, unilateral
resection had been performed more often in patients with
recurrence (85%) than in patients without recurrence (61%).
These data suggest that the extent of the initial procedure is
probably a crucial factor in determining recurrence and support the contention that conservative initial procedures are
associated with higher and earlier recurrence as a result of
growth of preexistent nodules.
From only the point of view of recurrence, total thyroidectomy would be the preferred surgical treatment for multinodular goiter. to In the hands of Reeve and colleagues, this
operation has resulted in almost no permanent complications and more and more endocrine surgeons are using this
approach.'! It should be stressed, however, that recurrent
laryngeal nerve palsy or permanent hypoparathyroidism
should not occur after thyroidectomy for benign disease, and
that surgical judgment and experience are essential when a
radical approach is considered.
THE CONTROVERSY OF POSTOPERATIVE
THYROXINE SUPPLEMENTATION
Whether T4 supplementation influences goiter recurrence rate

after thyroidectomy is a matter of controversy. T4 replacement
therapy is compulsory for patients rendered hypothyroid by
thyroidectomy, and there is no question about giving these
patients replacement therapy to keep their thyroid-stimulating
hormone (TSH) levels in the normal range. On the other
305
hand, there are no hard clinical data to support T 4 supplementation in euthyroid patients to prevent recurrence.
Because TSH may stimulate thyroid remnant growth, there
may be sound theoretical reasons to keep the serum TSH
concentrations low after thyroidectomy. Success with this
approach, however, has been far from uniform because factors
other than TSH influence thyroid growth and, eventually,
goiter recurrence.v'? Despite some contrary evidence, 13
during the 1980s some authorities were recommending routine
T 4 supplementation to prevent recurrences after surgery for
nontoxic goiter,":" This recommendation was largely
empirical and based on the understanding of the effects
of TSH on thyroid tissue growth." More recent reports,
however, do not support the benefit of routine T4 supplementation in preventing goiter recurrence. In a retrospective
study, Berglund and colleagues? showed no difference in
recurrence rates between patients who received T4 and those
who did not after partial thyroidectomy for benign goiter.
The recurrence rate was 10% in 29 patients receiving "prophylactic" T4, 7% in 46 patients receiving replacement T4
treatment, and 11% in 186 patients not receiving T4. There
were no differences in the TSH levels between patients with
and without recurrence. A prospective, randomized study by
Bistrup and colleagues' evaluated 100 patients consecutively operated on for nontoxic goiter. The treatment group
received 100 ug of L-thyroxine per day. Sixty-nine patients
had completed a 9-year follow-up, and the rate of palpable
recurrence was 14.5% in treated patients versus 21.8%
(not significant) in untreated patients. As in Berglund's
series, recurrence was independent of TSH status.
An aggressive TSH suppression approach was proposed
by Miccoli and coauthors.? who randomly assigned their
patients to substitutive (100 ug/day) or suppressive
(2.2 to 3 ug/kg per day) T 4 therapy. At 3 years, a 78% recurrence rate (palpable plus echographically detected) was
observed in the former group and 21% in the TSH-suppressed
group. These recurrence rates are the highest reported to
date, and doubts were expressed by discussants of the article
about the appropriateness of the initial operation. It is unlikely
that TSH-suppressive T4 therapy will ever be widely adopted
to prevent recurrence of benign thyroid disease. It requires
close monitoring for life as well as fine adjustment of the
T4 dosage. It demands strict compliance with the assigned
treatment and can have detrimental side effects. 1 Subclinical
hyperthyroidism induced by suppressive doses of T4 may
increase skeletal bone loss, particularly in postmenopausal
women, and may have adverse effects in elderly persons
with heart disease.l?"? Because many patients operated
on for nontoxic goiter are young, it is difficult to justify
suppressive treatment for life, whereas appropriate surgery
may result in long-term recurrence rates below 5%.
From the data reviewed, it is our opinion that prevention of
recurrence ultimately depends on more aggressive resection.
Routine postoperative T 4 supplementation seems unjustified.P
OTHER FACTORS INFLUENCING
GOITER RECURRENCE
Family history has been implicated in the postoperative

recurrence of goiter, and some authors recommend T 4
supplementation if there is a positive family history." In the
study by Berghout and colleagues," a family history of

goiter was found twice as often in patients with recurrent
goiter at follow-up as in those without recurrence (65%
versus 37%). Familial history was not found to influence
recurrence in the series by Kraimps and associates'': patients
with a positive family history had the same recurrence rate
as those without a positive family history. Note, however,
that the recurrence rate in this series of patients treated with
extensive operations was only 2.5%. It has been claimed
that recurrences may be higher in patients living in iodinedeficient regions and that this happens even when suppressive
doses of T4 are administered.' On the other hand, Steiner and
Zimmermann.P working in an endemic area, reported a reduction of recurrence by postoperative T4 supplementation. There
are no obvious reasons for these discrepancies.
A more recent issue is related to the intrinsic growth behavior of recurrent goiters. Harrer and coworkers'? found that
most nodules within multinodular goiters that had regrown
after a first subtotal thyroidectomy were of polyclonal rather
than monoclonal composition. This suggests that these lesions
are generated by de novo proliferation of cohorts of different
thyrocytes sharing the common trait of an exceedingly high
intrinsic growth rate or, alternatively, by unknown growthstimulating molecular events acting focally on clusters of
cells derived from different ancestors.
the initial procedure. These cases, however, usually represent

delayed treatment of a known, long-standing recurrence.
COMPARTMENTAL SYNDROMES
Fibrosis resulting from previous surgery around the recurrent

goiter and adjacent structures can cause severe compressive
symptoms, even in the absence of a large thyroid mass.
Fixation of strap muscles to the trachea closes the thyroid bed
medially, preventing central bulging of the goiter, and contributes to an increase of the thyroid compartment pressure. In
contrast, multinodular goiters that have not been operated on
can expand quite freely in the neck and may attain a considerable size before causing compression syndromes. Dysphagia,
dyspnea, and dysphonia are among the most common symptoms in patients with benign recurrent goiters referred for surgery (see Table 33-1). Vocal cord paralysis is occasionally seen
as a manifestation of compartmental syndrome in patients who
do not recall voice changes after the initial procedure until
some years later. The following is an illustrative example.
Recurrent goiter may arise with symptoms and signs varying
from a barely palpable asymptomatic nodule to a large cervicothoracic mass causing compartmental syndromes. Clinical
presentation is different if patients are diagnosed during a
regular follow-up study, in which recurrences are often
asymptomatic, or if they come from surgical series, in which
more severe symptoms are commonly required. In Berglund's
follow-up study," only 4 of the 26 recurrences observed
required surgery: 2 because of suspicion of malignancy and
2 because of compression symptoms. In the remaining
22 patients, recurrences were small and of little clinical
significance. On the other hand, in the surgical series of
Roeher and Goretzki," three quarters of patients complained
of severe compressive symptoms (Table 33-1).
TIME AFTER INITIAL SURGERY
The interval between thyroidectomy and clinical recurrence

or reoperation varies. Clinical recurrence after a correct initial operation is rarely seen before 4 to 6 years. The mean
interval from reported series varies from 4 to 9 years, but
many patients are referred to the surgeon 15 to 20 years after
When it occurs on the same side as the recurrent goiter,

vocal cord paralysis does not necessarily imply that the nerve
was injured at the initial operation; it may be compressed
or stretched and may regain its function when the thyroid
remnant has been removed. Recovery rate in this circumstance has been reported to be 38%.24
HYPERTHYROIDISM
Dorbach and Schicha" evaluated thyroid function in

69 patients with recurrent goiter a mean of 13.8 years after
thyroidectomy. A continuous increase in thyroid autonomy
was noted at the rate of about 4% per year. At 20 years, 70%
of recurrent goiters were functionally autonomous; thereafter, the prevalence of thyroid autonomy increased only
marginally to reach about 90% in the 40th postoperative
year. In the Roeher and Goretzki series,'> 18% of patients
had clinical hyperthyroidism. It appears that more and more
cells become autonomous over time in recurrent goiter, and
this is another argument for early surgical treatment.
Preoperative Assessment
Physical examination of patients with recurrent goiters may
reveal a hard cervical mass, barely movable on swallowing,
Surgical Management of Recurrent and Intrathoracic Goiters - - 307
sometimes resembling a carcinoma. Fine-needle aspiration

confirms the diagnosis of benign goiter in virtually all cases,
although occasionally carcinoma may be suspected. On the
other hand, a recurrent thyroid nodule after partial thyroidectomy for cancer may represent a benign nodule arising in the
contralateral lobe." If possible, the operative notes and
pathology reports from the initial thyroidectomy should
be obtained. Initial conservative surgery (isthmusectomy,
enucleation) makes re-exploration easier than initial extensive surgery, which may involve both sides of the neck. One
or more parathyroid glands may have been resected with the
thyroid, and this information may change the surgical strategy
to prevent permanent hypoparathyroidism. Laryngoscopy
should be performed routinely to ascertain whether prior
surgery or recurrent goiter may have caused vocal cord
paralysis. Normal voice should not prevent the surgeon from
ordering a laryngoscopy because contralateral vocal cord
compensation may minimize the clinical sequelae of previous nerve injury. Results of laryngoscopy should be made
known to the patient when the physician discusses the risk
of postoperative complications.
As in other thyroid diseases, thyroid function should be
determined before surgery. Patients presenting with hyperthyroidism should be treated with antithyroid drugs.
Because most, if not all, thyroid tissue will be removed, the
patient must be aware that T4 replacement therapy will be
necessary for life.
Serum calcium measurements are recommended.
Patients with recurrent goiters are usually normocalcernic,
but the true status of each parathyroid gland cannot be ascertained from preoperative calcium or parathyroid hormone
(PTH) studies. Consequently, the surgeon must be extremely
careful to identify and to preserve all viable parathyroid
tissue. Preoperative or intraoperative PTH assays on blood
drawn from the lowermost part of both internal jugular veins
could be used to determine whether parathyroid glands are
missing on one side. This might help the surgeon in planning
a more conservative surgery or in proceeding to parathyroid
autotransplantation if viability of identified parathyroid glands
seems doubtful.
Surgical Approach
Surgeons dealing with recurrent goiters need to be experienced in regular thyroid surgery and versatile enough to
recognize potential dangers, prevent technical mishaps, and
adapt their surgical strategy to the often unforeseen findings
at cervical exploration. The aim of surgical treatment for
recurrent goiter is to relieve the patients from compression
symptoms and to prevent any further recurrence. Total
thyroidectomy is thus the treatment of choice. This principal
aim should be balanced against the risk of nerve injury and
hypoparathyroidism. The surgeon should be satisfied carrying out a lesser procedure if, because of local conditions,
risk of injuring the recurrent nerve or the parathyroid glands
seems too high. In these cases, exhaustive hilar dissection
can be avoided and an intracapsular near-total or subtotal
resection can be performed. The surgical approach to
recurrent goiters depends mainly on three factors: the
type of initial procedure and the size and location of the
recurrence.
If the initial procedure was a conservative operation (isthmusectomy or nodule enucleation), reoperation should not
be too difficult because the dorsal aspects of both thyroid
lobes were probably left undisturbed. A midline or lateral
approach for total or subtotal resection is usually possible,
and surgery is similar to a standard procedure for multinodular goiter. The ease of finding the recurrent nerve and
parathyroid is influenced by the size and anatomy of the
underlying goiter. If the initial procedure was a totallobectomy, chances are the contralateral lobe was not mobilized,
and total thyroidectomy may be carried out with little
difficulty with few, if any, postoperative complications.P In
these cases, a lateral approach facilitates the exposure of the
upper pole and dorsal aspect of the remaining lobe. The
prior collar incision should be used. The skin flaps are elevated, and the lateral space of the neck is entered. The superficial neck fascia is divided sharply between the anterior
border of the sternocleidomastoid muscle and the sternothyroid muscle. The dissection is deepened and the intermediate
tendon of the omohyoid muscle transected. The medial
cervical fascia is then incised along the vascular sheaths,
and the middle thyroid vein is identified and ligated.
At this stage, if the goiter is large or if the patient's neck
is short or difficult to hyperextend, exposure of the upper
thyroid vessels may require dividing the strap muscles lateral to the thyroid cartilage. The upper pole vessels are
ligated on the surface of the thyroid to avoid injury to the
superior laryngeal nerve, and the thyroid is mobilized medially. Locating and encircling the main trunk of the superior
thyroid artery at this stage helps to define better the anatomy
of the goiter and to identify the recurrent laryngeal nerve.
The upper parathyroid gland and the recurrent nerve are
found, and the dissection is continued downward. If the thyroid has an intrathoracic extension, the hilum may lie very
posteriorly, and it may be preferable at this stage to pull the
thyroid out of the thorax before identifying the recurrent
laryngeal nerve (see later discussion of surgical approach to
intrathoracic goiter). Care is taken to identify the thyrothymic ligament and ligate it on the surface of the thyroid
to avoid damaging an intrathymic inferior parathyroid. The
lower pole of the thyroid is inspected to uncover any subcapsular inferior parathyroid gland that may require dissection or resection and autotransplantation if preservation of
its blood supply is not feasible. Medial rotation is completed, and the remaining isthmus is peeled off the trachea
and the strap muscles that are usually adherent to it.
The most difficult procedure for recurrent goiter is completion thyroidectomy after subtotal unilateral or bilateral
resection and reoperation to excise a remnant that has developed into a large thyroid nodule. In these cases, the surgeon
should proceed laterally. The most difficult step of this
procedure is dissecting the relapsing thyroid nodule off its
dorsal and lateral (vascular) adhesions and dissecting the
hilum of the inferior thyroid artery where the recurrent nerve
and the upper parathyroid gland may be encased in fibrous
tissue. Identifying the nerve in the lowermost part of the
neck and tracing it to the vascular hilum, where it intertwines with the terminal branches of the inferior thyroid
artery, may be a helpful maneuver. Alternatively, if dissection is deemed too dangerous, the surgeon may perform
subtotal or near-total intracapsular resection,8.15.26 leaving

0.5 to 2 g of thyroid tissue. In contrast to thyroidectomy
for cancer, there is no absolute need for total resection in
benign recurrent goiter, particularly if this increases the risk
of postoperative complications. As discussed earlier, when
operating on patients with prior vocal cord paralysis, one
should always attempt to identify and preserve the recurrent
laryngeal nerve.
Large recurrent goiters often have an intrathoracic extension because the undisturbed structures of the upper mediastinum allow the enlarging thyroid mass to expand caudally.
Their management is discussed later in this chapter.
and a 1.2% rate by Al-Suliman and colleagues.P It is not

possible to know with certainty how much viable parathyroid tissue remains, and where it remains, in a patient with
recurrent goiter. One of our patients experienced permanent
hypoparathyroidism after a completion thyroidectomy after
a prior total lobectomy.
Postoperative Complications
At the beginning of this century, Theodor Kocher warned
against the risks of reoperative thyroid surgery." Beahrs
and Sakulsky'? reported a high incidence of nerve palsies
when recurrent diffuse toxic goiter was treated by repeated
thyroidectomy. Although reoperation for Graves' disease is
no longer performed because of the alternative of radioiodine
ablation, reoperation for compressive or hyperfunctioning
recurrent goiter still accounts for about 5% of thyroidectomies in specialized units. This is currently the type of
thyroid operation with the highest rate of permanent recurrent
nerve palsy and hypoparathyroidlsm.P'P'"
The risk of permanent vocal cord paralysis was evaluated
by Weitensfelder and colleagues in a series of 525 thyroidectomies." The probability of recurrent nerve injury increased
in the following sequence: uncomplicated nodule < goiter <
thyroid cancer < recurrent goiter. Early palsies (3.2%) were
more frequent than permanent ones (0.8%); only one in four
early palsies became permanent. This 75% recovery rate
was similar to the 86% rate reported by Jatzko and
colleagues." The prevalence of permanent vocal cord
paralysis after repeated thyroidectomy for recurrent benign
goiter in reports from specialized thyroid units is shown in
Table 33-2. Permanent nerve injury is observed in very experienced hands, even when subtotal resections were performed
at reoperation.
Permanent hypoparathyroidism seems to be a problem of
less importance than recurrent nerve injury. In the series of
Levin" and Jatzko-? and their coworkers, no patient experienced permanent hypoparathyroidism after repeated
thyroidectomy for recurrent benign goiter. A 3% permanent
hypocalcemia rate was reported by Kraimps and colleagues"
Uncertainty about prior parathyroid status should make

the surgeon very cautious when identifying and dissecting
the parathyroid glands, particularly if the initial operation
was done in a nonspecialized setting. As suggested earlier,
intraoperative bilateral PTH assays may assist the surgeon in
decision making.
Intrathoracic Goiter
Mediastinal extension is common in large, bulky, multinodular goiters. Negative intrathoracic pressure and gravity
facilitate the descent of an enlarged thyroid gland.
Intrathoracic goiter is rarely 2%) a purely mediastinal tumor
developing in an embryonic ectopic remnant or in a fragment
of goiter left behind after an initial thyroidectomy.W" Because
lateral and medial expansion may be limited after previous
surgery, recurrent goiters often have more mediastinal
prolongation. Between 3% and 20% of all intrathoracic
goiters have undergone previous thyroid resections and are
recurrent goiters.24.33-37
Definition and Prevalence

Review of the definitions of intrathoracic goiter shows no
consensus on when a goiter should be considered intrathoracic. The most commonly accepted definition would include
all goiters with a lower pole lying below the thoracic
outlet." Other groups refer to substernal goiter only in cases
in which at least 50% of the thyroid mass is located below
the thoracic inlet. 33.34 The Lahey Clinic group defined mediastinal goiters as "those with a major intrathoracic component that required reaching into the mediastinum for its
dissection.v" This lack of agreement is reflected in the
reported prevalences for intrathoracic goiter, which range
from 4% to 20% of all operations for multinodular goiters.
Intrathoracic goiters are also referred to as substernal
goiters. Although the majority of intrathoracic goiters are
anteriorly situated and thus are truly substernal, others may
lie in the posterior mediastinum. Consequently, the term
intrathoracic is preferred.
Intrathoracic goiters usually occur late in life and have a
peak incidence in the sixth decade. The average ratio
between females and males is 3 to 4:1.38,39 In 20% to 30% of
patients, the thyroid can be barely palpable or not palpable
at all in the neck (grades I and II), and the thoracic extension
represents most of the bulk of the goiter.35.36 Between 6%
and 40% of patients reported in surgical series have no
symptoms but have undergone thyroidectomy as prophylaxis against the potentially severe complications of a large
intrathoracic thyroid mass. In these asymptomatic cases,
substernal goiters are usually incidentally discovered on a
plain chest radiograph.f The most common clinical manifestations of substernal goiters are related to compression or
displacement of the adjacent visceral, neural, and vascular
structures (Table 33-3). Tracheal obstruction and resulting
upper airway compression symptoms were observed in 20%
to 56% of the patients operated on for intrathoracic goiter in
some reports. Ranging from mild to severe, these symptoms
are isolated dyspnea, dyspnea with cyanosis, dyspnea with
cyanosis prohibiting physical efforts, suffocation, and choking requiring immediate resuscitation." Dyspnea or cough
may be worsened by some positions, such as lying flat or
rolling on one side.
The mechanism leading to airway obstruction is compression of the trachea by a goiter expanding between bone
structures (spine, sternum, and first rib). Melliere and
colleagues" observed severe airway compression by goiters
in 58 patients (2% of their thyroidectomy cases). Fifteen
were thyroid malignancies and 43 were benign goiters, of
which 16 had an intrathoracic substernal extension compressing the airway. Shaha and coworkers'? cared for 24 patients
admitted during a 4-year period with acute life-threatening
airway distress resulting from thyroid enlargement (in
9 patients, immediate intubation was required). Twenty of
these patients had benign goiter, 15 of them with marked
substernal extension. In patients requiring emergency care
for acute airway obstruction, surgery should be performed
as soon as possible, and patients should not be weaned from
the ventilator before surgery because this may be followed
by acute asphyxia." Occasionally, dyspnea resulting from
upper airway obstruction can mimic lung disease. In these
cases, it may be difficult to determine precisely which component is the main reason for the dyspnea. Lung function
tests aided by flow-loop studies may be very helpful in
determining the degree of airway obstruction.
Stephenson and associates'? determined peak expiratory

flow to investigatethe functional impact of substernal goiters.
The preoperative peak expiratory flow ratio (observed to
predicted) was significantly lower in patients with intrathoracic goiter, with a positive predictive value of 90%. This
reduced peak expiratory flow improved after thyroidectomy.
This test, along with failure of the peak airflow and forced
expiratory volume to respond to bronchodilators, may be
helpful in identifying the patients with respiratory disease
and associated intrathoracic goiters who may benefit from
thyroidectomy. The following is an illustrative example.
Entrapment of the recurrent laryngeal nerve or laryngeal

distortion may be the major cause of hoarseness found in
about one third of patients who have undergone thyroidectomy for intrathoracic goiter. Cho and coauthors-! reported
that vocal cord paralysis from benign thyroid conditions
may be particularly prevalent among patients with large
substernal goiters, and they attributed this to nerve compression, ischemia, or stretching. The true prevalence of
preoperative vocal cord paralysis in substernal goiters,
FIGURE 33-1. A, Chest radiograph of a 72-year-old woman

with dyspnea, reduced peak expiratory flow, and a massively
calcified cervicothoracic goiter.
B, Computed tomography (CT)
scan section at the level of the
subcricoid trachea showing narrowing of the airway lumen.
C, CT scan section showing
marked narrowingof the trachea at
the thoracic outlet. D, Downward
extension of the goiter to the
aortic arch 2 em above the carina,
however, is difficult to determine because laryngoscopy has

been carried out very selectively in symptomatic patients.
Furthermore, the rate of hoarseness is probably higher than
that of well-documented vocal cord dysfunction. As discussed
earlier, vocal cord paralysis can be reversed by thyroidectomy.24,28,35,37 Thus, when operating on patients with intrathoracic goiter and dysphonia, the surgeon should identify the
nerve and free it from surrounding fibrosis and adjacent
compressive structures. Occasionally, however, nerve injury
during a previous procedure or infiltration by an adjacent
malignancy makes the recovery of vocal cord function
impossible.
Lateral and posterior displacement of the esophagus
causes dysphagia in about one fourth of patients being
operated on for bulky intrathoracic goiters. However, these
symptoms do not severely interfere with swallowing;
aspirative complications and malnutrition have not been
reported. Esophagograms show esophageal compressions
and displacement by the thyroid mass but add little information to the management of these patients. Less frequently
(10% of cases), obstruction of venous return gives rise to a
fully or partially developed superior vena cava syndrome.
This can be obvious with cyanosis, dilation of superficial
facial and neck veins, and descending collateral venous

circulation (Fig. 33-2). Subclinical venous compression can
be diagnosed by having the patient raising the arms
(Marafion's maneuver or Pemberton's sign) and observing
distention of the external jugular and superficial neck veins.
Collateral circulation may rarely involve the upper esophagus with "downhill" varices developingtv'" and causing an
upper gastrointestinal hemorrhage. Superior vena cava
syndrome is reversed by thyroidectomy and is considered to
be an absolute indication for surgery."
Gross multinodular goiters, whether in the neck or mediastinum, tend to develop autonomous nodules, particularly in
patients with a prolonged history.15,25 Although in some reports
no patients with hyperthyroidism were observed,24.33,36
in others biochemical or clinical evidence of thyroid hyperfunction was found in a significant (15 % to 40%) proportion
of patients. 34,35,40 Hyperthyroidism is more common in
elderly patients. In Cougard and colleagues' series of
218 intrathoracic goiters.'? hyperthyroidism developed in
35% of patients 70 years or older and in only 17% of those
younger than 70 years, Hyperthyroidism in elderly patients
can have potentially lethal cardiac complications such as
congestive heart failure, arrhythmias, and worsening of
Surgical Management of Recurrent and Intrathoracic Goiters - -
311
FIGURE 33-2. A and B, Superior vena cava syndrome in a patient with intrathoracic goiter. A pyramid-shaped bilateral intrathoracic goiter
could not be retrieved through a collar incision, and thyroidectomy through a combined cervicomediastinal approach was carried out, with
complete relief of caval compression.
ischemic heart disease. Thyrotoxicosis may develop simultaneously as a result of hyperfunctioning "hot" nodules
(Plummer's disease), after administration of iodinated
contrast medium, or after T 4 is given in an attempt to inhibit
further growth of the goiter. Thus, it is important to identify
patients with hyperthyroidism because they should receive
definitive treatment, preferably surgical, as soon as possible.
Radioactive iodine has been used to control hyperthyroidism
in multinodular goiters, but it is often ineffective, repeated
doses are required, and long periods of time elapse before
obtaining the desired effects. Furthermore, radiation thyroiditis may occur soon after the administration of iodine 131 and
may precipitate an emergency situation in the patient with
airway obstruction.t'
In several series, the prevalence of cancer in intrathoracic
goiters ranged from 3% to 17% (Table 33-4), including both
overt malignancies and occult papillary carcinomas. It is
difficult to make an accurate preoperative diagnosis of carcinoma because the intrathoracic component cannot be reached
by a fine needle. Furthermore, the exact location of the malignant nodule is difficult to ascertain. A relatively high proportion of thyroid lymphomas (6 of 102 substernal goiters) has
been observed in the two series with the highest prevalence
of malignancy.v-" Advanced intrathoracic thyroid carcinoma
may pose significant surgical problems if infiltrating surrounding structures; biopsy plus tracheostomy, palliative
resection, and total thyroidectomy with or without laryngeal or
segmental tracheal resection have all been performed in these
circumstances.
Review of unusual clinical presentations of intrathoracic
goiters reveals a fair number of severe, albeit rare, complications. The following cases were collected from the literature
by Lawson and Biller38: hematemesis from downhill
esophageal varices, abscess formation, Homer's syndrome,
chylothorax from thoracic duct occlusion, and transient
ischemic attacks resulting from a "thyroid steal syndrome."
Fatal hematemesis has been described in a patient with fullthickness ulceration of the esophagus by a posterior substernal goiter." Axillosubclavian vein thrombosis was found in
one patient with substernal goiter compressing the innominate
vein."? Injury to the membranous portion of the trachea at
intubation for general anesthesia has occurred in at least two
patients as a result of the trachea being angulated anteriorly
by a posterior intrathoracic goiter" (1. M. Rodriguez, personal
communication); thyroidectomy and tracheal repair were
performed through sternotomy in both cases.
Preoperative Imaging and Assessment

Various reports have emphasized the usefulness of chest
radiographs and airway films in assessing the extent of tracheal displacement and obstruction caused by intrathoracic
goiters. 4 1,42 Chest radiographs were abnormal in 60% to
90% of patients included in four studies.33.35-37 Lateral chest
radiographs should also be taken to demonstrate any anterior
displacement of the trachea, which may render orotracheal
intubation dangerous (Fig. 33-3). Occasionally, lung metastasis from a thyroid carcinoma can be observed.P''?
Extrinsic pressure on mediastinal structures is best shown
by CT scanning, which is the most sensitive imaging technique for diagnosing intrathoracic goiter extension. 36,38-40,42
It should be obtained in patients with a history suggesting
Iodine 131 scintigraphy should always precede CT scanning because intravenous iodine administered for vascular
enhancement blocks iodine uptake by the goiter. Technetium
99m scintigraphy does not depend on iodine uptake by
FIGURE 33-3. Lateral cervicothoracic radiographic projection

showing marked anteriordisplacement of the trachea, widening of
the tracheovertebral space, and airway compression against the
sternal manubrium by a large (580 g) intrathoracic goiter.
compression symptoms and in those with nonpalpable lower

thyroid borders, particularly if chest radiographs show an
abnormal mediastinal outline or marked tracheal deviation.
CT scanning gives important information to the surgeon
regarding (I) the precise location of the intrathoracic extension; (2) the presence, extent, and situation of the continuity
between the cervical and the thoracic components of the
goiter; (3) definition of the limits of the lesion; (4) areas of
calcification; (5) degree of heterogeneity and cystification of
the intrathoracic portion; and (6) level and degree of tracheal
lumen reduction.
Nuclear magnetic resonance imaging may be superior"
because, in addition to the information provided by CT scanning, it has two advantages: it offers sagittal and coronal tomographic cuts, which further clarify the anatomy of the
intrathoracic goiter, and it delineates more precisely the relations among the goiter, the whole length of the trachea, and
the mediastinal vessels. Vascular invasion by a thyroid
malignancy may also be detected.
Thyroid scintigraphy has limited value in the preoperative
assessment of intrathoracic goiters. Iodine 131 scintigraphy
often fails to show the mediastinal prolongation2436,38,40
and adds little to the management of intrathoracic goiter.
In patients with subclinical or overt hyperthyroidism, it may
show hot hyperfunctioning nodules. The most useful indication for 131I scintigraphy is to clarify the nature of an isolated
mediastinal mass, and it should be ordered for patients in
whom CT scanning does not show mass continuity between
the mediastinum and the neck. The following is an example.
FIGURE 33-4. Chest radiograph (A) and iodine 131 scmtigram
(B) in a case of recurrent intrathoracic goiter independent of

the neck approached through a median sternotomy. Subtotal
thyroidectomy was performed 22 years before. The mass was
situated behind the ascending aorta.
the goiter, but because of the proximity of the goiter to the

thoracic cardiovascular blood pool, the findings may be
difficult to interpret. Its sensitivity has been reported to
be only 33%.49
Laryngoscopy should be carried out in patients presenting with hoarseness or dysphonia and in those who have
had prior neck surgery. Vocal cord paralysis may result
from (1) previous surgery, (2) compartmental syndrome, or
(3) invasion of the recurrent laryngeal nerve by a thyroid
malignancy. These different possibilities should be borne in
mind during operation.
Thyroid function tests must be performed before surgery
because hyper- or hypothyroidism may be associated with
large intrathoracic goiters. Hyperthyroid patients should be
treated with antithyroid drugs before surgery. Some authors"
add steroids to the antithyroid drugs to prevent worsening of
compartmental syndromes resulting from goiter inflammation. This practice, however, is not widespread, and most
surgeons would prefer to operate on patients not receiving
steroids. Failure to measure a recent thyroid hormone
concentration may precipitate perioperative metabolic problems. One of our patients experienced postoperative acute
myxedema despite a near-normal hormone concentration
1 month before surgery.
Surgical Treatment
Thyroidectomy is the preferred treatment for intrathoracic
goiter (Table 33-5). T4 treatment has repeatedly proved ineffective in reducing goiter volume" and may result in hyperthyroidism. A clinical trial using suppressive doses of
L-thyroxine(2.5 ug/kg per day) to reduce the size of sporadic
nontoxic goiters has shown that after 9 months of continued
treatment 58% of the patients responded (as determined by
ultrasonography). The mean reduction of goiter size was
25%. This benefit, however, was short lasting; 9 months after
the treatment was discontinued, the goiter volume regained

its basal value" Evidence supports a growing consensus
against the use of L-thyroxine treatment for goiter size reduction or goiter growth prevention."
CERVICAL APPROACH
More than 90% of intrathoracic goiters can be removed

through a standard collar incision. Several maneuvers facilitate approaching, dissecting, and delivering huge goiters into
the cervical wound. These are summarized in the following
description of a "standard" bilateral resection for multinodular intrathoracic goiter.
The best position of the patient on the operating table is
the semisitting Kocher position with hyperextension of the
neck. This reduces venous pressure in the upper trunk and
helps to minimize blood loss. To reduce further the pressure
in the neck, it may be helpful to divide the sternal head of
the sternocleidomastoid muscle and the strap muscles. This
maneuver also gives a wide exposure for approaching the
upper pole and the laterodorsal aspects of the goiter. Before
any attempt is made to mobilize the intrathoracic extension,
the upper thyroid vessels and lateral middle veins should be
divided on both sides. The surgeon then decides which is the
smaller of the two lobes and rotates it medially to identify
and encircle its inferior thyroid artery. The posterolateral
surface of the lower pole should be carefully inspected to
detect any subcapsular parathyroid gland that may require
autotransplantation in the sternocleidomastoid muscle.
During mobilization of bulky thyroid lobes, we have found
it useful to apply a small bulldog vascular clamp to the trunk
of the inferior thyroid artery. Perithyroid and hilar dissection
can then be carried out with a minimal blood supply to the
thyroid; the clamp is released after lobectomy is finished.
Pressure in the neck is greatly relieved at this stage, and
resection of the mobilized lobe can be accomplished.
Tracheal attachments of the dorsum of the thyroid are severed
as completely as possible without endangering the contralateral recurrent laryngeal nerve. Having freed as many cervical
attachments as possible, the surgeon now approaches the lobe
with a major intrathoracic component. Access to the hilum
may be difficult before the intrathoracic extension has been
brought up. If this is the case, no heroic efforts should be

made to identify the recurrent nerve at this stage; attention
is focused instead on delivering the thoracic goiter extension
into the neck. This is done by gently pulling up the thyroid
lobe while the surgeon frees loose adhesions surrounding
the mediastinal portion of the goiter with the index finger
and applies caudal to cephalad pressure onto it.
If this proves difficult, two additional maneuvers may be
helpful: (l) the finger of the surgeon can be replaced by. a
sterile "soup spoon," which breaks negative intrathoracic
pressure, reaches lower, and occupies less space th~n the
surgeon's finger 3452 ; and (2) intracapsular fragmentation of
the thyroid (morcellation) was proposed by Lahey to reduce
the size and soften the intrathoracic goiter extension and
facilitate its removal through the neck. This technique has
two drawbacks: major bleeding and tumor spillage. When
the goiter is obviously cystic and no fear of malignancy
exists, Allo and Thompson" occasionally used a variation of
this technique by introducing a metal suction device through
small capsular incisions. Katlic and colleagues-' also used
morcellation, aspiration, or both, in 5 of their 80 operations
for intrathoracic goiter, with good results. After the intrathoracic portion has been delivered into the neck, the operation
proceeds in a standard manner, identifying the recurrent
laryngeal nerve and the upper parathyroid gland. Use of
closed suction drains is advisable to evacuate blood from the
large remaining mediastinal cavity.
If the intrathoracic part is very difficult to mobilize
before the recurrent nerve is identified and the tracheal
attachments of the thyroid lobe are severed, the surgeon may
identify the nerve close to the inferior hom of the thyroid
cartilage where it enters the larynx and dissect it downward.
This is followed by section of the tracheal attachments.
By so doing, the cervical part is completely free and more
efficient upward traction, without fear of injuring the nerve,
can be exerted on the thoracic part of the goiter. Identification
of the recurrent nerve at the level of the cricoid cartilage,
however, is technically demanding and should not be
attempted by the less experienced surgeon.
STERNOTOMY AND COMBINED

MEDIASTINAL APPROACH
The anterior chest wall should be prepared and draped in all

patients undergoing thyroidectomy for large intrathoracic
goiters should sternotomy be required. Sternoto.my can be
carried out as a last resort or maneuver, or, better, It should be
planned electively for patients in whom preoperative imaging
demonstrates very bulky, low-lying, solid goiters with complex anatomic relations.
Between 2% and 11% of intrathoracic goiters have
required removal through a combined cervical and sternotomy approach. 32-42,49.53 Indications for this combined
approach include a large discrepancy between the diameter
of the thoracic inlet and that of the goiter (pyramidal or pearshaped intrathoracic extensions; see Fig. 33-5), superior
vena cava syndrome, retroesophageal extension, deepseated tumors reaching the carina, invasive carcinoma, and
acute respiratory distress. The specific reasons for performing sternotomy given in a number of studies are su~m~zed
in Table 33-6. The main advantage of sternotomy IS Widening of the thoracic inlet. Widening facilitates deeper blunt
dissection and exteriorization of large thyroid masses that
otherwise would require fragmentation. It may also help to
control bleeding in the occasional case in which mediastinal
vessels to the goiter are identified. If a carcinoma is present,
invading the lower trachea, sternotomy may be required to
achieve a radical resection.lv"
If sternotomy is used, the cervical part of the operation is
done first to control the major thyroid vessels. Leaving sternotomy to the end of the operation also has the advantage of
shortening the wound exposure time, thus reducing the risk
of infection. In cases of superior vena cava syndrome,
however, early sternotomy may be required to decompress
the large neck veins effectively. Partial or full median sternotomy is carried out. Partial sternotomy has the advantage
of being more cosmetic. It can be done by raising the lower
skin flap over the sternal manubrium, thus sparing a presternal skin wound.
The following case history represents a good example of

a patient with recurrent giant intrathoracic solid goiter who
underwent total thyroidectomy through a combined cervicomediastinal approach.
Widening the thoracic outlet by sternum splitting may

decrease the risk of recurrent laryngeal nerve injury in difficult
cases. In a study by Cougard and colleagues/" no permanent
nerve palsy was observed in 16 patients who had sternotomy,
whereas a 6.8% palsy rate was noted in patients operated on
through only a cervical incision.
THORACOTOMY
A half-century ago, there was uncertainty as to the best route
for resecting large intrathoracic goiters when access to
the chest was required.> Thoracotomy (usually right) was
proposed mainly by thoracic surgeons such as Clagett,
Sweet, and Ellis in the belief that most intrathoracic goiters
represented isolated thoracic masses and that posterior
goiters could not be safely removed through a neck incision.
Since then, experience has shown that approaching the
intrathoracic goiter through posterolateral thoracotomy
should be discouraged. There are several reasons for this.
Posterior thoracic goiters are no longer per se an indication
for thoracotomy because they can usually be delivered
through collar incision or median sternotomy. Major thyroid
vessels cannot be appropriately controlled from the thorax,
and the cervical extension of the goiter cannot be dissected
free from the adjacent structures. It is because of these
FIGURE 33-5. Recurrent goiter
witha largeintrathoracic extension

of the right lobe. A, Chest radiograph film shows lateral displacement of the trachea by a large
mediastinal mass. B, Computed
tomography scan shows downward prolongation of the goiter
past the aortic arch. C. Sagittal
section in a nuclear magnetic
resonance scan showsthe relationshipof the intrathoracic goiterwith
the venous innominate trunk, the
spine, and the right mainbronchus.
D. Coronal section shows tracheal
compression, pleural thickening
around the goiter, and relationship
withthecarina. Median sternotomy
was performed to allow blunt
finger dissection of the lower pole
of the right lobe lying behind the
vena cava on the right main
bronchus.

technical difficulties that thoracotomy is associated with
substantial risk of recurrent laryngeal nerve injury.37,55.56 If a
thoracotomy is carried out because an incorrect diagnosis of
purely posterior mediastinal "tumor" has been made, it often
requires conversion to a neck incision.'? Shahian and Rossi'?
made the case for exceptional circumstances that may
require thoracotomy: at the Lahey Clinic, two patients had a
cervical and thoracotomy approach in a 20-year period.
Both presented with a right posterosuperior mediastinal
goiter extending from a left thyroid lobe passing behind the
trachea and the esophagus. In our experience, however,
these "corkscrew goiters" can also be approached by a full
median sternotomy and opening of the right pleural cavity.
Gentle pressure on the posterior thyroid mass helps to
untwist the goiter around the tracheoesophageal axis.
SUMMARY
It is usually difficult to foresee which patients will require a

thoracic approach when operating on an intrathoracic goiter.
It is therefore advisable to prepare the surgical field for
sternotomy in cases of huge thoracic thyroid masses, especially if they are posterior, suspicious of being malignant, or
recurrent." Further studies based on preoperative imaging
techniques, anatomic landmarks, and volumetric studies may
serve to delineate further the subset of patients who require a
thoracic approach.
Postoperative Complications
The morbidity rate after surgery for intrathoracic goiters
ranges between 4% and 12% in various series from referral
institutions. The most common significant complications are
listed in Table 33-7. Patients with the highest complication
rates are those with thyroid malignancies and those undergoing a combined cervicomediastinal approach. Despite the
extensive perithyroidal dissection required to resect these
large goiters, permanent hypoparathyroidism is unusual in
the hands of experienced surgeons. To achieve these results,
knowledge of the altered anatomy is essential, as is proper
identification and eventually autotransplantation of any
parathyroid gland in the surface of the thyroid whose blood
supply cannot be guaranteed.
Recurrent laryngeal nerve paralysis results from not identifying the nerve and inadvertent injury or from stretching
during blunt dissection of large intrathoracic masses. As
previously stated, efforts to identify the nerve before the
intrathoracic goiter is fully mobilized may result in inadvertent injury. If the nerve is not transected, vocal cord paralysis
is usually (75%) temporary.
Tracheal softening leading to tracheal collapse and respiratory failure (tracheomalacia) is being reported exceptionally, even in series of patients operated on for airway
compression. In several major studies 32-3M1,42 encompassing
298 patients (including two series of patients operated on for
respiratory distress), only 2 patients were diagnosed with
tracheomalacia and required postoperative tracheostomy.3M2
Of the seven patients with tracheomalacia reported by
Geelhoed.l? three had recurrent goiters and one had a longstanding multinodular goiter. Methods for management of tracheomalacia are extensively reviewed in this study. External
splinting by custom-made rings or Marlex mesh has also been
tried.59 Tracheostomy, however, remains the standard treatment whenever tracheal softening is identified at surgery.
Summary
Operations on recurrent and intrathoracic goiters are associated with increased intraoperative technical difficulties and
permanent sequelae. Because compression symptoms are
common or may develop with time, surgery becomes the only
rational therapy. An appropriate preoperative assessment,
including laryngoscopy, CT scanning, and thyroid function
tests, and an experienced surgeon are essential for minimizing perioperative complications. Safe thyroid resection is
the aim, and the incidence of permanent vocal cord paralysis and hypocalcemia should be near zero when treating
these benign conditions.
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Surgical Management
of Advanced Thyroid
Cancer Invading the
Aerodigestive Tract
H. Dralle, MD M. Brauckhoff, MD A. Machens, MD O. Gimm, MD
Thyroid cancer invading the aerodigestive tract is uncommon

(Table 34-1). Apart from distant metastases, extrathyroid
invasion is the dominating risk factor for tumor recurrence
and mortality in thyroid cancer. [-3 Among the patients
with extrathyroid extension of thyroid cancer, those with tracheal or esophageal invasion have a worse prognosis in terms
of survival than those with invasion of other extrathyroid
structures." Apart from tumor extension, the extent of primary surgery as the mainstay of therapy in differentiated and
medullary thyroid carcinoma significantly affects tumor
recurrence and survival.v' In an investigation regarding
cancer-specific cause of death in thyroid cancer, local
complications from tumor growth accounted for 35% of
fatalities, distant metastases for 34%, local and metastatic
disease jointly for 28%, and complications related to therapy
for 4%.7
By direct tumor extension, thyroid cancer may take three
main directions of spread: (1) the central route, involving the
paratracheallymph nodes, the recurrent laryngeal nerve, and
the aerodigestive axis; (2) the lateral route, involving lymph
nodes of the lateral compartment, the carotid sheath; and
the lateral nerves; and (3) the mediastinal route, involving
the upper mediastinal lymph nodes, the great vessels, the
thymus, and other mediastinal organs. The four main types
of thyroid cancer, papillary, follicular, medullary, and undifferentiated thyroid carcinoma, differ with regard to tumor
biology and disease progression not only from each other
but also from squamous cell carcinoma of the head and
neck. Consequently, the efficacy of adjuvant treatment
modalities such as radioiodine therapy and percutaneous
irradiation varies significantly according to the tumor entity.
Unlike involvement of the lateral neck and mediastinum,
invasion of the aerodigestive tract has stirred considerable
controversy concerning indications, technique, and extent of
resection. Because patients with aerodigestive tract invasion
are generally older than patients without aerodigestive tract
318
invasiont'? and the aerodigestive tract is vitally important,

surgery in this setting poses a real challenge for both the
surgeon and the patient. Prevention and elimination of airway
obstruction are the primary objectives of surgical therapy,
while striving at the same time to preserve the patient's voice
capacity and quality of life. As in other complex diseases,
optimal selection of patients and outcome for thyroid cancer
invading the aerodigestive tract can be accomplished only in
a multidisciplinary approach. The preoperative work-up for
local and distant tumors relies on joint radiologic and nuclear
medicine expertise. The surgical resectability depends on
the cooperation of surgeons with anesthesiologists; ear, nose,
and throat specialists; and plastic, vascular, and thoracic
surgeons. Postoperative care requires the combined expert
knowledge from fields as diverse as radiology and nuclear
medicine (radioiodine therapy, percutaneous irradiation)
and advanced endoscopy (e.g., intraluminal stenting, laser
ablation).
During the past 4 decades, sophisticated surgical techniques of laryngotracheal resection have been developed
and have become the prerequisite to perform extended resections with minimal morbidity and mortality. Optimal survival can be achieved by radical resection of the primary
tumor at the first operation.' Hence, a thorough preoperative
ascertainment of tumor spread and a speedy referral of
patients to specialized centers for primary surgery are the
mainstay of therapy for thyroid cancer invading the aerodigestive tract.
Preoperative Assessment of
Local and Distant Disease
As invasion of the aerodigestive tract by thyroid cancer
remains asymptomatic for a long time, the diagnosis of
visceral infiltration is often not made preoperatively.
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - - 319
A heightened index of suspicion is warranted in patients

who have either sonographic evidence of airway invasion
or clinical symptoms of extrathyroid tumor growth such
as hoarseness, hemoptysis, and dysphagia. These patients
should undergo a thorough work-Up, including fine-needle
aspiration cytology, computed tomography, and/or magnetic
resonance imaging. In this setting, flexible laryngotracheobronchoscopy, pharyngoesophagoscopy, and endolurninal
biopsy are helpful in verifying full-thickness invasion of
the aerodigestive tract and mapping the longitudinal and
circumferential extension of tumor involvement. In the
absence of transmural involvement radiologically, endoscopy
is unlikely to yield additional information. Indirect laryngoscopy and direct laryngoscopy provide information on
preoperative vocal cord function (Fig. 34-1).
Every patient with locally advanced thyroid cancer should
be evaluated for his or her cardiovascular and pulmonary
performance and also undergo intensive imaging to identify
or exclude distant metastases (Fig. 34-2). Lung and bone
are the most common sites of distant metastases in thyroid
carcinoma.P Remarkably, only half of patients with pulmonary metastases die because of respiratory insufficiency.'
Bone metastases account for 30% to 40%7.14,15 and brain
metastases for 3% to 20%7,16-18 of cancer-specific fatalities.
FIGURE 34-1. Radiologic and endoscopic diagnosis of intramural and intraluminal invasion of upper airway in advanced thyroid cancer.
A and B. A 62-year-old woman with follicular thyroid carcinoma, insular type, invading the left wall of the cricoid and trachea (MRI).
C and D, A 35-year-old woman with recurrent follicular thyroid cancer with intraluminal invasion of the right lateral part and pars
membranacea of the upper trachea (MRI). E and F, A 61-year-old woman with recurrent papillary thyroid cancer invading the posterior
part of the larynx and upper trachea, endoscopy (E) and MRI (F).

Resectability:
Clinical check
Cervical US
assessment of
tumor type and
local extension
FNAC
Tracheal, esophageal
wall invasion
Operability:
assessment of
physical condition
and systemic
tumor extension
Complete medical
evaluation of physical
condition
FIGURE 34-2. Preoperative evalu-
ation of resectability and operability

in thyroid cancer patients with
aerodigestive invasion (ADI). CT =
computed tomography; FNAC =
fine-needle aspiration cytology;
MRI = magnetic resonance imaging; PET = positron emission
tomography; US = ultrasonography.
Imaging of lung, liver,

bone, brain (CT/MRI,
PET)
MUltiple progressive
lung and/or other
distant, mets
Walt and see
or palliation
Evidence suggests that fluorodeoxyglucose (FOG)

positron emission tomography (PET) may be suitable to
detect metastatic deposits from differentiated thyroid cancer
in patients who have elevated thyroglobulin levels but negative radioiodine scans. The detection rate of FOG-PET in
this setting was 70% to 80%. False-negative results were
obtained in patients who displayed low serum thyroglobulin
levels and/or minimal cervical lymph node enlargement. 19.20
On multivariate analysis, patients with a metastatic FDGPET volume of more than 125 mL had a significantly reduced
survival." FDG-PET may also be useful to detect metastatic
deposits from medullary thyroid carcinoma"
Selection of Patients
For patients with locally advanced thyroid cancer, especially
when it invades the aerodigestive tract, the key to success is
the selection of the best operation for the individual patient.
This allocation of the best operation must incorporate
aspects as diverse as technical resectability of the tumor,
progression of disease, and the patient's physical condition
and social background.
Local Resectability
Modem imaging techniques are highly accurate in determining the extent of local disease, not only in respect to soft tissue
and vascular invasion but also in terms of laryngeal, tracheal,
or esophageal invasion.2324 Therefore, not only must palliative
versus curative interventions be balanced against each other
but also various types of resection (see Fig. 34-2).
In contrast to primary squamous carcinoma, which
requires wide excisions, resectability of invasive thyroid
carcinoma can often be achieved, leaving only small margins
of normal tissue. When resection margins are involved histologically, the microscopic tumor deposits can sometimes
be ablated subsequently with radioiodine therapy provided
the residual tumor takes up iodine.
Irresectability from a technical point of view is ill defined
but mostly present in patients with mediastinal involvement
of the great vessels, including the innominate artery, trachea,
and esophagus. With widespread neck involvement, extensive
surgical procedures on the visceral axis are of limited value,
especially when tumor widely invades the carotid sheath.
In general, multiple distant metastases, undifferentiated
carcinoma, or non-Hodgkin's lymphoma precludes extensive
surgery on the aerodigestive tract. There are only a few

reports of successful resections on the aerodigestive tract
for undifferentiated thyroid carcinomas, associated with a
long-term palliation of 3 to 7 years. 12.25
Progression of the Disease

In patients with recurrent disease and poorly differentiated
carcinoma, progression of the disease should be considered.
This may be difficult because reliable biomarkers for tumor
progression are nonexisting. The role of distant metastases
is hard to evaluate. Patients with metastases confined to the
lung have an improved survival rate compared with those
with multiple-organ involvement, bone metastases only, or
other single-organ involvement.Fv" Only half of the patients
in the first group succumb to their pulmonary metastases."
Accordingly, most authors do not recommend excluding
surgery on the aerodigestive tract when the metastatic
disease is stable or only slowly progressing and confined
to the lung. 9,IO,28-31
Except for clinical risk factors such as disease progression
or local or distant tumor spread, there is only limited knowledge about biologic or molecular markers indicative of a dire
prognosis in thyroid cancer. Poorly differentiated tumors.F
an aneuploid DNA pattern," and nuclear atypia!' have been
encountered more frequently in patients with than without
tracheal invasion. The prognostic suitability of these and
others parameters such as p53,32 CD97,33 or E-cadherin34-36
remains to be elucidated. Owing to the lack of suitable prognostic biomarkers, clinical decision making continues to be
based on the presence or absence of clinical risk factors.
Physical and Mental Condition

of the Patient
Aerodigestive tract invasion is often associated with two major
pro~lems:
poorly differentiated thyroid cancers and elderly
patients. Although papillary thyroid carcinoma prevails in
all published series on aerodigestive invasion (Table 34-2),
~oorly
differentiated thyroid carcinomas may be more susceptible to laryngotracheal invasion than their well-differentiated
counterparts. 8,II,12,37,38 In addition, patients with aerodigestive
invasion are on average 5 to 10 years older than those without
aerodigestive invasion. 9,10-12 These increments in patients' age
require a careful evaluation of the patient's cardiovascular and
pulmonary performance and physical condition, all of which
tend to deteriorate with increasing age (see Fig. 34-2).
. In inoperable cases, a "wait and see" policy may be supenor to tracheostomy when the obstruction of the airway is
tolerable. In patients with progressive airway obstruction
and local irresectability, construction of a tracheostomy
should be avoided because of the associated decline in the
patient's quality of life. Instead, intraluminal stenting and
tumor ablation (e.g., by laser surgery) should be attempted
before resorting to permanent tracheostomy.
Surgical Approach
The first surgical attempts at trachea resections were reported
at the end of the 19th century by Gluck and Zeller (1881 )39
and Colley (1895).40 These authors used dogs for their
experiments on segmental resections of the neck trachea.

Reconstruction was performed using either circular anastomoses in a three-stage operation'? or a bayonet-shaped anastomosis in a one-stage operation." V. Eiselsberg, in 1896,
was the first to publish a circular tracheal resection with
primary anastomosis that was successful; the patient was a
46-year-old man. Before that period, tracheal stenoses were
treated only with tracheal dilatation, longitudinal tracheal
splitting, and/or placement of tracheal tubes." The milestones on the road toward a systematic approach to tracheal
resections were the development of intubation anesthesia
in the 1940s and 1950s42-44 and the technique of tracheal
release described in 1946.45
Preparation of the Patient

The patient is prepared for a cervical or cervicomediastinal
procedure. When a cervical evisceration is envisaged, the
preparation also involves the upper abdomen for a median
abdominal incision to harvest the intestinal graft. Intubation
is achieved either orally or through a preexisting tracheostomy. In the latter instance, the indwelling tracheal
cannula is exchanged for an oral endotracheal tube when
there is no proximal obstruction. For most extended cervical
operations, a low U-shaped collar incision is preferred,
which can be extended down to the xiphoid for complete
median sternotomy and mediastinal dissection. The cervical
cutaneous flap is developed upward to reach the cranial
larynx.
Cervical Exploration
The aim of cervical exploration is to determine resectability
and, when the tumor is resectable, to mobilize the tumor in
a centripetal direction, a procedure referred to as "encircling
the enemy." This technique affords an en bloc resection of
the whole surgical specimen, thus avoiding piecemeal resection of the tumor. Usually, the dissection starts at the anterior and medial aspect of the jugular vein and carotid artery
on the side with the most tumor. Precluding extensive
visceral resections, invasion of the carotid artery is a rare
phenomenon (Table 34-3), often indicative of poorly differentiated cancer. Combining carotid artery resection with
cervicovisceral resection carries a high risk of lethal complications, notably carotid rupture, and thus should be avoided.
Concomitant lateral lymph node metastases should be
dissected appropriately. Prophylactic dissections are not
recommended in order to preserve the soft tissues.
Surgical Technique of Radical Resection

of Aerodigestive Invasion
Tracheoesophageal invasion is often the result of direct invasion from the primary tumor but rarely arises from lymph
node metastases.v'" According to pathoanatomic studies of
Shin and coworkers" and Salassa and colleagues, this mode
of visceral invasion may be due to (1) the proximity of the
posterior thyroid capsule and the pretracheal fascia, (2) the
paucity of lymphatics and lymphatic invasion by thyroid
cancers of the posterior thyroid fascia, and (3) the presence
of potential lines of weakness in the tracheal wall where the
vessels penetrate perpendicular to the lumen (Fig. 34-3),
opening avenues for tumor invasion.
Considering these preformed pathways of tumor invasion, Shin and coworkers devised an anatomic staging
system according to the depths of tracheal invasion. This
system may be relevant not only for surgical decisions on
the extent of resection but also for estimating the prognosis
for the individual patient (Fig. 34-4). In their series, the
prognosis for patients with stages 1 to 3 (invasion of tracheal
wall without infiltration of the entire thickness of the
mucosa) was significantly better than that for patients with
stage 4 disease (invasion of tracheal wall with complete
mucosal invasion)."
The human arterial blood supply of the tracheoesophageal
axis is organized in a segmental fashion and substantially
differs from that in mammals, especially dogs. It has been
extensively studied by Miura and Grillo (1966) and Salassa
and coworkers (1977). From their studies, it can be concluded that the vascular pedicles of the lateral trachea, which
are essential for the nutrition of the tracheal cartilages, arise
from branches of the inferior thyroid, supreme intercostal,
subclavian, internal mammary, innominate, and bronchial
arteries (see Fig. 34-3). These vessels interconnect along the
lateral tracheal wall, forming a longitudinal anastomosis that
34-3. Macro- and

microarchitecture of arterial
blood supply of the tracheoesophageal tract. A. Left anterior
view. B, Right anterior view.
C, Microscopic blood supply.
(From Salassa JR, Pearson BW,
Payne WS. Gross and microscopical blood supply of the trachea.
Ann Thorac Surg 1977;24:100.)
FIGURE
FIGURE 34-4. Staging system for thyroid carcinoma invading the trachea. (From Shin DH, Mark EJ, Suen He, Grillo He. Pathologic
staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic mannerof extension to the trachea: A clinicopathologic study basedon 22 patients who underwent thyroidectomy and airway resection. Hum Pathol 1993;24:866.)
gives rise to the transverse intercartilaginous arteries of each

tracheal segment. The submucosal capillary plexus that is
fed by the transverse intercartilaginous arteries supplies the
posterior tracheal wall. Therefore, preservation of the lateral
vascular pedicles is of utmost importance when performing
tracheoesophageal resection. Unlike anterior dissection, vascular division close to the lateral wall is not recommended.
Only the vessels that supply the segment to be resected may
be ligated in order to maintain a sufficient blood supply. It
should also be noted that the removal of the thyroid gland,
although indicated in most patients with advanced thyroid
cancer, may be detrimental in some instances, because the
inferior thyroid artery largely contributes to the tracheal blood
supply. The esophagus can safely be separated from the
posterior tracheal wall without compromising arterial blood
supply when the lateral pedicle is preserved.
Technically, the extent and type of laryngotracheal resection depend on (I) localization of the invading cancer (larynx,
cricoid, or cervical trachea), (2) tumor extension in longitudinal and horizontal directions, and (3) tumor extension through
the tracheal wall (Shin grades I to 3 versus grade 4).

Considering the rates of involved structures in advanced thyroid cancer without and, in particular, with aerodigestive invasion, unilateral tracheal invasion with ipsilateral involvement
of the recurrent laryngeal nerve is by far the most prevalent
form of aerodigestive tract invasion from thyroid cancer
(see Table 34-3). Laryngeal and/or esophageal invasion is less
frequent. In contrast, invasion of the strap muscles and the
internal jugular vein in isolation is rather common.
Depending on the respective combination of the aforementioned resection criteria, six principal types ofstage- and
localization-oriented laryngotracheal tumor resections with
or without reconstruction can be distinguished (Fig. 34-5,
Table 34-4):
Type 1: Unilateral circumscribed tumor invasion at the
laryngotracheal angle, often associated with involvement of the ipsilateral recurrent laryngeal nerve. Tumor
invasion should not exceed more than 2 em in the
longitudinal direction and no more than one third of
the laryngotracheal circumference. This type of resection
Surgical Management of Advanced Thyroid Cancer Invading the Aerodigestive Tract - -
325
FIGURE 34-5. Types of laryngotracheal resection and reconstruction in invasive thyroid cancer.
("window" resection) can be reconstructed with a sternocleidomastoid flap covering the laryngotracheal wall
defect. A suprahyoidallaryngeal release is not necessary.
Type 2: Extent of tumor invasion is comparable to that
in type 1 but localizedinferiorto the laryngocricoidregion.
Reconstruction is similar to that in type 1 except for

the higher division of the sternocleidomastoid muscle.
In both types of reconstruction, a circular, airtight,
rnusculotracheal anastomosis is fashioned, suturing the
external muscular fascia onto the anastomosis. To this

end, a monofilic absorbable thread (3-0) and fullthickness running sutures are used.
Type 3: Unilateral tumor invasion involving more than
2 em in length and/or more than one third of the laryngotracheal circumference is best treated with a circular
laryngotracheal (type 3) or tracheal resection (type 4).
Because preservation of at least one recurrent laryngeal nerve is of paramount importance, type 3 requires
an oblique, sometimes S-shaped transection of the
trachea above and below the tumor, allowing congruent approximation of the resection margins.29.30.38.52.53
The tracheal anastomosis is usually constructed with
a monofilic absorbable thread (3-0) and full-thickness
interrupted sutures. Because of the proximity of resection anastomosis to the contralateral vocal cord, a
transient protective (mini)tracheotomy with sufficient
distance to the anastomosis'" is fashioned (Fig. 34-6).
Type 4: Tumor invasion of the cervical trachea that
extends more than 2 em in length and more than one
third of the tracheal circumference to one or both sides
of the trachea is best dealt with by circumferential
trachea resection and primary tracheal reconstruction.
Types 3 and 4 require to some extent careful tracheal
mobilization and, in most cases, a suprahyoidal release
of the larynx. 55.56 We and others suggest avoiding
extensive mediastinal mobilization to facilitate construction of the cervical anastomosis so as not to disrupt the vascular blood supply of the trachea.57
By a combination of anteflexion and mobilization of
both trachea and larynx, about 7 cm of resectional

length can be gained. 58,59 In type 4, routine tracheostomy is frequently unnecessary provided that at
least one recurrent laryngeal nerve is intact. To verify
recurrent laryngeal nerve integrity, we routinely monitor the recurrent laryngeal and vagal nerves intraoperatively using an electromyographic neuromonitoring
device. In both types of circumferential tracheal resection, we routinely protect the tracheal anastomosis
with a sternocleidomastoid muscle flap. Covering the
tracheal suture lines with a protective muscle flap is
crucially important in combined tracheoesophageal
resections, where the esophageal anastomosis directly
adjoins the tracheotracheal anastomosis, to decrease
the risk of esophagotracheal fistula formation.
Type 5: In types 5 and 6, the airway cannot be reconstructed because of extensive bilateral tumor invasion
of the laryngocricoid area. When the pharyngoesophageal segment is not involved, laryngectomy
without cervical esophagectomy is adequate. A terminal suprajugular tracheostomy is constructed.
Type 6: In bilateral laryngocricoid and transmural
pharyngoesophageal tumor invasion, total laryngotracheoesophagectomy and construction of a terminal
tracheostomy are inevitable. When only the cervical
digestive tract is involved, a free jejunal flap seems to
be the reconstruction of choice. 6o- 64 In this instance, we
prefer to connect the mesenteric artery of the graft to
the ipsilateral external carotid artery and the mesenteric
FIGURE 34-6. Oblique sleeve resection of the trachea with primary anastomosis (type 3). This 50-year-old woman had recurrent papillary
thyroid carcinoma (PTC) invading the left cricoid portion and the trachea. A, Preoperative magnetic resonance imaging scan. B, Tumor invasion of the left cricoid and upper trachea with infiltration of the left recurrent laryngeal nerve. C, View of the right portion of larynx and
trachea that shows no tumor invasion; the right recurrent laryngeal nerve remained intact. D, Oblique sleeve resection of the left cricoid with
resection of the cervical trachea. E, Primary anastomosis after laryngeal release. F, Resected specimen showing intraluminal tumor invasion.
vein of the graft to the internal jugular vein. It is of

utmost importance to free only very short vascular segments from the mesenteric fat pad to protect the vascular anastomosis from incidental kinking and ultimately
graft ischemia. The microvascular anastomoses are
fashioned using running sutures and a monofile, nonabsorbable thread (8-0) (Fig. 34-7). Only in the event
of jejunal graft failure or mediastinal extension of
esophageal resection would we opt for a gastric
graft65.66 or colon graft67,68 supplied by the left colonic
artery for digestive reconstruction.
The general placement of a soft drainage is not recommended. Although some of the numerous surgical details
may be controversial and subject to discussion, the following principles are of major importance.
Encircling the Front of Invasion at the Aerodigestive

Level and En Bloc Resection. En bloc resection is the
cornerstone of oncologic surgery, because it minimizes tumor

spillage and thus diminishes the risk of local recurrence.
In contrast to primary aerodigestive malignancies, thyroid
cancer invades the aerodigestive tract from the outside. Hence,
the first step of en bloc resection consists of encircling
the extraluminal specimen and dissecting it off adjacent
structures in a centripetal fashion. The aerodigestive tract
should be transected only after the extraluminal portions of
the tumor have been freed, thus ensuring that the whole
tumor is resected as a single specimen, with extraluminal and
intraluminal tumor extensions in continuity. To accomplish
this goal, the front of tumor invasion is narrowed down to
the point where the tumor penetrates the aerodigestive axis.
This crucial step of preparation is achieved by using optical
magnification, as for the entire operation.
Protection of the Ipsilateral Recurrent Laryngeal

and Vagal Nerve. The ipsilateral recurrent laryngeal nerve
is involved in up to 50% of advanced thyroid carcinomas

(see Table 34-3). Therefore, preserving nerve integrity on at
least one side is highly important to maintain postoperative
speech and respiration. Intraoperative neuromonitoring
helps to identify and preserve the nerve,69,70 especially at its
point of entry at the laryngotracheal angle. Most experts
agree that perineural tumor infiltration in differentiated
thyroid cancer does not warrant resection of the nerve, in
particular when the nerve is still functioning.P'P Minimal
residual disease at the nerve can be treated with postoperative radioiodine ablation without incurring higher rates of
recurrence or poorer surviva1.9.10.72 Nonfunctioning nerves,
however, should be resected, because nerve function will
not recover postoperatively when the nerve is infiltrated.
This situation is different from that in the nerve palsies
encountered in benign goiter, which may recover when the
nerve is released. When bilateral palsy of the recurrent laryngeal nerve cannot be avoided, we and others recommend
medialization of one vocal cord, which can be performed
during the same session or in the early postoperative period."
Window Resection. Window resection, as opposed to
circumferential (sleeve, circular) resection, denotes a fullthickness wedge resection leaving intact the continuity of the
residual trachea. Although most experts in tracheal resection
have incorporated window resections into their armamentarium (Table 34-5), this type of resection continues to spark
controversial debates. The main disadvantages of this type of
resection may be insufficient tracheal stability and a higher

risk of residual disease at the tracheal margins. Several techniques have been developed to prevent instability of the
residual trachea: coverage of the resectional defect with fascia
lata, either in isolation or supported by a muscle flap,74-76
a myoperiosteal flap from the sternocleidomastoid muscle,"
or autologous grafts from distant sites,?8-81 Window resection may be indicated for small, circumscribed, invading
tumors, especially when located at the laryngotracheal
angle, that do not exceed more than 2 em in length and one
third of the tracheal circumference. More extensive tumor
invasions should be treated with sleeve resection with
circular reconstruction.
Shaving Procedures. Shaving procedures summarize all
resectional techniques on the aerodigestive tract that preserve
wall continuity while risking leaving residual cancer.
Shaving procedures are contraindicated in patients with
intraluminal invasion when the intent is curative but may be
adequate in terms of long-term survival in patients who have
only superficial tracheal wall infiltration,4.9.10,25.37,71,73.82-86
The drawbacks of shaving procedures are the impossibility to assess reliably the extent of tracheal invasion and
the risk of producing tracheal ischemia, a disastrous complication that can emerge when the trachea is too vigorously
shaved, In an era of growing expertise in laryngotracheal
resections, the need to shave should be limited to patients
who either are unable to tolerate transmural resections or
have extensive local or distant disease precluding extended
resections from an oncologic point of view, Another subgroup
who might benefit from shaving are patients who have only
superficial but not intraluminal laryngeal invasion that otherwise would require laryngectomy.
Intraoperative Frozen Section, Safety Margins. The
purpose of obtaining frozen sections in thyroid cancers
invading the aerodigestive tract is to better define the tumor
type and to ensure that all surgical margins of the resectional
specimen are free of tumor. Although it should be possible
in most instances to discriminate at least between differentiated, medullary, and undifferentiated thyroid cancers, it may
not always be feasible on frozen section to exclude reliably
minimal invasive disease at the margins, which may become
apparent only on conventional histopathology. In the study
of Nishida and colleagues (1997), 11 of 40 patients who had
negative margins on frozen section were eventually found
to have positive margins on postoperative histopathology.
At least some of those patients who have positive margins
develop local recurrences. 31.87,88 Despite the lack of systematic studies, minimal margins of normal tissue seem to be
adequate in differentiated and poorly differentiated thyroid
cancers from an oncologic standpoint. This is in contrast
to squamous cell and anaplastic carcinomas of the upper
aerodigestive tract.
Mediastinal Tracheal Resection. Mediastinal tracheal
resection in thyroid cancer is rarely indicated. Tracheal invasion below the offspring of the innominate artery is often
associated with involvement of the great mediastinal vessels,
a constellation that frequently precludes radical resection on
oncologic grounds. The rare exceptions where resection of the
mediastinal trachea may be warranted include short-distance
invasions related to local recurrence or lymph node metastases. In addition to a complete sternal split, resections on
FIGURE 34-7. Cervical evisceration (type 6). This 69-year-old woman had recurrent follicular cancer. The patient came to operation with
tracheostomy and feeding tube via gastrostomy. A, Cervical exploration with assessment of resectability. E, Resection of larynx, cervical
trachea, and esophagus. C, Resected specimen showing tumor invasion of laryngotracheal (left) and pharyngoesophageal (right) areas.
D, First step of jejunal free graft transplantation: jejunoesophagostomy (end to end). E, Second step: hypopharyngojejunostomy (end to
end). F, Third step: arterial anastomosis with mesenteric artery and external carotid artery (end to end). G, Fourth step: venous anastomosis
with mesenteric vein and internal jugular vein (end to side). H, Gastrografin demonstration of intact digestive anastomoses at the seventh
postoperative day.
the mediastinal trachea necessitate a complete release of the

cervical and mediastinal trachea. This resection is fraught
with an increased risk of anastomotic leakage when the cuff
of the endotracheal tube is positioned over the tracheotracheal anastomosis.
Pharyngoesophageal Invasion. Pharyngoesophageal
invasion only is less frequent (see Tables 34-3 and 34-5) and
usually does not require reconstructions as complex as invasions of the upper airway. Because of its position behind the
trachea, transmural invasionof the esophagus mainly occurs in
combination with extensive laryngotracheal or tracheal invasion. In most instances, however, extramucosal esophageal
resection eradicates the tumor. The esophageal defect is closed
by simple approximation and primary suture of the extramucous esophageal wall. When a transmural esophageal resection is necessary, the remaining distance between the margins
after esophageal release determines whether simple approximation and primary suture are adequate or whether a jejunal
free graft is required for reconstruction.
Postoperative Care. Apart from the complexity of the
procedures themselves, the association between old age
and aerodigestive tract invasion demands the dedication
of surgeons, surgical residents, nurses, and ancillary staff
involved in postoperative care. Except for rare patients in
whom prolonged intubation and mechanical ventilation are
required for other reasons, patients with tracheal anastomoses should be extubated immediately after the operation.
Because of the inevitable contamination with the flora of
the upper aerodigestive tract, antibiotics should be routinely
administered preoperativelyfor prophylaxis. In laryngocricoid
resections, the moderate use of systemic steroids may reduce
laryngeal edema. When patients undergo prolonged intubation, both cuff pressure and cuff position relative to the
tracheal anastomosis must be repeatedly checked to avoid
local tracheal ischemia.
After reconstructions using a free jejunal graft, the jejunal graft must be closely inspected for mucosal ischemia as
an indicator of compromised graft perfusion, especially in
the immediate postoperative period. Vascular complications
are exceptional after the second postoperative day. Parenteral
feeding can be resumed 6 days after the jejunal transfer when
anastomotic leakage has been ruled out by a diatrizoate
meglumine (Gastrografin) swallow.
Complications. After such complex procedures, serious
early and late complications may ensue. The management
of these complications requires extensive experience and
skills. In 317 cervicovisceral resections reported on during
the last 3 decades, hospital mortality was approximately 4%
(see Table 34-5). The impact of the learning curve on morbidity was demonstrated in a multi-institutional study from
Japan." In this series, the complication rate of tracheoplasty
that was performed for a variety of conditions (l 0% of which
involved thyroid cancer) progressively declined since the
1960s. The complication rate increased significantly with
the extent of tracheal resection and was excessive after
resection of more than eight tracheal rings. Tracheal anastomosis with resorbable sutures tended to involve less complications than that with nonresorbable sutures. Surgical
experience obviously mattered more than the type of suture
used. Anastomotic dehiscence was the second most common
complication (33% of complicated cases), associated with a
48% death rate.
330 - -
Thyroid Gland
Apart from the high lethality of anastomotic dehiscence,

arterial rupture of the right common carotid artery or innominate artery, albeit rare, may emerge after tracheal resection,
typically during the second half of the first postoperative week.
First published by Korte" (1879) after simple tracheostomy,
this disastrous complication can develop after tracheal resection, mediastinal tracheostomy, cervical reoperation, and
after external irradiation with or without preceding cervical
operation.P" Risk factors predisposing to arterial rupture
include lymphatic fistula, hematoma, and wound infection.46-50
In some wound infections, Staphylococcus aureus was
identified as the infectious agent. Arterial rupture is a highly
dramatic and life-threatening event that necessitates immediate intervention to save the patient from instant exsanguination. Median sternotomy must be performed to obtain
control of the proximal innominate and subclavian arteries.
The arterial defect can be resected and then reconstructed,
using, for instance, a saphenous vein autograft.v"
Palliative Local Procedures. Palliative local procedures
are reserved for end-stage disease in patients with thyroid
cancer invading the aerodigestive tract when radical surgery
is not feasible or is contraindicated. With the advent of interventional techniques, in particular intraluminal stenting and
laser ablation,46-5o,96 extensive although not radical resections
that leave gross tumor at the resection margin are rarely indicated. Moreover, these new techniques relegate permanent
tracheostomy to a last-resort procedure reserved for desperate
situations.
Tracheostomy may not be a simple procedure in patients
who have extensive involvement of the aerodigestive tract
and, thus, patients are at an increased risk for major complications such as bleeding, infection, obstruction, or tracheoesophageal flstula.97,98 Therefore, tracheostomy should no
longer be portrayed as the one and only palliative alternative to
radical surgery.
Additive Treatment (Radioiodine Therapy. External
Irradiation). Radioiodine treatment and external irradiation
are recommended as additive therapies for thyroid cancer
patients who reveal bulky or minimal residual disease.
However, the efficacy of both modalities in achieving local
control of tumor is doubtful and unproved in this setting.
Radioiodine treatment in differentiated thyroid cancer responsive to radioiodine may be an effective adjunct to shaving
procedures when the residual tracheal invasion is minimal.
Conversely, some suggest that radioiodine treatment is not
effective for local tumor control after nonradical surgery.82
Some tumors also fail to recur after subtotal resection despite
positive surgical margins and the failure to initiate postoperative radioiodine ablation,87.88
Likewise, external irradiation for aggressive thyroid cancers has not always improved survival. 99-102 Nevertheless,
there are also proponents of external radiotherapy in differentiated thyroid carcinoma with extrathyroidal growth. 103-105
In most of these studies, the benefit was limited to local recurrence only, but survival was not improved,I06-108 Considering
these data, radioiodine treatment seems to be useful in minimal residual disease after shaving procedures or tracheal
resections and for patients with distant metastases that take
up 131I. Whether external irradiation has a role in patients with
major aerodigestive tract invasion is still to be elucidated.
When gross residual tumor remains after partial resection,
external radiotherapy may be unable to prevent local

recurrence." Therefore, external radiotherapy should be
reserved for patients who have irresectable progressive local
disease and patients who have positive tumor margins after
extensive resection.
Long-Term Results
after Surgery
In aerodigestive tract invasion, the type of thyroid cancer,
the presence of nonpulmonary distant metastases at initial
resection, the extent of local tumor invasion, and the patient's
age are the four universally recognized determinants of
survival. 5,8,12,29,3o Unfortunately, all clinical studies comparing
different surgical strategies, such as shaving procedures,
radical, incomplete, and palliative resections,4.9,IO,12,25,7I,73,8287,109,110 are retrospective and uncontrolled. In addition, the
populations studied are not comparable with regard to
the biologic determinants of survival (Table 34-6). None of the
studies excluded patients with intraluminal airway invasion,
whose survival is much lower. 5I For cure, these patients
would require complete resection of the involved part of the
airway. Given the rarity of thyroid cancer in general and
of aerodigestive tract invasion in particular (see Table 34-1),
it is virtually impossible to set up a controlled prospective
trail large enough to yield unbiased results for different
types of treatment.
Summarizing the data shown in Table 34-6, the following
conclusions can be drawn: at present, there are only eight
studies available that compare different surgical strategies for
thyroid cancers invading the aerodigestive tract. All studies
are retrospective and fail to specify known determinants of
survival such as patients' age, extent of tumor invasion, type
and differentiation of thyroid cancer, or presence or absence
of distant metastases. Keeping these shortcomings in mind,
shaving procedures, complete resections, or both clearly fared
better than incomplete resections in all seven pertinent
studies. 4,25,82,83,87,109,111 This finding was significant in three
studies,83,I09,l11 Comparing shaving and complete resections, four of six studies found no difference in terms of
surviva1.4,83,109,11O In only one of these six studies, survival
was significantly better in the complete resection group than
in the shaving group. III
In conclusion, incomplete resections are associated with
local recurrence and decreased survival. Nevertheless, some
patients may enjoy a remarkably long life after palliative
resection. With the exception of one study, complete resection and shaving procedures produced comparable results in
terms of survival. Although incomplete or shaving resections
are not indicated in patients with intraluminal invasion of
thyroid cancer, shaving resections may be beneficial in
case of superficial laryngotracheal invasion. In experienced
hands, deep wall invasion of the aerodigestive tract may be
treated by radical resection. In addition, owing to the lack of
controlled and unbiased data, the decision about the extent
of resection has to be based on individual factors such as
patient's age, type of tumor, progressive distant disease, and
physical and mental condition. Given the tremendous challenge posed by aerodigestive involvement, every effort must
be undertaken to prevent this disastrous condition by detecting
and eliminating thyroid cancer before it invades the aerodigestive tract.
Summary
Aerodigestive tract invasion by thyroid cancer affects approximately 6% of patients with thyroid cancer, representing
one of the most demanding disease-related complications in
endocrine surgical oncology. Two thirds of patients with
advanced thyroid cancer suffer from invasion of the upper
airway, whereas pharyngoesophageal involvement accounts
for only approximately 20% to 25%. Because of the more
aggressive biology of the tumors and older age of the patients,
aerodigestive tract involvement signifies a "negatively"
selected group of thyroid cancer patients. Aerodigestive
invasion poses a real challenge to both surgeon and patient.
Because the aerodigestive tract is located at the crossroads
of various medical disciplines, a joint interdisciplinary effort
is essential for the best outcome in these patients with
advanced thyroid cancer. When combined, modem diagnostic
technologies can often differentiate among extramural,

intramural, and intraluminal as well as local and distant
tumor invasion. Preoperative work-up of the patient is
directed at determining technical resectability and operability, both of which are prerequisites for surgery.
The surgical approach to the upper aerodigestive tract is
dependent on the extent of wall invasion and, for visceral
resection, on the anatomy and adequacy of the arterial blood
supply to the larynx, trachea, and esophagus. Accordingly,
there are six types of upper airway resection: type 1, window
resection at the laryngocricoid level; type 2, window resection of the trachea; type 3, oblique sleeve resection of the
laryngocricoid; type 4, horizontal sleeve resection of the
trachea; type 5, laryngectomy; and type 6, cervical evisceration. Resection with curative intent aims at removing the
extraluminal, intramural, and intraluminal portions of the
tumor in a single surgical specimen. As in other solid cancers,
centripetal preparation and en bloc resection are the
principles of oncologic surgery in thyroid cancer. Shaving
procedures violate these basic rules of surgical oncology.
Nonetheless, shaving procedures may be indicated in

elderly patients with partial-thickness invasion and/or
progressive multiple distant metastases that are not amenable
to resection.
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Potentially New Therapies in

Thyroid Cancer
Jin-Woo Park, MD Quan-Yang Duh, MD Orlo H. Clark, MD
Differentiated thyroid cancer (DTC) of follicular cell

origin is a fascinating tumor because of its varying aggressiveness. Fortunately, most patients with these cancers,
despite regional metastasis, can be cured by surgical resection, radioiodine ablation, and thyroid-stimulating hormone
(TSH) suppression therapy. Unfortunately, patients with
poorly differentiated thyroid cancers or anaplastic thyroid
cancers usually fail to respond to this combined therapy.
These tumors usually grow rapidly, invade adjacent structures, and spread to other parts of the body. During the
dedifferentiation process, they lose thyroid-specific gene
expressions, including the ability to take up and organify
radioiodine and to make thyroglobulin (TG). The methods
used to treat patients with DTC are therefore usually not
effective in these patients. These tumors also usually fail to
respond to alternative treatment with external radiation or
systemic cancer chemotherapy. Medullary thyroid carcinomas are also highly aggressive, and there is no alternative if
patients do not respond to surgical treatment. We therefore
need to develop novel treatments for these unfortunate
patients.
Advances in molecular and cellular biology make it possible to develop new therapeutic approaches to thyroid cancer.
These approaches can be divided largely into two categories
regarding treatment targets. Redifferentiation therapy targets
thyroid-specific genes to restore thyroid-specific differentiated function and to make the tumors respond to conventional therapy. The other possible category of treatment
targets several cancer-related genes or their products that do
not depend on thyroid-specific genes but depend on altered
characteristics of thyroid cancer cells during tumorigenesis
(Fig. 35-1).
Therapeutic approaches described in this chapter have
established effects in vitro, but the majority of them are not
ready for medical practice yet. Careful clinical trials and
analyses should be performed.
334
Restoration of Differentiated
Thyroid Function
Redifferentiating Agents
DTCs of follicular cell origin (papillary and follicular cancers)
are usually well differentiated and behave in a nonaggressive
manner. However, some lose differentiated functions (dedifferentiation) and behave more aggressively. These cancers
become refractory to thyroid-specific therapies that are
based on differentiated thyroid function such as radioiodine
therapy and thyrotropin (TSH)-suppressive therapy.
Restoring differentiated functions in these tumors may not
only slow tumor growth but also resensitize tumors to
thyroid-specific therapy such as treatment with radioactive
iodine. Redifferentiating therapies are tissue specific and
generally less toxic than nonspecific chemotherapy. There
are several redifferentiating agents for thyroid cancers:
(1) retinoids, (2) aromatic fatty acids, (3) peroxisome
proliferator-activated receptor y (PPARy) agonists, and
(4) histone deacetylase inhibitors.
RETINOIDS
Retinoids have been shown to modulate cell growth and differentiation by binding to their receptors' The mechanism
of action of retinoids is not completely understood. There
are two classes of receptors: retinoic acid receptor (RAR)
and retinoid X receptor (RXR). Each class has three subtypes, o, ~' and y.Although RAR and RXR function as either
homodimers or heterodimers, RAR-RXR heterodimers and
RXR-RXR homodimers are predominant. To activate transcriptional activity, RAR-RXR heterodimers bind to RA
response element (RARE) and RXR homodimers bind to
retinoid X response element (RXRE) (Fig. 35-2).2,3 RXRs
also heterodimerize with the vitamin D receptor (VDR),
thyroid hormone receptor (T3R), and PPAR.4
Potentially New Therapies in Thyroid Cancer - LOH 3p,

7q21.1-7q31.1,
10q, 17p,
T(2;3)(q13;p25)
Functioning
follicular
adenoma
Follicular
carcinoma
Follicular
adenoma
FIGURE 35-1. Proposed multistep
tumorigenesis model for thyroid carcinoma. LOH = loss of heterozygosity;
TSH-R =TSH receptor. (Modified from
Learoyd DL, Messina M, Zedenius J,
et al. Molecular genetics of thyroid
tumors and surgical decision-making.
World J Surg 2000;24:923.)
335
Poorly
differentiated
carcinoma
Thyrocyte
p53
Anaplastic
carcinoma
RET/PTe, trk
met, res, gsp
Braf
There are several natural retinoids or ligands such as alltrans-retinoic acid (all-trans-RA), 13-cis-RA, and 9-cis-RA.
All-trans-RA binds only with RAR, but 9-cis-RA binds with
both RAR and RXR. 13-cis-RA converts to all-trans-RA
in vivo. There are also synthetic ligands such as LGD1550
(RAR a1~/y agonist), tazarotene (RAR ~/y agonist), AM80
(RAR ex agonist), and LGDl069 (RXR agonist).
The antiproliferative and redifferentiating effects of
retinoids have been demonstrated in many human cancers,
including thyroid cancer.5 ,6 RA induces cell cycle arrest in
FIGURE 35-2. Basic mechanisms of action

of retinoids and peroxisome proliferatoractivated receptor y (PPARy). The retinoid
receptors are activated by specific ligands:
retinoic acid receptor (RAR) by all-transretinoic acid (all-trans-RA) or 9-cis-retinoic
acid (9-cis-RA); retinoid X receptor (RXR)
by 9-cis-RA. The PPARy is activated by specific ligands such as thiazolidinedione (TZD)
derivatives or aromatic fatty acids. Activated
receptors bind with each other and form
homo- or heterodimers. These in turn bind
to specific response elements to promote
the transcription of target genes: retinoic
acid response element (RARE), retinoid X
response element (RXRE), and PPAR response
element (PPRE). The transcription of these
genes then induces growth inhibition and
redifferentiation.
the Gon phase with a reduced level of cyclin D1 and cyclindependent kinase 2 (CDK-2) messenger RNA (mRNA)
and protein, which leads to reduced phosphorylation of the
retinoblastoma protein." RA treatment increased mRNA for
the sodium-iodide symporter (NIS) and radioactive iodine
uptake in vitro in human thyroid cancer cells."!" In clinical
trials, about 40% of patients treated with RA have had
increased radioiodine uptake. 11
Although these effects are generally reversible and usually
do not result in a dramatic clinical response, some patients

are helped by this treatment and combined treatment with
other drugs may improve the effect of this therapy.
AROMATIC FATTY ACIDS: PHENYLACETATE,
PHENYLBUTYRATE
There is increasing evidence that aromatic fatty acids such

as phenylacetate and phenylbutyrate induce tumor growth
inhibition and redifferentiation in vitro, in vivo, and also
in some clinical trials. 12-15 Aromatic fatty acids act through
multiple mechanisms. They can block the tumor cell access
to free glutamine and also block the isoprenylation of ras
family proteins. 16 Histone deacetylase inhibition and PPARy
activation are other suggested mechanisms of action. 17-19
Phenylacetate is a metabolite of phenylalanine. It accumulates in phenylketonuria and is associated with brain
damage. It has been used to treat children who have urea
cycle disorders. Phenylbutyrate metabolizes to phenylacetate
in humans. Phenylacetate often induces differentiation and
apoptosis in human cancer cell lines at concentrations that
have been safely used in humans. Phenylbutyrate seems to be
more potent in inducing apoptosis than phenylacetate." It is
also reported that aromatic fatty acids can modulate sensitivity
to chemotherapy when combined with chemotherapeutic
drugS.21-23
Kebebewand colleagues reported that phenylacetate induced
cytostasis in the GOII cell phase and induced radioiodine uptake
in thyroid carcinoma cell lines.24 They also reported that
phenylacetate decreased the TSH growth response, TG secretion, and the secretion of vascular endothelial growth factor
(VEGF) in the thyroid cancer cell lines.
Differentiating agents can be synergistic or additive in
combination with other differentiating agents acting by other
mechanisms. A combination of RA and phenyl acetate had
synergistic antiproliferative effects in follicular thyroid
cancer cell lines," Phenylbutyrate also seems to induce more
apoptosis than phenylacetate at the same concentration in
thyroid cancer cell lines.
PEROXISOME PROLIFERATOR-ACTIVATED
RECEPTOR YAGONIST
PPAR belongs to the nuclear hormone receptor superfamily

implicated in inhibition of cell proliferation and induction of
cell redifferentiation-" PPAR has three isoforms, ex, 8, and y.
They are ligand-dependent transcription factors that must
form heterodimers with the RXR receptor in order to bind to
their response elements (PPREs) and activate transcription
(see Fig. 35-2).27
Among numerous PPARy agonists, thiazolidinedione
(TZD) derivative antidiabetic drugs such as troglitazone,
pioglitazone, and rosiglitazone are newly discovered potent
PPARy agonists.P-" Investigations have shown that TZD
derivatives are not only insulin sensitizers but also inhibit
proliferation of human breast, prostate, bladder. colon, lung,
and gastric cancer cells in vitro. in vivo, or both. 30-35
In thyroid carcinogenesis, PPARyappears to play an important role, especially in follicular thyroid cancer. A chromosomal translocation creating a fusion protein of PAX8-PPARyl
was found in five of eight follicular thyroid carcinomas but
not in follicular thyroid adenomas or papillary thyroid carcinomas, and this abnormal fusion protein is a dominant negative suppressor of wild-type PPARyactivity.36
Ohta and colleagues reported antiproliferative effects in

vitro and growth inhibition in vivo of troglitazone in papillary
thyroid cancer cell lines.37 In our investigations, human thyroid
cancer cell lines express PPARy variably, and chromosomal
translocations involving PPARy are uncommon. Troglitazone
induced antiproliferation in papillary, follicular, Hilrthle cell,
and anaplastic thyroid cancer cell lines. Its action can be
explained in part by cell cycle arrest in the GOII phase and
apoptotic cell death. We also demonstrated downregulation of
CD97, a thyroid dedifferentiation marker, in thyroid cancer
cell lines treated with troglitazone." Treatment with PPARy
agonists might be a useful new medical therapy for patients
who have poorly differentiated thyroid cancers by inducing
growth inhibition and redifferentiation.
HISTONE DEACETYLASE INHIBITOR
Histone acetylation and deacetylation can modulate chromatin structure and regulate gene expression related to DNA
replication, transcription, differentiation, and apoptosis."
Reversible acetylation of s-amino groups of lysine residues
in the aminoterminus of histone is controlled by histone
acetyltransferases (HATs) and histone deacetylases (HDACs)
(Fig. 35-3). HATs lead to the relaxation of chromatin structure and transcriptional activation, whereas HDACs lead to
chromatin condensation and transcriptional repression of
target genes.'? There is increasing evidence that a disorder in
equilibrium of histone acetylation can be associated with
tumor development."
HDAC inhibitors such as depsipeptide (FR901228), trichostatin A, and suberoylanilide hydroxarnic acid (SAHA)
are promising new anticancer agents. HDAC inhibitors induce
hyperacetylation of chromatin and activate genes that are
related to differentiation and apoptosis in cancer cells. 42,43
Depsipeptide (FR901228) is currently in phase I clinical
studies and the results of treatments are promising.r'
In thyroid cancer cells, HDAC inhibitors inhibit cell proliferation by inducing apoptosis through activation of the
caspase cascade and cell cycle arrest at G[ and G 2/M by a
reduction in cdk2- and cdkl-associated kinase activities."
In addition to the antiproliferative effects, HDAC inhibitors
can modulate expression of several genes. Thyroid-specific
genes can be transcriptional targets controlled by the acetylation status of histones. In particular, Kitazono and coauthors
reported that depsipeptide markedly increased the mRNA
level of NIS and resultant radioiodine uptake in low concentrations." Zarnegar and colleagues demonstrated NIS
expression in different thyroid diseases. They also demonstrated that trichostatin A dramatically increases NIS expression and resultant radioiodine uptake in low concentrations.
Trichostatin A inhibits cell proliferation by inducing apoptosis
and cell cycle arrest at the G 2/M phase in a dose-dependent
manner," Methylation is another mechanism of transcriptional
repression of certain genes. Combinations of inhibitors for
these processes might be synergistic because these two
epigenetic processes are closely linked."
Gene Therapy
Cancer gene therapy is the transfer of nucleic acids that can
replace defective genes or introduce suicide genes or immune
modulator genes. During the past several years, there have
Potentially New Therapies in Thyroid Cancer - -
337
FIGURE 35-3. Reversible acetylation of histones by histone acetyltransferase (HAT) and histone
deacetylase (HDAC). Acetylation
status can affect transcriptional
activity of the specific gene by
transcriptional factor (TF).
been remarkable technical advances in terms of transfection

efficiency and tissue specificity, Gene therapy for cancer has
moved from success in laboratory practice to clinical trials.
Several genes have been considered as candidates for gene
therapy in thyroid cancer, Differentiation-related genes such
as p53, 1TF-l, PAX-S, and NIS were introduced to retard
cancer cell growth or induce redifferentiation. Thyroidspecific promoter and HDAC inhibitors have been used to
increase transcriptional activity and tissue specificity in thyroid cancer cell lines.49,50 Currently, many investigators are
trying to improve the efficiency of tissue-specific, multigene,
transfection therapy.
differentiation-related genes or other effective genes might be

needed, In addition to the role of wild-type p53 in dedifferentiation of thyroid cancers, thyroid-specific transcriptional
factors, such as TTF-l, TTF-2, and PAX-8, are closely
related to thyroid-specific differentiated functions such as
radioiodine uptake. 58-6o It was reported that overexpression
of TTF-l and PAX-8 restored TG gene promoter activity in
thyroid cancer cell Iines."' Further investigations are necessary to determine whether cotransfection of wild-type p53
and thyroid-specific genes is more effective in inducing
redifferentiation.
P53, TTF-l, PAX-B
After surgical resection of the thyroid gland and tumor in

patients with DTC of follicular cell origin, regional or distant
metastases are often effectively treated with radioiodine,
Iodide uptake by thyrocytes is mediated by NIS. Most differentiated thyroid carcinomas express NIS, and NIS expression correlates with clinical radioiodine uptake.f However,
some differentiated and most undifferentiated thyroid carcinomas fail to express NIS, These tumors lack the ability to take
up iodide and are thereby refractory to radioiodine therapy.63.64
Many investigators have tried to restore NIS expression
in thyroid cancer cells. 10,24,58 There are two remarkable
advances in this field: HDAC inhibitors and gene therapy
using the NIS gene. Cloning and characterization of the NIS
gene made it possible to try gene therapy using this gene in
both thyroid and nonthyroid malignancies. Several clinical
trials using NIS gene transfection for triggering significant
iodide uptake in nonthyroid tumors are under way.65-67
In thyroid cancer, transduction of human NIS (hNIS) in a
follicular thyroid cancer cell line (FfC-133) induced high
uptake of radioiodine in vitro and also in vivo in a xenograft
model/" Although the transduction of the hNIS gene can
induce radioiodine influx, it is followed by rapid efflux.
Most DTCs do not have p53 gene mutations, whereas some

poorly differentiated thyroid cancers, most anaplastic thyroid
cancers, and established thyroid cancer cell lines have p53
mutations.?' Several investigations suggest that undifferentiated thyroid carcinomas originate from differentiated ones,
It therefore appears that p53 mutations occur as a late
genetic event associated with dedifferentiation of thyroid
tumor cells and immortalization of cell lines.
Gene therapy with wild-type p53 in thyroid carcinoma
cells in culture that had a p53 mutation showed that it
(1) induced growth arrest (not apoptosisj.P (2) increased
thyroid-specific gene expression" (3) enhanced the
response to chemotherapy and radiation therapy,54,55 and
(4) downregulated expression of thrombospondin (TSP) 1 (not
VEGF),56,57 However, it seems unlikely that gene therapy with
wild-type p53 gene alone will become an effective treatment
in patients who have poorly differentiated thyroid cancer or
anaplastic thyroid cancer. It induced growth arrest rather than
apoptotic cell death in most studies and it rarely induced
thyroid-specific gene expression, especially for radioiodine
uptake. For it to be an effective treatment, cotransfection of
SODIUM-IODIDE SYMPORTER (NIS) GENE

Inhibition of iodide efflux has to be added for a therapeutic
application of the hNIS gene. Iodide efflux could be inhibited by cotransfection of the thyroperoxidase gene (TPO),
decreasing pendrin (PDS) gene activity, or combination with
lithium treatment. 69,70
For transcriptionally targeted gene therapy, the TG promoter can be used. Thyroid-specific transcription factors
such as TIF-l, TTF-2, or PAX-8 closely interact with the
TG promoter. TG promoter activity, however, may not
be enough in poorly differentiated and anaplastic thyroid
cancer cells that also have defects in these transcriptional
factors. Cotransfection of these genes may enhance TG
promoter activity."
Treatments Independent of
Differentiated Thyroid Function
Cytotoxic Drugs
GEMCITABINE
Gemcitabine is a new antimetabolite drug. Gemcitabine is a

deoxycytidine analog and induces antiproliferative activity
by phase-specific killing of cells undergoing DNA synthesis
and blocking the cell cycle progression through the GI/S
phase. Gemcitabine has dose-dependent synergistic activity
with cisplatin. Data from two randomized clinical studies
support the use of combined treatment with gemcitabine and
cisplatin for treatment of patients with locally advanced or
metastatic cancers including non-small cell lung cancer and
prostatic cancer. n ,73 Combination of gemcitabine and other
cytotoxic drugs such as vinorelbine, cyclophosphamide, or
paclitaxel is also currently under clinical study.
Antitumor activity of gemcitabine is also observed in thyroid cancer cells in vitro. Gemcitabine induced apoptosis,
cell cycle arrest in the S phase, and upregulation of Fas in
poorly differentiated or anaplastic thyroid cancer cell lines.r'-"
A multimeric form of gemcitabine appears to be more potent
for inhibition of tumor cell growth than the monomeric form
in thyroid cancer cells in vitro." In a medullary thyroid cancer
cell line, IT, gemcitabine also induced an antiproliferative
effect and decreased neuroendocrine activity." Gemcitabine
and cisplatin in combined treatment are also synergistic in
thyroid cancer cell lines. Voigt and colleagues reported that
combined treatment is schedule dependent and effective only
when gemcitabine is followed by cisplatin, not vice versa, in
anaplastic thyroid cancer cell lines."
Although small numbers of patients with thyroid cancer
were included in phase I clinical trials using gemcitabine,
further clinical studies are required to confirm the safety and
effectiveness of regimens including gemcitabine."
GELDANAMYCIN
Geldanamycin is a specific inhibitor of heat shock protein

90 (Hsp90). Hsp90 is one of the most abundant chaperone
proteins in the cytosol of eukaryotic cells. It helps newly
synthesized proteins make stable conformations (maturation)
or helps translocate them to their ultimate locations."? It
plays an important role in stress such as heat shock, and
it is associated with the mitogen-activated signal cascade.
It is also an essential component for fundamental cellular

processes such as hormone signaling, cell cycle control, proliferation, and differentiation under physiologic conditions.P
Although Hsp90 is essential for eukaryotic cells and its inhibition may cause significant toxicity, cancer cells appear to
be more sensitive to inhibition of this chaperone's activity,
Hsp90 expression can be upregulated by mitogen or growth
factor stimulation, and it is higher in tumors than in normal
tissues." Hsp90 may therefore playa critical role in tumor
cell growth or survival, or both. Several oncoproteins, such
as Raf-l, erbB family receptors, and mutant p53 proteins,
are reported to be substrates for Hsp90, and they can change
their conformation and be stabilized by Hsp90. 82-84
The National Cancer Institute screened drug sensitivity
to geldanamycin in 60 tumor cell lines in vitro and reported
that geldanamycin is a promising anticancer drug effective
at nanomolar concentrations." Our investigations using
human thyroid cancer cell lines demonstrated that geldanamycin inhibited cell proliferation, downregulated
oncoproteins, and inhibited epidermal growth factor
(EGF)-induced invasion. 86
Although geldanamycin is a novel anticancer drug based
on differential dependence on Hsp90 between cancer cells
and normal cells, significant side effects related to inhibition
of diverse substrates for Hsp90 are inevitable and may limit
its clinical usefulness, However, continued characterization
of the ansamycin binding site on Hsp90 will make
it possible to develop more substrate- or tissue-specific Hsp90
inhibitors. The results of a phase I clinical trial using the
geldanamycin analog 17-allylamino-17-dernethoxygeldanamycin (l7-AAG) were reported by Memorial SloanKettering Cancer Center.s? They suggested that clinically
achievable concentrations of 17-AAG exceed those that
were effective in preclinical models. Structurally different
Hsp90 binding drugs such as radicicol have also been
introduced as a second class of Hsp90 inhibitors.
Gene Therapy
Gene therapy in thyroid cancer can be designed to kill cancer
cells independent of thyroid-specific function. Suicide gene
therapy was designed to kill the thyroid cancer cells by
chemosensitization. Immune modulatory genes such as interleukin 2 (IL-2) and IL-12 have been studied for immunotherapy. A thyroid-specific promoter such as TG promoter can
make the gene therapy more tissue specific, and multigene
transduction can make the gene therapy more effective.
SUICIDE GENE
Suicide gene therapy is the transduction of chemosensitization genes that can transform a nontoxic form of a drug
(prodrug) into a toxic substance. A classic example of this
therapy is transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene with nucleoside analogs, such as
acyclovir or ganciclovir. It is, however, difficult to transfect
all of the target cells. A bystander effect is therefore an
important aspect of suicide gene therapy.V With a bystander
effect, this strategy has been evaluated for possible treatment of localized tumors. Suicide gene therapy is currently
in clinical trials for several human cancers including
melanoma, glioblastoma, and breast cancer.":"
Potentially New Therapies in Thyroid Cancer - - 339
HSV-tk and prodrug therapy has been reported to induce

antitumor activity in thyroid cancer cell lines in vitro and
in vivo/? A thyroid-specific promoter such as TG promoter
with or without the Cre-IoxP system (site-specific recombination system) increased tissue specificity and decreased
toxicity.93-95
INTERLEUKIN 2 AND INTERLEUKIN 12
IL-2 is associated with augmentation of antitumor T-cell and

natural killer cell activity; IL-12 also plays an important role
in the development of cellular immunity. Although systemic
administration of recombinant interleukins has demonstrated
antitumor activity, systemic toxicity with increasing dosage
and longer exposure has been observed. 96.97 Appropriate
local production of interleukins without systemic toxicity
can be achieved by gene therapy.
Gene therapy using IL-2 or IL-12 has been well studied in
medullary thyroid cancer models. In rat and mouse medullary
thyroid cancer models, transduction of IL-2 or IL-12 resulted
in tumor regression and loss of tumorigenicity without significant toxicity.98-IOO Gene therapies in these models also induced
regression of an established tumor at a distant site and longlasting tumor-specific immunity. Furthermore, combining suicide and immunoregulatory gene therapies (IL-2) enhanced
tumor growth inhibition and immune reaction in a rat xenograft
model.'?' Immunoregulatory genes can be added in multigene
therapy in combination with a thyroid-specific promoter.
ErbB Family of Tyrosine Kinase Receptors

The tyrosine kinase receptors of the ErbB family are important receptors involved in cellular proliferation, differentiation, and survival and are widely expressed in malignant
tissue. Overexpression of EGF receptor (EGFR) has been
associated with cell proliferation, invasion, angiogenesis,
and both chemoresistance and radioresistance. It is therefore
natural to target these receptors in cancer therapy.
EGFR and ErbB2 are frequently expressed in papillary
thyroid cancer and are reported to be associated with lymph
node metastases and recurrence. 102-105 Haugen and colleagues suggested autocrine stimulation of EGFR by transforming growth factor a (TGF-a) in papillary thyroid
cancers.l'" EGF and TGF-a enhanced invasion and growth
of DTC cells in vitro and in vivo by binding to the EGF
receptors. EGF- and TGF-a-mediated effects were blocked
by a monoclonal antibody to EGF receptor (Mab528) or
genistein, a tyrosine kinase inhibitor.l'" However, treatment
with anti-EGFR antibody alone failed to induce growth
inhibition. 108 Anti-EGFR antibody treatment may be effective
for therapeutic use in combination with other chemotherapeutic agents or conjugation with radioiodine.
Transduction of a normal human ErbB2 gene changed the
growth property of rat thyrocytes. Thyroid cells transformed
with ErbB2 can grow in the absence of thyrotropin and do
not respond to the growth-inhibitory effect of TGF_~.109
Ligand binding of both thyroid hormone (T3) and RA receptors inhibited the transcriptional activity of EGF receptor
and ErbB2 prornoter.!'?
Several compounds targeting the ErbB family or its
downstream cascade are in clinical studies and demonstrate
promising results (Fig. 35-4). IMC-225 (cetuximab,
anti-EGFR) and trastuzumab (Herceptin, anti-HER2/neu)

are monoclonal antibodies, and ZD1839 (Iressa) and
OSI-774 (Tarceva) are selective EGFR-tyrosine kinase
inhibitors.Ul-l'? To our knowledge, the therapeutic utility of
these drugs in patients with thyroid cancer has not been
evaluated.
Metalloproteinase Inhibitor
Matrix metalloproteinases (MMPs) and the plasmin activation system are proteolytic enzymes that play a crucial
role in extracellular matrix (ECM) degradation in many
cancers. This degradation is very important in tumor growth,
invasion, and metastasis. Angiogenesis requires MMPs
that degrade ECM for endothelial cell invasion. On the
other hand, MMPs also produce anti angiogenic protein
fragments. I13
MMP activity depends on interaction between MMPs,
membrane-type MMPs (MT-MMPs), tissue inhibitors of
matrix metalloproteinases (TIMPs), and ECM metalloproteinase inducer (EMMPRIN). Stromal cells make most
MMPs in cancers. Cancer cells induce synthesis of MMPs
by stromal cells through EMMPRIN and cytokine stimulatory mechanisms. 114
Thyroid cancer cells overexpress MMP-l, MMP-2 (or
increase the proMMP-2 activation ratio), MMP-9, and MTlMMP. Overexpression usually correlates with more aggressive behavior such as advanced stage, tumor invasion, and
lymph node metastases.I'>!'? Cytokines, growth factors,
and hormones can stimulate cancer cell invasion in vitro.
This stimulation occurs in part through MMP activity. The
modulation of MMPs appears to depend on the cell lines
and stimulator.Us!'? Thyroid cancer cell invasion can be
FIGURE 35-4. Strategies for ErbB family inhibition. mAb =

monoclonal antibody.

stimulated by IL-l, tumor necrosis factor a (TNF-a), EGF,
and TSH.I17,120.121.122 MMP-9 was induced by IL-l, TNF-a,
and phorbol esters but MMP-2 was not.'!? Growth factors generally upregulate expression of MMP-2 and MMP-9, but EGF
stimulation appears to increase invasion in part through MMP-l
in thyroid cancer cell lines.P' The effects of TSH on growth,
migration, and invasion of thyroid cancer cells were biphasic,
with an increase at low and a decrease at high concentrations.120 TSH induced invasion of thyroid cancer cells through
the activation of urokinase-like plasminogen activator (uPA)
and basement membrane type IV collagenase.P? but TSH
inhibited EGF-induced MMP-l expression.'!' Interaction
between thyroid cancer cells and tumor-derived fibroblasts
also appears to be important in the balance of MMP activity.'!"
Inhibition ofMMP activity has been studied as a new anticancer therapy. TlMPs are important in the homeostasis of
ECM by regulating the activity of MMPs. However, there is
increasing evidence that TlMPs are also involved in cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis
through MMP-dependent or MMP-independent pathways.
A treatment strategy using TlMPs is not appropriate because
of their paradoxical role in tumorigenesis.F'P" Several
orally active MMP inhibitors (MMPIs) have been developed:
marimastat (BB-25l6), prinomastat (AG3340), BAY
12-9566, CGS-27023A, and Col-3 (6-deoxy-6-demethyl4-dedimethylamino tetracycline). These drugs have
demonstrated anti-invasive, antimetastatic, and antiangiogenic
effects in preclinical studies. 125- 127
Among doxycycline and modified tetracyclines, Col-3
(metastat) is the most potent MMPI. Col-3 induced cell
cycle arrest at the GOIl phase, apoptosis, and necrosis
in vitro. Col-3 also decreased MMP-2, TIMP-l, and TIMP-2
secretion in vitro and inhibit cancer invasion in vitro.P? In
clinical studies, COL-3 demonstrated antitumor activity in
several human cancers. The most common adverse event
was dose-related photosensitivity.F'P? Yeh and coworkers
demonstrated that Col-3 effectively inhibited thyroid cancer
cell invasion in vitro at the clinically achievable concentration with no significant apoptotic cell death.!"
Some clinical trials using orally active MMPIs, however,
failed to achieve survival gain in phase III trials, although
results of these studies are incomplete.P" MMP activity
appears to be more important in early local invasion or
micrometastasis than established metastasis.'!' It is therefore still possible that MMPI treatment may be helpful in
early-stage cancer, after chemotherapy or radiation therapy,
or both. Further studies are needed in thyroid cancers.
Vascular Endothelial Growth

Factor Inhibitors
VEGF is a potent stimulator of endothelial cell proliferation
in vitro, promotes neoangiogenesis in vivo, and increases
vascular permeability. VEGF is overexpressed in most
human malignancies in which elevated VEGF expression is
associated with a more aggressive cancer.
High expression of VEGF was found in both chronic
lymphocytic thyroiditis and DTCs but not in poorly differentiated cancers. 131.132 Although it is controversial, there is
considerable evidence that VEGF overexpression in DTCs is
associated with aggressive clinical features, such as a larger
tumor and local and distant metastases. 133-135 Endothelial cells

lining tumor-embedded microvasculature express VEGF
receptors. 136 Transduction of VEGF to a thyroid cancer cell
line in vitro demonstrated that VEGF indirectly promotes
the growth of thyroid tumors by stimulating angiogenesis. 137
TSH can promote growth of thyroid cancer cells in part by
stimulating VEGF secretion, but short-term TSH stimulation
with recombinant human TSH (rhTSH) did not increase
serum VEGF levels significantly. 138.139
Redifferentiating agents such as phenylacetate inhibit
VEGF secretion in human thyroid carcinoma cells." The
neutralization of VEGF by anti- VEGF monoclonal antibody
inhibited tumor growth and neovascularization markedly in
the dermal matrix angiogenesis model in vivo.140 Manumycin
(a famesyltransferase inhibitor) also decreased VEGF and
inhibited endothelial cell proliferation. These effects were
enhanced by a combination of manumycin and paclitaxel (a
microtubule inhibitor) in an anaplastic thyroid carcinoma
mouse xenograft model. 141 A VEGF inhibitor appears to be
attractive treatment for thyroid cancers.
Conclusion
There are many potentially new medical treatments that
appear promising in vitro, in vivo, and in preclinical studies.
Clinical trials and more basic scientific research are necessary, but there is optimism about their effectiveness. We
hope that these new therapies and clinical trials will result in
their use for patients who do not respond to conventional
therapy and open the way to investigating novel treatment
targets based on newly extended molecular and cytogenetic
understanding of cancer.
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Comparative Genomic
Hybridization in Thyroid
Neoplasms
Daishu Miura, MD Nobuyuki Wada, MD Laurent Brunaud, MD
Thyroid tumors of follicular cell origin serve as a good

model for studying possible genetic events in tumor initiation, transformation, and progression. Fagin 1 and WynfordThornas-? proposed the multistep model of genetic
alterations for thyroid tumors that arise from follicular cells
(Fig. 36-1). They proposed a model with two main pathways: from follicular adenoma to follicular carcinoma and
from low-risk papillary carcinoma to high-risk papillary
carcinoma. Subsequently, these differentiated thyroid carcinomas may transform to anaplastic thyroid carcinoma. The
latter change, from differentiated to anaplastic, is associated
with p53 mutations.F'
Comparative genomic hybridization (CGH) is a genome
scanning technique that allows identification of changes in
a relative copy number of DNA sequences (gains or losses),
using DNA extracted from clinical tumor samples or cell
lines (Fig. 36-2).6 The fluorescence in situ hybridization
(FISH) reaction can also be used to detect gains and losses.
FISH, however, is restricted to the analysis of metaphase
nuclei only, whereas CGH is able to analyze interphase nuclei
from cells that are not actively proliferating.
In cancer cells, gains and losses of oncogenes and
tumor suppressor genes can be mirrored by chromosomal
abnormalities such as chromosomal deletions, monosomies, duplication, polysomies, and gene amplifications
such as homogenously staining regions or double-minute
chromosomes.'
Methods
DNA Extraction
High-molecular-weight whole genomic DNA (>4 kb) was
obtained for reference DNA from healthy female and male
donors and also for test DNA from samples. The normal reference DNA was prepared from peripheral lymphocytes, and
the test DNA was from tissue samples. DNA was extracted
after overnight proteinase K digestion followed by the phenol
chloroform isoamyl method and alcohol precipitation.
344
The concentration of reference and test DNA were measured

with a fluorometer.
Preparation of Metaphase Spreads

The quality of the normal metaphase spreads, to which reference and test DNA were hybridized, strongly influence the
reliability and sensitivity of CGH analyses. Metaphase
spreads were prepared from synchronized cultures of peripheral blood cells from a healthy male donor (Fig. 36-3).
T lymphocytes in RPMI 1640 medium were stimulated with
phytohemagglutinin and cultured for 72 hours. The cells
were then synchronized by treatment with 10-7 M methotrexate (MTX) for 15 hours to inhibit DNA replication, followed
by 10-5 M thymidine for 5 hours to release the cells synchronously from the MTX-induced block. Colcemid (l ug/ml.) was
added during the final 30 minutes of thymidine release.
Lymphocytes were fixed in a 3:1 solution of methanol and
acetic acid and dropped on precleaned microscope slides.
The slides were air-dried using a Thermotron environmental
chamber.
Comparative Genomic Hybridization

CGH was performed according to the protocol described
by Kallioniemi and associates," with slight modifications
using fluorochromes conjugated to dUTP for standard
nick translation (see Fig. 36-2).8 Test and reference DNA
were labeled using the nick translation reaction with
fluorescein-12 (FITC)-dUTP and Alexa Fluor 568-5-dUTP,
respectively. The size of DNA fragments was adjusted from
500 to 1500 bp for hybridization, depending on the amount
of DNA polymerases and incubation time. Approximately
200 ng each of FITC-labeled test and Alexa-568-labeled
reference DNA samples were hybridized to the normal
metaphase spreads. Twenty micrograms of unlabeled Cot-l
DNA was used to block the binding of repeated DNA
sequences. The DNA was denatured for 5 minutes at 73C
in hybridization solution (50% formamide, 10% dextran
Comparative Genomic Hybridization in Thyroid Neoplasms - - 345
FIGURE 36-1. Carcinogenesis in thyroid tumors.
sulfate, and 2X SSC, pH 7.0). Metaphase slides were also

denatured in a denaturing solution (70% formarnide, 2X SSe.
pH 7.0) for 3 to 5 minutes at 73C and dehydrated with
ethanol.Hybridizationwas performed in a chamber at 37C for
2 or 3 days. Posthybridization slides were washed three times
in washing solutions (50% formarnide, 2X sse, pH 7.0), once
in 2X SSC at 45C, once in 2X sse at room temperature,
twice in a PN buffer (0.1 M NazHP04, 0.1 M NaHzP04, 0.1%
NP-40, pH 8.0), and once in distilled water at room temperature. The slides were counterstained with 10 ul, of 0.4 I-1M
4',6-diarnidino-2-phenylindole (DAPI) in an antifade solution.
Digital Image Acquisition and Analysis

The three-color images-blue (DAPI), green (FITC), and
red (Alexa-568)-with appropriate light source and filters
were acquired using several different image acquisition systems (Figs. 36-4 and 36-5). At least 10 images of metaphase
FIGURE 36-2. Technique of comparative

genomic hybridization. Equal amounts of the
fluorochrome-labeled test and reference DNA
were hybridized to normal metaphase spreads
with unlabeled Cot-l DNA to block the binding
of repeated DNA sequences.
FIGURE 36-3. Schema of cell cycle.
spreads were used for each hybridization. These three-color

images were analyzed to determine the ratio of green and
red fluorescence intensity along each chromosome. Image
analysis typically involved normalizing the intensity of
green and red images, chromosome segmentation, background subtraction, medial axis calculation, integration of
fluorescence intensity in bands perpendicular to the medial
axis across each chromosome, and calculation of green-tored ratios along each medial axis. The green-to-red ratio
indicated the relative DNA sequence copy number at each
point in the test genome. At least six metaphase spreads were
analyzed per hybridization and the results were averaged.
The regions with a green-to-red ratio of more than 1.20 were
interpreted as gains and those with a ratio less than 0.80 as
losses. However, the results were dependent on the cutoff
values. Cot-l DNA inhibited binding of the labeled DNA
to the centromeric and heterochromatic regions, so that the
centromeric areas of chromosome 1, 9, 16, and Y and the

Normal metamorphosis chromosomes
FIGURE 36-4. Schema in digital image acquisition

and analysis.
p arm of acrocentric chromosomes (chromosomes 13-15,

21, and 22) could not be analyzed in this study. A positive
control with known chromosomal abnormalities and a negative control using normal human male and female DNA were
used in each hybridization as controls to verify the reliability
of this method.
Papillary Thyroid Carcinoma

DNA copy number changes are uncommon in papillary thyroid carcinomas as compared with other poorly differentiated
and well-differentiated thyroid carcinomas. Papillary thyroid
carcinomas in CGH studies have variable rates of genetic

aberrations and specific sites of aberrations. Nonetheless,
several common aberrations have been identified, including
gains on chromosomes lq, 5q, 6q 9q 13q, 19q, 2lq, 4 and 7,
and losses on chromosomes lp, 9q, 16q, 17, 19, and 22.9- 11
Hemmer and associates 10 found genetic aberrations in
only 3 (12%) of 26 papillary thyroid carcinomas and
reported a positive correlation between the presence of aberrations and older age (>70 years) and cervical lymph node
metastasis. Singh and colleagues!' identified genetic aberrations in 10 (48%) of 21 papillary thyroid carcinoma cases.
They reported that the loss of chromosome 22 was found
only in younger patients 45 years) and was associated
FIGURE 36-5. Comparative genomic hybridization image. The high intensity of green and red images demonstrates gains and losses on
chromosomes, respectively.
with a higher rate of regional lymph node metastasis. In our

study, no chromosomal aberration was found in 6 welldifferentiated papillary thyroid carcinomas, but 3 (43%) of
7 poorly differentiated papillary thyroid carcinomas had
chromosomal aberration. The most common chromosomal
site was a gain on lq in 2 (29%) of the 7 poorly differentiated papillary thyroid carcinomas (Table 36-1). This region
of lq abnormalities harbors a gene that encodes one of the
receptors for the nerve growth factor (NTRKl), which is
activated in about 15% of papillary thyroid carcinomas.'?
Clonal chromosomal aberrations have been identified
in almost half of the cytogenetically examined papillary
thyroid carcinomas by other methods than CGH. The most
frequent alteration has been an intrachromosomal rearrangement, a paracentric inversion in lOq (RET/PTC). This site
is frequently the only change, and it is not detectable by
CGH.IO.13-21
Follicular Thyroid Tumor

Thyroid tumors of follicular cell origin serve as a good
model for studying possible genetic events regarding tumor
origin, transformation, and progression. Multiple genetic
events appear to be responsible for the progression from
adenoma to carcinoma in some tumors (see Fig. 36-1).1.2.22.23
Follicular adenomas have close cytologic and morphologic
similarity to follicular carcinomas; the defining difference is
the presence of capsular invasion and/or vascular invasion in
carcinomas. Because of this similarity, it has been proposed
that follicular carcinomas originate from preexisting adenomas. Follicular adenomas could represent premalignant
tumors that could transform into carcinomas, through copy
number changes in critical genes controlling invasion,
angiogenesis, and metastasis. Clinical evidence that follicular carcinomas are obviously larger than follicular adenomas
supports this theory.
Hemmer and coworkers>'found that copy number changes
were more frequent in follicular carcinomas (9 [69%] of 13)
than in histologically benign follicular adenomas (14 [48%]
of 29) using CGH. However, the average number of copy
number changes was less in follicular carcinoma (1.6 changes
per case, range 0 to 6) than in follicular adenoma

(2.5 changes, range 0 to 12). On the other hand, Frisk and
associates-" subsequently described that the frequency of
aberrations was similar in follicular adenomas (8 adenomas,
1.9 changes/mean) and follicular carcinomas (13 carcinomas, 1.5 changes/mean), as well as in 8 minimally invasive
follicular carcinomas (1.5 changes/mean) and 5 widely invasive follicular carcinomas (1.6 changes/mean). Hemmer and
colleagues" reported that a loss of chromosome 22 or 22q
was particularly common in carcinomas (6 [46%] of 13)
whereas a loss of chromosome 22 was found in only 2 (7%)
of 29 adenomas. Moreover, loss of the chromosome 22 was
present in 7 (54%) of the 13 widely invasive follicular carcinomas but in none of the 7 minimally invasive carcinomas
(P = 0.04).10 Loss of chromosome 22 was also common in
older than in younger patients (P =0.01). A loss of lp was
frequent in follicular carcinomas (20%), whereas gains in
chromosomes 5, 7, 12, 14, and X were common in follicular
adenomas but not found in follicular carcinomas.s' A DNA
copy number loss was also common in l3q in follicular
carcinomas (25%).10 The common regions for DNA copy
number gain were in lq (25%) and in l7q (20%) for follicular carcinomas. Papillary carcinomas that also arise from
follicular cells have fewer chromosomal aberrations, especially losses, than follicular carcinomas. 10 One candidate for
the tumor suppressor gene in chromosome 22q is neurofibromatosis type 2 (NF2) located at 22q 12, and there may be
another putative suppressor gene distal to NF2. The significance of these and other suppressor genes located in 22q in
the genesis of follicular carcinoma is currently unknown.
Although formation of fusion genes PAX8-PPARyl caused
by a t(2;3)(q13;p25) has been observed in several cases
of follicular carcinomas." unfortunately it is difficult to
identify these chromosomal translocations using CGH.
Hurthle Cell Thyroid Tumor

Hiirthle cell thyroid tumors comprise 1% to 5% of all
thyroid neoplasms and have been classified as variants of
follicular thyroid tumors. They differ from follicular thyroid
carcinomas by their inability to trap radioiodine and by
HOrlhle cell
adenomas
Left: losses
Right: gains
FIGURE 36-6. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 15 Hiirthle cell adenomas and 13 Hiirthle
cell carcinomas.
HOrlhle cell
carcinomas
the accumulation of mitochondria and eosinophilic cytoplasm on histology. They are also more likely to be multifocal, have nodal metastasis, and appear to be clinically
aggressive. Hiirthle cell carcinomas are similar to follicular
thyroid carcinomas in that they usually cannot be diagnosed
by fine-needle aspiration biopsy or frozen section. It is also
difficult to distinguish Hiirthle cell adenomas from carcinomas preoperatively or intraoperatively. Some investigators
previously recommended that all Hiirthle cell tumors should
be considered as malignant and be treated aggressively
because of their malignant potential. 27.28 Others suggested
that Hiirthle cell tumors are separated into adenomas (which
have no capsular and vascular invasion) and carcinomas,
using similar criteria as used for follicular tumors. 29-32 Some
studies have suggested that patients with Hiirthle cell carcinoma do not necessarily have a worse prognosis than patients
with follicular thyroid carcinorna.Pr"
Hemmer and coworkers/" reported 3 of 4 Hiirthle cell adenomas had chromosomal aberrations. Frisk and associates"
also reported that 2 of 3 Hiirthle cell adenomas had chromosomal aberrations, as did 3 of 4 Hiirthle cell carcinomas.
Similarly, Tallini and colleagues-' documented that 6 of
7 adenomas and 3 of 4 carcinomas had chromosomal aberrations. We found chromosomal aberrations in 9 of 15 Hiirthle
cell adenomas and in 8 of 13 Hiirthle cell carcinomas." The
mean number of chromosomal gains and losses were 2.1 and
0.7 in 15 adenomas versus 4.2 and 0.8 in 13 carcinomas.
Although Hiirthle cell adenomas were more likely to have
fewer chromosomal aberrations than Hiirthle cell carcinomas,
in our study, this difference was not significant (P > 0.05)
(Fig. 36-6 and Table 36-2).
Our investigations have found that whole or focal chromosomal gains are relatively common in chromosomes 5, 7,
12, 17, 19, and 20 and losses are in chromosomes 2 and 9 in
both Hiirthle cell adenomas and carcinomas (see Fig. 36-6).36
Frisk and colleagues'" reported that loss of 9q 13-q21.3 was a
specific aberration in Hiirthle cell carcinomas. In our study,
gains in chromosome 12 were more common in Hiirthle cell
carcinomas than in Hiirthle cell adenomas and, in particular,

gains in l2q occurred more frequently in patients with
Hiirthle cell carcinomas who developed recurrent disease
(P < 0.001).36 Roque and coworkers'? have reported an
increased frequency of gains in chromosome 7 and 12
among different thyroid tumors (e.g., goiters, follicular adenomas, and follicular carcinomas). These findings support
the concept that some thyroid neoplasms develop in a multistep process. We also found that gains in 5p, 7, 19p, 19q,
and 20p were associated with a higher risk of tumor recurrence as well as l2q in patients with Hiirthle cell carcinoma
(Table 36-4).36 The presence of these chromosomal aberrations in primary Hiirthle cell carcinoma may predict developing recurrent disease. Erickson and associates'" reported
that loss of chromosome 22, by FISH, was associated with

deaths due to Hiirthle cell carcinoma.
Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma is an extremely aggressive
cancer, with a median survival after diagnosis of just a few
months.l? The outcome is so poor that the American Joint
Committee on Cancer (AJCC) classifies all patients with
this tumor as having stage 4 thyroid cancer. Fortunately,
anaplastic thyroid carcinoma accounts for less than 2% of
all thyroid carcinomas in the United States and has been
decreasing in incidence.f'-"
Hemmer and colleagues, to as previously mentioned,

reported that more chromosomal aberrations occurred in follicular thyroid carcinomas than in papillary thyroid carcinomas. They studied DNA copy number changes by CGH in
69 patients with thyroid carcinoma. Among the 20 follicular
thyroid carcinomas, there were 22 deletions and 26 gains
(median changes 2, range 0 to 8, for one sample). In contrast, among the 26 papillary thyroid carcinomas, there were
no deletions and 6 gains (median changes 0, range 0 to 4, for
one sample). Among the 13 anaplastic thyroid carcinomas,
there were 5 deletions and 27 gains (median changes 2,
range 0 to 13, for one sample). Their documentation of more
gains than losses in anaplastic thyroid carcinomas is similar
to our results.
By CGH analysis of 10 anaplastic thyroid carcinomas,
chromosomal aberrations were found in 5 of the 10 anaplastic thyroid carcinomas (Table 36-5).8 We identified 24 chromosomal aberrations, of which 22 were gains and 2 were
losses (Fig. 36-7). The two anaplastic thyroid carcinomas
(cases 9 and 10) that had the greatest number of chromosomal
aberrations (6 and 13) were found histologically in association with follicular thyroid carcinoma. The others with no
chromosomal abnormalities (cases 1, 2, and 6), or two or
fewer chromosomal abnormalities (cases 3, 4, and 5) were
histologically associated with papillary thyroid carcinoma.
The median numbers of chromosomal aberrations were 9.5
for anaplastic thyroid carcinoma associated with follicular
thyroid carcinoma versus 0.5 for those associated with
papillary thyroid carcinoma; this difference was significant
(P = 0.046). Two of the anaplastic thyroid carcinomas without known association with follicular or papillary thyroid
carcinoma had no chromosomal aberrations. We found that

DNA copy number changes in anaplastic thyroid carcinomas appear to parallel those of the associated follicular
or papillary thyroid carcinomas. Thus, after transformation
from follicular thyroid carcinoma or papillary thyroid carcinoma to anaplastic thyroid carcinoma, the cells appear to
retain their cytogenetic profile.
We found no significant correlation between the presence
of chromosomal aberrations and overall survival or other
clinicopathologic characteristics in our investigation (see
Table 36-5).8 The most common chromosomal aberrations
were gains in chromosome lq2l-qter in 3 of 10 anaplastic
thyroid carcinomas and gains in chromosome lOp and Xp in
2 of 10 anaplastic thyroid carcinomas (see Fig. 36-7). Two
of 3 anaplastic thyroid carcinomas that had a gain in lq were
associated with papillary thyroid carcinoma (see Table 36-5),
but neither had a known history of radiation exposure. The
region of lq aberrations found in these 3 anaplastic thyroid
carcinomas harbors a gene that encodes one of the receptors
for the nerve growth factor (NTRKI), which is activated in
about 15% of papillary thyroid carcinomas.P Activation of
NTRKI has been reported to be present in papillary thyroid
carcinomas that occur after exposure to radiation in children,
as well as RET/PTe chromosomal rearrangements.P'v"?
Human thyroid cancer cell lines had more chromosomal
aberrations than did frozen thyroid cancer samples in our
studies, consistent with other studies (Fig. 36-8 and
Table 36_6).8,10.48.49 More alterations may be required to
establish an immortalized cell line or that cultivating of cells
leads to the selection of cells that have more chromosomal
aberrations.P No common chromosomal aberrations by
Comparative Genomic Hybridization in Thyroid Neoplasms - -
351
FIGURE 36-7. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 10 anaplastic thyroid carcinomas.
CGH in anaplastic thyroid carcinoma were apparent when

we compared our findings to those reported in the literature
(see Table 36-6).

Apart from the RET protooncogene (RET) point mutation of
chromosome 10, no other genes have been found to be
involved in the original growth of medullary thyroid carcinomas. Germline RET mutations have been identified in
about 98% of patients with familial medullary thyroid carcinoma, and somatic RET mutations have been frequently
detected in sporadic medullary thyroid carcinomas.t! In sporadic medullary thyroid carcinomas, the RET gene is
mutated in codon 918, where a methionine is substituted to
a threonine (M918T).
Chromosomal aberrations have been detected by
CGH in approximately 50% to 60% of the patients with
medullary thyroid carcinoma.P>' The number of chromosomal aberrations in medullary thyroid carcinoma appears
to be lower than in other thyroid carcinomas that arise
from thyroid follicular cells.'? Frisk and coworkers>'
reported that chromosomal regions 19q, 19p, 13q, and llq
may be involved in medullary thyroid carcinogenesis but
that medullary thyroid carcinoma is a relatively genetically
stable tumor. Overall, the results of CGH investigations
in medullary thyroid carcinomas have suggested a normal
modal number of chromosomes with a marked tendency to
random hypodiploidy.P Hypodiploidy has also been found
in medullary thyroid carcinoma cell lines. 53
Limitations and Difficulties

of Comparative Genomic
Hybridization
CGH only detects genomic aberrations that involve loss
or gains of DNA sequences. Balanced translocations or
inversions are therefore not detectable, nor are small intragenic rearrangements and point mutations. CGH also only
detects DNA sequence copy number changes relative to the
average copy number in the entire tumor sample. The relative green-to-red ratios can be transformed to indicate actual
copy numbers if the absolute copy number in several loci are
independently determined or if the ploidy is determined by
DNA content analysis. 654
Pericentromeric and heterochromatic repeat regions,
unfortunately, cannot be reliably evaluated by CGH because
unlabeled Cot-I DNA blocks binding of the labeled
DNA to the pericentromeric and heterochromatic regions.
These DNA sequences are highly polymorphic in copy
number between individuals. Thus, ratio changes at or near
these regions should be interpreted cautiously, especially
when the test and reference DNA samples come from different individuals.>
CGH, unfortunately, cannot detect single-copy losses or
gains unless the extent of the region in loss/gain is greater than
about 10 Mb, Moreover, the CGH ratio may not be a quantitative measure of the number of copies lost or gained unless the
involved region is much greater than 10 Mb in extent.
Similar to other methods based on extracted DNA, CGH
requires that the tumor specimens be relatively free from
- - - FTC cell lines (FTC133, FTC236 , FTC238)
ATC cell line (AR081-1)
............ PTC cell line (TPC-1)
FIGURE 36-8. Summary of chromosomal aberrations analyzed by comparative genomic hybridization (CGH) in five thyroid cancer cell
lines: (I) FfC-133 was derived from a primary follicular thyroid cancer (FfC); (2) FfC-236 was derived from a lymph node metastasis of
FfC from the same patient as in FfC-133; (3) FfC-238 was derived from a lung metastasis ofFfC from the same patient as in FfC-133;
(4) AR081-1 was derived from an anaplastic thyroid cancer (ATC); and (5) TPC-I was derived from a papillary thyroid cancer (PTC).
surrounding normal tissues that dilute the green-to-red ratio

changes. If the normal tissue contribution is greater than
50% of the total DNA content, reliable detection of the ratio
becomes increasingly difficult. In addition to normal cell
contamination, intratumor genetic heterogeneity may also
dilute the green-to-red ratio changes detected by CGH. This
technique detects the average copy number of sequences in
all cells included in the specimen, so those aberrations that
are homogenously present (clonal) in the tumor cells are
more readily detected. In most cases, this is an advantage,
because the clonal changes are likely to represent the early
and most important changes. However, in multiclonal tumors,
the different genetic aberrations present in the individual
clones may sometimes balance one another or exist at too
Iowa frequency to be detected. 54
Conclusions
Investigations using CGH have identified several regions of
the genome with gains and losses that havepreviously not been
suspected to be involved in thyroid carcinoma. These regions
may contain important novel genes that are responsible for
thyroid tumor development and progression. Further investigations using higher resolution CGH analysis and a larger
series of tumors are required to validate and refine the locations of the common regions of loss and gain in each chromosome and to evaluate the significance of these genetic
events in the multistep model of thyroid carcinogenesis.
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Sodium-Iodide Symporter and

Radioactive Iodine Therapy
Rasa Zarnegar, MD
The treatment of patients with well-differentiated thyroid

cancer (WDTC) includes three modalities: thyroidectomy,
radioiodine (1311) ablation, and thyrotropin (thyroid-stimulating
hormone, TSH) suppression. Unfortunately about 25% of
WDTCs are initially resistant to 131 1, and about 50% of
recurrent thyroid cancers are also resistant to 131 1 treatment.
These patients have a worse prognosis, and several investigators have attempted to enhance radioiodine uptake in thyroid
cancer cells of follicular cell origin.P
Thyroid iodide uptake plays a critical role in the diagnosis and treatment of a variety of thyroid disorders. Since
the cloning of the sodium-iodide symporter (NIS),
research has been focused on methods of enhancing the
uptake of iodide in thyrocytes. NIS is an intrinsic plasma
membrane glycoprotein located on the basolateral membrane of thyroid follicular cells and is responsible for
iodine uptake into thyroid cells (Fig. 37-1).3,4 It plays
a critical role in the active transport of iodide from the
blood stream into thyrocytes and in a number of nonthyroid tissues, including the mammary glands during lactation, stomach, kidneys, and salivary glands. Functional
NIS expression on thyroid tissue is essential for the concentration of iodide in thyrocytes against a concentration
gradient. Iodide is a component of the thyroid hormones
triiodothyronine (T 3) and thyroxine (T 4), which playa role
in the metabolism, growth, and maturation of a variety of
organ systems.!
When thyroid cells transform into cancer cells, their ability
for iodine uptake is decreased." This is true for both papillary
and follicular thyroid carcinomas. Most Hurthle cell
carcinomas fail to take up enough 1311 for treatment to be
effective. Three mechanisms have been proposed for poor
iodide uptake in thyroid carcinoma: (I) NIS gene mutations,
(2) suppression of NIS gene expression, and (3) posttranscriptional modifications of the NIS protein. Therefore,
research is focused on increasing NIS symporter function in
a variety of tumors using specific drugs or gene therapy
followed by radioactive iodine ablation.
Molecular Characterization
of the NIS Gene
The molecular characterization of NIS was accomplished in
1996 when Dai and colleagues cloned the transporter' from
Xenopus laevis oocytes, using the complementary DNA
(eDNA) libraries derived from FRTL-5 cells (functional rat
thyroid-derived cell line). The eDNA encoding the human
NIS (hNIS) gene was identified on the expectation that hNIS
would be highly homologous to rat NIS'? The hNIS gene is
located on chromosome 19p12-13.2. It comprises 1929 base
pairs encoding a 643-amino acid glycoprotein with a molecular weight of 70 to 90 kd. The variable molecular weight
depends on the level of glycosylation of the protein. The
coding region of hNIS contains 15 exons and 14 introns and
codes for a 3.9-kb messenger RNA (mRNA).8 NIS is a
membrane protein with 13 transmembrane domains with an
extracellular NHz terminus and an intracellular COOH terminus (Fig. 37-2). The configuration of the NH z and COOH
termini have been confirmed by immunohistochemistry."
There are three potential asparagine (ASN) glycosylation
sites at positions 225, 485, and 497. 10 However, glycosylation has not been shown to affect the functionality, targeting,
or stability of the NIS protein." Findings derived from NIS
mutations that cause congenital iodide transport deficiency
(lTD) show that a spontaneous single amino acid substitution
of proline (Pro) instead of threonine (Thr) at position 354
(T354P) is the cause of congenital lack of iodide transport in
several patients.U'" This suggests that a hydroxyl group at
the ~ carbon position (Thr-354) is essential for NIS function.14
In the same patients, a mutation from valine-59 to glutamate
has also been discovered.P
Subsequent to the cloning of hNIS, cDNAs encoding NIS
have also been isolated from two other species, pig" and
mouse." Mouse NISI6 and rat NIS3 contain 618 amino acid
residues, whereas human NIS7 and pig NISI5 contain 643. A
highly conserved homologue among all isolated NIS proteins exists.
355

Colloid
FIGURE 37-1. Schematic representation of the iodide uptake and
biosynthetic pathways of thyroidhormones in thyrocytes. Iodine is

actively accumulated across the basolateral plasma membrane of
the thyrocyte in a processcatalyzed by the sodium-iodide symporter
(NIS). This transportis driven by the Na" gradientgenerated under
adenosine triphosphate (ATP) hydrolysis by Na+,K+-ATPase. The
iodideis passively translocated across the apical membrane of the
thyrocyte by the pendrin (PDS)proteininto the colloid, where it is
used to iodinate thyroglobulin (Tg). Iodine organification is catalyzed by thyroid peroxidase (TPO) and requires H202 The iodinated Tg, containing thyroid hormones, is stored in the colloid.
Thyroid hormones, thyroxine (T4 ) and triiodothyronine (T3) , are
released from Tg and secretedin the blood.All steps in the thyroid
hormone biosynthetic pathway are stimulated by thyroid-stimulating
hormone (TSH).TSH-R = TSH receptor.
NIS gene expression is high in thyroid, gastric, and lactating mammary glands, and lower levels are present in other
tissues including brain, small intestines, testes, skin, spleen,
ovary, and prostate."
Regulation of NIS Gene

Expression and Function
It has been known for decades that pituitary-derived TSH
increases iodide transport into the thyroid cells by way
of an adenylate cyclase-cyclic adenosine monophosphate
(cAMP)-mediated pathway.' Thyrotropin-releasing hormone
from the hypothalamus stimulates the release of TSH, whereas
T 3 and T 4 inhibit it. TSH binds the TSH receptor (TSHR) on
the basolateral membrane of the follicular cells, causing the
accumulation of iodide through the cAMP-mediated
increase of NIS transporter synthesis (see Fig. 37-1).17
Upregulation of thyroid NIS expression and iodide
uptake activity by TSH have been shown in in vitro and
animal modelsp-2o After withdrawal, a reduction in both

intracellular cAMP and iodide uptake activity is observed.
TSH stimulation has also been shown to affect cell polarization and spatial organization, leading to redistribution of the
NIS transporter from the cytoplasm to the cell membrane.
Therefore, TSH not only stimulates NIS transcription and
biosynthesis but also is required for NIS targeting to the
plasma membrane.
The NIS protein is targeted to the basolateral membrane of
follicular cells. Although the mechanism of this targeting is
not fully elucidated, several sorting signals in the COOH
terminus have been identified including the PDZ, dileucine,
and acid-based motifs. 21-23 Localization of NIS at the basolateral plasma membrane is important not only for iodide
transport in the thyroid gland but also for effective treatment
of thyroid disease with radioactive iodine. Impaired targeting
is one mechanism by which thyroid cancers have decreased
iodide uptake. 24.25 Therefore, it is important for the treatment
of thyroid cancer to determine the mechanisms that regulate
the subcellular distribution of NIS.
Phosphorylation, a common cellular mechanism for modulating protein activity, subcellular localization, and degradation, has been shown to playa role in the post-transcriptional
stabilization of the NIS protein. In the presence and absence
of TSH, the phosphorylation pattern of the NIS protein is
different." Although studies have not shown a role of phosphorylation in the targeting and stability of the NIS protein, its
role has been shown in the function of other transporters.
Iodide has also been shown to be a major regulator of
iodide uptake by the thyroid gland. In 1923, Plummer"
noted that high doses of iodide block thyroid function in
patients with hyperactive thyroid disease. However, it was
Wolff and Chaikoff who, in 1948, reported that the binding
of iodide in the rat thyroid in vivo was blocked when iodide
plasma levels reached a critical high threshold, a phenomenon
known as the acute Wolff-Chaikoff effect.28 Raben showed
that the acute inhibition of organic iodide binding is dependent on intrathyroid rather than plasma concentrations of
iodide by blocking iodide transport with thiocyanate." Studies
went on to show that the inhibitory effects of iodide on the
organification of iodine last 2 days, after which there is an
adaptation or escape from the effect" The Wolff-Chaikoff
effect and the ensuing escape constitute a highly specialized
autoregulatory system that protects the thyroid from iodide
overload but at the same time ensures adequate iodide
uptake for thyroid hormone synthesis.
The regulatory role of iodide in NIS function has been
explored with studies indicating that NIS transcription is inhibited by iodide. 31.32 Eng and colleagues.P>' however, showed
that iodide does not affect NIS gene transcription but rather
increases the rate of turnover of the NIS protein. However, it
is more likely that iodide affects NIS transporter protein at
multiple levels, inhibiting transcription and also increasing
turnover of the protein.
Although the major regulators of the NIS transporter are
TSH and iodide, there are associations between NIS regulation
and cytokines including tumor necrosis factor a. (TNF-a.),
TNF-~,
interferon-y, interleukin-l a. (IL-l o), IL-I~,
IL-6, and
transforming growth factor ~2' All these cytokines have been
shown to play an inhibitory role in NIS protein expression and
iodide uptake through decreased NIS gene transcription.31.35.36
Sodium-Iodide Symporter and Radioactive Iodine Therapy - - 357
FIGURE 37-2. Schematic model of

the human sodium-iodide symporter,
which represents an intrinsic membrane protein with 13 transmembrane
and 14 extramembranous domains
and 3 potential N-linked glycosylation sites. ExM = Extramembranous
domains.
NIS and Thyroid Cancer

As previously mentioned, the treatment of patients with
WDTC includes three modalities: thyroidectomy, radioiodine
(1311) ablation, and TSH suppression. Unfortunately, about
25% ofWDTCs are initially resistant and about 50% of recurrent thyroid cancers are resistant to 1311 treatment. These
patients have a worse prognosis, and many studies have
attempted to enhance radioiodine uptake in thyroid cancer
cells in such patients. 12,34,37,38
Since the discovery of the NIS gene, much attention has
been focused on the symporter because it is a marker for
differentiation and also the mechanism by which radioactive
iodide therapy works. Thyroid diseases directly affect the
function of the NIS symporter. Three mechanisms, as previously stated, have been proposed for poor iodide uptake in
thyroid carcinoma: (I) NIS gene mutations.t? (2) suppression
of the NIS gene expression,6.39-44 and (3) post-transcriptional
modifications of the NIS protein. 24,26
Congenital lTD is an infrequent autosomal recessive
condition caused by mutations in the NIS gene. The clinical
picture consists of hypothyroidism, goiter, low thyroid iodide
uptake, and low saliva-to-plasma iodide ratio. The incidence
of lTD is 1 per 4000 neonates. It has an irreversible effect
on the growth and development of the neonate, leading to
cretinism. Mutations in thyroid-specific molecules such as
thyroid peroxidase, thyroglobulin, and TSHR have been
identified. 45-47 NIS mutations have also been reported in congenital hypothyroidism resulting in the absence of the functional NIS symporter. Kosugi and coworkers" reported that
a T354P NIS gene mutation was found in seven Japanese
patients from five unrelated families. To date, approximately

60 cases of lTD belonging to 33 families have been
reported. Twenty-seven cases from 13 families studied have
been shown to have NIS gene mutations. 12.39,48-50
Thyroid cancer has not been shown to involve the mutations seen in congenital lTD. Russo and colleagues"
performed direct sequencing of NIS cDNA from five papillary and two follicular thyroid cancers and found no mutations in the NIS gene. The proposed mechanism of reduced
radioactive uptake in thyroid cancer has been associated
with decreased expression of the NIS gene. Bidart and
associates'? showed that NIS protein immunostaining is
increased in Graves' disease and reduced in Hashimoto's
and thyroid cancer. Our own studies have confirmed that
NIS gene expression is increased in Graves' disease and
hyperactive adenomas and reduced in Hashimoto's disease.
Also, expression of the NIS symporter is reduced in papillary, medullary, and follicular thyroid cancers. Schmutzler'"
found that the redifferentiation effect of retinoic acid in
thyroid cancer cells is associated with increased NIS gene
expression.
NIS gene expression not only may be deceased in thyroid
cancer but also may affect post-transcriptional targeting
of the NIS protein. Saito and colleagues" showed that 7 of
17 papillary thyroid carcinomas overexpressed the NIS gene,
but the NIS protein was located in the cytoplasm and not on
the cell membrane. In contrast, NIS protein expression was
barely detected in the paratumoral normal tissue. Contrary
to the results of Saito and colleagues, several investigators
have found absent or intermediate expression staining of the
NIS protein in differentiated thyroid cancer. 54,55
358 - -
Thyroid Gland
Loss of polarization and impaired membrane targeting of

other membrane proteins have been described in malignant
thyroid cancer. The epidermal growth factor receptor, as
detected by immunohistochemistry, was overexpressed and
localized not only pericellularly but also intracellularly
rather than exclusively localized on the basolateral membrane as in normal cells.
NIS must be expressed, targeted, and retained in the
appropriate plasma membrane surface in polarized epithelial
cells for active iodide transport to occur. TSH regulates NIS
distribution between the plasma membrane and intracellular
membrane compartments. In thyroid cancer cells, iodide
transport can still be present even in the absence of cell
polarization, but targeting to and retention in the plasma
membrane remain essential if active iodide transport is to
take place. Therefore, elucidating the mechanisms involved
in proper targeting and retention of NIS at the plasma membrane is essential to enhancing iodide uptake in thyroid
cancer cells.
Enhancing NIS Gene Expression

The NIS gene has become the focus of much attention in
the past decade as new drugs have been developed that can
enhance its expression.
Retinoic acid (RA) was the first drug identified to
enhance NIS gene expression. 1,53.56-60 9-cis-RA, a ligand for
both retinoic acid receptor (RAR)/retinoic X receptor (RXR)
heterodimers and RXRIRXR homodimers, markedly induced
NIS mRNA expression in a dose- and time-dependent fashion,
with maximal levels occurring at 12 hours. All-trans-RA,
an RAR-specific ligand, had similar potency. Combining an
RAR with an RXR-selective ligand enhanced both NIS mRNA
expression and iodide uptake. Similarly, a ligand for peroxisome proliferator-activated receptor y (PPARy), when combined with 9-cis-RA, synergistically increased both NIS
mRNA levels and iodide uptake. Schmutzler and colleagues"
showed that RA increased radioiodine transport in two different follicular thyroid carcinoma cell lines (FTC-l33 and
FTC-238), suggesting that RA may cause redifferentiation
of advanced thyroid carcinoma. However, clinical trials with
RA at our institution have not mirrored the results seen in
cell studies.
Histone deacetylase inhibitors are a group of anticancer
agents that function through mechanisms that are not yet
fully elucidated. Both hyperacetylation and hypoacetylation
of histones appear to play important roles in carcinogenesis
through gene regulation. Histone deacetylase inhibitors are
a unique group of drugs that are under investigation for
their role in the regulation of gene expression. Acetylation of
lysine residues within the arninoterrninal domains of the core
histones has been associated with the regulation of gene
transcription/" Histone hyperacetylation correlates with
increased gene transcription, whereas hypoacetylation correlates with decreased gene transcription. Although histone
acetylation does not disrupt individual nucleosomes, moderate
levels of acetylation can destabilize the higher order folding
of arrays of nucleosomes. Thus, acetylation of specific
lysine residues can regulate the chromatin binding or the
enzymatic activity of other nonhistone proteins. 63,64
A number of investigations, however, determined that the

up- or downregulation of genes by histone acetylation is not
ubiquitous for all genes in a cell. 64 Indeed, a global increase
in core histone acetylation did not induce widespread gene
transcription. 65 Histone acetylation neutralizes electrical
charges, separating DNA from the histones, thus allowing
nucleosomal DNA to become more accessible to transcriptional activators or repressors. Histone acetylation is believed
to stabilize local nucleosomal structures, thereby allowing
transcription factors and the basal transcriptional machinery
access to DNA. Hyperacetylation of histones has been shown
to open chromatin markedly, and it is required for transcriptional activation."
Histone acetylation is a reversible process. Histone acetyltransferases (HATs) transfer the acetyl moiety from acetyl
coenzyme A to lysine, neutralizing the positive charge in the
histones. Histone deacetylases (HDACs) remove the acetyl
groups, re-establishing the positive charge in the histones.
In studies at our institution, we found that trichostatin
A (TSA) enhanced NIS gene expression in thyroid cancer cell
lines with an associated increase in radioactive iodide uptake
in these cell lines.s? Depsipeptide (FR901228), another
HDAC inhibitor, has also be shown to increase NIS gene
expression in well-differentiated thyroid carcinoma cell
lines derived from follicular thyroid carcinomas (FTC-l33,
FTC-236) and anaplastic carcinomas (SW-1736, KAT-4).68
At low concentrations, these drugs have minimal cytotoxic
effects in cell lines (Fig. 37-3). Our studies with TSA
showed that at low concentrations this drug caused cells to
FTC 133
Hours
FIGURE 37-3. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide (MIT) assay for FfC-l33 after

treatment with trichostatin A (TSA), n = 3. TSA concentrations of
0, 10,50, 100,250,and 1000ng/mLwere usedin the cell line.Cell
proliferation wasmeasured relative to day 0 andrepresents an average measurement. The measurements were taken at 24, 48, and
72 hours. FfC-133 cell proliferation occurred in the presence
of TSA at concentrations up to 50 ng/mL, growth inhibition at
100, 250, and 1000ng/mL. FfC = follicular thyroid carcinoma.
Sodium-Iodide Symporter and Radioactive Iodine Therapy - - 359
The identification of drugs that can enhance the expression of the NIS gene does not have limited application to
differentiated thyroid cancers. NIS gene expression was
identified and characterized in the mammary gland by
Tazebay and coworkers.s? A report by Kagai and coauthors'?
showed induction of NIS gene expression and radioiodine
uptake in breast cancer cells following treatment with RA.
In the estrogen receptor-positive human breast cancer cell line
MCF-7, all-trans-RA treatment stimulated iodide uptake in
a time- and dose-dependent fashion up to approximately
9.4-fold. However, in estrogen receptor-negative human
breast cancer, no induction of iodide uptake was observed
after RA treatment. RA also did not induce increased iodide
uptake in prostate cancer cells (LNCaP), choriocarcinoma
cells (JEG-3), and lung cancer cells (A549, H460).
Therefore, the effect of RA is cell specific. The effects of
HDAC inhibitors in nonthyroidal carcinomas with respect to
iodide uptake have yet to be elucidated.
Cloning the NIS gene further allows the development of
novel cytoreductive gene therapy by directing the transfer of
the NIS gene into different tumor cells followed by radioiodine therapy. Early studies in transformed rat thyroid cells
(FRTL-Tc) without iodide transport activity showed that
transfection restores radioiodine accumulation activity in
vitro and in vivo." Mandell and colleagues" demonstrated
iodide accumulation in vitro and in vivo in several cancer
cell lines, including melanoma, liver, colon, and ovarian carcinoma cell lines, after retrovirus-mediated transfection with
the rat NIS gene. An in vitro clonogenic assay was used to
demonstrate that rat NIS-transduced cancer cell lines could
be killed selectively by the accumulated l3ll. Prostate cancer
cells (LNCaP) were shown to be killed selectively by accumulation of radioiodine after tissue-specific iodide uptake
by prostate-specific antigen promoter-directed NIS expression in vitro." In a study using adenovirus-mediated intratumoral NIS gene delivery, 3 mCi of 1311 intraperitoneally
injected 4 days after transfection in LNCaP xenografts
showed a clear therapeutic advantage with an 80% reduction
in volume." Rhenium 188, a chemical analog of technetium,
with the NIS transporter has been shown to deliver a radiation
dose 4.5 times higher than 1311. The next crucial step toward
clinical application of NIS gene delivery followed by radioiodine therapy will involve the generation and investigation
of safe and efficient gene delivery with vectors that can be
administered systemically, targeting specific tissue without
severe side effects.
C
FIGURE 37-4. Apoptosis assay by annexin V/PI staining and flow
cytometryusing trichostatin A (TSA) at concentrations of 0,50, 100,
and 500 ng/mL for 24, 48, and 72 hours. Cells are classifiedas viable,
early apoptosis, and nonviable. Treatmentwith up to 100 nglmLTSA
did not significantly affectthe numberof apoptotic cells.At 500 nglmL
TSA, 68.7% of the cells were nonviableafter 72 hours.
redifferentiate with an associated transient Gz/M arrest and

at higher concentrations caused cells to progress to apoptosis
(Fig. 37-4). If these results can be confirmed in vivo, these
drugs may be used clinicallyin the treatment of thyroid cancer
in combination with radioactive iodine therapy. Depsipeptide
is involved in several clinical trials for tumor redifferentiation
in advanced cancers, including thyroid cancer.
Conclusion
NIS research has become an exciting field with the cloning
of the NIS gene and investigations into the trafficking of the
symporter. NIS was used extensively in the management of
thyroid disease even before its molecular characterization
for radioiodine ablation. However, several thyroid cancers
have decreased NIS expression, and therefore radioiodine
therapy is less effective in the treatment of these tumors. The
investigation of RA and histone deacetylating inhibitors
such as depsipeptide and TSA, the possibility of enhancing
NIS gene activity, and methods to increase the effectiveness
of radioactive iodine therapy are entering clinical trials.

Treatment of nonthyroid tumors by transfecting tumor
cells with the NIS gene followed by radioiodine ablation
is also a field that requires further investigation. It has
become evident that continued study of the mechanisms
involved in NIS transporter synthesis and trafficking as well
as study of drugs and vectors for systemic administration of
the NIS gene will considerably affect the future of cancer
therapy.
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Parathyroid Embryology,
Anatomy, and Pathology
Miguel F. Herrera, MD Armando Gamboa-Dominguez, MD
A small gland located in the vicinity of the thyroid gland

was first described in 1880 by the Swedish anatomist
Sandstrom, 1 who named it "glandula parathyroideae." The
first anatomic descriptions of the parathyroid glands in
humans were published by Welsh in 18982 and Halsted and
Evans in 1907. 3 These authors demonstrated in their classic
studies that there are typically four parathyroid glands (two
on each side) with a relatively constant mutual location. It is
essential for the surgeon dealing with endocrine surgery to
be familiar with the embryology, anatomy, and histology
of parathyroid glands to appreciate the rationale of certain
surgical maneuvers and decisions.
Embryology
The thyroid, the parathyroid glands, and the thymus originate
from the embryonic pharyngeal region. The pharynx itself is
initially an endodermally lined cul-de-sac that forms the
cephalic extremity of the foregut. This is derived from a part
of the yolk sac. The foregut diverticulum is divided into a
more cranial pharynx and a more caudal proper foregut with
the appearance of the primordium of the pulmonary apparatus as a small ventral outgrowth. When the embryo is approximately 26 days old, lateral walls of the pharynx show a
nonuniform growth that forms five pairs of endodermally
lined pouches."
Only the first pouch persists as a large, hollow cavity to
form at least the greater part of the middle ear cavity and the
tympanic tube. The second pouch almost completely disappears. It is from the third and fourth pouches that the parathyroid and thymus glands develop, and they also contribute to
the formation of the thyroid gland. The fate of the fifth
pouch is uncertain. Each pair of parathyroid glands has a
different origin. The inferior parathyroid glands originate
from the third branchial pouch and, therefore, are designated
as parathyroid III, whereas the superior parathyroid glands
descend from the fourth branchial pouch and are referred to
as parathyroid IV. Figure 38-1 schematically depicts the
development and migration of the parathyroids.
Norris," basing his findings on a collection of 139 human

embryos, fetuses, and newborn children, studied the morphogenesis of the parathyroid glands. He divided the developmental process into five stages, as described next.
Preprimordial Stage
The preprimordial stage is represented by embryos from 4 to
8 mm in length. This stage makes up the embryonic development between the time of the formation of the pharynx
(foregut) and the earliest appearance of a recognizable
parathyroid anlage. The third and fourth pouches show
slight dorsal extensions. The third pouch, which has the
form of a tubelike lateral expansion from the embryonic
pharynx, makes contact with the ectoderm of the branchial
cleft and then continues its growth downward in the ventral
direction.
Early Primordial Stage

At this stage, the embryo is about 9 mm in length. The tissue
destined to become the parathyroids can be recognized.
Proliferation and differentiation of large, clear cells with
sharply demarcated polygonal outlines occur in the third and
four pouches. This proliferation results in a thickening of the
third diverticulum wall. The early primordium of parathyroid IV
adopts the form of a solid budlike nodule; the fourth pouch still
exists as a tubular diverticulum from the pharynx.
Branchial Complex Stage

At this stage, paired derivatives of the third and fourth pouches
become separated from each other to take up independent
positions. During the early stage, the branchial pouches are
joined to the pharynx; subsequently, the pharyngobranchial
ducts become drawn out, narrowed, and finally divided so that
at each side of the midline there is a pair of lobulated bodies.
One pair represents the thymus and parathyroid III (third
branchial complex), and the other represents the lateral thyroid
and parathyroid IV (fourth branchial complex).
365
366 - - Parathyroid Gland

and parathyroid III is at about the level of the lower pole of
the thyroid, parathyroid III increases in size and gradually
becomes constricted at its base of attachment, and complete
separation occurs. The two elements of the fourth complex
also grow and become constricted until the interlobular stalk
is divided. There is almost no descent of this complex, and
the isolation of parathyroid IV occurs when the lateral and
median thyroids become incorporated. The final position of
parathyroid IV in relation to the thyroid gland is determined
by the place at which the inclusion of the lateral thyroid
body occurs. Isolation of the parathyroid glands is usually
accomplished by the time the embryo is 20 mm in length.
Definitive Form Stage

This stage is the period from the end of the stage of isolation
to the time when the parathyroids assume their definitive
form. Alteration in form from a spherical or globular body
toward an ellipsoid shape occurs. The form of the parathyroid
glands is ultimately determined by their relation to adjacent
structures.
This embryologic relationship of the parathyroids, the thyroid, and the thymus makes the location of most parathyroid
glands predictable.
FIGURE 38-1. Origin of parathyroid glands from the third and
fourth pharyngeal pouches.
The median thyroid, which descended in an earlier stage

from a median diverticulum of the floor of the pharynx,
begins to grow out laterally and cephalocaudally in the form
of a flat plate that extends to both sides of the midline. This
plate begins to bend dorsally at its lateral edges and extends
more and more dorsally to intervene between the laterally
placed third branchial complex and the more medially
placed fourth branchial complex.
At the beginning of the branchial complex stage, the thymus
primordium and the parathyroid primordium are intimately
joined; however, the thymus enters into a period of rapid
ventral growth until it makes contact with the pericardium.
Parathyroid III, on the other hand, does not grow as rapidly
as the thymus and remains as a budlike projection from the
upper end of the thymus cord. Finally, parathyroid III takes
a spherical shape, intimately attached to the cephalic pole of
the thymus cord. At the end of this stage, the third branchial
complex migrates through the entire extent of the embryonic
neck, and separation of the parathyroid from the thymus
begins.
The position of the fourth complex in relation to the
median thyroid depends on changes in form, size, and position of the rapidly growing lateral lobe of the median thyroid.
During this time, parathyroid IV is still attached to the
lateral thyroid body. The brachial complex stage ends when
the embryo is approximately 18 to 20 mm in length.
Isolation Stage
This stage is characterized by separation of each branchial
complex. When the thymus and parathyroids have descended
Anatomy
Most humans have four parathyroid glands. The percentage
of individuals with supernumerary glands varies from 2.5%
to 22%. The presence of as many as eight parathyroid glands
has been reported, and different series have determined that
there is a wide variation in the number of individuals with
fewer than four glands. The exact number of individuals
with fewer than four glands may be impossible to determine
because the surgeon or researcher may not be able to find
one or more glands, and a missing gland could represent an
unobserved rather than an absent gland.
The parathyroid glands usually lie on the posterior surface
of the thyroid gland, each with its own connective tissue capsule surrounded by lighter colored fat globules. Figures 38-2
and 38-3 depict the normal location of parathyroid glands with
emphasis on their anatomic relations. The superior parathyroid
gland is normally located on the posteromedial aspect of the
thyroid gland near the tracheoesophageal groove. The majority of these glands are located within a circumscribed area
2 em in diameter, about 1 em above the intersection of the
recurrent laryngeal nerve and the inferior thyroid artery. They
may be either intimately associated with the cricothyroid
junction or tucked behind the upper and middle thirds of the
thyroid. When a gland is in intimate association with the
cricothyroid junction, it is suspended by a small pedicle and
enveloped by a pad of fatty tissue. When they are located on
the posterior surface of the upper pole, parathyroid glands
are invariably beneath a thyroid-investing fascial sheath.
Superior parathyroid glands can be located farther down,
sometimes obscured by the inferior thyroid artery or the
recurrent laryngeal nerve. A rather unusual location is above
the upper thyroid pole in the posterior aspect of the neck,
the retropharyngeal or retroesophageal space. True superior
intrathyroidal glands are rarely seen.
Parathyroid Embryology, Anatomy, and Pathology - - 367
FIGURE 38-2. Frontal view of the anatomic location of parathy-
roid glands.
The inferior parathyroid glands are more widely distributed. They are normally located on the posterolateral aspect
of the inferior pole of the thyroid gland, below the inferior
thyroid artery, although they may be located anterior, inferior, or lateral to the inferior thyroid pole. They are usually
surrounded by fat and sometimes may be in a fatty
FIGURE 38-3. Lateral viewof the anatomic location of upperand
lower parathyroid glands. A, Right. B, Left.
appendage of the inferior thyroid pole. Some of these inferior glands can be found high up on the thyroid lobe.
Another common location of the inferior parathyroids is the
region inferior to the thyroid, close to the thyrothymic ligament or within the cervical part of the thymus. Inferior
glands can also be located farther down in the thymus or
in the fatty tissue of the anterior mediastinum, at the carotid
bifurcation, or within the substance of the thyroid gland.
Most anatomic studies have not involved serial sections of
the thyroid gland, but Thompson and colleagues'' carefully
sliced all thyroid lobectomy specimens during a 10-year
period and found truly intrathyroid parathyroid glands in 3%
of the cases. They were all located in the lower third of the
thyroid and, therefore, were considered inferior parathyroid
glands. Failure of an inferior parathyroid gland to descend
during its embryonic development may result in a gland
located higher up in the neck, even above the upper thyroid
pole. These glands are usually surrounded by a remnant of
thymic tissue. When supernumerary glands exist, the fifth
gland is most often located in the thymus or in relation to the
thyrothymic ligament."? Figure 38-4 graphically demonstrates the frequency of anatomic locations of both superior
and inferior parathyroid glands as reported by Gilmour in a
study on 527 autopsies. 10
As previously stated, parathyroid glands can be either
extracapsular or intracapsular. When the gland is located
underneath the fibrous capsule of the thyroid, it is designated
intracapsular; whereas when it lies outside the capsule it is
termed extracapsular. This anatomic feature has great surgical importance. When an intracapsular gland is diseased, it
expands locally within the confines of the thyroid capsule and
remains in its place. An enlarged extracapsular parathyroid
gland, on the other hand, tends to be displaced to the area of
least resistance. Thus, an extracapsular gland at the cricothyroid junction falls into the posterior mediastinum and an
extracapsular gland within the thymus disappears behind the
clavicle and falls into the superior anterior mediastinum.
Symmetry of parathyroid glands varies for parathyroids
III and IV. Symmetry of superior glands is found in approximately 80% of the cases, whereas approximately 70% of
inferior glands are symmetrical. Relative symmetry of all
four glands is noted in approximately 60% of the cases. It is
important to note that symmetry is less marked when the
glands are located in an unusual site.?
When two parathyroid glands are intimately related
to each other and appear to be fused, they are known as
"kissing pairs." This is a rare finding. A kissing-paired
parathyroid can be differentiated from a bilobular gland by
the presence of a cleavage plane present in the kissing pair
and an intact capsule in the bilobulated gland.
The parathyroid glands vary in size, shape, and color.
They are spherical, somewhat flattened, or ovoid bodies
whose shapes are modeled by pressure from the surrounding
structures. The size of parathyroid glands varies from 4 to
6 mm in length and 3 to 4 mm in width. The average
parathyroid gland is about 5 x 3 x I mm. When they are
long, they tend to be narrow and thin. Conversely, when they
are short, they are wide and thick. The average weight of a
parathyroid is 35 to 40 mg, but it ranges from 10 to 70 mg.
The color of the glands varies with age. In the newborn. they
are gray and semitransparent. They are light pink in children,
FIGURE 38-4. Frontal view of the anatomic location

of upper and lower parathyroid glands as reported by
Gilmour,"
turning yellow in adults as their fat content increases. In

older adults, they become darker,"!'
Parathyroid glands may conceivably be confused with
small lobules of fat, with accessory nodules of thyroid
tissue, or even with lymph nodes. Several physical characteristics may help to distinguish one from the other. The
parathyroid glands are faintly globular or oblong structures
that are softer in consistency than the adjacent thyroid or
lymph nodes. Fat lobules are more friable than parathyroid
glands and do not have the gland consistency or the lacework of blood vessels on the surface. Lymph nodes have a
more rounded configuration and are more adherent to the
surrounding tissues. Thyroid nodules are always harder,
more reddish, and less homogeneous than parathyroid
glands. Parathyroid tissue is quite vascular, and on biopsy a
"blush" or diffuse bleeding can be seen on the cut surface.
Neither fat nor lymph nodes exhibit such a blush. 6,l 2,l 3
At surgery, the typical appearance of a parathyroid gland is
that of a small "body" that moves inside its own fat capsule
when gentle pressure on the surface is applied with a fine
surgical instrument.
Relation between the

Parathyroid Glands and the
Recurrent Laryngeal Nerve
Emphasis has been placed on the relationship of the parathyroid glands and the recurrent laryngeal nerve. A predictable
relation of both the superior and inferior parathyroid glands
to the recurrent laryngeal nerve is noted within a rectangular area that can be imagined visually when the lobe of the
thyroid is rotated medially. The superior boundary of this
rectangle is the most cephalad portion of the thyroid lobe;
the inferior boundary is a point on the trachea 4 em below
the inferior pole of the thyroid gland; posteriorly, the esophagus; and anteriorly, the surface of the thyroid lobe and
trachea. The usual course of the recurrent laryngeal nerve
should divide this rectangle into two triangles, one lying
ventral and the other dorsal to the nerve. After analyzing
100 autopsy specimens, Pyrtek and Painter" found that 93%
of parathyroid glands were situated in a predictable relation

to the recurrent laryngeal nerve (i.e., superior glands lying
posterior and superior to the nerve and inferior glands lying
anterior to the nerve). This supports the reliability of the recurrent laryngeal nerve as a guide for locating the parathyroid
glands.
Arterial Blood Supply

to the Parathyroids
On the basis of the study of 357 parathyroid gland pedicles,
Flament and colleagues" found a single artery supplying the
parathyroids in 80% of the cases. This artery was simple in
65% of the cases, bifurcated before its entry into the gland
in 30%, and divided into three branches in 5%. In 15% of
the total group, two distinct arteries were observed, in 4%
three were seen, and in 1%, even four separate arteries were
found.
The length of the artery is variable, usually between 8
and 12 mm. When long, the arteries are commonly tortuous;
when the pedicle is short, it holds the parathyroid hard against
its vessel of origin. Generally, pedicles of the superior
parathyroid are shorter than those of the inferior ones. Both
the superior and inferior parathyroid glands most frequently
borrow their blood supply from the inferior thyroid artery. In
particular, superior parathyroid glands receive their arterial
blood supply from this artery in approximately 80% of the
cases. In 15%, the blood supply is provided by the superior
thyroid artery, and in 5%, by anastomoses running between
the two systems. When the superior thyroid artery supplies
the superior parathyroid, the supply almost always comes
from the posterior branch or from an artery arising from
the posterior branch and destined for the esophagus or the
larynx. In approximately 10% of the cases, inferior parathyroid glands are vascularized by the superior thyroid artery,
anastomosis of both systems, or Neubauer's artery." This
figure is intimately related to the frequency of agenesis
of the inferior thyroid artery, which occurs in 1% to 6%
of cases.
In terms of parathyroid blood supply, certain practical
observations are worthwhile. A special tiny parathyroid
Parathyroid Embryology, Anatomy. and Pathology - - 369

artery always supplies the gland and is considered terminal.
Superior and inferior parathyroid arteries usually arise from
the glandular branch of the thyroid artery but can often arise
from the muscular or the esophageal branches. They can
also originate from an anastomosing channel between the
inferior and superior thyroid vessels. Very few, if any, vascular connections between the parathyroid glands and the adjacent connective tissue normally exist. The fine branches that
the parathyroid arteries give off to the surrounding fat end in
the fatty tissue, thus making it easier to enucleate the glands
with their involved fat than to liberate them from it. 3,14
Adenoma
Parathyroid glands consist of chief and oxyphil cells, fibrovascular stroma, and adipose tissue. Chief cells are identified
in children and adults; oxyphil cells are mainly observed in
adults. Chief cells constitute almost all the parenchyma and
measure 6 to 8 urn in diameter; their cytoplasm contains
argyrophilic granules and lipids. Clear cells have an optically
clear cytoplasm as a result of glycogen loss during histologic processing. The total number of oxyphil cells grows
with increasing age; however, this kind of cell is also identified in pediatric populations. It is associated with secretory
functions, contrary to the usual point of view that these are
degenerated cells. 15
Parenchymal cells are arranged in solid sheets, cords,
tubular structures, or, in 2% to 50%, microcystic formations.
The admixture of stromal and adipose elements varies with
age and function. The parenchyma-to-stroma ratio is used
as an indicator of a normocellular or hypercellular gland; the
median ratio is 50%, but the adipose tissue content varies
from 40% to 70% (Fig. 38-5). Therefore, some authors
consider the stromal-parenchymal index inadequate for separating normal from abnormal glands.l's'?
Primary hyperparathyroidism can be produced by three
different pathologic lesions: adenoma, hyperplasia, and carcinoma. The frequencies of these vary, mainly because of the use
of different criteria for their diagnosis in the various series.
An adenoma is a benign neoplasm composed of chief cells,

oncocytic cells, transitional oncocytic cells, or a mixture of
these cell types. They are responsible for 80% to 90% of
hyperparathyroidism cases and usually affect a single gland.
Adenomas are more frequent in females than males, at a
ratio of 3:1. Macroscopically, the affected gland is enlarged,
tan-brown, ovoid, well limited or encapsulated, and occasionally with areas of hemorrhage or cystic spaces (Fig. 38-6). In
smaller adenomas, a rim of normal glandular tissue is identified. The remaining glands are normal or atrophic. I?
Histologically, adenomas are encapsulated tumors composed of cohesive sheets of cells surrounded by a fine capillary
network. Occasionally, insular, tubular, trabecular, or acinar
patterns are observed. Stromal fat is scant or absent, and
the large, thick-walled veins typical of normal parathyroid
glands are lacking. However, these two criteria, classically
considered diagnostic of adenoma, have been regarded as
less relevant.F:" A rim of normal glandular tissue is always
identified in small lesions but is sometimes absent in large
adenomas even if serial sections are made. On the other
hand, adenomas are occasionally confused with hyperplastic
nodules admixed with normal glandular tissue in cases of
parathyroid hyperplasia. Because of the poor reproducibility
of histologic criteria to differentiate parathyroid adenoma
from hyperplasia, close cooperation between the pathologist
and surgeon is recommended.l?
In conclusion, a remnant of normal tissue is no absolute
prerequisite for a diagnosis of adenoma and is identified in
only 50% to 60% of proven adenoma cases (Fig. 38-7).
The precise histopathologic definition of parathyroid
adenoma has remained elusive. Studies using molecular
approaches have established that parathyroid adenomas are
clonal proliferations. Some studies demonstrated clonal
rearrangements of the parathyroid hormone gene and further
evidence for clonality through the analysis of the hypoxanthine phosphoribosyltransferase gene." Thus, the monoclonality of adenoma cells is usually reflected by their
monomorphic appearance, although cases with a mixed
FIGURE 38-5. A close l: 1 relation of epithelial and stromal cells

is observed in normal glands from adults.
FIGURE 38-6. Macroscopic aspect of a parathyroid adenoma

showing a nodular configuration with cystic degeneration in a
brown gland.
Pathology
FIGURE 38-7. Parathyroid adenoma. A rim of normocellular

parathyroid tissue with adipose cells surrounds a proliferation of
chief and oncocytic cells.
FIGURE 38-8. Parathyroid hyperplasia. Nodular proliferation of

parenchymal cells admixed with normocellular parathyroid tissue
at the periphery of a hyperplastic gland.
cellular population exist. The cells are larger than normal, and
the nuclei show hyperchromasia, atypia, and an increased
DNA content." Focally, there is syncytia formation, with
variable numbers of nuclei surrounded by basophilic cytoplasm, probably as a result of cell degeneration.
In classic chief cell hyperplasia, these cells are mixed

with oncocytic and transitional oncocytic cells. Stromal fat
cells are decreased, and vascular supply is provided by large,
thick-walled vessels. The parenchymal cells frequently
show a nodular arrangement, usually at the beginning of
the disease. These nodules consist of polygonal cells with
abundant cytoplasm and a medium-sized or small, centrally
located nucleus. In the internodular tissue, parenchymal
cells are mixed with stromal elements (Fig. 38-8). In the
occult form of parathyroid hyperplasia, confusion with a
parathyroid adenoma or a large normal parathyroid gland
can occasionally occur, and its functional significance is
uncertain.
To distinguish between parathyroid hyperplasia and
parathyroid adenoma, it is important to know the gross
appearance of all glands at surgery. 17 In primary chief cell
hyperplasia, enlargement of more than two parathyroid
glands is frequently observed, whereas the great majority of
adenomas involve a single gland. Hence, no single morphologic parameter is able to resolve the differential diagnosis
(Table 38-1); instead, the distinction between adenoma and
hyperplasia is based on the combination of gross features
plus histologic parameters. When a normal parathyroid
gland is documented histologically, most experts believe
that the abnormal gland or glands are adenomas.
Adenoma Variants
Oncocytic adenomas are rare neoplasms composed of oncocytic cells. Ultrastructural studies have revealed the presence
of abundant mitochondria in the cytoplasm of oncocytic cells.
The major criteria for the diagnosis of oncocytic adenomas,
according to Wolpert and coworkers.P are as follows:
(l) more than 90% of cells showing oncocytic features,
(2) histologically normal parathyroid tissue in a biopsy of
another gland, and (3) postoperative normocalcemia.
Lipoadenomas (hamartomas) are lesions consisting of
proliferation of stromal and parenchymal elements. Grossly
encapsulated, lipoadenomas appear soft, yellow-tan, and
lobulated. Histologically they are composed mainly of abundant adipose tissue with myxoid changes and fibrosis,
admixed with chief and oncocytic cells arranged in thin
branching cords."
Hyperplasia
Primary parathyroid hyperplasia is defined as an absolute
increase in chief cells, oncocytic cells, and transitional
oncocytic cells mixed with stromal elements in multiple
parathyroid glands, in the absence of a known stimulus for
parathyroid hormone hypersecretion. 17
Clinically, parathyroid hyperplasia does not differ significantly from adenomas. However, parathyroid hyperplasia is
associated with the dominantly inherited multiple endocrine
neoplasia (MEN) types land 2. In contrast, parathyroid
hyperplasia is generally absent in MEN 28. 23 In more
than half of the cases, the hyperplastic glands weigh less
than 1 g. According to macroscopic and microscopic morphology, three patterns of hyperplasia have been recognized:
classic, pseudoadenomatous, and occult."
Parathyroid Embryology, Anatomy, and Pathology - -
371
(posterior) side of the thyroid and are adjacent to the recurrent laryngeal nerve (upper posterior and lower anterior).
About 80% of patients with primary hyperparathyroidism
have solitary parathyroid tumors (adenomas), 1% have
carcinoma, and 19% have hyperplasia or more than one
abnormal parathyroid gland.
REFERENCES
FIGURE 38-9. Parathyroid carcinoma. Nodular arrangement of

neoplastic parathyroid cells surrounded by fibrous tissue. A, The
centers of the nodules show ischemic necrosis and calcification. B,
Intrathyroidal metastasis of parathyroid carcinoma: small nests of
neoplastic cells mixed with thyroid follicles.
Carcinoma
Parathyroid carcinoma is responsible for 0.5% to 2% of cases
of primary hyperparathyroidism. It is a slow-growing neoplasm of the parenchymal cells.'?
On gross examination, parathyroid carcinoma is an illdefined mass, usually larger than adenomas, with adherence
to surrounding tissues. The cut surface is irregularly nodular,
gray-tan, and firm. Microscopically, it consists of neoplastic
parenchymal cells that show atypia, mitotic figures, capsular
and vascular invasion, and, of paramount importance, thick
fibrous bands interspersed among the neoplastic cells. Not all
of these features can be observed in every case; fibrous bands
are present in 90%, mitotic activity in 80%, capsular invasion
in 75%, and vascular invasion in 10% of cases in some
series.17,25
The tumor cells making up parathyroid carcinoma are
arranged in trabecular, sheetlike, or rosette-like patterns.
Occasionally, the neoplastic cells form nodular structures
with central calcification and necrosis (Fig. 38-9). Nuclear
morphology is variable, from minimal atypia to marked
pleomorphism with clumped chromatin and enlarged
nucleoli.'? Cytoplasm is clear, eosinophilic, and granular,
sometimes mimicking the plasmacytoid cytoplasm of the
cells of medullary thyroid carcinoma.
Because cytologic features broadly overlap, the distinction
between parathyroid carcinoma and parathyroid adenoma is
mainly based on the invasive character of the former.17,25
Summary
The parathyroid glands ongmate from the third (lower
parathyroids) and fourth (upper parathyroids) branchial
pouches. These four glands are usually situated on the dorsal
1. Alveryd A. Parathyroid glands in thyroid surgery. Acta Chir Scand

1968;389: 1.
2. Welsh DA. Concerning the parathyroid glands: A critical anatomical
and experimental study. J Anat Physiol 1898;32:292.
3. Halsted WS, Evans HM. The parathyroid glandules. Their blood
supply, and their preservation in operation upon the thyroid gland.
Ann Surg 1907;46:489.
4. Boyd JD. Development of the thyroid and parathyroid glands and the
thymus. Ann R Coli Surg Engl 1950;7:455.
5. Norris EH. The parathyroid glands and the lateral thyroid in man: Their
morphogenesis, histogenesis, topographic anatomy and prenatal
growth. Contrib EmbryoI1937;159:249.
6. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary
hyperparathyroidism. Surgery 1982;92:814.
7. Akerstrom G, MaImaeus J, Bergstrom R. Surgical anatomy of human
8. Wang CH. The anatomic basis of parathyroid surgery. Ann Surg
1976;183:271.
9. McGarity WC, Bostwick 1. Technique of parathyroidectomy. Am Surg
1976;40:657.
10. Gilmour JR. Embryology of the parathyroid glands, thymus and certain
associated rudiments. J Pathol Bacteriol 1937;45:507.
11. Gray SW, Skandalakis JE, Akin JT, et al. Parathyroid glands. Am Surg
1976;40:653.
12. Curtis GM. The blood supply of the human parathyroids. Surg Gynecol
Obstet 1930;315:805.
13. Pyrtek LJ, Painter RL. An anatomic study of the relationship of the
parathyroid glands to the recurrent laryngeal nerve. Surg Gynecol
Obstet 1964;119:509.
14. F1ament JB, Delattre JF, Pluot M. Arterial blood supply to the
parathyroid glands: Implications for thyroid surgery. Anat Clin
1982;3:279.
15. Abu-Jawdeh GM, Roth SI. Parathyroid glands. In: Sternberg SS (ed),
Histology for Pathologists. New York, Raven Press, 1992,p 311.
16. Ghandur-Mnaymneh L, Cassady J, Hajianpour MA, et al. The parathyroid gland in health and disease. Am J Pathol 1986;125:292.
17. Delellis RA. Tumors of the parathyroid gland. In Atlas of Tumor
Pathology, 3rd series, fascicle 6. Washington, DC, Armed Forces
Institute of Pathology, 1993, p I.
18. Ghandur-Mnaymneh L, Kimura N. The parathyroid adenoma.
A histopathologic definition with a study of 172 cases of primary
hyperparathyroidism. Am J PathoI1984;115:70.
19. Bomstein-Quevedo L, Gamboa-DomfnguezA, Angeles-Angeles A, et aI.
Histologic diagnosis of primary hyperparathyroidism: A concordance
analysis between three pathologists. Endocr PathoI2001;12:49.
20. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal
parathyroid hormone genes in parathyroid adenomas. N Engl J Med
1988;318:658.
21. Mallette LE. DNA quantitation in the study of parathyroid lesions.
A review. Am J Clin Pathol 1988;98:305.
22. Wolpert HR, Vickery AL Jr, Wang CA. Functioning oxyphil cell
adenomas of the parathyroid gland. A study of 15 cases. Am J Surg
Pathol 1989;13:500.
23. DeLellis RA, Dayal Y, Tischler AS, et al. Multiple endocrine neoplasia
(MEN) syndromes: Cellular origins and interrelationships. Int Rev Exp
Pathol 1986;28:163.
24. Black WC, Haff RC. The surgical pathology of parathyroid chief cell
hyperplasia. Am J Clin PathoI1970;53:565.
25. Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases.
Cancer 1973;31:600.
Parathyroid Hormone:
Regulation of Secretion and
Jonas Rastad, MD, PhD Peter Ridefelt, MD, PhD Wen T. Shen, MD
The parathyroid gland is exceptional among human tissues

because its principal secretory product, parathyroid hormone
(PTH), is involved in a direct feedback loop, which tightly
regulates the serum calcium concentration. This secretion
is potently inhibited by calcium through calcium sensors
on the parathyroid cell surface, and PTH exerts its effects
through a specific receptor in the peripheral target tissues.
In the past, disturbances in this system were difficult to
recognize clinically because of inadequate assays for PTH
and calcitriol. Despite the improvements in these assays,
however, management of patients with the broad spectrum of
metabolic calcium disturbances is still complicated by limitations in knowledge. This chapter provides a background for
subsequent chapters on hyperparathyroidism by outlining the
normal physiologic regulation of PTH secretion, describing
the derangements in PTH and calcium regulation in primary
and secondary hyperparathyroidism (HPT), and defining the
current methods for determining serum PTH values.
Physiologic Regulation of
Parathyroid Hormone Release
Several endogenous substances, including peptides, steroid
hormones, and amines, have been found to influence PTH
release.I-' It is apparent, however, that calcium is the most
potent regulator of PTH secretion. Analyses of normal
parathyroid cells have shown that acute changes in extracellular calcium concentration induce rapid changes in PTH
release.v' Studies in vitro and in vivo5-9 support the concept
that the dose-response relationship between calcium and
PTH is inversely sigmoidal, with the steepest part of the
curve corresponding to the physiologic concentration range
for ionized calcium (Ca2+j) (Fig. 39-IA). Minor alterations
within the physiologic calcium concentration range can thus
induce considerable secretory responses (Fig, 39-2), and
372
reduction of ionized plasma calcium by 0.04 mmollL may

elevate serum PTH by 100% or more. Circadian variation
in serum PTH values differs between men and women, and
blunting of this variation in HPT seems to occur in vivo,10,I 1
whereas the presence and pathophysiologic significance of
rapid pulsations in the release of PTH await clarification. 12,13
Stepwise alterations in extracellular calcium concentration have suggested that more sudden changes may elicit
greater PTH responses, whereas rapid decreases in plasma
calcium may be counteracted most effectively." The amplitude and direction of the change in calcium concentration
also influence the magnitude of the secretory response. 15,16
A nonsuppressible component of PTH secretion persists
even when the extracellular calcium concentration is
markedly elevated (see Figs. 39-IA and 39-2). The extent of
this component is partly related to discrepant sensitivities
of PTH assays to different portions of the PTH molecule.
Under normal circumstances, the basal serum PTH value is
positioned closer to the level of maximal suppression than
stimulation, which implies a potential to counteract
decreased plasma calcium levels." The steep slope of the
dose-response relationship between external calcium and
PTH release in euparathyroid patients also supports the
notion that shifts in the position and slope of the doseresponse curve significantly influence the steady-state
serum PTH value.S'? Chronic changes in serum calcium
lead to a shift in the calcium-PTH dose-response curve,
whereas acute changes in serum calcium move the PTH
secretory responses along the prevailing dose-response
curve.7,8.14.18 Moreover, chronic hypocalcemia is characterized by a maintained, albeit numerically reduced, stimulation of PTH secretion in response to a further reduction of
the calcium concentration (Fig. 39-3).
The rapid effect of extracellular calcium on PTH release
suggests that calcium directly interferes with the PTH
release process, but the nature of this interference has been
Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - 30
~Bovine
100
80
."g
e,
- -0 - Adenoma
... c Primary hyperplasia

. MEN-I hyperplasia
....... Uremichyperplasia
25
,.
==o 20
E
a.
:::: 15
Q)
Ul
III
Q)
60
J:
...
c..
40
:::.. 10
en
5
oL--,-~---,--~~~~!!:::::=t:::::::=:i--",---,
20 Ol.------JI.------!-------!.
123
Extracellularcalcium (mM)
A
600
500
~
.s 400
1,
oo
'EUl
0.6
0.8
1.0
1.2
1.4
1.6
Ionized calcium (mmol L- l )
1.8
2.0
FIGURE 39-2. Inverse sigmoidal relationship between ionized

plasma calcium and intact serum parathyroid hormone (S-PTH) in
22 healthy controls (0) and 26 patients with sporadic primary
hyperparathyroidism (e) subjected to sequential citrate and calcium infusions. Values represent mean standard deviation. (From
Schwartz P, Sorensen HA, Transbol 1. Interrelations between the
calcium set-points of Parfitt and Brown in primary hyperparathyroidism: A sequential citrate and calcium clamp study. Eur J Clin
Invest 1994;24:553. 1994 by Blackwell Science.)
300
~ 200
373
100
1
2
Extracellularcalcium (mM)
B
FIGURE 39-1. Effects of increases in extracellular ionized calcium on parathyroid hormone (PTH) release (A) and steady-state
Ca2+i (B) of dispersed parathyroid cells from normal glands of
adult cattle, parathyroid adenomas (n = 22), hyperplastic glands of
sporadic primary hyperparathyroidism (HPT) (n = 9), and familial
HPT of multiple endocrine neoplasia (MEN) type I (n =8), as well
as hyperplastic glands of uremic patients with hypercalcemic HPT
(n = 23). PTH release is expressed in percentages of the release
at 0.5 mmol extracellular calcium, and cytoplasmic calcium is
measured with quin-2 in a cuvette system. Values represent mean
standard error and are recalculated and extended from Wallfelt and
colleagues."
only partially clarified. It has been demonstrated that external calcium mainly regulates secretion of newly synthesized
hormone, which may bypass the relatively few secretory
granules in the parathyroid cells.!? Intracellular degradation
with release of carboxyterminal PTH fragments occurs
especially at high extracellular calcium concentrations. This
attenuates the biologic activity of the secretory product
because the calcium-regulating properties of PTH reside in
its aminoterminal portion. The secretion of PTH is also
modulated by transcription of the PTH gene, which consists
of three exons and is located in chromosome 11 (1lp15).2o
PTH is synthesized as a precursor molecule (pre-pro-PTH)
and undergoes sequential cleavage." The pre-pro-signal
peptide is important for cellular transport and extrusion of

the intact (1-84) PTH molecule. A single amino acid mutation in this sequence has been found to cause insufficient
PTH secretion in familial hypoparathyroidism.P Similar
actions have also been ascribed to PTH itself, and this may
partially explain the existence of the carboxyterminal
portion of PTH.
Messenger RNA (mRNA) levels for PTH are increased
within hours by low extracellular calcium, consistent with
200
150
~
.s
J:
b: 100
en 50
,Cf
<'f'~'
E
::;,
lii
jTT~
Pre-op
05 days
.1 month
01 year
Ifl @~
Il
i,l
'! "
0'--------'-------'--------'
0.9
1.1
1.3
Plasma ionized calcium (mM)
1.5
FIGURE 39-3. Intact serum parathyroid hormone (PTH) in relation to the ionized plasma calcium concentration during a constant
infusion of edetic acid as well as an oral calcium load in 18 patients
with primary hyperparathyroidism before parathyroid surgery, as
well as 5 days, 1 month, and 1 year postoperatively. Values represent mean standard error and are recalculated and extended from
Graf and colleagues."

the effects of calcium on PTH secretion.P<' Furthermore,
calcitriol lowers PTH mRNA levels and inhibits PTH
secretlon.P-" This action is associated with a shift of the calcium dependence of PTH secretion toward lower calcium
values rather than interference with the slope of the doseresponse curve." Calcitriol binds to its receptor (vitamin D
receptor) and interacts with the 5' -flanking promoter region of
the PTH gene." The PTH gene also contains cyclic adenosine
monophosphate (cAMP)-responsive elements." whereby
its transcription may be regulated by, for example, corticosteroids, vasoactive intestinal polypeptides, and estrogen.
Intracellular Messengers
Regulating Parathyroid
Hormone Release
Regulation of hormone release involves translation of extracellular signals through interacting second messenger systems such as cytoplasmic Ca 2+ j , cAMP, and diacylglycerol
production through phosphoinositol hydrolysis. It has been
demonstrated that external calcium acts through all of these
messenger systems of the parathyroid cell." Calcium interferes with parathyroid adenylate cyclase and cAMP-dependent
protein kinases.F This mode of action has been seen in many
agents besides calcium and other cations that stimulate or
inhibit PTH release.' It is unlikely, however, that the regulation of parathyroid cell secretion by external calcium is controlled principally through cAMP-dependent mechanisms.
The same conclusion has been drawn for the pathologic

parathyroid tissue of patients with HPT, despite its altered
adenylate cyclase activity." It has also been demonstrated
that cAMP appears to regulate the release of PTH that is less
newly synthesized than that secreted under the influence of
external calcium." Although guanidine nucleotide-binding
(G) proteins regulate cAMP production, the role of G proteins in regulating parathyroid Ca 2+ j and PTH release is
unclear. 34
A rise in extracellular calcium momentarily elevates
Ca 2+ j to an unusually high level in normal human parathyroid cells.t-" As with calcium-regulated PTH secretion,
there is a sigmoidal but positive dose-response relationship
between Ca 2+ j and external calcium (see Fig. 39-IB). The midpoints of these dose-response curves for calcium-regulated
secretion and Ca 2+ j are correlated. Half-maximal inhibition
of PTH release is attained at lower external calcium concentrations than the corresponding elevation of Ca 2+ j . Moreover,
the secretion is inversely and linearly related to Ca 2+ j within
essentially physiologic and supraphysiologic concentrations
of calcium." In the very low concentration range of external
calcium, however, both Ca 2+ j and PTH release are stimulated
by a rise in external calcium. A stepwise increase in external
calcium elicits a biphasic Ca 2+ j response in normal parathyroid cells (Fig. 39-4A). This response consists of a rapid
Ca 2+ j transient peak followed by a slower steady-state elevation, which seems to persist for as long as the external
stimulus is maintained. The rapid Ca 2+ j peak may also be
induced in the absence of external calcium by inositol 1,4,
5-triphosphate-mediated release of intracellular calcium from
1000
i'
100
800
3.0
"iu
.~
en
lao
600
ell
Cii
Q)
Qi
'r 60
J:
1.0
l-
400
0..
40
200
;;c
30
-t
60
Time (sec)
"iu
Q)
en
ell
2.0
i'
S
:2
Qi
xe
w
0
I
30
60
90
Time (sec)
FIGURE 39-4. Effects of stepwise increases in extracellular calcium from 0.5 to 3.0 mmol/L on cytoplasmic calcium (A) and parathyroid
hormone (PTH) release (B) of normal bovine parathyroid cells loaded with intracellular concentrations of fura-2 of about 0.1 (0) and
0.5 (e) mmol/L. PTH and extracellular calcium concentrations in the perfusate were measured in 5-second samples. PTH release is
expressed in percentages of the initial secretion at 0.5 mmol/L extracellular calcium. Values represent mean standard deviation. (From
Wallfelt C, Lindh E, Larsson R, et al. Kinetic evidence for cytoplasmic calcium as an inhibitory messenger in parathyroid hormone release.
Biochim Biophys Acta 1988;969:257. Reprinted with permission of Elsevier Science-NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam,
The Netherlands.)
Parathyroid Hormone: Regulationof Secretionand LaboratoryDetermination - - 375

the endoplasmic reticulum.Fr" In contrast, the steady-state
Ca2+ j elevation depends on calcium influx through the
plasma membrane.t-" This permeability change may be
caused by a calcium-mediated increase in inositol tetrakisphosphate. Improvements in the technical handling of
parathyroid cells have confirmed that the steady-state Ca 2+ j
elevation actually consists of rather impressive oscillations
in the calcium concentration (unpublished data). The frequency, but not amplitude, of these oscillations is regulated
by external calcium, and the oscillations are sensitive to
calcium channel blockers (Fig. 39-5). Such oscillations are
expected to enhance the sensitivity of calcium-regulated
Ca2+ j and PTH release and to reduce intracellular exposure
to potentially damaging steady-state elevations in Ca 2+ j .
Moreover, a direct relationship between synchronized Ca 2+ j
oscillations and pulsatile hormone release has been established in other cell systems.'?
A strong argument for Ca 2+ j as the principal regulator of
PTH release has been built by studies of the kinetics of PTH
regulation by calcium." Parathyroid cells equipped experimentally with low calcium-buffering capacity demonstrated a
momentary rise in Ca2+ j, which rapidly reached a steady-state
level upon a stepwise increase in external calcium (see
Fig. 39-4). Cells provided with higher buffering capacity,
however, displayed slower calcium-induced rises in Ca 2+ j and
sluggish alterations in PTH release. High extracellular calcium also increases hydrolysis of the phosphoinositides into
not only inositol trisphosphates but also diacylglycerol,
whereby activation of classic protein kinase C is expected to
occur. Protein kinase C activation at low extracellular calcium
concentrations inhibits PTH release but stimulates PTH secretion at high external calcium levels." The role of protein
kinase C in PTH secretion remains to be elucidated because
there is discordant activation of protein kinase C at low and
inositol trisphosphate at high external calcium levels.42,43
Electrophysiologic analyses have demonstrated that inhibition of PTH release by high external calcium levels is associated with depolarization of the parathyroid cell." Studies
of transmembrane calcium fluxes, however, revealed that
calcium influx occurs through a calcium-activated and voltage-independent permeability and that calcium influx current
2.0
2.5
Cerium
~200
..s
"'ra 150
o
c
'E 100
~
Ci.
~
o
5
10
15
20
25
30
35
Time (min)
FIGURE 39-5. Microfluorometric measurement of the cytoplasmic calcium concentration in a normal human parathyroid cell
exposedto stepwiseincreases in the extracellular calcium concentration from 0.5 to 2.5 mmol/L (upper scale). Frequency of the
rhythmic Ca2+ j oscillations depends on the external calcium concentration, and they are abolishedby presenceof the inorganiccalcium channel blockercerium (200 umol/L),
causes the depolarization." A calcium receptor on the

parathyroid cell surface was postulated. This receptor was
unusual in that a verapamil analog, which blocks voltagesensitive calcium channels, would stimulate calcium influx
and raise the Ca 2+ j of the parathyroid cells. 45 Several other
divalent cations (e.g., magnesium) can cause transient rises
in Ca 2+ j by intracellular mobilization. Even the trivalent
cation lanthanum, which is restricted to the cell exterior, may
raise parathyroid Ca 2+ j and inhibit hormone release." These
findings provide additional arguments for the presence of a
surface cation sensor on the parathyroid cell. Activation of
this sensor seems to regulate phosphoinositol metabolism
and protein kinase C activity, whereas G protein involvement
in the messenger cascade is questionable. Moreover, Ga 3+
inhibits PTH release by an apparently different mechanism
from the sensor coupled to Ca 2\ 47 Consequently, there may
be several cation-sensitive mechanisms involved in the regulation of PTH secretion. Indeed, it has been postulated that
proteins with calcium receptor function are expressed not
only on parathyroid cells but also on proximal kidney tubule
cells, placental cytotrophoblasts, surfactant-producing alveolar pneumocytes, and thyroid C cells. 31,48 Such sensors may
thus be widely distributed and function at several sites in
systemic and cellular calcium homeostasis.
Parathyroid Calcium
Sensor Proteins
A calcium sensor protein on the parathyroid cell surface was
identified by monoclonal antibodies generated by immunization with human adenoma cells." Such a monoclonal
antibody abolished the calcium-regulated Ca 2+ j and PTH
release of normal and pathologic parathyroid cells. 50 ,51 The
antibody blocked the calcium-induced Ca 2+ j transient intracellular calcium mobilization as well as the steady-state
elevation resulting from calcium influx. Because the antibodies also competed with calcium binding to the parathyroid cell
surface, the findings supported the idea that the antibodies
interfered with the calcium sensor rather than an associated
calcium channel. A survey of normal human tissues revealed
that this calcium sensor was also expressed by the proximal
kidney tubule and placental cytotrophoblast cells."?
Cloning of the calcium sensor recognized by the antibodies
revealed a 500-kd glycoprotein with a single membranespanning domain; this protein belongs structurally to the
low-density lipoprotein (LDL) receptor superfamily.F
Particular homology was demonstrated with the rat
Heymann's nephritis antigen, which constitutes a large
glycoprotein of the proximal kidney tubule and possibly
serves as an autoantigen of experimental nephritis. The
calcium-binding motifs of the calcium sensor are probably
composed of repetitive epidermal growth factor (EGF)-like
modules, and calcium sensitivities of the LDL superfamily
of proteins are in the range of the extracellular concentration
of ionized plasma calcium. Kinetic studies of these proteins
indicate the presence of positive cooperativity for the interaction of calcium, whereby multiple binding sites can efficiently
alter protein signaling. Under these circumstances, cells
equipped with the sensor are allowed to respond efficiently
to the narrow alterations in Ca 2+ j , which are required for

adequate maintenance of systemic calcium homeostasis. A
receptor-bound 44-kd protein may help to translocate the
large sensor protein to the cell surface. Interestingly, the
calcium sensor is partially internalized in parathyroid carcinomas as well as in malignant tumors originating from
both the kidney tubules and placental cytotrophoblasts.P
Moreover, it seems to be involved in the regulation of cell
proliferation, at least in transformed cytotrophoblast cells.
Another protein with calcium-sensing function has been
identified in the bovine parathyroid by expression cloning
in oocytes." This 120-kd protein is G protein-coupled and
contains the characteristic seven-transmembrane domains of
peptide receptors as well as putative calcium-binding sites.
Transfection of this molecule to eukaryotic cells demonstrated linkage to regulation of Ca 2+j, but calcium sensitivity
of this protein is within a concentration range that exceeds
the ionized plasma calcium level. Receptors for this and
related proteins are also present in the cortex and outer
medulla of the kidney, the nervous system, and the thyroid.
The protein shows significant homology to glutamate receptors mostly expressed in the central nervous system and with
known association to voltage-dependent calcium channels.
Coupling of this protein to PTH release is at present unclear.
By linkage analysis using highly polymorphic DNA probes,
the gene for benign familial hypocalciuric hypercalcemia
(FHH) was mapped to chromosome 3q21-24 in four families (i.e., the location of the 120-kd protein gene).55FHH has
been coupled to mutations in this protein whereby its Ca 2+j
regulatory property is lost."
Regulation of Parathyroid
Hormone Release
in Hyperparathyroidism
Derangement of calcium-controlled PTH release is an obligatory characteristic of the pathologic parathyroid tissue from
hypercalcemic patients with adenoma and hyperplasia of
sporadic primary HPT; familial HPT resulting from multiple
endocrine neoplasias (MENs); secondary or tertiary HPT of
renal, gastrointestinal, and lithium-induced diseases; and
parathyroid carcinoma.s-" The disturbance is characterized
by variable calcium insensitivity of PTH secretion. The
calcium-PTH response curve is shifted to the right, and the
slope is decreased (see Figs. 39-lA and 39-3). The sigmoidal
dose-response relationship is essentially maintained, and
very few, if any, individuals demonstrate nonsuppressible
secretion. This shift in the position and the inclination of
the calcium-PTH curve correspond to similar changes in
the regulation of Ca 2+j within abnormal parathyroid tissues
(see Fig. 39-lB). The inverse linear relationship between
Ca 2+j and PTH secretion is thus maintained, but it is less
steep than in the normal parathyroid parenchyma. Rare
exceptions to this rule involve individuals with minimal
calcium suppression of PTH secretion despite considerable
increases in Ca 2+j.58-60 The calcium insensitivities of Ca 2+i
and PTH release correlate with one another and with the
degree of hypercalcemia in the patient.6.58 The correlation
with serum calcium values may explain the finding of less
pronounced derangements in calcium regulation of PTH
release among primary parathyroid hyperplasias 61,62 because

the chief cell hyperplasia of sporadic primary HPT might
be overrepresented in mild hypercalcemia.P There is also
evidence that the functional cellular abnormality may be
more pronounced in larger compared with smaller glands as
well as in nodular compared with diffusely enlarged portions
of hyperplastic parathyroid tissue. 64,65
The abnormal parathyroid tissue from patients with HPT
is also characterized by decreases in the maximal and minimal Ca 2+j values (Fig. 39-1B), which can be obtained at high
and low steady-state concentrations of extracellular calcium,
respectively.W? Corresponding changes, however, in the
rate of PTH secretion have not been consistently
observed.s-" Although the clinical significance of the PTH
secretory rate remains to be clarified.P patients with HPT
secrete more intact PTH during induction of both hypo- and
hypercalcemic conditions in vivo,7,8 This increase is partially
explained by the mass of parathyroid parenchyma, but this
is difficult to evaluate, especially because the cells of
abnormal glands are heterogeneous in their functional
derangement.sv'" Nevertheless, PTH release per unit cell is
reduced in HPT, and this reduction seems more pronounced
in larger parathyroid glands.6,68 Ca 2+j is poorly regulated in
oxyphilic parathyroid cells in comparison with chief cells
from the same glands, and the potential for PTH secretion of
these cells is unclear.f Another intriguing finding from studies of human parathyroid tissue is the presence of decreased
calcium sensitivity of Ca 2+j in the chief cells from normalsized glands associated with single parathyroid adenomas.P
Although the extent of this derangement is less pronounced
than in adenomas, it may explain why serum PTH is
transiently elevated after adenomectomy'<"
The consistent findings of impaired regulation of Ca 2+j,
despite maintained Ca 2+i inhibition of secretion in pathologic parathyroid cells, suggest that the principal pathophysiologic disturbance may be confined to the calcium sensing
and gating of the cell surface. This assumption is supported
by observations of normalization of the calcium-controlled
secretion upon experimental increases in calcium permeability of the surface membrane." It is also emphasized
by studies with monoclonal antiparathyroid antibodies,67,n
which reveal reduced expression of the 500-kd calcium
sensor in the pathologic parenchyma of all previously investigated adenomatous and hyperplastic glands. The reduced
immunoreactivity is accompanied by diminished mRNA
levels for the receptor protein. These derangements are
evidently not secondary to the hypercalcemia per se because
"rims of normal parathyroid tissue" outside adenoma capsules
as well as adenoma-associated glands display an intense and
virtually normal receptor expression.w'" The intensity of antibody reactivity, however, differs considerably within the
pathologic parathyroid parenchyma and further supports
variable secretory disturbances among the cells of individual
glands.
Elevated protein kinase C activity may contribute to the
hypersecretion of PTH in HPT.s' This elevation is presumed
to cause a right shift in the dependence of Ca 2+j on extracellular calcium, mainly through partial uncoupling of the calcium
sensor from the signaling machinery of the parathyroid cells."
Furthermore, the suppressive effects of calcitriol on PTH
mRNA synthesis are decreased in parathyroid adenomas,
Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - -
which may exhibit dysfunctional vitamin D receptors."

Because calcitriol inhibits the rate of PTH release without
altering the suppressive effects of calcium.P:" parathyroid
vitamin D resistance may contribute to PTH hypersecretion
even at normal calcitriol levels, A similar line of reasoning
applies to the evidence for a decreased number of vitamin D
receptors in the enlarged glands of patients with uremic
HPT,76 Because the prevalence of primary HPT rises with
age for both men and women,?? age-related reductions in the
serum calcitriol concentration, the concomitant elevation of
intact serum PTH values, and the reduced calcium responsiveness of PTH secretion substantiate a central role for calcitriol
in the pathogenesis of HPT.78
Parathyroid Cell Proliferation

HPT is invariably associated with an increased mass of
parathyroid parenchyma. The parenchymal cell weight,
however, may only be marginally elevated, and hypercalcemia
can be alleviated by excision of pathologic glands weighing
less than the normal parathyroid tissue of an individual. These
findings suggest that deranged secretory regulation rather than
increased cell mass is the principal cause of elevated serum
PTH levels and hypercalcemia of HPT. Indeed, it has been
suggested that a primary mutation increasing the secretory
set-point might initiate and stimulate cell proliferation and
that this stimulation declines when plasma calcium settles
at the genomically determined level." Increased cell mass
nevertheless may determine the portion of PTH secretion
not suppressible by calcium.s? whereby hypercalcemia
might be related to a complex mixture of increases in cell
number and rates of hormone secretion per cell. Parathyroid
cell turnover is normally very low, and the cells can be triggered to leave the quiescent Go stage by hypocalcemia and
calcitriol deficiency.F:" These findings may be clinically
relevant because reduced calcitriol levels are characteristically found even in subclinical disturbances of renal function.
This circumstance also includes many elderly patients, who
seem to display an unusual propensity for the development of
primary HPT, especially in climates associated with limited
sun exposure. 77,82 Parathyroid cells in culture display gradually increasing calcium insensitivities of Ca 2+ j and PTH
release, which develop in parallel to enhanced proliferation.F
Calcitriol inhibits proliferation but not hypertrophy and
functional dedifferentiation of cultured cells. Hitherto
unidentified factors in the circulation may interact in this
coupling of function to proliferation because serum-free
culture abolishes hyperplasia and decreased calcium sensitivity of cultured cells.P In this context, it is interesting to
note that a mitogenic factor with ability to stimulate
parathyroid cell replication has been reported in the plasma
of patients with MEN 1.84
The MENl gene has been mapped to chromosome llq 13
and might encompass the cell-signaling phospholipase
C~3.85
The constitutional mutation of this dominantly inherited disease is unmasked by loss of the wild-type allele,
which suggests that tumorigenesis is related to inactivation
of a tumor suppressor gene at the MENl locus." Similar
allelic losses have also been found in subsets of sporadic
parathyroid adenomas and consequently may represent
377
important promoters of parathyroid growth." Rearrangements

of the PTH gene and overexpression of the protooncogene
PRADl on chromosome llq13 have been identified primarily in large parathyroid adenomas. 88.89 The PRADl gene
encodes cyclin Dl, which is important in the Gl-S phase
transition that commits cells to divide."? Consistent with
findings of X-chromosome inactivation analysis," unequivocally enlarged MEN 1 lesions and a major proportion of
sporadic parathyroid adenomas are monoclonal tumors,
which may nevertheless develop polyclonal hyperplasia.F-"
In the multiglandular parathyroid involvement of sporadic
and MEN I-associated primary HPT, there is considerable
variation in expression of the 500-kd calcium sensor protein.
This phenotypic variation is particularly striking between
chief cell nodules of individual glands 67.94 and indicates that
such homogeneously appearing nodules may represent individual cell clones. Hyperplastic parathyroid tissue has not
been found to display a monoclonal pattern upon analysis of
restriction fragment length polymorphisms.?' This circumstance, however, does not exclude the presence of multiple
monoclonal lesions, which indeed has been suggested by
analysis of X-chromosome inactivation." Similarly, the
characteristically multiglandular and asymmetric parathyroid enlargement in uremic HPT may represent both monoclonal and polyclonal components together with complex
admixtures of vitamin D deficiency and parathyroid vitamin D
resistance. Indeed, the larger nodules from patients with
hypercalcemia of uremic HPT have displayed clonal allelic
losses involving the MENl gene on chromosome 11.96
Parathyroid carcinomas, but not adenomas, have also
revealed allelic losses of the retinoblastoma gene,"? and
increased expression of protooncogenes c-myc and c-fos has
been associated with parathyroid cell proliferation.?" It has
been demonstrated that sporadic parathyroid carcinomas
frequently possess mutations of the HRPT2 gene, which
encodes the parfibromin protein, and that these HRPT2
mutations have pathogenetic implications." These and
hitherto unrecognized secondary genomic alterations may
contribute to the appearance of complex and heterogeneous
characteristics upon analysis of pathologic parathyroid
tissue and highlight the limitations in our current knowledge
about the causes and pathogenetic mechanisms contributing
to parathyroid growth and secretory derangements in HPT.
Autocrine Regulation
of Parathyroid Cell Secretion
and Proliferation
Sparse information is available on the expression and
actions of growth factors in the parathyroid parenchyma.
Insulin-like growth factor I and its receptor seem to be
expressed by parathyroid tissue, and EGF may playa role in
cellular proliferation.l'" Fibroblastic growth factors (FGFs)
are mitogenic peptides synthesized by parathyroid epithelial
and endothelial cells. Production of acidic FGF increases
under hypocalcemic conditions, when high-affinity receptors
for this peptide seem to translocate to the parathyroid cell
surface.l'" Because the peptide lacks a classic consensus signal
peptide sequence, however, meager secretion from cells is

characteristic and perhaps involves mechanisms other than the
conventional endoplasmic reticulum-Golgi complex. 102
It has long been known that human parathyroid tissue
secretes chromogranin A, an equivalent to secretory protein
1.103 This acidic protein is costored in the secretory granules
and cosecreted with PTH in response to alterations in the
extracellular calcium concentration.Pv''" whereas calcitriol
exhibits opposite effects on PTH and chromogranin A gene
transcription.I'" Pancreastatin and other cleavage products
of the chromogranin A peptide precursor have been found to
inhibit PTH release in various species. 104,107,IOS The possibility of intraglandular autocrine or paracrine control of PTH
release exists. Theoretically, such a mechanism could participate in sharpening or elongating the responses of the parathyroid gland to secretory agonists or antagonists. The relevance
of this phenomenon remains to be elucidated, however,
because human pancreastatin I-52 and 34-52 fail to influence
human PTH release."? Moreover, the chief and oxyphil cells
of human parathyroid glands express PTH-related protein
(PTHrP) on the surface membrane, which may have paracrine
or autocrine roles in the adult parathyroid. I 10,111
Endothelin is a potent smooth muscle cell constrictor,
which exists in different isoforms and binds to specific
receptors. Endothelin is synthesized by parathyroid cells and
perhaps parathyroid endothelial cells, and endothelin receptors are expressed by the parathyroid parenchyma.l'<!"
Endothelin has been found to inhibit PTH release, and
endothelin mRNA production of the parathyroid is sensitive
to the extracellular calcium concentration. Moreover,
endothelin is unique because it seems to affect PTH release
by interfering with parathyroid Ca 2+ j (unpublished data).
These circumstances indicate that this protein may be an
autocrine or a paracrine regulator of PTH release, or both.
Peripheral Parathyroid
Hormone Metabolism
Intact PTH 1-84 is rapidly cleared from the human circulation and has a half-life of only a few minutes.19.114 This
degradation ensures that activation of the PTH receptor can
be closely regulated by parathyroid cell secretion of PTH.
Moreover, there is no evidence for dynamic regulation of
peripheral PTH metabolism. PTH clearance mainly depends
on high-capacity uptake of Kupffer cells in the liver and on
glomerular filtration. A small amount of PTH, however,
appears in the urine because of tubular reabsorption and
proteolysis. Circulating PTH is molecularly heterogeneous
and contains various carboxyterminal peptide sequences
arising by cleavage, mainly at residues 33 to 43. Although
only 15% of intact PTH 1-84 is metabolized to such circulating fragments, they make up at least half, and sometimes
substantially more, of the immunoreactive PTH in the circulation. 1I51I6 This discrepancy is due to the release of such
fragments from the parathyroid gland, sequestration from
Kupffer cells, and slower clearance from the circulation than
for intact hormone. The metabolism of these fragments
depends only on intact renal function; consequently, the
fragments are accumulated to a considerable degree in renal
insufficiency. In contrast, very few aminoterminal PTH
fragments exist in the circulation of euparathyroid individuals,
although these fragments may become appreciable in primary

and secondary HPT.
Parathyroid Hormone Receptor

To characterize normal and pathologic systemic calcium
homeostasis, it is pertinent to clarify some aspects of the
cloned PTH receptor,'!" Apart from the classic targets of
PTH in bone and kidney, the receptor has been demonstrated
in fibroblasts, chondrocytes, lymphocytes, smooth muscle
cells, and fat cells. This allows PTH to induce hypotension
and bowel relaxation and to influence chronotropism and
inotropism of the heart in addition to its classic actions
on bone turnover and calcium, phosphate, and vitamin D
metabolism in the kidney. The receptor also binds PTHrP
with similar efficiency. Because PTHrP exerts a variety of
hitherto partially clarified functions, studies on the common
PTH-PTHrP receptor and its actions are hampered by difficulties in determining the biologically relevant agonist.
Activation of the PTH receptor's cAMP-generating capacity
requires PTH amino acids 1-24, and PTH 1-34 is essentially
as potent as the full-length peptide. I IS However, various PTH
fragments may activate other second messenger systems
of the receptor with variable efficiency, whereby complex
modes of differential interactions may exist. Moreover,
specialized binding sites for midregional and carboxyterminal PTH sequences of unknown functional significance
may occur,'!"
The PTH receptor belongs to the growing family of
peptide receptors characterized by seven transmembrane
domains and G protein coupling. Expression of this receptor
is sensitive to PTH, and prolonged exposure to the ligand
can reduce the number of available receptors, whereby
target cell functions are less effectively activated. 120 HPT of
uremia is a striking example in this phenomenon, with its
frequently profound elevation of intact serum PTH levels
and comparably modest rise in serum calcium values.
Internalization and partial recycling of the receptor protein
are the mechanisms for this modulation. 12l Decreased affinity for PTH and desensitization of the cAMP response may
modulate the peripheral actions of PTH.122 Other substances
such as glucocorticoids as well as vitamin A and D metabolites may interfere with PTH receptor expression, although
their in vivo actions in humans remain to be established.
Inherited variants of pseudohypoparathyroidism may be
caused by dysfunctions in the PTH receptor, its associated
G proteins, and different second messenger systems such as
adenylate cyclase and phospholipase C. 123
Parathyroid Hormone Assays

Assaying for PTH in vivo has been notoriously difficult
because of its picomolar concentrations in the circulation
as well as its molecular heterogeneity. This heterogeneity is
due to parathyroid gland secretion of various carboxyterminal
PTH fragments (especially when PTH release is suppressed),
hepatic proteolysis, and accumulation of midregional and
carboxyterminal fragments caused by slow renal clearance in
Parathyroid Hormone: Regulation of Secretion and Laboratory Determination - - 379
kidney disease. In principle, PTH may be assayed for bioactivity as well as by radioimmunologic and immunometric
methods. Although the former two are currently of limited
clinical interest, their mechanisms deserve mention.
PTH bioassays use either directly analyzed cAMP concentrations in urine or cAMP production of cell systems to
assess biologic PTH activity of patients' sera. l24,125 Although
such assays may be sensitive in the range of picograms of
PTH (per milliliter), they are limited in routine use. These
techniques are laborious. They are hampered by the concomitant activation of the PTH-PTHrP receptor by both
ligands despite their very limited sequence homology.
PTHrP is the most common cause for humoral hypercalcemia of malignancy. PTH bioassays do not distinguish
between these two hormones. Moreover, cAMP responses
of the PTH-PTHrP receptor might mirror its activation only
partially because of the involvement of multiple second
messenger systems, whereby bioassays may underestimate
activity of circulating PTH.
Radioimmunoassays were previously the most widely
used means of PTH determination. This technique primarily
uses a polyclonal, high-affinity antibody to which binding of
radioiodinated PTH is allowed to compete with PTH to be
measured in serum. By generating standard curves for binding of the radioactive ligand as a function of its concentration, the amount of iodinated PTH not displaced from the
antibody can be used to approximate the concentration of
PTH in the serum sample. Naturally, a host of factors require
characterization and optimization to secure performance of
such analyses. Some of these factors are antibody affinity,
radiolabeling of PTH without interference with its
immunoreactivity, and stability of the tracer peptide to be
displaced.!" Particular problems have been caused by the
use of bovine PTH as a tracer. Bovine PTH was selected
because of its availability and the presence of tyrosine
residues suitable for iodination. To reduce other difficulties,
results have been reported in equivalents of pooled human
sera. Moreover, analysis with characterized human PTH
fragments has demonstrated multiple immunoreactivity of
available displacement assays despite their characterization
as "aminoterminal," "midregional," or "carboxyterminal." In
view of the substantially lower circulating concentration of
intact PTH in comparison with fragments encompassing
various portions distal to the aminoterminal region, radioimmunoassays have been dependent on satisfactory renal
function for reliable use in vivo and are variably limited in
the recognition of mild to moderate primary HPT as well
as the discrimination of HPT from other causes of
hypercalcemia. 127,128
Displacement assays separate patients with primary HPT
from overtly euparathyroid control subjects, provided that
renal function is normal.P? This separation, however, naturally depends on the biochemical decision levels by which
HPT is considered to prevail and current limits for the
application of operative treatment verifying existence of
the disease. Even with these assays, however, some 20% of
individuals with malignancy-associated hypercalcemia
demonstrate false-positive PTH elevations. This phenomenon is possibly related to circumstances other than limited
specificity toward PTHrP.129,130 Hypothetically, nonspecific
interaction of serum in these patients cannot be excluded as
a cause of this phenomenon. It might also be related to

disproportionally increased parathyroid gland secretion of
midregional and carboxyterminal PTH fragments recognized by these assays. Moreover, the total weight of abnormal parathyroid tissue is generally strongly correlated with
serum PTH measured by displacement assay, which indeed
also applies to total serum calcium.v' Because the variation
among patients is considerable, however, measurements
from many patients are required to establish these relationships. Neither biochemical variable, therefore, should be
expected to be applicable to predict the degree of glandular
enlargement.
Immunometric Assays
Routine diagnosis of primary HPT and evaluation of the
extent of secondary HPT have been greatly facilitated by
the development of immunometric "sandwich" assays. Briefly,
these assays use a pair of antibodies that recognize different
regions of PTH.131-134 One of these antibodies, preferentially
monoclonal, is immobilized, whereas a polyclonal antiserum with greater affinity is labeled with radioiodine
(immunoradiometric assay) or chemoluminescence.
Because of cooperation of the antibodies, such a sandwich
assay is more sensitive than either antibody alone in
displacement radioimmunoassays. With careful selection of
antibodies, the immunometric assays are specific and sensitive for intact PTH, which allows identification of insufficient PTH secretion of hypoparathyroidism as well as a
wide range of PTH levels without sample dilution.
Moreover, it is technically favorable to tag antibodies rather
than peptides. A vast excess of PTH fragments might hinder
a small fraction of intact PTH from binding to the immobilized antibody and from reacting in the assay, a circumstance that has been suggested to occur in analyses for PTH
of rare parathyroid gland aspirates.P" The immunometric
analyzing process is faster than with radioimmunoassays.
By reducing incubation times, the analysis can be done in
15 to 30 minutes and, consequently, can be used intraoperatively.136-138 Such speed of processing, however, is accompanied by a reduction in assay sensitivity.
Clinical analysis with immunometric PTH assays usually
separates hypercalcemic patients with HPT from patients
with other causes of hypercalcemia. This is particularly
evident with respect to malignancies of nonparathyroid
origin, although some 5% to 10% of these patients demonstrate intact serum PTH in the lower portion of the normal
range. Nonparathyroid tumors that produce intact PTH are
exceptionally rare. Examples of such tumors include ovarian
and small cell carcinomas as well as thymomas.P''<" The
immunometric assays demonstrate that clinically overt
derangements in renal function are accompanied by very
early elevation in intact serum PTH values. This circumstance reflects the onset of parathyroid gland hyperactivity
rather than accumulation from impaired clearance, although
indirect evidence suggests that a prolonged half-life of intact
serum PTH may exist, at least occasionally, in uremia.F'
The distribution of intact serum PTH values and recognition of primary HPT among otherwise healthy individuals
largely depend on how patients are recruited. In a health
screening study of 5200 menopausal women, biochemical

levels for the recognition of primary HPT were deliberately
set low to include those with mild disease (unpublished
data). Briefly, individuals demonstrating hypercalcemia
(albumin-corrected total serum calcium> 2.60 mmol/L) and
intact serum PTH greater than or equal to 25 ngIL (reference
range, 12 to 55 ng/L), serum calcium 2.50 to 2.60 mmol/L
and serum PTH greater than or equal to 35 ng/L, or serum
PTH greater than or equal to 55 ngIL in combination with a
previousserum calcium concentrationexceeding 2.55 mmol/L
were presumed to have primary HPT. Among the identified
individuals, about two thirds showed normal total and ionized serum calcium values, and a similar proportion (69%)
showed intact serum PTH within the reference range. Under
a stratified case-control treatment program, more than half
the patients have been subjected to parathyroid surgery.
These individuals were representative of the entire group
with respect to total serum calcium values, and operation
verified the presence of parathyroid abnormalities in all
of them. These findings are described not to provoke arguments about the indications for parathyroid exploration but
to demonstrate that even these limits appear to underestimate the prevalence of HPT, and that intact serum PTH
measured by immunometric assay may be normal in many
patients with mild HPT. The proportion of such patients is
assumed to be 5% to 20%.
Summary
Findings of parathyroid surface proteins acting as calcium
receptors have improved our understanding of the secretory
dysfunctions leading to the hypercalcemia of HPT, and it is
hoped that research on the regulation of function of these
proteins will provide new treatments for HPT. The diagnosis of HPT has improved substantially since the introduction
of sensitive and specific assays for the intact 84-amino acid
peptide. Such immunoradiometric or immunochemoluminescent sandwich assays should accurately differentiate
HPT from other causes of hypercalcemia. Moreover, these
assays enable recognition of most patients with HPT, but
their efficiency in this respect depends on applied criteria
for biochemical recognition and operative confirmation of
parathyroid disease.
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119. Rao LG, Murray TM. Binding of intact parathyroid hormone to rat
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Operation and Reoperation. Austin, Tex, RG Landes, 1994, p 167.
Diagnosis of Primary
Hyperparathyroidism
and Indications for
Parathyroidectomy
Geeta Lal, MD Orlo H. Clark, MD
Primary hyperparathyroidism is a relatively common problem,

and reportedly 100,000 new cases are detected each year in the
United States."One of every 500 women and 1 of every 2000
men older than 40 years have primary hyperparathyroidism.
A population-based study in Sweden suggested that about
2% of postmenopausal women have hyperparathyroidism.'
The disease entities to be considered in the differential
diagnosis of hypercalcemia are shown in Table 40-1. Primary
hyperparathyroidism and malignancy account for 90% of all
patients with hypercalcemia. Primary hyperparathyroidism
is the most common cause of hypercalcemia in outpatients,
whereas malignancy is the most common cause of hypercalcemia in hospitalized patients.'
Malignancy-associated hypercalcemia has traditionally
been considered to include three distinct syndromes:
(1) humoral hypercalcemia of malignancy, (2) hypercalcemia
associated with bone metastases, and (3) hypercalcemia associated with hematologic malignancy (multiple myeloma).
Humoral hypercalcemia of malignancy occurs in patients
with solid tumors of the lung, breast, kidney, head and neck,
and ovary without bone metastases and is known to be mediated primarily by parathyroid hormone-related peptide
(PTHrp).4 A comparison of the biochemical characteristics
of primary hyperparathyroidism and humoral hypercalcemia
of malignancy is shown in Table 40-2. PTHrP also plays a
role in the hypercalcemia associated with bone metastases'
and multiple myeloma." Interestingly, primary bone tumors
such as osteogenic sarcoma seldom cause hypercalcemia,"
Primary hyperparathyroidism may be distinguished from
the other causes of hypercalcemia by careful history, physical examination, and laboratory investigations.
384
Most patients diagnosed with primary hyperparathyroidism
today do not have the classic or historical clinical manifestations of this disorder such as osteitis fibrosa cystica,
nephrolithiasis, nephrocalcinosis, peptic ulcer disease, gout,
or pseudogout. The pentad of symptoms-painful bones,
kidney stones, abdominal groans, psychic moans, and fatigue
overtones-is more common, although most patients have
few dramatic symptoms. The symptoms and other associated
complications of primary hyperparathyroidism are listed in
Table 40-3. Several investigators have documented that manifestations such as fatigue, weakness, exhaustion, polydipsia, polyuria, nocturia, joint pain, bone pain, constipation,
depression, anorexia, nausea, heartburn, and several associated conditions such as nephrolithiasis and hematuria occur
more often in patients with primary hyperparathyroidism
than in those with thyroid nodules.v''' Furthermore, only
symptoms of fatigue, bone pain, and weight loss seemed to
correlate with the severity of hypercalcernia.f Younger
patients are more likely to present with nonspecific complaints such as fatigue and lethargy. II The pathophysiologic
mechanisms explaining why many of these manifestations
occur more often in patients with even mild primary hyperparathyroidism are unknown. However, studies have documented changes in neurotransmitters in the cerebrospinal fluid
of patients with primary hyperparathyroidism. 12
Several groups have used a standardized health status
assessment tool such as the SF-36 (the Medical Outcomes
Study Short-Form Health Survey) to assess symptoms and
Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - - 385
health state in patients with primary hyperparathyroidism.

This multidimensional health assessment tool has several
domains that evaluate physical function, role limitation
(physical and emotional), social function, bodily pain,
mental health, energy, and general health perception. 13
Burney and colleagues first demonstrated that patients with
primary hyperparathyroidism scored lower than healthy
control subjects in all domains of the SF-36. 14 Other studies
confirm that these patients are indeed impaired in several
domains'<'" and have also shown that the impairments in
functional status are independent of the degree of elevation
of serum calcium levels." Even patients with minimal
hypercalcemia and parathyroid hormone elevation benefit
from parathyroidectorny.!? More recently, Pasieka and
Parsons designed and validated a disease-specific surgical
outcome tool for patients with primary hyperparathyroidism.
The items in their Visual Analog Scale (VAS) questionnaire
include symptoms of bone and joint pain, fatigue, mood
swings, depression, abdominal pain, weakness, irritability,
memory loss, headaches, pruritus, increased thirst, and
proximal muscle weakness. The study group of patients with
primary hyperparathyroidism had significantly more symptoms than a comparison group of patients with nontoxic
thyroid disease."
Studies have also documented that patients with
primary hyperparathyroidism have an increased incidence of
fractures, 19 muscle weakness," and cardiovascular disease.v-?
Rarely, patients may be completely asymptomatic.

We documented truly asymptomatic hyperparathyroidism in
only 2% to 4.6% of consecutive patients referred for
parathyroidectomy.s-'?
On physical examination, patients may demonstrate signs

such as band keratopathy, a deposition of calcium in
Bowman's membrane just inside the iris of the eye. This
condition is caused by chronic eye diseases such as uveitis and
glaucoma and by trauma but also occurs in systemic conditions associated with high calcium or phosphate levels. It is
therefore not specific for primary hyperparathyroidism.P
Evidence of fibro-osseus jaw tumors should be sought.
Patients with this manifestation are more likely to develop
parathyroid carcinoma" The neck should be examined for
masses, thyroid nodules, and concurrent lymphadenopathy.
Parathyroid tumors are seldom palpable, except in patients
with profound hypercalcemia (~14 mg/dL). A palpable neck
mass in a patient with primary hyperparathyroidism is more
likely to be a thyroid lesion. However, approximately 50% of
parathyroid cancers are palpable.P
Laboratory Investigations
In patients with hypercalcemia, it is usually relatively easy
to make the diagnosis of primary hyperparathyroidism by
documenting an increased blood intact or two-site parathyroid hormone (PTH) level and normal or increased urinary
calcium concentration. The two-site or intact PTH (iPTH)
assays do not cross-react with PTHrP, the most common
peptide secreted by nonparathyroid cancers." PTHrP crossreacts with some mid- or C-terminal PTH assays and causes
a falsely elevated PTH value. Some patients may have more
than one reason for an increased calcium level, such as
metastatic breast cancer and primary hyperparathyroidism.
In these patients, an iPTH assay is most valuable for

documenting that primary hyperparathyroidism is also
present. In addition, the presence of a mild hypokale~c,
hypochloremic alkalosis points to mali~nancy
as th.e cau~atl~e
factor, whereas a mild hyperchloremic metabohc aCIdoSIS
suggests hyperparathyroidism. A few patients have also
been documented as having nonparathyroid tumors that
make pure PTH.27 In these situations, sele~tiv~
ven~us
catheterization for iPTH of the neck and mediastinal veins
as well as veins draining the tumor is useful in documenting
whether the hypercalcemia is caused by the tumor or by
coexistent primary hyperparathyroidism. Open or fine-need~e
biopsy of the tumor and assay for iPTH are also of help in
these rare situations."
The only other metabolic condition that can mimic primary
hyperparathyroidism from a laboratory point of view-that
is, increased blood calcium and increased iPTH-is benign
familial hypocalciuric hypercalcemia (BFHH).28,29 These
patients, however, have low urinary calcium. It is important,
therefore, to obtain a 24-hour urine sample for calcium and
creatinine to determine the urinary calcium level, especially
in patients who have never had documented normocalcemia.
Patients with BFHH have urinary calcium levels less than
100 mg per 24 hours and have family members younger
than 10 years with hypercalcemia, a situation that almost
never occurs in patients with sporadic hyperparathyroidism
or even in patients with familial hyperparathyroidism or
hyperparathyroidism associated with multiple endocrine
neoplasia (MEN) type 1 and MEN 2. Furthermore, the
serum calcium-to-creatinine clearance ratio is usually less
than 0.01 in patients with BFHH, whereas it is typically
greater than 0.02 in patients with primary hyperpar~thyroidism." BFHH is inherited in an autosomal dommant
fashion with nearly 100% penetrance but variable expression.
The genetic locus for BFHH maps to the long arm of chromosome 3 and has been identified as the calcium-sensing
receptor gene (CASR).31,32 Patients with BFHH are heterozygous for CASR mutations. When this is a homozygous mutation, the patient has neonatal hyperparathyroidism." The latter
is often life threatening and warrants total parathyroidectomy
. parathyroid
, autotransp lantati
WIth
antanon and cryopreserva ti o~. 3133
'.
Identifying patients with BFHH is crucial because these individuals do not benefit from parathyroidectomy.
Patients with primary hyperparathyroidism also often
have a low (50%) or low-normal (40%) blood phosphorus
level and an increased (>33) chloride-to-phosphorus ratio."
As mentioned earlier, a mild hyperchloremic metabolic
acidosis is often present. About 30% of patients with primary
hyperparathyroidism have an increased uric acid level, and
15% have an elevated alkaline phosphatase level. 34,35 Most
patients with primary hyperparathyroidism also have an
increased or high-normal 1,25-dihydroxyvitamin D 3 level."
It is also important to document the serum blood urea nitrogen and creatinine levels, and perform serum protein electrophoresis. The latter helps to eliminate the diagnosis of
multiple myeloma. Patients with primary hyperparathyroidism who have increased bone alkaline phosphatase (with
other normal liver enzymes) have high-turnover bone disease
and are susceptible to postparathyroidectomy hypocalcemia.
In patients with osteitis fibrosa cystica, the blood magn~sium and potassium levels can be low, and hypomagnesemia
can contribute to postoperative tetany.
Normocalcemic Hyperparathyroidism
Patients with primary hyperparathyroidism can also be normocalcemic. Most of these individuals are detected because
of recurrent nephrolithiasis or osteoporosis.'? The reasons for
normocalcemic hyperparathyroidism include (1) vitamin D
deficiency, (2) low serum albumin, (3) pancreatitis,
(4) increased phosphate intake, (5) excessive hydration, and
(6) a low-normal blood calcium set point with an increase
above the patient's normal calcium level but still within the
normal range.'? The diagnosis of normocalcemic hyperparathyroidism is usually made by documenting an increased
total PTH level with or without an increased blood ionized
calcium level. However, patients with renal leak hypercalciuria must be excluded. The increased PTH level in patients
with renal leak is secondary to the excessive calcium loss in
the urine; one can diagnose renal leak hypercalciuric patients
by treating them with thiazide diuretics, With treatment, the
urinary calcium level falls and the secondary increase in the
blood PTH also decreases to normal. In patients with normocalcemic hyperparathyroidism, the urine calcium and blood
PTH remain elevated." Normocalcemic hyperparathyroidism
is discussed in more detail Chapter 45.
Radiologic Investigations
Patients with classic osteitis fibrosa cystica have subperiosteal
bone resorption best observed on the radial aspect of the
middle and distal phalanges on hand radiographs. Other skeletal manifestations of severe primary hyperparathyroidism
include bone cysts, osteoclastomas or "brown tumors," pathologic fractures, and general demineralization. The skull may
exhibit a finely mottled, ground-glass appearance, with loss of
definition of the inner and outer cortices." Abdominal flat
plates or ultrasonography may reveal renal stones.
Bone densitometry studies are currently being performed
more frequently and may be utilized in assessing the effects
of primary hyperparathyroidism on bone. Primary hyperparathyroidism mainly leads to loss of bone at cortical sites
such as the distal radius. Bone density is relatively preserved
at sites such as the lumbar spine, which is rich in cancellous
bone.'? This is in contrast to the bone density changes seen
in menopause. In the latter, the lumbar spine is the major
target of bone mineral loss. Despite these findings, lumbar
spine density improves after parathyroidectomy.f-"
Localizing tests such as ultrasonography, sestarnibi scanning, magnetic resonance imaging, or computed tomography
scanning are used by some clinicians to make or confirm the
diagnosis of primary hyperparathyroidism. One should
emphasize, however, that the diagnosis of primary hyperparathyroidism is made by metabolic testing; localiza~ion
te~ts
often identify the tumor site but do not make the dIagnOSIS,
because both false-positive and false-negative localization
tests occur.'?
Indications for Operative

Treatment
As discussed earlier, the clinical profile of primary hyperparathyroidism has undergone a distinct change over the
past few decades, particularly with the introduction of automated blood chemistry panels. The 1990 National Institutes
of Health Consensus Development Conference on the
Management of Asymptomatic Primary Hyperparathyroidism
was convened to set forth evidence-based diagnosis and
management guidelines for this group of patients. The panel
recognized surgery as the only definitive treatment for
primary hyperparathyroidism and recommended parathyroidectomy for any individual with overt complications and
symptoms such as nephrolithiasis, fractures, and neuromuscular syndrome. In addition, surgery was recommended
for asymptomatic patients with' (1) serum calcium more
than 1 to 1.6 mg/dL (0.25 to 0.4 mM) above the accepted
normal reference range; (2) 24-hour urine calcium greater
than 400 mg (10 mM); (3) a 30% reduction in creatinine
clearance compared with age-matched normal individuals;
(4) bone mineral density more than 2 standard deviations
(SD) below that of age-, gender-, and race-matched controls;
(5) age younger than 50 years; and (6) in whom medical
surveillance is not possible or desirable.
The vague neurobehavioral axis symptoms (weakness,
increased fatigue without overt muscle weakness) were
deemed nonspecific and not sufficient in and of themselves
to recommend surgery, unless these symptoms were thought
to be related to hyperparathyroidism.
The panel also recommended that patients not undergoing surgery understand the importance of regular, longterm follow-up and undergo (1) biannual measurements of
blood pressure, serum calcium serum creatinine and creatinine clearance and (2) annual abdominal radiography
(and/or ultrasonography), 24-hour urine calcium test, and
bone mass measurement. Patients were also to be advised on
the importance of adequate mobility and seeking prompt
medical attention for any intercurrent illness causing dehydration, both of which can worsen existing hypercalcemia.
Since the last consensus meeting in 1990, there has been
an accumulation of data on the natural history of asymptomatic hyperparathyroidism and the long-term effects of
untreated hyperparathyroidism. Moreover, localizing studies
are more accurate, readily available, and utilized. Several
minimally invasive surgical approaches have also been developed, as have novel medical therapies. Therefore, a follow-up
Workshop on Asymptomatic Primary Hyperparathyroidism:
A Perspective for the 21st Century was held at the National
Institutes of Health in April 2002 to re-evaluate the recommendations of the previous consensus meeting. The revised
recommended indications for surgery along with the reasons
for the change are as follows":
1. Serum calcium greater than 1 mg/dL (0.25 mM) above
the upper reported normal reference range
The range was lowered because the panel believed that even
patients with this degree of elevation of serum calcium were
at risk for developing symptoms and complications of
hyperparathyroidism.
2. 24-hour urine calcium excretion 400 mg/day
(unchanged)
3. A 30% decrease in creatinine clearance compared
with age-matched control subjects (unchanged)
4. Bone density at the lumbar spine, hip, or distal radius
greater than 2.5 SD below peak bone mass (T-score
less than -2.5)
Hyperparathyroidism classically leads to loss of cortical
bone mass. However, a subset of patients with primary
hyperparathyroidism have marked bone density loss at sites
of cancellous bone such as the spine, and parathyroidectomy
has been demonstrated to increase bone mass at these
sites. 4445 T-scores, which represent deviations from an individual's optimal bone mass, seem to be a more reasonable
indicator of fracture risk than Z-scores, which compare bone
mineral density with that of age- and sex-matched cohorts.
Hence, the panel recommended bone mineral density measurement at three sites and a change to T- rather than Z-score
measurements.
5. Age younger than 50 years (unchanged)
6. Patients for whom medical surveillance is not possible
or desirable (unchanged)
The panel also cautioned against the use of neuropsychological abnormalities, cardiovascular disease, gastrointestinal
symptoms, menopause, and elevated serum or urine indices of
increased bone turnover as sole indications for parathyroidectomy. Rather, these factors should be weighed in the context
of the individual patient. Although bisphosphonates and calcimimetics show promise, data are insufficient to recommend
medical management in patients with asymptomatic primary
hyperparathyroidism and only parathyroidectomy offers
curative treatment. The new recommendations for follow-up
of patients not undergoing surgery are compared with the
previous recommendations in Table 40-4.
Rationale for Parathyroidectomy

There is good evidence that in about 80% of patients the
clinical manifestations improve after successful parathyroidectomy.8,9,10,46,47 Thus, fatigue, exhaustion and weakness, polydipsia, polyuria and nocturia, bone and joint pain,
constipation, nausea, and depression improve in some
patients.8.10,46,47 This is also true for associated conditions. In
these patients, new kidney stones usually stop forming,
osteoporosis stabilizes or improves, peptic ulcer disease
often resolves, and pancreatitis becomes less likely.46,47
Thus, both neuropsychiatric and somatic problems improve
in most, but not all, patients (Figs. 40-1 to 40_4).10,48
Increased fracture risk and weakness also improve after
successful parathyroidectomy in most, but certainly not all,
patients.Jv" Objective increase in muscular strength has
also been documented after successful parathyroidectomy."
Patients can also resume a regular diet with or without
calcium supplementation and hypercalcemia is not a concern
when patients are hospitalized for other medical problems.
Several quality of life studies have been performed using
standardized tools such as the SF-36 health survey in
patients with primary hyperparathyroidism, and demonstrated that patients experience an improvement in health
status and quality of life after surgical correction. 14-17,50
Furthermore, this benefit was independent of preoperative
calcium levels." Psychological distress, as measured by
the General Health Questionnaire, has also been shown to
be ameliorated by parathyroidectomy.-' In contrast to the

aforementioned generic quality of life tools, Pasieka and
Parsons have developed a patient-based outcome tool
specifically for primary hyperparathyroidism.F A multicenter study using this questionnaire indicated that the
Parathyroidectomy Assessment of Symptoms is a reliable
measure of the symptoms seen in patients with hyperparathyroidism, as shown in Figures 40-5 and 40-6, and that
these symptoms improve after parathyroidectomy.P
It therefore seems that there are both classic and more
subtle clinical manifestations of primary hyperparathyroidism
that warrant medical evaluation and, in most patients,
parathyroidectomy. This is especially true because parathyroidectomy, when performed by an experienced surgeon, is
successful in more than 95% of patients. Furthermore, the
operation usually takes less than 2 hours, blood is virtually
never required, complications occur in less than 2% of
patients, and hospitalization is usually for 24 hours, unless
the patient has other serious medical problems or severe
osteitis fibrosa cystica with a markedly elevated blood alkaline phosphatase level preoperatively," The latter patient
requires treatment with oral and intravenous calcium and
1,25-dihydroxyvitamin D (Rocaltrol, 0.25 to 1 ug orally
daily) postoperatively because of hypocalcemia and occasionally hypomagnesemia as a result of "bone hunger."
Another and perhaps more important reason for recommending parathyroidectomy is that patients with primary
hyperparathyroidism appear to be at risk for premature death
primarily because of cardiovascular disease and cancer, as
FIGURE 40-1. Changes in the frequency of symptoms after surgery in parathyroid and thyroid patients. (From Chan AK, Duh QY,
Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A case-control study.
Ann Surg 1995;222:402.)
Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy - -
FIGURE 40-2. Changes in the frequency
of associated conditions after surgery

in parathyroid and thyroid patients.
(From Chan AK, Duh QY, Katz MH,
et al. Clinical manifestations of primary
hyperparathyroidism before and after
parathyroidectomy: A case-control study.
Ann Surg 1995;222:402.)
FIGURE 40-3. Neuromuscular recovery after parathy-
roidectomy in primary hyperparathyroidism with patients

having thyroid operations as controls. (From Chou FF,
Sheen-Chen SM, Leong CPo Neuromuscular recovery
after parathyroidectomy in primary hyperparathyroidism.
Surgery 1995;117:18.)
so = standard deviation, Preop = preoperative
Postop = postoperative 1 week, Late = postoperative 4 weeks

P with paired t test
389
FIGURE 40-4. Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism with patients
having thyroid operations as controls. (From Chou FF,
Sheen-Chen SM, Leong CPo Neuromuscular recovery
after parathyroidectomy in primary hyperparathyroidism.
Surgery 1995;117:18.)
SD = standard deviation, Preop = preoperative

Postop = postoperative 1 week, Late = postoperative 4 weeks
P with paired t test
documented in the classic study by Palmer and coworkers>'

and confirmed by the studies of Sivula.t' Hedback21,56,57 and
their colleagues. Of equal importance, as documented by
Hedback and colleagues, is that the increased death rate, even
in patients with mild primary hyperparathyroidism, can be
reversed by successful parathyroidectomy. Of interest is the

finding that in young patients and in those with the least
severe hypercalcemia, the survival curve returns to normal
most quickly." Patients between the ages of 55 and 70 years
seem to receive the greatest survival benefit,21,56.57
FIGURE 40-5. Comparison of Parathyroidectomy Assessment of

Symptoms (PAS) scores between patients with primary hyperparathyroidism (HPT) and those with thyroid cancer at one center.
"P < .001; Pre op = preoperative; Post op = postoperative. (From
Pasieka J, Parsons L, Demeure M, et al. Patient-based surgical
outcome tool demonstrating alleviation of symptoms following
parathyroidectomy in patients with primary hyperparathyroidism.
World J Surg 2002;26:942.)
FIGURE 40-6. The Parathyroid Assessment of Symptoms (PAS)

scores from three centers over time, "P < .001; Pre op = preoperative;
Post op = postoperative. (From Pasieka J, Parsons L,
Demeure M, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients
with primary hyperparathyroidism. World J Surg 2002;26:942,)
Conclusion
In conclusion, the diagnosis of primary hyperparathyroidism can be made with nearly 100% confidence by documenting an increased serum PTH level in a patient with
increased ionized or total calcium without hypocalciuria.
Making the diagnosis is important, because preoperative
vague or classic symptoms or metabolic conditions associated with primary hyperparathyroidism often improve after
parathyroidectomy, as does long-term survival.
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17. Talpos GB, Bone HG 3rd, Kleerekoper M, et al. Randomized trial of
parathyroidectomy in mild asymptomatic primary hyperparathyroidism: Patient description and effects on the SF-36 health survey.
Surgery 2000;128:1013.
18. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief
of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513.
19. Kenny AM, MacGillivray DC, Pilbeam CC, et al. Fracture incidence
in postmenopausal women with primary hyperparathyroidism. Surgery
1995;118:109.
20. Joborn C, Joborn H, Rastad J, et al. Maximal isokinetic muscle
strength in patients with primary hyperparathyroidism before and after
parathyroid surgery. Br J Surg 1988;75:77.
21. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in

patients operated on for primary hyperparathyroidism. World J Surg
1990;14:829.
22. Hedback G, Oden A. Increased risk of death from primary hyperparathyroidism-An update. Eur J Clin Invest 1998;28:271.
23. Sugar A. Conjunctival and corneal degenerations. In: Yanoff M,
Duker JS (eds), Ophthalmology, 2nd ed. Philadelphia, Mosby,
2004, p 449.
24. Szabo J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-jaw
tumor syndrome: The endocrine tumor gene HRPT2 maps to chromosome Iq21-q31. Am J Hum Genet 1995;56:944.
25. Kebebew E. Parathyroid carcinoma. Curr Treat Options Oncol
2001;2:347.
26. Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of
a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807.
27. Strewler GJ, Budayr AA, Clark OH, Nissenson RA. Production of
parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 1993;76:1373.
28. Heath H 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol
Metab Clin North Am 1989;18:723.
29. Gunn IR, Wallace JR. Urine calcium and serum ionized calcium, total
calcium and parathyroid hormone concentrations in the diagnosis of
primary hyperparathyroidism and familial benign hypercalcaemia. Ann
Clin Biochem 1992;29:52.
30. Marx SJ, Attie MF, Stock JL, et al. Maximal urine-concentrating ability:
Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1981;52:736.
31. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human
Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993;75:1297.
32. Chou YR, Brown EM, Levi T, et al. The gene responsible for familial
hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated
families. Nat Genet 1992;1:295.
33. Fujimoto Y, Hazama H, Oku K. Severe primary hyperparathyroidism
in a neonate having a parent with hypercalcemia: Treatment by total
parathyroidectomy and simultaneous heterotopic autotransplantation.
Surgery 1990;108:933.
34. Clark OH. Hyperparathyroidism. In: Oh C (ed), Endocrine Surgery of
the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985, P 172.
35. Duh QY, Morris RC, Arnaud CD, Clark OH. Decrease in serum uric
acid level following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 1986;10:729.
36. Bilezikian JP, Silverberg SJ, Gartenberg F, et al. Clinical presentation
of primary hyperparathyroidism. In: Bilezekian JP, Marcus R, Levine
MA (eds), The Parathyroids. New York, Raven Press, 1994, p 457.
37. Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery.
Arch Surg 1992;127:1157.
38. Bringhurst FR, Demay MB, Kronenberg HM. Hormones and disorders
of mineral metabolism. In: Williams RH, Wilson JD (eds), Williams
Textbook of Endocrinology. Philadelphia, WB Saunders, 1998, p 1155.
39. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary
hyperparathyroidism. J Bone Miner Res 1989;4:283.
40. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Increased bone mineral
density after parathyroidectomy in primary hyperparathyroidism. J Clin
41. Silverberg SJ, Shane E, Jacobs TP, et al. A IO-year prospective study
of primary hyperparathyroidism with or without parathyroid surgery.
N Engl J Med 1999;341:1249.
42. Arici C, Cheah WK, ltuarte PH, et al. Can localization studies be used
to direct focused parathyroid operations? Surgery 2001;129:720.
43. Bilezikian JP, Potts IT Jr, El-Hajj Fuleihan G, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism:
A perspective for the 21st century. J Clin Endocrinol Metab
2002;87:5353.
44. Abe Y, Ejima E, Fujiyama K, et al. Parathyroidectomy for primary
hyperparathyroidism induces positive uncoupling and increases bone
mineral density in cancellous bones. Clin Endocrinol (Oxf)
2000;52:203.
45. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: A new
indication for surgery in primary hyperparathyroidism. J Clin

46. Uden P, Chan A, Duh QY, et al. Primary hyperparathyroidism in
younger and older patients: Symptoms and outcome of surgery. World
J Surg 1992;16:79l.
47. Clark OH. "Asymptomatic" primary hyperparathyroidism: Is parathyroidectomy indicated? Surgery 1994;116:947.
48. Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery
after parathyroidectomy in primary hyperparathyroidism. Surgery
1995;117:18.
49. Deutch SR, Jensen MB, Christiansen PM, Hessov I. Muscular
performance and fatigue in primary hyperparathyroidism. World J Surg
2000;24:102.
50. Sheldon DG, Lee FT, Neil NJ, Ryan JA Jr. Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg
2002;137:1022.
51. Okamoto T, Kamo T, Obara T. Outcome study of psychological
distress and nonspecific symptoms in patients with mild primary
hyperparathyroidism. Arch Surg 2002;137:779.
52. Pasieka JL, Parsons LL. A prospective surgical outcome study
assessing the impact of parathyroidectomy on symptoms in patients
53.
54.
55.
56.
57.
with secondary and tertiary hyperparathyroidism. Surgery 2000;

128:531.
Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical
Palmer M, Adami HO, Bergstrom R, et al. Survival and renal function in
untreated hypercalcaemia. Population-based cohort study with 14 years
of follow-up. Lancet 1987;I :59.
Sivula A, Ronni-Sivula H. Observations on 334 patients operated on
for primary hyperparathyroidism. Ann Chir GynaecoI1985;74:66.
Hedback G, Oden A, Tisell LE. The influence of surgery on the risk of
death in patients with primary hyperparathyroidism. World J Surg
1991;15:399.
Hedback G, Oden A, Tisell LE. Parathyroid adenoma weight and the
risk of death after treatment for primary hyperparathyroidism. Surgery
1995;117:134.
Natural History of Untreated

Primary Hyperparathyroidism
Goran Akerstrom, MD Ewa Lundgren, MD
In the early descriptions of patients with primary hyperparathyroidism (HPT), the disease was recognized as a rare
disorder and was associated with severe incapacitating bone
symptoms, prevalent renal stones, devastating muscular
weakness, and often early death from renal failure. Since the
introduction in the mid-1970s of automated equipment allowing routine measurements of serum calcium by multiphasic
laboratory screening on liberal indications, primary HPT has
been diagnosed with increased frequency. I The disease has
been revealed to be particularly prevalent in postmenopausal
women, and many such patients have had a milder ailment
than was common some decades ago. These patients have
typically lacked the bone or renal stone complications of
HPT and have instead exhibited vague symptoms of fatigue
or psychiatric disability or have appeared asymptomatic.P
Because general policies of management in primary HPT
have been based on studies of symptomatic patients, it has
not been obvious that primary HPT detected at a mild and
uncomplicated stage requires the same treatment.
Accordingly, it has been suggested that subsets of patients
with primary HPT may be subjected to surveillance rather
than surgery.v' Concomitantly, the diagnosis of HPT has
become easier and more precise with the introduction of
new methods for measurement of intact serum parathyroid
hormone (PTH). HPT can now be diagnosed with assurance,
even in cases with no more than borderline elevations of
serum calcium.v'
Epidemiology
Epidemiologic data on the prevalence of primary HPT are
sparse for most countries. An autopsy study of a Swedish
population revealed parathyroid adenoma in 2.4% and
"subclinical" disease represented by micronodular chief cell
hyperplasia in another 7%, with an apparent continuum of
abnormality ranging from hyperplastic micronodular lesions
to the adenomas." Borderline hypercalcemia could be clinically detected in occasional patients with hyperplastic
glands containing larger, predominant nodules or in those
with tiny adenomas, whereas more marked elevation

of serum calcium was associated with adenomas of more
conspicuous size.? The histologic abnormalities were particularly common in older individuals of both genders and related
to histologic signs of nephrosclerosis, even in the absence of
clinically detectable renal dysfunction," These findings substantiate the presence of prevalent subclinical and clinical
parathyroid disease within the elderly Swedish population.
They also mirror problems in clinical management of patients
with primary HPT because an increased incidence of micronodular hyperplasia and tiny adenomas has been encountered
when patients with borderline hypercalcemia have been liberally submitted to parathyroid exploration."!"
Population screening has confirmed the prevalence of
parathyroid disease in Sweden, but it has also demonstrated
that prevalence data depend on the age of the population
studied as well as the level of hypercalcemia that is used to
distinguish patients with HPT from normal individuals. I 113
Accurate screening for detection of hypercalcemia also
requires that repeated serum calcium determinations be used
in such surveys. I 1.13
A health screening survey of employees aged 20 to
63 years within Stockholm County in Sweden included
repeated measurements of serum calcium and revealed
hypercalcemia supposedly resulting from HPT, with an overall prevalence of 0.4% to 0.6%.11 Elevated serum calcium
levels were detected in approximately 0.3% of men and 1%
of women older than 50 years. This screening used serum
calcium levels greater than 2.65 mmol/L (10.6 mg/dL) to
define hypercalcemia, and older age groups, in which HPT
is in fact most common, were not included.
In another health screening survey in Gavle County of
Sweden, 16,401 individuals had repeated serum calcium
determinations over a 2-year period (1969 and 1971).13
Altogether, 172 individuals were found to have hypercalcemia, with serum calcium levels higher than the normal
reference of 2.60 mmol/L on both occasions, without other
obvious reasons such as vitamin D or oral calcium medication or malignancy." This corresponded to approximately
1% of the population, 0.3% of men and 1.6% of women.
393

In women older than 60 years, the prevalence of hypercalcemia was close to 3% (Fig. 41-1),13,14 Female predominance
in screening surveys may be partly related to significantly
higher normal means of serum calcium in postmenopausal
women than in men of the same age, implying that even
minimal increases in serum calcium could be more easily
detected. 13 This probably does not explain a female overrepresentation in clinically detected HPT, which is also likely
to be related to regulatory disturbances within the diseased
parathyroid tissue. Although most of the hypercalcemic
individuals in this study did not have a parathyroid operation
and the diagnosis is not undisputable, it is reasonable to
assume that the majority of them had HPT.13,14
In a population screening in which serum calcium levels
were determined in conjunction with a mammographic
health survey, a comparable prevalence of HPT of 2.2%
was found for postmenopausal women with a mean age of
59 years." The majority of hypercalcemia cases were borderline, and most of the individuals were elderly. Similar high
prevalence estimates of hypercalcemia and presumable HPT
were documented in a more recent health screening survey
from Norway.16 Although figures depend on definition criteria,
the disease can be expected in at least 2% of postmenopausal women.P:" Reports from the United States and
Europe have suggested that the incidence of HPT may be
declining, perhaps because of more restricted use of multichannel screening tests for hypercalcemia.lv't-"
Comparison of health survey figures and hospital statistics in Sweden and the United States indicates that even if
surgery were done for relatively liberal indications, currently
only about one tenth of all patients with HPT in the population are subjected to parathyroidectomy.13,19,20 Considering the
high prevalence figures of the health surveys, it is reasonable
that studies aim to clarify whether surgery for primary HPT
is also of benefit for patients with a mild, asymptomatic, and
uncomplicated disease or whether such patients may be
safely monitored without surgery.
Women (n=149)
Number
31
70- Men (n=27)

Number
60-69
50-59
40-49
30-39
48
OJ
If
41
26
2
25-29
r,
20
10
10
Per million
20
30
FIGURE 41-1. Prevalence of hypercalcemia in men and women of

different age groups in the Gavle County Health Survey. (Adapted
from Palmer M, Jakobsson S, Akerstrom G, et al. Prevalence of
hypercalcemia in a health survey: A 14-year follow-up of serum
calcium levels. Eur J Clin Invest 1988;18:39. Copyright 1988 by
Blackwell Science Ltd.)
Follow-up of Health
Survey-Detected Hypercalcemia
In the Stockholm health survey, 27 randomly selected
hypercalcemic patients underwent neck exploration, and all
were found to have parathyroid adenoma." Another group
of 23 hypercalcemic patients (mean age, 55 years) was
monitored with regular checkups and compared with ageand sex-matched normocalcemic control subjects during
a to-year period." Their initial mean serum calcium of
2.75 mmollL remained unchanged during the study period,
and there was no notable deterioration of kidney function
in routine serum analyses. A significant elevation of systolic
and diastolic blood pressures in the hypercalcemic individuals compared with control subjects at initiation of the
follow-up persisted throughout the 10-year study period. 2l,22
In the Gavle health survey, the mean age of hypercalcemic
individuals was 59 years, and their mean serum calcium was
2.72 mmol/L." Eleven patients initially had surgery because
of marked hypercalcemia (2.83 to 3.63 mmollL), and
another 21 underwent surgery between 1971 and 1983 to
1984 when a follow-up study was performed." The majority of the patients with hypercalcemia were neither informed
about their hypercalcemia nor treated. At the follow-up
study in 1983 to 1984,57 patients had died and 7 were lost
to follow-up. Scrutiny of patients' records did not indicate
that any of these individuals had had severe hypercalcemia
or renal insufficiency.P'P Of the remaining 95 patients,
47 still had a serum calcium level greater than 2.60 mmollL
in 1983 to 1984, and 48 subjects with serum calcium levels
slightly below this normal limit had displayed intermittent
hypercalcemia in the intervening years. 13 For the majority of
hypercalcemic individuals, the serum calcium remained
more or less constant throughout the study period, and no
patient (including those who subsequently had parathyroid
surgery) showed markedly progressive hypercalcemia or an
abrupt rise in serum calcium levels.P Serum creatinine
levels were above normal in 15 patients at the 1983 to 1984
follow-up, but only 3 patients had a more marked elevation
of serum creatinine, and these individuals had either urea
nitrogen above normal at the initial screening or obvious
nonparathyroid causes of renal impairment.P
Using national registration numbers and the causes of
death registry, survival was compared between individuals
who were hypercalcemic at the 1969 to 1971 survey and
matched normocalcemic control subjects." Survival during
the l4-year follow-up was significantly lower among the
hypercalcemic individuals.P The difference in survival
steadily increased and became more marked after 5 years
from the initial health survey.F' The hypercalcemic individuals also had significantly higher diastolic and systolic
blood pressures as well as serum uric acid and a tendency
toward higher glucose and cholesterol levels. Using multivariate analyses, higher levels of serum calcium were associated with increased mortality in patients older than 60 years,
but this effect diminished in the oldest age groups. Life table
analyses revealed a significant difference in survival
between hypercalcemic persons and control subjects at
age 70 or younger but not for those older than 70 years
(Fig. 41_2),23 The increased mortality in the hypercalcemic
Natural History of Untreated PrimaryHyperparathyroidism - - 395
... ~~
FIGURE 41-2. Survival curves for
hypercalcemic subjects and matched
control subjects from the Gavle
County Health Survey. (From
Palmer M, Adami H-O, Bergstrom
R. et al. Survival and renal function
in persons with untreated hypercalcaemia: A population-based cohort
study with 14 years of follow-up.
Lancet 1987;1:59. by the Lancet
Ltd., 1987.)
Subjects> 70 years
Subjects s 70 years
All subjects
__...._"'"._ / Controls
.....
'"--
t..-i
"1
/'
Hypercalcemics
50
p=0.9
p=0.0025
p=0.0135
,
10
13
10
13
10
13
Time offollow up (years)
group was not due to any single disease group, but the
number of deaths caused by cardiovascular diseases was
predominant and distinctly higher than expected. No deaths
were caused by hypercalcemic crisis, renal failure, or other
conditions that were obviously related to the hypercalcemic
state." When examined for symptoms, the hypercalcemic
individuals exhibited similar but less significant psychiatric
symptoms when compared with patients with clinically
detected primary HPT14.24.25 but more symptoms than the normocalcemic control patients. The hypercalcemic individuals
were subsequently subjected to a 25-year follow-up, showing
a tendency to lowering (or even normalization) of the hypercalcemia but continuing to have increased mortality in comparison with control subjects." The excess mortality was
significant among individuals 70 years of age or younger and
was valid for cardiovascular disease only."
The studies indicate that the risk for progression of hypercalcemia or marked deterioration of renal function is low in
borderline hypercalcemic primary HPT. The risk for subclinical renal impairment in HPT and thereby reduced levels
of active vitamin D, which could contribute to the increased
cardiovascular death rate (and also to lowering or normalization of the hypercalcemia), has been emphasized.'? The raised
mortality has, however, not been found in all series28.29
and may depend on the severity and duration of HPT.27
The psychiatric disturbance may be a notable complication in
individuals with intellectual occupations and cause states of
confusion in elderly people but may not always be impressive
in patients with borderline hypercalcemia.P
Conservative Follow-up in
Clinically Detected Primary
Hyperparathyroidism
In 1981, Scholz and Purnell reported a prospective lO-year
follow-up study from the Mayo Clinic aiming to evaluate the
disease course in patients with asymptomatic primary HPT
who were not subjected to surgery.30.31 This study remains
the most important long-term follow-up of conservatively

managed primary HPT; it was initiated in 1968 and terminated in 1980.30.31 The intent was to clarify the natural
history of the disease and to determine possible risks for
progression into a symptomatic or complicated stage that
ultimately would require surgery. A further aim was to determine whether such progression could be detected before
significant complications developed." Patients included in
this study had serum calcium levels of less than 11 mg/dL
(2.75 mmollL), normal renal function (evaluated by serum
creatinine), absence of roentgenographically demonstrated
bone disease (evaluated by roentgenography of the thorax,
hands, and skull), and absence of metabolically active or
infected renal lithiasis or nephrocalcinosis (investigated by
excretory urography). When radioimmunoassays for PTH
determination became available during the study, it was also
required that the patients have inappropriately elevated PTH
to establish the diagnosis definitively. The patients were
subjected to a comparatively extensive follow-up.
Altogether, 142 patients (Table 41-1) ultimately fulfilled
the criteria for participation in the study. During the first
30 months of the study, 21 patients (15%) underwent
parathyroid surgery; in the next 30 months, 3 additional
patients (2%) underwent surgery; and during the last 7 years
before completion of the follow-up, still another 9 patients
(6%) were subjected to surgery, that finally 33 (23%) of
all patients underwent operation. One of these patients
had probable hypercalcemic crisis. Sixteen patients had
previous negative parathyroid explorations and were
excluded from the final evaluation. Of the unoperated
patients, 32 died during the follow-up period, 10 declined
follow-up, and 9 could not be traced when the study was
terminated. Of the 42 patients remaining in the unoperated
group, 12 became spontaneously normocalcemic, and there
was some doubt regarding the original diagnosis in these
cases; 30 patients with persistently elevated serum calcium
were available for follow-up in 1980, and in all of them
the diagnosis was supported by elevated PTH levels.
Cumulative follow-up data were obtained for 24 of these
30 patients and revealed no progression in 21 patients;
1 patient had advancing osteoporosis, 1 showed a modest

increase in serum calcium, and another experienced a rise in
serum creatinine. When deceased and noncompliant patients
were excluded, the final compilation of data (including
patients undergoing parathyroid surgery) revealed increased
serum calcium in 10% of the patients (including one patient
with probable hypercalcemic crisis, but a subtle rise in others),
decreased renal function in 8%, active renal stone disease in
6%, bone disease in 5%, and psychological problems to
the extent that parathyroid surgery was indicated in 5%
(Table 41-2). The authors concluded that, for the comparatively few patients in whom adequate data could be collected
for the whole study period, marked disease progression was
noted only in a minority. Although the authors recommended
surgical exploration by an experienced surgeon for the patients
with asymptomatic HPf, they also concluded that patients
who declined surgery or who had contraindications to operation could be monitored with minimal risk provided that the
patients and their physicians were willing to commit themselves to a rigid follow-up program. However, the authors
noted that the conservative follow-up had been time consuming and expensive, and it had been difficult to make the
patients comply with this type of follow-up.
Several authors have subsequently reported conservative
management of patients with primary HPT. Most of these
studies have comprised fewer patients, some of whom had
persistent hypercalcemia after failed parathyroid operations
and others had surgery deferred because of associated illness. Many such patients have had higher serum calcium
levels, and some already had symptoms or complications of
parathyroid disease before the conservative follow-up.
Rohl and colleagues'" thus monitored 30 patients with
more severe hypercalcemia for an average of 3 years. Renal
lithiasis developed in seven patients and bone disease in one
patient; the total incidence of symptoms or complications
was 27%.
Adams'! described 31 patients with serum calcium levels
less than 3.0 mmollL who were managed conservatively for
1 to 12 (mean, 4) years. Before the study, 12 patients had
typical clinical features of primary HPT, mainly renal
stones. Eighteen patients were considered asymptomatic;
many of these were elderly women, often with hypertension.
The patients had repeated measurements of serum calcium,
creatinine, and alkaline phosphatase levels during follow-up.
One of the patients with renal stones experienced deteriorating renal function, poorly controlled hypertension, and a
marked rise in serum calcium, for which parathyroid surgery
was ultimately required. A large parathyroid tumor was
resected, but renal function and hypertension did not
improve. In two other patients, a rise in serum calcium was
partially attributed to thiazide treatment and thyrotoxicosis,
respectively. No patient experienced life-threatening hypercalcemia, and mean serum calcium and creatinine levels did
not change significantly during the follow-up. The authors
concluded that they had failed to identify any criterion
whereby patients who were destined to experience progressive disease could be identified. In this study, minor fluctuations in serum calcium were common and were thought to
be mainly methodologic. Some patients, however, displayed
more distinct variations, and the serum calcium levels were
then typically lower during the winter, apparently related to
a fall in vitamin D levels (Fig. 41-3). The author concluded
that patients with HPT who avoid sun exposure can experience osteomalacia and lower serum calcium levels.
Van't Hoff and coworkers" described 32 patients with
primary HPT monitored for a mean of 4 years. Many of
these patients had failed operations or were considered unfit
to undergo parathyroid operation because of associated
diseases, and some patients had refused surgery. Several
patients had renal stones, and some had a serum calcium
level greater than 3.0 mmollL prior to follow-up. Although
the mean serum calcium and mean serum creatinine did
not change significantly for the whole group of patients
during the conservative management, one patient with a
serum calcium level of 3.3 mmollL experienced pancreatitis
and impaired renal function, and three patients underwent
parathyroid surgery. The frequency of symptomatic renal
stones and complications may have indicated a more liberal
attitude toward operation.
Natural History of Untreated Primary Hyperparathyroidism - -
2.9
E 2.7
E
2.5
1'0]
Phosphate
0.5
1,5]
~
0.5
S
i i i
WSW
WSW
FIGURE 41-3. Seasonal variations in the serum concentrations of

calcium and parathyroid hormone (iPTH) in a patient with asymptomatic hyperparathyroidism. S = summer; W = winter (arrows).
(From Adams PH. Conservative management of primary hyperparathyroidism. J R Coli Physicians Lond 1982;16:184.)
Paterson and colleagues" reported on 14 patients who for

various reasons were not operated on and were managed
conservatively for 5 to 23 years. One patient had osteitis
fibrosa and died with fibrosarcoma, four patients originally
presenting with renal calculi experienced further episodes of
renal stones, and serum creatinine levels were finally raised
in two patients. Three patients experienced progressive
hypercalcemia.
Corlew and associates" reported a more carefully
explored series of 47 patients with primary HPT who either
refused surgery or were not offered this option, some of
whom were considered poor surgical risks. The diagnosis
was accurately established in these patients by measurement
of albumin-corrected serum calcium and intact PTH. The
patients were classified into three groups on the basis of
their levels of serum calcium; one fourth had serum calcium
levels higher than 2.78 mmol/L. Sixteen of the 47 patients
(34%) either died or suffered from complications that the
authors considered to be possibly related to primary HPT,
such as peptic ulcer disease (8 patients), with bleeding
in some cases; renal failure (5 patients); renal calculus
(1 patient); hypercalcemic crisis (1 patient); and ventricular
conduction defect (1 patient). With the exception of the
patient with hypercalcemic crisis, who initially belonged to
the group with the lowest serum calcium levels, the serum
calcium levels did not change significantly during the
follow-up period. It was, however, impossible for the authors
to predict the likelihood of progression or the severity of
complications. The authors concluded that they had found
nonoperative management inappropriate in good-risk primary
HPT patients with reasonable life expectancy, and they
suggested that most patients with significant elevation of
serum calcium should undergo surgery.
397
Heath and Heath" reviewed 122 personal patients with

primary HPT who were managed conservatively. Parathyroidectomy was recommended for patients with complications and definite symptoms of the disease, whereas for
asymptomatic patients and those with mild, nonspecific
symptoms, surgery was offered only if they were young; the
threshold for being young declined during a 10-year period
from 60 to 40 years. Diagnosis was based on hypercalcemia
associated with elevated or high-normal serum PTH levels.
The most common symptom in men was renal stones and
in women tiredness and lethargy, and these symptoms were
present in 10% of the conservatively monitored group.
Ninety-five patients were available for follow-up after a
mean of 6 years; in four patients, renal stones developed but
serum calcium and creatinine levels did not deteriorate.
Fifteen patients died. Although no deaths were attributable
to HPT, the group of patients who subsequently died had a
rise in serum creatinine levels, but because these patients
had several other medical problems, this was not necessarily
related to the parathyroid disorder. Thirteen patients were
lost to follow-up.
Rubinoff and coauthors'" reported a retrospective cursory
screening of symptoms and complications in 160 patients
who were found to be hypercalcemic on routine multiphasic
laboratory examination, and they compared each hypercalcemic person with a matched normocalcemic control subject
for a mean follow-up of 8.5 years. Fifteen patients had a
parathyroid adenoma removed during the study. Apart from
a higher incidence of hypertension and gallstones among the
hypercalcemic individuals, the study recorded no differences
regarding symptoms or routine estimates of renal function
when comparison was made with control subjects.
Posen and colleagues'? reported a retrospective survey of
142 patients who underwent successful parathyroid surgery,
another 33 patients who had persistent hypercalcemia after
a neck exploration, and 90 patients in whom surgery was
deferred for various reasons. Although selection bias and
variable follow-up (mean, 3 years) might have influenced
the outcome in this study, the authors found a similar rate of
vertebral crush fractures in all three groups. Forearm osteodensitometry showed higher bone mineral content in the group
subjected to successful parathyroid surgery. One patient with
persistent HPT experienced progressive, severe osteoporosis
during conservative management and died with multiple spontaneous fractures.
These studies seem to substantiate the results of the
Scholz and Purnell" study in that rapidly progressive disease
is relatively rare in patients with primary HPT. A minority of
patients experience a marked increase in serum calcium or
serum creatinine, but because such progression cannot be
predicted in the individual patient, careful and close follow-up
is mandatory if parathyroidectomy is not done. The studies
indicate that renal damage may be irreversible, and conservative management, therefore, appears inappropriate in
patients with more marked elevation of serum calcium or
notable signs of renal function deterioration. Evidently, such
patients should be offered a chance of amelioration of the
parathyroid disease even if this should require a reoperative
parathyroid procedure.
Rapid progression of hypercalcemia may occur unexpectedly, as emphasized by Corsello and colleagues,"

who within a 2-year period had five patients who experienced rapidly increasing serum calcium levels and
"parathyroid crisis" while being monitored for mild primary
HPT. One patient had parathyroid carcinoma, initially
presenting with mild hypercalcemia; the others had benign
parathyroid lesions.
Rao and coworkers" examined the course of untreated
mild asymptomatic primary HPT fortuitously discovered by
multiphasic biochemical screening. Patients in this study
had hypercalcemia persisting at repeated measurements,
with serum calcium levels between 2.65 and 3.0 mmollL,
and inappropriately high PTH levels or elevated nephrogenous cyclic adenosine monophosphate. The patients lacked
symptoms attributable to HPT, showed no evidence of active
renal stone disease, had serum creatinine levels less than
133 umol/L, had no radiographic osteitis fibrosa, and had
a forearm bone density measurement that was not less than
2.5 standard deviations below the expected level.
Of the original 198 patients subjected to conservative
follow-up, 80 patients remained with adequate data from
repeated measurements of bone density, serum calcium, and
creatinine. These patients had a mean age of 61 years and
initial mean serum calcium of 2.77 mmollL. They were
monitored for 1 to 11 (median, 3.2) years at regular intervals
of 6 to 12 months. The mean initial and final levels of serum
calcium, serum creatinine, creatinine clearance, PTH (midand C-terminal assay), and forearm bone mineral density at
proximal and distal sites of the radius normalized for age,
gender, and race were virtually identical. A modest increase
in alkaline phosphatase levels was noted in persons with
longer follow-up and was apparently related to increased age.
No episodes of worsening of hypercalcemia were noted, and
there were no changes in renal function or appearance of
symptoms of renal lithiasis. The initial mean levels for proximal and distal forearm bone density were significantly
reduced, but there was no accelerated bone loss during
follow-up apart from that expected with increasing age.
The authors suggested that the lack of progression of
biochemical parameters or bone loss in primary HPT was
compatible with a biphasic disease course. They suggested
that an initial short period of disease progression was likely
to be followed by a long period of disease stability because
they would otherwise have noted derangement of biochemical parameters or accelerated bone loss. The observations were
considered to support nonsurgical surveillance in patients with
mild asymptomatic and uncomplicated primary HPT, but the
authors were unable to obtain adequate follow-up information in more than half of the original group of patients who
had been managed conservatively. A subsequent report from
the same authors'? included an additional 26 patients who
initially had shorter follow-up. This increased the length of
the study period to slightly more than 4 years without
changing the biochemical parameters or the conclusions of
the study.
Rudnicki and Transbel'" reported time-limited follow-up
in 24 patients with mild primary HPT for an average of
nearly 3 years and found that mean ionized serum calcium
levels remained stable, whereas levels of intact serum PTH
increased significantly. A subgroup of patients whose PTH
levels increased by 78% also had a small but significant
increase in serum ionized calcium, whereas in the remaining
patients serum PTH levels increased modestly (22%) and

ionized calcium levels were unchanged. The serum creatinine concentrations were stable throughout the study. The
authors concluded that other studies of mild to moderate
primary HPT did not include information on the course of
parathyroid function and that primary HPT may progress
even when serum calcium levels remain unchanged. They
further emphasized that conditions commonly associated
with old age, such as poor vitamin D intake and impaired
vitamin D synthesis, could be responsible for impairment of
intestinal calcium absorption, with a resulting compensatory
hypersecretion of PTH.
Silverberg and coworkers" reported a lO-year prospective follow-up of 121 HPT patients, 61 of whom were
subjected to parathyroidectomy (according to indications
established at the National Institutes of Health Consensus
Conference Statement, 1991, concerning diagnosis and
management of asymptomatic HPT4), whereas 60 patients
did not undergo surgery. The majority of nonoperated
patients were asymptomatic, but in some patients surgery
was not undertaken despite the presence of kidney stone
disease. All nonoperated symptomatic patients with kidney
stones experienced progressive disease with recurrent stone
attacks during follow-up, whereas none of the operated
patients had such recurrences. Among nonoperated, asymptomatic patients, 27% had progressive disease with worsened hypercalcemia, increased hypercalciuria, and decrease
in bone mineral; the remaining patients had apparently
stable disease. The authors concluded that women with HPT
seemed to be at risk for disease progression with significant
loss of bone mineral, especially at menopause, and should
therefore be liberally considered for parathyroidectomy.
They also inferred that some asymptomatic patients experience disease progression over time, and all patients not
undergoing surgery should therefore have biannual measurements of serum calcium, urinary calcium excretion, and
bone mineral density.
Progression of Symptoms
The clinical manifestations of HPT tend to be related to the
level of hypercalcemia, even if this is not always evident
because of slow disease progression, individual susceptibility,
and to some extent also gender and age dependence of symptoms." Younger men are particularly likely to experience renal
stones, sometimes even with only mild hypercalcemia. For
renal stones, the individual susceptibility is more important
than the level of hypercalcemia, and the risk for this particular
symptom is probably most efficiently revealed by the patient's
history. Urinary calcium excretion has been an uncertain
predictor of the risk for kidney stones among patients who
have previously not had this symptom.f Males excrete 25% to
30% more calcium in the urine than females, and whites also
have higher excretion than blacks." In postmenopausal
women, renal stones occur infrequently (generally less than
5%) and are often clinically silent.
Osteitis fibrosa cystica is now an uncommon finding in
patients with primary HPT and is most often seen in patients
with severe hypercalcemia. Bone density measurements
have, however, demonstrated an average reduction in
Natural History of Untreated Primary Hyperparathyroidism - - 399
cortical bone of nearly 20% among current patients with

primary HPT, and the bone loss tends to be most pronounced
in postmenopausal women.44-49 Total and trabecular bone
mass is often significantly but less markedly reduced.r'r"
Bone density measurements are recommended at the distal
radius, hip, and lumbar spine because a subset of patients
have more apparent reduction in the spine than other sites."
The risk for fracture appears to be increased for the vertebra,
distal leg, and forearm and returns to normal after parathyroid surgery.SO,SI The bone loss may be most evident at the
time of menopause and may constitute an important indication for surgery in female patients." No bone loss has been
detected in postmenopausal women with borderline hypercalcemia, but losses were significant when the serum calcium
level was higher than 2.74 mmol/L."
In postmenopausal women with primary HPT, a neuropsychiatric disability with symptoms of tiredness, lethargy,
weakness, and easy fatigue is the most common feature.
Although these are not traditional symptoms of HPT, they
are typical for the disease, and many patients report
improvement after successful parathyrotdectomy." The
oldest patients may present with mental confusion, even
without profound hypercalcemia, and their mental capacity
may recover dramatically after operation.f It is important
that these symptoms be recognized as features of the disease
and constitute indications for surgery. The psychiatric
disability is generally more evident when serum calcium
levels are more markedly elevated, but the effects of surgery
on the symptoms may sometimes be difficult to predict in
individual patients."
Clinically evident renal failure is currently an unusual
complication of primary HPT. Reductions of creatinine
clearance and urinary concentrating capacity, however, occur
in more than one third of patients with mild hypercalcemia,
indicating that impairment of glomerular as well as tubular
function may occur silently.'? Serum creatinine measurements are crude estimates and rise only after creatinine clearance is substantially reduced, and creatinine levels also
decrease with declining muscle mass of aging."? Reduction
of creatinine clearance is a complication of the disease and
an evident indication for surgery."
Hypertension is twice as common in patients with primary HPT as in the general population and may be more
severe in association with impaired renal function. However,
it does not parallel the degree of hypercalcemia and is generally unaffected by parathyroid surgery.47A8,S2 Hypertension
and other risk factors for cardiovascular disease may also
be of concern with respect to decreased survival in primary
HPT,26,27 which is evident also in mild hypercalcemia. 23,26,27,34,53.s4 Hypercalcemia and primary HPT have
been associated with increased risk of death in cardiovascular disease in Scandinavian studies but not in two North
American series. 26-29 The increased mortality has appeared
related to the severity of HPT and renal function impairment." HPT of significant degree or long duration may
cause renal impairment that is not always disclosed by
creatinine values, and resulting reduced levels of active vitamin D may contribute to development of cardiovascular
disease. The increased death risk has appeared reversed
if patients with primary HPT have been operated on at an
earlier disease stage.
Summary
Indications for parathyroidectomy are indisputable in
patients with primary HPT who exhibit clear and classic
symptoms or marked hypercalcemia. The value of parathyroidectomy in asymptomatic patients with mild to moderate
hypercalcemia has, however, been debated. Studies of the
natural history of untreated primary HPT document that
rapid increases in the serum calcium level, progression
of symptoms or complications, or both is uncommon in
patients with borderline hypercalcemia. Less clear is our
knowledge about the long-term consequences of somewhat
more marked hypercalcemia because no study has yet
presented adequate follow-up of such patients for a prolonged
period of time. It appears as if many patients with moderately elevated serum calcium levels 3.0 mmollL) have
symptoms and silent complications of HPT if they are carefully studied. Although rapid progression of hypercalcemia is
unusual, serum calcium levels, nevertheless, tend to increase
progressively over years of observation in some patients.
This advancing hypercalcemia may be obscured by
declining levels of active vitamin D, resulting from dietary
deficiency, lack of sun exposure, and impairments of renal
function. Because these factors lower serum calcium levels,
progression of HPT may not be detected. 7,ss.s6 The impact of
such relative vitamin D deficiency may be difficult to determine and may simultaneously be part of the pathogenesis of
primary HPT in elderly people.
The natural course of primary HPT is causally related to
the genetic and functional abnormalities within the diseased
parathyroid tissue. Variable tumor biology and clinical
progression may, therefore, depend on heterogeneity of tumor
genetics.V Occasionally, patients' metabolic problems
progress rapidly and are then reflected in excessively raised
serum calcium values. These patients may have parathyroid
tissues that harbor exceptional and critical mutations
with oncogene activation or recruitment of growth factors.
A PRADl oncogene rearrangement has been described in
this context and has been associated with the largest
parathyroid adenomas, whereas a menin gene abnormality
has also been evident in sporadic, mild HPT.S8 Rare patients
with initially mild hypercalcemia but rapidly advancing
disease may have parathyroid carcinoma.v' In addition, stepwise "clinical" progression may occur during observation in
patients with primary HPT, possibly representing development of secondary mutations that cause accelerated growth
of the tumor. Thus, a history of mild primary HPT has been
reported in up to one third of patients with hypercalcemic
crisis. Because it is not yet possible to predict whether
progressive disease will occur in any patient, extended
follow-up is crucial if surgery is deferred in primary HPT.S9.6O
Younger patients seem to be at greater risk for progressive
disease.
The absence of marked progression of complications
in most patients with mild primary HPT allows medical
surveillance in older persons with borderline hypercalcemia
(i.e., with increments of serum calcium to less than 2.75 to
2.85 mmol/L, or 11.0 to 11.4 mg/dL) and in those with
associated illnesses. Medical surveillance is probably
inappropriate in younger patients and in those with more
marked hypercalcemia. Nonoperative management in any

circumstance requires that the presence of symptoms or
complications be carefully excluded and that precise monitoring of symptoms and metabolic function be done." A new
consensus statement" has substantiated a risk for disease
progression if patients with HPT are monitored without
surgery and therefore issued a general recommendation for
parathyroidectomy in patients with serum calcium values
raised 0.25 mmol/L above the normal reference.
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45. Lafferty FW, Hubay CA. Primary hyperparathyroidism. A review of
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Natural History of Untreated Primary Hyperparathyroidism - - 401

51. Vestergaard P, Mosekilde L. Fractures in patients with primary hyperparathyroidism: Nationwide follow-up study of 1201 patients. World J
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52. Heath H III. Clinical spectrum of primary hyperparathyroidism:
Evolution with changes in medical practice and technology. J Bone
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53. Hedback G, Tisell L-E, Bengtsson B-A, et al. Premature death in
patients operated on for primary hyperparathyroidism. World J Surg
1990;14:829.
54. Hedback G, Oden A, Tisell L-E. The influence of surgery on the risk
of death in patients with primary hyperparathyroidism. World J Surg
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55. Turner G, Brown RC, Silver A, et al. Renal insufficiency and
secondary hyperparathyroidism in elderly patients. Ann Clin Biochem
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Arch Surg 1992;127:1157.
57. Arnold A. Genetic basis of endocrine disease 5. Molecular genetics of
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58. Carling T, Correa P, Hessman 0, et aI. Parathyroid MEN] gene mutations in relation to clinical characteristics of nonfamilial primary
59. Sarfati E, Desportes L, Gossot D, et al. Acute primary hyperparathyroidism. Br J Surg 1989;76:979.
60. Bondeson A-G, Bondeson L, Thompson NW. Clinicopathological
peculiarities in parathyroid disease with hypercalcaemic crisis. Eur J
Surg 1993;159:613.
Metabolic Complications of
Gerhard Prager, MD Claudette Abela, MD Bruno Niederle, MD
In 1925, the Viennese surgeon Felix Mandl removed for the

first time a parathyroid tumor in a patient with symptomatic
primary hyperparathyroidism (PHPT).1 The patient was
confined to bed and suffered from classic renal and osseous
symptoms: recurrent renal calculi, osteitis cystica fibrosa,
disabling bone pain, and fatigue. Postoperatively, the patient
improved dramatically but unfortunately died 10 years later
from the consequences of progressive renal disease.F Since
then there has been a dramatic improvement in the outcome
of patients with PHPT after parathyroidectomy.' Careful
analysis of patients with PHPT reveals that postoperative
metabolic complications occur in patients with a long
history of PHPT.3,4 For example, the death rate related directly
or indirectly to PHPT ranges from 1% to 12%. Death in
patients with PHPT is mainly caused by cardiovascular disease
(~68%S)
and acute or chronic renal failure (~8%3).
Over the last 50 years, the clinical picture of PHPT has
changed from a "rare" illness characterized by bone disease
and renal calculi to a "common" disease characterized by
more subtle or no clinical manifestations.f Articles from
Scandinavia and North America':" have documented an
increasing number of patients with PHPT who are diagnosed because hypercalcemia is detected on undirected routine serum calcium determinations and the diagnosis
confirmed by parathyroid immunoassays.f-"!' PHPT is a relatively common, worldwide disorder with a reported incidence ranging from 0.1 % in Central Europe,'? Australia, 12
and South Africa" to as high as 0.52% in Sweden.v?"
Heath 14 in England reported that among his patients with
PHPT, fewer than 10% have renal calculi and fewer than
10% have bone disease, whereas more than 80% have either
vague ill health or are asymptomatic,
PHPT patients may be classified as symptomatic, minimally symptomatic, or asymptomatic. Symptomatic patients
have renal, skeletal, or gastrointestinal disease or a
combination. Osseous disease is defined as osteitis fibrosa,
subperiosteal resorption, pathologic bone fractures, and aeroosteolysis. Minimally symptomatic patients have bone pain,
diffuse osteopenia, or hypertension and the so-called hypercalcemia syndrome, which includes depression, lethargy, apathy,
402
weakness, loss of memory, confusion, insomnia, headaches,

and myopathy with muscular weakness as well as other
general manifestations like polyuria and polydypsia, weight
loss, vomiting, nausea, or epigastric discomfort without any
apparent organic origin.' Asymptomatic patients have neither
symptoms nor signs attributable to PHPT (Table 42-1),
In this chapter, we describe metabolic manifestations and
complications other than the typical well-known, classic
manifestations in both treated and untreated patients with
PHPT that are described elsewhere in this textbook.
Several metabolic complications are not usually attributed
to PHPT. Patients with PHPT, for example, may have
impaired glucose tolerance and diabetes mellitus. IS,16 Both
hyperuricemia-!? and hyperlipidemia's may be increased in
patients with PHPT, These conditions may have an adverse
effect on hypertension and concomitant cardiovascular
disease, and these conditions may contribute to the increased
morbidity and mortality in patients with PHPT, even after
successful parathyroidectomy. 11,19,20
The severity of the metabolic manifestations that occur in
patients with PHPT cannot be predicted by the presence or
absence of symptoms. Age, serum calcium level, and renal
function are similar in patients with or without symptoms,":"
although asymptomatic patients appear to have slightly
lower serum calcium levels (Table 42-2). Some symptoms
and metabolic changes improve, at least in part, after
parathyroidectomye-P On the other hand. about one quarter
of asymptomatic patients develop symptoms of PHPT within
1 decade."
Arterial Hypertension
In 1958, Hellstrom and associates'? suggested a relationship
between hypertension and PHPT; these authors reported that
53% oftheir 95 patients had blood pressures of 1501100 mm
Hg or greater. Several series have quoted a prevalence ranging from 21 % to 57% (Table 42_3).28-33 This wide range may
be a result of different patient ages as well as different definitions of hypertension. Lafferty!' showed that hypertension
Metabolic Complications of Primary Hyperparathyroidism - - 403
was twice as common among hyperparathyroid patients

compared with the general population.W PHPT and hypertension are associated with an increased risk of cardiovascular disease and possibly stroke.r' Bostrom and Alverydr' as
well as Palmer and colleagues'" reported a higher mortality
rate (61%) mainly because of cardiovascular disease in
patients with hypercalcemia and PHPT. Unfortunately,hypertension failed to improve in 92% after parathyroidectomy."
The pathogenesis of hypertension in patients with PHPT
has not been completely defined. Studies involving the
renin-angiotensin system suggest no direct relationship
with the hypertension.v-" Salahudeen and coworkers"
found no correlation between blood pressure and total serum

calcium in PHPT patients." This is in contrast to the situation with essential hypertension in which a significant positive correlation between blood pressure and total serum
calcium has been described.tv" as well as an inverse correlation or no correlation between serum ionized calcium
and hypertension.v-t' Parathyroid hormone (PTH) is said

to play a permissive role in the hypertensive action of
hypercalcemia.tv" Bernini and associates" compared plasma
renin activity in patients with PHPT and essential hypertension and a normotensive control group. They only found
a weak relation between PTH and plasma renin activity,
suggesting that hypertension in PHPT is probably of heterogeneous origin.

As mentioned, the response of hypertension after successful parathyroidectomy has been variable. Successful cure of
hyperparathyroidism only occasionally leads to a lowering
of blood pressure to normal. Renal impairment also
usually does not improve after successful parathyroidectomy.27.37.39.47.48 Salahudeen and colleagues'? suggested that
impaired renal function in PHPT may be the primary event
to hypertension.f because the glomerular filtration rate
measured by chromium l-edetic acid clearance did not
change after parathyroidectomy in their careful study.
Declining renal function, in the absence of obstructive renal
calculi and nephrocalcinosis, can be related to progressive
hypertension.w"
The reaction of normotensive PHPT patients to pressor
agents has been studied by Rodriguez-Portales and Fardella."
Normotensive parathyroid patients had an abnormal response
to pressor agents (i.e., norepinephrine and angiotensin II)
similar to that found in patients with idiopathic hypertension.
This abnormality persisted 6 months after surgical cure even
if the blood pressure remained within the normal limits.
Lewanczuk and Pang" reported the presence of a parathyroid hypertensive factor (PHF), which is assumed to be
secreted by the parathyroid glands. PHF is a circulating hypertensive factor found in a proportion of patients with essential
hypertension as well as in spontaneously hypertensive rats.
Preoperative values of this factor were raised in hypertensive
patients with PHPT. Patients with PHPT and PHF preoperatively had lower blood pressures after successful parathyroidectomy and PHF levels became undetectable. These
results suggest that the parathyroid gland can express PHF in
humans and that such expression may be responsible for a
proportion of the.high incidence of hypertension in PHPT.52
Middeke and Schrader'" showed that hypertensive PHPT
patients had a normal circadian blood pressure profile with a
normal nocturnal blood pressure fall. The circadian nocturnal
blood pressure profile tends to fall by about 15 mm Hg in
systolic and diastolic readings and was no different from
that seen in normotensive subjects, as opposed to other secondary forms of hypertension (e.g., renal and endocrine
forms of hyperthyroidism, primary hyperaldosteronism, and
Cushing's syndrome).
After successful parathyroidectomy, blood pressure in
hypertensive PHPT patients usually remains mainly
unchanged4.36.37.39.48,49.54-56 and may increase with time. 27,3o,57
Follow-up studies as long as 22 years after successful
parathyroidectomy showed increased hypertension in 9.2%
of symptomatic patients and 13.3% of minimal symptomatic
patients, whereas asymptomatic patients showed no elevation
of blood pressure.t'" The onset of hypertension after
parathyroidectomy in PHPT patients who were normotensive
occurs in 17% to 33% of patients. 21
On the contrary, reversibility in the form of improvement
or normalization of hypertension after parathyroidectomy
has also been observed. Improvement in 20% to 50% of
patients has been reported.27,58-62
Because hypertension only decreases in a few patients
after parathyroidectomy, hypertension is not an indication
for surgery in patients with otherwise uncomplicated mild
PHPT,37.48.49 However, hypertension is more common after
parathyroidectomy in patients who were symptomatic.
Cardiovascular Disease
Another interesting finding is the concurrent incidence of
cardiovascular disease.l'" Cardiovascular complications are
the most common cause of death in patients with successfully treated and untreated PHPT.3,19,20,35 In a follow-up
study of 12.3 years, Hedback and colleagues'? showed that,
of 896 PHPT patients, 294 had died during follow-up. One
hundred-fifty-six patients (53%) died from cardiovascular
disease-50 (32%) patients from myocardial infarction, 44
(28%) from stroke, 53 (34%) from heart failure, and 9 (6%)
from generalized atherosclerosis. Ronni-Sivula" reported
that 23 (68%) of the 34 patients with PHPT who died did so
from cardiovascular disease-l 8 (53%) from cardiac disease,
4 (12%) from stroke, and 1 (3%) from vascular disease
(thrombosis of the mesenteric artery)]. In this study, there was
no difference in the mortality between minimal symptomatic
and asymptomatic patients.
Bondeson and coworkers's reported that 132 (44%) of
300 patients with PHPT had coronary artery disease preoperatively. Langle and associates-' reported that 11 (23%) of
48 patients with minimal symptomatic and 5 (7%) of 77 of the
symptomatic patients suffered from coronary heart disease,
whereas 64 (48%) of 132 showed hypertrophy of the left
ventricular wall. A study performed on 54 patients with PHPT
and 54 age- and sex-matched controls showed a significant
incidence of aortic (63%) and mitral valve (49%) calcifications in PHPT patients compared with the 13% found in the
normocalcemic controls. Metastatic myocardium calcification was noted in 69% of the patients." The full pattern of
cardiac abnormalities, although mild, was exhibited in
asymptomatic patients.P These findings suggest that metabolic disorders occur even in patients with asymptomatic
PHPT and raise the question whether so-called asymptomatic
PHPT actually exists. According to these findings, Smith and
colleagues's found an increased arterial stiffness in patients
with mild to moderate PHPT. This provides a mechanism for
the development of left ventricular hypertrophy in normotensive PHPT patients and is likely to contribute significantly
to both cardiovascular morbidity and mortality. In contrast to
these studies, Barletta and coworkers's found neither pathologic echocardiographic parameters nor an alteration of
the mechanical properties of the brachial and carotid arteries
before or after successful parathyroidectomy in 14 patients
with mild asymptomatic PHPT.
The improved survival after parathyroidectomy raises the
question about whether early operation could influence the
course of these cardiac manifestations. Regression of left
ventricular hypertrophy and a slower progression of cardiac
calcifications has been documented postoperatively.W"
Some investigators believe that elevation of cytoplasmic
calcium increases aortic pressure, elevated wall tension, and
adrenergic stimulation'" and results in cardiac hypertrophy.
Because all the hypertensive patients in the study by
Stefenelli and associates's had antihypertensive therapy and,
therefore, had a mean resting blood pressure similar to that of
the nonhypertensive patients, the higher incidence of hypertrophy is likely to be a consequence of elevated PTH or
calcium concentrations rather than a consequence of raised
blood pressure. This finding may explain the reversibility of
cardiac hypertrophy after parathyroidectomy.

Endothelium-independent vasodilation was found to be
impaired in PHPT patients without clinical evidence of
coronary heart disease compared to normocalcemic control
subjects. 68,69 In a follow-up study," the restoration of normocalcemia by parathyroidectomy could not improve the vascular reactivity, but on the other hand, no further progression
of vascular disease could be seen.
Despite evidence from long-term follow-up, it is still
controversial as to whether parathyroidectomy significantly
decreases the morbidity and mortality associated with
hyperparathyroidism.V" A 15-year follow-up of operated
and unoperated PHPT patients showed that mild PHPT is
associated with an increase in blood pressure with age.
However, this particular study showed aggravation of hypertension after parathyroid surgery.'?
Hedback and associates'S" reported an increased risk of
premature death in patients after parathyroidectomy in all age
groups, with the highest relative risk of death occurring in
patients between 55 and 70 years of age. The risk in younger
patients and in those with less severe disease returned to a
normal survival curve most quickly after successful parathyroidectomy. There was also a shift from an increased risk of
death toward a normal risk of death as time passed after surgery, indicating a positive effect of parathyroidectomy on survival. Over the years, there has been a change in trend toward
a more rapid normalization of the risk of death (i.e., approximately after 5 years if the patient was operated on in 1980, but
not until after 9 years if operated on in 1975). This effect
appears to be due to the increased number of mild cases in the
more recent series that benefited from early detection and
treatment. This study indicated that patients with PHPT of
shorter duration have less risk of death. In a further study," the
same authors showed an increased risk of death for patients
undergoing surgery for mild or moderate PHPT in Sweden
between 1987 and 1994. The recent publication of their longterm findings showed "a 50% increased death risk of hypertensive hyperparathyroid patients compared with that of the
normotensive patients, but the yearly death risk decrease after
surgery for the hypertensive patients was almost doubled as
compared with the decrease of the normotensive patients.
Cardiovascular disease was directly related to serum calcium
level, adenoma weight, osteitis fibrosa, and serum creatinine
and inversely related to glomerular filtration rate and urine
osmolality'T
In another follow-up study of 14 years, the overall survival
in 172 untreated hypercalcemic subjects with mild hyperparathyroidism was lower than that of the matched normocalcemic subjects. This trend became obvious within 5 years of
presentation." These results support the recommendation for
parathyroidectomy for virtually all patients with PHPT.
Psychiatric Symptoms
Several authors have documented the common occurrence of
nonspecific symptoms such as weakness, fatigue, and mental
depression in PHPT.7,24,25 A wide spectrum of psychological
symptoms ranging from mild personality changes to severe
depression and psychosis has been described. These psychiatric symptoms develop in PHPT patients irrespective of the
serum calcium level. Joborn and colleagues" reported that
hypercalcemic patients with asymptomatic PHPT (i.e., no

kidney stones or osteitis fibrosa cystica) presented with
similar although less pronounced psychiatric disturbances as
did patients with symptomatic PHPT,
Confusion and delirious states sometimes dominate the
clinical picture and occur in about 5% of cases. 75-79 Peterson"
correlated the level of hypercalcemia to the severity of the
psychiatric symptoms. He also reported the return to the premorbid mental status postoperatively. Personality changes
and affective disturbances were associated with plasma calcium levels of 12 to 16 mg/elL (3 to 4 mmol/L). Acute organic
brain syndromes with altered levels of consciousness, paranoid ideation, and hallucinations were noted at plasma calcium levels of 16 to 19 mg/elL (4 to 4.5 mmol/L)." However,
even slight increases in the serum calcium and PTH levels
may produce serious psychiatric symptorns.Y'" Joborn and
colleagues" reported that 10 of 13 patients with organic brain
syndrome had senile dementia. Twelve of these patients were
admitted to a mental hospital. Eight of these patients
improved after parathyroidectomy, and 7 of them were able to
return to their homes. The postoperative improvement was
related to the duration of the mental symptoms. All 8 patients
who improved had a clinical history of dementia of fewer than
2 years. Patients with a longer history of mental illness were
likely to recover. These studies document that impressive psychological improvement can occur after successful parathyroidectomy in patients with PHPT.81,82
Psychosis involves the disturbance of thought content,
thinking processes with perceptual aberrations, paranoid
or persecutory ideation, and delusions." Hallucinations and
delusions have been reported to occur in about 10% of
patients who have psychiatric symptoms,?6,83 Recovery from
paranoid states after parathyroidectomy becomes evident
after 48 hours."
Solomon and coworkers'" showed that all 18 patients suffering from PHPT had clinical multidimensional psychological distress in the individual areas of obsession-compulsion,
interpersonal sensitivity, depression, anxiety, hostility, psychosis, sleep disturbance, and lack of concentration."
Depression and lethargy are the most common characteristics experienced by this group of patients.80 An improvement
approaching normal was achieved 1 month after surgery.
Solomon and coworkers'" found no group differences for
somatization and phobic anxiety before and after parathyroidectomy in their 18 patients. Clark and associates.s'
however, did document more symptoms in patients with PHPT
and resolution of somatic symptoms as well as neuropsychiatric symptoms after parathyroidectomy. No correlation was
found between the clinical symptoms and the biochemical
constellation.rv"
Serious depression is noted in about 10% of patients with
PHPT and may be associated with headache (Table 42-4).76
Fatigue normally develops first. Anxiety, depression, and
irritability have been noted in up to one third of cases.P
The severity of psychiatric symptoms is not linearly related
to the degree of hypercalcemia or to PTH values/" The psychological symptoms generally begin to improve within
1 month after successful parathyroidectomy.5,ll,21,24.25,75,80,85,86
Disturbances in monoamine turnover have been documented in patients with PHPT and psychiatric syrnptoms.f-"
The cerebrospinal fluid (CSF) concentrations of total and
ionized calcium were higher in 22 unselected PHPT patients.

CSF concentrations of PI'H were also higher than in the reference group; monoamine metabolites 5-hydroxyindoleacetic
acid (5-HIAA) and homovanillic acid were lower. 5-HIAA
correlated inversely with CFS ionized calcium. Endogenous
depression has been reported to coincide with lowered
monoamine metabolites. The central neurotransmitter activity
might be influenced by the higher calcium concentrations
present in the CSF. Sedation and depression have also been
associated with higher CSF calcium concentrations." The
precise neurophysiologic reasons for the psychological
changes have yet to be clarified, although it has been
suggested that excess PI'H enhances the permeability of the
blood-brain barrier, raising the CSF concentration of calcium,
albumin, and urate. After successful parathyroidectomy, both
total and ionized CSF calcium decrease." Postoperative
follow-up shows major improvements in anxiety, cognition,
depression, fearfulness, and confidence.
Preoperative electroencephalograms obtained from seven
patients with asymptomatic PHPI' and mild from hypercalcemia were generally abnormal, showing a shift of frequencies toward abnormal slower frequencies 7 Hz; normal
range is >9 Hz).89 All seven patients had normal electroencephalograms 3 to 5 months postoperatively. However, this
small group of patients showed no consistent postoperative
improvement in any of the psychological parameters,
although patients with secondary hyperparathyroidism
did.89 A biochemical relationship was not found.t"
In a recent study, Prager and colleagues?" demonstrated a
significant improvement of the patients' cognitive performance (concentration, retentiveness) by parathyroidectomy,
applying standardized psychological tests. No correlation
between the improvement of concentration/retentiveness
and the serum calcium and PI'H levels, age, and gender was
found in this study.
Pasieka and coworkers?' developed a patient-based surgical outcome tool. They found a significant improvement in
the quality of life and self-rated health after parathyroidectomy in patients suffering from PHPI'; these findings were
confirmed by Sheldon and coworkers'? using the Short Form
Health Survey (SF-36).
Neuromuscular Disease
Neuromuscular disease mainly manifests itself as fatigue
and weakness, especially in the proximal muscles of the
lower extremities.v" Aching muscles, paresthesias, and
unsteadiness of gait have also been reported.V? The incidence

of these symptoms varies from 30% to 80%,83,93 probably due
to the criteria used, diligence of the respective observers,
and patient selection.
Muscle weakness and fatigability are subjective symptoms. Both symptoms can be explained by decreased muscle
strength on the one hand or lack of mental energy from
depression and lethargy on the other hand. Hedman and
associates?" studied an unselected series of PHPI' patients to
assess the association between these symptoms and muscle
strength before and after surgery, A significant increase in
the isokinetic strength of knee extension and knee flexion at
higher angular velocities was found 3 months after surgery,
suggesting that type II (fast twitch) muscle fibers were
predominantly affected. The results of this study support the
clinical impression that PHPI' surgery is beneficial to patients
with muscular symptoms.rv" Joborn and colleagues."
however, were unable to find any significant abnormalities
of nerve conduction velocity or neuromuscular transmission
in unselected PHPI' patients."
Joborn and coworkers documented that even patients
with mild to moderate HPI' without apparent muscular
symptoms had impaired muscle function. Reinvestigation
6 months postoperatively showed improvement in only
one patient who had severe preoperative muscular symptomatology.P-" A 1988 study" showed no significant difference in muscle strength between those patients with
subjective impairments and the control patients. Seven
months postoperatively, the PHPT patients had increased
their muscle strength by 8%. These studies demonstrate that
patients with PHPI', especially those with neuromuscular
symptoms and muscle weakness, improve their muscle
strength slightly after parathyroidectomy.
Patten and associates'" concluded, on the basis of
the clinical, electromyographic, and biopsy evidence, that
the neuromuscular abnormality in PHPI' is probably neuropathic in origin." Electromyograms of 12 patients showed
short-duration, low-amplitude motor unit potentials in some
patients and abnormally high-amplitude, long-duration
polyphasic potentials in others. Motor nerve conduction
velocities and distal sensory latencies were normal. The
major finding on muscle biopsy was atrophy of both type I
(slow twitch) and type II muscle fibers, with type II fibers
being more extensively involved. With the restoration of
normocalcemia, neuromuscular symptoms improved within
days to weeks after surgery.88
In contrast, Turken and colleagues" demonstrated that 22
(52%) of 42 patients had neuromuscular symptoms consisting

either of muscle cramps (45%), paresthesias (45%), or both
(18%). No patient showed classic hyperparathyroid neuromuscular disease (muscle weakness, atrophy, hyperreflexia, abnormal gait, or tongue fasciculations). Electromyographic and
nerve conduction studies were performed in 9 patients with
neurologic abnormalities." None showed myopathy or signs
of motor unit denervation. These results differed significantly
from those reported earlier," There is clearly a trend toward
subtle, earlier neuropathy that also manifests itself among socalled asymptomatic patients. Unfortunately, Turken and colleagues did not report the postoperative results."
Carbohydrate Metabolism
It has been frequently reported that PHPT patients have a
higher risk of developing impaired glucose tolerance or diabetes mellitus. 315,16,18,99 Hyperinsulinemia in patients with
PHPT suggested that these patients have a reduced insulin
sensitivity and therefore impaired glucose tolerance. lOO- 105
Several studies have shown that up to 8% of patients with
PHPT suffer from diabetes mellitus as compared with 2% of
normocalcemic patients (Table 42_5).16,18,99,106,107
Whether diabetes mellitus itself is associated with the metabolic abnormalities in PHPT alone or with other known risk
factors such as age, obesity, and hypertension is uncertain.
Kumar and colleagues 108 showed that PHPT patients have a
higher tendency to develop diabetes mellitus in the absence
of the earlier mentioned risk factors. Those PHPT patients
with impaired glucose tolerance are also likely to have
reduced beta cell function. Reduced beta cell function may
be a result of the direct effects of PTH and calcium on beta
cells, reducing insulin-secretory capacity.'?' Patients lacking
adequate beta cell function may therefore acquire overt diabetes because of the reduced capacity of insulin secretion.
On the other hand, other studies in nondiabetic hyperparathyroid patients have shown no major change in glucose
tolerance in the presence of hyperinsulinemia, suggesting a
state of insulin resistance. 101.105.110
A complete understanding of the pathophysiologic mechanisms responsible for the disturbed carbohydrate metabolism in patients with PHPT is not yet known. Downregulation
of the insulin receptor has been shown to be present in
patients with PHPT. Hyperinsulinemia with mild suppression
of endogenous glucose turnover after a glucose load test
seems to explain this phenomenon.l'<'!'
In ViV0 1l2 and in vitro!" studies have indicated that PTH

also has a stimulatory effect on hepatic glucose production,
necessitating a compensatory augmentation of beta cell insulin
production. Although Bevilacqua and coworkers 114 failed to
detect any effect of acute PTH administration in dogs on
hepatic or peripheral glucose metabolism, acute exposure of
the pancreatic islets cells to PTH has a direct effect on glucoseinduced insulin secretion. 109 This effect was modulated by an
increase in cytosolic calcium.l'" whereas chronic administration of PTH was associated with inhibition of insulin release.l"
Hellman I 16 was able to demonstrate the positive influence
of hypercalcemia on glucose-induced insulin secretion and
on insulin secretion independent of glucose and, therefore,
the induction of hyperinsulinemia.
Hypophosphatemia might also contribute to the insulin
resistance and downregulation of insulin receptors in patients
with PHPT. In vivo glucose studies have shown a decrease in
insulin-induced peripheral glucose uptake under hypophosphatemic conditions. I 17
Kautzky-Willer and colleagues'P? showed that after
parathyroidectomy in patients with PHPT, severely impaired
insulin resistance definitely improved. Basal as well as
stimulated insulin secretion levels are reduced after parathyroidectomy, although both values fail to return to normal.
An improvement in insulin sensitivity also occurred in nondiabetic PHPT patients after parathyroidectomy, whereas
normalization of insulin secretion was observed only in
patients with normal glucose tolerance. l OO ,103
The normalization of biochemical abnormalities, especially
that of calcium, has a much greater impact on insulin sensitivity than on insulin secretion. 100 Postoperative correction of the
hypercalcemic state leads to an increased insulin sensitivity
and, therefore, to the possibility of severe hypoglycemia in
insulin-dependant diabetes. 15,118 Improved metabolic control
was achieved in 27% of patients with PHPT after parathyroidectomy.P Prager and associates 102 also showed partial
improvement in glucose utilization after parathyroidectomy.
These patients were clinically symptomatic, and this might
explain the more pronounced disturbance of carbohydrate
metabolism.
Despite the factors just mentioned, Ljunghall," Bannon, I 19
and their coworkers found no significant changes in the
requirement for insulin in insulin-requiring diabetics after
parathyroidectomy.
Valdemarsson and associates'j" found 26.4% of their study
population to have some form of impairment of glucose
metabolism compared to a 4% to 6% prevalence of noninsulin-dependent diabetes in a well-defined region in their

country, suggesting a more frequent disturbance of glucose
metabolism in patients suffering from PHPT. In this study, a
significant decrease of glucose in patients with unknown
diabetes or impaired glucose tolerance could be shown.
In summary, PHPT worsens coexisting diabetes mellitus.
PHPT is associated with an abnormal glucose metabolism as
a result of alterations in insulin sensitivity, as well as changes
in endogenous glucose turnover and beta cell secretion.
Parathyroidectomy corrects some of these biochemical
parameters, mainly insulin hypersecretion and insulin resistance, but it only partially ameliorates the metabolic state.
Lipoprotein Metabolism
Discrepant findings on lipoprotein metabolism in PHPT
include increased and decreased levels of serum triglycerides,
decreased serum cholesterol, increased serum very-lowdensity-lipoproteins (VLDL), and no changes at all.121-124
Hagstrom and colleagues-" found decreased high-densitylipoprotein (HDL) cholesterol, increased total triglycerides,
and VLDL cholesterol, and an elevated atherogenic index in
patients with mild PHPT. Parathyroidectomy normalized the
dyslipidemia within 1 year. Five-year surveillance of PHPT
patients without treatment was found to be associated with a
maintained increase in total triglycerides and the atherogenic index and a decrease in HDL cholesterol levels. These
findings favor operative intervention rather than conservative surveillance, even in patients with asymptomatic, mild
PHPT. It has also been reported that increased PTH levels
both in vivo and in vitro increase lipolysis, perhaps causing
the elevated VLDL levels. 126. 127
In a further study, Valdemarsson and coworkers'P found
9.2% of their patients with PHPT to have preoperative
hypertriglyceridemia. They did not observe any significant
changes of the mean cholesterol or triglyceride levels in
their patients 1 year after operation, but they did find a
significant decrease of triglycerides in the male subgroup.
The authors speculated that this difference could be related
to the activity of lipoprotein lipase, a key enzyme in triglyceride degradation known to be affected by insulin.
Hyperuricemia
Hyperuricemia occurs frequently in PHPT. Auerbach and
associates' showed that 22 (32%) of 56 patients had uric
acid concentrations greater than 7 mg/dL. Postoperatively,
there was no significant change in 6 patients (27%). In
14 patients (64%), the serum level fell by more than
1 mg/dl..?? Duh and colleagues'? reported similar findings in
a larger group of patients. An increased concentration of
urate in PHPT has been described by several authors. 1?128.129
Valdemarsson and coworkers-" found a significant
decrease of serum urate among men and women 1 year after
successful surgery for PHPT. Furthermore, they showed a
significant correlation between ionized calcium and intact
PTH and urate, indicating an influence of PTH on urate
metabolism. In a further study, Westerdahl and associates'P
found urate to be an independent risk factor for the presence

of clinically relevant atherosclerotic disease in patients
with PHPT.
Chondrocalcinosis and
Pseudogout
Chondrocalcinosis is defined as the deposition of calcium
salts in articular hyaline cartilage and fibrocartilage.P' This
study showed that most patients were asymptomatic (21 of
71 [30%]) and that only 4 (5.6%) of 71 had intermittent
attacks of pseudogout. Chondrocalcinosis and pseudogout
are said to be sufficiently frequent (3.8%) in hyperparathyroidism such that screening of such patients is warranted.P?
Occasionally, pseudogout is the initial manifestation. It is
characterized by arthritis and pain in one or more joints
associated with the presence of calcium pyrophosphate
dihydrate crystals in the synovial joint fluid. Acute attacks
of pseudogout arthritis may be precipitated by transient or
rapid changes in the serum calcium concentration. A rapid
change in calcium concentration is often seen after successful
surgery, causing attacks of pseudogout, which may complicate the postoperative clinical picture. Unlike the predominance of gouty arthritis, pseudogout rarely involves the
foot. The most common joint involved is the knee; less
commonly involved are the elbows, wrists, and ankles.
Radiographic features of chondrocalcinosis include calcification of articular cartilage and joint effusion that may be
characteristic enough to suggest PHPT. Identification of the
crystals through aspiration is diagnostic for pseudogout.
A series of eight patients in whom pseudogout arthritis
developed as the initial clue to PHPT had no further arthritic
complaints 6 weeks postoperatively.-" In the same study,
12 patients developed pseudogout acutely after parathyroidectomy. Nonsteroidal anti-inflammatory analgesics brought
relief from these symptoms.P? It seems that parathyroidectomy prevents the progression of chondrocalcinosis and
in general relieves symptoms, although acute episodes of
pseudogout and gout may occur after parathyroidectomy,
usually at the nadir of postoperative hypocalcemia.
Summary
Neither the degree of hypercalcemia nor the degree of
PTH serum level determines the metabolic complications
in patients with PHPT. Insidious abnormalities occur in
renal function, bone, carbohydrate and lipid metabolism, uric
acid metabolism, and cardiovascular metabolism. Beneficial
results of parathyroidectomy are unfortunately limited by
the degree of irreversible organ damage that occurs prior to
parathyroidectomy. Therefore, some of the associated manifestations such as renal disease and hypertension become
irreversible and may be progressive, despite successful
parathyroid surgery.3.4.20.21,133
Untreated PHPT also carries an increased risk of death,
particularly from cardiovascular diseases.!" This risk
gradually decreases with time after parathyroidectomy,
and surgery is the only therapy proven to be curative for
PHPT.14,35,134

Surgical treatment for patients with asymptomatic, minimally symptomatic, and symptomatic hyperparathyroidism
may prevent the consequent development of complications
such as renal impairment or hypertension and relieve neuropsychiatric disorders, glucose intolerance, and other clinical
manifestations.P'r" Asymptomatic patients appear to receive
the same metabolic benefits on bone and renal dysfunction
as well as other clinical manifestations as do symptomatic
patients, and they return more quickly to a normal life
expectancy after successful parathyroidectomy.19,24,25,71,l35,136
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Natural History of Treated

Lars-Erik Tisell, MD, PhD
In 1925, Mandl of Austria performed the first operation for primary hyperparathyroidism (PHPT).I His patient had sustained
a spontaneous thigh bone fracture and was immobilized. Three
months after a parathyroid adenoma had been excised, the
patient could walk with crutches. The effect of the operation
was conspicuous. During the next 4 decades, most patients
with PHPT continued to have obvious symptoms relieved by
surgery.
In the mid-1960s, the number of operations for PHPT
started to increase in most centers. This also happened at our
hospital, but the number of patients with substantial disease
remained remarkably constant.' In patients with mild hypercalcemia, with few or no symptoms, it is difficult to register
any immediate positive effects of surgery. Therefore, controversy exists as to whether surgical therapy should be used in
such patients. In one study, one third of the population of
asymptomatic patients had silent complications such as premature osteopenia and abnormal renal function.' Martin and
colleagues" found that the bone loss of mineral content as a
result of PHPT is only partially reversible. However, at that
time, they and others' believed that surgery for PHPT should
not be undertaken solely to prevent osteoporosis. The results
of some studies suggest an improvement of muscle strength
and psychiatric symptoms after surgery for mild PHPT.6.7
Other observations indicate increased morbidity and mortality
among patients with mild hypercalcemia who are observed
without surgical treatment. 8 Some studies suggest that PHPT
may cause lasting damage, resulting in increased morbidity
and mortality for a long time after the parathyroid surgery.':"
If PHPT is indeed a risk factor for increased morbidity and
premature death, a positive attitude toward early surgery is
indicated for patients with asymptomatic PHPT.
Mortality after Surgery for Primary

Hyperparathyroidism
Three Scandinavian studies examined long-term mortality
after surgery for PHPT. Basic data from the three
Scandinavian series are given in Table 43-1. The first two
series included patients who had been treated during the
same 24-year period.v'? The third series included more

patients than the other two together and covered a 30-year
period. This series also had the longest follow-up. I 1-13 In the
Helsinki study, for the first time, the long-term mortality
after surgery for PHPT was compared with that in contemporary control subjects matched for gender and age.?
Surgical Complications and Cure of Primary

Hyperparathyroidism
None of the series provided information regarding recurrent
nerve palsy. Postoperative hypoparathyroidism occurred in
3.4% of the patients in the Uppsala series." In the Goteborg
series, hypoparathyroidism occurred in 2.45%. After exclusion
of patients who underwent reoperation, patients with multiple
parathyroid gland disease, and patients with concomitant
thyroidectomy for thyroid tumor, only three patients who
experienced hypoparathyroidism remained in the Goteborg
series. This shows that hypoparathyroidism is a rare complication in patients with a single parathyroid adenoma. I I The
cure rate of PHPT among the survivors at the time of followup was 94% in the Helsinki series" and 91% in the Uppsala
series.'? In the Goteborg series, the cure rate was 97%,
defined as a stable serum calcium concentration of less than
2.55 mmollL during the first postoperative year. I I
Postoperative Mortality
Two of the series supplied information about the mortality
within 1 month after surgery (Table 43-2). In the Goteborg
study, the mortality for the first half of the series was 1.56%.
During the last half of the series, only 1 of 448 patients
(0.22%) died postoperatively. II
Long-Term Mortality
In the Helsinki series, patients undergoing surgery for appendicitis, varicose veins, or hemorrhoids and matched for age
and gender were used as control subjects." In the Uppsala
and Goteborg studies, patients were assigned to control
groups on the basis of Swedish population statistics and were
413
matched for gender, age, and calendar year of surgery.IO12

During 5 years of observation, the increased mortality in
the Helsinki study was 3.9% of the PHPT population (see
Table 43-2). The relative risk (RR) of death compared with
control subjects was 1.62, with a 95% confidence interval (CI)
of 0.91 to 2.94 (Table 43-3). The increased mortality among
the PHPT patients was significant (P < .05) (Table 43-4).9 In
the Goteborg study, the observed mortality was increased by
13.2% in the PHPT population compared with the expected
mortality after a follow-up period of 12.9 6.1 years. The RR
was 1.67 and the CI was 1.49 to 1.87. The increase in mortality was highly significant (P < .001).11 In the Uppsala study,
the relative cumulative survival ratio between observed
survival for the PHPT patients and the expected survival was
below I throughout the follow-up period. The decrease in survival after surgery for PHPT was statistically significant only
for females between 4 and 12 years after surgery. The survival
rate was reduced by 4% after 14 years. The approximate RR
in the Uppsala study was 1.45 (see Table 43-3) as calculated
on the basis of available data from Palmer and coworkers. 10
The RR represents the ratio between the death hazard
functions of the PHPT group and those of the controls. The
quotient is a function of time after surgical treatment. In the
Goteborg series, it was shown that the RR decreased with
time after surgery," In this presentation, the RR is presented
as one figure for each series (see Table 43-3). This figure is
the mean of the quotients in an interval of postoperative years.
The Helsinki, Uppsala, and Goteborg studies involved
patients undergoing surgery for PHPT at the three hospitals
during the study periods. The three studies showed increased
long-term mortality after surgery for PHPT.9.ll In the largest

study with the longest follow-up, the increased mortality was
13.2% of the PHPT population (118 patients).'!
Risk Factors
In the Goteborg study.P it was found that age, calendar year
of surgery, and time elapsed since surgery were significantly
(P < .00 I) and independently correlated with the risk of death
(Table 43-5). The importance of calendar year of surgery and
time elapsed since surgery is exemplified in Figure 43-1 by
patients who were 65 years old at surgery. The RR was twice
as high in 1965 as in 1980. For patients operated on in 1965,
it took 12 to 14 years before the RR returned to a normal
survival curve, whereas in patients operated on in 1980 it
took approximately 5 years. The serum calcium concentrations were positively related to the risk of death (P < .01).
Both the preoperative serum calcium and serum creatinine
concentrations decreased continuously (P < .001) during the
period from 1953 to 1982. Consequently, patients operated
on during the early years of the study had a more severe disease. This explains in part why an early calendar year could
be a risk factor for premature death. The RR of death was
raised in all age groups, but patients 55 to 70 years of age
at surgery had the highest RR. It was thought that young
people had a better restorative capacity and that the aged had
many other risk factors, making the risk of PHPT relatively
less important. The increase in RR was less pronounced as
time passed after surgery but was a consistent finding in all
age groups.
Natural History of Treated Primary Hyperparathyroidism - -
In the Uppsala study," serum calcium concentrations and

year of surgery did not influence survival. In the Helsinki
study," serum calcium concentrations were significantly
higher (P < .01) in patients who died than in other patients.
In this study, it was noted that the mean parathyroid adenoma
weight was higher in the patients who died during follow-up.
In the Goteborg series, 13 the weight of the parathyroid adenoma was found to be a predictive factor for the risk of death
(P < .001). In the series of713 patients with a single adenoma,
the adenoma weights ranged from 75 to 18,100 mg. The
median adenoma weight was 610 mg. The adenoma weight
at the 20th percentile was 267 mg and at the 80th percentile
was 1625 mg. An increase in parathyroid weight from 267 to
1625 mg implied an increase in mortality of 57%. Adenoma
weight was significantly correlated with the risk of death
(P < .01) even when the influence of the serum calcium concentration had been eliminated. In all other studies and analyses concerning long-term survival, the PHPT populations had
been compared with control subjects. In this analysis, for the
first time, an increased mortality in the PHPT population
415
could be shown by using a factor bound to PHPT itself. This

provides strong independent support for the results of the
previous studies.
Causes of Death
In all three studies,":'! increased mortality from cardiovascular disease was found among the PHPT patients (Table 43-6).
The increased mortality was statistically confirmed in the
Op 1965
Op 1970
Op 1975
Op 1980
Relative Risk
3.5
F..;",,;,...-----------------:l
3.0
2.5
2.0
................
1.5
"
" "
----------------------==--', ----
"
1.0
Op
10
15
Time after surgery, years
FIGURE 43-1. Chart showing the association between a later year

of operation, a lower relative risk for death, and a more rapid postoperative return to the normal survival curve. This figure represents
patients who were 65 years old at the time of surgery for primary
hyperparathyroidism. (From Hedback G, Oden A, Tisell LE. The
influence of surgery on the risk of death in patients with primary
hyperparathyroidism. World J Surg 1991;15:400.)
Helsinki (P < .05) and Goteborg (P < .00l) studies. In the

Goteborg series, 157 patients, or 63 more than expected, died
from cardiovascular disease during the follow-up period. In
the Helsinki study, 15 more patients than control subjects died
from cardiovascular disease. The follow-up studies did not
add any information on the mechanisms causing the increased
mortality in cardiovascular disease. However, it is interesting
that echocardiographic studies have shown a high incidence
of left ventricular hypertrophy in patients with PHPT.16,17 In
one of these studies, a significant partial regression of the left
ventricular hypertrophy was noted 12 months after cure of
PHPT.17 Other data have suggested that the echocardiographically measured left ventricular mass is a strong predictor of
cardiovascular morbidity and mortality.lv'?
A significant increase (P < .(01) in death from malignant
disease was found only in the Goteborg study. In that study,
72 patients died of malignant diseases (i.e., 27 more than
expected). These malignancies were of 24 different types.
Adenocarcinoma of the pancreas, including the papilla of Vater
region, was the only tumor that occurred in a significantly
increased number (P < .05).11 Table 43-6 shows the percentages of the three main causes of death. It was found that the
percentage of patients who died from malignant disease
increased with the length of follow-up (see Table 43-1). In the
Goteborg study, the long observation time with many deaths
helped to detect the association between PHPT and death from
malignant disease. The results of the other studies with shorter
follow-up periods do not conflict with the observation in the
Goteborg study. A link between PHPT and malignant disease
had previously been found in a series of 4163 persons who had
been reported to the Swedish Cancer Registry because they had
surgery for parathyroid adenomas." It is also interesting in this
connection that hypercalcemia can induce mitotic activity.2 1,22
Renal disease was the third most common cause of death.
In the Goteborg series, 21 of the 25 deaths from renal disease occurred during the first half of the series. The decrease
in mortality from renal disease is not only an effect of early
surgery for PHPT but also a result of better treatment of
patients with renal stones, impaired glomerular filtration
rate, or renal infections.
General Discussion
In view of the high prevalence figures for PHPT found in
population studies, it is apparent that only a proportion of all
subjects with PHPT are surgically treated. 23,24 This is also
true in the city of Goteborg, where the medical community

has a liberal attitude toward PHPT surgery.
Subjects who are under medical care for other diseases
are more likely to have PHPT diagnosed and treated. This
means that a possible bias has been introduced in all three
Scandinavian studies. In the Goteborg study, this possibility
was considered.'! A selected series was formed by excluding
171 patients who had their PHPT diagnosed during treatment or follow-up for a disease that could cause increased
mortality. These diseases were myocardial infarction, heart
failure, arrhythmia, hypertension of more than 2 years' duration
before detection of raised serum calcium concentrations,
stroke, diabetes, and malignant tumors. In the selected series,
the mortality was still significantly higher than expected
(P < .(01), as was the mortality from cardiovascular (P < .00 l)
and malignant diseases (P < .01). The RR in the selected
series was 1.43, with a CI of 1.23 to 1.64 (see Table 43-3).
The increased mortality in the selected series during the
observation period was 7.8% of the PHPT population, which
was 5.4% less than in the total series (see Table 43-2). From
the analyses of the selected series, it is obvious that PHPT
by itself is associated with an increased risk of premature
death from cardiovascular and malignant diseases.
Ninety-two percent of the exclusions had been made
because of the very two diagnoses that in the selected series
had been significantly linked to the increased mortality among
PHPT patients. This suggests that when forming the selected
series, some patients could have been incorrectly excluded
and that the correct value for mortality from PHPT in the
total series should be between 7.8% and 13.2%. The total
series shows the risk of premature death in all patients who
undergo surgery for PHPT. The selected series shows the
minimum value for the increased risk of death caused by
PHPT itself. The selected series proves that PHPT causes
irreversible damage to the body. In a separate study, it was
found that the parathyroid adenoma weight was a highly significant predictive factor for the risk of death. This finding
was made in the PHPT series itself without using any control
subjects. This independent observation strongly supports the
association between PHPT and premature death. 13 Premature
aging could be a possible explanation for the premature
deaths from cardiovascular and malignant diseases. The
observation that women with PHPT on average experience
menopause 4.5 years earlier than control subjects supports
this hypothesis.P
The severity of PHPT is usually classified by the serum
calcium concentrations. In a 1991 study, asymptomatic and
symptomatic PHPT patients had similar preoperative serum
calcium concentrations." These findings suggest that serum
calcium alone is not responsible for the severity of PHPT.
An increase in serum calcium concentrations over that found
at diagnosis is seldom found in untreated PHPT patients,
even if they are monitored for a long time. 24,27 This means
that the duration of the disease can differ considerably among
patients with the same serum calcium concentrations, The
possible role of duration of disease is seldom mentioned when
discussing the morbidity of PHPT. A long-term, prospective,
randomized study with two arms, surgery and nonsurgery, is
needed to obtain more exact information about the impact of
PHPT duration on morbidity and mortality. For ethical reasons, only asymptomatic patients can be included in such
Natural History of Treated Primary Hyperparathyroidism - - 417
a study. In a previous study of patients with asymptomatic

PHPT, there was a waning interest on the part of many patients,
making it difficult to continue the study." The experience from
that study suggests that a prospective, randomized study
aimed at defining the influence of PHPT duration on longterm survival is not easily undertaken.
The Goteborg study covered 30 years." During the early
part of this period, serum calcium determinations were not
routinely done for ambulatory and hospitalized patients, and
PHPT was considered a rare disease. Therefore, at that time,
the duration of the disease before surgery was probably much
longer than during the end of the period, when serum calcium determinations were routinely done. The longer duration of PHPT could have contributed to the higher mortality
found during the early period of the study. However, the
patients then usually had higher serum calcium concentrations than later, and we know that a high serum calcium concentration is a risk factor for mortality (see Table 43-5). Using
a survival test, it was found that the relationship between
calendar year and risk of death was significant even when
the influence of the serum calcium concentrations had been
eliminated. 12 This suggests that calendar year of surgery was
associated with another risk factor besides the high serum
calcium concentration. From this reasoning, it seems logical
to assume that the extra risk factor associated with early
calendar year is long duration of PHPT.
It is impossible to estimate the exact duration of PHPT
before diagnosis, but the size of a parathyroid adenoma must
be related to the time of its growth and hence to the duration
of PHPT. This should be true even if there are observations
suggesting that both cell division and parathyroid tumor
growth decline during the life span of the tumor," As mentioned, in the Goteborg studies, it was found that the parathyroid adenoma weight was a highly significant predictive factor
for the risk of death after cure of PHPT.13 The adenoma weight
and the serum calcium concentration were significantly
correlated (P < .001). When the influence of the adenoma
weight had been eliminated, the serum calcium concentration did not show any correlation with the risk of death. On
the other hand, adenoma weight was significantly correlated
with risk of death even when the influence of the serum
calcium concentrations had been eliminated (P < .01). These
calculations show that the parathyroid adenoma weight is a
more powerful predictive factor for increased mortality than
the serum calcium concentration. 13 A plausible hypothesis to
account for this observation is that patients with heavier
adenomas had a longer duration of PHPT before they were
operated on and were, therefore, subjected to more severe
and more lasting damage. In the Goteborg study, a shift from
an increased risk of death to a normal risk occurred as time
passed after surgery.P This positive effect of surgery was
most apparent in recent years, when there was a more positive attitude to the diagnosis and treatment of PHPT. For
65-year-old patients operated on in 1980, it took about
5 years for the survival curve to return to normal. Thus, in
untreated patients with PHPT, the risk of death increases
with time, whereas after surgical cure of PHPT the risk
decreases with time. These observations are strong arguments for early surgery in patients with PHPT.
The risk of increased cardiovascular morbidity and premature death in PHPT has also been discussed in several
other studies. Grey and colleagues found that postmenopausal

women with mild asymptomatic PHPT had increased body
weight and total body fat mass and also a more android
fat distribution than age-matched control subjects. They
thought that these findings could be relevant to the increased
incidence of cardiovascular disease in PHPT.29 A large
Danish study showed that patients operated on for PHPT had
an increased incidence of myocardial infarcts up to 10 years
before surgery. This risk fell to a normal level after surgery.
In this study, mortality after surgery was higher than in the
general population between 1979 and 1990 but not between
1991 and 1997.30 In a German series, 383 patients with PHPT
were observed prospectively after surgery during a period of
10 years. It was found that the mortality in the study population was significantly higher than in the control subjects. The
prevalence of patients with symptomatic PHPT in this series
was 94%.31 In an interesting study, it was found that increased
cardiovascular mortality was found in patients with mild
hypercalcemia followed up for 25 years." In another study, it
was found that higher serum calcium by itself was associated
with increased risk for premature death. The mortality rate in
relation to a single serum calcium value was examined in a
large population during a mean follow-up of 10.8 years. It was
found that men who were younger than 50 years and had
serum calcium values greater than 2.45 mmollL had an
increased mortality of 20% compared with those with lower
serum calcium levels; those with serum calcium greater than
2.60 mmollL had a doubled risk rate. The excess mortality was
largely attributable to cardiovascular diseases but also to a significant excess mortality because of malignant disease.P
In Europe, several studies have shown an increased risk
of premature death in patients operated on for PHPT. Such
results were not obtained in studies conducted in the United
States at the Mayo Clinic. The patients in the Mayo Clinic
series were operated on from 1980 to 1984, and 43% of the
1052 patients in the series had symptomatic PHPT.34 In
1974, a screening program was started at the Mayo clinic,
for the early detection of patients with PHPT using routine
measurements of serum calcium levels. This program was
still ongoing when the 1052 patients referred to above were
diagnosed with PHPT. In any 3-year period, more than 90%
of Olmsted County residents had at least one measurement
of serum calcium level. 35 The patients in the Goteborg series
had surgery from 1953 to 1982. Clinical data for the first
274 patients in this series were published in 1973. 36 Eightyseven percent of these patients had PHPT with classic
symptoms, and 20 of the 200 patients with renal stones
recalled that they had their first renal colic more than
20 years before the diagnosis of PHPT. This means that, in
these patients, the actual onset of PHPT predated the clinical recognition by more than 2 decades. In this early series,
29 patients were diagnosed with "hypercalcemic crises."
These patients from the 1950s and 1960s did not represent
our current patients, but their inclusion in the analyses made
it possible to define a number of risk factors for premature
death and to study the impact of surgery on survival.
Mild hypercalcemia in patients followed for more than
2 decades is accompanied by premature cardiovascular
death.P The exemplary screening program at the Mayo
Clinic, with early diagnosis and operations, seems to eliminate the risk for premature death in patients with PHPT.
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und generalisierten Ostitis fibrosa. Arch Klin Chir 1926;143:245.
2. TisellLE, Hedback G, lansson S, et al. Management of hyperparathyroid
patients with grave hypercalcemia. World 1 Surg 1991;15:730.
3. Mitlak HE, Daly M, Potts IT lr. Asymptomatic primary hyperparathyroidism. 1 Bone Miner Res 1991;6(SuppI2):103.
4. Martin P, Bergman P, Gillet C, et al. Partially reversible osteopenia
after surgery for primary hyperparathyroidism. Arch Intern Med 1986;
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5. Silverberg Sl, Shane E, de la Cruz L, et al. Skeletal disease in primary
hyperparathyroidism. 1 Bone Miner Res 1989;4:283.
6. Hedman I, Grimby G, Tisell L-E. Improvement of muscle strength
after treatment for hyperparathyroidism. Acta Chir Scand 1984;
150:521.
7. Joborn C, Hetta 1, Rastad 1, et al. Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in patients with primary hyperparathyroidism. BioI Psychiatry 1988;23:149.
8. Corlew DS, Bryda SL, Bradley EL, et al. Observations on the course
of untreated primary hyperparathyroidism. Surgery 1985;98:1064.
9. Ronni-Sivula H. Causes of death in patients previously operated on for
primary hyperparathyroidism. Ann Chir GynaecoI1985;74:13.
10. Palmer M, Adami HO, Bergstrom R, et al. Mortality after surgery for
primary hyperparathyroidism: A follow-up of 441 patients operated on
from 1956 to 1979. Surgery 1987;102:1.
11. Hedback G, Tisell LE, Bengtsson BA, et al. Premature death in patients
operated on for primary hyperparathyroidism. World 1 Surg
1990;14:829.
12. Hedback G, Oden A, Tisell LE. The influence of surgery on the risk
of death in patients with primary hyperparathyroidism. World 1 Surg
1991;15:399.
13. Hedback G, Oden A, Tisell LE. Parathyroid adenoma weight and the
risk of death after treatment of primary hyperparathyroidism. Surgery
1995;117:134.
14. Rudberg C, Akerstrom G, Palmer M, et al. Late results of operation for
primary hyperparathyroidism in 441 patients. Surgery 1986;99:643.
15. Ronni-Sivula H, Sivula A. Long-term effect of surgical treatment on
the symptoms of primary hyperparathyroidism. Ann Clin Res
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16. Symons C, Fortune F, Greenbaum RA, et al. Cardiac hypertrophic cardiomyopathy and hyperparathyroidism-An association. Br Heart 1
1985;54:539.
17. Stefenelli T, Mayr H, Bergler-Klein 1, et al. Primary hyperparathyroidism: Incidence of cardiac abnormalities and partial reversibility
after successful parathyroidectomy. Am 1 Med 1993;95:197.
18. Levy D, Garrison Rl, Savage DD, et al. Prognostic implications of
echocardiographically determined left ventricular mass in the
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19. Koren Ml, Devereux RB, Casale PN, et al. Relation of left ventricular
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20. Palmer M, Adami HO, Krusemo VB, et al. Increased risk of malignant
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cohort study. Am 1 EpidemioI1988;1127: 1031.
21. Perris AD, MacManus IP, Whitfield IF, et al. Parathyroid glands and
mitotic stimulation in rat bone marrow after hemorrhage. Am 1 Physiol
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22. Elias AN, Sharma BS, Stokes ID, et al. Immunological aberration in
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1976;200:131.
24. Palmer M, Bergstrom R, Akerstrom G, et al. Survival and renal function in untreated hypercalcaemia, population-based cohort study with
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25. Christensson T. Menopausal age of females with hypercalcaemia: A
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26. Harrison Bl, Wheeler MH. Asymptomatic primary hyperparathyroidism. World 1 Surg 1991;15:724.
27. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism:
lO-year prospective study. Mayo Clin Proc 1981;56:473.
28. Parfitt AM, Willgoss D, lakobi 1, et al. Cell kinetics in parathyroid adenomas: Evidence for decline in rates of cell birth and tumour growth,
assuming clonal origin. Clin Endocrinol (Oxf) 1991;35:151.
29. Grey AB, Evans MC, Stapleton IP, et al. Body weight and bone mineral
density in postmenopausal women with primary hyperparathyroidism.
30. Vestergaard P, Mollerup CL, Frekjaer VG, et al. Cardiovascular events
before and after surgery for primary hyperparathyroidism. World
1 Surg 2003;27:216.
31. Walgenbach S, Hommel G, Bernhard G, et al. Operative Therapie des
primaren Hyperparathyreoidismus. Zentralbl Chir 2000; 125:666.
32. Lundgren E, Lind L, Palmer M, et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia
followed up for 25 years. Surgery 2001;130:978.
33. Leifsson BG, Ahren B. Serum calcium and survival in a large health
screening program. 1 Clin Endocrinol MetabI996;81:2149.
34. Soreide lA, van Heerden lA, Grant CS, et al. Survival after surgical
treatment for primary hyperparathyroidism. Surgery 1997;122:1117.
35. Wermers RA, Khosla S, Atkinson sr, Hodgson SF, O'Fallon WM,
et al. The rise and fall of primary hyperparathyroidism: A populationbased study in Rochester, Minnesota, 1965-1992. Ann Intern Med
1997;126:433.
36. Romanus R, Heimann P, Nilsson 0, et al. Surgical treatment of hyperparathyroidism. Prog Surg 1973;12:22.
Asymptomatic Primary
Hyperparathyroidism
Janice L. Pasieka, MD
Historical Perspective
Osteitis fibrosa cystica was first described in the 18th century,
although not so named until 1891, when von Recklinghausen
reported three patients with giant cell pseudotumor of the
bone. 1 Interestingly, one of these patients had a "reddish
brown lymph node" below the thyroid. In 1925, Felix Mandl
successfully removed a parathyroid adenoma from the neck
of a patient suffering from von Recklinghausen's disease."
Between 1925 and 1932, all patients operated on for primary
hyperparathyroidism (1 0 HPT) had the bone manifestations
of osteitis fibrosa cystica. In 1932, however, Albright noted
that 80% of all patients with 10 HPT treated at that time had
nephrolithiasis. He wondered whether some patients might
have renal stones without bone disease. In 1932, he found a
patient who presented with renal calculi without significant
bone disease, in whom a parathyroid adenoma was found at
operation.' Over the next 30 years, as clinicians recognized
nephrolithiasis as a manifestation of 10 HPT, the incidence
of von Recklinghausen's bone disease declined and most
patients with 1 HPT were found to have renal calculi alone
or in combination with other early signs of bone disease such
as the presence of subperiosteal erosions. Until the mid-1960s,
clinically apparent 10 HPT was considered to be relatively
uncommon. Occasionally, however, 10 HPT was sometimes
discovered by serendipity in patients with an elevated serum
calcium level." With the advent in the 1960s of autoanalyzers
and routine screening of serum calcium levels, the prevalence
of HPT increased to 0.1% to 0.4% as more patients with
fewer clinical manifestations of the disease were diagnosed.'
0
Asymptomatic
HyperparathyroidismDoes It Exist?
With the earlier detection of the disease, the presenting clinical manifestations of 1 HPT have changed drastically since
the first successful parathyroidectomy in 1925. The classic
symptoms of severe bone pain from osteitis fibrosa cystic a,
0
nephrolithiasis, significant myopathy, and significant neuropsychiatric impairment are seen in less than 20% of the
patients who currently present with 10 HPT.6Unlike the presentation in the days of von Recklinghausen and Albright, today
only 15% to 20% of patients with 1 HPT present with
nephrolithiasis and less than 3% of patients display evidence
of osteitis fibrosa cystica."?
This change in the presentation of 10 HPT led to a 1990
National Institutes of Health (NIH)-sponsored consensus
conference that developed guidelines for surgery in HPT.IO
The consensus panel agreed that parathyroidectomy was indicated in all symptomatic patients as well as in all "asymptomatic" patients with risk factors for progression of their
disease such and marked hypercalcemia, hypercalciuria,
or renal insufficiency, marked bone mineral density (BMD)
loss, and those younger than 50 years.!" In a reconvening of
the NIH consensus panel in 2002, very little had changed.
The new guidelines reduced the limits of hypercalcemia to
0.25 mmol above the normal reference, and altered the criteria
of BMD loss from z scores to t scores. lOa The panel continued
to recommend surgical intervention for all symptomatic
patients and those who demonstrated end-organ physiologic
effects of the disease. The controversy lies in the NIH
consensus panel's definition of an asymptomatic patient. If
one limits the definition of symptomatic HPT to the classic
symptoms, including nephrolithiasis, significant myopathy,
and evidence of osteitis fibrosis cystica, it is true that the
majority of patients today with 1 HPT (over 80%) are
asymptomatic.S'P" Asymptomatic, however, implies free of
symptoms and complications of the disorder. Today, there is
considerable evidence that many patients with HPT suffer
from vague, nonspecific, but nonetheless real manifestations
of the disease. 6,15-23 Surgeons have long observed improvement in many of these nonspecific symptoms following
parathyroidectomy. Furthermore, many patients with 10
HPT do not realize until after parathyroid surgery just how
severe their symptoms were. 15,17,18,24,25
Jobom and colleagues investigated psychiatric symptoms
in 59 consecutive patients with 10 HPT.26 Utilizing a
Comprehensive Psychopathological Rating Scale, they found
that the majority of patients with HPT had considerable
0
419

psychiatric symptoms compared with healthy control subjects.
The most pronounced symptoms were fatigue, lassitude,
failing memory, difficulty concentrating, sadness, and inner
tension. After successful parathyroidectomy, there was a
marked improvement in the mental health of these patients.
This was one of the first surgical studies that tried to quantify the nonclassic symptoms and the surgical effect in
patients with 10 HPT.
In a population-based screening study from Sweden,
Lundgren and coworkers found that fewer than 24% of their
10 HPT patients suffered from the classic symptoms.
However, the patients with 10 HPT had more psychiatric complaints of lassitude, fatigue, irritability, and lack of sexual
interest than their age-matched control subjects."
Others have demonstrated similar results, with the HPT
patients' experiences with more symptoms than population
norms. Chan and colleagues reported a case-control series of
121 patients from 1986 to 1991 with 10 HPT utilizing a preoperative symptom questionnaire that was filled out at their
first visit to the surgeon and again when they were recalled in
June 1991. They found that the majority of the 10 HPT patients
were indeed symptomatic preoperatively (95%) and that
most patients experienced a subjective improvement in their
preoperative symptoms following parathyroidectomy. 18
More recently, Hasse and associates'> set out to answer
the question of just "how asymptomatic is asymptomatic 10
HPT?" In their cohort study of 582 consecutive patients with
10 HPT, 86 patients who were considered asymptomatic preoperatively participated in the follow-up questionnaire given
at a median of 72 months postoperatively. The follow-up
assessment consisted of the Short Form 36-item (SF-36)
quality of life (QOL) instrument and a graded questionnaire
that included 19 classic and nonclassic symptoms. They
found that in retrospect only 9.3% of the asymptomatic
patients were truly asymptomatic. Postoperatively, 81%
of the asymptomatic patients reported an improvement in
their preoperative state. From this study, it would appear that
apparently asymptomatic 10 HPT patients realized symptoms only in retrospect and that these symptoms could not be
predicted preoperatively, because they become apparent
only after treatment.
These studies all suggest that asymptomatic 10 HPT patients
might have the same subjective benefit from parathyroidectomy as symptomatic patients. Asymptomatic 10 HPT
patients treated conservatively have no frame of reference
to validate whether or not they are truly asymptomatic.
In an observational study by Silverberg and colleagues of
121 10 HPT patients, they claimed that 101 (83%) were
asymptomatic." Patients were randomly assigned. Half (61)
underwent parathyroidectomy with a normalization of
their biochemical values and an increase in their BMD. The
remaining 60 patients underwent observation and, during the
1O-yearfollow-up period, 22 (37%) demonstrated a progression of their disease. Despite these results, they concluded
that with clinical follow-up most asymptomatic patients
with 10 HPT could be monitored safely without parathyroidectomy. The authors commented that the nonspecific
manifestations of 10 HPT were not included in their criteria
for symptomatic disease because quantitative measures of
these manifestations were not yet available. It is, therefore,
likely that the number of patients who were symptomatic in
their observation group and the number of patients who

demonstrated progression of their disease were underestimated. Silverberg's study, like many others in the literature,
illustrates the need for validated instruments that can measure the impact of intervention on these nonspecific manifestations of HPT.24
Utilization of Outcome
Patient-Based Instruments
In the past, the vague, nonspecific nature of these nonclassic
symptoms in HPT limited the ability of clinicians and investigators to quantitate these symptoms with validated outcome tools. Today, patient-based outcome instruments are
utilized to provide a better understanding of the impact of a
disease on a patient's well-being and of the effectiveness of
intervention on a disease process.P-" Several authors have
demonstrated an improvement in the ability to concentrate,
in cognitive function, and in some of the psychiatric symptoms such as depression following parathyroidectomy by
utilizing generic neuropsychiatric assessment toolS. 19,23,25,26
Others have attempted to illustrate the effect that 10 HPT has
on the patient's functional health status and well-being as
well as demonstrate the impact of surgical intervention on
these parameters utilizing a generic QOL instrument, the
SF-36 form.21.32-34 The SF-36 form defines eight domains of
health status: general health, physical function, physical and
emotional role limitations, social function, mental health,
bodily pain, and energy or fatigue.
Burney and colleagues were the first to utilize the SF-36
form and demonstrate that 10 HPT patients had a marked
impairment in their health status and QOL scoring significantly lower in seven of the eight measured domains compared with population norms before parathyroldectomy.P'"
Sustained improvement in six of the eight domains was
demonstrated following parathyroidectomy. Talpos and
coworkers randomly assigned 53 asymptomatic patients
to surgery versus observation alone." The authors demonstrated a statistically significant improvement in two of the
eight domains of the SF-36 health survey, those of social
functioning and emotional role limitations, in the surgically
treated group. These studies give insight into the impact of
the nonclassic symptoms of HPT on a patient's well-being
and how parathyroidectomy can affect the patient's overall
health. Although these observations are important, the
generic nature of the SF-36 outcome tool makes it less
responsive to clinical changes that may have occurred after
parathyroidectomy. 3D A disease-specific outcome measurement tool would be more responsive to the subtle clinical
changes that have been observed retrospectively by patients
and their surgeons.'?
A disease-specific outcome tool for HPT has been
validated. This instrument, including both the classic and
nonclassic symptoms, has been utilized at the University
of Calgary as well as in a multicenter trial studying the
impact of parathyroidectomy on patients with HPT.16,17,35
Parathyroidectomy Assessment of Symptoms (PAS) scores
were obtained for 13 disease-specific items preoperatively,
7 to 10 days postoperatively, at 3 months, and at 1 year. The
higher the PAS score, the higher the patients ranked their
Asymptomatic Primary Hyperparathyroidism - -
experience of the symptom. We found that the 10 HPT

patients were more symptomatic preoperatively than the
thyroid comparison group. Following surgical intervention,
the HPT patients experienced a significant decrease in their
PAS scores in the first study period and this decreasing trend
continued out to 1 year. 1617,35 In contrast, the thyroid comparison group demonstrated no change in their PAS scores
throughout the study (Fig. 44-1).
In a further subset analysis of the University of Calgary's
patients, Sywak and coworkers found that 22 of 117 patients
with 10 HPT who underwent successful parathyroidectomy
had none of the NIH criteria for parathyroidectomy and
by definition were free of all classic symptoms." The preoperative PAS scores were equally high in both the 22 patients
without NIH criteria for surgery and the 95 patients in whom
at least one of the NIH criteria was present. More important,
both of these 10 HPT groups were significantly more symptomatic preoperatively than the nontoxic thyroid comparison
group. AlII HPT patients reported a significant improvement
in their symptom scores after parathyroidectomy (Fig. 44-2).
Looking specifically at the nonclassic symptoms of fatigue,
depression, irritability, mood swings, and forgetfulness, we
found that all of these symptoms improved at l-year follow-up
in the 10 HPT patients, in contrast to no change demonstrated in these symptoms in the thyroid comparison group
(Fig. 44-A and B). We concluded that the so-called asymptomatic patients were indeed suffering from reversible, nonspecific manifestations of the disease and felt the guidelines
for parathyroidectomy should be broadened to include the
nonclassical manifestations of 1 HPT.
0
Treatment of Asymptomatic
Hyperparathyroidism
The changing presentation of 10 HPT is a result of the increased
recognition of a milder form of the disease. The intention of
the NIH consensus guidelines for parathyroidectomy was to
FIGURE 44-1. The Parathyroidectomy Assessment of Symptoms

(PAS) scores for primary hyperparathyroidism (HPT).The HPT
patients were significantly more symptomatic than the thyroid
comparison group preoperatively (P < .05). After surgery, the HPT
patients demonstrated a significant decrease in their PAS scores
(P < .05). The thyroid comparison group demonstrated no change
in their PAS scores throughout the study.
421
FIGURE 44-2. The Parathyroidectomy Assessment of Symptoms

(PAS) scores for primary hyperparathyroidism (HPT). Group A
had at least one of the National Institutes of Health (NIH) criteria
for parathyroidectomy present preoperatively. Group B patients
had none of the NIH criteria present and were "asymptomatic."
Group C consisted of the thyroid comparison group. Groups A and
B were significantly more symptomatic than group C preoperatively (P < .05). After surgery, there was no difference in the PAS
scores between any of the three groups.
help guide the clinician to the appropriate treatment

for patients with mild 10 HPT.1O Parathyroidectomy remains
the only definitive treatment of HPT, reversing the manifestations of the disease and correcting the biochemical
abnormalities in over 95% of patients. 936,37 There is little
debate about the need for parathyroidectomy in overtly
symptomatic patients. Other criteria developed at the
NIH conference included age younger than 50, marked
hypercalcemia (>2.85 mmollL), marked hypercalciuria
(>10 mmol/ day), reduction in creatinine clearance, and
bone loss more than 2.5 standard deviations compared to
healthy controls. These criteria were thought to reflect the
physiologic end-organ effects of HPT and thus were likely to
identify the patients at risk for developing complications of
the disease. Additional criteria for surgery that are utilized
by some authors include vertebral bone osteopenia, vitamin D
deficiency, recent fracture history, and perimenopausal
status for women.F Although rare, there are patients with 10
HPT in whom vertebral osteopenia is more marked than
cortical bone loss. Parathyroidectomy has been shown to result
in a significant improvement in vertebral bone density and
only a modest increase in cortical bone density at lO-year
follow-up.P-'? It appears that the patients with significant
vertebral osteopenia would benefit the most from parathyroidectomy. Receptors for vitamin D metabolites in the
parathyroid glands have been shown to suppress parathyroid
hormone (PTH) secretion. It has been postulated that
vitamin D deficiency results in even higher PTH levels in
patients with HPT. Correcting the vitamin D deficiency may
be associated with a worsening hypercalcemia, and thus
these patients would benefit from parathyroidectomy before
addressing their vitamin D deficiency.P'" Although the
increased risk of fracture in HPT is not clearly established
in the literature, fractures, particularly cortical fractures,
suggest an accelerated course of the disease and therefore
FIGURE 44-3. The item-specific Parathyroidectomy Assessment of Symptoms (PAS) scores for the nonspecific symptoms of hyperparathyroidism (HPT). A, PAS scores of the HPT patients, ~emonsr:ating
a s~gnifi~ant
improvement i~ all five items at I-year follow-up
(P < .05). B, PAS scores of the thyroid patients, demonstratmg no difference m their scores for all five Items at I-year follow-up.
have been utilized as an indication for surgery by some

authors. 12,41-44
Using the NIH definition of symptomatic disease,
approximately 50% of patients with 10 HPT have at least
one of the NIH criteria for parathyroidectomy," For the
remaining 50% of patients, some authors have suggested
conservative management with yearly monitoring of physiologic parameters such as serum calcium, BMD, and renal
function. 6,11,13.28,45 In the prospective trial involving 10 HPT
patients randomly assigned to surgery versus observation,
Silverberg and colleagues found that 37% (22 of 60) of the
observation group demonstrated progression of their disease." The majority of these patients were found to have a
decrease in their BMD over time, in contrast to the
parathyroidectomy group, who demonstrated a significant
increase in their BMD. Of the 60 patients in the observation arm, 52 were considered asymptomatic. At 10-year
follow-up, 38 of these asymptomatic patients demonstrated
no significant progression of their disease. This study illustrated that there is a subgroup of patients with 10 HPT that,
when followed closely, demonstrates little progression in
the physiologic parameters affected by HPT, such as BMD
and renal function. It is, however, likely that the investigators have underestimated the population of symptomatic
patients and failed to study the impact of the nonspecific
symptoms on the patients overall.
There continues to be considerable debate among surgeons and endocrinologists concerning the appropriate treatment of mild, nonprogressive 10 HPT. Outcome studies that
assess the impact of parathyroidectomy beyond the physiologic parameters of the disease have clearly demonstrated an
improvement in the patients' well-being and general health.
These studies, however, have been for the most part surgical
studies and, because of the inherent referral basis, still do
not clearly resolve the debate. Until a randomized study is
performed that includes both classic and nonclassic symptoms and measures not only the impact on the physiologic
parameters but also the impact on the patient's healthrelated QOL, the debate over the management of 10 HPT
will continue.
Summary
The clinical manifestations of 10 HPT have evolved during
the past 4 decades. Today, fewer than 20% of patients suffer
from the classic symptoms of 10 HPT initially described in
the 1920s to 1940s. Many patients today suffer from vague,
nonspecific, but nonetheless real manifestations of the disease. It appears from the data achieved with patient-based
outcome instruments that very few patients suffering from
10 HPT are truly asymptomatic. More important, many of
these nonclassic symptoms improve after parathyroidectomy. It, therefore, becomes important for the primary care
clinician not only to assess the physiologic parameters of 1
HPT but also to be aware of the expanding definition of
symptoms associated with this disease. With the broadened
guidelines for parathyroidectomy, it appears that the majority
of patients with 10 HPT require parathyroidectomy and,
more important, benefit from such intervention.
0
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lOa. Bilezikian JP, Potts IT, Fuleihan G, et aI. Summary statement from
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12. Bilezikian JP. Primary hyperparathyroidism. When to observe and
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18. Chan AK, Duh Q, Katz MH, et al. Clinical manifestations of primary
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19. Prager G, Kalaschek A, Kaczirek K, et al. Parathyroidectomy
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38. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Increased bone mineral
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41. Larsson K, Ljunghall S, Krusemo UB, et al. The risk of hip fractures
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42. Kenny AM, MacGillivary DC, Pibeam CC, et al. Fracture incidence in
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43. Melton LJ, Atkinson EJ, O'Fallon WM, Heath H. Risk of age related
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Normocalcemic
Hyperparathyroidism
Jack M. Monchik, MD, FACS
Hypercalcemia as manifested by an elevated total serum

calcium has traditionally been an important parameter in the
diagnosis of primary hyperparathyroidism (PHPT). Initial
studies of patients with PHPT stressed the rather constant
elevation of the total serum calcium in this entity.
Intermittent or no elevation of the total calcium was considered to be rare, if not impossible.l' Subsequent reports have
identified patients with PHPT with subtle hypercalcemia
defined as intermittent, minimal, or no elevation of the total
calcium. For the purpose of this chapter, these patients are
considered to have normocalcemic hyperparathyroidism.
Most of these patients have renal stone disease and, to a
much lesser degree, skeletal abnormalities.f" The introduction of bone densitometry with dual energy x-ray absorptiometry (DEXA) scans for screening for osteoporosis has
identified an additional group of patients with normocalcemic hyperparathyroidism. This diagnosis of normocalcemic hyperparathyroidism is a challenge that must be
considered in all patients with metabolic complications of
PHPT. Solving this diagnostic problem is dependent on an
understanding of calcium metabolism.
Distribution of Calcium
in the Body
Bone accounts for 98% of the calcium content in the body.
Calcium in bone is present largely in the form of hydroxyapatite crystals, which are relatively insoluble. One percent
of the total body calcium is in a soluble form in extracellular
and intracellular fluid compartments, and another 1% is
freely exchangeable within extracellular fluid."
Calcium in serum is present in three distinct fractions in
equilibrium. Figure 45-1 graphically displays the approximate distribution of calcium in serum. The ionized and complexed calcium together make up the ultrafiltrable fraction.
Ultrafiltrable calcium represents about 50% of the total
serum calcium. Ionized calcium accounts for 90% of the ultrafiltrable calcium and about 45% of the total serum calcium.
424
Complexed calcium is that fraction of the ultrafiltrable

component that is ionically bound to citrate, phosphate, and
carbonate, which represents approximately 10% of the ultrafiltrable calcium." Protein-bound calcium dependent on pH
and temperature represents about 50% of the total serum
calcium. Eighty percent of the protein-bound calcium is
bound to albumin and 20% is bound to globulin; therefore,
hypoalbuminemia can significantly lower the total serum
calcium. The total serum calcium is reduced 0.8 to 1.0 mg/dL
for each I-g/IOO mL reduction in the serum albumin. to
Calcium Homeostasis
Calcium homeostasis is maintained by the complex interrelationship of parathyroid hormone (PTH), vitamin D and its
derivatives, and calcitonin. The polypeptide PTH contains
84 amino acids. Once secreted by the parathyroid glands, it
undergoes immediate degradation into the amino (N) and
carboxyl (C) terminal fragments. The N-terminal fragment
is biologically active but is rapidly cleared from the circulation, whereas the C-terminal fragment is biologically inert
and is predominantly cleared from the circulation by the
kidney. This fragment persists for a longer period in the circulation, particularly in patients with renal failure. 11-13 Intact
PTH (iPTH), the 1-84 molecule, is the major circulating
form of biologically active PTH. Most of the currently used
serum PTH assays measure iPTH.14
The secretion of PTH is regulated by serum ionized
calcium acting through a sensitive calcium-sensing receptor
that is highly expressed on the surface of the parathyroid cells.
Activation of this receptor by a small increase in ionized
calcium activates second messengers such as intracellular
calcium and inositol through one or more guanine nucleotidebinding (G) proteins to inhibit PTH secretion. Deactivation of
this receptor by a small decrease in serum ionized calcium
results in stimulation of PTH. Ionized calcium is, therefore,
considered to be the physiologically active component of the
total serum calcium. IS The parathyroid cells also have a
Normocalcemic Hyperparathyroidism - - 425
PROTEIN BOUND
50%
Bound to Globulin
20%
ULTRAFILTRABLE
50%
IONIZEDCALCIUM
45%
Complexed
10%
FIGURE 45-1. Distribution of calciumin serum.
vitamin D receptor. The binding of calcitriol (l,25-dihydroxyvitamin D) inhibits PTH secretion." Hyperphosphatemia
stimulates PTH secretion primarily through induction of
hypocalcemia but to a lesser extent through direct stimulation,
particularly in patients with advanced renal failure.
The major target organs for PTH are the kidneys, skeletal system, and intestine. PTH functions by binding to
receptor sites in bone and kidney, resulting in stimulation
of production of cyclic adenosine monophosphate (cAMP),
which acts to carry out the cellular response of that specific
target tissue.'?
The predominant response by the kidney to PTH is to
increase the tubular resorption of calcium and to decrease
the tubular resorption of phosphorus.P:'? The other important function of PTH on the kidney is to increase the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D,
which acts to increase the intestinal absorption of calcium."
The action of PTH on the bone to regulate serum calcium is
through the remodeling effect of osteoclast and osteoblast
activity. The osteoblasts and their precursor cells in bone
have a PTH receptor site, and binding to this site results in
the production of cAMP. The osteoclasts do not have a PTH
receptor site but are stimulated indirectly through the cAMP
response in the osteoblasts." Coordinated actions of PTH on
bone, kidney, and intestine result in an increase flow of calcium into the extracellular fluid and an increase in the serum
calcium.
PTH provides the predominant means of immediate regulation of the extracellular calcium. Although physiologically important, vitamin D action affects day to day calcium
balance as opposed to the more immediate direct action of
PTH.17 Calcitonin has a much smaller role in calcium homeostasis. Calcitonin is secreted by the parafollicular cells of the
thyroid and inhibits bone resorption. Extremely high levels
of calcitonin found in medullary carcinoma of the
thyroid do not result in hypocalcemia.P
Ionized Calcium
The measurement of ionized calcium appears to have a
major role in the identification of symptomatic patients with
PHPT with minimal, intermittent, or no elevation of the total
calcium. 6,7,23 Ionized calcium is measured with a calciumselective ion flow-through electrode system.>' This system
for measuring ionized calcium was first introduced in 1967
and has since undergone several design changes that have
resulted in improved precision.
Previous articles and continuing experience indicate
that the serum ionized calcium is superior to total calcium
in detecting PHPT in patients with intermittent, minimal, or
no elevation of the total calcium. Ionized calcium is of no
added benefit for diagnostic purposes in patients with elevated total serum calcium. Hypersecretion of PTH increases
serum calcium by increasing the tubular resorption of calcium, increasing the net bone resorption and, to a lesser
extent, increasing the intestinal absorption of calcium. One
can justifiably question why total calcium is not increased
in all patients with PHPT, assuming a normal serum albumin
and no pancreatitis, increased phosphate intake, or hypomagnesemia, factors known to cause a decrease in the total
serum calcium. Some authors have attributed the normal
total serum calcium in normocalcemic hyperparathyroidism
to an increased ratio of ionized and ultrafiltrable calcium
to total calcium compared to normal individuals. Elevated
serum PTH has been postulated to decrease the binding of
calcium to protein and therefore increases ionized calcium
at the expense of the protein-bound fraction. 6,23.25 An alternative explanation postulated for normocalcemia in patients
with PHPT is a generalized resistance to the action of PTH
on bone and kidney."
Ultrafiltrable Calcium
Ultrafiltrable calcium has also been used for identification
of normocalcemic PHPT. A comparative study of ultrafiltrable ionized and total calcium in symptomatic patients with
intermittent or no elevation of the total calcium showed that
ionized calcium was a more sensitive indicator of PHPT in
this group of patients.F In this study, ultrafiltrable calcium
was a more sensitive indicator of hypercalcemia than total
calcium but did not reach statistical significance.
Renal Calculi
Most patients with normocalcemic hyperparathyroidism
are identified because of renal calculi and many of these
patients have hypercalciuria. Most patients with renal calculi and hypercalciuria, however, have idiopathic hypercalciuria, a condition also associated with normocalcemia.
Patients with idiopathic hypercalciuria have 24-hour urinary
calcium values of 250 mg per 24 hours or higher in females,
300 mg per 24 hours or higher in males, or 4 mg/kg in males
or females on a daily intake of 1000 mg of calcium.i" These
criteria are useful even when diet is uncontrolled because
urine calcium excretion varies only slightly in normal
FIGURE 45-2. Concurrent values of ionized and

total calcium in a patient with renal calculi and intermittent elevation of the total calcium level. A
parathyroidadenomaweighing 200 mg was removed
at surgery. (From McLeod MK, Monchik JM,
Martin HE The role of ionized calcium in the
diagnosis of subtle hypercalcemia in symptomatic
primary hyperparathyroidism. Surgery 1984;95:667.)
CONSECUTIVE CONCURRENT VALUES (different days)
individuals when dietary calcium intake is widely altered.P

A small fraction of these patients with hypercalciuria have
normocalcemic HPTH.3o Figure 45-2 shows concomitant
ionized and total calcium values in a patient with nephrolithiasis and intermittent elevation of the total calcium, and
Figure 45-3 demonstrates a patient with renal calculi with
no elevation of the total calcium.
Since the original description of idiopathic hypercalciuria
by Albright and associates in 1953, several hypothesis have
been advanced to explain this entity." Increased intestinal
absorption, diminished tubular resorption of calcium resulting in a renal calcium leak, and a primary phosphate leak
have been postulated.P'>' In practice, the classification of
idiopathic hypercalciuria stone formers into renal calcium
leak, primary intestinal hyperabsorption, or primary phosphate leak is time consuming, expensive, not reproducible,
and does not appear to influence the outcome of treatment.
The differentiation of hypercalciuric stone formers with
normocalcemic hyperparathyroidism from those with one
of the subtypes of idiopathic hypercalciuria is of prime
importance because of the success of parathyroid surgery in
preventing further stone formation. Failure to accurately

separate stone-forming patients with normocalcemic hyperparathyroidism from those with idiopathic hypercalciuria
has led to inappropriate neck exploration. Parathyroid surgery in patients with idiopathic hypercalciuria has resulted
in finding no abnormal parathyroid tissue and continued
stone formation."
The renal calcium leak subtype of idiopathic hypercalciuria
can have an elevated serum PTH secondary to compensation
by the parathyroid glands to increased renal loss of calcium.
The serum ionized or total calcium is not elevated in this
or other subtypes of idiopathic hypercalciuria." The
absence of an elevated serum ionized or total calcium makes
further testing necessary to distinguish this entity from
normocalcemic hyperparathyroidism. This subtype of idiopathic hypercalciuria can sometimes be separated from
normocalcemic hyperparathyroidism by treatment with a
thiazide diuretic. The thiazide diuretic reduces the excessive
loss of urinary calcium, causing the serum calcium to rise
slightly but not above, the normal range, and resulting in a
decrease of the serum PTH into the normal range.F-"
TOTAL CALCIUM (mg %)
12.0
11.0
10.0
9.0~
8.0
FIGURE 45-3. Concurrent values of ionized and
IONIZED CALCIUM (mg %)
PATH.: Adenoma
7.0
6.0
5.0~~R_~_[E2ill~~_R
4.0
3.0..l....--+---+---I----I--~I--~I--~-__+-__+-~
NORMAL RANGE
1
2
3
4
5
6
7
8
CONSECUTIVE CONCURRENT VALUES (different days)
10
total calcium levels in a patient with renal calculi

and all normal total calcium levels. A parathyroid
adenoma weighing 440 mg was removed at surgery.
(From McLeod MK, Monchik JM, Martin HE The
role of ionized calcium in the diagnosis of subtle
hypercalcemia in symptomatic primary hyperparathyroidism. Surgery 1984;95:667.)
I have shown that ionized calcium is more sensitive

than total calcium in diagnosing PHPT in patients with
nephrolithiasis and minimal or no elevation of the
total calcium.i-" We recommend three consecutive days
of ionized and total calcium as a screening study for
hyperparathyroidism in patients with nephrolithiasis with
minimal or no elevation of the serum total calcium. A serum
iPTH should be done on at least one day. An elevated iPTH
may be the only clue to the diagnosis of normocalcemic
hyperparathyroidism.26
Bone Disease
Although historically most patients with normocalcemic
hyperparathyroidism were identified because of renal calculi,
an increasing number of patients have recently been identified by screening patients for osteoporosis with dual-energy
x-ray absorptiometry (DEXA) scans.
Traditionally, hyperparathyroidism was associated with
overt bone disease in a significant number of patients. This
traditional bone disease was frequently symptomatic and
associated with radiologic findings such as bone cysts,
brown tumors of the long bones, subperiosteal resorption
of the distal phalanges and clavicles, and "salt and pepper"
demineralization of the skull. The increased awareness of
the diagnosis of PHPT and multichannel blood screening
studies have resulted in an earlier diagnosis of this condition
and considerably fewer patients with these classic bone
findings. The introduction of screening for osteoporosis
with DEXA scans has identified an increasing number of
patients with severe osteopenia or osteoporosis." Hyperparathyroidism is considered an important cause of osteoporosis as a consequence of its known catabolic effect
promoting osteoclast activity and bone resorption. The
human skeleton consists of cortical and trabecular bone.
Cortical bone is the compact layer, which predominates in
the shafts of the long bones. Trabecular bone is composed
of a series of thin plates, which form the interior meshwork
of bones, particularly the vertebrae, pelvis, and end of long
bones. The major site of bone mineral loss in PHPT appears
to be cortical bone; therefore, the DEXA scan of the distal
radius is more sensitive than that of the spine or hip in
detecting bone loss due to PHPT. 4o The diagnosis of PHPT
should be pursued in patients with severe osteopenia or
osteoporosis because of the favorable outcome of parathyroid surgery. Correction of PHPT results in stopping the
accelerated bone loss attributable to the hyperparathyroidism and a 10% to 12% increase in bone mass in trabecular as well as in cortical bone. This increase lasts at least
a decade after successful parathyroid surgery.'" Patients with
a low vertebral bone density demonstrated a marked
increase in bone density after surgery. This group experienced a 20% increase in vertebral bone density over a 4-year
period." This indicates that remineralization after surgical
correction of PHPT involves a generalized increase in bone
mass, not just cortical bone mass.
Minimal, intermittent, or no elevation of the total calcium
in patients with PHPT and osteoporosis is not uncommon. A
study at Rhode Island Hospital identified 64 patients from
January 1995 to June 1999 with osteoporosis defined by a

t score of 2.5 or less who underwent parathyroid surgery.
Fifteen (23%) of these patients had 40% of their preoperative total calcium values within the normal range and 6 (9%)
of these patients had no preoperative elevated total calcium,
These 6 patients had a total of 44 concomitant serum ionized
and total calcium measurements; 42 of the ionized calcium
values were elevated and 2 were normal. Each of these
patients had at least one elevated value for iPTH.43
Patients with severe osteopenia or osteoporosis who
do not have an elevated serum total calcium should be
screened on 3 consecutive days for serum ionized and total
calcium and a serum iPTH on at least 1 day to minimize
the risk of missing the diagnosis of normocalcemic
Diagnostic Studies
All patients with recurrent renal calculi and or severe
osteopenia or osteoporosis should be screened for PHPT
because of the benefits provided by surgical correction.
Patients with the combination of an elevated serum ionized
calcium and an elevated iPTH have hyperparathyroidism,
even in the absence of elevated serum total calcium. An elevated serum iPTH in the absence of elevated ionized or total
calcium does not confirm the diagnosis of normocalcemic
hyperparathyroidism. The iPTH can be elevated in the
absence of an elevated ionized or total calcium in the renal
leak form of idiopathic hypercalciuria and vitamin D deficiency.36.44 The iPTH may return to normal with treatment
with a thiazide diuretic in the renal leak form of idiopathic
hypercalciuria. Patients with vitamin D deficiency have a low
25-hydroxyvitarnin D level, and their serum PTH cannot be
corrected by vitamin D replacement. In patients in whom the
combination of 3 consecutive days of concomitant serum
ionized and total calcium and intact parathyroid hormone
screening cannot provide a definitive diagnosis, the oral calcium loading study may be helpful. 26.44
An elevated serum iPTH with no elevation in the ionized
or total calcium is not uncommon. In a study of 178 patients
with PHPT 27 patients (15%) had no elevation of the total
or ionized calcium. The diagnosis in these patients was
established by an oral calcium loading study showing the
serum ionized calcium increasing to a supranormal value
with only a minimal decrease in iPTH. 26
An oral calcium loading study can be accomplished in an
office setting. The patient is given an oral dose of 1000 mg
of elemental calcium. A baseline serum iPTH is obtained
prior to giving the oral calcium load, and subsequent serum
iPTH values are obtained at 30, 60, and 120 minutes after
giving the oral calcium load. Figure 45-4 illustrates the suppression of iPTH in 18 normal controls, which shows that
all but 2 of these patients exhibited suppression to 70% or
more of the baseline level of iPTH at 60 minutes after the
oral calcium load. Figure 45-5 shows the results of the oral
calcium loading study in 6 patients with recurrent renal
calculi with normocalcemic or subtle hyperparathyroidism.
Five of these 6 patients did not suppress to less than 70% of
the baseline iPTH. These results and our continuing

IRMA PTH
(Percent of Baseline)
140
120
100
IRMA PTH
(Percent of Baseline)
140120
100
80
80
60
60
40
40
20
20
0-L...--+-------1f------+--------i
BASE LINE
30
60
120
TIME (Minutes)
0-4----1-------l.----..+-------j
BASE LINE
30
60
120
TIME (Minutes)
FIGURE 45-4. Percentage of change in intact parathyroid

hormone values expressed as a percentage of the baseline values
during the oral calcium loading test in 18 normal control subjects.
IRMA PTH = immunoradiometric assay of parathyroid hormone,
(From Monchik JM, Lamberton RP, Roth U. Role of the oral
calcium loading test with measurement of intact parathyroid
hormone in the diagnosis of symptomatic subtle primary
hyperparathyroidism. Surgery 1992;112:1103.)
FIGURE 45-5. Percentage of change in intact parathyroid hormone values expressed as a percentage of the baseline values
during oral calcium loading in six patients with nonnocalcemic
hyperparathyroidism. IRMA PTH = immunoradiometric assay of
parathyroid hormone. (FromMonchikJM, LambertonRP, Roth U.
Role of the oral calcium-loading test with measurement of intact
parathyroid hormone in the diagnosis of symptomatic subtle primary hyperparathyroidism. Surgery 1992;112:1103.)
experience with the oral calcium-loading study emphasize

that no single test can be expected to reliably identify all
patients with normocalcemic hyperparathyroidism.
Subsequent unpublished data from our institution have
provided further confirmation that a completely normal
suppression of iPTH can occur with oral calcium loading in
patients with PHPT.
ionized calcium. All patients with recurrent renal calculi,

severe osteopenia, or osteoporosis should be screened
for PHPT because of the benefits of surgical correction.
We suggest screening these patients with three consecutive
days of serum ionized and total calcium and intact parathyroid hormone on one day.
Summary
This chapter focuses on the physiology of calcium metabolism and the static and dynamic testing pertinent to the
diagnosis of normocalcemic hyperparathyroidism in symptomatic patients with renal calculi or osteoporosis. An
important group of patients with PHPT and recurrent renal
calculi or severe osteopenia or osteoporosis has minimal,
intermittent, or no elevation of the serum total calcium. The
ionized calcium has been shown to be a more sensitive indicator of PHPT in this situation than total calcium. Patients
with an elevated serum ionized calcium and iPTH have
PHPT even in the absence of elevated serum total calcium.
Treatment with a thiazide diuretic or correction of vitamin D
deficiency may be necessary to separate patients with normocalcemic hyperparathyroidism from those with the renal
leak form of idiopathic hypercalciuria or vitamin D deficiency. The oral calcium loading study can be helpful in
identifying normocalcemic hyperparathyroidism in patients
with normal or no elevation of the total calcium or
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Localization Studies in
Hyperparathyroidism
Jose M. Rodriguez, MD P. Parrilla, MD
The surgical management of patients with hyperparathyroidism (HPT) is successful in more than 90% of cases.l-'
Furthermore, in specialized centers, the morbidity rate of
parathyroidectomy is lower than 1%.4-8
Patients with persistent HPT (hypercalcemia persists or
recurs within 6 months after surgery) or, less commonly,
recurrent HPT (hypercalcemia recurs after >6 months of
nonnocalcemia) necessitate reoperation. In these cases, the
morbidity rate increases up to 10% for permanent recurrent
laryngeal nerve injury and to 35% for hypoparathyroidism.tP
A successful neck exploration for HPT is primarily
dependent on the experience of the surgeon, the anatomic
location of the parathyroid glands (normal or ectopic sites),
and the presence of a single adenoma as opposed to
multiglandular disease or carcinoma.l" The most common
causes of recurrent or persistent disease are unlocated
parathyroid adenoma (80%),15,16 undiagnosed second adenoma (~9% of cases),'? misdiagnosis of parathyroid hyperplasia as adenomatous disease, and parathyroid carcinoma. 18
Supernumerary glands account for 15% to 25% of failed
cases. 19-21 We found ectopic parathyroid tumors in 5% to
11% of failures (thymus, intrathyroid, undescended, in the
retroesophageal space and in the carotid sheath).IO,15,22,23 In
these cases of persistent or recurrent HPT, surgical intervention is most difficult because of the loss of normal tissue
planes (as also occurs after extensive thyroid surgery) and
the possibility that the missed parathyroid gland is situated
in an ectopic position. Localization studies in these patients
reduce operating time, avoid unnecessary dissection, reduce
operative morbidity, and improve the success rate. I,24
In cases of persistent or recurrent HPT, one must first
confirm the diagnosis of HPT and review previous surgical
and pathology reports. With this information, we can usually
determine whether the patient has a single adenoma,
a double adenoma, parathyroid hyperplasia or, rarely, a
carcinoma.
Localization studies can be selected according to availability, cost, and experience.P Surgery for persistent or
recurrent HPT should be performed only after positive
localization studies. Various localization techniques that are
430
no longer used include esophageal fluoroscopy." cineradi-
ography.'? and thermography-" Currently, we classify localization methods as preoperative (invasive or noninvasive)
and intraoperative (Table 46-1),
Noninvasive Preoperative
Methods
Ultrasonography
High-resolution ultrasonography (US) (7.5 or 10 MHz) was
introduced by Edis and Evans in 1979. 29 It enables exploration of the thyroid, carotid, and jugular areas and the
cervical area between the thyroid cartilage and the sternal
margin (Fig, 46-1). The advantages are that it is easy to
perform, is well tolerated by the patient, does not require the
injection of contrast medium, does not emit radiation, and
can be done quickly and inexpensively. Unfortunately, the
retroesophageal, retrotracheal, retrosternal, and deep cervical glands are difficult to locate by US. However, intrathyroid adenomas can be localized better with US than with
other techniques although they can also be confused with a
thyroid nodule. 30-32 The sensitivity of US varies according to
the ultrasonographer's experience, the frequency of the transducer, the resolution of the image, and the size of the parathyroid gland.P The sensitivity of US reported in the literature
varies greatly, from 22% to 82%.1,10,11,13,15,18,34-42
False-positive results are caused by thyroid nodules
(6% to 15% of patients with HPT have associated thyroid
lesions),3,33 adenopathy, and even esophageal lesions. Metal
clips can make interpretation more difficult. The percentage
of false-positive results is usually about 15% to
20%.10,15,30,36,37 Only Carlson and associatesf reported 4%
false-positive results, but with a sensitivity of only 22%.
Endoscopic US has also been used to locate posterior
glands adjacent to the esophagus. Henry" diagnosed 52%
of parathyroid tumors using endoscopic US, Catargi and
colleaguesv reported the sensitivity of endoscopic US was
71 %, In both studies, endoscopic US was better than
Localization Studies in Persistent or Recurrent Hyperparathyroidism - -
431
usually more frequent than with other techniques and may

reach up to 50%.1,34,51
Magnetic Resonance Imaging
conventional US. Color Doppler US has been used in an

attempt to differentiate thyroid from parathyroid tumors,
depending on vascularity (thyroid lesions and large parathyroid tumors are more vascular). However, as Gooding and
Clar06 have reported, no clear differentiation can be established by Doppler US alone.
Computed Tomography
Computed tomography (CT) is a less sensitive method
than magnetic resonance imaging (MRI). It is relatively
expensive, exposes the patient to radiation, and requires the
administration of contrast material to obtain the best results.
It is useful for ectopic parathyroid glands (retrotracheal,
retroesophageal, and mediastinal) but is less effective for
those in a normal location. Metal clips can also distort the
image. Furthermore, peri thyroid lymphadenopathy and even
the existence of tortuous or arteriosclerotic vessels may
make localizing abnormal parathyroid glands difficult." The
sensitivity of CT reported in the literature ranges from
16% to 70%.10,13,15.18.35-37,39-41,48-50 False-positive results are
FIGURE 46-1. Ultrasonogram showing intrathyroidal parathyroid

adenoma.
Although CT and MRI both provide excellent anatomic

details, MRI is preferable because it does not require the
administration of contrast material, there are no artifacts
from the clips left in the neck, and shoulder artifact is not
a problem. However, MRI is expensive, A parathyroid tumor
usually has a low signal intensity in Tl-weighted imaging
(similar to muscle or thyroid) and a high signal intensity
(more than or the same as fat) in T2-weighted imaging
(Fig. 46_2).48 Not all adenomas have the same image
characteristics.P
MRI is especially useful for identifying ectopic parathyroid glands. Of 121 patients undergoing reoperation for HPT,
MRI located 79% of the ectopic glands and only 59% ofthose
were situated in a normal position" Superior parathyroid
glands are more difficult to localize because they usually lie
posterior to the thyroid at the level of the cricoid cartilage. 53
The sensitivity for MRI is greater than for CT scanning,
ranging from 50% to 88%.1,13,15,18,34-38,41,49,54,55 Thyroid
abnormalities and enlarged lymph nodes are a frequent
cause of false-positive results. 55,56 The most common
discernible causes for false-negative MRI imaging were
adenomas situated closely adjacent to a thyroid goiter and
cases of parathyroid hyperplasia. The results obtained for
hyperplasia are worse than parathyroid adenomas, probably
because of the size of the gland,35,41.53,57 although not all
authors agree." Gadolinium can also improve the differential contrast with the adjacent tissues. 59,60
Thallium 201-Technetium Tc 99m

Pertechnetate Scanning
Thallium uptake by parathyroid adenomas was initially
reported by Fukunaga and associates.s' The clinical application was performed using technetium 99m together with
thallium 201. 62,63 Subtraction of the two images obtained
help locate the abnormal parathyroid gland or glands. The
advantages of thallium 20l-technetium 99m pertechnetate
(TI-Tc) scanning are its availability, low risk, minimum
FIGURE 46-2. T2-weighted magnetic resonance image with left

upper parathyroid adenoma (arrow).

irradiation, and low operator dependence. Tumors located in
perithyroid areas, especially next to the inferior pole, are
localized more effectively.'" Conversely, no more than 50%
of glands in the mediastinum are localized. False-negative
results also depend on the size of the parathyroid glands,
because parathyroids weighing less than 0.5 g are usually
not detected.
The most common cause of false-positive results was
patient motion during examination. Also, thyroid lesions
such as adenomas, carcinomas, multinodular goiters, or
enlarged lymph nodes also cause false-positive results.f
Price,66 in a 1993 review of 1432 patients requiring
parathyroid reoperation in whom Tl-Tc scanning was used,
found an average sensitivity of 55% (range, 45% to 68%);
12% ofresults were false positive. The sensitivity of Tl-Tc
was even lower than 25% in the studies by Miller,36
Doherty," and their coworkers.
Tl-Tc scintigraphy was a widely used localization study
for parathyroid glands until the introduction of sestamibi
scanning.
Technetium 99m Sestamibi Scintigraphy

In 1988, Coakley and associates'" reported using technetium
99m sestamibi for cardiac function studies. Chiu and
colleagues'< demonstrated the incorporation of technetium
99m into the cytoplasm and mitochondria of mouse fibroblasts in response to certain stimuli. Parathyroid cells have a
large amount of mitochondria, which enables technetium
99m sestamibi to enter more intensely into the neighboring
thyroid tissue.s? O'Doherty and coworkers" compared
technetium 99m sestamibi and thallium 201 uptake and
observed a greater uptake per gram of sestamibi in the
parathyroid tissue. Recent studies relate the sestamibi
uptake with the absence of P-glycoprotein in parathyroid
adenomas," or even with the cellular proliferation ratio.P
There are three different technetium scanning methods.
1. Single-isotope dual-phase scan. The simplest procedure
was described by Taillefer and associates as the
double-phase study.73 A single radioisotope scan is
performed with cervicothoracic planar imaging at 10
to 15 minutes and also at 2 to 3 hours. For the cervical
area, a pinhole collimator can be used selectively to
improve the resolution. The late phase (2 to 3 hours) is
usually preferable for detecting abnormal parathyroid
glands because the thyroid clears the uptake faster
than the parathyroid adenomas.
2. Dual-isotope subtraction scan. Tc 99m sestamibi is used
in conjunction with another radionuclide specific to the
thyroid. Iodine 123 or Tc 99m pertechnetate (low cost
and quicker) are used for the thyroid subtraction.Y"
3. Three-dimensional studies. The major drawback of
anterior planar views (the most frequently used) is the
lack of spatial localization of the uptake. A combination of lateral or oblique planar views may help to find
abnormal parathyroid glands from adjacent and/or
superimposed strucrures.F:" With the help of the
computed reconstruction of sagittal or transverse scans
or even with three-dimensional images, single-photon
emission computed tomography (SPECT) allows
better localization of the uptake. 79-81 This is especially
useful in case of a mediastinal location. 82
FIGURE 46-3. Tc 99m sestamibi: left lower parathyroid adenoma

and thyroid adenoma follicular (false positive).
The sensitivity reported for sestamibi in persistent or

recurrent HPT ranges from 57% to 85%,13.15,18.37-43,50,54,55,83
but most of the series are close to 80%, There are not
significant differences between the use of the single-isotope
dual-phase and the dual-isotope subtraction scan, but
SPECT improves the results. 84
The most common cause of false-positive results is the
coexistence of benign thyroid disease (adenomas or multinodular goiter) (Fig. 46-3).85 Also, the presence of follicular,86 papillary," and Hurthle cell thyroid carcinomas."
primary thyroid lymphomas." and lymph nodes?" account
for false-positive sestamibi results (see Fig. 46-3). Falsenegative results, as in our own experience, are related more
to the smaller size of the gland. Intrathyroid, mediastinal
(Fig. 46-4), or deep cervical parathyroids can be localized
using technetium 99m sestamibi (i.e., its accuracy is not
FIGURE 46-4. Tc 99m sestamibi scan demonstrating a mediastinal parathyroid adenoma.
Localization Studies in Persistent or Recurrent Hyperparathyroidism - -
433
FIGURE 46-5. Undescended parathyroid adenoma in a Tc 99m

sestamibi scan.
related to location) (Figs 46-5 to 46-8; see also Figs. 46-3

and 46-4). Sestarnibi is inaccurate in patients with multiple
adenomas or parathyroid hyperplasia because often only one
of the multiple abnormal glands is identified.
Tc 99m tetrofosrnin is another isonitrile derivative of
pertechnetate. The uptake of tetrofosrnin in parathyroid
tissue is similar to sestarnibi, but the thyroid washout rate
is slower.90-93 The diagnostic sensitivity of tetrofosrnin is
identical to sestamibi using a dual-tracer subtraction method
but is markedly lower with the single-tracer method."
Tc 99m furifosrnin is also a useful tracer in parathyroid
tumors, but the experience reported is limited."
FIGURE 46-7. Intrathyroid adenoma (Tc 99m sestamibi scan).
In some cases, positron emission tomography (PET)

(lsF-fluorodeoxyglucose or lie-methionine) has been used
because of its increased uptake in neoplastic tissue. 96-98 The
results are good; however, there are a limited number of
studies published and the cost of PET scanning is high.
The characteristics of the most common noninvasive
localization methods are shown in Table 46-2.
Invasive Preoperative Methods

Invasive localization studies are indicated when the combined results of the noninvasive tests are negative, equivocal,
or conflicting.
FIGURE 46-6. Recurrent hyperparathyroidism in hyperfunctioning parathyroid cyst adenoma in a patient with multiple endocrine
neoplasia type 1 (Tc 99m sestamibi scan).
FIGURE 46-8. Sestamibi scan with thymic parathyroid adenoma.
Fine-Needle Aspiration
Fine-needle aspiration (FNA) of the parathyroid tumor performed under sonographic guidance can improve the results
obtained with US. FNA enables cytologic examination of
parathyroid hormone (PTH) measurement in the aspirate.
When the aspiration is positive for PTH, it confirms the
diagnosis of a parathyroid tissue." PTH determination is
more helpful than cytologic examination for diagnosing
parathyroid lesions because cytologists often have difficulty
in differentiating between a parathyroid gland and thyroid
tissue, and the sample may also be insufficient.l'" Karstrup
and associates'?' diagnosed 100% of the cases by bioassay
but only 60% by cytologic examination. McFarlane and
colleagues 102 also published excellent results for PTH assay
(specificity 100% and sensitivity 70%). Some clinicians
have recommended injection of 95% ethanol into parathyroid neoplasms to produce necrosis. Unfortunately, the
tumor may recur after the ethanol injection, and recurrent
laryngeal nerve injury also occurs. Furthermore, parathyroid
tissue is also unavailable for histologic examination or for
cryopreservation.
Parathyroid Arteriography
Proper parathyroid arteriography includes examination of
both thyrocervical trunks (to look for parathyroid glands in
the superior mediastinum, tracheoesophageal groove, or
intrathyroid or juxtathyroid location glands), the internal
mammary arteries (glands in the thymus and anterior mediastinum) and carotids (juxtathyroid or undescended glands),
and sometimes the selective catheterization of the superior
thyroid artery. Parathyroid adenomas appear highly vascularized and oval or round (see Fig. 46-9). The sensitivity
obtained with digital subtraction arteriography is around
60% to 65%; it is a difficult and expensive technique. 15,102,103
In selected cases, it is possible to do an angiographic
embolization of the localized adenoma (Fig, 46-9),104
because this helps document the exact location of the

parathyroid tumor.I'" Nilsson and coworkers.l'" however,
published significant results with sampling from large veins
such as the jugular vein, innominate vein, and superior cava.
A twofold gradient between the intact parathyroid hormone
(iPTH) concentration in peripheral blood and that in the
selective venous sample (SVS) establishes the site of the
venous drainage of the tumor. The problem arises in cases
in which this gradient is not attained and localization is
uncertain.l'" The sensitivity of the SVS ranges from 63%
to 83%.13,15.37,50,53,83.102,108 Jones and coworkers.l'" from the
University of California-San Francisco, reported 64 patients
with an exact location in 75% of cases, and the SVS was not
useful for the surgeon in only 17% of the cases.
This technique is the most sensitive and lateralizes about
80% of parathyroid tumors. 37,107.109 Furthermore, it is just as
accurate for mediastinal glands as for cervical glands and
depends on gland function rather than gland size. It is also
helpful when there is more than one abnormal parathyroid
gland and can convert an equivocal noninvasive study into a
positive one.
The reported sensitivity of localizing studies for persistent or recurrent HPT is shown in Table 46-3.
In cases of recurrent HPT after total parathyroidectomy
with autotransplant in the forearm, the first localizing study
to do is the iPTH gradient. PTH assay in the basilic vein of
both arms draining the graft, with or without ischemic
Selective Venous Sampling for Parathyroid

Hormone Assay
Angiography is performed primarily to outline the ve?ous
drainage, and it can obtain a sample for PTH assay. It IS an
expensive technique and requires an expert radiologist
because it is technically difficult. The samples must be taken
as selectively as possible from the smallest venous branches
FIGURE 46-9. Ectopic mediastinal adenoma is shown in an internal mammary arteriogram.
Localization Studies in Persistent or Recurrent Hyperparathyroidism - - 435
blockade, is usually diagnostic when there is at least a

twofold increase in relation to the other arnl.llO.lll It is recommended to do at least two positive studies before surgery.
Sestamibi, CT scan or MRI, and clinical palpation of the
arm may also be necessary. 112
In parathyroid carcinoma, CT and MRI are especially
useful for detecting mediastinal and thoracic recurrences."
US can be used for detecting cervical parathyroid carcinoma
recurrence. Sestamibi allows for whole-body scanning and
therefore may detect distant metastases.
Intraoperative Localization
Methods
Intraoperative Ultrasonography
High-resolution intraoperative US may be useful once the
peak of the learning curve has been reached and operating
time can be reduced significantly. Kern and colleagues"
found it to be more effective than any other preoperative
technique for intrathyroid or perithyroid glands. The benefit
of the routine use of intraoperative US in reoperative
parathyroid surgery has not been established.
Radio-Guided Parathyroid Surgery

Tc 99m sestamibi is the most common localization test in
recurrent parathyroid disease. It is possible to use an intraoperative gamma probe to detect abnormal parathyroid tissue.
This method permits minimally invasive surgery (including
video-assistedparathyroidectomy). Some authors report excellent resultsll3 117; however, longer follow-up and more studies
are necessary before this procedure can be applied routinely.
The problems of this approach are false-positive results

(thyroid disease), cost, and longer operative time.
Intraoperative PTH
Determination of intraoperative PTH (IOPTH) may confirm
the removal of the hyperfunctioning parathyroid tissue, thus
reducing the operative time. 1I8 . 119 If the basal levels of
IOPTH drop more than 50% 10 minutes after parathyroid
resection, it is indicative of successful surgery. Irvin and
coworkers 120.121 reported a sensitivity of 93% with this
method. These results have been confirmed by others," but
most patients had single adenomas. Perhaps, in persistent
parathyroid hyperplasia or double adenomas, the interpretation of the results is more difficult. Occasionally, the IOPTH
drop is less than 50%, especially if the initial basal iPTH
levels are not very high. For these reasons, this method needs
a careful interpretation by the surgeon, considering also the
previous sestamibi imaging and the surgical findings. 113
Injection of methylene blue or toluidine blue is of little
value and is not used.
Conclusions
Positive localization studies are necessary before neck
explorations for persistent or recurrent HPT. Noninvasive
imaging methods should be used first, and Tc 99m
sestamibi is the most accurate localizing study. Localization
studies should be used complementarily, such that the
results obtained individually improve significantly if the
studies are combined or concordant. Sestamibi and US may
be useful and inexpensive initial imaging studies. SVS, an
excellent invasive method, must be used if the rest of the
imaging studies are negative or discordant. IOPTH may be

useful in some cases but does not replace good surgical
experience and interpretation.
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Technique of
Parathyroidectomy
H. Jaap Bonjer, MD, PhD Hajo A. Bruining, MD, PhD
One of the pioneers of parathyroid surgery, Edward

D. Churchill, stated in 1931 that "the success of parathyroid
surgery must lie in the ability of the surgeon to know a
parathyroid gland when he sees it, to know the distribution
of the glands, where they hide, and also to be delicate
enough in technique to be able to make use of this
knowledge,"! More than half a century later, this statement
still describes perfectly the fundamentals of successful
parathyroid surgery. Therefore, the embryology and
anatomy of parathyroid glands are discussed before the
description of the technique of parathyroidectomy.
Embryology of Parathyroid
Glands
The parathyroid glands develop from the third and fourth
pharyngeal pouches.? The upper parathyroid glands
originate from the dorsal tips of pharyngeal pouch IV.3 The
ventral portion of pharyngeal pouch IV consists of the
ultimobranchial body, which is incorporated into the lateral
part of the developing thyroid and eventually supplies the
parafollicular or C cells. The common embryologic origin
of the lateral part of the thyroid and the upper parathyroids
accounts for the occasional intrathyroidal location of upper
parathyroids, although this is a rare observation."
The lower parathyroid glands arise from the dorsal part
of pharyngeal pouch III. The thymus, which originates from
the ventral part of pharyngeal pouch III, and the lower
parathyroid gland descend as a complex in a plane ventrally
to pharyngeal pouch IV. Therefore, the lower parathyroids
are usually found in a more anterior position than the upper
parathyroids. At the caudal descent, the lower parathyroid
usually dissociates from the thymus and is ultimately
located near the lower pole of the thyroid. The caudal migration of the complex of the lower parathyroid and thymus can
vary widely. In the case of absence of migration, the lower
parathyroid gland is found cranially to the upper pole of the
thyroid, mimicking a superior parathyroid. Thymic tissue
surrounding the undescended parathyroid can clarify the
true origin of the ectopic parathyroid gland. The absence of

thymic tissue caudally to the thyroid is another indicator of
an undescended lower parathyroid. When the lower parathyroid remains attached to the thymus during caudal migration,
it becomes positioned in the anterosuperior mediastinum.
Anatomy of Parathyroid Glands

Number of Parathyroid Glands
The presence of four parathyroid glands is most common in
humans. In dissection studies of 428 human subjects by
Gilmour, four parathyroid glands were found in 87% of all
patients and three parathyroids in 6.3%.5 Akerstrom and
colleagues reported comparable rates in an autopsy study of
503 cases." Four parathyroids were found in 84% and three
parathyroids in 3% of all patients in this study. The occurrence of supernumerary parathyroid glands is a rare entity
that nevertheless has important clinical consequences,
particularly in patients with hyperparathyroidism resulting
from multiple-gland disease. In a series of 2015 patients
who were operated on for primary hyperparathyroidism, a
hyperfunctioning supernumerary fifth parathyroid caused
hypercalcemia in 15 patients (0.7%).7 Nine of these patients
required reoperations to reveal the parathyroid tumor.
The majority of these fifth gland tumors were located in the
mediastinum, either in the thymus (n = 7) or related to the
aortic arch (n = 3). Edis and Levitt" reported a rate of
persistent hyperparathyroidism of 10% resulting from
an enlarged supernumerary parathyroid in patients with secondary hyperparathyroidism. In a series of 762 patients with
primary hyperparathyroidism, Wang and coworkers documented 6 patients with persistent hyperparathyroidism
caused by hyperfunctioning supernumerary glands (0.6%),
all of which were located in or in close association with
the thymus." In a dissection study of 428 cases, Gilmour
found supernumerary parathyroid glands in 29 cases
(6.7%).5 Five parathyroids were observed in 25 cases
(5.8%),6 parathyroids in 2 cases (0.05%),8 parathyroids in
1 case, and 12 parathyroids in another case. Akerstrom and
439

colleagues concluded in an autopsy study that most supernumerary glands were either rudimentary or divided." When
supernumerary parathyroids weighing less than 5 mg were
excluded, there were 24 cases of supernumerary glands
(5%). These supernumerary parathyroids were most frequently found in the thymus or in relation to the thyrothymic
ligament.
Location of Parathyroid Glands

The location of parathyroid glands varies widely as a result
of differences in degree of migration during embryologic
development. Superimposed on the various locations of
parathyroid glands are the displacements of parathyroid
glands that become enlarged in the process of ensuing
hyperparathyroidism. Enlarged parathyroid glands tend to
migrate in an areolar plane, which offers little resistance as
a result of gravity and perhaps swallowing and lower intrathoracic pressures.!" In some patients, these migrations result in
considerable displacement of parathyroid tumors. Awareness
of the common "pathways" of migration is invaluable in
parathyroid surgery.
Eighty percent of the upper parathyroid glands are found
at the cricothyroid junction, about 1 em cranial to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery (Fig. 47-1).6 The upper parathyroids, which are
tucked posteriorly to the upper pole of the thyroid, are usually covered by a fascial sheath connecting the thyroid to
the pharynx. More anteriorly situated upper parathyroids are
located on the surface of the thyroid, frequently underneath
the capsule of the thyroid. The unique feature of these subcapsular parathyroids is the freedom of movement of the
parathyroids within the capsule. This feature distinguishes
FIGURE 47-1. Locations of the upper parathyroid glands. The

more common locations are indicated by darker shading. The
numbers represent the percentages of glands found at the different
locations. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical
anatomy of human parathyroid glands. Surgery 1984;95:17.)
parathyroids from thyroid nodules, which cannot move freely.

The occurrence of intrathyroidal parathyroids is rare and
controversial. A subcapsular parathyroid is easily confused
with a true intrathyroidal parathyroid, which is surrounded by
thyroid tissue. Akerstrom and colleagues noted true upper
intrathyroidal parathyroid glands in three cases (0.2%) among
503 autopsies.f Wang considered the upper parathyroid
gland the most likely to be intrathyroidal because of the
close embryologic relationship of the primordium of the upper
parathyroid gland with the lateral complex of the thyroid. 1I
However, Wheeler and coauthors'? reported eight intrathyroidal parathyroid tumors in 7 patients (3.5%) in a series of
200 patients undergoing exploration of the neck for hyperparathyroidism. Seven of these eight intrathyroidal parathyroids were considered to be lower parathyroid glands. The
incidence of intrathyroidal parathyroids ranges from 0.5% to
3% in the literature.l':'>"
Normal upper parathyroid glands are found in the retroor paraesophageal space in I % of all cases. IS This space
is the site where enlarged upper parathyroids descend to
the superoposterior mediastinum. The importance of this
ectopic location of upper parathyroid glands is illustrated in
Figure 47-2. In a series of 104 patients with persistent
hyperparathyroidism, 34 parathyroid tumors were found in
the superoposterior mediastinum.'?
34
21
19
13
10
5
1
1
SUPERIOR POSTERIOR MEDIASTINUM

ANTERIOR MEDIASTINUM
BEHIND UPPER POLE OF THYROID
BEHIND CLAVICLE WITHIN THYMIC TONGUE
BEHIND LOWER POLE OF THYROID
BEHIND ESOPHAGUS
BEHIND ANGLE OFTHE JAW
INTRATHYROIDAL
FIGURE 47-2. Sites of 104 missing parathyroid tumors. (From

Wang CA. Parathyroid re-exp1oration: A clinical and pathological
study of 112 cases. Ann Surg 1977;186:142.)
Technique of Parathyroidectomy - -
The distribution of locations of the lower parathyroid

glands varies more widely (Fig. 47-3). More than half of the
lower parathyroids are located around the lower pole of the
thyroid. Twenty-eight percent of the lower parathyroids
are found in the thyrothymic ligament or within the thymus.
A rare location of lower parathyroids is high in the neck
at the carotid bifurcation, resulting from absence of embryologic migration. When lower parathyroid glands become
enlarged, they tend to migrate into the anterior mediastinum.
Figure 47-2 shows that one third of all missed parathyroid tumors were found in the thymus or in the anterior
mediastinum.
Gross Features of Parathyroid Glands

It is essential in parathyroid surgery to distinguish between
normal and hyperfunctioning parathyroid glands. Hyperfunctioning parathyroid glands are enlarged. Therefore, definition
of the normal size of a parathyroid gland is crucial. The size
of normal parathyroids varies considerably because parathyroids are easily molded as a result of their soft consistency.
The shape of the parathyroid gland is dependent on its
anatomic position. Parathyroids that are located in loose
tissue have an oval, bean, or teardrop shape. When parathyroids lie underneath a capsule, their shape is flat with sharp
edges. Although a particular shape of a parathyroid gland is
not associated with hyperfunction, a spherical shape often
indicates hyperactivity of the parathyroid.P
441
Because the shape of parathyroids is diverse, the parenchymal weight of parathyroid glands is the most reliable parameter for parathyroid function.P The weight of parathyroid
glands attains its maximum in men in the third decade of
life. 22 In women, there is a progressive rise until about the
age of 50 years. The weights of parathyroid glands are lower
in patients with chronic illnesses, except renal disease, and
lower in women than in men.P The weights of the lower
parathyroids are greater than those of the upper parathyroids. The normal weight of a parathyroid gland remains
uncertain. An upper limit of normal parenchymal weight of
38 mg for a single gland was reported by Gilmour and Martin."
Dufour and Wilkerson found an upper normal limit of 49 mg
for the parenchymal weight of a single gland.P Akerstrorn
and colleagues found a maximal normal glandular weight of
59 mg in an autopsy study of 368 cases without evidence of
hyperparathyroidism." Dufour and Wilkerson demonstrated
that 95% of the individual glands weighed between 8.2 and
75.0 mg. It should be noted that an overlap of the weights of
normal and abnormal parathyroid glands exists. In our series
of 1080 patients with hyperparathyroidism, several patients
became normocalcemic after removal of abnormal parathyroid
glands weighing only 60 mg. Underestimation of the weight of
parathyroid glands can easily occur when the parathyroid
lies underneath the capsule of the thyroid and only part of the
parathyroid can be examined. Therefore, the entire parathyroid
should be exposed before assessing its weight. Alternatively,
the weights of parathyroid glands, which are surrounded by
an abundance of fat, can be overestimated.
The color of normal parathyroid glands ranges from
yellowish brown to reddish brown. The color depends on
the amount of fat, number of oxyphil cells, and degree of
vascularity.P Enlarged parathyroid glands display colors
varying from dark brown to light yellow. In secondary or tertiary hyperparathyroidism, the enlarged parathyroids sometimes have a typical gray color. Parathyroid carcinomas can
also have a grayish white surface.
Blood Supply of Parathyroid Glands

Preservation of the blood vessels supplying the parathyroid
glands in parathyroid surgery is essential to prevent damage
to normal parathyroid glands. Most parathyroid glands have
a single artery (80%).26 The length of the parathyroid artery
can vary from I to 40 mm. In general, the parathyroid glands
derive their arterial branches from the inferior thyroid artery.
However, 20% or more of the upper parathyroid glands are
vascularized by the superior thyroid artery. Delattre and
coworkers" found in an autopsy study that 10% of the lower
parathyroid glands were dependent on an anterior branch of
the superior thyroid artery. In most of these cases, the inferior
thyroid artery was absent, which is not unusual at the left side.
Mediastinal parathyroids often have an artery that is a thymic
branch of the internal mammary artery." The venous return of
parathyroid glands runs almost parallel to the arterial vessels.
0.2
FIGURE 47-3. Locations of the lower parathyroid glands.
The more common locations are indicated by darker shading. The
numbers represent the percentages of glands found at the different
locations. (From Akerstrom G, Malmaeus J, Bergstrom R. Surgical
anatomy of human parathyroid glands. Surgery 1984;95:17.)
The diagnosis of hyperparathyroidism should be confirmed
by the assessment of an elevated serum parathyroid hormone
level using a two-site immunoassay.P" Localization studies

of enlarged parathyroid glands are necessary only in patients
having exploration of the neck for persistent or recurrent
hyperparathyroidism and in patients undergoing parathyroidectomy with local anesthesia.P-" We believe that pre- and
postoperative laryngoscopy to assess vocal cord function is
mandatory in (para)thyroid surgery.P
Anesthesia
Exploration of the neck is performed preferentially under
general anesthesia with endotracheal intubation. In patients
who are unfit for general anesthesia, an enlarged parathyroid
gland can be removed under local anesthesia when localization
studies have demonstrated the exact site of the parathyroid
tumor. 33
Positioning of the patient on the operating table is of paramount importance. The patient's neck should be extended
dorsally to provide optimal access to the neck. Care should
be taken not to overextend the neck to prevent postoperative
occipital head pain. The arms of the patient should lie alongside the body to allow the surgeon and the assistant to stand
on both sides of the neck. Long ventilation tubes facilitate
placement of the ventilator at some distance from the operating table, which creates space for the operating team. The
ventilation tubes can be fixed on the head of the patient
using a sheet or a special Velcro band (Fig. 47-4). The second
assistant can stand at the head of the table. Replacement of
the endotracheal tube in the case of rupture of the cuff is
difficult when the patient's head is covered with drapes.
Therefore, we recommend packing of the oropharynx with a
gauze strip to prevent gas leakage from any cause.
Exploration of the Neck

The use of magnifying glasses (2x) facilitates exploration of
the neck. Fine bipolar forceps are a valuable asset to prevent
diathermic injury of the recurrent laryngeal nerve. The ligation of small vessels is best done with a fine right-angled
dissection clamp. A symmetrical collar incision is made,
FIGURE 47-4. Positioning of the patient on the operating table for

(para)thyroid surgery. The neck is hyperextended, and the ventilation tubes are fixed on the head.
preferentially in a natural skin crease, 3 to 4 em cranially to

the suprasternal notch. An incision that is located too close
to the suprasternal notch is likely to become a hypertrophic
scar. The incision should not extend beyond the sternocleidomastoid muscles. After incising the platysma, the cranial
skin-platysma flap is dissected upward to the notch of the
thyroid cartilage and downward to the suprasternal notch.
A self-retaining retractor is used to withdraw the upper and
lower skin-platysma flaps. A midline incision is made in
the cervical fascia from the cricoid cartilage down to the
suprasternal notch. The sternohyoid and sternothyroid muscles are separated from the underlying thyroid and thymus.
If present, the middle thyroid vein must be divided to allow
the thyroid lobe to be retracted anteriorly and medially.
Transection of the strap muscles is unnecessary because
they can be retracted sufficiently by a wide blunt retractor,
held by the second assistant standing at the head of the operating table, who has the second best view of the operating
field, which is important for surgical education. The thyroid
lobe can be retracted by an Allis clamp or stitch. It is essential to free the thyroid and thymus from the strap muscles,
from the cricoid cartilage to the suprasternal notch, to obtain
complete exposure of the lateral aspects of the thyroid and
the thymus. Fascial sheaths covering the thyroid should be
removed until the surface of the thyroid is shiny; otherwise,
subcapsular parathyroid glands can easily be overlooked.
The fascia between the common carotid artery and the thyroid
should be opened alongside the carotid artery to have access
to the retroesophageal space. On the right side, care should
be taken to avoid injury to a nonrecurrent laryngeal nerve at
this step because this anomaly is more common on the right
side.34 Throughout the entire procedure, the surgical field
should be kept as bloodless as possible to prevent discoloring
the parathyroid glands, which impedes their identification.
Parathyroid glands are often (partially) surrounded by
fat. Therefore, any lobule of fat at the predilection sites of
parathyroids should be inspected. When the thin fascia that
covers the fat lobule is carefully opened, the parathyroid
gland usually "pops" out. Normal parathyroid glands have a
basic light brown color. The color is important to differentiate parathyroid glands from fat, which is more yellow, and
from thyroid nodules, which are more red in color. Another
important feature of parathyroid glands is their freedom of
motion in relation to the thyroid gland. When looking for
a parathyroid, it can be helpful to strike along the thyroid
with a peanut sponge to find moving structures. A thyroid
nodule can mimic a parathyroid gland but is more firmly
attached to the thyroid and does not have a distinct vascular
stalk. In the thyrothymic ligament or in the thymus, parathyroid glands can easily be confused with lymph nodes.
However, the consistency oflymph nodes is firmer than that
of parathyroids. Lymph nodes are also grayer than parathyroids. Palpation is another valuable method to detect
parathyroid tumors. In particular, enlarged upper parathyroids, which have descended dorsally to the inferior thyroid
artery, can often be more readily palpated than seen. On the
other hand, a negative palpation does not exclude the presence of a parathyroid tumor because the consistency of
parathyroids can be similar to that of the surrounding tissue.
A sense of abnormal local "fullness" may indicate the presence of a parathyroid tumor.
Technique of Parathyroidectomy - -
During the dissection of parathyroid glands, the vascular anatomy should be kept in mind. Dissection of the
upper parathyroid gland should be started at the dorsal
tip of the upper parathyroid to prevent injury to the
parathyroid vessels, which usually ascend from the inferior
thyroid artery. The dissection of the lower parathyroid
gland should start at the caudal end of the parathyroid
because the vascular hilus is on the cranial side of the lower
parathyroid. When a normal parathyroid gland becomes
devitalized during dissection, it should be cut with a razor
knife in small fragments of I mm! and replanted in the
sternocleidomastoid muscle. The recurrent laryngeal nerve
is not exposed routinely because the risk of injury to this
nerve is very low when delicate dissection is performed.'?
However, the surgeon should realize that the nerve can
be embedded in the anterior or medial capsule of an enlarged
upper parathyroid gland or in the dorsal capsule of an
enlarged lower parathyroid.
The parathyroid exploration is usually started by searching for the right upper parathyroid gland. The right upper
parathyroid is usually located behind or on the dorsum of
the thyroid cranial to the inferior thyroid artery. The posterior aspect of this part of the thyroid can be visualized adequately when the thyroid is retracted medially, the upper
part of the strap muscles retracted cranially, and the middle
part of the strap muscles retracted laterally. Retraction of
the strap muscles is best done by the second assistant with
blunt retractors while standing at the head of the operating
table. Gentle dissection of the fat lobules and fibrous
attachments of the thyroid reveals the majority of the upper
parathyroid glands. The dissection should be constantly
done under direct vision to prevent injury of the recurrent
laryngeal nerve, which runs anteriorly and medially to the
upper parathyroid gland. When the upper parathyroid
cannot be found in its usual site, the para- and retroesophageal space dorsal to the inferior thyroid artery should
be palpated. In the case of a descended upper parathyroid
tumor, dissection is facilitated when the assistant pushes the
descended parathyroid in a ventrocranial direction. When
considerable descent of an upper parathyroid has taken
place, the tumor can usually be moved upward by gentle
digital teasing. If regular dissection and digital exploration
have proved negative, the capsule of the upper pole of the
thyroid gland should be opened eventually to inspect for a
subcapsular-intrathyroidal parathyroid.
After this step, the exploration should proceed to the
right lower parathyroid gland. The search for the lower
parathyroid gland should start with thorough inspection
of the lower pole of the thyroid, the thyrothymic ligament,
and the thymus. When the lower parathyroid is not visualized at inspection, the junction of the thyrothymic ligament and the lower pole of the thyroid should be dissected.
In many cases, the lower parathyroid hides in the fat
between the inferior thyroid veins. Subsequently, the posterior aspect of the lower thyroid lobe should be inspected.
If the lower parathyroid has not been identified after these
steps, the thin sheath covering the thymus should be
incised. Rarely, a parathyroid tumor on the anterior surface
of the thyroid gland has been described. After this procedure, the other side of the neck should be explored in a
similar fashion.
443
Biopsies of Parathyroid Glands

The role of biopsies during parathyroid surgery is limited."
Some authors rely on the microscopic features of parathyroids to distinguish adenomas from hyperplastic glands.36-39
However, no single criterion has proved irrefutable in
making this differentiation.w" In a study of the histology
of parathyroid glands in 236 patients with primary hyperparathyroidism, significantly different morphologic features
in adenomas and primary hyperplasias could not be demonstrated." Therefore, the surgeon should assess the size and
color of the parathyroid glands and determine which
parathyroid glands are abnormal. Description of the disease
of hyperparathyroidism as "single-glanddisease" or "multiplegland disease" is a consequence of lack of microscopic distinction between adenomas and hyperplasia. The role of the
pathologist intraoperatively is limited to the identification of
parathyroid tissue."
Taking biopsy specimens of parathyroid glands routinely
increases the incidence of postoperative transient hypocalcemia/" Kaplan and coworkers'? compared the rates of postoperative transient hypocalcemia in one group of patients
with hyperparathyroidism having biopsies of all parathyroids
with those of another group having occasional biopsies.
The rates of postoperative transient hypocalcemia were 48%
and 26%, respectively. In our series of patients with nonfamilial hyperparathyroidism operated on before 1989, I of
156 patients with single-gland disease developed permanent
hypoparathyroidism, probably as a result of routine biopsies
of all parathyroid glands.
An alternative method to differentiate between normal
and abnormal parathyroid glands is the density test, as proposed by Wang and Rieder.48 The density test measures the
difference in total fat content of two parathyroid glands. A
low intercellular fat content indicates hormonal hyperfunction. However, detailed studies of normal parathyroid glands
have shown wide variations in the amounts of intercellular
fat. Seventy-five percent of normal glands have been shown
to have less than 30% intercellular fat and 50% of normal
glands less than 10% intercellular fat. With these data, estimations of intercellular fat content have become practically
useless as a parameter of normality.f'-" Tibblin and colleagues used the amount of intracellular fat to delineate
normal and abnormal parathyroid glands." Normal parathyroid glands contain easily detectable amounts of intracellular
fat, whereas in abnormal glands intracellular fat is decreased
or absent. However, these are not consistent findings.
Approximately 10% of parathyroid adenomas have significant amounts of intracellular fat, and hyperplastic glands
can stain for varying amounts of intracellular fat."
Resection of Parathyroid Tissue

In patients with nonfamilial hyperparathyroidism and
patients with multiple endocrine neoplasia (MEN) type 2
syndromes, only enlarged parathyroid glands with an estimated weight greater than 40 mg should be removed.44 53,54
In patients with a solitary enlarged parathyroid gland, the
vascular stalk of the tumor should be ligated and the tumor
removed. At the dissection of the parathyroid tumor, the
capsule of the parathyroid should not be opened to prevent

seeding of parathyroid tissue, which can cause recurrent
hyperparathyroidism.v-" The removed parathyroid tumor
should be weighed on precise scales before formalin fixation and sent to the pathologist for frozen section confirmation of the presence of parathyroid tissue. The normal-sized
parathyroid glands should be marked with a fine nonabsorbable suture to facilitate identification of the parathyroid
glands when a reoperation for recurrent hyperparathyroidism
is necessary.
In the case of enlargement of two or three parathyroid
glands, the enlarged glands should be removed. In our series
of 179 patients with multiple-gland disease, 120 patients had
two enlarged parathyroid glands, 40 had three enlarged
glands, 18 had four enlarged glands, and 1 had five enlarged
glands. After selective removal of the enlarged glands,
irrespective of their microscopic appearances, the rate
of recurrent hyperparathyroidism was 1.8% after an average
follow-up of 13.5 years.f If all parathyroid glands are
enlarged, the left and right thymus should be removed
because supernumerary parathyroid glands are frequently
located in the thymusf To prevent postoperative hypoparathyroidism, a remnant of approximately 50 mg of parathyroid
tissue should be left behind. An easily (re)accessible
parathyroid gland with a reliable vascular stalk should be
chosen for this purpose.
In patients with secondary hyperparathyroidism, familial
hyperparathyroidism, or MEN 1 syndrome, all parathyroid
glands are involved. The rate of recurrent hyperparathyroidism in these patients ranges from 10% to 50%.58-60
A subtotal parathyroidectomy should be performed, leaving
behind a well-vascularized remnant of a lower parathyroid
with the dimensions of a normal gland. The thymus should
be removed bilaterally because a supernumerary parathyroid gland is located in the thymus in 3% to 5% of all
patients."I,62 An alternative for subtotal parathyroidectomy is
total parathyroidectomy with autotransplantation of parathyroid tissue into the forearm muscles, combined with cryopreservation of some parathyroid tissue. 63
derivative) should be added to the oral medication. Symptoms

of muscular cramps and "tetany" must be promptly countered
with administration of intravenous calcium.
In some patients, symptoms of tetany may develop while
the serum calcium level is normal. This is probably due to a
rapid decrease in serum calcium after removal of the parathyroid tumor, causing increased neural excitability, but may
also persist after calcium replacement resulting from an
accompanying hypomagnesemia.v'
Troubleshooting for a Missing

Parathyroid Gland
The enlarged parathyroid gland can remain undiscovered
after routine exploration of the neck in some patients. Several
of such "classic" situations are described next. It is of great
importance to identify the normal parathyroid glands during
the exploration of the neck because a parathyroid missed at
its normal localization can indicate the site of the migrated
enlarged parathyroid.
Situation 1. Three normal parathyroid glands have been
identified but the (right) upper parathyroid gland cannot be
localized (Fig. 47-5). In this circumstance, the space dorsal
to the thyroid gland and the esophagotracheal groove should
be explored. The space between the esophagus and the vertebrae should be opened. Digital palpation for the parathyroid tumor can be helpful.
Situation 2. Three normal parathyroids have been identified, but the (right) lower gland is absent at the lower pole of
the thyroid and in the thyrothymic ligament (Fig. 47-6). The
thymus on the side of the missing lower parathyroid should be
exposed. The thymus is lighter in color and smoother than
the surrounding fat. The retrosternal part of the thymus can
be mobilized by applying light tension on the thyrothymic
ligament while freeing the thymus by delicate blunt dissection
with a peanut sponge.s" As the extraction of the thymus
Closure of the Neck Incision

After completion of the parathyroidectomy, the operative
field is thoroughly checked for hemostasis. A low-pressure
suction drain can be used. The strap muscles and the
platysma muscle are closed with an absorbable suture. The
skin is closed intracutaneously.
Postoperative Care
A successful parathyroidectomy results in a decrease in
the serum calcium level, which usually reaches its nadir
48 hours after the operation. Postoperative hypocalcemia
is most frequent in patients with severe skeletal depletion of
calcium, resulting in "bone hunger." The manifestations of
hypocalcemia include numbness around the mouth, tingling
of the fingertips, muscle cramps, carpopedal spasms, anxiety, convulsions, main d'accoucheur (Trousseau's sign), and
opisthotonos.f If symptoms appear, calcium should be
administered. Patients with hypocalcemia should be given
a maximum of 3 g of calcium orally per day. In the event
that this treatment is ineffective, alfacalcidol (a vitamin D
FIGURE 47-5. Situation 1. (Modified from Thompson NW,

EckhauserE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
Technique of Parathyroidectomy - - 445

Eckhauser E, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)

proceeds, a small clamp can be moved downward on the

thymus to extract the thymus out of the mediastinum. Use
of careful blunt dissection prevents injury of the large mediastinal vessels.
When the parathyroid tumor has not been found after performing the steps described in situations I and 2, an intrathyroidal parathyroid tumor should be considered. Incision of
the thyroid capsule can reveal an intrathyroidal parathyroid.
If a parathyroid tumor has not been found at this point, the
carotid sheath should be opened from the level of the carotid
bifurcation to the base of the neck. When this step has also
proved negative, the superior or inferior pole of the thyroid
gland should be excised for a missing upper or lower parathyroid gland, respectively.
Situation 3. Three normal parathyroids have been localized, but the (left) lower gland is missing (Fig. 47-7). At the
level of the superior thyroid artery and anterior to the carotid
bulb, an enlarged parathyroid gland with a thymic remnant
is encountered. A maldescended fourth pharyngeal pouch is
likely, resulting in a cranial position of the upper parathyroid
gland. This has been described by Edis and colleagues as an
undescended "parathymus,"?
Situation 4. Four normal parathyroids have been visualized (Fig. 47-8). Increased levels of parathyroid hormone
rule out another cause of hypercalcemia. This situation is
not uncommon and can be due to a tumor originating from
a supernumerary (fifth) parathyroid gland located in the
thymus. Resection of the left and right thymus is indicated.
Situation 5. One parathyroid is missing and a contralateral (left lower) gland seems slightly enlarged; the other
parathyroids are normal (Fig. 47-9). This is an awkward
situation because it is impossible to determine intraoperatively
whether this slightly enlarged parathyroid is hyperfunctioning.
In the case of moderate hypercalcemia with a mild clinical
picture, the slightly enlarged parathyroid can be removed
and the procedure completed. In severe disease, the steps in
situations I and 2 should be followed. Also, a concomitant
other cause of hypercalcemia may be present (e.g., sarcoidosis

or malignancy).
Situation 6. On one side, two normal parathyroids are
demonstrated; on the other side, a normal parathyroid has
been found just below the crossing of the recurrent laryngeal
nerve and the inferior thyroid artery (Fig. 47-10). In this
situation, it is unclear whether an upper or lower parathyroid
is missing; consequently, there is uncertainty about the
localization of the parathyroid tumor. In such a case, a virtual coronal plane should be drawn through the recurrent
laryngeal nerve.f When the normal parathyroid is located
anterior to this plane, the normal parathyroid is the lower
parathyroid. If the normal parathyroid is located dorsal to
the coronal plane, it is the upper parathyroid.


EckhauserE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery 1982;92:818.)
Normal parathyroid glands should never be removed

when a parathyroid tumor cannot be found at an exploration
of the neck for hyperparathyroidism. Removal of normal
parathyroids never decreases hypercalcemia. On the contrary,
it can cause permanent hypoparathyroidism when a successful
reoperation is performed.
A primary sternotomy should be considered only in
patients with life-threatening hypercalcemia.
Mediastinotomy
A mediastinotomy should be undertaken only after thorough
exploration of the neck, including inspection of the para- and
retroesophageal space and the left thymus and right thymus.
The anterior mediastinum is exposed through an additional vertical incision from the suprasternal notch to the second or third
intercostal space on either the right or left side. A complete sternotomy is done when the posterior mediastinum is explored.
Appropriate care should be taken not to injure the internal
mammary vessels or the pleura. The left innominate vein can
be retracted or divided to inspect the anterior mediastinum.
In a series of 400 patients with primary hyperparathyroidism, 84 mediastinal parathyroid tumors were observed/"
Only 19 (5%) parathyroid tumors had to be removed through a
mediastinotomy. Conn and coworkers reported that only 22%
of all mediastinal parathyroid tumors required splitting of the
sternum to remove the tumors." In this study, a mediastinal
parathyroid tumor was not found when thallium-technetium
scanning, computed tomography scanning, magnetic resonance imaging, or angiography of the mediastinum did not
detect a parathyroid tumor. In a large series of 2770 patients
with primary hyperparathyroidism, only 38 patients (1.4%) had
a mediastinotomy to remove an enlarged parathyroid gland."
Thoracoscopy has been reported to be a successful minimally invasive technique to remove parathyroid tumors located
deep in the mediastinum.F
The parathyroid glands that require a mediastinotomy for
removal are either ectopic lower parathyroids, which descended
into the anterior mediastinum during embryologic development, or supernumerary parathyroids. The blood supply of
these mediastinal parathyroids is usually derived from the
internal mammary vessels. Approximately 70% of the mediastinal parathyroid glands are found within or attached to the
thymus. 69,71 Other locations of mediastinal parathyroids are at
the ascending aorta, aortic arch, and its major branches and
occasionally on the pericardium.
Lateral Approach for

Parathyroid Exploration
The lateral approach for parathyroidectomy was first
described by Peind." This approach involves dissection
between the anterior border of the sternocleidomastoid
muscle and the posterior border of the strap muscles." The
omohyoid muscle is usually divided. Retraction of the sternocleidomastoid muscle and the carotid sheath laterally and
the strap muscles medially exposes the lateral aspect of the
thyroid gland, the tracheoesophageal groove, the recurrent
laryngeal nerve, and the parathyroid glands.
The lateral approach is preferable in parathyroidectomy
under local anesthesia because the limited dissection and
moderate retraction of the neck muscles are well tolerated by
patients.s" Another indication for the lateral approach is
parathyroidectomy after previous neck surgery. The lateral
approach in these patients provides a dissection plane more
likely to be devoid of scar tissue from the previous operation."
Summary
An understanding of the embryology of the parathyroid

glands and the ability to distinguish between a normal and
an abnormal parathyroid gland are essential for successful
Technique of Parathyroidectomy - - 447
parathyroid surgery. A systematic approach knowing the

routine and unusual locations for parathyroid glands results
in successful parathyroidectomy in more than 95% of
patients with primary hyperparathyroidism. Normal
parathyroid glands should not be removed, and biopsy
should be done selectively. Routine biopsy of normal
parathyroid glands results in more hypoparathyroidism.
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42. Nishiyama RH. Pathology of parathyroid tumors. In: Thawley SE,
Panje WR (eds), Comprehensive Management of Head and Neck
Tumors. Philadelphia, WB Saunders, 1987, p 1650.
43. Bonjer H1. Single and Multiple Gland Disease in Primary Hyperparathyroidism [thesis]. Rotterdam, The Netherlands, Erasmus
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44. Bonjer HJ, Bruining HA, Birkenhager lC, et al. Single and multigland
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45. Nishiyama RH. The intraoperative diagnosis of parathyroid lesions.
Acta Chir Aust 1994;112:8.
46. Edis AJ, Beahrs OH, van Heerden lA, Akwari OE. "Conservative" versus
"liberal" approach to parathyroid neck exploration. Surgery 1977;82:466.
47. Kaplan EL, Bartlett S, Sugimoto 1, Frediand A. Relation of postoperative hypocalcemia to operative techniques: Deleterious effect of excessive use of parathyroid biopsy. Surgery 1982;92:827.
48. Wang CA, Rieder SV. A density test for the intraoperative differentiation of parathyroid hyperplasia from neoplasia. Ann Surg 1978;187:63.
49. Dekker A, Dunsford HA, Geyer Sl, The normal parathyroid gland at
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50. Dufour DR, Wilkerson SY. The normal parathyroid revisited:
Percentage of stromal fat. Hum PathoI1982;13:717.
51. Tibblin S, Bondeson AG, Ljungberg O. Unilateral parathyroidectomy in
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52. Bondeson AG, Bondeson L, Ljungberg 0, Tibblin S. Fat staining in
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Clinicopathologic analysis of 191 cases. Hum PathoI1986;17:1255.
53. Thompson NW, Sandelin K. Technical considerations in the surgical
management of primary hyperparathyroidism caused by multiple gland
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54. Wells SA, Leight GS, Hensley M, Dilley WG. Hyperparathyroidism
associated with the enlargement of two or three parathyroid glands.
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55. Akerstrorn G, Rudberg C, Grimelius L, Rastad 1. Recurrent hyperparathyroidism due to parathyroid tissue. Acta Coo Scand 1988;154:549.
56. Rattner DW, Marrone GC, Kasdon E, Silen W. Recurrent hyperparathyroidism due to implantation of parathyroid tissue. Am 1 Surg
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57. Bonjer HI, Bruining HA, Bagwell CB, et al. Primary hyperparathyroidism: Pathology, flow cytometric DNA analysis, and surgical treatment. Crit Rev Clin Lab Sci 1992;29:1.
58. Lamers CBHW, Froeling PGAM. Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis type 1
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59. Clark OH, Way LW, Kunt TK. Recurrent hyperparathyroidism. Ann
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60. Marsden P, Day JL. Hyperparathyroidism: The risk of recurrence. Clin
61. Palmer JA, Sutton FR. Importance of a fifth parathyroid gland in the
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62. Goretzki PE, Dotzenrath C, Rocher 00. Management of primary
hyperparathyroidism caused by multiple gland disease. World J Surg
1991;15:693.
63. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy
versus total parathyroidectomy versus total parathyroidectomy and
autotransplantation in secondary hyperparathyroidism: A randomized
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64. Clark OH, Siperstein AE. The hypercalcemic syndrome: Hyperparathyroidism. In: Friesen SR, Thompson NW (eds), Surgical
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Lippincott, 1990, p 311.
65. Granberg PO, Cederrnark B, Farnebo LO, et al. Parathyroid tumors.

Curr Probl Cancer 1985;9:32.
66. Ahlers J, Rothmund M. Die cervicale Thymektomie als
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Hyperparathyroidismus. Chirurg 1980;51:629.
67. Edis AJ, Purnell DB, van Heerden lA. The undescended "parathymus":
An occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg 1979:190:64.
68. Pyrtek U, Painter RL. An anatomic study of the relationship of the
parathyroid glands to the recurrent laryngeal nerve. Surg Gynecol
Obstet 1964;9:509.
69. Nathaniels EK, Nathaniels AM, Wang CA. Mediastinal parathyroid
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70. Conn JM, Goncalves MA, Mansour KA, McGarity WC. The mediastinal parathyroid. Am Surg 1991;57:62.
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Experience with 38 tumors requiring mediastinotomy for removal. Ann
Surg 1981;193:805.
72. Prinz RA, Lonchyna V, Camaille B, et al. Thoracoscopic excision of
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73. Feind CR. Re-exploration for parathyroid adenoma. Am J Surg
1964; 108:543.
74. Stevens JC. Lateral approach for exploration of the parathyroid gland.
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Surgical Approach to Primary

Hyperparathyroidism
(Bilateral Approach)
Quan-Yang Duh, MD
Surgery offers the only definitive treatment for patients

with primary hyperparathyroidism. I The success of
parathyroidectomy depends on the skill and judgment of
the surgeon. The best surgical approach should give the
highest rate of cure with the lowest rate of complications.
In this chapter, issues that influence surgical strategy are
discussed. A strong case is made for surgeons to have a
good understanding of the embryologic development of the
parathyroid glands and to have experience in exploring
thoroughly both sides of the neck during the initial operation for primary hyperparathyroidism. Advances in localization studies and intraoperative parathyroid hormone
(PTH) monitoring allow the surgeon to limit the extent of
exploration in some patients. Bilateral exploration of all four
parathyroid glands, however, remains the "gold standard,"
against which the results of other approaches are evaluated.
Bilateral exploration is necessary in patients who are at high
risk for having multiple-gland disease, such as those with
familial syndromes and those with negative localization
studies. When in doubt, bilateral exploration, identifying all
four parathyroid glands, is most likely to result in the highest
success rate.
Indications for
Parathyroidectomy
Primary hyperparathyroidism is a common disease in nontropical areas of the world. It is found in 1 in 2000 men and
in 1 in 500 women after menopause and is more common
in elderly people. Because hypercalcemia is frequently
detected by routine laboratory studies and because of the
availability of specific, sensitive, and accurate assays for
intact PTH, most patients are diagnosed now at an early
stage. Thus, it is uncommon to see patients with severe
primary hyperparathyroidism with osteitis fibrosa cystica or

nephrolithiasis with renal dysfunction.
Etiology of Primary
Hyperparathyroidism
About 80% of patients with primary hyperparathyroidism
have a single adenoma, 15% have hyperplasia of all four
glands, and 5% have double adenomas.? The cause of
parathyroid adenoma or hyperplasia is not known. Head and
neck irradiation increases the risk of primary hyperparathyroidism by 11% per centigray.v' Ten percent of parathyroid
adenomas have a PRAD-I oncogene (cyclin D gene activated
by PTH promoter). Mutations in the calcium sensor protein
appear not to be an important cause of primary hyperparathyroidism.' although decreased calcium receptor has
been described in parathyroid adenomas and in hyperplastic
parathyroid glands in patients with chronic renal failure.
Retinoblastoma tumor suppressor gene is found to be frequently mutated in parathyroid cancers," whereas p53 mutations are rare.' Two thirds of apparently sporadic parathyroid
cancers have mutations in the HRPT2 gene, the gene responsible for the hyperparathyroidism-jaw tumor syndrome.!
Patients with multiple endocrine neoplasia (MEN) types 1
and 2A are more likely to have hyperparathyroidism, as are
family members of patients with familial hyperparathyroidism. In the mouse, deletion of the MEN 1 tumor suppressor gene in the parathyroid gland results in parathyroid
neoplasia and hypercalcemic hyperparathyroidism." Patients
with Cowden's disease'? (breast cancer, thyroid neoplasm,
and gastrointestinal polyps) and McCune-Albright syndrome!'
(caused by activating mutations of the stimulating guanosine
triphosphate-binding protein) are also at higher risk for
developing primary hyperparathyroidism.
449
Diagnosis of Primary
Hyperparathyroidism
The biochemical diagnosis of primary hyperparathyroidism
is made by documenting an elevated serum PTH in a patient
with hypercalcemia (serum calcium> to.5 mg/dL) without
hypocalciuria. Patients with benign familial hypocalciuric
hypercalcemia (BFHH) are also hypercalcemic and have an
inappropriately high PTH. Virtually all patients with other
causes of hypercalcemia have a suppressed serum PTH
level. Patients with BFHH have elevated levels of PTH
in the presence of hypercalcemia because of mutations in
the gene encoding the extracellular calcium sensor
protein, making the parathyroid cells less sensitive to
hypercalcemia.P BFHH can be suspected on the basis of a
family history and identified by low urinary calcium excretion (calcium clearance less than 1% of creatinine
clearance).
Cancer is the other most common cause of hypercalcemia." Patients with hypercalcemia of malignancy can
be diagnosed by a thorough history and physical examination. Many solid tumors associated with hypercalcemia
secrete parathyroid hormone-related protein (PTHrP);
others cause hypercalcemia through cytokines or by direct
bone destruction. With the exception of some very rare
renal cell carcinomas and ovarian carcinomas that secrete
PTH, none of these patients have elevated serum PTH
levels.
Other laboratory findings consistent with primary hyperparathyroidism include a low serum phosphorus level
2.5 mg/dL), elevated serum chloride level (> 107 mmol!L),
and elevated serum chloride-to-phosphate ratio (>33). Some
patients have elevated serum levels of alkaline phosphatase
and uric acid. Subperiosteal resorption can be demonstrated
in hand radiographs of patients with elevated alkaline
phosphatase levels. It is rare in other patients with primary
Mild Primary Hyperparathyroidism

The symptoms and signs of mild primary hyperparathyroidism can be more subtle and less specific, such as
fatigue, weakness, lethargy, depression, memory loss, personality changes, constipation, and decreased bone density.
It is controversial whether to operate on patients with few
or no symptoms or metabolic problems and minimal hypercalcemia. A prospective study of patients with primary
hyperparathyroidism showed, however, that truly asymptomatic patients are uncommon: less than 5% of patients."
Many patients with these nonspecific symptoms improved
after a successful parathyroid operation compared with a
control group of patients who underwent thyroidectomy.
Ninety-five percent had improvement of one or more symptoms after parathyroidectomy, and 55% felt better overall
(compared with 30% after thyroidectomyj.P The severity
of hypercalcemia did not correlate with the presence of
these symptoms before parathyroidectomy; neither did it
correlate with the improvement in symptoms after successful surgery.l-!"
Benefits of Parathyroidectomy
in Patients with Primary
Hyperparathyroidism
Patients with untreated primary hyperparathyroidism have
an increased risk of death from cardiovascular disease and
cancers. This increased risk of death is similar in magnitude
to that associated with smoking, and the risk appeared to
correlate with parathyroid tumor size and the peak calcium
level. 17,18
Parathyroidectomy benefits most patients with primary
hyperparathyroidism. Muscle strength and fine motor
function'? as well as psychiatric symptoms'" improve within
1 month after parathyroidectomy. The incidence of renal colic
decreases from 66% to 2% per year 1 year after parathyroidectomy." Left ventricular hypertrophy also improves
within 1year after parathyroidectomy.P Bone mineral density
improves after parathyroidectomy in patients with asymptomatic primary hyperparathyroidism, and the improvement is
sustained for at least 4 years after parathyroidectomy.-'
Quality of life measurement also improves after
parathyroidectomy.t'
Surgical Strategy in
Patients with Primary
Hyperparathyroidism
The primary goal of parathyroidectomy for patients with
primary hyperparathyroidism is to cure the primary hyperparathyroidism and to achieve normocalcemia. The best
surgical strategy should achieve this goal with minimal complications, such as persistent hyperparathyroidism, recurrent
hyperparathyroidism, postoperative hypoparathyroidism,
and recurrent laryngeal nerve injury, and with efficient use
of operating time and resources.
The most important variable that influences the success
of parathyroidectomy is the experience of the surgeon.
The success rate for parathyroidectomy reported by most
endocrine surgery centers is 95% or better. The rate of
persistent hyperparathyroidism can be as high as 30%
in less experienced hands." Persistent hyperparathyroidism
is usually caused by missing an ectopic tumor or missing
one of the multiple abnormal glands." Recurrent hyperparathyroidism usually occurs in patients with familial disease, such as those with familial hyperparathyroidism and
MEN 1.26
It is more cost-effective to have a higher success rate
in the initial operation than to rely on reoperation when
the initial operation fails. Although reoperation for hyperparathyroidism can be successful 90% of the time.i? it costs
twice as much because of the need for preoperative localization studies.l" and the risk of recurrent nerve injury is
higher.
The general principles that my colleagues and I follow
for surgical exploration in patients with primary hyperparathyroidism are listed in Table 48-1.
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - -
451
Double adenomas are more common in older patients;

the incidence is about 9% for patients older than 60 years."
Finding only a minimally enlarged parathyroid gland in a
patient who has severe hypercalcemia should also raise the
suspicion that another larger parathyroid tumor is present
and should be found and resected. When frozen section
reveals an oxyphil adenoma, one should also identify at least
four parathyroid glands because some oxyphil adenomas are
nonfunctional. Interestingly, double adenomas are not distributed randomly; it is much more likely to have bilateral
upper gland double adenomas than would be predicted by
random distribution.P
Initial Operation
No routine localization study is necessary before the initial
neck exploration for patients with primary hyperparathyroidism.29.30 A small, low cervical incision along the skin
crease is made. The strap muscles are dissected and separated
but are not divided. The surgical plane of dissection is different for parathyroidectomy and thyroidectomy. For thyroidectomy, I dissect as close to the thyroid gland as possible,
taking individual branches of the thyroid vessels on the thyroid
gland and leaving the parathyroid glands lateroposteriorly in
the surrounding tissue to preserve vascularity when the thyroid
gland is removed. For parathyroidectomy, I dissect more
laterally along the carotid sheath, leaving the parathyroids
on the posterior surface of the thyroid gland, thus making
them easier to find. Both sides of the neck are explored, and
all four glands are tentatively identified before any gland is
resected. I rarely perform mediastinotomy during initial
operation unless the patient is severely hypercalcemic
(serum calcium> 14 mg/dL after optimal medical treatment)
because many of these can be removed by thoracoscopy or
mediastinoscopy."
Single Adenoma
When a single large parathyroid tumor is found, the remaining three parathyroid glands are identified. The large tumor
is then excised and confirmed by frozen section. If there is
doubt about the nature of the normal-appearing parathyroid
glands, a biopsy of one of them can be performed by placing
a titanium clip at the tip of the gland away from the hilum to
avoid devascularizing the gland. The risk of postoperative
hypoparathyroidism is increased if biopsies of all normal
parathyroid glands are performed routinely, so routine biopsy
of all normal parathyroid glands should be discouraged.l? An
experienced surgeon can accurately identify 95% of normal
parathyroid glands, even without frozen section.
Double Adenomas
When two enlarged parathyroid glands are found, the
remaining two normal glands should also be identified. One
or both of the normal-appearing glands should be biopsied,
marked with a titanium clip, and confirmed by frozen section. This avoids leaving two hyperplastic glands should the
patient have parathyroid hyperplasia and asymmetrically
enlarged glands. The two tumors should then be excised and
confirmed by frozen section.
Hyperplasia
When all the glands are enlarged (>7 mm in largest dimension), the patient has hyperplasia. A subtotal parathyroidectomy is indicated. My routine procedure is to identify all
four glands and then perform a biopsy on the one that
appears the least abnormal and is away from the recurrent
laryngeal nerve, leaving a 50-mg remnant marked by a titanium clip. After the parathyroid tissue is confirmed by frozen
section and the remnant appears to be well vascularized and
viable, the remaining three abnormal glands can be excised
and confirmed by frozen section. If the remnant appears dusky
and its viability is questionable, with a high risk of postoperative hypoparathyroidism, it is completely excised, and a
second gland should be chosen for subtotal resection, and so
on. Performing the subtotal resection first before removing
the rest of the abnormal glands gives four chances to leave a
perfect remnant. Bilateral cervical thymectomy should be a
routine part of the operation in patients with hyperplasia
because supernumerary glands occur in 20% of patients and
are usually situated in the thymus or perithymic fat. Some
parathyroid tissue, preferably that from the least abnormal
hyperplastic parathyroid gland, should be cryopreserved. If the
patient becomes hypoparathyroid later, the tissue can then
be autotransplanted. Total parathyroidectomy with autotransplantation to the forearm is an alternative that I do not
usually use. It has a lower risk of recurrence but a higher risk
of hypoparathyroidism than subtotal parathyroidectomy for
parathyroid hyperplasia.
Total parathyroidectomy is indicated in children with
severe neonatal hypercalcemia because of the high risk
of persistent hyperparathyroidism after a subtotal
parathyroidectomy. Parathyroid tissue should also be
cryopreserved.
Parathyroid hyperplasia occurs in 15% to 20% of cases
in various published series. When hyperplasia is found, one
should be suspicious of familial hyperparathyroidism or
MEN. Patients with a family history of hyperparathyroidism
tend to have a more severe presentation clinically, are more
likely to have multiple gland disease, and are at higher risk
for persistent or recurrent hyperparathyroidism after
parathyroidectomy. Thyroid anomalies may also be associated with parathyroid hyperplasia. 34 If thyroid hemiagenesis
or agenesis of the isthmus is found in a patient with primary hyperparathyroidism, parathyroid hyperplasia should
be suspected.
Multiple Endocrine Neoplasia and Familial

Hyperparathyroidism
Patients with MEN 1 and familial hyperparathyroidism without other endocrine disorders usually, but not inevitably, have
hyperplasia; the gland size can vary significantly. When all
glands are enlarged, a subtotal parathyroidectomy or a total
parathyroidectomy with autotransplantation as well as bilateral thymectomy is indicated; some parathyroid tissue should
be cryopreserved. In patients with MEN 1 who have one or
two enlarged parathyroid glands, resection of only these
glands with biopsy of the normal-appearing glands is an
adequate operation with a higher risk of recurrent hyperparathyroidism over the patient's lifetime.P One alternative
is a unilateral clearance of all parathyroid tissues from the
affected side of the neck, including a unilateral cervical
thymectomy, so that if hyperparathyroidism recurs in the
remaining glands, the reoperation will be needed only on the
contralateral side."
Patients with MEN 2A can also have hyperparathyroidism. All of these patients warrant total thyroidectomy and possible central neck node dissection to treat or
prevent medullary thyroid cancer. In contrast to patients
with MEN I, those with MEN 2A are likely to develop
hypoparathyroidism after a subtotal parathyroidectomy. One
should, therefore, resect only the enlarged glands and biopsy
and mark the normal-appearing glands. Patients with MEN 2A
are much less likely to develop recurrent hyperparathyroidism than those with MEN I or familial hyperparathyroidism without MEN.35 Total parathyroidectomy with
autotransplantation is more aggressive than necessary for
these patients.
Location of Parathyroid Glands

An ectopically situated parathyroid tumor is a common cause
of persistent hyperparathyroidism (Fig. 48-1). This is one
reason why an experienced surgeon achieves a 95% success
rate for the initial parathyroid operation, by knowing where the
parathyroid glands are commonly found, whereas an inexperienced surgeon has only about a 70% success rate.25
The inferior parathyroid glands and the thymus develop
embryologicallyfrom the third branchial pouch. They descend
from the upper neck down to the anterior mediastinum.
Ectopic lower parathyroid glands can, therefore, be found anywhere along this long path of descent. The lower parathyroid
glands are usually on the surface of the lower pole of the
thyroid gland or in the thyrothymic ligament. They are frequently found within or adjacent to the thymus in the upper
anterior mediastinum and are rarely found in the carotid
sheath. The most common position of the inferior parathyroid
gland is anteroinferior to the junction of the inferior thyroid
artery and the recurrent laryngeal nerve.
The superior parathyroid glands develop from the fourth
branchial pouch. They descend less than the third branchial
pouch and, therefore, become the superior glands. The superior glands vary less in position than the inferior glands. The
most common location for the superior gland is just superoposterior to the junction of the inferior thyroid artery and the
recurrent laryngeal nerve at the level of the cricoid cartilage.
The superior parathyroid gland is frequently found in the
FIGURE 48-1. Locations of parathyroid tumors found at reoperation after a failed initial operation. Most of these parathyroid tumors
can be excised through a neck incision, and most would have been
found at the initial operation if the common ectopic locations were
thoroughly explored in both sides of the neck. (From Shen W, Duren
M, Morita E, et aI. Reoperation for persistent or recurrent primary
hyperparathyroidism. Arch Surg 1996;131:861. 1996, American
Medical Association.)
tracheoesophageal groove posteriorly and may descend along

the esophagus into the posterior mediastinum. Intrathyroidal
parathyroid glands occur in about I % of patients and may
originate from a superior or an inferior parathyroid gland.
Intrathyroidal parathyroid glands account for about 12% of
failed initial operations. Ultrasonography helps identify
these tumors."
Focused or Unilateral Neck

Exploration Versus Bilateral
Neck Exploration for Primary
Hyperparathyroidism
Rationale for Focused or Unilateral
Exploration
Currently, there are three different approaches to parathyroidectomy; they differ in the extent of exploration. For the
bilateral approach, the surgeon explores and identifies all four
parathyroid glands. For the unilateral approach, the surgeon
identifies two glands on the same side of the neck. For the
focused approach, only one gland (the presumed single adenoma) is identified.
There are potential advantages of a focused or unilateral
approach for parathyroidectomy. In theory at least, not having
to find all the other parathyroid glands when a parathyroid
adenoma is already identified can shorten the operating time
and lower the risk of injury to the recurrent laryngeal nerve
and other normal parathyroid glands. A focused approach
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - - 453
requires localization studies to pinpoint the most likely location of the adenoma. In the past, my colleagues and I used
the focused approach routinely only in patients undergoing
reoperations to avoid unnecessary dissection in scarred tissue;
this is possible with the aid of multiple localization studies.'?
With the widespread use of preoperative localization studies in patients undergoing the initial operation, the focused
approach has gained popularity. Several techniques have been
described; many are called "minimally invasive parathyroidectomy," including small lateral incision, local anesthesia,
gamma probe guidance, and video-assisted techniques. In
general, for a successful focused approach to parathyroidectomy, the surgeon needs to know where to start the operation
(localization studies) and when to stop (intraoperative PTH
monitoring or by calculation of probabilityl.P'-"
If bilateral exploration is planned for the initial operation,
no localization studies or intraoperative monitoring of PTH
is necessary because 95% of the abnormal glands can be
found by the surgeon without these studies. There is controversy regarding whether routine use of localization studies
for initial parathyroid surgery is economically justifiable or
necessary. If a focused or unilateral approach is planned, a
localization study is necessary to help the surgeon decide
where to start the exploration.
In the traditional unilateral approach, the surgeon chooses
the side of initial exploration randomly and does not use
localization studies or PTH monitoring.t" One side of the
neck is chosen randomly for the initial exploration. If a localization study has been done and it is positive, the side of the
neck where the adenoma is expected is explored. If an abnormal gland and a normal gland are found and confirmed by
frozen section, the abnormal gland is presumed to be the only
adenoma that is causing the patient's primary hyperparathyroidism. The contralateral side is not explored. If the initial
side shows two normal parathyroid glands, the contralateral
side is then explored to look for the adenoma. If two abnormal glands are found on the initial side, hyperplasia is presumed, and the contralateral side is explored to perform a
subtotal parathyroidectomy. If only one gland is found on the
initial side, the contralateral side is also explored/?
For focused exploration, localization studies are used to
direct where the exploration should be started. Intraoperative
PTH is used to monitor the drop in PTH; a greater than
50% drop from either the baseline or preexploration level
(whichever is higher) 10 minutes after excising the adenoma
predicts a successful operation." Once the adenoma is
found and the intraoperative PTH confirms that there
are no more pathologic parathyroid glands remaining, which
occurs in almost all cases of patients with a single adenoma,
the operation is concluded. There is controversy, however,
regarding the accuracy of intraoperative PTH monitoring to
predict the presence of a second adenoma or hyperplasia." It
has been shown that double adenomas are found in fewer
patients when focused exploration is used than when bilateral
exploration is used. The discrepancy is caused by some large
glands that are either "nonsecreting large parathyroid glands"
or "latent adenomas." Long-term follow-up is needed to
distinguish between the two possibilities.
There is an alternative way to perform a focused parathyroidectomy without using intraoperative PTH monitoring.
Both sestamibi scanning and ultrasonography are performed.
In two thirds of patients, both studies show a single adenoma

and are concordant in location. Focused exploration in this
subgroup of patient is successful in 96% without using intraoperative PTH monitoring.F
Although it may seem obvious that complications should
occur less with a focused or unilateral approach compared
with a bilateral approach, it remains to be proved. Studies
comparing the results of a focused or unilateral approach
with those of a bilateral approach have not compared them
by intent." Series of bilateral explorations routinely include
complicated cases of multiple adenomas and hyperplasia,
whereas series of focused or unilateral approaches have
selected the patients who are likely to have a single adenoma
and thus less likely to have failure or complications. Operating
time perhaps should be shorter for the more limited
approaches, but it is mostly surgeon dependent." Some
proponents of bilateral exploration argue that exploring
the remaining normal glands should not take longer than
the time spent waiting for the results of intraoperative PTH.
There are no prospective randomized studies comparing
these approaches.
Incidence of Multiple-Gland Disease and

the Accuracy of Localization Studies and
Intraoperative PTH Monitoring Determine
the Success of the Focused or the Unilateral
Approach
The most serious potential problem of the focused or unilateral exploration is failure to identify a second adenoma or
hyperplasia. This risk depends on the percentage of patients
with multiglandular disease, the accuracy of localization
studies to identify multiglandular disease, and the accuracy
of intraoperative PTH monitoring to identify a residual
pathologic parathyroid gland.r' The long-held belief that
15% to 20% of patients have multiglandular disease is being
challenged by some series with excellent short-term results
after a focused approach aided by preoperative sestarnibi
scanning and intraoperative PTH monitoring showing that
only 5% of patients have multiglandular disease.f Most
studies have shown that localization studies are much less
accurate for multiple-gland disease than for a single adenoma. The sensitivity of most studies is greater than 80%
for a single adenoma but much lower for multiglandular
disease. 46,47 A rule of thumb is that one third of patients with
multiglandular disease would have a negative scan, one third
would have a scan consistent with a single adenoma, and one
third would have a scan showing more than one abnormal
gland.f The accuracy of intraoperative PTH monitoring for
multiglandular disease also remains controversial."
Difficulty in Determining Whether a

Parathyroid Tumor is an Adenoma
or Hyperplasia
Inherent in the strategy of focused or unilateral exploration is
the assumption that one can identify an abnormal parathyroid
gland as an adenoma or as part of generalized hyperplasia.
Most endocrine surgeons and experienced endocrine pathologists believe that one cannot make a definitive diagnosis
of adenoma versus hyperplasia by examining only the

abnormal gland. Characteristics other than size of the gland
can help distinguish between an adenoma or a hyperplastic
parathyroid gland and a normal gland. Abnormal or hypercellular parathyroid tissue is darker, firmer, and more vascular;
sinks in saline; and has a low fat content and high cellularity.
A compressed rim of normal parathyroid tissue is suggestive
of an adenoma, but there are many exceptions.
Data from physiologic and molecular studies support the
existence of double adenomas. Intraoperative PTH monitoring shows that in some patients the PTH level does not
become normal until a second adenoma is excised. 48,49 Many
parathyroid tumors that are considered hyperplastic histologically can be shown to be monoclonal tumors. 50
Conclusion
Primary hyperparathyroidism can be definitively diagnosed
on the basis of an elevated serum PTH in hypercalcemic
patients without hypocalciuria. Asymptomatic patients with
minimal hypercalcemia appear to benefit from successful
parathyroidectomy, and 95% of patients can be cured when
treated by an experienced endocrine surgeon. Focused exploration and unilateral neck exploration are acceptable when the
probability of multiglandular disease is low; the success rate
is high if two preoperative localization studies show concordance or a successful localization study is combined with
intraoperative PTH monitoring. Bilateral neck exploration,
however, remains a safe approach with an excellent success
rate. Whether the focused or unilateral exploration is superior
to the bilateral approach in success rate, complication rate, or
cost-effectiveness remains to be proved by a prospective randomized study.
REFERENCES
1. NIH conference. Diagnosis and management of asymptomatic primary
hyperparathyroidism: Consensus development conference statement.
2. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of
double adenoma in patients with primary hyperparathyroidism.
BrJ Surg 1995;82:926.
3. Schneider AB, Gierlowski TC, Shore-Freedman E, et aI. Dose-response
relationships for radiation-induced hyperparathyroidism. J Clin
4. Tezelman S, Rodriguez JM, Shen W, et aI. Primary hyperparathyroidism in patients who have received radiation therapy and in patients
who have not received radiation therapy. J Am Coil Surg 1995;180:81.
5. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis
of the extracellular Ca 2+-sensing receptor gene in human parathyroid
tumors. J Clin Endocrinol Metab 1995;80:3107'
6. Cryns VL, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumorsuppressor gene in parathyroid carcinoma. N Engl J Med 1994;
330:757.
7. Hakim JP, Levine MA. Absence of p53 point mutations in parathyroid
adenoma and carcinoma. J Clin Endocrinol Metab 1994;78:103.
8. Shattuck TM, Valimaki S, Obara T, et aI. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J
Med 2003;349: 1722.
9. Libutti SK, Crabtree JS, Lorang D, et aI. Parathyroid gland-specific
deletion of the mouse Menl gene results in parathyroid neoplasia and
hypercalcemic hyperparathyroidism. Cancer Res 2003;63:8022.
10. Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric
carcinoma as manifestations of Cowden's disease. Surgery 1995;
118:115.
II. Cavanah SF, Dons RF. McCune-Albright syndrome: How many
endocrinopathies can one patient have? South Med J 1993;86:364.
12. Pearce SH. Clinical disorders of extracellular calcium-sensing and

the molecular biology of the calcium-sensing receptor. Ann Med
2002;34:201.
13. Deftos LJ. Hypercalcemia in malignant and inflammatory diseases.
14. Eigelberger MS, Cheah WK, Ituarte PH, et al. The NIH criteria for
parathyroidectomy in asymptomatic primary hyperparathyroidism: Are
they too limited? Ann Surg 2004;239:528.
15. Chan AK, Duh QY, Katz MH, et aI. Clinical manifestations of primary
hyperparathyroidism before and after parathyroidectomy: A casecontrol study. Ann Surg 1995;222:402.
16. Siperstein AB, Shen W, Chan AK, et aI. Normocalcemic hyperparathyroidism: Biochemical and symptom profiles before and after surgery.
Arch Surg 1992;127:1157.
17. Hedback G, aden A, Tisell LE. Parathyroid adenoma weight and the
risk of death after treatment for primary hyperparathyroidism. Surgery
1995;117:134.
18. Ogard CG, Engholm G, Almdal TP, Vestergaard H. Increased mortality in patients hospitalized with primary hyperparathyroidism during
the period 1977-1993 in Denmark. World J Surg 2004;28:108.
19. Chou FF, Sheen-Chen SM, Leong CPo Neuromuscular recovery after
parathyroidectomy in primary hyperparathyroidism. Surgery 1995;
117:18.
before and after parathyroid surgery. Am J Med 1994;96:101.
21. Jabbour N, Corvilain J, Fuss M, et aI. The natural history of renal
stone disease after parathyroidectomy for primary hyperparathyroidism.
22. Stefenelli T, Mayr H, Bergler-Klein J, et al. Primary hyperparathyroidism: Incidence of cardiac abnormalities and partial reversibility
after successful parathyroidectomy. Am J Med 1993;95: 197.
23. Silverberg SJ, Gartenberg F, Jacobs TP, et aI. Increased bone mineral
density after parathyroidectomy in primary hyperparathyroidism.
24. Pasieka JL, Parsons LL, Demeure MJ, et aI. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J
Surg 2002;26:942.
25. Malmaeus J, Granberg PO, Halvorsen J, et aI. Parathyroid surgery in
Scandinavia. Acta Chir Scand 1988;154:409.
26. Shen W, Duren M, Morita E, et aI. Reoperation for persistent or recurrent
primary hyperparathyroidism. Arch Surg 1996;131:861; discussion 867.
27. Weber CJ, Sewell CW, McGarity We. Persistent and recurrent sporadic
primary hyperparathyroidism: Histopathology, complications, and
results of reo peration. Surgery 1994;116:991.
28. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for
primary hyperparathyroidism. Surgery 1994;116:954.
29. Oertli D, Richter M, Kraenzlin M, et al. Parathyroidectomy in primary
hyperparathyroidism: Preoperative localization and routine biopsy of
unaltered glands are not necessary. Surgery 1995;117:392.
30. Roe SM, Bums RP, Graham LD, et al. Cost-effectiveness of preoperative localization studies in primary hyperparathyroid disease. Ann Surg
1994;219:582.
31. Prinz RA, Lonchyna V, Camaille B, et al. Thoracoscopic excision of
J Surg 1992; 16:791.
33. Milas M, Wagner K, Easley KA, et al. Double adenomas revisited:
Nonuniform distribution favors enlarged superior parathyroids (fourth
pouch disease). Surgery 2003;134:995; discussion 1003.
34. Duh QY, Ciulla TA, Clark OH. Primary parathyroid hyperplasia associated with thyroid hemiagenesis and agenesis of the isthmus. Surgery
1994;115:257.
35. Kraimps JL, Duh QY, Demeure M, Clark OH. Hyperparathyroidism in
multiple endocrine neoplasia syndrome. Surgery 1992;112:1080.
36. Feliciano DY. Parathyroid pathology in an intrathyroidal position.
Am J Surg 1992; 164:496.
37. Rodriguez 1M, Tezelman S, Siperstein AE, et aI. Localization procedures in patients with persistent or recurrent hyperparathyroidism.
Arch Surg 1994;129:870.
38. Carty SE, Worsey J, Vnji MA, et aI. Concise parathyroidectomy: The
impact of preoperative SPECT 99mTc sestamibi scanning and
intraoperative quick parathormone assay. Surgery 1997; 122: 1107;
discussion 1114.
Surgical Approach to Primary Hyperparathyroidism (Bilateral Approach) - - 455

39. Irvin GL 3rd, Dembrow VD, Prudhomme DL. Clinical usefulness
of an intraoperative "quick parathyroid hormone" assay. Surgery
1993;114: 1019; discussion 1022.
40. Wang CA. Unilateral neck exploration for primary hyperparathyroidism. Arch Surg 1990;125:985.
41. Haciyanli M, Lal G. Morita E, et al. Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in
patients with primary hyperparathyroidism and double adenoma. JAm
Coll Surg 2003;197:739.
42. Arici C, Cheah WK, Ituarte PH, et aI. Can localization studies be used
to direct focused parathyroid operations? Surgery 2001;129:720.
43. Wei JP, Burke OJ. Analysis of savings in operative time for primary
hyperparathyroidism using localization with technetium 99m sestamibi
scan. Am J Surg 1995;170:488.
44. Proye CA, Carnaille B, Bizard JP, et al. Multiglandular disease in
seemingly sporadic primary hyperparathyroidism revisited: Where are
we in the early 1990s? A plea against unilateral parathyroid exploration. Surgery 1992;112:1118.
45. Carneiro DM, Irvin GL 3rd. Late parathyroid function after successful
parathyroidectomy guided by intraoperative hormone assay (QPTH)
compared with the standard bilateral neck exploration. Surgery
2000;128:925;discussion 935.
46. Heller KS, Attie IN, Dubner S. Parathyroid localization: Inability to
predict multiple gland involvement. Am J Surg 1993;166:357.
47. Thompson GB, Mullan BP, Grant CS, et aI. Parathyroid iinaging with
technetium-99m-sestarnibi: An initial institutional experience. Surgery
1994; 116:966.
48. Weber CJ, Ritchie JC. Retrospective analysis of sequential changes in
serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999;126:1139; discussion 1143.
49. Kao PC, van Heerden JA, Taylor RL. Intraoperative monitoring of
parathyroid procedures by a 15-minute parathyroid hormone immunochemiluminometric assay. Mayo Clin Proc 1994;69:532.
50. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid
tumors in chronic renal failure and in primary parathyroid hyperplasia.
Surgical Approach to Primary

Hyperparathyroidism
Anders O. J. Bergenfelz, MD, PhD Sten A. G. Tibblin, MD, PhD
The purpose of surgical treatment in primary hyperparathyroidism (PHPT) is to remove enough abnormal parathyroid
tissue to make and keep the patient normocalcemic. Patients
with PHPT caused by a solitary parathyroid adenoma are
almost always cured by removal of this adenoma. To accomplish unilateral neck exploration, the side on which the
adenoma is located has to be known preoperatively, and this
should be a true solitary adenoma rather than hyperplasia
or multiple adenomas.
When Felix Mandl operated on his first patient for PHPT,
the general belief was that enlarged parathyroid glands
were the result of bone disease and deficiency of parathyroid
activity; his patient, Albert, initially received a parathyroid
homograft from a deceased patient. When the treatment
failed to improve Albert's condition, Mandl had the knowledge, confidence, and courage to re-explore the patient and
remove the pathologic parathyroid gland with at least temporary cure of the patient. I In the early days of parathyroid
surgery,removal of the enlarged gland was usually successful.
However, with the recognition of primary parathyroid hyperplasia as a distinct histopathologic entity, it became obvious
that more parathyroid tissue had to be removed.' To be sure
not to miss multiglandular disease, a bilateral neck exploration was advocated. Some surgeons even recommended
incisional biopsy of the three normal-appearing parathyroid
glands when a solitary parathyroid tumor was identified.
Later, Paloyan and associates" suggested that all patients
with PHPT had hyperplasia and should, therefore, be treated
by subtotal parathyroidectomy. During the 1970s, when the
number of patients diagnosed with PHPT rapidly increased,
it became obvious that bilateral neck exploration with
biopsy of all glands had its price because some patients
experienced postoperative hypocalcemia. In a Scandinavian
survey, including more than 600 parathyroid operations
performed during 1 year, hypocalcemia occurred postoperatively in about 15% of patients." Hypocalcemia occurred
456
less often in patients undergoing only excision of the adenoma

rather than biopsy and removal of more than one gland." A
unilateral approach in patients with PHPT had been originally
advocated in the 1970s by C. A. Wang.s He used intraoperative
oil red 0 staining and the saline float test to help determine
whether a parathyroid gland was normal or abnormal.
Unilateral parathyroidectomy was introduced in our department in 1977, and the initial 5-year results were presented
in 1982.6
The principle for the unilateral approach is to restrict the
neck exploration to the side on which the solitary adenoma is
located. Originally, we did not use any localization studies;
consequently, about half of our patients had unilateral
approaches because 50% of the solitary adenomas were
found on the left side and 50% on the right side. When
a parathyroid adenoma was localized intraoperatively, the
ipsilateral normal-appearing parathyroid and the adenoma
were both removed, thus eliminating presumably all
parathyroid tissue on this side. If the wrong side happened
to be explored first, the two normal parathyroids were left
intact and a contralateral exploration was performed. Again,
both the adenoma and the normal parathyroid glands
were removed on the second side. Intraoperative frozen
section histopathologic examination was used to confirm
the diagnosis of a solitary adenoma and a normal-sized
parathyroid gland.
Histopathologic Varieties
of PHPT
A variety of pathologic conditions cause PHPT (Fig. 49-1).

The most common cause of PHPT (85% to 90%) is a solitary benign parathyroid adenoma. Malignant tumors of the
parathyroid gland are extremely unusual, occurring in less
than 1% of cases; parathyroid cancers are sometimes difficult
to distinguish from atypical adenomas. Parathyroid tumor
metastases are certainly a sign of malignancy. Chief cell
Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - -
457
HYPERPARATHYROIDISM
FIGURE 49-1. Various forms of hyperparathyroidism encountered in the surgical practice. MEN = multiple endocrine neoplasia.
hyperplasia (four-gland parathyroid hyperplasia) constitutes

about 10% to 15% of all cases of PHPT. It affects all glands,
but the hyperplasias may vary considerably in size, color,
and configuration. Findings of microscopic areas of nodular
hyperplasia have been described by Harrison and colleagues," and their biologic significance seems to be minimal. Hyperplasia is identified as primary when there is no
obvious reason for it to occur. Secondary hyperparathyroidism (HPT) is usually caused by end-stage renal disease.
Secondary HPT usually resolves after successful kidney
transplantation.
Sporadic multiple adenomas can occur synchronously
or metachronously. Multiple adenomas occur much more
frequently in patients with multiple endocrine neoplasia
(MEN) 1 or 2 and in patients with familial HPT without other
endocrinopathies.
Oil red 0 staining of parathyroid tissue, as introduced by
Roth and Gallagher"and modified by Ljungberg and Tibblin,9
has helped pathologists distinguish between normal and
abnormal parathyroid tissue and between solitary adenoma
and hyperplasia. True solitary adenomas often have a compressed rim of normal parathyroid tissue. Characteristically,
the red stain is taken up by the suppressed chief cells, whereas
the hyperactive adenomatous cells do not take up this fat
stain. In the normal parathyroid, there is a homogeneous
picture of chief cells stained red by the oil red 0 as an
expression of the suppression. These criteria help differentiate between a solitary adenoma and a hyperplastic gland,
although some pathologists believe that it is impossible to
differentiate between a hyperplastic gland and an adenomatous gland without histologic evidence of another normal
gland. The advantageof giving the pathologista whole normalappearing parathyroid gland is to eliminate the possibility of
four-gland parathyroid hyperplasia as a cause of PHPT.
The cooperation of an experienced pathologist is essential. It is a great advantage for the pathologist if the
suppressed rim of normal parathyroid cells can be identified.
The surgeon can help the pathologist by tying a suture
around the vascular pedicle of the gland because the vessels
often first enter the normal compressed tissue of the
adenoma. Intraoperative oil red 0 staining is performed as a
complement to the conventional hematoxylin-eosin method.
Although this technique improves the diagnostic accuracy
and microscopic interpretation in some cases, it is still difficult to be completely sure of this diagnosis. Thus, among
165 consecutive patients with PHPT, all of whom had their
parathyroid stained by hematoxylin-eosin and oil red 0
intraoperatively, 8% were judged equivocal."
Results of Unilateral
Parathyroidectomy (Original
Approach)
When patients are considered for unilateral parathyroidectomy, it is important to exclude familial HPT because these
patients usually have multiple abnormal parathyroid glands.
Patients who had previous operations in their neck for either
parathyroid disease or thyroid disease are not candidates
for unilateral parathyroidectomy because the functional
parathyroid reserve cannot be evaluated.

Identification of a normal parathyroid gland is easy in most
instances, but occasionally it is difficult or even impossible.
Extensive exploration to identify normal parathyroid glands
should be avoided because it might result in ischemia of
the normal glands. When original exploratory principles were
followed in 102 patients in which the side of the parathyroid
neoplasm was unknown preoperatively, the intended operation
could be performed in 88 patients (i.e., unilateral parathyroidectomy either with or without bilateral exploration). In
14 patients, various examples of atypical exploration of
normal parathyroid glands were applied. I I Most commonly,
one or two of the normal glands were missing.'! In a multicenter study, including five departments of surgery, unilateral
neck exploration was compared to bilateral neck exploration in
regard to long-term effects on the serum calcium level.P In
each department, the prevailing exploratory principles were
strictly defined. All patients from a 5-year period fulfilling
these definitions and other inclusion criteria were analyzed
postoperatively and after 8 to 9 years with regard to calcium
status. Two percent of the patients who underwent unilateral
operations had hypercalcemia after 8.7 years, whereas 5% of
those patients who had a bilateral neck exploration had hypercalcemia after an average follow-up time of 8.0 years.
Permanent hypocalcemia occurred in 2% and in 6% of those
patients who had a unilateral and bilateral neck exploration,
respectively. Nonnocalcemia was observed in 96% of patients
who had unilateral neck exploration. In patients who had bilateral neck exploration, 89% were normocalcemic.P
Also, the frequency of early postoperative hypocalcemia
was significantly lower in the patients who had unilateral
neck exploration as compared to patients who had bilateral
neck exploration. None of the patients who had a unilateral approach had a postoperative serum calcium below
2.00 mmollL, whereas among patients who had a bilateral
approach 19% had serum calcium levels below 2.00 mmollL.
Preoperative Localization
Without preoperative localization, the chance of exploring the
correct side in which the parathyroid adenoma is located is
50%. 6 If the adenoma is not found on the initial side, the contralateral side has to be explored, which increases operative
time and possibly morbidity. The accuracy of available imaging studies for parathyroid localization depends on the size and
position of the adenoma, the degree of parathyroid hyperfunction, and other unknown factors. In patients with mild PHPT
and a small parathyroid adenoma, localization studies are less
successful. This is one reason that preoperative localization
procedures are generally considered unnecessary and costly"
by most surgeons who routinely perform bilateral neck exploration. An experienced surgeon is able to find the abnormal
parathyroid gland or glands in 92% to 98% of patients. 14
Ultrasonography of the neck gives good results when the
adenoma is large, when it is situated in the neck, and when
there is a normal thyroid gland." The accuracy of ultrasonography for localizing parathyroid neoplasm is operator and
equipment dependent. When ultrasonography is combined
with fine-needle aspiration biopsy and parathyroid hormone
(PTH) sampling of the suspected lesion, the accuracy of the
method when positive approaches 100%.16
Isotope methods for parathyroid localization studies have

been used extensively during the past 20 years. Thalliumtechnetium subtraction scintigraphy was initially used but
has been replaced by sestamibi scintigraphy, which has
high sensitivity and positive predicted value for solitary
parathyroid adenomas." By adding delayed sestamibi scans'?
and single photon-emission computer tomography" or
oblique views with a higher dose of Tc 99m sestamibi," an
even higher accuracy might be possible. Although sensitive
for localizing a solitary parathyroid adenoma, sestamibi
scintigraphy is less accurate for identifying multiglandular
disease. 2o-22 Furthermore, small parathyroid adenomas are
localized less accurately.22,23
We have used selective venous sampling and intact PTH
assay in two variations. First, we have used it preoperatively
to help identify the region of the elusive parathyroid tumor.>'
We have also directly punctured the jugular veins and
obtained blood for PTH sampling after induction of anesthesia.
For the latter studies, we used a rapid method for the analysis
of intact PTH levels. A high degree of specificity (92%)
could be reached with this method; the sensitivity
was 64%.25 This test is more reliable when the parathyroid
adenoma is the superior gland and drains directly into the
jugular vein. When the parathyroid adenoma is in the lower
gland position, the accuracy is lower. Hence, the ideal localization procedure has yet to be developed. Currently, we
advocate the use of preoperative localization procedures in
the following clinical situations: (1) in patients with previous thyroid or parathyroid surgery and (2) in patients in
whom a focused parathyroid exploration is planned.
Intraoperative Monitoring
ofPTH
Intraoperative measurement of intact PTH concentration
during parathyroidectomy was first described by Nussbaum
and associates.i" A highly sensitive intact PTH assay was
modified, enabling the incubation time to be shortened to
about 15 minutes. After removal of a parathyroid adenoma,
there is a sharp decrease in the PTH level if the PHPT was
due to a solitary parathyroid adenoma (Fig. 49-2). Several
groups-"!' have subsequently reported similar findings. An
even shorter turnaround time is possible when the analytic
equipment, including proper laboratory personnel, is situated in the operating room." When a macroscopic diagnosis
is strongly suggestive of a solitary adenoma, the wound may
be closed but the patient is kept under anesthesia. When the
PTH level fails to drop after removal of the suspected adenoma, the removed gland either is not of parathyroid origin or
is a normal parathyroid gland (Fig. 49-3). When the removed
lesion is of parathyroid origin and the PTH level decreases
less than 60% at 15 minutes after gland removal, parathyroid hyperplasia or double parathyroid adenoma should be
suspected and a comprehensive bilateral neck exploration
performed (Fig. 49-4).29 The quick intact PTH assay offers
the advantage of a functional evaluation of the surgical
procedure and therefore renders intraoperative histologic
examination unnecessary.
Some surgeons have proposed that when the same solitary
parathyroid tumor is identified by both sestamibi scintigraphy
Surgical Approach to Primary Hyperparathyroidism (Unilateral Approach) - -
Excision of enlarged parathyroid gland
Excision of enlarged parathyroid gland
100
100
Q)
Q)
::J
::J
75
75
Ql
Ql
.5:
Qj
::l
.c 50
.5:
'5
Qj
50
'5
~
e....
459
J:
6:
25
OL-,..----,------,----,
10
15
and ultrasonography, a focused parathyroid exploration can

be done with a 95% success rate." Other surgeons suggest
that from a cost-effective standpoint, same-day PTH testing
for minimal invasive parathyroidectomy is superior to intraoperative PTH monitoring.>' Clearly, these issues can only
be definitively resolved by a multicenter, prospective, randomized trial.
125
Excision of
parathyroid
adenoma
100
,,
..
75
50
25
5 10 15
10
Time (min)
15
- - Patients with parathyroid adenoma N =43
Time (min)
FIGURE 49-2. Decline of intact parathyroid hormone (PTH) after

excision of one enlarged parathyroid gland in 43 patients with
primary hyperparathyroidism due to a solitary parathyroid
adenoma. Results are shown as a percentage of baseline value and
means ( SD).
Excision of two
normal parathyroid glands
25
Ilr- -t>.
NO.1)
v- -..., No.2
0- - -0
0---0
Patients with primary parathyroid

No.3 hyperplasia
NO.4
FIGURE 49-4. Decline of intact parathyroid hormone (PTH) in

four patients with primary parathyroid hyperplasia at 15 minutes
after removal of one enlarged gland compared with 43 patients
with primary hyperparathyroidism due to solitary parathyroid
adenomas. Individual values are shown for the patients with
hyperplasia, whereas for those with parathyroid adenoma the mean
is shown (2 SD).
Surgical Treatment of PHPT

under Local Anesthesia
Some patients with PHPT have coexisting severe cardiovascular disease and respiratory insufficiency.Pv" Surgical
removal of parathyroid adenomas under local anesthesia'r' !
was initially proposed as an attractive alternative to longterm medical treatmenr'v" or percutaneous biochemical
ablatiorr'" for high-risk patients. Focused parathyroidectomy
under local or regional anesthesia has been proposed as an
alternative to operation under general anesthesia for most
patients with PHPT.45-48 Parathyroid exploration under local
anesthesia is well tolerated by patients, and heart rate and
blood pressure fluctuate less than in patients having neck
exploration under general anesthesia.t"
For patients who have a focused parathyroidectomy
under local anesthesia, accurate localization studies are of
paramount importance. If noninvasive localization studies
are performed, we recommend that the results of at least two
tests should agree for definite localization because of a high
incidence of false-positive results." As an alternative, ultrasonography combined with fine-needle aspiration for PTH
sampling of the suspected lesion may be used."
10 15
Time (min after gland excision)
FIGURE 49-3. In a 45-year-old woman with primary hyperparathyroidism, two parathyroid glands were interpreted as being
macroscopically enlarged and excised. Frozen section showed
normal parathyroid tissue. The parathyroid hormone (PTH) level
did not decrease until a 0.38-g parathyroid adenoma was removed.
Data are shown as a percentage of baseline value.
Minimal Invasive
Parathyroidectomy
Owing to the advancement in preoperative localization procedures, as well as intraoperative PTH monitoring and refinement of surgical technique, endoscopic and video-assisted
parathyroidectomyhave recently been introduced and are proposed to improve cosmesis and reduce postoperative pain.50-55
Conversionto standard bilateral neck exploration occurs in 8%
to 15% of the patients,52,56 which is close to the 7% reported
with a conventional minimal invasive parathyroidectomy."
Advantages of Unilateral
Parathyroidectomy
Good results have been claimed by the proponents of the
unilateral approach, with a decreased risk of hypocalcemia I 1,12.58,59 and vocal cord injury.58 Furthermore, focused
parathyroidectomy has been suggested to lower costs, shorten
hospital stay, and enhance recovery time.6-63 In agreement
with these studies, a systematic review comparing unilateral
with bilateral neck exploration indicated a tendency to favor
the unilateral procedure.v'
Recently, the first prospective, randomized, controlled
trial comparing unilateral and bilateral neck exploration for
PHPT was reported.P Cure rate and costs did not differ
between the two groups. However, the patients in the bilateral group had a higher incidence of early symptomatic
hypocalcemia and lower serum calcium values on postoperative days I to 4 compared with patients in the unilateral
group. In addition, in patients with PHPT due to a solitary
parathyroid adenoma, unilateral neck exploration was associated with a shorter operative time. Complications occurred
mainly in the bilateral group.P
Conclusion and Future Aspects

High-quality preoperative localization procedures such as
sestarnibi scintigraphy and ultrasonography as well as the
introduction of intraoperative monitoring for intact PTH
serum levels have facilitated the treatment of patients with
solitary parathyroid adenoma. Minimal invasive parathyroidectomy is the ideal surgical treatment for patients with
PHPT due to a single parathyroid adenoma. In a survey of the
members of the International Association of Endocrine
Surgeons, more than half of them indicated that they current!y
perform minimal invasive parathyroidectomy and use the
technique for an average of 44% of the patients with PHPT.65
Several questions need to be addressed in the future,
such as the role of video-assisted parathyroidectomy
compared to a focused conventional approach, and the
precise role for parathyroidectomy under local anesthesia.
Furthermore, although a 5-year follow-up has shown that
measurement of intraoperative PTH can predict long-term
operative success.t" long-term data from prospective,
randomized trials are necessary to provide the answer to a
possible difference in long-term normocalcemia between
the different surgical strategies.
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the intact PTH during surgery for primary hyperparathyroidism.
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30. Ryan MF, Jones SR, Barnes AD. Modification to a commercial immunoradiometric assay permitting intraoperative monitoring of parathyroid
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33. Miura D, Wada N, Arici C, et aI. Does intraoperative quick parathyroid
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34. Agarwal G, Barakate MS, Robinson B, et aI. Intraoperative quick
parathyroid hormone versus same-day parathyroid hormone testing for
minimally invasive parathyroidectomy-A cost-effectiveness study.
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35. Palmer M, Bergstrom R, Akerstrom G, et aI. Survival and renal
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36. Palmer M, Adami HO, Bergstrom R, et aI. Mortality after surgery
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37. Ronni-Svivula H. Causes of death in patients previously operated on
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40. Bergenfelz A, Algotsson L, Ahren B. Surgery for primary hyperparathyroidism performed under local anaesthesia. Br J Surg
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42. Lafferty FW, Hubay CA. Primary hyperparathyroidism: A review
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43. Jansson S, Tisell LE, Linstedt G, Lundberg PA. Disodium pamidronate
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44. Karstrup S, Transbol I, Holm HH, et aI. Ultrasound-guided chemical
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45. Chapuis Y, Fulla Y, Bonnichon P, et aI. Values of ultrasonography sestamibi scintigraphy and intraoperative measurement of 1-84 PTH for
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46. Inabnet WB, Fulla Y, Richard B, et aI. Unilateral neck exploration
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47. Chen H, Sokoll LJ, Udelsman R Outpatient minimally invasive

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48. Ditkoff BA, Chabot J, Feind C, et aI. Parathyroid surgery using monitored anesthesia care as an alternative to general anesthesia. Am J Surg
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49. Harness JK, Ramsberg SR, Nishiama RH, et aI. Multiple adenomas
of the parathyroids: Do they exist? Arch Surg 1979;114:468.
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51. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted
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53. Dralle H, Lorenz K, Nguyen-Thanh P. Minimally invasive videoassisted parathyroidectomy-selective approach to localized single
gland adenoma. Langenbecks Arch Surg 1999;384:556.
54. Miccoli P, Bendinelli C, Berti P, et aI. Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: A prospective randomized study. Surgery 2000;128:121.
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56. Henry JF, Iacobone M, Mirallie E, et aI. Indications and results of
video-assisted parathyroidectomy by a lateral approach in patients with
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59. Westerdal J, Lindbom P, Valdemarsson S, et aI. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism.
Arch Surg 2000;135:142.
60. Irvin GL III, Sfakianakis G, Yeung L, et aI. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;
131:1074.
61. Udelsman R. Six hundred fifty-six consecutive explorations for
primary hyperparathyroidism. Ann Surg 2002;235:665.
62. Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive
minimally invasive parathyroid explorations. Ann Surg 2000;232:331.
63. Udelsman R. Is unilateral neck exploration for parathyroid adenoma
appropriate? Adv Surg 2000;34:319.
64. Reeve TS, Babidge WJ, Parkyn RF, et aI. Minimally invasive surgery
for primary hyperparathyroidism: Systematic review. Arch Surg
2000; 135:481.
65. Sackett WR, Barraclough B, Reeve TS, Delbridge LW. World-wide
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137:1055.
66. Westerdahl J, Lindblom P, Bergenfelz A. Measurement of intraoperative parathyroid hormone predicts long-term operative success. Arch
Surg 2002;137:186.
Minimally Invasive
Parathyroid Surgery
Paolo Miccoli, MD Piero Berti, MD
Minimally invasive procedures proposed for the treatment

of primary hyperparathyroidism (PHPT) have become widespread after the first operation performed by Michel Gagner
in 1996.1 This term, however, can be misleading if one
assumes that the simple shortening of the surgical scar is
enough to define a surgical procedure as minimally invasive.
In fact, if one uses the guidelines of the 1990 National
Institutes of Health Consensus Conference as the starting
point, all operations other than bilateral exploration with
possible biopsy of suspected enlarged parathyroid glands
constitute less invasive surgery; however, less invasive does
not mean minimally invasive.
The concept of invasiveness cannot be limited only to the
length of the skin incision but must be extended to other
structures, and above all this reduction in invasiveness must
not decrease the operative field of vision. For this reason,
an endoscope is usually (although not always) used in minimally invasive procedures. This chapter examines mainly
endoscopic procedures. These can be performed either with
gas flow insufflation and trocars or with external retraction
instead of gas insufflation.
Techniques
Although several approaches have been proposed as endoscopic parathyroidectomy, the most commonly used are
the (1) endoscopic parathyroidectomy (Gagner, 1997),2
(2) video-assisted parathyroidectomy with external retraction
(Miccoli, 1997),34 and (3) videoscopic parathyroidectomy
by a lateral approach (Henry, 1998).5
Endoscopic parathyroidectomy was the first technique
described for endoscopic parathyroidectomy. It uses steady
gas flow, not exceeding 8 mm Hg pressure." A 5-mm endoscope (0 degrees when starting and 30 degrees once the subplatysmal plane is reached) is inserted through a central neck
trocar and two or three additional trocars are used for the
instruments (Fig. 50-1). Needlescopic instruments are used.
462
The subplatysmal plane is dissected to obtain a good working space. The space anterior to the sternocleidomastoid
muscle is then opened and the strap muscles are retracted
medially to expose the thyroid lobes. The parathyroid glands
are explored after the thyroid is dissected from the investing
fascia. Once the parathyroid adenoma is completely mobilized, the vascular pedicle is dissected and divided between
two 5-mm clips. The gland is then extracted in a small
sac made from a fingertip from a surgical glove. A quick
parathyroid hormone assay (qPTHa) is performed 10 and
20 minutes after resection. A bilateral exploration is possible with this technique.
Video-Assisted Parathyroidectomy
Video-assisted parathyroidectomy is a technique that
requires no trocars or gas insufflation. The patient's neck is
not hyperextended so as to allow a sufficient operative space
under the strap muscles. A 15-mm transverse incision is
made 2 em above the sternal notch; even minimum bleeding
should be avoided since gasless procedures cannot take
advantage of the hemostatic effect of gas pressure. The strap
muscles are then separated in the midline longitudinally for
not more than 3 em. One retractor laterally retracts the strap
muscles on the side of the suspected adenoma gently to
include the carotid artery while the other one retracts medially to include the thyroid lobe. The thyrotracheal groove is
then exposed after cutting the middle thyroid vein between
the clips. The lobe is mobilized from the strap muscles using
only small spatulas under direct vision.
A 30-degree endoscope, 5 mm in diameter, is then introduced through the incision, and from this point on the entire
procedure is performed endoscopically using small reusable
surgical instruments (spatulas, forceps, scissors, and vascular clips) (Fig. 50-2). Three surgeons are generally involved
in this video-assisted procedure: (1) the operator, (2) the first
assistant (holding the endoscope and a spatula-aspirator),
and (3) a second assistant holding the retractors, one more
than during the endoscopic procedures. Usually, only one
side of the neck is explored, but the opposite side can be
explored through the same incision if necessary. Once the
Minimally Invasive Parathyroid Surgery - - 463
FIGURE 50-1. Endoscopic approach (Gagner procedure).
adenoma is located it is dissected without disrupting the

which ~s
capsule using spatuias. The pedicle. of t~e gl~d,
well visualized under optical magnification (FIg. 50-3), IS
then clipped. The adenoma is then retrieved.throug~
the skin
incision. The incision is generally closed WIth a skin sealant
while the surgeon is waiting for the result of the qPTHa.
Lateral Approach Parathyroidectomy

The lateral approach parathyroidectomy, as described by
Henry and associates,' uses a 12-mm. skin incision on ~e
medial border of the sternocleidomastoid muscle on the SIde
of the lesion. A lO-mm trocar is inserted, through which a
a-degree lO-mm endoscope is inserted with low-~ressure
(8 mm Hg) insufflation. Two small trocars (3 mm) are Inserted
below and above the first trocar along the medial margin of
the sternocleidomastoid muscle for instruments (Fig. 50-4).
The adenoma is gently dissected by the surgeon, who needs
only one assistant to hold the camera. Once completely
FIGURE 50-2. Video-assisted parathyroidectomy

procedure).
FIGURE 50-3. Video-assisted parathyroidectomy-intraoperative

view. PA = parathyroid adenoma.
isolated, the gland is partly extracted and its pedicle is ligated

externally using a conventional forceps; qPTHa is also used.
A bilateral exploration is not possible with this technique,
which is a lateral approach.
Other Approaches
In addition to endoscopic operations, other "minimally invasive" approaches to parathyroid surgery have been proposed,
some based on the use of intraoperative nuclear mapping first
described by Norman and Chheda,' and all characterized by
small skin incisions (3 to 4 ern) directly over the supposed
adenoma.f A clearly positive preoperative scintigraphic
localization study is mandatory for these focused procedures.
Some single, well-defined parathyroid adenomas can be visthey repr~ible by ultrasonography but not by scintigrap~y;
sent 10% of patients undergoing an endoscopic procedure In
our experience. They are excellent candidates for any of the
endoscopic or video-assisted parathyroidectomies but not for
a radio-guided parathyroidectomy.
(Miccoli
FIGURE 50-4. Lateral approach (Henry procedure).
Indications
Generally, the ideal patient for minimally invasive parathyroidectomy is one with sporadic PHPT and a single, welllocalized adenoma in a virgin neck. There is debate about
the percentage of patients who are eligible for minimally
invasive parathyroidectomy-this depends on the selection
criteria used by the surgeon. In our experience, these criteria were modified by the experience acquired during the
development of our technique and the continuing improvement of surgical instrumentation.
Contraindications may be absolute or relative. Absolute
contraindications include the following:
Large goiters
Recurrent disease
Extensive previous neck surgery
Multiple endocrine neoplasia and familial PHPT
Parathyroid carcinoma
Relative contraindications include the following:
Adenomas larger than 3 em (depending on their shape,
even larger adenomas can be removed)
Lack of preoperative localization (a bilateral exploration can be performed through a central incision)
Neck surgery on the opposite side of the suspected adenoma (a lateral access can be used)
Previous neck irradiation or small thyroid nodules
(concurrent thyroidectomy is possible)
Careful selection of the patient is most important
to achieve an excellent outcome and to keep the conversion rate low. Although these criteria are presumably shared
by most surgeons performing minimally invasive parathyroidectomy, the percentage of patients eligible for this
surgery has varied greatly, from as little as 25%9 to as much
as 66%.10
Conversion: When, Why?

As in many other fields of endoscopic surgery, converting to
open surgery is sometimes necessary. In minimally invasive
parathyroid surgery, it is due to both technical difficulty
of the procedure and drawbacks that are peculiar to parathyroid surgery. Thyroid abnormalities can cause bleeding or
difficult dissection. Suspicion of malignancy, intrathyroidal
parathyroid adenoma, and prolonged exploration time are also
reasons for conversion.
Although most minimally invasive procedures are
targeted parathyroidectomies (identifying only the adenoma)
that have been validated by qPTHa2,4 or postoperative
scintigraphy,"!' we prefer a unilateral exploration (identifying both an adenoma and a normal gland), which is almost
always possible when using the endoscope. Before elective
conversion, at least one side of the neck should have been
explored thoroughly. Then, if a lateral approach was used,
one should convert to open operation; however, if a central
approach was used, contralateral exploration is still possible
by the endoscopic technique. We explore the contralateral
side endoscopically only if the procedure has not taken too
long (l to 1.5 hours) and if preoperative localization studies
were not definitive. In our experience, an open operation
does not guarantee that the adenoma will be easily found.
In three cases out of nine conversions in our series, the
adenoma was still not found even after an extensive open

exploration (see "Results").
Complications
To define a new procedure as safe and effective, we need to
demonstrate that both its complication rate and its success
rate are comparable or better than those obtained by traditional surgery. This is particularly difficult when comparing
endoscopic parathyroidectomy to traditional parathyroidectomy, which has a success rate of 95%12 with a negligible
complication rate. These complications include recurrent
nerve palsy and hypoparathyroidism. Hypoparathyroidism
is particularly rare, probably due to minimal manipulation
required by endoscopic surgery and improved visualization.
This is in contrast to the traditional approach of extensive
bilateral neck exploration and sometimes frequent biopsy.
Thus, the incidence of postoperative hypocalcemia, either
transient or permanent, is significantly less after minimally
invasive parathyroidectomy.P This rate is similar to that of
open unilateral exploration. The use of qPTHa also avoids
the unnecessary removal of enlarged glands with normal
function and minimizes postoperative hypoparathyroidism. 14
Recurrent nerve palsy is rare in all the series with rate of
I % or lower both in traditional operations15 and in endoscopic approaches. !1.I6
There is no evidence of an increased rate of persistent
disease after the adoption of minimally invasive parathyroidectomies. Our persistence rate is lower than 2% in
almost 300 cases; other published rates of persistent disease
also do not exceed 4% to 5%,5.10.11.16-18 which is similar to
the results obtained by traditional surgery. 12.15 Nevertheless,
it should be noted that patients undergoing minimally invasive parathyroidectomies are a selected group and this could
bias the results.
Advantages and Disadvantages

It is difficult to assess the advantages offered by minimally
invasive parathyroid surgery because of the many different
techniques considered minimally invasive. Similarly, "conventional parathyroidectomy" includes both bilateral and
unilateral explorations. Furthermore, early sporadic reports
of minimally invasive parathyroidectomy included only few
cases that had inadequate follow-up and were not prospective studies.
Possible advantages include cosmetic outcome and
postoperative distress. There are two prospective papers comparing a minimally invasive to a conventional approach, both
based on less than 50 patients, concluding that patients have
less discomfort postoperatively after minimally invasive operations using a radio-guided'? or video-assisted approach.'?
The advantage of the cosmetic outcome is generally considered obvious because a scar of I to 2 em tends to be better
accepted than a 4- to 6-cm scar in the same region. Patients'
satisfaction evaluated in a prospective study by means of
a visual analog scale score proved to be significantly better
in a minimally invasive video-assisted parathyroidectomy
versus a conventional procedure. 19
Minimally Invasive Parathyroid Surgery - - 465

The duration of hospitalization cannot constitute a further
advantage because parathyroid surgery is now frequently
performed on an outpatient basis, even under locoregional
anesthesia, whether the patient is undergoing a minimally
invasive" or a conventional parathyroidectorny.P
Endoscopic procedures are generally more expensive and
thus a disadvantage. The expenses are due to surgical instrumentation and the technical support needed to set up a new
procedure, as well as the longer duration of the procedure.
The additional costs of preoperative imaging studies are
also widely accepted by surgeons using the conventional
approaches? I so this is not an issue.
Furthermore, for minimally invasive surgery using a central
approach, bilateral exploration is possible. thus making preoperative localization theoretically superfluous. 1I Similarly,
qPl'Ha is used in both conventional and endoscopic operations, and its cost has sharply decreased lately, matching
that of frozen section. Many surgeons consider it technically demanding, but the surgical equipment required does
not differ much from that needed for other laparoscopic
procedures.P
Finally, the higher cost due to longer procedure duration
occurs at the beginning of the surgeon's experience. The
learning curve (Fig. 50-5), however, clearly shows that a
reasonable operating time can be reached after the first
30 operations and it rivals that of conventional surgery.
A significant disadvantage for the endoscopic procedures is
the need for general anesthesia, whereas in conventional surgery locoregional anesthesia might be used." This issue is
less relevant in Europe, where the problem of surgery on an
outpatient basis is not considered of paramount importance.
In our center, patients undergoing video-assisted parathyroidectomy are discharged within 24 hours (overnight stay).
Results
Our experience consists of 282 patients who underwent
minimally invasive video-assisted parathyroidectomy
(MIVAP) from February 1997 to April 2002. They represented 76% of a total of 370 referred to our department in
the same period for PHPl'. Correct preoperative localization
70
65.4
60
lil
Q)
50
"5
c
Q)
40
30
ci. 20
0
27.5
24.4
25
10
0
1997 1998 1999 2000 2001 2002
FIGURE So-S. Learning curve associated with minimally invasive
video-assisted parathyroidectomy. Op. = operating.
of the lesion was considered mandatory before performing

MIVAP.This consisted of either an ultrasound examination or
a double-phase Tc 99m sestamibi scan. In many cases, both
imaging studies had already been performed before referral.
The mean age of the patients was 56 13 years (range, 20
to 87 years); there were 224 women (79.5%) and 58 men
(20.5%). The mean operative time of the procedure was
39 22 minutes (range, 10 to 180 minutes). Fifteen patients
had a concurrent video-assisted thyroid resection for associated diseases (microfollicular nodule, small papillary
cancer), including 11 thyroid lobectomies (8 ipsilateral and
3 contralateral) and 4 total thyroidectomies.
Conversion to traditional cervicotomy was required in
20 patients (7%) (Table 50-1). The reasons for conversion
were multiglandular disease in 4 (double adenoma); intrathyroid adenoma in 3; difficult dissection in 2; negative exploration in 9 (in 3 cases the adenoma was not found even after
conversion); intraoperative suspicion of parathyroid carcinoma
in 1 (confirmed by frozen section and thus treated with synchronous thyroid lobectomy); and inadequate intraoperative
PTH assay in 1. The conversions for double adenoma and
intrathyroid lesions occurred at the beginning of our experience, when we were concerned about the prolonging the
operation. More recently, when a further adenoma (even
contralateral) or intrathyroid adenoma was suspected, we
always continued with the video-assisted technique to perform
a bilateral exploration or even a thyroid lobectomy (if
necessary).
The mean size of the removed adenoma was 1.8 em in its
largest diameter. The lesion was superior right in 20.5% of
cases, superior left in 23.1 %, inferior right in 23.8%. and
inferior left in 32.6%.
Patients are usually discharged after careful evaluation
overnight for clinical symptoms of hypocalcemia and for
serum calcium measurement.
There were two permanent laryngeal nerve palsies
(0.7%) (6 months after surgery). There was one case of postoperative bleeding (0.3%) from a displaced clip on a middle
thyroid vein, which required a reoperation 2 hours after surgery. Transient hypocalcemia occurred in 10 patients (3.5%)
(Table 50-2).
Five (1.7%) patients had persistent hyperparathyroidism.
In three patients, the adenoma was not found at exploration
even after conversion. These patients are being re-evaluated.
In two patients, the persistence was due to a false-positive
qPTHa. A second exploration revealed a second adenoma
missed at the time of the first operation. Both missed second
adenomas were at the opposite side of the first operation,

and they were successfully treated again by the MIVAP
approach.
In this series, six patients had previously undergone thyroid surgery and two patients had undergone a prior exploration for PHPT. We successfully used a lateral approach in
these patients so as to avoid adhesions in the midline.
Conclusions
Fewer patients now undergo classic open bilateral neck
exploration for PHPT because of the desire for smaller
scars, shorter postoperative stay, and less postoperative distress. Better preoperative localization studies now allow for
patient selection for targeted parathyroidectomies with low
rates of persistent disease.P Endoscopic parathyroidectomy
offers thorough exploration of the neck, unilaterally-' or
even bilaterally.l'P' The use of qPTHa reduces the possibility of missing a second adenoma or a hyperplasia. In our
experience, qPTHa has helped avoid conversion to open surgery in 2% of our patients.
Endoscopic parathyroidectomy is an excellent option. In
contrast, radio-guided parathyroidectomy is logistically
demanding, requiring nuclear mappings and coordination
among the nuclear medicine physician, the operating room
staff, and the surgical team." Endoscopic parathyroidectomy allows for neck exploration of two glands and, with a
central incision, even bilateral exploration of four glands.
This is not possible by the lateral approach.
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Jean Francois Henry, MD Frederic Sebag, MD
Since the first successful parathyroidectomy performed in

1925 by Felix Mandl of Vienna, I bilateral exploration and
four-gland exploration has been considered the traditional
approach in patients with primary hyperparathyroidism
(pHPT). Performed by an experienced surgeon, this procedure
is certainly one of the most gratifying of all operations. The
success rate is reported to be of more than 96% with a concomitantly negligible operative mortality and morbidity rate?
Nevertheless, today the surgical management of PHPT is
in transition. The development and improvement of pre- and
intraoperative localization methods, the introduction of intraoperative quick parathormone (QPTH) assessment, and the
minimally invasive surgery revolution are the main reasons
that have pushed surgeons at least to investigate the feasibility
of other parathyroid procedures.
Several new minimally invasive techniques for parathyroidectomy have been developed: the unilateral approach.r"
radioguided surgery.'t? mini-open invasive techniques (miniincision with or without local anesthesiaj.v!" and video-assisted
or fully endoscopic techniques. I 1-21 These techniques have two
common threads: they all have a limited incision compared
with the classic open transverse cervical incision, and the surgery is targeted to one specific parathyroid gland. In most cases,
the exploration of other glands is not performed or is limited.
Minimally invasive techniques are particularly suitable
for parathyroid surgery for several reasons: they are only
ablative procedures that do not require any elaborate surgical reconstruction, most parathyroid tumors are small and
benign, and reduction in the length of the scar to about 10
to 15 mm is appealing to many patients.
It has been demonstrated that endoscopic parathyroidectomy is a feasible surgical procedure. Curiously, the first
endoscopic removal of enlarged parathyroid glands was not
from the neck but from a major ectopic location in the
mediastinum." The first case of an endoscopic parathyroidectomy in the neck was reported by Gagner in 1996. 11 Since
then, the application of endoscopic techniques for parathyroid surgery has become more and more widely reported.
endoscopic when endoscopic equipment is used during the

procedure. Techniques such as video-assisted parathyroidectomies that require the endoscope during one step but not
necessarily during the whole operation should also be
considered endoscopic procedures.
The three endoscopic neck procedures in most widespread use are described in the following. Other techniques
that have been proposed but are less commonly used are the
axillary approach-" and the anterior chest approach.'?
Surgical Technique
Minimally Invasive Video-Assisted

Parathyroidectomy
The term endoscopic parathyroidectomy must be clearly

defined: a parathyroidectomy can be considered to be
Minimally invasive video-assisted parathyroidectomy

(MIVAP) was described by Miccoli and colleagues."
Pure Endoscopic Parathyroidectomy

This technique, first described by Gagner, II is carried out
entirely under a steady gas flow. The patient is placed supine
with the neck less hyperextended than for open operation
to allow room for insufflation. Under general anesthesia, the
neck area is prepared and draped in the fashion typical for
conventional surgery. A 5-mm skin incision is made just
above the sternal notch in the lower midline of the neck and
a 5-mm trocar is inserted. Then, a 5-mm scope is introduced
and a larger subplatysmal space is created by blunt dissection with the tip of the scope. Carbon dioxide insufflation is
started at 12 to 15 mm Hg but can be decreased to 8 to
10 mm Hg. When enough space has been created, the midline
is opened and the strap muscles retracted in order to expose
the thyroid lobes. Two or three additional trocars are used:
one 2-mm trocar is placed laterally above the clavicle on
the side of exploration; another 2-mm trocar is placed at
the midline just below the thyroid cartilage. An optional
second 5-mm trocar is placed at the anterior border of the
sternocleidomastoid muscle (SCM) below the angle of the
mandible. Needlescopic instruments are used. A bilateral
parathyroid exploration is possible with this technique.
When the tumor is discovered and freed, it is placed in a
bag, made from the tip of the finger of a rubber glove, and
removed through the 5-mm port site. Subcuticular sutures
and Steri-Strips or glue are used to close the skin incisions.
467

The patient is placed in the supine position with the neck
in slight extension. A 15-mm skin incision is made at the
suprasternal notch. The cervical midline is opened, and
complete dissection of the thyroid lobe is achieved by blunt
dissection with small instruments under endoscopic vision
using a 30-degree 5-mrn endoscope. Small conventional
retractors maintain the operative space. Small instruments,
2 mrn in diameter, are used for the dissection. The harmonic
scalpel is very useful, particularly during the dissection of
the superior thyroid pedicle. The procedure is carried
out only through the initial midline incision. There is
no need for an additional trocar or for gas insufflation.
This technique also permits bilateral exploration. The surgeon
must be aided by two assistants.
Endoscopic Parathyroidectomy by
Lateral Approach24
In both techniques described previously,access to the parathyroid is achieved through the midline. The midline approach is
suitable for superficially located parathyroids, which in most
cases means the inferior glands located at the lower pole of
the thyroid lobe or in the thyrothymic tracts. However, for
superior adenomas that tend to migrate posteriorly,the midline
approach requires complete exposure and medial retraction of
the thyroid lobe. This is sometimes difficult, particularly in
patients with a short wide neck or with large thyroid glands.
Conversely, the lateral approach or back door approach,
already described by Feind in open surgery for parathyroid
re-exploration," allows direct access to the lateral and
posterior aspects of the thyroid lobe and therefore to the
posteriorly located parathyroids.
The patient is placed in the supine position but without
extension of the neck. Under general anesthesia, a l2-mrn
transverse skin incision is made on the anterior border of the
SCM, 3 to 4 em above the sternal notch. Through this incision, the fascia connecting the posterior portion of the strap
muscles to the carotid sheath is gently divided with scissors,
far enough to visualize the prevertebral fascia. When enough
space has been created, two 2- to 3-mrn trocars are inserted on
the line of the anterior border of the SCM, 3 to 4 em above
and below the first skin incision. A lO-mrn trocar is inserted
through the l2-mrn skin incision (Fig. 51-1). The working
space is easily created with minimal dissection and maintained with low CO2 pressure at 8 mrn Hg. At this low pressure, there is no risk of subcutaneous emphysema or
pneumomediastinum. Unilateral video-assisted parathyroid
exploration is then carried out using a lO-mrn O-degree endoscopic camera. The dissection is performed using 2- or 3-mrn
instruments: graspers, scissors, and cautery hook. The
anatomic structures, posterior aspect of the thyroid lobe,
esophagus, trunk and branches of the inferior thyroid artery,
inferior laryngeal nerve, and thyrothymic tract, can be
explored. During the exploration, one can identify both the
adenoma and the ipsilateral parathyroid gland but contralateral exploration is not possible. When the adenoma
has been completely dissected, the vascular branches of its
pedicle are coagulated with the cautery hook. Then, small
adenomas are grasped and directly extracted through the
10-mm trocar; large adenomas that cannot be introduced into
the 10-mrntrocar are extracted directly through the trocar site,
FIGURE 51-1. Endoscopic parathyroidectomy by a lateral

approach: trocar positions.
with the thyroid lobe being retracted medially and anteriorly

with a small conventional retractor. There is no need to place
the gland into a sterile plastic bag. Draining is not necessary.
The lateral approach is a rapid, direct, and bloodless
approach. In our opinion, it is the procedure of choice in most
cases because it provides the best access to the posterior aspect
of the thyroid lobe. It is therefore applicable in all cases in
which the parathyroid lesions are located posteriorly, meaning
superior parathyroid glands, because their enlargement pushes
them to migrate posteriorly and slide along the prevertebral
plane next to the lateral esophageal border. The lateral
approach is also ideal for inferior parathyroid glands located
posterior to the inferior poles of the thyroid lobe. It is in these
cases that they become intimate with the recurrent laryngeal
nerve. The lateral view permits easy identification of the nerve
abutting the adenoma and therefore allows a secure dissection.
However, the lateral approach is not suitable for superficially located parathyroids, which means the inferior glands
located at the lower pole of the thyroid lobe or in the thyrothymic tracts. These glands can easily be reached through a
l5-mrn skin incision at the suprasternal notch. The procedure
is carried out between the strap muscles with the assistance of
a 5-mrn endoscope (0 or 30 degrees). All maneuvers are therefore performed openly without gas insufflation. All instruments are introduced through the midline incision. There
is no need for an additional trocar. Because of their anterior
locations, the dissection of these glands remains anterior to
the trachea and does not require the previous identification of
the recurrent laryngeal nerve, which runs more posteriorly.
Parathyroid glands deeply located in the thymus can also be
removed endoscopically using this midline access.
Contraindications
Not all patients presenting with PHPT are candidates for this
surgery. Contraindications are mainly due to a larger goiter,
Endoscopic Parathyroidectomy - -
previous surgery in the parathyroid vicuuty, suspicious

multiglandular disease, and equivocal preoperative localization studies. Depending upon the operator's experience and
according to the specific technique utilized, these contraindications can become relative. The central approach appears to
be the best one for cases in which a bilateral exploration is
anticipated or localization is uncertain.
Occasionally, endoscopic parathyroidectomy by the lateral
approach can be performed in patients who have previously
undergone contralateral neck operation or tracheotomy.
According to certain authors, more than 60% of patients with
PTHP are candidates for video-assisted parathyroidectomy."
The endoscopic dissection of large adenomas (>3 ern) can
be difficult because the working area remains limited. With
limited experience, some surgeons can encounter major difficulties that may lead to capsular rupture and local seeding
of parathyroid adenomatous cells. When this happens, a conversion is recommended. Nevertheless, some large but elongated adenomas, especially if situated in the posterosuperior
mediastinum, can be removed endoscopically. The pedicle
can be easily dissected at the level of the inferior thyroid
artery, and their shape is amenable to expeditious extraction.
Patients with suggested multiglandular disease are not
eligible for these procedures. Endoscopic parathyroid procedures should be reserved for patients with sporadic PHPT.
All endoscopic parathyroid surgeons consider that the
adenoma should be clearly localized before the operation.
Therefore, the surgeon is highly dependent upon the quality
of preoperative imaging to make a judicious choice for
an endoscopic approach. Once contraindications have been
eliminated, all patients with sporadic primary PHPT are
considered candidates for this procedure. The choice between
approaches is dependent on the quality and adequate interpretation of preoperative imaging studies. If the cervical
ultrasonography and the nuclear scan do not correlate with
a unique lesion at the same site, a traditional open cervical
transverse incision is preferable. However, if the lesion is
unique and confirmed by both studies, an endoscopic
approach can be proposed. Depending on a posterior or anterior location, one can choose a central or lateral approach
(Fig. 51-2).
Absolute contraindications remain the presence of a
carcinomatous parathyroid gland, voluminous goiter, or
both, no matter the experience of the surgeon or type of
endoscopic technique employed.
Finally, endoscopic thyroidectomy and parathyroidectomy
can be performed at the same time through the midline, but
these procedures are indicated for small suspicious thyroid
nodules less than 2.5 em in diameter associated with PHPT.
Results
In cases of removal of mediastinal parathyroid adenomas by
thoracoscopy, the advantages to the patient are irrefutable.
However, taking into account the excellent results of the traditional bilateral cervical exploration, the same advantages
are more difficult to demonstrate for all cervical approaches.
Two studies comparing conventional parathyroid surgery
with endoscopic techniques have clearly shown a diminution
of postoperative pain and better cosmetic results with
.:
469
Sestamibi scan + Ultrasonography
<.
Single focus
-:
No single focus
<,
Anterior
location
Posterior
location
Endoscopic
midline
approach
Endoscopic
lateral
approach
Open
conventional
approach
FIGURE 51-2. Algorithm for the surgical management of patients

eligible for an endoscopic parathyroidectomy.
endoscopic tecbniques.Pr" MIVAP is also associated with

a shorter operative time." Those results await confirmation
by further randomized studies.
In our opinion, compared with other minimally invasive
procedures performed without the endoscope, endoscopic
techniques are safer. The endoscope provides a greater and
better surgical image, with magnification of all anatomic
structures. By direct vision through mini-incisions, it is probably more difficult to get an adequate view of structures, and
it is our belief that optimal conditions for exploration are not
met even if surgeons use frontal lamps and surgical loops.
According to the type of access, conversion to conventional
parathyroidectomy is necessary in 8% to 15% of cases,26.29,30
Main causes for conversion include difficulties of dissection,
false-positive results of imaging studies, and multiglandular
disease not detected by preoperative imaging but correctly predicted by QPTH assay results. Therefore, as with other minimally invasive techniques, the availability of the QPTH assay
is of utmost importance. The overall accuracy of intraoperative
QPTH monitoring is reported to be 97%.31 This test may be
especially useful when localization studies are less certain.
The risk of multiglandularity is nearly zero when both studies
are positive for the same lesion site. This has been found to be
3.6% when only one localization study is positive versus
31.6% when both are negative"; the less certain the localization studies, the more certain the need for QPTH assay.
In experienced hands, endoscopic parathyroid techniques
are as safe as the standard open procedure. There is no mortality. The incidence of recurrent nerve palsy is very low,
less than 1%. Once again, we think that the use of the endoscope allows the surgeon to perform a dissection as safely
as in open surgery. The rate of transient hypocalcemia is
reduced, between 2.5% and 3.2%.17,27 Similar findings have
been reported with other minimally invasive techniques.P
This may be the result of a less extensive dissection and the
targeted removal of the adenoma.
Carbon dioxide insufflation may cause hypercarbia,
respiratory acidosis, and subcutaneous emphysema.

Nevertheless, insufflation is harmless as long as the procedure is performed under low pressure.
Endoscopic procedures can be performed in less than
I hour and the operating time improves dramatically after
the first procedures. The operating time may be even shorter
than that of conventional cervicotomy, but it must be kept
in mind that it is a focused operation and not a bilateral
exploration. Endoscopic procedures are better performed
under general anesthesia. Trocars are badly tolerated by
patients under local anesthesia. In addition, swallowing and
spontaneous breathing present impediments when dissecting
in such a small operative space. Therefore, as for the conventional operation, in most cases one night of hospitalization is necessary. Whether endoscopic techniques are
actually less costly than conventional parathyroidectomy is
questionable."
After surgery, 95% to 100% of patients are normocalcemic. However, it should be kept in mind that these excellent results have been obtained in a group of carefully
selected patients; these patients are considered to present a
sporadic PHPT with a solitary adenoma clearly localized by
imaging studies. In addition, the risk of persistent PHPT is
minimized by the use of intraoperative QPTH assessment.
The learning curve must be considered. First of all, one
must emphasize the need for expertise in performing conventional open parathyroidectomy. Mentoring by a surgeon
who has experience with endoscopic neck techniques is
recommended. These new operations are technically more
challenging than standard cervical exploration. They should
be confined to tertiary care centers.
Experience with Endoscopic

Parathyroidectomy by the
Lateral Approach
We developed the technique for endoscopic parathyroidectomy by the use of a lateral approach on the line of the
anterior border of the SCM in 1998.13 Since then, over the
course of 5 years (1998 to 2002), we operated on 528 patients
with PHPT.34 An endoscopic approach was proposed for
patients with sporadic PHPT, without associated goiter and
without previous neck surgery, in whom a single adenoma
was localized by means of sonography and sestamibi scanning. The procedure was performed by a lateral approach
with insufflation for patients with adenoma located deep in
the neck and by a gasless midline approach for patients with
adenoma located anteriorly. QPTH assay was used during
the surgical procedures. Blood was drawn at the time of
intubation, first skin incision, adenoma extraction, and 5 and
15 minutes after extirpation. The highest preexcision level
of QPTH falling more than 50% was considered significant.
Calcemia, phosphoremia, and PTH were systematically
evaluated in patients on days 1 and 8, 1 month, and I year after
surgery. All patients underwent preoperative and postoperative investigations of vocal cord movements.
Of the 528 surgical patients, 228 (43%) had a conventional
open approach and 300 (57%) an endoscopic technique.
Patients who underwent an open approach had some contraindications to an endoscopic approach: a large multinodular
goiter that needed an associated thyroidectomy in 99 cases,

previous cervical surgery in 42 cases, suspicion of multiglandular disease in 25 cases, inconclusive localizing studies in
48 cases, and other reasons in 14 cases (Table 51-I).
Endoscopic parathyroidectomy was performed in
300 patients with sporadic PHPT, by a lateral approach in
282 cases and by a central approach in 17 cases. One patient
underwent thoracoscopy for an adenoma located very low in
the anterior mediastinum. Of the 17 patients who had a central approach, 2 had an associated lobar thyroidectomy. The
median operative time recorded was 50 minutes, which was
lowered to 41 minutes in the last 100 cases. Recurrent laryngeal nerves were identified in 94.6% of cases, as was the
ipsilateral parathyroid gland in 63.8% of cases when a lateral approach was used.
We were obliged to perform 42 conversions (14%) to
open conventional surgery (Table 51-2). Causes for conversion included nothing found after a 2-hour search (11 cases),
difficulties of dissection or a large adenoma taking most of
the working space (7 cases), false-positive imaging studies
(11 cases), and inadequate fall of rapid PTH assay
(13 cases). Interestingly, 10 of the 13 patients had a multiglandular disease during open conversion and 3 had a falsenegative QPTH assay. Thus, multiglandular disease was not
detected by preoperative imaging in 10 cases but, in all
10 cases, was correctly predicted by QPTH assay.
Postoperative morbidity included permanent recurrent
laryngeal nerve damage in one patient, two hematomas in
the SCM muscle, and five capsular tears. The capsular disruptions occurred during the dissection of large and fragile
adenomas weighing on average 4200 mg. There was no
mortality, and most patients were discharged without morbidity from the hospital the next day. Two patients were left
with hypercalcemia; persistent PHPT is suspected in the
first patient, and another cause of hypercalcemia is likely in
the second patient. With a median follow-up of 20.5 months,
I of 150 patients had recurrent hypercalcemia after removal
of an adenoma, whereas for 15 months the patient had
normal serum calcium levels.
Conclusion
In contrast to the surgeon performing open surgery, in which
surgery alone can be successful in more than 95% of cases, the
endoscopic parathyroid surgeon must depend on multiple
Endoscopic Parathyroidectomy - - 471
techniques such as preoperative specialized imaging, intraoperative QPTH assessment, and use of special surgical
instruments.
The possible advantages of endoscopic parathyroidectomy are a better cosmetic result and more comfort for the
patient.
Endoscopic parathyroidectomy should not be opposed
to conventional parathyroidectomy. Theses operations will
probably tum out to be complementary in the future.
Endoscopic parathyroidectomy should be reserved for
patients with sporadic PHPT, with a single adenoma clearly
localized preoperatively.
Among many minimally invasive techniques applied to
parathyroidectomy, the endoscopic technique has the main
advantage of offering a magnified view that permits a
precise and careful dissection with minimal risks.
The lateral approach is particularly suitable for patients
with adenoma located posteriorly in the neck. The central
access is reserved for inferior adenomas located anteriorly.
As with other minimally invasive techniques, a longer
follow-up is needed before one can evaluate the real risk of
recurrent PHPT following endoscopic techniques.
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15. Gauger PG, Reeve TS, Delbridge LW. Endoscopically assisted
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18. Yeung GHC. Endoscopic surgery of the neck. A new frontier. Surg
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Intraoperative Parathyroid
Hormone Assay as a Surgical
Adjunct in Patients with
Sporadic Primary
Hyperparathyroidism
George L. Irvin III, MD Denise M. Carneiro, MD
Many techniques have been tried during parathyroidectomy

to differentiate between normal and abnormal parathyroid
glands and to predict operative success. At present, none is
superior to the intraoperative measurement of parathyroid
hormone (PTH) by a quick assay (QPTH) in predicting
operative outcome during parathyroidectomy. This surgical
adjunct allows the surgeon to quantitatively determine intraoperatively when all hyperfunctioning parathyroid tissue has
been excised. Furthermore, in the case of multiglandular
disease (MGD), QPTH accurately identifies the presence of
additional hypersecreting glandes), guiding the surgeon to
further exploration.
Since first suggested in 1988by Nussbaum and coworkers,
the intraoperative monitoring of intact parathyroid hormone
(PTH) levels has been adopted as a quantitative predictor
of postoperative serum calcium levels in the treatment of
sporadic primary hyperparathyroidism (SPHPT) in many
institutions.l" This surgical adjunct became a real intraoperative tool in 1991 with an immunoradiometric assay and
was later changed to a more stable, practical, sensitive, and
nonradionuclear two-site antibody immunochemiluminescent assay (leMA) in 1993.15. 16 This rapid PTH assay
became commercially available as a point of care system in
1996 and is the most widely used intraoperative method for
hormone measurement in the United States.
The operative results, using this surgical adjunct to guide
the resection during parathyroidectomy, are reported with
success rates ranging from 94% to lOO%.1.2.5-9.1l-13.17-25
However, the accuracy of QPTH in guiding the surgeon
intraoperatively to a successful outcome is directly related
to the protocol and criteria used to interpret the measured
hormone levels. The intraoperative hormone assay only provides PTH levels at specific times during the operation;
therefore, the surgeon's knowledge of the timing of sample
collection and interpretation of changes in the hormone
472
values are necessary to ensure a high rate of success. At the

University of Miami, this assay is used to (1) determine
the complete excision of all hyperfunctioning parathyroid
tissue before the operative procedure is finished; (2) guide
the surgeon to further cervical exploration when the PTH
levels do not drop sufficiently; (3) differentiate parathyroid
from nonparathyroid tissues biopsied using measurement
of PTH levels in fine-needle aspiration (FNA) samples;
(4) localize the side of the neck harboring the hypersecreting
parathyroid(s) through differential jugular venous sampling
when the preoperative localization study is equivocal; and
(5) safely allow limited parathyroidectomy with resection of
only hypersecreting glandes) along with preservation of the
normally functioning parathyroids in patients with SPHPT.
The traditional parathyroidectomy, associated with a
bilateral neck exploration, is intended to excise all abnormal
glands while preserving all macroscopically normal
parathyroids. A "limited parathyroidectomy" is guided
by QPTH and helped by preoperative localization studies
in an attempt to achieve operative success with rapid, minimal
dissection. This quantitative operative approach allows
the excision of only the hypersecreting parathyroids with
preservation of the remaining normally secreting glands,
despite their macroscopic appearance, without disturbing
or visualizing them. When a secure diagnosis of SPHPT
is obtained (hypercalcemia, elevated PTH levels, normal or
high 24-hour urinary calcium levels, and normal renal function) and the patient has defined indications for parathyroidectomy, a preoperative localization study is performed
in an attempt to guide the surgeon to the side of the neck
harboring the hypersecreting parathyroid gland. The localization study should not be used to diagnose, indicate, or
contraindicate parathyroidectomy. It is used only for guidance of a targeted neck or mediastinal exploration when
positive. Even when localization studies are negative,
Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - -
patients with definitive surgical indications are entitled to

limited parathyroidectomy guided by QPTH. 26
This chapter describes in detail the authors' 9-year experience in developing, improving, and testing the most ac~urate intraoperative QPTH criterion for predicting operative
outcome in patients with SPHPT.
473
Enlarged right inferior

parathyroid gland excision
_ 100
92
PTH pg/mL
Ql Ql
,s~
Ei
ef..c... 50
0._
Established Criterion for

Evaluation of Intraoperative
Hormone Levels
e~
(/!F
"C.c
The QPTH criterion to predict operative success (no~al

or
low calcium levels for at least 6 months after parathyroidectomy) used in our institution is a drop i~ the PT.H ~e~el
of 50% or more from the highest level, either premcision
or pre-excision, 10 minutes after complete resection of
all hyperfunctioning tissue. This criterion was studied and
selected before 1993 when the assay was used with previously standard bilateral neck explorations and has proven to
be effective through prospective use in patients with SPHPT
since. 2,3,18,20-22,27 If there is not a sufficient drop in the
hormone level at the lO-minute interval following the excision
of a suspected gland, further cervical exploration is mandatory
in an attempt to find and resect the remaining hyperfunctioning parathyroid tissue. Figure 52-1 graphically pictures ~e
intraoperative PTH results obtained in a patient with eXCIsion of a single hyperfunctioning parathyroid gland. The
92% drop in the PTH level 10 minutes after excision of a
single tumor confirms that no other hypersecreting parathyroid glands are present and predicts postoperative eucalcemia, Further neck exploration in an attempt to visualize
and/or biopsy the remaining normally secreting parathyroid
glands is not necessary. Figure 52-2 shows the PTH levels
measured by QPTH in a patient with two hyperfunctioning
parathyroid glands. After excision of an enlarged parathyroid gland in the right superior position, the hormone level
did not decrease 50% from the pre-excision level, signifying
that further exploration was necessary. This led to the
461
_ 100
~~
Ei
,g0._
Ii:
-
Ql
o Ql
en
~
"C.c
~~
PTH pg/mL
350
50
92%
Parathyroid
adenoma
- - -_ _ 38
O-+------,.------r---.,-------,
Pre-incision Pre-excision
5min
10 min
Timed operative blood samples

FIGURE 52-1. Timed measurements of intraoperative hormone
levels before and following excision of a single hypersecreting
parathyroid gland. Intact parathyroid hormone (PTH) levels are
expressed in picograms per milliliter. The lO-minute postexcision
sample represents a 92% drop in hormone level from the highest
pre-excision value. At 10 minutes following the excision of all
hypersecreting glands, a drop in the hormone level greater than
50% from the highest peak before tumor excision meets the
criterion for predicting postoperative normal or low serum calcium
levels.
43
Enlarged rightsuperior
parathyroidgland excision
58%
43
PrePre- 5 min 10 min Pre- 5 min 10 min

incision excision
excision 2
FIGURE 52-2. Hormone levels obtained during parathyroidectomy in a patient with multiglandular disease. A drop of 30% after
excision of the right superior parathyroid resection did not predict
a return to eucalcemia. Further exploration resulted in excision
of a hypersecreting gland in the right inferior parathyroid gland
with a decrease of 58% in the hormone level predicting operative
success. PTH = intact parathyroid hormone.
discovery and excision of the second hyperfunctioning

parathyroid gland, in the right inferior position, resulting in a
drop in the PTH level of 58% 10 minutes after gland resection,
predicting a return to eucalcemia.
It is important to define the QPTH data used to predict
operative outcome. As shown in Table 52-1, a true-positive
QPTH result is defined as a sufficient drop in the hormone
level 10 minutes after the resection of all hyperfunctioning
tissue in a patient that returned to normal or low serum
calcium levels lasting at least 6 months after parathyroidectomy. A true-negative result is present when the hormone
level fails to fall below 50% at the 10-minute interval
and the patient remains or returns to hypercalcemia within
6 months following parathyroidectomy. A true-negative
QPTH result is also defined as a PTH level that does not
drop below 50% after resection of a parathyroid gland or a
mistaken nonparathyroid tissue, thus avoiding operative failure by pointing out the presence of MGD or missed overactive
glandes). A false-positive result is determined if the hormone
level drops 50% or more but the patient has persistent hypercalcemia within 6 months after resection. The visualization
of an enlarged, but normally functioning, parathyroid gland
after the excision of a single tumor followed by a sufficient
hormone level drop is not considered a false-positive result.
A false-negative result is defined if the PTH level does not
drop in 10 minutes and the patient has a successful return
to low or normal calcium levels lasting at least 6 months.
Hormone levels that drop in 20 minutes or later after gland
excision in a postoperative eucalcemia patient are also
considered false-negative QPTH results. Occasionally, these
delayed drops influenced the surgeon to discontinue the
cervical exploration but are considered false negative when
analyzing results. Table 52-1 shows how the QPTH results,
with the described criteria to predict postoperative calcium
levels, are defined.
The criterion published from this institution has matured
over the years, becoming more accurate in predicting operative outcome. The present criterion no longer requires a
474 -
Parathyroid Gland
drop in the hormone level at 10 minutes after tumor resection below the preoperative (preincision) level as stated
in the past.2 If a drop below the preincision level is required
to minutes after gland resection, a decrease in test sensitivity with an increase of the number of false-negative results
is encountered. The use of such a requirement would mislead the surgeon to perform further exploration in many
patients already successfully treated. The pre-excision
sample should be taken specifically just before clamping the
gland blood supply and not when the parathyroid is identified or during surgical manipulation.W? Some authors
require a return to a normal range of PTH levels after resection to predict operative success.t-" Our experience in 401
patients using the assay to guide parathyroidectomy has
shown that hormone dynamics calculated as a percentage
change between the levels during the operation is more
accurate in predicting operative outcome than a return of the
PTH levels to normal range. Furthermore, the quick assay is
not reliable for absolute values of PTH in the lower range of
the assay standard curve. Variation of the "quick assay"
values expressed in picograms per milliliter is often present
when compared with the standard 2-hour assay, even though
the coefficient correlation is excellent.
Intraoperative Protocol:
Blood Sample Collection
Time and Processing
In the operating room, a 14- or l6-gauge cannula is placed
into an antecubital or other available peripheral vein. If not
available, an arterial line can be used. This vascular access
is maintained without heparin using a saline drip with
extension tubing and a three-way stopcock at the head ofthe
table. This allows blood sampling at the required intervals.
Such access can also be used by the anesthesiologist as long
as administered drugs are not collected with the blood samples used for PTH measurement. The blood volume required
for the measurement depends on the surgeon's protocol and
assay methodology. Usually, no more than 2 mL of whole
blood is necessary, but it is wise to save a few milliliters of
whole blood for control and future correlation if unexpected
results are found postoperatively. For instance, if a patient
has a sufficient PTH drop intraoperatively but has persistent
hypercalcemia and elevated PTH (false positive), the saved
intraoperative frozen plasma samples should be measured

again and the intraoperative results reviewed for technical
errors. Blood sample dilution, an incorrect standard assay
curve, or high coefficient variation may lead to incorrect
interpretation of hormone levels. In an attempt to avoid this
problem, 4 to 5 mL of whole blood is drawn into a syringe
after the intravenous tubing has been cleared of residual
saline solution by a previous extraction with a separate
syringe until undiluted blood is available. Once the syringe
with whole blood is handed off the table, it is transferred
into an ethylenediaminetetraacetic acid (EDTA) glass tube.
The tube is inverted several times to ensure proper anticoagulation. Sampling can be done by anesthesia personnel at
any time requested by the surgeon. The part of these blood
samples that is not used for intraoperative measurement
should be later separated by centrifugation and the plasma
frozen for future control use.
Routinely, there are four samples drawn at specific
intervals: before the skin incision (1); just before clamping
the blood supply of a completely dissected suspicious
parathyroid gland (2); and at the 5-minute (3) and to-minute
(4) intervals after the interruption of the blood supply and
excision of this gland. The first sample is taken before the
incision is made and serves as a baseline, or preincision,
PTH level. A PTH level measured for diagnosis before
the operation cannot be used as the preincision value or for
hormone dynamic calculation. All samples must be measured
with the same conditions and by the same assay standard
curve at the time of the operation. The second sample, called
pre-excision, is taken after complete dissection of the
suspected tissue and just before clamping its blood supply.
This sample is important since some patients have a substantial increase in the circulating hormone during manipulation,
making this pre-excision sample necessary to meet the criterion of a 50% drop in to minutes, as shown in Figure 52-3.
In some patients, the pre-excision level will be decreased if
the blood supply to the hypersecreting gland is interrupted
early during dissection. When this occurs, the higher preincision sample should be used to calculate the drop in PTH
level at 10 minutes. If the pre-excision sample is taken too early
(e.g., before or during gland manipulation), the peak of the
hormone level might be missed, leading to a false delay in
the hormone decay at the to-minute interval.Such a false delay
is probably due to an unmeasured, very high, pre-excision
PTH level. This phenomenon has been observed by others
as well." A 5-minute sample taken after gland resection is
Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - - 475
595
PTH pg/mL
76% from pre-excision
o +----........------r----~---.,
Pre-incision Pre-excision
40% from pre-incision

5min
10 min
FIGURE 52-3. Representation of intraoperative hormone monitoring in a patient with a single gland involved. During resection of
the parathyroid gland, the intact parathyroid hormone (PTH) level
increased significantly, leading to a 76% drop in 10 minutes after
gland resection and predicting operative success. This graph shows
the importance of the pre-excision sample sample in some patients.
If only the preincision sample had been measured, the criterion
would not have been met in 10 minutes with a drop of only 40%.
This false-negative result can and was prevented by a correct registration of the peak of the hormone caused by gland manipulation.
optional and is measured in an attempt to predict a rapid fall

in the PTH level before the 1Qminutc interval, allowing the
surgeon to close the cervical incision earlier. Manipulation
of normal parathyroid glands can elevate PTH; therefore,
before the 5-minute sample is taken, cervical manipulation,
except for fascia and skin closure, should not be performed.
Since only 81% of successfully treated patients have a 50%
or greater drop in hormone level at 5 minutes, a sample
taken 10 minutes after gland resection is always indicated.
This last measurement will determine operative success or
not. If a significant hormone level drop is not found in
10 minutes, the surgeon should continue further neck exploration for an additional hyperfunctioning gland(s). The same
protocol is used for each gland or suspected tissue resected
with pre-excision, and 5 and 10-minute levels measured.
The Intraoperative PTH Assay

The samples are measured in a short time, as they are drawn,
by any available rapid assay for PTH. Most assays available
for intraoperative use at the present time are two-site antibody
ICMAs that are performed in the operating room or at a
nearby central laboratory. The technique differs between
assays, with results provided to the surgeon ranging from 8 to
30 minutes from the time of blood collection, depending on
the assay and/or location of the laboratory.I.3,5,9,17,19,2I.24,28-30
For obvious reasons, we prefer and work with point of care
assays, which provide results in 8 minutes, with a technician
present in the operating room to use the hormone information in a timely fashion to guide the operative decision
process. Since there are several commercially available assays
to measure PTH in a rapid manner, we do not intend to
describe the assay's technique itself. 1,3,5,9, 17,19,21,24,28-30 Each
assay has advantages and disadvantages. One fact is
common in all quick assays: the published normal ranges
are inaccurate at times. These assays demonstrate, with good
efficacy, the percentage change in the hormone levels during
surgery, but absolute PTH values, especially at the low

concentrations, are not always accurate. In our experience,
the normal range can differ from the published directional
insert, especially when different batches of antibodies are
used. If the normal range is used as a part of the criterion,
the laboratories should evaluate their own normal range for
its population, which should be rechecked over a period
of time and with each new batch of antibodies. A change of
normal range does not affect intraoperative use as long as
the standard assay curve is acceptable before the procedure
and all samples are measured against the same curve.
Advantages of QPTH
and Criterion
The QPTH as used with the described criterion not only can
determine when complete resection of all hypersecreting tissue
is accomplished but the assay can also guide the surgeon in
localizing the offending gland(s).
Biochemical Fine-Needle Aspiration

This useful technique, as first described by Perrier and
coworkers, consists of determining PTH levels in tissue samples obtained from FNA. The PTH levels in these samples
differentiate parathyroid from other tissues, such as thyroid
nodules or lymph nodes, with a specificity of 100%,31
A 25-gauge needle attached to a syringe is used to collect the
tissue sample. The aspirated content in the needle is diluted
with 1 mL of saline solution, centrifuged for 10 seconds, and
the supernatant is used for PTH measurement by the rapid
assay. This technique provides timely tissue identification
without frozen section, and it can be helpful when gland
identification is difficult-for example, in the case of an
intrathyroidal parathyroid or an indeterminate thyroid
nodule. Such quick tissue identification may decrease the
operative time by preventing the further dissection of
suspicious but nonparathyroid tissue.
Differential Internal Jugular

Venous Sampling
This technique, which is positive in 70% of cases, can guide
the surgeon to the side of the neck harboring the hypersecreting parathyroid gland when other preoperative localization studies are equivocal. These results were also found
by other authors. 32,33 Internal jugular vein punctures, as
caudal as possible, are performed before skin incision.
Samples from each jugular and a peripheral vein are measured for PTH simultaneously. Figure 52-4 demonstrates a
positive differential jugular venous test in a patient with
a left-sided hypersecreting parathyroid gland. This single
overactive gland was not identified on preoperative localization studies, but a clear differential in hormone levels
allowed a successful unilateral neck exploration that was
confirmed by QPTH. In our experience, few patients had a
negative preoperative imaging study and a differential jugular venous sampling that did not localize the overactive
parathyroid to the appropriate side of the neck.
476 -
Parathyroid Gland
213 pg/mL
Peripheral vein
FIGURE 52-4. Representation of the differential jugular venous

sampling and measurement ofPTH levels with rapid assay performed
in the operating room just before skin incision. In this patient with
a negative sestamibi scan, the differential jugular venous sampling
pointed out the presence of a hyperfunctioning parathyroid in the left
side of the neck, allowing a successful unilateral neck exploration
confirmed by QPTH. (From Irvin GL ill, Carneiro DM: Rapid
parathyroid hormone assay-guided exploration. In: van Heerden JA,
Farley DR reds], Operative Techniques in General Surgery.
Philadelphia, WB Saunders, 1999, p 18.)
Limited Parathyroidectomy, Shorter

Operative Time, and Cost Savings
After the excision of the hypersecreting glandes) has been
ensured by meeting the QPTH criterion, the surgeon may
discontinue any further neck exploration without examination and/or biopsy of the remaining parathyroid glands. This
decreases the operative time, in that a continued search
for the often hard to find, normally functioning glands is
unnecessary. This is usually accomplished with a limited
unilateral neck exploration. Most patients are sent home
after parathyroidectomy without an overnight hospital stay.
With biochemical confirmation predicting a return to eucalcemia, frozen section histopathology is not necessary,
thereby decreasing the operative time, allowing outpatient
procedures, and decreasing the charges to the patient for
parathyroidectomy.v'<v-"
Improved Success Rate

QPTH and the described criterion have improved the success
rate of initial and reoperative parathyroidectomy in patients
with SPHPT.20.24.25
Limitations of the
Established Criterion
It is important to understand that QPTH only measures PTH
levels at any given time during parathyroidectomy. Most
published limitations of the intraoperative assay are related
to the protocol and criteria used to interpret the intraoperative hormone values and not to the assay itself. The
use of different protocols and criteria in interpreting
the hormone levels has led to reports that differ in degrees
of accuracy.17.19,23,27,29,35-43
1. QPTH and criterion do not predict the size of the

remaining normally secreting parathyroid glands.
Some surgeons using QPTH during bilateral neck explorations have published the finding of a second
enlarged, but not hypersecreting, gland after successful
resection of a single adenoma confirmed by the drop
in hormone levels, Because these enlarged, normally
functioning glands are interpreted as "second adenomas" and are excised, the QPTH results were reported as
false positive because eucalcemia is achieved,36.37,39,41,43
The criterion used in our series does not predict the
size of the remaining normally functioning glands.
These glands were not hypersecreting either at the
time of the surgery or found to be responsible for
hypercalcemia during the postoperative period, which
averaged 3 years." This emphasizes that abnormal
secretion is not necessarily associated with parathyroid gland size.44,45 This can also be supported by
the fact that when parathyroid resection is guided
by hormone secretion, 6% fewer glands are excised
with a 98% success rate, when compared with gland
resection guided by the surgeon's judgment of gland
size. Therefore, we can conclude that those enlarged
glands left in situ were not hyperfunctioning."
2. QPTH and criterion do not predict PTH levels in postoperative eucalcemic patients.
Some authors have pointed out that the use of QPTH in
parathyroidectomy, with this described criterion, fails
to predict high PTH levels in postoperative eucalcemic
patients. It is known that despite the operative approach
used, PTH levels are found to be elevated in 8% to
17% of eucalcemic patients following successful
parathyroidectomy. Many of these patients return to
normal PTH levels months later.46-49 Carty,"
Bergenfelz," and their associates have suggested that
these high PTH levels are compensatory, with parathyroid glands responding to a deficit in total body calcium.
We observed no difference in intraoperative hormone
dynamics found in eucalcemic patients presenting with
normal or high postoperative PTH levels,
3. QPTH and criterion do not predict late recurrence.
No difference was found in the operative hormone
dynamics between long-term postoperative eucalcemic patients and those who developed recurrent
hypercalcemia.
4. QPTH and criterion do not identify the secretion of the
first glands resected in a MOD case.
If, after resection of an enlarged parathyroid gland, the
hormone level does not drop sufficiently and a second
gland is found and resected with a sufficient hormone
drop, it is not possible to evaluate the parathyroid hormone secretion of the first resected gland. QPTH does
not differentiate this gland from an enlarged normally
functioning parathyroid, because the hormone level
remained high after its removal.
5. The described criterion does not accurately predict
the postoperative outcome in patients with secondary
hyperparathyroidism (HPT) and multiple endocrine
neoplasia (MEN).
The outcome of patients with secondary HPT and MEN
may be predicted by a different criterion, but a drop of
Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - -
50% in the hormone level from the highest preincision

or pre-excision level, as measured by the current PTH
assays, does not accurately predict outcome in patients
with these diseases. 28,30,43,50,51 One must not combine
QPTH results in secondary, tertiary HPT, and MEN
patients in an attempt to evaluate the usefulness of
QPTH and the described criterion in the treatment of
SPHPT, since the outcome and etiologies are differenr."
Disadvantages of QPTH
and Criterion
The disadvantages of QPTH and the criterion are as follows:
1. QPTH cannot guarantee operative success.
QPTH predicts, but does not prevent, operative failure in
patients whose offending gland(s) could not be found
by localization studies, differential jugular venous
sampling, and careful bilateral neck exploration
performed by an experienced surgeon. In addition, it
cannot prevent operative failure due to misdiagnosis.
2. QPTH accuracy is criterion and protocol dependent.
If the surgeon is not aware of the possible mistakes and the
need for a strict protocol of blood collection and interpretation of the changing hormone values during the
procedure, the accuracy of QPTH will decrease considerably. There are several different protocols and criteria
to evaluate intraoperative PTH levels. Some studies
used criteria that require a drop in the PTH level of 60%
or 70%, 10 or 15 minutes after gland resection, to predict operative success.v" Others required a drop in the
PTH level and its return to the published normal range,
or a value below the preincision level, to predict
cure. 4, J7, 19.29.35 The different criteria used for evaluating
hormone dynamics have different sensitivities and
specificities in predicting operative outcome. For
instance, in an attempt to not overlook any patients with
MOD (QPTH false positive), some require a greater
percentage drop in the PTH level at 10 minutes to predict a postoperative return to eucalcemia. Such a change
in the criterion leads to an increased number of patients
that will not have a sufficient hormone drop in 10 minutes even though they had complete resections of all
hypersecreting glands (QPTH false negative). This
alteration increases the specificity of this surgical
adjunct but decreases its sensitivity, making the use of
intraoperative assay less beneficial. 27
3, The assay is technician dependent.
This surgical adjunct is dependent on the expertise of the
technician in performing the test, handling the blood,
and running the assay itself as a functioning system.
Plasma pipetting and blood dilutions with a high
coefficient variation of the samples, inability to solve
system problems (antibodies, washer system and
luminometer breakdowns), and delay in sample drawing are all factors that are dependent on good technical skills. The usefulness of QPTH will improve as the
assay becomes more automated.
4. The cost of QPTH is high.
This surgical adjunct is expensive. The benefits of
QPTH, however, compensate for its cost by allowing a
477
shorter operative time, decreasing the need for frozen

section histopathology and eliminating an overnight
hospital stay. In an attempt to make QPTH more
affordable, some hospitals locate this surgical adjunct
at the central laboratory where the system can be used
for other purposes without dislocating a technician to
the operative room. This limits the use of intraoperative hormone dynamics since the assay turnaround
time is prolonged. If the number of samples obtained
during parathyroidectomy is reduced to decrease costs
(e.g., if the pre-excision sample is omitted from the
protocol), the accuracy of the assay will decrease.
Results of "Limited"
Parathyroidectomy
Guided by QPTH
Since 1993, in our institution, exploration and parathyroid
resection have been guided exclusively by hormone dynamics
using a rapid leMA point of care assay. Bilateral neck exploration is no longer performed as a standard procedure and is
done only when indicated by QPTH or when a preoperative
localization study has initially guided the surgeon to the incorrect side of the neck. From September 1993 until July 2002,
403 consecutive patients with SPHPT were operated on. Of
these, 401 patients had the intraoperative hormone assay used
during their parathyroidectomy. Two patients were excluded
because technical problems made the assay unavailable.
All patients had total serum calcium levels measured within 1
or 2 days postoperatively, and then a designed follow-up
was sought, with measurement of total serum calcium and
PTH levels at 2 months, 6 months, and yearly intervals,
Definitions used with this data analysis are as follows:
Operative success is considered when a patient has
normal or low calcium levels for at least 6 months after
parathyroidectomy.
Operative failure is defined as persistent hypercalcemia
and elevated PTH levels occurring within 6 months
of parathyroidectomy.
Recurrent disease is defined as hypercalcemia and high
PTH levels occurring later than 6 months following
a successful parathyroidectomy.
MGD is considered the presence of two or more hyperfunctioning glands at the time of parathyroidectomy.
Recurrent HPT after single gland resection is not
considered MOD.
Out of 401 consecutive patients with SPHPT undergoing
parathyroidectomy (359 initial and 42 reoperations), 391 had
normal or low calcium levels in the first days after surgery,
with 10 patients (5 initial and 5 reoperations) continuing
with persistent hypercalcemia. Since all the resections were
guided by hormone dynamics instead of the surgeon's judgment of gland size, 97% patients were successfully treated
with only one gland excised. Twelve patients with MOD had
the QPTH and criterion pointing out the presence of additional hyperfunctioning gland(s) at the time of the surgery,
whereas in two patients the QPTH failed to identify MOD.
To evaluate operative success and the accuracy of the
intraoperative hormone assay using our criterion, results are
478 -
Parathyroid Gland
reported in all patients followed for 6 months or longer,

including all known operative failures in the immediate
postoperative period.
Initial Parathyroidectomy
From 294 consecutive patients with more than 6 months of
follow-up (an average of 34 months [range, 6 to 98 months]),
including all known operative failures, 262 had initial
parathyroidectomies. Two-hundred-fifty-seven patients (98%)
had successful procedures and five were operative failures.
During the operative procedure, QPTH correctly predicted
postoperative outcome in 254 (97%) of 262 patients, including 4 of 5 operative failures. Using the protocol and the
criterion described in this chapter, QPTH wrongly predicted
the postoperative outcome in eight patients, with one falsepositive result and seven false-negative results. The falsenegative results did not lead to unnecessary neck exploration
in these patients since a 20-minute postexcision sample was
drawn that showed a sufficient hormone drop to lead the surgeon to suspend further exploration. The delayed hormone
drop was probably due to a premature timing of the preexcision sampling or unavailability of this important sample
because of venous access problems. A false delayed drop is
the result of a missed peak of the hormone level and not due
to a delayed metabolism. There was one false-positive result
leading to an operative failure within this 9-year period. This
patient had a parathyroid cyst ruptured during dissection with
an increase in the peripheral PTH level to 1100 pg/mL. With
a drop of 62% in 10 minutes and 80% in 20 minutes, further
neck exploration was not performed. Even though this is only
a hypothesis, we believe that this fluid, with a high content of
PTH spilled in the operative field, altered the hormone
dynamic, thus generating a false-positive result. On the other
hand, QPTH predicted the presence of MGD in 8 of
9 patients. The incidence of MG in this group presenting with
a success rate of 98% is 3.4%. In addition, QPTH pointed out,
with a specificity of 100%, the continued presence of a hyperfunctioning gland in patients in whom nonparathyroid tissue
was mistakenly resected as a gland (26 of 35 patients with
true-negative results not caused by MGD).
Using this operative approach with QPTH guiding an
initial limited parathyroidectomy, 238 (91%) of 262 patients
had a successful unilateral neck exploration. In terms of
length of stay, 183 (70%) of 262 patients were discharged
on the day of surgery or stayed at the hospital overnight for
social reasons (living alone or out of town). The average
operative time for these 262 initial patients was 60 minutes
(range, 15 to 300 minutes).
Reoperative Parathyroidectomy
From the 294 consecutive patients with more than 6 months
of follow-up, including all known operative failures, 32 were
reoperative cases from which 27 (84%) were successfully
treated with a limited parathyroidectomy and unilateral neck
exploration. QPTH correctly predicted the postoperative
outcome in 31 of 32 patients (27 true positive and 4 true
negative). There was one false-positive result due to a
technician's error. The falsely elevated pre-excision PTH

level in this patient was later found to be wrong by measurement of control serum. There were no false-negative results
in this group. In two patients with MGD, QPTH predicted
failure intraoperatively despite the resection of one or more
parathyroid glands. In addition, QPTH identified the resection of nonparathyroid tissue misinterpreted as parathyroid
glands in 8 patients, with a total of 13 true-negative results.
The reoperative patients had an average operative time of
108 minutes (range, 35 to 325 minutes), with 6 of these
patients eligible for same-day discharge.
QPTH Results: "Biochemical"

FNA, Differential Jugular
Venous Sampling, and
Sestamibi Scans
A "biochemical" FNA of tissue for hormone content was
performed multiple times in 32 patients. This technique had
a sensitivity and specificity of 100% in differentiating
parathyroid from nonparathyroid tissue.
Differential jugular venous sampling was performed in
89 patients with positive results (high levels on the side of
the tumor) in 70%.
In our series, the sestarnibi scan results, based on the
radiologist's interpretation, correctly localized the offending
parathyroid gland(s) (true positive) in 317 (79%) of
401 patients. In 26 patients, the scan incorrectly localized the
overactive parathyroid gland (false positive/false negative).
A second overactive gland was overlooked by the sestamibi
scan in 12 of 401 patients (true positive/false negative), and
another 11 had a second spot(s) falsely identified as positive
(true positive/false positive). Of 22 patients with completely
negative scans, 13 had differential jugular venous sampling.
Eight of these patients had a positive differential allowing a
successful unilateral neck exploration.
The sestamibi scans were incorrect in 20% of cases.
The QPTH was useful in identifying and correcting these
mistaken localization studies in all 80 patients (20%) with
the use of differential venous sampling and the intraoperative
PTH monitoring interpreted with the described criterion.
QPTH and Criterion Accuracy

In predicting postoperative serum calcium levels, the intraoperative PTH hormone assay, using the described criterion, has
a sensitivity of 98%, specificity of 97%, positive predictive
value of 99%, negative predictive value of 90%, and overall
accuracy of 97% in the 401 patients with SPHPT. Analyzing
only those patients with more than 6 months of follow-up,
including all known operative failures, the sensitivity, specificity, and accuracy remained unchanged.
Conclusion
The intraoperative measurement of parathyroid hormone is
an established surgical adjunct that can be of help during
Intraoperative Parathyroid Hormone Assay as a Surgical Adjunct in Patients with Sporadic Primary Hyperparathyroidism - - 479
parathyroidectomy in patients with SPHPT. This rapid assay

has been shown to be effective in ensuring operative success
with a limited operative approach that allows minimal dissection and selected gland excision. A specific protocol for
defining hormone dynamics and a strict criterion for predicting operative success are necessary. With the method
described in this chapter, the surgeon can excise only the
hyperfunctioning parathyroid gland(s) without visualizing
or disturbing the remaining normally functioning parathyroids. This surgical adjunct also redefines MGD. Instead of
the traditional method of identifying abnormal glands based
on size, weight, and/or histopathology, QPTH allows a precise recognition of gland hyperfunction based on hormone
secretion during parathyroidectomy. The QPTH-guided
parathyroidectomy is as successful as a bilateral neck exploration. Guided by hormone levels, parathyroidectomy has
evolved into a highly successful and rapid operation, usually
requiring minimal dissection, performed in an ambulatory
setting.
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17. Burkey SH, Van Heerden JA, Farley DR, et al: Will directed parathyroidectomy utilizing the gamma probe or intraoperative parathyroid
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29. Inabnet WB, Fulla Y, Richard B, et al: Unilateral neck exploration
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30. Seehofer D, Rayes N, Ulrich F, et al: Intraoperative measurement of
intact parathyroid hormone in renal hyperparathyroidism by an inexpensive routine assay. Langenbecks Arch Surg 2001;386:440.
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33. Udelsman R, Osterman F, Sokoll LJ, et al: Rapid parathyroid hormone
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34. Irvin GL III, Sfakianakis G, Yeung L, et al: Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074.
35. Agarwal G, Barakate MS, Robinson B, et al: Intraoperative quick
parathyroid hormone versus same-day parathyroid hormone testing
for minimally invasive parathyroidectomy: A cost-effectiveness study.
Surgery 2001;130:963.
36. Gauger PG, Agarwal G, England BG, et al: Intraoperative parathyroid
hormone monitoring fails to detect double parathyroid adenomas:
A two-institution experience. Surgery 2001;130:1005.
37. Gordon LL, Snyder WH, Wians F Jr, et al: The validity of quick
intraoperative hormone assay: An evaluation in seventy-two patients
based on gross morphology criteria. Surgery 1999;126:1030.
38. Libutti SK, Alexander HR, Bartlett DL, et al: Kinetic analysis of
the rapid intraoperative parathyroid hormone assay in patients during
operation for hyperparathyroidism. Surgery 1999; 126:1145.
39. Miura D, Wada N, Arici C, et al: Does intraoperative quick parathyroid
hormone assay improve the results of parathyroidectomy? World J
Surg 2002;26:926.
40. Nussbaum SR, Thompson AR, Hutcheson KA, et al: Intraoperative
measurement of parathyroid hormone in the surgical management of
41. Perrier ND, Ituarte PH, Morita E, et a1: Parathyroid surgery: Separating
promise from reality. J Clin Endocrinol Metab 2002;87:1024.
480 -
Parathyroid Gland
42. Starr FL, DeCresce R, Prinz RA: Normalization of intraoperative

parathyroid hormone does not predict normal postoperative parathyroid hormone levels. Surgery 2000;128:930.
43. Weber CJ, Ritchie JC: Retrospective analysis of sequential changes in
serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999;126:1139.
44. Berger AC, Libutti SK, Bartlett DL, et al: Heterogeneous gland size
in sporadic multiple-gland parathyroid hyperplasia. J Am Coil Surg
1999;188:382.
45. Liechty RD, Teter A, Suba EJ: The tiny parathyroid adenoma. Surgery
1986;100:1048.
46. Bergenfelz A, Valdemarsson S, Tibblin S: Persistent elevated serum
level of intact parathyroid hormone after operation for sporadic
parathyroid adenoma: Evidence of detrimental effects of severe
parathyroid disease. Surgery 1995;119:624.
47. Lundgren E, Rastad J, Ridefelt P, et al: Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in
sporadic primary hyperparathyroidism. Surgery 1992;112:1123.
48. Tisell L-E, Jasson S, Nilsson B, et al: Transient rise in intact parathyroid hormone concentration after surgery for primary hyperparathyroidism. Br J Surg 1996;83:665.
49. Westerdahl J, Lindblom P, Bergenfelz A: Measurement of intraoperative parathyroid hormone predicts long-term operative success. Arch
Surg 2002;137:186.
50. Clary BM, Garner SC, Leight GS Jr: Intraoperative parathyroid
hormone monitoring during parathyroidectomy for secondary hyperparathyroidism. Surgery 1997;122:1034.
51. Tonelli F, Spini S, Tommasi M, et al: Intraoperative parathormone
measurement in patients with multiple endocrine neoplasia type 1
syndrome and hyperparathyroidism. World J Surg 2000;24:556.
Parathyroid Hyperplasia:
Parathyroidectomy
Saif AI-Sobhi, MD Orlo H. Clark, MD
More than one abnormal parathyroid gland is present in

about 20% of patients with primary hyperparathyroidism
(HPT) and in virtually all patients with secondary HPT.
When all parathyroid glands are enlarged and hyperplastic, these patients have diffuse hyperplasia. In some
patients with primary or secondary hyperplasia, the size of
the parathyroid glands varies considerably. More than one
abnormal parathyroid gland may occur in patients with other
histologically proven normal parathyroid glands; these
patients have double or triple adenomas.'
Problems exist that contribute to the controversy as to
how patients with primary and secondary HPT and multiple
abnormal parathyroid glands should be managed. For
example, patients with familial parathyroid disease are more
likely to have multiple abnormal parathyroid glands (",80%)
and experience recurrent disease than are patients with
sporadic disease.P There is also no consensus as to the
precise size of the parathyroid remnant to leave at subtotal
parathyroidectomy, the precise amount of parathyroid tissue
to autotransplant, and the site to autotransplant into during
total parathyroidectomy with autotransplantation. We recommend parathyroid cryopreservation for all patients having
subtotal or total parathyroidectomy with autotransplantation
in case the parathyroid remnant or autotransplanted tissue
does not function adequately. Long-term follow-up
studies are also necessary to determine the incidence of
hypoparathyroidism and recurrent or persistent HPT after
subtotal or total parathyroidectomy with autotransplantation.
Better histologic and molecular biologic criteria must be
developed to determine precisely whether an abnormal
parathyroid gland is an adenoma or a hyperplastic gland.
Embryology and Anatomy

of Parathyroid Gland
Normal parathyroid glands originate from the third and
fourth pharyngeal pouches and are of endodermal origin."
The inferior parathyroid glands and the thymus are derived
from the third pharyngeal pouch, whereas the superior
parathyroid glands arise from the fourth pharyngeal pouch.'

Because third pharyngeal pouch derivatives (i.e., the inferior
parathyroid glands and thymus) migrate farther, these
parathyroid glands are more likely to be in ectopic or aberrant positions than are the superior parathyroid glands.
Despite this observation, about 80% of the inferior parathyroid glands are situated anterior to the recurrent laryngeal
nerve on the lower (dorsal position) aspect of the thyroid
gland, within 1 em of where the inferior thyroid artery
crosses the recurrent laryngeal nerve (Fig. 53-1). About 15%
of lower parathyroid glands are found in the thymus or
perithymic fat." Occasionally, parathyroid glands fail to
descend. This results in an "undescended parathymus,"?
The superior parathyroid glands are usually situated at
the level of the cricoid cartilage. They are more dorsal in
position than the inferior parathyroid glands. When not
found at this site, they often descend caudally along the
esophagus and sometimes (especially when abnormal) into
the posterior mediastinum (Fig. 53-2). Superior parathyroid
glands may be situated intrathyroidally, within the carotid
sheath, or may also fail to descend and be situated in the
pharyngeal musculature.f Supernumerary parathyroid
glands occur in about 20% of patients and can be situated in
normal or ectopic sites. Supernumerary parathyroid glands
situated at ectopic sites in patients with multiple adenomas
are a common cause of persistent HPT. When four normal
parathyroid glands are identified in a patient with primary
HPT, the fifth supernumerary parathyroid gland is almost
always situated in the mediastinum, usually within the
thymus or peri thymic fat.
Parathyroid Morphology
Most people (80%) have four parathyroid glands. Normal
parathyroid glands measure up to 7 mm in maximal diameter and usually weigh between 15 and 65 mg; all parathyroid glands weigh less than 300 mg.? About 20% of persons
have more than four parathyroid glands, and about 5% have
fewer than four (Fig. 53-3). Parathyroid glands assume
481

adults because there is little intraparathyroidal fat. At
puberty, the normal parathyroid glands assume a light beigebrown color, and 70% to 80% of the chief cells have intracellular lipid droplets.t-'! Normal parathyroid glands are a
darker brown than the adjacent fat, which is yellow. They
also differ from lymph nodes, which are more pinkish and
"glassy" in color, and the thymus, which is whiter.
Hypercellular parathyroid glands are darker brown than
normal parathyroid glands because they have little intracellular fat, and parathyroid adenomas often have a compressed
rim of more normal beige-colored parathyroid tissue. In
general, parathyroid adenomas are firmer than hyperplastic
parathyroid glands found in patients with primary parathyroid hyperplasia. Hyperplastic parathyroid glands are
more likely to be lobular than are parathyroid adenomas
(Fig. 53-5). Hyperplastic parathyroid glands in patients with
secondary HPT tend to be darker, firmer, and better encapsulated than those in patients with primary hyperplasia.
Parathyroid carcinomas are rare and occasionally occur in
patients with parathyroid hyperplasia and in those with
familial HPT.12-14 Parathyroid carcinomas are usually harder
and more fibrotic than adenomas, have a whitish color, are
irregular, and often invade the adjacent tissues."
FIGURE 53-1. The recurrent laryngeal nerve and its relationship
to the parathyroid glands. (From Clark OR [ed], Endocrine Surgery
of the Thyroid and Parathyroid Glands. St. Louis, CV Mosby, 1985.)
Etiology of Hyperplasia
different shapes. About 83% are bean shaped, oval, or spherical, whereas about II % are elongated, 5% are bilobated,
and 1% are multilobated (Fig. 53_4).10.11
The color of the parathyroid glands depends on the ratio
of parathyroid cells to intracellular parathyroid fat. In newborns and infants up to 3 months old, the normal parathyroid
glands are gray, glistening, and semitransparent. Children
have relatively darker or browner parathyroid glands than
The development of hyperplastic parathyroid glands in patients

with renal failure is primarily due to hypocalcemia, although
other factors, including low calcitriol or 1,25-hydroxyvitamin D 3, high phosphate levels, and local growth factors,
are involved. The decrease in serum calcium levels results
from a decrease in the enzyme Ia-hydroxylase in the kidney
that converts 25-dihydroxy vitamin D3 to 1,25-dihydroxyvitamin D. Hyperphosphatemia in patients with renal failure
decreases the activity of la-hydroxylase. The consequent
decrease in 1,25-dihydroxyvitamin D results in decreased
Large
parathyroid
adenoma
FIGURE 53-2. CT scan of the mediastinum shows

a large parathyroid adenoma in the right superior
mediastinum. The patient is a 72-year-old man with
persistent primary hyperparathyroidism after subtotal
resection of three hypercellular parathyroid glands.
Parathyroid Hyperplasia: Parathyroidectomy - - 483
FIGURE 53-3. Common bean-shaped adenomatous hyperplasia
and enlarged right upper and right and left lower hyperplastic
parathyroid glands.
53-5. Multilobed parathyroid gland (hyperplastic gland)

a 62-year-old woman with multiple endocrine neoplasia I and
multiple abnormal parathyroid glands.
~IGURE
III
calcium absorption from the gastrointestinal tract and lower

serum calcium levels. The parathyroid glands, therefore,
compensate by increased secretion of parathyroid hormone
(PTH). In general, the size of the hyperplastic glands in
patients with secondary hyperplasia as documented by ultrasonography or surgery correlates with the degree of elevation
of serum PTH levels. 16
The cause of primary parathyroid hyperplasia or multiple
abnormal parathyroid glands is less clearly understood.
Certainly, patients with both multiple endocrine neoplasia
(MEN) types I and 2 as well as those with familial non-MEN
primary HPT have multiple abnormal parathyroid glands. 1719 Patients with MEN I have had a chromosomal abnormality documented on chromosome 11,20 and patients with MEN
2A and MEN 2B have point mutations on RET protooncogene." Patients exposed to low-dose therapeutic radiation
also are more likely to acquire parathyroid as well as thyroid
neoplasms.t-" Whether parathyroid hyperplasia occurs more
often than in sporadic disease is unknown. Children given
Bilobated
the diuretic furosemide (Lasix) experience parathyroid

hyperplasia as the parathyroids enlarge to compensate for
increased urinary calcium loss."
Neonatal HPT has been documented to be caused by specific point mutations on chromosome 3.25,26 These patients
have homozygous mutations, whereas patients with benign
farnili.al hypocalciuric hypercalcemia have heterozygous
mutations at the same sites. 25,26 Patients with neonatal HPT
require total parathyroidectomy with autotransplantation
and cryopreservation, whereas those with benign familial
hypocalciuric hypercalcemia should be treated nonoperatively because they do not appear to be adversely affected
by the hypercalcemia, and virtually all patients experience
recurrent hypercalcemia after parathyroidectomy."
Studies have been performed to determine whether
hyperplastic glands and parathyroid adenomas are monoTheoretically, the parathyroid
clonal or ~0~yclonaI.28-30
adenoma ongmates from one cell because it is a neoplasm
r~ther
than a hyperplastic growth of normal parathyroid
tissue. One study, however, showed that only 75% of adenomas are monoclonal.P Hyperplasia theoretically originates
from more than one cell. However, studies showed that in
patients with MEN I large glands are monoclonal, whereas
small glands are often polyclonal.v-? Further studies are
required to better clarify the mechanisms of parathyroid
overgrowth.
Multilobated
Indications for
Parathyroidectomy
FIGURE 53-4. Hypercellular parathyroid glands are usually oval

or kidney shaped but occasionally are elongated, bilobated, or
mUl~lobated.
(From Akerstrom G, Malmaeus J, Bergstrom R.
Surgical anatomy of human parathyroid glands. Surgery 1984;95: 14.)
The indications for parathyroidectomy in patients with

parathyroid hyperplasia resulting from secondary HPT are
(1) a calcium-to-phosphorus product greater than 70; (2) a
serum calcium greater than 11.5 mg/dL; (3) symptoms of
Oval, bean-shaped,
or spherical
Elongated

bone pain and pruritus; (4) osteitis fibrosa cystica; (6) tumoral
calcinosis; and (7) calciphylaxis.W"
With primary HPT, it is difficult to know preoperatively
whether a patient will have a solitary adenoma or multiple
abnormal parathyroid glands. The diagnosis of primary HPT
is usually relatively easy to establish on the basis of hypercalcemia and an increased intact or two-site PTH level in a
patient without hypocalciuria. Most patients with hypercalcemia lasting longer than 6 months have primary HPT.
Some patients with primary HPT can be suspected of having
multiple abnormal parathyroid glands on the basis of preoperative localization studies, although localization studi~s
are unreliable in patients with multiple abnormal parathyroid
glands'"; that is, they often identify only one abnormal gland
when more are present.
Because virtually all patients with primary HPT benefit
symptomatically and metabolically and have improved
survival after successful parathyroidectomy, we recommend
parathyroid exploration and parathyroidectomy for most
patients when a surgeon experienced in this field is available."
When parathyroidectomy is performed by an experienced
surgeon, the complication rate is less than 1%, blood transfusions are not required, and the duration of hospitalization
is usually 1 day, unless the patient has severe osteitis fibrosa
. or ot her
seri
. me diica 1 pro bl ems. 36'37
cystica
er senous
preoperative
Patients with osteitis fibrosa cystica can be identified
preoperatively because they have elevated serum alkaline
phosphatase levels." Radiographs of the hands in such
patients are useful for documenting subperiosteal resorption
(Fig. 53-6).
Operative Treatment
Although successful parathyroid operations have been done
since the first successful operation in Vienna in 1925 by
Felix Mandl, there has been controversy regarding the surgical management of the parathyroid glands in patients with
primary and secondary hyperplasia."
Cope'? identified patients with primary hyperplasia and
recommended subtotal parathyroidectomy. Stanbury," in
1960, recommended a similar operation for patients with
secondary HPT resulting from renal failure. Ogg, in 1967,
recommended total parathyroidectomy without autotrans.
. patients
.
. h second ary (rena1) HPT42-45
P1antation
In
WIt
.
Although this operation may be acceptable for patients who
are not candidates for kidney transplantation, aparathyroid
patients are extremely difficult to manage metabolically
after successful renal transplantation, and we do not believe
these patients should undergo total parathyroidectomy.
Aparathyroid patients with chronic renal failure can also
acquire low-turnover bone disease with increased bone pain.
Alveryd and associates, in 1968,70 first recommended
total parathyroidectomy with parathyroid autotransplantation into the muscle in the neck. Wells and colleagues.tv" in
1973, recommended autotransplantation into the forearm
muscle so that one could document whether the autotransplanted hyperplastic parathyroid tissue was functioning by
sampling the blood for PTH in a vein just proximal to the
transplant site." Wells,46,47 Wagner/" and Brennan" and
their colleagues subsequently documented the effectiveness
of cryopreserving parathyroid tissue for patients who may
or may not have any remaining parathyroid after parathyroidectomy. Unfortunately, cryopreserved parathyroid tissue
functions adequately only in about 60% of patients, whereas
primarily autotransplanted parathyroid tissue functions
adequately in about 90% to 95% of patients. 51-55
We recommend subtotal rather than total parathyroidectomy with autotransplantation for virtually all patients with
primary or secondary HPT and parathyroid hyperplasia."
We base this recommendation on our own experience as
well as on a review of the literature. We realize that other
endocrine surgeons recommend total parathyroidectomy
with primary autotransplantation, especially for patients
with familial disease or secondary HPT because of the
higher recurrence rate in these patients.56-58 We also recommend total parathyroidectomy and autotransplantation for
patients with neonatal HPT, because the recurrence rate is
very high,4l,59 and in noncompliant patients with secondary
HPT. We cryopreserve parathyroid tissue in virtually all our
patients treated with either subtotal or total parathyroidectomy
and for all patients requiring reoperation.
Operative Technique
FIGURE 53-6. Radiograph of hands in patient with hyperparathyroidism; osteitis fibrosa cystica is also shown. Subperiosteal
resorption is best seen on the radial aspect of the middle digit of
the second and third phalanges.
A Kocher incision is used. All the parathyroid glands are

identified. If all the glands are abnormal, the parathyroid
gland closest in size to normal and the farthest from the
recurrent nerve should undergo biopsy or subtotal resection
first before the other hyperplastic glands are removed. The
parathyroid remnant should be about 50 mg, which is
the size of a normal parathyroid gland.
The selected parathyroid gland undergoes biopsy or

subtotal resection initially to ensure that the remaining
parathyroid remnant from which a biopsy has been taken has
an adequate blood supply. When the remnant tissue is of
questionable viability, it should be removed and another
parathyroid gland should undergo biopsy or subtotal resection.
In all patients with parathyroid hyperplasia, we recommend
thymectomy because a fifth parathyroid gland is found
in the thymus in 13.7% to 25% of patients.P'" When a
biopsy specimen is taken from the parathyroid remnant,
the site is marked with a silver clip or stitch. As previously
mentioned, using this technique, we have had no patients
with persistent hypoparathyroidism.
Patients treated with subtotal parathyroidectomy have
few complications, and permanent hypoparathyroidism and
recurrent HPT vary considerably (Tables 53-1 to 53-4).

Some of the reported differences perhaps are due to "bone
hunger" resulting from osteitis fibrosa cystica. These
patients may experience profound postoperative hypocalcemia, but PTH levels are increased or normal. Most of
these patients eventually become normocalcemic. As mentioned, we recommend cryopreserving parathyroid tissue
in all patients undergoing subtotal or total parathyroidectomy
with autotransplantation as insurance against possible permanent hypoparathyroidism. Some centers report a high incidence of permanent hypoparathyroidism (see Table 53_1),61.62
which we believe is unacceptable after initial operations
for patients with primary or secondary HPT. The incidence
of permanent hypoparathyroidism should be less than 1%.
For the small number of patients in whom recurrent HPT
develops after subtotal parathyroidectomy (see Table 53-2),

the remnant parathyroid tissue can usually be relatively
easily and safely removed because its position was marked
at the initial operation and its relationship to the recurrent
laryngeal nerve was also clearly described in the operative
note. Numerous studies 63-67 suggest that subtotal parathyroidectomy is the procedure of choice for most patients with
parathyroid hyperplasia.
Total Parathyroidectomy
and Autotransplantation
During this operative procedure, all parathyroid glands are
identified and removed. We also recommend removing the
thymus via the cervical incision in these patients because
the thymus is a frequent site for supernumerary parathyroid
glands. All tissue is confirmed histologically by frozen section
examination, and tissue from the more normal-appearing
hyperplastic parathyroid gland is placed in iced physiologic
saline for autotransplantation and cryopreservation. About
12 to 15 l-mm pieces of this parathyroid tissue are then
autotransplanted into separate pockets in the forearm
muscle.46,47 One-millimeter pieces of parathyroid tissue
ensure better tissue perfusion, and separate pockets are used

in case a hematoma develops, which might compromise
the viability of the autotransplant. Numerous studies have
documented that PTH can be measured in the transplanted arm
and that a gradient can be determined by measuring the PTH
after 2 weeks in both arms. When the PTH level is twofold
or greater on the side of the transplanted tissue, the autotransplanted tissue is working. To determine if the patient's
systemic PTH value is normal, serum PTH and calcium levels
should be measured in the opposite arm. An advantage of
autotransplantation over subtotal parathyroidectomy is that
the hyperplastic parathyroid graft can be excised, under local
anesthesia, if it overfunctions. To remain viable, the autotransplanted parathyroid tissue must invade into muscle. Removal
of all autotransplanted parathyroid tissue from the forearm
can, thus, sometimes be difficult.
Late failure of the transplanted tissue also sometimes
occurs perhaps because of fibrosis. 52,68 Both early and late
permanent hypoparathyroidism are more common after
total parathyroidectomy with autotransplantation than after
subtotal parathyroidectomy (see Table 53-1).
We believe, as mentioned, that parathyroid tissue should
be cryopreserved in patients having subtotal or total parathyroidectomy as well as in patients having reoperations as
insurance against permanent hypoparathyroidism. We advocate total rather than subtotal parathyroidectomy in the
following circumstances:
I. For patients with secondary HPT who are noncompliant and will not take their medication to suppress
parathyroid stimulation
2. For agonal patients who will not tolerate general
anesthesia
3. For technical reasons when it is difficult to preserve
viable parathyroid tissue on a vascular pedicle
4. For patients with neonatal HPT27,41
Cryopreservation of
Parathyroid Tissue
Parathyroid tissue to be cryopreserved is confirmed to be
parathyroid tissue by frozen section examination, and a
portion is immediately placed on ice in physiologic saline.
The tissue is subsequently placed into a Petri dish in RPMI1640 tissue culture medium. The cold parathyroid tissue is
sectioned into 1- to 2-mm pieces with a scalpel blade. Using
sterile technique, about five to eight pieces are placed into a
cryovial, and several vials are usually prepared. We then add
0.5 mLof20% dimethyl sulfoxide in RPMI-I640 and 0.5 mL
of RPMI-I640 containing 20% of serum from the patient per
vial. The tissue is transferred first to the -80 0 C freezer to
freeze slowly (temperature decreases about 10 C per minute);
then it is transferred to be stored in liquid nitrogen. Complete
patient information and location are documented in case the
tissue is subsequently needed to treat hypoparathyroidism.
Long-Term Results of
Different Techniques
About 95% of patients with primary hyperplasia improve,"
and most patients with secondary HPT also experience
dramatic clinical improvement (see Table 53-3). Lundgren
and coworkers?' reported a 73% incidence of permanent
hypocalcemia after total parathyroidectomy with autotransplantation. Rothmund and others52.56.70 reported no difference in the incidence of hypocalcemia after total or subtotal
parathyroidectomy, but the number of patients was small
and follow-up time was short.53 Mozes and coworkers in
1980 reported that 25% of their patients experienced late
failure of the parathyroid graft.68 These data, we believe,
support subtotal parathyroidectomy for most patients. None
of our patients have experienced permanent hypoparathyroidism, although recurrent HPT has OCCUlTed. The relative
incidences of complications after total and subtotal parathyroidectomy are documented in Tables 53-1 and 53-2.
Summary
Parathyroidectomy should be performed by surgeons with
experience in this field. Patients with secondary HPT and
hyperplasia are somewhat more difficult to manage than
those with primary HPT because recurrent and persistent
disease is more common. We believe that most patients with
either primary or secondary hyperplasia are best managed

with subtotal rather than total parathyroidectomy.
Total parathyroidectomy with parathyroid autotransplantation, however, is useful in selected patients. Cryopreservation
of parathyroid tissue should be done in all patients treated
with either total or subtotal parathyroidectomy and in
patients requiring reoperation to decrease the risk of possible
permanent hypoparathyroidism.
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in Multiple Endocrine
Neoplasia Syndromes
Mauricio Sierra, MD Helene Gibelin, MD Jean-Louis Kraimps, MD
Multiple Endocrine Neoplasia 1

When talking of multiple endocrine neoplasia type I (MEN 1),
a proper definition is difficult to establish because the syndrome can result from up to 20 different combinations of
endocrine and nonendocrine tumors.P No definition could
cover all registered cases or families. Thus, a patient with
MEN 1, or Wenner's syndrome, is one who presents with
alterations of hypersecretion or hyperplasia, or both, from two
of the three main MEN I-related endocrine tumors-that is,
parathyroid adenomas, enteropancreatic endocrine tumors,
and pituitary tumors. These alterations mayor may not
occur simultaneously. Familial MEN 1 is defined as a case
of MEN 1 plus at least one first-degree relative with one of
the three aforementioned tumors.
The MEN 1 gene location was first described in 1997.3-6
It is located at chromosome llq13 and consists of 10 exons
with an 1830-bp coding region that encodes a novel
610-amino acid nuclear protein named menin.? Genetic linkage and germline mutation studies have established that familial MEN 1 always arises from the same locus at chromosome
llq13 and always from the same gene.3,4,8- IO MEN 1 mutations are diverse and have been predicted to change the
amino acid chain in menin. These mutations render menin
absent or truncated, the so-called first hit. This condition is
inherited as an autosomal dominant trait and predisposes the
individual to neoplasias of certain tissues. A combination of
the first hit with a somatic or postnatal loss of the other copy
of MEN 1 in one cell (the second hit) initiates neoplastic
clonal expansion. The final result is inactivation of the tumor
suppressor MEN 1 gene and tumor growth, hyperplasia, or
hypersecretion of the referred glands. I 1-14
The fact that an inherited alteration is the origin of the
MEN syndromes explains the aggressive nature of hyperparathyroidism (HPT) in these patients, A different approach
in the diagnosis and special considerations before, during,
and after surgery are warranted.
Clinical Aspects
Although the occurrence of MEN syndromes in the population
is rare (l in 5000 to 50,000 births)," primary hyperparathyroidism (PHPT) is by far the most common endocrinopathy in MEN 1, reaching almost 100% penetrance by age
50 years. 15-17 Patients present with HPT as the primary form of
expression of MEN 1. However, symptoms arise at age 20 to
25,30 years earlier than their sporadic counterparts. Patients
usually complain of weakness, fatigue, constipation, or bone
pain. Hypercalcemia per se increases secretion of gastrin
from gastrinomas, and it is not unusual for patients to present with signs and symptoms of HPT associated with those
of acid hypersecretion from Zollinger-Ellison syndrome."
Less frequently, patients can present with urolithiasis,
psychiatric alterations, renal insufficiency, or cardiovascular
disease. Mild symptoms of HPT may be masked by those of
other endocrine disorders such as gastrinoma, insulinoma,
or acromegaly. 16
Diagnosis
In evaluating patients with PHPT, MEN syndromes should
always be considered. An adequate account of the signs and
symptoms and family history of endocrine disease should be
noted. Upon interview, symptoms of parathyroid disease
may be present in 90% to 100% of patients, of endocrine
pancreas 80%, pituitary 65%, adrenal cortex 36%, and thyroid
24%. Manifestations of the MEN syndromes may develop at
different times, and not all patients present initially with the
complete syndrome.P:'?
Thus, PHPT is diagnosed pretty much in a straightforward
manner as in other cases of HPT. Serum calcium elevation
with marked hypersecretion of parathyroid hormone
(PTH) is the rule. Mild hypercalciuria and an elevated
chloride-to-phosphate ratio can also occur.
Four-gland disease is generally present in these patients.
This is the reason why preoperative imaging studies play
489

little part in the diagnostic algorithm for patients with
PHPT and MEN 1.Although ultrasonography, 99mTc sestamibi
scanning, and magnetic resonance imaging have proven sensitivity, they provide limited information and are not really
cost -effecti ve.
The usefulness of the "quick" PTH assay has been
demonstrated in surgery for sporadic cases of PHPT. The
sensitivity and specificity of the study are high and, although
expensive, the study has been proved cost-effective. Most
studies have been done in patients with adenomas; however,
one report has addressed the use of the assay in patients with
MEN 1 undergoing total parathyroidectomy. PTH levels
decreased in a stepwise fashion but had good predictive
value related to the extent of surgical treatment and postoperative normocalcemia."
High-frequency ultrasonography and nuclear mapping
can help identify ectopic or supernumerary tissue in patients
with hyperplasia. To our knowledge, these studies remain to
be used in patients with MEN 1.21
Treatment
PHTP in MEN 1 patients poses a clear challenge because of
the nature of the disease and high rate of recurrence. This
should be explained to the patient and the family before the
intervention. Notes of the procedure must describe the technique in detail, and remaining tissue must be marked in case
reoperation should become necessary.
Treatment should be directed not to a tumor but to all the
abnormal or potentially abnormal glands. Therefore, efforts
should be directed to identify all four glands. Supernumerary
glands are not uncommon, occurring in approximately 15%
of the population. One should look for ectopic tissue, especially in the thymus and perithymic fat. As with other forms
of HPT, there is no method that best describes how to differentiate an adenoma from hyperplasia. Hyperplasic glands can
vary in size, and this asymmetry may cause the surgeon to
mistake an enlarged gland for an adenoma. As a consensus,
two enlarged glands are considered as hyperplasia." Failure
to identify all parathyroid tissue results in persistent or
recurrent hypercalcemia.
Parathyroidectomy was usually recommended before
treating gastrinoma because of the effects of hypercalcemia
on acid secretion.P However, proton pump inhibitors have
demonstrated efficacy equal to that of parathyroidectomy, and
this has ceased to be considered an indication for surgery."
Because complete exploration and identification of the four
glands are required during surgery, minimally invasive surgery has no role in the treatment of these patients. Complete
neck exploration is not feasible using this technique.
Controversy exists about the extension of parathyroidectomy. An aggressive treatment has been proposed as an
option because of the high rate of recurrence or persistent
hypercalcemia in these patients.P The fact that cure rates
after re-exploration in patients with persistent or recurrent
hypercalcemia were lower than those of patients undergoing
primary operation is another argument in favor of total
resection. Morbidity associated with a second cervical
exploration with scarred tissue in case of postoperative
hypercalcemia is avoided by removing grafted tissue from
the forearm.
After total parathyroidectomy and autotransplantation,

5.6% of patients develop permanent hypoparathyroidism
and 30% develop hypercalcemia postoperatively." We consider this rate of hypoparathyroidism too high. Autotransplantation does not prevent postoperative hypoparathyroidism,
and the most frequent cause of recurrence or persistence of
HPT is not overgrowth of hyperplasic grafts but failure to
identify and resect one or more supernumerary glands in the
neck or mediastinum. Because of this, we advocate subtotal
parathyroidectomy with bilateral thymectomy and cryopreservation. In case hypoparathyroidism develops, transplantation can be accomplished in the forearm with local
anesthesia as an outpatient procedure.P'"
Occasionally, a single parathyroid tumor may be encountered during surgery.16.30,31 If this is the case, all glands must be
identified and marked and biopsy specimens sent for frozen
section evaluation. We recommend removal of the affected and
the normal-appearing ipsilateral gland. Inspection of ectopic
or supernumerary glands along with thymectomy without
damaging the circulation of the normal contralateral glands
is recommended. With this procedure, recurrent hypercalcemia and postoperative hypoparathyroidism are avoided
in most cases.
It is estimated that 20% to 100% of patients with PHPT and
MEN I have recurrences 8 to 12 years after operation. 28,32-35
Patients operated at an early age are the group with the highest risk of recurrence. This is why the term "cure" is not
appropriate in these patients. The first step is to reconfirm the
diagnosis. If recurrence is indeed the case, imaging studies
are in order. A combination of ultrasonography, 99mTc sestarnibi scanning, and/or magnetic resonance imaging is indicated. A diagnostic accuracy of up to 87% is achieved with
this combination.v-v-'? Selective venous sampling can be
added if the former studies are negative or nonconfirmatory.
The latter study improves accuracy by 95%.35,38 This algorithm helps the surgeon to plan the procedure and reduces the
complication rate associated with a reintervention. Previous
operative notes and pathology reports should be reviewed.
Resecting the tissue identified by localization studies is the
primary objective. For lesions located in the anterior mediastinum, a cervical approach may be indicated. Thoracoscopy
may help avoid a sternotomy in selected cases. Autotransplantation should be performed in the same operation if subtotal
parathyroidectomy was the initial procedure, and cryopreservation of fresh tissue is recommended.
In the past, medical treatment had no part in the treatment
of patients with PHPT and MEN 1.39 Calcimimetics, which
decrease PTH release directly acting on the calcium-sensing
receptor, may also decrease parathyroid growth. Trials
are under way to evaluate their role as primary treatment or
alternative therapy for recurrent cases of PHPT.
Follow-up and Screening

Long-term follow-up in these patients is warranted to detect
recurrences early as well as the development of other
endocrine tumors. Annual measurements of calcium and PTH
levels should be scheduled, with determinations of the appropriate hormones or markers to detect other pathologies. II
Most laboratories use direct DNA sequencing strategies
for screening kindreds of patients with MEN syndromes.
Familial Hyperparathyroidism in Multiple Endocrine Neoplasia Syndromes - -
Indications and methods have been described and are

beyond the scope of this chapter." The process is complicated
because family members are tested for a disease for which
they are asymptomatic. Psychological syndromes that arise
from being identified as carriers or noncarriers during the
screening process have also been described.v-v A multispecialty approach is recommended. Whether a positive screening test for MEN I could eventually indicate a prophylactic
procedure remains to be discussed."
Multiple Endocrine Neoplasia 2

MEN 2 syndrome is an autosomal dominant inherited disease,
affecting approximately 500 to 1000 kindreds.P Medullary
thyroid cancer (MTC), pheochromocytomas, and parathyroid hyperplasia are the typical association for patients with
MEN 2A. MEN 2B patients present with tumors from the
adrenal medulla, intestinal and mucosal ganglioneuromatosis,
and a characteristic marfanoid habitus. Other less frequent
variants include familial medullary thyroid carcinoma
(FMTC), MEN 2A with cutaneous lichen amyloidosis, and
MEN 2A or FMTC with Hirschsprung's disease. All variants of MEN 2 show high penetrance for MTC. More than
90% of all MEN 2 carriers show evidence of MTC as a solitary thyroid nodule or as an abnormal elevation of serum
thyrocalcitonin in their life span.P
The gene responsible for MEN 2 has been mapped to
chromosome 10.23,44,45 The RET gene is located near the
centromere and encodes a plasma membrane-bound tyrosine
kinase enzyme termed ret. Through an inherited mutation
that changes an amino acid, RET is activated, causing oncogenic or transforming changes.
Primary HPT occurs in 20% to 30% of MEN 2A
patients. 23,29,46,47 The relationship between specific mutations
and syndromic features has been established. The highest
frequency of pheochromocytoma and HPT occurs in those
who are found to have a mutation on codon 634, more
specifically, C634R.48 The prevalence of HPT is high, however, irrespective of the mutation detected (i.e., C634Y,
C634S, C634F, C634G, C634W). It has been suggested that
HPT is an earlier component of the syndrome.
Patients are 30 years or older at diagnosis. They occasionally have classic symptoms of HPT, hypercalciuria, or
even renal calculi. However, asymptomatic hypercalcemia is
usually found during the work-up for a patient with a solitary
thyroid nodule or MTC. One or more enlarged glands can be
found incidentally during thyroid surgery.
The evolution of HPT is milder than that of its MEN I
counterparts, and it is rare for patients to develop HPT after
the thyroid gland has been removed. A theory of a parathyroid
growth-stimulating factor from C cells has been proposed but
not proved.
Diagnosis
The diagnostic algorithm for patients with HPT and MEN 2
is the same as that for patients with other forms of HPT.
Hypercalcemia and PTH elevation confirm the diagnosis,
along with an elevated chloride-to-phosphate ratio and mild
hypercalciuria.
491
Ruling out excessive catecholamine production is mandatory in these patients because of the morbidity and mortality
associated with operating on patients with coexistent
pheochromocytoma. If the diagnosis is made, pheochromocytoma is dealt with and HPT operated on later.
The treatment of patients with MEN 2A deals primary with
the MTC. A total thyroidectomy with central node dissection is
performed. Total parathyroidectomy with forearm autotransplantation is recommended by some authors for this reason."
Disease is milder in these patients, however,and we consider a
total resection too aggressive. To date, the rate of postoperative
hypoparathyroidism remains high. This may also be the case
with the association of parathyroidectomy and thyroidectomy
with lymph node excision.
If hyperplasia is encountered during surgery, we recommend identification of the four parathyroid glands and resection of only macroscopically enlarged tissue. 16,46,47 A search
for ectopic parathyroid tissue and a cervical thymectomy
should be added to the procedure. Cryopreservation is done
routinely if there is concern about the development of postoperative hypoparathyroidism. This technique is associated
with a low rate of persistent or recurrent HPT.
Follow-up and Screening

Because of the other two components of the MEN 2A
syndrome, life-long follow-up is mandatory. Serum thyrocalcitonin and calcium levels are measured periodically.
Screening for the syndrome in kindreds of patients with
MEN 2A involves demonstration of the RET mutation in
chromosome 10.49. 5 1 A provocative screening test for thyrocalcitonin has lost its role in the detection of kindreds with
MEN 2. Pentagastrin is not always available, and the study is
uncomfortable for individuals. Prophylactic surgery is indicated for patients with a positive RET mutation test, even
at a young age. Genetic testing in this instance has demonstrated an impact on the clinical course of these patients.
Summary
PHPT occurs in MEN I and less frequently in patients with
MEN 2A. The gene responsible for MEN I is located in
chromosome 11q13. An inherited mutation "inactivates"
menin, a nuclear protein, predisposing these patients to
tumor growth and hypersecretion. The gene responsible for
MEN 2A has been mapped to chromosome 10. The RET
protooncogene is activated, causing oncogenic growth or
transformation. HPT occurs more frequently in patients with
a codon C634R mutation. Hyperplasia of the four glands is
the rule. Patients may present with symptoms of hypercalcemia, although a thorough clinical history and laboratory
work-up are advised to rule out other endocrinopathies. HPT
in MEN I is more aggressive, and there is a high rate of persistent or recurrent HPT. Patients with MEN 2 may develop
hypoparathyroidism associated with thyroidectomy for MTC.
We recommend subtotal parathyroidectomy with thymectomy and cryopreservation for patients with MEN I. A more
conservative approach can be used for patients with MEN 2A
because the disease is not as aggressive and PHPT is not
always present at the time of diagnosis.
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4. Lemmens I, Van de Ven W1M, Kas K, et al. Identification of the
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patients. 1 Clin Endocrino1 Metab 1998;83:3004.
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12. Brown EM, Pollak M, Hebert SC. The extracellular calcium-sensing
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14. Mutch MG, Dilley WG, Sanjurjo F, et al. Germ1ine mutations in
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18. lensen RT. Management of the Zollinger-Ellison syndrome in patients
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19. Boey lA, Cooke TJC, Gilbert 1M, et al. Occurrence of other endocrine
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results after operative treatment of primary hyperparathyroidism
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or less extended operation essential? Eur 1 Surg 2001;167:173.
26. Feldman AL, Sharaf RN, Skarulis MC, et al. Results of heterotopic
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33. Clark OH, Okerlund MD, Moss AA, et al. Localization studies in
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34. Hellman P, Skogseid B, Oberg K, et al. Primary and reoperative
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36. De Feo ML, Colagrande S, Biagini C, et al. Parathyroid glands:
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37. Shen W, Duren M, Morita E, et al. Reoperation for persistent or recurrent primary hyperparathyroidism. Arch Surg 1996;131:861.
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39. Silverberg Sl, Bone HG, Marriott TB, et al. Short-term inhibition of
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with primary hyperparathyroidism. N Engl 1 Med 1997;337:1506.
40. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis
and therapy of MEN type 1 and type 2. 1 Clin Endocrinol Metab
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41. Goretzki PE, HoppnerW, Dotzenrath C, et al. Genetic and biochemical
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42. Kinder BK. Genetic and biochemical screening for endocrine disease.
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43. Kopp I, Bartsch D, Wild A, et al. Predictive genetic screening and
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44. Eng C, Clayton D, Schuffenecker I, et al. The relationship between
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multiple endocrine neoplasia type 2. International RET mutation consortium analysis. lAMA 1996;276:1575.
45. Ponder BA1, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet
1988;1:397.
46. Kraimps Jl., Denizot A, Camaille B, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: Retrospective French
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(GETC, French Calcitonin Tumors Study Group), French Association
of Endocrine Surgeons. World 1 Surg 1996;20:808.
47. Raue F, Kraimps Jl., Dralle H, et al. Primary hyperparathyroidism in
multiple endocrine neoplasia type 2A. 1 Intern Med 1995;238:369.
48. Schuffeneker I, Virally-Monod M, Brohet R, Ie Groupe D'Etude des
Tumeurs a Calcitonine. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. 1 Clin Endocrinol
Metab 1998;83:487.
49. Easton DF, Ponder MA, Cummings T, et al. The clinical and screening
age-at-onset distribution for the MEN-2 syndrome. Am 1 Hum Genet
1989;44:208.
50. Lips C1M. Clinical management of the multiple endocrine neoplasia
syndromes: Results of a computerized opinion poll at the Sixth
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neoplasia type 2A. Ann Surg 1994;220:237.
Shih-Ming Huang, MD
Although most cases of primary hyperparathyroidism (HPT)

occur sporadically, familial clusters have been reported.
Most of these familial cases occur in association with multiple endocrine neoplasia (MEN). Goldman and Smyth in
1936 were the first to report a patient with familial HPT who
had no other manifestations of MEN.l Many more familial
cases have subsequently been reported.l" Similarly to the
classification of medullary thyroid cancer, HPT can be
classified into four types: (1) sporadic HPT, (2) familial
HPT with MEN 1 and 2, (3) non-MEN familial HPT
(NMFH) or familial isolated HPT(FIH), and (4) non-MEN
familial HPT associated with jaw tumor syndrome. Because
NMFH is uncommon, these patients are frequently included
in the series of patients with familial HPT with MEN, or
they are confused with patients with benign familial
hypocalciuric hypercalcemia (BFHH).7,34 From our experience at the University of California, San Francisco (UCSF)
(Table 55-1) and from a review of the literature.t" we confirm that NMFH is a distinct entity.-?
This chapter emphasizes the clinical characteristics and
management of NMFH, In the literature, NMFH has been
associated with an increased risk of parathyroid cancer, especially when associated with the jaw tumor syndrome.21,33,35-43
Familial HPT occurring in infants (familial neonatal HPT) is
different from NMFH in adults. Neonatal HPT occurs in children of parents with BFHH, and most patients have high serum
calcium levels.44-56 Patients with neonatal primary HPT have a
specific chromosomal defect on chromosome 3 and always
present before 10 years of age. Patients with NMFH almost
always develop hypercalcemia after 10 years of age. Patients
with NMFH are diagnosed by means of family history.A thorough personal family history must be taken concerning the
clinical manifestations of MEN 1 and 2, Laboratory tests
should include prolactin,gastrin, chromogranin, and pancreatic
peptide to rule out MEN-associated parathyroid disease.
Progressive genetic mapping has proved useful in excluding
the possibility of MEN 1, MEN 2, or BFHH'
Non-MEN Familial
Hyperparathyroidism
Clinical Features
The clinical information concerning the 16 patients with
NMFH from 14 families treated at UCSF is summarized
in Table 55-1. The most striking clinical feature of NMFH is
the high incidence of profound hypercalcemia, which rarely
occurs in patients with sporadic HPT or HPT associated
with MEN 1 or 2. In the UCSF series, the patients with
NMFH had hypercalcemia ranging from 10.5 to 20.3 mg/dL
(mean, 13.9 mgldL); 44% of these patients had profound
hypercalcemia (serum calcium> 15 mg/dL), and 31% presented in hypercalcemic crisis, requiring emergency hospitalization. As seen in Table 55-2, 45% of 51 patients in the
literature presented with a serum calcium of 15 mg/dL or
greater and 67% with a serum calcium of 13.5 mg/dL or
greater. Thus, unlike the non-MEN familial medullary thyroid cancer that is less aggressive than sporadic medullary
thyroid cancer or MEN 2B, NMFH appears to be more
aggressive than other forms of the disease.
One third to one half of the patients with NMFH experience nephrolithiasis. One fifth of the patients have severe
osteoporosis, and osteitis fibrosa cystica with brown tumors
is more common. Other nonspecific symptoms or signs that
occur more frequently in the patients with primary HPT,
including hypertension, fatigue, weakness, pancreatitis, or
peptic ulcer, may also be common in patients with NMFH,
but currently there is insufficient information to know with
certainty. Four patients in the UCSF series were asymptomatic initially, but two of these initially asymptomatic
patients experienced hypercalcemic crises when the disease
persisted after the initial parathyroidectomy at another
medical center.
The mean age of the patients with NMFH at initial diagnosis was 43.5 years (range, 12 to 86 years) in the UCSF
493
series, which is older than that of patients in other reports

(mean, 32.3 years; range, 12 to 68 years) but is similar in
that of patients with MEN 157-68 and younger than that of
patients with sporadic primary HPT.69 Both genders are
affected, Some patients experience NMFH as children but
rarely, if ever, before 10 years of age.
The mechanism of inheritance of NMFH is unknown. In
contrast to the autosomal dominant inheritance characteristic
of MEN, Law and colleagues reported on an autosomal
recessive inheritance of NMFH in three siblings.'? The
inheritance of NMFH may therefore vary and be more
complex. Restriction fragment length polymorphism linkage analysis showed the presence of HPT to be linked to a
locus on chromosome llq13 (near or identical to the MEN 1
gene) in members of a family with NMFH, and genetic mapping found few families with NMFH that have incomplete
expression or a subset of MEN 1.70-76 No distinctive genetic
abnormalities, except NMFH with tumors of jawbones, have
been found to date with NMFH.33,77
Associated Diseases
Coexistent thyroid disease occurred in 62% of patients with
NMFH in the UCSF patients, and 19% of the patients
had coexistent papillary thyroid cancer. Because thyroid
abnormalities are common in patients with other types of primary HPT,78-82 this apparent increase in frequency of benign
and malignant thyroid neoplasms may not be statistically
significant.
Fibroosseous tumors of the mandible or maxilla (i.e.
tumors of the lower and upper jawbones) or so-called
NMFH-JT or FlH-JT, rather than brown tumors caused
by osteitis fibrosa cystica, have been associated with patients
with NMFH in 28 families in the literature, and genetic
studies have revealed that this disorder is autosomal dominant and linked to chromosome lq25_q31.19,2J.23-33.38,77,83
In addition, 16 of these 28 families have family members
with parathyroid cancer, Other associations such as colon
cancer, diabetes mellitus, breast cancer, neurilemoma, and
sarcoidosis are also occasionally described.
Familial Hyperparathyroidism - -
Initial
Impression
Initial
Operation
Final
Pathology
Cure 4
9--remove
one adenoma
4--remove
two adenomas
495
Recurrent 3
-E
34 Y r ~
10 yr ~
8yr~1
Persistent 2
c u re 2
~2
Persistent 2 ~
~1
8] 3 --subtotal--Cure 3 ------8] 3
parathyroidectomy
Hyperparathyroidism
Multiple abnormal parathyroid glands (two or more) were
present in 75% of patients treated at UeSF and in 45% of
patientsreported in the literature with NMFH (see Table 55-2).
Persistent or recurrent (normocalcemia for at least 6 months
after parathyroidectomy) HPT occurred in 44% of patients
treated at UeSF and in 20% of patients reported in the literature (see Table 55-2).A shorter duration of follow-up probably
accounts for the lower incidence of recurrence reported in the
literature. As with MEN 1,84 supernumeraryglands were found
in 19% of patients treated at UeSF with NMFH, which is similar to the rate reported in patients with MEN and contributed
to the high incidence of persistent or recurrent disease.
Because three of our patients experienced recurrent HPT
after 8, 10, and 34 years of normocalcemia, respectively
(Fig. 55-1), postoperative normocalcemia does not preclude
subsequent recurrence of the disease. Long-term follow-up
of these patients, as well as screening of family members, is
essential.
Surgical Treatment
The more aggressive biologic behavior of the parathyroid
disease in patients with NMFH, as well as the high incidence of multiple abnormal glands and supernumerary
glands and high recurrence rate, warrants a somewhat more
aggressive surgical approach. Failure in these patients, as in
others with primary HPT, was usually due to failure to identify and remove parathyroid glands in their usual location
as well as failure to identify and remove supernumerary
parathyroid glands. Because parathyroid rests or supernumerary glands are often present in the thymus or perithymic
tissue, we advocate bilateral cervical thymectomy with
removal of all perithymic fat.
FIGURE 55-1. UCSF patients' data on persistent or recurrent

hyperparathyroidism and pathology. ITQ]N = one abnorm~and,
no. of cases; ~N = two abnormal~nds,
no. of cases; l1QjN =
three abnorm~lands,
no. of cases;~N
=four abnormal glands,
no. of cases; ~ N = five abnormal glands, no. of cases.
If all glands appear to be abnormally enlarged, we recommend subtotal parathyroidectomy, leaving about 50 mg of the
most normal parathyroid glands with bilateral thymectomy.
Although total parathyroidectomy with autotransplantation
has been recommended for patients with hyperplasia and
familial disease, we believe this results in an increased frequency of hypoparathyroidism and thus prefer subtotal
resection. For patients with recurrent or persistent disease,
we recommend total parathyroidectomy with autotransplantation to the forearm and cryopreservation. Although cryopreserved parathyroid tissue functions adequately in only
about 60% of patients, it is still useful in these patients for
preventing permanent hypoparathyroidism. Postoperatively,
it is often difficult to know whether a patient has bone hunger
or permanent hypoparathyroidism. The intact parathyroid
hormone (PTH) assay helps to differentiate between these
two conditions. When a solitary adenoma is found and the
three other parathyroid glands appear normal, we recommend removal of the adenoma, ipsilateral thymectomy, and
removal of the normal-appearing gland on the same side to
confirm that it is not hyperplastic. If there is recurrence, this
side of the neck usually does not have to be reexplored.
When double adenomas are found, a similar surgical
approach to patients with a solitary adenoma can be applied:
the pathologic glands should be removed, and one of the
normal-appearing parathyroid glands is excised or undergoes biopsy, preferably leaving parathyroid tissue on only
one side of the neck.
Key Points for Differential Diagnosis

Defined NMFH is diagnosed by excluding other cases of
familial hypercalcemia with HPT. The three following

disorders should be considered. First, BFHH is known as an
autosomal dominant, symptomless, nonprogressive, lifelong
hypercalcemic disorder with 100% penetration. Individuals
with BFHH show abnormal parathyroid and renal responsiveness to changes in extracellular calcium levels.t'
Linkage studies have demonstrated that the disease locus
in most BFHH patients is located on chromosome 3q13.3q2l68,-69, and the defect has proven to be the calciumsensing receptor (CASR) gene. 86-91 Rare kindreds are linked
to a defect on chromosome 19p13.3 or 19q13.86,92 Patients
with BFHH are heterozygous for this mutation, whereas
patients with neonatal HPT tend to be homozygous for the
mutation,93,94
Patients with BFHH are hypercalcemic before age
10 years. The serum calcium level is usually moderate (the
values were 10.9 0.1 mg/dL in a study of 21 BFHH families?') and never greater than 14 mg/dL.85-88,95-102 The symptoms and signs are usually vague or mild, Although the
incidence of gallstone, diabetes mellitus, relapsing pancreatitis, and myocardial infarction is slightly increased, the
incidence of nephrolithiasis is normal. Occasionally, fatigue,
mental problems, headaches, arthralgia, and polydipsia may
be noted. 97,101 These patients do not appear to benefit from
parathyroidectomy.P'v'P However, patients with neonatal
HPT need to be treated by total parathyroidectomy with
parathyroid autotransplantation and cryopreservation.w''"
In 20% of BFHH patients, the serum PTH is usually
normal'" or mildly elevated.f-"? The normal or mildly elevated PTH values in the presence of hypercalcemia imply
or represent a set-point error of parathyroid function and
parathyroid cells insensitive to serum calcium because of
functional loss of the CASR. 89,98 The parathyroid glands
are normal grossly and histologically demonstrate mild
hyperplastic changes.l'"
Hypocalciuria is another important feature because the
capacity of renal tubular reabsorption of calcium increases
in patients with BFHH. Because magnesium is handled
similarly to calcium by the kidney in these patients, about
half of the patients with BFHH have an elevated serum magnesium concentration.f The urinary calcium level of less
than 0.01 for the urinary calcium-to-creatinine clearance
ratio (Cca/Ccr) is the most reliable diagnostic criterion for
BFHH to distinguish it from primary HPT.85 Genetic mapping is another powerful diagnostic tool for differentiating
BFHH from primary HPT.
Medical or surgical therapy is unnecessary and uniformly
ineffective. 101. 102 Hypercalcemia usually persists after partial
parathyroidectomy and permanent hypocalcemia after total
parathyroidectomy.
Second, MEN 1 is a genetic autosomal dominant disorder
characterized by multiple neoplasms of the parathyroid, neuroendocrine tumors of the pancreas, and neoplasms of the
anterior pituitary gland. Multiple lipomas and carcinoid
tumors are also more common in patients with MEN 1, The
predisposing genetic defect has been assigned to chromosome
region llqll-q13 by linkage analysis. 57.58 Germline mutations have been identified in about 90% of MEN 1 families.
The mutations included nonsense, missense, splice,
frameshift, and in-frame deletions. 104 - 106
The clinical features of MEN 1 depend on the number and
combinations of endocrine glands that are hyperfunctioning.
Although Majewski and coworkers suggested an "all or

none" phenomenon in which the affected members invariably have pathologic changes if tissue from these three
glands are examined.t" there is considerable variation of
the endocrine glands of patients with MEN 1. Not only do the
features of MEN 1 vary among members within the same
family, but also some families with MEN 1 may have different degrees of penetration. In addition, the age at which the
clinical manifestations of MEN 1 develop can differ considerably from one family member to another, which is also
true for NMFH.
Most often, the first sign of MEN 1 is HPT. HPT usually
antedates other manifestations of MEN L60 Virtually all
individuals who inherit the trait experience hypercalcemia
by the age of 40 years. 61,62 Periodic testing should begin at
about 12 years of age and be repeated yearly; a normocalcemic person older than 50 years is unlikely to have inherited the MEN 1 gene. The incidence of clinically detectable
islet cell lesions increases as patients grow older. Because
some islet cell tumors fail to elaborate functioning hormone,
the absence of any clinical syndrome does not rule out the
presence of a pancreatic islet cell tumor, A secretin provocative test for gastrin helps to make the diagnosis in patients
with a "silent" gastrinoma, Pituitary tumors are common in
MEN 1 patients. About one third of patients with MEN 1
experience pituitary tumors and clinical symptoms. Autopsy
studies demonstrate that pituitary microadenomas occur
even more often. 63
Although DNA genetic techniques are being developed
to diagnose patients with MEN 1 and familial HPT,57 a
detailed family history concerning the presence of ulcer
disease, renal stones, or recognized parathyroid, pancreatic,
or pituitary tumor is essential. Patients with MEN 1 also
often have multiple lipomas and angiomas. The following
three points are crucial for excluding the possibility of MEN 1
from patients with familial HPT:
1. Autopsy data of family members with isolated familial HPT showing that no pancreatic or pituitary tumors
are present.
2. Repeated laboratory tests for gastrin, prolactin,
insulin, glucagon, pancreatic peptide, corticotropin,
and growth hormone for family members yielding
normal results.
3. Genetic mapping of chromosome 11 to detect MEN 1
gene mutations or the possibility of incomplete phenotype expression of MEN 1.
The hypercalcemia in most patients with MEN 1 is usually mild (serum calcium level less than 11 mg/dL), and
most of these patients are relatively asymptomatic, The
mean serum calcium level is usually less than 12 mg/dL and
rarely greater than 14 mg/dL,60,64.65,67 although one patient
has been reported with a calcium level of 16 mg/dL. 64
Patients with MEN 1 and HPT usually have multiple
abnormal parathyroid glands with a high incidence of supernumerary glands." Subtotal parathyroidectomy or total
parathyroidectomy with autotransplantation is recommended
by most authorities in this field. Among our patients with
primary HPT and MEN, we have identified two populations
of patients: one population has solitary or double adenomas
and recurrence is uncommon, whereas the other group
has diffuse hyperplasia and persistent or recurrent disease
Familial Hyperparathyroidism - -
is common.v' We recommend a similar operative strategy for

treating patients with HPT and MEN 1 and for patients with
NMFH.64 Both groups are susceptible to recurrent HPT.
Third, MEN 2 is known to be an autosomal dominant
cancer syndrome characterized by medullary thyroid cancer,
pheochromocytoma (usually bilateral), and HPT. The genes
responsible for MEN 2 have been mapped to genetic intervals
within lOql1.2 107,108 and a mutation in either exon 10 or 11.
A point mutation of the ret protooncogene has been found
in more than 95% of the patients with MEN 2A.109,11O
MEN 2B is also an autosomal dominant disease, attributable
to a site-specific point mutation on codon 918 of the ret
protooncogene.l'" characterized by medullary thyroid
cancer, pheochromocytoma, and the presence of mucosal
neuromas, ganglioneuromatosis, or marfanoid habitus,
producing a distinct clinical phenotype. HPT is a very rare
component of MEN 2B.
Medullary thyroid cancer or C-ce1l hyperplasia is the
dominant feature and usually is first seen in all the affected
members, III but the penetrance of pheochromocytoma or
HPT is variable. The prevalence of HPT varies from 0% to
70% (median about 20%), and the prevalence of pheochromocytoma ranges from 5% to 95%.112-114 HPT is the least
common feature of MEN 2 and tends to develop later than
medullary thyroid cancer or C-ce1l hyperplasia, usually after
the third decade of life. lIS A normal serum calcitonin level
excludes the possibility of MEN 2 in patients without
previous total thyroidectomy.
The reason for the different penetrance of HPT in MEN 2
is unknown. The increased calcitonin levels in patients with
medullary thyroid cancer do not account for the HPT
because patients with sporadic medullary thyroid cancer or
those with MEN 2B do not have parathyroid tumors. Of
interest, primary HPT rarely develops in individuals who
undergo total thyroidectomy at a young age.!"
Removed parathyroid glands from patients with MEN 2A
usually demonstrate chief cell hyperplasia.U':'!? Even in
patients with normocalcemic MEN 2A, enlarged parathyroid glands or normal-appearing parathyroid glands are
often microscopically hyperplastic when removed at total
thyroidectomy.U? The parathyroid glands are often asymmetrically involved. I 18 We recommend a conservative selective
approach to the parathyroid glands in these patients because
postoperative hypocalcemia is more common than persistent
or recurrent hypercalcemia.
Only about 30% of patients with HPT and MEN 2A have
symptoms, and most of these patients have only slightly
elevated serum calcium levels.!" The most common
clinical manifestations reveal colic and nephrolithiasis.
Hypercalcemic crisis or significant bone disease rarely
occurs. 67,l17 At the Mayo Clinic, for patients with MEN 2A
and HPT, the serum calcium level ranged from 10.2 to
13.5 mg/dL (mean, 10.7 mg/dL).
As mentioned, because an unacceptable consequence of
subtotal parathyroidectomy or total parathyroidectomy with
autotransplantation in patients with MEN 2 and HPT is
hypoparathyroidism, we and others''? recommend excision
of only grossly enlarged parathyroid glands, and at least one
or two normal-sized glands should be left intact and marked
with a metal clip or suture to facilitate their identification
if reoperation becomes necessary. This recommendation is
497
based on the findings that selective parathyroid excision has

cured most patients with MEN 2 and HPT and recurrent
HPT is rare in these patients.
Non-MEN Familial
Hyperparathyroidism
and Parathyroid Cancer
Both parathyroid cancer and NMFH are rare parathyroid
disorders. The association of these rare conditions suggests
a common cause. Until 2002, 29 patients with NMFH and
parathyroid cancer in 22 families were reported. 16,21,23,27-33,35,43
Sixteen of these families have NMFH-JT or FIR-JT, and
about one fourth of reported NMFH families have one or
two affected members suffering from parathyroid cancer.
Endocrinologists and surgeons should be aware of this association for proper management of these patients.
Clinical Features
Reviews of 15 cases of NMFH and cancer were reported
before 1993. The mean age of the patients with NMFH and
parathyroid cancer at initial diagnosis was 30 years (range, 14
to 43 years), which is considerably younger than that of other
patients with parathyroid cancer (50 years) (Table 55_3).41
Seven males and eight females were affected. The clinical
manifestations among these patients were similar to those
of other patients with parathyroid cancer. The mean serum
calcium level was 16.1 mg/dL, and one third presented in
hypercalcemic crisis. Sixty-one percent of these patients had
severe osteitis fibrosa cystica and 30% had nephrolithiasis.
Twenty-three percent presented with a palpable neck mass.
Pathogenesis
In some patients with NMFH and parathyroid cancer,
one or more of the other parathyroid glands were also
abnorma1.21,35,43 This occurrence raises the possibility of the
transformation of benign parathyroid neoplasms to parathyroid cancer similar to the transformation of C-ce1l hyperplasia to medullary thyroid carcinoma. In most studies,
however, there is no evidence of transformation proceeding
from hyperplastic glands to parathyroid cancer because 60%
of these patients have only parathyroid cancer. 36.37,39-42

NMFH-JT or FIH-JT is known to be linked to chromosome
Iq25-q31 abnormalities. NMFH and parathyroid cancer
arising without tumors of the upper and lower jawbones
have never, to our knowledge, been identified with a specific
genetic mutation.P although three somatic chromosome
abnormalities (reciprocal translocation between chromosomes 3 and 4, trisomy 7, and a pericentric inversion in chromosome 9) were also noted in cultured parathyroid cells
from one patient with NMFH and parathyroid cancer."
At operation, when one encounters a parathyroid tumor
that is hard, grayish white, lobulated, or invasive, parathyroid cancer must be suspected. An en bloc excision of the
parathyroid neoplasm and ipsilateral thyroid lobe or other
adherent tissues is recommended (especially for patients
with profound hypercalcemia). For such patients with recurrent or metastatic disease, an aggressive surgical approach,
even when palliative, is recommended to palliate symptoms of
HP'f'I1 and to decrease the metabolic problems. Persistent or
recurrent hypercalcemia occurred in about 40% of the patients
with NMFH and parathyroid cancer, a rate similar to that
reported for patients with sporadic parathyroid carcinoma.
Familial Neonatal
Hyperparathyroidism
Neonatal HPT is a rare disorder. It is usually associated
with severe hypercalcemia, requiring urgent treatment.
More than 50 cases of neonatal HPT have been reported
in the literature. 44-56,89,119-126 They may be sporadic or familial. Hillman and colleagues first drew attention to the
familial occurrence of neonatal HPT.119 About half of the
patients with neonatal HPT have a documented familial
inheritance.44-56,120,121 Two types of inheritance-autosomal
dominant and autosomal recessive-have been reported in
neonatal HPT. The documentation of seven cases from three
families suggests an autosomal recessive transmission.'!"!"
Other cases of neonatal HPT are associated with BFHH.
Patients with BFHH appear to have a benign course with
normal survival. In contrast, children with neonatal HPT
often have a poor clinical course. Pollak and associates'?
demonstrated that a single defective allele causes BFHH,
whereas two defective alleles cause severe neonatal HPT,
and the genetic defect maps to the CASR gene on chromosome 3q13.3-21. Genetic studies also showed that a de novo
CASR gene mutation resulted in sporadic neonatal HPT,127,128
and infants with a homozygous CASR gene mutation or
infants with a heterozygous mutation,89,93,94 delivered by a
normal mother, develop neonatal HPT.89,127
At birth, newborns are usually normal in terms of size
and weight. Both genders are affected. The clinical manifestations usually become evident during the first week of life
but may not be recognized until 3 or 4 months of age or later.
Severe hypotonia is almost always present in children
with profound hypercalcemia. Failure to thrive is common
and is usually combined with digestive disorders, including
constipation, anorexia, difficult feeding, vomiting, and ileus.
Some infants present with dehydration, and renal stones have
been reported in three infants. Advanced demineralization is
present in most children, and limb and thoracic cage deformities or pathologic fractures have been reported.
At neck exploration, the parathyroid glands are diffusely

enlarged and chief cell hyperplasia is evident histologically.123
Medical management, including vigorous hydration, should
be instituted in all patients and may be successful in milder
cases,46,51,52 although urgent parathyroidectomy is recommended for most patients with severe urgent conditions.
Because of the high recurrence rate after subtotal
parathyroidectomy, total parathyroidectomy with immediate
autotransplantation or with late autotransplantation of cryopreserved parathyroid tissue is recommended. After total
parathyroidectomy and parathyroid autotransplantation,
some infants have modest hypercalcemia, a normal serum
PTH level, hypermagnesemia, and relative hypocalciuria,
similar to patients with BFHH. 49 All newborns from families
with BFHH must have a serum calcium determination.
Summary
NMFH is a distinct clinical entity. The definite diagnosis
can be made either by complete clinical work-up or by
genetic study to exclude the possibility of MEN 1, MEN 2,
or BFHH. These patients are younger and more susceptible
to the development of profound hypercalcemia or hypercalcemic crisis than are patients with sporadic HPT or those
with HPT and MEN. Patients with NMFH also appear to
have a higher incidence of parathyroid cancer and perhaps
thyroid neoplasms. Patients with NMFH-JT have unique
genetic mutations that are often associated with an extraordinarily high incidence of parathyroid cancer. Patients with
NMFH, like those with MEN 1, frequently have multiple
abnormal parathyroid glands, either synchronously or
metachronously, and, therefore, are at risk for persistent or
recurrent disease. NMFH is a unique disease that warrants
appropriate recognition, screening of family members,
aggressive treatment, and long-term follow-up.
Patients with neonatal HPT differ from those with NMFH,
although both often present with profound hypercalcemia.
Neonatal HPT is associated with BFHH. Determination of the
serum calcium level at birth is most important in patients with
BFHH to detect this condition early and treat it appropriately.
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Metabolic Complications
of Secondary
Hyperparathyroidism
Juan J. Sancho, MD Antonio Sitges-Serra, MD
The term secondary hyperparathyroidism (SHPT) means that

external factors stimulate the parathyroid glands to increase
the production of parathyroid hormone (PTH) and eventually
to develop hyperplastic or adenomatous overgrowth, or both.
The most common condition causing the parathyroid
glands to grow is chronic renal failure (CRF). The often
used term renal hyperparathyroidism reflects this fact.
SHPT may develop, however, in a variety of conditions such
as idiopathic hypercalciuria,' hypennagnesuria, osteomalacia,
rickets, malnutrition, or osteoporosis' with low serum levels
of 1,25-dihydroxyvitamin D3 (1,25-[OHhD 3, calcitriol).'
Hyperparathyroidism in psychiatric patients receiving longterm treatment with lithium is also associated with parathyroid hyperplasia.'
In this chapter, the pathogenesis of SHPT related to CRF,
its metabolic complications, and its relationship with the
clinical manifestations of CRF are reviewed.
Pathogenesis of Secondary
Hyperparathyroidism
Stimulated by the description of enlarged parathyroid glands
in uremic patients by Albright and colleagues,' the Viennese
pathologists Pappenheimer and Wilens6 were the first to attribute parathyroid hyperplasia to CRE Since then, researchers
have attempted to link decreased kidney functions with the
biochemical, morphologic, and clinical manifestations of
SHPT. The task has proved to be difficult because both the
excretory and endocrine functions of the kidney are impaired
in CRE In addition, the treatment of CRF and its complications contribute to the pathogenesis of SHPT, complicating
the complete explanation of the pathophysiology of SHPT.
The past 30 years have witnessed a dramatic improvement in our understanding of the factors involved in the
pathogenesis of renal SHPT. The first landmarks were the
502
development of the radioimmunoassay" for PTH fragments

and later an immunoradiometric assay for intact PTH(l-84).
Understanding some factors in the pathogenesis of SHPT,
such as hypocalcemia, hyperphosphatemia, decreased 1,25(OHhD 3 levels, altered PTH metabolism, skeletal resistance
to PTH, and the changed set-point in PTH production, provided the initial body of knowledge to help rationally treat
these patients. The other advances took place at the biomolecular and genetic levels. They include the discovery of
receptors for calcium and calcitriol in the parathyroid cells,
their regulation, and the implications of polymorphism; the
identification of the PTH gene; and the demonstration of
monoclonality in some parathyroid hyperplasia nodules.
Increased PTH levels cause, besides the classic skeletal
disorders, many clinical manifestations of SHPT. A PTHmediated elevation of cytosolic ionized free calcium (Ca 2+;)
is responsible for much of the generalized organ dysfunction
in CRF.7 It also has to be taken into account that the assay
used for the dosage of "intact PTH" has also been found to
detect "7-84" fragments, with a potentially inhibitory effect
on the action of the whole hormone, Intact PTH assays also
react with non-(l-84)PTH, large carboxyltenninal (C) fragments with a partially preserved aminotenninal (N) structure. They account for up to 50% of intact PTH in renal
failure and may be implicated in PTH resistance."
The following are the main pathogenic factors linking
CRF and SHPT.
Before Kidney Transplantation

HYPOCALCEMIA
Hypocalcemia is not a primary event in CRF but a consequence of hyperphosphatemia, bone resistance to PTH, and
low circulating calcitriol, each playing a dominant role in
different stages of SHPT. The fact that serum calcium is
normal in more that 50% of patients with CRp9 is explained
Metabolic Complications of Secondary Hyperparathyroidism - -
by the gradually increasing PTH secretion to maintain serum

calcium levels.
PTH raises the serum calcium level through its effects
on bone and kidney; calcitriol produces similar effects by
working in concert with PTH on bone and by enhancing calcium absorption in the gastrointestinal tract. High serum
concentrations of calcium inhibit the synthesis of preproPTH
messenger RNA (mRNA) and secretion of PTHlO by the
parathyroid cells. PTH stimulates the synthesis of calcitriol
by enhancing renal Iu-hydroxylase activity, whereas calcitriol inhibits the synthesis and secretion of PTH by impairing PTH gene expression. I I
Parathyroid gland becomes hyperplastic in response to
prolonged hypocalcemia. 12 Hypocalcemia is a potent stimulator of PTH mRNA synthesis. This stimulation, however,
is independent of the cytosolic calcium concentration of the
parathyroid cell. Although little is known about the regulation
of parathyroid cell proliferation, constant stimulation of
PTH mRNA synthesis is associated with the development of
parathyroid hyperplasia.P:'"
DIMINISHED SYNTHESIS OF CALCITRIOL
The kidney produces calcitriol," the most active metabolite

of vitamin D. The synthesis of calcitriol from 25-(OH)D3by
the renal enzyme Iu-hydroxylase is stimulated by PTH, by
hypocalcemia per se, and by hypophosphatemia.
Calcitriol exerts its actions on mineral metabolism
through the bone, the gut, the parathyroid glands, and the
kidney. On the bone, calcitriol works in concert with PTH
to mobilize calcium by enhancing osteoclastic activity and
recruiting stem cells to differentiate into osteoclasts. It also
has an indirect action in ossification, probably by recruiting
cells into osteoblasts, which in tum are responsible for bone
mineralization." Calcitriol promotes the intestinal absorption of calcium by enhancing the expression of the calciumbinding protein (calbindin)." On the parathyroid glands,
calcitriol inhibits PTH synthesis and secretion by increasing
the sensitivity of the parathyroid cell to calcium.'? inhibiting
PTH gene expression.V'P and inhibiting parathyroid cell
proliferation." Calcitriol also appears to upregulate its own
receptor in the parathyroid gland." In addition, the hypercalcemic effect of calcitriol indirectly inhibits PTH synthesis
and secretion. On the kidney, calcitriol promotes phosphorus
excretion."
There is considerable evidence that patients with
advanced renal failure, despite elevated serum PTH levels,
have reduced or even undetectable levels of calcitriol.Pv"
although in mild uremia calcitriol levels are only slightly
reduced or even normal. 25.26
The reduction of renal mass and the hyperphosphatemia
are the main reasons for calcitriol deficiency. A relative
resistance of lre-hydroxylase to the effect of PTH has
also been advocated." Extrarenal production of calcitriol
from macrophages, keratinocytes, and aortic endothelial
cells might compensate for the decrease in renal production."
but this occurs only after high doses of 25-(OH)D 3.
Although the metabolic clearance rate of calcitriol is also
decreased in CRF, it does not compensate for the low
calcitriol production.r"
The decreasing ability of the failing kidney to hydroxylate 25-hydroxyvitamin D causes an absolute or relative
503
deficiency of calcitriol that plays a key role in the genesis of

SHPT. 23.24 Low calcitriol levels impair the mobilization of
calcium from the bone and the absorption of calcium by the
intestine. Its suppressive effect on PTH secretion is lifted."
and the renal reabsorption of phosphate is enhanced. In
addition, low levels of calcitriol may lower the response of
the parathyroid glands to serum ionized calcium.P Calcitriol
receptors are diminished in the parathyroid glands of CRF
patients, rendering the glands less responsive to the inhibitory
action of 1,25-(OH)zD3, and therefore contribute to the
development of SHPT.3'
PHOSPHATE RETENTION
First proposed by Neil Bricker32.33 as the clue for the "tradeoff' hypothesis, the role of phosphate retention as a major
factor in the pathogenesis of hypocalcemia and SHPT was
emphasized by Slatopolsky and coworkers.Y''? An imbalance between dietary intake of phosphate and the decreased
renal excretory capacity leading to phosphate retention and
directly to SHPT is not likely to be the initial pathogenic
event-" because hyperphosphatemia is not demonstrable in
early CRF during fasting or after an oral phosphate load."
The origin of hyperphosphatemia in the CRF patient is
doubled. The dietary intake of phosphate, greatly increased
in the patient taking phosphate, adds to the effect of reduced
excretion of phosphate by an insufficient kidney subject to
the stimulus of increasing levels of PTH.
The original observation that reducing the phosphate
intake in proportion to the decrease of glomerular filtration
prevented the progression of SHPT led to the theory that
hyperphosphatemia caused SHPT by directly lowering ionized calcium. Upon revision, it has been shown that in
patients with a moderate degree of CRF, phosphate restriction suppresses PTH secretion by increasing serum calcitriol
through a direct effect on the kidney." However, studies
in patients and dogs with advanced renal insufficiency have
demonstrated that phosphate per se, independent of the levels
of calcitriol or ionized calcium, can stimulate the secretion
of PTH.20 Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol and by a
post-transcriptional mechanism increases PTH synthesis and
secretion.P On the other hand, intracellular phosphate retention, which may develop as renal insufficiency ensues, may
interfere with the action and production of calcitriol,"
adding the effect of phosphate retention to that of diminished calcitriol production.
RESISTANCE OF BONE TO PARATHYROID
HORMONE EFFECT
PTH exerts one of its main actions by inducing bone remodeling and liberating calcium to the extracellular compartment. The osteoblast has PTH receptors and binding of PTH
activates osteoclasts, probably in concert with calcitriol. In
the presence of an increased concentration of PTH, infusion
of PTH did not cause as much increase in serum calcium. 4o-42
The mechanisms responsible for this blunted calcemic
response include (1) low levels of calcitriol,43.44 which prevent activation of osteoclasts; (2) phosphate retention,"
either through a direct effect or by diminishing calcitriol
production; and (3) downregulation of PTH bone receptors
by high levels ofPTH.45 The latter is increasingly recognized

to play a major role in the decreased response to PTH in
renal failure."
The progressive bone resistance to the calcemic effect of
PTH sets up an endless loop of increased need for PTH to
maintain serum calcium levels, causing parathyroid hyperplasia and resulting in a progressively demineralized bone
matrix.
transplant recipients may continue to have persistent HPT

and hypercalcemia. 12
The following are some of the factors that may prevent
the involution of the hyperplastic parathyroid gland even
after the primary stimulus (i.e., kidney failure) has been
removed.
PARATHYROID HORMONE SET-POINT CHANGES
Renal function rarely returns completely to normal" and it

is possible that the mild degree of renal insufficiency slows
or prevents the involution of parathyroid glands. In some
series, an inverse correlation between serum PTH levels and
creatinine clearance suggests that impaired renal function is
responsible for post-transplantation SHPT.55.56
The PTH set-point is defined as the serum calcium concentration that decreases the maximal PTH level by 50%.46
In early CRF, there is a shift in the PTH set-point rendering
the parathyroid relatively insensitive to the suppressive
effects of calcium.P''? In advanced CRF and in patients
having maintenance hemodialysis, changes in the set-point
appear to be dependent on the particular form of their bone
disease and calcitriol status.'? Changes in the set-point may
be a function of changes in the parathyroid cell calcium
receptor" mediated by low levels of calcitriol.20
Specifically, it has been suggested that a calcium-sensing
receptor gene polymorphism (codon G990R) influences the
responsiveness of the parathyroid gland to changes of extracellular ionic calcium in uremic patients. The glands of
patients with the GG genotype of the calcium-sensing
receptor gene may be more sensitive to extracellular ionic
calcium changes." The vitamin D parathyroid receptors
are also diminished. The parathyroid cell becomes more
resistant to the suppressive effects of calcium and of
calcitriol, and therefore excessive PTH is secreted at a given
serum calcium concentration.
IMPAIRED GRAFT FUNCTION
PARATHYROID AUTONOMY
Initially, some authors have postulated autonomous parathyroid activity, when PTH production could no longer be regulated by serum calcium (or the set-point was altered so that
hypercalcemia was considered "normal" by the parathyroid
glands).
NONSUPPRESSIBLE PARATHYROID
HORMONE SECRETION
Kidney transplantation is the best treatment for SHPT.48 The

hyperfunction of the parathyroid glands, however, may continue or even become apparent after kidney transplantation.
The recognition that the PTH secretion could not be totally

suppressed by calcium infusion in these patients led to the
concept of nonsuppressible PTH secretion. In this theory,
the parathyroid cells are not autonomous but instead diminish their PTH production to a minimum after transplantation. The increased PTH level is then the result of an
increased number of parathyroid cells, each secreting a
minimum amount of PTH that cannot be suppressed even
when the serum calcium level is elevated." This nonsuppres sible PTH secretion then also increases calcitriol
production by the transplanted kidney, leading to
hypercalcemia.57
PREVALENCE
SLOWINVOLUTION OF PARATHYROID GLANDS
The prevalence of persistent SHPT after kidney transplantation has been reported to be 8% to 50%,49-52 depending on
when hypercalcemia is assessed and how SHPT is treated
before and after kidney transplantation.
Absence of hypercalcemia does not mean normal
parathyroid function. Elevated intact PTH and abnormal
bone biopsy persist in 50% to 70% of recipients with a longterm graft.50,53
Hypercalcemia of more than 1 year is found in one third
of the transplant recipients. The hypercalcemia resolves in
50% of the patients in the first month after kidney transplantation, 85% on the first 6 months, and 95% after 6 months.
The hypercalcemia is not dependent on age, postoperative
medication, preoperative serum calcium, or alkaline phosphatase levels/"
Hypercalcemia after transplantation is due to the continuous hyperfunction of hyperplastic parathyroid glands. In
patients with a well-functioning kidney transplant, factors
such as calcitriol deficiency, hyperphosphatemia, and skeletal resistance of PTH action are no longer present.
Although the prevalence of hypercalcemia in patients
after kidney transplantation has decreased because of better
control of SHPT before transplantation, some renal
The nonsuppressible PTH secretion theory depends on an

increased parathyroid mass that involutes slowly. In a
detailed review, Parfitt" outlined possible reasons for this
slow involution, including the low rate of parathyroid cell
turnover inherent in the parathyroid gland, the inefficiency
of cell deletion mechanisms, and the slow rate at which
parathyroid glands become smaller in response to
hypercalcemia.
After Kidney Transplantation
INSUFFICIENT CALCITRIOL SECRETION
Vitamin D metabolism is usually normal within I week after

transplantation, irrespective of the onset of diuresis or the
dose of cyclosporine A,52 However, vitamin D metabolism
may remain impaired in 20% of kidney transplant recipients/"
perpetuating after kidney transplantation the most important
pathogenic factor of SPTH.
PARATHYROID HORMONE SET-POINT
There is insufficient information about the PTH set-point in

patients after transplantation with or without hypercalcemia,
but it is likely that a PTH set-point is restored slowly after
transplantation. Many patients are found to have high intact
PTH for calcium levels after kidney transplantation.
Metabolic Complications of Secondary Hyperparathyroidism - -
Clinical Manifestations of
Secondary Hyperparathyroidism
Replacement of the kidney's excretory function by dialysis
has prolonged life, but it has also revealed the extent and
importance of its endocrine functions." Patients with CRF
have considerable morbidity and mortality. Classic clinical
manifestations of SHPT come from bones (pain, deformities,
fractures), from metastatic calcifications, and from skin (pruritus, calciphylaxis). Patients with CRF also suffer from a wide
range of organ dysfunctions that were attributed to a "uremic
toxin." As we begin to understand the physiopathology of
CRF, we recognize that many organ derangements are the
consequences of the effects of high PTH levels on cellular
metabolism.
Bone Disease
Musculoskeletal problems remain among the main limitations of the quality of life of patients with renal failure, in
particular those treated with long-term maintenance dialysis.
The mechanical problems caused by uremic bone disease
include fractures of long bones, crush vertebral fractures,
and rib fractures. Bone pain is a common manifestation,
insidious in appearance and more frequent in the lower back,
hips, and legs.
In children, growth retardation is common and may be
worsened by other factors such as chronic acidosis, malnutrition, and low levels of somatomedin.w" Skeletal deformities
are common in uremic children because of the intense
remodeling. In adults, deformities arise mainly from vertebral
fractures producing kyphosis and lumbar scoliosis.
TYPES OF BONE DISEASE
Histologic skeletal abnormalities develop early in patients

with chronic renal disease. Bone resorption, the most
common abnormality, occurs in several locations (subperiosteal, subchondral, trabecular, endosteal, and subligamentous), whereas brown tumors and periosteal reaction
are less common. Osteosclerosis primarily affects the axial
skeleton, and associated osteoporosis and osteomalacia
cause generalized osteopenia. Bone biopsies reveal increased
PTH activity on bone in half of the patients whose glomerular filtration rate has fallen to 50% of normal or less. In the
early stages, mild hyperparathyroid bone disease is seen.
When the glomerular filtration rate falls to between 20 and
40 mL/min, bone biopsies show a mineralization defect."
Youth, female gender, tubulointerstitial types of nephropathy, and a long duration of uremia appear to be independent
risk factors for the development of bone disease."
Bone disorders in renal failure have a wide spectrum of
histologic types, including the classic osteitis fibrosa, osteomalacia, a mixed form (with features of both osteitis fibrosa
and osteomalacia), aluminum osteodystrophy, and adynamic
bone disease. The form and severity of the bone disease
depend on the gender and age of the patient; the severity and
duration of the CRF; the metabolic acidosis; the characteristics of the dialysis; the calcitriol and PTH levels; the dietary
calcium, phosphate, and aluminum load; additional medications (specially steroids); and the associated endocrine
505
diseases (frequently diabetes mellitus). In addition, parathyroidectomy and renal transplantation can suddenly modify
the precarious adaptation of the long-deranged mineral
metabolism.
In addition to the defects in bone formation and mineralization, patients receiving long-term hemodialysis may have
bone deposits of ~2-microglobulin,
which per se cause bone
disease and increase the risk of fractures.f
High-Turnover Hyperparathyroid Bone Disease.
Osteitis fibrosa cystica (although no inflammatory process
was ever identified) is the result of long-standing hyperparathyroidism. Seen in 5% to 30% of dialyzed patients, it
rarely arises before initiation of dialysis.v' It is characterized
by an increase in the osteoblast surface, an increased
number of osteoclasts and osteoblasts, and accelerated bone
resorption and bone formation. Woven osteoid is increased,
with a random arrangement of collagen instead of the
normal lamellar pattern and deposition of amorphous calcium phosphate instead of hydroxyapatite.f In advanced
cases, collagen deposition produces fibrosis and cysts
(hence fibrosa cystica) replacing the bone marrow. The
resulting structure, even with an increased bone mass, consists mainly of frail woven bone prone to fractures.
Low-TurnoverBoneDisease. The other end of the spectrum is associated with a relative PTH deficiency, a decrease
in the osteoblast surface, and paucity of bone cells, with a
profound decrease in the number of active remodeling sites.
Aluminum overload contributes significantly to low-turnover
bone disease, and it occurs in 30% to 85% of these patients.v'
Patients with low-turnover bone disease tend to become
hypercalcemic, have aging of bone caused by stunted bone
remodeling and microfractures, and are at higher risk for
fractures.P The term low-turnover aluminum-associated bone
disease (LTAABD) has been used to describe this histologic
lesion.P Other factors that reduce bone turnover, such as
parathyroidectomy, diabetes." and medication, can account
for a significant proportion of low-turnover bone disease.
Patients with high-turnover hyperparathyroid bone disease
and LTAABD present with similar clinical and laboratory features; therefore, differentiating these two bone abnormalities
is often difficult. An erroneous diagnosis of osteitis fibrosa
cystica may lead to parathyroidectomy that exacerbates
aluminum deposition and low-turnover bone disease."
Within this group, two subgroups can be identified. When
reduced mineralization is coupled with a parallel decrease in
bone formation, the end result is "adynamic uremic bone
disease." When reduced mineralization precedes or is more
pronounced than the decreased collagen deposition, "lowturnover osteomalacia" is the consequence. 12
The use of peritoneal dialysis with a supraphysiologic
level of calcium in the dialysate, use of calcium-based phosphate binders, and diabetes appear to be independent pathogenic factors for the development of adynamic uremic bone
disease." Most patients with uremic bone disease, however,
have a mixed form (mixed uremic osteodystrophy) with or
without aluminum deposition.
DIAGNOSIS OF UREMIC OSTEODYSTROPHY
No serum biochemical or other noninvasive test can diagnose unequivocally renal osteodystrophy or can distinguish
different forms of the disorder with reasonable sensitivity

and specificity. Bone biopsies remain the surest and most
rational approach." Hypercalcemia, for example, may be
present in patients with either low-turnover osteomalacia or
hyperparathyroid bone disease. Although the desferrioxamine test was once advocated for the diagnosis of aluminum
overload/'? it has proved useful in only a small fraction of
those who have low serum PTH levels and gives false-negative
results in many patients.l? Also, the radiographic findings
are not specific and the radiographic signs of oxalosis can
mimic those of hyperparathyroid bone disease." Positron
emission tomography (PET) scanning of bone using fluoride
has been advocated to differentiate low-turnover from highturnover renal osteodystrophy and to provide quantitative
estimates of bone cell activity that correlate with histomorphometric data. 10
Extraskeletal Calcification
There are three kinds of extraskeletal calcification: visceral,
periarticular, and vascular. Visceral calcifications may involve
the lungs (causing restrictive lung disease), myocardium.TP
mitral valve," kidneys, skeletal muscle, breast." and
stomach. Penile calcification may produce impotence, and
its prevalence is probably underestimated.P Patients with
visceral calcifications have hyperphosphatemia, an elevated
calcium-phosphorus product, and high levels of PTH.43
Periarticular calcification produces calcific periarthritis and
small-joint effusions, and radiography usually shows the
calcification around the joint. Vascular calcification, in both
large and small vessels, occurs in 20% of patients with endstage CRF76 and may cause falsely elevated blood pressure
readings.f Calcium deposits on the conjunctiva can cause a
red eye syndrome. Parathyroidectomy rarely affects vascular
calcification but usually diminishes nonvascular calcium
deposits."
Pruritus
Pruritus affects up to 85% of patients receiving hemodialysis,
and it may be a major and distressing symptom. Although
dramatic improvement of pruritus has been repeatedly
observed after parathyroidectomy.P''" PTH does not seem to
be directly involved in its patbogenesis.v-f Serum phosphate, calcium, and magnesium and especially their ionic
products may cause pruritus or are markers of an as yet
unknown prurogen.v-"
Calciphylaxis
Calciphylaxis, an uncommon syndrome of disseminated calcification, is a severe complication of SHPT. It results in soft
tissue calcification and vascular medial calcinosis leading
to ischemic tissue necrosis. Patients present with painful,
violaceous, mottled lesions that progress to skin and subcutaneous tissue necrosis, nonhealing ulcers, and gangrene.
Lesions are characteristically located in the hands and
fingers, lower extremities, and sometimes lower abdomen.
Gangrene of fingers and toes frequently requires amputation, produces nonhealing wounds, and can lead to sepsis
and death." Patients usually have a high Ca-P product but
not necessarily extremely high PTH levels. It has been
described after kidney transplantation and also after recurrent

SHPT.62 The prognosis for patients with calciphylaxis is
dismal, with mortality approaching 50%. When signs and
symptoms of calciphylaxis are recognized, the patient
should be treated with phosphate binders and timely
parathyroidectomy'v" A mathematical expression involving the Ca-P product and the alkaline phosphatase and
PTH levels has been developed to help identify high-risk
patients.t"
Anemia
Normochromic, normocytic anemia is a prominent complication of CRF. In addition to decreased erythropoietin production, iron deficiency, systemic infections, aluminum toxicity,
and increased hemolysis are contributing factors in some
patients. Increased PTH levels may cause anemia by inhibition of erythropoiesis." shortening red blood cell survival,
and inducing bone marrow fibrosis." Parathyroidectomy
improves the hematocrit in many patients with SHPT.89-91
Recombinant human erythropoietin is used to treat
anemia in CRF patients. The dose of erythropoietin required
to achieve an adequate hematocrit response may depend
on the severity of SHPT and the extent of bone marrow
fibrosis.f? Hypertension is its most serious side effect.
Insulin Resistance
Treatment of SHPT by correcting phosphate retention
improves glucose intolerance with increased insulin
secretion." Diabetic patients with CRF have lower serum
calcium and intact PTH levels than nondiabetic patients.
Osteitis fibrosa is noted radiologically in a third of nondiabetic patients but in none of the diabetic patients. Because of
the lower PTH level, low-turnover bone disease is a special
problem for the diabetic patient receiving dialysis."
Insulin secretion may be impaired in CRF related to
SHPT.95 The impaired insulin secretion in association with
peripheral resistance to the action of insulin causes glucose
intolerance in CRF. The impaired insulin secretion induced
by excess PTH may be related to the effect of PTH on the
pancreatic islets to increase intracellular calcium. A calcium
channel blocker prevents calcium accumulation in the islet
cells, antagonizes the effect of PTH, reverses the abnormalities in insulin release, and normalizes glucose tolerance in
animals with CRF.96
Calcitriol modulates secretion of insulin by the beta cell.
The regulation of insulin secretion in uremia is affected
directly by the low calcitriollevel and indirectly by the low
PTH level, both independently of serum calcium."?
Hypertension
Arterial hypertension is a cause and also a consequence of
CRF. Cytosolic calcium metabolism is altered in the saltdependent type of essential hypertension and also in CRF
patients. Patients with CRF and overt SHPT have more
severe hypertension'" and a higher intracellular calcium
content?' than uremic patients without bone resorption and
SHPT. Parathyroidectomy lowers blood pressure in a significant proportion of patients with SHPT.l00 Calcitriol causes
Metabolic Complications of Secondary Hyperparathyroidism - - 507
hypertension,'?' whereas PTH is a vasodilator and calcium has

a hypotensive effect. An identified parathyroid hypertensive
factor,102,103 a 3000-d protein-lipophospholipid.Pv'P' may be
the cause of hypertension in genetically hypertensive rats, 106
salt-sensitive low-renin essential hypertension in humans, 107
and hypertension associated with primary hyperparathyroidism. 107.108 This parathyroid hypertensive factor is
secreted by the parathyroid gland!'? and its secretion is inhibited by calcium. 110 The role of parathyroid hypertensive factor
in SHPT, however, has not been studied.
Hyperlipemia
Hyperlipidemia is common in CRF, but the underlying
mechanisms are not clearly defined. Experimental and clinical
data have shown that SHPT may be the cause of hypertriglyceridemia. Excess PTH reduces postheparin lipoprotein
lipase activity in plasma, impairing lipid removal from the
circulation.I? There is a significant positive correlation
between serum levels of alkaline phosphatase and triglycerides in patients with SHPT. Serum triglycerides may
become normal after parathyroidectomy in some patients
with hypertriglyceridemia.'!' Both hyperlipemia and hyperphosphatemia promote atherosclerosis and may explain the
high prevalence of coronary heart disease in CRF patients.U?
Impaired Phagocytosis
Polymorphonuclear leukocytes in patients with CRF have
elevated basal levels of cytosolic calcium, reduced ATP
content, and impaired phagocytosis. Excess PTH seems to
cause these abnormalities and may be prevented by either
reducing the levels of PTH or blocking its action with
verapamil. 113
Clinical Manifestations of Secondary

Hyperparathyroidism after Kidney
Transplantation
Although post-transplantation SHPT most often follows an
asymptomatic course, it can cause significant morbidity and
give rise to serious complications.F' Symptoms resemble
those of primary hyperparathyroidism such as increased
bone resorption, nephrolithiasis, and pancreatitis.
Increased bone resorption may persist'!" and osteopenia
may be present for as long as 96 months after transplantation because of preexisting osteodystrophy, SHPT, and
steroids given to control graft rejection.57. I 15 Steroid-induced
osteopenia is more intense in the spine than in cortical
bone.P Avascular necrosis of the hip joint, highly prevalent
among transplant recipients, correlates more with steroid
therapy than with the degree of SHPT.
Nephrolithiasis occurs in 5% to 10% of transplanted
kidneys and may appear years after transplantation. It may
arise as an asymptomatic radiologic finding, as painless
hematuria because the grafted kidney is denervated, or
as painless ureteral obstruction causing oliguria and
hydronephrosis.V!" Although it can be precipitated by other
factors, SHPT is the main cause of nephrolithiasis in transplanted kidneys. Hypercalciuria, common in hypercalcemic
transplant recipients, also predisposes to stone formation.P
Pancreatitis occurs in 2% to 6% of kidney transplant

recipients. Among those with hypercalcemia, acute pancreatitis has a prevalence of 11%.117 Hypercalcemia is a more
important cause of acute pancreatitis than immunosuppressive therapy, gallstones, alcoholism, or steroids in these
patients.V!"
Summary
SHPT after chronic kidney disease can lead to clinically significant bone disease. Additional consequences include soft
tissue and vascular calcification, cardiovascular disease, and
arteriole calcification, and it may contribute to the increased
risk of cardiovascular morbidity and mortality among
uremic patients. The pathogenesis of SHPT comprises
decreased 1,25-(OHhD3 levels, hyperphosphatemia, altered
PTH metabolism, skeletal resistance to PTH, and possibly
gene-mediated changes in the sensitivity of the parathyroid
cell to the effects of calcium and calcitriol. The treatment
of CRF and its complications may also contribute to the
pathogenesis of SHPT. After kidney transplantation,
impaired graft function, some level of parathyroid autonomy, nonsuppressible PTH secretion, and a slow involution
of parathyroid glands may cause persistent parathyroid
overgrowth.
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117. Frick TW, Fryd DS, Sutherland DE, et al. Hypercalcemia associated
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Surgical Approach
to Secondary
Hyperparathyroidism
Juan J. Sancho, MD, PhD Antonio Sitges-Serra, MD, PhD
Indications for Surgery

Pretransplantation
Parathyroidectomy (PIX) is indicated when medical treatment
fails to control progressive secondary renal hyperparathyroidism (SHPT) (Table 57_1).1-3 Clinical manifestations
include persistence or worsening of skeletal symptoms, pruritus, and extraskeletal calcifications."
Because high parathormone (PTH) levels may worsen
many disorders associated with chronic renal failure (CRF),
other potential indications include hypertension, anemia,
deranged myocardial function, and peripheral neuropathy.'
High intact PTH (iPTH) (1-84) levels and a proven highturnover bone disease are prerequisites for considering a
CRF patient with SHPT for surgery>" Calciphylaxis is an
absolute indication for immediate PTX.5.9
Post-Transplantation
PTX is indicated in some patients after kidney transplantation
because of clinical manifestations similar to those of primary
hyperparathyroidism: hypercalcemia plus nephrolithiasis,
acute pancreatitis, changes in mental status (lethargy, irritability, confusion), or overt bone disease.'? Mild hypercalcemia
alone does not appear to be a serious threat to the patient with
a transplanted kidney, but impaired renal function in the
presence of high PTH and hypercalcemia should be an
indication for PTX, 11.12 as is the association of kidney stones
and long-standing hypercalcemia.13,14 Whether asymptomatic
hypercalcemia alone is an indication for PTX in renal transplant recipients is controversial.
Post-transplantation hypercalcemia can arise with four
different patterns: (1) subacute severe hypercalcemia, (2) transient hypercalcemia, (3) persistent hypercalcemia, and (4)
hypercalcemia appearing after a period of normocalcemia.v'>
The indications for surgery are summarized in Table 57-2.
510
SUBACUTE SEVERE HYPERCALCEMIA
Now an exceptional occurrence, severe hypercalcemia (serum

calcium greater than 13 mg/dL) usually arises shortly after
renal transplantation. It requires prompt PTX, especially if it
threatens graft function. J 5-18
TRANSIENT HYPERCALCEMIA
Hypercalcemia after kidney transplantation resolves spontaneously in two thirds of the patients; 85% of them become
normocalcemic during the first year. lO,17 In addition to overt
post-transplantation SHPT, hypercalcemia can be caused
by hypophosphatemia.l'' and the latter is exacerbated by
the normally functioning kidney and high levels of PTH
from a still hyperplastic parathyroid glands.'? Resorption
of calcium phosphate salts may explain hypercalcemia and
hyperphosphatemia in some patients. 15,16 Moreover, a preexisting vitamin D intoxication can be unmasked by the transplanted kidney. For the aforementioned reasons, the mild
hypercalcemia present during the first 6 to 12 months after
kidney transplantation is not an indication for surgery.
PERSISTENT HYPERCALCEMIA
Whether the state of hypercalcemia is considered permanent

depends on the investigators; the criteria range from
6 months to 6 years after transplantation. The old liberal
approach of PTX for patients with more than 6 months of
hypercalcemia-P has progressively been replaced by a more
conservative approach in which the clinical status and the
kidney function are closely monitored' and PTX is not even
considered for 2 years if the graft is functioning. In any case,
the longer the duration of hypercalcemia, the less likely it
is to resolve spontaneously. Only 25% of cases of hypercalcemia persisting more than 12 months after transplantation
resolve spontaneously."
Two groups of patients may be considered for surgery
for asymptomatic persistent hypercalcemia: those with
Surgical Approach to Secondary Hyperparathyroidism - -
511
and acute pancreatitis, or graft failure. I? When a previously

normocalcemic transplant recipient develops hypercalcemia, graft failure should be ruled out. If graft failure is not
the cause of hypercalcemia, PTX should be considered to
prevent the development of complications of hyperparathyroidism or graft failure.
Preoperative Care
hypercalcemia that is not likely to resolve spontaneously

and those with hypercalcemia lasting more than 2 years.
A serum calcium level of 12 mg/dl," and borderline hyperphosphatemia 10 are good predictors of hypercalcemia that
will not resolve spontaneously. The tolerable limits of serum
calcium in persistent hypercalcemia vary among authors and
are between 11.0 and 13.0 mg/dL. 3,1O,15,16,18 Elevated serum
alkaline phosphatase levels have also been advocated as an
independent predictor of persistent hypercalcemia. 3,1O,15,16,18
A declining alkaline phosphatase level after transplantation
may, however, be due to inhibition of osteoblasts by steroids
and thus would be an unreliable marker of bone resorption
after transplantation." Some authors did not find elevated
serum alkaline phosphatase predictive of persistent hypercalcemia.'? There may be a sound set of reasons for withholding PTX in those patients (fear of precipitating an adynamic
bone disease or a high surgical risk), but expecting its spontaneous resolution is certainly not one of them."
Prophylactic PTX in asymptomatic patients with persistent
hypercalcemia may reduce the incidence of subsequent
nephrolithiasis, acute pancreatitis, and vascular calcifications that are potentially graft and life threatening. I?
RELAPSING HYPERCALCEMIA
Relapsing hypercalcemia is a rare condition. The few cases

reported have associated complications, such as nephrolithiasis
Preoperative preparation of dialysis patients includes control

of hyperkalemia, hypomagnesemia, and hypervolemia and
careful evaluation and treatment of hypertension and cardiovascular disease.P Patients should receive oral calcitriol
(1 ug) before surgery to avoid severe postoperative hypocalcemia. Patient should be dialyzed no longer than 1 day
before PTX and then again no later than 2 days after the
operation.
When PTX is performed after kidney transplantation,
immunosuppressive medication does not have to be interrupted in the perioperative period. Replacement steroid
doses should be administered."
Localization
Localization studies of the parathyroid glands are discussed
in detail elsewhere in this book. Some issues, however, are
unique to SHPT. Because image-based localizing tests depend
on gland size and patients with SHPT tend to have large
glands, the specificity and positive predictive value of
computed tomography (CT) scanning, ultrasonography, and
thallium-technetium (Tl-Tc) scintigraphy are much higher
for SHPT than for primary hyperplasia."
Ultrasonography has found to be useful for screening
and follow-up of SHPT.26,2? It has a reported sensitivity of
45% to 70%.28,29 When large glands are not found by ultrasonography in patients with severe SHPT, they are usually
situated in the superior mediastinum, behind the trachea
or esophagus, or deep within the neck. 29 CT scanning and
magnetic resonance imaging should then be the studies of
choice.

Although Tl-Tc scintigraphy also has greater success in
finding the parathyroids in patients with SHPT than in those
with primary hyperplasia." its sensitivity is only 30% to
55%.25.31,32
CT scanning has a sensitivity of only 50% in SHPT,25.28.31.32
but it is better than ultrasonography in localizing glands in
the mediastinum.P Finally, 99mTc sestamibi-P'T subtraction
scanning is positive in 88% of cases but has an overall sensitivity of only 67% for the localization of all hyperplasic
glands, in relation to the functional status of the glands and
not their weight'"; it is sometimes extremely useful in identifying an ectopic or supernumerary gland, or both.P
Surgical Management
The critical factor for successful PTX is a highly skilled surgeon experienced in parathyroid surgery. The second most
important factor is the localization of all parathyroid tissue,"
and that is closely linked to the former. All efforts should
be made to locate all parathyroid glands, knowing that in
15% of these patients a fifth'" or even a sixth gland may be
hidden in an ectopic situation.
The patient is placed in a semi seated Kocher position.
A standard collar incision is made and meticulous hemostasis
is maintained throughout the procedure. Some authors routinely divide the strap muscles to obtain better exposure."
but it is usually not necessary.
The thyroid gland is widely exposed, the middle thyroid
vein is ligated and transected, and the thyroid lobe is retracted
medially and the carotid sheath laterally. The recurrent laryngeal nerve is exposed. The search for the parathyroid glands is
then started, first in their normal location. The principle of "not
removing anything before seeing everything" certainly applies
here. All four, or more, parathyroid glands should be exposed
and a confirmatory frozen section of each one obtained.
Approximately 80% of the superior parathyroid glands
are located within a circumscribed area of 1 inch above the
intersection of the recurrent laryngeal nerve and the inferior
thyroid artery. The glands are frequently secluded in the
connective tissue that binds the posterior edge of the thyroid
lobe to the larynx. The posterior thyroid capsule should be
incised and the superior pole vessels divided if the upper
glands are not found.
To find the lower glands, the inferior poles of the thyroid
should be cleared from fat and all tissue within I inch from
the inferior pole of the thyroid dissected free and removed.
Approximately 15% of lower glands are found in the
thoracic inlet within the thymus.
Regardless of the glands found, the thymus is routinely
resected to ensure removal of possible supernumerary
glands, an ectopic fourth or fifth gland (10% of the cases"),
or rudimentary parathyroid tissue. The prethymic fascia
extending from the middle cervical fascia is incised to identify the thymus. The thymus is then mobilized upward, using
a small gauze swab to gently dissect the surrounding soft tissues from it. Veins draining the thymus into the innominate
vein should be carefully ligated to avoid bleeding."
When a gland is not found in its orthotopic location or
within the thymus, the relatively avascular paraesophageal,
paralaryngeal, retroesophageal, and retropharyngeal regions
should be carefully dissected." Next, the carotid sheath

should be incised from its emergence from the mediastinum
to the bifurcation. Finally, if a gland is still missing, a thyroid lobectomy is considered. Although true intrathyroidal
parathyroid glands occur in only 2%, some parathyroid
glands are so closely attached to the thyroid capsule that thyroid lobectomy may be required to identify them." Once all
the parathyroid glands have been exposed, the subsequent
steps depend on the procedure chosen.
If subtotal PTX is planned, the smallest parathyroid is
selected. The nonvascular pole of the gland is excised, leaving in place a 40- to 60-mg remnant. If there are doubts
about the viability of the remnant, the gland is completely
excised and the next best gland is selected in tum. All the
remaining glands must be left in place until a viable, properly sized, well-colored remnant has been obtained. Only
then are the remaining glands resected. We usually try to
leave the remnant from a superior gland. The upper glands
commonly have good vascular attachments to the thyroid
capsule, and blood supply to lower glands may be interrupted during thymectomy. Lower gland remnants can also
descend into the mediastinum, making an eventual reoperation
more difficult.f The remnant is marked with nonreabsorbable material (ideally a titanium clip and a long silk
thread). If only three parathyroid glands are found after
exhaustive search, all three are removed. Thirty percent of
the patients can be expected to have persistent hyperparathyroidism if this contingency arises.!?
If total PTX and autotransplantation are planned, all four
glands are resected and the most suitable gland is selected
to obtain the autograft." Using glands with nodularity for
the graft carries a high risk of graft-dependent recurrence.v"
A 40- to 60-mg portion of the gland is sliced into l-mm
fragments and 10 to 20 fragments are placed into several
separate intramuscular pockets in the nondominant forearm,
as far as possible from present and planned arteriovenous fistula location. The muscle pockets are closed with nonreabsorbable material to facilitate localization in case reoperation
for recurrence is needed.
Although exceptional, parathyromatosis is a potential
cause of unexpected recurrence.f Care should be taken,
therefore, to avoid breaking the parathyroid gland capsule
and spilling parathyroid cells on the operative field.
Intraoperative measurement of iPTH 15 or 30 minutes
after removing all parathyroid tissue using a quick assay is
found to be valuable where available, signaling either the
end of the procedure or an overlooked fifth gland. 44.45
Cryopreservation should be routine in case permanent
hypoparathyroidism develops. The technique and results
obtained with cryopreserved parathyroid tissue are discussed elsewhere in this book.
Type Of Surgical Procedure

The two accepted surgical procedures for the management
of SHPT are subtotal parathyroidectomy (sPTX) and total
PTX with parathyroid autotransplantation (PTX + AT). Total
PTX46.47 is still supported by some groups on the basis of
lower recurrences, but in these patients the bone does not
mineralize in the absence of PTH and the patient must
Surgical Approach to Secondary Hyperparathyroidism - - 513
undergo life-long treatment with vitamin D and oral calcium.'

The rationale for choosing a procedure to treat parathyroid
hyperplasia and the relative merits and risks of each
approach are discussed in detail in a separate chapter.
Subtotal Versus Autotransplantation Trials

There are many reports supporting one procedure versus the
other, but trials dealing specifically with SHPT are scarce.
In a prospective randomized trial, Rothmund and coworkers'"
found that PTX + AT was superior to sPTX in a group of
40 patients. During a mean follow-up of nearly 4 years, four
patients in the sPTX group developed recurrence. Bone pain
was alleviated in a significantly higher proportion of
patients with PTX + AT. The other clinical responses were
similar in both groups. One criticism of the study is that they
left a larger remnant (60 to 80 mg) than the size recommended by other authors (40 to 60 mg). When evaluating
this trial, one should keep in mind that the author's team was
well known for their previous excellent results in a large
series of PTX + AT. 49
There are several reports comparing both techniques'v-' in
a retrospective sequential design. They found both techniques
to have similar results, but the authors recommended one
procedure over the other on the basis of theoretical merits.
Proye and coworkers considered the technique less important
than the accuracy of indication for operation and the complete
localization of all parathyroid tissue'" because one third to

one half of the recurrences arise from an overlooked gland
(ectopic or supernumerary, or both) in the neck.
Different ways to report results make comparison among
the reports of a single technique inappropriate (Table 57-3).
In assessing the merit of each technique, one should keep in
mind that most authorities find the technique they routinely
use and have more experience with to be most appropriate.
Subtotal Parathyroidectomy
The success of sPTX depends mainly on the size and viability of the remnant. Remnants that are nodular are more
likely to grow and cause recurrent disease.
sPTX has the theoretical advantage of inducing less postoperative hypocalcemia because the remnant continues to function. If persistent or recurrent hyperparathyroidism occurs, the
gland is in the neck or, exceptionally, in the mediastinum. The
main disadvantage is that reoperations are tedious and carry an
increased risk of recurrent laryngeal nerve injury.
The overall results from large series showed that 10% to
16% had postoperative hypercalcemia, 8% required reoperation because of remnant growth, and 4% to 25 % had
hypocalcemia longer than 12 months after operation.
Compared with PTX + AT, successful sPTX provided less
immediate relief of bone pain but carried less risk of postoperative low-turnover bone disease. ss-s8
Total Parathyroidectomy and

Autotransplantation
AS THE TECHNIQUE OF CHOICE
Success of total PTX and autotransplantation depends

mainly on the absence of nodularity of the gland from which
the graft is obtained and the number and weight of the fragments implanted. Graft-dependent recurrence is three times
higher when implanting a nodular gland instead of a diffusely hyperplastic one.59 Most published series did not consider this as a source of variability and therefore may have
had higher recurrence rates than are theoretically possible.
The advantage of autotransplantation is that if hyperparathyroidism recurs, the graft can be partially resected
under local anesthesia. Nevertheless, reresection may be
necessary and sometimes a tumor-like growth develops in
the implant, making it difficult to remove. The Casanova test
requires total ischemic blockade of the arm bearing the
parathyroid graft and measuring PTH levels proximally and
distally to the blockade. It is used to assess graft function
after PTX + AT or to determine the site of recurrence/"
Published series show a 5% to 38% rate of postoperative
hypercalcemia, 2% to 6% rate of recurrence requiring graft
resection, and 5% to 30% rate of hypocalcemia lasting more
than 12 months. 21,49,61-65
AS AN ALTERNATIVE TECHNIQUE
Even surgeons who routinely perform sPTX for SHPT use

PTX + AT in some selected cases: when thyroidectomy is
necessary because of thyroid disease, when the viability of
the remnant is in doubt in sPTX, or when the remnant overgrows and causes recurrence.e'>'
Complications of Parathyroidectomy
The mortality after PTX for SHPT is less than 1%.4
Hyperkalemia is the single most preventable cause of death.
Infection, cardiac complications not related to hyperkalemia,
acute hypocalcemia, pancreatitis, and respiratory complications are other miscellaneous causes of mortality.
TRANSIENT HYPOCALCEMIA
Hypocalcemia occurs in 20% to 85% of patients after PTX for

SHPT. These patients usually develop the classic symptoms
of numbness, paresthesias, and tetany cramps the day after
PTX if hypocalcemia is not prevented. The causes of hypocalcemia include increased deposition of calcium in bone
("hungry bone" syndrome), uncoupling of bone formation
and resorption." hypoparathyroidism resulting from failure of
the parathyroid remnant or autograft, and hypomagnesemia.?"
Hypocalcemia is more common in patients with more
severe preoperative bone disease and can be anticipated in
those with elevated serum levels of alkaline phosphatase."
Serum potassium, calcium, phosphate, and magnesium should
be carefully monitored. Intravenous calcium gluconate in
10% solution or diluted in 5% dextrose may be needed if the
serum calcium falls below 7.5 mg/dL.
Once the acute episode is controlled or if the hypocalcemia is mild, oral calcium is given in doses of up to 6 g
of elemental calcium per day.24 Phosphate binders should be
adjusted to maintain serum phosphate concentration between
3.5 and 5.0 mg/dL. Oral calcitriol (0.5 to 4Ilg/day) should be

given in addition to calcium to control hypocalcemia.s?
When postoperative hypocalcemia is likely, prophylactic
calcium and calcitriol administration can be started before
or immediately after surgery. Calcitriol (2 ug) given during
dialysis has been used for 5 days before the operation to prevent postoperative hypocalcemia.'
Patients receiving peritoneal dialysis can be given
intraperitoneal calcium therapy to control hypocalcemia.v
Supplementation with elemental magnesium at 1 mEq/kg
per day should be started if the serum magnesium concentration drops below 1.5 mg/dL. 24 If not properly treated,
hypocalcemia can lead to tetany and convulsions, especially
during the later hours of hemodialysis. Hypocalcemic seizures
can cause multiple fractures.'
PERMANENT HYPOPARATHYROIDISM
The prevalence of permanent hypoparathyroidism varied

greatly from 0%48 to 73%2 in early series but is most
commonly between 4% and 12%. Parathyroid autotransplants can fail and cause hypocalcemia up to 2 years after
surgery.'? It is difficult to assess the exact percentage of
hypoparathyroidism because of retrospective analysis and
reporting heterogeneity (see Table 57-3).
Patients with hypoparathyroidism need vitamin D and calcium supplementation for life. The hypocalcemic symptoms
can be exaggerated after a kidney transplantation reversing
the acidemia. Hypercalcemia can also occur because of
vitamin D intoxication.
PERSISTENCE AND RECURRENCE
The prevalence of persistent or recurrent hyperparathyroidism is between 2% and 12%. In one third to one half
of the cases, the recurrence is due to an incomplete first operation: less than four glands were found, cervical thymectomy
was not performed, or there were supernumerary glands in
the neck or mediastinum.P These patients have hypercalcemia, elevated iPTH levels, and persistence or worsening of
clinical manifestations. If sPTX was the initial operation, reexploration of the neck and PTX + AT are indicated. If PTX +
AT was the initial operation, the Casanova test should be
performed. Graft resection or re-exploration of the neck is
then indicated, depending on the site of recurrence. In all
cases of repeated neck operations, imaging studies should
be done to localize the recurrent disease. Reoperations for
hyperparathyroidism are treated in detail in another chapter
of this book. Some authors suggest that the recurrent tumor
can be injected with ethanol under ultrasonographic guidance, but recurrent nerve injury has been reported. 6469-71
Clinical Course after Successful

Parathyroidectomy
The overall clinical result is considered good in 70% to 85%
of the patients. Bone pain improves in few days in 60% to 80%
of patients, joint pain in 85%, and malaise in 75%.4Abdominal
pain and irritated eyes are less likely to improve." Muscle
weakness is relieved in one third of the patients and radiologic
Surgical Approach to Secondary Hyperparathyroidism - -
signs improve in 95%.48 Itching decreases overnight in almost

all patients and disappears in 60% to 80%.4,48
Successful PTX improves nonvisceral calcification in
50% to 60% but does not change arterial calcification
despite reduction in the Ca-P product and PTH. Small
peripheral arterial calcification may even develop or
progress in as many as 56% of the patients after PTX.65
Bone Disease
A rapid decrease in serum parathyroid hormone level after
PTX appears to suppress bone resorption as well as cause a
transient marked increase in bone formation and an increase
in normal lamellar osteoid seams." PTX decreases resorption surfaces and osteoclast number as well as bone formation rate."
A much debated issue is the development of aluminumrelated osteomalacia after PTX. Some reports showed that
PTX did not enhance accumulation of bone aluminum
or increase the prevalence of clinical bone disease during
dialysis.I" whereas other reports clearly demonstrated aluminum accumulation in bone after PTX.75 If aluminum is
available to bone (through ingestion of phosphate binders or
through the dialysate) or if there was an aluminum-related
bone disease before surgery, it deposits in the low-turnover
post-PTX bone. If, however, vitamin D levels are maintained
and calcium is available, no low-turnover aluminum-related
bone disease should arise. Symptomatic osteomalacia after
PTX usually indicates that surgery was unnecessary and that
the hypercalcemia was due to aluminum toxicity. The bone
mass density of the lumbar spine can be significantly
increased with postoperative supplementation with vitamin D
and calcium."
Calcium Metabolism
Immediately after PTX, serum PTH and calcium concentrations decline abruptly. Serum alkaline phosphatase, usually
elevated before surgery, increases in the immediate postoperative period and then declines with time." A strong correlation has been noted between the degree of hypocalcemia
after the operation and the level of serum alkaline
phosphatase before the operation.?" Circulating levels of
calcitriol also decrease after PTX, further contributing to
hypocalcemia."
Anemia
Anemia improves in CRF patients after PTX.80 PTX
increases serum erythropoietin and blood reticulocytes in
50% of the patients. 81,82 Normalizing levels of PTH, extraor intracellular calcium and phosphorus, and increased
tissue sensitivity to erythropoietin after PTX could all be
responsible." ,83,84
Summary
Before kidney transplantation, PTX is indicated when
medical treatment fails to control progressive hyperparathyroidism. High PTH levels and high-turnover bone disease
515
are prerequisites for surgically treating this condition.

Calciphylaxis is an absolute indication. The main posttransplantation indication is a persistent or symptomatic
hypercalcemia. The keys to a successful surgery are to locate
all parathyroid glands and leave 40 to 60 mg of viable tissue
as a remnant in the neck or as an autotransplant in the forearm.
In any case, minute details of the surgical technique influence the outcome. The most frequent postoperative sequel is
persistent or recurrent hyperparathyroidism.
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Chung Yau Lo, MB, BS(HK), MS(HK), FRCS(Edin), FACS
Jon A. van Heerden, MB, ChB, MS(Surg)[Minn], FRCS(C), FACS
The prospect of an imminent, initial, cervical exploration for

biochemically proven hyperparathyroidism (HPT) invariably results in a release of endogenous endorphins in the
experienced endocrine surgeon. In stark contrast, the
prospect of cervical re-exploration for the same disease, by
the same endocrine surgeon, invariably results in an increase
in the secretion of fractionated urinary catecholamines.
What is the reason for these opposite reactions when operating for the same disease entity in the same anatomic region
of the body? In the first instance, the surgeon can accurately
predict that the operation will usually be a technically easy
one, that the cure rate (return to a normocalcemic state) will
be high (>98%) both short and long term, and that the operative procedure will be accompanied by a negligible operative mortality and morbidity.' We have, at times, jokingly
stated that the surgical team should in fact reimburse the
patient for being allowed to perform the operation. In direct
contrast, the surgeon can accurately predict that in a sizable
percentage of patients undergoing reoperation, the surgical
procedure will be a technically demanding one (a "no-fun
case"), that the success rate will be 10% to 15% lower than
in the primary procedure, and that the operative and postoperative complications will be considerably higher.
It is fairly obvious that there would be no need for reoperative surgical procedures for HPT if the initial exploration
was uniformly successful. This is unfortunately not the case,
and it behooves all of us to re-examine the causes for initial
failed cervical exploration and the overall approach to this
challenging group of patients.
Causes of Failed Initial

Exploration for
Hyperparathyroidism
HPT following a prior cervical or mediastinal exploration
for hypercalcemia can be divided arbitrarily into persistent
(defined as hypercalcemia recurring within 6 months after
initial operation) or recurrent (hypercalcemia recurring after
6 months of normocalcemia following initial operationj.i-'
518
The former denotes missed pathology and the latter refers

to newly developed pathology. The distinction of these two
categories has been loosely applied since it is possible that
a physiologically insignificant amount of hyperfunctioning
tissue that was present at the first operation could proliferate
and produce a biochemical recurrence several years later?
It has been estimated that 2% to 10% of surgical failures
may be attributed to an incorrect diagnosis." However, this
is much less of a problem today with the advent of a reliable
radioimmunoassay for intact parathyroid hormone (PTH).
In patients with renal disease, PTH clearance is compromised by impaired renal clearance and may lead to spurious
elevations of PTH levels if the hormone is measured by
assays that fail to detect intact PTH molecular structures. In
such circumstances, the measurement of PTH using doubleantibody methods will help resolve this issue. Another,
albeit rare, diagnostic pitfall are patients with benign familial hypocalciuric hypercalcemia (BFHH). This disorder is
associated with moderate hypercalcemia and normal or
slightly elevated blood PTH levels. BFHH can be diagnosed
by a positive family history of hypercalcemia at times associated with unsuccessful parathyroid surgery, a 24-hour urinary
calcium excretion of less than 100 mg, and the calculated
value of calcium-to-creatinine clearance ratio of less than
0.01. 4 Other causes of hypercalcemia (intake of thiazide
diuretics or lithium, vitamin D intoxication, sarcoidosis, multiple myeloma, malignancy, and paraneoplastic syndromes)
rarely cause confusion today in the diagnosis of primary
HPT. This is largely due to the accuracy and sensitivity of
the currently available intact PTH assays.
In contrast to the incorrect diagnosis of primary HPT,
inexperience on the part of the surgeon is a major cause of
surgical failure because of the lack of knowledge regarding
parathyroid embryology and knowing the usual "hiding
places" of the parathyroid glands; the inability to recognize
and excise an abnormal gland; failure to recognize and adequately treat multiple gland disease; failure to locate an
ectopic gland; the presence of supernumerary glands; errors
on frozen section examination; incomplete excision of invasive parathyroid carcinoma; or parathyromatosis (i.e., multiple nodules of hyperfunctioning parathyroid tissue scattered
Parathyroid Reoperations - -
through the neck and mediastinum) due most often to

spillage of diseased tissue during removal or rarely due to
abnormal embryologic development. The anatomy and
embryologic descent of the parathyroid glands are variable
in 20% of patients.' Inability to recognize an anomalous
location of an abnormal gland or the inability to perform a
bloodless, thorough dissection of the neck is a common
cause for failed cervical exploration by the inexperienced
endocrine surgeon,
Although multiple-gland disease accounts for 5% to 15%
of patients undergoing initial exploration, up to 37% of
patients who come to reoperation have multiple-gland disease rather than a single adenoma. 2,3,6,7 This heterogeneous
group of patients includes patients with familial HPT and
multiple endocrine neoplasia (MEN) types I and 2. The logistic difficulty in diagnosing some of these rare conditions can
be attributed to a negative family history and the disparity of
size of the enlarged glands, although all are hypercellular
(unequal or asymmetrical hyperplasia).
In general, the location and excision of an adenoma,
visual identification of all parathyroid glands, and biopsy of
a second suspicious gland constitute a safe and effective
strategy for most patients with primary HPT undergoing
initial operation. In multiple-gland hyperplasia, it is vitally
important to adequately reduce the amount of functioning
parathyroid tissue to prevent recurrence without being
overly aggressive and creating an aparathyroid state with the
need for chronic calcium and vitamin D supplementationa regimen that is unpleasant for the patients and that has a
poor rate of patient compliance. Subtotal parathyroidectomy
(3.5-g1and resection: leaving 50 mg viable parathyroid
tissue) or total parathyroidectomy with immediate forearm reimplantation is considered the treatment of choice for
patients with familial HPT.8,9 The incidence of supernumerary
("fifth") glands in 1% to 6% of patients with MEN 1 adds
further surgical difficulty. Routine transcervical thymectomy for the possible removal of a supernumerary fifth
gland is indicated in all patients with MEN 1. Undoubtedly,
failure to identify multiple-gland disease and to remove
adequate functioning parathyroid tissue, the presence of
supernumerary and ectopic glands, regrowth of remnant
glands, or autograft hyperfunction invariably lead to persistent or recurrent hypercalcemia."
Despite the success of this approach, there is a steady
push toward a more limited, or focused, cervical exploration,
often under local anesthesia and increasingly on an outpatient basis.' Considerable interest has been focused on the
adoption of minimally invasive approaches including endoscopic, video-assisted, and radio-guided parathyroidectomy
for primary HPT.IO,II Application of these techniques
depends on an accurate preoperative sestamibi scanning or
the use of intraoperative gamma probe technology to locate
the adenoma as well as the increasing availability of the
intraoperative "quick" PTH assay to confirm surgical success,
However, the fact that there are numerous types of minimally invasive parathyroidectomy, and that no firmly established method has been accepted as the standard technique,
makes evaluation and comparison with the open approach
difficult. 10 These new approaches should be evaluated carefully and compared objectively with the excellent results
obtained when surgical expertise alone is used. 1 In addition,
519
these techniques can be applied only to selected patients'<"

and have potential pitfalls that could result in surgical failure. 14
Persistent or recurrent HPT occurs in a small but significant
proportion of patients after the initial exploration and continues to pose a management dilemma and technical challenge to the surgeon. The newer techniques and technology
need to be particularly carefully evaluated in this complex
subset of patients with HPT.
Approach to the Reoperative

Patient
Confirmation of Diagnosis
When the initial operation fails to return a patient to the normocalcemic state or if hypercalcemia recurs after initial but
temporary postoperative normocalcemia, the patient joins
a special selective group of patients quite distinct from
patients being considered for primary operation. It is
extremely important that the diagnosis of primary HPT be
reconfirmed rigorously. The confirmation of primary HPT
should be based only on the stringent criterion of elevated,
or inappropriately elevated, PTH in the presence of elevated
ionized serum calcium. In some instances of suspected primary HPT, another cause for hypercalcemia may be present,
such as sarcoidosis, vitamin D excess, metastatic malignant
disease, multiple myeloma, and so forth. A repeated careful
history taking and physical examination should be conducted.
A detailed family history usually helps determine whether
multiple-gland disease or BFHH should be suspected.
Patients with a positive family history of less severe disease
and failed cervical explorations should raise the suspicion of
BFHH. A selection of pertinent diagnostic tests should be
tailored to the individual patient to confirm or refute the
clinical suspicion. When faced with this complex subgroup
of patients, the surgeon and the endocrinologist thus need to
ask and answer the simple question: "Does this patient have
unequivocal primary HPT?"
Evaluation of Indications Versus

Risk of Reoperation
In a classic study by Purnell and associates" of a large
number of patients with asymptomatic HPT being followed
without operation, it was clearly demonstrated that 20%
developed compelling indications for operation within 5 years.
Parathyroidectomy for asymptomatic HPT results in normalization of biochemical values and bone density, and approximately one quarter of those who did not undergo operation
did have some progression for periods of up to 10 years. 16
Cervical exploration seems justified in all patients with
documented primary HPT since normocalcemia is restored
in more than 95% of patients, mortality is nearly nil, and
morbidity is rare when the operation is performed by an
experienced endocrine surgeon. 1 However, in contrast with
patients with primary HPT, this liberal indication should be
reconsidered cautiously in patients with recurrent or persistent primary HPT. In the reoperative situation, the obliteration of tissue planes by scar tissue leads to a greater risk of
injuring surrounding structures (laryngeal nerve or normal

multifactorial cardiac risk scheme (Table 58_2).18 In patients
with severe underlying cardiovascular diseases as exemplified by high ASA class or Goldman scores, the potential
benefit of subjecting the patient to reoperation should be
balanced against the surgical risk. It is in this group of
selected patients that medical or nonoperative intervention
may be considered as an alternative to surgical treatment,
albeit rarely.
Review Previous Operative Notes

and Pathology Reports
parathyroid glands) and an even higher chance of operative

failure compared with the initial exploration. The risk of
subjecting a patient to a second surgical procedure that may
be an operative failure is frustrating to both the surgeon and
patient. The statement, "The second most difficult decision
in surgery is to advise operation-the most difficult decision, though, is the one to reoperate!" by Organ is seldom
more true than in reoperative parathyroid surgery.
Once the diagnosis has been reconfirmed by pertinent
laboratory tests, the potential benefit of re-exploration is
weighed against the operative risk in the individual patient.
Some suggest that patients with asymptomatic mild hypercalcemia with serum calcium levels below 12 mg/dL
(normal, 7.9 to 10.1 mg/dL) should be followed up at least
3 to 6 months after failed initial exploration." During this
period of observation, initial operative tissue injury will
slowly heal, mature, and facilitate subsequent re-exploration.
In addition, a small number of patients with apparently
failed primary operations revert to a normocalcemic state
within a few months after operation and may remain so. This
may be due to inadvertent devascularization of the abnormal
parathyroid gland during mobilization. Similarly, the decision to reoperate should be considered in conjunction with
the objective assessment of operative risk of the patient
using the American Society of Anesthesiologists (ASA)
physical status classification (Table 58-1) and the Goldman
Once the diagnosis of persistent or recurrent primary HPT

is biochemically reconfirmed, indications exist to warrant
reoperation, and there is no contraindication to surgery, collection and careful review of all surgical and pathologic
information about the initial exploration is mandatory. It is
of paramount importance for the surgeon who is to undertake the re-exploration, and not only the endocrinologist, to
evaluate the operative dictation regarding the prior exploration. It is important to determine whether the initial operation was thorough enough to conclude that the missing
glandes) is most likely in the mediastinum or whether the
exploration was of such a nature that, in all likelihood, the
offending glands remain in the neck (this is by far the most
common occurrence). The previous operative record should
be carefully studied, and if there is any uncertainty, the initial
operating surgeon should be contacted to clarify the findings.
The histopathologic slides of resected specimens should be
subjected to review and verification by an experienced
endocrine pathologist. The finding of abnormal parathyroid
tissue in the first operation may point to inadequate treatment of multiple-gland disease. In many instances, careful
and objective assessment of preceding operative and pathologic details can give valuable clues as to the thoroughness
of prior exploration, the expected anatomic location of the
missing gland, the underlying parathyroid pathology (missing adenoma, hyperplasia, ectopic gland, supernumerary
gland, or recurrent carcinoma) and help in the subsequent
identification of the abnormal parathyroid glandes).
Parathyroid Reoperations - - 521
Consider Alternative Therapeutic

Modalities: Medical Versus
Ablative Therapy
For patients who are not operative candidates because. of
prohibitive medical comorbidity or excessiv~
reopera~lVe
morbidity and for those who refuse reoperation, medical
therapy and other nonoperative intervention should be considered when there is a compelling indication to treat the
hypercalcemic state. Although there is currently no eft:ective
medical therapy for primary HPT, adequate hydratlOn~
a
furosemide diuretic, and phosphate therapy (as the last choice
when not contraindicated) may help to reduce serum calcium
levels. Estrogen may also be helpful in postmenopausal
women with osteopenia or osteoporosis. Fine-needle aspiration of suspected hyperfunctioning parathyroid tissue to
obtain tissue for cytologic examination or fluid for PTH
assay can be performed under ultrasonography (US) or computed tomography (CT) guidance. 19,20 This technique ~an, be
combined with alcohol ablation of the hyperfunctioning
gland" once the lesion has been confirmed ~ither
cyto.lo.gically or biochemically. Partial ablation of a smgle remammg
enlarged gland may be possible to avoid aparathyroid state."
In addition, angiographic ablation of the hyperactive
parathyroid gland with ionic contrast material has ~lso bee.n
reported." This technique is applicable for poor-risk surgical patients with persistent HPT or those with mediastinal
parathyroid adenomas to avoiid me diIan sternotomy. 23
However, the role of nonoperative ablation of hyperfunctioning parathyroid gland is still not well established. Nerve
injury has been associated with alcohol injection and no
tissue is available for cryopreservation, autotransplantation,
or histology. These nonoperative procedures should be
reserved for highly selected patients and performed by
experts in this specialized area, after in-depth consultation
between the surgeon, the endocrinologist, and the radiologist
who is to perform the procedure. Close follow-up of serum
calcium level is required, and repeat treatments may be necessary because recurrence of hypercalcemia is likely."
Plan Appropriate Cost-Effective

Localizing Modalities
Although the role of routine preoperative localizing studies in
patients with primary HPT undergoing an initial conventional
operation remains controversial because of the extremely
high success rate achieved by an experienced surgeon without the aid of localizing studies,'? there are clear-cut indications for preoperative localizing studies prior to secondary
exploration,2.3.5-8.20,24-29 particularly when the initial exploration was thorough. Localization tests should, however,
never be performed to confirm the diagnosis of primary
HPT. They should only be performed once the diagnosis of
persistent or recurrent primary HPT is reconfirmed and
reoperation is deemed feasible. Preoperative localization in
such patients may shorten operative time, improve surgical
results, and reduce operative complications.
In the past, many modalities of noninvasive or invasive
imaging were applied preoperatively to localize the parathyroid glands, including barium esophagography, selenomethionine and 1131 scanning, cine-esophagraphy, thyroid
lymphography, and thermography, all with limited

success rates. Table 58-3 shows the different preoperative
localizing studies currently employed for parathyroid
localization with their rates of accuracy in various reported
series. 2.3,6,7,20.24-30
For patients who have previously undergone a limited
initial cervical exploration, US using a lO-MHz small-part
probe often detects a missed cervical gland, o~ on occas~on,
a thyroid nodule that may represent an intrathyroidal
parathyroid adenoma. This noninvasive, inexpensive m.odality should be employed as t~e initial.loca~izi~g
mod~hty
~f
choice. A drawback of US IS that visualization behmd air
(the trachea) or bone (the clavicles) is extremely limited,
and good results are only obtained by an experienced ultrasonographer. Radionuclide isotope imaging with technetium
99m sestarnibi-iodine 123 imaging (TSS) may complement
US in detecting abnormal glands in the neck and is particularly useful as an adjunct to US in localizing abnormal
parathyroid tissue in patients with mediastinal a~~ singl~gland disease.'? A combination of US and sestamibi sca~ IS
recommended as the initial, and perhaps only, preoperatIve
localization test in reoperations for suspected parathyroid
adenomas." CT scan and magnetic resonance imaging
(MRI) should be reserved for patients if both of these imaging techniques have failed and when the abnormal gland is
suspected to be located in the mediastinum. Invasive procedures, including selective angiography or selective venous
sampling for PTH, should be performed extremely rarely, in
highly selected patients, and only if other noninvasive measures fail to localize the abnormal glandes). Figure 58-1 summarizes the algorithm for management of persistent or
recurrent primary HPT before reoperation.
Operative Aspects
Cervical Exploration
At the time of initial cervical exploration, it is generally recommended that ideally all four glands should be identified
and the abnormal glandes) be removed. However, in the
reoperative situation, the objective is to locate the abnormal
gland and remove it without disturbing (and perhaps devascularizing) normal glands. Prolonged attempts to identify

Persistent/recurrent primary HPT
+
+
Confirm diagnosis
Evaluate operative
indications ~
/
No
Yes
Observation
Assess operative risk

(ASA and Goldman class)
/'
Low risk
High risk
Localizing studies, assess operative

records, review prior pathology
Ablative or
medical therapy
Cervical mediastinal
exploration
FIGURE 58-1. Algorithm for management of persistent or recurrent

primary hyperparathyroidism (HPT). ASA = American Society of
Anesthesiologists.
normal parathyroid glands embedded in scarred tissue

invariably result in their devascularization and destruction.
Re-exploration generally returns the surgeon to the neck
unless there is compelling evidence in the preoperative evaluation that the missing gland is located in the mediastinum
since the neck remains by far the most common site of
previously missed glands; in addition, ectopic glands in the
superior mediastinal thymus (the second most common site
for a missed gland) can almost always be retrieved via a
standard cervical incision.
A generous incision should be made through the previous
operative incision if it is appropriately placed, followed by
elevation of ample skin flaps. Exposure via the lateral
approach by entering a plane lateral to the strap muscles and
medial to the sternal head of the sternocleidomastoid muscle
can avoid the scarred median tissue. The tracheoesophageal
groove and retrothyroid regions, where most of the missed
glands reside, can be entered via this previously undissected
plane. The initial exploration should be directed toward
those target areas as suggested by localization studies, combined with evaluation of previous operative and pathologic
findings.
The recurrent laryngeal nerve should be identified whenever possible and traced generously to preserve its integrity
once the thyroid gland is reflected medially to expose the
retrothyroid area. The commonly found "anomalous" positions of an inferior gland include the posterior or lateral surface of the thyroid gland beneath a thin layer of thyroid
capsule, the thyrothymic ligament, and the thymic tongue in
the anterosuperior mediastinum. Arrested descent of the
inferior parathyroid gland ("parathymus") during embryologic development may leave the gland high in the neck,
sometimes as far superiorly as the angle of the mandible.
The inferior gland in this location is thus superior to the

superior parathyroid gland. A search along the embryologic
descent path of the inferior parathyroid gland should be
made from the angle of the mandible to the superior mediastinum. The carotid sheath should be opened and explored.
The superior mediastinum can be quite thoroughly explored
via the cervical incision, removing a major portion of the
thymus gland. For suspected abnormal superior glands, the
superior thyroid pedicle should be ligated and divided to
facilitate exposure of the posterior aspect of the superior
thyroid pole. The retroesophageal area should be thoroughly
explored by entering this space immediately superior to
the inferior thyroid artery. Inserting a finger into this space
toward the posterosuperior mediastinum allows for accurate
digital palpation of a space where large glands are often
missed by an inexperienced surgeon at the initial operation.
A superior gland descending in this groove may thus be
located inferior to the inferior parathyroid gland.
The contralateral side should be explored in a similar
manner if exploration of the first side is negative. If exploration fails after a thorough bilateral search, thyroid lobectomy should be considered on the side of greater suspicion
searching for the rare true intrathyroid parathyroid adenoma.
Most of these glands can be suspected because of a nodule
seen by US. A staged mediastinal exploration can be considered after appropriate mediastinal localization studies have
been performed. It is prudent that all suspicious tissue
removed be sent for frozen section and that an intraoperative
dialogue (correlating the operative findings and histopathology) with an experienced pathologist ensue; this dialogue is
crucial.
Mediastinal Exploration
The surgeon should be satisfied that a thorough and complete cervical re-exploration has been performed before
proceeding to mediastinal exploration unless there is compelling evidence from preoperative localization studies that
the missing gland is located in the mediastinum. The mediastinum is entered by a partial or complete sternal split or
via a thoracoscopic approach. Once the mediastinum is
opened, the search for the parathyroid should begin with the
thymus gland. Most mediastinal parathyroid glands are
located intrathymically at the level of innominate vein in the
anterior superior mediastinum. A small number are situated
low in the anterosuperior mediastinum between the thymus
and pleura, adjacent to the great vessels along the aortic arch
or in the aorticopulmonary window. Occasionally, a missing
superior gland may be located in the posterosuperior mediastinum in the retroesophageal space, posterior to the carina,
or in the right subpulmonary artery space.
Intraoperative Localization
Several intraoperative localization tests, including intraoperative US, methylene blue staining, intraoperative venous
sampling for PTH measurement, and gamma probe examination have been described in the reoperative situation.
Intraoperative US performed by an experienced radiologist
can help guide dissection." It images more abnormal glands
than preoperative US and may help locate an intrathyroid or
Parathyroid Reoperations - - 523
retrothyroid parathyroid gland encased in scar tissue or an

ectopic gland within the carotid sheath. The use of intraoperative methylene blue injection has not been as helpful
in reoperative cases as in initial operations because of the
relative nonspecificity of the test.' The rapid intraoperative
PTH assay enables the surgeon to perform selective venous
sampling intraoperatively and to localize and lateralize an
abnormal gland by detecting an increase in PTH level on the
side of the tumor. In addition, this technique enables the
surgeon to confidently confirm the adequate removal of
hyperfunctioning tissue, especially in multiple-gland disease,
and improve the overall surgical success rate." Minimally
invasive radio-guided parathyroidectomy using the gamma
probe allows a directed dissection with a small incision and
is associated with a high success rate in patients with positive sestamibi scans requiring reoperation."
Cryopreservation and Autotransplantation

Cryopreservation of a portion of excised parathyroid tissue
in the reoperative situation has been regarded as stateof-the-art practice to correct postexploration hypocalcemia.
A portion of the parathyroid gland is sliced into pieces and
cryopreserved for future delayed autotransplantation in the
event that the patient develops permanent hypoparathyroidism postoperatively. Controversy exists whether to
perform immediate autotransplantation after removal of all
parathyroid tissue in the reoperative situation and thus achieve
a 90% success rate when using fresh parathyroid tissue in
comparison to a 50% success rate when delayed transplantation is employed." However, it is generally advantageous
to delay transplantation to observe the biochemical response
after operation unless three or four parathyroid glands have
already been removed. The presence of a fifth supernumerary gland or the possibility of persistent hypercalcemia makes
us cautious about immediate autotransplantation. Although
cryopreservation plays an integral role in reoperative
parathyroid surgery, the rate of cryopreservation usage is low.
and unfortunately not all patients are rendered normocalcemic after autotransplantation of cryopreserved parathyroid
tissue."
Brief Review of Results of

Reoperative Parathyroid
Surgery
A summary of results reported by referral centers with
extensive experience in parathyroid reoperations is shown in
Table 58-4. Some of these results included all patients with
persistent or recurrent HPT, but others, such as at the
National Institutes of Health, only included patients with
sporadic disease and one abnormal gland. From 1989 to 1997
at the Mayo Clinic, 124 patients with benign persistent or
recurrent primary HPT underwent 106 cervical explorations
(86%), 9 mediastinal explorations alone (7%), and 9 (7%)
combined cervical-mediastinal explorations.i" In this series,
US had an accuracy of 65%, a sensitivity of 75%, and a positive predictive value of 78%. Sestamibi scanning was accurate in 67% with a sensitivity of 82% and a positive
predictive value of 79%. CT scanning of the mediastinum
was accurate in 53% and had a sensitivity of 40% and a positive predictive value of 80%. Cure of hypercalcemia was
achieved in 88% of patients. Morbidity was incurred in 15%
of patients, with permanent hypoparathyroidism accounting
for most of the morbidity (89%). Immediate forearm autotransplantation was performed in 13 patients, and 4 (32%)
patients remained hypoparathyroid. Delayed autotransplantation was carried out in 4 patients with a 25% graft
success rate.
Neither cure rates nor operative morbidity have changed
appreciably over the past 2 decades despite the application
of sestamibi scanning and intraoperative PTH monitoring.P
Multiple-gland disease continues to represent the principal
cause of failure in reoperative parathyroid surgery and most
missed abnormal glands reside in normal anatomic locations.
Of the 15 patients who remained hypercalcemic following
their reoperative surgery, 11 (73%) had multiple-gland disease based on previous records, histologic examination, and
preoperative localization tests. The overwhelming majority
of glands removed were in normal anatomic positions (76%)
in the neck. Of glands not in a normal position (n = 26),
8 were found in the mediastinum, 7 were intrathyroidal,
6 were within the carotid sheath, 3 were anterior to the

trachea, and 2 were retroesophageal.
The anatomic site of disease at reoperation is well documented in various large series and is shown in Table 58-5.
Although the success rate of reoperation in experienced

hands ranges from 82% to 98%, the fact that more than 40%
of missing glands were found in normal anatomic positions
challenges all surgeons who operate on primary HPT to
strive for cure in the primary operation rather than submitting a patient to the risk of a reoperation-or rendering the
reoperative endocrine surgeon to chronic excessive catecholamine secretion.
Illustrative Cases
FIGURE 58-2. Ultrasonography of the neck showing a suspicious

enlarged parathyroid gland posterior to the lower pole of the right
lobe of the thyroid (see Case I).
Parathyroid Reoperations - -
525
Summary
Patients with persistent or recurrent PHPT may present a
challenge, even for the experienced parathyroid surgeon.
Surgeons must reconfirm the diagnosis, consider the risks
and benefits of reoperation, and review the operative note(s),
pathology report(s), and results of the localization tests. The
success rate of reoperation is quite good, especially in a
patient whose tumor is identified by the preoperative localization tests, but the complication rate is appreciably higher
than during initial parathyroid operations.
REFERENCES
Reoperative Pearls
Reconfirm the diagnosis of HPT

The surgeon must review prior operative notes
Assess patient risk factors
Pathologist must re-review prior pathology slides
Missed gland usually is in the neck
Judicious, cost-effective parathyroid gland localization
Consider lateral cervical approach
Remember that if the inferior gland is missing, look
superior to the superior gland for the inferior gland
and, similarly, if the superior gland is the missing one,
look inferior to the inferior for the superior gland.
FIGURE 58-3. Radionuclide scintiscan demonstrating a suspicious

uptake in the anterior mediastinum near the left main bronchus (see
Case 2).
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exploration and technical aspects of re-operation in primary hyperparathyroidism. World I Surg 1992;16:562.
28. Jarhult I, Nordenstrom I, Perbeck L. Reoperation for suspected primary
hyperparathyroidism. Br I Surg 1993;80:453.
29. Weber CI, Sewell CW, McGarity We. Persistent and recurrent sporadic
primary hyperparathyroidism: Histopathology, complications, and results
of operation. Surgery 1994;116:982.
30. Thompson GB, Mullan BP, Grant CS, et al. Parathyroid imaging utilizing
technetium-99m-sestamibi: An initial institutional experience. Surgery
1994;116; 966.
31. Feingold DL, Alexander HR, Chen CC, et al. Ultrasound and sestamibi
scan as the only preoperative imaging testes in reoperation for parathyroid adenomas. Surgery 2000;128:1103.
32. Irvin GL III, Molinari AS, Figueroa C, et al. Improved success rate in
reoperative parathyroidectomy with intraoperative PTH assay. Ann
Surg 1999;229:874.
33. Norman I, Denham D. Minimally invasive radio-guided parathyroidectomy in the reoperative neck. Surgery 1998;124:1088.
34. Caccitolo lA, Farley DR, van Heerden lA, et al. The current role of
parathyroid cryopreservation and autotransplantation in parathyroid
surgery. Surgery 1997;122:1062.
Hypoparathyroidism and
Pseudohypoparathyroidism
Mary Ruppe, MD Martha A. Zeiger, MD Suzanne Jan de Beur, MD
Hypoparathyroidism can result from either decreased secretion of parathyroid hormone (PTH) or target organ resistance
to PTH. The etiologies of decreased secretion of PTH include
the destruction of the parathyroid glands as a complication
of head and neck surgery; genetic defects, such as mutations
in the PTH or the calcium-sensing receptor genes; developmental defects, such as DiGeorge's syndrome; autoimmune
destruction, as in the polyglandular autoimmune endocrinopathies (autoimmune polyendocrinopathy--candidiasisectodermal dystrophy [APECED] syndrome); and infiltrative
diseases, such as hemochromatosis or Wilson's disease. In
contrast with true hypoparathyroidism, hypocalcemia and
hyperphosphatemia in pseudohypoparathyroidism (PHP) is
accompanied by an elevated serum level of PTH and results
from resistance to the action of PTH rather than to PTH deficiency. The etiology of the hormone resistance observed in
this group of related syndromes is a G-protein defect that
results in impaired signaling in a variety of receptors, including the PTH receptor. Hypomagnesemia, depending on the
severity and duration, may also result in either decreased
secretion of or resistance to PTH.
HypoparathyroidismPostsurgical
Surgical destruction of the parathyroid glands is the most
common cause of hypoparathyroidism. Hypoparathyroidism
can occur after any surgical procedure that involves the anterior neck but is most commonly seen as a complication
of parathyroid surgery or thyroid surgery, or after extensive
resection for head and neck cancer. Trauma to the parathyroid vascular pedicles or inadvertent removal of the glands
leads to either transient or permanent hypoparathyroidism.
Estimates of the incidence of post-thyroidectomy hypoparathyroidism vary widely, ranging from 6.9% to 46% for
transient and 0.4% to 33%\ for permanent hypoparathyroidism. A survey by the American College of Surgeons
reported an incidence of hypoparathyroidism following total
thyroidectomy of 8%.2 A multicenter prospective trial of
5846 patients undergoing total thyroidectomy revealed an

incidence of transient hypoparathyroidism of 7.3% and
permanent hypoparathyroidism of 1.5%. J Characteristics
of the surgical procedure associated with an increased risk
of hypoparathyroidism were a greater extent of surgical
resection and central rather than peripheral thyroid artery
ligation, the latter of which is less likely to preserve the vascular supply to the parathyroid glands. Following total thyroidectomy, more experienced surgeons report fewer complications,
including hypoparathyroidism.'
Surgical removal of hyperfunctioning parathyroid tissue
often results in transient hypoparathyroidism because the
remaining normal parathyroid tissue had been previously
suppressed by hypercalcemia. Postsurgical hypoparathyroidism is usually manifest within the first 24 to 48 hours
following surgery. Generally, calcium values and parathyroid responsiveness improve within 1 week after surgery. If
the preexisting hyperparathyroidism resulted in excessive
bone resorption, then a more severe, protracted form of postparathyroidectomy hypocalcemia referred to as "hungry
bones" may ensue. Once the PTH-stimulated bone resorption is halted by parathyroidectomy, then calcium and phosphorus are rapidly deposited into the bones, precipitating
symptomatic hypocalcemia and hypophosphatemia. Patients
with preoperative evidence of parathyroid bone disease such
as osteitis fibrosa cystica, resorption of the distal phalanges,
an elevated alkaline phosphatase, or those with renal
osteodystrophy are at high risk for developing hungry bone
syndrome and should be monitored carefully for the development of postoperative hypocalcemia and treated aggressively. Hungry bone syndrome is typically associated with
more severe, symptomatic hypocalcemia and may require
treatment for several weeks to months before biochemical
parameters normalize. An elevated serum PTH level distinguishes hypocalcemia of hungry bones from other forms of
post-parathyroidectomy hypocalcemia (Table 59-1).
The typical signs and symptoms associated with hypocalcemia are neuromuscular irritability, including perioral or
acral paresthesias; muscle cramps that may progress to
carpopedal spasm, laryngospasm, bronchospasm, or even
527
tetany; and central nervous system deficits as subtle as mood

lability or as profound as stupor. Simple bedside maneuvers
such as the Chvostek's sign and Trousseau's sign can reveal
the presence of neuromuscular irritability. Chvostek's sign is
described as circumoral twitching following tapping of the
facial nerve. This sign is present in 10% to 30%4 of normal
individuals; therefore, if it is to be used as a postoperative
marker of hypocalcemia, it is important to verify that it is
not present preoperatively. Trousseau's sign is carpal spasm
that is elicited after inflation of a blood pressure cuff to
20 mm Hg above the patient's systolic blood pressure for
3 minutes. Severe hypocalcemia may also manifest as prolongation of the QT interval or nonspecific changes on an
electrocardiogram.
Treatment decisions for postoperative hypoparathyroidism are based on the degree of hypocalcemia, the rapidity of its development, and severity of the symptoms.
In severe cases (calcium level < 7.5 mg/dL or severe symptoms), intravenous administration of calcium salts is required.
A recommended approach includes using 10 ampules of
calcium gluconate (90 mg of elemental calcium per lO-mL
ampule) in I L of 5% dextrose with an initial infusion rate
of 100 mL/hour. With frequent monitoring of serum calcium
levels (usually every I to 2 hours), the infusion rate is titrated
to keep the calcium level in the low-normal range. Once
stabilized, the patient may be converted to a regimen of oral
calcium and calcitriol as described later.
If the patient is asymptomatic with mild hypocalcemia
(7.5 to 8.5 mg/dL), oral therapy consisting of up to 1000 mg
of elemental calcium every 6 hours and 0.25 to 2.0 ug/day
of calcitriol [I,25-(OH)z]vitamin D3 should be instituted.
As with intravenous therapy, the oral doses can be titrated
to keep the calcium in the low-normal range. Magnesium
levels should be monitored and repleted because hypomagnesemia results in both impaired PTH secretion and PTH
resistance. In most cases, treatment with calcium and
vitamin D is short term and necessary only until the residual
parathyroid tissue begins to function.
Pseudohypoparathyroidism
PHP is a heterogeneous group of disorders characterized by
hormone resistance-the hallmark of which is PTH resistance. Typically, these patients present with hypocalcemia
and hyperphosphatemia that is due to impaired target tissue
responsiveness to PTH rather than PTH deficiency.
Two genetically distinct forms of PHP type I have been
described. The more common variant, termed PHP type La,
is an autosomal dominant disorder with resistance to multiple
hormones (PTH, thyroid-stimulating hormone, luteinizing

hormone, gonadotropin hormone-releasing hormone) and
a constellation of developmental defects termed Albright's
hereditary osteodystrophy (AHO). These defects include
short stature, obesity, round facies, brachymetacarpia, subcutaneous ossification, and mental deficiency.' Patients with
PHP type Ia have mutations in maternal GNASl alleles that
abrogate expression or activity of G; the heterotrimeric G
protein that couples receptors to activation of adenylyl
cyclase." Identical mutations in paternal alleles are associated with AHO and normal hormone responsiveness, a variant termed pseudo-pseudohypoparathyroidism (PPHP).7
PHP type lb is a less common and clinically distinct variant of PHP that has also been linked to the GNASllocus. 8.9
Subjects with PHP Ib lack features of AHO, show renal
resistance to PTH as the only manifestation of hormone
resistance, and have normal Gsa activity in tissue. PHP Ib
arises as a result of an imprinting defect that affects expression of GNASl in the proximal renal tubule and is the basis
for this disorder. Specifically, patients with PHP lb have
paternal-specific patterns of cytosine methylation within differentially methylated regions of maternally inherited GNASl
alleles.'? The specific genetic mutation(s) that accounts for
this methylation defect is unknown.
Biochemically, PHP l a and lb lead to functional
hypoparathyroidism. Laboratory evaluation reveals hypocalcemia, hyperphosphatemia, and elevated levels of PTH
(Table 59-2). In addition, individuals with PHP la may
also manifest biochemical evidence of hypothyroidism,
gonadotropin resistance, and growth hormone deficiency. In
contrast, individuals with PPHP do not exhibit hormone
resistance and have normal calcium, phosphorus, and PTH
levels. Confirmation of the diagnosis of PHP l a or lb can
be accomplished by monitoring urinary cyclic adenosine
monophosphate and phosphate excretion following infusion
of PTH. 11 Although a reliable diagnosis of PHP Ia may be
made on clinical grounds, the molecular genetic diagnosis
of PHP l a requires identification of heterozygous inactivating mutations in GNASl. This genetic test is now available
at several centers. There is currently no commercially available genetic test for PHP lb.
The basic principles associated with the treatment of
PHP are similar to those for postoperative hypoparathyroidism, with the mode of treatment being dictated by the
severity of the hypocalcemia, the rapidity of development of
the hypocalcemia, and the presence of signs and symptoms
of hypocalcemia. Intravenous infusion of calcium is
required in patients with acute hypocalcemic crises.
Long-term maintenance therapy consists of oral administration of calcium and vitamin D.
Hypoparathyroidism and Pseudohypoparathyroidism - -
Summary
Hypoparathyroidism is most commonly caused by surgery
for parathyroid disease, thyroid disease, or extensive head
and neck tumors. Patients with hypoparathyroidism often
display signs and symptoms of hypocalcemia and exhibit
diminished serum calcium, elevated serum phosphorus, and
reduced serum PTH. In contrast, patients with the rare
disorder PHP manifest functional hypoparathyroidism with
hypocalcemia and hyperphosphatemia, yet they exhibit
elevated PTH levels due to PTH resistance rather than PTH
deficiency. The basis of the PTH resistance is decreased Gsa
activity, resulting in impaired signaling through a number of
hormonal receptors, including the PTH receptor. Severe
hypocalcemia resulting from any cause can be life threatening; therefore, establishing the appropriate diagnosis and
initiating prompt therapy are critical. Close monitoring is
indicated to determine if long-term therapy is necessary.
REFERENCES
I. Thomusch 0, Machens A, Sekulla C, et al. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: A
multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180.
2. Foster RS. Morbidity and mortality after thyroidectomy. Surg Gynecol
Obstet 1978;146:423.
529
3. Sosa J, Bowman H, Tielsch 1. The importance of surgeon experience

for the clinical and economic outcomes from thyroidectomy. Ann Surg
1998;228:320.
4. Hoffman E. The Chvostek sign: A clinical study. Am J Surg 1958:
96:33.
5. Albright F, Burnett CH, Smith PH. Pseudohypoparathyroidism:
An example of "Seabright-Bantam syndrome." Endocrinology 1942:
30:922.
6. Patten JL, Johns DR, Valle D, et al. Mutation in the gene encoding the
stimulatory G protein of adenylate cyclase in Albright's hereditary
osteodystrophy. N Engl J Med 1990;322:1412.
7. Levine MA, Jap TS, Mauseth RS, et al. Activity of the stimulatory
guanine nucleotide-binding protein is reduced in erythrocytes from
patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: Biochemical, endocrine, and genetic analysis of
Albright's hereditary osteodystrophy in six kindreds. J Clin Endocrinol
Metab 1986;62:497.
8. Juppner H, Schipani E, Bastepe M, et al. The gene responsible for
pseudohypoparathyroidism type Ib is paternally imprinted and maps in
four unrelated kindreds to chromosome 20qI3.3. Proc Nat! Acad Sci
USA 1998;95: 11798.
9. Jan de Beur SM, O'Connell JR, Peila R, et al. Refinement of the
pseudohypoparathyroidism type Ib locus to a region including GNASI
at 20q13.3. J Bone Miner Res 2003;18:424.
10. Liu J, Litman D, Rosenberg MJ, et al. A GNASI imprinting defect in
pseudohypoparathyroidism type lB. J Clin Invest 2000;106:1167.
II. Mallette LE, Kirkland JL, Gagel RF. Synthetic human parathyroid
hormone (1-34) for the study of pseudohypoparathyroidism. J Clin
Cryopreservation of
Parathyroid Tissue
Andrew Saxe, MD Glenn Gibson, BA
Historical Aspects
Technical Issues
The earliest English language reference to cryopreserving

parathyroid tissue that we have been able to establish is by
Blumenthal and Walsh in 1950. 1 Their study was designed
to evaluate the histologic appearance of previously frozen
thyroid autotransplants in guinea pigs. They compared autotransplants with and without thyrotropin and preservation at
-70C with preservation at -190C. They concluded that the
lower temperature better preserved thyroid architecture. In a
single preparation, however, a parathyroid gland previously
maintained at -70C appeared "well preserved" and "similar
to a parathyroid observed in a control autotransplant." The
study did not include functional analysis of the frozen thyroid
or parathyroid tissue.
To facilitate studies of the emerging science of cryobiology, Russel and colleagues- investigated technical aspects of
cryopreserving tissue. They recognized the need for a functional assessment of success and used parathyroid tissue
because they could measure reversal of hypocalcemia in
parathyroidectomized rats. They emphasized the value both
of using glycerol as a cryoprotectant and of a slow, -1C/min
freezing rate. Their work was repeated by Huggins and Abo.'
who emphasized the importance of removing the cryoprotectant after thawing and before reimplantation.
The "modem" era of clinically applicable parathyroid
cryopreservation was ushered in by Wells and Christiansen."
They were able to demonstrate in rats that parathyroid tissue
frozen at -1C/min in autologous serum and dimethyl sulfoxide (DMSO) as a cryoprotectant could function as assessed
by restoration of normocalcemia and return of hypocalcemia
on removal of the transplant.
For a more complete discussion of other investigators'
contributions to the history of developing clinically useful
parathyroid cryopreservation, the reader is referred to reviews
by Saxe' and Niederle and colleagues.f
Saxe and coworkers 7 explored methodologic aspects of

cryopreserving human parathyroid tissue. They quantitated
the rate of freezing of parathyroid tissue under a variety of
conditions, including placing tissue directly into vaporphase liquid nitrogen, directly into a -70C freezer, into a
programmable freezer, and into an ethanol bath placed in a
-70C freezer. They demonstrated that when using the inexpensive ethanol bath method, the freezing rate was influenced by the volume of ethanol but not by the number of
vials being frozen or by the mass of tissue within each cryopreservation vial (100 mg tissue versus 200 mg tissue per
vial). By measuring the in vitro viability of cell suspensions
derived from patients' samples maintained as long as
50 months, they concluded that there was no difference in
cell viability between fresh tissue and tissue frozen by any
technique that used a -1C/min freezing rate. Wagner and
colleagues" demonstrated increased necrosis of parathyroid
tissue frozen at -2C/min compared with that of tissue
frozen at -1C/min. Saxe and coworkers 7 also found no difference in viability among samples from the same patient
assessed at varying times after cryopreservation and no difference in viability between cryopreserved adenoma and
hyperplastic parathyroid tissue.
530
Our Current Cryopreservation Technique

Tissue is harvested in the operating room as promptly
as possible and placed immediately in chilled, sterile
RPMI-I640 culture medium for transport to the laboratory.
If medium is not available, saline is a better alternative than
water. Under a laminar flow hood, using sterile technique,
tissue is bathed in chilled RPMI-I640 in a Petri dish on ice,
and adherent fat and capsule are stripped from the parathyroid parenchyma. The tissue is divided (freehand) into cubes,
Cryopreservation of Parathyroid Tissue - -
approximately 1 to 2 mm per side. Two solutions are

prepared on ice in separate test tubes: 20% (by volume)
solutions of autologous serum and of DMSO in RPMI-1640.
These can be conveniently prepared by placing 4 mL of
RPMI -1640 in each of two test tubes on ice and adding 1 mL
of autologous serum to the first and 1 mL of DMSO to
the second. If large amounts (several grams) of tissue are to
be cryopreserved, 2 mL of serum or DMSO added to 8 mL
of RPMI-I640 is suggested.
Before introducing tissue to the vial, 0.6 mL of the
20% serum solution is added to each 2.0-mL cryopreservation vial (Coming, Coming, NY) on ice. Approximately
20 pieces of tissue are added to each cryopreservation vial
while the vials are kept on ice. After tissue has been placed
in all vials, 0.6 mL of the 20% DMSO solution is added to
each vial in the same order so that chilled DMSO is added
to tissue that has been chilled by the 20% serum RPMI1640. Vials are mixed by gentle agitation and then left on ice
for 5 minutes. If fewer than 18 vials are to be stored, we now
use a Mr. Frosty Cryo 1C Freezing Container (Nalge,
Rochester, NY) by adding 250 mL of chilled isopropyl
alcohol (kept overnight in a 4C refrigerator) to the reservoir
and placing the device in a -70C freezer overnight. At a
convenient time the next day, we transfer the vials for longterm storage in a -135C freezer. If an electric -135 freezer
is not available, storage in vapor-phase nitrogen is satisfactory.
If more than 18 vials are to be stored, we place the vials in
a test tube rack that is placed in a metal pan with internal
dimensions of approximately 29 x 18 em, to which is added
1000 mL of chilled (4C refrigerator overnight) ethanol.
The pan volume-ethanol ratio does influence freezing rate.
The pan is covered with aluminum foil and placed in a -70C
freezer overnight.
Our Technique for Thawing the Tissue

A tube of 20% patient's serum (by volume) in RPMI-I640
is prepared as previously discussed and placed on ice.
Cryopreservation vials are removed from the long-term
storage freezer and placed in a 37C water bath. The vials
are gently agitated until the ice has nearly completely melted
and only a core of frozen RPMI-I640 remains. At that
point, the vial is opened and 0.5 mL of freshly prepared
serum-RPMI-1640 solution is added. The vial is returned to
the water bath and agitated until the ice crystal is completely
melted. Then, 0.5 mL of the liquid vial contents is aspirated
with a sterile pipette and replaced with 0.5 mL of fresh
serum-RPMI-I640. The vial is now placed on ice and the
cycle of aspirating vial contents and replacing with fresh
serum-RPMI-I640 is repeated three times. The intention is
to dilute the DMSO while the tissue remains chilled. After
the vial contents have been exchanged four times, the tissue
is removed, placed in a fresh container with fresh RPMI1640, and kept on ice until used.
If the tissue is to be used as an autotransplant, a piece is
submitted for bacteriologic culture and for frozen section to
confirm its identity as parathyroid. We have given patients
perioperative antibiotics prophylactically. Using blunt dissection, several pockets are created in the selected muscle and
then observed for hemostasis. In an absolutely dry pocket,
5 to 10 pieces of gland tissue are inserted, and the pocket
531
is closed with nonabsorbable material that can serve as a

marker for relocating the pocket if necessary. We believe
that a hematoma in the pocket may interfere with revascularization of the tissue fragments.
Typically, 20 pieces of tissue are transplanted. Almost
certainly, some cases of graft failure are due to transplantation of insufficient viable tissue. At present, however, there
is no rapid method for assessing the function of cryopreserved
tissue on a "per unit mass" basis and no practical method,
therefore, for determining the correct number of pieces to be
placed in the muscle pockets.
Variations of Cryopreservation
Variations on this technique of cryopreservation have been
introduced periodically. Basile and colleagues? reported successfully cryopreserving rat parathyroid tissue and, in a single
case, human parathyroid tissue using Waymouth's solution
in place of RPMI-I640 and placing cryopreservation vials
with tissue into a -80C freezer (without chilled ethanol) for
16 hours before long-term storage in liquid nitrogen.
Kapur and associates'? placed rat parathyroid tissue in
15% DMSO-Hanks basic salt solution in a -20C freezer
for 24 hours and were able to demonstrate function in 7 of
10 animals that underwent autotransplantation with cryopreserved tissue.
The rates of viability of cryopreserved parathyroid tissue
in vitro and in vivo are displayed in Table 60-1.
Evaluation of Function
Assessing the function of transplants with fresh parathyroid
tissue can be difficult because normocalcemia attributed to
transplanted tissue may be due to residual in situ parathyroid
tissue. Evaluating the function of cryopreserved transplants
is usually more straightforward because patients receive
cryopreserved grafts only for well-established hypoparathyroidism. In this setting, one may reasonably consider that
return of serum calcium, parathyroid hormone, or urine
cyclic adenosine monophosphate (cyclic AMP) toward
normal after these transplants is a reflection of successful
cryopreservation. Clinical results with cryopreserved autotransplants are displayed in Table 60-2.
Several studies also provide confidence that cryopreserved parathyroid tissue retains the same (but not necessarily normal) physiology that it displays in the fresh state
(Table 60-3). Several investigators have demonstrated
preservation of calcium-mediated suppression of parathyroid hormone (Fig. 60_1).11.15 McHenry and coauthors"
reported that parathyroid tissue cryopreserved as tissue
pieces better preserved calcium-mediated suppression than
the same tissue first dispersed and cryopreserved as cell
suspensions. Wagner and colleagues'? found that cryopreservation preserved the parathyroid hormone secretory rate
(parathyroid hormone release per 105 viable cells) but that
the number of nonviable cells varied with both freezing
rate and other poorly understood factors. Saxe and Gibson"
found no difference between fresh and cryopreserved
human parathyroid tissue with respect to lithium-stimulated
tritiated thymidine incorporation. On the other hand,
Hetrakul and coworkers'? reported loss of mitochondrial

activity as assessed by sestamibi uptake in cryopreserved
versus fresh human parathyroid tissue.
Although few studies have been designed to address the
question directly, there is evidence from several investigators that the length of storage does not affect the viability or
function of cryopreserved parathyroid tissue.4 ,7,1I,1 Z,15, 18-Z3
It appears that tissue is lost during the freezing and thawing
processes rather than by attrition during storage.
Indications for Transplantation

with Cryopreserved Tissue
The indications for autotransplantation with cryopreserved
tissue are straightforward: persistent, "permanent" hypocalcemia in patients for whom cryopreserved tissue is available.
There is no fully agreed-on definition of permanent hypocalcemia; however, dependence on oral calcium and vitamin D
Cryopreservation of Parathyroid Tissue - -
for 6 months seems reasonable. Patients with disabling symptoms may undergo transplantation sooner," Measurement of
parathyroid hormone to distinguish postoperative parathyroid hormone deficiency from "bone hunger" is warranted
before the physician embarks on autotransplantation.
Although routine cryopreservation is difficult to justify
because of the low incidence of postoperative hypocalcemia,
surgeons managing patients at higher risk for hypocalcemia
should be knowledgeable about techniques of cryopreservation and parathyroid transplantation, and their institutions
should have appropriate facilities. An informal survey of
several clinical investigators reported rather similar impressions: resected parathyroid tissue is cryopreserved, if ever,
only from patients at high risk for postoperative hypoparathyroidism, and only a handful of patients have undergone autotransplantation with cryopreserved tissue. As discussed in
Chapter 59, patients well recognized as being at higher risk
for postoperative hypoparathyroidism are those undergoing
IN VITRO PTH RELEASE BY HUMAN PARATHYROID CELLS

100
0--0 FRESH (n = 5)
::J'
<
::E 75
o-
6 CRYOPRESERVED (n = 5)
::E
u.. 50
L\
'I
~
~
::I: 25
lo,
0.4
"
-6
0.8
Ionized Ca++[mM]
FIGURE 60-1. Comparison of suppression of parathyroid

hormone (PTH) release in vitro in both fresh tissue (0) and after
20 to 220 days of cryopreservation of tissue (l; mean of five
patients at each point. (From Brennan MF, Brown EM. Prediction
of in vivo function of human parathyroid tissue autografts by in
vitro testing. World J Surg 1980;4:748.)
533
reoperative thyroid surgery, those who have multiple hyperplastic parathyroid glands resected, and those undergoing
reoperation for persistent or recurrent hyperparathyroidism.
Thyroid Disease
Transplantation with cryopreserved tissue does not playa role
in either primary or secondary operations for thyroid disease.
Recognition that parathyroid tissue has become devascularized warrants immediate transplantation of the tenuous
parathyroid to the sternocleidomastoid muscle. Frozen section analysis of a small piece of the tissue to be transplanted
is mandatory. As pointed out by Lahey.>' it can be difficult to
distinguish a lymph node with metastatic thyroid cancer
from a parathyroid gland.
Multiple-Gland Disease: Initial Surgery

Multiple-gland disease can be anticipated in patients with
multiple endocrine neoplasias, familial disease, and secondary hyperparathyroidism. Two surgical strategies are widely
used: (1) subtotal (3.5-gland excision) parathyroidectomy
leaving tissue attached to its native blood supply and
(2) total parathyroidectomy and autotransplantation to
forearm muscles or subcutaneously. Regardless of the strategy
selected, cryopreservation of resected parathyroid tissue
as a backup is warranted. Autotransplantation with fresh
tissue is not uniformly successful, as reflected by an incidence
of postoperative hypoparathyroidism of approximately 10% in
patients undergoing total parathyroidectomy with immediate
autotransplantation.' Autotransplantation with biopsy-proven
cryopreserved tissue offers the patient a second chance to be
free from calcium supplements.
Reoperative Parathyroid Surgery

An important part of planning reoperative parathyroid surgery
is the review of operative and pathology notes by the surgeon
and the review of resected tissue by a pathologist. Should it
be determined that the patient's only functioning parathyroid tissue is a single remaining adenoma, resection with
immediate transplantation of a portion of the adenoma and
cryopreservation of the remaining tissue are preferred over

angiographic ablation.
Another situation that may be anticipated by a review of
operative documents and histologic slides is that of reoperation for multiple-gland disease. Saxe and Brennan" reported
a 54% incidence of spontaneous normocalcemia and a 12%
incidence of persistent hypercalcemia in 26 such patients
who underwent attempted total parathyroidectomy without
immediate autotransplantation. Of particular interest were
13 patients who had histologically documented four-gland
resections. Fully 69% of those patients remained normocalcemic (seven patients) or hypercalcemic (two patients) without
calcium supplementation or autotransplantation. This indicates
that in this setting even patients undergoing intentional
removal of all parathyroid tissue may (unpredictably) have
residual tissue. The seven normocalcemic patients might
well have become hypercalcemic had they received immediate autotransplants. The authors concluded that for patients
undergoing intentional "total parathyroidectomy" at reoperation for multiple-gland disease, a prediction of inevitable
hypocalcemia is unwarranted and immediate autotransplantation with fresh tissue is unwise. They recommended
restricting autotransplantation (with cryopreserved tissue)
to patients with documented hypoparathyroidism.
Research
Cryopreservation of parathyroid tissue has utility beyond
autotransplantation for treatment of hypoparathyroidism.
Research using parathyroid tissue can be facilitated by harvesting tissue on the day of resection for use at a time convenient
to the investigator. Access to a "bank" of cryopreserved tissue
frees the investigator from the vagaries of the operating
room schedule and permits accumulation of masses of tissue
sufficient to perform complex experiments. It also permits
comparison of several patients' tissues in a single experiment
as well as the same patient's tissue in several experiments.
Cryopreserved tissue has been used in the investigation
of several aspects of physiology: comparison of hormone
release in adenoma versus hyperplasia," effect of lithium on
thymidine incorporation," parathyroid immunology.Pr"
effect of cimetidine on hormone secretion.i? effect of phorbol
ester on hormone secretion," mitochondrial incorporation
of sestamibi.!? and generation of microcapsules of parathyroid tissue.'? In general, cryopreservation appears to preserve
parathyroid function, although there does appear to be a
difference in preservation of estrogen receptors in fresh versus
cryopreserved human parathyroid tissue (Table 60-4),31
For in vitro experiments, we have used the following
protocol for preparation of cell suspensions. Thawed tissue
is placed in 10 mL of a 0.5-mg/mL collagenase (Boehringer
Mannheim, Indianapolis, IN) in RPMI-I640 solution. The
culture tube containing the tissue is placed in a 37C shaking
water bath and agitated gently (92/min) for 30 to 60 minutes.
Because the viability of cryopreserved cells is variable, we
have used an additional step to remove necrotic cells
and enrich the proportion of viable cells. A stock solution of
isotonic Percoll (Pharmacia, Uppsala, Sweden) is made by
mixing Percoll with lOx phosphate-buffered saline (PBS).
Working solutions of 25% and 75% stock solutions are made
by dilution in PBS. In a 12- x 75-mm culture tube, 1.5-mL
portions of the 25% and 75% stock solutions are added below
the parathyroid cell suspension using a spinal needle, and the
tube is centrifuged at 450 g for 15 minutes. The superficial
0.5 mL containing debris and necrotic cells is discarded. Of
the remaining Percoll gradient, 1.5 mL is aspirated, diluted
with 3.5 mL of culture medium, recentrifuged, and resuspended in whatever solution is to be used for the experiment.
Conclusion
In conclusion, techniques for preparing and transplanting cryopreserved parathyroid tissue have been presented. Surgeons
who perform parathyroid surgery should be familiar with these
techniques. The success rate of using this technique is about
70% (see Table 60-2) versus better than 90% with autotransplantation of fresh parathyroid autografts.
REFERENCES
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2. Russel PS, Wood ML, Gittes RF. Preservation of living tissue in the
frozen state: A study using parathyroid tissue. J Surg Res 1961; I:23.
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In: Norman JC (ed), Organ Perfusion and Preservation. New York,
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Cryopreservation of Parathyroid Tissue - 4. Wells SA, Christiansen C. The transplanted parathyroid gland:
Evaluation of cryopreservation and other environmental factors which
affect its function. Surgery 1974;75:49.
5. Saxe A. Parathyroid transplantation: A review. Surgery 1984;95:507.
6. Niederle B, Roka R, Brennan ME The transplantation of parathyroid
tissue in man: Development, indications, technique, and results. Endocr
Rev 1982;3:245.
7. SaxeAW, Gibson GW. Kay S. Characterization of a simplified method
of cryopreserving human parathyroid tissue. Surgery 1990;108:1033.
8. Wagner PK, Seesko HG, Rothmund M. Replantation of cryopreserved
human parathyroid tissue. World J Surg 1991;15:751.
9. Basile C, Drueke T, Lacour B, et al. Total parathyroidectomy and
delayed autotransplantation using a simplified cryopreservation
technique: Human and animal studies. Am J Kidney Dis 1984;3:366.
10. Kapur MM, Mehta SN, Moulik BK, et al. Parathyroid preservation and
transplantation. Indian J Med Res 1976;64: 1793.
II. Herrera MF, Grant CS, van Heerden JA, et al. The effect of cryopreservation on cell viability and hormone secretion in human parathyroid
tissue. Surgery 1992;112:1096.
12. Wagner PK, Rumpelt HI, Krause U, et al. The effect of cryopreservation
on hormone secretion in vitro and morphology of human parathyroid
tissue. Surgery 1986;99:257.
13. Saxe AW. The effect of phorbol ester on in vitro release of parathyroid
hormone from abnormal human parathyroid cell. Surgery 1987;102:932.
14. Brennan MF, Brown EM. Prediction of in vivo function of human
parathyroid tissue autografts by in vitro testing. World J Surg 1980;4:747.
15. McHenry CR, Stenger DB, Calandro NK. The effect of cryopreservation
on parathyroid cell viability and function. Am J Surg 1997;174:481.
16. Saxe AW, Gibson G. Lithium increases tritiated thymidine uptake by
abnormal human parathyroid tissue. Surgery 1991;110:1067.
17. Hetrakul N, CivelekAC, Stagg CA, Udelsman R. In vitro accumulation
of technetium 99m-sestamibi in human parathyroid mitochondria.
Surgery 200 I; 130:10II.
18. Goudet P, Cougard P, Zeller V, et al. Transplantation of human
cryopreserved adenomatous and hyperplastic parathyroid tissue to the
hypocalcemic nude mouse. World J Surg 1993;17:628.
19. Brennan MF, Brown EM, Spiegel AM, et al. Autotransplantation of
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20. Rothmund M, Wagner PK. Assessment of parathyroid graft function
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21. Saxe AW, Spiegel AM, Marx SJ, et al. Deferred parathyroid autografts
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Carty SE, Norton JA. Management of patients with persistent or
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Mozes MF, Soper WD, Jonasson 0, et al. Total parathyroidectomy
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Tolloczko T, Wozniewic B, Sawicki A, et al. Cultured parathyroid
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Wells SA, Gunnells JC, Gutman RA, et al. The successful transplantation of frozen parathyroid tissue in man. Surgery 1977;81:86.
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Hypercalcemia of Malignancy
and Parathyroid
Gordon J. Strewler, MD
Hypercalcemia is a relatively common complication of

malignant tumors, occurring in 5% to 10% of all cancers.
The incidence of hypercalcemia in malignancy is 15 cases
per 100,000 person-years, about one half the incidence of
primary hyperparathyroidism, 1 and it is the most common
cause of hypercalcemia in hospitalized patients.? In 1924,
Zondek and colleagues' first described hypercalcemia as a
complication of cancer, and in 1941 Albright! proposed that
hypercalcemia may be caused by humoral factors rather
than direct resorption of bone by metastatic tumor. Our
understanding of the causation and treatment of the syndrome
of hypercalcemia in malignancy has burgeoned rapidly since
1980.5.6
Clinical Syndrome of
Hypercalcemia in Malignancy
The onset of hypercalcemia in malignancy is usually rapid,
and hypercalcemia is often manifested as confusion, stupor,
nausea, vomiting, or dehydration. The offending neoplasm
is almost always evident clinically, even when hypercalcemia
is its initial manifestation. Thus, physical examination, a
chest radiograph, complete blood count, and urinalysis disclose the underlying tumor in about 98% of patients. Given
these characteristics, it is not surprising that malignancy is
the most common cause of hypercalcemia in hospitalized
patients but is a rare cause of hypercalcemia in an office
practice, which is dominated by patients with primary
hyperparathyroidism and other forms of chronic, minimally
symptomatic hypercalcemia. Because hypercalcemia usually
occurs in advanced malignancy, the prognosis is poor, with
a median survival of only 4 to 8 weeks after the discovery of
hypercalcemia.' Exceptions to this rule are breast carcinoma
and multiple myeloma. In both these disorders, successful
therapy for the underlying malignancy may provide long
survival in the hypercalcemic patient.
536
Tumors Causing Hypercalcemia

Table 61-1 shows the frequency of individual tumors in
collected series of patients with hypercalcemia. The most
common single cause of hypercalcemia is lung carcinoma.
Lung carcinomas with squamous or large-cell histology
produce hypercalcemia frequently, but small-cell carcinoma
almost never does." About two thirds of lung cancer patients
have bone metastasis when hypercalcemia develops. In the
remainder, hypercalcemia clearly has a humoral basis, usually
humoral secretion of the parathyroid hormone-related protein
(PTHrP), as discussed later. Together, lung carcinoma,
breast carcinoma, and multiple myeloma account for more
than 50% of all cases of malignancy-associated hypercalcemia. Among other solid tumors, the most common are
squamous carcinomas of the esophagus and female reproductive tract and renal carcinoma. Gastrointestinal tumors
and prostate carcinoma are less common causes of hypercalcemia. Among hematologic malignancies, hypercalcemia is
common in multiple myeloma but distinctly uncommon in
lymphomas and leukemia.
Pathogenesis of Hypercalcemia
Parathyroid Hormone-Related Protein
By far the most common cause of hypercalcemia in cancer
is secretion of a protein similar to parathyroid hormone
(PTH).5,6 The PTHrP is a distinct gene product with
sequence homology to PTH only in a limited domain at
the aminoterminal end of the molecule, where 8 of the first
13 amino acids in the two proteins are identical (Fig. 61-1).
Although tightly circumscribed, this region of homology is
critical, for the aminoterminal domain is the region required
for activation of the receptor shared by the two proteins, the
PTH-PTHrP receptor. Overall, PTHrP is 139 to 173 amino
acids long compared with the 84-amino acid PTH molecule.
Hypercalcemia of Malignancy and Parathyroid Hormone-Related Protein - - 537
The two are cousins not only structurally but also in ancestry;
shared features of gene structure and chromosomal location
indicate that their genes arose from a common ancestral gene,"
Because PTH and PTHrP share a receptor, it can be anticipated that their biologic actions and the clinical syndrome they
produce will be similar.'? Both produce humoral hypercalcemia by increasing resorption of bone throughout the skeleton and by increasing the renal resorption of calcium, and
both produce relative hypophosphatemia through a phosphaturic effect at the kidney," Most tumors that produce PTHrP,
such as squamous and renal carcinomas (see Table 61-1),
cause hypercalcemia without bone metastasis in a large fraction of cases (Table 61-2). Even in squamous and renal carcinoma patients who do have bone metastasis, the primary
cause of hypercalcemia is probably humoral secretion of
PTHrP because the serum level of PTHrP is better correlated
with the serum calcium and phosphorus than is the number
or size of bone metastases.
Overall, about 80% of hypercalcemic cancer patients have
increased serum levels of PTHrP, which can be measured in
two-site, aminoterrninal, or midregion assays (Fig. 61_2).11-15
This group includes most solid tumor patients but only a few
FIGURE 61-1. Primary structures of the

aminoterminal part of parathyroid hormonerelated protein (PTHrP) and of parathyroid
hormone. The human sequences I to 34 are
compared. Identical amino acids are highlighted.
patients with multiple myeloma, lymphoma, or leukemia.

However, one leukemia, the adult T-cell leukemia syndrome,
produces hypercalcemia in an extraordinarily high percentage
of cases (about 60%) by direct secretion of PTHrP from
malignant T Iymphocytes.ls" This is of particular interest
because the adult T-cell leukemia syndrome, which is rare
in the United States but endemic in Japan and the Caribbean
basin, is caused by infection with a retrovirus, human T-cell
leukemia-lymphoma virus (HTLV) type 1. It appears that a
protein encoded in the genome ofHTLV-1 can directly activate
transcription of the PTHrP gene in T cells. 19
It is likely that, in addition to humoral hypercalcemia,
PTHrP can produce local osteolytic hypercalcemia by direct
activation of osteoclasts in the vicinity of bone metastases.
The best example is breast carcinoma. Unlike most other solid
tumors, breast carcinoma produces hypercalcemia mainly in
patients with extensive bone metastases (see Table 61-2).
About 50% of these patients have elevated serum levels of
PTHrP,11-15 presumably indicative of humoral hypercalcemia.
However, metastases to bone are immunohistochemically
positive for PTHrP in 92% of cases compared with 17% of
nonosseous metastases." This suggests either that tumor
cells that secrete PTHrP have an advantage in bone (perhaps
because they induce local resorption) or that the bone environment induces the expression of PTHrP. In either case,
PTHrP could act locally to produce osteolysis. Transfection
of the PTHrP gene into breast carcinoma cells increases the
number of bone metastases, and animals with such metastases
are hypercalcemic but do not have increased levels of circulating PTHrp.21 On the basis of this evidence, it seems likely
that PTHrP can act as either a humoral factor or a local
osteolytic factor in breast carcinoma.
Secretion of PTHrP also causes hypercalcemia in a few
benign conditions. The best example is pheochromocytoma. 22,23 Hypercalcemia can also be a part of the watery
diarrhea with hypokalemic alkalosis syndrome produced by
tumors that secrete vasoactive intestinal peptide. Because
these are closely related to pheochromocytomas in their
histology and origin, it is likely that PTHrP will be incriminated as the cause of hypercalcemia in these tumors as well,
but this has yet to be confirmed, PTHrP is produced by the
mammary gland and appears to be associated with hypercalcemia in two benign conditions of the breast: hypercalcemia
complicating Iactation" and massive mammary hypertrophy
and hypercalcemia."

unlike PTH, the humoral regulator of calcium homeostasis,
PTHrP is a local regulator of growth and differentiation." Its
best established role is to stimulate the proliferation of chondrocytes in the growth plate and retard the mineralization of
hypertrophic cartilage. Targeted ablation of the PTHrP gene
in the mouse produced an embryonic lethal disorder characterized by short-limbed dwarfism and premature mineralization of cartilage." In postnatal life, PTHrP appears to regulate
the differentiation of skin and skin appendages" (its expression in keratinocytes probably explains the high incidence of
hypercalcemia in squamous carcinomas that originate from
this cell type). In addition, PTHrP is involved in regulation
of the mammary gland" and is secreted into milk at levels
1O,OOO-fold higher than serum levels." As a product of a variety of smooth muscle beds (vascular,31 gastrointestinal,
bladder.P uterine") that is released in response to stretch 32,33
and functions as a smooth muscle relaxant,34-36 PTHrP is a candidate for short-loop, local regulation of smooth muscle tone.
1,25-Dihydroxyvitamin D
Although PTHrP was not identified until 1983 and was

not purified and cloned until 1987, there is now little doubt
about its primary role in the causation of hypercalcemia in
solid tumor patients. Less certain, but of intense interest, is
the role of this protein in normal physiology. It appears that,
Probably the most important cause of hypercalcemia in

lymphoma is production of the active vitamin D metabolite
1,25-dihydroxyvitamin D(l,25-(OH)z-D) in lymphoma
tissue.'? About half of lymphoma patients who present
with hypercalcemia have inappropriately high serum
1,25-(OH)z-D levels. 38.39 In a few cases, lymph node tissue
from such patients has been shown to produce 1,25-(OH)z-D
FIGURE 61-2. Plasma concentrations of parathyroid hormone-related protein (PTHrP) in patients with hyperparathyroidism (HPT),
normocalcemic patients with malignancy (Normocalc), and patients with hypercalcemia of malignancy resulting from a solid tumor (Solid)
or a hematologic malignancy (Hematol). Radioimmunoassay (RIA) was used for arninoterminal PTHrP(1-34) (left), an immunoradiometric
assay for PTHrP(1-74) (middle), and an RIA for midregion PTHrP(53-84) (right). The hatched area represents the normal ranges, and the
dotted line represents the limits of detection; the numbers attached to each group indicate the number of patients. In the PTHrP(1-74) assay,
the group Solid includes five patients classified as having the local osteolytic type of hypercalcemia (delta) and two patients with lymphoma.
Note the different scales of the y axes. (Modified from Budayr AA, Nissenson RA, Klein RF, et al. Increased serum levels of a parathyroid
hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807; Burtis WJ, Brady TJ, Orloff 11, et al.
Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer.
N EngI J Med 1990;322: 1106; and Blind E, Raue F, Gotzmann J, et al, Circulating levels of midregional parathyroid hormone-related protein
in hypercalcemia of malignancy. CUn Endocrinol [Oxf] 1992;37:290.)
in vitro from 25-0HD.40 Challenge of normocalcemic lymphoma patients with the precursor sterol 25-0HD resulted
in increased serum 1,25-(OH)z-D levels, increased serum
calcium levels, and suppression of PTH.40 In contrast,
healthy individuals regulate the conversion of substrate to
1,25-(OH)z-D so precisely that virtually no abnormality of
calcium homeostasis is induced by the administration of
vitamin D. The abnormal responsiveness of normocalcemic
lymphoma patients to vitamin D indicates that the fundamental abnormality in lymphoma, unregulated extrarenal
production of 1,25-(OH)z-D, is actually more common than
hypercalcemia. As would be expected from this interpretation,
hypercalciuria is more common than hypercalcemia in lymphoma patients'? and presumably provides a compensatory
mechanism to deal with the inappropriate synthesis of 1,25(OH)z-D. In all regards, this syndrome resembles the hypercalcemia of sarcoidosis, the first proven instance of
extrarenal production of 1,25-(OH)z-D in hypercalcemia.t'v?
As in sarcoidosis, hypercalcemia in lymphoma is frequently
responsive to administration of corticosteroids.
Parathyroid Hormone
Ectopic secretion of genuine PTH from extraparathyroid
tumors, once thought to be common, is now recognized as
extremely rare. Only a few authenticated cases have been
reported,43.44 including a single case that fulfills the most
rigorous criterion for proof of ectopic hormone production:
demonstration of an arteriovenous (AV) gradient for PTH
across the tumor." Most of the tumors reported to secrete
PTH ectopically have had small-cell histology. The diagnosis
should be considered in patients with malignant tumors
(particularly small-cell tumors), hypercalcemia, and elevated
PTH levels. However, most cases meeting this definition
prove to have a malignant tumor with coincident primary
hyperparathyroidism because this coincidence is more likely
than the truly rare syndrome of ectopic PTH secretion. Thus,
exploration of the parathyroid glands is indicated in patients
with a malignant nonparathyroid tumor who require treatment for hypercalcemia, unless the malignant neoplasm can
be shown to produce PTH by immunohistochemistry or,
better, by demonstration of an AV gradient for PTH across
the tumor. The diagnosis of ectopic hyperparathyroidism has
been made to date by exclusion in patients with normal
parathyroid glands.
Prostaglandins
Once thought to be the dominant mechanism by which nonparathyroid tumors produce hypercalcemia, the production
of prostaglandins is now thought to be a rare cause of
hypercalcemia. It is not possible to give a precise incidence
or to describe a unique clinical syndrome. Nonetheless, a
few well-documented cases in which prostaglandins were
high and hypercalcemia was reversed by inhibition of
prostaglandin synthesis seem authentic."
Local Osteolytic Hypercalcemia

Local osteolysis around osseous tumors can produce hypercalcemia. The predominant mechanism involves the activation of
osteoclasts by secretion of bone-resorbing cytokines. The

list of cytokines with osteoclast-activating activity includes
interleukin-I, tumor necrosis factor o, interleukin-6, and transforming growth factor c, as well as PTHrp.47 As discussed,
there is accumulating evidence that PTHrP is the local
osteolytic factor that produces hypercalcemia in breast
carcinoma. The other classic example of local osteolytic
hypercalcemia is multiple myeloma. Although this is a
very common syndrome, with at least one third of myeloma
patients experiencing hypercalcemia at some time during
their disease, the offending cytokine has not been identified
with certainty. Cultured human myeloma cell lines produce
bone-resorbing factors that can be neutralized with antisera to
interleukin-Ijr" or tumor necrosis factor ~ (lymphotoxin)."
However, it is not clear whether either of these, or a third
factor, is responsible for the syndrome observed in patients.
Differential Diagnosis
The most important consideration in the differential diagnosis
of hypercalcemia in a patient with a malignant neoplasm is
intercurrent primary hyperparathyroidism. One clue to this
possibility is the presence of chronic hypercalcemia, especially
hypercalcemia that predates discovery of the malignant tumor.
It is important to measure the PTH level in all patients with
cancer and hypercalcemia, using a two-site assay for intact
PTH (immunoradiometric or immunochemoluminescent).
In such assays, the level of PTH is consistently suppressed
below 20 ng/L (2 nmollL) in patients with malignancyassociated hypercalcemia. I 1,50 (Older midregion and aminoterminal assays were not able to detect suppression of PTH in
patients with nonparathyroid hypercalcemia and should not be
used in this setting.) The finding of a high-normal or increased
level of intact PTH suggests the presence of primary hyperparathyroidism. In a 1994 study of 123 consecutive hypercalcemic patients, 6 (5%) had biochemical evidence of
primary hyperparathyroidism together with a malignant
neoplasm." As mentioned, true ectopic secretion of PTH is
rare, which should be considered in patients with inappropriately increased PTH levels in the presence of a malignant
neoplasm in whom a thorough exploration of the parathyroid
glands was negative.
It is probably unnecessary to measure PTHrP or 1,25(OH)z-D in all patients with malignancy-associated hypercalcemia. In the typical patient with a diffusely metastatic
solid tumor and a suppressed level of PTH, determination
of PTHrP is unlikely to change either the diagnosis or the
management. Some studies have suggested that high PTHrP
levels predict a poor response to antiresorptive therapy of
hypercalcemia, but as discussed later (under "Treatment of
Hypercalcemia"), it is not clear whether this effect is robust
enough to mandate additional laboratory testing. However,
in lymphoma patients, a determination of 1,25-(OH)z-D
may guide the subsequent treatment of hypercalcemia with
corticosteroids. Assays ofPTHrP and 1,25-(OH)z-D are also
indicated in hypercalcemic patients with suppressed PTH
levels but without an obvious malignancy.
The serum or plasma level of PTHrP can be determined
in aminoterminal.l-!" midregion," or carboxyterminal
radioirnrnunoassays (RIAs) or in two-site immunoradiometric
assays (lRMAs).52.53 Both aminoterminal RIAs and IRMA

assays for PTHrP are currently available commercially in the
United States. Although the absolute level of PTHrP is considerably higher in midregion RIAs than in aminoterminal
assays or IRMAs, all classes of assays perform similarly in
the setting of malignancy-associated hypercalcemia (see
Fig. 61-2). IRMA assays for PTHrP are highly sensitive and
specific. However, they require collection of blood in special
tubes containing protease inhibitors because proteases present in serum are capable of cleaving the PTHrP molecule at
a site that disrupts the two-site assay.
Treatment of Hypercalcemia
There are two points of attack on hypercalcemia.t'Y One is
to inhibit osteoclastic bone resorption, thus reducing the
flux of calcium into the extracellular fluid. The other is to
increase the urinary excretion of calcium, potentiating the
only homeostatic mechanism to clear an excess calcium load.
The urinary clearance of calcium is often impaired in patients
with malignancy-associated hypercalcemia. The glomerular
filtration rate is reduced both by direct effects of hypercalcemia and by the dehydration and prerenal azotemia that
result from impaired urinary concentrating ability. In patients
with PTHrP-induced hypercalcemia, the renal tubular reabsorption of calcium is also increased. Thus, the first line of
attack on hypercalcemia is usually to correct dehydration
and increase the urinary clearance of calcium by inducing a
saline diuresis. If necessary, the urinary clearance of calcium
can be greatly enhanced with the use of loop diuretics such
as furosemide together with saline infusions to induce a massive natriuresis and calciuresis. However, close monitoring of
central pressures, serum potassium, and serum magnesium
and replacement of urinary losses of fluids and electrolytes
are necessary to carry out this mode of therapy safely.
Several potent and effective inhibitors of bone resorption
are available for acute treatment of hypercalcemia. The bisphosphonate agent parnidronate disodium is administered
in a single intravenous infusion of 60 to 90 mg over 6 to
24 hourS.56. 57 Normocalcemia results in 80% to 90% of
patients, although the nadir of the serum calcium concentration is not reached until about 5 days after administration.
The efficacy and safety of pamidronate make it the agent of
first choice. The mean duration of the response is I to 2 weeks,
and patients can be retreated on relapse. Pamidronate is
considerably more potent and more effective than the older
bisphosphonate etidronate disodium, but several other new
bisphosphonates will prove equally effective. Among these,
alendronate disodium and clodronate have had extensive
trials, but neither is yet approved.
Synthetic salmon calcitonin in large doses of 200 to
800 U/day reduces the serum calcium level rapidly and is
a useful adjunct to pamidronate, whose action has a delayed
onset. However, refractoriness to calcitonin ensues within
2 to 4 days. In patients who are refractory to pamidronate
and calcitonin, the cytotoxic antibiotic plicamycin
(mithramycin) is useful. Although effective, plicamycin is
no longer considered the drug of first choice because of
its hepatic, renal, and bone marrow toxicity after repeated
administration.
PTHrP has the same hypocalciuric effect on the kidney as

PTH. For this reason, it was anticipated that patients with
high levels of PTHrP might be relatively refractory to agents
targeted to osteoclastic bone resorption. Several studies have
shown that nonresponders to pamidronate treatment have
higher serum PTHrP levels than responders. 5l ,5S,59 However,
this relationship is a weak one that has not been observed
consistently'"; most patients with PTHrP-induced hypercalcemia respond to pamidronate treatment. Thus, the finding
of a high PTHrP level should not influence the choice of
therapy. In PTHrP-induced hypercalcemia, however, it is
doubly important that aggressive measures to increase the
urinary calcium clearance be instituted.
Definitive treatment of the underlying neoplasm is also
indicated. The treatment is rarely surgical because the
cancer is usually advanced and diffuse by the time hypercalcemia supervenes. Chemotherapy of breast carcinoma,
multiple myeloma, lymphoma, and leukemia is usually successful in hypercalcemic patients. In solid tumors other
than breast carcinoma, chemotherapy is less valuable:
chemotherapy has failed in many patients before the appearance of hypercalcemia.
Summary
Hypercalcemia is a common end-stage problem in patients
with malignant neoplasms. Malignancy is the most common
cause of hypercalcemia in hospitalized patients, whereas
primary hyperparathyroidism is the most common cause of
hypercalcemia in nonhospitalized patients. PTHrP is the
most common cause of hypercalcemia in patients with
cancer. There are now PTHrP assays to quantitate PTHrP
levels. Unfortunately, there are no good means of treating
patients with malignant tumors and high PTHrP levels, and
most patients die within 8 weeks.
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19. Dittmer J, Gitlin SD, Reid RL, et a1.Transactivation of the P2 promoter
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28. Wysolmerski JJ, Broadus AE, Zhou J, et al. Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes
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31. Hongo T, Kupfer J, Enomoto H, et a1.Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells
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32. Yamamoto M, Harm SC, Grasser WA, et al. Parathyroid hormonerelated protein in the rat urinary bladder: A smooth muscle relaxant
produced locally in response to mechanical stretch. Proc Nat! Acad
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33. Thiede MA, Daifotis AG, Weir EC, et al. Intrauterine occupancy controls expression of the parathyroid hormone-related peptide. Proc Natl
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34. Winquist RJ, Baskin EP, Vlasuk GP. Synthetic tumor-derived human
hypercalcemic factor exhibits parathyroid hormone-like vasorelaxation in renal arteries. Biochem Biophys Res Commun 1987;
149:227.
35. Nickols GA, Nickols MA, Helwig JJ. Binding of parathyroid hormone
and parathyroid hormone-related protein to vascular smooth muscle of
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36. Mok LL, Cooper CW, Thompson Je. Parathyroid hormone and
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duodenal smooth muscle. Proc Soc Exp BioI Med 1989;191 :337.
37. Seymour JF, Gagel RF. Calcitriol: The major humoral mediator of
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Blood 1993;82: 1383.
38. Adams JS, Fernandez M, Gacad MA, et al. Vitamin D metabolitemediated hypercalcemia and hypercalciuria patients with AIDS and
non-AIDS-associated lymphoma. Blood 1989;73:235.
39. Seymour JF, Gagel RF, Hagemeister FB, et al. Calcitriol production
in hypercalcemic and normocalcemic patients with non-Hodgkin
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40. Davies M, Hayes ME, Yin JA, et a1. Abnormal synthesis of 1,25dihydroxyvitamin D in patients with malignant lymphoma. J Clin
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42. Stern PH, De Olazabal J, Bell NH. Evidence for abnormal regulation of
circulating 1 alpha, 25-dihydroxyvitamin D in patients with sarcoidosis
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43. Strewler GJ, Budayr AA, Clark OH, et a1. Production of parathyroid
hormone by a malignant nonparathyroid tumor in a hypercalcemic
patient. J Clin Endocrinol Metab 1993;76: 1373.
44. Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of
parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989;68:976.
45. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma. N Engl J Med
1990;323: 1324.
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47. Mundy G. Hypercalcemic factors other than parathyroid hormonerelated protein. Endocrinol Metab Clin North Am 1989;18:795.
48. Kawano M, Yamamoto I, Iwato K, et at. Interleukin-l beta rather than
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49. Garrett IR, Durie BGM, Nedwin GE, et a1.Production of lymphotoxin,
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50. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive twosite immunoradiometric assay of parathyrin and its clinical utility in
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51. Wimalawansa SJ. Significance of plasma PTHrP in patients with
hypercalcemia of malignancy treated with bisphosphonate, Cancer
1994;73:2223.
52. Burtis WJ, Brady TG, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients
with humoral hypercalcemia of cancer. N Engl J Med 1990;322: 1106.
53. Fraser WD, Robinson J, Lawton R, et a1. Clinical and laboratory studies of a new immunoradiometric assay of parathyroid hormone-related
protein. Clin Chern 1993;39:414.
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1992;326: 1196.
55. Nussbaum SR. Pathophysiology and management of severe hypercalcemia. Endocrinol Metab Clin North Am 1993;22:343.
56. Gucalp R, Ritch P, Wiernik PH, et a1. Comparative study of
pamidronate disodium and etidronate disodium in the treatment
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95:297.

58. Dodwell OJ, Abbas SK, Morton AR, et al. Parathyroid hormonerelated protein (50-69) and response to pamidronate therapy for
tumour-inducedhypercalcaemia. Eur I Cancer 1991;27:1629.
59. Body 11, Dumon IC, Thirion M, et al. Circulating PTHrP concentrations in tumor-induced hypercalcemia: Influence on the response to
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1993;8:701.
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malignancy-associated hypercalcemia on serum parathyroid
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Hiroshi Takami, MD
The most generally accepted criteria for the diagnosis of

hypercalcemic crisis include a statement about the severity
of the hypercalcemia (usually Ca >14.5 mg/dl.)! and that it is
associated with acute symptoms and signs that can be reversed
by correcting the hypercalcemia. I Primary hyperparathyroidism (PHPT) and malignancy are the main causes of hypercalcemic crisis. Hypercalcemic crisis secondary to PHPT has
been referred to in the literature as acute HPT, parathyroid
crisis, parathyroid poisoning, parathyroid intoxication,
parathyrotoxicosis, and parathyroid storm.r'' The manifestations include weakness, nausea and vomiting, drowsiness,
stupor, coma, constipation, and tachycardia.Y Severe lifethreatening symptoms and signs of hypercalcemia constitute a
"crisis," and rapid diagnosis and treatment are essential to
avoid significant morbidity or mortality? The emergency treatment of hypercalcemic crisis is the same regardless of the
cause, and an emergency diagnostic algorithm must be followed to demonstrate or rule out PHPT. Serum calcium should
be lowered during the etiologic work-up for hypercalcemia.
Earlier fluid replenishment and optimized strategies for the
intensive care of critically ill hypercalcemic patients have
made hypercalcemic crisis a rare event. to
Incidence and Etiology

of Hypercalcemic Crisis
The incidence of hypercalcemic crisis has never been determined. Bondeson and colleagues 11 reported a 10% incidence
of hypercalcemic crisis as a complication in 514 cases of
PHPT presenting between 1961 and 1988. Hypercalcemic
crisis secondary to PHPT is commonly caused by a large
parathyroid mass but may also be caused by carcinoma or
hyperplasia.>' Bondeson and colleagues, II however, reported
that the distribution of parathyroid pathology (adenoma,
hyperplasia, and carcinoma) causing hypercalcemic crisis
was the same as that of PHPT not complicated by hypercalcemic crisis. Parathyroid carcinoma is usually associated with
much higher parathyroid hormone (PTH) and calcium levels
than nonmalignant PHPT, and the incidence of hypercalcemic
crisis complicating it may be as high as 14%.12 Maselly and
coworkers" reported that 10 of 325 consecutive PHPT
patients went on to develop hypercalcemic crisis and that 9 of
the 10 patients had a single adenoma. The risk of developing

hypercalcemic crisis in untreated PHPT is low. Only 1 of a
group of 47 patients observed over a 5-year interval developed hypercalcemic crisis,'? and only 1 of 142 patients, or
0.7%, of the patients in a prospective series at the Mayo
Clinic observed for 10 years developed hypercalcemic crisis
related to PHPT. 15 Fitzpatrick- reported that age at the time
of clinical presentation of hypercalcemic crisis is the same
as or lightly lower than the average age of PHPT patients at
the time of presentation.v'v-" Other authors have reported
a wide age distribution but that most cases develop in the
sixth decade of life. 2,4 The male/female ratio (1.0:1.1) was
found to be similar to the distribution of parathyroid carcinoma"?" but markedly different from the gender ratios in
series of PHPT. 16 17
The principal causes of hypercalcemia in inpatient and
outpatient settings differ? The two most common causes of
hypercalcemia, malignancy and PHPT, are also the most
common causes of hypercalcemic crisis in hospitalized and
ambulatory patients, respectively, accounting for more than
90% of patients (Table 62-1). However, there are many
other causes of hypercalcemic crisis. In granulomatous
diseases, macrophages activated by the granuloma can
metabolize 25-hydroxyvitarnin D (25-0H vitamin D, calcidiol) to the more active 1,25-dihydroxyvitarnin D 3 (l,25(OHh
vitamin D, calcitriol) and produce endogenous hypervitaminosis D, and on rare occasions the resultant increase in
intestinal calcium absorption leads to hypercalcemic crisis,"
Less commonly, some lymphomas have been associated
with excess endogenous 1,25(OHh vitamin D production
and sometimes cause hypercalcemic crisis." The mechanism of the hypercalcemia in hyperthyroidism is a direct
stimulatory effect of thyroxine on osteoclastic bone resorption,' and hypercalcemia caused by this mechanism may
occur when young patients with hyperthyroidism are immobilized. Hypercalcemia may mask the usual hypermetabolic
signs of thyrotoxicosis and make the hyperthyroidism more
difficult to diagnose.
The most common cause of hypercalcemia in inpatient
settings is malignancy.P There are three separate syndromes
in which malignant tumors can result in life-threatening
hypercalcemic crisis: a syndrome of humoral hypercalcemia
caused by endocrine and paracrine mediators, a syndrome of
543
hypercalcemia associated with localized osteolytic disease,

and a syndrome of hypercalcemia associated with multiple
myeloma and related hematologic malignancies. Humoral
hypercalcemia of malignancy (HHM) results from elaboration
of a bone-resorbing substance by the tumor, most often PTHrelated polypeptide (PTHrP). This 146-amino acid polypeptide is homologous to PTH in 8 of its first 13 aminoterminal
residues, and it binds to the PTH receptor and produces the
same hypercalcemic effects as PTH on end-organs: bone,
gut, and kidney." Because PTHrP is secreted by solid malignancies in a manner that is not subject to the feedback regulation by serum calcium that occurs with PHPT, PTHrP
secretion may cause an unrelenting hypercalcemic state.
Humoral mediators of hypercalcemia in malignancy lead to
increases in bone resorption by increasing osteolytic activity, and they probably also lead to complex disturbances in
calcium homeostasis in the kidney and gut. Solid tumors of
the lung, head, neck, kidney, pancreas, and ovary are often
associated with humorally mediated hypercalcemia and produce factors, including PTHrP, that are potent activators of
osteoclastic bone resorption and cause hypercalcemia in vivo.?
Hematologic malignancies, most notably multiple myeloma,
secrete a number of cytokines, which act locally in the bone
marrow to stimulate osteoclastic bone resorption.'
Clinical Features
of Hypercalcemic Crisis
A serum calcium level of 14.5 mg/dL or higher must generally be considered a medical emergency, and most patients
are symptomatic." Nevertheless, because relatively asymptomatic patients with a serum calcium of 20 mg/dL, and
even patients with levels below 14.5 mg/dL, have presented

in hypercalcemic crisis," the serum calcium level should
not be the sole marker used to define hypercalcemic crisis. 1
The severity of the hypercalcemia is usually proportional to
the increase in PTH level. 9 The serum PTH level of patients
in hypercalcemic crisis is almost always at least twice the
normal level, and as many as 40% to 50% have a palpable
mass on physical exarnination.s-"
Mild to moderate hypercalcemia may be manifested only
by anorexia, malaise, weakness, osteoporosis, and kidney
stones. When these manifestations develop slowly, as they
do in many mildly hyperparathyroid patients, their presence
may be recognized only retrospectively, after parathyroidectomy,?26 Hypercalcemia causes anorexia, polyuria, nausea,
and vomiting, and the resultant dehydration may be profound."
Isolated components of the syndrome are often nonspecific
and observed in many other diseases,'? but the simultaneous
presence of several of these components strongly suggests
hypercalcemia.
The renal symptoms of hypercalcemic crisis are polyuria
and polydipsia. The neurologic symptoms are less characteristic and include depression, anxiety, and psychosis.
Gastrointestinal symptoms are nausea, vomiting, constipation, peptic ulcer, and pancreatitis. Gastric acid secretion
and pancreatic enzyme secretion are increased.!" Cardiac
symptoms also are nonspecific. A shortened QT interval and
tachycardias may be observed. The mechanism of hypertension attributable to PHPT is unclear,'? Hypercalcemic crisis
is a constellation of the preceding signs and symptoms,
including psychological disturbances (ranging from drowsiness to stupor to coma), renal insufficiency, and cardiac
dysrhythmias (bradyarrhythmias, bundle branch blocks,
complete heart blocks, and cardiac arrest)." (The preceding
signs and symptoms are mild and usual, but the signs with
italic letters are severe and not common.) Hypercalcemia of
malignancy must be considered in cases with a history of,
for example, breast cancer, in women, and lung cancer or
myeloma, in both sexes.'?
Diagnosis
A complete history and physical examination and a review
of the medical records are the most important elements in
the emergency diagnosis of hypercalcemic crisis." Patients
with PHPT rarely experience hypercalcemic crisis, and those
who do usually have a long-standing history of progressive
symptoms of hypercalcemia. Most patients presenting with
hypercalcemia secondary to malignancy have an antecedent
diagnosis of malignancy, and many are already hospitalized
when severe hypercalcemia develops.
A serum calcium assay should be performed in all patients
who present with psychological disturbances, renal insufficiency, cardiac dysrhythmias, and neurologic abnormalities,"
The most accurate and useful laboratory test for ruling
out hypercalcemia is the ionized calcium assay," but most
hospitals measure total serum calcium (ionized plus proteinbound calcium) unless the ionized calcium level is requested.
If an ionized calcium assay is not available, total serum
calcium may be measured and the value corrected for the
measured albumin level.
Hypercalcemic Crisis - -
The most specific laboratory test in the differential diagnosis of hypercalcemia is the serum intact PTH assay?"
An increased intact PTH level and calcium level are almost
pathognomonic of HPT. Before the radioimmunoassay for
intact PTH became available, the PTH assays in common
use measured the PTH C-terminal or midregional fragment."
Although detection of an elevated intact PTH level is a
useful means of diagnosing PHT, the test usually takes a few
days to complete and is of no immediate use in the management of hypercalcemic crisis. The quick intact PTH assay
developed by Irvin and colleagues," however, has allowed
rapid differential diagnosis of hypercalcemic crisis. It is an
immunochemiluminometric assay and has a turnaround time
of only 10 minutes." Conditions besides PHPT in which the
intact PTH level is increased include hypocalcemia, secondary
HPT (with low to low-normal serum calcium), and tertiary
HPT (with normal to increased serum calcium) after a history
of long-standing renal insufficiency? The intact PTH levels in
patients with secondary HPT are characteristic of the patientto-patient variability of the half-life of intact PTH and its
molecular heterogeneity and biphasic metabolism.P-"
Hypercalcemia secondary to malignancy occurs in
patients whose diagnosis of malignancy is already established.' Most patients who present with nonparathyroid
hypercalcemia have malignant disease. It is important to
establish whether the patient has HHM or skeletal metastases. Hypercalcemia develops before death from the malignancy in 30% of patients with carcinoma of the breast, 10%
of patients with squamous cell carcinoma of the lung, and
smaller percentages of patients with carcinoma of the esophagus, skin, kidney, pancreas, liver, colon, and ovary.v'"
Reliable assays for PTHrP are now available, but it takes
several days to obtain the results, and they cannot be relied
on as an adjunct to the emergency management of hypercalcemia.? If the PTHrP levels are low, other osteolytic factors
may be produced by the tumor, and other cases are associated
with the production of interleukin-l, -6, or -11; transforming
growth factor a or ~; interferon; or granulocyte-macrophage
colony-stimulating factor. 10
Paraneoplastic production of ectopic PTH is extremely
rare.32 If familial hypocalciuric hypercalcemia (FHH) is
suspected, an above-normal 24-hour urine calcium or a calcium clearance-to-creatinine ratio greater than 0.01 in patients
who have never been documented to be normocalcemic
rules out FHH. I The serum 25-0H vitamin D level may be
checked if excessive vitamin D intake is suspected. The
serum 1,25(OHh vitamin D level is high normal or mildly
elevated in patients with PHPT. A cost-effective and accurate diagnosis of HPT can be made by documenting
increased calcium and intact PTH levels in patients who are
not hypocalciuric.
545
Maternal PTH levels increase to enhance gastrointestinal

absorption of calcium during pregnancy," thereby facilitating placental transport of calcium to the fetus. The degree of
hypercalcemia, however, may be blunted by the physiologic
hypoalbuminemia of pregnancy. Some of the criteria used to
make the diagnosis of hyperparathyroidism in nonpregnant
patients should be adjusted (i.e., lower calcium and higher
PTH levels should be used) because of the physiologic
increase in maternal PTH levels associated with pregnancy
and the normally depressed maternal calcium levels.
The maternal hypercalcemia accompanying maternal
HPT depresses fetal parathyroid function." After birth, the
neonate no longer has access to maternal serum calcium and
is unable to mobilize calcium adequately from bone because
of depressed parathyroid function, resulting in a risk of
neonatal tetany. The pregnant woman, in tum, is at risk for
hypercalcemic crisis. Placental delivery of calcium to the
fetus is greatest during the third trimester and is protective
for the mother.P:" Because this protection is lost with the
delivery of the child, the neonate is at greatest risk for tetany
several hours after delivery, and the mother is at greatest risk
for hypercalcemic crisis during the same period.F'"
The incidence of fetal complications has been reported
to be 53% for treated mothers 35 ,40 and 80% for untreated
mothers.f 27% to 31% of whose infants die in the neonatal
period. 35,40 Other complications include intrauterine growth
restriction, low birth weight, preterm delivery, and intrauterine fetal demise. 3335,40-42 Postpartum neonatal hypocalcemic
tetany has been reported to occur in 50% of infants born
to untreated mothers," The diagnosis of HPT in pregnant
patients is most commonly made postpartum when the infant
develops neonatal tetany.'?
If hypercalcemia is not controlled medically, parathyroidectomy by an experienced surgeon should be
recommended despite advanced gestation.'? Urgent parathyroidectomy using improved technology is the best option, even
in late gestation. Developments in surgical technology have
greatly improved the safety of parathyroidectomy.P'P
Innovations such as the intraoperative quick PTH assay," sestamibi scintigraphy/<" and radioguided parathyroidectomy'"
have allowed the development of minimally invasive parathyroidectomy, and several investigators have reported high success rates using these techniques, with reductions in incision
length, operation time, and length of hospital stay in nonpregnant patients with PHPT.43-45,49 These methods may not
be used in pregnant women, but they offer the theoretical
advantage of maximizing surgical efficacy while minimizing invasiveness and operation time. 50,5 1 An alternative
option is medical control, such as with bisphosphonates and
calcitonin. The diagnosis and management of this condition
are imperative because it poses a significant risk to the
mother as well as the fetus.
in Pregnancy
Treatment
PHPT associated with pregnancy is a rare condition.Pr"

Although the exact incidence of PHPT during pregnancy is
unknown, the incidence of PHPT in women of childbearing
age is estimated to be approximately 8 cases per 100,000
population per year."
The first step in the management of hypercalcemic crisis is

to lower the serum calcium level and then identify its etiology. Therapy must be directed toward increasing the urinary
excretion of calcium and decreasing bone resorption.l"
Increasing renal calcium excretion in hypercalcemic crisis

by means of hydration and loop diuretics (furosemide)
is quicker and easier than decreasing bone resorption
(Table 62-2).1 Immediate therapy must achieve as rapid and
complete volume reexpansion as practicable.' Intravenous
infusion of normal saline is indicated to promote renal calcium
excretion and restore cardiovascular function. 52 A 500-mL
intravenous bolus of normal saline should be administered
initially," and the patient's volume status should be monitored for adequate replenishment and to avoid fluid over10ad.1 Usually the goal should be 2 to 8 L per day, and when
the kidneys have begun to respond to rehydration, a loop
diuretic may be administered to accelerate calciuresis.P
Loop diuretics have a profound effect on sodium and water
excretion.> Lower doses stimulate natriuresis, which is
accompanied by calciuresis,'? but if sodium excretion
exceeds the rate of replacement with intravenous normal
saline, renal sodium-conserving mechanisms are activated,
limiting calcium excretion and exacerbating the hypercalcemia." A direct calciuretic effect of loop diuretics can be
expected at high doses of 100 mg/hour.S' and aggressive
fluid hydration in combination with loop diuretics is effective in lowering serum calcium by 1.5 to 2.0 mg/dL in 24 to
48 hours.' Many patients with hypercalcemic crisis and
patients with hypercalcemic crisis with intercurrent cardiac
or other illnesses require admission to the intensive care unit
for cautious monitoring of vital signs, central venous pressure, urine output, and serum and urine electrolyte levels.
It is reasonable to administer moderate doses of loop diuretics to older patients with mildly impaired cardiovascular
function when there is concern about volume overload.>'
Thiazide diuretics should not be used because they increase
distal tubular reabsorption of calcium and may exacerbate
the hypercalcemia." The routine approach, saline solution
administration, is ineffective in patients with severely
impaired renal function, and hemodialysis against a zero or
a low calcium dialysate concentration may be necessary."
Some cases of hypercalcemia caused by HPT are refractory to hydration and diuresis, and inhibitors of osteoclastic
bone resorption are indicated when a 24- to 48-hour period
of treatment has failed. However, in most patients with HPT,
administration of normal saline and loop diuretics may be
the only treatment necessary before parathyroidectomy."
Parathyroidectomy is the definitive treatment for PHPT and
should not be delayed when a patient in hypercalcemic crisis
has recovered in response to treatment. Ultrasonography is
essential as a preoperative localization test and is generally

positive in patients with hypercalcemic crisis because the
parathyroid masses of such patients are usually large.
However, sestamibi scintigraphy is available if localization
of the parathyroid mass is not definitive. Computed tomography and magnetic resonance imaging are more expensive
and less accurate. The intraoperative quick PTH assay biochemically confirms that adenomas have been completely
excised.P-" Radioguided parathyroidectomy, which can be
quickly performed by a significantly less invasive procedure,
has been developed.f
When initial therapy has been instituted, administration
of inhibitors of osteoclastic bone resorption should be
considered.' The agents available to inhibit bone resorption include bisphosphonates, calcitonin, plicamycin
(mithramycin), glucocorticoids, and gallium nitrate.' The
choice of agent should be based on the etiology of the
hypercalcemia, the pharmacodynamics of the agent, its
onset and duration of action, the route of metabolism, and
potential side effects.l-' Administration of bisphosphonates
should be considered early in patients with HHM.
Bisphosphonates are chemical analogs of pyrophosphate
and directly inhibit osteoclast function. Available agents are
etidronate, clodronate, pamidronate, and ibandronate.!? and
each member of the bisphosphonate family appears to have
its own mechanism of osteoclast inhibition.r' The advantage
of the more potent bisphosphonates is the ability to use
smaller doses, which means a shorter infusion time. 54
Ibandronate can even be administered as a bolus to patients
with normal renal function. Bisphosphonates provide a
slower onset of action and longer duration of effectiveness,
and because they are poorly absorbed when administered
orally, intravenous administration is necessary. Multiple
infusions of the second-generation bisphosphonate
pamidronate (Aredia) in conjunction with volume replenishment may decrease the serum calcium level to the normal
range within 7 days in about 75% of patients with hypercalcemia of malignancy.-S" Pamidronate therapy may be complicated by mild hyperthermia, gastrointestinal symptoms,
hypophosphatemia, hypokalemia, and hypomagnesemia.
Pamidronate is a more potent and possibly less toxic bisphosphonate than etidronate, a first-generation bisphosphonate
that is often used in the treatment of Paget's disease of bone.
Calcitonin (salmon, human) is a polypeptide secreted
by the C cells of the thyroid and is a potent inhibitor of
Hypercalcemic Crisis - -
osteoclastic bone resorption. In pharmacologic doses, it

promotes calciuresis." and its hypocalcemic effect is the
most rapid among the agents, occurring within 2 hours of
dosing in most patients, and is sustained for up to a week."
This early loss of effectiveness has been termed the "escape
phenomenon" and may be overcome by concomitant use of
glucocorticoids.V'" The escape phenomenon during continued treatment with calcitonin is thought to result from
downregulation of calcitonin receptors on the surface of
osteoclasts.?' Calcitonin is best used as adjunctive therapy
with other antiresorption agents or calciuric agents. 1,3,54
Combining the rapid hypocalcemic effects of calcitonin with
the more delayed effect of a bisphosphonate is a reasonable
approach to patients in severe hypercalcemic crisis. 62-6s The
onset of the antihypercalcemic effect is observed within
2 hours after combination therapy consisting of a single
intravenous injection of pamidronate and serial intramuscular
injections of calcitonin, and the effect is of sufficient duration
(Fig. 62_1).64,65 Pamidronate and calcitonin do not interfere
with each other, and their combined use to treat hypercalcemia is rapid, effective, and safe. It is an aid to the safe
performance of surgery in PHPT patients, appears to be useful
in improving quality of life, and is therapeutically effective in
patients with malignancy-associated hypercalcemia.
Plicamycin (mithramycin), a compound produced by
Streptomyces microorganisms, inhibits osteoclast RNA
synthesis." It was of great utility in the prebisphosphonate
period but is hardly ever needed today because of the availability of the highly potent bisphosphonates.'? It has a spectrum of severe side effects (hepatotoxicity, nephrotoxicity,
and thrombocytopenia).
547
Glucocorticoids are effective in the treatment of hypercalcemia secondary to vitamin D or A intoxication, hyperthyroidism, and granulomatous diseases, but they function by
decreasing calcium absorption from the gut, and several
days may be required before their full therapeutic effect is
realized."
Gallium nitrate appears to act by inhibiting osteoclast
function, but its exact mechanism of action is unknown, S4 Few
clinicians are familiar with the drug, and because it is nephrotoxic, gallium is generally reserved for cases of hypercalcemia that have not responded to one of the other available
agents."
Intravenous phosphate lowers serum calcium by promoting

its deposition in bone and soft tissues but may have serious
adverse effects, including extraskeletal calcium deposition?
Summary
Hypercalcemic crisis is a reversible, curable, life-threatening
disorder. If proper treatment is not initiated promptly, rapid
progression to death may occur. The most common cause of
hypercalcemia in hospitalized patients is malignancy,
whereas PHPT is the most common cause in ambulatory
patients. Emergency treatment is the same regardless of the
cause of the hypercalcemia and consists of fluid administration and promotion of calciuresis with normal saline and loop
diuretics. Other agents, such as bisphosphonates and calcitonin, may be added later. Parathyroidectomy by an experienced surgeon after fluid replenishment and initial lowering
of the serum calcium level is the only effective treatment of
PHPT. Patients in hypercalcemic crisis should be treated in
intensive care units.
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FIGURE 62-1. Changes in corrected serum calcium levels after

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Parathyroid Carcinoma
Kerstin Sandelin, MD, PhD
Malignant transformation of a parathyroid gland is a truly

rare phenomenon, and in most reported series of patients
with primary hyperparathyroidism (PHPT) the incidence of
carcinoma is less than I %. The inability to distinguish
between some benign and malignant neoplasms still remains
an important problem. Furthermore, the clinical course of
malignant parathyroid tumors is quite variable. It is not
uncommon to ascertain the diagnosis only after the tumor
recurs locally or distant metastases develop. There are a
few collective reviews and series from major cancer and
endocrine surgical centers in which both clinicians and
pathologists have presented data. I -5 Still, our knowledge
about this unusual tumor has not increased much, and the
treatment modalities are limited. Surgical excision remains
the only potential method of curing this tumor, providing it is
locally resectable. With the introduction of bisphosphonates,
symptomatic, nontoxic, short-term palliation became available. In this chapter, the characteristic features of parathyroid
carcinoma are emphasized, including its mode of presentation, clinical course, histopathologic findings, and biologic
characteristics. Treatment options are discussed.
Incidence and Prevalence

The incidence figures have not actually been affected since
the introduction of autoanalyzers. As PHPT is no longer rare
and is frequently diagnosed biochemically, the relative incidence of carcinomas has fallen because the majority of
malignant cases present with symptomatic hypercalcemia
(Table 63-1). Centers that have reported a higher incidence
in the past may have had a selection bias as a result of being
referral centers. The current exceptions are the Japanese
centers that report a 10-fold higher incidence rate," for
which epidemiologic factors may be responsible as well as
infrequent screening for hypercalcemia. Familial segregation
of parathyroid carcinoma is described in isolated familial
hyperparathyroidism (HPT) and in association with multiple
endocrine neoplasia (MEN) type 1.7-12 In two such independent families, no MEN I genetic deletions were
found.l-'? The hyperparathyroidism-jaw tumor syndrome
(HPT-JT), an autosomal dominant disorder, encompasses
fibro-osseous lesions of the mandible and maxilla including
uniglandular benign and malignant parathyroid neoplasms.
Previous radiation to the neck region associated with parathyroid carcinoma has been reported, although the association of
radiation-induced benign tumor formation is more common.P
Concomitant benign and malignant parathyroid tumors can
occur." Gender and age have not proved to have predictive
value because parathyroid carcinoma equally affects both
genders and the peak age of diagnosis in the fifth decade of
life is only slightly younger than that for patients with
benign HPT.4,15-17
The differential diagnosis between severe benign HPT and
parathyroid carcinoma is difficult. Therefore, every case
involving the rapid onset of symptoms of HPT should be
considered suspect for carcinoma. The target organs for
HPT-induced hypercalcemia are the skeleton (40% to 70%),
the kidneys (30% to 60%), and to a lesser extent the digestive
system (i.e., pancreas and stomach-duodenum) (15%). In
addition, general symptoms such as nausea, anorexia, constipation, polydipsia and polyuria, muscle weakness, fatigue, and
depression are common findings. A palpable cervical mass is
encountered in approximately 5%.10,15.17-20 Marked hypercalcemia, low serum phosphorus if renal function is not impaired,
and a substantial elevation of serum parathyroid hormone
(PTH) are common findings. With today's assays, which measure intact PTH, the diagnosis of PHPT is quickly established, and hypercalcemia caused by other malignancies can
be ruled out. Moreover, there is no evidence that PTHrelated peptide (PTHrP) regulates serum calcium levels in
adults, although PTH and PTHrP have a similar sequence of
amino acids near the aminoterminus." Nonfunctioning
parathyroid carcinomas, with a normal serum level of PTH,
do occur but only in 5% of all parathyroid carcinomas."
Localization Studies
As discussed in Chapter 46, localization studies are rarely
ever necessary in primary operations for PHPT, whereas
they are usually considered mandatory in reoperative cases
regardless of the cause of the lesion. Doppman-' and Kaplan
and colleaguesf rightly argued that the best localization
549
procedure is to find an excellent parathyroid surgeon.

Ultrasonography, computed tomography (CT), magnetic resonance imaging, and scintigraphy with thallium or sestamibi
all are highly efficient in the hands of a skilled operator.
An additional advantage of ultrasonography is that it can be
used during the operation, when it can relate the tumor to
adjacent anatomic structures. For localization of recurrences
or metastatic spread, a CT scan of the mediastinum, lungs,
and abdomen may be of value in detecting mediastinal, lung,
and liver metastases. Selective venous sampling for PTH,
including distant samplings of iliac veins, may even detect
remote lesions." In combination with any of the noninvasive
techniques, it regionalizes the area of maximum secretion
of PTH. A previous thyroid lobectomy affects the venous
drainage and should be considered in evaluating the results
of the venous sampling.P
Operative Findings and

Histopathologic Characteristics
Some macroscopic features are valuable in the intraoperative
assessment of a potentially malignant tumor. These include
color and findings by palpation. A grayish white tumor that is
hard and grossly adherent to adjacent structures is highly suggestive of malignancy. Nonetheless, in a series of 95 cases of
parathyroid carcinoma collected from centers with much experience in endocrine surgery, there was no correlation between
macroscopic and microscopic findings. Invasiveness was
recorded at histopathologic re-evaluation in only half of the
tumors- Twenty percent of the patients were initially operated
on for a benign diagnosis. Other studies have also confirmed
the discrepancies in the gross appearance of the lesions."
Glandular weight is more likely to be prominent, but again size
alone cannot discriminate between benign and malignant
tumors. The median glandular weight, available for evaluation
in 35 of 95 cases, was greater than 4 g (range, 1 to 40 g).2
A major reason for the differences in incidence among
centers can be the histologic criteria used. This has probably
led to overdiagnosis of carcinoma in some series. 26-28 If only
variables such as invasive growth pattern and metastases are
used, the incidence is lower. Of 20 patients of Smith and
Coombs,' at least 5 had no evidence of local infiltration,
recurrence, or metastases. In Shane and Bilezikian's review,

10 of 62 patients did not have these findings of malignancy.t-'
In the previously mentioned series of 95 cases, presence or
absence of local infiltrative growth pattern and metastases
were used as absolute diagnostic criteria.' Two distinct groups
could be separated. Fifty-six cases fulfilled these criteria,
and 39 were called equivocal because these findings were
absent. In the latter group, the tumors exhibited combinations
of features such as fibrous bands, trabeculae, cellular atypia,
and mitotic figures. None of these recurred during a median
follow-up of 7 years (range, 0 to 22 years).
In a second study, a more detailed histopathologic evaluation was undertaken, and a cytometric assessment of the crude
DNA content of the tumor cell nuclei was also performed."
There were significant differences between the carcinomas
and the equivocal tumors in that the carcinomas predominantly showed a solid growth pattern with marked fibrosis.
Even acinar and follicular structures were noted in tumors
that eventually recurred. Among the cytologic features, the
carcinoma cells were markedly atypical with macronucleoli
(Fig. 63-1). These cells showed great variations in size and
shape. In one third of the tumors that metastasized, no nuclear
atypia could be demonstrated. Mitotic rate as a cell cycle
marker has been one of the classic features for diagnosing
parathyroid carcinoma. There was a significant difference in
mitotic rate between carcinomas and the equivocal cases. Also,
metastasizing tumors had a significantly elevated mitotic rate
compared with nonrecurrent invasive tumors. Nevertheless, in
20% of the carcinomas, no mitosis was found in available
sections analyzed. Necrosis has not been frequently
described previously but was found in 30% of the carcinomas.
In Table 63-2, a comparison of the histologic and cytologic
features for both tumor groups is given. The aggressiveness
of the tumors correlated with the histocytologic appearance,
whereas nuclear atypia, necrosis, and mitotic activity were
more frequent in metastasizing tumors than in invasive but
nonrecurrent tumors.
Biologic Markers
Parathyroid cells are characterized by very low turnover.
Parfitt proposed a model of tumor formation starting from a
Parathyroid Carcinoma - - 551
FIGURE 63-1. Histologic section from a parathyroid carcinoma with

enlarged nuclei and macronucleoli. (From Bondeson L, Sandelin K,
Grimelius L. Histopathological variables and DNA cytometry in
parathyroid carcinomas. Am J Surg Pathol 1993;17:825.)
set-point mutation leading to cell proliferation. Further mutational events that occur in the cell cycle can cause tumor
formation that is either benign or malignant.30
An altered DNA content (i.e., nondiploid) has been associated with a proliferative state of the tumor as a result of
genetic instability. It is considered one of the earliest cellular events during malignant transformation. Numerous studies have demonstrated a relationship between the DNA
content of the tumor cell nuclei and the clinical outcome.
Patients with diploid tumors fare better than those whose
tumors contain an aberrant crude DNA content.J!-34 The
ploidy pattern remains stable during tumor progression, as
has been shown in studies of primary tumors and metastases. Quantitative DNA assessments have been performed
in parathyroid carcinomas, and contradictory results were
obtained.2.9.27.29.35-43 In the series of 95 cases, there was a
clear association between an aberrant DNA content and an
infiltrative growth pattern. The clinical course, measured as
freedom from disease, also correlated with the DNA content. 2
When the DNA content was related to morphologic and
cytologic features, significant associations were found
between aberrant DNA values and the presence of necrosis,
nuclear atypia, and mitosis."
The proliferative activity, measured as percentage of
cells in S phase, was significantly higher in a group of
15 parathyroid carcinomas compared with 31 normal and
benign tumors.t? A number of cell cycle markers such as
mitotic figures have been used to assess the malignancy
potential of parathyroid tumors. The cellular phosphoprotein
p53 is a cell cycle regulator, and its role is to inhibit the

progression of cells from G[ to S phase. Mutations of the
p53 gene are common in human malignancies. However,
neither benign nor malignant parathyroid tumors have been
found to have p53 mutations." The parathyroid adenomatosis
1 gene (PRADlIcyclin Dl) encodes a protein closely associated with the cyclins that are important cell cycle regulators.
Approximately 5% of benign parathyroid tumors have
shown rearrangements of the PTH gene and PRADJ on chromosome 11.45.46 The same group of investigators reported
that the retinoblastoma tumor suppressor gene RB, also a
cell cycle regulator, was inactivated in parathyroid carcinomas. This was further supported by loss of expression, as
determined by immunohistochemical staining. Conversely,
benign parathyroid neoplasms showed no inactivation or
loss of expression of RB.47 Frequent chromosomal imbalances
were found in a series of 29 carcinomas studied with comparative genomic hybridization." The gene encoding HPTJT is a tumor suppressor gene called PARAIBROMIN, and
its location is mapped to lq21-q32. There is reduced penetrance in females, and only 10% to 15% of patients manifest
with a parathyroid carcinoma although serum calcium is
markedly elevated." Two articles have reported the presence
of somatic and gerrnline mutations of the HRPT2 gene in
sporadic parathyroid carcinoma.v-"
Treatment Modalities
Patients with parathyroid carcinoma frequently present with
symptomatic hypercalcemia. They need prompt treatment
and correction of renal and cardiac dysfunction because of
the metabolic consequences of the high serum calcium
levels. Rehydration with saline and additional electrolytes,

including magnesium, restores glomerular function and
increases urinary excretion. Loop diuretics also increase urine
calcium secretion, provided that the patient is well hydrated.
Calcitonin is an osteoclast inhibitor and promotes urinary
calcium excretion. Its duration is short, waning after 48 to
72 hours of use. For preoperative treatment, however, a longer
acting regimen is not always necessary. Plicamycin is an
effective, short-acting osteoclast inhibitor that can be administered repeatedly. Its disadvantage is potential toxicity and
patients' inability to tolerate adverse reactions such as nausea
and vomiting. Phosphate, as either an oral or an intravenous
compound, is effective in lowering serum calcium levels but
is also poorly tolerated because of gastrointestinal side effects,
and it can cause severe calcification in soft tissues when used
intravenously.
The bisphosphonates are pyrophosphate analogs and potent
osteoclast inhibitors by inhibiting bone resorption when binding to hydroxyapatite. They also act as direct inhibitors of
the formation of osteoclasts. 48,50.51-53 Three bisphosphonates
are available at present, pamidronate, etidronate, and
clodronate. The three compounds vary slightly in their mechanisms of action with regard to the effect on bone mineralization. Pamidronate is the most potent agent and causes
a reduction in serum calcium levels within 24 to 48 hours.
In patients with impaired renal function, repeated doses over
2 to 4 days may be given. Etidronate and clodronate also
exist as oral compounds but are poorly absorbed. For prolonged use, clodronate can be given initially as an infusion
with an expected effect after 2 to 5 days and then administered orally. No series have compared the effect of the
various types of bisphosphonates in parathyroid carcinoma,
but Ralston and colleagues showed in a small series that
pamidronate had the longest median time to relapse, 23 days,
compared with 12 days for the other two in cancer-associated
hypercalcemia.v-" Only anecdotal reports on treated
parathyroid carcinoma patients exist. With an initial good
response and few side effects, however, the bisphosphonates
are the preferred antihypercalcemic drugS.25,42.52,53 Gallium
nitrate is a radionuclide that also has antineoplastic properties,
and it lowers serum calcium levels by inhibiting bone resorption. Its effect on parathyroid carcinoma is limited to a few
cases reported in the literature. WR 2721 acts by inhibiting
PTH secretion, but, as with gallium nitrate, the experience is
limited. 5355
It is highly unlikely that radiation therapy or different kinds
of chemotherapy are of any benefit to patients with recurrent
disease. Nonetheless, each case should be assessed individually because responders to either therapeutic modality have
been described.V"
In approximately 20% of all primary operations, the
diagnosis of parathyroid carcinoma was not expected either
preoperatively or during the procedure.s" Nevertheless, the
initial neck exploration is the most crucial time for achieving
adequate local excision. The tumor should be excised en bloc
with any locally invaded tissue such as a contiguous ipsilateral thyroid lobe. Capsular rupture must be avoided. Under
no circumstances should an open biopsy be performed on a
suspicious parathyroid tumor during an operation. Even rupture of a benign parathyroid tumor may cause future problems. It may be very difficult to differentiate benign tumor
seeding (parathyromatosis) from carcinoma.V'" If the tumor
looks suspicious for carcinoma, it should be regarded as such

until proved otherwise. Wider excisions and prophylactic
neck dissections do not improve the prognosis.F" Lymph
node metastases are uncommon, but any enlarged nodes in
the ipsilateral central compartment should be excised. The
recurrent laryngeal nerve has only rarely been infiltrated by
tumor growth. Therefore, a careful dissection of the nerve is
worthwhile unless it was proved dysfunctional preoperatively.
Recurrent Parathyroid
Carcinoma
The cervical region is by far the most common site for
implants and local metastatic disease. However, parathyroid
carcinoma does metastasize distantly, predominantly to the
lungs, the liver, and the skeleton. Before any reoperative
procedure, a careful study of previous operative notes to
determine the initial location of the tumor and that of the
other glands is recommended. Also, any previous archival
tumor sections should be reviewed because the initial diagnosis may be incorrect. Time to recurrent disease is variable.
In a series of 40 patients with metastatic disease, the median
time to recurrence was 33 months (range, 1 to 228 months ).16
An aggressive surgical approach to recurrent diseases is
often beneficial to the patient, and even repeated surgical procedures such as wedge resections for lung metastases are indicated. Surgical excision of metastatic lesions has been the
single most effective treatment in palliating hypercalcemia. 16,42
For the histopathologic evaluation, it is advisable to obtain
multiple sections. Whenever possible, some tumor tissue
should be snap frozen in liquid nitrogen and stored at -70 0 C.
This allows some of the molecular studies that still require
fresh frozen tumor tissue. The technical considerations for
reoperative HPT are outlined in another chapter.
Prognosis
Patients with parathyroid carcinoma represent a heterogenous
group. Some patients are "cured" for as long as a decade or
more, whereas some with aggressive tumors experience recurrence early, with both local and distant spread. Of 40 patients
with metastatic disease monitored over a median period of
7 years, 20 (50%) were still alive after 5 years and 14 (35%)
after 8 years." Lifetime monitoring of patients with parathyroid carcinoma, with periodic measurement of serum calcium
levels, is therefore advised. On the basis of histopathologic
findings and biologic markers such as DNA ploidy and
S phase, additional information about the prognosis can be
obtained. With the rapid developments in molecular biology
and cytogenetics, there is still hope for the development of
discriminating markers and specifically designed anticancer
drug therapy that might reduce the need for repeated surgery,
with its associated morbidity.
Summary
Parathyroid carcinoma is the least common malignancy
among endocrine tumors. It varies in malignant potential
Parathyroid Carcinoma - - 553
from a minimally invasive local tumor with slow progression to an aggressive tumor with hematogenous metastasis
and a rapid course, often with a fatal outcome because of
unremitting hypercalcemia. The histopathologic pattern of
these tumors more often shows prominent nuclear atypia,
frequent mitosis, and an aberrant ploidy pattern with chromosomal rearrangements compared with benign parathyroid
neoplasms. Recognition by the surgeon that the parathyroid
tumor is malignant and performance of an adequate en bloc
removal of the primary lesion, when appropriate, offer the
best chance of local cure for a patient with this unusual
malignancy.
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Surgical Embryology and

Anatomy of the Adrenal
Glands
Raducu Mihai, MD, PhD, MRCS John R. Farndon, BSc, MD, FRCS
The adrenal glands were first described in 1552 by
Bartholomaeus Eustachius in his Opuscula Anatomical as
"glandulae renis incumbentes" (glands lying on the kidney).
His work was printed again in 1722 by Lancisus, long after
Galen, da Vinci, and Vesalius failed to recognize their existence.? In 1629, Jean Riolan of Paris introduced the term
capsulae suprarenales, which persisted for many years.?
Their function remained controversial for the next 300 years.
In 1716, the Academie des Sciences de Bordeaux offered a
prize for the answer to the question "What is the purpose of
the suprarenal glands?" but no progress was achieved. In the
18th century, Edward Home thought that they "form a reservoir in which some other substance is laid up in store, till
wanted.'? In 1805, Cuvier defined the anatomic division into
a cortex and a medulla" without suggesting any functional
role of the adrenals.
In 1855, Thomas Addison of Guy's Hospitals published his
clinicopathologic observations of 11 patients with destruction
of both adrenal glands and described the eponymous clinical
syndrome. The following year, Brown-Sequard" performed
unilateral and bilateral adrenalectomy in animals and provided the first experimental confirmation of Addison's
theory that the adrenal glands were essential to life.
In 1895, the London physiologists George Oliver and
Edward Sharpey-Schafer described the presence of a substance in the adrenal medulla that elevated the blood pressure
in dogs and named it adrenaline.' Their observation was
confirmed in 1897 by John Abel, professor of pharmacology
at the Johns Hopkins University School of Medicine, who
isolated the active compound and named it epinephrinei
In 1901, epinephrine was purified from the adrenal gland;
subsequently, epinephrine and norepinephrine were first
synthesized by Frank Stolz in Germany in 1904.9 In the 1940s,
von Euler'? and Holtz and associates I I identified norepinephrine in nerve endings and the adrenal gland, and the
a-adrenergic and ~-adrenergic
receptors were first described
by Ahlquist in 1948. 12
Surgery of the adrenal glands emerged as part of abdominal surgery at the end of the 19th century, when abdominal
masses were found at operation or autopsy to be adrenal
in origin. Slowly, different adrenal syndromes and tumors
were distinguished. In 1865, DeCrecchio first reported congenital adrenal hyperplasia in a female pseudohermaphrodite.
In 1886, Frankel':' described a type of tumor for which the
pathologist Pick in 1912 proposed the name pheochromocytoma." from the Greekphaios (dark or dusky) and chroma
(color). In 1912, Harvey Cushing described the classic features of his eponymous syndrome, IS and in 1955, Conn
reported the first patient with primary hyperaldosteronism. 16
In the early 1960s, Sipple'? and Werner" described patients
with multiple endocrine tumors (multiple endocrine neoplasia
[MEN] syndromes).
Successful surgical treatment of adrenal disease evolved
from 1889, when Knowsley-Thomton reported the removal
of a large adrenal tumor.' In 1926, Roux in Lausanne,
Switzerland, and Charles Mayo in Rochester, Minnesota, successfully removed a pheochromocytoma.
Efforts to provide substitutive therapy in patients with
adrenocortical insufficiency were made as early as 1856 by
Brown-Sequard, and early attempts at adrenal transplantation
were made by Pybus in 1924 in patients with Addison's
disease.!? Introduction of cortisone replacement therapy in
1949 was preceded in the 1930s by the work of Reichtenstein
and Shopper in Switzerland" and Kendall?' of the Mayo
Clinic, whose biochemical studies led to the understanding
of the structure and synthesis of adrenocortical steroids.
Their work resulted in the award of the Nobel Prize in
physiology and medicine in 1950.
More recent advances have dramatically changed the
understanding of adrenal physiology and pathology. The
hypothalamic factor controlling the pituitary-adrenal axis
(corticotropin-releasing hormone [CRH]) was characterized
and synthesized by Vale and coworkers in 1981. 22 The structure of corticotropin precursor-pro-opiomelanocortin
(POMC), its messenger RNA, and its gene have been
described. Specific intracellular location of the steroidogenic
557
558 - - Adrenal Gland

cytochrome P-450 enzymes and the genes that encode them
have been identified. The elucidation of the structure of the
steroid receptors and the genes that encode them provides
insight into the mechanism by which the steroid-receptor
complex interacts with specific DNA areas (called glucocorticoid response elements) to regulate transcription of target
genes.
Therapeutic possibilities have increased significantly,
from the first synthesis of corticosterone in 1949, to the first
inhibitors of steroidogenesis in the 1960s, to the recent development of inhibitors of steroid receptors (as mifepristone
[RU-486]).
Surgical intervention continues to play an important role in
many diseases of the hypothalarnic-pituitary-adrenal axis. An
understanding of the embryology and anatomy of the adrenal
glands is an essential prerequisite to successful and effective
adrenal surgery.
Embryology
The adrenals have a dual origin: the cortex arises from mesoderm, whereas the medulla has a neuroectodermal origin.
The cortex starts to develop in the fifth week of gestation
as a proliferation of coelomic mesothelium into the underlying
mesenchyme between the root of the dorsal mesogastrium
(the root of the mesentery) and the urogenital ridge (the
mesonephros and the developing gonad). This close proximity
explains why ectopic adrenal tissue has been described to be
located below the kidneys and associated with the testes or
ovaries.
Initially, large acidophilic cells form the fetal or primitive
cortex (Fig. 64-1A).23 Shortly afterward, a second wave of
cells from the mesothelium penetrates and surrounds the
original acidophilic cells; these cells, smaller than those of
the first wave, later form the definitive cortex of the gland.
The proliferating adrenal tissue extends from the level of
the thoracic segments 6 to 12 and becomes larger than the
kidney at midgestation." The fetal cortex undergoes rapid
degeneration in the first 2 weeks after birth, so that

it accounts for only one quarter of the cortical mass at age
2 months and has vanished by 1 year. The fascicular and
reticular zones of the adult cortex proliferate from the
glomerular zone after birth and are fully differentiated by
about the 12th year.24
The embryogenesis of the adrenal medullary cells starts in
the second month of gestation. Before this, during the fourth
week of embryonic life, the neural plate develops and then
infolds to form the neural tube. A portion of the neuroectoderm adjacent to the tube separates and remains between the
neural tube and the definitive ectoderm as the neural crest.
Cells derived from the neural crest (sympathogonia) migrate
ventrally from the apex of the neural tube to the dorsal aorta
(where they aggregate and differentiate into neuroblasts
to form sympathetic neurons) or to the adrenal primordia
(where they differentiate into pheochromoblasts to form
chromaffin cells) (Fig. 64-1B).25
Some primitive adrenal medullary cells remain closely
associated with the developing sympathetic nervous system
and give rise to the extra-adrenal chromaffin cells and chromaffin bodies. Extra-adrenal chromaffin cells are, therefore,
found in the abdominal preaortic sympathetic plexus or in
the paravertebral sympathetic chain. Postnatally, most of the
extra-adrenal chromaffin cells begin to degenerate, whereas
those of the adrenal medulla complete maturation.
In the fetus, catecholamine secretion increases in
response to hypoxia and hypoglycemia.P The chromaffin
reaction is positive by the fifth month of fetal life, but epinephrine is present as early as the third month.
The fate of the cells migrating from the neural crest can
be altered by changing their environment (for reviews, see
Le Douarin's study"). Progenitors from the fetal adrenal
gland have been isolated and proven to be bipotential (able
to develop into either chromaffin cells, under the effect of
high concentration of glucocorticoids, or sympathetic
neurons). Glucocorticoids act through type II receptors to
upregulate the expression of phenylethanolamine N-methyltransferase (PNMT) and the epinephrine-synthesizing
FIGURE 64-1. Embryology of human adrenals. A, Longitudinal sectionof a human embryo at 50 days postconception. Note the size of
the adrenal in relation to the kidney primordium. A =adrenal cortex; L =liver; G =gut; Gn =gonad; K =kidneyprimordium; S =spine.
B, Section of human embryoat 56 days postconception. At this stage,medullary cells (M) haveinvaded the adrenalcortex. The kidney pri-
mordium (K) has further evolved. Sections were stained with hematoxylin-eosin. (Courtesy of Professor Jeremy Berry, Department of
Paediatric Pathology, St. Michael'sHospital, Bristol, England.)
Surgical Embryology and Anatomy of the Adrenal Glands - - 559
enzyme and also act negatively to inhibit the neural differentiation induced by nerve growth factor (Fig. 64-2).
The plasticity characteristic of the early development of the
sympathoadrenalcells is maintained later in life. For example,
intracerebraltransplantationof adrenal medullary cells into the
paraventricular areas in humans has been attempted as treatment for patients with Parkinson's disease; the transplanted
cells produce dopamine, confirming the theory of the adrenal
medullaas a catecholarninergic ganglion, and hence ameliorate
the symptoms of Parkinson's disease (which is due to a degenerative loss of dopaminergic neurons in the basal ganglia).
Development of Adrenal Arteries

The acquisition of a vascular supply occurs at a very early
stage in development. Capillaries, which arise from the adjacent mesonephric arteries, penetrate the cortex in a radial
manner. The arterial blood supply during fetal period is
highly variable in both the origin and the number of adrenal
arteries, as well as in the asymmetry of the blood supply
between the left and right adrenal glands. Initial branches
Bipotential sympathoadrenal _
progenitor
F~~;~:
arise from the aorta, from the vessels to the septum transversum (later the central part of the diaphragm), and from
the mesonephric arteries. The inferior phrenic artery is the
main arterial supply for the fetal adrenal."
Embryology and Steroidogenesis

Function in the fetal cortex begins as early as the seventh
week of gestation'" and steroidogenesis in the outer layers
begins toward the end of the second trimester and is maximal by the third trimester.
It has generally been considered that the major role of the
primate placenta is to convert biologically active cortisol
to its inactive metabolite cortisone (which does not bind
to the glucocorticoid receptor) and so protect the fetus from
the relatively high concentrations of steroid present in the
maternal circulation. The placenta plays a pivotal role in the
sequence of events culminating in fetal adrenal development
and function.
The fetus produces large amounts of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) from circulating
SA-1+
HNK-1+
B2-
depolariZ/"
~B2+
~
SA-1+
Committed neuroblast
SA-1+
Chromaffin precursor
NGF!
High
glucocorticoid
NF+
SCG10++
Sympathetic neuron
PNMT+
Adrenergic chromaffin cell

~
chromaffin-specific gene expression
IlIIIIIIIlI neuron-specific gene expression

FIGURE 64-2. Progressive stages in the development of sympathoadrenal (SA) lineage. Changes in marker expression that correlate with
these stages are shown. Cross-hatched lines in the bipotential SA progenitor indicate that both neuron-specific and chromaffin-specific
genes are coexpressed. Monoclonal antibodies (HNK-l) are used to isolate bipotential SA progenitors from rat adrenal glands. SA-l antigen is a chromaffin cell marker and B2 antigen is specific for neuronal precursors. High levels of glucocorticoids induce differentiation of
chromaffin cells. SA progenitor cells initiate neuronal differentiation in response to basic fibroblast growth factor (FGF), lose competence
to respond to glucocorticoids, subsequently develop a dependence on nerve growth factor (NGF) for further maturation and survival, and
when mature, can be identified with the use of antineurofilament (NF+) antibodies. PNMT = phenylethanolamine N-methyitransferase.
(Adapted from Anderson DJ. Molecular control of cell fate in the neural crest: The sympathoadrenal lineage. Annu Rev Neurosci
1993;16:129.)

acetate and cholesterol. The placenta then removes sulfate
from DHEA-S, which is further transformed by 3~-hydroxysteroid dehydrogenase (3~-HSD)
(an enzyme not present in
the fetal adrenal cortex) and used in the estrogenic pathway.
The availability of DHEA-S for placental estrogen production is controlled by a positive feedback loop in which estrogen enhances production of precursor DHEA-S from fetal
adrenal cells. The large amounts of estrogen produced by
the placenta indicate the presence of an intact and functional
fetoplacental unit.
The fetal adrenal does not develop the enzymatic capacity
to produce cortisol de novo (i.e., from endogenous cholesterol)
until very late in gestation because of a lack of key ratelimiting steroidogenic enzymes (as 3~-HSD).
At midgestation,
essentially 100% of cortisol in fetal serum is of maternal
origin. The increased placental oxidation of cortisol to cortisone provides the stimulus for fetal hypothalamic-pituitary
axis function and the timely onset of de novo cortisol production. It is postulated that because the fetal production
of corticosteroids is reduced, the adrenals are stimulated
continuously by high levels of corticotropin and become
enlarged." At term, less than 50% of fetal cortisol originates
from hormone produced by the maternal adrenal.
Clinical Aspects
At birth, the gland is about one third the size of the kidney,
whereas in the adult, it is only about one thirtieth. This change
in proportions is due not only to renal growth but also to
involution of the fetal cortex after birth, so that by the end of
the second postnatal month its weight is only half that at
birth. In the latter half of the second year, the gland begins
to increase in size and gradually attains its birth weight at or
just before puberty, after which it only increases slightly in
weight in adult life.
ACCESSORY TISSUE
Small accessory suprarenal glands, which may consist of cortical tissue only, often occur in the areolar tissue around the
principal glands. They are sometimes present in relation to the
sympathetic plexus and in relation to structures derived from
the urogenital ridge: epididymis, vas deferens, broad ligament
of the uterus, ovarian pedicle, or within the ovary or testis.
Adrenocortical rests may occur in 50% of newborn infants
but tend to atrophy and disappear after a few weeks. They persist and enlarge in the adrenogenital syndrome or any condition of continued corticotropin stimulation. Those within the
scrotum may be misinterpreted as testicular tumors.
Ectopic medullary tissue also occurs, occasionally in
conjunction with cortical tissue but more often alone, as isolated masses along the abdominal aorta or in association
with the sympathetic chain and the plexus (the retroperitoneal celiac plexus). These have been described by
Zuckerkandl." whose name is associated with an especially
large mass that may occur anterior to the aorta and distal to
the origin of the superior mesenteric artery. Coupland characterized these masses as paraganglia or chromaffin bodies.
Ten percent of pheochromocytomas develop in "accessory" sites, particularly in ganglia around the aorta at the
level of the kidney, anterior to the inferior aorta (at the level
of the organ of Zuckerkandl), in the mediastinum, or in
the bladder. Occasionally, they have been reported in the neck,

sacrococcygeal, anal, or vaginal areas. The incidence of extraadrenal pheochromocytoma is higher in children than adults.
Tumors of sympathoadrenal lineage (affecting mainly
children) correspond to discrete stages of differentiation in
this lineage and are derived from the neural crest cells. They
can be located in the adrenal medulla and sympathetic ganglia
and are often associated with excessive production of catecholamines and catecholamine metabolites. Neuroblastoma,
the most immature and malignant of these tumors, can be
considered derivatives of primitive sympathogonia or neuroblasts. Ganglioneuroblastomas are partially differentiated
neuroblastomas, and ganglioneuroma is the benign form,
derived from sympathetic ganglion cells. Tumors showing
an immature (neuroblast) phenotype appear to have a latent
capacity to differentiate into more mature tissue and have a
much higher probability of spontaneous remission than those
of chromaffin type. Potential therapy for the more malignant
chromaffin-like tumors might involve in situ conversion
to neuroblastic-type tumors using nerve growth factor or
glucocorticoid antagonists."
Chromaffin cells are included in the amine precursor
uptake and decarboxylation (APUD) cell group described
by Pearse" on the basis of functional characteristics and
embryologic origin. Tumors of the chromaffin tissue can
occur in association with tumors of other cells of the APUD
system, such as medullary carcinoma of the thyroid and
hyperparathyroidism (as in MEN 2 syndrome).
Anatomy
The adrenals are retroperitoneal organs resting on either side
on the crura of the diaphragm. They lie on each side of the
vertebral column (TlI-12), against the superomedial surface
of the corresponding kidney, and are surrounded by a thin
layer of loose areolar connective tissue and a thick fibrous
capsule. This makes them easily separated from the superior
pole of the kidney. The adrenal glands are held in position
by numerous fibrous bands and vascular attachments.
Macroscopic Aspect
The adrenal glands are darker yellow and have a finely granular surface and firm consistency compared with the surrounding perirenal fat. Each gland in the adult measures
about 50 mm vertically, 30 mm transversely, and 10 mm in
the anteroposterior plane (Fig. 64-3). Each gland normally
weighs about 4 to 5 g regardless of age, body weight, and
gender but may weigh as much as 22 g at autopsy, apparently
because of the stress of terminal illness. The glands' yellowish
brown color is due to the presence of lipoid substances.
Up to 3% of normal adults may have macroscopic nodules in the adrenal gland." Micronodular changes are seen
in two thirds of normal adults.P
Relations
The right adrenal gland is triangular or pyramidal, with
the apex superior and the base embracing the kidney (see
Fig. 64-3). It lies anterior to the diaphragm and the right
Surgical Embryology and Anatomy of the Adrenal Glands - -
561
FIGURE 64-3. Macroscopic appearance of the adrenal glands.

The size and shape of normal adrenal glands can be seen.
A, Superior view. B, Inferior view. C, Cross section of the
adrenal gland; the yellowish outer cortex can be differentiated
from the brown medulla. The dark staining of the innennost
part of the cortex (the zona reticularis) is due to the presence
of lipofuscin within its cells. The adrenal vein emerging
from the medullary area is easily seen. (Courtesy of Dr. Ed
Sheffield, Department of Histopathology, Bristol Royal
Infirmary, Bristol, England.)
kidney and posterior to the inferior vena cava and the right
lobe of the liver. Superiorly, the gland is in contact with the
bare area of the liver. If the inferior layer of the right triangular or coronary ligament of the liver is especially high, the
right adrenal gland may reside partially in the upper part of
the right paracolic gutter (Morison's pouch), where it is
immediately in contact with peritoneum. Its hilum is on its
anterior surface, a little inferior to the apex, and usually a
single right adrenal vein emerges from the hilum.>'
The left adrenalgland is crescentic and semilunar in shape
(see Fig. 64-3) and extends further inferiorly on the medial
margin of the kidney. It is related anteriorly to the stomach
and pancreas and posteriorly to the diaphragm. Unlike the
right adrenal, the left adrenal gland is largely covered anteriorly by peritoneum of the lesser sac. If the reflection of the
gastrophrenic ligament is far medially, it is also covered by
the peritoneum of the greater sac in the region of the left
paracolic gutter.A variable small area of the left adrenal gland
may lie in immediate contact with the stomach, near the cardioesophageal junction, with no intervening peritoneum
(where the left gastric artery, from its position on the left
crus of the diaphragm, enters the lesser omentum to gain the
lesser curvature of the stomach). 34
Each gland has an anterior and posterior surface and a
medial border, and the topographic anatomic relations are
summarized in Table 64-1. These relationships are important for understanding the radiologic anatomy (Fig. 64-4).
The adrenal glands have a proper capsule that invests
them closely, which extends as connective tissue septa carrying vessels into the interior of the gland. In addition, they
share with the kidneys a second capsule-the perirenal
fascia (Gerota's fascia); a considerable amount of fat lies
within the perirenal space between the perirenal fascia of
Gerota and the true capsules of the adrenals and the kidneys.
Superiorly, the perirenal fascia is enclosed and fades out
on the inferior surface of the diaphragm; inferiorly, the
perirenal fascia is open and the perirenal fat merges with that
of the iliac fossa, which could explain cases of mobile or
ectopic kidneys. The anterior lamina of the perirenal fascia
fades out in the fascia over the aorta, inferior vena cava,
and other midline structures; the perirenal space does not
extend across to the other side." The inclusion of the adrenal glands within Gerota's fascia is of importance surgically
because the adrenals may be dissected from within the
perirenal fat without compromising the peritoneum or the
midline structures.
Outside Gerota's fascia lies the pararenal fat, anterior to
which is the fascia of Zuckerkandl. It limits the retroperitoneum anteriorly and represents a remnant of the old
mesentery of the ascending and descending colon and
562 - -
Adrenal Gland
duodenum that have become secondarily adherent to the

posterior abdominal peritoneum during development.
Kocher's maneuver in the mobilization of the duodenum and
pancreas takes advantage of the loose adhesions in the plane
of Zuckerkandl's fascia.
Arterial Supply
The glands have a profuse arterial supply with three main
groups of vessels that divide before entering the gland and
have three distinct sources: the inferior phrenic artery, the
aorta, and the renal artery.
As the inferior phrenic arteries pass just above and
medial to the suprarenal glands, each artery usually gives off
a series of branches into the gland on its own side before it
supplies the diaphragm. These arteries constitute the superior

suprarenal arteries, which enter the upper part of the gland
over a considerable extent.
There usually is at least one artery to each gland from the
aorta, just above the origin of the renal arteries: the middle
suprarenal artery. One or more arteries reach the gland from
the adjacent renal artery, and these are the inferior suprarenal
arteries.
In addition to these three regular sources of blood supply,
other vessels running close by may also supply branches to
the suprarenal gland. Most constant of these are branches from
the intercostal, the left ovarian, or the left internal spermatic
arteries.
Because any arteries approaching the gland may branch
and rebranch, the number of vessels entering it may be
FIGURE 64-4. Radiologic anatomy of the adrenal glands. A, CT section in the horizontal plane. The superior relationship with the liver
and diaphragm and the inferior relationship with the right kidney can be seen. B, MRI in the longitudinal (axial) plane from a patient with
right adrenal tumor. (Courtesy of Dr. Julian Cabala, Department of Radiology, Bristol Royal Infirmary, Bristol, England.)

quite numerous. There is no regular position in which these
branches enter the gland. This anatomic detail is important
for two reasons: (1) when approaching the adrenal glands,
dissecting within the perirenal fat, encountering these small
arteries and veins heralds proximity of the gland; and (2) the
feeding vessels bleed in an irritating manner unless dealt
with by diathermy or clip ligature.
Most of the branches of the suprarenal arteries ramify
over the capsule before entering the gland and dividing
within to form a narrow subcapsular plexus. Short cortical
arteries arising from the subcapsular plexus give rise to an
extensive network of sinusoidal capillaries that occupies the
interstices among clusters of cells in the zona glomerulosa
and among the cell columns of the zona fasciculata, and then
form a deep plexus located in the zona reticularis. These
capillaries are fenestrated; pores range in size from 100 nm
in the outer cortex to 250 nm in the inner fasciculata and
reticularis. There is no direct arterial blood supply to the
zonae fasciculata and reticularis (Fig. 64_5).36,37
From the deep plexus, small venules pass between chromaffin cells of the medulla to the medullary veins, which
they enter by passing between prominent bundles of longitudinally arranged muscle fibers. It appears that these bundles
of fibers regulate blood flow at the corticomedullary junction
(at the deep aspect of the zona reticularis). Because this would,
in turn, control the rate of blood flow through the zona reticularis and zona fasciculata, it could provide part of a control
mechanism for the availabilityof corticotropin to the secretory
cells of these regions and hence of its possible uptake.
Some major arterial branches bypass the system
described previously and supply the medulla directly to provide a dual blood supply, indirect and direct. Blood coming
through the indirect route (i.e., by way of the cortical sinusoids) is sufficiently rich in glucocorticoids to induce and
maintain synthesis of PNMT, the enzyme needed for the
synthesis of epinephrine from norepinephrine. More than

95% of epinephrine originates from the adrenal medulla
because of this anatomic-biochemical proximity. Changes in
the relative blood supply may, therefore, have profound physiologic consequences. Medullary capillaries are fenestrated,
which may allow free diffusion of released catecholamines.
Despite the rich vascularity, the blood flow of the normal
adrenal is about 10 mUmin, but the supply to both the medulla
and the cortex increases under stress; corticotropin produces
an immediate increase in blood flow to the adrenals.
Venous Drainage
In contrast to the arteries, the main drainage of the gland is
usually into a single large suprarenal (central) vein, leaving
the gland through the hilum.
The right one is short (0.5 em) and drains directly into the
inferior vena cava. Ligature of the right adrenal vein can,
therefore, be difficult, and individual peculiarities of the local
anatomy sometimes oblige the surgeon to side-clamp the
vena cava.
On the left side, the suprarenal vein is longer (",,2 ern) and
is usually joined by the inferior phrenic vein, which empties
into the left renal vein. Smaller emissary veins may drain into
the inferior phrenic, renal, and, rarely, hepatic portal veins."
The central vein has two to four conspicuous longitudinal
smooth muscle bundles, the function of which is unknown.
Presumably, they constrict the outflow from the gland and
may increase the exposure of cortical cells to systemic
factors (corticotropin) and the exposure of medullary cells to
cortisol.
Lymphatic Drainage
There are two plexus: one deep to the capsule and one in the
medulla. Many lymph vessels leave the suprarenal gland and
end in the lateral aortic lymph nodes and in the para-aortic
nodes near the crus of the diaphragm and the origin of the
renal artery. Some lymphatic vessels pierce the diaphragm
and drain toward the thoracic duct or the posterior mediastinum, which explains the development of distant and
early metastases of cortical malignant tumors. When operating on a suspected malignant tumor of the adrenal glands,
immediately adjacent, para-aortic, and paracaval nodes must
be checked for evidence of local metastasis.
Nerve Supply
FIGURE 64-5. Scanning microscopy of adrenal vessels. (From

Kikuta A, Mukarami T. Microcirculation of the rat adrenal gland:
A scanning electron microscope study of vascular casts. Am J Anat
1982;164:22.)
The medulla is a neuroendocrine transducer, a structure that

transforms the nervous signal (encoded electrically as action
potentials) into an endocrine signal (chemically encoded).
There is a rich nerve supply consisting of myelinated cholinergic preganglionic sympathetic fibers, which pass through
the hilum and synapse on cells in the medulla. These fibers
terminate in synapses with the pheochromocytes, which are,
therefore, equivalent to postganglionic sympathetic neurons.
The cell bodies of the neurons innervating the adrenal medulla
originate in the intermediolateral cell column between T3
and L3. The greater proportion of the innervation reaches
the adrenals through the ipsilateral greater thoracic splanchnic nerve (T5 to T9).
564 - -
Adrenal Gland
Catecholamines are released into the systemic circulation

after stimulation of the greater splanchnic nerve. Its
branches end in relation to the medullary cells in a manner
comparable to the synapse: acetylcholine is released on
stimulation, acts on muscarinic receptors on the pheochromocytes' membranes, and alters their permeability, permitting
influx of calcium, which triggers exocytosis of catecholamines. The medullary cells stand in the same relation
to the preganglionic sympathetic fibers as the postganglionic
cells.
Relative to its size, the adrenal has a larger autonomic
supply than any other organ. Spinal cord transection above
T3 is usually associated with deficient epinephrine secretion.
The role of sympathetic input on catecholamine release is
also demonstrated by the decrease of plasma catecholamine
levels in normal people after treatment with clonidine
(a central (X2 agonist) or pentolinium (a ganglion-blocking
agent). A pheochromocytoma, unlike the normal adrenal
medulla, is not innervated, and catecholamine release is not
initiated by nervous impulses. The suppression tests with
clonidine and pentolinium, therefore, fail to inhibit plasma
catecholamine levels in patients with pheochromocytomas.
The adrenal cortex receives only a vasomotor nerve
supply. Sympathetic axons innervate the subcapsular arteriolar plexus. In addition, zona glomerulosa cells and the subcapsular plexus are innervated by axons containing vasoactive
intestinal polypeptide and neuropeptide Y.These axons arise
and radiate outward from the adrenomedullary cells; their
function is unknown, but they may be involved in the
paracrine control of steroidogenesis.
Microscopic Anatomy
On section, each gland consists of a thick outer cortical layer
and a thin, inner medullary portion (see Fig. 64-3C).
The external cortical zone is rich in lipids and so is yellowish and has a firmer consistency than the reddish brown and
well-vascularized medulla.
The adrenal is enveloped in a thin capsule from which
septa carrying blood vessels penetrate the cortex in a radial
fashion, converging on the medulla. There is a concentration
of connective tissue at the boundary between the cortex and
the medulla, the so-called medullary capsule. The medulla
does not extend throughout the full length of the gland but is
concentrated in the central part and is absent from the attenuated edges (see Fig. 64-3C).
The cortex makes up to 80% to 90% of the volume of a
normal gland, whereas the medulla constitutes 10% to 20%.
Hyperplasia may occur in the cortex or medulla'? and disturb
the normal corticomedullary ratio, and each is usually associated with hyperfunction syndromes.
The classic description of the adrenal cortex comprising
three concentric layers-zona glomerulosa, zona fasciculata,
and zona reticularis (Fig. 64-6A)-dates from the earliest
studies.t?
The outermost layer, or zona glomerulosa, is so termed
from the arrangement of the columnar epithelial cells in clusters or short anastomosing cords (see Fig. 64-6A). It constitutes about 15% of the cortex. The cells are smaller than
in the deeper cortex and have relatively little cytoplasm
in proportion to the nucleus. They have a heavily stained
heterochromatic nucleus with one or two nucleoli. The cytoplasm is less acidophilic than elsewhere and has an intermediate number of lipid inclusions (as viewed under
electron microscopy and in sections stained for lipids, as with
Sudan black B fat stain)." The Golgi system appears polarized toward the nearest blood vessel. In electron micrographs,
cells of the zona glomerulosa are joined by occasional desmosomes and a few small gap junctions." The zona glomerulosa cells produce the mineralocorticoid aldosterone.
The zona fasciculata constitutes about 75% of the cortex
and is made up of pale-stained, polyhedral, vacuolated cells
arranged in a parallel array (see Fig. 64-6A) at right angles to
the capsule (a disposition imposed by the radial arrangement
of the sinusoidal vessels)." The cells have a large amount of
cytoplasm relative to the nucleus. The cytoplasm contains
large vacuoles that are birefringent, sudanophilic, and
osmiophilic; these lipid droplets probably represent sites of
cytoplasmic storage of the steroids and their precursors.
Hyperplasia of focal areas and the production of adenomas
or cortical nodules are common in this metabolically active
zone. On electronic microscopy, cells from the zona fasciculata present with features typical of steroid-secreting cells:
large vacuoles, rounded mitochondria with particular tubular cristae, and very extensive smooth endoplasmic reticulum, which occupies 40% to 45% of the cell volume. The
Golgi system is well developed and has many areas of continuity with the endoplasmic reticulum.
The inner zone of the adrenal cortex-the zona reticularis-has cells arranged in large clusters (see Fig. 64-6A).
This zone is sharply demarcated from both the fasciculata
and the medulla. It is highly variable in thickness and in
degree of vacuolation and lipid content of the cells and can
be a reserve from which new cells are added to the fasciculata. In electron micrographs, the cells appear less active
than those of the fasciculata; the endoplasmic reticulum is
far less extensive, the Golgi complex is small, and lipid
droplets are relatively few.36 The zonae fasciculata and reticularis secrete the glucocorticoid cortisol and the weak adrenal androgen DHEA.
The significance of zonation in the adrenals is not clear,
but it occurs slowly after birth parallel with regression of the
fetal cortex and is not completed until late in the first year.
Functional differences do not provide an adequate explanation for the different arrangements and morphology of the
cells. It has been proposed that maintenance of normal adrenal size and function may involve cell division in the zona
glomerulosa, subsequent centripetal cell migration and differentiation in the fasciculata, and eventual senescence and
death in the reticularis. Although the adrenal zonae fasciculata and reticularis clearly have the ability to regenerate
from subcapsular remnants, even in ectopic locations." it is
less clear whether this capability is used in the maintenance
of normal adrenal anatomy. Not all of the labeling experiments with 3H-thymidine provide evidence for centripetal
cell movement.f It is likely that, once formed, the cells of
the three zones do not move appreciably and are replaced by
local mitotic activity." From a functional point of view,
chronic corticotropin stimulation and the consequent exposure to an increased glucocorticoid concentration change the
phenotype, structure, and responsiveness of glomerulosa cells
to that of fasciculata cells.f After continuous stimulation,
FIGURE 64-6. Histologic appearance of the adrenal glands (hematoxylin-eosin stain, medium power). The three layers of the cortex can
be identified. A, The outer zona glomerulosa (G). B, The well-represented zona fasciculata (F). C, The innermost zona reticularis (R). The
prominent zona fasciculata and reticularis are also shown at higher power. D. Electron microscopy of a chromaffin cell. The numerous
catecholamine granules (G) with a dense core can be observed. The nuclei (N) and mitochondria can be identified. (Courtesy of
Dr. Ed Sheffield, Department of Histopathology, Bristol Royal Infirmary, Bristol, England.)
corticotropin converts the innermost fasciculata cells to

the reticularis phenotype, a process that extends outward
until the reticularis may completely replace the zona
fasciculata.f
After removal of one adrenal gland, the remaining gland
undergoes compensatory hypertrophy, dependent mainly on
the presence of corticotropin but also influenced by other
hormones such as the NHrterminal fragment of POMC.
Similarly, the presence of an autonomous adenoma in one
gland produces severe atrophy in the other because of the
lack of trophic corticotropin effects (autonomous secretion
of cortisol by the adenoma blocks by feedback the secretion
and synthesis of CRH and hence of corticotropin). The
recovery of an intact adrenal-pituitary axis and a normalsized remaining gland may take up to 2 years.
The medulla is made up almost entirely of rounded clusters or short cords of chromaffin cells that are in intimate
relation to capillaries and venules. These cells are large,
irregularly shaped polyhedrons, with acidophilic cytoplasm
and pale vesicular nuclei; they are surrounded by nerves,
connective tissue, and blood vessels."
Cells from the adrenal medulla give characteristic color
reactions determined by their content of catecholamines. With
dichromate salts, they give the brown chromaffin reaction
(brown staining of the granules resulting from oxidation and
polymerization of the catecholamines in the granules); with
ferric chloride, a green Vulpian reaction; and with silver
salts, an argentaffin reaction. With histochemical staining
reactions, two kinds of chromaffin cells can be distinguished
between (1) those storing norepinephrine, which have a low
566 - -
Adrenal Gland
affinity for the dye azocarmine, are autofluorescent, give

argentaffin and potassium iodide reactions, and are free for
acid phosphatase; and (2) those storing epinephrine, which
have a strong affinity for azocarmine, are not fluorescent or
reactive with silver and iodate, and exhibit a positive phosphatase reaction."
Electron microscopy reveals that chromaffin cells
contain very large numbers (up to 30,000 granules per cell)
of membrane-bound electron-dense granules, 1()() to 300 urn
in diameter, similar to those in synaptic nerve endings (see
Fig. 64-6B). These granules are important in the storage and
secretion of catecholamines; they contain catecholamines,
adenosine triphosphate, chromogranins, enkephalins, and
the enzyme dopa hydroxylase (a major protein of the granule membrane)." Individual chromaffin cells contain large
amounts of either norepinephrine or epinephrine; in humans,
the normal adrenal medulla has cells in which epinephrine is
predominant (85%) because of the high activity of PNMT
induced locally by the high level of glucocorticoids.
In contrast with these "traditional" data, in a recent study
of 15 patients with pheochromocytomas, we found no correlation between noradrenaline output and the number or percentage of noradrenaline-type granules. In a tumor secreting
only adrenaline, adrenaline-type granules were predominant
(77%) but the proportion of adrenaline-type granules in
tumors with normal adrenaline output varied widely (7% to
89%). These data suggest that other factors determine the
secretory patterns in pheochromocytomas.f
Imaging Consequences
Because of the central location within the abdominal cavity
and the vicinity of numerous viscera, plain films are rarely
informative. Occasionally, a large adrenal mass may be suggested by the downward displacement of the kidney, but
this appearance is rarely seen, and differentiation from renal,
splenic, pancreatic, gastric, and retroperitoneal tumors
requires further investigation.
Calcification may be seen in the adrenal glands and can
be idiopathic or result from neonatal causes (infarction,
hemorrhage, infection), maternal diabetes mellitus, tuberculosis, histoplasmosis, cyst, tumor, and Addison's disease."
Retroperitoneal pneumography is now obsolete.
Ultrasonographic visualization of the adrenal is not an
easy technique and may produce false-positive results, but
an accuracy of 70% has been described. Ultrasonography is
considered to be the investigation of choice in the neonate
and young child, when the relatively small amount of
retroperitoneal fat makes computed tomography (CT) scanning a less satisfactory technique. The adult adrenal gland is
slightly more echogenic than the kidney. A left adrenal mass
should be distinguished from normal splenic vessels, splenic
lobulation, and masses arising from the kidney, spleen, and
pancreas. A mass within the right adrenal gland must be differentiated from the right crus of the diaphragm, retrocavallymphadenopathy, and masses arising from the liver and kidney.
Ultrasonography is useful in assessing the development of
the fetal adrenals. They appear as disklike structures medial
to the kidney in transverse scanning through the fetus and as
heart-shaped structures of low echogenicity superiorly and
medially to the kidney in the longitudinal plane. It is possible to monitor a linear increase of the adrenal area, circumference, and length during the 20th to 40th weeks of
gestation."
CT scans identifies the adrenals in nearly all patients and
has a reported accuracy of more than 90% in the diagnosis of
adrenal masses. The normal glands have a variable appearance on the CT scan. Usually, the right gland is linear or
V shaped, with the medial and lateral limbs posteriorly; the
medial limb is more caudal and is larger, measuring up to
4 em in length. The left adrenal gland is V shaped, is triangular, or has a Y configuration, with its apex anteromedial
and its limbs posterior (see Fig. 64-4A).46
Absolute criteria for enlargement of the adrenals on the CT
scan do not exist. Convexity of the adrenal outline is significant and should be considered abnormal. By comparison
with the right crus of the diaphragm, a normal adrenal gland
should not be thicker than the crus.
Fine-needle biopsy under CT or ultrasonographic control
can be performed in the diagnosis of incidentaloma (nonfunctioning adrenal tumor identified on a routine scan) after
a pheochromocytoma has been ruled out.

The normal adrenals are best seen on Tl-weighted
sequences, in which cortex may be differentiated from
medulla. The T2-weighted images appear to be suitable to
help differentiate benign from malignant adrenal neoplasms
(see Fig. 64-4B).46
Radionuclide Imaging
Iodine 131-metaiodobenzylguanidine (MIBG) and iodine
123-MIBG) concentrate in the adrenergic neurotransmitter
vesicles, and this is used for demonstrating pheochromocytomas. Selenium 6-selenomethylnorcholesterol and 1311_6~_
iodomethylnorcholesterol are used for steroidogenesis and
allow imaging for adrenal hyperplasia and adenomas; suppression of the normal tissue with dexamethasone enhances
uptake into the adenomas and provides a better image."
Surgical Applications
Because of their fairly central position in the abdominal
cavity, the adrenal glands cannot be felt, and few tumors
grow large enough to be palpated. Approaches to the gland
can be made through the posterior, lateral, and anterior surfaces. Laparoscopic adrenalectomy has become in recent
years the technique of choice for most adrenal tumors.
Surgical techniques are described in greater detail in other
chapters of this book. The anatomic landmarks are mentioned here as an introduction.
Open Adrenalectomy
POSTERIOR APPROACH
The posterior approach, originally described by Young," offers

the technical advantage of being extraperitoneal, extrapleural,
and subdiaphragmatic and the clinical advantage of being
Surgical Embryology and Anatomy of the Adrenal Glands - -
associated with a low postoperative morbidity. The incision

is usually over the 11th rib. Structural stratification of the
posterior thoracic wall in this region'? is summarized in
Table 64-2.
During right adrenalectomy, the dissection plane encounters the costopleural sinus, which can be reflected superiorly; rarely, it might be necessary to incise the pleura and
diaphragm. After incision of Gerota's fascia, dissection
between the right kidney and the vena cava allows identification of the adrenal gland. Posteriorly and laterally, dissection can proceed quickly because few major vessels cross
567
this space. When dissecting on the medial aspect, it must be

remembered that there is usually only one adrenal vein and
that this is often only I em wide and only 2 to 3 mm long.
The vein is sometimes found at the upper pole of the adrenal gland, and its point of entrance into the cava lies immediately beneath the liver. Once the adrenal vein has been
divided, the tumor usually becomes much more mobile, and
remaining connections can be divided safely.
Left adrenalectomy has fewer pitfalls. It is important to
recognize and protect the spleen and to differentiate the inferior surface of the pancreas, which may look similar to an
edge of the adrenal gland. Definitive pedicles may not be

identified so clearly, but important tethering feeding vessels
that fix the gland medially inferiorly and superiorly must be
divided. The left adrenal vein may be identified as a discrete
vessel entering the renal vein, and its length and width allow
control and safe ligature division.
ANTERIOR APPROACH
The anteriorapproach was initially advocated by Cahill, one

of the pioneers of adrenal surgery," because of the advantage of simultaneous bilateral exploration, but it is more difficult, more time consuming, and associated with a greater
morbidity (especially in the obese patient with Cushing's
syndrome). It is advantageous especially when the adrenal
disease is bilateral, when the tumor is large (> 10 em), or
when there are preoperative indications that the tumor has
invaded surrounding anatomic structures. Because of the
progress in preoperative diagnosis and localization, the use
of the anterior approach is decreasing.
A long, curved transverse incision ("reversed smile") is
used, with the center point situated halfway between the
umbilicus and the xiphisternum. A vertical (midline or paramedian) incision has also been advocated. The anatomic
stratification in the incision line is outlined in Table 64-2.
Left Adrenalectomy. There are three ways of accessing

the adrenal region."
1. Incision of the posterior parietal peritoneum lateral
to the left colon, continued upward, dividing the
splenorenalligament (important relations are with the
spleen, the splenic vessels, and the pancreas, which
are enveloped by the splenorenal ligament, and caution should be used to avoid injury)
2. Opening of the lesser sac through the gastrocolic
omentum (incision should be longitudinal, outside of
the gastroepiploic arcade)
3. Through the left mesocolon, with the problem of
maintaining the main branches of the middle and left
colic arteries forming the vascular arcade and yet
allowing enough space.
Anterior access to the adrenal gland allows easy recognition of the hilum and isolation of the adrenal vein from the
elements of the renal pedicle.
Right Adrenalectomy. After mobilization of the hepatic
flexure of the colon, the liver is carefully retracted upward; to
provide maximum exposure of the adrenal gland, the falciform
and the right triangular ligaments are carefully divided. The
duodenum is mobilized in its second portion (Kocher's maneuver) by incision on its lateral aspect (the avascular peritoneal
SurgicalEmbryology and Anatomy of the Adrenal Glands - - 569

reflection), allowing exposure of the vena cava, the right adrenal gland, and the upper pole of the right kidney. In this area,
there are important relations to remember with the common
bile duct and the gastroduodenal artery. The critical step is the
clamping of the right adrenal vein because it is short, leaves the
gland on its anterior aspect, and enters the vena cava on its posterior surface.
Early control and ligation of the adrenal vein in surgery
for pheochromocytomas have been advocated in an attempt
to control the amount of catecholamines released in circulation during tumor handling. Whichever technique of adrenalectomy is chosen, however, it is clear to any operator that
this ideal is not easily achieved, and in some approaches the
adrenal vein might be the last connection to be divided,
allowing severance of the tumor from the patient.
completed upward. For adrenals greater than 5 em, the lateral and superior dissections are completed first; dissection
is then carried caudally to identify the adrenal vein, which is
clipped and divided.
RETROPERITONEAL LAPAROSCOPIC
ADRENALECTOMIES
Laparoscopic surgery of the adrenal glands is described in

detail in Chapter 74.
The largest experience has been with nonfunctioning
adrenal masses (incidentalomas) and with aldosteronomas.
The laparoscopic dissection of Cushing's adenoma has been
described as moderately difficult due to the relatively higher
retroperitoneal fat content present in these patients. Bilateral
adrenalectomies for Cushing's disease have been described
in patients who failed transsphenoidal pituitary ablation.
Laparoscopic removal of pheochromocytoma has proved to
be a safe alternative in skilled hands. The role of laparoscopic
adrenalectomy for isolated adrenal metastases is still
controversial.
Contraindications to laparoscopic adrenalectomy include
adrenal carcinoma and adrenal masses greater than 10 em.
One approach used by some surgeons is to create a space

around the adrenal gland with an air-filled balloon inserted
retroperitoneally. This allows for minimal trauma to organs
within the peritoneal cavity. The patient is placed in prone
jackknife position and a balloon trocar is placed in the
retroperitoneal space, insufflated, and then removed.
Operative and retracting ports are placed.
Left Adrenalectomy. Laparoscopic ports to insert
a camera and instruments (usually three or four ports) are
positioned below the left rib cage. The left adrenal gland is
exposed after the spleen is freed up from attachments over
the adrenal, the colon is moved down, and the tissue over the
upper pole of the kidney opened to reveal the adrenal gland.
The inferomedial border of the gland is identified and
dissected, exposing the left renal vein. The vein is divided
along with remaining vascular twigs.
Right Adrenalectomy. Laparoscopic ports (four or five)
are inserted along the right rib cage for camera, instruments,
and a liver retractor. Mobilizing the right lobe of the liver from
the tissues of the back of the abdomen is critical. Once the
retroperitoneum is exposed and the liver retracted, the vena
cava is exposed and, by following it, the adrenal vein is
identified. Depending on the anatomy of the region and the
reason for the adrenalectomy procedure, the adrenal vein or
veins may be divided early. Alternatively, arterial branches
into the gland may be divided at this point before the vein is
clipped, stapled, or oversewn.
TRANSABDOMINAL LAPAROSCOPIC
ADRENALECTOMY
Summary
Left Adrenalectomy. The splenic flexure is mobilized

medially to expose the lienorenal ligament . The ligament is
then incised to demonstrate the short gastric vessels posteriorly behind the stomach. This allows the spleen to fall
medially, exposing the retroperitoneal space. The adrenal
gland, the adrenal mass, and the adrenal vein are identified.
Grasping the perinephric fat, the lateral and anterior parts of
the adrenal gland are dissected avoiding to grasp the adrenal
gland or tumor directly, because the tissue may tear.
For smaller adrenals 5 em), the gland is dissected inferomedially. This allows for early identification and clipping
of the adrenal vein. As dissection is continued upward, adrenal branches of the inferior phrenic vessels are clipped. For
larger glands, dissection proceeds superiorly, clipping the
adrenal branches of the inferior phrenic vessels.
Right Adrenalectomy. A retractor is placed through the
most anterior port and the right hepatic lobe is retracted
anteriorly. The lateral right hepatic attachments are divided
along with the right triangular ligament. The adrenal and its
mass are identified. The inferolateral edge of the right adrenal gland is identified and dissected inferiorly.
For glands less than 5 em, the right adrenal vein is visualized early and taken. The adrenal branches of the inferior
phrenic vein are clipped and divided as the dissection is
Understanding the embryology, anatomic relationships, and

neurovascular supply of the adrenal glands helps the clinician interpret localization studies and choose the appropriate
adrenal operation for individual patients.
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2. Welbourn RB. The History of Endocrine Surgery. New York, Praeger,
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3. Home E. Lectures on Comparative Anatomy, Vol 5. London, Longman,
Ress, Home, Brown & Green, 1828, p 259.
4. Cuvier GLC. Lecons D' Anatomie Comparee. Paris, Baudonin,
1800-1805.
5. Addison T. On the Constitutional and Local Effects of Disease of the
Suprarenal Capsules. London, Samuel Highley, 1855.
6. Brown-Sequard CEoRecherches experimentales sur la physiologie et al
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20. Reichtenstein T, Shopper CWO The hormones of the adrenal cortex.
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37. Kikuta A, Mukarami T. Microcirculation of the rat adrenal gland: A scanning electron microscope study of vascular casts. Am J Anat 1982; 164:22.
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their connections with azygos veins. J Anat 1986;146:105.
39. Camey JA, Sizemore GW, Tyce GM. Bilateral adrenal medullary hyperplasia in multiple endocrine neoplasia type 2: The precursor of bilateral
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41. Belloni AS, Neri G, Musajo FG, et al. Investigations on the morphology and function of adrenocortical tissue regenerated from the capsular fragments autotransplanted in the musculus gracilis of the rat.
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Pharmacology of Adrenal Cortical Hormones. New York, Pergamon
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Adrenal Physiology
Staffan Grondal, MD, PhD Bertil Hamberger, MD, PhD
The normal adrenal gland in humans weights 5 to 7 g and is

4 to 5 em long, 2 to 3 em wide, and I em thick. The paired
adrenal glands are situated on the anteromedial aspect of the
kidneys. The adrenal has two functional entities, the adrenal
cortex and the adrenal medulla. Although there are some
developmental and functional relationships between the
cortex and the medulla, they are discussed separately.
Adrenal Cortex
Functional Morphology
The adrenal cortex constitutes about 85% of the whole
gland. The cortex surrounds the medulla and is arranged in
three zones: zona glomerulosa, fasciculata, and reticularis
(Fig. 65-1). The zona glomerulosa lies just under the capsule
and is thin. It constitutes about 15% of the cortex or may
present focally with small round cells with a small cytoplasmic
volume. The zona fasciculata is broad. It constitutes about
70% of the cortex, with larger cells with abundant cytoplasm
("clear" cells). Closest to the adrenal medulla lies the zona
reticularis, with cells of intermediate size ("compact" cells).
The adrenal gland is highly vascularized. Three major arteries
from the aorta, inferior phrenic artery, and renal arteries as
well as up to 50 arterioles course through the cortex and via
capillaries anastomose to veins that pass the medulla and
enter a central vein. The blood supply of the cortex is
thereby mainly separated from that of the medulla, but the
outer part of the medulla is reached by cortisol-rich blood.
The right adrenal vein is 2 to 5 mm long and drains directly
into the inferior vena cava, whereas the left adrenal vein is
longer and drains into the left renal vein.
Functional Zonation
Aldosterone is synthesized and released only from the zona
glomerulosa, whereas the zona fasciculata synthesizes mainly
cortisol, dehydroepiandrosterone (DHEA); other androgens
and estrogen are synthesized in both the zona reticularis and
zona fasciculata (see Fig. 65-1). DHEA sulfate (DHEA-S) is
the quantitatively dominating steroid from the adrenal cortex
and is released primarily from the zona reticularis.'
Biosynthesis of Corticosteroids
Plasma cholesterol is the major source of substrate used for
steroid synthesis by the adrenal cortex." Pregnenolone, the
origin of all steroid hormones (C21, C19, CI8), is formed
from cholesterol after hydroxylation and enzymatic cleavage
of the side chain within the mitochondria. The synthesis of
steroid hormones from pregnenolone is dependent on several
metabolizing enzymes localized in the mitochondrion and
microsomes (Fig. 65-2). Steroid hormones are metabolized
by the liver and excreted in the urine as more water-soluble
conjugates with glucuronic acid or sulfates.
Aldosterone
Pregnenolone is 21-hydroxylated in the endoplasmic
reticulum and, after 11- and 18-hydroxylation, aldosterone
is formed, It is secreted in its free form and is also bound
with low affinity to albumin. The main effects of aldosterone
and other mineralocorticoids are to maintain normal Na"
and K+ concentrations and extracellular fluid volume.
Synthesis and secretion of aldosterone are regulated
mainly by angiotensin II and changes of the plasma levels
of potassium and sodium.' A decrease of the intravascular
volume is registered in the renal juxtaglomerular cells,
located in the wall of the afferent glomerular arteriole, and
leads to a release of renin. These cells also respond to
~-adrenergic
stimuli and prostaglandins. Renin cleaves
angiotensinogen to angiotensin I, which is converted to
angiotensin II by angiotensin-converting enzyme.
Angiotensin II, in itself a potent vasoconstrictor, binds to
membrane receptors on the zona glomerulosa cell surface.
Aldosterone biosynthetic enzymes are activated through
phospholipase C inositol triphosphate diacylglycerol, which
increases the intracellular calcium concentration."
Increments of serum potassium significantly increase
serum aldosterone. Sodium depletion stimulates the conversion of corticosterone to aldosterone, but large changes of
plasma sodium are necessary.' Adrenocorticotropic hormone (ACTH, corticotropin) has only a permissive role in
the synthesis of aldosterone. Consequently, a prompt control
of sodium and potassium intake as well as pharmacologic
571
572 - -
Adrenal Gland
The layers of the adrenal gland and their hormone production
FIGURE 65-1. Schematic of the adrenal

glands with the zones and the corresponding
hormones produced.
agents affecting the renin-angiotensin system, ~-adrenergic

receptors, and prostaglandins are necessary when investigating
aldosterone secretion.'
Cortisol
In the endoplasmic reticulum, pregnenolone is converted
to progesterone and 17a-progesterone is 21-hydroxylated to
l l-deoxycortisol, and in the mitochondrion, II-deoxycortisol
is hydroxylated to cortisol. After secretion, most of the
cortisol (80%) that circulates in plasma is bound with high
affinity to a corticosteroid-binding globulin, transcortin,

whereas an additional 15% is bound to albumin and less
than 10% is free.' Synthesis of cortisol is completely regulated by ACTH, which binds to receptors of the adrenal cell
surface. The action of ACTH is mediated by the adenylate
cyclase-cyclic adenosine monophosphate-protein kinase A
system." Initially, the conversion rate of cholesterol to
pregnenolone increases; more chronic ACTH stimulation
increases the corticosteroid enzyme activity, and hypertrophy
of the adrenocortical cells occurs.' Serum levels of cortisol
show a specific diurnal rhythm, with highest levels in the
Dehydroepiandrosterone
Androstenedione
Estradiol
Estrone
FIGURE 65-2. Steroid biosynthesis

in the adrenal cortex and the major
urinary metabolites. Mitochondrial
and microsomal cytochrome PA50
enzymes catalyze the conversion
of steroids.
Adrenal Physiology - - 573

early morning and low levels at night. 1 The serum cortisol
level is continuously regulated by a feedback mechanism on
the hypothalamus and pituitary.
Patients treated with replacement or pharmacologic doses
of exogenous glucocorticoids usually have low or absent
measurable corticotropin in the serum. Patients receiving
pharmacologic doses of steroids are unable to respond with
increased endogenous cortisol secretion in response to surgical stress. Accordingly, these patients need to receive a stress
dose of steroids when in a physiologically stressful state.
Sex Steroids
The adrenocortical sex steroids DHEA and andostenedione
are formed after 17a-hydroxylation of pregnenolone or
progesterone and side chain removal from carbon 17. They
are secreted mainly as sulfates and are converted in peripheral
tissues from relatively weak adrenal androgens to testosterone
and estrogens. ACTH stimulates the synthesis and secretion
of adrenal androgens, but there is no diurnal variation of
DHEA-S in serum'?
Physiologic Effects of
Corticosteroids
Aldosterone
Aldosterone regulates electrolyte excretion and the intravascular volume through its effects on the distal tubules and
cortical collecting tubes of the kidney. It binds to a mineralocorticoid receptor in the cytosol and moves into the
nucleus to increase transcription." The early effect is to
increase the Na absorption through the Na channels. Via
changes in electrical potential across the renal tubule, K and
H secretion are increased. This leads to an expanded intravascular volume and suppresses renin secretion. Chronically
increased aldosterone secretion is characterized by
increased peripheral vascular resistance and persistent high
blood pressure.
Cortisol
Cortisol exerts its effect by regulating gene transcription
after binding to glucocorticoid receptors within the cell."
Cortisol has a large number of metabolic effects on several
tissues. However, many of the effects of glucocorticoids are
based on studies of patients, animals, and cells with nonphysiologically high or low levels of glucocorticoids.
Glucocorticoids are necessary for maintaining hepatic
glycogen stores. They stimulate protein catabolism and
lipolysis and cause hyperinsulinemia.' Cortisol is required
for maintenance of normal blood pressure. The effect on
immunologic function of glucocorticoids in physiologic
levels is not clear, but glucocorticoid excess suppresses
both immunologic and anti-inflammatory responses.
Glucocorticoids have a weak mineralocorticoid effect and
influence calcium homeostasis by decreasing intestinal
calcium absorption and increasing urinary calcium excretion. I In pharmacologic doses, cortisol causes osteoporosis.
The effects of cortisol on the central nervous system manifest
as changes in excitability, behavior, and mood. 1
Adrenal Androgens
The physiologic effects of DHEA-S, DHEA, and androstenedione are relatively weak, and they undergo conversion to
testosterone in peripheral tissue. In females, androgens produced by the adrenal glands sustain normal pubic and axillary
hair growth, and after menopause the adrenal glands are a
major source of estradiol. However, in males, the high
amount of androgens produced by the testis exceeds that
produced by the adrenal glands. 1
Adrenal Medulla
Chromaffin Cells
The adrenal medulla constitutes about 15% of the adrenal
and is surrounded by the cortex. The major constituent of
the medulla, the catecholamine-containing cells, are of two
types: the norepinephrine and the epinephrine cells. These
cells are often called chromaffin cells because they stain
with chromium salts, and this was an early method used to
detect these cella.' Chromaffin cells in adults are primarily
confined to the adrenal medulla, although they also occur in
extra-adrenal locations. They may give rise to extra-adrenal
paraganglioma in the organ of Zuckerkandl (distal aorta), in
the bladder, in the neck and, more rarely, at other sites.'? In
addition, the adrenal medulla contains sympathetic ganglion
cells, connective tissue, and blood vessels. The adrenal
medulla has an arterial supply via several small arteries and
a venous outflow to the central adrenal vein.
The epinephrine cells in the medulla are localized close
to the cortex, where they are exposed to high cortisol levels
of portal venous effluent. Cortisol is required for the induction of phenylethanolamine N-methyltransferase (PNMT),
the methylating enzyme that converts norepinephrine to
epinephrine (Fig. 65-3). Chromaffin cells in extra-adrenal
locations usually do not produce epinephrine, probably
because of a lack of cortisol to activate PNMT.11 The preganglionic cell bodies are located in the intermediolateral
cell column in the spinal cord. Their axons pass the sympathetic ganglia and reach the adrenal gland via the splanchnic
nerves and innervate the chromaffin cells.
Transmitter Mechanisms
SYNTHESIS
The catecholamines are synthesized from tyrosine, which is

converted to dihydroxyphenylalaline by the cytosolic
enzyme tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis (see Fig. 65-3),12 and further converted
to dopamine by dopa decarboxylase. Dopamine is taken up
into granular vesicles and converted to norepinephrine via
dopamine ~-hydroxylase
(DBH). This uptake is an adenosine
triphosphate (ATP)-requiring process, in which the uptake of
dopamine prevents its degradation by cytoplasmic monoamine
oxidase. Norepinephrine is stored in the granular vesicles in
a complex where one catecholamine molecule is coupled to
four ATP molecules. Certain chromaffin cells contain the
enzyme PNMT, which converts norepinephrine to epinephrine. Neuropeptide Y (NPY), enkephalins, somatostatin, and
chromogranins are also stored in the granular vesicles.
Norepinephrine
Epinephrine
MAO
MAO
~
COMT
Dihydroxymandelic acid
COMT
MAO
When the adrenal medulla is stimulated, the chromaffin cell

membrane depolarizes, secretory vesicles fuse with the
cell membrane, and the vesicular content is released via
exocytosis.P All components of the granular vesicles are
released: catecholamines, DBH, NPY, enkephalins, and
chromogranins. Because of a rich vascular supply, most
released substances are transported away from the medulla
and direct reuptake back into the chromaffin cells only plays
a minor role compared to sympathetic nerves. The physiologic importance of the released substances in addition to
catecholamines is not clear. NPY has been shown to have
vasoconstrictive effects, although it is much weaker than the
catecholamines.!" Enkephalins may function as analgesics
during stress. 15 The chromogranins may be of importance
for storage of neurotransmitters and may also serve as peptide
precursors. 16
DEGRADATION
The degradation of norepinephrine and epinephrine is

shown in Figure 65-4. Monoamine oxidase is present in
mitochondria of most cells and catalyzes the deamination
of catecholamines. Catechol O-methyltransferase induces
methylation of catecholamines or their deaminated metabolites to the major final product, vanillylmandelic acid. In the
liver and gut, conjugation with sulfuric or glucuronic acid
takes place, and these substancesare then excreted in the urine.
Only a small amount is excreted as free dopamine,
norepinephrine, and epinephrine in the urine.
Determination of Release from the

Adrenal Medulla
Free urinary catecholamines most likely reflect an estimation
of the sympathoadrenal activity during the sampling period.
In urine, vanillylmandelic acid and metanephrine levels also
give a good indication of adrenal medulla catecholamine
secretion. Plasma catecholamines are usually determined as
unconjugated free and protein-bound levels. Under basal
conditions, only a small amount of plasma norepinephrine
COMT
IMetanephrine I
INormetanephrine I
SECRETION
FIGURE 65-3. Synthesis of catecholamines in the adrenal medulla.

DOPA = dihydroxyphenylalaline.
MAO
Vanillylmandelic acid
FIGURE 65-4. Degradation of norepinephrine and epinephrine.

MAO = monoamine oxidase; COMT = catechol O-methyltransferase.
(normal, 0.6 to 2 nmol/L) originates from the adrenal

medulla, because the major part of the norepinephrine is
secreted from the sympathetic nerves. In contrast, plasma
epinephrine (normal, 0.1 to 0.3 nmol/L) is secreted only by
the adrenal medulla. The half-life of plasma epinephrine and
norepinephrine is very short (l to 2 minutes), and the variations in plasma norepinephrine are a reflection of variations
in sympathetic tone. Because of the effective mechanism
for reuptake into sympathetic nerves, venous plasma catecholamines show variations related to the sampling site.
More recently, measurement of plasma normetanephrine
and metanephrine has been shown to be more reliable for
evaluating hypersecretion of catecholamines from the adrenal
medulla because their half-life in plasma is much longer
than norepinephrine and epinephrine. I?
Physiologic Effects
Catecholamines exert their effect on specific adrenergic
receptors. These receptors are transmembrane proteins
known to be encoded by separate genes. Initially a- and
~-adrenergic
receptors were identified and their subtypes
have been characterized. The at receptors mediate vascular
stimulation
smooth muscle contraction. ~l-receptor
increases heart rate and myocardial contractility, whereas
~2 receptors are involved in smooth muscle relaxation. The
~3 receptors regulate lipolysis and energy expenditure.
Catecholamines influence almost all tissues and organs in
the body. Catecholamines have profound cardiovascular and
metabolic effects and also influence the secretion of many
hormones.t The major effects are cardiovascular, with contraction of blood vessels and increasing heart rate and force.
Catecholamines also exert effects on extravascular smooth
muscle, causing both contraction and relaxation. In addition,
catecholamines affect metabolism by increasing oxygen
consumption and heat production, and they also regulate the
mobilization of glucose and fat stores.
Adrenal Physiology - -
Basal secretion of catecholamines from the adrenal

medulla is low. Substantial stimulatory conditions such as
trauma and surgical stress are required to increase catecholamine secretion from the adrenal medulla. The release
of epinephrine is of interest in special conditions. IS
Epinephrine is released from the adrenal medulla during an
operation at the time of intubation and skin incision. High
levels of epinephrine are also found during traumatic events,
such as myocardial infarction and pain or fear. During severe
hypoglycemia, epinephrine levels may be up to 50 times the
basal level, owing to stimulation of glucose-sensitive neurons
in the central nervous system.
Summary
The adrenal gland has two functioning endocrine units, the
cortex and the medulla. The cortex secretes corticosteroids,
including the major glucocorticoid, cortisol, and the major
mineralocorticoid, aldosterone. The cortex also secretes
DHEA-S and, to a lesser extent, androgens and estrogens.
Glucocorticoids are necessary for life, and their secretion is
regulated by the hypothalamic-pituitary-adrenal axis. The
medulla primarily secretes the catecholarnines epinephrine,
norepinephrine, and dopamine.
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lipoprotein-cholesterol and its utilisation for steroid synthesis in the
adrenal cortex. Rec Progr Horm Res 1979;35:215.
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3. Quinn S, Williams G. Regulation of aldosterone secretion. Annu Rev

PhysioI1988;50:409.
4. Berridge M. Inositol triphosphate and calcium signalling. Nature
1993;361:315.
5. Greenspan FS, Gardner DG. Basic and Clinical Endocrinology.
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6. Gill G. ACTH regulation of the adrenal cortex. Pharmacol Ther
1976;2:313.
7. Simpson E, Waterman M. Regulation of the steroidogenic enzymes in
the adrenal cortical cell by ACTH. Annu Rev PhysioI1988;50:427.
8. Horisberger J, Rossier B. Aldosterone regulation of gene transcription
leading to control of ion transport. Hypertension 1992; 19:211.
9. Gustafsson J-A, Carlstedt-Duke J, Poellinger L, et al. Biochemistry,
molecular biology of the glucocorticoid receptor. Endocr Rev
1987;8:185.
10. Manger WM, Gifford RWJ. Pheochromocytoma. New York, SpringerVerlag, 1977.
II. Wurtman R, Axelrod J. Control of enzymatic synthesis of adrenaline
in the adrenal medulla by adrenal cortical steroids. J Bioi Chern
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12. Kopin I. Catecholamine metabolism and the biochemical assessment of
sympathetic activity. Clin Endocrinol Metab 1977;6:525.
13. Dahlstrom A, Belmaker S, Sandler M (eds). Part A: Basic aspects and
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New York, Wiley, 1988, p 279.
14. Lundberg 1M, Torssell L, Sollevi A, et al. Neuropeptide Y and sympathetic vascular control in man. Regul Pep 1985;13:41.
15. Lewis JW, Tordoff MG, Sherman IE, et al. Adrenal medullary
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core vesicles of endocrine and nervous tissue. J Anat 1993;183:237.
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Adrenal Imaging Procedures

Andreas Zielke, MD Matthias Rothmund, MD
Modalities for Imaging

the Adrenal Gland
Evaluation of a patient with an adrenal gland mass is
founded on a thorough history and physical examination,
followed by appropriate biochemical tests. After the diagnosis has been established, imaging procedures are used for
localization and presurgical planning. Improvements of
functional and anatomic imaging procedures allow reliable
preoperative evaluation of virtually all adrenal masses.
Computed tomography (CT) and magnetic resonance imaging (MRI) are the main modalities used to localize adrenal
tumors. The best radiologic imaging test is CT scanning, and
it is usually the only imaging study required. In this chapter,
we review adrenal imaging techniques and discuss their
indications and limitations. We also present flowcharts
showing how the most prevalent adrenal diseases, including
incidentaloma of the adrenal gland, should be approached.
Computed Tomography
CT is the modality most commonly used to evaluate a
patient suspected of having an adrenal mass.' CT accurately
delineates the location, size, and configuration of the mass;
local invasion; and affected adjacent lymph nodes or distant
metastases.' For routine applications, l-cm contiguous
scans in the adrenal area are usually obtained. For smaller
masses (e.g., in primary hyperaldosteronism) thinner scans,
such as 0.5-cm slices, are necessary. The normal right adrenal
gland is a comma-shaped gland of roughly I x 2 x 0.5 cm,
and the left adrenal is a lambda-shaped gland of roughly
similar size. The normal adrenal gland is approximately
the same size as the diaphragmatic stripe seen on CT
(Fig. 66-1). The right adrenal gland is usually directly
posterior to the inferior vena cava, and the left adrenal is
anterior to the upper portion of the kidney and adjacent to
the aorta. Although intravenous contrast material is not
routinely used, it is useful for differentiating vascular structures from the adrenal or for enhancement characterization
of adrenal tumors. Oral contrast media to opacify bowel
may be required for extra-adrenal pheochromocytomas and
for delineation of adrenal carcinomas. Despite the merits
of CT scanning, it lacks specificity. For example, adrenal
576
adenomas, carcinomas, and pheochromocytomas cannot be

differentiated by plain CT scanning. Cysts and myelolipomas are the only conditions that are reliably diagnosed by
CT. In cases of Addison's disease, CT scanning may reveal
atrophy;' but as exemplified in this condition, much of its
capacity to differentiate one lesion from another is based on
size rather than specific tissue characteristics.' False-negative
examinations result largely from trying to image tumors
smaller than 1 em in diameter.

MRI is increasingly used because it can reveal tissue-specific
characteristics, which allows the examiner to differentiate
metastases, adrenocortical carcinoma, and pheochromocytoma
from adenoma, lipoma, myelolipoma, and cysts." Because
MRI does not use ionizing radiation, it is an attractive
modality for evaluating children and pregnant women."
Tl-weighted images allow relatively fast data acquisition,
which may be accelerated by using paramagnetic contrast
media such as gadolinium-diethylenetriaminepenta-acetic
acid (DTPA), resulting in a reduction of motion artifact and
increasing the sensitivity for identifying adrenal lesions.
T2-weighted sequences reveal characteristic signal intensities
in certain conditions and help with the differential diagnosis."
Some studies have suggested that MRI can differentiate nonfunctioning from malignant adrenal lesions," but because of
similar characteristics of some tumors, the results are not reliable enough to use in selecting therapy.S?
Adrenal Scintigraphy
Adrenal scintigraphy provides localization and functional
information and is therefore helpful for differentiating certain
adrenal neoplasms. Scintigraphy is often used in conjunction
with CT or MRI because it offers much less anatomic information than other modalities. Numerous radiolabeled pharmaceuticals are being investigated to provide improved
localization tests for the adrenal cortex and medulla.
Iodocholesterol-labeled analogs such as l31I-6~-iodomethyl 19-norcholesterol (NP-59) and 75Se-6~-selenomethyl
cholesterol are used to scan the adrenal cortex.V' Studies using
NP-59 make use of the fact that adrenal lesions can be distinguished on the basis of intact steroidogenesis pathways and
Adrenal Imaging Procedures - - 577
noninvasive, and involving no ionizing irradiation, which

makes it attractive for evaluating children and pregnant
women. For children, ultrasonography has been very effective,
whereas in adults, visualization of the right adrenal is successful in approximately 90% of cases and for the left the success rate is only 75%.14 Ultrasonography delineates lesions
of 2 em or larger and is helpful in differentiating cysts from
solid masses and in evaluating involvement of large vessels
and liver metastases. 15 Ultrasonography is an ideal screening
modality for adrenal neoplasms and for following the
progression of adrenal masses. Ultrasonography is not as
accurate as CT. It requires an experienced interpreter and is
notoriously operator dependent.'
Arteriography and Adrenal Venography
FIGURE 66-1. CT images of normal adrenal glands. A, The

medial limb of the right adrenal gland (arrow) is dorsal to the
inferior vena cava and ventral to the upper pole of the kidney.
B. The left adrenal gland (arrow) has an inverted V appearance.
(From Davidson AJ, Hartman DS. Radiology of the Kidney and
Urinary Tract, 2nd ed. Philadelphia, WE Saunders, 1994, p 716.)
the presence of abundant intracellular cholesterol. However,

imaging requires several days, which is unacceptable in
some cases. Moreover, in several comparative studies, CT
required less time to perform and interpret, cost less, used
less ionizing radiation, and provided similar diagnostic
accuracy. to
Metaiodobenzylguanidine (MIBG) is the most frequently
used radionuclide for imaging the adrenal medulla. MIBG is an
analog of guanethidine. It is taken up by adrenergic granules
and adrenal medulla cells because of its structural similarity to
norepinephrine. However, it has essentially no pharmacologic
effect. II Because MIBG is concentrated in catecholamine
storage vesicles, it allows functional assessment of adrenal
medullary tissue and is diagnostic for pheochromocytomas."
Iodine 131 MIBG is the most commonly used isotope, but
123I_MIBG has resulted in more accurate delineation of pathologic tissues than 13II_MIBG and provides superior dosimetry. 13
MIBG studies take 3 days to complete, and their spatial resolution is poorer than that provided by CT scans.
Ultrasonography
Controversy exists regarding the efficacy of ultrasonography
in the evaluation of adrenal tumors. Ultrasonography offers
the particular advantages of being less expensive, being
Considered invaluable tools in differentiating hyperplasia

from carcinoma in the 1980s, arteriography and adrenal
venography have almost completely been replaced by CT
and MR!. In general, these invasive methods should be
reserved for the rare instance in which CT or MRI provides
insufficient information. Arteriography in patients with
pheochromocytoma may be hazardous, and venography may
be dangerously invasive, especially in children; it has been
associated with significant morbidity in pediatric cases. 15
Selective arteriography, however, may be helpful if it is
difficult to determine whether a mass on CT is suprarenal or
renal in origin. 16
Venography, often used in combination with selective
venous sampling, is employed more often than arteriography. I?
Although the method successfully approaches the left adrenal
gland in virtually all cases, this cannot always be accomplished for the right gland and demands an experienced radiologist. Venography with selective adrenal sampling is useful
in examining patients with hyperaldosteronism or Cushing's
syndrome when the clinician cannot discriminate by CT or
MRI between hyperplasia and adenoma, and it is occasionally useful for determining the source of ectopic corticotropin (ACTH) production. Complications occur in about
5% of patients and consist mainly of contrast extravasation
and hematoma and rarely of adrenal vein thrombosis and
adrenocortical insufficiency. I?
Hyperadrenocorticism
The most common cause of Cushing's syndrome is exogenous
administration of corticosteroids. Regarding the remaining
organic causes, approximately 70% of patients with Cushing's
syndrome have pituitary Cushing's, resulting in bilateral
adrenocortical hyperplasia and cortisol excess. Ten percent
have adrenal adenomas, 10% have adrenal carcinomas, and
8% to 10% have ectopic Cushing's or extrapituitary ACTHproducing tumors, including small cell lung cancers, cancers
of the pancreas, carcinoid tumors, medullary thyroid cancers,
and other neoplasms.
Computed Tomography Studies

The initial localizing procedure of choice for patients with
adrenal Cushing's syndrome is a contrast-enhanced CT scan

gland, and only few adenomas show contrast enhancement.
Large or heterogeneous tumors with areas of low density
caused by necrosis or hemorrhage and calcifications should
raise the suspicion of carcinoma and prompt a search for
local invasion or distant metastases.
CT may also be helpful in evaluating hyperplasia
(Fig. 66-3). In fewer than half of cases with ACTH-dependent
Cushing's syndrome, CT reveals bilaterally enlarged adrenal
glands with uniform thickening of both limbs. Careful
examination of the entire gland is mandatory for
differentiating adenoma from the rare incidence of
a dominating nodule in macronodular hyperplasia. The
absence of an adrenal tumor and an apparently normal
adrenal morphologic pattern on CT in biochemically proven
Cushing's disease suggests adrenal hyperplasia.
Other Imaging Modalities

FIGURE 66-2. CT scan of an adrenocortical adenoma causing
Perinephric fat provides excellent contrast for MR!. Fast,

gadolinium-enhanced MRI can detect lesions less than I em
in diameter, but it provides little additional information if a
CT examination has already been performed.
Ultrasonography may be difficult to perform in cases of
Cushing's syndrome because of the truncal obesity of the
patients. Ultrasonography can identify large tumors, but it is
of limited value as a routine adrenal imaging modality for
these patients.
Adrenal venography with selective venous sampling for
cortisol allows differentiation of adrenal tumors (i.e., unilateral
peak cortisol concentrations) from hyperplasia (i.e., bilateral
increased cortisol concentration). Selective venous sampling,
however, is unable to differentiate malignant from benign
adrenal lesions, although malignant tumors are more likely
to secrete multiple hormones.'?
Cushing's syndrome. Contrast-enhanced CT depicts a 2.5-cm,

solid, homogeneous, well-delineated left adrenal tumor. The
diagnosis of adrenocorticism was established biochemically.
of 10-mm collimation, with even narrower collimation in

equivocal cases. CT can detect virtually all adrenal masses
that are large enough to cause Cushing's syndrome. The
abundant perinephric fat in most patients with corticoid
excess allows the adrenal gland to be displayed clearly, and
tumors at least I em in diameter are identified routinely
(Fig. 66-2). Adrenal adenomas causing Cushing's syndrome
are usually 2 to 5 em in diameter, and CT detection
approaches 98%.18 The density, although variable, is mostly
similar to the soft tissue density of the adjacent adrenal
Clinical Suspicion of Cushing's Syndrome

Biochemistry
ACTH dependent
ACTH independent
No further
adrenal imaging
CT
FIGURE 66-3. The flowchart
Typical adenoma or
typical carcinoma
shows the procedures used in

imaging the adrenal glands for a
possible case of Cushing's syndrome. ACTH = corticotropin;
19NP-59 = l3lI-6~-iodomethyl
norcholesterol.
Equivocal or suspected hyperplasia
Scintigraphy-NP-59 uptake
Surgery
None
(cancer)
Surgery
Bilateral
(hyperplasia)
Observe/treat
Unilateral
(adenoma)
Surgery
Adrenal Imaging Procedures - -
579
Because abdominal CT provides excellent results, adrenocortical scintigraphy using NP-59 is recommended only for
selected patients. NP-59 scintigraphy has been recommended
in cases of adrenal hyperplasia, for which it has an overall
accuracy of 90% to 95% in experienced hands. Scintigraphy
is performed without dexamethasone suppression, and images
are obtained 5 to 7 days after administration of the tracer.
Bilateral uptake suggests adrenal hyperplasia, and unilateral
uptake, secondary to contralateral adrenal suppression, indicates an adrenal adenoma. Bilateral nonvisualization of the
adrenals has been associated with carcinoma because of the
lack of tracer uptake by malignant tumors.v" However,
other factors resulting in bilateral nonvisualization, such
as hypercholesterolemia and glucocorticoid administration,
should be excluded. NP-59 scintigraphy has failed to gain
popularity in many institutions because of limited experience
with the isotope, the time required to complete the study,
high costs, and the need for an investigational new drug
approval for its use.
FIGURE 66-4. Contrast-enhanced CT scan of a patient with
primary hyperaldosteronism identifies a 1.5-cm-diameter, wellmarginated, rounded adenoma adjacent to the right adrenal gland.
The aldosteronoma is isodense with adjacent adrenal tissue.
Notice the normal size and appearance (lambda shape) of the left
adrenal gland.
Primary Hyperaldosteronism
Seventy-five percent of patients with primary hyperaldosteronism have benign adrenal adenomas, and 25% have idiopathic
hyperplasia of the zona glomerulosa. Fewer than 1% have
adrenocortical cancer. In patients with primary hyperaldosteronism, it is essential to determine whether it is caused by
an adrenal adenoma or by hyperplasia because virtually
all patients with adenomas benefit from surgical treatment
(i.e., abatement of hypokalemia and lower blood pressure),
but most patients with hyperplasia do not. 20
Because of their small size, these tumors may be missed

during CT scanning, resulting in a sensitivity of 85% with a
positive predictive value of up to 100%.21,22 Five percent to
15% are not identified, leaving a sizable group of patients
for whom scintigraphy and venous sampling playa major
role (Fig. 66-5). Isodense small lesions close to the apex of
the adrenal are the ones most likely to be missed. If CT
reveals a unilateral mass in a patient with biochemically
proven primary aldosteronism, no further studies are usually
required. If CT findings are negative or equivocal, adrenal
venous sampling should be performed,
Selective adrenal venous sampling has identified a hypersecreting abnormality in almost 100% of cases in selected
series.' Combined CT and selective adrenal venous sampling
approaches a sensitivity of 100% in identifying the cause of
primary aldosteronism.P In the case of an aldosteronoma,
Aldosteronomas are usually small lesions, averaging 0.6 to
1.8 em in diameter. CT scanning, therefore, requires 0.3- to
O.5-mmcontiguous slices in the adrenal area, and the patient's
cooperation is necessary for achieving adequate sensitivity.P"
Aldosteronomas often appear as well-marginated, rounded
tumors that are isodense or, less frequently, hypodense compared with adjacent adrenal tissue (Fig. 66-4). They typically
are not enhanced after administration of a contrast agent.
Biochemically Confirmed Primary Hyperaldosteronism
CT

shows the diagnostic modalities
used in imaging the adrenal glands
for a suspected case of hyperaldosteronism. NP-59 = 1311-6~-iodomethyl 19-norcholesterol.
I
Typical adenoma or
typical carcinoma
Surgery
Equivocal or symmetric enlargement
I
Scintigraphy-NP-59 uptake
I - - - IJ'-------
Early unilateral
adenoma
Early bilateral
hyperplasia
Surgery
Observe
NP-59 not available
\
Late bilateral
or none
Nond/agnostic
Venous sampling

unilateral peak levels are found on the side of the tumor.
In bilateral adrenal hyperplasia, venous sampling yields
symmetrically elevated levels. When performing selective
venous sampling, the clinician must obtain blood samples
for aldosterone and for cortisol.P Simultaneous measurement
of cortisol permits verification of the source of the sample and
correction for a dislodged catheter or dilution. Venous sampling is considered the "gold standard" for localizing aldosteronomas by several researchers, although most clinicians use
it only selectively for patients with equivocal studies.s'

Immunoiodocholesterol-labeled analogs (e.g., NP-59) have
been successfully used to image aldosteronomas.P The sensitivity varies greatly among series (50% to 90%), indicating
problems inherent in the technique." Pretreatment with dexamethasone enhances accuracy, and discontinuation of diuretics and antihypertensive agents is required. Unfortunately, the
test is time consuming, requiring 2 to 7 days. An asymmetric
pattern identifies an aldosteronoma taking up the radionuelide. Idiopathic hyperplasia is functionally depicted as bilateral foci of moderate NP-59 uptake within 72 to 120 hours
after administration. Bilateral uptake seen after more than
120 hours during constant dexamethasone suppression is
considered nondiagnostic.F Sensitivity depends primarily
on the adenoma's size, and the results of NP-59 scans are
less accurate for patients with very small adrenal neoplasms
and negative CT scans. Small and hypovascular aldosteronomas are also difficult to identify by ultrasonography,
MRI, or arteriography.
Pheochromocytoma
normal-appearing adrenal gland, contiguous thin sectioning

(0.5- to 1.0-cm slices) is recommended" Pheochromocytomas
show a wide range of morphologic patterns; most pheochromocytomas are rounded masses with homogeneous densities similar to or less than that of liver tissue, and they may
occasionally show a hemorrhagic, cystic ("Swiss cheese")
appearance or calcified lesions (Fig. 66-6). Despite this
heterogeneity, diagnosis of malignancy is unreliable unless
local invasion or metastases are apparent.
The diagnostic capability of CT scanning may be
increased with contrast enhancement, but there is a small
and unpredictable risk of precipitating a hypertensive crisis,
making a-adrenergic blockade before invasive localization
studies essential.28 Contrast enhancement of the tumors
is irregular; the periphery of these tumors is often more
intensely enhanced. Plain CT is highly accurate (-95%) for
intraglandular lesions, but it is less useful in identifying
extra-adrenal lesions and lesions in MEN patients, for which
it is only 60% to 80% sensitive. CT scanning is even less
accurate in evaluating patients with metastatic or recurrent
disease (sensitivity of about 60%).8.26.28 Contrast enhancement is essential to provide acceptable sensitivity for detecting extra-adrenal pheochromocytomas, especially those in
the neck and mediastinum.P
CT scanning in combination with MIBG (MIBG-CT)
appears to be the procedure of choice for identifying extraadrenal, ectopic tumor locations. MIBG is selectively taken
up by the adrenal medulla and by pheochromocytomas and
has been especially useful in evaluating ectopic disease and
malignant pheochromocytomas (Fig. 66-7). It is the recommended procedure for patients with recurrent or metastatic
disease." Some experts recommend MIBG scanning as the
initial diagnostic procedure for every patient suspected of
In planning the localization of a pheochromocytoma, one

should consider whether the tumor is sporadic or familial
and whether the patient is an adult or child. Most pheochromocytomas are sporadic (85%), and 15% are familial and
occur in patients with multiple endocrine neoplasia (MEN)
type 2, neurofibromatosis, or Sturge-Weber syndrome.
Although 85% of the tumors are unilateral, bilateral
pheochromocytomas are found in 50% of familial cases.
About 15% of pheochromocytomas are malignant and are
usually distinguishable clinically only by the absence or
presence of local invasion and metastases. Tumors in extraadrenal locations, which are more likely to be malignant, are
found in only 15% of adults, but in children the incidence
rises to about 25%. Fewer than 2% of tumors are found in
the mediastinum, neck, or head.
Because pheochromocytomas have usually attained a considerable size before being discovered, CT28.29 and Tl- and
T2-weighted MRI scans reliably detect pheochromocytomas, with an accuracy of almost 100%.8.26 After peroral
contrast preparation of the bowel, an abdominal CT scan
from the diaphragm distal to the aortic bifurcation is
performed as the initial imaging procedure. Because tumors
may extend superiorly and inferiorly from an otherwise
FIGURE 66-6. Contrast-enhanced CT scan of a patient with

pheochromocytoma manifesting as a rounded mass with density
similar to or slightly less than that of liver tissue. The tumor has
several cystic lesions, giving it a "Swiss cheese" appearance.
Despite this heterogeneity, a diagnosis of malignancy is unlikely.

sequences using gadolinium-DTPA enhancement enable
determination of vascular invasion by these tumors."
However, because the spatial resolution of MRI is inferior to
that of CT, routine scanning should be done with CT.
Moreover, CT has greater sensitivity in detecting liver metastases than MRI.
FIGURE 66-7. Metaiodobenzylguanidine scanning confirms a

left adrenal pheochromocytoma, identified as a mark on top of the
left of the two symmetrically depicted kidneys, together with an
ectopically located second tumor at the level of the aortic bifurcation (marker).
having pheochromocytoma because this modality detects most
tumors.P:" For diagnostic use, a tracer dose of 0.5 mCi is

given, imaging the adrenals in only a few normal control
subjects. For localizing primary, metastatic, and recurrent
disease, this approach has a false-negative rate of 11.4%
and a false-positive rate of 1.8%.35 MIBG has been used
for radioablative treatment of unresectable or metastatic
pheochromocytomas. Although there have been some good
responses, overall, it has been disappointing."
Positron emission tomography has been used after
administration of 2-fluorine-18-fluoro-2-deoxY-D-glucose
(FDG). The method was found promising for localization
of pheochromocytomas in the 10% of patients with falsenegative MIBG scintigrams."
Pheochromocytomas are localized and characterized by
MRI. The approach is at least equivalent to CT for localization
of adrenal pheochromocytomas that are larger than 2 em.'
Tumors tend to be hyperintense on T2-weighted pulse
sequences." Because of the consistency of hyperintensity,
recurrent tumor, metastatic disease, and extra-adrenal
pheochromocytomas are readily identified, and in this instance
MRI is more accurate and sensitive than CT. Moreover, owing
to the marked hyperintensity of functioning pheochromocytomas on T2-weighted pulse sequences, MRI permits differentiation of pheochromocytomas from nonfunctioning adrenal
neoplasms. Tumors of the urinary bladder or the paracardiac
region, which are difficult to evaluate by CT, are clearly
recognized by MRI. In one study, T2-weighted MRI and
MlBG-CT scans were nearly equivalent for localizing and
staging adrenal pheochromocytomas.w" T'l-weighted MRI
In the rare event that these noninvasive techniques fail, arteriography may be useful. However, patients must be treated
with a-adrenergic blockade (e.g., phenoxybenzarnine) to
should be used in a
avoid hypertensive crisis. ~-Blockade
patient with tachyarrhythmias whose tumor secretes epinephrine rather than norepinephrine. Arteriography should
include the superior, middle, and inferior adrenal arteries
and may be enhanced by subtraction techniques, especially
in the 15% of tumors displaying no or only moderate hypervascularization. Selective venography and selective venous
sampling of veins in the abdomen, pelvis, and chest may
very occasionally be useful for diagnosing small lesions,
especially intraglandular lesions or tumors at ectopic sites.
A positive result allows the physician to narrow the specific
region for further anatomic imaging. However, these techniques require great care and may be dangerous (Fig. 66-8).
Incidentalomas of the
Adrenal Gland and
Adrenocortical Carcinoma
The frequent use of imaging procedures, especially ultrasonography and CT, results in the discovery of unsuspected
adrenal masses. So-called incidentalomas or adrenalomas
are the most common reason the clinician becomes concerned about the adrenal gland. Incidentalomas have been
found in 0.6% to 4.3% of patients or at autopsy.42,43 The
major concern when evaluating a patient with an incidentaloma is whether the tumor is functioning and whether it is
benign or malignant (Fig. 66-9).
Certain information helps determine management of
patients with incidentalomas. Tumors that are homogeneous, have a smooth contour with well-delineated margins,
and are smaller than 4 em on ultrasonography or CT are
usually benign. Two thirds of adrenal carcinomas are functioning tumors." Most patients with adrenocortical carcinomas present with tumors larger than 6 em in their greatest
diameter at the time of diagnosis.s When metastatic disease
to the adrenal is suspected, percutaneous biopsy is useful;
however, it is unable to distinguish between an adrenocortical
adenoma and carcinoma. Most patients with CT-confirmed
diagnoses of simple adrenal cysts or adenomyelolipomas do
not require adrenalectomies. The masses should be monitored for growth.
The most common cause of nonfunctioning adrenal
masses is cortical adenomas, followed by metastases to the
adrenals, myelolipomas, ganglioneuromas, adrenal cysts,
and a multitude of other rare findings, some of which have
specific CT and MRI characteristics. Of all incidentally
discovered masses, 6.5% are pheochromocytomas'? and

Biochemically Confirmed Pheochromocytoma
Abdominal CT
Negative
(adrenal)
Positive
(adrenal)
Surgery
MIBG Scintigraphy-131I uptake
1--1- - 1
Negative
Negative
PET (FOG)
scan
Positive
MRI
(abdomen/chest/pelvis)
Surgery
Repeat using
1231-MIBG or
perform MRI
MIBG not available
Negative
Refer for
MIBG
Positive

shows the diagnostic procedures
used in imaging the adrenal glands
for a suspected pheochromocytoma.
FDG = 2-fluorine-18-fluoro-2deoxy-n-glucose; MIBG = metaiodobenzylguanidine; PET
positron emission tomography.
Surgery
Positive
Surgery
7% are aldosteronomas." The probability of an incidentaloma being an adrenal adenoma producing excess glucocorticoids is estimated at 0.035%; this number falls to
0.01 % in the absence of hypertension and obesity. Primary
adrenal carcinomas, overall, are rare tumors, with an estimated annual incidence of 0.06 to 0.27 per 100,000 persons,
resulting in an estimated prevalence of less than 0.06% of all
incidentalomas.v
FIGURE 66-9. Contrast-enhanced CT scan shows a right adrenal

carcinoma of considerable size (13 x 10 ern). In this carcinoma,
areas of low attenuation, suggesting tumor necrosis, are not appreciable, but the tumor is heterogeneous.
Adrenal Adenomas
Typically, a nonhyperfunctioning adenoma is a welldelineated, rounded, homogeneous mass. Calcification may
occur but is uncommon, as is central necrosis or hemorrhage.
The sizes of incidentally detected adenomas range from 0.5
to 6 cm.? However, CT does not reliably differentiate benign
adenomas from malignant lesions." Densities range from
approximately 0 to 30 HU.47 One study suggested that CT
attenuation values may enable one to differentiate nonhyperfunctioning adenomas (:::;5 HU) and metastases from
hyperfunctioning adenomas (~16.5
HU); values in excess of
20 HU were indicative of malignancy?"
If available, NP59 scintigraphy should be performed
because increased tracer uptake by a nonhyperfunctioning
lesion detected by ultrasonography or CT (i.e., concordant
uptake) indicates that the lesion is benign. Discordant
uptake indicates that the lesion is a complex adenoma
with hemorrhage or calcification (i.e., decreased, absent, or
distorted uptake) or not an adenoma at all, requiring further
assessment.48
Adrenal adenomas larger than 1.5 em are reliably
detected by MRI, and MRI may be used to characterize an
adrenal mass. For example, a decrease in the tumor's signal
intensity compared with the liver or fat signal intensity on
Tl- and T2-weighted MRI images occurs with adrenal
adenomas, but relative increases in signal density occur for
carcinomas and functioning adenomas. However, at present,
the data are insufficient for directing therapy.'"
Metastases
The adrenal gland is a common site of metastatic disease.
In a series of 1000 consecutive postmortem examinations
of patients with epithelial malignancies, adrenal metastases

were found in 27%.50 Despite the impressive figure, even
in patients with a predisposition for metastatic disease, such
as those with lung cancer, the most likely cause of an incidentally discovered adrenal mass is adrenal adenoma."
However, bilateral, nonfunctioning masses in a patient with
known cancer are likely to be metastatic disease. Overall,
the radiologic appearance of metastases is not specific.
During CT scanning, a metastasis usually appears as a solid
mass, and if less than 3 em in diameter, it is often homogeneous. Adrenal metastases may be impossible to differentiate from adenomas, pseudocysts, or inflammatory masses.
Features suggesting metastases include larger sizes (>3 em),
poor definition of margins or invasion of adjacent tissue,
inhomogeneous attenuation (i.e., hemorrhage or necrosis), and
a thick, perifocal, irregularly enhancing rim. 52
MRI has been used in differentiating metastatic disease
from primary adrenal neoplasms with some success, but
indeterminate findings occur for about one third of these
patients.P Several studies have suggested that there are
intensity cutoff points below which all lesions are adenomas
and above which all lesions are carcinomas.s-'! However, the
accuracy of MRI as a single modality for determination of
the nature of these lesions remains to be proved.
It appears that percutaneous fine-needle aspiration biopsy
is still the most effective and definitive method for confirming metastatic disease. With experienced cytopathologists,
the method gains a positive predictive value of approximately 100% and an overall diagnostic accuracy of 80% to
100%. Adrenal biopsy is an invasive method, and complications may occur, including pneumothorax or bleeding.
Pheochromocytoma must be ruled out before needle biopsy
is done.
If adrenocortical carcinoma is suspected on clinical
grounds, CT scanning should be performed. Characteristics
of adrenocortical cancer, such as poorly defined, irregular,
or lobulated margins; large, central areas or multiple, scattered areas of decreased attenuation; irregular contrast
enhancement; and signs of local invasion, are helpful in

establishing the diagnosis. 54.55 CT scanning also provides
information about local tumor extension, liver metastases,
and resectability. Differentiating adrenocortical carcinoma
from other lesions is usually not a problem because most
carcinomas have attained considerable size at the time of
diagnosis (Fig. 66-10).8 MRI may be helpful in evaluating a
suspected adrenal carcinoma because a high signal intensity
on T2-weighted or gadolinium-DTPA Tl-weighted images
supports the diagnosis of malignancy and allows the assessment of vascular extension and venous invasion.v-" This finding may eliminate the need for venography or arteriography.
Summary
For patients with Cushing's syndrome and adrenal neoplasms,
abdominal CT scanning is almost 100% accurate, and falsenegative results in cases of biochemically proven Cushing's
syndrome are rare. For these patients, normal adrenal
morphologic patterns seen on CT scans suggest adrenal
hyperplasia. When CT and MRI findings are nondiagnostic,
adrenocortical scintigraphy using iodocholesterols is
helpful.
For patients with biochemically proven primary hyperaldosteronism, abdominal CT scanning with contiguous
0.3- to 0.5-cm collimation of the adrenal is the localization
procedure of choice. When a unilateral adrenal lesion is
identified, no further imaging is necessary. When CT scanning is normal, equivocal, or depicts bilateral adrenal
masses, adrenal venous sampling with aldosterone and
cortisone testing should be done.
For patients with biochemically proven pheochromocytomas, abdominal CT scanning has nearly 100% accuracy.
When intravenous contrast enhancement is required,
patients must be prepared with (l- and ~-adrenergic
blockade.
For patients with negative studies or for patients with recurrent
or metastatic disease, MIBG or MRI scanning is helpful.
MIBG scanning is also the modality of choice for patients
with MEN syndromes.
Incidentaloma discovered by US or CT
History, physical examination, and
biochemical test to assess function

shows the diagnostic procedures
used in imaging incidentalomas.
FNAC = fine-needle aspiration
cytology; US = ultrasonography.
Hormone-secreting
tumor
Hormonally silent
tumor
Forfurtherimaging
referto other algorithms
Repeat or
review CT
Cyst
Adenolipoma
Myelolipoma
Carcinoma
Observe
Surgery
Known
malignancy
FNAC
<3.5 em
I
Observe
>3.5 em
Surgery
Incidentalomas are the most common adrenal tumors

requiring evaluation by the clinician. Most masses are benign.
When CT scanning fails to show a cyst, adenomyelolipoma,
or carcinoma, biochemical studies are necessary to determine
whether the tumor is functioning. All functioning adrenal
tumors and most nonfunctioning adrenal tumors larger than
4 em in the maximal diameter should be removed, especially
if the tumor is heterogeneous and has an irregular contour.
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25. Gross MD, Shapiro B, Gerkin RJ, et al. Scintigraphic localization of
adrenal lesions in primary aldosteronism. Am J Med 1984;77:839.
26. Herd GW, Semple PF, Parker D, et al. False localization of aldosteronoma by dexamethasone-suppressed adrenal scintigraphy. Clin
Endocrinol (Ox) 1987;26:699.
27. van Erkel AR, van Gils APG, Lequin M, et al. CT and MR distinction
of adenomas and nonadenomas of the adrenal gland. J Comput Assist
Tomogr 1994;18:432.
28. Radin DR, Ralls PW, Boswell WD Jr, et al. Pheochromocytoma:
Detection by unenhanced CT. AJR Am J Roentgenol 1986;146:741.
29. Raisanen J, Shapiro B, Glazer GM, et al. Plasma catecholamines in
pheochromocytoma: Effect of urographic contrast media. AJR Am J
30. Shin MS, Gupta KL, Ho KJ, et al. Thoracic pheochromocytoma:
Computerized tomographic characteristics. South Med J 1986;79:244.
31. Quint LE, Glazer GM, Francis IR, et al. Pheochromocytoma and paraganglioma: Comparison of MR and CT with MIBG scintigraphy.
Radiology 1987;165:89.
32. Francis IR, Gross MD, Shapiro B, et al. Integrated imaging of adrenal
disease. Radiology 1992; 184: I.
33. Mazley PD, Kim CK, Mahsin J, et al. The efficacy of iodine 123 MIBG
as a screening test for pheochromocytoma. J Nucl Med 1994;35: 1138.
34. Dunn GD, Brown MJ, Sapsford RN, et al. Functioning middle
mediastinal paraganglioma (phaeochromocytoma) associated with
intercarotid paragangliomas. Lancet 1986; 1:1061.
35. Shapiro B, Sisson JC, Eyre P, et al. 1311_MIBG_A new agent in
diagnosis and treatment of pheochromocytoma. Cardiology
1985;72(Suppl I): 13.
36. Beierwaltes WHo Update on basic research and clinical experience
with MIBG. Med Pediatr OncoI1987;15:163.
37. Shulkin BL, Koeppe RA, Francis lA, et al. Pheochromocytomas that
do not accumulate MIBG: Localization with PET and administration of
FDG. Radiology 1993; 186:711.
38. Falke THM, vanGils APG, vanSeters AP, Sandler MP. Magnetic
resonance imaging of functioning paragangliomas. Magn Reson Q
1990;6:35.
39. Velchnik MG, Alavi A, Kressel HY, Engelman K. Localization of
pheochromocytoma: MIBG, CT, MRI correlation. J Nucl Med
1990;30:328.
40. van Gils APG, Falke THM, van Erkel AR, et al. MR imaging and
MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas. Radiographies 1991; II :37.
41. Smith SK, Turner DA, Matalon DAS. Magnetic resonance imaging
of adrenal cortical carcinoma. Urol Radiol 1989; II: I.
42. Abecassis M, McLoughlin MJ, Langer B, et al. Serendipitous adrenal
masses: Prevalence, significance, and management. Am J Surg 1985;
149:783.
43. Glazer HS, Weymann PJ, Sagel SS, et al. Nonfunctioning adrenal
masses: Incidental discovery on computed tomography. AJR Am J
Roentgenol 1982; 139:81.
44. Copeland PM. The incidentally discovered adrenal mass. Ann Intern
Med 1983;98:940.
45. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected
pheochromocytoma: Review of a 50-year autopsy series. Mayo Clin
Proc 1981;56:354.
46. Ross NS, Aron DC. Hormonal evaluation of the patient with an
incidentally discovered adrenal mass. N Engl J Med 1990;323:1401.
47. Dunnik NR. Adrenal imaging: Current status. AJR Am J Roentgenol
1990;154:927.
48. Gross MD, Shapiro B, Francis IR, et al. Scintigraphic evaluation of
clinically silent adrenal masses. J Nucl Med 1994;34:1145.
49. Mezrich R, Banner MP, Pollack HM, et al. Magnetic resonance
imaging of adrenal glands. Urol Radiol 1986;8: 127.
50. Abrams HL, Spiro R, Goldstein N, et al. Metastases in carcinoma:
Analysis of 1000 autopsied cases. Cancer 1950;3:74.
51. Oliver TW, Bernardino ME, Miller JL, et al. Isolated adrenal masses in
non-small cell bronchogenic carcinoma. Radiology 1984;153:217.
52. Berland LL, Koslin DB, Kenney PJ, et al. Differentiation between
small benign and malignant adrenal masses with dynamic increment
CT. AJR Am J Roentgenol 1988; 151:95.

53. Chezmar JL, Rabbins SM, Nelson RC, et al. Adrenal masses:
Characterization with Tl weighted MR imaging. Radiology 1988;
166:357.
54. Dunnick NR, Heaston D, Halvorsen R, et al. CT appearance
of adrenal cortical carcinoma. J Comput Assist Tomogr 1982;
6:978.
55. Hussain S, Belldegrumn A, Seltzer SE, et al. Differentiation of

malignant from benign adrenal masses: Predictive indices on computed
tomography. AJR Am J Roentgenol 1985;144:61.
56. Falke TH, Peetoom JJ, deRoos A, et al. Gadolinium DTPA enhanced
MR imaging of intravenous extension of adrenocortical carcinoma.
J Comput Assist Tomogr 1988;12:331.
Clinically Inapparent Adrenal

Mass (Incidentaloma or
Adrenaloma)
Dimitrios A. Linos, MD, FACS
Historically, the adrenal tumor that was discovered incidentally, usually during an imaging procedure such as computed
tomography (CT), magnetic resonance imaging (MRI), or
ultrasonography for symptoms unrelated to adrenal disease,
(e.g., back pain) was called an incidentaloma:'
As more physicians (and patients on their own) ordered
these easily available imaging studies for common diseases
potentially related to adrenal pathology (and not the known
syndromes), such as mild and nonparoxysmal hypertension,
diffuse obesity, and diabetes, an increasingly number of
unsuspected (but hardly incidental) adrenal tumors were
found. I have proposed that these tumors be included with
the true incidentalomas under the broader term adrenaloma
because they share the same diagnostic and therapeutic
dilemmas.? The term adrenaloma implied that the discovered tumor (incidentally or not) derives from the adrenal but
is not obviously an aldosteronoma, a Cushing's syndrome
adenoma, a pheochromocytoma, a virilizing or feminizing
tumor, or a functioning adrenal carcinoma.
Recently, at a State of the Science Conference at the
National Institutes of Health Conference, the term clinically
inapparent adrenal mass was coined.' The widespread
teaching is that most adrenalomas are indolent tumors,
nonfunctioning and asymptomatic, causing no harm to the
patient.t-' Recent studies, however, have shown that a high
percentage of these tumors can be subclinically functioning,
causing symptoms milder than those encountered in the
well-known adrenal-hyperfunctioning syndromes but still
harmful to the patient.v!" Thus, the screening tests of serum
potassium, urinary vanillylmandelic acid (VMA), and serum
cortisol do not suffice and more detailed and in-depth laboratory investigation is necessary. The fear of adrenal carcinoma that dictated the approach to these tumors in the past
(with the main emphasis on the size of the tumor) should be
changed to the fear of the subtle function of these usually
benign adrenal cortical adenomas with coexistent metabolic
pathology (e.g., hypertension, obesity, diabetes).
586
Frequency
The overall frequency of adrenal adenomas in 87,065 autopsies in 25 studies was 5.9% (range 1.1% to 32%).15 The
frequency of adrenal masses discovered by CT, MRI, or
ultrasonography is somewhat lower. Abecassis and associates" in a 2-year period examined 1459 patients and found
63 (4.3%) with adrenal masses. Of those, 19 patients (1.3%
of examined patients and 30% of patients with adrenal masses)
had adrenalomas. At the Mayo Clinic.!? in a 5-year period,
61,054 patients underwent CT scanning. In 2066 patients
(3.4%), an adrenal abnormality was found; among these,
259 patients (12.5%) had an adrenaloma or adrenal lesion
larger than 1 em, without biochemical evidence or symptoms suggestive of cortical or medullar hypersecretion or
general constitutional symptoms suggestive of malignant
disease. Similar findings have been described in more recent
studies. 18-2o Thus, in the era of widespread use of highresolution ultrasonography, new-generation CT scans, and
MRl, we can anticipate a 5% incidence of adrenalomas.
Pathology
Most surgically removed clinically inapparent adrenal masses
have been classified as nonfunctioning cortical adenomas.v"
Benign masses such as nodular hyperplasia, adrenal cysts,
myelolipomas, ganglioneuromas, hematomas, hamartomas,
hemangiomas, leiomyomas, neurofibromas, teratomas, as
well as infections (tuberculosis, fungal, echinococcosis,
nocardiosis) are also included in the pathology of these
resected tumors (Fig. 67-1). Potentially lethal neoplasms,
however, such as pheochromocytomas and primary carcinomas are always first on the list of resected adrenalomas.P'P'
Pheochromocytoma is the most frequently found hormoneproducing adrenaloma that occasionally has a normal preoperative laboratory evaluation.P<" Few cases of aldosteronomas
Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - - 587
FIGURE 67-1. Adrenalomas. A, Adenoma (in subclinical Cushing'S syndrome). B, Pheochromocytoma (in subclinical pheochromocytoma). C, Aldosteronoma (in subclinical aldosteronism). D, Adrenal cyst. E, Myelolipoma. F, Schwannoma. G, Primary adrenal carcinoma.
H, Secondary adrenal carcinoma: a solitary metastasis from cervical cancer on which surgery was performed 10 years previously. (From
Linos DA: Management approaches to adrenal incidentalomas [adrenalomas]: A view from Athens, Greece. Endocrinol Metab Clin North
Am 2000;29:141.)
588 - -
Adrenal Gland
and androgen-producing adenomas have been described

among cases of surgically removed adrenalomas.t'" In a large,
multicenter, retrospective Italian study of 380 surgically
treated adrenalomas (out of 1096 collected), 198 (52%) were
cortical adenomas, 47 (12%) were cortical carcinomas, 42
(II %) were pheochromocytomas and 93 were other less
frequent tumors.'
The Goal of Evaluation

Although by definition the clinically inapparent adrenal
masses appear "nonfunctioning," on the basis of clinical and
essential laboratory findings more and more investigators
have shown that a high percentage of them may be subclinically functioning and/or associated with other metabolic
abnormalities. In a multicenter, retrospective evaluation
of 1096 patients with adrenal incidentaloma, the work-up
revealed that 9.2% had subclinical Cushing's syndrome,
4.2% had pheochromocytoma, and 1.6% had clinically
unsuspected aldosteronornas.P
Rossi and colleagues'? followed prospectively 50 consecutive patients with clinically inapparent adrenal masses.
Detailed hormonal investigation found 12 (24%) of 50 to
have subclinical Cushing's syndrome defined as abnormal
response to at least two standard tests of hypothalamuspituitary-adrenal axis function in the absence of clinical
signs of Cushing's syndrome. In the same study, 92% of
patients had hypertension, 50% obesity, 42% type 2 diabetes
mellitus, and 50% abnormal serum lipid concentration.
The clinical and hormonal features improved in all
patients treated by adrenalectomy but were unchanged in all
those who did not undergo surgery (follow-up, 9 to
73 months).
All 13 patients who had resection of truly nonfunctioning
adenomas because of large size had improved clinically to
such an extent that antihypertensive and antidiabetic therapy
was reduced or discontinued. All the improvements persisted
during the follow-up.
Another multicenter study'? of 64 consecutive patients
with clinically inapparent adrenal masses found a higher
than expected prevalence of abnormal glucose tolerance in
39 patients (61%). The same authors," following 62 consecutive patients with clinically inapparent adrenal masses, found
abnormal glucose tolerance in 66%.
Midorikawa and coworkers,'! studying 15 patients with
clinically inapparent adrenal masses (4 with subclinical
Cushing and 11 with truly nonfunctioning tumors), found a
high prevalence of altered glucose tolerance and insulin
resistance. Adrenalectomy reversed insulin resistance in all
patients with subclinical functioning and truly nonfunctioning
adrenal adenomas.
Terzolo and associates! followed 41 patients with clinically inapparent adrenal masses (12 with subclinical
Cushing's syndrome) and compared them with 41 controls.
They found that the 2-hour postchallenge glucose was significantly higher in patients than in controls. Similarly, both
systolic and diastolic blood pressures were higher in patients.
The calculated whole-body insulin sensitivity index (derived
from the oral glucose tolerance test) was significantly
reduced in the patients. They concluded that patients with
these tumors (subclinically functioning or nonfunctioning)
display some features of the metabolic syndrome such as

impaired glucose tolerance, increased blood pressure, and
high triglyceride levels.
Garrapa and colleagues" evaluated body composition
and fat distribution, as measured by dual-energy x-ray
absorptiometry (DEXA), in women with nonfunctioning
clinically inapparent adrenal masses and in women with
Cushing's syndrome compared with healthy controls
matched for age, menopausal status, and body mass index.
Women with clinically inapparent adrenal masses had larger
waist circumference, reflecting intra-abdominal fat. The blood
pressure was higher in patients with these tumors than
controls, and 50% of patients were hypertensive. High-density
lipoprotein (HDL) cholesterol levels and triglyceride mean
values were also higher in patients with clinically inapparent
adrenal masses than in controls. If central fat deposition,
hypertension, and low HDL are important risk factors for cardiovascular disease, then patients with clinically inapparent
adrenal masses, whether subclinically functioning or nonfunctioning, are at higher risk than the general population
for cardiovascular disease.
Chiodini and coworkers" performed a longitudinal study
evaluating the rate of spinal and femoral bone loss levels
in 24 women with clinically inapparent adrenal masses.
They were divided into two groups on the basis of the
median value of urinary cortisol excretion. The group with
higher cortisol values (subclinical Cushing levels) had more
lumbar trabecular bone loss than those with low cortisol
secretion (not hypersecreting tumors).
Therefore, the "cavalier" attitude toward clinically inapparent adrenal masses should be changed. These tumors are at
an intermediate stage, between normal and pathologic. They
should be screened to rule out (1) subclinical Cushing's
syndrome, (2) subclinical pheochromocytoma, (3) subclinical
primary aldosteronism, and (4) adrenal carcinoma (primary
or solitary metastasis).
Screening for Subclinical

Cushing's Syndrome
Patients with subclinical Cushing's syndrome have none of
the signs and symptoms of the typical Cushing's syndrome
(e.g., plethora, moon face, central obesity, easy bruising,
proximate muscle weakness, acne, osteoporosis). The frequency of subclinical Cushing's syndrome among patients
with adrenaloma ranges from 12% to 24%.10,36
Depending on the amount of glucocorticoids secreted,
the clinical significance of subclinical Cushing's syndrome
ranges from slightly attenuated diurnal cortisol rhythm to
atrophy of the contralateral adrenal gland, a dangerous
condition after unilateral adrenalectomy if appropriate
therapeutic measures are not taken early enough."
The best screening test for autonomous cortisol secretion
is the short dexamethasone suppression test. A 2- or
3-mg dose is better than the usual l-mg dose to reduce falsepositive results. A suppressed serum cortisol 3 ug/dl, or
80 nmollL) excludes Cushing's syndrome. A serum cortisol
greater than 3 ug/dl. requires further investigation, including
a confirmatory high-dose dexamethasone suppression test
(8 mg), corticotropin-releasing hormone test, and analysis of
diurnal cortisol rhythm. If serum cortisol concentrations are
not suppressible by high-dose dexamethasone, the diagnosis
Clinically Inapparent Adrenal Mass (Incidentaloma or Adrenaloma) - -
of subclinical Cushing's syndrome is established. Another

suggested test is the growth hormone response to growth
hormone-releasing hormone. A blunted growth hormone
release might prove a sensitive and early sign of subclinical
Cushing's syndrome." As already discussed, glucose tolerance is altered in patients with clinically inapparent adrenal
masses (with and without subclinical Cushing), and a glucose
tolerance test is recommended in patients with clinically
inapparent adrenal masses. lO,12,38 Finally, bone mineral
density of the spine should be performed to detect
reduced bone mass in patients with subclinical Cushing's
syndrome. 14
Adrenal scintigraphy with 1311-6~-iodomethylnorcholesterol (NP-59) can reveal a "functioning" but not "hypersecretory" tumor when there is an uptake of the nucleotide in
the tumor site and no uptake in the contralateral suppressed
gland. Some authors 39,40 suggested a significant positive
correlation between abnormal cortical secretion and NP-59
uptake, making NP-59 scanning a cost-effective diagnostic
tool for evaluating clinically inapparent adrenal masses.
Others" found it cumbersome because it requires several
days to obtain the images and it is unable to take up NP-59
in the presence of hemorrhage or inflammation; they recommend no routine use of NP-59 scanning.

Pheochromocytoma
The typical patient with pheochromocytoma is hypertensive
and may have paroxysmal hypertension and related symptoms (headache, hypertensive crisis, sweating, and cardiac
arrhythmias). The proposed term subclinical pheochromocytoma refers to the totally asymptomatic clinically inapparent
adrenal masses that histologically proves to be a pheochromocytoma. In several series of clinically inapparent adrenal
masses, the frequency of pheochromocytomas ranges from
10% to 40%.31,33 Although the percentage of asymptomatic
pheochromocytomas among patients with nonfunctioning
adrenal tumors is relatively high, most test positive on
hormonal evaluation, which is a measurement of 24-hour
urinary metanephrines and VMA or fractionated urinary
catecholamines. In the National Italian Study Group,
27 patients (3.4% of the total patients with incidentaloma)
were found to have pheochromocytoma; 24-hour urinary
catecholamine and VMA concentrations were elevated in
86% and 4.6% of patients, respectively.F indicating that a
combination of tests is more useful clinically than an individual test. The efficacy of single-voided ("spot") urine
metanephrine and normetanephrine assays for diagnosing
pheochromocytoma has been documented. Such tests may
avoid the inconvenience of 24-hour urine collection."
There is no indication for routine use of 1311-metaiodobenzylguanidine (I-MIBG) scintigraphy in the evaluation of an adrenaloma unless catecholamine and urinary
metabolites are elevated.
Because there are cases of clinically inapparent adrenal
masses that preoperatively had negative urinary VMA,
metanephrines, and MIBG scanning but that intraoperatively behaved (with later histologic proof) as pheochromocytomas, prophylactic measures should always be taken
(e.g., arterial line, immediate access to intravenous nitroprusside [Nipride]) during surgery.
589

Primary Aldosteronism
The typical primary aldosteronism is characterized by hypertension with hypokalemia, elevation of plasma aldosterone,
and suppressed plasma renin activity. Subclinical primary
aldosteronism describes the patient with adrenaloma who
is normotensive or hypertensive with normokalemia.
More than 40% of patients with primary aldosteronism are
normokalemic; therefore, the previously recommended
measurement of potassium as the only test to rule out
primary aldosteronism in the case of clinically inapparent
adrenal masses should be abandoned.f Instead, a detailed,
time-consuming evaluation is necessary, especially in all
hypertensive patients, to rule out primary aldosteronism,
which may be the cause of hypertension in up to 15% of
these patients.v" In a normotensive patient with a serum
potassium level greater than 3.9 nmol/L, no further hormonal
evaluation is necessary. The screening for subclinical primary
aldosteronism should include, in addition to serum potassium, the upright aldosterone level to plasma renin activity
(PRA) ratio, since a single value of aldosterone may be
normal. Patients with two or more samples with a positive
aldosterone-PRA ratio (>40) should undergo the fludrocortisone suppression test (0.4 mg every day for 4 days) or the
acute saline suppression test (2 L of 0.9% NaCl solution
infused intravenously over 4 hours) to confirm the diagnosis.
Bilateral adrenal venous sampling with measurements of
aldosterone and cortisol levels is the necessary next step to
lateralize and determine the subtype of primary aldosteronism
to identify the patient who will be cured through surgery.
Screening for Adrenal Carcinoma

The risk of a clinically inapparent adrenal mass harboring a
primary carcinoma of the adrenal is very low." The annual
incidence of the latter has been estimated to range from 1 case
per 600,000 to 1 case per 1.6 million persons. Its prevalence
is approximately 0.0012%.46 In contrast, metastatic carcinoma to the adrenal is a common finding in patients with
lung, breast, colon, and other extra-adrenal malignancies.
In published series of surgically resected adrenalomas, the
frequency of histologically confirmed primary adrenal
carcinoma ranges from 4.2% to 25%.7 The frequency of
adrenal metastasis from lung cancer at autopsy ranges from
17% to 38%. In patients with adrenal mass in the setting of
extra-adrenal malignancy, the probability of this mass being
metastatic ranges from 32% to 73%.5,33,47
SIZE OF TUMOR
The size of a clinically inapparent adrenal mass is frequently

used to predict potential malignancy and the need for
surgery. Although most clinically treated adrenal malignancies
are discovered when they are larger than 6 em in diameter,
several reports have described very large tumors that never
metastasized and small adrenal tumors that did (Fig. 67-2).
In several series, adrenocortical carcinomas with a maximum
diameter of 3 em or less have been described. 15,33,37,47
The size of a clinically inapparent adrenal mass as reported
on a CT scan is usually smaller than the size reported on
the histology report. This underestimation ranges from
16% to 47%.48 In an analysis of the CT and histology reports

one may see a irregular, blurred, heterogeneous tumor with
areas of necrosis; such lesions are suggestive of malignancy,
especially if enlarged lymph nodes or local invasion is also
detected."
On MRI studies, one should look for heterogeneously
increased, early T2-weighted signal, weak and late enhancement after gadolinium injection, or an intravascular signal
identical to the tumor signal. When NP-59 scintigraphy is
available, the lack of (or very weak) uptake in the tumor and
normal contralateral uptake is suspicious for malignancy.
Positron emission tomography (PET) can be used following
the administration of 2-deoxy-2[18F]-fluoro-D-glucose
(lsF-FDG). The 18F_FDG PET scan is a useful tool confirming
isolated metastases and selecting patients for adrenalectomy.
It has been used in studies to distinguish between primary
and metastatic adrenal lesions, especially in patients with
other primary malignancies (Fig. 67-3).50
FINE-NEEDLE ASPIRATION
FIGURE 67-2. This larger than 6 em, clinically inapparent adrenal

mass was suspicious for malignancy on CT scan (A) but histologically was proved a benign cortical tumor (8).
of 76 patients with various diseases, we found" that the

mean estimated diameter of the adrenal tumor was 4.64 em
on the CT report when the real size (pathology report) was
5.96 cm. Further analysis of different CT scans revealed a
consistent underestimation in all groups. In the group of
adrenal tumors with a maximum diameter of less than 3 em,
the mean diameter reported on CT was 2.32 em in contrast
to the true histologic size of 3.63 em (P < 0.001). We therefore proposed the formula
Histologic size = 0.85 + (1.09 x CT size)
to correct the underestimated CT size so as to use the size
criterion more accurately."
A recent study" showed that the above "Linos formula"
turned out to be significantly more accurate than direct
radiologic measurements in predicting the real pathologic
size of the tumor.
IMAGING
In addition to assessing distant metastasis and tumor size,

imaging studies may suggest malignancy. On a CT study,
Fine-needle aspiration (FNA) biopsy of a clinically inapparent adrenal mass has a limited role. It is useful in cases of
coexistent extra-adrenal carcinoma (usually lung cancer) to
confirm the radiologic evidence of adrenal metastasis.
In a study by Silverman and coworkers," 3 of 33 FNA
specimens that contained "benign" adrenal tissue were later
proved to be malignant. Each malignant lesion was smaller
than 3 em in diameter. In 14 patients in whom the FNA was
nondiagnostic, two masses proved to be malignant. Generally,
FNA cannot differentiate cortical adenoma from carcinoma
because it cannot detect invasion of the tumor into the capsule.
Although it has been suggested that FNA is useful in the
differential diagnosis of a cystic adrenal mass, we strongly
object to such practice because cystic pheochromocytomas
are prevalent. Diagnostic puncture of such a lesion (or of a
rare cystic echinococcal parasitic cyst) can be harmful to
the patient. The possibility of seeding a malignant adrenal
neoplasm in the retroperitoneum is an additional reason that
FNA should be discouraged.
Genetic and Molecular

Biology Studies
Currently, the only accepted criteria to determine whether
a clinically inapparent adrenal mass is benign or malignant
are metastasis (synchronous or metachronous) and local
invasion into adjacent structures. The mapping and identification of genes responsible for hereditary syndromes
(e.g., multiple endocrine neoplasia type 1, Li-Fraumeni
syndrome) have increased our understanding of adrenocortical tumorigenesis. Oncogenes and tumor suppressor genes
involved in adrenal carcinomas include mutations in the
p53 tumor suppressor gene. Among those, the Ki-67 index
(percentage of immunopositive cells), when above 5%, can
be a useful indicator in the differentiation of adenomas from
carcinomas.P Adrenal carcinomas are monoclonal, whereas
adrenal adenomas may be polyclonal in approximately 25%
to 40% of cases." Although these findings do not have
direct clinical application, it is hoped that future research
will facilitate the diagnosis and predict the natural course of
these tumors.
FIGURE 67-3. The positron

emission tomography scandetected
a small isolatedadrenal metastasis
(arrow) (witha concurrent negative
CT scan) in this 69-year-old man
who had been treatedfor mesothelioma in the past. Laparoscopic
adrenalectomy allowed full extirpationof this single metastasis.
Management of Clinically
Inapparent Adrenal Masses:
Surgery Versus Follow-Up
Several recent studies that we briefly discussed demonstrated
the following:
1. A relatively high percentage of clinically inapparent
adrenal masses, especially adrenal cortical adenomas,
are subclinically functioning.
2. A relatively high percentage of patients with a clinically
inapparent adrenal mass display pathologic features
such as impaired glucose tolerance, insulin resistance,
increased blood pressure, high triglyceride levels, low
HDL, central fat deposition and reduced trabecular bone
mineral density.
3. When adrenalectomy was done in patients who either
had proven subclinical hypercortisolism or even truly
nonfunctioning tumors, the associated abnormalities and
symptoms (e.g., hypertension, obesity, altered
glucose tolerance) were normalized or significantly
improved.
In the era of laparoscopic adrenalectomy that carries
a minimal mortality and morbidity, it appears logical to advocate surgery in patients with a clinically inapparent adrenal
mass when
1. There is laboratory evidence for a subclinically functioning tumor.
2. There are associated pathologic features such as hypertension, impaired glucose tolerance (or diabetes),
pathologic triglyceride profile, central fat deposition,
and reduced bone mineral density.
3. There is clinical and radiologic evidence for primary
or solitary metastatic adrenal carcinoma.
The age and the anxiety of the patient should also playa role
in the decision to operate or not.
Conservative management is recommended for those
patients with clinically inapparent adrenal mass in whom
1. There is no clinical or laboratory evidence for subclinical function of the tumor.
2. There are no associated symptoms potentially related
to the clinically inapparent adrenal mass.
3. There is no suspicion of adrenal carcinoma.
In these patients a yearly check-up should be continued for
5 to 10 years with the main emphasis on the possibility that
the silent, nonfunctioning tumor may develop hyperfunction.
Limited, complete follow-up studies (with repeated radiologic and hormonal evaluation) have been performed on
patients with clinically inapparent adrenal masses. Barzon
and associates" followed 75 patients with clinically
592 - -
Adrenal Gland
inapparent adrenal mass, for a median of 4 years, and found

9 of them to have enlargement. Overt Cushing's syndrome
developed in two patients, subclinical Cushing's syndrome
in three, and clinical pheochromocytoma in one. No patient
had a malignancy. The estimated cumulative risks for mass
enlargement and hyperfunction were 18% and 9.5%, respectively, after 5 years, and 22.8% and 9.5% after 10 years.
In another study,55 53 patients with clinically inapparent
adrenal masses were followed for 6 to 78 months (median,
24 months). During the follow-up, 22 lesions (41.5%)
increased in size and 6 lesions (11.3%) decreased in size or
disappeared. No clinically inapparent adrenal mass grew
or developed hypersecretion. Thus, during follow-up of the
truly nonfunctioning clinically inapparent adrenal masses,
yearly hormonal evaluation should be emphasized rather
than repeating imaging studies.
What is the Best Surgical Approach

in the Management of Clinically
Inapparent Adrenal Masses?
Traditionally, surgical approaches to the adrenals have been
anterior transperitoneal, posterior extraperitoneal, and thoracoabdominal (for large tumors)." The application of laparoscopic techniques in the surgery of the adrenal glands has
essentially replaced all traditional open approaches in the
same manner as laparoscopic cholecystectomy has replaced
traditional open cholecystectomy. Because there are so
many benefits associated with the laparoscopic approach,
open adrenalectomy should be reserved for very large adrenal carcinomas invading the surrounding tissue. We have
compared the anterior, posterior, and laparoscopic approach
in 165 patients who underwent adrenalectomy between
1984 and 1994.57 Although in this study we included our
early cases and learning experience, the advantages of the
laparoscopic approach were clearly shown in terms of morbidity (12.2% in the anterior approach, 8.1% in the posterior
approach, and 0% in the laparoscopic approach), mean operating time, mean length of postoperative hospitalization
(8.1 vs. 4.5 vs. 2.7 days), and minimal postoperative pain.
The lack of long incisions and their immediate and longterm complications (e.g., wound infection, hernia, esthetic
dissatisfaction) and the opportunity for an early return to full
activity make the laparoscopic approach the procedure of
choice for nearly all clinically inapparent adrenal masses,
including the laparoscopically removable primary or secondary carcinomas (see Fig. 67_3).31.58 Although the posterior
open adrenalectomy has more advantages than the anterior
open adrenalectomy, the advantages of anterior laparoscopic
adrenalectomy outweigh the advantages of the posterior
laparoscopic approach.v-" The anterior (or lateral) laparoscopic adrenalectomyenables the removal of large tumors, the
performance of additional procedures (e.g. cholecystectomy),
and the performance of bilateral laparoscopic adrenalectomies when indicated. 61.62 We have simplified'< the anterior
laparoscopic technique, which has become easier and more
"friendly" to the surgeon compared to the originally
described techniques.P Thus, more and more surgeons will
switch to the laparoscopic approach for the management of
adrenal tumors.
Summary
The adrenal tumors that are not apparently clinically functioning and often (but not always) are incidentally found
(incidentalomas/adrenalomas) are becoming more prevalent
and constitute a diagnostic and therapeutic problem. The purpose of the diagnostic approach is to confirm whether these
tumors are (1) subclinically functioning and/or (2) suspicious
for malignancy.
Therefore the diagnostic process should include the
following:
1. The short dexamethasone suppression test (2 mg
of dexamethasone) followed by the high-dose test
(8 mg of dexamethasone) if serum cortisol is greater
than 3 ~g/dL to rule out subclinical Cushing's syndrome.
2. Measurement of 24-hour urine metabolites of catecholarnines (metanephrines, normetanephrines) to rule
out subclinical pheochromocytoma (when the patient
is normotensive).
3. Measurement of the upright aldosterone level to
plasma renin activity (PRA) ratio in addition to the
potassium level to rule out subclinical aldosteronism
(normotensive or hypertensive with normokalemia
patient)
Because of the recently described association of these
adrenal tumors to the metabolic syndrome, we have to add
the following diagnostic tests:
Glucose tolerance test
Bone mineral density studies
Body composition and fat distribution by DEXA
The suspicion for malignancy or not is mainly supported
by the imaging studies (CT, MRI, PET scan, ultrasonography) as well as the size of the tumor. The role of the FNA
biopsy is limited and indicated only when a primary malignancy coexists (to rule out metastasis). The clinical application of genetic and molecular biology tests for these tumors
is limited. Once the diagnostic evaluation is complete, the
therapeutic management dilemma of conservative versus
surgical resection is addressed.
All tumors that have no laboratory evidence of hypersecretion and no clinical and/or imaging suspicion for
malignancy need to be treated conservatively with annual
hormonal and imaging study follow-up. All tumors that have
laboratory evidence of autonomy and subclinical functioning,
especially in patients who belong to the metabolic syndrome
(e.g., hypertension, obesity, glucose intolerance) need to be
treated surgically. The anterior laparoscopic adrenalectomy
offers minimal cost (e.g., less pain, less hospital stay, faster
recovery, excellent cosmetic results). Other factors such as
the age of the patients and their overall clinical condition
and anxiety level will determine the best management of
adrenalomas.
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Hyperaldosteronism
Takao Obara, MD Yukio Ito, MD Masatoshi Iihara, MD
Hyperaldosteronism occurs in primary and secondary

forms. In this chapter, we describe the characteristic features
of primary hyperaldosteronism and discuss the rational
surgical management of this disorder. Primary hyperaldosteronism is characterized by excessive secretion of aldosterone
from the adrenal gland associated with suppression of plasma
renin activity (PRA), which usually results in hypertension and hypokalemia. Conn first described this
syndrome in 1954. I Primary hyperaldosteronism is an
uncommon but potentially curable cause of hypertension.
The development of simplified testing and improvement of
localization studies have allowed this condition to be diagnosed accurately and the tumor removed more precisely,
Nevertheless, the most appropriate diagnostic approach for
selecting surgically curable forms of primary hyperaldosteronism remains a matter of controversy.
There are several subtypes of primary hyperaldosteronism. Aldosterone-producing adrenocortical adenoma and
idiopathic hyperaldosteronism (bilateral adrenal hyperplasia)
are the two most common subsets and account for 95% of
all cases.s-' An aldosterone-producing adenoma is usually
treated by unilateral adrenalectomy, whereas idiopathic
hyperaldosteronism does not respond to surgical treatment
and is best managed medically. Uncommon forms of primary
hyperaldosteronism include primary adrenal hyperplasia.v'
aldosterone-producing carcinoma.s-' and glucocorticoidsuppressible hyperaldosteronism.s-? Primary adrenal
hyperplasia is morphologically similar to idiopathic hyperaldosteronism but mimics aldosterone-producing adenoma
in response to biochemical tests and unilateral adrenalectomy. Glucocorticoid-suppressible aldosteronism (familial
hyperaldosteronism type 1) is familially inherited in an autosomal fashion and is caused by the presence of a chimeric
gene, consisting of the regulatory region of a gene coding
for the enzyme ll~-hydroxylase
(CYPllBl), adrenocorticotropin (ACTH), and the coding region of the gene for
aldosterone synthesis (CYPllB2).8 Hence, aldosterone
synthesis is primarily regulated by ACTH, resulting in
excessive aldosterone production. This condition can be
controlled by glucocorticoid administration. Familial hyperaldosteronism type 2 refers to the familial occurrence of
aldosterone-producing adenoma, adrenal hyperplasia, or

both.IO,11 The appropriate treatment of primary hyperaldosteronism depends on the correct differential diagnosis of
these subtypes.
Pathologic Features
Aldosterone-producing adenomas are usually solitary
tumors involving only one adrenal gland (Fig. 68-1). Most
adenomas are smaller than 2 em in diameter. The mean
diameter in 210 patients with surgically proven aldosteroneproducing adenomas in our series was 1.8 em, which is consistent with previous reports. 12 The cut surface usually has a
characteristic golden yellow appearance. Microscopically,
the typical tumor is mostly composed of large lipid-laden
clear cells. In contrast, idiopathic hyperaldosteronism
usually affects both adrenal glands and appears as micronodular or macronodular hyperplasia.
Despite these typical pathologic features of adenoma and
hyperplasia, there is a pathologic continuity between predominant unilateral adenoma and macronodular and micronodular hyperplasia. For instance, the extratumoral cortex of a
solitary adenoma is not always normal: it may be hyperplastic or occasionally atrophic. Macroscopic or microscopic
nodules often accompany aldosterone-producing adenoma
(Fig. 68-2). Of our patients, 19% had multiple macronodules in association with distinct adenoma and an additional
43% had adenoma-associated micronodules.P Other authors
have reported similar frequencies (55% and 42%) of macronodular or micronodular lesions associated with adenoma.lv"
Macronodular hyperplasia and nonfunctioning cortical nodules associated with adenoma are not always distinguishable
histologically. Patients with macronodules associated with
adenoma are likely to have severe, prolonged hypertension.
In addition, rare cases of bilateral solitary adrenal
adenomas'v" and unilateral adrenal hyperplasia'> have been
reported. These variable presentations thus reflect the fact
that clinical primary aldosteronism is not a single pathologic
entity, and they have important clinical implications with
regard to therapy.
595
596 - -
Adrenal Gland
FIGURE 68-1. Cut surface of an adrenal gland showing a typical

aldosterone-producing adenoma.
Clinical Characteristics
The diagnosis of primary hyperaldosteronism is usually
made between the ages of 30 and 60 years. The disease is
more common in women than in men. The ages of the patients
in our series ranged from 17 to 74, with a mean of 47.0 years.
The female-to-male ratio was 1.5:1 (131:85) in our series,
which corresponds to that in most other studies. 17.23
The hypertension of primary aldosteronism is moderate
to severe and is indistinguishable from that seen in other
disorders. The highest blood pressure recorded in our series
was 3001150 mm Hg, and malignant hypertension is rare in
this disorder. The duration of hypertension before recognition of hyperaldosteronism is variable. Among our patients,
the duration of documented hypertension ranged from 1 to
480 months (median, 104 months), corresponding to that
in other reports.17.22.23 The other characteristic symptomsmuscle weakness, cramping, intermittent paralysis, headaches,
polydipsia, polyuria, and nocturia-are mainly attributable
to hypokalemia. Because many patients were initially treated
medically for hypertension by the referring physician
without a diagnosis, the precise incidence of symptoms
specific for hyperaldosteronism is not always clear. Periodic
paralysis has been considered to be a common presenting
symptom in Asian patients.v-" In our series, the incidence
was approximately 23%.
Hyperparathyroidism or prolactinoma coexistent with
primary aldosteronism has been reported. Gordon and
Stowasser" reported that 14 of 596 patients with primary
hyperaldosteronism had hyperparathyroidism, and 4 had
pituitary adenoma. In our series, two patients had primary
hyperparathyroidism and another had prolactinoma. Some
of these patients may have rare multiple endocrine neoplasia
(MEN) type 1.26.28 Whether this combination of endocrine
disorders represents a variant of MEN or two sporadic
conditions is unknown. Family history and testing for gerrnline
MEN I gene mutation on chromosome 11 as well as documenting hypercalcemia and hyperparathyroidism should
clarify this situation.
FIGURE 68-2. Cut surfaces of adrenal glands removed from

patients with primary hyperaldosteronism, showing an adenoma
associated with macronodular lesions (arrows) (A) and double
adenomas (B). (From Ito Y, Fujimoto Y, Obara T, et aI. Clinical
significance of associated nodular lesions of the adrenal in patients
with aldosteronoma. World J Surg 1990;14:331.)
Screening for and Diagnosis

of Primary Aldosteronism
The prevalence of primary hyperaldosteronism in an unselected hypertensive population is probably around 2%,2.29,30
although several studies have reported higher figures of 10%
to 15%.31,32 The recent increase in the reported prevalence
of primary hyperaldosteronism is likely to reflect improvement in screening methodologies as well as selection bias.
Nevertheless, it seems a reasonable idea that primary hyperaldosteronism is more common than previously estimated,
not only in white but also in Asian hypertensive patients.3.33.34
Most patients with primary hyperaldosteronism have
hypokalemia (serum potassium concentration less than
3.4 mEq/L), especially on sodium loading. Although diuretic
therapy itself is the most common cause of hypokalemia in
patients with hypertension, these patients should have both
PRA and plasma aldosterone concentration (PAC) measured
to test for primary hyperaldosteronism. In 7% to 38%
of patients with primary aldosteronism, the serum level of
Hyperaldosteronism - - 597
potassium is reported to be normal. 30,35,36 Therefore,

normokalemia does not exclude primary hyperaldosteronism, Because of the high proportion of normokalemic
patients, Gordon and colleagues'? recommended extending
the screening for aldosteronism from hypertensive patients
who are hypokalemic or resistant to medical therapy to
all hypertensive patients, Furthermore, approximately 1% of
patients with incidentally discovered adrenal masses associated with hypertension have aldosteronoma, Consequently,
they need to be tested for hyperaldosteronism,
Screening for primary hyperaldosteronism can be performed by measurement of both PRA and PAC. Hiramatsu
and coworkers" first described the raised ratio of PAC to
PRA as a useful screening tool for diagnosis of aldosteroneproducing adenoma among hypertensive patients, Its diagnostic accuracy was soon confirmed by other investigators.Pr'?
The cutoff value of the ratio differs from 20: 1 to 50: 1 when
expressing PAC in ng/dL and PRA in ng/ml.Zhr, The screening strategy is further improved by using not only the
PAC to PRA ratio but also elevated levels of PAC, thus
distinguishing primary aldosteronism from other causes of
hypertension, Weinberger and Fineberg" found that the use
of a PAC to PRA ratio of more than 30 and a PAC value
greater than 20 ng/dL provided a sensitivity of 90% and a
specificity of 91 % for identification of primary hyperaldosteronism, Young recommended using a PAC to PRA ratio of
20 and greater with a PAC of 15 ng/dL or higher to diagnose
primary aldosteronism.Pv" The ratio of PAC to PRA may be
a sensitive screening test even in patients still taking antihypertensive drugs." However, because many antihypertensive
medications-particularly spironolactone, angiotensinconverting enzyme inhibitors, and diuretics-affect reninaldosterone regulation, they should be discontinued 4 to
6 weeks before diagnostic studies are performed. Some
patients require continued use of antihypertensive medication
to avoid severe hypertension. Antihypertensive agents such as
prazosin, guanethidine, and guanadrel are recommended,
The diagnosis of primary aldosteronism can be confirmed
in almost all cases if the PAC (normal 2,2 to 15 ng/dL) is
increased in conjunction with suppressed PRA (below 0,2
to 0.5 ng/mL/hr) in a hypertensive patient, specifically one
who demonstrates hypokalemia. An elevated basal PAC
and a PAC to PRA ratio greater than 50: 1 are also reliable
criteria for diagnosis.f'-"
When the results of hormonal measurements are equivocal, additional tests are helpful. The diagnosis of primary
aldosteronism in a suspected case can be confirmed by
demonstrating either inability to suppress aldosterone
production with a high-sodium diet or inability to stimulate
PRA with a low-sodium diet. Both measurement of urinary
aldosterone levels during oral administration of salt and
measurement of PAC with intravenous salt loading are used
to evaluate the lack of suppressibility of aldosterone
secretion,3,30,34,35,42 On sodium loading, primary hyperaldosteronism is confirmed if there is a failure to suppress PAC
below 10 ng/dL,30 In primary hyperaldosteronism, 24-hour
urinary excretion of aldosterone exceeds 12 Ilg,3,34 However,
the risk of increasing the intake of sodium in patients with
severe hypertension must be carefully considered, Captopril,
an angiotensin-converting enzyme inhibitor, has also been
used to demonstrate the lack of the suppressibility of
aldosterone.r' but its true value is limited." Fludrocortisone

administration is also used as a confmnatory test for primary
hyperaldosteronism.l'r" but its validity has not been fully
evaluated.f Lack of stimulation of PRA can be demonstrated after diuretic administration (furosemide) and after
the patient has been standing for 2 hours, 16
Biochemical Differentiation
between Aldosterone-Producing
Adenoma and Idiopathic
Hyperaldosteronism
When the diagnosis of primary hyperaldosteronism has been
made, the distinction between a discrete aldosterone-secreting
adrenocortical neoplasm and idiopathic hyperaldosteronism
remains critical in the selection of patients who will benefit
from adrenalectomy; this operation is more likely to correct
hyperaldosteronism and hypertension in patients with
aldosterone-producing adenoma than in those with idiopathic
hyperaldosteronism,
Postural response and decrease in aldosterone concentration can be used to differentiate between aldosteroneproducing adenoma and idiopathic hyperaldosteronism
related to bilateral hyperplasia." In patients with idiopathic
hyperaldosteronism, PAC usually increases after standing for
4 hours, whereas a postural decrease in PAC is characteristic
of patients with aldosterone-producing adenoma, This
phenomenon is due to the fact that aldosterone-producing
adenomas are relatively unresponsive to angiotensin but still
follow the corticotropin circadian rhythm, whereas in idiopathic hyperaldosteronism aldosterone production is influenced by the slight increases in PRA and cortisol levels that
occur in an upright position,
Unfortunately, this postural test of PAC for differentiating between aldosterone-producing adenoma and idiopathic
hyperaldosteronism is not always reliable because falsenegative results for the postural response of PAC have
occurred, 12.13,1 8,47,48 In a review of 16 articles, Young and
Klee reported that the accuracy of the postural study was
85% in 246 patients with surgically verified aldosteroneproducing adenomas, 12 In our previous series, many patients
with adenoma (43%) showed an anomalous response to
the postural test." Presumably, stress during the test caused
corticotropin release, which resulted in elevation of PAC.
Measurement of plasma 18-hydrocorticosterone (I8-0HB)
concentration has also been reported to be useful for determining whether a patient with primary hyperaldosteronism
has an aldosterone-producing adenoma or idiopathic hyperaldosteronism.t? A plasma 18-0HB level greater than
100 ng/dL is usually associated with an aldosterone-producing
adenoma." However, the assay of 18-0HB is not commonly
available, and the cumulative diagnostic accuracy for
aldosterone-producing adenoma based on four separate
studies was reported to be 82%,12
It appears that none of the currently available biochemical
studies can correctly distinguish between patients with idiopathic hyperaldosteronism related to bilateral adrenal hyperplasia and those with aldosterone-producing adenoma with
100% accuracy, Diagnosis of idiopathic hyperaldosteronism
598 - -
Adrenal Gland
on the basis of biochemical studies alone would exclude a

considerable number of patients with aldosterone-producing
adenomas from curable adrenalectomy. Moreover, the
subtypes termed primary adrenal hyperplasia and aldosteroneproducing renin-responsive adenoma have been said to
be correctable by unilateral adrenalectomy.50 The former
exhibits the features of aldosterone-producing adenoma in
terms of postural response and 18-0HB excess, and the
latter responds to postural stimulation in the same way as
idiopathic hyperaldosteronism.50
Localization studies are indicated in all patients in whom
the diagnosis of primary aldosteronism has been confirmed
because aldosterone-producing adenomas and idiopathic
hyperaldosteronism are not always distinguishable by
biochemical tests. Visualizing an adrenal tumor or detecting
unilateral excessive aldosterone production by means of
localization studies greatly facilitates the selection of patients
for adrenalectomy. Figure 68-3 is an algorithm for selecting
the patients who are most likely to benefit from unilateral
adrenalectomy. At most institutions, including our own,
the adrenal computed tomography (CT) scan is the initial
localizing procedure. An adrenal tumor with homogeneous,
negative CT attenuation before and after enhancement is
likely to be an aldosterone-producing adenoma (Fig. 68-4).
The procedure is noninvasive and can be performed on an
outpatient basis. The sensitivity of locating adenomas with
the new generation of high-resolution CT scanners ranges
from 82% to 90%.12.16.18.51
Young and Klee stated that in a patient with primary hyperaldosteronism, if a solitary unilateral adrenal macroadenoma
larger than I ern along with a normal contralateral adrenal
gland is found on CT scanning, no other subtype studies

are necessary and unilateral adrenalectomy should be
considered.F Doppman and colleagues'? also stated that
patients with an obvious unilateral nodule and a normal
contralateral gland on CT scanning do not require further
localization study. It is also worth noting that, although
aldosterone-producing adrenal tumors are rarely malignant,
unilateral large (4 em and greater) adrenal tumors are likely
to be adrenocortical carcinomas.
Although the CT-based diagnosis of adenoma is reliable
with acceptable certainty, it is worth noting that the CTbased diagnosis of hyperplasia is unreliable.F The presence
of non-aldosterone-secreting nodules in the ipsilateral or
contralateral adrenal gland associated with an adenoma may
result in a misdiagnosis as hyperplasia. In addition, hyperplasia may be associated with a unilateral macronodule and
cause an erroneous diagnosis of an adenoma. Therefore, all
patients with unilateral adenomas as small as 1 em or bilateral nodules on CT and those with bilateral normal glands
require further localization studies using isotope adrenal
scanning or selective adrenal venous sampling for aldosterone and cortisol levels, or both.
Adrenal scanning with 13II-6~-iodomethyl-19-norcholesterol (NP-59) during dexamethasone suppression is considered the next choice for locating a hyperfunctioning adrenal
gland if CT scan results are not definitive.P>' Problems with
adrenal scintigraphy include the requirement of 5 to 7 days for
completion and the need to block the thyroid to prevent uptake
of radioiodine. Furthermore, the laterality of NP-59 uptake
depends primarily on the adenoma size.55 Unfortunately, this
technique has insufficient diagnostic accuracy for smaller
tumors.
Adrenal venous catheterization with blood sampling
to measure aldosterone and cortisol concentrations is still
the most accurate test for the differential diagnosis of
I Confirmed primary hyperaldosteronism I
...
Unequivocal findings
I
Unilateral
adrenal tumor
>4-5 cm
I Adrenal CT scan I
I
Equivocal findings
...
Unilateral attenuated
adrenal tumor
>1cm
Lateralized
No tumor found
Unilateral adrenal tumor <1 cm
Bilateral adrenal masses
lodochloseterol (NP-59) scan

with dexamethasone suppression
Ambiguous ~
Adrenal v,enous
sampling
Lateralized
Open
unilateral
adrenalectomy
Laparoscopic
unilateral
adrenalectomy
~AmbigUOUS
Medical therapy
(spironolactone)
FIGURE 68-3. An algorithm for selecting

patients with primary aldosteronism for unilateral adrenalectomy. CT = computed tomography.
FIGURE 68-4. A typical CT scan finding in a patient with an

aldosterone-producing adenoma. Note the attenuated lesion in the
left adrenal gland (arrow).
primary hyperaldosteronism.52.56-60 Some investigators

claim that adrenal venous sampling is a routine part of investigations for patients with primary hyperaldosteronism.56 It,
however, is invasive and is usually reserved for patients in
whom both CT and isotope scanning of the adrenals are
inconclusive. Complications, such as rupture and thrombosis
of the adrenal veins, bleeding, or adrenal infarction, have
occurred. In addition, correct catheterization in both adrenal
veins is essential. Catheterization of the right adrenal vein is
often difficult, and failure to do so decreases the reliability of
this procedure. The study, therefore, requires an experienced
angiographer. Blood samples are obtained from each adrenal
vein and from the inferior vena cava for measurement of both
aldosterone and cortisol concentrations, preferably with
ACTH stimulation.
Infusion of ACTH before and during the procedure minimizes episodic changes in aldosterone secretion caused by
stress-induced endogenous ACTH release. Patients receive
an intravenous bolus of 0.25 mg of cosyntropin (synthetic
ACTH) 15 minutes before blood sampling, followed by an
infusion of 0.25 mg of corticotropin in 250 mL of normal
saline at a rate of 4 to 6 mL/min throughout the procedure."
Alternatively, an infusion of cosyntropin at 0.05 mg/hr
is started 30 minutes before adrenal catheterization and
continued throughout the procedure.v-"
Comparison of ratios of aldosterone to cortisol in the
adrenal veins and the inferior vena cava below the renal
veins (or a peripheral vein) allows detection of unilateral or
bilateral sources of aldosterone hypersecretion (Fig. 68-5,
Table 68-1). The cutoff value for lateralization is controversial. An aldosterone-to-cortisol ratio fourfold greater than
that in the other adrenal vein is considered indicative of a
unilateral aldosterone-producing tumor.59.60
Surgical Treatment
We believe that virtually all patients who prove to have a
unilateral aldosteronoma or unilateral excessive aldosterone
FIGURE 68-5. CT scans of the abdomen revealed a lO-mm nodular lesion (arrow) in the right adrenal gland (A) and thickened limb
(arrowhead) of the left adrenal gland (B) in a 48-year-old patient
with primary hyperaldosteronism (a ratio of plasma aldosterone
concentration to plasma renin activity of 370). Adrenal venous
sampling lateralized excessive secretion of aldosterone to the right
gland (see Table 68-1), and this was confirmed at surgery.
production are acceptable candidates for adrenalectomy.

The treatment of choice for aldosterone-producing adenoma
and primary adrenal hyperplasia is unilateral adrenalectomy.
To decrease the surgical risks, hypokalemia should be
corrected before the operation by the administration of
spironolactone, oral potassium, or both. Several studies
have shown that normalization of blood pressure with
spironolactone before the operation is a good predictor of
the successful treatment of hypertension after unilateral
adrenalectomy.14.15.19.23 We are, however, often unable to
evaluate an isolated response to spironolactone because
other antihypertensive medications have usually been
600 - -
Adrenal Gland
previously administered. In addition, spironolactone is equally

effective in controlling arterial pressure in patients with aldosterone-producing adenoma and those with idiopathic hyperaldosteronism, irrespective of the different responses of the
blood pressure in patients with these two conditions after
unilateral adrenalectomy." We, therefore, do not use the
response to spironolactone alone as a criterion for selection of
adrenalectomy in patients with primary hyperaldosteronism.
Laparoscopic adrenalectomy is currently recommended
as the optimal approach for primary hyperaldosteronism,
although traditionally unilateral adrenalectomy by either a
flank or posterior approach was the procedure of choice.
The details of the operative technique for laparoscopic
adrenalectomy are given elsewhere in this text as well as in
the literature. 62-64 Laparoscopic adrenalectomy has been
used since 1992.65-67 Many studies have shown that this
procedure has several advantages over open adrenalectomy,
such as less postoperative blood loss, earlier recovery, and
a smaller wound.68-73 The operative time and operative complications are not significantly different from those of open
adrenalectomy. During the past 6 years, we have performed
75 laparoscopic adrenalectomies for aldosterone-producing
adenomas. The average total operating time was 181 minutes,
and the average blood loss was 27 mL-similar to that
reported by others.
Most laparoscopic adrenalectomies for aldosteroneproducing adenomas involve total removal of the adrenal
gland. Several studies have reported that laparoscopic
adrenal-sparing surgery is feasible and effective in the treatment of patients with primary hyperaldosteronism.r'" The
idea of adrenal-sparing surgery or partial adrenalectomy was
initially advocated in open surgery." The need for adrenal
preservation by partial adrenalectomy for patients with
aldosterone-producing adenoma is unclear because long-term
adrenal problems are rare after unilateral adrenalectomy.
Outcome: Risk Factors for

Postoperative Persistent
Hypertension
Removal of the hyperfunctioning adrenal gland normalizes the
renin-aldosterone system and corrects the hypokalemia. We
have had a 98% success rate with unilateral adrenalectomy
in our 216 patients with primary hyperaldosteronism.

Five patients had persistent hyperaldosteronism after unilateral adrenalectomy. These included three with idiopathic
hyperaldosteronism who were thought to have an adenoma
before surgery, one who was thought to have primary adrenal hyperplasia without a concurrent adenoma, and another
with an aldosterone-producing carcinoma. Another patient
had bilateral macronodular hyperplasia and eventually
underwent bilateral adrenalectomy that resulted in resolution of both the hyperaldosteronism and hypertension.
The long-term cure rate of hypertension by unilateral
adrenalectomy for patients with primary hyperaldosteronism averages 69% in reported series.P In our present series
of 210 patients with aldosterone-producing adenoma, 60%
became normotensive (defined as a blood pressure lower
than 140/90 mm Hg) without medication, and 40% improved
markedly but have remained hypertensive since the operation.
The incidence of persistent hypertension in our series is
comparable to that in previous reports, with relief of
hypertension in 31% to 80% of patients. 14 16.I 7,19-23.78-81 This
variation in the rate of resolution of hypertension after
adrenalectomy might be influenced by the use of different
definitions of normal blood pressure (160/95 mm Hg versus
140/90 mm Hg) and unequal duration of follow-up. It is
worth noting that normalization of blood pressure does not
always occur immediately after surgery. It takes more than
1 year for some patients to become normotensive.F
Identification of patients who are likely to have persistent
hypertension after an adrenal operation is clinically important.
Several authors have investigated various discriminant
factors of persistent hypertension after removal of an adrenallesion. We previously reported that age, gender, and the
pathologic features of the resected adrenal gland are statistically significant prognostic factors of persistent hypertension after unilateral adrenalectomy in patients with primary
hyperaldosteronism.P In the present expanded series,
univariate analysis showed that several variables, including
age, gender, duration of known history of hypertension, and
preoperative ratio of PAC to PRA, had a significant effect on
postoperative hypertension (Table 68-2).
However, a stepwise logistic regression analysis showed
that only two factors-age and gender-remained as significantly prognostic factors (Table 68-3). There was a strong
positive correlation between increasing age and duration of
hypertension among our patients. Overlap effects of these
Hyperaldosteronism - -
two factors on the logistic model have diminished the significant association between duration of hypertension and
postoperative blood pressure control. To propose that the
older the patient who undergoes adrenalectomy, the greater
the chance of postoperative hypertension, seems reasonable
because the persistent hypertension is probably the result
of reduced ability to reverse pathologic vascular changes,
It also suggests that early diagnosis and operative intervention at a younger age result in a more favorable outcome,
Similar studies have shown that a significant correlation
exists between age, or duration of hypertension, and postoperative blood pressure control. 19,79,83,84 Women seem to have
a better response than men, a finding that agrees with other
reports,21,83
In some studies, a positive family history of hypertension
is predictive for persistent hypertension after adrenalectomy.23,81 This variable probably reflects the fact that patients
with persistent hypertension have concurrent refractory
essential hypertension. Other investigators have shown various predictive factors, such as 24-hour urinary aldosterone
excretion. We have previously reported that the presence of
601
macro- or micronodules associated with a distinct adenoma

was an independent prognostic factor for a poorer outcome
of hypertension. It is debatable whether macro- or micronodular hyperplasia is the cause or the result of aldosterone
excess. Moreover, distinction between nonfunctioning
cortical nodules associated with adenoma and macronodular
hyperplasia is not always possible, either histologically or
clinically. Because preoperative aldosterone excess and its
metabolic consequences have been corrected in our patients
following unilateral adrenalectomy, we believe that most
of the nodules are not aldosterone-producing hyperplastic
lesions but instead may result from severe prolonged
hypertension. 13,82 Although the significance of macro- and
micronodules in addition to an obvious adenomatous tumor
remains to be determined, current findings indicate that their
presence does not necessarily preclude the diagnosis of
aldosterone-producing adenoma.
Summary
Primary hyperaldosteronism accounts for about I % to 2%
of patients with hypertension but appears to be the most
common form of secondary hypertension, It should be
suspected in patients with hypokalemia or hypertension
refractory to treatment. The diagnosis of hyperaldosteronism is usually made by documenting an increased serum
or urinary aldosterone level in a patient with a low PRA.
However, patients with aldosterone-producing adenomas
cannot be distinguished from those with idiopathic hyperplasia by biochemical studies alone. Thus, localization studies, including CT scanning, NP-59 scanning, and selective
venous catheterization for aldosterone and cortisol levels,
are mandatory. Unilateral adrenalectomy corrects the
hypokalemia in virtually all patients and hypertension in

about 60% of patients. Laparoscopic unilateral total
adrenalectomy is the standard procedure for patients with
aldosterone-producing adenomas.
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Adrenocortical Carcinoma:
Nonfunctioning and
Functioning
Charles A. G. Proye, MD Jon Armstrong, MD Francois N. Pattou, MD
Adrenocortical carcinomas account for 0.02% of all carcinomas and rank among the least common malignant endocrine
tumors. However, after anaplastic thyroid carcinomas, they
are the most malignant endocrine tumors. From 20% to 40%
have metastasized at the time of presentation, and the overall
5-year survival is 19% to 35%.1.2 Early surgery with adrenalectomy is the only means of cure.
Incidence
Functioning adrenocortical neoplasms with clinical manifestations of hypersecretion occur in 4 cases per million and
roughly half are adenomas and the rest carcinomas.
Adrenocortical carcinomas at autopsy account for 2.5 cases
per million. Hence, the suggested incidence of nonfunctioning adrenocortical carcinomas should be 0.6 to 1.7 cases per
million.'
If these figures are matched with the prevalence of adrenal masses found incidentally (i.e., 0.6% to 1.3% of the
ambulatory population), it is evident that, in the setting of
the adrenal "incidentalorna," nonfunctioning adrenocortical
carcinomas are an uncommon cause. Van Heerden and
colleagues" reported that only 4 of 342 (1.2%) patients with
incidentalomas at the Mayo Clinic had adrenocortical
cancers. Our experience in Lille, France, of adrenal incidentalomas is consistent with this finding. Among 213 adrenal
incidentalomas, of which 103 were operated, there were 5
(2%) adrenocortical carcinomas.t Pheochromocytomas and
metastasis to the adrenal gland should be the primary
concern in this setting, because they occur in 1% to 15% and
4% to 22%, respectively."
The characteristics of 54 adrenocortical carcinomas,
among 486 patients who underwent adrenal surgery, are
listed in Table 69-1.
604
Clinical and Biochemical Tests

Suggesting Malignancy
Some features of a nonmetastatic adrenal tumor, regardless
of the size, are highly suggestive of malignancy, especially
if combined. These are as follows:
Clinical
Abrupt onset of disease
Pyrexia
Abdominal pain
Abdominal mass
Inferior vena caval compression or obstruction
Associated breast carcinoma, osteosarcomas, or brain
tumors (Li-Fraumeni syndrome)
Clinical and biochemical
Mixed hormone secretion
Mild androgenic changes (an indication of the secretion
of precursors)
Feminizing syndrome
Ectopic secretion syndrome
Biochemical
Urinary ketosteroid production in excess of 30 to
40 mg/day
Elevated dehydroepiandrosterone levels observed in 80%
of cases"
Inactive precursor secretion, pregnenolone and aldosterone
precursors, especially 18-hydroxylated compounds?
Criteria of Malignancy of
Cortical Tumors
The criteria determining whether an adrenal neoplasm is
benign or malignant are not precise. Currently, the only
accepted criteria are metastasis, either synchronous or
Adrenocortical Carcinoma: Nonfunctioningand Functioning - - 605
metachronous, and local invasion into surrounding structures. Adrenal tumors metastasize to the lung (72%), the
liver (55%), the peritoneum (33%), the bone (24%), the contralateral adrenal (15%), and the brain (10%).
Local recurrence at reoperation is not an absolute criterion
of malignancy because intraoperative disruption of the capsule
of a benign tumor may result in local seeding, with growth
and apparent invasion.
Large adrenal neoplasms are more likely to be malignant.
Critical size and weight usually range from 6 to 10 em in
diameter and from 40 to 100 g, respectively. The size suggestive of malignant tumors may be greater for androgensecreting tumors than for other tumors.
Not all patients with adrenocortical carcinomas have
metastatic disease at presentation, nor do all of these cancers
exceed 6 em in diameter. Therefore, the clinical problem is
to determine whether an adrenal mass is likely to be malignant
at an early stage. In general, adrenal tumors larger than 4 em
in maximal diameter should be removed for fear of malignancy. Independent of the size, some other features in nonfunctioning tumors help determine whether a patient is best
treated medically or surgically. Features other than size
suggesting malignancy include:
1. Heterogeneous pattern on computed tomography (CT),
magnetic resonance imaging (MRI), or ultrasonography
2. Irregular surface
3. Adjacent adenopathy
A method of defining malignancy histologically has been
relatively simply defined by Weiss.8 This classification incorporates nine histologic features (Table 69-2). The presence
of three or more of these features in a specimen correlates
well with a clinically malignant outcome.
The Weiss histopathologic system is now the most commonly used method for assessing malignancy because of its
simplicity, reliability, and excellent interobserver agreement. 9
Some of the criteria are, however, less reliable than others,
and a statistically modified system of weighting has been
proposed? (2 mitotic rate x 2 cytoplasm x abnormal mitosis x
necrosis x capsular invasion) with a significant correlation
with the Weiss system.
Cytologic criteria are not consistent enough to predict
tumor behavior; cellular atypia and abundance of mitosis are
only suggestive, as is aneuploidy flow cytometry.'? Needle
biopsy is not recommended for diagnosis because it cannot
differentiate between an adrenocortical adenoma and an
adrenocortical carcinoma. There is also concern about rupture
of the tumor capsule. A high mitotic index is perhaps more
of prognostic than diagnostic significance in malignant
adrenocortical cancers.'! Needle biopsy is, however, useful
when metastatic disease to the adrenal is suspected.
Major diagnostic problems arise in the evaluation of
patients with tumors between 3 and 6 em in diameter,
exhibiting weak mitotic activity, with few areas of necrosis
without obvious capsular invasion. In such cases, immunohistochemistry may prove helpful as benign tumors stain
positively for vimentin (connective cell antigen) in 14%
of cases versus 80% to 90% for malignant tumors.
Synaptophysin (neuroendocrine cell antigen) is also more
often expressed in malignant tumors. 12 MIB-l, another
immunohistochemical marker, has also shown promise in
delineating benign from malignant adrenal tumors.v"
Women are affected twice as often as men. Three clinical
patterns can be encountered.
1. A mass syndrome without any clinical evidence of
hypersecretion (30% of cases). The patient complains of a
large and sometimes huge flank tumor discovered by himself
or herself. Alternatively, the tumor may be discovered by the
patient's physician when the patient presents with a flank
pain or pyrexia of unknown origin (possible tumor necrosis
factor [TNF] secretion), asthenia, or weight loss. The erythrocyte sedimentation rate is often elevated. Subtle signs of
hormonal secretion can be discovered, for instance, glycosuria
or a shadow of a mustache above a woman's lip. In addition,
there may be signs of inferior vena caval compression or
FIGURE 69-1. A, Patient with a palpable left abdominal mass. B, Adrenocortical carcinoma specimen
weighing 4.6 kg. C, Neoplastic thrombi extracted
during operation from the inferior vena cava.
obstruction (i.e., ankle edema) leading to MRI and intraoperative findings of neoplastic caval thrombus (Fig. 69-1).
Tumor rupture or hemorrhage is rarely encountered.
2. An overt clinical syndrome of hypersecretion (60% of
cases). Women younger than 40 years are more often
affected. In patients with malignant adrenocortical tumors,
the syndrome is of almost pure hypercortisolism in 30% of
such cases, virilization in 22%, feminization in 10%, hyperaldosteronism in 2.5%, and mixed secretions in 35%.1.12
Although adrenocortical carcinomas account for 5% to 10%
of cases of hypercortisolism, 80% are due to corticotropinsecreting pituitary tumors. Notably, however, 40% of
patients with Cushing's syndrome and adrenal neoplasms
have malignant tumors. Virilizing tumors are malignant in
30% of cases, feminizing tumors in men are virtually always
malignant, and pure aldosterone-secreting tumors are
malignant in less than 1% of cases.!" Mixed secretion is
highly suspicious of malignancy. Ectopic hyperinsulinism
with hypoglycemia (Anderson's syndrome) or ectopic
hyperparathyroidism with hypercalcemia has been reported,

occasionally occurring synchronously in the same patient
(Fig 69-2).15
3. The adrenal incidentaloma (10% of cases?). The
smallest reported metastasizing adrenocortical carcinoma
was 3 em in diameter and weighed 25 g.16 Metastases
occurred postoperatively. There is no evidence in the literature
that solid, nonsecreting adrenal incidentalomas smaller than
3 em in diameter are malignant (i.e., metastatic at presentation). Nevertheless, the referring physician may question
whether benign adrenocortical adenomas could tum into
malignant tumors. Current genetic and biochemical studies
do not support this possibility. Most adrenocortical carcinomas
are monoclonal, whereas the majority of adrenal adenomas
are polyclonal.'? Conversely, genetic changes in locus
llp15 are common in adrenocortical carcinomas and very
rarely seen in adrenal adenomas." Point mutations of ras
genes are equally encountered in 12% of adrenal carcinomas
and adenomas.'? Subsequent studies may clarify whether a
Adrenocortical Carcinoma: Nonfunctioning and Functioning - - 607
FIGURE 69-2. Anderson's syndrome (ectopic hyperinsulinism)

in a patient with a 2.2-kg adrenocortical carcinoma showing
a confluent area of necrosis.
subset of adrenal adenomas are susceptible to malignant

change or whether adrenocortical carcinomas begin de novo.
The likelihood of malignancy for tumors increases with
size from 1.5 to 6 em in diameter but remains limited
because only I in 4000 cases (0.03%) are malignant,"
Operating on all patients with incidentalomas would probably result in more surgical deaths than patients cured by
removing small adrenocortical carcinomas. However, in
young patients, life-long observation may be unacceptable
and may not be cost-effective, and benign adrenocortical
adenomas are less common in young patients.
For patients with adrenal tumors larger than 6 em in
diameter, adrenocortical carcinomas account for up to 15%
of cases. 6,12,20,21 Surgery is therefore recommended.
Preoperative Imaging and

Suspicion of Malignancy
In addition to distant metastases and tumor size, imaging
studies can provide information suggestive of malignancy,
Imaging findings suggestive of malignancy include the
following:
CT
Stippled calcifications
A poorly delineated, rugged, somewhat square-shaped
tumor, with the periodic appearance of prominent
buds; very different from the round adenoma
(Fig. 69-3)
Areas of necrosis
Aortocaval adenopathies
Evidence of local invasion; note that CT is known to
overestimate the extent of liver and caval invasion
MRI
Heterogeneously increased early T2-weighted signal
Weak and late enhancement after injection of
gadolinium
FIGURE 69-3. Computed tomography scan showing a budding

tumor in a patient with Cushing's syndrome and an adrenocortical
carcinoma.
Finding of an intravascular signal identical to the tumor

signal is of paramount importance and diagnostic of
malignancy
131I-6~-iodomethylnorcholesterol
(NP-59) scintigraphy
Lack of or very weak uptake in the presence of a normal
contralateral uptake"
However, 18 cases of adrenocortical carcinomas exhibiting
clear uptake of NP-59 have been described." Virtually all of
them were highly differentiated carcinomas with overt clinical
hypersecretion.
Bone scintigraphy-Tc 99m
Should be performed routinely in all patients with a
suspicion of adrenocortical carcinoma
When disseminated metastases are seen a palliative
treatment rather than surgical resection is indicated
As mentioned, needle biopsy should not be used because
of its lack of sensitivity and risk of a capsular tear with
tumor spillage, except in some patients for diagnosis of
probable metastatic tumors to the adrenal.
Staging, Surgical Indications,

and Preoperative Treatment
Adrenocortical carcinomas are classified according to
stages described by MacFarlane and modified by Sullivan
(Table 69-3).
This classification has one major drawback (i.e., malignancy in stage I is based on histologic criteria only).
Whether all of these tumors are malignant is unknown, and
the assumption that all are malignant may lead to an overly
optimistic affirmation of the results of surgery.
All tumors at stage I, II, or III, whether diagnosed preoperatively or intraoperatively, should be resected, The need to
operate on patients with stage IV disease and distant metastases is controversial because these patients have an average
postoperative survival of 3 months and a l-year actuarial
survival of 10%. Widespread metastases in elderly patients
should dissuade against surgical treatment. Conversely, in
young patients, a solitary metastasis should not be a contraindication to surgery, and in rare cases pre- and postoperative adjunctive chemotherapy has provided long-lasting
survival with complete remission.
Preoperative treatment with mitotane (8 to 12 g/day) is indicated in two situations: metastatic disease and severe hypercortisolism. Mitotane successfully treats Cushing's syndrome
in up to 75% of patients-" and sometimes causes partial or
dramatic shrinkage of the primary tumor and the metastases.
Cortisol replacement therapy is essential because hypocortisolism results in some patients. Unfortunately, many patients
cannot tolerate the nausea and other side effects of mitotane,
which limits its successful application. We recommend using
mitotane for 3 or 4 weeks before surgery, and patients who
respond to mitotane have a more favorable prognosis.
Mitotane has a long half-life, and monitoring of serum
levels can allow a lower maintenance dose for better tolerance. Alternatively, ketoconazole (400 mg/day) can be used
to control the hypercortisolism.
Macroscopic Morphology,
Preoperative Imaging, and
Surgical Strategy
At the time of surgery, most adrenocortical carcinomas are
large tumors, ranging from 5 to 28.5 em in diameter (average,
12.4 em) and from 33 to 3100 g in weight (average, 849 g)
according to Javadpour.P In our experience, the largest
tumor weighed 4600 g (see Fig. 69-1A and B).
The capsule of these grayish white tumors can be thick or
thin. When thin with large superficial veins, the capsule is
susceptible to rupture and local seeding. When thick, the
capsule sticks to adjacent organs, the liver or the kidney,
which may be invaded. Such adhesions may lead to extensive
surgery; thus, it is often wiser to search for a plane of cleavage
under the liver or the kidney capsule. It is necessary to bear
in mind that CT scans often overestimate the local invasion.
Macroscopic venous invasion is common and more often
observed on the right side (20% of surgical cases), often
encompassing the inferior vena cava. Surgeons should
obviously be prepared for this situation. The neoplastic

thrombus of an adrenocortical carcinoma invades the venous
wall more frequently than a renal adenocarcinoma and can
reach up to the right atrium. Assessment or exclusion of
venous invasion may influence the surgical strategy, and in
some cases it is necessary to use cardiopulmonary bypass.
Therefore, careful evaluation of the inferior vena cava,
suprahepatic veins, and the right atrium by MRI, Doppler
flow studies, and right atrium echography is mandatory. The
effectiveness of MRI has eliminated the need for inferior
vena cava phlebography.
Involved regional nodes occur in 10% to 45% of cases
and should be resected with the tumor. They do not impede
the surgical strategy."
Surgical Strategy and Technical

Operative Risks
A wide surgical exposure is mandatory for primary vascular
control, tumor removal with associated lumbar fossa clearance, and aortocaval node dissection, with a possible extension
to the adjacent organs and sometimes to the inferior vena
cava. Therefore, a posterior approach is not indicated in
these patients with large and often invasive tumors. There
currently appears to be no place for laparoscopic surgery.
Some huge right-sided tumors, creeping behind the liver,
still require a thoracoabdominal approach. In all other cases,
either right- or left-sided, an extended subcostal transverse
laparotomy is the best choice, with a view to possible extension by sternotomy if extensive inferior vena cava extension
is suspected or present. Access to the right adrenal vein is
difficult, especially in patients with large tumors. On the left
side, by contrast, it is relatively easy if Catell's maneuver is
used as a first step, combining mobilization of the right
colon to the left and a Kocher maneuver to expose the
left renal and adrenal veins at the vena cava before tumor
manipulation.
All adjacent invaded organs should be resected while
ensuring a functioning kidney on the contralateral side. Formal
liver resection is rarely needed and may require vascular
exclusion of the liver. Often, a cleavage plane can be found
under the liver capsule. Left pancreatectomy with splenectomy
is sometimes indicated on the left side for adequate resection
of large invasive tumors. The adjacent kidney is rarely invaded
by the tumor, but nephrectomy is often helpful, if there
are dense adhesions, to obtain proper aortocaval clearance.
Liberal use of resorbable clips is recommended for adequate

lymphostasis and sometimes for control of the thoracic duct
at its origin.
Extension to the inferior vena cava is the major surgical
challenge, especially on the right side (15% to 20% of
cases). Direct invasion, if extensive, makes resection difficult
and cure unlikely. Limited invasion can often be treated by
wedge resection. Occasionally, segmental caval resection is
necessary, with or without a graft, utilizing a bypass procedure. Limited intracaval thrombus can be flushed either
directly? or with a combination of caval clamping, vascular
exclusion of the liver, and the use of a large Fogarty catheter
in the atrium." If the thrombus extends superiorly to the
right atrium, a thoracoabdominal or combined sternotomylaparotomy is mandatory for primary control of the inferior
vena cava in the pericardium. If it invades the right atrium,
cardiopulmonary bypass with cardiac arrest is required. Use
of external venovenous bypass remains controversial, but it
appears to be useful in selected cases. I,29,30 A solitary liver
metastasis should be removed when it can be done safely.
Care must be taken to avoid rupturing the capsule to prevent
local recurrence. We always use drains and recommend
cryopreserving tumor tissue for subsequent biochemical and
genetic studies.
Specific Postoperative Care

Not uncommonly, within hours after surgery, patients may
exhibit hemodynamic manifestations of septic shock with
negative blood cultures. This may be due to release of TNF
and TNF-like or other factors during tumor manipulation.
Symptomatic treatment is effective. Initially, stress doses and
then maintenance doses of hydrocortisone are mandatory for
patients with secretory tumors and for patients treated
preoperatively with mitotane and ketoconazole. Drains are
removed after the resumption of food intake to decrease the
chance of a problematic chylous fistula.
Overall Results and Prognostic

Factors
Unfortunately, the intra- and postoperative mortality within
30 days of operation is about 10%.1,4 Most of the mortality
occurs in poor-risk patients with stage III or IV disease
undergoing an extensive resection, with an occasional death
from pulmonary embolism after isolated adrenalectomy.
A review of 548 patients with adrenocortical carcinomas
from seven large series in the literature from 1980 to 1990,1
of whom 290 were operated on with curative intent, revealed
the following
1. Overall mean survival was 29 months, ranging from
33 to 71 months for the curative group and from 6 to 27
for the noncurative group.
2. Actuarial5-year survival rates ranged from 16% to 34%
overall and from 32% to 62% for the curative group.
The results of a French nationwide survey during the
same period are shown in Figure 69-4. The overall survival
rate was 34% and for the curative group was 42%. The survival
- Overall patients (n=156)

--- Complete resection (n=128)
._-- Incomplete resection (n=28)
% Survival Rate
100
Ip-o- , 02
80
60
40
20
OL..-
,_~O&J?L
j~)
---:'-,
10 years
FIGURE 69-4. Survival curves of patients overall and of patients

with complete and incomplete resections. (From Icard P, Chapuis Y,
Andreassian B, et al. Adrenocortical carcinoma in surgically
treated patients: A retrospective study on 156 cases by the French
Association of Endocrine Surgery. Surgery 1992;112:972.)
rate for patients undergoing an incomplete resection was 9%

at 1 year,'
Tumor stage was the most important factor predicting
prognosis, with a 5-year actuarial survival of 53% for locally
invasive carcinomas (stage I, 33% and stage II, 55%). The
survival rate was 24% in patients with stage III disease and
0% in patients with stage IV disease (Fig. 69_5).1,4,17
The patients who were younger than 35 years with nonfunctioning tumors or with tumors that secreted androgen
had slightly better survival. Gender, tumor size, associated
nephrectomy, and cellular lymphadenectomy had no impact
on survival.v'v'?
Surgery of Metastases and

Recurrences
Metachronous surgery for solitary metastases is rarely helpful,
but reoperation for local recurrences is advisable when
complete resection is possible. Such patients have a 5-year
survival rate of 28%.1,17,29,30
Adjuvant Therapy
Mitotane, or o,p'-DDD, is the only drug that has proved
to be effective in some patients. Recommended dosages of
% Survival Rate
- Local cancers (n=83)

- - - Locoregional cancers (n=39) P< 0.001
._.- Metastatic cancers (n=34)
100
80
60
40
20
,,,
r----l
:, (6)
53% (24)
----L._.
'.- :
2
~~).
(5)
1..- 124
% (6)
_-_t
----. ---1.._._._ _._.
10
years
FIGURE 69-5. Survival rates in relation to extent of disease. (From

Icard P, Chapuis Y,Andreassian B, et al. Adrenocortical carcinoma
in surgically treated patients: A retrospective study on 156 cases
by the French Association of Endocrine Surgery. Surgery 1992;
112:972.)

100
iI
75
...
-.
II.
- - - - With op'-DDD
II
~.~ 50
I-
"l._ ..
::J
en
Without op'-DDD
.. -,v,
25
-1-1
25
50
75
----1
100 125 150 175 200 225 250

Time (wk)
FIGURE 69-6. Stage IV survival. Effect of mitotane (o,p'-DDD).

(From Icard P, Goudet P, Charpenay C, et al. Adrenocortical
carcinomas: Surgical trends and results of a 253-patient series from
the French Association of Endocrine Surgeons study group. World
J Surg 2001;25:891.)
8 to 12 g1day are unfortunately associated with neurotoxicity,

nausea, intractable diarrhea, and adrenal insufficiency
requiring cortisol substitution. Thus, only 60% to 70% of
patients can tolerate this therapy." Numerous studies have
shown that mitotane fails to improve overall survival l,2,4.32-35
and that no more than 20% of patients respond in terms of
tumor growth. In patients with metastases, however,
mitotane can improve survival. In a French retrospective
study of 253 patients with adrenocortical carcinoma,
mitotane was given as an adjuvant therapy in 53.8% of the
cases. The survival advantage of mitotane was apparent only
in stage IV disease (Fig. 69-6).
Each of the preceding series also included more than a
few anecdotal cases of tumor recurrences and metastases
shrinking impressively for I to 2 years, with survival up to
8 years, and even a few cases of surgically verified disappearance of metastases in patients who received mitotane.I.30.32.36
We are also aware of unpublished data on overgrowth or
reappearance of metastases when mitotane was discontinued
after years of response to the drug. The only long-term survivors after surgery for metastatic adrenocortical carcinoma
have received mitotane therapy. Personally, even after surgery
for stages I and II adrenocortical carcinoma, we would recommend life-long treatment with mitotane if it is tolerated
because it is the best hope for long-term survival.
Various other combination chemotherapy regimens are
currently under evaluation. In one phase II trial using a
combination of mitotane with infusional doxorubicin, vincristine, and etoposide in patients with metastatic adrenocortical carcinoma, responses were obtained in 22% of
patients.'? The superiority of this regimen over single-agent
mitotane is debatable, however. More effective P-glycoprotein
antagonists are needed.
Radiation therapy is usually ineffective.i-"
in Childhood
Patients younger than 16 years with adrenal neoplasms are
more likely to have malignant tumors than adults. A survey
of the English literature between 1956 and 1986 provided

209 cases of children with adrenocortical neoplasms.t? 66%
of which were malignant. Average size and weight of malignant versus benign tumors were 9 versus 4 em and 466
versus 43 g, respectively. The female/male ratio was 2.2:1,
and the mean age at presentation was 4.6 years (range, 5 days
to 16.5 years). Hirsutism was the most common presenting
symptom (51%), followed by hypercortisolism (30%) and
feminization (10%); 8% of the tumors were nonfunctional.
Of interest is the association with congenital abnormalities
such as hemihypertrophy, Beckwith-Wiedemann syndrome,
vascular malformations, urologic abnormalities, and tumors
of the central nervous system. Adrenal neoplasms have also
been reported in patients with salt-losing congenital
hyperplasia."
The biochemical profile in children is similar to that in
adults. Surgery is the only means offering cure. The role of
adjuvant therapy is unproved. Average survival is 24 months
but can reach up to 8 years. It should also be kept in mind
that 40% of neuroblastomas are located in the adrenals and
are now commonly diagnosed by antenatal ultrasonography.
Summary
Adrenocortical carcinoma is a rare tumor, and, unfortunately,
patients with this neoplasm have a grim prognosis. Early
detection and surgical removal offer the only chance of cure.
Further studies must be done to detect and then treat patients
with small malignant tumors and to develop new forms of
adjuvant therapy.
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3. Copeland PM. The incidentally discovered adrenal mass. Ann Surg
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4. van Heerden JA, Grant CS, Weaver AL. Primary carcinoma of the
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10. Hosaka Y, Rainwater LM, Grant CS, et al. Adrenal carcinoma: Nuclear
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11. Weiss LM, Medeiors LJ, Vickery AL. Pathological features of
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13. Vargas MP, Vargas ill, Kleiner DE, et al. Adrenocortical neoplasms:
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14. Ludwig B, Nierderle B, Roka R, et aI. Isolieter prirnarer aldosterismus
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15. Proye C, Fossati P, Ben Soussan D, et aI. Syndrome d' Anderson avec
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16. Gicquel C, Lelond-Rrancillard M, Bertagna W, et al. Clonal analysis of
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18. Gicquel C, Bertagna X, Schneid H, et al. Rearrangements at the IIpl5
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Cushing's Syndrome
Gennaro Favia, MD Franco Lumachi, MD Maurizio Iacobone, MD
In 1932 Harvey W. Cushing, a Boston neurosurgeon,

defined a syndrome characterized by muscular weakness,
obesity, abdominal striae, diabetes, and arterial hypertension,
which he called "pituitary basophilism," implying that it was
a specific pituitary disease. 1 Today, all conditions resulting
in chronic glucocorticoid excess are known as Cushing's
syndrome. Iatrogenic Cushing's syndrome is due to increased
glucocorticoid intake and should be distinguished from the
primary form. Spontaneous Cushing's syndrome may be of
pituitary or ectopic origin (corticotropin dependent) or
of adrenal origin (corticotropin independent).
Epidemiology and Pathogenesis

Cushing's syndrome account for only 0.2% of all causes of
arterial hypertension in the general population, with a prevalence of 1 to 10 cases per million per year.' Corticotropindependent Cushing's syndrome is found in more than 80%
of patients. Chronic corticotropin hypersecretion results in
hyperplasia of the reticularis and fasciculata zones of the
adrenal cortex, with hyperproduction not only of cortisol but
also of deoxycorticosterone and androgens. Two forms
of Cushing's syndrome result from increased corticotropin
levels: pituitary-dependent Cushing's syndrome and ectopic
Cushing's syndrome.
Pituitary-dependent Cushing's disease is the more
common form (70%) of Cushing's syndrome and is caused
by corticotropin-secreting pituitary adenomas or microadenomas that are usually smaller than 1 em; 50% are 5 mm or
less. Invasive adenomas and malignant pituitary tumors have
rarely been reported.
These tumors are more common in women than in men
(male/female ratio, 1:8) and occur most often during the
second and third decades of life, but the age at diagnosis
may range from childhood to 70 years.'
Ectopic Cushing's syndrome accounts for 10% of
patients, and patients usually present clinically with a rapidly
progressive course. The most common tumors causing ectopic
Cushing's syndrome are small cell carcinoma of the lung
(50%), malignant tumors of the thymus (20%) or the pancreas
(10%), carcinoid tumors, medullary thyroid carcinomas, and
pheochromocytomas.t-' Ectopic Cushing's syndrome occurs
612
more often in men (male/female ratio, 2: 1) and in the fourth

and fifth decades of life.
The second type is corticotropin-independent Cushing's
syndrome. Cushing's syndrome may be caused by a unilateral cortisol-secreting adrenocortical adenoma (10%) or
carcinoma (10%). Primary adrenal hyperplasia is a rare
cause of corticotropin-independent Cushing's syndrome.
Because adrenocortical tumors secrete increased amounts of
cortisol, corticotropin production is suppressed. In patients
with adrenal carcinoma, the typical features of Cushing's
syndrome are often accompanied by signs of virilization.
Corticotropin-independent Cushing's syndrome occurs
more frequently in women (adenoma: male/female ratio,
1:3; carcinoma: male/female ratio, 1:2) and in the third and
fourth decades of life."
Clinical Features
The clinical manifestations of Cushing's syndrome usually
begin gradually (Table 70-1). Patients frequently report
increasingly severe asthenia, enhanced appetite, and weight
gain. In premenopausal women, oligomenorrhea is common
and may occur before any other apparent clinical change.
Typically, these patients have centripetal obesity with
"moon face," fullness of the supraclavicular fat pads, and
a "buffalo hump." The limbs look thin in relation to the rest
of the body, and muscular hypotrophy accentuates this
characteristic appearance (Fig. 70-1A). Subsequently, skin
changes take place: the epiderrnidis and subcutaneous tissue
become thinner, and purplish red striae can be seen on the
flanks, the abdomen, and the limbs. The skin becomes fragile,
with loss of its elasticity, and extensive bruising is common
even after only minimal injury (Fig. 70-1B). Mild or
moderate arterial hypertension is quite characteristic of
Cushing's syndrome and occurs in 70% of patients, as does
osteoporosis. More rarely, pathologic fractures, muscular
weakness, renal stones, poly arthralgia, and, in some cases,
neuropsychiatric signs and symptoms occur. Laboratory
abnormalities are listed in Table 70-2. An abnormal oral glucose tolerance test, postprandial hypoglycemia, and secondary
hyperinsulinemia are relatively common. The most frequently
observed case is that of an obese women 30 to 35 years old,
Cushing's Syndrome - - 613
with oligomenorrhea, slight hirsutism, and moderate arterial

hypertension. Today, because of the precision of laboratory
and imaging studies, Cushing's syndrome is being diagnosed
earlier in its course, so that clinical and laboratory manifestations are less apparent. Representativepatients with cortisolsecreting adrenal adenomas treated during the years 1980 to
1990 are shown in Figure 70-2.
When Cushing's syndrome is suspected and iatrogenic
causes have been excluded, the diagnosis should be confirmed
by both an overnight dexamethasone suppression test (1 mg
of dexamethasone is given at 11 PM, and a plasma cortisol
measurement is obtained in the morning) and the 24-hour
urinary free cortisol measurement. When the dexamethasone
suppression test is normal (plasma cortisol < 50 mmol/L) and
the urinary free cortisol is normal 135 nmol/24 hours), the
patient does not have Cushing's syndrome. False-positive
tests may occur as a result of (1) chronic intake of certain
drugs (barbiturates, phenytoin, rifampicin) or alcohol
(which accelerates cortisol metabolism); (2) the presence of

a serious illness or stressful event, chronic diseases (renal
failure), or major depressive states (which stimulate the
secretion of glucocorticosteroids); and (3) obesity and highestrogen states (estrogen therapy, pregnancy), but in the
obese patients the urinary free cortisol is usually normal.
When the results are equivocal, the 2-day test (0.5 mg dexamethasone every 6 hours for 2 days) lowers the plasma
cortisol concentration below 50 nmol/L in patients without
endogenous Cushing's syndrome.
To establish whether the form is corticotropin dependent
or independent, the following are performed: (1) measurement
of basal plasma corticotropin and urinary free cortisol excretion after high-dose (8 mg) dexamethasone (2 mg every
6 hours for 2 days, or 8 mg at 11 PM as a single dose)
administration (patients with pituitary Cushing's syndrome
suppress to less than 10% of baseline, whereas those
with cortisol-secreting adrenocortical tumors or ectopic
corticotropin production do not); (2) corticotropin-releasing
hormone (CRH) stimulation test (patients with pituitarydependent Cushing's syndrome are responsive, increasing
plasma cortisol levels by more than 50%); and (3) bilateral
selective venous catheterization of the inferior petrosal veins
after CRR stimulation (patients with pituitary Cushing's
syndrome have an increase in corticotropin versus peripheral
or prestimulation levels greater than 50%).7
In pituitary Cushing's syndrome, plasma corticotropin
levels are slightly increased or normal and are suppressed by
high-dose dexamethasone. One should be aware that some
carcinoid tumors behave metabolically like corticotropinsecreting pituitary tumors. In ectopic corticotropin syndrome,
plasma corticotropin levels are generally markedly elevated
and cortisol secretion is not suppressed by dexamethasone.
Patients with cortisol-secreting adrenal tumors have a suppressed hypothalamic-pituitary axis. Plasma corticotropin
levels are low or undetectable, and there is no suppression
by dexamethasone. If the results are doubtful, one should
carry out a CRH stimulation test; patients with pituitary
Cushing's syndrome have an exaggerated response regarding
both corticotropin and cortisol compared with that obtained
in patients with an adrenal tumor or in normal subjects
(Fig. 70-3).
Localizing Procedures
FIGURE 70-1. A, Typical clinical features of a patient with
marked Cushing's syndrome. B, Abdominal cutaneous striae.
The adrenal imaging techniques used as localizing procedures are adrenal scintigraphy, computed tomography (CT),
FIGURE 70-2. Differentclinical appearances of patients withCushing's syndrome in relation to earlydiagnosis. A to C, The faces of some
patientsobserved in 1982, 1987, and 1995, respectively.
and magnetic resonance imaging (MRI) scanning.

Radiocholesterol scintigraphy is very useful in patients with
Cushing's syndrome because it evaluates both adrenals
simultaneously.S? In patients with adrenocortical hyperplasia resulting from a corticotropin-dependent syndrome,
scintigraphy shows bilateral uptake (Fig. 70-4A). In the
presence of a cortisol-secreting adenoma, focal uptake is
observed, and scintigraphy accurately depicts the suppression of the contralateral adrenal gland (Fig. 70-4B). When
an adrenal tumor is present, either CT or MRI scanning
localizes the tumor and documents the size of the mass
and its relationship to the surrounding structures (Fig. 70-4C
and D). In selected patients with a unilateral adrenal mass,
image-guided fine-needle aspiration cytology may be performed when requested for surgical planning."
MRI scanning is preferable to CT scanning for identifying pituitary adenomas. MRI scanning, however, may fail to
localize pituitary tumors smaller than 5 rnm, and nonfunctioning micropituitary tumors occur in up to 25% of the
population. Bilateral selective venous catheterization of the
inferior petrosal sinus with CRR stimulation is the most
sensitive test for confirming the presence of a pituitary
adenoma and in most cases can identify the side
of the microadenoma.!' Furthermore, plasma values of corticotropin (ipsilateral, peripheral) with a ratio higher than
1.5: I rule out ectopic corticotropin secretion.' Selective
venous catheterization of other veins is occasionally helpful
for identifying ectopic corticotropin-secreting tumors, as is
MRI with Tl- and TI-weighted images for bronchial
adenomas in the chest or pancreatic carcinoid tumors in the
abdomen. Figure 70-5 shows a useful algorithm for the evaluation of a patient with Cushing's syndrome, as suggested by
Kaye and Crapo."
Treatment
Pituitary-Dependent Cushing's Syndrome
The aim of treatment of Cushing's syndrome is to reduce
cortisol secretion to normal. Formerly, bilateral adrenalectomy
was used for treating patients with pituitary-dependent
Cushing's syndrome, but this treatment has long been replaced
by direct pituitary surgical treatment.
Patients with pituitary-dependent Cushing syndrome can
be treated by (I) trans sphenoidal microsurgery with tumor
...:... .
...:... .
-;.
j
~
~
..................................................................................
; .....
15'
30'
45'
60'
90'
time
-.--+-
normal
adrenal adenoma
----+-
pituitary-dependent
ectopic ACTH
120'
FIGURE 70-3. Responses of

plasma corticotropin (ACTH)
(pmollL) to corticotropin-releasing
hormone (CRH) (0.1 Ilglkg intravenously) in control subjects
(normal) and patients with cortisolsecreting adenoma, pituitarydependent Cushing's syndrome,
andectopic corticotropin syndrome.
Cushing's Syndrome - -
615
FIGURE 70-4. A, Bilateral uptake

with ?5Se-norcholesterol scintigraphy in a case of bilateral
adrenal hyperplasia resulting
from pituitary-dependent Cushing's
syndrome. B, Scintigraphic pattern
in a 30-year-old woman with a
cortisol-secreting adenoma of
the left adrenal gland. Computed
tomography scan (C) and magnetic
resonance imaging (D).
removal, (2) pituitary irradiation, (3) pharmacologic therapy,

or (4) bilateral adrenalectomy.
Selective pituitary transsphenoidal microsurgery is the
treatment of choice in pituitary-dependent Cushing's
syndrome when an experienced neurosurgeon is available.
A rhinoseptal approach is utilized with an operating microscope. Incising through the sublabial mucosa, the surgeon
removes the nasal spine and the lower part of nasal septum
to reach the sphenoid bone. The floor of the sella is entered
through the sphenoidal sinus. The dura mater, on which the
pituitary rests, is incised. If the adenoma has not previously
been visualized by MR!, the anterior pituitary is incised
horizontally; this enables a microadenoma to be removed in
more than 65% of cases." When no tumor is evident, a
partial hypophysectomy is usually performed, and approximately two thirds of the gland is removed. The cure rate
is about 90% 2 years after surgery and 70% or less at
10 years.P:" The best results are obtained in patients who
have had micro- or macroadenomas localized by CT or MR
scanning preoperatively and the pituitary tumor completely
removed. Because a second trans sphenoidal operation has a
success rate of less than 50%, pituitary irradiation may represent an alternative second-line treatment." Major complications after selective microsurgery, such as meningitis or
oculomotor dysfunction, are uncommon, accounting for less
than I % of cases. I? However, most patients develop transient corticotropin, thyroid-stimulating hormone (30% to
40%), and gonadotropin (35% to 50%) deficiency, requiring
postoperative glucocorticoid and L-thyroxine support,
usually for less than 6 months. Transient (20%) or, rarely,
permanent diabetes insipidus may also occur.15.17.18
Pituitary irradiation has limitations because it is not
selective and may be used as first treatment only in adult
patients in whom any surgical approach has been excluded
(high surgical risk, low compliance).19 Reported response
rates are 50% to 60%, and the resolution of clinical manifestations is slow (2 to 4 years or longer) and unpredictable.
Moreover, after pituitary irradiation, about 50% of patients
experience hypopituitarism and require replacement therapy
with glucocorticoids, L-thyronine, testosterone, estrogen, or
a combination." Newer forms of radiotherapy involving
stereotactic computer-assisted linear accelerators or cobalt 60
radiation sources (gamma knife) have been used in patients
with pituitary-dependent Cushing's syndrome, both as
first-line treatment and after failed pituitary surgery. 20.2I
Radiosurgery using photon energy with a gamma beam
should be considered a valuable complement to transsphenoidal surgery, but its effectiveness has still to be confirmed,
long-term prospective studies are needed, and delayed
recurrences or hormone deficiencies may occur. 21,24

1-mg overnight dexamethasone
suppression test
Normal
ACTH by RIA
High-dose (8-mg) dexamethasone suppression test>
Undetectable-to-Iow ACTH
Lack of suppression
Normal-to-very elevated ACTH

Lack of suppression
Equivocal
results
Normal-to-elevated ACTH
Suppression
CRH stimulation test

Inferior petrosal
sinus sampling
If tumor not apparent
Adrenal CT
( 1. Chest CT
2. Abdominal CT
Pituitary MRI
FIGURE 70-5. Algorithm for the evaluation of a patient with suspected Cushing's syndrome. The asterisk indicates that if the overnight
high-dose dexamethasone suppression test is validated in the outpatient setting, it should be used at this point. The classic high-dose dexamethasone suppression test or corticotropin-releasing hormone (CRH) stimulating test may be used. CT = computed tomography;
MRI =magnetic resonance imaging; RIA =radioimmunoassay. (Modified from Kaye TB, Crapo L. The Cushingsyndrome: An update on
diagnostic tests.Ann Intern Med 1990;112:434.)
Medical treatment is usually used for limited periods of

time or before surgery to control corticotropin and cortisol
hypersecretion. The drugs that influence pituitary secretion
(cyproheptadine, lisuride, bromocriptine) have produced
only temporary results in a very few patients. Ketoconazole,
600 to 1200 mg/day orally, inhibits the cytochrome P-450
enzymes P-450scc and P-450cll and subsequently various
steps of steroid biosynthesis. It has been used for long-term
therapy, even though its therapeutic effects tend to decrease
with time, and transient hepatotoxicity may be observed.P'"
Mitotane (o,p'-DDD), 2 to 4 g/day orally, is a relatively
effective drug for inhibiting cortisol secretion. It causes
selective destruction of the fasciculata and reticularis zones
of the adrenal cortex and subsequently inhibits adrenal
steroidogenesis. Although mitotane is highly effective, the
decrease of cortisol production requires several weeks to
be useful for patients, and strict monitoring of urinary free
cortisol is required. About 80% of patients, unfortunately, have
several side effects (nausea, vomiting, diarrhea, skin rash)
and toxic effects, so that it is used almost exclusively for
treating patients with adrenal carcinoma.P?" Metyrapone,
an l1~-hydroxylase
(cytochrome P-450cll) inhibitor, may
be effective for reducing cortisol secretion, blocking the
last step of adrenal steroid biosynthesis. However, it often
results in adverse general effects (dizziness, nausea) and
increases both corticotropin and androgen levels, resulting in unbearable worsening of hirsutism in women.
Aminoglutethimide, which inhibits the cytochrome
P-450scc, has also been utilized in combination with
metyrapone, with similar side effects, especially in patients
who do not respond to mitotane." Mifepristone (RU 486) is

a 19-norsteroid antiprogestin and a potent glucocorticoid
antagonist that has both contraceptive and abortifacient
effects." It has selective affinity for glucocorticoid receptors, resulting in increased hypercortisolism. Clinical improvement requires high doses (10 to 20 mglkg per day) of drug,
and experiences are limited."
Bilateral adrenalectomy is therapeutically effective for
treating patients with corticotropin-dependent Cushing's
syndrome, especially in the following situations'": (l) after
unsuccessful pituitary treatment or when transsphenoidal
surgery is technically difficult, dangerous, or impossible;
(2) in patients with rapidly progressive and severe hypercortisolism; (3) for the palliative treatment of patients with
ectopic corticotropin syndrome; and (4) in patients with
primary adrenal bilateral hyperplasia. The rapid cure of
Cushing's syndrome after bilateral adrenalectomy is associated with occasional morbidity, but life-long replacement
therapy is required.P-?
When the need for adrenalectomy has been established,
preoperative treatment both to restrict cortisol secretion and
to correct its metabolic effects must be undertaken.
Ketoconazole, which inhibits steroid production, is used
most often for this purpose. Liver function studies should be
evaluated periodically. Before surgery, diabetes mellitus and
hypertension should be treated and coagulation studies
done. Prophylactic anticoagulation using low-molecularweight heparin (enoxaparin, 40 to 80 mg once daily) or
unfractionated heparin (5,000 to 15,000 units twice daily)
for at least 2 weeks is started 6 to 8 hours after operation
to prevent thromboembolic complications, which in the past

have affected such patients. 19 After bilateral adrenalectomy,
steroid replacement therapy with glucocorticoids (hydrocortisone or cortisone acetate) must be given and mineralocorticoids (fluorhydrocortisone acetate) are also sometimes
required (Table 70-3).
The immediate and late complications of adrenal surgery
vary according to the surgical approach and expertise.
Anterior, lateral, and posterior approaches were used in the
past. We preferred the flank incision because that provided
excellent exposure and was associated with fewer complications compared with anterior approaches.v" More recently,
a bilateral laparoscopic approach has been proposed, and it
represents a safe and effective procedure.P-" Potential
advantages of this technique include shorter hospitalization,
decreased requirement for postoperative analgesia, and
decreased postoperative morbidity related to incisional
complications." Cure rate and morbidity are similar for
laparoscopic and open adrenalectomies, and the main complication is due to capsular disruption, with adrenal tissue spreading and, consequently, recurrences of hypercortisolism."
Laparoscopic adrenalectomy does not modify the risk of
thromboembolism and the intraoperative or early postoperative bleeding compared with open adrenalectomy; thus,
heparin prophylaxis is mandatory, and use of intermittent
compression devices has also been suggested.v-"
In 1960, Nelson and colleagues'" reported on patients
who experienced cutaneous hyperpigmentation and pituitary
neoplasm after bilateral adrenalectomy. Nelson's syndrome
is an important sequela of bilateral adrenalectomy in patients
with Cushing's syndrome. The estimated cumulative risk of
development of Nelson's syndrome after adrenal surgery is
13% after 2 years and 29% after 10 years.'? Symptoms
include headache, visual field defects, and hypopituitarism
resulting from the aggressive expanding intrasellar neoplasm.
These patients need to be treated by pituitary surgery, radiotherapy, or both. Prophylactic pituitary irradiation does not
always prevent the onset of Nelson's syndrome, and
the time of adrenalectomy is a predictive factor for its
development.v-v-" To avoid or limit this complication and
obviate the need for life-long replacement therapy, some
surgeons relied on subtotal adrenalectomy. Because of the
high incidence of recurrence in Cushing's disease, subtotal
adrenalectomy has been abandoned. Adrenal autotransplantation has been used to avoid hypoadrenalism, but successful
results are uncommon.w" Unilateral adrenalectomy followed
by external pituitary irradiation has also been proposed as
an alternative to bilateral adrenalectomy." We believe that
617
bilateral adrenalectomy is indicated for some patients with

pituitary Cushing's syndrome. When CT, MRI, or inferior
petrosal venous sampling reveals a pituitary adenoma,
transsphenoidal surgery, pituitary irradiation, or radiosurgery is the treatment of choice. However, when these
localizing procedures fail to demonstrate the site of corticotropin hyperproduction, bilateral adrenalectomy rather
than a "blind" hypophysectomy should be considered.P-"
Figure 70-6 shows the therapeutic approaches for treating
patients with pituitary-dependent Cushing's syndrome.
Ectopic Corticotropin Syndrome

When the site of the tumor causing ectopic corticotropin
syndrome is known and the tumor can be completely
resected, this is the most effective treatment. Unfortunately,
small benign and malignant carcinoid tumors may not be
localized. In these patients the aim of therapy is to reduce
adrenal corticosteroid synthesis. Ketoconazole or the
somatostatin analogs (octreotide) are more effective and
rapid in action than mitotane.v-" Bilateral adrenalectomy is
recommended for patients whose increased cortisol secretion
cannot be controlled with medication and for patients who
acquire carcinoma of the lung or pancreatic carcinoids and
have a dismal prognosis. Patients with malignant thymomas
or metastatic medullary thyroid carcinoma can live for years
PITUITARY-DEPENDENT GUSHING'S SYNDROME
transsphenoidal microsurgery
radiation therapy
I
I
relapse------,
cure
follow-up
transsphenoidal microsurgery
radiation therapy
I
I
relapse
bilateral adrenalectomy 1
FIGURE 70-6. Therapeutic ways of correcting pituitary-dependent

Cushing's syndrome (see text).
618 - -
Adrenal Gland
with incurable neoplasms. The mean survival is even better

for patients with bronchial carcinoids.v'?
Corticotropin-Independent Cushing's
Syndrome
ADRENAL ADENOMAS
Patients with corticotropin-independent Cushing's syndrome

resulting from an adrenal adenoma can be successfully
treated by unilateral adrenalectomy. The preoperative treatment is the same as that described for patients undergoing
bilateral adrenalectomy. The postoperative replacement
therapy is also similar except that cortisone acetate alone is
used. The replacement therapy is gradually reduced to
enable the remaining adrenal gland and pituitary to function
normally. This can usually be accomplished by 6 months but
occasionally takes as long as 18 months after unilateral
adrenalecromy.P-" Laparoscopic adrenalectomy has now
become the "gold standard" for adrenalectomy in patients
with cortisol-secreting adenomas, but it should be performed
by skilled teams to avoid complications such as capsular disruption, which may lead to recurrences.34.36.49 In the past, the
morbidity rate after unilateral adrenalectomy was 30%, with
appreciable (l % to 5%) mortality. 50 In more recent series,
major complications (splenectomy, hemorrhage, pulmonary
embolism, respiratory failure) and minor complications
(wound infection, bronchopneumonia) have been reduced to
less than 5% and 10%, respectively, approaching the rate
reported for patients with other adrenal diseases.v-" The longterm cure rate with surgical removal of a cortisol-secreting
adrenal adenoma is virtually 100%.
ADRENAL CARCINOMA
Adrenal carcinoma accounts for only 5% to 10% of cases of

Cushing's syndrome. Malignancy is often suspected because
of the rapid onset of symptoms and the mixed pattern of hormonal secretion and because the tumors are usually large
(greater than 5 em), irregular, and heterogeneous on MRI or
CT scanning. Surgical removal is the only potentially curative
procedure, and an open transabdominal approach is mandatory. For patients with stage IV disease, the only possible
treatment, at least initially, is chemotherapy. Unfortunately,
adrenocortical carcinoma is an aggressive tumor, and
extensive surgery does not appear to improve survival. 6.52
Adjuvant radiotherapy has a limited impact on prognosis,
even when initiated soon after tumor resection, and it is
effective in only about 15% of patients. 6.53 Mitotane therapy
is effective in about 20% of patients, and in some patients an
impressive reduction occurs in the adrenal tumor itself as
well as in the metastases, with long-term survival of up to
8 years. 25.26 If mitotane produces no response, occasional
favorable results have been reported with cisplatinum, but
survival is usually only 2 or 3 years and long-term results are
disappointing, especially in patients with stage ill or IV
disease, who make up more than 60% of cases. 47.53
PRIMARY ADRENAL HYPERPLASIA
A corticotropin-independent syndrome of hypercortisolism

resulting from multiple bilateral hyperfunctioning adrenal
nodules ranging from microscopic to 3 em in size, with
suppression of corticotropin secretion, has been described.l"
The pathologic and radiologic features are difficult to

distinguish from those of bilateral hyperplasia that occurs
in patients with pituitary-dependent Cushing's syndrome.55
Familial cases in patients with hyperpigmentation and cardiac
or cutaneous myxomas are reported (Carney's syndromej.v
In patients with nodular adrenal hyperplasia, cortisol levels
do not decrease after dexamethasone, plasma corticotropin
levels are undetectable, and scintigraphy reveals bilateral
adrenal uptake." When corticotropin independence is
demonstrated, bilateral adrenalectomy is recommended.
Results
In patients with adrenal adenoma, unilateral adrenalectomy
gradually leads to the disappearance of the signs and symptoms of Cushing's syndrome, and these patients have excellent long-term survival. The first clinical and metabolic
changes disappear within 4 to 6 weeks. Muscular weakness
also disappears, and female patients may become pregnant.
Resolution of the cutaneous alterations, including hirsutism
and hypertension, takes longer. Obesity and the abdominal
fat distribution regress slowly, and it often takes 12 months
for the physical appearance of these patients to recover
(Fig. 70-7).
Recovery is slower after bilateral adrenalectomy for
pituitary-dependent Cushing's syndrome. Moreover, some
patients remain hypertensive (30%) with diabetes (20%) and
obesity (20%).30 These patients may have a reduced working
capacity, but their survival is similar to that seen in the
general population. 14 In 30% of cases, Nelson's syndrome is
a problem. All patients after bilateral adrenalectomy must
undergo periodic check-ups. Supplemental steroid treatment
must be taken at times of stress.
Summary
Cushing's syndrome may be classified as either corticotropin
dependent (Cushing's disease or pituitary Cushing's syndrome and ectopic corticotropin syndrome) or corticotropin
independent (adrenal adenoma or carcinoma). Cushing's
disease accounts for about 70% of all cases. Clinical features
of Cushing's syndrome include obesity, facial plethora,
hirsutism, menstrual disorders, hypertension, and other
manifestations, as listed in Table 70-1. An overnight dexamethasone suppression test and measurement of free cortisol in
a 24-hour urine sample establish the diagnosis. When the
plasma cortisol is normal 50 mmol/L) after overnight
l-mg dexamethasone administration, and urinary free
cortisol is also normal, Cushing's syndrome is excluded.
MRI scanning of the pituitary or adrenals is useful for
identifying the site of the tumor.
Selective venous sampling of the inferior petrosal veins
bilaterally is helpful in some patients in whom it is difficult
to determine whether pituitary or ectopic Cushing's syndrome
is present. Pituitary Cushing's syndrome is treated by
transsphenoidal microsurgery or by radiation therapy. Bilateral
adrenalectomy or medical adrenalectomy is usually used for
recurrent cases. Ectopic Cushing's syndrome is treated, when
possible, by removing the corticotropin-secreting tumor.
619
FIGURE 70-7. Results in patients before

and after adrenalectomy for Cushing's
syndrome. A and B, A 27-year-old
man with pituitary-dependent Cushing's
syndrome at operation and 18 months
after bilateral adrenalectomy, respectively.
C and D, The same patient for whom data
were presented in Figure 70-4 before and
15 months after left adrenalectomy,
respectively.
Unfortunately, most of these neoplasms cannot be localized,

so that bilateral adrenalectomy is required. Primary adrenal
neoplasms should be removed by adrenalectomy.
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after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab
1995;80:165.
42. Demeter JG, Jong SA, Brooks MH, et al. Long-term results of adrenal
autotransplantation in Cushing's disease. Surgery 1990;108:1117.
43. Miyauchi A, Kihara M, Matsusaka K, et al. Successful autotransplantation of an adrenal gland using a new method of omental wrapping:
report of a case. Surg Today 1999;29:960.
44. Nagesser SK, van Seters AP, Kievit J, et al. Treatment of pituitarydependent Cushing's syndrome: Long-term results of unilateral
adrenalectomy followed by external pituitary irradiation compared to
transsphenoidal pituitary surgery. Clin Endocrinol (Oxf) 2000;52:427.
45. Winquist EW, Laskey J, Crump M, et al. Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic
adrenocorticotropin production. J Clin Oncol 1995;13: 157.
46. De Herder WW, Lamberts SW. Octapeptide somatostatin-analogue
therapy of Cushing's syndrome. Postgrad Med J 1999;75:65.
47. Kasperlik-Zaluska AA, Pietraszek A, Makowska AM, et al. Occult
ectopic adrenocorticotropic hormone syndrome. Lancet. 2001;
358:149.
48. Doherty GM, Nieman LK, Cutler GB Jr, et al. Time to recovery of the
hypothalamic-pituitary-adrenal axis after curative resection of adrenal
tumors in patients with Cushing's syndrome. Surgery 1990;108:1085.
49. Brunt LM, Moley IF, Doherty GM, et al. Outcomes analysis in patients
undergoing laparoscopic adrenalectomy for hormonally active adrenal
tumors. Surgery 2001;130:629.
50. Welbourn RB. Survival and causes of death after adrenalectomy for
Cushing's disease. Surgery 1985;97:16.
51. Bonjer HI, Sorm V, Berends FJ, et al. Endoscopic retroperitoneal
adrenalectomy: Lessons learned from 111 consecutive cases. Ann Surg
2000;232:796.
52. Favia G, Lumachi F, D' Amico DF. Adrenocortical carcinoma: Is prognosis different in nonfunctioning tumors? Results of surgical treatment
in 31 patients. World J Surg 2001;25:735.
53. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992;112:963.
54. Kirshner MA, Powell RD Jr, Lippsett MB. Cushing's syndrome:
Nodular cortical hyperplasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor. J Clin Endocrinol
Metab 1964;24:947.
55. Swain IM, Grant CS, Schlinkert RT, et al. Corticotropin-independent
macronodular adrenal hyperplasia: A clinicopathologic correlation.
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56. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas,
spotty pigmentation, and endocrine overactivity. Medicine (Baltimore)
1985;64:270.
Pheochromocytoma
Clive S. Grant, MD
...in the right adrenal gland a tumor was palpable...the

patient's blood pressure had been running at a normal
level, perhaps 150 systolic. She almost immediately
then went into cardiac arrest. Cardiac massage through
the diaphragm was not effective and accordingly after
this was tried for thirty or forty seconds the chest was
opened and inside another thirty or forty seconds, 1
didfeel a satisfactory beat was established. As soon as
the heart began to beat again, the blood pressure was
very high being well over 250.... We proceeded with
the operation and with some difficulty from bleeding
and exposure, removed the pheochromocytomas from
the right side.... As soon as the tumor was removed on
this side, the bottom fell out of the patient's blood
pressure and she required a triple amount ofLevophed
to maintain her pressure at 100 mm Hg.
From the operative note on a patient operated by
Dr. Priestley in August 1961. The patient survived and
recovered well.
From a surgeon's perspective, the ultimate surgical challenge
might be characterized as one that requires careful thought
and preparation preoperatively, a technically challenging
operative procedure in the presence of risk and pressure, and
the gratification that follows when the tumor has been successfully excised and the patient can be reassured that the
tumor, which may have posed even life-threatening risk,
has been removed and he or she is cured. In every regard,
the surgical excision of a pheochromocytoma fulfills these
criteria. To achieve a successful outcome requires specific
knowledge and careful attention to detail throughout the
entire course of the patient's management. Patients look to
surgeons as the key individuals in the overall management
of this tumor. However, to accept this role responsibly
requires a team effort with close interaction with the endocrinologist, radiologist, and anesthesiologist, who play integral
parts in the patient's care. This central leadership role of the
surgeon requires an understanding of all facets of the care.
History
In 1886, Frankel first described pheochromocytoma at
autopsy. I Not until 1926 did May0 2 at the Mayo Clinic and
Roux ' in Switzerland successfully remove these adrenal

tumors. Interestingly, neither of these tumors was diagnosed
preoperatively. As late as 1951, only 125 operations for
pheochromocytoma had been reported, which included
33 deaths resulting from both severe hypertension during
resection and hypotension after removal of the tumor," With
the use of two new pharmacologic agents, phentolamine for
hypertension and noradrenaline for hypotension, only 5 years
later, Priestley and colleagues reported the successful excision
of 61 pheochromocytomas in 51 patients without a death.'
Incidence
Pheochromocytoma has an incidence of 2 to 8 cases per
million persons annually.-" which constitutes a curable form
of hypertension in 0.1% to 1% of hypertensive patients," and
as many as 800 persons may die annually in this country
from associated complications." Of patients with pheochromocytomas discovered only at the time of autopsy, 75% died
suddenly from either myocardial infarction or a cerebrovascular catastrophe. Moreover, one third of the sudden deaths
occurred during or immediately after unrelated minor
operations. 10
Clinical Features
The overwhelming majority of pheochromocytomas are
sporadic in origin (80% to 90%) but may be associated with
other diseases (see later). Pheochromocytoma has been
termed a "10% tumor" because roughly 10% of these tumors
are malignant, multifocal, bilateral, arise in extra-adrenal
sites, and occur in children.
Manifestations of catecholamine excess form a wide
spectrum in these patients, the foremost being hypertension.
In our experience, nonfunctioning pheochromocytomas
are distinctly uncommon, as nearly all patients with these
tumors, at least in retrospect, demonstrate some characteristic
symptom or sign, especially accentuated at the time of
operative tumor manipulation. However, between 1978 and
1995,15 (10%) of 150 patients with benign sporadic adrenal
pheochromocytomas diagnosed at the Mayo Clinic had the
tumors discovered serendipitously on radiologic examination
as an incidental adrenal mass lesion. 11 The constellation of
621

headache, sweating, palpitations, and paroxysmal hypertension is prototypical of these symptoms.F The hypertension
may be so severe that peripheral blood pressure measurements may be difficult to obtain because of the extreme
vasoconstriction. Cardiac decompensation suggestive of acute
myocardial infarction can also occur, sometimes precipitated
by partial necrosis of the tumor with sudden release of a
bolus of epinephrine and norepinephrine into the bloodstream (Fig. 71-1).
After these acute episodes the blood pressure may remain
elevated, return to normal, or even fall to hypotensive levels.
Sustained hypertension is present in approximately 50%
of patients with pheochromocytoma, mimicking the more
common "essential" hypertension. A number of factors, some
simply causing mechanical pressure on the tumor, have been
identified as causative of the paroxysms: urination (with
tumors of the urinary bladder), vigorous physical exercise,
defecation, sexual intercourse, and ingestion of alcohol. In
unprepared patients, severe and even lethal paroxysms have
been associated with invasive procedures such as angiography, labor and delivery, diagnostic needle biopsy," general
anesthesia, and surgical procedures. Less stereotypical are
symptoms such as nausea, lassitude, heat intolerance, anxiety,
FIGURE 71-1. A, CT scan of patient coincidentally found to have

pheochromocytoma during medical evaluation in preparation for
knee surgery as a result of excessive sweating. B, CT scan of the
same patient only 10 days later, 2 days after patient was admitted
through the emergency room with chest pain, vasoconstriction, and
electrocardiographic changes worrisome for myocardial infarction.
Note that the back wall of the tumor is blurred, consistent with
acute necrosis and release of catecholarnines.
abdominal pain, and pallor, plus signs of Raynaud's

phenomenon, fever, or the glucose intolerance of diabetes.
Diagnosis
Biochemical testing for pheochromocytoma, in addition to
patients with obvious characteristic paroxysmal episodes,
should include patients with unusually labile or intermittent
hypertension or pregnant patients with new hypertension (in
the absence of preeclampsia), those with a family history of
pheochromocytoma or one of the associated conditions (see
later), and children with hypertension. Also, when an adrenal
tumor is discovered by computed tomography (CT) or
magnetic resonance imaging (MRI) scans in the evaluation
of other symptoms, screening tests for pheochromocytoma
should be performed.
Even though some controversy may exist regarding the
optimal single test to establish the diagnosis, we have long
relied on 24-hour urine collection for metanephrines and
fractionated catecholarnines, determined by high-pressure
liquid chromatography. Increases in "mets and cats" have
been diagnostic in 99% of our pheochromocytoma patients
in the last 20 years. 14 This is dependent on eliminating interfering substances or recognizing other situations that might
render the tests inaccurate. For example, methylglucarnine,
a component of many iodine-containing contrast media,
may falsely lower metanephrine levels for up to 72 hours
after their use.? In addition, labetalol, a combination of
a and ~ blockers, must be avoided prior to testing. Tricyclic
antidepressants are the agents that interfere most frequently
with the interpretation of 24-hour urine metanephrines and
catecholarnines. They should be tapered and discontinued
prior to hormone determinations.P Also, measurements of
urinary catecholamines and metabolites may be invalid in
patients with advanced renal insufficiency, patients taking
levodopa, or patients under major physical stress (e.g., stroke,
surgery, or obstructive sleep apnea).
Provocative pharmacologic testing using glucagon,
histamine, metocloprarnide, or naloxone, coupled with
timed samples for plasma catecholarnines, was useful previously. However, because in 542 patients with normal urinary
metanephrines and catecholarnines, not a single patient
tested positively with provocative tests, they are no longer
utilized. 16
Plasma free metanephrine has an extremely high sensitivity rate of 99% for the presence of pheochromocytoma'?
and is valuable in testing for the presence of a pheochromocytoma in genetically predisposed patients. However, used
as a general screening test, it has a troubling 10% falsepositive rate. We rely on urinary testing as the primary
method of diagnosis and screening.
Tumor size has been related to the ratio of unmetabolized
catecholarnines versus their metabolic products. Tumors
weighing less than 50 g have more rapid turnover rates,
releasing norepinephrine and epinephrine directly into the
circulation. In contrast, a larger fraction of the catecholarnines
in larger tumors are metabolized into metanephrines and
vanillylmandelic acid prior to release into the circulation. 18
None of the biochemical tests is specific for the presence of
malignancy.
Pheochromocytoma - - 623
FIGURE 71-2. Patient with multiple endocrine neoplasia type 2A

with gross bilateral pheochromocytomas imaged well by CT scan
(A) and showing the tumors (B).
Localization
Computed Tomography
Whereas 3 decades ago bolus nephrotomography or angiography might have provided the mainstay of localization, three
excellent localization modalities are currently available. Soon
after the development of CT scanning, the adrenal was noted
to be exceptionally well depicted.'? and CT is now considered the most reliable, efficient, precise, and widely available localization technique (Fig. 71-2). Because 90% of
tumors are located in the adrenal glands, a high-quality CT
scan is likely to identify virtually all of these tumors
as well as image the normal contralateral gland. However,
because it is a purely anatomic representation, additional
extra-adrenal pheochromocytomas may be overlooked.
Therefore, patients should be routinely scanned from the
diaphragm to at least below the bifurcation of the aorta. In
addition, the radiologist must be reminded to avoid use of
glucagon during the examination as this may precipitate a
paroxysmal attack.

MRI not only defines the anatomy but on T2-weighted
images, pheochromocytomas and paragangliomas frequently
show a characteristic and nearly unique high-intensity
signal (Fig. 71-3). Owing to this special imaging distinction,
which was 100% effective in the series by Doppman and
FIGURE 71-3. A, T2-weighted MRI image of paraganglioma

located between aorta and inferior vena cava, which it compresses.
The bright white appearance of the tumor is typical of pheochromocytoma or paraganglioma when imaged by T2-weighted MRI.
B, Gross appearance of paraganglioma showing somewhat gelatinous
cut surface with some central necrosis.
colleagues.P MRI provides both anatomic and physiologic

imaging capabilities, in contrast to CT scanning. Other
advantages that may cause MRI to challenge CT scanning
as the optimal localization test include its lack of radiation
exposure, the clear definition of surrounding vascular structures, and the lack of interference from preexisting metal
clips. The disadvantages at present include relative lack of
availability, claustrophobia that some patients feel during
the examination, cost, and the anatomic detail, which is not
quite as precise as that shown by current CT technology.
In fact, MRI can miss small pheochromocytomas, as
depicted in the scan in Figure 71-4. Both CT and MRI provide excellent images of the liver and periaortic lymph
nodes, both possible sites of metastatic disease.
Metaiodobenzylguanidine
Using either 1311_ or 1231-tagged metaiodobenzylguanidine
(MIBG) nuclear medicine scintigraphy, abnormal adrenergic
624 - -
Adrenal Gland
FIGURE 71-4. A, MRI scan demonstrated the characteristic bright

white appearance of a pheochromocytoma on the right (short
arrow) but was not interpreted to show the small tumor on the left
(area just beyond the long, angled arrow). B, Gross cut specimens
of the right (top) and left (bottom, less than I em in size).
tissue can be demonstrated. MIBG is taken up and concentrated within adrenergic vesicles in pheochromocytomas,
paragangliomas, and their metastases with 80% to 90%
sensitivity.P-" MIBG scans are most valuable to image or
search for bilateral tumors such as in multiple endocrine
neoplasia (MEN) type 2 syndromes or to identify multiple
tumors (Figs. 71-5 and 71-6). The advantage of physiologic
localization is unfortunately somewhat offset by the added
complexity of the examination. To prevent its ablation, the
thyroid must be blocked by oral iodine consumption before
and after administration of the radioactive iodine. Repeated
scans may be required for up to 72 hours to obtain optimal
images, and localization is not precise, usually requiring
correlation with anatomic detail provided by either CT or
MRl scans (Fig. 71-7). However, mediastinal and intracardiac
tumors" have been localized by this method as well as bone
metastases missed by conventional bone scans.s' These
three examinations complement each other and should be
used for their specific advantages as indicated by the clinical
situation. In a large series of 315 patients from the
University of Michigan, where this test was developed, 1231
did not reveal unsuspected metastatic or bilateral disease in
any of the 48 patients with a unilateral pheochromocytoma."
It was concluded that in this setting, the addition of 1231
MIBG scintigraphy was unnecessary. This contradicts a
report from the National Institutes of Health26 that supports
FIGURE 71-5. A, Metaiodobenzylguanidine scan, anterior view,

demonstrating bilateral adrenal pheochromocytomas in a patient
with multiple endocrine neoplasia (MEN) type 2A syndrome.
B, Of importance, in the photograph of the gross appearance of
the bilateral tumors is the multinodular appearance of the right
adrenal, characteristic of MEN syndrome.
the addition of MIBG scintigraphy as a minimum confirmatory test (and to exclude malignancy) in all patients with an
adrenal pheochromocytoma.
Preoperative Management
Ever since the sentinel publication by Priestley and colleagues'
that linked their dramatic improvement in surgical mortality
to the use of pre- and intraoperative pharmacologic agents to
blunt the wide swings in blood pressure, we have utilized
a-blockade routinely. Even when the patient's blood pressure is normal preoperatively, severe hypertension can occur
with mild tumor manipulation intraoperatively, especially
with inadequate preparation. One full week of phenoxybenzamine (Dibenzyline) should be considered the minimum
interval for this preparation and has largely prevented these
occurrences in our experience. This drug is a long-acting,
noncompetitive a blocker with a starting dose of 10 mg
twice a day, which is increased until hypertension is
controlled and the patient experiences some degree of
Pheochromocytoma - -
625
FIGURE 71-6. A, MRI clearly shows right adrenal

pheochromocytoma, compressing the posterior aspect
of the inferior vena cava-a common finding. B,
Metaiodobenzylguanidine scan of the same patient
does not image the tumor.
FIGURE 71-7. A, Metaiodobenzylguanidine (MIBG) scan shows intense uptake on the right (arrows), inferior to the liver (L) and below
the usual location for an intra-adrenal tumor. R = rib. B. CT scan of same patient as in A shows the tumor (arrow) between the aorta (A)
and vena cava (V). C = renal cyst; K = kidney; L = liver. C, MIBG scan of a patient with von Rippel-Lindau syndrome who had a right
adrenal pheochromocytoma (short arrow) plus a paraganglioma (long arrow) located in the left renal hilum. (Bright sites on each side are
anatomic markers.) This patient also had cerebellar hemangioma, optic nerve tumor, multiple, bilateral renal cell carcinomas, and pancreatic cysts. D, Cut sections of right adrenal tumor (center), remaining normal right adrenal (left), and small left paraganglioma (right)
removed from patient with MIBG shown in C.

orthostatic hypotension. The daily doses may be increased to
160 mg. This process is carefully monitored on an outpatient
basis, with liberal use of fluids and salt to help replenish the
contracted intravascular volume. Commonly encountered
side effects include nasal stuffiness, lassitude, nausea, indigestion, and sedation and may also serve as a monitor for
adequacy of preparation. In contrast to findings of others
who have used a-blockade selectively with success,"
a reduction in operative mortality from 18% to 2% was
attributed to appropriate preoperative blockade." Reasonable
alternative medications, with which we have minimal
experience, are the selective ai-antagonists prazosin/?
(Minipress) and doxazosin (Cardura)." They are shorter
acting than phenoxybenzamine and have the theoretical
advantage of shortening the postoperative hypotensive
effect. Calcium channel blockers have been successfully utilized in some European centers on the basis of the arterial
vasodilation without the side effects of u-blockade.i? These
agents inhibit calcium influx at the cellular level, thereby
modifying hormone synthesis, release, and action."
Somewhat more controversial and certainly less critical
is the use of a ~-blocker.
We may initiate this medication
3 days preoperatively to help control preoperative tachycardia
and intraoperative arrhythmias. Propranolol (lnderal), in a
dosage of 10 mg three times daily, has been our choice.
Alternative cardioselective agents include atenolol
(Tenormin) and metoprolol (Lopressor). Typically, arrhythmias occur during times of hypertension coincident with
tumor manipulation. Discontinuing tumor manipulation is
the most important step to reduce the hypertension and can
be supplemented with pharmacologic agents. Controlling
the hypertension is often the most effective method of
controlling the arrhythmias. ~-Blockade
should not precede
a-blockade because it could lead to unopposed a-mediated
vasoconstriction with the potential for resultant congestive
heart failure." The combined a and ~ blocker labetalol
(Trandate) has been effective in our as well as others'
experience.F Conceptually, however, less flexibility exists
with the fixed combined effect.
Intraoperative Management
Before the patient undergoes induction of anesthesia, appropriate pharmacologic agents must be available. Adequate
peripheral access plus a radial arterial catheter, in addition to
a urinary catheter, is routinely utilized and, rarely a Swan-Ganz
catheter may be placed if indicated on the basis of cardiac
disease or other problem. Sodium nitroprusside (Nipride)
was previously the intraoperative agent of choice for rapid
control of acute hypertension. It is a powerful direct-acting
vasodilator that can deliver profound hypotension immediately after its infusion. In contrast to the bolus effect of
phentolamine (Regitine), it has the advantage that within
seconds of discontinuing the infusion, the hypotensive effect
ends, allowing nearly second-by-second blood pressure control. However, in the last 10 years, Nipride has been used
only on rare occasion, replaced by intermittent small doses
of esmolol (Brevibloc). Dopamine was the agent previously
used to treat hypotension coincident with tumor excision.
It has been replaced by short bolus administration of
ephedrine or phenylephrine. Blood infusion to replace

hemorrhagic loss as well as to fill the dilated vascular tree
after tumor removal was much more commonly needed
previously than in current practice. Lidocaine is rarely necessary initially as a bolus followed by a constant infusion if
ventricular arrhythmias persist.
Operative TechniqueLaparoscopic Approach

Since the publication of the last edition of this text, a dramatic and exciting change in the overall approach to adrenalectomy has occurred. Whereas previously only a limited
number of laparoscopic adrenalectomies had been reported
in total,32 some involving significant bleeding" and a few
including removal of pheochromocytomas.t->' laparoscopic
adrenalectomy has become the accepted standard method,
even to remove pheochromocytomas. Multiple advantages
of the laparoscopic approach have been demonstrated,
including reduced pain, smaller incisions, more rapid
recovery both in hospital and after dismissal, and fewer
complications.P''?
Using a lateral decubitus position, a pneumoperitoneum
is established and three or four trocars are placed coursing
around beneath the costal margin toward the flank. On the
right, the triangular ligament is dissected and the liver is
retracted medially. On the left, the spleen and pancreas are
mobilized and, by gravity, fall anteriorly and medially, thereby
exposing the left adrenal area. On either side, methodical,
careful dissection and controlling of all vessels are critical to
success. Placing the pheochromocytoma into a bag facilitates
extraction of the tumor, and it is withdrawn through one
of the larger trocar sites, which may need to be enlarged
somewhat. Improvements in the optics of the camera, the use
of a harmonic scalpel, and refinements to the instrumentation
have further enhanced this approach.
Relatively few studies have been devoted to laparoscopic
adrenalectomy specifically of pheochromocytoma. Cheah
and coworkers" published a series of 39 laparoscopic
adrenalectomies for pheochromocytoma, only 1 required
hand assistance for a 15-cm tumor. The postoperative hospitalization was limited to 1 to 2 days, facilitated by adequate
preoperative preparation and definitive localization studies
in addition to the laparoscopic approach. In three series,39.41
a 20% to 23% major complication rate was reported for
laparoscopic adrenalectomy for pheochromocytoma, but this
is the exception in most published series. Comparing
22 patients with pheochromocytoma evenly divided between
laparoscopic and conventional anterior adrenalectomy,
Inabnet and coauthors-? found no clinically important
differences in intraoperative hemodynamic parameters
between the two groups.
The surgical experience with pheochromocytomas at the
Mayo Clinic during the era of laparoscopic adrenalectomy
started in October 1995. A total of 131 pheochromocytomas
were operated from October 1995 through April 2004,
including 86 (66%) laparoscopic adrenalectomies, 7 (5%)
that were converted from laparoscopic to open, 35 (27%)
performed as an open anterior approach, and 1 (1%)
each utilizing a posterior approach and a hand-assisted
laparoscopic approach. One patient had the operation

aborted because of extreme hypertension with induction of
anesthesia; the patient was more aggressively prepared with
additional a-blocking medication and subsequently underwent successful laparoscopic adrenalectomy. This singledisease experience is extracted from 393 laparoscopic
adrenalectomies on 345 patients from 1993 through April
2004. The mean operative time for the laparoscopic patients
was 141 minutes (range, 48 to 324 minutes) and mean
hospital stay was 2.6 days, which compare favorably with
216 minutes and 3.1 days reported by Brunt and colleagues.f
These pheochromocytoma patients included six (5%) with
MEN 2A, four (3%) each with MEN 2B and von HippelLindau (VHL) syndrome, and three with neurofibromatosis.
Phenoxybenzamine (Dibenzyline) was the medication
used in 94% of patients for preoperative a-adrenergic
blockade, extending for an average of 15 days (range, 2 to
40 days). Despite this preparation, 69% of patients developed
either hypertensive or hypotensive episodes intraoperatively,
for which they were given intravenous medication. The mean
maximum and minimum systolic blood pressures were
192 (peak, 310) and 83 mm Hg (lowest, 31), respectively.
However, no patient had a complication related to these
episodes. A single patient died postoperatively because of
a bowel perforation unrelated to the adrenalectomy. No
patient has suffered recurrent or metastatic disease, including
peritoneal or port site contamination.f Nearly 40% of these
tumors were discovered as "incidentalomas" in an abdominal
imaging study obtained for unrelated reasons. The open
anterior approach was utilized in patients who were undergoing other open abdominal operations, patients with tumors
larger than approximately 8 em, or at times when a partial
adrenalectomy was elected in patients with some form of
familial disease.
The principles for excision of pheochromocytomas irrespective of surgical method include complete removal with
the tumor intact, minimizing wide blood pressure fluctuations.
Laparoscopic adrenalectomy for pheochromocytoma is a
challenging technique that should be undertaken only by
experienced laparascopists who also have knowledge and
operative experience in managing adrenal disorders.
Anterior Approach
At times, either for intra-abdominal procedures that cannot
be accomplished laparoscopically or for other reasons, an
anterior open approach may be chosen. A surgical headlight
may be helpful in the dissection of these tumors, which can
be situated very high and deep in the retroperitoneum.
Right Adrenal
We prefer the exposure of a right adrenal pheochromocytoma through a long right subcostal incision with the patient
positioned supine, sometimes with elevation of the right side
of about 15 degrees. After standard exploration, the liver is
retracted superiorly and its attachments are freed from the
retroperitoneum. A mechanical retractor is helpful to elevate
the right costal margin, and the assistant retracts medially
and inferiorly on the duodenum and porta hepatis.
627
Occasionally, mobilization of the hepatic flexure of the

colon and kocherization of the duodenum may be helpful to
gain wider exposure. Because the most critical zone of
dissection is the superomedial aspect ofthe right adrenal, the
adrenal vein, the safest method involves dissecting toward it
from both above and below.
Initially, the retroperitoneal attachments to the liver are
incised, allowing some elevation of the liver. The retroperitoneum is incised over the superolateral aspect of the tumor
and then carried medially until curving slightly over its
superomedial aspect. Similarly, the retroperitoneal layer
overlying the inferior vena cava (IVe) above the duodenum
is incised, the lateral edge of the IVC is defined, and dissection proceeds superiorly. As the IVC is dissected toward the
tumor, transection of one or two small branches from the
anterior surface of the IYC to the caudate lobe of the liver
further opens the dissection space. At least one fourth of the
tumor may reside behind the IVC, and a vein retractor
should be positioned to retract the vein medially and slightly
anteriorly. Gentle lateral and inferior traction by the surgeon
on the tumor helps exaggerate the angle between the adrenal
vein and vena cava to facilitate visualization of the short,
broad adrenal vein as it enters the posterior aspect of the
vena cava. This is preferably controlled by large clips or
suture ligated and the vein is transected. Typically, a significant drop in blood pressure occurs with this step, but other
small venous connections are not rare, usually emptying
into the renal vein inferiorly. Sometimes identified only by
palpation as a tethering band at the superomedial "comer"
of the tumor is the arterial branch from the inferior phrenic
artery. This should be controlled, because failure to attend to
this vessel probably accounts for significant bleeding that
may be falsely attributed to adrenal venous bleeding. Other
important arterial blood supply and less constant veins
are located inferomedially, connecting to the aorta, renal
arteries, and the renal vein. Control of these vessels completes
the dissection.
Left Adrenal
A left adrenal tumor is exposed through a long left subcostal
incision, with rib retraction similar to that for the right
adrenal. Exposure can be achieved either by gaining access
through the lesser sac and approaching the tumor directly
under the pancreas or by mobilizing the spleen and pancreas
out of their bed to the patient's right, thereby widely exposing
the adrenal area. Usually, we mobilize the omentum from
the midtransverse colon to the splenic flexure. Adhesions
from the posterior wall of the stomach to the pancreas are
lysed, and the pancreas is elevated by incising along its inferior border and mobilized by gentle blunt dissection. A
retractor under the stomach and pancreas exposes the adrenal gland and tumor. The spleen can often be left in its bed
but, if necessary, can be fully mobilized from its lateral
attachments and short gastric vessels. Particularly when
the tumor is quite large, the spleen and the body and tail of
the pancreas are retracted out of the operative field to the
patient's right upper quadrant. The critical zone of the left
adrenal-the adrenal vein-is located inferomedially. If the
renal vein can be visualized easily, early in the dissection, it
should be ligated. Often, however, the tumor is large enough
628 - -
Adrenal Gland
to overlap the renal vessels, and initial dissection to gain

more mobility of the tumor should be directed to free the
superior border of the gland. As with the right side, the arterial branch of inferior phrenic artery must be controlled.
As the renal vein is dissected, a branch of the renal artery
commonly courses immediately adjacent to the posterior and
lateral aspect of the tumor, in jeopardy of inadvertent injury.
Care must be exercised to protect this vessel by dissecting it
away from the tumor. Once the adrenal vein is transected, the
inferomedially located arterial branches must be controlled.
Posterior Approach
In contrast to prior recommendations by us and others, we
now feel that the technology is sufficiently accurate to allow
a posterior approach for pheochromocytomas as well as
most other benign adrenal tumors. The minimum investigations to allow this approach include both physiologic and
anatomically precise preoperative imaging tests to ensure
that the tumor is intra-adrenal and to exclude additional
tumors (Fig. 71-8). Key technical points for excision of
pheochromocytomas from the posterior approach include
the following: (1) manipulation of the tumor by this
approach may exceed that by the anterior approach; (2) on
both sides, the tumor is initially exposed by dissecting its
superior border first, with anatomic landmarks being the
diaphragm superiorly, the inferior phrenic vein superomedially

on the left, and the liver on the right.
Paragangliomas
By virtue of their location, paragangliomas may present difficult challenges and require special care to prevent serious
hemorrhage. However, even when located between the aorta
and vena cava and obscured by the portal triad, it is rare for
these vessels to be invaded, and meticulous dissection is
rewarded with tumor removal, protecting these vessels.
Because 40% of these tumors are malignant, careful search
for and removal of lymph node and liver metastases should
be undertaken if possible.
Postoperative Management
When the blood pressure has reached stability in the operating
room with the use of fluids, blood, and vasopressors, if
necessary, patients often remain remarkably normotensive
throughout their remaining hospital course. However, persistent need for vasopressors may be required until the
combined effect of the phenoxybenzarnine plus lack of the
intense catecholamine stimulation resolves. Monitoring in
an intensive care unit may be indicated for 24 hours
but is rarely necessary beyond this time. Approximately
2 weeks after the operation, a 24-hour urine collection for
metanephrines and catecholarnines should be obtained. This
establishes that all tumor has been removed and sets a baseline for future reference. Because metastatic disease may not
become apparent for over 5 years," similar annual screening
should continue for at least that long.
Pathology
FIGURE 71-8. A, CT scan of a relatively large right pheochromocytoma, located in the adrenal gland. B, Gross photograph demonstrates
a tumor slightly larger than 5 cm. This tumor was removed by a
posterior approach.
Pheochromocytomas are of variable size, ranging from 1 em

to several kilograms, but are normally between 50 to
200 mg. In sporadic pheochromocytomas, even though lobulated, the tumor is actually a single neoplasm. In contrast,
familial tumors are often bilateral and usually multicentric.v
In MEN 2 syndromes, even though synchronous bilateral
pheochromocytomas may not be present, the adrenal
medulla is hyperplastic and is thought to represent pretumor
change analogous to C-cell hyperplasia and medullary thyroid
carcinoma. Fed by a rich blood supply, pheochromocytomas
often have a purplish gray hue when resected and frequently
show demarcated areas of cystic necrosis.
As stated previously, nearly 90% of pheochromocytomas
are located within the adrenal glands. The remaining 10% to
15% are found from the neck to the bladder, typically along
the course of the sympathetic chain. The most frequent
extra-adrenal site is at the aortic bifurcation, the so-called
organ of Zuckerkandl. Nearly 98% of pheochromocytomas
are located in the abdomen, but they can be found in the
neck, mediastinum, intracardiac area, or along the sympathetic
chain in the chest. Extra-adrenal tumors are more frequently
malignant, approximately 40% in our experience.v-'?
There is consensus agreement that histopathology, even
including intratumoral capsular and vascular invasion or
FIGURE 71-9. A, Posterior view of metaiodobenzylguanidine

scan demonstrating an obvious, single, left adrenal pheochromocytoma. B, The gross tumor shows that the adrenal vein has been split
down into the tumor capsule, and the bulging tumor can be seen
pouting out through the cut end of the adrenal vein. There was no
sign of malignancy in this patient, and catecholamines and
metanephrines returned to normal postoperatively.
marked cellular pleomorphism, is unreliable to predict

malignancy in pheochromocytomas (Fig. 71_9).44,48,49
However, in a review of 184 patients with pheochromocytomas and paragangliomas, approximately one third each
had diploid, tetraploid, and aneuploid patterns on flow
cytometric nuclear DNA analysis. None of the diploid tumor
patients died of disease, and the only disease recurrence was
a new, primary contralateral intra-adrenal tumor in a patient
with MEN 2 syndrome who was subsequently cured following
adrenalectomy."
Special Situations
Malignancy
As has been emphasized previously, there are no certain
cytologic characteristics that distinguish benign from malignant pheochromocytomas. The presence of local invasion
into surrounding soft tissue or the presence of these tumors
in sites other than along the sympathetic chain is the only
reliable indicator of malignancy. Patients with apparently
benign, sporadic, well-encapsulated tumors have developed
629
distant metastases that have proved fatal (Fig. 71-10).51 The

most common sites of metastases are bone (especially spine,
skull, and ribs), lung, liver, and retroperitoneal Of mediastinal
lymph nodes. 52 Even though in isolated instances patients
with distant metastases have lived for long periods of time,
the usual 5-year survival ranges from 30% to 45%.8
Most recurrent pheochromocytomas are functioning,
similar to the primary tumor. Detection is-reliable utilizing
24-hour urine determinations for metanephrines and catecholamines. The extent and locations of the metastases can
be determined most accurately with MIBG scanning (see
earlier)," although false-negative scans occur in about 10%
of patients.
If recurrences are surgically resectable, reoperation
seems worthwhile and we have used this effectively for
long-term palliation or even cure.P Bone pain can be
palliated effectively with external beam radiation treatment.
Between 50% and 75% of patients with metastatic
pheochromocytomas gain benefit from therapeutic 1311
MIBG as measured by tumor shrinkage or decrease in
circulating catecholamines.>' A report of 33 patients with
metastatic disease showed a median survival of 4.7 years and
a 5-year survival rate of 45% after treatment." A survival
advantage seemed to correlate with a higher initial dose of
approximately 500 mCL Bone marrow suppression occurred
in 12%, and three treatment-related deaths were recorded.
Combination chemotherapy using cyclophosphamide, vincristine, and dacarbazine has been proved effective against
malignant pheochromocytoma, with tumor and biochemical
responses of 57% and 79%, respectively.'<? Side effects
included the known hematologic, neurologic, and gastrointestinal effects associated with the drugs, but without serious
sequelae.
Extra-Adrenal Pheochromocytomas
(Paragangliomas)
For purposes of this discussion, the terms extra-adrenal
pheochromocytoma and paraganglioma are used interchangeably. Even though chemodectomas and glomus jugulare
tumors are technically included within this category, they
are part of a group termed branchiomeric paragangliomas
and are usually negative for chromaffin staining and rarely
functional. 58 They are much more frequent (69%) than those
located below the neck (31%).59 In addition, paragangliomas
arising in the retroperitoneal region along the aorta and iliac
bifurcation (along the sympathetic chain) are most often
functional.
Paragangliomas are often multicentric, malignant in 40%
to 50%, functional, may be associated with intra-adrenal
pheochromocytomas, occur more often in children, and may
be associated with familial syndromes such as neurofibromatosis, VHL disease, and Carney's syndrome (see later).
Sixty-six patients had surgery at the Mayo Clinic for
catecholamine-producing paragangliomas between 1952
and 1992.60 Familial disease was present in 9 patients
(14%), and 10 patients (15%) also developed adrenal
pheochromocytoma. Fifty-three tumors developed in
14 patients with multiple paragangliomas, 38 abdominal
and 15 thoracic. Disease persisted in 15 patients postoperatively,and 9 of 50 patients initially cured developed recurrence.
FIGURE 71-10. A, CT scan of a patient with a 7-cm
well-circumscribed left adrenal pheochromocytoma.

B, Metaiodobenzylguanidine scan, posterior thorax
view, showing several "hot spots" along the vertebral
column that corresponded to metastatic pheochromocytoma. C, Gross appearance of the tumor. No gross
local invasion outside the tumor capsule was evident.
Nevertheless, the 5-, 10-, and 20-year survival rates were

86%, 80%, and 80%, respectively. Risk factors for death
from paragangliomas were tumor size greater than 5 em,
metastatic disease, and tumor invasion.
Paragangliomas located in the bladder are most often
located near the trigone, and more than 80% can be identified by cystoscopy." They are malignant in about 15%
of cases. Symptoms are most frequently associated with
micturition, and hematuria occurs in over half of cases.
Treatment usually requires partial cystectomy rather than
transurethral resection.
Pheochromocytoma and Pregnancy

Even though extremely rare, the combination of pheochromocytoma and pregnancy would rank in the "life-threatening"
risk category. Reports of maternal mortality of 40% and
a fetal death rate of 40% to 56% have been published.P
Critical to appropriate management is considering and
testing for the diagnosis. Urinary catecholamines do not fall
outside the normal values during normal pregnancy/? MRI
is the localization test of choice because it does not involve
any radiation. Preoperative a-blockade is like that in
nonpregnant patients, using phenoxybenzarnine or prazosin.
The addition of ~-blockade
is also recommended for the
usual 2 to 3 days preoperatively.
Beyond the 24th week, a reasonable attempt to bring the
fetus to a safe gestation is reasonable but requires very close
monitoring.P Most commonly, under a single anesthetic,
cesarean section followed immediately by tumor excision

can be accomplished successfully.v' One case report gave a
detailed description of a patient managed with initial cesarean
section followed by a successfullaparoscopic adrenalectomy
2 weeks later. 65
Multiple Endocrine Neoplasia

Type 2 Syndrome
Pheochromocytomas constitute one component of several
unusual syndromes, including MEN type 2 (medullary thyroid carcinoma, pheochromocytoma, primary hyperparathyroidism, or mucocutaneous neuromas). Whereas nearly all
individuals who inherit the ret protooncogene for these
autosomal dominant diseases develop medullary thyroid
carcinoma, the penetrance of pheochromocytoma and
hyperparathyroidism is variable." This is clearly related
to the kindred, with all affected members developing
pheochromocytomas in some families whereas fewer than
10% may develop these tumors in other families. Overall,
approximately 40% develop pheochromocytomas.
When a patient develops biochemical evidence of
pheochromocytoma and also has confirmed MEN 2 syndrome, bilateral adrenal medullary hyperplasia is always
present." However, synchronous true tumors are not always
present, and this has raised considerable controversy about
the appropriate management of the contralateral "normal"
gland. Arguments against routine bilateral adrenalectomy
include the following?": (1) as many as 50% do not need it
at least within 5 years, (2) no hypertensive crises developed
in the patients who had undergone only unilateral adrenalectomy, and (3) 23% of patients in whom bilateral adrenalectomy was performed experienced at least one attack of
acute addisonian crisis. Others have advocated contralateral
adrenalectomy only when a tumor of 5 cm or larger has
developed/"
We previously advocated bilateral adrenalectomy even if
a macroscopic contralateral tumor was not identified by preoperative imaging." Reasons for this included (1) the risk of
malignancy, rare but identified in two patients; (2) the uncertain timing of catastrophic complications of even small
pheochromocytomas; and (3) the uncommonly serious
nature of problems resulting from bilateral adrenalectomy,
both early postoperatively and in the long term.?" However,
we have changed our viewpoint and recommend, similarly
to Lairmore and colleagues.F delaying contralateral adrenalectomy until symptoms develop or a tumor becomes obvious on CT scan. The risk of developing a contralateral
pheochromocytoma in patients with MEN 2 was 33% by
5 years and 52% by 12 years of follow-up.f and the average
time to develop a contralateral pheochromocytoma was
13 years. Partial adrenalectomy for pheochromocytoma in
patients with MEN 2 and VHL disease has been reported,":"
but 20% recurred in one series 74 and there has been variable
success in preserving adrenocortical function. For example,
despite normal basal cortisol levels, a subnormal response
to corticotropin (ACTH) stimulation was present in two
reported patients." In 1998, Janetschek and colleagues"
were the first to report laparoscopic adrenal-preserving
surgery for bilateral adrenal tumors. In the MD Anderson
experience," cortical-sparing adrenalectomy was performed
in 22 patients with bilateral pheochromocytoma, of whom
13 (59%) were steroid independent, but only 4 of 15 (27%)
treated patients had a normal response to cosyntropin
stimulation. Three (10%) had recurrent pheochromocytoma
in the remnant.
of pheochromocytoma developing in patients with VHL

varies from 10% to 19%, but the key is the particular family
transmission pattern, which ranges from 0% to 92%.79 These
tumors are more frequently bilateral, extra-adrenal, and may
be malignant. Even apparently sporadic unilateral pheochromocytomas have been diagnosed with VHL. In an unselected series of patients with resected pheochromocytomas,
19% were eventually found to be carriers ofVHL.80That VHL
and pheochromocytomas may be associated with a MEN
variant is suggested by the coexistence of these two conditions
plus nonfunctioning islet adenomas or carcinomas.t'-"
Carney's syndrome includes the association of gastric
epithelioid leiomyosarcoma, pulmonary chondroma, and
extra-adrenal paraganglioma.83
Summary
The triad of headaches, sweating and hypertension is
classical for pheochromocytoma, but these potentially lifethreatening tumors can be clinically silent, and approximately 10% present as incidentally discovered tumors on
imaging tests. Urinary total metanephrines and fractionated
catecholarnines are 98% sensitive and specific in establishing the diagnosis. At least 90% of pheochromocytomas are
benign, but long-term follow-up remains necessary as specific criteria for malignancy are lacking except local extratumoral invasion and proven metastases. Paragangliomas
may be located anywhere along the sympathetic chain from
the neck to the bladder, and are more frequently malignant
and multiple than intra-adrenal pheochromocytomas.
Preoperative preparation with a-blockade is required and
most intra-adrenal tumors can be safely removed by laparoscopic adrenalectomy. Intraoperative blood pressure is most
volatile at the time of induction of anesthesia and tumor
manipulation, but can usually be well managed pharmacologically. Adrenergic symptoms are cured and hypertension
is ameliorated or cured with tumor removal.
Children
In nearly 20 years at a major referral center for pheochromocytomas, only 14 children with this tumor were surgically
treated." As with adults, the diagnosis relies on urinary
metanephrines, the localization studies include CT, MRI,
and MIBG scans, and preoperative blockade remains
equally important with the same medications. However, as
opposed to the disease in adults, pheochromocytomas in children are more often associated with the MEN 2 syndromes,
more often bilateral, extra-adrenal yet less commonly malignant, and arise more frequently with sustained hypertension.
After resection, all 14 of these children were reportedly alive
and well and normotensive without medication."
Associated Conditions
Pheochromocytoma can develop in association with other
neuroectodermal disorders such as von Recklinghausen's
neurofibromatosis, Sturge-Weber syndrome, tuberous sclerosis, and VHL syndrome (retinal hemangiomatosis, cerebellar hemangioblastoma, pheochromocytoma, renal cysts or
carcinomas, and pancreatic cysts and tumors). The incidence
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Addison's Disease and Acute

Adrenal Hemorrhage
Patricia J. Numann, MD
Adrenal insufficiency was first recognized in 1855,

when Thomas Addison 1 published the monograph, "On the
Constitutional and Local Effects of Disease of the
Supraadrenal Capsules." He described 11 patients with
"general languor and debility, remarkable feebleness of the
heart's action, irritability of the stomach, and a peculiar
change of the color of the skin." The primary cause historically was adrenal destruction from tuberculosis. By the tum
of the 20th century, surgery of the adrenal glands was being
performed. Death after adrenalectomy was thought to be
due to the accumulation of toxic products they were believed
to remove. In 1927, the development of an adrenal extract
named "cortin" improved the management of adrenalectomized patients.' In 1937, deoxycortisone was synthesized;
in 1948, cortisone was isolated; and between 1952 and
1955, aldosterone was isolated and synthesized. Availability
of these steroids and the understanding of their physiologic
role dramatically altered the course of adrenal insufficiency.
The adrenal gland produces glucocorticoids and mineralocorticoids. Glucocorticoid production is regulated by the
hypothalamic-pituitary-adrenal axis. In response to a variety
of stimuli from within the brain, corticotropin-releasing
factor (CRF) is released into the portal circulation of the
pituitary, which in tum stimulates the secretion of adrenocorticotropin (corticotropin). Corticotropin then enters the
systemic circulation, where it stimulates the production and
secretion of glucocorticoids and, to a lesser extent, mineralocorticoids. In the adrenal cortex, corticotropin stimulates
the conversion of cholesterol to corticosteroids. Adequate
circulating levels of corticosteroids returning to the brain
inhibit the production of CRF and corticotropin. Cortisol,
corticotropin, and CRF are secreted with a diurnal variation,
with levels higher in the morning than in the afternoon.
Plasma cortisol levels are highest at 8 AM and lowest
between 10 PM and 2 AM.
Stress disrupts the diurnal variation of steroids. Cortisol
levels remain high until the stress has subsided. Harris and
colleagues demonstrated baseline cortisol levels averaging
28 mg/dL after surgery for trauma (normal < 10 mg/dl.j.'
Even with no postoperative complications, urinary cortisol
levels remained elevated for 4 days. The magnitude and
length of the stress determine the magnitude and length of
634
the increased cortisol production. The physician's ability to

recognize the increased need for cortisol and to replace it
in the surgical patient depends on knowing this response to
stress.
Adrenal insufficiency (Addison's disease) is rare. Although
the exact incidence in the United States is currently unclear,
in 1974, in Denmark, the incidence was 60 per 1 million."
The decline of tuberculosis transiently reduced the incidence of Addison's disease, but now acquired immunodeficiency syndrome (AIDS) and autoimmune adrenalitis are
again increasing the rate. Recognition and appropriate treatment of adrenal insufficiency in the surgical patient are
critically important because the failure of the corticosteroid
response during stress is usually fatal.
Many patients come to surgery with an established diagnosis of adrenal insufficiency resulting from primary adrenal or pituitary disease. Although the diagnosis should have
been established in most patients with primary adrenal
insufficiency, some may inadvertently come to surgery
without a diagnosis and may experience addisonian crisis
as a result of surgical stress. Many other patients come to
surgery with the potential for adrenal insufficiency because
of chronic suppression of their adrenal by exogenous corticosteroid therapy or by a hyperfunctional adrenal or pituitary tumor. A small group of surgical patients experience
acute adrenal insufficiency during the course of their illness
(Table 72-1).
Primary Insufficiency
Autoimmune adrenalitis is the most common form of adrenal
insufficiency, accounting for two thirds or more of primary
adrenal failure cases. Association of Addison's disease with
other autoimmune diseases is common. In 1981, Neufeld
and coworkers proposed a classification system for these
polyglandular autoimmune (PGA) syndromes that divided
those associated with Addison's disease into type I and
type 11. 5
Patients with PGA-I syndrome have hypoparathyroidism,
chronic mucocutaneous candidiasis, or both, as well as
infrequent other autoimmune diseases associated with their
Addison's Disease and Acute Adrenal Hemorrhage - - 635
Addison's disease. PGA-I syndrome usually arises in childhood or early adulthood. In PGA-II syndrome, Addison's
disease occurs in association with autoimmune thyroiditis
and insulin-dependent diabetes but without hypoparathyroidism or chronic mucocutaneous candidiasis. PGA-II
syndrome occurs in older patients, generally between the
second and fifth decades of life.! Both of these entities may
occur in the familial form. PGA-II syndrome is more
common and accounts for more than 50% of patients with
Addison's disease.t Young women with spontaneous premature ovarian failure should also be suspected of having
autoimmune adrenal insufficiency." Discoveries in genetics
have provided valuable insights into the development of
these syndromes and adrenal function,"
AIDS patients are at risk for adrenal insufficiency from
multiple causes. AIDS patients' adrenal glands may be infiltrated by multiple infections and malignant processes,
including cytomegalovirus, Mycobacterium tuberculosis or
M. avium-intracellulare, Pneumocystis carinii, toxoplasmosis, histoplasmosis, Kaposi's sarcoma, and lymphoma. The
human immunodeficiency virus may invade the adrenal. The
adrenal is the preferred site of cytomegalovirus in the AIDS
patient." Autoimmune adrenalitis also occurs. Drugs used in
the treatment of AIDS-related diseases such as ketoconazole, corticosteroids, rifampin, and phenytoin may also contribute to impaired adrenal function. Thrombocytopenia
may lead to acute adrenal hemorrhage. The severe hypocholesterolemia seen in some AIDS patients may lead to
impaired corticosteroid production. 10
The basic illness of AIDS mimics adrenal insufficiency
with lethargy, hyperpigmentation, weight loss, and hyponatremia. A high index of suspicion must be maintained to
diagnose Addison's disease appropriately in the AIDS
patient. Similarly, surgeons consulted to see the AIDS
patient with abdominal pain, hypotension, or sepsis must
keep Addison's disease in the differential diagnosis.
Standard endocrine testing and computed tomography
(CT) scans of the abdomen help establish the diagnosis.
Empirical corticoid therapy in the severely ill patient may be
indicated because the delay to obtain appropriate testing

might prove fatal.
Tuberculosis, which was once the most common cause
of adrenal insufficiency, had diminished in incidence for
many years but is now again increasing. Tuberculosis is an
opportunistic infection in patients with AIDS and other
debilitated patients, and it may insidiously or acutely produce adrenal insufficiency with the classic symptoms.
Disseminated histoplasmosis, which occurs more commonly
in the Ohio, Tennessee, and Piedmont plateau areas of the
United States, commonly results in adrenal insufficiency. 1 I
Other fungal infections such as blastomycosis, cryptococcosis, and coccidioidomycosis may also lead to adrenal insufficiency. The clinical picture is further confused because
drugs such as ketoconazole, fluconazole, and rifampin used
to treat some of these disorders may also result in adrenal
insufficiency.
Rare genetically determined diseases such as familial
glucocorticoid deficiency, adrenoleukodystrophy, and adrenomyeloneuropathy also produce adrenal insufficiency. The
diagnosis in these patients is usually clearly established
before surgery, and appropriate perioperative steroid management is the only issue in these patients. Adrenal insufficiency
also results from pituitary dysfunction such as pituitary
adenomas, postpartum pituitary hemorrhage (Sheehan's
syndrome), and corticotropin deficiency. These conditions
must be recognized as requiring additional steroid coverage
during surgical stress.
Surgical Adrenal Insufficiency

Bilateral adrenalectomy and hypophysectomy are obvious
causes of adrenal insufficiency. Not so obvious is the adrenal suppression that may result from removal or infarction
of a hyperfunctional unilateral adrenocortical tumor or a
functioning adrenal tumor. Certainly, all patients undergoing
hypophysectomy, bilateral adrenalectomy, or unilateral
adrenalectomy should receive stress-dose steroid therapy.
Infarction of a unilateral functioning adrenal tumor may
be more difficult to recognize. Steroid coverage is sometimes
given for unilateral adrenalectomy even when no corticoid
production of the tumor can be identified preoperatively.
Secondary Adrenal
Insufficiency Related to
Exogenous Steroid Usage
Overall, the most common adrenal insufficiency is the secondary adrenal insufficiency resulting from exogenous steroid
usage. Numerous and diverse conditions are treated with
corticosteroids: inflammatory bowel disease, asthma, arthritis, and dermatologic conditions, to name a few. Inhaled
steroids are a mainstay of therapy for asthma and can
produce the potential for adrenal insufficiency in both children and adults.P Corticosteroids are part of the therapeutic
regimen of transplantation immunosuppression and cancer
chemotherapy. Short courses of high-dose corticosteroids are
used in numerous inflammatory conditions. Corticosteroid
use is so common that an inquiry regarding corticosteroid
636 - -
Adrenal Gland
use should be made of every patient preoperatively.

The trauma patient unable to give a history should be suspected of having used steroids. Exogenous corticosteroid
therapy even for only a few days may produce some inability of the pituitary-adrenal axis to respond to stress. The
generally accepted rule is to provide stress-dose steroids to
any patient undergoing surgical stress who has received
steroids for more than 1 week within the previous year.
Adrenal suppression has been identified in patients using
high-dose steroids for very short periods of time, and the
longer the steroid use, the longer the impairment may last.
No study has definitively answered how short an exposure
to how much steroid is the minimum amount to suppress
adrenal function. Graber and colleagues studied 14 patients:
8 after resection of a functioning cortical adenoma and 6
after supraphysiologic doses of steroids for 1 to 10 years.
During the first month without therapy, corticotropin failed
to increase in these patients, despite low cortisol levels.
During the second to fifth months, plasma corticotropin rose
to normal or supernormal values but the plasma corticosteroid response to corticotropin remained subnormal.
During the sixth to ninth months, the plasma and urinary
corticoid levels were normal, but adrenal responsiveness
could be demonstrated only with supernormal levels of
corticotropin. After 9 months, pituitary-adrenal responses
returned to normal. 13 Even though the series is small, this
study demonstrates the fallacy of using baseline steroid
levels to determine the adequacy of adrenal function and the
length of time necessary for return to normal.
Stress-Induced Adrenal Insufficiency

Merry and colleagues, in 1994, reported on a small group
of patients who had transient corticotropin deficiency, which
caused postoperative acute adrenal failure." These patients
presented with unexplained postoperative hypotension.
Schlaghecke and coworkers, in a series of 279 patients,
demonstrated that corticosteroid reserve cannot be reliably
determined on the basis of dose and duration of therapy.P
Plasma baseline cortisol levels were similarly unreliable.
Because there is no simple, reliable method of determining
the adrenal response to stress and definitive testing is time
consuming and costly, empirical steroid administration to
cover the period of stress is conventional.
The magnitude and duration of stress requiring increased
corticosteroid production have been studied in numerous
circumstances. In particular, the methods of assessing
adequacy of adrenal function and the routine use of corticosteroids in the critically ill, septic, intensive care unit patient
have been the subject of extensive controversy. Manglik
and associates, in a prospective clinical trial involving
100 patients, found that 9% of septic patients failed the ACTH
stimulation test and 4% of septic patients had occult pituitary disease or secondary adrenal insufficiency." Jurney
and colleagues demonstrated no advantage of routine evaluation of baseline cortisol or corticotropin stimulation studies
in the intensive care unit.'? Baseline cortisol levels were not
useful in predicting adrenal insufficiency. Patients with low
baseline cortisol levels did not necessarily have impaired
corticotropin stimulation. Although baseline cortisol levels
did correlate with survival, patients with the highest levels
had the worst prognosis. Barton and coworkers demonstrated a positive correlation of plasma cortisol with injury
severity score (ISS) in patients with minor or moderate
injuries but a negative correlation with high ISS scores, no
difference between head-injured and non-head-injured
patients, and no difference with age or time of day when
samples were taken. 18
A study of intensive care unit patients performed by
Rivers and coworkers again raises the question of critical
illness increasing the probability of adrenal insufficiency.
They studied 104 patients with severe sepsis or septic shock.
They described a group with functional hypoadrenalism,
who exhibited any hypoadrenal laboratory values. They
found an improvement in vasopressor-dependent refractory
hypotension, even in the group with normal adrenal function. This study suggests that we need to reconsider our
assessment of adrenal insufficiency and our use of corticosteroids in the severely ill. They recommended considering
hydrocortisone treatment in patients older than 55 years
in the presence of continued need for vasopressors after
adequate volume resuscitation. 19
Corticotropin stimulation studies remain reliable at determining adrenal response in the trauma victim. The cosyntropin stimulation test is used to determine whether the
adrenal cortex is able to respond normally to this corticotropin analog by increasing the production of corticosteroids. Serum cortisol level is measured at 0, 30, and
60 minutes after intravenous or intramuscular injection of
250 ug of cosyntropin. Patients with a normal adrenal
response should increase the serum cortisol level by at least
7 ug/dl, or have a peak level of at least 20 ug/dl., Harris and
colleagues performed urinary and plasma cortisol and
cosyntropin (synthetic corticotropin) stimulation studies on
30 patients after traumatic injury and 125 after extensive
elective abdominal or thoracic operation. Levels were similar in both groups. With an uncomplicated clinical course,
the levels returned to normal in 1 to 2 days." They found a
mean stimulated serum cortisol level of 44.5 12.0 ug/dl,
and concluded that a stimulated mean cortisol level of
greater than 20.5 ug/dl, would include 97.5% of normal
subjects. Any value less than 20.5 ug/dl, should be considered indicative of adrenal insufficiency. Stress levels of
steroids should, therefore, be maintained at high doses for at
least 48 hours and raised again if complications ensue.
Current recommendations for steroid coverage of
patients anticipated to have adrenal insufficiency as a result
of previous steroid therapy are empirical. For major surgical
procedures, 100 mg of hydrocortisone hemisuccinate is
administered intravenously the evening before surgery, the
morning of surgery, and every 8 hours for 24 hours until
the major stress of the operation is resolved. Usually,
48 hours is required for major operations with continued
high-dose steroids if complications arise. If high-dose
steroids are required for fewer than 72 hours, rapid tapering
over 5 to 7 days can safely prevent adrenal insufficiency. For
minor outpatient procedures, 100 mg of hydrocortisone at
the induction of anesthesia followed by the usual oral doses
postoperatively is sufficient. Numerous other steroid regimens
exist, but advantages of one over the other are unproved.
Rarely is the addition of mineralocorticoid necessary in this
acute setting."
Addison's Disease and Acute AdrenalHemorrhage - - 637
Adrenal Insufficiency Occurring

Acutely in the Surgical Patient
Acute adrenal insufficiency occurring in the surgical patient
is rapidly fatal if unrecognized. Bilateral adrenalectomy and
hypophysectomy are obvious causes of acute adrenal insufficiency. Numerous drugs used in the surgical patient may
cause adrenal insufficiency. The most treacherous condition
is bilateral adrenal hemorrhage, which may occur in association with anticoagulant therapy, thrombocytopenia, hypercoagulable states, trauma, or the stress of sepsis or bums.
Acute Adrenal Insufficiency

Related to Bilateral
Adrenal Hemorrhage
Although historically bilateral adrenal hemorrhage is associated with meningococcemia in children (WaterhouseFriderichsen syndrome), bilateral adrenal insufficiency
occurs most commonly in adults in association with anticoagulant therapy. Clinical conditions producing coagulopathies
such as thrombocytopenia, anticardiolipin antibody, and
lupus anticoagulant also result in bilateral adrenal hemorrhage. Trauma, either directly or through the destruction of
the blood supply to the adrenal, may result in bilateral adrenal hemorrhage. Septicemia, although more commonly a
cause of adrenal hemorrhage in children, may lead to adrenal hemorrhage in adults. Stress associated with illness,
sepsis, or bums may lead to bilateral adrenal hemorrhage.
Because of the rapidly fatal outcome of bilateral adrenal
hemorrhage, the surgeon must suspect this clinical entity in
these settings.
Although Goolden in 1857 22 recognized the clinical
entity of bilateral adrenal hemorrhage, not until the advent
of CT scans was the diagnosis made premortem. In 1965,
Amador reviewed the 20 cases previously reported as well
as 10 cases gleaned from the 4325 autopsies performed at
Peter Bent Brigham Hospital in Boston from the widespread
use of anticoagulant therapy in 1949 until December 1962. 23
Amador suggested that this form of acute adrenal insufficiency, which resulted from bilateral adrenal hemorrhage,
might not be so rare; adrenal insufficiency was not suspected
during the lifetime in any of the 10 cases studied." Of the
20 previously reported cases, 3 were suspected and treated
premortem.P The first case of successful diagnosis and
treatment was reported by Thorn and colleagues in 1956. 24
In 1978, Xarli and coauthors reviewed 135 cases and added
22 of their own." They found the incidence to be as high as
1.1% of autopsied patients.P Siu and associates reported only
11 patients successfully diagnosed and treated premortem
before 1981. 26 Between 1981 and 1990, Siu found 18 cases
at the Mayo Clinic that were successfully diagnosed." In 16
of the 18 cases, CT scans of the abdomen established the
finding of adrenal hemorrhage. Fortuitously, the signs and
symptoms of bilateral adrenal hemorrhage led to obtaining a
CT scan in many instances. Espinosa and coworkers found a
significant incidence of lupus anticoagulant or anticardiolipin antibodies in patients suffering adrenal hemorrhage;
therefore, all patients with adrenal hemorrhage should be

checked for antibodies."
Stress may lead to bilateral adrenal hemorrhage or may
cause acute adrenal insufficiency without hemorrhage. The
bum patient is an example of this dual situation apparently
related to a similar stress. Among 807 patients treated at
Parkland Hospital over the previous 6 years, Murphy and
colleague'" found 3 patients in whom acute adrenal insufficiency developed. They reviewed the existing theories of the
pathophysiology of adrenal insufficiency in the bum patient.
Vaughan and associates demonstrated cortisol levels three
to four times higher than normal in patients with bums
greater than 30%. These patients lost their diurnal rhythm.
Bum size correlated with cortisol but not corticotropin
levels." Hemorrhagic cortical necrosis is the most common
pathologic finding associated with this acute adrenal insufficiency." The clinical picture is that of sudden and rapid
cardiovascular collapse, which is frequently interpreted as
sepsis.
Surgical stress seems to be a contributing factor to the
development of bilateral adrenal hemorrhage or adrenal
insufficiency.t" Alford and coauthors reported that 5 of
4364 patients undergoing cardiac surgical procedures experienced bizarre and confusing postoperative courses ultimately
proved to be adrenal insufficiency." Adrenal insufficiency
has been reported as an unexpected finding in a small
number of patients after virtually any surgical procedure or
severe physiologic stress (Table 72-2).
Although therapeutic anticoagulation with heparin or
warfarin is the factor most commonly implicated in bilateral
adrenal hemorrhage, even prophylactic subcutaneous
heparin has been found to produce this problem.F The cause
of the hemorrhage with heparin may be related more to
heparin-induced thrombocytopenia than to abnormalities of
the coagulation cascade.P Conditions associated with coagulopathies such as idiopathic thrombocytopenic purpura,
antiphospholipid antibodies, anticardiolipin antibody, and
other thrombogenic states have been associated with adrenal
hemorrhage."

The pathophysiology of adrenal hemorrhage remains
unclear. Excessive anticoagulant does not seem to be responsible because transient prothrombin time abnormalities
occur in only half of the patients." Heparin-induced thrombocytopenia may playa role." The fragile blood supply may
contribute to the hemorrhage. The adrenal is supplied by 50
to 60 small arterial branches from three suprarenal arteries.
These arteries feed a subcapsular plexus, which drains through
a few venules into medullary sinusoids. Vasoconstriction or
hypervascularity could raise adrenal venous pressure, causing hemorrhage.P The single central vein and its thick
longitudinal muscle bundles may make it vulnerable to
formation of platelet thrombi, stasis, and thrombosis."
Stress elevates corticotropin levels, which increase oxygen
uptake by the adrenals and increase adrenal perfusion.'? Focal
necrosis may increase the vulnerability to hemorrhage.
Hemorrhagic cortical necrosis is the most common pathologic finding associated with acute adrenal insufficiency"
The clinical scenario described by Amador remains
unchanged today.P The sudden onset of steady pain in the
upper abdomen, flanks, and lower back, accompanied by
mild tenderness, heralds the development of rapidly progressive deterioration. Initially, abdominal distention and obstipation are present. Listlessness and fatigue progress to
lethargy and disorientation. Tachycardia and hypotension are
late signs. Fever, cyanosis, and severe hypotension are terminal events.P Rao and colleagues observed that significant
premonitory hypotension did not occur before catastrophic
hypotension and shock.'? Only approximately half of the
patients had a systolic blood pressure less than 100 mm Hg
before shock." In the group of patients receiving anticoagulants, the clinical manifestations usually occurred within
10 days of instituting therapy.P Individuals at risk were usually already severely ill. Elderly patients with preexisting
heart disease, thromboembolic disease, or coagulopathy had
a higher risk. Adrenal hemorrhage was more likely to
happen in the postoperative period."
Routine laboratory test results that may suggest the diagnosis of adrenal hemorrhage are a sudden drop in hematocrit,
hyponatremia, hyperkalemia, leukocytosis, eosinophilia, mild
azotemia, mild acidosis, hypercalcemia, and an elevated
serum alkaline phosphatase. Eosinophilia in particular
should arouse suspicion, because only 3% of acutely ill
patients have eosinophilia. Of those, 23% have acute adrenal insufficiency." Hyponatremia, although not always present, is the most consistent finding.
The clinical picture of sepsis and acute adrenal insufficiency may be identical. Invasive monitoring may demonstrate severe hypotension 80 mm Hg), hyperdynamic
cardiac indexes (cardiac index > 4 Lrnin/m"), low systemic
vascular resistance 500 dyne-sec/em' rrr'), and multipleorgan failure in patients who respond poorly to corticotropin
stimulation.'? Lawton described a similar finding and underscored the importance of considering adrenal insufficiency.t"
CT scans obtained for evaluation of the clinical symptoms
reveal the bilateral adrenal hemorrhage. CT scans reveal
bilaterally oval or round adrenal masses of high density
relative to the adjacent liver (Fig. 72-1). Initially, these
masses may appear similar to lymphoma (Fig. 72-2).
Resolution of the masses over time supports the diagnosis
of adrenal hemorrhage." Adrenal enlargement persists for at
FIGURE 72-1. Computed tomography scan of the adrenal gland

demonstrates large, dense globular adrenals (arrows) consistent
with bilateral adrenal hemorrhage.
least 3 to 6 months after adrenal hemorrhage.f Unilateral

adrenal hemorrhage is a far more common incidental finding
on CT scan. One must consider that unilateral involvement
has occurred in an already abnormal adrenal. If it does not
resolve, an underlying adrenal tumor must be considered.
When the diagnosis of adrenal insufficiency is suspected,
immediate treatment with 100 mg of hydrocortisone should
be given with a baseline cortisol obtained at the same time.
Delay for any further testing is inappropriate in this potentially life-threatening situation. Recovery or stability occurs
rapidly, frequently within 1 hour. After initial hydrocortisone
therapy, when the clinical situation stabilizes, the patient
can be switched to dexamethasone, which, as a synthetic
steroid, is not detected in the steroid assays and allows
further diagnostic testing. Hydration and correction of the
hyponatremia are necessary. Large doses of hydrocortisone,
FIGURE 72-2. Computed tomography scan demonstratesmassive

enlargement of right adrenal and less enlargement of the left as a
result of non-Hodgkin's lymphoma. Note the similarityof shape to
the adrenals in Figure 72-1.
Addison's Disease and Acute Adrenal Hemorrhage - -
100 mg intravenously every 6 hours, should be continued

during the period of stress and instability. Mineralocorticoids
are not usually necessary at this time. If confirmatory studies
are desired, the patient should be switched to dexamethasone
at least 24 hours before testing. Hydrocortisone, 100 mg, is
equivalent to 3 mg of dexamethasone. Steroid therapy should
be tapered to standard replacement therapy (hydrocortisone
at 12 to 15 mg/m- per day) as rapidly as possible. However,
the risk of adrenal insufficiency is greater than the risk of
excess steroids in the seriously ill patient. When maintenance
levels are achieved, mineralocorticoid (fludrocortisone
acetate [FlorinefAcetate], 0.1 mg) should be added to the regimen if impaired salt-retaining ability is evident." Adrenal
insufficiency after bilateral adrenal hemorrhage should be
considered permanent. 30 Recovery of adrenal function has
been reported, and evaluation for return of function at a later
date is appropriate.f
Bilateral Adrenal Metastases

Adrenal metastases are common. Adrenal gland metastases
have been found at autopsy in as many as 42% of lung
cancers, 16% of stomach cancers, 58% of breast cancers,
50% of malignant melanomas, and 25% of lymphomas.f
Functional adrenal insufficiency occurs late in the course of
the disease. It is estimated that more than 90% of functional
tissue must be destroyed before the development of adrenal
insufficiency."
Drugs Causing Adrenal

Insufficiency
A variety of drugs used in the surgical patient may inhibit
adrenal function (Table 72-3). Drugs used to inhibit steroidogenesis or exert adrenolytic activity such as aminoglutethimide,
metyrapone, and o,p'-DDD (mitotane) require careful monitoring of adrenal function and frequently require steroid
replacement. Rifampin and ketoconazole also cause adrenal
insufficiency. Phenobarbital accelerates the catabolism of
cortisol. The anesthetic agent etomidate may suppress adrenal
steroidogenesis for as long as 4 days."
Summary
Although adrenal insufficiency is a relatively rare clinical
problem, failure to recognize and treat this condition frequently proves rapidly fatal. Suppression of adrenal function
as a result of prior steroid use is the most common cause
639
of adrenal insufficiency in the surgical patient. A careful

history of steroid usage must be obtained from all patients.
Adequate steroid coverage for the duration of stress is
necessary in these patients as well as in other patients previously taking steroids for the established diagnosis of adrenal
insufficiency. More treacherous is the development of acute
adrenal insufficiency in the patient receiving anticoagulants,
with a coagulopathy, suffering from a thromboembolic
disease, receiving steroid-altering drugs, or with malignancy.
Any stressed patient is a candidate for adrenal hemorrhage
and insufficiency. Any critically ill patient, particularly
septic patients, should be suspected of having adrenal insufficiency. Unanticipated hypotension and shock in any person
should always raise the question of adrenal insufficiency.
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44. Kung AW, Pun KK, Lam K, et aI. Addisonian crisis as presenting
features in malignancies. Cancer 1990;65:177.
Open Operative Approaches

to the Adrenal Gland
Roderick M. Quiros, MD Scott M. Wilhelm, MD Richard A. Prinz, MD
Adrenal diseases demand a thorough understanding of both

endocrine physiology and surgical anatomy. Although they
are rare entities, advances in computed tomography (CT)
and other imaging modalities have increased detection of
adrenal abnormalities that require evaluation to determine if
surgical intervention is needed.
Several open approaches have been used for adrenalectomy. The transperitoneal approach was first performed by
Thornton in 1889 to remove a 20-pound adrenal tumor with
the left kidney in a 36-year-old woman.' The flank approach
described by Mayo in 1927 was used to resect a pheochromocytoma.? The posterior approach was reported by Young
in 1936.3
Each of these approaches has advantages and disadvantages. The appropriatechoice can be made only after weighing
a number of factors, such as the nature of the disease (including the possibility of malignancy) and the patient's condition, habitus, and anatomy. Other considerations include the
presence of unilateral or bilateral disease and the surgeon's
familiarity with the various approaches.
Recently, laparoscopy has been used for the surgical
treatment of adrenal disease. Since the early reports of this
technique, laparoscopy has become the method of choice for
removing many adrenal lesions.t" Most surgically treatable
adrenal masses are unilateral and/or benign, making them
ideal for laparoscopic surgery. The operative principles that
underpin the laparoscopic approach, such as familiarity with
retroperitoneal anatomy, are identical to those for the open
approaches. There are, however, several indications when
open adrenalectomy is still warranted.
1. An adrenal mass with preoperative suggestion of
malignancy as noted by invasion of surrounding structures, associated lymphadenopathy, or venous extension of the tumor into the renal vein or inferior vena
cava (lVC) should be resected through an open
approach.
2. Evidence of local invasion found during laparoscopic
adrenalectomy should prompt conversion to an open
procedure to facilitate a definitive en bloc resection.
3. Bleeding that cannot be controlled during a laparoscopic adrenalectomy,most commonly from an adrenal
vein laceration, requires conversion to an open adrenalectomy. This problem happens more frequently during
dissection of the right adrenal vein because it is very
short and has a posterior lateral insertion into the IVC.
This type of bleeding can be extremely difficult to
control laparoscopically, and prompt conversion may
be lifesaving.
4. Recurrence of a previously resected adrenal mass
necessitates an open adrenalectomy. This is most often
encountered with malignant pheochromocytomas or
adrenocortical carcinomas. Re-excision is best performed by an open approach because of the scarring
and loss of tissue planes after the initial operation.
5. With virilizing adrenal tumors, an open approach
should be seriously considered, because 70% to 85%
of these rare tumors are actually functional adrenocortical carcinomas.P In light of the extremely high rate
of malignancy, we would be cautious and not recommend a laparoscopic approach.
6. Finally, tumor size must be considered. Lesions above
6 cm have a greater risk of malignancy. Even for
lesions that are certainly benign, size greater than 8
to 10 em may be a relative indication for an open
adrenalectomy, especially for surgeons without substantial knowledge of retroperitoneal anatomy and
advanced laparoscopic skills."
This chapter reviews the surgical anatomy of the adrenal
glands and describes the four primary open approachesanterior, thoracoabdominalllateral transthoracic, posterior,
and flank-used to expose the adrenal glands.
Surgical Anatomy
The adrenal glands are paired structures adjacent to the
upper poles of the kidneys in the retroperitoneum. Each
gland weighs 3 to 8 g. The right adrenal is triangular and
slightly smaller and more superiorly located than the left
gland. The left adrenal gland is elongated and flatter than the
right gland. Both glands are contained within Gerota's fascia
and are directly surrounded by fat and connective tissue.
641

The glands themselves may be differentiated from the surrounding adipose tissue by their golden, yellow-brown color.
The right adrenal gland is bordered by the IVC medially, the
bare area of the liver anteriorly, and the diaphragm both superiorly and laterally. Division of the right triangular ligament
of the liver, which provides lateral fixation of the liver, can
facilitate exposure of the right adrenal by allowing retraction
of the right hepatic lobe both anteriorly and medially."
The left adrenal gland is bordered by the aorta medially, the
cardia of the stomach and the pancreatic tail anteriorly, the
left renal vein inferiorly, and the diaphragm superiorly and
laterally. The arterial supply to the adrenals may be variable,
although in most patients it comes from the inferior phrenic
artery superiorly, the aorta laterally, and the renal artery
inferiorly. The venous supply is more constant but may pose
a greater technical problem if not understood. The right
adrenal gland is drained by a short adrenal vein that enters
the IVC posterolaterally. Because of its location, and because
it can be difficult to visualize, it is at risk for injury. The
resultant hemorrhage is often difficult to control. The left
adrenal gland drains into the left renal vein and is usually
fairly prominent.
Preoperative Preparation
Patients undergoing adrenal surgery require thorough preparation. Such preparation is especially necessary when one uses
an open approach. Venous thromboembolism is not uncommon postoperatively, so intermittent pneumatic compression
of the legs or some other method of preventing deep venous
thrombosis should be considered. Caution is necessary when
using anticoagulants because of the risk of retroperitoneal
hemorrhage postoperatively. A modified bowel prep using
a clear liquid diet and cathartics should be given the day
before surgery so the large intestine will not be filled with
feces. The effects of excess hormone secretion should be
reversed whenever possible. Patients with aldosteronomas
should have potassium deficits corrected. Preoperative use
of spironolactone or arniloride may facilitate this. The adverse
effects of cortisol excess can be blunted by giving metyrapone,
ketoconazole, or mitotane. Vitamin A can counteract some
of the poor wound healing that is seen in Cushing's syndrome; 25,000 to 50,000 IV/day can be given orally for the
week before the operation and intramuscularly until the
patient is able to resume oral intake. Patients with pheochromocytomas should have their hypertension controlled with
an a-blocking agent or a calcium channel blocker. Inhibiting
the vasoconstrictive effects of catecholarnines allows the
patient to replenish their intravascular volume deficit. Betaadrenergic blockade should be used in patients with tachycardia, arrhythmia, or pure epinephrine-secreting tumors but only
after a-adrenergic blockade has been achieved. Autologous
blood can be obtained if a need for transfusion is anticipated.
incision is the bilateral subcostal or chevron, which affords

easy access to all retroperitoneal structures. This incision provides excellent lateral, superior, and inferior exposure of not
only both adrenals but also the surrounding solid organs. A
unilateral subcostal incision can be used for disease confined to the ipsilateral adrenal, but this incision can substantially limit the extent of exposure of the opposite adrenal gland
and the rest of the abdominal cavity. A midline incision can
also be used.
The advantage of the anterior approach is that it allows
access to both adrenal glands through one incision (chevron
or midline) with the patient in one position on the operating
table (supine). The anterior approach also allows for exploration of the rest of the peritoneal cavity and provides adequate access and exposure for resection of almost any size
tumor. Invasion into structures such as the diaphragm and liver
or involvement of the IYC may necessitate a more radical
approach, which is discussed in the section devoted to the
thoracoabdominal approach.
For right-sided lesions, dissection begins with mobilization
of the hepatic flexure of the colon to allow it to be retracted
inferiorly. This also exposes the C loop of the duodenum,
which can be "Kocherized" to allow for improved access to
the IVC for identification and ligation of the right adrenal
vein. Usually, the Kocher maneuver is unnecessary since the
right adrenal vein enters the IYC above the duodenum.
Next, the lateral attachments of the right lobe of the liver, the
triangular ligament, are mobilized to allow superomedial
retraction of the liver (Fig. 73-1). With large adrenal tumors,
the gland may extend well beyond Morison's pouch into
the retrohepatic space. When this is encountered, complete
Anterior Approach
The anterior approach is the most commonly used of the
open approaches. This operation is carried out through incisions with which general surgeons are familiar. Our preferred
FIGURE 73-1. Retraction of the liver superiorly usually gives

adequate exposure of the right adrenal gland. (From Prinz RA.
Mobilization of the right lobe of the liver for right adrenalectomy.
Am J Surg 1990;159:337.)
Open Operative Approaches to the Adrenal Gland - - 643
FIGURE 73-2. A, If access to the

right adrenal is not obtained by
retraction of the liver, the right
lobe can be mobilized by incising the triangular ligament. B,
Rotation of the right lobe of
the liver anteromedially provides
wide exposure to both the adrenal
and the inferior vena cava. (From
Prinz RA. Mobilization of the right
lobe of the liver for right adrenalectomy. Am J Surg 1990;159:337.)
A
mobilization of the right lobe of the liver may be required to
ensure a safe en bloc resection of the tumor (Fig. 73-2).10 This
is done by incising the falciform ligament over the anterior
surface of the liver and the entire right triangular ligament.
This exposes the bare area of the liver, which is carefully
dissected away from the diaphragm. Care must be taken to
identify any inferior phrenic veins and the right hepatic vein,
which can be easily injured as the liver is retracted toward
the midline and cause rapid and troublesome hemorrhage.
With the liver now mobilized, the adrenal gland can be
safely dissected, with improved visualization of the junction
of the right adrenal vein and the IVC. Care must also be
taken not to rotate the liver so far medially as to compress
the IVC and decrease venous return, resulting in hypotension. Proper communication between the surgeon and anesthesia team during this maneuver is critical.
Once the gland has been exposed and its relationship to
the IVC clarified, the right adrenal vein can be sought. It
normally drains the adrenal gland from the superomedial
aspect and enters the cava in a posterolateral position. Early
vein ligation is important with pheochromocytoma to avoid
excessive catecholamine release into the systemic circulation with manipulation of the gland during the rest of the
dissection. With large tumors of any type, whether functional or nonfunctional, further dissection of the gland along
its superior and medial borders (along the IVe) may make
identification of the adrenal vein easier. This vein is typically
short (4 to 10 mm) and wide (4 to 7 mm) as it enters the IYC.
A suture ligature of the adrenal vein as it enters the IVC is
wise since avulsion of a simple free tie placed on this critical venous branch can cause life-threatening hemorrhage.
Many large tumors extend posterior to the cava, which
necessitates its gentle retraction with a vein retractor or
sponge stick to complete the dissection. This retraction can
easily dislodge a poorly secured ligature on the adrenal vein,
again leading to major hemorrhage.
The remainder of the dissection consists of ligating any
other accessory venous branches and the circumferential
arterial arcade supplying the gland. Alternatively, hand-held
harmonic scalpel units are now available that can be used to
complete the rest of the dissection without the need for any
further ligatures similar to a laparoscopic approach. Of note,
the harmonic scalpel should not be used to transect the
adrenal vein due to its size and thin-walled nature.
B
A small extension of tumor thrombus into the IYC discovered during dissection can be managed through the anterior
approach. IVC tumor thrombus is considered regional disease
and should not preclude resection of the adrenal tumor. II The
tumor thrombus is not typically adherent to the endothelium
of the IVC and is often extracted without difficulty. Care
must be taken to have adequate control of the proximal and
distal IVC to avoid tumor embolization during this maneuver.
Preoperative imaging of extension of adrenal tumors into the
IVC is discussed further in the section dealing with the
thoracoabdominal approach.
Left-sided lesions can be approached in a similar fashion
depending on the surgeon's preference and the extent and
location of the tumor with respect to the pancreas and spleen.
The first maneuver entails mobilizing the splenic flexure of the
colon at least one third of the distance down the left paracolic
gutter, along its lateral peritoneal attachments, and then across
the gastrocolic ligament to the area of the inferior mesenteric
vein. This allows inferior retraction of the transverse and left
colon. Opening the gastrocolic ligament exposes the inferior
border of the pancreas, which must be inspected for evidence
of invasion. If the adrenal gland extends posteriorly to the
pancreas, the lateral attachments of the spleen and the
splenocolic ligament can be taken down. Along with opening the retroperitoneum along the inferior border of the
pancreas, these maneuvers allow superomedial reflection of
both the spleen and pancreas for improved exposure of a
retropancreatic adrenal tumor. Care must be taken with the
spleen to avoid capsular tears from excessive traction.
Splenectomy may become necessary if this occurs and patients
should understand the possibility of this complication and the
potential for postsplenectomy sepsis. The need for proper
immunization is clear should this occur.
The left adrenal vein typically exits the left adrenal gland
at its inferomedial border and drains directly into the left
renal vein. It should be sought in this position and again be
appropriately ligated. Tumor extension into the left adrenal
vein usually extends into the left renal vein toward the IVC.
Options for resection include tumor extraction, as mentioned for the right adrenal gland, or ligation of the left renal
vein distally near its insertion into the IVC (assuming the
tumor does not extend into the cava) and proximally just
medial to the entrance of the adrenal vein. The gonadal and
lumbar veins, which enter the renal vein closer to the kidney

(proximal to the entrance of the adrenal vein in the renal
vein), are not typically involved with tumor thrombus and
should provide adequate drainage for the left kidney.
However, the inferior phrenic vein, which enters the renal
vein medial to the adrenal vein, is typically involved with
tumor thrombus and must be sought and ligated. The
remainder of the dissection involves the same principles as
those discussed for the right adrenal dissection.
ThoracoabdominallLateral
Transthoracic Approach
The thoracoabdominalllateral transthoracic approach requires
a large incision and opening of both the thoracic and peritoneal cavities. Because it provides only unilateral adrenal
gland exposure, it is generally reserved for the following
highly specific surgical circumstances:
1. For very large tumors with substantial involvement of
surrounding structures (especially the pancreas, spleen,
and diaphragm on the left side and the liver, IVC, and
diaphragm on the right), this approach affords the widest
exposure of the adrenal gland and surrounding
structures.
2. For local tumor extension into the IVC, a thoracoabdominal approach can provide the best exposure.
Determination of vascular involvement by adrenal tumors
preoperatively is critical to planning the operative approach.
Ultrasound and CT have both been used for this purpose.
Both imaging modalities can often depict a filling defect in the
IYC suggestive of tumor extension. However, ultrasound can
be limited in the obese patient (especially seen in Cushing's syndrome) or if there is a marked amount of bowel gas present.
Magnetic resonance imaging (MRI) has emerged as the best
test to evaluate caval involvement and can determine the
extent of caval tumor extension all the way to the right
atrium.P This may change as CT angiography continues to
improve.
One other imaging modality that is evolving in determining
IVC invasion or tumor thrombus within the IVC is intracaval
endovascular ultrasonography, (ICEDS). Here, a 20- to 30-MHz
(high-frequency) 360-degree rotating ultrasound probe is
inserted into the femoral vein and advanced into the IVC.
Kikumori and coworkers demonstrated a 100% sensitivity,
100% specificity, and 100% positive predictive value for
ICEDS for accurately determining either IVC wall invasion
or tumor thrombus in the IVC in nine patients with adrenal
tumors.'? CT scan by comparison in this study had 100%
sensitivity, 14% specificity, and only a 25% positive predictive
value for these same parameters preoperatively. MRI was not
used in this study. This endovascular ultrasonographic technology has also been applied to the portal vein to determine
invasion by pancreatic cancer. 14 Although studies with ICEDS
have contained small numbers of patients and have not been
comparatively evaluated with MRI, this evolving tool may
help guide some future adrenal resections. However, its
invasive nature and need for special technology and user
expertise limit its widespread use.
The patient is positioned in either a full lateral or a semioblique (45-degree-angle) position with the operative side
up and the opposite side in the decubitus position. We favor
the lateral position, but both can afford adequate exposure.

The patient is situated on the operating table such that the
IOth rib is superior to the center break in the table and the
12th rib is inferior to the break. The table is then jackknifed
to open the space between these ribs and expand the chest
wall. The kidney rest can be extended for further exposure
but should generally be done after the chest is opened to
avoid undo tension with possible rib fracture, especially in
patients with Cushing's syndrome who may have very brittle bones due to osteopenia or osteoporosis as a consequence
of their hypercortisolemia.
For a right-sided approach, the incision begins over the
right 10th rib near the lateral border of the sacrospinal muscle
(Fig. 73-3). It is carried over the rib along the anterior abdominal wall across the costal cartilage and then down onto the
anterior abdominal wall toward the midline rectus muscle. The
rib and abdominal muscles are exposed and the lOth rib is
resected subperiosteally as far back as its angle. The pleural
cavity is then entered. The diaphragm is divided well lateral to
avoid injury to the phrenic nerve and its branches. The lung
can be protected with moistened laparotomy pads and a large
Finochietto retractor is used to open the incision. The dissection in the abdomen can be carried retroperitoneally or, if
tumor extension necessitates, the peritoneum can be opened.
The lung is retracted superiorly along with the liver, and the
renal fascia (Gerota's fascia) is incised. The kidney can then be
retracted inferiorly to expose the adrenal gland. The gland is
then excised as previously mentioned.
On the left side, the adrenal gland resides slightly lower
than on the right, just as the kidney does. Therefore, the
incision should begin over the 11th rib for proper exposure
(Fig. 73-4). On this side, it may be possible to avoid entering the pleural cavity by dissecting the parietal pleura off the
diaphragm. The rest of the technique is similar to the rightsided approach.
On either side, if the peritoneum has been opened, it is
reapproximated along with the diaphragm with a single continuous absorbable suture. A tube thoracostomy is placed in
the pleural cavity and the muscle layers of the abdominal
and chest walls are reapproximated. For tumors with caval
extension into the right atrium, this incision can be combined with a median sternotomy for improved exposure. Either
venovenous bypass or full circulatory arrest with extracorporeal bypass and oxygenation can be used if necessary.
Preoperative suspicion and proper imaging are critical to
10th Rib
FIGURE 73-3. For removal of the right adrenal gland through a

thoracoabdominal approach, the incision follows the course of the
12th rib from the lateral border of the sacrospinalis muscle to just
beyond the costal margin.
Open Operative Approaches to the Adrenal Gland - -
11th Rib
645
12th Rib
FIGURE 73-4. Adrenalectomy by the lateral or thoracoabdominal
FIGURE 73-5. The patient is placed in the prone position for a

posterior adrenalectomy. Thebreak in thetable should be beneath the
12th rib. Padding is placed to allow chest expansion for respiration
and to avoid any pressure points.
avoiding intraoperative surprises necessitating unplanned

measures as drastic as this.
midline, and its attachment to the 12th rib is severed. The

middle lamella of the lumbodorsal fascia underlying the
sacrospinalis is incised to expose the quadratus lumborum
and the transversalis fascia. Insertion of the index finger
under the incised middle layer of the lumbodorsal fascia
and sharp division of the posterior subcostal ligament
releases the pleura from the 12th rib. The periosteum of the
12th rib is then incised and stripped before the rib is
resected. The 12th intercostal nerve should be identified
and preserved throughout these steps. Once the 12th rib
is removed, the retroperitoneum is entered. Proper retraction
is critical at this point. Typically, upward retraction of the
11th rib reveals the reflection of the parietal pleura and
the lateral arcuate ligament of the diaphragm. The pleura is
retracted upward. If the pleura is inadvertently opened, it
can be repaired over suction catheters that are withdrawn
as the incision in the pleura is closed under positive-pressure
ventilation. Postoperatively, a chest tube is usually not
necessary.
With retraction of the 11th rib, a layer of perinephric fat
becomes visible. Dissection through this layer reveals Gerota's
fascia, which is entered to reveal the kidney. This is then manually depressed to expose the adrenal gland. Rotating the
superior pole of the kidney caudally and posteriorly facilitates
exposure of the adrenal gland, which can be readily identified
from the surrounding perinephric fat by its characteristic
gold-brown color.The gland can then be dissected out starting
superiorly and progressing caudally. Care must be taken in
handling the gland, which can be friable. To reduce the risk
of breakage, spillage of cells, and autotransplantation, the
gland should be handled by its surrounding adventitia. The
multiple tributary blood vessels should be clipped, ligated,
or cauterized, although the actual arterial branches to the
gland are not typically identified during the procedure. Care
must be taken to avoid avulsing the adrenal vein, which
itself is doubly ligated or stick-tied with a silk suture and
divided. The relative shortness of the right adrenal vein predisposes it to an avulsion or tear with resulting major hemorrhage from the IVC. If this occurs, stick sponges should
be applied to the cava proximally and distally to the tear,
which is subsequently repaired with a 4-0 Prolene in running or interrupted fashion.
Once the gland is dissected out from the perinephric fat
and all blood vessels have been appropriately divided, the
gland may be removed. The perinephric fat should be carefully inspected for bleeding as well as for ectopic adrenal
approach is performed with the patient in the lateral decubitus

position. The incision extends along the bed of the 11th rib for a
left adrenalectomy.
Posterior Approach
The posterior approach provides the most direct route to
the adrenal glands. Compared to the other approaches, no
major muscles are transected and little dissection is
required to expose the adrenal glands. A large transabdominal wound is avoided. It has the purported advantage of
decreased postoperative ileus, since the peritoneal cavity is
not entered. Patients are able to ambulate and take a normal
diet early after operation, and their hospital stay is often
shortened. The posterior approach is effective for the exposure and removal of glands up to 5 em in diameter. Glands
larger than this may be difficult to resect with this
approach. It has the disadvantage of exposing only one
individual gland with each incision, so two incisions are
necessary if this approach is used for bilateral adrenal
pathology. In addition, exposure of the adrenal veins can
prove difficult, mandating close attention to prevent venous
avulsion and uncontrolled hemorrhage. This approach
should not be used for large adrenal masses that mandate
wide exposure and early vascular control; if used, it should
be reserved for bilateral hyperplasia (Cushing's disease) or
small, benign adenomas.
Proper positioning is crucial in facilitating this approach.
After the patient is intubated, he or she is placed prone, with
the break of the table at the level of the 12th rib (Fig. 73-5).
Pillows are placed under the patient's abdomen and lower
legs, and the operating table is jackknifed to hyperflex the
patient's back. Flexion of the knees, along with placement
of sequential compression devices on the lower legs, reduces
the likelihood of deep venous thrombosis. A hockey stick
incision starting approximately 5 ern lateral to the midline of
the vertebral column, progressing downward and outward
in curvilinear fashion at the level of the 10th rib, over the
12th rib, and extending toward the iliac crest is typically
described. We usually use a straight incision that follows
the oblique course of the 12th rib and have found that it
provides sufficient exposure. Division of subcutaneous fat
exposes the latissimus dorsi. This is transected with cautery,
revealing the sacrospinalis muscle, which in turn is divided
to expose the 12th rib. The sacrospinalis is retracted toward

rests that may be present. When hemostasis is achieved, and
all satellite adrenal tissue removed, the wound may be closed
in appropriate layers.
Flank Approach
Like the posterior approach, the flank approach is extraperitoneal. It is most useful for obese patients in whom exposure
offered by other approaches would be compromised. In these
patients, the flank approach uses gravity to assist with retraction by allowing the patient's adipose tissue to fall away
from the incision. The flank approach is also useful in the
presence of a large adrenal mass in a patient with scarring
and adhesions in the abdomen from previous surgeries.
Finally, the flank approach is used when a laparoscopic procedure is converted to an open approach, as the patient will
already be in the lateral decubitus position. Disadvantages of
this approach are that exposure is only unilateral, and may be
limited, particularly on the right side. It is therefore best suited
to patients with small, unilateral adrenal disease. Compared to
the posterior approach, however, the larger flank incision
allows the surgeon to place both hands into the incision.
The patient is placed in the lateral decubitus position
after being intubated. The abdominal pannus, if present,
should fall forward. The operating table is flexed to maximize the distance between the costal margin and the iliac
crest. An intercostal (Turner-Warwick), transcostal, or subcostal incision may be used. 15,16 The incision is made at the
tip of the lith or 12th rib (approximately the midaxillary
line) and extends along the border of the rib posteriorly. The
latissimus dorsi, external and internal obliques, transversus
abdominis, and intercostal muscles are divided along the
upper margin of the rib. Intercostal or transcostal incisions
provide better exposure than the subcostal incision, particularly for glands in a cephalad position. A plane between the
diaphragm and retroperitoneum is then developed, facilitating entry into the retroperitoneal space. Alternatively, the
flank approach can be accomplished transthoracically prior to
entry into the retroperitoneum. The procedure then follows
as in the posterior approach.
Summary
There are a number of open and laparoscopic approaches for
adrenalectomy. Each has its own particular advantages and
disadvantages. Surgeons treating adrenal disease should be
familiar with each of the approaches and their indications.
This will allow them to select the approach that is best suited
for dealing with their individual patient's specific problem.
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3. Young HH. A technique for simultaneous exposure and operation on
the adrenals. Surgery 1936;63: 179.
5. Constantino GN, Mukalian GG, Vincent GJ, Kliefoth WL Jr.
Laparoscopic adrenalectomy. J Laparoendosc Surg 1993;3:309.
6. Brunt LM, Molmenti EP, Kerble K, et al. Retroperitoneal endoscopic
adrenalectomy: An experimental study. Surg Laparosc Endosc
1993;3:300.
7. Imai T, Tobinaga J, Morita-Matsuyama T, et al. Virilizing adrenocortical adenoma: In vitro steroidogenesis, immunohistochemical studies of
steroidogenic enzymes, and gene expression of corticotropin receptor.
Surgery 1999;125:396.
8. Derksen J, Nagesser SK, Meinders AE, et al. Identification of virilizing adrenal tumors in hirsute women. N Engl J Med 1994;331:968.
9. Jossart GH, Burpee SE, Gagner M. Surgery of the adrenal glands.
10. Prinz RA. Mobilization of the right lobe of the liver for adrenalectomy.
Am J Surg 1990;159:336.
II. Brennan ME Adrenocortical tumors. CUIT Surg Ther 2001;7:620.
12. Wajchenberg BL, Albergaria-Pereira MA, Medonca, et al. Adrenocortical
carcinoma: Clinical and laboratory observations. Cancer 2000;88:711.
13. Kikumori T, Imai T, Kaneko T, et al. Intracaval endovascular ultrasonography for large adrenal tumor [Abstract]. Presented at the
American Association of Endocrine Surgeons Annual Meeting, 2003.
14. Kaneko T, Nakao A, Inoue S, et al. Intraportal endovascular ultrasonography in the diagnosis of portal vein invasion by pancreaticobiliary carcinoma. Ann Surg 1995;222:711.
15. Riehle RA, Lavengood R. An extrapleural approach with rib removal
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Michel Gagner, MD, FRCSC, FACS Ahmad Assalia, MD
Recent advances in minimally invasive techniques have

made it possible to perform complex surgical procedures
laparoscopically. The adrenal gland lends itself well to
laparoscopic removal because of the small size of the gland,
the benign nature of most adrenal tumors, and the difficulty
in the access to the glands via the open approach. Since its
first description in 1992, I laparoscopic adrenalectomy has
proved to be the procedure of choice for the surgical treatment of benign adrenal disease. Multiple reports have
consistently demonstrated the well-known benefits of minimally invasive surgery, including decreased analgesic
requirements, less blood loss, and shorter hospital stay and
recovery time, over the conventional approach.r" These
results were not surprising considering that the procedure,
similar to laparoscopic cholecystectomy, avoids an upper
abdominal incision; does not require any reconstruction;
benefits from magnification and clarity of view; is commonly
performed for benign disease; and mostly involves small,
easily extractable specimens. Proper application of minimally invasive surgery to the adrenal gland must take into
account expertise in both endocrine and laparoscopic
surgery. For successful adrenalectomy, one must have
knowledge of the anatomy and disease process, maintain
meticulous hemostasis, and delicately handle tissue.
With conventional adrenalectomy, the surgical approach
varied according to size, location, possibility of multiple
tumors, patient habitus, and tumor invasiveness. These
conventional approaches include the posterior, flank, thoracoabdominal, and transabdominal approaches. All these
open procedures invariably require large incisions and rib
resections with the posterior approaches, resulting in
significant postoperative morbidity (including chronic
pain syndromes because of injury to intercostal and other
nerves)." Although these conventional approaches will
undoubtedly still be required for certain adrenal pathologies,
laparoscopic adrenalectomy, eliminating many of the problems of open surgery, has become the gold standard for
resection of most adrenal diseases.
Indications
The indications for laparoscopic adrenalectomy are basically the same as those for open adrenalectomy, with few
exceptions. These indications include the following:
1. Functional adrenal cortical masses: (1) Cushing's
syndrome caused by benign cortisol-producing adenoma; (2) Cushing's disease after failed pituitary surgery or after failure to control or find an ectopic
adrenocorticotropic hormone (ACTH)-producing
tumor; (3) aldosterone-producing adenoma (Conn's
syndrome); and (4) rare virilizing/feminizing secreting
tumors
2. Functional medullary adrenal masses: benign adrenal
pheochromocytoma
3. Nonfunctional adrenal tumors: (1) benign-looking
incidentalomas (nonfunctioning adenomas) confined
to the adrenal glands and meeting accepted criteria
for adrenalectomy (>4 cm at presentation or growth
during follow-up); (2) benign symptomatic lesions;
and (3) rare entities such as cyst and myelolipoma
Laparoscopic adrenalectomy has been reported for
several other conditions'P''? but is not currently considered
standard. These include neuroblastoma and congenital adrenal hyperplasia in children and isolated adrenal metastases.
General contraindications for laparoscopy include unacceptable cardiopulmonary risk and uncorrectable/untreated
coagulopathy. Additional relative contraindications for laparoscopic approach include previous surgery or trauma in the
direct vicinity of the adrenal gland, diaphragmatic hernia, and
surgeon's inexperience.' Obesity and previous major abdominal surgery are no longer contraindications for laparoscopic
adrenalectomy.
Currently, in experienced hands, the only specific absolute
contraindications to laparoscopic adrenalectomy are known
large adrenocortical carcinoma with frank tumor invasion
to adjacent structures and metastatic pheochromocytoma to
647
648 - -
Adrenal Gland
periaortic nodes. In these cases, an open procedure is

preferred to allow an en bloc resection and node dissection
to be performed.
Although controversy exists over the maximum acceptable tumor size for laparoscopic adrenalectomy, laparoscopy
may not be generally advisable for adrenal tumors larger than
12 to 14 em because of the technical difficulties associated
with such surgery and the malignant potential of these large
tumors. Nevertheless, the indications and contraindications
of laparoscopic adrenalectomy are currently dictated mainly
by the experience of the individuallaparoscopic surgeon.
Preoperative Evaluation
and Preparation
Adequate metabolic work-up and accurate radiologic evaluation of adrenal disease preoperatively are crucial.
Specific Diseases
INCIDENTALOMA
To determine whether an incidental adrenal mass in an asymptomatic patient is functional is obligatory, because virtually all
functioning tumors should be excised and preoperative preparation is crucial for minimizing perioperative complications.
In these instances, the evaluation should include a thorough
history and physical examination and biochemical screening
for occult aldosteronomas, pheochromocytomas, and glucocorticoid-producing adenomas. Serum potassium, sodium,
free testosterone, dehydroepiandrosterone (DHEA), and
estradiol are measured. Plasma cortisol and corticotropin
measurement in the morning and in the afternoon, or urine
cortisone for 24 hours, are performed to rule out Cushing's
syndrome. If there is any suspicion that the cortisol level is
abnormal, then measurements are repeated after administration of I mg of dexamethasone (occasionally after 8 mg),
and a blood sample is obtained at 8 AM the following morning
for plasma cortisol. A 24-hour urine sample is collected, and
vanillymandelic acid, metanephrine, catecholamine, and
creatinine levels are determined. A metaiodobenzylguanidine (MIBG) nuclear scan is useful for identifying adrenal
and ectopic pheochromocytomas as well as metastatic
pheochromocytoma, whereas an iodocholesterol scan helps
identify adrenal tumors in patients with functional adrenocortical adenomas. Patients with Cushing's syndrome
usually experience life-threatening hypocortisolism postoperatively unless they receive replacement cortisol and salt after
adrenalectomy. Measurements of DHEA are helpful because
these levels are low in patients with adrenocortical adenomas
and elevated in patients with adrenocortical carcinomas.
PRIMARY HYPERALDOSTERONISM
A computed tomography (CT) scan or magnetic resonance

imaging (MRI) scan is obtained, as well as plasma aldosterone level, renin activity, and plasma and urinary sodium
and potassium levels. Patients with primary hyperaldosteronism have high plasma aldosterone levels and low renin
activity. Patients with aldosterone-secreting adenomas have
a paradoxical fall in plasma aldosterone levels after standing
for 4 hours, whereas in normal individuals and those with
bilateral adrenal hyperplasia, the plasma aldosterone level

increases. If a patient has hyperaldosteronism, bilateral
adrenal hyperplasia (i.e., idiopathic hyperaldosteronism)
must be ruled out before surgery. Iodocholesterol (NP-59)
scanning under dexamethasone suppression is useful for
localizing adenomas in these patients, although highresolution CT scanning is the most commonly used test.
Occasionally, selective adrenal catheterization is helpful for
determining the site of the hyperfunctioning tumor.
PHEOCHROMOCYTOMA
Patients with pheochromocytoma should undergo adequate

blockade with an a. blocker for at least 7 days before adrenalectomy. Treatment with ~ blockers is useful for tachycardia,
but a. blockers and hydration should always be started first.
The calcium channel blockers are an alternative for patients
who cannot tolerate the a. or ~ blockade. CT scanning is the
most commonly used imaging modality, although some
groups routinely obtain MRI with a T2-weighted signal to
rule out bilateral or metastatic disease." MIBG scans are
useful in localizing extra-adrenal tumors and metastatic disease. The finding of positive nodes along the periaortic chain
or close to the bladder is a contraindication for laparoscopy'
CUSHING'S SYNDROME AND DISEASE
Dexamethasone suppression test is performed with samples

obtained at 8 AM after the patient has been given I mg of dexamethasone (occasionally after 8 mg) at 11 PM the previous
evening. For some patients, documenting the 8 AM and
8 PM cortisol levels is helpful to determine whether the
normal diurnal levels are lost. CT or MRI scans of the pituitary and adrenal area as well as iodocholesterol nuclear
scanning are also useful in selected patients. For Cushing's
disease or pituitary Cushing's syndrome, the work-up is
similar. For patients with Cushing's syndrome, petrosal
sinus venous sampling after stimulation of corticotropin
secretion by corticotropin-releasing factor (CRF) is helpful
in determining whether a patient has pituitary or ectopic
Cushing's syndrome. Patients with pituitary Cushing's syndrome have a threefold increase in ACTH in the petrosal vein
after CRF stimulation. Bilaterallaparoscopic adrenalectomy
is useful in patients with failed transsphenoidal surgery for
pituitary Cushing's syndrome and in some patients with
ectopic Cushing's syndrome when the corticotropin-secreting
tumor cannot be removed.
Patient Preparation
Symptomatic patients with functional tumors require correction of fluid and metabolic abnormalities (e.g., hypokalemia,
metabolic alkalosis, and hyperglycemia) and control of
hypertension and other symptoms related to hormone
excess. Patients with Cushing's syndrome can be treated
with ketokenazole or the antiglucocorticoid agent RU 486.
Postoperatively, these patients require glucocorticoid
replacement to avoid postoperative adrenal insufficiency.
Patients with hyperaldosteronism are treated with spironolactone. Patients with pheochromocytoma are managed with
fluids, a. blockade and, if necessary, ~ blockade. Finally, in
patients with suspected malignancy, a thorough evaluation
for metastatic disease should be undertaken.
Laparoscopic Adrenalectomy - - 649
Operative Technique
Anesthesia
Several laparoscopic approaches to the adrenal glands are

recognized, including the following:
1. Transabdominal lateral-with the patient in the lateral
decubitus position
2. Transabdominal anterior-with the patient in the supine
position
3. Retroperitoneal endoscopic adrenalectomy-lateral

or posterior
Although the retroperitoneal approach is advocated by
some authors.U"? the technique of choice by most surgeons
performing laparoscopic adrenalectomy is the transabdominallateral approach, originally described by us in 1992.1,18
Positioning of the patient in the lateral decubitus position
uses gravity to help retract the surrounding organs (including the bowel), and effectively exposes the adrenal gland
for laparoscopic intervention. As a result, there is reduced
dissection and minimal retraction of the vena cava and other
adjacent structures.
Herein, the details of our originally described transabdominallateral approach are followed by short comments on
other techniques. The patient is positioned to maximize the
distance between the costal margin and the iliac crest. This
is achieved by adjusting the operating table in the jackknife
position, with the patient placed in the lateral decubitus
position with the operated side up. Sufficient padding is
placed over pressure points and the patient is strapped and
taped in position. The surgical prep should extend from the
nipple to the anterosuperior iliac spine, and from the midline
anteriorly to the spine posteriorly. This allows for conversion
to an open procedure should this be necessary.
Transabdominal Laparoscopic
Left Adrenalectomy
Patients are placed in the lateral decubitus position with the
left side up. The surgeon and the assistant stand on the side
opposite the diseased gland (Fig. 74-1). A flank cushion
is positioned under the patient's right side and the table is
flexed so that the left side is hyperextended (Fig. 74-2).
The left arm is extended and suspended. The surgical area is
prepared as previously described. An open technique is used
to access the abdominal cavity in the left subcostal area at
the level of anterior axillary line, and carbon dioxide, up to
15 mm Hg of pressure, is insufflated. One lO-mm trocar is
then inserted into this site, and a 30-degree, lO-mm laparoscope is introduced, through which the abdominal cavity is
explored. If the inspection is satisfactory, two more 5- or
lO-mm trocars are inserted under direct vision into the flank,
depending on available instrumentation: one under the 11th
rib and one slightly more anteriorly and medially to the first
trocar. Occasionally, a fourth trocar is needed for retraction
and is inserted at the costovertebral junction dorsally (see
Fig. 74-2). All trocars should be at least 5 em and, more optimally, 8 to 10 em apart. The laparoscope is then inserted in
the most anterior trocar and the surgeon works with a twohand technique through the other two trocars. Working with
the laparoscopic scissors with cautery or the ultrasonic
scalpel in the right hand and a curved dissector in the left
hand, the surgeon mobilizes the splenic flexure medially to
surgeong
Instrument table
FIGURE 74-1. Laparoscopic left adrenalectomy: operating room
layout.
move the colon from the inferior pole of the adrenal and
expose the lienorenal ligament (Fig. 74-3). This mobilization allows instruments to be inserted more easily and helps
prevent inadvertent trauma to the colon or spleen during
instrument insertion. Then, the lienorenal ligament is
incised inferosuperiorly approximately 1 cm from the spleen
(Fig. 74-4). The dissection is carried up to the diaphragm and
stopped when the short gastric vessels are encountered posteriorly behind the stomach. This maneuver allows the spleen
to fall medially, thus exposing the retroperitoneal space
(Fig. 74-5). The lateral edge and anterior portion of the adrenal gland become visible in the perinephric fat superiorly
and medially. If necessary, a fourth 5-mm trocar is inserted
dorsally at the costovertebral angle to gently retract largesized spleens and open the space or to push the left kidney
or the surrounding fat downward to better expose the inferior pole and lateral edge of the adrenal gland. This trocar
should always be inserted after the previous three because
the splenorenalligament must be opened first, so the trocar
can pass over the lateral and superior borders of the kidney.
This port, however, is usually not necessary in patients with
a normal-sized spleen. Laparoscopic ultrasound may be
used as an adjunct to identify the adrenal gland, the mass
within the gland, and the adrenal vein.' The dissection ofthe
adrenal gland can be easy or difficult, depending on the type
of perinephric fat that is present. 1\\'0 types of fat are encountered: (1) the soft, nonadherent, areolar fat that is easy to
dissect; and (2) dense, adherent fat that contains multiple small
Table flex
point
Bean
bag
Scope--4e
Grasper
Endoshear
Retractor
..--.."....-.>,---lIiac crest
FIGURE 74-2. Upper, Positioning of the patient for left laparoscopic adrenalectomy. Lower, Trocar sites for left laparoscopic
adrenalectomy.
veins originating from the retroperitoneum. To avoid fracture

of the adrenal capsule, it is helpful to leave a little periadrenal fat on the adrenal, so that this tissue, rather than the
adrenal itself, is retracted. Grasping the perinephric fat, the
surgeon dissects the lateral and anterior part of the adrenal
gland. Hook electrocautery or ultrasonic scalpel is a useful
FIGURE 74-3. Dissection of the splenic flexure.
FIGURE 74-4. Dissection of the lienorenal ligament and splenic

mobilization.
instrument for this phase of dissection. Once the lateral

portion of the adrenal gland has been exposed, the patient is
moved to the Fowler's position to permit further downward
migration of the bowel loops and the spleen. Any saline irrigation, bleeding, or oozing flows downward away from the
area of the dissection. The dissection can be continued either
inferiorly, so that the left adrenal vein can be clipped early
in the dissection or start superiorly and go down medially
to clip the adrenal vein last. The dissection depends on the
exposure gained after the spleen has been mobilized, the
type of disease, and the size of the adrenal mass. In large
adrenals (>5 em), the left adrenal vein may be difficult to
visualize. In such cases, dissecting the lateral and superior
adrenal poles first allows better mobilization and makes
clipping the adrenal vein easier later during the dissection.
In smaller adrenals 5 em), it is feasible and easy to dissect
and clip the adrenal vein. Most left adrenal veins are about
10 mm in diameter and can be clipped with medium to large
FIGURE 74-6. Control of the left adrenal vein.
titanium clips placed with a clip applier. With a right-angled

dissector, the adrenal vein is dissected from its insertion into
the left adrenal gland. It is not necessary to identify and
dissect the origin of the vein from the left renal vein. The
adrenal vein is clipped about 1 cm from the renal vein: two
clips are placed proximally to the gland and two are positioned distally (Fig. 74-6). The vein is then divided with
laparoscopic straight scissors. At this point, adrenal mobilization becomes easy. It is grasped on the perinephric fat
with the left-hand grasper and pushed upward and laterally
to permit dissection of the medial and superior portions.
This dissection is accomplished with hook cautery or ultrasonic scalpel. The inferior phrenic arterial branches often
require ligation as they approach the superior pole of the left
adrenal gland. Once the adrenal gland is free, hemostasis
is verified by repeated irrigation and aspiration. The gland is
then extracted in total after it is placed in an appropriately
sized impermeable nylon bag. The bag is removed through
the most anterior trocar by spreading the abdominal wall
musculature using a Kelly clamp. The incision may have to
be enlarged to remove large specimens (>4 to 5 em) without
rupturing the bag. Drainage is seldom necessary unless pancreatic injury is suspected. All fascial incisions are closed
with 2-0 absorbable sutures, and skin incisions are closed
with 4-0 subcuticular absorbable sutures.
which seldom needs to be mobilized. The third trocar is then

inserted into the most anterior position of the subcostal area
between the epigastrium and the anterior axillary line. This
most medial trocar should be lateral to the edge of the ipsilateral rectus muscle.
The last trocar is introduced at the costovertebral subcostal
angle after the peritoneal reflection of the lateral edge of the
right kidney has been dissected to avoid injury to the right
kidney. Four trocars are necessary because the right lobe of
the liver must be retracted to expose the most medial aspect
of the right adrenal gland (Fig. 74-7). It is, therefore, crucial
that the liver retractor be inserted under direct vision,
through the most anterior port, so that the right hepatic lobe
can be lifted and pushed anteromedially. The laparoscope is
removed from the first placed trocar and inserted in the
second one, and the surgeon works with the two most lateral
trocars. The camera can also be positioned dorsally, and the
surgeon works with the two trocars in the middle to obtain
another view of the dissection field. This is especially useful
for dissecting the superior aspect of the adrenal gland. The
liver often must be mobilized to obtain the best exposure of
the junction between the adrenal gland and the inferior vena
cava (Fig. 74-8). The right lateral hepatic attachments and
the triangular ligament are therefore dissected from the
diaphragm using laparoscopic scissors or an ultrasonic
scalpel. This dissection permits more effective retraction to
push the liver medially using a fan or some other atraumatic
retractor. This is the key for providing adequate exposure of
the right adrenal vein and its entry into the vena cava. We
prefer to create a right-angled plane between the anterior
aspect of the right kidney and lateral portion of the liver.
This plane provides enough space to work and adequate
exposure in case of bleeding. Laparoscopic ultrasound may
Transabdominal Laparoscopic
Right Adrenalectomy
Patients are positioned in the lateral decubitus position with
their right side up. Pneumoperitoneum is established in the
same way as for left adrenalectomy. An open technique is
used to access the abdominal cavity approximately 2 em
below and parallel to the costal margin. A lO-mm trocar is
inserted at this site for the 3D-degree angled laparoscope.
Inspection of the abdominal cavity is carried out. Under direct
vision, three additional lO-mm trocars are inserted 2 em
below and parallel to the costal margin. The second trocar is
positioned in the right flank, inferior and posterior to the tip
of the 11th rib just above the hepatic flexure of the colon,
FIGURE 74-7. Trocar sites for laparoscopic right adrenalectomy.
652 - -
Adrenal Gland
---:--+"""T'iiJ;-\!-- Stomach
Inferior
phrenic vein
Adrenal vein
Hepatic
flexure
~~~~e!~~~-Adrenal
artery
Kidney--+-_
FIGURE 74-8.
be of assistance in identifying the anatomy. The right gland

is dissected next. If the mass is smaller than 4 em in diameter, gaining access to the right adrenal vein initially is possible, which permits easier dissection of the rest of the adrenal
gland. The inferolateral edge is mobilized, and dissection is
continued medially and upward, along the lateral edge of the
vena cava. The adrenal vein should be seen at this stage.
This vein is often short and sometimes broad. Usually, the
vein can be clipped with medium to large titanium clips,
and at least two should be applied at the vena cava side
(see Fig. 74-8). If there is not enough space for clips, then a
vascular cartridge of a 30- or 35-mm laparoscopic stapler is
used for secure division of the right adrenal vein. Smaller
veins may be encountered superiorly; these should be
clipped or cauterized to prevent bleeding. The superior pole
of the gland is dissected next, and small branches from the
inferior phrenic vessels can be clipped or cauterized with a
hook cautery or ultrasonic scalpel. Again, a Fowler's position permits all fluids to migrate downward. The lateral
border of the gland is then dissected from the perinephric fat
using the same instruments. Meticulous dissection close to
the gland prevents tearing of the lateral branches of the vena
cava and other vessels from the retroperitoneum. If a large
mass is encountered, we prefer to dissect laterally and
superiorly first and then move down along the vena cava to
reach the adrenal vein. Once the mass has been dissected
free, it is placed in impermeable nylon bag and removed
through the most anterior trocar site. All wounds are closed
as described for the left side. The fascia of the fourth
(dorsal) trocar site is not closed because of the depth of this
wound.
Retroperitoneal Endoscopic Adrenalectomy

The retroperitoneal endoscopic approach has been advocated
by a few laparoscopic surgeons.I'"!? The main advantage of
this approach is that adrenal resection can be performed in
a patient with intra-abdominal adhesions due to previous
surgery. In our experience, it is rare that conversion to open
procedure is required due to adhesions.' Another theoretical
benefit of this approach is decreased physiologic impact on
the cardiovascular and respiratory systems. However, the
initial concerns over hypercarbia and other hypothetical
detrimental effects were not supported in a study comparing
both approaches." The main drawback is the quite small
operative field, usually restricting this approach to small
glands of less than 5 to 6 em in diameter. This limited field
and exposure can also be a major disadvantage in case of
Laparoscopic Adrenalectomy - -
vascular injury, making control and repair more difficult

than in the transabdominal approach. Other disadvantages
include the lack of anatomic landmarks and the inability
to explore the abdominal cavity, particularly the liver.
The retroperitoneal approach can be performed in two ways.
Lateral Decubitus Approach. The positioning of the
patient is the same as for the lateral transabdominal
approach. Creation of the retroperitoneal space is commonly
done with disposable dissection balloons, and the peritoneal
sac should be mobilized to prevent perforation of the peritoneum and injury to viscera. The trocars are inserted after
creation of the space and are close to the costal margin,
Prone Jackknife Approach. This approach is essentially the same as the former one, except for the positioning
of the patient. The patient is placed in the prone position,
with moderately flexed hips and the arms extended cephalad.
The advantage of this technique is that it is not necessary to
change the patient position for bilateral exploration, theoretically allowing a shorter operative time. However, rapid
conversion to open surgery for bleeding is difficult in this
position.
Transabdominal Anterior
The transabdominal anterior laparoscopic approach can be
a lengthy procedure owing to the difficult dissection of the
splenic flexure, spleen, and the pancreatic tail on the left
side and the duodenum on the right. In addition, on the right
side, the adrenal vein, found posteriorly to the vena cava, is
difficult to dissect and control. Although in bilateral adrenalectomy it is not necessary to change the position of the
patient, the average operating time is similar to the lateral
transabdominal approach. Because of its drawbacks, most
surgeons have abandoned this approach.
Bilateral Laparoscopic Adrenalectomy

The indications for bilateral laparoscopic adrenalectomy
include the following":
1. Cushing's disease refractory to transsphenoidal pituitary resection and/or irradiation
2. Cushing's syndrome due to ACTH-independent
macronodular or micronodular adrenal hyperplasia
3. Ectopic ACTH syndrome, when the primary tumor
cannot be resected or medical treatment has failed
4, Conn's syndrome caused by bilateral adrenal adenomas
5. Bilateral pheochromocytoma
Other less prevalent relative and possible indications
include (1) unilateral pheochromocytoma in multiple
endocrine neoplasia (MEN) type 2A, due to the fact that in
50% of cases a metachronous lesion develop in the contralateral side within lO years of resection of the affected side/";
(2) idiopathic hyperaldosteronism caused by bilateral symmetrical adrenal hyperplasia refractory to medical treatment;
and (3) congenital bilateral adrenal hyperplasia, which is difficult to manage medically.'?
There are several possible surgical approaches for bilateral
laparoscopic adrenalectomy.
Transabdominal Lateral Approach. The transabdominallateral approach is the preferred approach in our opinion.
653
The patient is placed in the lateral decubitus position; usually

the left side is operated first because it is easier. After
all trocar sites are closed, the patient is repositioned and
redraped to expose the right side. A 15- to 20-minute
turnover time is necessary, not significantly adding to the
operative time.' We prefer this bilateral approach, because
gravity aids the dissection when the patient is in the lateral
decubitus position and it offers a wide operative field and
better control of blood vessels. Furthermore, it may be safer
than the retroperitoneal approach for the right adrenal,
where a better control of a possible major vascular injury
(i.e., vena cava) is needed. We have successfully performed
bilateral laparoscopic adrenalectomy within a reasonable
period using a bilateral lateral technique.' Using this
approach, Chapuis and associates," with the largest published
series on bilaterallaparoscopic adrenalectomy in 24 patients
with Cushing's syndrome, reported no major postoperative
complications, The operative lengths have ranged from
243 to 386 minutes for the reported bilateral procedures
using this approach.
Retroperitoneal Approach. This can be accomplished
using the lateral or the posterior methods described earlier.
The few series with data on bilaterallaparoscopic lateral and
posterior retroperitoneal approaches have not shown greater
hypercarbia than with the lateral transabdominal approach. 22-24
Anterior Approach. Despite its theoretical advantage in
bilateral adrenalectomy, the drawbacks regarding difficulty
in exposure and dissection have led most surgeons to abandon
this approach.
No randomized, prospective studies have been conducted
to compare laparoscopic bilateral adrenalectomy with open
bilateral surgery. However, the available literature on bilateral laparoscopic adrenalectomy is encouraging, with low
morbidity and mortality rates. 1,3,2 I,22.25,26 In the setting of
Cushing's syndrome, the morbidity and mortality rates of
the laparoscopic approach are noticeably lower than for
open surgery. 1,3,21,22 The typical operative length for bilateral
laparoscopic adrenalectomy, including all approaches, is
approximately 300 minutes. 19 There have been some reports
of operative times longer than 300 minutes with cases of
hypercarbia requiring hyperventilation but without significant sequelae.F" Fernandez-Cruz and colleagues27,28 have
recommended helium pneumoperitoneum for the bilateral
laparotomy procedure to prevent carbon dioxide retention
and acidosis. The use of helium is strongly recommended by
this group, especially in patients with pheochromocytoma
with previous cardiovascular or respiratory disorders.P
Laparoscopic Partial Adrenalectomy

Possible indications for adrenal-sparing surgery include
bilateral pheochromocytoma and well-circumscribed bilateral cortisol or aldosterone-producing adenomas. The purpose is to avoid life-long cortisol replacement therapy." The
operative technique involves basically the same initial steps
as for total adrenalectomy. After exposing the adrenal glands,
dissection is first performed at the inferior borders and
then carried upward along the lateral aspect using a hook
cautery or ultrasonic scalpel and a gentle grasping forceps.
Ultrasound of the gland is then performed using a flexible
7.5-MHz, lO-mm diameter probe to demonstrate the location
654 - -
Adrenal Gland
of the adrenal vein and the arterial supply and to confirm the
location and borders of the adrenal lesion. At this stage, the
adrenal lesion can be easily dissected free and elevated.
While concomitantly displaying the margins of the tumor
with the ultrasound, the harmonic shears are used to bloodlessly transect the adrenal gland away from the lesion. The
excised specimen is then placed in a bag, retrieved, and sent
for immediate histopathologic examination to confirm
histology and assess the margins. At least a 5-mm rim of
normal adrenal tissue is preferred.
Needlescopic Adrenalectomy
The availability of 2-mm instrumentation and camera technology has triggered the emergence of needlescopic surgery.
The rationale behind this technique is to further minimize
the abdominal wall trauma, and hence speed the convalescence and improve cosmesis. The positioning of the patient
and the number of trocars are similar to the traditional laparoscopic adrenalectomy. A 10 to l2-mm trocar is inserted into
the superior aspect of the umbilicus to accommodate the
10-mm angled scope, under which most of the procedure is
conducted. It also enables the use of larger instruments
should they be required (e.g., vascular endostapler) and the
retrieval of the specimen. During these steps, the procedure
is monitored through the 2-mm needlescope. In the left side,
two additional trocars of 2- and 5-mm are used, and in the
right side, a fourth 2-mm trocar is used for liver retraction.
Placement of the 2-mm ports does not require skin incisions.
These ports can be readily inserted through a needle-like
puncture. Thus, at the end of the procedure, these miniature
puncture sites require no skin closure, except for Steristrips.
The 5-mm port is used by the surgeon's dominant hand to
accommodate larger instruments such as scissors, electrocautery, suction-irrigation devices, and clip appliers.
Dissection is carried out using 2-mm graspers, scissors, and
hook electrocautery, and vascular control is achieved
with electrocautery (unipolar or bipolar) and a 5-mm clip
applier.
Postoperative Care
Oral fluids are started on the day of surgery. Nasogastric
tubes are unnecessary for most patients. If a Jackson-Pratt
drain has been inserted at surgery, it is removed the next
morning. Oral analgesics are provided to help patients tolerate the postoperative pain. However, during the first 12 hours,
some patients require parenteral analgesia. The postoperative
course is similar to that for laparoscopic cholecystectomy,
except that some endocrine disorders necessitate hormonal
support and additional clinical laboratory data. Unexplained
hypotension, fever, and confusion may be due to acute
adrenocortical insufficiency. These patients should have
blood drawn to determine cortisol levels and be immediately
treated with 100 mg of hydrocortisone intravenously. Most
patients are ambulatory by the evening of the procedure, and
most are allowed to leave by the third postoperative day.
However, discharge may be delayed in patients who require
substantial hormonal support or adjustments of antihypertensive medications.
Outcome
Since its advent in 1992, laparoscopic adrenalectomy has
gained worldwide acceptance, with a rapidly increasing numbers of reports being published in recent years. In a search
of the literature, we were able to retrieve more than 500 articles dealing with laparoscopic adrenalectomy. Table 74-1
summarizes the reported results of selected large series of
laparoscopic adrenalectomies performed with different
laparoscopic techniques. Although no prospective, randomized series exist, numerous studies have compared laparoscopic with open adrenalectomy (either retrospectively or
nonrandomized prospectively), documenting the safety,
decreased analgesic postoperative requirements, enhanced
recovery, shorter hospital stay, and cost-effectiveness of the
laparoscopic approach. 4-8,24.30-39 No differences in patient
population, indications for surgery, or mean size of lesions
were noticed. Our own experience, presented here, with
100 procedures in 88 patients.' further supports the superiority
of this procedure.
Table 74-2 lists the indications and pathology for our procedures. The overall mean age was 46 years (range, 17 to
84 years), and the ratio of female to male was slightly higher
than 2: 1, Fifty-two of the adrenalectomies were performed
in the left, and 10 were performed bilaterally, The mean
operating time was 132 minutes (range, 80 to 360 minutes).
In our initial experience, a right-sided procedure required an
average of 138 minutes compared with 102 minutes for a
left-sided procedure. However, review of the last 30 cases
showed the time required for both sides is essentially equal.
The time required for bilateral adrenalectomy averaged
approximately 45 minutes longer than the combined averages for the unilateral procedure alone. The indications for
bilateral adrenalectomy are listed in Table 74-3. The average
length of stay was 2.4 days (range, 1 to 6 days), and the
average size of the lesions was 4.95 cm (range, 0,7 to
12 em), The estimated intraoperative blood loss was approximately 70 ml., and the mean number of postoperative
narcotic injections was 5.5.
Complications
Conversion to open surgery was necessary in three patients
(3%). These conversions occurred in our first attempt at
laparoscopic adrenalectomy in a patient with a l5-cm right
adrenal angiomyolipoma, in a second patient with a locally
invasive retroperitoneal sarcoma, and in a third patient
with adrenal adenocarcinoma invading into the inferior
vena cava,
More than half of our patient population (55%) had
undergone previous abdominal surgery. We have not viewed
this as a contraindication for laparoscopic approach, and no
conversions occurred because of adhesions. We performed
one procedure 6 weeks after a laparotomy that failed to find
the adenoma. In addition, 20 of the 88 patients underwent
other associated laparoscopic procedures at the time of their
adrenalectomy. These are listed in Table 74-4.
Of the 100 procedures, 12% had postoperative complications, which are listed in Table 74-5.
Reoperation within 30 days of surgery was required on
two occasions (2%) for evacuation of a retroperitoneal
hematoma in a patient who had been anticoagulated for mitral

valve prosthesis and for postoperative acute cholecystitis in
the second case. These procedures were accomplished laparoscopically with uneventful recovery thereafter. There have
been no wound complications, and there was no mortality.
Additional reported complications may result from injury
to structures in the area of dissection, adjacent to the adrenals, including the kidney, colon, tail of the pancreas, and the
stomach on the left side. On the right side, the liver and the
duodenum are at risk.
Because both adrenals are located in close proximity to

major blood vessels (the hilum of kidneys and the vena cava),
massive bleeding is a potentially disastrous complication.
Furthermore, dissection high in the abdomen could result
in diaphragmatic injury, leading to potential tension
pneumothorax. A multi-institutional study by Terachi and
associates from Japan evaluated 370 patients who underwent laparoscopic adrenalectomy" There was no mortality.
Overall complications developed in 57 patients (15%),
intraoperative in 33 patients (9%) and postoperative in
24 patients (6%). Conversion to open surgery was necessary
in 13 cases (3.5%). The 33 intraoperative complications
involved vascular injury in 22 patients (5.9%) and visceral
injury in 11 patients (3%). The 22 vascular injuries involved
injuries to the vena cava in 2 patients, renal vein in
2 patients, adrenal vein in 4 patients, other adrenal vessels in
11 patients, and other vessels in an additional 3 patients. The
11 visceral injuries included the liver in 4 patients, spleen in 3,
pancreas in 2, gallbladder in 1, and adrenal gland in 1. The

24 postoperative complications involved bleeding in
6 patients, wound infection in 4, atelectasis in 3, ileus in 2,
pneumothorax in 1, and other in 8. Most complications were
minor and were treated laparoscopically. Henry and coworkers reported the complications of laparoscopic adrenalectomy
in 169 consecutive procedures." There was no mortality.
Twelve patients (7.5%) had significant complications: three
peritoneal hematomas requiring (in two cases) laparotomy,
and (in one case) transfusion; one parietal hematoma; three
intraoperative bleeding episodes without need for transfusion; one partial infarction of the spleen; one pneumothorax;
one tumor disruption; and two venous thromboses. Another
large multi-institutional study from France'? reported a similar complication rate of7.7% occurring in 10 patients out of
130 cases of laparoscopic adrenalectomy. Neither this study,
nor others,40,43-45 has found significant differences between
transperitoneal and retroperitoneal approaches, except for
the risk of the intraperitoneal visceral injury.
PHEOCHROMOCYTOMA
Pheochromocytoma constituted 25% of the pathologies in

our series. These tumors were larger than in patients with
other diseases (6.3 vs. 3.9 em [P < 0.05]). In addition, operative time was longer (2.5 vs. 1.8 hours [P < 0.05]). During
the removal of these tumors, hypertension occurred in 56%
of patients and hypotension in 52%. Moreover, 7 of 12
(",,60%) of our postoperative complications were observed in
this subset. Associated MEN 2A syndrome was identified in
six patients and MEN 2B was found in two patients. Several
studies have addressed the issue of hemodynamic changes
during laparoscopic adrenalectomy for pheochromocytoma

compared to open surgery.46-48 The laparoscopic approach has
resulted in less" or comparable'<" hemodynamic changes
compared to the traditional open surgery, although patients
who underwent laparoscopy had a more rapid postoperative
recovery. The retroperitoneal approach seems to offer no
advantage over the intraperitoneal approach," and carbon
dioxide pneumoperitoneum is well tolerated in this subset of
patients.f In a literature review of large series of more than
300 laparoscopic adrenalectomies exclusively for pheochromocytoma, no mortality has been reported to date. 28,48.50-61
These cases included familial multiple endocrine hyperplasia syndromes, bilateral pheochromocytoma, and extraadrenal pheochromocytoma. Both transperitoneal and
extraperitoneal approaches were used. Although earlier
experience was associated with more blood loss, longer operative time, and more complication rate compared to other
pathologies.v-" the more recent large series demonstrated
no significant difference. The occurrence of hypertension
postoperatively is rare, and hypertension was cured in almost
all patients.
OTHER HORMONE-SECRETING TUMORS
With regard to the functional outcome in other hormonally

active tumors, during our follow-up period (range, 1 to
44 months), patients appear to have responded well to
laparoscopic adrenalectomy. Two were found to have renovascular hypertension, and none had hormonal recurrence.
The renal arteriograms showed no stenosis and, in addition,
excluded the possibility of superior arteriolar renal occlusions by metal clips. One patient operated on for Cushing's
disease who had a partial response to ACTH stimulation,
however, still had serum cortisone levels below the normal
range by the end of the follow-up period. Other authors52.62-65
have uniformly reported excellent results comparable with
those of open surgery. The Mayo Clinic group reported
bilateral laparoscopic adrenalectomy in 19 patients with
ACTH-dependent Cushing's syndrome in whom the ACTHsecreting neoplasm could not be removed.f All patients
experienced resolution of the signs and symptoms of
Cushing's syndrome as well as weight loss, improved
glucose tolerance, and improved control of blood pressure.
No residual cortisone secretion was detected. Similar success
rates were reported by others in more than 100 cases with
Cushing's disease and syndrome.21.22.25 Rossi and associates'" reported the effectiveness of laparoscopic adrenalectomy in 30 patients with primary hyperaldosteronism.
Twenty-nine of 30 patients (95%) were rendered
normokalemic, and persisting hypertension was present in
10 of 30 patients (33%). In these patients, the hypertension
was easily controlled medically. Duration of the hypertension before surgery was a significant risk factor for persistent hypertension. Several other articles specifically focusing
on laparoscopic adrenalectomy for aldosteronoma revealed
that hypertension was cured or significantly improved in
greater than 90% of patients.64.66.67 In a recent study by
Brunt and colleagues'? involving 72 patients with hormonally active adrenal tumors, laparoscopic adrenalectomy
resulted in an excellent clinical outcome. Resolution of
clinical and biochemical signs was accomplished in 34 of
34 patients with pheochromocytoma, 25 of 26 patients with
Laparoscopic Adrenalectomy - -
aldosteronomas, 5 of 5 patients with cortisol-producing

adenomas, and 3 of 3 patients with ACTH-dependent
Cushing's syndrome. Two patients with MEN 2 had contralateral pheochromocytomas removed 4 and 5 years after the
initial surgery. Surprisingly, persistent hypertension necessitating medications was present in 72% of patients with aldosteronomas, although 92% of these patients had significantly
improved blood pressure control after surgery. Recurrent
hypokalemia developed in 1 patient (4%) with a cortical
nodule in the contralateral adrenal. The authors concluded'?
that the clinical and biochemical cure rates are comparable
with those of open adrenalectomy during long-term follow-up.
Outcome for Malignancy

Concerning the outcome of laparoscopic adrenalectomy in
the setting of malignancy, 8 of our patients had malignant
diseases. Six had primary adrenal cancer (3 pheochromocytomas and 3 nonfunctioning tumors that showed microscopic features of carcinoma), and 2 had metastatic adrenal
secondaries. None had evidence of local recurrence during
follow-up (range, 1 to 44 months). Laparoscopic adrenalectomy for solitary adrenal metastasis or cancer has also been
investigated at few centers, and to date, very few references
are available in the literature. The experience from the
Cleveland Clinic in 11 patients was reported by Heniford
and coworkers.f All of the tumors except one were due to
metastatic cancer. The metastatic sources included renal cell
cancer, lung cancer, colon cancer, and melanoma. The mean
size of the tumors was 5.9 em (range, 1.9 to 12 em), One
patient required conversion to open surgery due to local
invasion of the tumor into the vena cava. At a mean followup of 8.3 months, there were no port site or local recurrences. One patient developed a new hepatic nodule, 10 of
the 11 patients were alive by the time of the report, and
I died of extensive brain metastasis from melanoma. Valeri
and associates'? addressed the same issue of adrenal masses
in 8 patients with primary lung cancer (7 patients) and renal
cancer (1 patient). The adrenal lesions appeared during
follow-up evaluation or at the time of diagnosis of the
primary malignancy. All patients underwent laparoscopic
adrenalectomy with complete removal of the lesions.
Histology confirmed the metastatic origin in 6 patients,
and 2 lesions proved to be nonfunctioning adenomas.
Three patients died later of brain metastasis, accounting for
a 3-year survival rate of 63%. The authors claimed that
laparoscopic adrenalectomy allows for a much more aggressive approach to adrenal masses demonstrated at follow-up
evaluation in patients with primary lung or kidney cancer
with no evidence of masses at other locations. Two other
reports on laparoscopic adrenalectomy for large (>6 em) and
potentially malignant tumors were recently published and
documented favorable outcome. 69 70 In the study by Henry
and associates.s? out of 6 patients with adrenocortical carcinoma, only 1 patient developed liver metastasis and died
6 months after surgery. The other 5 patients were disease
free during a follow-up period ranging from 8 to 83 months.
The largest series with the longest follow-up to date was
recently published by Kebebew and colleagues." It included
23 patients who had a laparoscopic approach for suspected
and unsuspected malignant adrenal tumors. Six of the
657
patients had primary adrenal cancers, 13 had adrenal metastasis, 2 had lymphomas, and 2 cases had no evidence of
cancer. The tumor resection margin was negative in all
adrenalectomies. There were three locoregional recurrences
in the 6 patients with primary adrenal cancer and no port site
recurrences. There were four distant recurrences in 13 patients
with metastatic adrenal tumors. The disease-free survival
was 65% at a mean follow-up period of 3.3 years (range, 1
to 7 years). These results were comparable with the known
results for conventional surgery.P In all these studies, no major
complications occurred. Conversions were required only in
patients with intraoperative evidence of tumor invasion. The
laparoscopic removal achieved tumor-free resection margins
in all patients, and no port site metastasis was reported.
Laparoscopic Ultrasound
We used laparoscopic ultrasonography in 15 selected cases.
In 1 patient it showed the location of a 0.7-cm aldosteronoma
in an adrenal gland after open surgery failed to find the
organ. In 2 patients, no adenoma was found, necessitating only
biopsy and closure rather than adrenalectomy. In 2 patients
with large masses (10 and 12 em), no extra-adrenal or lymph
node involvement was found. The masses were completely
removed laparoscopically and proved to be histologically
benign. In I patient, vascular invasion of an adrenal adenocarcinoma was found, leading to conversion to successful
open resection. In I patient with metastatic cancer, the invasion of periadrenal fat was demonstrated, and the lesion was
removed with negative margins. In an additional 2 cases, it
helped identify the right adrenal vein, which facilitated dissection and control. Finally, bilateral hyperplasia was found
in another case, requiring bilateral adrenalectomy.
Other groups reported similar results using laparoscopic
ultrasonography in adrenalectomy.P'?" Brunt and associates?"
used it in 27 patients and concluded that laparoscopic
ultrasound provided useful information to the surgeon in
11 of 28 procedures (39%) by (1) localizing the adrenal
gland and tumor and/or guiding the dissection, (2) demonstrating that tumors larger than 4 em were confined to the gland,
and (3) investigating suspected pathology in other organs.
Mean time for ultrasound was 10.9 minutes, and calculated
hospital charges were $602. There were no intraoperative
complications. Siperstein and colleagues75 found that it
helped in identifying small tumors in obese patients operated
on through the posterior approach. Especially in patients
with nodular hyperplasia, laparoscopic ultrasound enabled
the complete excision of all lesions by demonstrating the
absence or presence of residual tumor tissue in the adrenal
bed after resection." Thus, the information obtained from
ultrasonography in many instances can affect the progression of the operation. It is a simple technique that can be
easily mastered.
Discussion
More than a decade after the advent of laparoscopic adrenalectomy, the worldwide accumulated experience indicates that the
procedure is safe and successful, and it is now considered an
658 - -
Adrenal Gland
established and preferred treatment for most endocrine and

neoplastic disorders affecting the adrenal gland.
Comparison with Open Adrenalectomy

The results of laparoscopic adrenalectomy must be compared
with those of conventional open surgery. There are no
prospective, randomized studies comparing open with
laparoscopic adrenalectomy. The excellent results, reported
in the available retrospective comparative studies, make such
research unnecessary and possibly unethical. In our own
retrospective, comparative analysis.' we have found no difference in operating time or dimensions of the adrenal gland.
The estimated blood loss was 70 mL for the laparoscopic
adrenalectomy versus 200 mL for the open adrenalectomy.
The mean hospital stay for the laparoscopic surgery was 3
versus 9 days for the open group. The analgesia requirements
and the mean time for ambulation were also significantly
lower in the laparoscopic group. Other studies have reported
similar outcomes. 4-8. 24,30-39 The Cleveland Clinic retrospective comparison of 110 laparoscopic and 100 open adrenalectomies showed the superior results of the laparoscopic
approach." Open adrenalectomy was performed by various
standard approaches. The laparoscopic group was superior in
surgical time, blood loss, narcotic analgesic requirements,
intensive care unit admissions, resumption of oral fluid
intake, and mean hospital stay. Although intraoperative
complication rate was similar, there were fewer postoperative
complications in the laparoscopic group. Of special interest
is the study by Thompson and coworkers" from the Mayo
Clinic, who compared the laparoscopic transabdominal
laparoscopic approach in 50 patients with the open posterior
approach in 50 well-matched patients. In addition to the
other reported advantages of laparoscopy, late incision neuromuscular complications developed in 54% of the open
group, chronic pain syndrome in 14%, and flank numbness
in 10%. A recent meta-analysis of the English literature by
Brunt" compared the complications of laparoscopic with open
adrenalectomy. Complications were tabulated from 50 studies
of laparoscopic adrenalectomy involving 1522 patients and
48 studies of open adrenalectomy comprising 2273 patients.
Among the reports, 22 compared laparoscopic with open
adrenalectomy from within a single institution. They concluded that laparoscopic adrenalectomy resulted in fewer
adrenalectomy-related complications than those seen historically with open adrenalectomy. Fewer wound and pulmonary
complications and fewer incidental splenectomies are the
primary reasons for this improved outcome. Finally, another
variable of concern, addressed by several authors, is the cost
of the procedure compared with that of open surgery.5,6,8,31,38
Although Thompson and coworkers" found higher costs
with the laparoscopic procedure, most other reports found
no significant difference in overall cost between the two
approaches. However, the earlier return to work in patients
undergoing laparoscopic adrenalectomy would be associated with lower costs if is taken into consideration.
Choices of Approach
The technique of choice by most surgeons performing
laparoscopic adrenalectomy is the transabdominal lateral
approach. Several authors have successfully documented

the feasibility, safety, and effectiveness of endoscopic adrenalectomy via the retroperitoneal approach in tumors less than
5 to 6 cm. 14,15.17,78,79 Since the peritoneum is not violated and
the bowel is not mobilized with the retroperitoneal approach,
it was postulated to be less invasive and lead to better results,
especially in small lesions and in obese patients. 17,24
Siperstein and associates.P in a series of 31 patients, concluded that although more demanding, the retroperitoneal
approach should be considered in patients with tumors less
than 6 em, bilateral tumors, or extensive previous abdominal
surgery. In another large series from the Netherlands, the procedure was described in 111 consecutive cases and showed
comparative results with the transabdominal approach.I''
These authors recommended the procedure for benign adrenal
tumors less than 6 em. Nevertheless, case history analysis has
revealed no apparent difference in patient outcome, morbidity, or operative time for the two approaches. 14.15,44A5,8o
Moreover, in our experience and the experience of others,"
the transperitoneal approach has not caused bowel injury or
other complications. Comparison between the two techniques
has in fact indicated no real difference for small tumors,
although for lesions larger than 5 to 6 cm, the transabdominal
route is considered preferable." Disadvantages of the
retroperitoneal approach include a lack of anatomic landmarks and a restricted working space. This combination of
technical difficulties renders the retroperitoneal approach
unsuitable for tumors larger than 6 em. On the other hand, a
major advantage of the transperitoneal approach is that the
abdominal cavity, and particularly the liver, can be explored.
In patients with pheochromocytoma, the liver can be examined by inspection and ultrasound and suspicious lesions may
be biopsied. Moreover, in our personal experience with the
retroperitoneal approach, the exposure was inferior to that
obtained via the transperitoneal approach.
Contraindications to
MALIGNANCY
The available data suggest that there are few absolute contraindications for laparoscopic adrenalectomy. We consider
invasive adrenal carcinoma to be the only absolute contraindication for the laparoscopic approach owing to the
possible extent and complexity of the operation required.
An open technique also may be more desirable for patients
with malignant pheochromocytoma when metastatic nodes
are present in the periaortic chain or close to the bladder.
Several authors differentiate between the biologic behavior
of adrenal metastasis and primary adrenal cancer as to their
suitability for the laparoscopic procedure.l':" Because solitary adrenal metastasis from an extra-adrenal primary is
usually small and confined within the adrenal, the laparoscopic approach has considerable appeal for this specific
indication.>' Conversely, adrenal cancer is usually larger and
often locally invasive. An important limitation in this regard
is that adrenal imaging and even fine-needle aspiration are
often inaccurate to diagnose or exclude adrenal malignancy." Since no reliable and accurate preoperative diagnostic test to diagnose adrenal malignancy exists, it is difficult to
determine when an open approach should be used. An initial
laparoscopic approach can be used to establish the diagnosis

with low morbidity and allows curative resection in most
instances." Laparoscopic ultrasound is a simple and effective intraoperative technical adjunct that may be used to
evaluate the nature and invasiveness of the suspected adrenal
mass. Obviously, in patients who prove to have local invasion
during surgery, the laparoscopic approach should be converted
to an open procedure to allow curative, wide, radical resection.
The limited experience to date with laparoscopic adrenalectomy in malignant disease is promising, with short-term
results comparable with those of conventional surgery.69,71
Thus, it appears that a laparoscopic approach is reasonable
for metastatic adrenal disease, provided the primary cancer
is controlled and there is no evidence of extra-adrenal
disease. Similarly, for primary neoplasms, if complete
resection is technically feasible and there is no evidence
of local invasion, an initial laparoscopic approach is an
acceptable option in experienced hands at selected
centers. 51,69,71
SIZE
The maximal acceptable size of a lesion appropriate for

laparoscopic adrenalectomy is another unsettled issue.
Although size per se is not a definite contraindication,
laparoscopy is not advisable for masses larger than 12 to
14 em because of the increased incidence of malignancy
and the technical difficulties associated with their removal.
The largest lesion that we have resected was 14 em, but such
a mass makes the dissection difficult and time consuming.
The exposure also is problematic because of the limited
space available in this area, Large masses frequently have
unusual and numerous retroperitoneal feeding vessels that
require tedious and lengthy dissection. Only surgeons with
extensive laparoscopic experience should attempt resection
of larger adrenal masses. Generally, the indications and contraindications for laparoscopic adrenalectomy, including the
maximal size limit and other issues, are dictated largely by
the experience of the individual surgeon.
Incidentaloma
Management of incidentally discovered adrenal masses is
still controversial. Although adrenocortical carcinomas are
usually larger than 6 em, incidentally detected cancers 3 to
5 em or even smaller have been reported.51.82 Another confounding factor is that CT scanning underestimates by 20%
to 40% adrenal tumor size compared with actual size on
histopathology, 82 Definite indications for adrenalectomy
include sizes larger than 4 cm, hormonally active lesions, suspicious characteristics on imaging studies, and documented
increase in size. Because of the excellent results of the
laparoscopic procedure, we and others" prefer laparoscopic
adrenalectomy instead of observation for the young and
low operative risk patients with 3- to 5-cm adrenal masses.
Another argument against the watchful conservative policy
in such cases is that most adrenal nodules increase in size
with age" and the need for imaging and biochemical testing
continues throughout the patient's life, Moreover, the patient
is spared the anxiety, expense, and time lost from repeated
follow-up appointments and the associated studies
needed.
The New Gold Standard

The accumulated evidence indicates that laparoscopic
adrenalectomy in patients with hormonally active tumors is
the new gold standard. This minimally invasive technique
has become the procedure of choice for hyperaldosteronism,37,63,64 Cushing's syndrome and disease,3,21,22,25,26,62,67
and pheochromocytoma. 20,28,48,50,53,54.58
Bilateral laparoscopic adrenalectomy appears to be safe
and effective in patients with pituitary-dependent Cushing's
syndrome after failed transsphenoidal surgery and in cases
with ectopic ACTH syndrome when the primary tumor
cannot be identified or rernoved.S After initial reluctance
and skepticism, it is now obvious that laparoscopic resection
of pheochromocytomas can be accomplished safely despite
frequent episodes of hemodynamic variability equal to those
of historical open control subjects. The earlier recovery,
fewer complications, and lack of endocrine recurrence make
this approach the procedure of choice for the management
of pheochromocytoma.W? In addition, a recent publication
by Brunt and colleagues'? has reported favorable results in
cases of unilateral and bilateral familial pheochromocytoma
(patients with MEN 2A, MEN 2B, von Hippel-Lindau
disease, and neurofibromatosis type 1). Another large series
from Germany" has documented the successful outcome
of endoscopic approach in 61 chromaffin neoplasms
(52 pheochromocytomas and 9 paragangliomas), The patient
population included a wide spectrum of this disease: unilateral, hereditary, bilateral, recurrent, and multiple tumors.
In patients with bilateral disease, partial bilateral adrenalectomy was performed and achieved preservation of adrenocortical function in 86% of cases, without evidence of
recurrence after 3 years of follow-up. Thus, in patients with
hormonally active tumors of the adrenal, the procedure has
proved feasible and safe and offered all the advantages of
minimally invasive surgery. Additionally, it resulted in an
excellent functional outcome and was associated with clinical
and biochemical cure rates comparable with those of open
surgery during long-term follow_up.3,52,53,55,57,62-64
Recent Advances
Recent advances and innovations in laparoscopic adrenalectomy have been introduced. Outpatient laparoscopic
adrenalectomy has been performed in selected low-risk
patients with small adrenal tumors (mainly hyperaldosteronism, excluding pheochromocytoma) with satisfactory
results. 65,83 To further minimize the morbidity of conventional laparoscopic procedures, needlescopic technique,
using smaller ports, was reported by several groupS.84-86
The limited experience to date with a small number of
patients showed that the procedure was feasible and resulted
in improved wound cosmesis. It decreased postoperative
pain and hospital stay without prolonging operative time."
The continued technologic advances, offering more effective
2-mrn instruments, may convince more surgeons to try this
new technique. Nevertheless, randomized, prospective trials
comparing needlescopic with conventional laparoscopy are
still needed to validate these favorable initial results.
Laparoscopic cortical-sparing surgery in selected patients
with bilateral pheochromocytoma and well-circumscribed
660 - -
Adrenal Gland
bilateral cortisol or aldosterone-producing adenomas 29,59,87-91

has been reported. This approach may be valuable in those
who would otherwise require life-long adrenal replacement
therapy after complete adrenal gland extirpation. It was
also used in patients with unilateral aldosterone-producing
adenomas." Our limited experience" and that of others 87 -91
confirms the technical feasibility and safety of laparoscopic
partial adrenalectomy. The recurrence rate after bilateral
pheochromocytomas in patients with MEN syndromes
approaches 20%.29,90 For this reason, some authors advise
against adrenal-saving surgery in these instances. Intraoperative ultrasound is useful since one cannot rely solely on
the direct laparoscopic view. Whenever tumor and normal
parenchyma cannot be differentiated intraoperatively, total
adrenalectomy becomes unavoidable. Total adrenalectomy is
also undisputed in cases of suspected malignancy. There
have been no studies showing failed adrenal function
because of adrenal vein ligation; however, one should
attempt to preserve the main vein during adrenal-sparing
surgery. In case of severe hypertension during surgery for
pheochromocytoma, it has been suggested to temporarily
occlude the vein with a laparoscopic bulldog clamp."
To preserve cortical response to stress, adrenal-sparing
surgery may be valuable in selected patients. However, large
prospective series with long-term follow-up are required
before drawing definite conclusions.
Other technical advances include the thoracoscopic transdiaphragmatic approach to the adrenal gland." adrenal
cryoablation," and robotic laparoscopic adrenalectomy.'<"
Finally, has the widespread introduction of laparoscopic
adrenalectomy broadened the indications of adrenalectomy
and changed the pattern of referral? Two recent publications 99100 found that the introduction of laparoscopic
adrenalectomy has resulted in an increase in the number of
patients referred and, consequently, more adrenalectomies
are performed. One study showed that the criteria for patient
selection did not change but more patients with adrenal
metastasis and incidentalomas were operated on laparoscopically.?? However, the other study indicated that this was due
to an increased number of cases with hyperaldosteronism
and pheochromocytoma, with no change in the number of
operations for incidentalomas and metastasis. 100
Conclusions
After a decade of worldwide experience, laparoscopic adrenalectomy has successfully passed its "definition" phase and
achieved maturation. Based on our experience, and that of
others, laparoscopic adrenalectomy is a well-established
technique and is currently the treatment of choice for benign
functioning and nonfunctioning neoplasms of the adrenal
gland. Although other laparoscopic approaches are feasible,
they have their limitations and offer no clear advantage over
the lateral transabdominal approach, the preferred technique
practiced by most surgeons performing laparoscopic adrenalectomy. The limited experience with the procedure in malignancy shows some promise, but its role is yet to be clarified.
Currently, invasive adrenocortical carcinoma and metastatic
pheochromocytoma to periaortic nodes are the only absolute
contraindications. Only experienced laparoscopic surgeons
should attempt laparoscopic resection of large masses and,

generally, the minimally invasive technique is not advisable
for lesions greater than 12 to 14 em.
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Anatomy and Embryology

of the Pancreas
Christopher R. McHenry, MD
Embryology
The pancreas is a derivative of the caudal part of the primitive
foregut. It develops embryologically from dorsal and ventral
pancreatic primordia, which appear at days 26 and 32 of
fetal development, respectively. 1 The dorsal pancreatic bud
originates as an endodermal outpouching from the dorsal
aspect of the duodenum, and the smaller ventral pancreatic bud
arises from the base of the hepatic diverticulum, closely related
to the common bile duct (Fig. 75-1).2 As the descending duodenum rotates, the ventral pancreas migrates posteriorly and
subsequently fuses with the dorsal pancreas at the end of the
sixth week of fetal development' (see Fig. 75-1). The ventral
anlage develops into the head and uncinate process of the
pancreas. Malrotation of the ventral pancreas may result in
an annular pancreas, a congenital malformation characterized by a ring of normal pancreatic tissue that surrounds the
second portion of the duodenum and causes duodenal constriction and obstruction.
With the fusion of the dorsal and ventral pancreatic primordia, the individual ductal systems coalesce with one another.
The main pancreatic duct of Wirsung is formed from the
anastomosis of the entire duct of the ventral pancreas, which
forms the duodenal end of the main duct, with the distal portion of the duct of the dorsal pancreas (see Fig. 75-1). The
duct of Wirsung is the main drainage conduit for pancreatic
exocrine secretion and, together with the common bile duct,
opens into the duodenum through the major papilla. The proximal portion of the dorsal pancreatic duct may involute or
persist as the accessory duct of Santorini, which empties
into the duodenum through the minor papilla. In approximately 5% to 10% of individuals, the ducts fail to join and
persist as two separate ductal systems, a congenital anomaly
known as pancreatic divisum.v'
The cells of the pancreas appear during the third month of
fetal development. They form as a result of the budding and
rebudding of cells derived from the pancreatic primordia."
The terminal portions of the budding cells develop a characteristic acinar arrangement, and the proximal portions form
multiple short ductal tributaries that drain exocrine secretions
from the acini into the main pancreatic duct. The endocrine
pancreas is composed of the islets of Langerhans, which

develop from the parenchymal cells of the pancreas at the
end of the third month of fetal life and are found as clusters
of cells throughout the acini of the pancreas. The pancreatic
islet cells produce peptide hormones, which, in contrast to
exocrine secretions, are delivered directly into the bloodstream. Insulin and glucagon secretion from the islet cells
begin as early as the fifth month of fetal development.v"
Metaplasia of pluripotential endodermal cells of the primitive foregut has been postulated to be a source for ectopic or
aberrant pancreatic tissue.? which has been reported to be present in 2% of all autopsies." Ectopic pancreatic tissue may
manifest as a nodular submucosal mass in the gastrointestinal
tract? and may be affected by the same pathologic conditions
that affect the normal pancreas. Islet cells are found only in
ectopic pancreas involving the stomach and duodenum and
may be a source for extrapancreatic islet cell neoplasms. 10
Anatomy of the Pancreas

The pancreas is a mixed endocrine and exocrine gland that
is located in the retroperitoneum within the epigastric and the
left hypochondriac regions of the abdomen. It extends transversely across the posterior abdominal wall from the medial
aspect of the descending portion of the duodenum, where it
is fixed, to the hilum of the spleen, where it is relatively
mobile. The stomach overlies the pancreas anteriorly. The
pancreas lies across the inferior vena cava, portal vein, aorta,
superior mesenteric, and splenic vessels (Fig. 75-2). It measures 15 to 20 em in length and extends across the vertebral
bodies of either the first or second lumbar vertebra. The
adult pancreas weighs 80 to 90 g and has an average width
and thickness of 3 em and 1 to 1.5 em, respectively."
The exocrine pancreas is a compound acinar gland
made up of secretory units that consist of individual acinar
and centroacinar cells and ducts that penetrate the lumen
of the acini. The exocrine pancreas constitutes the bulk of
the parenchyma. Interspersed among the acinar cells are
the islet cells of Langerhans. The islet cells are arranged in
well-vascularized clusters throughout the exocrine pancreas.
665
666 - -
Endocrine Pancreas
Ventral
pancreatic
primordia
Accessory duct of---l_-1j..

Santorini
Main pancreatic duct of
Wirsung
c
FIGURE 75-1. A, The dorsal and ventral pancreatic primordia at the end of the fifth week of fetal development. The arrow indicates the
path of posterior migration of the ventral pancreatic primordia. B, Anatomic relationship of the pancreatic primordia and ductal systems
following rotation of the duodenum and posterior migration of the ventral pancreatic primordia. C, Fusion of the dorsal and ventral pancreatic primordia and coalescence of the individual ductal systems.
They consist of four different cell types: alpha, beta, delta,

and clear cells. The alpha cells produce glucagon and constitute 20% of the islet cell population. Beta cells account
for approximately 70% of the islet cells and are responsible
for insulin production. Delta cells account for 5% to 10% of
the islet cells and function primarily as paracrine cells producing somatostatin for internal regulation of alpha- and
beta-cell secretion. They are also known to produce gastrin
and pancreatic polypeptide. Clear cells account for less than
5% of all islet cells, and their functional significance has yet

to be delineated.
Divisions of the Pancreas

Although there are no distinct anatomic demarcations, the pancreas is commonly divided into five parts: the head, uncinate
process, neck, body, and tail (see Fig. 75-2). The head of
the pancreas is adherent to the concavity of the descending
Anatomy and Embryology of the Pancreas - -
667
Left adrenal
Right adrenal
Splenic artery
Gallbladder
Accessory duct of
Santorini
Left kidney
Superior
mesenteric
vessels
., Pancreatic duct
of Wirsung
Uncinate
Inferior
vena cava
FIGURE 75-2. Topographic anatomy of the pancreas.
duodenum, with which it shares a common blood supply

from the superior mesenteric and gastroduodenal arteries.
As a result, total resection of the head of the pancreas requires
removal of the second and most of the first and third portions of the duodenum. The anterior surface of the head of
the pancreas is adjacent to the pylorus and the first portion
of the duodenum. Its posterior surface lies in close proximity
to the medial border of the right kidney and in contact with
the right renal vessels, inferior vena cava, and left renal vein.
The terminal portion of the common bile duct is embedded
within the posterior surface of the head of the pancreas in
85% of individuals. 12
The uncinate process projects medially from the left lower
aspect of the head of the pancreas. In most cases, it extends
behind the portal vein and the superior mesenteric vessels and
anterior to the aorta and the inferior vena cava. The uncinate
process is characterized by considerable variation in the extent
of projection from the head of the pancreas and may occasionally be absent.
The neck of the pancreas is a 2-cm segment that overlies
the confluence of the superior mesenteric and splenic veins,
forming the portal vein. There are usually no venous branches
that empty into the portal or superior mesenteric veins anteriorly. A cleavage plane between the pancreas and the underlying veins is usually present and can be delineated by simple
blunt dissection. This is clinically important for assessment of
the resectability of pancreatic malignancy.
The body of the pancreas overlies the aorta and the superior mesenteric artery and extends upward and to the left,
usually crossing the second lumbar vertebra. It is intimately

associated with the left adrenal gland, left kidney, and
splenic artery and vein, which course along its superior
aspect. Because of its relationship to the vertebral bodies, the
body of the pancreas is the segment where transection secondary to blunt trauma most commonly occurs. Small venous
tributaries from the body of the pancreas empty into the
splenic vein and are a potential source of troublesome bleeding when preservation of the spleen is attempted in patients
undergoing distal pancreatectomy. Anteriorly, the body of
the pancreas is covered by peritoneum separating the stomach
from the pancreas. It is also the site for attachment of the
transverse mesocolon. The middle colic artery originates
from the superior mesenteric artery from beneath the body
of the pancreas and emerges from between the peritoneal
leaves of the transverse mesocolon.
The tail of the pancreas is the narrow, mobile segment
found within the lienorenal ligament along with the splenic
vessels. It lies anterior to the left kidney and renal vessels at
the level of the 12th thoracic or first lumbar vertebra. The
tail of the pancreas terminates near or within the hilum of
the spleen and, therefore, is also the region of the pancreas
most at risk for injury during splenectomy.
Arterial Supply and Venous Drainage

of the Pancreas
The blood supply of the pancreas is predominantly derived
from the pancreaticoduodenal and the splenic arteries
668 - - Endocrine Pancreas
Common
hepatic a.
Posterosuperior
pancreaticoduodenal a. _--,'--_ _--=~
Splenic nodes
Anterosuperior
pancreaticoduodenal a.
Caudal
pancreatic
artery
Inferior pancreaticosplenic nodes
Pancreaticoduodenal
nodes
Transverse pancreatic a.
Duodenum
Anterior and posterior
inferior pancreaticoduodenal a.
Superior mesenteric a.
FIGURE 75-3. Arterial blood supply and lymph nodes of the pancreas.
(Fig. 75-3). All of the main arterial and venous channels

of the pancreas are posterior to the main pancreatic duct.
The head of the pancreas and the duodenum receive their
blood supply from an arcade of vessels formed by the anastomosis of the anterosuperior and posterosuperior pancreaticoduodenal arteries with the anteroinferior and posteroinferior
pancreaticoduodenal arteries (see Fig. 75-3). The superior
pancreaticoduodenal arteries are branches of the gastroduodenal artery, and the inferior pancreaticoduodenal arteries
are branches of the superior mesenteric artery. The uncinate
process receives its blood supply primarily from collateral
vessels arising from the inferior pancreaticoduodenal arteries.
The uncinate process may also be supplied by small perforating branches that arise directly from the superior mesenteric artery.
The neck, body, and tail of the pancreas receive their
blood supply from the transverse pancreatic artery, which
courses inferiorly and posteriorly through the gland, and
multiple small branches from the splenic artery that anastomose with the transverse pancreatic artery (see Fig. 75-3).
The transverse pancreatic artery is the principal blood supply
for the main pancreatic duct. It is a branch of the dorsal pancreatic artery, which arises from the splenic artery in 37%,
celiac artery in 33%, superior mesenteric artery in 21%, and
hepatic artery in 8% of the population." A right branch of
the dorsal pancreatic artery provides additional blood supply
to the head and uncinate process of the pancreas, anastomosing with the posterosuperior pancreaticoduodenal
arcade. A caudal pancreatic artery, which may arise from the
splenic artery or the left gastroepiploic artery at the hilum of
the spleen, is a variable source of blood supply for the tail of

the pancreas.
The veins draining the pancreas are parallel and superficial
to the arterial blood supply. Four pancreaticoduodenal veins
form the venous arcade, which drains the head and uncinate
process of the pancreas.' The anterosuperior pancreaticoduodenal and both inferior pancreaticoduodenal veins empty
into the superior mesenteric vein. The posterosuperior pancreaticoduodenal vein empties into the portal vein above the
superior margin of the pancreas. These veins and other
smaller tributaries from the head of the pancreas terminate
in the lateral or posterior aspect of the superior mesenteric
and portal veins and may be injured with traction on the
head of the pancreas.
The neck, body, and tail of the pancreas are drained by
multiple small venous tributaries that empty into either the
splenic vein superiorly or the transverse pancreatic vein
inferiorly. The transverse pancreatic vein eventually empties
into the inferior mesenteric vein. Ligation of the splenic vein
during distal pancreatectomy requires splenectomy, whereas
ligation of the splenic artery does not require resection of the
spleen because the spleen still receives blood from the left
gastroepiploic artery through the short gastric arteries.
Anomalous Arterial Supply

There are a number of important arterial anomalies that the
endocrine surgeon should be able to recognize to avoid injury
during pancreatic resection. The most common anomaly is
an aberrant right hepatic artery arising from the superior
Anatomy and Embryologyof the Pancreas - - 669

mesenteric artery, which was reported by Michels to be
present in 26% of cadavers." The aberrant right hepatic
artery may course behind the head of the pancreas and be at
risk for injury during pancreaticoduodenectomy. In 2% to
4.5% of individuals, the common hepatic artery may arise
from the superior mesenteric artery and course posterior to
the pancreatic head before dividing into right and left hepatic
arteries. I Injury to this aberrant common hepatic artery may
result in both hepatic and duodenal ischemia and necrosis.
An anomalous middle colic artery, originating from the
superior mesenteric artery, has also been reported, and it may
course directly through the head of the pancreas and be at
risk for injury during pancreaticoduodenectomy. I All of the
anomalous pancreatic arteries arising from the superior
mesenteric artery have been reported to pass anterior or posterior to or directly through the head of the pancreas."
Ducts of the Pancreas

The pancreas has a main pancreatic duct of Wirsung and an
accessory duct of Santorini (see Fig. 75-2). The main pancreatic duct courses from the tail of the pancreas through the
pancreatic parenchyma close to its posterior surface and
midway between the superior and inferior margins of the pancreas. It receives multiple small ductal tributaries throughout
the body and tail of the pancreas and then courses caudally
through the head of the pancreas, where it receives ductal
tributaries from the uncinate process.
The main pancreatic duct usually joins with the common
bile duct in the head of the pancreas to form a short, dilated
common channel known as the ampulla of Vater.The ampulla
of Vater enters the duodenum through the major papilla,
which is located on the posteromedial wall of the second
portion of the duodenum, an average of 10.6 em from the
pylorus. IS Rarely, the major papilla may be in the third portion of the duodenum. I The ampulla of Vater varies in length
from 1 to 14 mm and is 5 mm or smaller in size in 75% of
the population. 16 Michels reviewed the collective experience
of 25 investigators who examined 2500 autopsy specimens
and determined that a true ampulla of Vater was present in
64%, and the common bile duct and main pancreatic duct
entered the duodenum through separate orifices in 14% of
this population. 14 The ampulla of Vater, when present, or the
intramural portion of the common bile duct and pancreatic
duct is surrounded by smooth muscle fibers that form a
sphincter complex known as either as the sphincter of Oddi
or the sphincter of Boyden. The sphincter mechanism ranges
in length from 6 to 30 mm and is responsible for controlling
the release of exocrine secretions from the pancreatic and
common bile ducts. I
The diameters of the different segments of the main pancreatic duct have been determined by endoscopic retrograde
cholangiopancreatography, and they vary from 0.9 to 2.4 mm
in the tail, 2 to 4 mm in the body, and 3.1 to 5.3 mm in the head
of the pancreas.' Duct dilation has been defined as a diameter
of 8 mm or greater.i-" In patients with intractable pain secondary to chronic pancreatitis, longitudinal Roux-en-Y pancreaticojejunostomy is usually reserved for patients with a
pancreatic duct diameter of 8 mm or greater. 17 The length of
the pancreatic duct, determined from autopsy specimens, is
generally between 20 and 25 em."
The accessory duct of Santorini is usually smaller than

the main pancreatic duct. It is formed from the persistence
of the proximal portion of the duct from the embryologic
dorsal pancreas. It usually drains the anterosuperior portion
of the pancreatic head, communicates with the main pancreatic
duct, and in 70% of the population opens into the duodenum
through the minor papilla, which is 2 em cranial and slightly
anterior to the major papilla. The minor papilla is most often
directly posterior to the gastroduodenal artery and thus is
at risk for injury during surgery for peptic ulcer disease.
Variations in the pancreatic ductal anatomy are common and
include absence of a minor papilla in 30%, no connection
between the accessory and main pancreatic ducts in 10%,
and variable degrees of suppression in the development of
the accessory or main pancreatic ducts." To avoid injury to
the accessory pancreatic duct in patients undergoing gastrectomy or peptic ulcer surgery, duodenal dissection should
end proximal to the gastroduodenal artery. This is especially
important in the rare patients in whom the accessory duct
constitutes the major drainage of the pancreas.
Lymphatic Drainage
The lymphatic drainage of the pancreas follows the course
of the blood vessels (see Fig. 75-3). There is no standard terminology for the lymph nodes of the pancreas. I The head
and uncinate process of the pancreas are drained by pyloric
and pancreaticoduodenal lymph nodes. The neck, body, and
tail of the pancreas are drained by pancreaticosplenic lymph
nodes. The pyloric, pancreaticoduodenal, and superior
pancreaticosplenic lymph nodes drain to the celiac nodes,
whereas the inferior pancreaticosplenic nodes drain to the
superior mesenteric and periaortic nodal basins. Pansky
described five pancreatic lymph node groups on the basis
of studies of metastatic drainage: superior, inferior, anterior,
posterior, and splenic. 13 From these five lymph node basins,
lymphatic drainage proceeds centrally by two major pathways. The anterior, superior, and splenic lymphatic channels
drain to the celiac nodes with progression to the hepatic
nodes, whereas the posterior and the inferior nodes drain
to the superior mesenteric and periaortic nodal chains.
Both pathways subsequently drain through the thoracic duct
and serve as a potential source for supraclavicular nodal
metastasis.
Nerves of the Pancreas

The pancreas is innervated by both sympathetic and parasympathetic nerve fibers through the splanchnic and vagus nerves,
respectively. In general, the nerves innervating the pancreas
follow the course of the pancreatic blood vessels. Both the
splanchnic and vagus nerves carry visceral efferent (motor)
and visceral afferent (sensory) fibers. The splanchnic nerves
carry preganglionic efferent fibers to their cell bodies
located in the celiac ganglion. Postganglionic fibers arising
from the celiac ganglion form an extensive celiac nerve
plexus, which follows the arteries to reach the pancreas. The
celiac division of the posterior trunk of the vagus nerve supplies preganglionic parasympathetic fibers to the pancreas,
which pass through the celiac ganglion without synapsing.
The fibers end in the cell bodies within the parenchyma of
Surgical Exposure of
the Pancreas
FIGURE 75-4. The gastrinoma triangle.
the pancreas, which then give rise to the postganglionic

parasympathetic fibers innervating the pancreas. The functions of the sympathetic and parasympathetic innervation
are to regulate pancreatic blood flow, influence acinar and
centroacinar cell secretion, and contribute pain fibers to the
pancreas.
In patients with pancreatic cancer, effective pain relief
may be obtained by interruption of painful stimuli at the
level of the celiac plexus or splanchnic nerves. This seems
to be best accomplished by chemical splanchnicectomy
performed at the time of laparotomy.P-" Intraoperatively,
20 mL of 50% alcohol is injected under direct vision along
both sides of the celiac axis." This has been associated with
pain relief in more than 80% of patients, the majority of
whom obtain permanent pain relief."
Exposure of the pancreas in patients with islet cell neoplasms

is preferably obtained through an upper midline or a bilateral subcostal incision. Intraoperative evaluation of patients
with pancreatic islet cell neoplasms requires a meticulous
examination of the entire pancreas for tumor masses that are
frequently small (less than 2 em) and multiple. The duodenum and peripancreatic lymph nodes are also carefully
examined because they may be sites of extrapancreatic islet
cell tumors. The liver is examined for evidence of metastatic
disease. In patients with gastrinoma, 90% of all tumors and
virtually all occult tumors have been found in the gastrinoma
triangle." The gastrinoma triangle is defined as the anatomic
region bound by the junction of the cystic duct and common
bile duct superiorly, the second and third portions of the
duodenum inferiorly, and the junction of the neck and body
of the pancreas medially (Fig. 75-4).23 Insulinomas and nonfunctional islet cell tumors are evenly distributed throughout
the head, body, and tail of the pancreas, whereas glucagonomas are primarily situated in the tail of the pancreas.i"
The pancreas is exposed by retracting the stomach
upward and the transverse colon downward and dividing the
gastrocolic omentum (Fig. 75-5). The body and tail of the
pancreas are mobilized by incising the peritoneum along its
inferior border (Fig. 75-6), allowing access to the avascular
plane posteriorly for bidigital palpation (Fig. 75-7), which is
important for detection and assessment of tumor size and
determination of proximity to the main pancreatic duct.
Complete evaluation of the head of the pancreas
requires incision of the lateral attachments of the duodenum
(Fig. 75-8). To facilitate duodenal mobilization, the hepatic
flexure of the colon is mobilized, and then the lateral
FIGURE 75-6. Incision of the peritoneum along the inferior edge

of the pancreas using a right-angle clamp and the electrocautery.
(From McHenry CR. Pancreatic islet cell tumors. In: Baker RJ,
Fischer IE reds], Mastery of Surgery, 4th ed. Philadelphia,
Lippincott, Williams & Wilkins, 2001, p 557.)
Anatomy and Embryology of the Pancreas - -
671
FIGURE 75-7. Bidigital palpation of the pancreas after the peritoneum along the inferior edge of the pancreas has been incised
from the left of the superior mesenteric vein to the spleen. The spleen
has been mobilized. (From McHenry CR. Pancreatic islet cell
tumors. In: Baker RJ, Fischer JE reds], Mastery of Surgery, 4th ed.
Philadelphia, Lippincott, Williams & Wilkins, 2001, p 557.)
peritoneal attachments of the second portion of the duodenum are incised. Mobilization is continued proximally and
superiorly, dividing the avascular portion of the hepatoduodenal ligament, which allows visualization and palpation of
the common bile duct. The duodenum is further mobilized
distally and inferiorly so that the inferior vena cava and the
aorta can be visualized. This allows the surgeon to perform
FIGURE 75-9. Palpation of the head and uncinate process of the

pancreas after an extended Kocher maneuver has been completed.
(From McHenry CR. Pancreatic islet cell tumors. In: Baker RJ,
Fischer JE reds], Mastery of Surgery, 4th ed. Philadelphia,
Lippincott, Williams & Wilkins, 2001, p 556.)
bidigital palpation of the head and uncinate process of the

pancreas (Fig. 75-9).
Intraoperative assessment of the size, location, and proximity of islet cell tumors to the main pancreatic duct is important
for deciding the best operative management. Enucleation
remains the procedure of choice for small benign islet cell
tumors (less than 2 em) not in proximity to the main pancreatic duct." Enucleation is also recommended for malignant
islet cell tumors of the head or uncinate process of the pancreas
when feasible. Intraoperative ultrasonography, the single best
study for localizing tumors of the endocrine pancreas, may
help facilitate enucleation by defining the relationship of the
islet cell tumor to the pancreatic duct. Distal pancreatectomy
and pancreaticoduodenectomy are appropriate for treatment
of larger islet cell neoplasms, neoplasms in close proximity
to the main pancreatic duct, and tumors deep in the pancreatic parenchyma where tumor enucleation is not possible.i"
With successful preoperative localization of a solitary,
benign insulinoma, enucleation may be accomplished laparoscopically with the use of laparoscopic ultrasonography.P
Summary
FIGURE 75-8. A Kocher maneuver is performed by dividing the

lateral peritoneal attachments of the duodenum with a Metzenbaum
scissors and reflecting the duodenum medially. (From McHenry CR.
Pancreatic islet cell tumors. In: Baker RJ, Fischer JE reds],
Mastery of Surgery, 4th ed. Philadelphia, Lippincott, Williams &
Wilkins, 2001, p 556.)
The management of islet cell tumors requires a thorough

knowledge of pancreatic anatomy and embryology. Optimal
surgical exposure and meticulous intraoperative evaluation
of the pancreas are necessary to identify tumor masses,
which are frequently less than 2 em in size. The surgeon
should understand the anatomy of the pancreatic duct and be
able to determine its proximity to the tumor. Intraoperative
ultrasonography is a useful study for localizing tumors of
the endocrine pancreas and may help define the relationship
of an islet cell tumor to the pancreatic duct. The gastrinoma

triangle, duodenum, and peripancreatic lymph nodes are
other potential sites for extra pancreatic islet cell tumors. In
most patients, resection of an islet cell tumor can be accomplished by enucleation. When pancreatic resection is necessary, the surgeon should be aware of the potential anomalous
arterial supply and be able to recognize the arterial anomalies when they occur in order to avoid injury.
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1. Skandalakis U, Rowe JS, Gray SW, Skandalakis JE. Surgical embryology and anatomy of the pancreas. Surg Clin North Am 1993;73:661.
2. Streeter JL. Developmental horizons in human embryos. Descriptions
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3. Caudal part of the foregut. In: Langman J (ed), Medical Embryology,
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4. Development of the digestive and respiratory systems and the body cavities. In: Patten BM, Carlson BM (eds), Foundations of Embryology, 3rd
ed. New York, McGraw-Hill, 1974, p 459.
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6. Fallin LT. The development and cytodifferentiation of the islets of
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7. Skandalakis JE, Gray SW, Rowe JS, Skandalakis L1. Anatomic complications of pancreatic surgery. Contemp Surg 1979; 15:17.
8. Pearson S. Aberrant pancreas: Review of the literature and report of
three cases, one of which produced common and pancreatic duct
obstruction. Arch Surg 1951;63:168.
9. Keeley 11. Intussusception associated with aberrant pancreatic tissue.
Report of a case and review of the literature. Arch Surg 1950;
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10. Howard JM, Moss HN, Rhoads JE. Collective review, hyperinsulinism
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II. Quinlan RM. Anatomy and embryology of the pancreas. In: Zuidema
GO (ed), Shackelford's Surgery of the Alimentary Tract. Philadelphia,
WB Saunders, 1991.
12. Baldwin WM. The pancreatic ducts in man, together with a study of the
microscopical structure of the minor duodenal papilla. Anat Rec 1911;
5:197.
13. Pansky B. Anatomy of the pancreas. Emphasis on blood supply and
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14. Michels MA: Blood Supply and Anatomy of the Upper Abdominal
Organs. Philadelphia, JB Lippincott, 1955.
15. Flati G, Flati 0, Porowska B, et al. Surgical anatomy of the papilla of
Vater and biliopancreatic ducts. Am Surg 1994;60:712.
16. RienhoffWF Jr, Pickerell KL. Pancreatitis: An anatomic study of pancreatic and extrahepatic biliary systems. Arch Surg 1945;51 :205.
17. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100 patients with
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18. Gray SW, Skandalakis JS, Rowe JS, Skandalakis JE. Surgical anatomy
of the pancreas. In: Nyhus LM, Baker RJ (eds), Mastery of Surgery.
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19. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma of the pancreas. Surgery 1982;91: 123.
20. Lillemoe KD. Current management of pancreatic carcinoma. Ann Surg
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21. Flanigan DP, Kraft RO. Continuing experience with palliative chemical
splanchnicectomy. Arch Surg 1978;113:509.
22. Stabile BE, Morrow OJ, Passaro E Jr. The gastrinoma triangle: Operative
implications. Am J Surg 1984;147:25.
23. Howard TJ, Zinner MJ, Stabile BE, Passaro E. Gastrinoma excision for
cure. Ann Surg 1990;211:9.
24. Yeo CJ, Want BH, Anthone GHJ, Cameron 11. Surgical experience
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25. Iihara M, Kanbe M, Okamoto T, et al. Laparoscopic ultrasonography
for resection of insulinomas. Surgery 2001; 130:1086.
Multiple Endocrine
Neoplasia Type 1
Geoffrey B. Thompson, MD William F. Young, Jr., MD
Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal

dominant-inherited disorder affecting tumorigenesis in at
least eight endocrine and nonendocrine tissues whose components were first recognized in the early 20th century. In
1903, Erdheim' described a patient with a pituitary adenoma
and parathyroid hyperplasia discovered at autopsy. Gerstel?
reported on a patient with acromegaly and a severe peptic
ulcer diathesis in 1938. Wenner;' in 1954, identified the
autosomal dominant nature of the disease that bears his name
(Wenner's syndrome, now referred to as MEN 1). Children
of an affected parent have a 50% chance of inheriting the
disease predisposition that is noted to be highly penetrant.
Larsson and associates," in 1988, mapped the gene associated with MEN 1 (MEN1) to the long arm of chromosome 11
(llq13). MEN1 is a tumor suppressor and encodes a widely
expressed protein called menin. Clinical expression of the
genotype requires not only inheritance of an MEN1 gerrnline
mutation but also inactivation of the wild-type MEN1 allele
derived from the unaffected parent.>? Mutations in the gene
lead to widespread endocrine tumorigenesis. Approximately
90% of affected kindred members have mutations detectable
by genetic testing, and the phenotype develops in virtually
all individuals with gerrnline mutations.
Epidemiology and Clinical

Presentation
The true prevalence of MEN 1 is likely underestimated; data
suggest a prevalence of 0.2 to 2/100,000. 8 Major clinical
manifestations in MEN 1 include the "3Ps": primary hyperparathyroidism (HPT) (95%), pancreatic endocrine tumors
(PETs) (50% to 75%), and pituitary tumors (30% to 55%).
Expression of the disease rarely occurs before 10 years of
age and most often presents between 20 and 40 years of
age. 9. 10 Two of the three major lesions must be present for
the clinical diagnosis in probands. In family members of
known MEN 1 kindreds, the presence of one major lesion is
diagnostic (Table 76-1).11 Clinical diagnosis is confirmed by
genetic testing.
All three major clinical manifestations arise in less

than 12% of affected patients.'! Any of these three clinical
manifestations may be the first component precipitating a
diagnosis, but in most patients, primary HPT appears by the
3rd or 4th decades of life. Biochemical abnormalities can be
detected decades before clinically overt symptoms become
manifest. 13 For example, biochemical abnormalities may be
noted in affected adolescents in their mid to late teens when
careful, regular screening is performed. 14 Studies have shown
that delaying screening until clinical symptoms develop can
be associated with locally advanced disease or distant metastatic disease in as many as 50% of patients with PETs. 13
Less common, but overrepresented, manifestations in
MEN 1 include adrenocortical tumors.P"? foregut carcinoid
tumors,18-23 nonmedullary thyroid neoplasms (mostly
follicular),24.25 and a host of unusual cutaneous/mucosal or
visceral abnormalities, including multiple subcutaneous and
visceral lipomas, multiple facial angiofibromas, hypomelanotic macules, gingival papules, and collagenomas.P'F Rare
associations with MEN 1 also include meningiomas, ependymomas, pinealomas, renal cancers, rhabdomyosarcoma,
leiomyosarcoma, and pancreatic ductal adenocarcinoma.A"
The Molecular Biology of MEN 1

The gene responsible for MEN 1 was identified in 199729
and is located on chromosome llq13. MEN1 spans 9 kb of
genomic DNA and consists of 10 exons containing an
1830-base pair coding region. MEN1 encodes a 610-amino
acid nuclear protein, referred to as menin.4.29-32 Menin is
localized to the nucleus and interacts with the activating
protein 1 transcription factor JunD and other proteins involved
in transcription and cell growth regulation.Y" MEN1 mutations are spread over the entire coding region (exons 2 to 10);
approximately 50% are frameshift, 24% are missense, 20%
are nonsense, and 7% are deletion or in-frame insertion
mutations." MEN1 acts as a tumor suppressor gene, and
tumor development follows Knudson's "two-hit" hypothesis.'?
Hence, individuals affected with MEN 1 inherit one MEN1
673
Who Should Be Considered

for Genetic Counseling
and Testing?
allele with a gerrnline mutation (the "first hit"), and tumorigenesis in specific tissues then occurs after a second deleterious
mutation (the "second hit") is acquired in the remaining wildtype allele in a single cell." Such homozygous-inactivating
MEN] mutations result in menin protein absence or truncation, and neoplastic clonal expansion from that cell is then initiated. Thus, the mechanism for tumor formation in MEN 1
involves loss of menin function in a tumor precursor cell.
Unlike the RETprotooncogene (associated with MEN 2),
mutations in MEN] do not clearly demonstrate significant
genotype-phenotype correlations. 36,38-4o Recent studies have
found preliminary data suggesting that mutation type or
location within MEN] may be associated with clinical
presentation." However, the limited data available regarding
genotype-phenotype correlations do not currently warrant
modification of clinical management.
Several analytic approaches to identifying MEN] mutations
have been used, but most laboratories currently use direct
DNA sequencing. The first step in the analysis of a sporadic
case or a patient in a kindred with suspected or proven MEN 1
is to identify the specific MEN] mutation in germline DNA.
Germline testing requires peripheral blood from an affected
index case. In most probands, a disease-causing mutation is
identified. Because MEN] somatic mutations are commonly
found in endocrine tumors, tumor DNA is rarely useful in
distinguishing germline mutations.t'r'"
It is estimated that more than 10% of gerrnline MEN]
mutations arise de novo and can subsequently be passed
to future generations.Pr" Mutations in MEN] are highly
penetrant; approximately 50% of mutation carriers are
symptomatic by 20 years of age, and nearly 100% are symptomatic by 60 years of age. Most large series have failed
to find MEN] gerrnline mutations in 10% to 20% of index
cases,31.38.44-46 likely reflecting undetected mutations, such
as large deletions that are transparent to DNA sequence
analysis or mutations in another unknown gene. MEN1 mutational analysis is clinically available in at least four molecular genetics laboratories in North America.
In general, genetic screening of presymptomatic individuals

is appropriate when early therapeutic interventions are available for the tumors diagnosed, particularly when diagnosed
at a preclinical stage. Although this has not been proven in randomized, prospective studies of MEN 1 patients and remains
somewhat controversial, there is an increasing body of evidence to support this contention, particularly with regard to
MEN 1 pancreatic neuroendocrine tumors. 13,47.52 Although
early recognition and intervention with regard to parathyroid and pituitary neoplasia does not prolong survival, it
can reduce or prevent morbidity associated with hormonal
overactivity and mass effect.
Clinical screening of at-risk family members belonging to
known MEN 1 kindreds should begin in adolescence, a time
when biochemical abnormalities can begin to be detected
long before overt clinical manifestations and metastases
occur. 13 If a familial mutation has been identified, a negative
genetic test in an at-risk family member precludes the need
for routine, lifelong biochemical screening and imaging.
However, if a mutation is not detected in a proband, further
testing for MEN] mutations in at-risk family members is not
indicated, and presymptomatic testing is not possible by
direct DNA testing. In these cases, at-risk family members
must continue to be clinically monitored throughout their
lifetimes. Such families in which a mutation cannot be identified may consider pursuing linkage analysis, a less direct
method of tracking the disease allele through the family.
Because the process of genetic testing can be complicated, genetic counseling is recommended for all families
considering this option. Presymptomatic testing of at-risk
family members can be emotional, and families may benefit
from a session with a genetic counselor. The genetic counselor acts as a guide, explaining the pros and cons of testing
as well as aiding with interpretation of the results should the
family choose to proceed.
Regarding testing of apparently sporadic MEN 1
patients, mutation screening should be considered in young
patients 50 years of age) with HPT, particularly in those
with multi gland disease or recurrent HPT in the absence of
renal disease. Consideration should also be given to testing
patients with prolactinomas because up to 14% of such
patients may actually have MEN 1. Testing is also appropriate for patients with multiple pancreatic neuroendocrine
tumors (calcium levels should be checked in all patients
with solitary PETs), patients with any MEN 1 lesion and
an adrenal lesion, and patients with bronchial and thymic
carcinoids (Table 76-2).13
Pituitary Tumors
In MEN 1 kindreds, pituitary tumors are found less frequently than primary HPT or PETs.4o Signs and symptoms
related to a pituitary adenoma are the initial clinical presentation of MEN 1 in up to 25% of "first in the kindred"
cases but in less than 10% of familial cases that are
Multiple Endocrine Neoplasia Type 1 - - 675

successful pharmacologic or surgical treatment of the pituitary tumor, MEN 1 patients should continue to be evaluated
with periodic pituitary tumor screening since a second pituitary adenoma may arise from the remaining pituitary tissue.
diagnosed prospectively.53 The estimated prevalence of pituitary tumors in MEN 1 patients ranges from 10% to 60%.53-55
For example, in a series of 324 patients with MEN 1, pituitary adenomas occurred in 197 (42%); mean age at diagnosis was 38 years (range, 12 to 83 yearsj." In most MEN I
patients, the pituitary tumors are macroadenomas (>10 mm)
(Fig. 76-1).56 All subtypes of pituitary adenoma have been
reported in MEN 1, but most frequently they are prolactinomas (""60%). Patients may present with amenorrhea/galactorrhea in women, symptoms related to hypogonadism in
men, and/or sellar mass effect symptoms. 53,56,5? Less common
pituitary tumor subtypes in MEN 1 include somatotroph
adenoma (acromegaly; ",,25%), corticotroph adenoma
(Cushing's syndrome; ",,5%), and clinically nonfunctioning
pituitary tumors (",,10%). Monitoring for pituitary tumor
development in the MEN 1 patient should include measurement of serum prolactin and insulin-like growth factor 1 as
well as imaging of the pituitary by magnetic resonance
imaging (MRI) every 2 to 3 years." In patients with an
abnormal pituitary MRI, hypothalamic-pituitary testing
should be completed to characterize the type of the pituitary
adenoma and its effects on the secretion of other pituitary
hormones. Treatment of pituitary tumors in MEN 1 is guided
by the adenoma subtype and is identical to that in patients
with sporadic pituitary tumors (Fig. 76-2). In addition, after
Most MEN 1 patients develop hypercalcemia and primary

HPT by the 4th decade of life. 58 Shepherd described elevated ionized serum calcium levels in 66% of patients
younger than 25 years of age, 85% of patients between 25
and 55, and 87% of patients older than 55 in a large cohort of
MEN 1 family members.58 Skogseid and colleagues described
a mean age of onset of HPT at less than 19 years." This is
in sharp contrast to patients with sporadic primary HPT
who typically present in their 50s and 60s.
Primary HPT is the initial clinicallbiochemical manifestation of MEN 1 in 60% to 90% of patients, but the percentage
may be as low as 30% in young at-risk patients who are
screened. 53
A serum factor mitogenic for parathyroid cells has been
isolated in MEN 1 patients at levels 20 times those of
normal subjects. Parathyroid mitogenic factor has far greater
activity than any other measurable growth factor, and its
activity has been quantified by in-vitro studies."
Diagnosis
The diagnosis of primary HPT (Table 76-3) is dependent on
demonstrating an inappropriate immunometric parathyroid
hormone (PTH) level in the face of an elevated ionized serum
calcium level. Hypocalciuria due to benign familial hypocalciuric hypercalcemia (BFHH) should be ruled out by calculating
the calcium-creatinine clearance ratio:
(24-hour urine calcium x serum creatinine) + (24-hour
urine creatinine x serum calcium)
FIGURE 76-1. Head MRI showing coronal (A) and sagittal (B) views of a prolactin-secreting pituitary macroadenoma (arrows) in an
18-year-old young man with multiple endocrine neoplasia type 1. The patient presented with a 5-year history of daily headaches, vision
loss, and delayed sexual maturation. The serumprolactin level was 6309 ng/mL(normal, I to 15 ng/mL).
FIGURE 76-2. Endonasal transsphenoidal

pituitary surgery. (Mayo. 2001.)
and by obtaining a detailed family history. Calcium-creatinine

clearance ratios lower than 0.01 are indicative of BFHH.
Imaging clearly has a role in the evaluation and management
of patients with sporadic HPT, of whom 85% have a solitary
adenoma, rendering many of these patients candidates for a

directed surgical approach.60-62 The benefits of minimally invasive parathyroidectomy in this subgroup of sporadic patients
appear real. In MEN 1 patients, however, the pathology is that
of asymmetrical hyperplasia involving all parathyroid
glands. Therefore, regardless of imaging, all glands must be
explored and a transcervical thymectomy performed to rule
out a supernumerary or ectopic gland, which is seen in as
many as 20% of MEN I patients. Imaging in the setting
of multigland disease is often misleading and frequently
demonstrates only the dominant gland or glands.v'
Sestamibi parathyroid scanning (SPS) 64 and percutaneous
neck ultrasound'" typically demonstrate only the dominant
gland or glands in MEN 1 patients, that if treated as such,
will lead to persistent HPT for the unknowing and inexperienced surgeon.f SPS may, on occasion, demonstrate an
ectopic or supernumerary gland that may be easier to find with
preoperative knowledge of its whereabouts. These include
hyperplasticglands located in the low anterior,middle, and deep
posterior mediastinum; the undescended and intrathyroidal
glands; and the rare intrapharyngeal gland. Imaging does,
however, become essential in MEN 1 patients with recurrent
disease (discussed later). 65-73
Management of MEN 1
lIY1Pe~arathyroidism
The timing of parathyroidectomy is an important issue.

MEN 1 HPT involves all parathyroid tissue; thus, any treatment surgeons provide is considered palliative.Y" Attempts
at eradicating all parathyroid tissue can result in a treatment
that is far worse than the disease itself (permanent

hypoparathyroidism). In the past, 40% to 50% of MEN 1
patients presented with nephrolithiasis; however, more
recently, patients are being explored for mild or relatively
asymptomatic disease. In patients with mild disease, it is
appropriate to delay surgery until the serum calcium level
is ~l mg/dl, above the upper limit of normal." Other
indications include nephrolithiasis/nephrocalcinosis, hypercalciuria, glomerular filtration rate decreased by ~30% for ageand gender-matched controls, worsening bone (hip, radius, or
spine) mineral density, especially when the T-score is less than
-2.5 (2 SD from normal controls)," and pancreatitis." Vague
neuropsychiatric disturbances and muscle weakness are less
specific indicators. MEN 1 patients with hypergastrinemia and
hypercalcemia should undergo early parathyroidectomy.Y'"
Hypercalcemia is a potent stimulus for gastrin secretion.
Control of hypercalcemia can lower or even normalize serum
gastrin levels, often alleviating symptoms in MEN 1 patients
with Zollinger-Ellison syndrome (ZES),79,80
Operative Approach
A Kocher collar incision is made. The incision is deepened
down through the platysma, and superior and inferior subplatysmal flaps are developed. The median raphe is divided
and the strap muscles are retracted laterally without division. The thyroid lobes are sequentially elevated, and all
four parathyroid glands and any supernumerary glands are
exposed. Most supernumerary glands are located in proximity to the other glands or less often in ectopic locations.
Transcervical thymectomy should be performed to rule out
a supernumerary gland and to evaluate the thymus for a carcinoid tumor. Failure to identify a superior gland necessitates
mobilization of the superior thyroid pole by individually ligating the superior thyroid artery and vein or their branches on
the thyroid capsule. This helps avoid injury to the external
branch of the superior laryngeal nerve. Rotation of the upper
pole upward and outward often brings the superior gland into
view. Larger superior glands can migrate along the tracheoesophageal groove, into the retroesophageal space, and down
into the posterior mediastinum. These can usually be elevated
into the wound with adequate exposure and gentle traction.
Missing inferior glands should be sought within the thymus,
the carotid sheath, in an undescended location in front of the
carotid bifurcation, and just beneath the thyroid capsule, typically along its inferior pole. The rare undescended superior
parathyroid gland can be located within the pharyngeal musculature. Intraoperative ultrasonography (IOUS) may be of
aid in locating ectopic glands within the neck.81
Once four glands have been identified and the transcervical thymectomy has been performed, the surgeon then proceeds with a subtotal parathyroidectorny.P It is our preference
to leave behind an inferior gland or a portion thereof, depending on its size. Leaving an inferior gland or remnant makes
reoperation safer because of the inferior gland's distance
from the recurrent laryngeal nerve. If a superior gland is
much smaller or grossly normal compared to the rest, we
would consider leaving this as the remnant. The vascularized
remnant should be approximately 50 to 60 mg in weight.83-85
The remnant should be prepared prior to excising the other
glands so as to ensure its viability prior to completing the
subtotal parathyroidectomy. If the remnant becomes devascularized, it should be removed and the other inferior gland
trimmed. The remnant or remaining gland should be tagged
with a nonabsorbable suture or preferably a metal clip.
Additional parathyroid tissue should be cryopreserved or
immediately autotransplanted (multiple small pieces totaling 50 to 60 mg) into a small, infraclavicular, subcutaneous
pocket. Despite earlier reports regarding the efficacy of cryopreservation'f" and the viability of cryopreserved tissue
in vitro studies/" we have used few of the hundreds of cryopreserved specimens stored at Mayo Clinic. When used,
rarely have these delayed autotransplants resulted in meaningful restoration of normal parathyroid function. It is now
this surgeon's (GBT) practice, when performing a subtotal
parathyroidectomy, to transplant 50 to 60 mg of nonmalignant parathyroid tissue into a chest wall subcutaneous pocket
just below the clavicle. If the immunometric PTH level is
~l pmollL (normal, 1 to 5 pmollL) 24 hours postoperatively,
the transplant is removed at the bedside. If the postoperative
immunometric PTH is below the level of detection, the transplant is left in place. Time will tell whether graft-dependent
recurrences will be easier to detect and manage in this
location, but it is thought to be the case. By placing the graft
close to the deltopectoral groove, below the clavicle, selective
venous sampling (SVS) (subclavian vein) can be used along
with SPS and ultrasound to evaluate for graft-dependent
recurrence.
Another option for managing MEN 1 primary HPT is total
parathyroidectomy, transcervical thymectomy, and immediate
forearm autotransplantation. 86,87,9O Autotransplantation is
classically carried out by implanting 10 to 15 (l-mm) pieces
of fresh tissue into multiple pockets of the nondominant,
brachioradialis forearm muscle. Each site is marked with a
fine, monofilament nonabsorbable suture for future reference. The forearm skin incision should be made in a longitudinal fashion so as to avoid confusion with regard to a
self-inflicted wound. Recurrence rates are extremely low following total parathyroidectomy, but permanent hypoparathyroidism rates can be unacceptably high.91.93 Later explantation
is also more formidable with regard to intramuscular implants.
Persistent/Recurrent Hyperparathyroidism
in MEN 1 Patients
Permanent hypoparathyroidism occurs in less than 10% of
patients undergoing subtotal parathyroidectomy, and most
series describe rates in the range of 1% to 2%.92-95 The rates
of permanent hypoparathyroidism range from 10% to 30%
for patients undergoing total parathyroidectomy with immediate autografting. 85.92 Total parathyroidectomy, however,
has been associated with recurrence rates as low as 0 (range,
o to 60%), whereas recurrence rates for subtotal parathyroidectomy have never been reported less than 4% (range,
4% to 20%).83,85,91-97 Persistent HPT is generally less than
5% with both procedures.v-'? Malmaeus and coworkers
found that when 1 to 2.5 glands were removed, persistent
HPT occurred in 24% and recurrent disease in 62%. The
recurrence and persistence rate was 0 in 18 patients undergoing total parathyroidectomy (Table 76-4).92
Persistent HPT occurs because of misdiagnosis of hyperplasia and incomplete resection. Recurrent HPT is generally
the result of failure to locate one or more supernumerary

glands or is due to hyperfunction of the cervical remnant or
(forearm) autograft.
When evaluating a MEN 1 patient for persistent/recurrent
disease, it is essential to first re-establish the diagnosis.
Elevated ionized calcium, a detectable and inappropriate
immunometric PTH level, and a calcium-creatinine clearance ratio higher than 0.01 confirm and re-establish the
diagnosis. Review of previous operative records and prior
pathology slides is essential to the understanding of what was
and was not accomplished at past exploration.A direct fiberoptic laryngoscopy should be performed to evaluate cord
function prior to re-exploration. In addition, an assessment
of HPT-associated morbidity should be ascertained (kidney,
ureter, bladder films with tomograms, creatinine clearance,
and bone mineral density) to evaluate the risk-benefit ratio
for reoperation.
Imaging is essential in the reoperative setting,64-73 and
operative success appears to correlate with an increasing
number of concordant tests.64 Preoperative localization is
critical because of scarring, loss of normal tissue planes, and
the increased likelihood of ectopic/supernumerary glands in
the reoperative setting.
Percutaneous ultrasonography, SPS, computed tomography (CT), MRl, SVS, and angiography all have been used
with varying degrees of success in reoperative MEN 1 HPT
patients (Table 76-5).
Today, our test of choice remains sestamibi parathyroid
subtraction scanning with 1231. 98-100 Subtraction scanning
with either 1231 or 99mTc pertechnetate is superior to nonsubtraction studies (delayed imaging or washout studies).
Subtraction with 1231 appears to provide sharper images
and may be superior in the setting of multigland disease.I?'
The combination of oblique planar images and singlephoton emission CT yields the most sensitive information
(Figs. 76-3A and 76-4A).102 Sensitivities in the range of
70% to 85% have been reported.98-102 SPS falls short in
patients with multigland disease (but less so when only one
or two glands remain) and in patients with nodular thyroid
disease. It is particularly helpful in patients with mediastinal
and ectopic glands/"
Cervical ultrasonography is the second most frequently
used imaging study. It is very observer dependent, with
reported sensitivity rates varying between 25% and
90%.60.65-68 The Mayo Clinic and the University of
California-San Francisco have reported sensitivities of 48%
to 55% with large numbers of patients.P'" Ultrasound is hampered by thyroid nodules, enlarged lymph nodes, and tumors
directly adjacent to the trachea and bony structures. Using
ultrasound guidance, a fine-gauge needle can be inserted
into the gland in question. Cells can then be sent for cytology and the aspirated effluent for immunometric PTH
levels.F" Marked elevation in immunometric PTH levels
(several thousands) is pathognomonic for abnormal parathyroid tissue, and rarely are the results equivocal.
MRl provides less scatter artifact from previously placed
metal clips. It is particularly helpful for imaging ectopic
glands. Parathyroids demonstrate high signal intensity
on T2-weighted MR images (~fat).
Sensitivity ranges
from 60% to 80% have been reported in more recent
studies. 72,73,104-1l0 Today, it is also possible to perform
computed fusion studies correlating findings on MRI/CT
with those seen on nuclear scintigraphy.'!'
CT is most useful for identifying ectopic glands within
the mediastinum. It requires the use of intravenous ionized
contrast material and carries with it true-positive rates of
only 24% to 52%.65,69,70.71 CT is particularly hampered by
the presence of previously placed metal clips.
If two of the tests discussed earlier (sestarnibi/ultrasound,
ultrasound/fine-needle aspiration, sestamibi/MRl or CT) are
concordant, then surgery is the next step. If only one test is
positive, or if there is equivocation or marked discordance
among the tests, then consideration should be given to
SVS.ll2 Immunometric PTH gradients are sought by selectively catheterizing and sampling various cervical and mediastinal veins, comparing the immunometric PTH levels to
those of a peripheral vein. If a forearm autograft is present,
gradients can be determined by sampling veins from both
arms. 112 Peripheral forearm samples can be measured before
and after inducing temporary limb ischemia with a tourniquet
to check for graft-dependent recurrence (Casanova test).lI3
The National Institutes of Health reported that SVS
FIGURE 76-3. A, Sestamibi parathyroid scintigraphy demonstrating an abnormal left superior parathyroid gland on oblique image.
B, "Lateral approach" to superior parathyroid during reoperation for recurrent hyperparathyroidism. (Mayo, 1999.)
localized (or regionalized) 76% of previously missed adenomas with a 4% false-positive rate.'? The true-positive rate for
SVS at University of California-San Francisco was 69% with
a false-positive rate of 15%.71
Selective angiography has been used as a last resort
because of anecdotal reports regarding cerebrovascularevents.
Selective arterial catheterization of the common carotid,
thyrocervical, and internal mammary arteries has been
reported to demonstrate a vascular blush in 60% to 80% of
patients.69.114-116 The hypocalcemic stimulus of selective
intra-arterial injection of nonionic contrast material has also
been used to augment immunometric PTH levels during
venous sampling of the superior vena cava.116 Angiography
has also been used for ablation of mediastinal glands supplied by branches of the bronchial and internal mammary
arteries.114
The decision to operate on patients without localization
or with only one positive test must be individualized based
on the degree of disease-related morbidity and sound clinical
judgment. In patients with minimal or no overt complications and calcium levels lower than 11 to 11.5 mg/dL, an
argument can be made for waiting 3 to 6 months and then
reimaging. IOUS and radioguided surgery following a preoperative injection of sestamibi may serve as useful adjuncts
to the surgeon, particularly in some of the more challenging
cases. 82,117-119
Intraoperative PTH monitoring may be useful in determining the completeness of resection in both first-time
and reoperations for MEN 1 HPT.120.121 Although the 50%
rule (>50% drop in serum PTH levels from baseline within
10 minutes of parathyroid resection) is thought to apply in
all cases, we have had false-positive results in patients with
multigland disease when the immunometric PTH level fell
between 50% and 70%.64 Our preference following subtotal,
total, or completion parathyroidectomy is to see the intraoperative PTH level fall to normal or undetectable levels at
15 minutes following excision of the presumptive last gland.
False-negative and positive studies do occur.122
Operative Approach in Persistent/Recurrent

Hyperparathyroid MEN 1 Patients
The operative plan is generally that of a directed approach
based on preoperative imaging and the number of glands
previously removed.
The previous collar scar is excised for an optimal
cosmetic result. Subplatysmal flaps are created, and the
parathyroids are approached from lateral to medial via
the "lateral approach" (see Fig. 76-3B). This provides an
unscarred path to the tracheoesophageal groove. A plane is
developed between the sternocleidomastoidand strap muscles.
The omohyoid tendon is divided along with branches of the
7~.
A, Sestarnibi parathyroid
scintigraphy demonstrating intrathymic
mediastinal parathyroid gland. B, Transcervical thymectomy during reoperation for
persistent hyperparathyroidism. (Mayo,
FIGURE
1999.)
ansa cervicalis to the strap muscles. The contents of the

carotid sheath are carefully retracted laterally, and the tracheoesophageal groove is exposed low in the neck to visualize
the recurrent laryngeal nerve in an unviolated plane. Once
the nerve is exposed, the direction of the operation is determined by the findings on the preoperative imaging studies.
An inferior gland within the thyrothymic ligament can be
reached by grasping the ligament anterior to the trachea and
beneath the strap muscles. The thymus is then teased into
the wound with gentle traction, dividing lateral venous tributaries to the innominate vein between fine metal clips.
Dividing the strap muscles at the level of the clavicle can
facilitate exposure. Our preferred alternative is to incise the
median raphe low in the neck and expose the thymus
anteriorly (see Fig. 76-4B). The thymus is extracted until the

enlarged parathyroid gland is fully exposed. Upward retraction
of the manubrium facilitates the dissection. The feathered
end of the thymus is transected between right-angled clamps
and removed. If the gland is within the tracheoesophageal
groove (superior gland), it is often apparent as the groove is
approached from lateral to medial. Once the nerve is exposed
low in the neck, its entire course throughout the neck should
be carefully exposed. This is facilitated by dividing the superior thyroid vessels and mobilizing the superior pole of the
thyroid lobe up and out of the wound. The retroesophageal
space and upper posterior mediastinum can be reached from
the lateral approach, as can the carotid sheath, carotid
bifurcation, thyroid, and pharyngeal musculature. IOUS can
Multiple Endocrine Neoplasia Type 1 - -
be used to visualize nonpalpable intrathyroid and intrapharyngeal tumors, as well as carotid sheath and undescended
glands.
Once the offending gland has been removed, it is kept
sterile on iced saline. Intraoperative PTH monitoring is
performed. If the PTH falls to low-normal or undetectable
levels or at least to below 70% of baseline within 15 minutes
of excision, one can safely terminate the exploration after
transplanting 50 to 60 mg of parathyroid tissue into the nondominant brachioradialis muscle (or infraclavicular subcutaneous region). If levels do not fall, unilateral or bilateral
re-exploration should proceed via lateral and anterior (for
thymic glands) approaches until all offending tissue is
removed and confirmed by intraoperative PTH. The goal of
reoperative parathyroid surgery in MEN 1 should be to eliminate all parathyroid tissue and autotransplant 50 to 60 mg of
tissue into an extracervical site. There is an exception, however, to this rule. In the era of minimally invasive parathyroidectomy, unsuspecting surgeons may perform excision of a
dominant gland based on SPS. If such a patient turns out to be
an MEN 1 proband or kindred member, the limited dissection
still allows one to go back and perform a subtotal parathyroidectomy. Given the risk of permanent hypoparathyroidism
following total parathyroidectomy, this seems appropriate if
a 50- to 60-mg inferior remnant can be left on the contralateral
or ipsilateral side to the prior minimally invasive procedure.
Deep-seated mediastinal glands pose a special challenge.
Less than 2% of all parathyroid operations require a noncervical approach. Most thymic glands can be reached via a cervical approach, but when this is not possible, options include
a partial or full median sternotomy, a limited left anterior
thoracotomy (Chamberlain procedure), video-assisted
endoscopic/thoracoscopic approaches, and conventional
posterolateral thoracotomy.123,124 Abnormal glands in the
aorticopulmonary window require left thoracotomy or full
median sternotomy, taking care to avoid injury to the left
recurrent laryngeal nerve as it courses along the ligamentum
arteriosum. Tumors in the right middle mediastinum (adjacent to the right pulmonary artery and tracheal bifurcation)
are best accessed via a right posterolateral thoracotomy.
Angiographic ablation has been used successfully for elimination of select tumors whose blood supply is derived from
branches of the internal mammary or bronchial arteries. I 14,125
Graft-dependent recurrences can be managed with surgical excision under local anesthesia. Intramuscular grafts
can be challenging to explant and debulk.P' giving rise
to consideration for infraclavicular subcutaneous implants.
Another management option for graft-dependent and
remnant-dependent recurrences is ultrasound-guided percutaneous ethanol ablation.P? This is not curative and will
require future retreatment. However, given the palliative
nature of surgery for MEN 1 HPT, this offers a nonoperative
approach for normalizing calcium and PTH levels, albeit
for short periods. Recurrent laryngeal nerve injury can occur
when alcohol ablation is used for remnant-related recurrences.
681
occurs in 10% to 30% of reoperations, with a permanent

recurrent laryngeal nerve injury rate of 1% to 5%.83,90.93.128
Pancreatic/Duodenal
Neuroendocrine Tumors
Background
Pancreatic and duodenal neuroendocrine tumors represent
the second most frequent classic manifestation in MEN 1P
These neoplasms become clinically apparent in 50% to 75%
of kindred mernbers.P Autopsy studies have demonstrated
histologic changes in more than 80% of MEN 1 patients. 129- 131
The MEN 1 pancreas is characterized by multiple microadenomas and macroadenomas (Fig. 76-5), islet hypertrophy,
hyperplasia, and dysplasia, as well as islet cell carcinomas;
nesidioblastosis occurs rarely.132,133 PETs may arise from
precursor cells within the pancreatic ducts. Neoplastic cells
are argyrophilic and contain secretory granules. Most tumors
stain positive for chromogranin A, synaptophysin, and neuronspecific enolase with immunohistochemistry.Pt!" The
tumors are generally solid, but large cystic variants have been
reported (Fig. 76_6).136,137 Cellular pleomorphism is common
even in adenomas, and the diagnosis of malignancy can
be made with certainty only in the presence of metastatic
Results of Reoperative Surgery

Normocalcemia is achieved in the reoperative setting in 20%
to 65% of cases, with subsequent recurrences occurring in 30%
to 60% (Table 76_6).83.90,93.128 Permanent hypoparathyroidism
FIGURE 76-5. Multiple islet tumors in a patient with multiple

endocrine neoplasia type I with endogenous hyperinsulinism.
FIGURE 76-6. CT scan (A) and distal pancreatectomy/splenectomy specimen (B) in a patient with multiple endocrine neoplasia type 1
with large cystic islet cell carcinoma.
disease or by demonstrating direct invasion of contiguous

structures. Elevation of biochemical serum markers is frequent, even in the absence of an overt clinical syndrome.P
These markers include pancreatic polypeptide (PP), insulin,
glucagon, gastrin, proinsulin, somatostatin, vasoactive
intestinal polypeptide (VIP), parathyroid hormone-related
peptide (PTHrp), and neurotensin.13.138.139
Approximately 50% of MEN 1 patients with PETs
have duodenal carcinoids.PThese are typically small 5 to
10 mm), submucosal, and multiple. Duodenal carcinoids
in MEN I typically secrete gastrin but may also produce
serotonin and somatostatin.l-P More than 90% of MEN I
gastrinomas are duodenal in origin; the remainder are
pancreatic. Although most duodenal carcinoids can be
found in the first and second portions of the duodenum,
they can be found throughout the duodenum.I'" This has
important implications when planning an exploratory
duodenotomy.
When discovered, nearly 50% of pancreatic and
duodenal endocrine tumors have metastasized to regional
lymph nodes or the liver.130-135.141 All pancreatic/duodenal
endocrine tumors are capable of malignant transformation,
and this is especially true for nonfunctioning tumors. Size
does not necessarily correlate with malignant behavior. 136.137
Although there is a correlation between primary tumor size
greater than 3 em and the presence of liver metastases.I"
even the smallest tumor is capable of spreading to regional
lymph nodes. Pancreatic and duodenal endocrine tumors are
the number one causes of tumor-related death in MEN 1
patients. 135.141.142
Although genotype-phenotype correlations are not well
understood in MEN I, genetic testing is now available that
is capable of identifying MEN1 mutations in up to 90% of
probands" An increasing body of evidence suggests that
morbidity can be reduced and survival prolonged with early
detection of PETs in at-risk MEN 1 family members, hence
highlighting the potential importance of presymptomatic
testing. 12,47.50.140 No data exist, however, from randomized,

controlled, prospective studies, and it is unlikely that there
will ever be such trials given the small number of patients,
the safety of proposed therapeutic interventions, and the
evidence available from noncontrolled prospective and
retrospective studies.
Biochemical Screening
Skogseid and associates'V" have recommended an annual
biochemical screening program beginning in adolescence
that consists of measuring glucose, insulin (proinsulin),
gastrin, PP, glucagon, and chromogranin A (sensitivity, 35%
to 70%) (Table 76-7). PP is a nonspecific islet cell tumor
marker whose levels must be adjusted for age. High levels
correlate with large, radiographically detectable tumors.If
Chromogranin A is the most sensitive of the markers mentioned but generally requires a larger tumor burden for easy
detection. I44,145 False-positive results have been reported in
the setting of hypertension, renal disease, stress, and inflammatory bowel disease. Gastrin levels are rarely elevated in
young patients. When basal gastrin levels are increased,
it is usually an indicator of multiple duodenal carcinoids or
a larger pancreatic primary. 13
A standardized meal test with measurement of serum
PP and serum gastrin responses enhances the specificities
of both of these latter two markers in predicting the presence of pancreatic and duodenal endocrine tumors.l'" An
abnormal response for serum PP is a value that is greater
than 2 SDs above the mean for healthy controls. 146
Similarly, a doubling of postprandial gastrin levels to twice
the upper limit of normal is considered a positive test. 146
Antral G-cell hyperplasia, however, can give a similar gastrin
response.
To improve the specificity of the screening program,
Skogseid and associates have insisted that two independent
serum markers be elevated and increasing over a
683
FIGURE 76-7. Endoscopic ultrasonography of a hypoechoic islet

cell tumor in the pancreatic body (arrow).
Imaging
6-month interval.l-!" Insulin and proinsulin are dependent

serum markers, as is an abnormal response for PP and
gastrin following a standardized meal stimulation test.13.146
When the basic biochemical screening program is positive,
it is reasonable to extend the investigations to other less
common markers including VIP, calcitonin, PTHrp, and
24-hour urinary 5-hydroxyindoleacetic acid. If elevated, these
may serve as useful markers in future follow-up. Hormonal
profiles may change with time, may be polyhormonal, and
may differ from primary tumor to metastases.P Elevations in
the beta and alpha subunits of human chorionic gonadotropin
may be indicators of malignant transformation.P Formal
72-hour fasts for insulinoma and provocative testing for
gastrin are applied selectively.
Conventional imaging (percutaneous ultrasound, CT, MRI)

modalities for the early detection of pancreatic duodenal
endocrine tumors is fraught with hazard; both low sensitivities and specificities have rendered the earlier mentioned
biochemical screening protocol even more important.F'{"
The sensitivity for endoscopic ultrasonography, however,
may be as high as 90% (Fig. 76_7).149.151 Diagnostic accuracy
increases when somatostatin receptor scintigraphy (Fig. 76-8)
correlates with endoscopic ultrasonographic findings.ISO.ISI
Endoscopic ultrasonography also offers the opportunity for
directed fine-needle aspiration cytology. We discourage this
for tumors in the pancreatic head because efforts at enucleation
may be thwarted by even the slightest amount of bleeding and
inflammation. If this does occur, surgery should be delayed
for several weeks to allow resolution to take place. The efficacy
of PET scanning for pancreatic duodenal endocrine tumors
remains to be determined. 152
Who Should Undergo Surgery?

Patients with two rising independent serum markers, regardless of negative imaging, should be explored (Table 76_8).13
FIGURE 76-8. Somatostatin receptor scintigraphy (left [anterior] and right [posterior]) demonstrating a gastrinoma in the region of the
duodenum with multiple hepatic metastases.
FIGURE 76-9. Enucleation of an islet cell tumor in the pancreatic

head. Dissection of the pancreas "away from tumor" using an
endarterectomy spatula and minimal bipolar cautery is illustrated.
(From Thompson GB. Islet cell tumors. In: Mayo Clinic
Gastrointestinal Surgery. Philadelphia, WB Saunders, 2003.)
Other Pancreatic Endocrine Tumors

An elevated biochemical marker and an unequivocal
imaging study (endoscopic ultrasonography plus fine-needle
aspiration) or concordant endoscopic ultrasonography and
somatostatin receptor scintigraphy in the absence of
biochemical markers would be the other indications, in
the absence of distant metastatic disease.'! In carriers of
germline mutations who have a single positive biochemical
marker, imaging should be carried out yearly (but every
3 years for those with negative biochemistryj.P Some
centers now rely exclusively on endoscopic ultrasonography
for screening, but further validation is warranted.
Hypoglycemic Syndrome
Insulinoma associated with endogenous hyperinsulinism is the most common functioning PET in MEN I
patients younger than 25 years of age." Although these
patients often have multiple pancreatic tumors, typically
only one is the source of insulin excess.P This raises the
question of whether selective arterial calcium stimulation
testing with hepatic vein sampling for insulin should
be considered. 139,153 Although insulinomas are most often
benign, there is no effective medical therapy. Without
surgery, hormonal sequelae remain debilitating and lifethreatening.
Surgery involves an 80% distal pancreatectomy to the right
of the superior mesenteric vein with enucleation (Fig. 76-9)
of any remaining pancreatic head tumors, using IOUS.154
This removes the insulinoma(s) as well as many of the nonfunctioning tumors capable of malignant transformation.
Splenic preservation may be possible in young, thin patients
by carefully separating the splenic vein from the underside
of the gland using fine metal clips and an ultrasonic dissector. Small spleens can be preserved on the short gastric
vessels alone. Recurrence rates in patients with MEN I
are higher than in sporadic cases but nonetheless are
acceptable. 13 Leaving behind 20% of the pancreas generally
limits recurrences and avoids endocrine insufficiency in
most cases.
MEN 1 patients with malignant islet cell tumors (glucagonomas, VIP tumors, PTHrp tumors, and some insulinomas)
deserve an equally, if not more aggressive approach, including an 80% distal pancreatectomy, splenectomy, and
lymphadenectomy, along with enucleation of any residual
tumors. Isolated liver metastases or a finite number of multiple hepatic metastases can be successfully managed, with
excellent control of hormonal sequelae, using a combination
of hepatic resection and radiofrequency thermal ablation. 155,156
Zollinger-Ellison Syndrome
Gastrinomas represent the most common functioning
pancreatic/duodenal endocrine tumors in MEN 1 patients. 157
Nearly one third of ZES patients are MEN I kindred members,
and more than 50% of MEN 1 patients have hypergastrinemia.
In the past, surgery for MEN I ZES was carried out with
reluctance, if at all. 158-160 Cure rates were low, based on normalization of gastrin levels, and medical therapy in the form
of proton pump inhibitors (PPIs) has been extremely effective at eliminating peptic acid sequelae. Medical therapy
does not, however, prevent malignant transformation, nor
does it prevent the development of metastatic disease.P?
Presently, 30% to 50% of patients undergoing surgical
exploration have at least regional nodal metastases, many of
which are amenable to resection, often providing excellent
palliation. 125,161 More than 80% of gastrinomas in MEN 1
patients are duodenal in origin.50.140.157 In addition, ZES
patients appear at greater risk for malignant transformation
of nonfunctioning tumors when compared to other MEN I
patients. 13,162,163 Norton and colleagues have shown that
patients with nodal metastases can achieve similar survival
benefits with operative intervention compared to those without lymph node involvemenr"! Gastrin levels often rise late
in MEN 1 patients. Once the gastrin level is elevated, 30%
to 50% of patients already harbor nodal metastases even in
the face of negative imaging studies. Resection of larger
(>3-cm) PETs does not appear to reduce the risk of developing liver metastases, once again making a strong argument for
screening, early detection, and early surgical intervention. 164
The procedure most often performed has been popularized

by Dr. Norman Thompson at the University of Michigan at
Ann Arbor (Fig. 76_10).125,157,162,165 The surgery is carried
out after adequate treatment with PPIs to heal active ulcers.
Antibiotics and deep venous thrombosis prophylaxis are
provided. The abdomen is thoroughly explored through a
transverse epigastric or chevron incision. Careful attention
is paid to the liver, which is explored both by palpation and
IOUS. The gastrocolic omentum is completely mobilized
off the transverse colon from left to right, entering the lesser
sac. Both colonic flexures are mobilized and retracted caudally. The duodenum is widely kocherized out to the ligament of Treitz. The avascular plane along the inferior border
of the pancreas is incised and the pancreatic body is freed to
its superior border, The lienorenal and lienophrenic ligaments are divided using electrocautery, and the spleen, body,
and tail of the pancreas are mobilized to the splenic veinsuperior mesenteric vein junction. The inferior mesenteric
vein may require division to further facilitate exposure. The
superior mesenteric vein is then isolated from the neck of
the pancreas. Division of the anteroinferior pancreaticoduodenal vein, as well as the right gastroepiploic vessels, augments exposure of the uncinate and pancreatic head and
reduces the risk of avulsing these delicate veins as the operation proceeds. At this point, careful bidigital palpation of
the entire gland is carried out along with IOUS in anteroposterior planes and transverse-longitudinal directions. Special
attention is paid to the location of the pancreatic and bile
ducts and their relationship to nearby islet cell tumors.
Lymph nodes are removed from along the posterior aspect of
the pancreatic head, the hepatoduodenalligament, the subpyloric region, branches of the celiac artery, and the proximal
superior mesenteric artery. In patients with hypergastrinemia,
a longitudinal duodenotomy is made along the free wall of
the second portion of the duodenum. The duodenal wall is
FIGURE 76-10. Eighty percent distal pancreatectomy (splenic

preserving), enucleations (pancreatic head), exploratory duodenotomy, and lymphadenectomy for a patient with multiple endocrine
neoplasia (MEN) type I and Zollinger-Ellison syndrome.
(Courtesy of Dr. Norman Thompson, University of Michigan, Ann
Arbor, Michigan.)
685
carefully palpated between thumb and index finger proximally across the pylorus and distally beyond the ligament of
Treitz. The duodenal mucosa is intussuscepted into the duodenotomy for further inspection and palpation. Smaller carcinoids are excised submucosally; larger tumors may require
full-thickness excision. The duodenotomy is then closed longitudinally with interrupted, 3-0 absorbable suture to avoid
luminal narrowing. An 80%distal resection is performed to the
right of the superior mesenteric vein. Splenic preservation is
carried out in the absence of large malignant tumors, as previously described. Any remaining tumors are enucleated using
an endarterectomy spatula, bipolar cautery, and fine metal
clips, carefully dissecting the pancreas away from the tumor
so as to avoid pancreatic ductal injury (see Fig. 76-9).
Enucleation sites are left open, and closed-suction drainage
catheters are left in place. When available, intraoperative
gastrin and insulin assays can be confirmatory. IOUS can help
determine the integrity of the pancreatic duct following
completion of the enucleation(s). The abdomen is closed in a
standard fashion, and intravenous PPIs are continued in the
postoperative period. A fasting basal serum gastrin level should
be obtained prior to dismissing the patient; slight elevations
may be due to PPIs. Oral PPIs are continued for 1 month
while the duodenotomy heals. Failure to achieve eugastrinemia mandates continuation of medical therapy. Pancreatic
pseudocysts and fistulas are the most common complications,
affecting 10% to 20% of patients. Conservative management
with closed-suction drainage and time usually results in the
resolution of most of these problems.
Thompson has the largest series (over 40 patients) of
MEN l/ZES patients having undergone this procedure. One
half remain eugastrinemic. Distant metastases and death
have rarely occurred with follow-up as long as 4 decades.
Clearly, this surgery has had a profound impact on the natural
history of the disease in this surgeon's hands (personal
communication). 157,162
Other operative approaches include total pancreatectomy,
pancreatoduodenectomy, and pancreas-sparing duodenectomy.166 Total pancreatectomy may leave the patient with
a treatment that is far worse than the disease itself, but it
does play a role in patients with large malignant tumors
throughout the gland and in patients with a strong family
history of highly lethal pancreatic and duodenal endocrine
tumors. Pancreatoduodenectomy is reserved for patients
with extensive duodenal and pancreatic head disease, whereas
pancreas-sparing duodenectomy with enucleations is an
option for patients with a large tumor burden in the duodenum
but few tumors in the pancreas. This can be combined with
a distal pancreatectomy.
Locoregional recurrences can be safely re-resected in
selected cases. In other situations, completion pancreatectomy
may be a good option in the absence of distant metastases.
The management of advanced disease may involve
hepatic resection and radiofrequency ablation (open or percutaneous) of liver metastases. 155.156 This can provide excellent palliation with regard to both hormonal sequelae and
survival. When surgery is no longer an option, stabilization
and hormonal control can also be achieved with the longacting form of octreotide (Sandostatin LAR).167 Combination
chemotherapy,168-170 most often with streptozotocin and
doxorubicin or 5-fluorouracil, has demonstrated temporary
responses in as many as two thirds of patients treated.

a-InterferonI67.171 has also been employed in select cases,
providing effective palliation. Rarely has liver transplantation
been considered for disease confined to the liver.
Adrenal Neoplasia
and Hyperplasia
Thirty-five percent to 40% of MEN 1 patients harbor
adrenocortical lesions, and these are clearly overrepresented
in the MEN 1 syndrome.P"? Most lesions are hyperplastic,
bilateral, and nonfunctioning. Aldosterone- and cortisolsecreting adenomas, however, have been reported.P"?
Hypercortisolism in MEN 1 can be the result of an ACTHsecreting pituitary process, a cortisol-secreting adenoma!
carcinoma or, rarely, due to an adrenocorticotropic hormone
(ACTH)- or corticotropin-releasing factor-producing islet
cell tumor or thymic carcinoid.P Adrenocortical carcinomas
have also been described in MEN 1 patients, most often in
association with insulin-producing islet cell tumors.17.25.172
This raises the possibility of a shared underlying genetic
cause or a trophic effect of insulin on adrenocortical cells.
Carcinoid Tumors
Carcinoid tumors (particularly foregut) are also overrepresented in MEN 1 patients. 18-22 They are all capable of
behaving in a malignant fashion and as a group represent
the second most common cause of tumor-related deaths in
MEN 1 patients after pancreatic neuroendocrine tumors.
Thymic carcinoids are highly aggressive. Management of
such foregut tumors is by appropriate surgical resection.
Transcervical thymectomy performed as part of HPT operations is not a guarantee against future development of
thymic carcinoids.F'<"
Gastroduodenal carcinoid tumors can be nonfunctioning
or associated with gastrin or serotonin production.s-!"
Duodenal carcinoids are the principle cause of ZES in MEN
1 patients.22.5o.14o They are often multiple and frequently
metastasize to regional lymph nodes and subsequently to the
liver. Gastric carcinoids can be gastrin producing (highly
malignant) or can evolve secondary to the hypergastrinemia
from gastrin-producing duodenal carcinoids (enterochromaffin cell hyperplasiaj.i-!" Treatment requires excision
and lymphadenectomy and, less often, gastrectomy or
pancreatoduodenectomy, depending on the extent of foregut
involvement.
Summary
MEN 1 syndrome is an autosomal dominant-inherited tumor
disorder caused by mutations in the MEN] tumor suppressor
gene (chromosome llqB). The diagnosis is made in probands
by documenting two of the three major manifestations
(multigland primary HPT [>95%], pancreatic neuroendocrine
tumors [50% to 75%], or pituitary tumors [30% to 55%])
or by demonstrating one major manifestation in an at-risk
family member of a known MEN 1 kindred. Genetic testing
identifies a mutation in up to 90% of MEN 1 kindreds. Other

overrepresented tumors include adrenal neoplasia, foregut
carcinoid tumors, and a number of unusual cutaneous abnormalities. Primary HPT is the most common manifestation
and is seen in more than 95% of MEN I patients. Palliation
of HPT is best achieved with subtotal parathyroidectomy
and transcervical thymectomy. Prolactinomas are most
often managed with dopamine agonists. Failures of medical
therapy and large (compressive) macroadenomas, both functioning or nonfunctioning, are best managed with endonasal
trans sphenoidal adenomectomy. Pancreatic and duodenal
neuroendocrine tumors are the most frequent cause of tumorrelated deaths in MEN 1. Nonfunctioning islet cell tumors
are most frequent in screened patients, and duodenal gastrinomas are the most frequent cause of a functioning syndrome (ZES). This is followed by hyperinsulinism and, less
often, the glucagonoma or VIP tumor syndromes. Pancreatic
resection is clearly indicated and beneficial for patients with
hyperinsulinism, glucagonomas, VIP tumors, and larger nonfunctioning tumors. There is increasing evidence suggesting
that early surgical intervention for MEN l/ZES patients and
patients with subclinical pancreatic neuroendocrine tumors
does result in prolonged palliation and a reduction in the rate
of malignant transformation. Since biochemical abnormalities
can be detected decades prior to the development of overt clinical symptoms, genetic testing, biochemical screening, and
imaging of appropriately selected patients appear warranted.
Acknowledgments
The authors thank Abbie L. Young, MS, and Dr. Britt Skogseid for their
critique of this chapter.
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148. Kisker 0, Rothmund M. Localization of endocrine pancreatic tumors.
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Surgery 1994;116: 1131.
150. Zimmer T, Stolze1 U, Bader M, et al. Endoscopic ultrasonography and
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151. Proye C, Malvaux P, Pattou F, et al, Noninvasive imaging of insulinomas
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152. Ahlstrom H, Eriksson B, Bergstrom M, et at. Pancreatic neuroendocrine tumors: Diagnosis with PET. Radiology 1995;195:333.
153. Doppman JL. Insulinoma localization studies: Questions and
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154. Rasbach DA, van Heerden JA, Telander RL, et al. Surgical management of hyperinsulinism in the multiple endocrine neoplasia type I
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155. Siperstein AB, Rogers SJ, Hansen PD, Gitomirsky A. Laparoscopic
thermal ablation of hepatic neuroendocrine tumor metastases.
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156. Que FG, Nagomey DM, Batts KP, et al. Hepatic resection for
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158. Yu F, Venzon DJ, Serrano J, et at. Prospective study of the clinical
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160. Norton JA, Fraker DL, Alexander HR, et al, Surgery to cure the
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162. Thompson NW. Management of pancreatic endocrine tumors in
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163. Burgess JR, Greenaway TM, Parameswaran V, et al. Enteropancreatic
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165. Mullan MH, Gauger PG, Thompson NW. Endocrine tumours of the
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174. Sugiura H, Morikawa T, Itoh K, et al. Thymic carcinoid in a patient
with multiple endocrine neoplasia type I: Report of a case. Surg
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175. Teh BT. Thymic carcinoids in multiple endocrine neoplasia type 1.
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176. Jensen RT. Management of Zollinger-Ellison syndrome in patients
with multiple endocrine neoplasia type 1. J Intern Med 1998;243:477.
Transplantation of Endocrine
Cells and Tissues
Alan P. B. Dackiw, MD, PhD Martha Zeiger, MD
Hormone replacement therapy for endocrine deficiency may

not completely achieve the physiologic independence of a
normally functioning system, because the complex metbolic
interactions of hormones and their targets often cannot be
wholly reproduced. Investigators have explored transplantation of endocrine tissues and cells with varying degrees of
clinical success. Although autotransplantation (the movement
of tissue or cells from one location to another in the same
individual) as evidenced by the success of parathyroid autotransplantation has found clinical applicability, allotransplantation (transplantation of tissue or cells from one individual
to another in the same species) has been limited by rejection.
Xenotransplantation (transplantation with another species'
tissue) has remained investigational. Table 77-1 shows a
number of endocrine deficiency states that might be amenable
to transplantation of endocrine cells or tissues. However,
advances have been made in the field of pancreatic islet cell
transplantation that, in addition to thyroid transplantation,
parathyroid transplantation, and adrenal transplantation, are
discussed in this chapter.
Thyroid
Clinical transplantation of thyroid tissue has not been
widely utilized as thyroid hormone replacement therapy is
safe, effective, and cost-effective in treating postoperative
or disease-induced hypothyroidism in most patients.
Autotransplantation of thyroid tissue has been performed
mainly in two clinical scenarios, following resection of
lingual thyroid and following thyroidectomy for multinodular
goiter or Graves' disease. Numerous case reports documenting
these transplants have appeared in the literature dating back
to more than 50 years ago. I - 13 Long-term follow-up of autotransplanted thyroid tissue has been reported. Sheverdin
reported the results of a 15-year observational study of autotransplanted thyroid gland fragments in 1992. 12 Mild
hypothyroidism was noted in 3.2% of the transplant recipients
during the first 6 months after operation. In the nontransplantation group, postoperative hypothyroidism developed
in 6.6% of the patients during the same period of time. The
author's conclusion was that autotransplantation of part of
the resected thyrotoxic thyroid gland was an effective method

of preventing postoperative hypothyroidism. Successful autotransplantation of thyroid has also been reported by other
groups" with follow-up of up to 37 years." Transplanted
thyroid fragments have been placed in both the abdominal
wall" and neck.'! Steinwald, Neinase, and their colleagues
have also reported successful cases of autotransplantation
of lingual thyroid into muscle with long-term follow-up of
16 and 5 years, respectively.P-'?
Cryopreserved thyroid tissue has also been
autotransplanted." Follow-up studies have reported optimal
freezing conditions for cryopreservation." Specifically,
l-rnm thyroid pieces are placed into the freezing medium,
which consists of culture medium supplemented with 10%
fetal bovine serum and 10% dimethyl sulfoxide. The tissue
is cooled slowly to -80 0 C with prefreezing incubation at
4 0 C for 1 hour and subsequently kept in liquid nitrogen for
preservation. The number of surviving cells in this study
under optimal conditions was 1.24 to 2.03 (1.71 0.40) x 106
per 0.1 g of tissue, and recovery was 25.2% to 58.0%
(45.5% 14.6%).
As a follow-up to this work, Shimizu and coworkers
reported a trial of autotransplantation of cryopreserved thyroid
tissue for postoperative hypothyroidism in patients with
Graves' disease.P At the time of subtotal thyroidectomy, the
surgical specimen was partially cryopreserved until it was
subsequently used for autotransplantation. Four patients with
postoperative hypothyroidism underwent autotransplantation
of cryopreserved thyroid tissues. These patients had previously required 50 to 150 ug/day of thyroxine at 1.8, 3.4, 3.5,
and 2.8 years after operation. For the transplantation procedure, 2.5 to 3.5 g of cryopreserved thyroid tissue was
autotransplanted into the forearm muscle of each patient
(Fig. 77-1). In three of the patients, thyroxine administration
could be discontinued and the clinical symptoms of
hypothyroidism disappeared because of a decreased serum
thyroid-stimulating hormone (TSH) level. Pathologic and
immunohistochemical examinations of the thawed cryopreserved tissue demonstrated well-preserved thyroid structure
and thyroglobulin-positive follicular cells with colloid,
suggesting that the transplanted material was functional. In
addition, 1231 scintiscanning in two patients showed an
691
accumulation of radioactive iodine at the transplantation

sites. One patient, who was able to discontinue thyroid hormone for 6 months, subsequently required supplementation
because of recurrent hypothyroidism. The importance of
close follow-up of patients with residual native thyroid
tissue or autotransplanted tissue is emphasized because of
the potential for recurrent hyperthyroidism and even thyroid
storm."
FIGURE 77-1. Transplantation of cryopreserved thyroid tissue

into the brachioradialis muscle. Defrosted thyroid tissue (2.5 g) is
transplanted into several pockets that are created in the brachioradialis muscle. (From Shimizu K, Kumita S, Kitamura Y,et aI. Trial
of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves' disease. JAm Coll
Surg 2002;194:14.)
Others have also had success with thyroid autotransplants and autotransplantation of cryopreserved tissue in the
abdominal wall and forearm. 2223 Roy and coauthors
reported 15 patients with benign thyroid disorders (7 with
Graves' disease and 8 with multinodular goiter) who underwent modified subtotal thyroidectomy and autotransplantation of 3 to 5 g of thyroid tissue in the sternocleidomastoid
muscle. The transplanted tissue was functional in six of the
eight patients with multinodular goiter and four of the seven
patients with Graves' disease. All of the patients with
multinodular goiter and a functional transplant became
euthyroid within 6 months postoperatively. Although the
transplanted tissue was functional in four patients with
Graves' disease, only one became euthyroid; the other three
required supplemental hormone therapy for postoperative
hypothyroidism. This study demonstrated the ability of
autotransplanted thyroid tissue to survive, function, and
grow in muscle; however, long-term functional studies from
these reports are pending.
In addition to thyroid autotransplantation, studies have
evaluated the feasibility of thyroid allografts and xenografts.
Raaf and colleagues evaluated isogeneic and allogeneic
thyroid grafts in thyroidectomized recipient rats." Grafts,
either fresh or cultured, were placed in hamstring muscle
pockets or under the renal capsule. Survival and function of
the grafts were evaluated by restoration of normal levels
of serum thyroxine, weight gain, kidney transarnidinase (a
thyroxine-induced enzyme), and the histologic appearance
of re-excised implants. Isografts, fresh and cultured, functioned well as ectopic thyroid glands, although restoration
of normal serum thyroxine levels was more rapid for the
fresh implants. Fresh allografts functioned transiently but ultimately failed because of rejection. No function was detected
for cultured allografts, and rejection was seen histologically.
The rat thyroid allograft therefore differs from the rat
parathyroid allograft, which can often function for several
months despite histologic evidence of rejection. Thus, in
this study, maintenance of thyroid cells in tissue culture
prior to implantation did not appear to alter the long-term
immunogenicity of the graft.
Methods designed to overcome rejection include immunosuppression, immunomodulation, and immunoisolation.P
Attempts have been made to reduce the immunogenicity by
immunomodulation of the thyroid allograft. Iwai and
coworkers pretreated thyroid cells with anti-Ia antibody or
antidendritic cell antibody." Initially, thyroids of C67BU6J
mice were treated with collagenase, and the follicles were
isolated using a Percoll density gradient technique. These
follicles were treated with anti-Ia antibody (Ab) or antidendritic cell antibody plus complement in order to eliminate
dendritic cells. The follicles were then mixed with agarose
and transplanted under the left renal capsule of BALB/c
mice. One hundred days after transplantation, acceptance of
the grafts was verified by both histologic study and the
incorporation of 1251 into the grafts. Allografts treated with
complement were rejected, whereas allografts treated with
antibody plus complement were accepted. When nontreated
thyroids of C57BU6J mice were grafted under the right
renal capsule of BALBIc mice that had accepted dendritic
cell-depleted thyroids of C57BU6J mice, the nontreated
thyroids were rejected. These findings indicate that the
Transplantationof EndocrineCells and Tissues - - 693

dendritic cells play an important role in the rejection of
mouse thyroid allografts, and that the depletion of dendritic
cells permits allografts to be accepted without inducing
donor-specific tolerance and might be developed as a viable
strategy for the treatment of patients with congenital or
acquired hypothyroidism.
Yoshizaki and colleagues also examined the efficacy of
thyroid allotransplantation for the therapy of hypothyroidism
in the rat model. 27 Transplanted thyroid function was determined by the 1251 uptake ratio and evaluated by immunohistochemical and microautoradiographic assessments. Fully
allogeneic thyroid glands cultured for 8 to 24 hours in
Hanks' balanced salt solution at pH 6.3 or 7.2 were transplanted into rats under the kidney capsule. Five weeks after
allotransplantation, thyroid glands cultured for 16 hours at
pH 6.3 demonstrated prolonged survival. The authors concluded that this procedure could be used as an initial therapy
not only for patients who have undergone total thyroidectomy but also for patients with primary hypothyroidism.
Other techniques to protect allogeneic thyroid tissue have
also been examined. A technique of encapsulating thyroid
tissue (immunoisolation) with an artificial membrane to protect against rejection has been reported.P The membrane is
constructed of calcium alginate and a poly-r.-lysine coating;
it prevents the diffusion of large molecules such as hemoglobin but freely permits the passage of smaller molecules such
as thyroxine and culture medium. Because larger molecules
are excluded, the contents of the microcapsules are protected from rejection. In this study, in vitro cultured,
microencapsulated rabbit thyroid tissue secreted triiodothyronine (T3) and thyroxine (T4 ) and achieved concentrations
of 8.68 2.93 and 245.23 124.87 nmollL after 3 days.
These levels remained stable for 6 to 9 days of incubation.
The authors concluded that these microcapsules showed
promise as a treatment modality and as a possible solution
to the problem of immune isolation.
Braun and colleagues also reported a method of
encapsulating thyroid tissue." These investigators used an
encapsulation method involving the precipitation of a
polyelectrolyte complex membrane of cellulose sulfate and
polydimethyldiallylammonium chloride in syngeneic
thyroid transplantation. Half a thyroid gland was placed
beneath the kidney capsule, either after being encapsulated
or as a nonencapsulated control graft. In euthyroid as well as
hypothyroid recipients, the grafted tissue was viable for up
to 12 weeks. Furthermore, the hypothyroid state, which was
characterized by markedly diminished 1251 incorporation in
the thyroid, no body weight gain, and undetectable serum
T4 concentrations, was compensated by the grafted tissue.
However, the encapsulated grafts were associated with
lower iodine incorporation, T4 secretion, and body weight
gain compared with nonencapsulated control grafts. It was
thought that this might be due to a partial restriction of TSH
by the capsule membrane. The authors concluded, however,
that the cellulose sulfate membrane is biocompatible
and enables the functional survival of syngeneic grafted
tissue.
A new method for thyroid transplantation across major
histocompatibility complex (MHC) barriers using allogeneic
bone marrow transplantation has been reported." Previously, it
was demonstrated that allogeneic bone marrow transplantation
after lethal irradiation elicits donor-specific tolerance for

organ or tissue transplantation across MHC barriers and that
portal venous administration of donor bone marrow cells
elicits donor-specific tolerance across MHC barriers with two
administrations of an immunosuppressant (cyclosporine or
FK-506).31 Lee and coworkers used this central and intrahepatic tolerance-inducing system to establish a method for
thyroid transplantation. In addition to sublethal (6 to 5 Gy)
irradiation, recipient B6 (H-2 b) mice received intraperitoneal
injections with the myeloablative drug busulfan on day -2 to
provide sufficient space for the donor hematopoietic cells to
expand in the recipients. To induce intrahepatic tolerance,
donor BALB/c (H-2 d) bone marrow cells were treated with
neuraminidase, which enhances the trapping of intravenously
injected bone marrow cells in the liver. After the injection of
the neuraminidase-treated bone marrow cells, the thyroid
organs from the BALB/c mice were engrafted under the
renal capsules. A 90% graft survival rate was obtained over
100 days with a combination of busulfan administration,
6-Gy irradiation, and intravenous injection of neuraminidasetreated bone marrow cells. T cells collected from the tolerant
recipients suppressed the proliferative responses to donor
alloantigens. The authors concluded that this regimen
prevented the rejection of thyroid allografts.
Further studies have examined the mechanism of thyroid
allograft rejection. Niimi and colleagues found that the overexpression of heme oxygenase-l correlated with the protection
of fully allogeneic thyroid grafts from rejection. 32,33 In these
studies, one lobe of the thyroid was transplanted under the
kidney capsule. C57BL/l0 (H-2 b) thyroids were rejected in
naive CBA (H-2 k) mice within 14 days after transplantation.
However, when mice were treated with anti-CD4 monoclonal antibodies, all grafts survived for more than 60 days.
The first grafts still survived after second C57BLlI0 or
BALB/c (H-2 d) thyroid grafts that were transplanted into the
same recipients were rejected acutely, which suggests that
the primary grafts were modified under anti-CD4 antibody
treatment. To confirm this hypothesis, C57BL/l0 thyroid
grafts from anti-CD4 antibody-treated mice were retransplanted. All grafts survived in naive mice, which correlated
with the overexpression of heme oxygenase-l in the grafts.
An inhibitor of heme oxygenase-l (zinc protoporphyrin) or
control compound (copper protoporphyrin) was injected
intraperitoneally after transplantation of C57BLllO thyroid
grafts into the primary CBA recipients that had been treated
with anti-CD4 antibody. The grafts in mice that had been
treated with zinc protoporphyrin, but not copper protoporphyrin, were rejected when retransplanted to naive recipients,
suggesting that overexpression of heme oxygenase-l correlated with the protection of fully allogeneic thyroid grafts
from rejection when retransplanted into naive recipients.
Human thyroid xenografts have also been transplanted
into immunodeficient mice in models to study Graves' disease,
and these studies have demonstrated functioning human thyroid tissue that remains responsive to TSH stimulation.t'-"
Thus, although thyroid autotransplantation is feasible, currently the applicability of thyroid allotransplantation or
xenotransplantation in humans remains investigational as
thyroid hormone replacement therapy has generally been
satisfactory in treating both disease-induced and postoperative
hypothyroidism and avoids immunosuppression.
694 - -
Endocrine Pancreas
3.0
Parathyroid
The treatment of surgically acquired and idiopathic
hypoparathyroidism requires life-long treatment with vitamin
D and oral calcium supplementation. This is not, however, a
perfect physiologic replacement because, although it sufficiently regulates blood calcium and phosphate levels, it does
not reverse the lowered urinary calcium reabsorption and
excessive urinary calcium excretion, which may result in
renal stones." Owing to the complexity of parathyroid hormone's metabolic interactions, clinical hypoparathyroidism
is one of the most difficult of all endocrine disorders to treat.
Autotransplantation of parathyroid tissue in humans is well
established and widely practlced.P:" Although parathyroid
allotransplantation is well established in animal models, it is
rarely performed in humans and has rarely been used clinically because its advantages have been outweighed by the
need for immunosuppression. Allotransplantation of parathyroid tissue in humans may be desirable, however, for treating
long-term hypoparathyroidism (e.g., after inadvertent
removal of parathyroid glands during thyroid surgery). Studies
have attempted to reduce the immunogenicity of parathyroid
tissue similarly to thyroid tissue. Microencapsulation, as
noted before, is a technique that was first attempted in islet
cell transplantation. Hasse and colleagues have been able to
achieve long-term success in a rat model.f After isolation
and tissue culture, tissue pieces from parathyroid glands of
280 Lewis rats were encapsulated in barium alginate and
grafted into hypocalcemic DA rats. From the 7th to the
90th day after transplantation, the recipient rats (DA rats)
showed a normal serum calcium concentration, demonstrating
the successful long-term survival and function of microencapsulated allotransplanted parathyroid tissue.
This group subsequently evaluated the feasibility of
parathyroid xenotransplantation.P In this study, human
parathyroid tissue was microencapsulated and transplanted
into the rat and the effect of this microencapsulation on
xenotransplanted human parathyroid tissue was evaluated
over a 30-week course. Functionally human parathyroid
tissue was able to replace that of the rat. All animals that had
received the microencapsulated parathyroid tissue were
normocalcemic for 16 weeks and 27 of 40 animals were
normocalcemic at the end of the study. In contrast, serum
calcium concentrations dropped to postparathyroidectomy
levels within 4 weeks in the animals that had received native
tissue only. Histologic evaluation of the explanted, functionally successful xenografts showed vital parathyroid tissue
inside intact microcapsules surrounded by a small rim of
fibroblasts. Fibrotic nonfunctioning parathyroid remnants
were demonstrated in animals with nonencapsulated
parathyroid tissue. These authors established the feasibility
of microencapsulation of human parathyroid tissue and ability
to preserve its viability over long periods in vivo, even with
xenotransplanted tissue. Thus, transplantation of human
parathyroid tissue and maintenance of its physiologic function
were achieved without postoperative systemic immunosuppression in a xenotransplant model. 44,45 The group validated
this model with an amitogenic alginate, and this technique
has now been used clinically where parathyroid transplantation was performed without immunosuppression (Fig. 77_2).46
40
35
::J
~
'0
2.5
30
2.0
25 ::J
E
OJ
20
.s
iii
(J
iii
15
1.5
- 0 - Total calcium
_iPTH
1.0
10
5
0
-3 -2 -1 0 1 2 3 4 5 6 7 8 9 1011 12
VVeeks
Transplantation
FIGURE 77-2. Calcium and intact parathyroid hormone (iPTH)

concentrations before and after parathyroid allotransplantation.
Hasse and colleagues'" succeeded in parathyroid allotransplantation in two human subjects without immunosuppression. The
donor for the patients was an ABO-compatible, human leukocyte
antigen (HLA)-mismatched patient with parathyroid hyperplasia
caused by secondary hyperparathyroidism.After parathyroidectomy,
the tissue was cut into l-mm! pieces and immersed in amitogenic
2% sodium alginate. The suspension was passed through a spray
nozzle for encapsulation with a constant flow of 6.5 Llmin. The
microencapsulated parathyroid cells were cultured and 20 microcapsules were transplanted into the brachioradialis muscle of the
nondominant forearm of the patients. After transplantation, the
recipients had normal levels of calcium and iPTH without
immunosuppression. (From Lee MK, Bae YH. Cell transplantation
for endocrine disorders. Adv Drug Deliv Rev 2000;42: 103.)
Prior to these techniques utilizing immunoisolation, other

investigators also studied parathyroid allotransplantation
using other techniquesv'? leading to attempts at parathyroid
allotransplants in humans.P Duarte and coauthors reported
on a 25-year-old woman with idiopathic hypoparathyroidism
that had been diagnosed when the patient was 4 years of
age.!' Long-term medical management with vitamin D and
oral calcium supplementation was complicated by multiorgan
calcinosis and renal failure. At the age of 21 years, the
patient received a successful cadaveric renal allograft;
however, 4 years later, she developed calcinosis cutis with
widespread skin necrosis. Medical control of calcium and
phosphate metabolism was unsatisfactory, and the skin necrosis became progressive and life threatening. A parathyroid
allograft that was performed with tissue from a parathyroid
adenoma resulted in normalization of the serum calcium and
phosphorus levels with arrest and subsequent healing of the
skin necrosis. Later failure of the parathyroid allograft was
followed by successful retransplantation of normal parathyroid tissue from a cadaveric organ donor.5 I In addition,
Tolloczko and colleagues reported on patients with postoperative hypoparathyroidism (after thyroid operations) who
were treated with cultured, hormonally active, living and
ABO-compatible parathyroid cells. 52. 54 Tissue was harvested
from two patients with secondary hyperparathyroidism. In
these studies, hormonal activity of the graft was variable
but lasted up to 14 months. Others have also attempted
Transplantationof EndocrineCells and Tissues - - 695

parathyroid allotransplantation to treat intractable
hypoparathyroidism.P-"
Similar to the immunoisolation provided by encapsulation,
other methods to avoid long-term immunosuppression such
as immunomodulation have been employed in order that
parathyroid allotransplantation be feasible. Pretransplantation
treatment of the graft to eliminate passenger cells is one
such method. An alternative approach is short-term treatment
of the recipients with cyclosporine. Bloom and associates
cultured parathyroid glands from Lewis X Brown Norway
rats for 1 week and treated them with antiserum directed
against class II MHC antigens. 57 Treated glands were then
transplanted into hypocalcemic Wistar-Furth recipients that
previously received 30 mg/kg cyclosporine once a day for
3 days before transplantation. At 280 days after transplantation, 67% of the recipients had functional parathyroid
allografts. Control rats (no cyclosporine; fresh, untreated
glands) rejected these grafts within 28 days. Control rats
given 3 days of cyclosporine and transplanted with fresh,
untreated glands had functional grafts for greater than 56 days
(median survival, 80.5 days). The authors concluded that
prolongation of allograft survival with short-term, preoperative
cyclosporine demonstrates the efficacy of immunosuppression
given at the time of antigen presentation. This course of
cyclosporine was even more effective when the recipient
received a graft whose passenger cells were eliminated.
Some sites in the body may also be immunoprivileged.
The lateral ventricle of the brain has been investigated
as a potential immunoprivileged site for viable parathyroid
allograftS. 58,59 Yao and colleagues allotransplanted parathyroid
tissue from histoincompatible rats that survived and
remained functional for more than 3 months in the cerebral
ventricles of recipient F344 rats. Microscopic examination
proved that the allotransplanted parathyroid tissues retained
normal histologic features. In contrast, when the parathyroid
was placed beneath the renal capsule, the allografted
parathyroid tissue uniformly lost its capacity to liberate
parathyroid hormone within 1 month, and only residual scar
tissue remained at the transplantation site. After allotransplantation of parathyroid tissue into the cerebroventricle, the
serum concentrations of both Ca 2+ and parathyroid hormone
were maintained at levels similar to those before parathyroidectomy, until the time of sacrifice. The thymus has also
been reported as an immunoprivileged site for parathyroid
autotransplants.s"
As noted, parathyroid autotransplantation is a well-defined
clinical entity with an interesting history37.39 and is most
often performed for a parathyroid inadvertently removed
during thyroid surgery or when it cannot be preserved on its
vascular supply. Autotransplantation may also be performed
in the management of the patient with parathyroid hyperplasia
or secondary hyperparathyroidism. As this is the technique
most commonly performed by the endocrine surgeon, the
technique of autotransplantation is reviewed here.
Parathyroid tissue to be autotransplanted is temporarily
stored in iced saline solution. A muscle pocket is created
(generally in the sternocleidomastoid or the forearm, although
the subcutaneous space has also been used). It is important
to avoid bleeding in the pocket as hematoma formation
prevents subsequent vascularization of the autograft; thus,
packing the pocket for several minutes to ensure hemostasis
is advised. Multiple pockets may also be created, and we

do so to maximize subsequent autotransplant success and
decrease the risk of loss related to hematoma. The parathyroid
tissue (approximately 1- x l-mm pieces) is placed into the
pocket(s). The pocket may be closed with a Prolene suture,
clip, or both, to mark the transplant site as hyperparathyroidism may develop after autotransplantation of histologically normal parathyroid tissue. For this reason, it is
important to mark the site of the parathyroid autotransplant." In addition to the immediate transplantation of fresh
tissue, cryopreserved tissue may be autotransplanted in this
manner. The specific techniques of cryopreservation have
been described in detail and are widely used. 62,63
Thus, although parathyroid autotransplantation is well
established clinically, allotransplantation may hold promise
for the future. Cultured fetal parathyroid gland cells have
been used in treating patients with hypoparathyroidism.v'
Whether these techniques or stem cell technology will have
utility in the treatment of hypoparathyroid patients will
require further elucidation.
Adrenal
Adrenal cortical insufficiency (Addison's disease) occurs
with a prevalence of 93 to 110 per million population.P
Etiologies of Addison's disease include bilateral adrenal
dysfunction induced by autoimmune reactions and tuberculosis, carcinoma, hemorrhage, and infarction. In addition,
patients with multiple endocrine neoplasia type 2, von
Hippel-Lindau disease, and familial pheochromocytoma
who have had bilateral adrenalectomy for pheochromocytoma
are another population who require life-long steroid replacement therapy.
Life-long steroid hormone replacement (cortisone and
mineralocorticoid) is the only available therapy for acquired
or congenital adrenal cortical insufficiency. In contrast to
exogenous thyroid hormone replacement therapy, adrenal
hormone replacement therapy is less physiologic and more
difficult to regulate. More important, it does not adequately
or autonomously substitute the hormone peaks required in
physiologic stress situations or replace the physiologic circadian secretion of corticosteroids. Inappropriate replacement
in adrenal insufficiency can result in persistent metabolic
abnormalities in an overtreated patient (hypertension, glucose
intolerance, osteoporosis) or persistence of the addisonian
state in an undertreated patient (hypotension, electrolyte
abnormalities).
A more physiologic strategy to replace adrenal cell function
in patients with adrenal insufficiency would be to transplant
autologous or allogeneic adrenal cortical cells into addisonian
patients. This approach has been evaluated by a number of
investigators.
As early as 1951, Patino and Fenn reported the successful
transplantation of a human embryonic adrenal gland in a
patient with Addison's disease/" Rodent models of adrenal
cell transplantation have been studied more recently. Ricordi
and colleagues found that culture of donor tissue followed
by short-term recipient treatment with cyclosporine allowed
30-day survival of adrenal cortical tissue in a rat model.f
They also reported that parathyroid and adrenal medulla

transplants were often infiltrated by mononuclear cells;
however, adrenal cortical tissue was well preserved after
transplantation. A potential mechanism for this is discussed
subsequently.
Scheumann and colleagues conducted similar experiments in which adrenal cortex from rats was isolated from
the medulla by collagenase digestion and implanted under
the kidney capsule of recipient rats.68 The recipient rats'
native adrenals were subsequently removed. The corticosterone levels of the transplanted animals were close to
normal and the animals survived for 8 weeks. Surviving
adrenal cortical cells could be demonstrated in the explanted
grafts by immunohistochemistry. An interesting subsequent
finding by these investigators was that isolated, purified
zona glomerulosa cells (usually responsible for aldosterone
synthesis), when transplanted, had the ability subsequently
to express the enzyme cytochrome P-4S0 11~, which is necessary for corticosterone synthesis/" These results suggest
that glomerulosa cells are able to take over and maintain the
physiologic function of the entire adrenal cortex.
Hornsby and colleagues developed a mouse model in
which xenotransplanted adrenal cortical tissue was formed
in immunodeficient mice by using techniques of cell transplantation. In this model, cells of bovine and of adult and
fetal human origin can be transplanted subcutaneously in
severe combined immunodeficient (SCID) mice after being
embedded in collagen gel. At this site the cells survived,
became vascularized by host endothelial cells, secreted
steroid into the circulation, and replaced adrenal function in
adrenalectomized animals.P:" Additional review of these
studies examined some of the potential mechanisms of
growth of the xenotransplanted cells." In these experiments,
bovine adrenal cortical cells in a small cylinder were introduced beneath the kidney capsule in rats (Fig. 77-3). In this
model, the extent to which the transplanted cells became
lined by host endothelial cells was correlated with higher
degrees of proliferation and nuclear p21, suggesting that
vascularization is the critical step for the survival of the
transplanted cells."
The immune response to transplanted adrenal cortical
cells has also been evaluated. Ellerkamp and coworkers cultured allogeneic adrenal cortical cells in mixed lymphocyte
cultures to examine the alloimmune response." In this
model, the presence of adrenal cortical cells potently suppressed the allogeneic immune response. Interestingly, this
effect was only in part due to the secretion of corticosteroids
as demonstrated in experiments using the steroid receptor
antagonist mifepristone (RU 486). These data thus suggested an immunomodulatory property of adrenal cortical
cells in addition to the effect of the secreted corticosteroid.
Seeliger and colleagues also studied a model of cellular
adrenal cortical transplantation." They demonstrated that
syngeneic transplantation resulted in physiologic corticosterone levels early after transplantation, whereas fully
MHC-incompatible grafts were rejected. Recipients of
Kb-transgenic grafts (expression of the transgenic MHC class
I molecule showed unimpaired adrenocortical function but
did not tolerize toward Kb-transgenic skin grafts. Possible
mechanisms suggested included a local immunomodulatory
effect of glucocorticoids secreted by the graft and low
immunogenicity of the relatively small numbers of transplanted cells in this model, in which a single cell suspension
of adrenocortical cells was grafted under the kidney capsule.
Interestingly, an adrenal cell transplantation model has
also suggested the mechanism of adrenal cortex zonation."
In this model, purified cell suspensions of glomerulosa and
fasciculata cells were obtained by density gradient separation and were transplanted under the kidney capsule either
immediately or after a 29-day culture period. Cells derived
from the zona glomerulosa maintained viability, produced
both aldosterone and corticosterone, and regenerated a
neocortex with cells that histologically resemble both zona
glomerulosa and zona fasciculata cells and thus are suitable
for adrenocortical transplantation. In contrast, cells derived
from the zona fasciculata maintained viability but did not
regenerate zona glomerulosa and did not produce aldosterone. These results suggest that the cell migration model,
in which zona glomerulosa cells can acquire the phenotype of
zona fasciculata cells as they can migrate centripetally,is more
likely the correct explanation of adrenocortical zonation.
Other studies have evaluated the role of intercellular
adhesion molecule I (ICAM-I) in adrenal transplantation."
Fragmented adrenal glands of wild-type B lO.BR (H-2k) and
wild-type or ICAM-I-deficient BALB/c (H-2d) mice were
transplanted beneath the kidney capsule of adrenalectomized BI0.BR mice (complete MHC haplotype disparity
FIGURE 77-3. Experimental transplantation

of adrenal cortical cells. The host is a scm
mouse. A small polycarbonate filter is
inserted beneath the capsule of the kidney.
The cylinder creates a space beneath the
capsule into which the cells are introduced.
Tissue becomes visible within the cylinder
with evidence of new blood vessel formation
from the capsule and surrounding connective
tissue. (From Hornsby Pl. Transplantation of
adrenocortical cells. Rev Endocr Metab
Disord 2001;2:313.)
Transplantation of Endocrine Cells and Tissues - -
in the latter). In this model, ICAM-l deficiency significantly

prolonged the survival of adrenal grafts. Although markedly
reduced reserve capacity was observed, the authors concluded
that fragmented adrenal grafts were able to maintain physiologic basal corticosterone levels and that autologous or
MHC-compatible allogeneic transplantation of adrenal grafts
may replace oral hormone substitution in humans.
Thomas and colleagues evaluated the transplantation of
human adrenal cells into SCID mice." Human adrenocortical cells from postnatal donors were transplanted beneath
the kidney capsule of adrenalectomized scm mice together
with mitomycin C-treated 3T3 cells that secrete fibroblast
growth factor. Adrenocortical cells from seven donors, male
and female, ranging from 6 to 50 years of age, were used.
Vascularized adrenocortical tissue formed at the site of
transplantation. Cortisol, the normal human glucocorticoid,
was present in the plasma of animals, replacing corticosterone, the mouse glucocorticoid. Some animals also had
measurable aldosterone. The tissue formed from the transplanted cells showed histologic and ultrastructural features
of normal adrenal cortex. This study demonstrated that tissue
formed from transplanted human adrenocortical cells is able
to replace the essential functions of the adrenal gland in
scm mice and that transplanted human endocrine cells can
functionally replace a surgically removed endocrine organ
in a host animal. Further studies from this group investigated
the role of the animal's host adrenal glands in adrenal cortical
cell transplantation." Classic organ and tissue transplantation studies have suggested that the success of transplantation depends on the activity of the pituitary gland and other
endocrine systems and is therefore influenced by the host
animals' own adrenal glands. These cell transplantation
experiments, involving the introduction of bovine adrenocortical cells into scm mice, did produce transplant tissues in
the presence of the host animals' adrenal glands. However,
the tissue that formed was small and its cells also smaller
than usual. When the adrenals of such animals were removed
in a second surgical procedure, the transplants showed a
rapid increase in steroidogenic function and a slower
increase in size over several weeks. The conclusions from
these studies were that the initial process by which transplanted adrenocortical cells organize into a tissue structure
is not affected by the presence of the host animals' adrenal
glands but the growth of the transplants is limited until the
adrenal glands are removed.
Perhaps, in the future, adrenal regeneration may be feasible by engineering embryonic stem cells to express an adrenal cell phenotype. Studies have found that stable
expression of steroidogenic factor I (SF-I) is sufficient to
alter embryonic stem cell morphology, permit cyclic adenosine monophosphate- and retinoic acid-induced expression
of the endogenous side chain cleavage enzyme gene, and
consequently promote steroidogenesis in embryonic stem
cells.s? The clinical applicability of adrenal cell transplantation requires further investigation.
697
history of medicine. Beta-cell replacement therapy is the

only treatment that reestablishes and maintains long-term
physiologic normoglycernia." because intensive subcutaneous insulin regimens cannot completely mimic the physiologic fluctuations of in vivo insulin secretion.f The two
options for replacement of beta-cell function in patients are
whole-organ pancreas transplantation and islet cell transplantation. Although diabetes mellitus is not generally managed by the endocrine surgeon, whole-organ pancreas
transplantation and islet cell transplantation are addressed
briefly here for completeness. These topics have been
expertly reviewed,81-83 and the reader is referred to these and
the referenced studies for further detail.
Pancreas Transplantation
Whole-organ pancreas transplantation is a major surgical
procedure with a significant rate of morbidity and the need
for immunosuppression. However, it improves the patient's
quality of life and reverses some diabetic complications, and
up to 82% insulin independence at I year is reported.f
Pancreas transplantation can be performed simultaneously
with kidney transplantation (SPK), as occurs in approximately 90% of patients, or after kidney transplantation (4%)
and in specialized enters in nonuremic patients as pancreas
transplantation alone (6%).82 Survival rates are better for
SPK because acute rejection can be treated earlier, coinciding
with the simultaneous rise in serum creatinine that is indicative
of acute rejection of the kidney. Pancreas transplantation in
a nonuremic patient is performed more rarely. These patients
have "brittle" (labile) diabetes or hypoglycemic unawareness that is regarded as potentially more harmful than the
combined risk of the immunosuppression and surgical risks.
The University of Minnesota has the largest experience
(n = 225), with acceptable rates of graft survival (80% at
1 year) and survival of patients (90% at 1 year).84
A combination of long waiting lists and restrictions dictated
by organ allocation policies has prompted many pancreas
transplantation centers to encourage initial kidney transplantation using a living donor kidney and follow-up with a
cadaver pancreas as a separate procedure.P The University
of Maryland has taken this option one step further by offering
simultaneous living kidney (using laparoscopic nephrectomy
for the donor nephrectomy) and cadaver pancreas transplantation (SPLK) when a donor pancreas becomes available."
With this single recipient surgical procedure, they reported
1-year actuarial survival of 94% and 86% for the kidney and
pancreas, respectively. As a result, they noted that the waiting time for SPK at their center has been reduced by 45%.
The group in Minneapolis also continues to promote living
donation of both pancreas and kidney (SLPK) and have
reported 115 procedures." However, there is a long learning
curve and the need for meticulous donor evaluation to minimize the metabolic and surgical complications for the donor.
Islet Cell Transplantation
Pancreas
The introduction of insulin therapy for the management of
diabetes mellitus is one of the greatest milestones in the
The main advantages of islet cell transplantation are that it is

generally a minor radiologic procedure with low morbidity
and mortality and can be performed before the onset of
debilitating diabetic complications (Fig. 77-4). The history
FIGURE 77-4. Pancreas transplantation

is associated with insulin independence
in more than 80% of patients but is a
complicated procedure with significant
perioperative morbidity. Islet cell transplantation with its reduced antigen load,
technical simplicity, and low morbidity
has the potential to restore glucose
homeostasis and prevent long-term complications. (From Lakey JR, Burridge
PW, Shapiro AM. Technical aspects of
islet preparation and transplantation.
Transpl Int 2003;16:613.)
of islet cell transplantation has been reviewed." In the past,

however, results have been poor because of the variability of
the multiple steps in the islet cell isolation process, the need
for diabetogenic immunosuppression agents, and the challenges with rejection monitoring." The islet isolation procedure is challenging as the pancreas requires donor retrieval
in the same manner as whole-organ pancreas transplantation, a short cold ischemic time, digestion with collagenase,
cell separation and centrifugation, resuspension, and then
intraportal injection.f Perhaps as a result of this prolonged,
difficult islet isolation process, the l-year insulin-independent graft survival was only 14% in 37 patients in the international islet transplant registry from 1998 to 1999.
A landmark study at the University of Alberta in
Edmonton, Canada, reported 100% success in seven patients
using a new immunosuppression protocol, a milestone
achievement that reinvigorated the enthusiasm for and interest in islet transplantation worldwide.f? The success of the
Edmonton protocol includes careful recipient selection,
transplantation of an appropriate islet cell mass, avoidance
of steroids, and use of sirolimus, low-dose tacrolimus, and
daclizumab.P Generally, more than one donor has been
required to achieve sufficient islet cell numbers, with the
second and subsequent donor islets transplanted freshly as
they became available. Selection of patients included a
history of at least 5 years of type I diabetes; failure of optimal
insulin therapy, usually with life-threatening hypoglycemia;
and the benefits of transplantation must outweigh the risk
of life-long immunosuppression. An update of the
Edmonton results was presented by Shapiro at "200 I:
A Transplant Odyssey Congress" in Istanbul with reported
I-year insulin-independent graft survival of 80% for
20 patients. The results of the Edmonton group have been
validated in other institutions (Minneapolis, Miami, Milan,
Geneva, Giessenj.f
Although pancreas allotransplantation is more advanced

clinically than that of the other endocrine organs discussed,
both whole-organ pancreas transplantation and islet cell
transplantation are dependent on cadaveric organs, and thus
only a small number of diabetic patients can be treated in
this manner. Whether islet cells will ultimately be generated
from stem cells or precursor cells to expand the number of
cells available for transplantation requires further study.
The future and potential transplantation therapies available
both for the management of patients with diabetes and the
care of other patients with the endocrine deficiencies discussed in this chapter are indeed exciting and challenging.
In the future, the endocrine surgeon may not only resect
abnormal thyroid, parathyroid, adrenal, and pancreatic tissue
but also routinely transplant normal cells or tissues to
replace lost endocrine function.
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Pancreatic Endocrine
Physiology
Bo Ahren, MD, PhD Maria Sorhede Winzell, PhD
Historical Introduction
Islet Function
In 1869, Paul Langerhans showed that islands of characteristic cells are distributed throughout the pancreas and that
these islands are richly innervated. 1After the demonstration
that diabetes evolves after pancreatectomy? it was suggested
in 1901 that the disease is caused by lack of a factor produced by these islets of Langerhans.' Although several
researchers were close to the discovery of insulin, the critical pieces of work in this area were performed by Banting,
Best, MacLeod, and Collip in the early 1920s.4 The structure
of insulin was established in the 1950s; insulin was the first
protein ever to be structurally defined." Other landmark discoveries have been the radioimmunoassay determination of
insulin in 19606 and the identification of the gene coding for
insulin in 1977.7
The islets also produce other regulatorypeptides, apart from
insulin, and four major hormones are known to be produced
by the different islet endocrine cells. The idea that the islets
also produce a factor that increases blood glucose was proposed by Murlin and colleagues in 1923,8although glucagon
was not isolated until 1955.9 In 1968, pancreatic polypeptide
(PP) was identified, 10 and in 1974, it was discovered that the
islets also produce somatostatin.'! During the 1980s, the
microanatomy of the islets with endocrine cells, nerves, and
blood vessels was characterized (Fig. 78_1).12-16 Other contributions to our knowledge of the endocrine pancreas
include characterization of the cell biologic processes underlying the exocytosis of the peptide-storing secretory granules
(Fig. 78_2),17 the regulation of expression of the islet peptide
genes, 18 and the understanding of the failure of the B cells as
a key contributor to the development of type 2 diabetes."
A key role for the pancreatic islets is to deliver an optimal

amount of peptide hormones into the bloodstream to optimize
carbohydrate metabolism. Of most importance in this
respect is insulin, which facilitates the transport of glucose
into insulin-dependent cells for storage as glycogen and fat
with a concomitant reduction in blood glucose and free fatty
acid levels as a consequence. One of the most important
target organs for insulin action is the liver, in which at least
50% of the insulin secreted from the endocrine pancreas is
extracted before reaching the systemic circulation. Other
important target organs are skeletal muscle and adipose
tissue, which express the insulin receptor. Insulin reduces
circulating levels of glucose by inhibiting glucose release
from the liver and augmenting glucose uptake in skeletal
muscle and adipocytes. Glucagon is also an important
hormone regulating carbohydrate metabolism. Glucagon
increases blood glucose levels mainly by increasing hepatic
glucose delivery through stimulation of glycogenolysis.
A thorough understanding of the regulation of carbohydrate
metabolism therefore requires a detailed knowledge of the
pancreatic islets and their anatomy and physiology as well
as pathophysiologic importance for conditions of impaired
glucose tolerance and diabetes.
The authors have been supported by Swedish Research Council Grant

l4X-6834, the Albert Pablsson, Crafoord, and Novo Nordic Foundations,
the Swedish Diabetes Association, and the Faculty of Medicine, Lund
University.
Islet Anatomy
The endocrine pancreas consists of the pancreatic islets, which
are distributed throughout the pancreas and form, in adults,
approximately 1% to 2% of the pancreatic mass. The individual islet is a well-organized microorgan (see Fig. 78-1).
Each islet comprises a number of cells, and the islets vary in
size from one or a few cells to a few thousand endocrine
cells. The different islet cell types show a typical arrangement. In the center of each islet, a core of B cells exists,
701
FIGURE 78-1. Functional anatomy of a typical islet of Langerhans. The insulin-producing B cells (gray) are located in the center of the
islet with the glucagon-producing A cells, the somatostatin-producing D cells, and the pancreatic polypeptide-producing F cells (white)
located in the periphery. The arterioles penetrate to the center of the islet structure, where permeable, fenestrated capillaries are formed.
This organization of the blood supply suggests that artery-borne hormones such as GIP, GLP-l, and CCK and nutrients such as glucose
first reach the B cells and that the B cells can affect the other cell types in an endocrine fashion. Sympathetic, parasympathetic, and afferent sensory nerves innervating the islet release various neurotransmitters involved in the regulation of insulin secretion. ACh = acetylcholine; CCK = cholecystokinin; CGRP = calcitonin gene-related peptide; GIP = gastric inhibitory polypeptide; GLP-l = glucagon-like
peptide I; GRP =gastrin-releasing peptide; NE = norepinephrine; NPY = neuropeptide Y; PACAP =pituitary adenylate cyclase-activating
polypeptide; PP = pancreatic polypeptide; VIP = vasoactive intestinal peptide.
constituting approximately 60% to 80% of all islet cells.

Surrounding these B cells, there is a mantle zone consisting of
the glucagon-producing A cells, the somatostatin-producing
D cells, and the PP-producing F cells. The A and F cells
show a characteristic mutual distribution; the tailor dorsal
portion of the pancreas is rich in A cells but poor in F cells,
with the reverse relation between these cell types in the head
or ventral portion of the gland" Another characteristic of
the islet cells is that they produce a number of different peptides besides the four major islet hormones (Table 78-1).
B Cells
Insulin
The main peptide produced by the B cells is insulin. In
humans, the gene coding for insulin is located on the short
arm of chromosome 11, in region p15. 21.22 The regulation of
the gene expression has been shown to reside in a 350-bp
Sf-flanking region. This region contains a proximal promoter
region and a distal transcriptional enhancer region. The
enhancer region, in tum, is composed of several different
sequences to which nuclear regulatory proteins bind to stimulate or inhibit the promoter. The transcription of the insulin
gene is subjected to regulation because, for example, it is
stimulated by glucose through the formation of a substrate
formed by the aerobic glycolysis of the hexose.P Also, cyclic
adenosine monophosphate (cAMP) and phorbol esters
activate insulin gene transcription," and the amount of insulin

messenger RNA (mRNA) is increased when the demand for
insulin is enhanced (e.g., after partial pancreatectomyj.P
Several transcription factors have been demonstrated to bind
to cis-regulatory elements on the promoter region of the
gene, such as Beta2, pdxl (also called ipfl), and MafA, and
gene disruption studies have demonstrated critical roles of
these factors in insulin gene expression.v-" Therefore, transcription factors, nutrients, and other regulators of B-cell
function have the capability to alter the amount of available
insulin by influencing the transcription of the gene message.
After the transcription, the mRNA coding for insulin
passes to the endoplasmic reticulum, where the message is
translated. A signal peptide is removed, and proinsulin is
formed. The translation of insulin mRNA to proinsulin, like
the transcription of the insulin gene, has also been shown to
be under the regulation of a variety of factors, for example,
glucose.i? After its synthesis, proinsulin is packaged in the
secretory granules; inside these, the peptide is cleaved to
insulin and C peptide, which are extruded in equimolar
amounts through an exocytotic process when the B cells are
activated.P The final exocytosis of the secretory granules is
regulated by a variety of factors, mainly nutrients, hormones,
and nerves. This regulation has been extensively studied
during the last 3 decades. I? Thus, through influences on at
least three levels of regulation within the B cell (transcription,
translation, exocytosis), the peripheral demand for insulin is
tightly controlled to optimize carbohydrate metabolism.
Pancreatic Endocrine Physiology - -
703
FIGURE 78-2. Schematic overview of cell biologic processes involved in the stimulation of insulin secretion from the pancreatic B cell.
Glucose is transported into the B cell by facilitated transport by the glucose transporter (GLUT2). Within the B cell, glucose is metabolized and adenosine trisphosphate (ATP) is generated. ATP then inhibits K+ permeability by closing the ATP-regulated K+ channels.
Accumulation of K+ inside the B cell leads to depolarization of the plasma membrane, which in turn transforms the voltage-dependent
calcium (Caz+) channels into an open state. The influx of Caz+ leads to an increase in the concentration of free cytoplasmic Ca z+.
Cytosolic Caz+ acts in several ways to increase the rate of exocytosis of insulin from the insulin-storing secretory granules. For example,
Caz+ is required for the activation of protein kinase C (PKC), protein kinase A (PKA), and calmodulin, all of which phosphorylate specific
proteins required for initiation of the exocytotic process. Caz+ is also a cofactor for the activation of the receptor-coupled enzyme phospholipase C (PLC). PLC activation can be initiated by activation of G-protein-coupled cholecystokinin (CCK) and acetylcholine (ACh) receptors. PLC activation leads to the hydrolysis of the plasma membrane phospholipid phosphatidylinositol bisphosphate (PIP z) into
diacylglycerol (DAG) and inositol trisphosphate (lP 3) . DAG activates PKC and IP 3 liberates Caz+ from intracellular storage sites (i.e., the
endoplasmic reticulum). Interaction of glucagon-like peptide I(GLP-I) or gastric inhibitory peptide (GIP), with their specific receptors on
the B-cell plasma membrane, results in elevated intracellular levels of cyclic adenosine monophosphate (cAMP), which activates PKA.
Activation of PKA affects the production of lipid signals by activation of hormone-sensitive lipase (HSL). HSL hydrolyzes stored triglycerides and increases the intracellular concentration of fatty acids (FAs), which are converted to acyl-CoA. Acyl-CoA has multiple effects
on the B cell, functioning as a signaling molecule in potentiating glucose-stimulated insulin secretion. Extracellular fatty acids may also
interact with a plasma membrane-bound receptor (GPR40) to stimulate insulin secretion directly by potentiating the increase in intracellular Ca z+ caused by glucose. Phospholipase A z (PLA z) activation yields arachidonic acid (AA), which has been proposed to liberate Ca z+
from intracellular stores. It should be noted that interactions and cross-talk between the different intracellular messenger systems as well
as the action of substances inhibitory of insulin secretion have not been taken into consideration in this figure.
Islet Amyloid Polypeptide

The islet B cells also produce islet amyloid polypeptide
(lAPP, or amylin), which was initially purified from amyloid
deposits in an insulinoma." lAPP was later demonstrated to
be a normal constituent of the B cells." This peptide has
been shown to contain 37 amino acids and shows a high
degree of structural similarity to the neuropeptide calcitonin
gene-related peptide (CGRP).33.34 The lAPP gene is localized to chromosome 12, and it codes for an 89-amino acid
proIAPP.35 In the B cells, lAPP is stored in the secretory
granules'" and is released from the cells together with and in
parallel with insulin." Some studies, however, have suggested that insulin and lAPP are not released in absolute
parallelism'" and the levels of insulin mRNA and lAPP
mRNA seem to be regulated in a nonparallel fashion under
certain conditions."
The function of lAPP is poorly understood. A local regulatory role to restrain insulin secretion has been suggested
because the peptide inhibits insulin secretion.vv" The finding that an lAPP antagonist exaggerates insulin secretion in
rats may suggest that under physiologic conditions lAPP
restrains insulin secretion.F Therefore, lAPP secreted from
the islet B cells seems to function as an inhibitor of the
activity of the B cells.
In addition to potential effects of lAPP to inhibit insulin
secretion, the main interest in lAPP has been concentrated
on its ability to form amyloid fibrils, which occurs in the
islets during the development of type 2 diabetes. 34,43-45
Exaggerated release of lAPP with the subsequent formation
of islet amyloid and deterioration of islet function has, therefore, been an intriguing speculation as a pathogenetic event
for the development of diabetes.
Pancreastatin
Another peptide that is produced by the islet B cells is
pancreastatin, which is a carboxyterminal ami dated
49-amino acid peptide initially purified from the pancreas

and found to inhibit glucose-stimulated insulin secretion
from the perfused rat pancreas." Pancreastatin is cleaved
from chromogranin A before its storage in B-cell secretory
granules.f The peptide is released from the pancreas in
parallel with insulin.f inhibits insulin secretion, and stimulates
glucagon secretion.i? The physiologic function of pancreastatin is not known.
A Cells
Glucagon
The most important peptide produced in the A cells is
glucagon. The glucagon gene is composed of six exons and
five introns, and the gene is expressed not only in the islet
A cells but also in the intestinal L cells and the brain. The
glucagon gene codes for a 160-amino acid proglucagon,
which is posttranslationally cleaved to several different
peptides." An important difference exists between the pancreatic A cells and intestinal L cells with regard to cleavage
of proglucagon and the final formation of different
glucagon-related peptides. Thus, in the pancreatic A cells,
three different peptides are formed: glucagon, glicentinrelated polypeptide, and a larger peptide, called the major
proglucagon fragment, which in its sequence contains the
sequence of glucagon-like peptide I (GLP-I) and GLP-2. In
contrast, in the intestinal L cells, GLP-l and GLP-2 are
formed as separate peptides and, in addition, oxyntomodulin
is formed. 50
It is known that glucagon gene expression, glucagon

synthesis, and glucagon secretion are stimulated by various
amino acids (e.g., arginine) and hormones that increase
cAMP formation and inhibited by glucose and insulin.
Often, the B and A cells are reciprocally regulated, which is
illustrated by glucose stimulating the B cells but inhibiting
the activity of the A cells. Because insulin and glucagon
counteract the effects of each other on glucose metabolism,
such a reciprocal regulation is functional. However, some
stimuli activate both cell types (e.g., vagal nerve stimulation)." Such combined activation of both insulin and
glucagon cells could be of importance for the rate of glucose
turnover, which increases when glucagon activates hepatic
glucose delivery concomitantly with insulin facilitating
peripheral glucose uptake. This may be of physiologic
importance after food intake, when facilitated transport of
nutrients to target cells is required without an exaggerated
increase in the circulating levels of the nutrients.
Peptide YY
Besides glucagon, other peptides seem to be produced by
the pancreatic A cells. One such peptide is peptide YY
(PYY), which is a 36-amino acid peptide that shows structural similarities to neuropeptide Y (NPY) and pp.52 Thus,
PYY has been confined to secretory granules of the islet
A cells.P The function of PYY produced by the islet A cells
is not known, although the peptide has been shown to inhibit
the secretion of both insulin and glucagon.P>'
Pancreatic Endocrine Physiology - - 705
D Cells
F Cells
Somatostatin
Pancreatic Polypeptide
In 1974, it was shown by immunocytochemistry that the islet

D cells contain somatostatin, which was initially described
the year before as a hypothalamic peptide inhibiting the
secretion of growth hormone.'! It is now known that in the
islet D cells, the somatostatin gene codes for prosomatostatin, which is a 92-amino acid peptide.P Prosomatostatin is
processed to three different peptides: the 14-amino acid
peptide somatostatin-14 (prosomatostatin [78-92]), which is
the main product in the islet D cells; a fragment consisting
of the 12 aminoterminal amino acids of somatostatin-28
(prosomatostatin [64-76]); and a larger fragment, corresponding to prosomatostatin (1-64).55 The secretion of somatostatin from the islet D cells seems to be regulated in parallel
with that of insulin. For example, glucose, amino acids, and
sulfonylureas'" as well as vagal nerve activation'? stimulate
somatostatin secretion, whereas sympathetic nerve activation inhibits somatostatin secretion.P Somatostatin is, however, a widespread regulatory peptide and the contribution
of the islet source of somatostatin to the circulating pool
of somatostatin is negligible; hence it is not possible to study
regulation of islet release of somatostatin by measuring
circulating levels of the peptide.
Somatostatin is a powerful inhibitor of both insulin and
glucagon secretion.P However, the physiologic function of
the islet somatostatin is not established, and the parallel activation of Band D cells, often in a reciprocal fashion with
that of the A cells, is poorly understood. Previously, it was
thought that somatostatin inhibits the secretion of both
insulin and glucagon through a paracrine factor,'? but later
studies have questioned whether the somatostatin released
from the peripherally located D cells ever reaches the A
and B cells in quantities sufficient to exert any effect. 13
Therefore, more studies are required to address the potential
local role of somatostatin. Another hypothesis is that locally
released somatostatin from the peripheral islet D cells functions to restrain exocrine pancreatic secretion because the
microanatomy of islet vessels indicates that the effluent
vessels from the islet periphery reach the exocrine tissue'?
and somatostatin is a powerful inhibitory substance of
exocrine secretion.59 However, this hypothesis needs direct
experimental support before it gains general acceptance.
PP was first described as a contaminant of a chicken insulin

extract. 10 It is known today that the PP is produced by the
pancreatic F cells. PP consists of a 36-amino acid sequence
and is produced by cleavage from a 95-amino acid precursor/"
The F cells are particularly abundant in the ventral portion
of the pancreas, where the F cells seem to replace the A cells
in the mantle zone of the islet. Because PP secretion is stimulated by vagal activation, it has been suggested that plasma
PP levels offer a good parameter for vagal activity.'" The
peptide has been shown to inhibit the secretion of pancreatic
juice and bile and to suppress insulin secretion,65.66 which
might be of importance for interprandial homeostasis,
although the physiologic role of PP is yet to be established.
Diazepam-Binding Inhibitor
Another peptide that is produced by the human D cells is
diazepam-binding inhibitor (DBI), which is an 86-amino
acid peptide that binds to the benzodiazepine recognition
site within the y-aminobutyric acid (GABA)-receptor complex. 6o Immunocytochemical studies have localized DBI to
D cells in human islets, although in rat islets the peptide
seems to be confined to the A cells." Because DBI inhibits
glucose-stimulated insulin secretion,61,62 the two peptides
produced by the D cells, somatostatin and DBI, both restrain
insulin secretion, and a tempting speculation is that the
role of the D cells is to inhibit B-cell activity, although, as
previously stated, the islet paracrine concept has not been
established.
Islet Blood Flow

The pancreatic islets have a rich blood supply compared
with the surrounding exocrine tissue. Approximately 10% of
the pancreatic blood flow is directed to the islets, which
make up only approximately 1% to 2% of the pancreatic
mass. The microvasculature of the pancreatic islets exhibits
a characteristic feature, which has been carefully studied in
the rat." It has been shown that the arterioles nourishing an
islet enter into the central B-cell mass, where fenestrated
and highly permeable capillaries are formed (see Fig. 78-1).
The capillaries then pass out from the central B-cell mass to
the mantle zone, where they either empty into venules or
anastomose with the capillaries of the exocrine parenchyma.
Careful studies have also presented evidence that within the
central B-cell mass, approximately 8 to 10 B cells are distributed around a central capillary/" This microvascular
organization makes it likely that the nourishing blood passes
first through the central B-cell mass before reaching the
peripherally located A, D, and F cells.
This anatomy of the islet vessels is probably of importance for the function of the islet because blood-borne substances first reach the B cells before they can affect the other
cells. Also, insulin secreted from the B cells reaches the other
cells in high concentrations and, therefore, affects the secretion of glucagon and somatostatin in an inhibitory direction.
In contrast, because of the flow direction within the islet, the
products from the A and D cells probably do not reach the
B cells; therefore, it seems unlikely that the stimulatory
action of glucagon and the inhibitory action of somatostatin
with regard to insulin secretion are exerted by local
endocrine effects within the islets. The islet microvasculature
anatomy also suggests that anastomoses between the islet
and exocrine capillaries result in an insular acinar portal
system, which suggests that the peptides secreted from the
islet cells reach the acinar cells in high concentrations. 14
The regulation of the islet blood flow has not been studied
in such a great detail as that of islet hormone secretion. It
seems, however, that the blood flow in the islets is controlled
differently from that in the exocrine tissue. For example,
glucose, vagal nerve activation, and lAPP all increase the
relative fraction of islet blood flow versus total pancreatic
blood flow.68.69
Islet Nerves
The pancreatic islets are richly innervated by the autonomic
nerves (see Fig. 78-1).15,16 These nerves are postganglionic
sympathetic nerves with their nerve cell bodies in the
celiac ganglion, and postganglionic parasympathetic nerves
with their nerve cell bodies in intrapancreatic ganglia.
Preganglionically, the nerve impulses pass through the
splanchnic and vagus nerves, respectively. The nerves primarily innervate the vessels, but some fibers also enter into
the islets and terminate in close proximity to the islet
endocrine cells. Electrical activation of the nerves has been
shown to exert profound influences on insulin and glucagon
secretion. Thus, activation of the sympathetic nerves inhibits
insulin but stimulates glucagon secretion, whereas activation of the vagus nerves stimulates both insulin and
glucagon secretion. Besides the classic neurotransmitters
norepinephrine and acetylcholine, the islet nerves have also
been shown to harbor various neuropeptides (see Table 78-1).
A large number of studies have examined the role of these
neurotransmitters in pancreatic islet physiology.
Islet Neurotransmitters:
Sympathetic Effects
It was initially thought that the neurotransmitter mediating
the sympathetic effects is norepinephrine because this is the
classic adrenergic neurotransmitter and is known to inhibit
glucose stimulated insulin secretion." However, combined
adrenergic blockade does not abolish the influences of sympathetic nerve stimulation on insulin and glucagon secretion
and norepinephrine only partially reproduces the stimulation
of glucagon secretion that accompanies sympathetic nerve
activation.I'r? Therefore, the sympathetically induced influences on islet hormone secretion seem to be partially nonadrenergic. Such effects may be mediated by neuropeptides
confined to sympathetic nerve terminals, such as NPy73 and
galanin." This hypothesis is supported by the findings that
both NPY and galanin are released from the pancreas during
sympathetic nerve stimulation and that both of these neuropeptides inhibit insulin secretion and stimulate glucagon
secretion.P:" In addition, NPY may be involved in the regulation of pancreatic blood flow because perivascular adrenergic
nerves contain NPy73 and NPY has profound vasoconstrictor influences on the pancreas.I? Therefore, it is established
that sympathetic nerve activation inhibits insulin but stimulates glucagon secretion, although the neurotransmitter
involved on these actions has not been finally defined. It is
tempting to speculate that different neurotransmitters are
involved under different conditions in the sympathetic regulation of islet function. For example, the inhibition by sympathetic nerve activation of basal insulin secretion might be
mediated by a neuropeptide (NPY, galanin, or both), whereas
the inhibition of glucose-stimulated insulin secretion might
be mediated by norepinephrine.
Catecholamine Effects
The influence of catecholarnines on insulin secretion was
initially thought to be inhibitory because norepinephrine and
epinephrine were demonstrated to reduce the insulin secretory response to glucose. 70,80,81 However, the influences of the
catecholamines are dependent on the degree of expression of
various adrenergic receptors. Thus, activation of postsynaptic
a-adrenergic receptors, mainly of the lXz subtype on the islet
B cells, inhibits insulin secretion.f whereas activation of the
~-adrenergic
receptors, mainly of the ~2 subtype, stimulates
insulin secretion." On the other hand, with regard to
glucagon secretion, catecholarnines seem to be stimulatory
through the activation of both a- and ~-adrenergic
receptorS.84.85
Islet Neurotransmitters:
Parasympathetic Effects
Both acetylcholine and the cholinergic agonist carbamoyl
choline stimulate insulin secretion.l" It has, therefore, been
thought that acetylcholine is the mediator of vagal effects
on islet function. However, results of studies on the possible
involvement of acetylcholine as the neurotransmitter in
vagally controlled islet hormone secretion have questioned
this hypothesis. Thus, in the pig, vagally induced insulin and
glucagon secretions are not totally inhibited by atropine,"
whereas in the dog, glucagon secretion during vagal nerve
activation is not inhibited by atropine." This suggests that
noncholinergic involvement exists after vagal nerve activation of islet hormone secretion, at least in some species.
Studies of the nature of this noncholinergic involvement
have proposed that vasoactive intestinal polypeptide (VIP),
pituitary adenylate cyclase-activating polypeptide (PACAP),
and gastrin-releasing polypeptide (GRP) may be involved.
Nerves containing the 28-amino acid neuropeptide VIP
have been demonstrated in the endocrine pancreas."
Furthermore, VIP is released from the perfused pancreas
during vagal nerve activation.f" and VIP potently stimulates
insulin and glucagon secretion. 16 Moreover, islet nerves also
contain the 38-amino acid neuropeptide PACAP, and
PACAP is a powerful stimulator of insulin and glucagon
secretion as demonstrated in several species, including
humans.89-91 The physiologic importance of PACAP for
normal islet function is also supported by studies in mice
genetically deficient in one of the PACAP receptors, which
show impaired glucose-stimulated insulin secretion.P?
Similarly, nerves containing the 27-amino acid peptide GRP
exist in the pancreas." GRP is released from the pancreas
during vagal nerve activation." and GRP stimulates the
secretion of insulin and glucagon." The influences of the
parasympathetic nerves and their neurotransmitters, acetylcholine, VIP, PACAP, and GRP, are probably of main importance after food intake, when activation of these nerves
contributes to the marked insulin response.
Cholecystokinin Nerves
Cholecystokinin (CCK) immunoreactivity occurs in islet
nerves, although the nature of these nerves is yet to be
defined." Because it is known that CCK potently stimulates
insulin secretion." the CCK nerves may be of importance
for islet function. However, the physiologic importance of
the islet CCK nerves remains to be established.
Sensory Nerves
The endocrine pancreas is innervated by sensory afferent
nerves as well as by the sympathetic and parasympathetic
nerves." These sensory nerves seem to harbor CGRP and
substance P as neurotransmitters.P'?' Both these neuropeptides inhibit insulin secretion." The role of these sensory
nerves in the regulation of islet function has been examined
with the use of the neurotoxin capsaicin, which destroys
sensory nerves." Using a neonatal model with capsaicin
treatment in mice, a sensory denervation was created, and it
was demonstrated that CGRP and substance P were partially
or completely depleted from islet nerves after such treatment, indicating that this is a suitable model for studying the
function of the sensory nerves in the endocrine pancreas."
Interestingly, it was demonstrated that such treatment potentiates insulin secretion and increases glucose tolerance."
Thus, sensory nerves seem to restrain glucose tolerance.
The Gut and Insulin Secretion

It has long been known that oral ingestion of glucose results
in high levels of plasma insulin, although the increase in
plasma glucose is only marginal. 100,101 This is due to the
action of gut hormones, called incretins, that are released into
the circulation during meal intake and stimulate insulin secretion. The most important incretins are glucose-dependent
insulinotropic polypeptide (GIP; also called gastric
inhibitory polypeptide) and GLP_1. IOZ,103 GLP-l is a
3Q-amino acid peptide produced in the L cells in the distal
part of the small intestine, and GIP is a 42-amino acid peptide produced in the K cells in the duodenum and proximal
portion of the small intestine. They are both released into
the circulation during the first 15 minutes after initiation of
food intake, and they both stimulate insulin secretion. Their
importance as incretin hormones is illustrated by findings
that insulin secretion and glucose tolerance are impaired in
mice with genetic deletion of the GIP receptors'?' and the
GLP-l receptors. 105
GLP-l is the most important incretin hormone. 103,106,107
This peptide is processed from proglucagon in the intestinal
L cells and released into the blood during meal ingestion.
GLP-l potently stimulates insulin secretion at concentrations that are produced by food intake. The peptide has, in
addition, been of interest as a potential novel treatment
modality in diabetes because of its combined effect to
stimulate insulin secretion, inhibit glucagon secretion, and
reduce blood glucose levels by a "peripheral" effect. 108,109 It
should be recalled that GLP-l is not produced in the pancreatic A cells but only in the intestinal L cells because of the
cell-specific posttranslational modification of proglucagon
related to differential expression of proconvertases. A problem in developing GLP-l as a treatment for type 2 diabetes
is that it is rapidly degraded by means of the enzyme dipeptidyl peptidase IV (DPPIV)."O This enzyme is expressed in
several tissues, including endothelial cells, liver, gut, and
kidney, and cleaves the two aminoterminal amino acids from
GLP-l, making the truncated form inactive in stimulating
insulin secretion. Because of this, the half-life of GLP-l is
only a few minutes. Attempts to overcome this drawback

when developing GLP-l for treatment include production of
DPPIV-resistant GLP-l analogs and development of agents
that inhibit the activity of DPPIy'"O Both these approaches
have been successful, and clinical trials have been undertaken with both of them. III,IIZ
Cell Biology of Islet B Cells

The cell biology of the islet cells has been studied in great
detail regarding the underlying mechanisms of secretion
of insulin from the islet B cells (see Fig. 78-2). The most
important regulator of insulin secretion is glucose, which
enters the cells through a specific glucose-transporting
protein, GLUT-2. 113,1l 4 GLUT-2 is insulin independent in
its action, and its capacity for transporting glucose is high.
Hence, the intracellular glucose concentration rapidly equilibrates with the extracellular concentration, indicating that
GLUT-2 is not the rate-limiting step for B-cell function.
When glucose has entered the B cells, it is phosphorylated
by glucokinase to glucose 6-phosphate.1 15 The glycolytic
activity in the glucose-exposed islet is basically regulated by
glucokinase acting as the rate-limiting enzyme in the flux of
substrates through the glycolysis. The glucokinase activity
has therefore been recognized as the B-cell glucose sensor. I 16
After its phosphorylation, glucose is metabolized and
adenosine triphosphate (ATP) is formed. 117 An increased
intracellular content of ATP or rather an increased ratio of
ATP to ADP (adenosine diphosphate) leads to closure of
specific ATP-regulated potassium (K+) channels in the plasma
membrane. I 18 This leads to a decreased outflow of K+ from
the B cells, which, in turn, depolarizes the cells, resulting
in the opening of L-type voltage-sensitive Ca z+ channels. 119
This causes a massive inflow of Caz+ from the extracellular
space because the cytoplasmic free concentration of Ca z+
under resting conditions is only approximately 100 nmollL,
whereas extracellularly it is approximately 1.2 mmollL (i.e.,
more than 10,000 times that of the cytoplasm). The massive
inflow of Ca z+ raises the cytoplasmic Ca z+ concentration.P"
which is necessary for exocytosis of the insulin secretory
granules. 17 This chain of events is of importance for the first
phase of glucose-stimulated insulin secretion. Interestingly,
oral hypoglycemic agents, such as sulfonylureas, which are
commonly used to treat patients with type 2 diabetes, also
initiate insulin secretion by inducing closure of the ATPregulated K+ channels.'?' Furthermore, several inhibitors of
insulin secretion act by opening these K+channels and thereby
induce hyperpolarization and closure of the voltage-sensitive
Ca z+ channels, for example, diazoxide.F' which is used in the
treatment of insulinomas, and the neuropeptide galanin.F'
Hence, the activity of the ATP-regulated K+channels and the
degree of polarization of the B-cell plasma membrane are of
great importance for insulin secretion.
However, for the maintenance of a sustained elevation of
the secretory rate of the islet B cells, mechanisms other than
those initiated by depolarization and uptake of Ca" are of
importance (see Fig. 78-2). One such mechanism is the formation of cAMP, which is stimulated by glucose through
activation of adenylate cyclase.P' Cyclic AMP activates

protein kinase A, which stimulates the exocytosis of
granules. 17 Several factors besides glucose that affect insulin
secretion modulate the cellular content of cAMP. For example, the inhibitors of insulin secretion galanin and PYY
reduce islet cAMP,54.123 whereas the insulin-promoting
peptides glucagon and GLP-I increase the islet content of
CAMP.125,126 The actions of cAMP and protein kinase A
require a stimulatory level of glucose; hence, this pathway
is regarded as a modifier of glucose-stimulated insulin
secretion. It has been proposed that islet cAMP is under the
influence of a variety of G proteins of both a stimulatory and
an inhibitory nature.F'
Besides the uptake of extracellular Ca 2+ and the formation of cAMP, insulin secretion may also be stimulated by
factors that increase the hydrolysis of membranous phosphoinositides through the activation of phospholipase C,17.128
which causes the hydrolysis of phosphatidylinositol
4,5-bisphosphate, yielding inositol l,4,5-trisphosphate (IP 3)
and diacylglycerol (DAG). IP 3 diffuses into the cytoplasm
and activates specific IP 3 receptors on intracellular Ca 2+
storage sites, which further enhances the cytoplasmic
concentration of Ca 2+ and potentiates insulin secretion.
Furthermore, DAG and Ca 2+ activate protein kinase C (PKC),
which through a direct action on the exocytotic machinery
stimulates insulin secretion.!" Cholinergic agonists, CCK,
and the neuropeptide GRP all stimulate insulin secretion
mainly through this phospholipase C pathway.96,130,131
Glucose has also been shown to stimulate the formation
of arachidonic acid in the endocrine pancreas through activation of phospholipase A 2 (PLA 2).132 Because an inhibitor
of PLA 2, p-amylcinnamoylanthranilic acid, has been
demonstrated to inhibit markedly both arachidonic acid
formation and insulin secretion after glucose activation of
isolated islets, it has been proposed that this pathway is of
importance for insulin secretion. 133 A mediator of this pathway might be liberation of intracellular Ca 2+, which is
induced by arachidonic acid. 133 However, it has also been
suggested that the main function of PLA 2 is to maintain the
intracellular stores of insulin rather than being required for
the initiation of insulin secretion.P"
Besides these signaling pathways, lipids are also involved
in intracellular signaling and insulin secretion (see Fig. 78-2).
During glucose metabolism in B cells, the cytosolic concentration of long-chain acyl coenzyme A (LC-CoA) increases.P'
and a model for second-phase insulin secretion is based on
the knowledge that when glucose is metabolized there is
increased production of citrate in the Krebs cycle in the
mitochondria. Citrate is transported into the cytosol, where
it is converted to malonyl CoA, a potent inhibitor of carnitine palrnitoyltransferase I (CPT-I), which transports longchain fatty acids into the mitochondria, where they are
oxidized. Thus, the transport of long-chain fatty acids is
inhibited during glucose metabolism and the concentration
of LC-CoA increases in the cytosol. LC-CoA has been
found to have effects on the ATP-regulated K+ channels-"
and on PKC activation137 and to influence directly the secretion of insulin by facilitating the fusion of secretory granules
with the B-cell plasma membrane. 138
Lipid signaling molecules involved in insulin secretion
may also be derived from the breakdown of intracellular
triglyceride stores. Hormone-sensitive lipase, the enzyme
known to hydrolyze stored triglycerides in adipose tissue, was
found to be expressed and also active in B cells.P? supporting

a role for endogenous lipolysis in regulation of insulin secretion. It is thus possible that hydrolysis of B-cell triglyceride
stores plays an important role in stimulus-secretion coupling
by increasing the intracellular concentration of fatty acids,
which are converted to acyl CoA by acyl CoA synthase,
thereby contributing to increased LC-CoA concentration in
the cytosol.
Besides this mechanism mediating lipid-induced insulin
secretion, it has also been suggested that fatty acids activate
intracellular pathways through binding to receptors that are
expressed on the surface of the cells.l'? GPR40 is a G-proteincoupled receptor that is highly expressed on B cells. By binding of long-chain fatty acids to GRP40, glucose-stimulated
insulin secretion is potentiated. Fatty acid activation of
GPR40 results in increased intracellular Ca 2+ and potentiation of glucose-stimulated insulin secretion. Therefore, both
glucose and nonglucose stimuli are of importance for insulin
secretion through perturbing intracellular pathways. Many
of these have been characterized in detail through intense
research work during the last 3 decades. Still, however, the
complete nature of the cell biology of the B cells is not
established.
Cell Biology of Islet Non-B Cells

The mechanisms by which nutrients stimulate insulin
secretion, including the signal transduction pathways of the
B cells, have been extensively studied. Much less is known
about the other islet cell types, including the mechanisms
behind modulation of glucagon secretion. Glucagon is
secreted from A cells in response to low blood glucose, and
thus the secretion is decreased as glucose increases. It has
been shown that pyruvate metabolism in the mitochondria is
implicated in the initiation of glucagon secretion141 and that
the mechanism of action seems to involve closure of ATPregulated K+ channels, which have been shown to be
expressed on islet A cells together with voltage-dependent
Ca 2+ channels.142.143 Furthermore, as in most exocytotic
events, Ca 2+ and ATP are required in glucagon secretion. In
B cells, glucose increases ATP production and elevates intracellular Ca 2+; however, in A cells, ATP production is much
less increased and Ca 2+ is barely changed after glucose stimulation."" By contrast, A cells respond to pyruvate with both
increased ATP production and Ca 2+ influx, whereas B cells
do not, because of low expression of pyruvate transporters.
Thus, the coupling ofATP generation and Ca 2+ elevation differs between A and B cells, and it has been suggested that
the simultaneous activation of B cells inhibits glucagon
secretion."! The insulin granules contain several substances
that may be involved in the inhibition of glucagon secretion,
including islet amyloid polypeptide, zinc, ATP, and possibly
glutamate. Other data suggest that zinc is important in
inhibiting glucagon secretion. 141
Pulsatility of Islet Hormone

Secretion
A characteristic of islet hormone secretion is its oscillatory
or pulsatile pattern. For example, insulin secretion has been

shown to occur in a periodic manner, with a rapid periodicity of approximately 8 to 15 minutes and a slower oscillation
at intervals of 80 to 150 minutes.I44-146 In vitro studies have
demonstrated that the oscillation of insulin secretion is an
intrinsic characteristic of the B cells."? The oscillation of
insulin secretion is accompanied by similar oscillations in
the concentration of the cytoplasmic free Ca 2+,148 and a
model has been proposed suggesting that raising the glucose
level initiates oscillations in glycolysis and an oscillatory
nature of the formation of ATP, which, in tum, causes
oscillatory patterns of changes in membrane depolarization
and Ca 2+ influx.r'" The ATPIADP ratio has been shown to
oscillate in normal B cells. ISO
The reason for insulin secretion to oscillate is not completely known, but it could be to prevent the continuous
elevation of stimulatory metabolites, which may lead to
desensitization and downregulation of responses. The mechanism behind the metabolic oscillations is based on detailed
studies of spontaneous oscillatory glycolysis in skeletal
muscle extracts. In skeletal muscle, the oscillations are
driven by autocatalytic activation of the muscle isoform of
the key enzyme phosphofructokinase by its product fructose
1,6-bisphosphate, resulting in large oscillations in the
ATPIADP ratio. 151 The time course of changes in metabolic
and ionic parameters involves earlier changes in the
ATP/ADP ratio and in metabolites such as malonyl-CoA,
which occur before Ca 2+ or insulin secretion. ISO Besides the
oscillation of the individual B cells, islets also oscillate
together, suggesting that several islets function as a unit,
which results in regular oscillation of circulating levels of
insulin.P? The synchronization of the individual islets has
been suggested to be governed by the pancreatic ganglia and
therefore to be neural.F' which is supported by the finding
that after islet transplantation, oscillation develops at the
time when the transplanted graft is innervated.'>
That this is of physiologic importance is illustrated by
the fact that the characteristic of the oscillatory pattern is
altered in type 2 diabetes. ISS In healthy subjects, almost
all pulsatory phases of insulin secretion occur in association
with an accompanying oscillatory change in plasma glucose
levels, whereas this temporal association is weaker in
diabetics. 155 It is tempting to speculate that this altered relation between glucose and insulin oscillations is of pathophysiologic importance for the development of type 2 diabetes.
Endocrine Pancreas and

Type 2 Diabetes
From the previous discussions, it is clear that the endocrine
pancreas is a complexly regulated organ that integrates
incoming impulses of nutrient, hormonal, and neural nature,
The endocrine pancreas converts these impulses to an optimal secretion of the islet hormones mainly for the regulation
of carbohydrate homeostasis. An example of the consequences that follow derangement of the endocrine pancreas
is type 2 diabetes, A primary event during the development
of this disease is a reduced action of insulin on the activation
of peripheral insulin receptors.P" This results in a compensatory increase in insulin secretion, which explains the
hyperinsulinemia that accompanies states with peripheral
insulin insensitivity, such as obesity. The relation between
c:
Ul
.5
"5
Ul
.s
Insulin sensitivity
FIGURE 78-3. Schematic illustration of the relation between

insulin sensitivity and insulin secretion. During progression to
insulin resistance (i.e., low insulin sensitivity), insulin secretion is
increased in a compensatory manner, The relation between the two
variables is nonlinear and best described by a hyperbolic function.
If insulin secretion is adequate in relation to insulin sensitivity,
normal glucose tolerance (NOT) remains. However, if the B cells
fail to compensate insulin resistance adequately, impaired glucose
tolerance or type 2 diabetes develops.
insulin sensitivity and insulin secretion is tightly regulated,

and careful mathematic analyses have shown that the
relation displays a curvilinear function that is best fit by a
hyperbolic function (Fig.78_3),157,158 as first demonstrated
by Bergman and collaborators in the early 1980s.157 Hence,
when insulin resistance develops, normal islet function ensures
adequate hyperinsulinemia. These patients thus have normoglycemia and hyperinsulinemia. This is, for example, seen
in the many subjects with obesity, who have insulin resistance but have compensated with a sufficient increase in
insulin secretion to avoid glucose intolerance.
However, in patients who proceed to type 2 diabetes, there
is a defect in glucose action on the B cells, leading to impaired
glucose-stimulated insulin secretion, making it impossible
for the B cells to compensate fully for the peripheral insulin
insensitivity. This leads to hyperglycemia and diabetes,I9,I59
Hence, the main defect in type 2 diabetes is defective beta
cells; insulin resistance can be regarded as a risk factor
because it may unmask the defective islet function. Also, the
ability of the A cells to respond properly with inhibition of
glucagon secretion when the glucose level is increased is
impaired in diabetes.P? This leads to hyperglucagonemia,
which, together with the insufficient hyperinsulinemia,
increases the hepatic glucose output and reduces the glucose
uptake in peripheral tissues, which are the metabolic signs of
type 2 diabetes. Central to the disease is the inability of the
B cells to respond normally to increased glucose levels. This
may be due both to impaired function of the individual B cells
and to reduced number of B cells, for example, through apoptosis. 160 The cellular biology basis for this defect is still poorly
understood. For the development of type 2 diabetes, furthermore, it has been demonstrated that it is mainly the first, initial, phase of insulin secretion that is of importance. 161 Hence,
appropriate early treatment of the disease is augmentation
of the first or early phase of insulin secretion (the first 10 to
15 minutes) after meal ingestion, which is instituted by rapid
secretagogues such as nateglinide and repaglinide-" together
with improvement of insulin resistance by life style intervention and drugs such as metforrnin and thiazolidinediones.
Endocrine Pancreas and

Hypoglycemia
An important physiologic role of the endocrine pancreas
is protecting the body against hypoglycemia, which is
undertaken by the release of glucagon to counteract the fall
in glucose. A large number of studies have been directed
at establishing the mechanisms underlying the glucagon
response to hypoglycemia, and it has been demonstrated that
it is caused by an increase in both parasympathetic and sympathetic neural activity and by elevated levels of epinephrine
secreted by the adrenal medulla. 162 The importance of the
neural effects for this response has been demonstrated in
humans, in whom infusion of a ganglionic blocker has been
found to inhibit the glucagon response to hypoglycemia.lf
A similar response is that seen during neuroglycopenia,
when a local reduction of glucose in the brain cells initiates
activation of the autonomic nervous system to increase the
. some species,
. also
secretion of glucagon and, m
so imsu lin. 64.164
Neuroglycopenia is induced experimentally by an intravenous injection of the glucose analog 2-deoxyglucose,
which competes with glucose and creates a state of intracellular glucose deprivation, stimulating the discharge of both
the sympathetic and parasympathetic branches of the autonomic nervous system. This is followed by activation of
glucagon secretion, which is inhibited by both muscarinic
blockade by atropine and a-adrenergic receptor blockade
by phentolamine.P' Also, chemical sympathectomy by
6-hydroxydopamine and adrenalectomy reduce the neuroglycopenia-induced glucagon secretion, which shows that
this important counterregulation is mediated by both pancreatic nerves and the adrenals.l'" Hence, the autonomic
nerves, together with the direct action of low glucose and the
intraislet reduction of insulin, are of importance for a normal
glucagon response to hypoglycemia, which is of major
importance for avoiding hypoglycemic reactions during
intense insulin treatment in diabetes. In fact, the risk for
hypoglycemia is an important limiting factor for the treatment
of many patients.l'"
Endocrine Pancreas and Stress

Another important role of the endocrine pancreas is its
involvement in the hyperglycemia that accompanies various
kinds of stress. A few examples of stress are illustrated.
Physical Exercise
During physical exercise, there is an increased hepatic glucose
output, which underlies the hyperglycemia, as a result of
increased activity in the sympathetic nerves and elevated
arterial epinephrine levels.l'? Accompanying these changes
is an inhibition of insulin secretion and a stimulation of
glucagon secretion, which exaggerate the hepatic glucose
output and also reduce the peripheral glucose uptake. This
optimizes the availability of glucose to the central nervous
system during stress. A system for studying the mechanisms of
these influences was previously introduced in the swimming
mouse model, in which standardized 2-minute swimming is
accompanied by a 50% inhibition of glucose-stimulated

insulin secretion.l'" It was subsequently shown that both
chemical sympathectomy and adrenalectomy prevented the
impaired glucose-stimulated insulin secretion that occurred
during swimming, 169 which shows that both the sympathetic
nerves and the adrenals are of importance in this response.
Thus, it might be assumed that stress stimulates the sympathetic nervous system, which inhibits insulin secretion
through local release of norepinephrine as well as through
arterially borne epinephrine. It has also been demonstrated
that galanin immunoneutralization prevents the inhibition
of glucose-stimulated insulin secretion that accompanies
swimming.P" which indicates that the neuropeptide galanin,
occurring in pancreatic adrenergic nerve terminals (see prior
discussion), contributes, along with norepinephrine, to the
islet response to swimming stress. In any case, the neural
influences on islet function are of great importance for the
glucose adaptation to the increased demand during exercise.
Hemorrhagic Stress
An important factor for the restoration of blood volume
during bleeding is an increase in the plasma glucose level,
which induces osmotic absorption of fluid into the blood
vessels. Elegant studies by Jarhult!" have shown that the
increase in plasma glucose during bleeding is induced by
increased hepatic glucose delivery caused by increased
activity in the sympathoadrenal system. The mediating
link seems to be alterations in islet function because bleeding is accompanied by impaired insulin secretion, resulting
in unchanged or low plasma insulin levels in spite of
hyperglycemia'?" together with increased glucagon secretion.!" Direct studies to examine the underlying mechanisms have shown that bleeding causes activation of the
arterial baroreceptors in the carotid sinuses because of
hypotension, which elicits activation of the sympathetic
nerves causing inhibition of insulin secretion and stimulation of glucagon secretion through direct islet effects. The
increased glucagon-insulin ratio, together with increased
arterial concentrations of epinephrine resulting from the
release of catecholamine from the adrenal medulla, stimulates glucose release from the liver, which increases
plasma glucose levels and accentuates the gluco-osmotic
force to restore the blood volume.
Sepsis
In contrast to hemorrhagic stress, the metabolic stress in sepsis
and bums is usually not accompanied by hyperglycemia.
Instead, it is the overall glucose turnover that seems to be
activated, with preservation of normoglycemia.l?" Only in
advanced cases, and late during the course, hyperglycemia
develops as a result of impaired peripheral glucose
uptake.I" The endocrine pancreas seems to mediate the
increased glucose turnover. For example, in a study of
18 septic patients, hyperinsulinemia evolved during the initial,
normoglycemic phase, whereas inadequate insulin secretion
was seen only in the late hyperglycemic phase.!" During
late stages, cytokines, endotoxins, and other mediators
impair both peripheral glucose uptake and insulin secretion,
which cause hyperglycemia.'?' During the final stage, the
Pancreatic Endocrine Physiology - -
hepatic glucose delivery drops, leading to hypoglycemia.

Hence, the endocrine pancreas ensures an optimal discharge
of insulin until the septic insult becomes too strong. The
mechanism of the hypersecretion of insulin during sepsis
remains to be established. In one study, it was demonstrated
that the glucose-induced insulin secretion from isolated islet
cells was the same in septic rats as in control rats, indicating
first, that islet cells derived from septic animals have a
preserved insulin secretory capacity and second, that the
hypersecretion observed in vivo is probably mediated by an
indirect mechanism, hypothetically by neural influences or
inflammatory mediators.!"
Endocrine Pancreas after

Food Intake
An important function of the endocrine pancreas is to
deliver an optimal amount of insulin after a meal and to
ensure optimal metabolism of the ingested nutrients to store
the absorbed fuels as glycogen or fat or both. At least three
different mechanisms account for this delivery of insulin.
First, before the food is ingested or absorbed, insulin secretion is rapidly stimulated. This is evident from a study in the
rat in which ingestion of glucose raised plasma insulin levels
within 2 minutes, yet plasma glucose levels did not start
to increase until 3 minutes. 176 Also, rats given meals without
any digestible nutrients showed a clear-cut early insulin
response. 177 Because this preabsorptive insulin secretion has
been shown to be inhibited by atropine, it has been assumed
that this early phase of food-stimulated insulin secretion is
mediated by parasympathetic nerves.!" This has been confirmed in a study in humans, in whom autonomic blockade
by trimetaphan has been shown to abolish the cephalic phase
of insulin secretion.!" This phase has been suggested to be
of great importance for the prevention of glucose intolerance
after meal intake. Thus, inhibition of the cephalic phase of
insulin secretion by trimetaphan was associated with defective glucose tolerance in humans.!" Similarly, a study has
shown that sham-feeding improves glucose intolerance. 179
The second mechanism underlying food-stimulated
insulin release is mediated by the incretins from the gastrointestinal tract, mainly GIP and GLP-I (see prior discussion). Finally, a third mechanism is the ingested nutrients,
most notably glucose and amino acids, which by themselves
stimulate insulin secretion. These different mechanisms
ensure the optimal amount of insulin be delivered to the
blood, optimizing carbohydrate metabolism.
Summary
The endocrine pancreas is a well-organized and tightly
controlled micro-organ producing a variety of biologic active
peptides of particular importance for carbohydrate metabolism and the regulation of blood glucose levels. It integrates
the signals generated by the autonomic nervous system and
arterially borne hormones and nutrients to produce an
optimal discharge of the various bioactive regulatory peptides.
The micro-organ is of utmost importance for metabolic
homeostasis after food intake, during starvation, and under
711
various conditions of stress. Furthermore, impairment of

islet cell function results in severe metabolic consequences
(e.g., impaired glucose tolerance and diabetes). An understanding of the physiologic and pathophysiologic processes
in relation to glucose metabolism requires a detailed knowledge of the endocrine pancreas, its synthesis of the various
regulatory peptides, and the regulation of peptide synthesis
and secretion by hormones, nutrients, and neural influences.
We are gaining a more detailed understanding of the mechanisms that regulate the synthesis and secretion of the islet
cell hormones, and what is now evident is the critical importance of defective B cells for the development of type 2
diabetes. Future studies may more clearly define the
involvement of the endocrine pancreas in various forms of
stress and in the development of glucose intolerance and
diabetes.
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Insulinomas
Jeffrey D. Wayne, MD Edwin L. Kaplan, MD
Insulinomas remain one of the most interesting endocrine

tumors because of the diversity of symptoms associated with
their hormonal secretion and because of the frequent inability
of standard preoperative imaging studies to locate these small
tumors. Advances in the diagnosis, localization, and surgical
management of insulinomas are presented in this chapter.
Specifically, the novel, minimally invasive techniques of
endoscopic ultrasonography with fine-needle aspiration and
laparoscopic pancreatectomy with splenic preservation are
highlighted.
Tumors of pancreatic islet cell origin were described by
Nicholls I as early as 1902, well before the discovery of insulin
by Banting and Best in 1922.2 It was known that some
islet tumor extracts produced hypoglycemia when introduced
into dogs; however, not until insulin was discovered was
the significance of this observation appreciated. Harris'
described the clinical pathophysiology of hyperinsulinemia
in 1924 but did not associate the presentation of symptoms
with islet cell adenomas of the pancreas. Shortly thereafter,
Wilder and colleagues reported the first exploration for this
tumor by William 1. Mayo in 1926.4 Unfortunately, the
patient, a physician with an 18-month history of severe hypoglycemic attacks, was found to have a large, unresectable
malignant insulinoma with hepatic metastases. The patient
died within 1 month of surgery. An autopsy also revealed
the presence of renal calculi, suggesting that this patient
had multiple endocrine neoplasia type 1 (MEN 1). Roscoe
Graham of Toronto reported the first successful resection of
an insulin-secreting tumor." By enucleating a 2- to 3-cm
malignant insulinoma, Dr. Graham was able to palliate his
patient's hypoglycemic symptoms for a 14-month period.
Evarts Graham was the first surgeon to espouse the concept
of a blind subtotal pancreatectomy for cases of undetected
insulinoma. Finally, in 1935, Whipple and Frantz described
the classic clinical triad, now know as Whipple's triad, to
help improve the diagnosis of this condition, after noting a
40% negative laparotomy rate for suspected insulinoma,"
Pathophysiology
The pathophysiology of an insulinoma is based on excessive
secretion of insulin, which results in the clinical presentation
of hypoglycemia. During the 1960s, insulinomas and other
endocrine tumors of the gastrointestinal tract were found
to share common cytochemical characteristics as well as
a common neuroectodermal origin. This diverse group of
tumors was thus classified under the amine precursor uptake
and decarboxylation (APUD) concept," Although the APUD
concept is no longer accepted in its entirety, it played a very
useful role at the time by allowing an explanation for the
association of insulinomas with other neuroendocrine
tumors under MEN 1. MEN 1 has now been definitively
linked to a loss of heterozygosity on chromosome 11
(llq13).8 The gene for this disorder, called menin, has been
described. In MEN 1, insulinomas are often associated with
hormone-secreting tumors of the parathyroid, pituitary,
adrenal cortex, and thyroid glands. In such patients, a variety
of symptoms may be present, and diagnosis based on clinical findings alone is often difficult.
Zeiger and Norton? reported the increased expression of
messenger RNA encoding for the alpha subunit of the G,
protein, seen in insulinomas but not normal endocrine
tissues. G proteins, known to mediate hormonal transmembrane signaling, are thus thought to playa role in the unregulated secretion of insulin seen in these tumors. This seminal
work has paved the way for further studies of the molecular
basis of insulinoma and other endocrine neoplasms.
To appreciate the modem tests used to diagnose an insulinoma requires an understanding of islet cell function.
Insulin is released from the secretory granules within the
cytoplasm of beta cells of the pancreatic islets (Fig. 79-1).
Before exocytosis occurs, the inactive precursor, proinsulin,
is proteolytically cleaved into insulin and a 31-amino acid
connecting peptide called C peptide'? (Fig. 79-2). Some
conversion of proinsulin to insulin may occur after it is
secreted; however, the majority of the granule composition
within the beta cells consists of equimolar amounts of
C peptide and hormonally active insulin.
715
FIGURE 79-1. Electron micrograph of the neurosecretory

granules of a beta cell. Note the crystalline appearance as a result
of the presence of insulin (arrows).
Clinical Aspects
Signs and Symptoms
The symptoms of an insulinoma are based on profound
hypoglycemia with a lack of glycogen in the brain but also are
due to the release of epinephrine secondary to a low serum
glucose level. The signs and symptoms are best classified
"-CELL
ER
into neurologic, cardiovascular, and gastrointestinal manifestations'! (Table 79-1). Neurologic symptoms are most
frequent and range from apathy, dizziness, clouded sensorium, and strange behavior to convulsions in very severe
cases. In other instances, profound central nervous system
depression occurs with coma and even death if left
untreated. Cardiovascular signs and symptoms, such as
palpitations, tachycardia, and chest pain, are less common
and are primarily due to catecholamine release in response
to low serum blood sugar levels. Gastrointestinal symptoms,
such as hunger, nausea, and vomiting, may also occur in
about 10% of patients, but by far the vast majority of symptoms are neurologic in nature. Many patients with insulinomas are obese because they find that they can prevent
symptoms by eating more frequently.
The diagnosis of insulinoma is often delayed and can
take as long as several months to years, depending on
the severity of symptoms and frequency of hypoglycemic
attacks. Delays in diagnosis are due in part to the variability
and severity of the clinical presentations but certainly
depend on physician awareness as well. The attacks are
usually associated with fasting; most commonly, they occur
before breakfast and during the late afternoon. However,
attacks of fasting hypoglycemia may occur during exercise
as well. It must be understood that the severity of the clinical presentation predicts neither the size nor the malignant
potential of the insulinoma.
Differential Diagnosis of Hypoglycemia

FIGURE 79-2. Secretion of insulin from the pancreatic islet beta
cells: Schema of rough endoplasmic reticulum (ER), where proinsulin is synthesized, and secretion granules, where proinsulin is
cleaved into insulin and C peptide. (From Rubenstein AH, Kuzuya H,
Horwitz DL. Clinical significance of circulating C-peptide in diabetes mellitus and hypoglycemia disorders. Arch Intern Med
1977;137:625. Used with permission. 1977, American Medical
Association. )
As shown in Table 79-2, there are many causes of hypoglycemia. Hypoglycemia may be due to inhibition of glucose
production in the liver and stimulation of glucose utilization
by adipose and muscle cells. Hypoglycemic attacks secondary to an insulinoma are predominantly due to an overuse of
glucose by the cells in the body. These attacks are episodic
because of the intermittent secretion of insulin, especially in
Insulinomas - - 717
to the overuse of glucose in the case of an insulinoma or to

the underproduction of glucose. In many other instances,
including alcoholism and hormone insufficiency syndromes,
hypoglycemia can be due to antibodies that bind to insulin
and release it inappropriately. This may be seen in multiple
myeloma and systemic lupus erythematosus. A differentiation can often be made clinically by the amount of glucose
that must be infused intravenously to prevent hypoglycemia
and by testing for anti-insulin antibodies. Daily hepatic
production of glucose ranges from 100 to 200 g. If more
than 200 g of glucose is required to offset the hypoglycemia,
the patient suffers from overuse of glucose, which would
support the diagnosis of insulinoma.P
Diagnosis
The limitations of a clinical diagnosis for insulinoma
became apparent as early as 1935, when Whipple noted that
40% of explorations performed for insulinoma up to that
time failed. Noting the numerous causes of hypoglycemia,
Whipple set forth the strict diagnostic triad that bears his
name: (1) the signs and symptoms of hypoglycemia occur
during periods of fasting or exertion; (2) at the time of
symptoms, blood sugar levels must be less than 45 mg/dL;
and (3) symptoms are ameliorated by the administration of
oral or intravenous glucose." Although these criteria still
hold true, the diagnosis of insulinoma has been refined by
our better understanding of the pathophysiology of normal
and aberrant insulin secretion and our ability to measure
circulating levels of insulin, C peptide, and proinsulin.
Glucose and Insulin Levels
early cases. It is not until advanced or metastatic disease is

present that persistent hypoglycemia may ensue.
This state of excessive glucose utilization should be
differentiated from hypoglycemia that occurs after eating
(see Table 79-2). Postprandial or reactive hypoglycemia
is a much more common problem. It can occur in healthy
individuals or in patients who have undergone previous
gastric surgery. Patients after gastric resection, bypass, or
drainage procedures often experience hypoglycemia as part
of a "dumping" syndrome, which may also include diarrhea,
and a host of other systemic symptoms secondary to
catecholamine release. 12
In contradistinction, patients with insulinomas suffer hypoglycemiaafterfasting or exercise. Fasting hypoglycemia is due
Currently, the diagnosis of insulinoma is confirmed by

demonstrating a circulating insulin level that is inappropriately high for the serum glucose level, measured at the time
of hypoglycemia (Fig. 79-3). When a patient presents with
symptoms of hypoglycemia (i.e.. coma, convulsions, or
other neurologic symptoms), blood samples should be taken
for the determination of both insulin and glucose levels.
Samples should be drawn as early as possible to avoid
complications of hypoglycemia and before treatment with
glucose. Also, later, epinephrine secretion may cause mobilization of liver glycogen with a compensatory rise in serum
glucose, possibly masking the hypoglycemia associated with
an insulinoma. Although normal serum glucose levels are
60 to 95 mg/dL, symptoms of hypoglycemia usually do not
occur until levels are less than 50 mg/dL. Normal serum
insulin levels are typically below 30 ~U/mL.
Insulin-Glucose Ratio
The insulin-glucose (I1G) ratio provides a relationship
between these two values that aids in the determination of
the presence of an insulinoma. In a normal individual, the
ratio is always less 0.4, but in patients with an insulinoma
the ratio approaches 1.0 and may in some cases exceed 1.0.
The I1G ratio is important because as many as one third
of patients with an insulinoma have insulin levels within
normal limits when they have symptomatic hypoglycemia.
80
70
60
:;
60
ep(.OOI
50
~o
.. 40
.
--
Op<.OOI
..J
20
20 CD
10
10
75
iIi
-~#
Vl_
::l
30 0
0
0
30
10
Q)
.a8
0..-
..J
~Q.
gj
ii:
e;;,
E
u.i
I/)
0
40 U
50~
40
~E 30
<ll:S 20
E::I.
70
:l.
80
8 E 50
......... . . . . . ----.. . . ...........
-- -- ............
l~25
BA.M.
10
11
12 NOON
FIGURE 79-4. Levels of plasma insulin and blood glucose

during the last 4 hours of a 12-hour fast in a patient with an
insulinoma. (From Kaplan EL, Arganini M, Kang S-J. Diagnosis
and treatment of hypoglycemic disorders. Surg Clin North Am
1987;67:395.)
0
Normols
n=33
Adenomol
n=22
FIGURE 79-3. Plasma insulin (in microunits per milliliter) and

blood glucose (milligrams per deciliter). Relationships after
overnight fasting in 33 normal persons and in 22 patients with
solitary beta islet cell adenomas. Both plasma insulin and blood
glucose show highly significant differences between the two
groups. IRI = immunoreactive insulin. (From Harrison TS.
Hyperinsulinism and its surgical management. In: Hardy JD
red], Rhoads' Textbook of Surgery: Principles and Practice.
Philadelphia, JB Lippincott, 1977.)
Fasting Test
As most patients with an insulinoma have intermittent
attacks, the physician is unlikely to see patients while they
are acutely hypoglycemic. The most reliable method for documenting a hypoglycemic episode is the prolonged fasting
test. This is the "gold standard" of testing. After baseline
circulating insulin and glucose levels are obtained, the
patient fasts for 72 hours or until hypoglycemic symptoms
occur. Serum glucose levels are checked at regular intervals,
usually every 1 to 2 hours and more frequently when the
glucose level falls below 50 mg/dL. Simultaneous insulin
levels are obtained with the onset of symptoms or if the glucose level falls below 50 mg/dL.
Within 24 hours of fasting, 75% of patients with an
insulinoma have glucose levels less than 38 mg/dL, and in
25% the glucose level is less than 30 mg/dL. In normal
individuals, the serum glucose and insulin levels both fall;
thus, the I/O ratio remains less than 0.4. In patients with
an insulinoma, however, the serum insulin level remains
elevated because of autonomous secretion of insulin by the
tumor (Fig. 79-4) and the I/O ratio rises." The fasting test is
diagnostic of insulinoma in 70% to 80% of patients at
24 hours, 90% to 95% of patients at 48 hours, and 98% of
patients at 72 hours.
Measurement of Proinsulin and C Peptide

Proinsulin is the precursor molecule for insulin and is found
in the rough endoplasmic reticulum of the beta cells in the
pancreatic islets. As shown in Figure 79-2, the proteolytic
conversion of proinsulin results in the formation of equimolar amounts of insulin and its connecting peptide, C peptide.
In the presence of an insulinoma, there is an elevation of
both proinsulin and C peptide.P'" Furthermore, proinsulin
levels, which are usually less than 20% of the total immunoreactive insulin in normal individuals, are elevated in the
presence of an insulinoma. Levels higher than 50% are
thought by some to be diagnostic of an islet cell carcinoma.
Finally, should the diagnosis still be in doubt, measurement
of circulating C peptide may be helpful. The normal C peptide
level is less than 1.2 ng/dL.
There are two specific instances in which measurement
of C peptide levels has been particularly helpful. The first is
in patients with insulin-dependent diabetes mellitus. Such
patients may have circulating antibodies to insulin that interfere with the measurement of insulin in the blood. Elevated
levels of C peptide help confirm the diagnosis of insulinoma
in such patients. The second situation in which the C peptide
level is most useful is in patients who are surreptitiously
injecting insulin. Commercial insulin has no C peptide; thus,
these patients have low levels of C peptide in the setting of
a high insulin level and hypoglycemia.
Interpretation of the Fasting Test

Plasma Insulin Concentrations. A plasma insulin
concentration of 6 JlU/mL (36 pmol/L) by radioimmunoassay
(or 3 JlU/mL by immunometric assay) when the plasma
glucose concentration is below 45 mg/dL (2.5 mmol/L) indicates an excess of insulin and is consistent with insulinoma.
Unfortunately, plasma glucose concentrations fall below
50 mg/dL (2.8 mmol/L) in some normal subjects and remain
above 50 mg/dL in an occasional patient with an
insulinorna."
Insulinomas - - 719
Plasma C Peptide Concentrations. It is essential to

measure plasma C peptide at the end of the fast; measurement
of plasma proinsulin can also be helpful. Measurements of
plasma C peptide distinguish endogenous from exogenous
hyperinsulinemia. In patients in whom plasma glucose
concentrations fall below 45 mg/dL (2.5 mmollL), there is
no overlap in the values in insulinoma patients and normal
subjects at a plasma C peptide value of 0.2 nmollL. All
insulinoma patients have higher values and all normal subjects
who are hypoglycemic have lower values. For plasma proinsulin, the diagnostic criterion for insulinoma is 5 pmollL or
greater. 16
Provocative Tests
For patients in whom the diagnosis of insulinoma is suspected
but other tests have been normal or equivocal, provocative
tests may be used." A brief description of such tests follows.
Glucagon Test
Glucagon stimulates the release of glucose from liver
glycogen stores, thereby producing a rise in blood glucose
levels. A baseline glucose level is obtained, and then 1 mg
of glucagon is injected intramuscularly. Serum glucose
levels are then obtained at 15 minutes, 30 minutes, and subsequent 30-minute intervals for 3 hours. Normally, there is a
rapid rise in serum glucose levels during the first hour, with
a return to fasting glucose levels by 3 hours. Reactive hypoglycemia does not occur. In the presence of an insulinoma,
however, there is a greater than normal rise in the glucose
levels, followed by severe hypoglycemia in the presence of
elevated levels of insulin. This test is positive in 72% of
patients with insulinomas.
Glucose Tolerance Test

A glucose tolerance test may also indicate the presence of an
insulinoma. Fifty grams of glucose in 100 mL of water is
given orally and serum glucose levels are measured at 0, 30,
60, 90, 120, and 180 minutes. Normally, the peak glucose
level is reached by 1 hour, and does not exceed 160 mg/dL.
The normal serum fasting glucose level is regained at 2 hours.
Patients harboring an insulinoma have an exaggerated
hypoglycemic phase during which glucose levels may fall
20 mg/dL or more below fasting levels and remain
depressed for several hours. Symptoms of hypoglycemia
may be present. This test is noted to be positive in 60%
of insulinoma patients.
Calcium Infusion Test

Kaplan and colleagues demonstrated that infusion of calcium
results in a rise of serum insulin, C peptide, and proinsulin
levels in patients with an insulinoma'? (Fig. 79-5). In this
study, calcium was infused at a concentration of 5 mglkg per
hour, and hypoglycemia was noted to occur within 2 hours.
In normal individuals, glucose and insulin levels remain
normal in response to calcium infusion. More recently, this
FIGURE 79-5. Calcium infusion test. A patient with a welldifferentiated malignant insulinoma experienced hypoglycemic
symptoms nearly 1112 hours after the start of the calcium infusion
(*). Insulin levels increased maximally at 30 minutes, which was
accompanied by a threefold increase in proinsulin (shaded bar).
(From Kaplan EL, Rubenstein AH, Evans R, et a1. Calcium infusion: A new provocative test for insulinomas. Ann Surg
1979;190:501.)
test has been modified. A rapid intravenous calcium injection may be used preoperatively to confirm the diagnosis of
insulinoma," or calcium may be infused intra-arterially as
part of a localization study. This approach is described in
greater detail subsequently.'? Calcium stimulation tests are
used in infants with nesidioblastosis as well.
Pathology
Insulinomas tend to be small lesions. A full 40% are 1 em or
less in diameter at the time of operation, with 66% smaller
than 1.5 em and 90% less than 2 em in maximal diameter."
These lesions are distributed equally in the head, body, and
tail of the pancreas. Ectopic tumors are rare (less than 1%),
and when present they are found in close proximity to the
pancreas. Malignant insulinomas are rare, accounting for
5% to 10% of cases. Malignancy is defined by evidence of
local invasion into surrounding soft tissue or by the presence
of distant (lymph node or liver) metastases. Multiple tumors
are present in 8% to 17% of cases. When insulinomas
are multiple, MEN 1 should be suspected (Fig. 79-6A).
Approximately 10% of patients with hyperinsulinism have
MEN 1.21 Hyperparathyroidism resulting from chief cell
hyperplasia (Fig. 79-6B) and pituitary microadenomas
resulting in hyperprolactinemia are the most common associated findings in this group of patients.
Preoperative Localization
Studies
Because of the small size, possible occurrence throughout
the pancreas, and potential multiplicity of insulinomas, most

localize as few as 35% of insulinomas (range, 11% to 50%).23
The sensitivity can be increased by the use of bolus injections
of intravenous contrast material coupled with 3- to 5-mm
cuts through the pancreas. When such dynamic, triphasic
CT scans are obtained, localization rates of 63% or higher
have been reported.P CT scans also readily identify liver
metastases should they be present.

Magnetic resonance imaging (MRI) has localization rates
comparable to those reported for triphasic CT scanning.
Local expertise and availability thus often dictate which
imaging modality is used. As an example, two small studies
with 10 and 11 patients each revealed localization rates of
100% when gadolinium-enhanced and fat-suppressed MRI
images were obtained.s'r"
Angiography
FIGURE 79-6. Pathologic specimen from a patient with multiple

endocrine neoplasia I syndrome. This patient presented with hypoglycemia. Exploration of the pancreas revealed multiple benign
insulinomas (as seen on cross sections, arrows) within the tail of
the pancreas (A), necessitating a distal pancreatectomy. B, The
patient later experienced hyperparathyroidism and was found to
have parathyroid hyperplasia. A subtotal parathyroidectomy was
performed.
experienced endocrine surgeons obtain one or more localization tests before embarking upon operative exploration.
Ultrasonography
Transcutaneous ultrasonography has proved to be of limited
efficacy in the evaluation of pancreatic insulinomas in many
institutions"; however, some investigators remain enthusiastic about its efficacy as a first-line modality.F The reported
sensitivity of preoperative ultrasonography is about 50%
(range, 20% to 70%) and is dependent on the experience of
the examiner. For tumors smaller than 1 em in diameter,
the sensitivity is less than 40%. Furthermore, false-positive
results may occur in up to 25% of cases." Advantages
include the noninvasive nature of this examination and its
relatively low cost.
Computed Tomography
As with ultrasonography, the role of computed tomography
(CT) scanning is limited in the localization of insulinomas
as a result of the small size of the majority of the tumors
(Fig. 79-7B). Routine preoperative CT scanning may
Most insulinomas are highly vascular tumors and produce

a distinctive blush on angiography'? (see Fig. 79-7C). With
the use of selective arterial injections, magnification views,
and digital subtraction techniques, preoperative localization
of these tumors can be obtained in 75% to 80% of cases,
with a false-positive rate reported to be as low as 5%.23
As with other modalities, results are dependent on the size
of the lesion, its location in the pancreas, and the experience
of the radiologist.
Percutaneous Transhepatic Portal

Venous Sampling
Percutaneous transhepatic portal venous sampling (PTPVS)
is one of the most sensitive methods for regionalizing an
insulinoma to the head, body, or tail of the pancreas. In
an interventional radiology suite, the portal venous system
is reached through the liver parenchyma, and a catheter is
passed through the portal vein into the splenic and superior
mesenteric veins. Blood samples are then taken along these
veins and at the entrances of the major pancreatic draining
veins. Insulin, proinsulin, and C peptide levels can then be
measured (see Fig. 79-7D). An insulin concentration that is
2 standard deviations higher than baseline in the portal vein
indicates that the insulinoma lies in the area drained by that
particular vein.23
This test can regionalize the tumor to an area of the pancreas (head and neck, body, or tail) but it does not identify a
specific site. Usually, more than 15 samples must be taken
at 2-cm intervals for the test to be considered valid. The
average sensitivity of PTPVS is 82% (range, 70% to 95%)
in the hands of experienced practitioners. Disadvantages
of this technique include the occurrence of false-positive
results and the morbidity associated with percutaneously
cannulating the portal vein through the liver.
Arterial Stimulation and Venous Sampling

Selective arterial injection of calcium as a means of regionalization of an insulinoma has also been reported and is one
Insulinomas - -
721
FIGURE 79-7. Preoperative localization studies for insulinomas. A, Percutaneous ultrasonography. Arrows delineate two hypoechoic
regions within the pancreatic head. B, Computed tomography scan. Arrows depict insulinoma in the dorsum of the pancreas. C. Subtraction
during the arterial phase of this celiac artery angiography clearly demonstrates the tumor (arrows) in the head of the pancreas.
D, Percutaneous transhepatic portal venous sampling. Insulin radioimmunoassay demonstrates peak levels (227 and 329 flUlmL) in the
area of the tail of the pancreas. (A, B. and D. From Bottger TC, Junginger T. Is preoperative radiographic localization of islet cell tumors
in patients with insulinoma necessary? World J Surg 1993;17:427. C, From Kaplan EL, Lee C-H. Recent advances in the diagnosis and
treatment of insulinomas. Surg Clin North Am 1979;59:119.)
of the best tests available.19 The test is a modification of the

selective arterial secretin injection as developed by Imamura
and Takahashi" for regionalization of gastrinomas and takes
advantage of the fact that calcium is a potent stimulant
of insulin release from insulinomas.F:" This technique
requires the placement of arterial and venous catheters by
femoral puncture. The venous catheters are maneuvered into
the hepatic veins (Fig. 79-8A). Selective arteriography of
the gastroduodenal, splenic, common hepatic, and superior
mesenteric arteries is then performed. After this, calcium
gluconate is injected into each artery, and blood samples are

taken from the hepatic veins at 0, 30, 60, and 120 seconds
for measurement of insulin levels. A twofold elevation of
insulin in the 30- or 60-second sample indicates a positive
test result. A positive test after injection of the gastroduodenal or superior mesenteric artery, for example, indicates that
the tumor lies in the head and neck region of the pancreas
(Fig. 79-8B). Conversely, a positive insulin response to
injection of the splenic artery with calcium indicates the
presence of a tumor in the body and tail region. A positive

Hepatic vein
50
INSULIN (iJUlmJ)
-------------------------1
Hepatic
10
o
o
L-
Catheter for sampling

of hepatic venous blood
Catheter for injection

of calcium
.L-
0.6
..1-
....L.....
1.6
TIME (min)
GDA
Splenic
-'--_S.M~
2
FIGURE 79-8. A, Schema for selective arterial stimulation and venous sampling(ASVS). Standard pancreaticarteriography includes selective injections of contrast material into the gastroduodenal artery (Gastr.duod.a.), proximal splenic artery (Spl.a.), superior mesenteric artery
(a.), and commonhepatic artery (Comm.hep.a.). After each selectivearteriogram, calcium gluconate (0.025 mEq Ca2+/kg) dilutedin saline to
a 5-mL bolus is injected rapidly throughthe proximallypositioned catheter in each selectively catheterized artery. Five-milliliter samples of
blood are obtainedfrom the right hepatic vein before calcium injection and at 30, 60 and 120 seconds after calcium injection. Each plasma
sampleis frozenuntil assayed for insulin.A twofold rise in insulin levels after injectionof the gastroduodenal or superiormesenteric arteries
localizes the tumor to the pancreatichead and uncinate process; a twofold rise after injection into the splenic artery localizesthe insulinoma
to the body and tail. E, Results of selective intra-arterial calcium stimulationtest (ASVS) in a patient with an insulinoma of the pancreatic
head. Note that when calcium was injected into the gastroduodenal artery (GDA), a rapid rise of circulating insulin occurred (within
30 seconds). No elevation in insulinvaluesfollowedinjectionsof calciuminto the superiormesentericartery (SMA), splenic artery, or hepatic
artery. (A, Modified from Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization
of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg 1987;205:230; technique modifiedfrom DoppmanJL et al.27 E, From DoppmanJL,
MillerDL, Chang R, et al. Intraarterial calcium stimulation test for detectionof insulinomas. World J Surg 1993; 17:439.)
response to calcium infusion of the hepatic artery indicates

radiographically occult hepatic metastases.
Doppman and colleagues first described the technique
of arterial stimulation and venous sampling (ASVS) in nine
patients and reported a sensitivity of 66%.27 A subsequent
report by Defreyne and associates also documented two
patients in whom occult insulinomas were accurately localized by ASVS and confirmed by surgery." The advantages
of ASVS over PTPVS are twofold: (1) there is decreased
morbidity, because there is no need for hepatic puncture,
and (2) the technique is far less time consuming, adding
only a few minutes to standard selective arteriography. When
invasive testing is required, ASVS has supplanted PTPVS
for regionalization of insulinomas in most referral centers.P
To illustrate the utility of ASVS, researchers at the
National Institutes of Health analyzed 25 patients who
were studied with multiple imaging modalities, including
ASVS.30 They found correct localization in the pancreas in
94% of patients so studied. The sensitivity of other forms of
imaging in the same patients was 13% for transabdominal
ultrasonography, 24% for CT, 45% for MRI, and 43% for
arteriography. This test and transgastric ultrasonography
(discussed later) are the two most effective localization tests
available.
Isotope-Labeled Somatostatin Analysis

A great deal of interest has been generated by octreotide
scintigraphy of endocrine tumors. Tumors that contain
somatostatin receptors have been shown to bind isotopelabeled octreotide both in vivo and in vitro (Table 79-3).
Effective scanning that enables localization of both primary
and metastatic insulinomas has been achieved (Fig. 79-9).
Krenning and coauthors summarized their work using
indium-labeled octreotide on a variety of endocrine tumors
(see Table 79-3). Most endocrine tumors of the pancreas
demonstrate somatostatin receptors in vitro. They were able
to visualize 14 of 23 insulinomas (61%) by octreoscan.v-P
Other modifications of this technique that have been tried
include use of a hand-held Geiger counter for intraoperative
localization of small primary and occult metastatic foci'"
and use of radiolabeled vasoactive intestinal peptide as the
localizing agent. Using this method, Virgolini and coworkers were able to visualize the primary tumor correctly in
four of four patients with insulinomas.l"
Endoscopic Ultrasonography
Endoscopic transgastric ultrasonography (with radial scanning of 360 degrees and an ultrasonographic frequency of
InsuIinomas - - 723
the pancreatic duct can also be seen in most cases. Fineneedle aspiration may be added to the procedure when diagnosis is required (see "Laparoscopic Resection'Y" Finally,
this method of localization was shown to be cost-effective
in a case-control study of 36 patients who underwent EUS
versus 36 retrospective control patients who underwent
localization in the pre-EUS era." EUS was able to reduce
localization charges significantly, largely through a reduction in diagnostic angiography and venous sampling
procedures. As with any ultrasonographic test, however,
results are operator dependent.
Intraoperative Ultrasonography
The first report of intraoperative imaging of an insulinoma
by ultrasonography was by Lane and Coupland in 1982.38 In
1985, Norton and colleagues reported the first intraoperative
localization by ultrasonography of an insulinoma that had
eluded preoperative identification." In the last 20 years,
numerous studies have documented that intraoperative ultrasonography (IOUS) is a very sensitive method for the
localization of pancreatic insulinomas (Fig. 79-llA). The
reported sensitivity of IOUS is 75% to 91%, and it improves
with experience.f-" In addition, IOUS can provide valuable
information about the relationship of the tumor to critical
structures such as the pancreatic duct, portal vein, common
bile duct, and superior mesenteric vessels. This technique is
shown in Figure 79-l2A. Note that full mobilization of the
pancreas is required to perform the procedure properly.
Intraoperative Palpation
7.5 MHz) has shown widespread efficacy in the diagnosis of

benign and malignant pancreatic disease (Fig. 79-10). In
expert hands, endoscopic ultrasonography (EUS) has been
shown to have a sensitivity of greater than 80% for the
diagnosis of insulinomas, especially when located in the
pancreatic body and head." The relationship of the tumor to
FIGURE 79-9. Isotope-labeled

somatostatin scanning. Indium
l l I-diethylenetriamine pentaacetic
acid (DTPA)-octreotide scan of
a patient with an insulinoma within
the head of the pancreas at
24 hours (A) and 48 hours (B). The
tumor is represented by a hot spot
just medial to the right kidney
(arrow). (From van Eyck CHJ,
Bruining HA, Reubi J-C, et al. Use
of isotope-labeled somatostatin
analogs for visualization of islet
cell tumors. World J Surg 1993;
17:444.)
Most insulinomas of the pancreas can be palpated by carefully exploring the pancreas at the time of surgery. The sensitivity of palpation is 75% to 95% in different studies and
depends on the experience of the surgeon." Small tumors
and those located in the pancreatic head and uncinate
process are generally more difficult to palpate. The combination of IOUS and palpation has been reported to increase
the sensitivity to 100%.42 Like mus, proper intraoperative
palpation requires full mobilization of the pancreas.
FIGURE 79-10. Endoscopic ultrasonography of the pancreas.
A, Preoperative localization of a suspected insulinoma of the

pancreatic neck. B, Transgastric fine-needle aspiration confirmed
the presence of an insulinoma, which was later resected by

enucleation. (Courtesy of RameezAlasadi, MD.)
Are Preoperative Localization

Tests Beneficial?
There is no question that preoperative localization tests are
essential for all reoperative cases of insulinoma. However,
for the initial operation of an insulinoma, some differences
of opinion exist. Some investigators shun most preoperative
testing and rely almost exclusively on IOUS with careful
palpation. 40 ,43 Others, however, favor administering a battery
of preoperative localization tests before the initial operation.
In a national study of German institutions, it was shown that
when no invasive preoperative localization studies were
used, 7.4% of all insulinomas were undetected at operation.
However, when invasive testing was employed, the negative
laparotomy rate dropped to 3.7%.23 It should be remembered that there is a learning curve associated with the use
of IOUS, and thus in many centers the use of currently available localization studies does aid in curative surgery for
small, occult insulinomas. In general, we start with transgastric ultrasonography and proceed to calcium-stimulated
arteriography if the former study is negative.
FIGURE 79-11. Intraoperative sonogram. A, Insulinoma of the
tail of the pancreas.The arrowsdesignate the insulinoma, which is

hypoechogenic compared with the surrounding pancreas. B, A
hypoechoic tumor (T) of the pancreas is visualized by intraoperative ultrasonography. Note that the pancreatic duct (arrow) and its
proximity to the tumor are clearly shown. (A, From Kaplan EL,
Arganini M, Kang S-l. Diagnosis and treatment of hypoglycemic
disorders. Surg Clin North Am 1987;67:395-410. B, From Zeiger
MA, ShawkerTH, Norton lA. Use of intraoperative ultrasonography to localize islet tumors. World J Surg 1993;17:448.)
Perioperative Management
of Serum Glucose
Preoperative Management
Until the tumor is removed, the mainstay of therapy is the
prevention of hypoglycemia. This may entail frequent meals
and minimizing prolonged exercise. Intravenous glucose
Insulinomas - - 725
79-12. Intraoperative
ultrasonography (lDUS). A. IOUS
of the head of the pancreas using a
lO-MHz probe after extensive
kocherization of the duodenum.
B. IOUSof the bodyand tail of the
pancreas after extensive mobilization along its inferiorand superior
borders. C. IOUS of the body and
tail of the pancreas posteriorly
after medial reflection of the
spleen and tail of the pancreas.
D. IOUS of the liver depicting a
right hepatic lobe tumor surrounded by major hepatic vessels.
(From Zeiger MA, Shawker TH,
Norton JA. Use of intraoperative
ultrasonography to localize islet
cell tumors. World J Surg 1993;
FIGURE
17:448.)
should be given the night before surgery, especially after the

patient ceases oral intake. Administration of diazoxide or the
somatostatin analog octreotide is employed preoperatively
in some centers, not only to control hypoglycemic attacks
but also to determine the patient's response and tolerance to
such therapy should surgical exploration be unsuccessful.
We rarely use diazoxide preoperatively because it interferes
with the intraoperative glucose monitoring.
requires insulin therapy unless the patient was diabetic

preoperatively. This rebound hyperglycemia usually resolves
spontaneously within 1 week, although it may last longer.
Diabetes mellitus may occur in the minority of patients who
require a significant pancreatic resection.
Intraoperative Management
Operative exposure may be achieved through a bilateral subcostal or long midline incision. Upon entering the peritoneal
cavity, a thorough exploration is performed to exclude
metastatic disease. Tru-Cut needle or wedge biopsy of any
suspicious liver lesions is performed and suspicious lymph
nodes are sent to the pathologist for frozen section analysis.
A generous Kocher maneuver is then performed from the
level of the right gonadal vein to the aorta medially. At this
time, the head and neck of the pancreas may be carefully
palpated (Fig. 79-13A). The omental bursa is then divided to
the left of the midline, allowing access to the lesser sac.
Mobilization of the body and tail of the pancreas is then
begun in the usual fashion, by dividing the peritoneum along
the inferior aspect of the gland. The inferior mesenteric vein
may be divided at this point if necessary. Careful visual
inspection and manual palpation of the body and tail of the
pancreas are then undertaken (Fig. 79-13B). To examine the
posterior aspect of the gland, the spleen must be mobilized
by incising its attachments to the diaphragm, kidney, and
colon. IOUS may now be performed.
Frequent blood sugar determinations are necessary to prevent

hypoglycemia during the operation. Our current protocol is
to monitor blood sugar levels at 15- to 3D-minute intervals
both during the procedure and for several hours thereafter.
A rise in serum glucose suggests that a curative operation
has been performed. However, this is not always the case,
especially when multiple tumors are present, such as in
MEN 1. Thus, several groups have investigated the technique of intraoperative insulin measurement." Using a rapid
radioimmunologic assay, Proye and colleagues described a
sensitivity of 84% with specificity and positive predictive
values of 100% for this new technique. Clearly, this technique warrants further study.
Postoperative Management
After the successful removal of an insulinoma, a short period
of hyperglycemia usually occurs. Hyperglycemia rarely
Operative Approach
FIGURE 79-14. An insulinoma of the inferior surface of the body

of the pancreas is demonstrated. This was easily enucleated.
IODS is invaluable when performing enucleation of lesions

in the head of the pancreas. Care must be taken to avoid
injury to the main pancreatic and common bile ducts.
Cannulating the common bile duct through the cystic duct
and inflating the balloon at the ampulla of Vater may also be
employed. However, the main factor in preventing a fistula
is to stay immediately on the capsule of the tumor and to use
gentle, blunt dissection.
FIGURE 79-13. A, After a generous Kocher maneuver of the duodenum, the pancreatic head should be palpated between the thumb
and fingers. B, The gastrocolic omentum is divided and the stomach
is elevated. The body and tail of the pancreas are gently mobilized.
The areas can now be visualized and palpated carefully. (From
Findley A, Arenas RB, Kaplan EL. Insulinoma. In: Percopo V,
Kaplan EL [eds], GEP and Multiple Endocrine Tumors. Padova,
Italy, Piccin Nuova Libreria SpA, 1996, P 314.)
When an insulinoma has been located, an attempt to

enucleate it should be made, regardless of its location within
the gland (Fig. 79-14). Distal pancreatectomy is performed
in the setting of multiple lesions within the body and tail
(see Fig. 79-6) if the lesion is large and malignancy cannot
be excluded (Fig. 79-15) or if the lesion abuts the pancreatic
duct. Enucleation of lesions intimately associated with
the pancreatic duct predictably leads to fistula formation.
Most lesions of the head of the pancreas are enucleated
(Fig. 79-16). Only rarely should a pancreaticoduodenectomy
be performed for a benign lesion. Occasionally, the Whipple
procedure may be indicated for a malignant lesion of the
head or uncinate process with regional nodal involvement.
FIGURE 79-15. A distal resection was performed for this large

lesion of the tail of the pancreas. A lymph node metastasis was
present; thus, this was a malignant insulinoma.
Insulinomas - - 727
benign tumot/" Preoperative testing, usually by EUS with
fine-needle aspiration, is required to ensure correct localization and to exclude malignancy. IOUS is frequently employed.
One of the largest series to date reported an average hospital
stay of only 5 days after such an approach was used for
10 endocrine tumors of the pancreas, 7 of which were insulinomas, either sporadic or multiple." Both enucleation and
distal resections of the pancreas can be performed by this
technique. Although these initial results are encouraging in
this highly selected group of patients, conversion to an open
procedure was required in 2 patients and postoperative
fistulas were noted in 5 of 18 (28%) total patients in the series.
Complications
As discussed earlier, transient elevations in serum glucose
may be observed postoperatively but are rare beyond several
weeks when tumors are enucleated. Diabetes increases with
the extent of the pancreatic resection. Persistent hypoglycemia
is currently less than 5% in cases of benign insulinoma."
Hypoglycemia is common, however, in cases of malignant
insulinoma when not all tumor can be resected. Other
postoperative complications include hemorrhage, abscess,
pancreatitis, and pancreatic duct or biliary fistulas."
Long- Term Therapy

for Hypoglycemia
FIGURE 79-16. A, Insulinoma of the head of the pancreas (arrow).

These lesions can almost always be enucleated. During enucleation, careful blunt dissection should be used immediately on the
capsule of the insulinoma to prevent damage to the common bile or
pancreatic duct, which could result in a fistula. B, This lesion was
carefully enucleated and proved to be benign.
If MEN 1 is suspected, a thorough exploration of the

pancreas is mandatory to exclude multiple lesions.
Additional lesions may then be enucleated. However, in
most instances of MEN 1, a distal pancreatectomy with enucleation of any remaining lesions of the head of the pancreas
is preferable.
Finally, if all efforts at exploration fail to identify the primary lesion, the operation should be terminated and the
patient referred to a center of excellence. Although blind
distal resection of the pancreas was advocated in the past,
the development of modem localization studies such as
EUS and ASVS allows the eventual detection of almost all
insulinomas."
Laparoscopic Resection
Originally described in 1996, laparoscopic distal pancreatectomy for the removal of an insulinoma is an approach that
appeals to many who view a laparotomy with extensive
retroperitoneal dissection as excessive to treat what is a usually
As noted previously, the first appropriate therapy for a failed

operation is a referral to a high-volume center where localization studies will be performed and a surgical cure should
be obtained in the majority of patients at reoperation.
Several drug regimens have been employed in patients with
unresectable disease.
Diazoxide
Diazoxide is a nondiuretic benzothiadiazine. Both in vitro
and in vivo studies have shown that diazoxide reduces
insulin secretion and raises circulating glucose levels by
acting directly on the beta cells as well as by other extrapancreatic mechanisms.t" Side effects include hypotension,
peripheral edema, hirsutism, nausea, and vomiting. Studies
have shown that its efficacy in controlling hypoglycemia is
approximately 60% in patients with insulinomas."
Somatostatin Analogs
Somatostatin analogs have been used for treatment of different types of endocrine tumors with considerable success.P
Octreotide acetate is an analog that has retained the active
region of somatostatin but with certain modifications that
make the derivative more resistant to peptidase degradation
while increasing its biologic availability. Octreotide has
been used to reduce hypoglycemic attacks in patients with
unresectable insulinomas. A typical starting dose is 100 ug,
given intravenously or subcutaneously every 8 hours. Doses
may be increased to as high as 600 to 1500 ug per day.52
Long-acting somatostatin preparations, which may be
administered on a monthly basis, are now also available.
Other Therapeutic Approaches

The effectiveness of chemotherapy against malignant insulinomas is limited at best. Regimens including streptozocin in
combination with 5-fluorouracil and doxorubicin are usually
employed." Hepatic artery chemoembolization has been tried
with some success, as has operative debulking. Given the
considerable morbidity of a hepatic resection in the setting
of unresectable disease, radiofrequency ablation of hepatic
metastases from a pancreatic insulinoma has been reported. 54
This is a procedure that may be performed percutaneously in
the outpatient setting in highly selected patients with limited
hepatic metastases.
Summary
Insulinomas are usually small, solitary tumors except in
patients with MEN I, in whom multiple tumors are the rule.
Ninety percent of insulinomas are benign. Patients with
insulinomas may experience neurologic, cardiovascular, and
gastrointestinal symptoms. In most patients, the diagnosis
can be made by documenting inappropriately high circulating insulin and C peptide levels at the time of profound
hypoglycemia, along with the absence of sulfonylureas in
the urine. Provocative tests are sometimes necessary to
confirm the diagnosis. Preoperative localization studies,
especially transgastric ultrasonography and highly selective,
calcium-stimulated arteriography with insulin measurement
(ASVS), appear to decrease failure rate and are used frequently by many surgeons, although they are essential only
in the reoperative setting. In experienced hands, surgical
cure may be obtained in more than 95% of cases.
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InsuIinomas - -
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Arch Surg 1999;134:818.
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729
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A national UK survey. Postgrad Med J 1997;73:640.
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in patients with islet cell tumors. World J Surg 1993;17:504.
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Clin Endocrinol (Oxf) 2002;56:557.
Localization of Endocrine
Pancreatic Tumors
Volker Fendrich, MD Matthias Rothmund, MD
The functioning endocrine tumors of the pancreas most

often encountered are insulinomas and gastrinomas. Both
tumors cause spectacular clinical syndromes, hyperinsulinism and the Zollinger-Ellison syndrome (ZES), respectively.
The tumors are often difficult to localize because they are
almost always smaller than 2 em in diameter. Duodenal gastrinomas are usually even smaller than 1 ern. This is not
the case for the rarer functioning endocrine pancreatic tumors
such as glucagonomas, vasoactive intestinal polypeptide
tumors, somatostatinomas, and the nonfunctioning tumors,
which are usually large and easy to localize by standard
localization techniques such as abdominal ultrasonography
(US), computed tomography (CT), or magnetic resonance
imaging (MRI). Therefore, this chapter focuses mainly on
the localization of insulinomas and gastrinomas and
includes only briefly the nonfunctioning tumors; the rarer
tumors mentioned previously were excluded. Because the
approach to localize insulinomas and gastrinomas differs in
patients with the multiple endocrine neoplasia type 1 (MEN 1)
syndrome compared with sporadic tumors, localization in
MEN 1 is discussed separately.
However, localization techniques should not be used to
make the diagnosis of hyperinsulinism or ZES. They should
be used only after the diagnosis is made on the basis of the
patient's history as well as clinical and laboratory data.
Insulinomas
Ninety percent of insulinomas are benign and are smaller
than 2 em in diameter. Ninety-nine percent are located in
the pancreas. A variety of preoperative imaging modalities
for the detection of insulinomas are currently available, such
as US, CT, MRI, somatostatin receptor scintigraphy (SRS),
and various invasive methods, including endosonography
(ES), selective angiography (SA), selective portal venous
730
sampling (PVS), and selective hepatic venous sampling

after arterial stimulation (modified Imamura procedure).
But those procedures often fail to detect the tumor. On the
other hand, there is agreement that skilled surgeons who are
experienced in careful and meticulous exploration of the
pancreas as well as in the use of intraoperative US (IOUS)
can achieve much better results than any of the preoperative
methods mentioned, including a combination of most. 1,2
Endosonography (ES) is the most sensitive preoperative
procedure. It was introduced in the 1980s and provides direct
visualization of the pancreas and is able to detect tumors
down to 0.3 to 0.5 em in diameter (Fig. 80-1). An early study
by Rosch and colleagues in 19923 identified endocrine
tumors by ES in the head of the pancreas in 95% of their
patients and in the body and tail in 78% and 60%, respectively (Table 80-1). One year later, Palazzo and coworkers"
underlined its accuracy for localizing small endocrine pancreatic tumors. Thirteen insulinomas less than 15 mm in
diameter were imaged by ES, US, and CT. Accuracy for
these procedures was 79%, 7%, and 14%, respectively. Since
then, we and other have confirmed the results of this method,
which is superior to CT, US, MR!, SA, and SRS,5-6 despite
the fact that the sensitivity decreases the more left sided the
insulinomas are situated. Richards and associates found 83%
sensitivity ofES for pancreatic head insulinomas versus 37%
for distal pancreatic insulinomas." On the basis of these
results, ES is the method of choice if one wants to use preoperative imaging. It is mandatory before reoperation or if
laparoscopic resection is planned.
CT scanning is probably still the most widely used noninvasive technique for initial localization of insulinomas.
It has shown varying results in several extensive studies,
with a sensitivity of only 25% to 70%. The most important
reason for this is that the sensitivity of CT to localize tumors
accurately is dependent on the size and location of the
neoplasm. 1,6,9-18 Perhaps new techniques such as multislice
Localization of Endocrine Pancreatic Tumors - -
731
FIGURE 80-1. Preoperative endosonography shows a typical

22-mm hypoechoic insulinoma (arrows) in the head of the pancreas.
D I and D2 = tumor margins.
FIGURE 80-2. Transverse preoperative ultrasonography (5-MHz

linear-array transducer) shows typical hypoechoic insulinoma
(15 mm) (TV) within the echogenic parenchyma of the pancreatic
head (P), AO = aorta; VC = vena cava; WS = spine.
spiral CT, which is capable of investigating the whole gland

in thin sections in 10 to 15 seconds, could improve these
numbers (see Table 80-1).
Preoperative US offers a less expensive alternative but is
extremely operator dependent. In addition, the sensitivity of
US ranges from 0% to 62% and does not exceed that of CT
(Fig. 80-2; see Table 80-1).1,6,9-14,16-18
In MRI technique, the improved technology in software,
gadolinium-gated studies, magnetic echo delays, and the
introduction of oral contrast agents have led to better results
in detecting insulinomas. 17,19,20 Today, Tl-weighted fatsuppressed images are acquired in arterial phase, portal
phase, and equilibrium phase following the administration
of intravenous gadolinium.'? However, on the basis of published studies, the sensitivity of MRI is usually 15% to 50%
(see Table 80_1).6,9,11,17
In the 1970s, SA was considered a useful localization

procedure for detecting insulinomas. Because islet cell
tumors are well vascularized, they can be detected by the
hypervascular blush if the catheter is placed in the appropriate artery. Different series have shown sensitivity between
35% and 91% (see Table 80-1). However, more recently a
decrease in its use has been noted because the excellent
sensitivity just mentioned could not be reproduced by many
authors. SA also usually identified the larger tumors, which
would be relatively easy for experienced surgeons to find at
exploration.w"
Using selective PVS, insulin levels in blood samples

obtained from specific sites along the splenic, mesenteric,
pancreaticoduodenal, and portal veins are measured. This
procedure requires transhepatic catheterization of these
veins. It is maximally invasive and can be associated with
serious complications. Significantly increased hormone

concentrations from one area compared with others are considered a positive study result. Although PVS could reach
sensitivity rates of 80% to 100%6,9.11-15,21 (see Table 80-1),
the procedure does not really localize but only helps to
regionalize the tumor to the part of the pancreas drained by
a particular vein. 22
SRS was believed to be a promising method after the
initial data were published. Large numbers of somatostatin
receptors (SS-Rs) are found on most endocrine pancreatic
tumors. At least five different human SS-R subtypes have
been cloned. Octreotide binds with high affinity to SS-R
subtype 2 (sst2) and sst5. 23 The efficacy of SRS using this
agent in 350 patients with proven endocrine tumors was evaluated in a European multicenter trial.24 The highest success
rates were observed with glucagonomas (100%), vasoactive
intestinal polypeptide-secreting tumors (88%), gastrinomas
(73%), and nonfunctioning islet cell tumors (82%).
Insulinomas were detected in only 46% to 63% of cases due
to the low incidence of sst2 on insulinoma cells. Therefore,
the method is already losing favor (see Table 80-1).
In this context, a modification of the Imamura method is
also worth mentioning. In this procedure, known as arterial
stimulation and venous sampling, calcium gluconate is injected
into various gastroduodenal and splenic arteries. After the
injection, blood is obtained for insulin assay from the
hepatic veins. 25 Doppmann and others demonstrated high
(88% to 100%) sensitivity rates 25-27 of this method, which is
less painful, is less difficult for the interventional radiologist
to perform, and is associated with fewer complications than
transhepatic catheterization of the pancreatic veins.
Daggett and colleagues 1 were the first to show that intraoperative exploration of the pancreas might be the best
method to localize insulinomas. In their survey, 29 patients
underwent laparotomy for suspected insulinoma. The
tumors were correctly localized before operation in 13% by
CT, in 18% by US, in 25% by selective PVS, and in 50% by
SA. On the other hand, the tumors were detected and
resected in 27 of these 29 patients at surgical exploration
of the pancreas, Since then, many studies 2,lO,13,14,17,18,21 confirmed these results, and our survey" of 40 patients with
insulinoma has shown that the tumor was correctly localized
before operation in 65% by ES, 37% by SA, 33% by CT and
US, 15% by MRI, and 0% by SRS. On the other hand, all
tumors were identified and resected using IOUS and meticulous palpation of the pancreas after extensive mobilization
of the gland.
to determine the relation of the tumor to the pancreatic duct.

This should be performed by an experienced surgeon who is
familiar with IOUS or asks an ultrasonographer to participate, If one desires a preoperative method besides US or CT,
ES is the procedure of choice, but it can be omitted according to our experience. For patients requiring reoperation or
for patients in whom laparoscopic resection is planned, ES
is recommended as the second procedure after US or CT.
When no lesion is identified and one can rely on the biochemical tests for diagnosis, laparotomy should follow.
Gastrinomas
Eighty percent to 90% of all gastrinomas are located in the
so-called gastrinoma triangle, which includes the duodenum,
the pancreatic head, and the hepatoduodenal ligament." In
contrast to previous reports, which stated that 80% of all
gastrinomas are localized in the pancreas and only 20% in
the duodenum, Sugg and colleagues-? showed that 70% to
80% of gastrinomas are found in the duodenal wall. The size
of gastrinomas varies with the site of the tumors; pancreatic
gastrinomas are often larger than I em, whereas gastrinomas
of the duodenum are usually smaller than 1 em." Therefore,
it is nearly impossible to identify duodenal gastrinomas by
preoperative imaging procedures.P
In 1999, Norton and colleagues" presented their results
of surgical resection in more than 150 patients with ZES. In
patients with sporadic ZES gastrinomas were detected by US
in 24% (Fig. 80-3), by CT in 39% (Fig, 80-4), by MRI in
46%, and by SA in 48%. In approximately one third of
patients with sporadic gastrinomas, the results of conventional
imaging studies were negative, Different studies on patients
with ZES confirmed these results. 3,4,19,29,32 As mentioned
previously, ES is able to detect even small tumors in the
pancreas. After first reports.v' many studies confirmed these
results; for example, Zimmer and colleagues found pancreatic
gastrinomas by ES in 79%.33 Anderson and coworkers' were
able to localize all 36 pancreatic gastrinomas investigated by
ES, whereas SA detected only 44% of the lesions.
Recommendation
We recommend US or CT scan as the only preoperative test
before primary operations, not to find the tumor but to
exclude metastases of possibly malignant insulinomas,
which are usually found in the liver. The patients should
then undergo laparotomy that includes meticulous surgical
exploration, including an extended Kocher maneuver to be
able to palpate the head of the pancreas and mobilization of
the body and tail from the retroperitoneum (including the
spleen if necessary) to examine the distal pancreas carefully
and completely. IOUS should then be used to confirm the
presence of tumor or to find nonpalpable lesions and also
FIGURE 80-3. Transverse preoperative ultrasonography (5-MHz

linear-array transducer) shows typical hypoechoic gastrinoma
(20 mm) (TV) within the echogenic parenchyma of the pancreatic
head (PA). CO = confluence.
Localization of Endocrine Pancreatic Tumors - -
FIGURE S0-4. Enhanced computed tomographic scan demonstrates a 16-mm enhancing gastrinoma in the pancreatic head.
The European multicenter trial to evaluate the efficacy

of SRS showed positive results for pancreatic gastrinomas in
73%.24 In a prospective study comparing the sensitivity of
SRS with that of CT, MR!, US, and SA in detection of primary and metastatic pancreatic gastrinomas, SRS altered
clinical management in 47% of instances and had superior
sensitivity and specificity." Cadiot and coauthors" compared the results of SRS with those of conventional imaging
techniques, including ES, and with surgical findings in
21 consecutive patients with ZES. SRS added information
to other imaging results and improved the preoperative
detection of extrapancreatic gastrinomas. By combining
SRS with ES, they were able to detect 90% of the tumors.
Our experiences with SRS do not show any advantage when
compared with the localization methods mentioned
previously.F The gastrinomas that were visualized were either
larger than 1 em in diameter or had widespread metastases
(Fig. 80-5). Invasive localization methods, such as PVS and
the selective intra-arterial injection of secretin combined
with venous sampling (Imamura technique), show comparatively high sensitivity of 77% and 100%, respectively;
FIGURE S0-5. Somatostatin receptor scintigraphy shows two

circular enhancements that represent two retroperitoneal tumors
(arrow). The primary tumor, a gastrinoma, couldnot be identified.
733
however, they allow only regionalization and not exact

localization of the tumors 29,31,36,37.38 (Table 80-2).
Again it seems that the best method for localization is
surgical exploration and IOUS (Fig. 80-6). The sensitivities
of palpation and IOUS are 91% and 95%,39 respectively. We
recommend a surgical approach similar to that used for
patients with insulinomas, including preoperative US or CT
scan to rule out large tumors with liver metastases and then
IOUS. A study from the National Institutes of Health tested
four different intraoperative procedures." All 31 duodenal
tumors were detected after longitudinal incision of the
second part of the duodenum and separate palpation of the
posterior and anterior walls. The second best result was
achieved by intraoperative endoscopy and transillumination
of the duodenal wall (64%). Standard palpation and IOUS,
on the other hand, detected only 61% and 26% of gastrinomas, respectively. Norton and colleagues underlined the
importance of duodenotomy (DUODX) in patients with
ZES.4o They performed DUODX in 79 patients and did not
perform DUODX in 64 patients. Gastrinoma was found in
98% with DUODX compared with 76% with no DUODX.
They could show that the use of routine DUODX increases
the short-term and long-term cure rate.
Recommendation
On the basis of these studies and our own experience, we
recommend using either US or CT and SRS before primary
operations, mainly for staging of the disease. This should be
followed by exploratory laparotomy including DUODX and
complete mobilization of the pancreas followed by IOUS.
For reoperative cases ES and the Imamura technique should
be used to localize or regionalize solitary or multiple
tumors.
Multiple Endocrine
Neoplasia Type 1
Nearly all patients with MEN 1 develop islet cell tumors of
the pancreas, mostly gastrinomas (70%) or insulinomas (30%).
Other endocrine pancreatic tumors such as glucagonomas
and nonfunctioning tumors are rare. The endocrine pancreatic
tumors in patients with MEN 1 are always multiple, small,
and distributed throughout the entire organ. Gastrinomas are
often found when they have already attained an advanced
stage with metastases to regional lymph nodes and rarely the
liver. In MEN 1 insulinomas, about 90% of patients have
multiple tumors. Most often, only the large insulin-secreting
tumors are localized by CT, US, and angiography, whereas
small tumors remain undetectable.
Spiral CT with contrast enhancement, MRI at high resolution, and positron emission tomography have all been used
to identify MEN 1 endocrine pancreatic tumors, but they
have generally been unable to reveal the small lesions."
These methods, especially CT, can be used selectively, with
longer intervals for screening. They can also be used to determine the anatomy and to exclude liver metastases and other
extrapancreatic tumor burden. As mentioned previously,
SRS had superior sensitivity and specificity in detection of
pancreatic endocrine tumors compared with conventional
imaging methods." Although even SRS fails to identify

tumors smaller than I em in diameter, it may verify the
endocrine nature of a tumor and may visualize metastatic
spread within the abdomen, especially the presence of extraabdominal metastases, so we recommend the use of SRS in
patients with MEN I preoperatively and with longer intervals
for screening.
ES has proved particularly sensitive for detection of
tumors in the pancreatic head and body. ES had a sensitivity
of 70% to 90% and has been convincingly shown to reveal
lesions as small as 5 mm in diameter, and it now appears to
be the outstanding method for screening of MEN I patients
(Fig. 80_7).33,42,43 On the other hand, because ES has poor
results in detecting tumors in the duodenal wall.v' an adequate surgical exploration of the pancreas, including the
duodenum if ZES is present, seems to be superior to preoperative imaging procedures, especially if combined with
IOUS and DUODX. 31
The intra-arterial stimulation test (Imamura test) using

pentagastrin or calcium to stimulate gastrin and insulin
secretion, respectively, is very accurate for regionalization
of hormone excess with both gastrinomas and insulinomas,
but it has not been routinely applied in many series.37 .44
In patients with ZES, one study using PVS showed a
sensitivity of only 50%.36 In a survey by Sheppard and colleagues," eight of nine patients with MEN I had an identifiable hormone gradient on PVS. On the other hand, none of
the patients was cured of ZES despite the fact that islet cell
tumors were removed from the region of the gastrin gradient
in five of six patients. The authors concluded that PVS is
not successful in selecting patients for curative surgery.
With respect to PVS, the interpretation of regionalization
findings is fairly difficult because of multiple occurrences of
insulinomas. Thus, this technique provides little information
to improve surgical results. O'Riordain and associates'?
FIGURE S0-7. Preoperative endosonography shows one of multiple

FIGURE SO-6. Longitudinal intraoperative ultrasonography
(7.5-MHz linear-array transducer) of the pancreatic head demonstrates an 8-mm hypoechoic gastrinoma (arrow). This gastrinoma
was not identified by any preoperative imaging procedure.
nonfunctioning endocrine pancreatic tumors in a 20-year-old patient

with multiple endocrine neoplasia type 1. It demonstrates a 15-mm
typical hypoechoic tumor (arrowheads) in the tail of the pancreas. D I
and D2 =tumor margins; V lienalis =splenic vein; cauda pancr =pancreatic tail; largearrow, pancreatic duct; small arrows, splenic artery.
Localization of EndocrinePancreaticTumors - - 735

confirmed this observation and showed in 18 patients that
small tumors could not be localized, although preoperative
imaging studies including intraoperative palpation and
IOUS were used. In this study, 17 of 18 patients were cured
after a 75% to 85% subtotal distal pancreatectomy, including enucleation of tumors from the head of the pancreas.
Similar findings had previously been reported by Demeure
and coworkers."
Recommendation
Surgery is the treatment of choice in MEN 1 pancreatic
tumors if no extensive extrapancreatic (hepatic) spread is
present. Because for both MEN 1 gastrinomas and MEN 1
insulinomas the procedures are standardized, localization is
of limited importance. In MEN 1 gastrinomas, the procedure
of choice is probably distal pancreatectomy, exploration of
the duodenum after DUODX, enucleation of tumors of the
pancreatic head, and regional lymph node dissection
(according to Thompson and colleaguesj.t" We and other
authors recommend'? a pylorus-preserving pancreaticoduodenectomy because most MEN 1 gastrinomas are situated in
the head of the gland (gastrinoma triangle) and duodenal
gastrinomas almost always recur after local excision.
Therefore, localization of tumors within the pancreas is of
little value. This is more so in MEN 1 insulinomas, for which
distal pancreatectomy and enucleation of tumors from the
head of the gland can be called a standard procedure.
Therefore, localization procedures make sense only to show
tumors in the head.
On the basis of the studies mentioned previously, we
recommend using preoperative US or CT and SRS to localize large tumors and to show liver metastases and other
extrapancreatic metastatic spread; we also recommend ES
preoperatively to localize tumors outside the pancreatic
region resected.
In patients with recurrent or persistent disease, other localization techniques such as the Imamura procedure are useful.
Nonfunctioning Tumors
Islet cell tumors are called "silent" or "nonfunctioning" if
they are not associated with a specific clinical syndrome,
such as ZES. Either these tumors do not secrete enough
hormones to produce a clinical syndrome or the secreted
hormone does not cause specific symptoms (e.g., pancreatic
polypeptide-secreting tumor). Preoperatively, US and CT
scanning are the procedures of choice and are usually effective because these tumors are relatively large, usually more
than 5 em in diameter." Also, SRS can be performed to
differentiate endocrine from non endocrine pancreatic
tumors. We recommend that all patients with nonfunctioning tumors undergo CT or US to localize the tumor and to
exclude diffuse metastases.
Summary
Preoperative US or CT scanning is helpful in patients with
endocrine pancreatic tumors to show large primaries and
metastases if malignancy is present. No other procedures

are necessary and indicated for patients who have not
had previous operations. ES can be used preoperatively in
gastrinomas or insulinomas if a laparoscopic approach is
planned. At laparotomy, IOUS is useful for patients with
gastrinoma and insulinoma. Because about 70% of gastrinomas are located in the duodenum, a DUODX is necessary
to identify these often small tumors. For patients with persistent or recurrent gastrinoma or insulinoma, a similar
approach is used, including ES and the Imamura procedure.
The results of localization procedures in patients with
MEN 1 gastrinomas or insulinomas have been frustrating
because these patients usually have multiple small tumors
throughout the gland. On the other hand, both tumor syndromes are treated by standardized resections, leading to
limited value of these techniques.
Acknowledgment
We thank Prof. Kann, Department of Internal Medicine and Endocrinology,
for giving us the endosonography figures.
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Pancreatic Surgery for

Endocrine Tumors
Norman W. Thompson, MD
A variety of surgical procedures are useful in the treatment

of endocrine tumors of the pancreas. The selection of a
specific surgical technique or procedure in the management of an endocrine tumor of the pancreas depends on a
number of important factors that must be considered in each
case: the functionalnature of the tumor,its benignity or malignancy, and whether it is a component of multiple endocrine
neoplasia (MEN) type 1 or is sporadic in its occurrence.
Furthermore, when a tumor is malignant, one must determine whether it invades essential contiguous structures such
as the superior mesenteric vessels or whether metastases
are present but are limited to lymph nodes. Usually hepatic
metastasis implies incurability, although a solitary liver
metastasis from an islet cell tumor should be treated aggressively, provided that the primary tumor can be completely
removed. For the purposes of this discussion, endocrine
tumors are classified into those that are sporadic and those
that are associated with MEN 1. They are then further subdivided into those that are functional and those with no
apparent hormonal activity.
Sporadic Endocrine Pancreatic

Tumors
The most common functional endocrine tumor of the pancreas is the insulinoma; unlike other tumors in this category
it is usually benign (90%).1,2 As a result, most can be treated
by enucleation when located in the head or uncinate process.'
In our experience in managing more than 75 insulinomas
during the past 25 years, only two insulinomas arising in the
head required a pancreatoduodenectomy for excision. One
was because of malignant local infiltration and the other
was a small benign tumor that was neither palpable nor
detectable with intraoperative ultrasound because it was
isoechoic. It had been localized to the pancreatic head with
selective arterial stimulation using calcium and hepatic
venous insulin assays. In all other patients with benign

insulinomas arising in the head or uncinate, enucleation
could be accomplished after adequate mobilization. To
accomplish this, an extended Kocher maneuver of the duodenum to the level of the superior mesenteric vein is often
necessary. After this extended mobilization has been performed, frequently several small branches of the superior
mesenteric vein from the uncinate process must be divided
between ligatures so that the entire uncinate can be palpated
and exposed when the superior mesenteric vein is retracted
medially (Fig. 81-1). Fine metal clips are used to secure
small pancreatic vessels because a plane is developed
between the tumor capsule and the surrounding parenchyma
using a fine-tip mosquito hemostat.
The approach to the insulinoma may be either anterior or
posterior depending on an evaluation after bimanual palpation or ultrasonography to determine which surface the
intraparenchymal tumor most closely approximates. Many
insulinomas are partially visible on one surface or another,
making that decision obvious in those cases. With careful
technique, even tumors that are very close to either the
common bile duct or major pancreatic duct can be enucleated without jeopardizing these structures. After enucleating
a tumor in approximation to the major pancreatic duct, it is
prudent to inject secretin intravenously and carefully evaluate for any exocrine secretion leak. We make no attempt to
oversew the enucleation site but do place a Jackson-Pratt
drain in its location.
For insulinomas involving the neck, body, or tail, the
decision to enucleate or resect is based on the size of the
tumor and its specific location with respect to the pancreatic
duct. Most insulinomas along either edge of the body or tail
and those apparent on either the anterior or the posterior
surface of the neck, body, or tail can be enucleated safely
without resection. However, if a plane between the tumor
capsule and the pancreatic parenchyma cannot be easily
established, resection is indicated.'
737
FIGURE 81-1. Illustration of an insulinoma in the uncinate

process exposed in full after mobilization and retraction of the
superior mesenteric vein. The enucleation site is left open.
In approximately 5% of insulinomas, the only manifestation of malignancy is local infiltration. These tumors are usually curable by resection if no hepatic metastases are present.
When resection is indicated on the basis of location or size,
we attempt splenic preservation whenever possible. This is
usually feasible unless the splenic vein is within the posterior
pancreatic parenchyma. If malignancy is suspected, a distal
resection in continuity with the spleen and peripancreatic
lymph nodes is performed. For patients with hypoglycemia
caused by islet cell hyperplasia or nesidioblastosis rather than
a tumor, a distal pancreatectomy to the level of the superior
mesenteric vein is performed in those whose hypoglycemia is
responsive to a trial of preoperative diazoxide testing. A more
extensive (85%) resection is done in those patients who are
refractory to this drug in preoperative testing.' We currently
use only endoscopic ultrasonography (EUS) for preoperative
localization when positive." If an insulinoma is not identified,
we use a selective calcium arterial stimulation test with
insulin samples from the right hepatic vein.? This technique
regionalizes the tumor or identifies those with multiple sites
of insulin hypersecretion and is equally sensitive as selective
venous sampling, which we formerly used.' This is done in
preference to relying solely on intraoperative ultrasonography
for localization in the infrequent patient in whom an insulinoma cannot be palpated after a complete exploration.s?
Blind distal pancreatectomy is avoided when a tumor is not
found and is, in our opinion, never indicated in a patient who
has not had localization preoperatively or who has a negative
intraoperative ultrasonographic examination. When there is
evidence that the disease is multifocal (hyperplasia or nesidioblastosis), a distal pancreatectomy is performed, and its
extent is based on preoperative diazoxide testing.
Sporadic Gastrinomas
Unlike insulinomas, most gastrinomas are malignant. However,
unless detected at a stage in which hepatic metastases are
already present, most patients are candidates for a curative

procedure. The surgical treatment of gastrinoma is dependent on its location, whether within the pancreatic
parenchyma or arising within the duodenal wall. Our experience is similar to that of others who have noted that
sporadic gastrinomas are always solitary tumors; those
within the pancreas causing Zollinger-Ellison syndrome
(ZES) are invariably larger than I em in diameter and can be
readily identified at exploration. to
Although most gastrinomas are within the gastrinoma
triangle, a pancreatic gastrinoma can arise from the neck or
body of the pancreas as well. For these unusual patients, a
distal pancreatectomy is preferable to enucleation because
of the greater likelihood that the neoplasm is malignant.
When the gastrinoma is within the pancreatic head or uncinate, we attempt enucleation and reserve resection (pancreatoduodenectomy) for when there is local infiltration and
absence of hepatic metastases.v!' Surprisingly, in nearly all
gastrinomas of the head without liver metastases, it has been
possible to enucleate the tumor. When no neoplasm is found
within the pancreas after its complete mobilization and
exploration, it should be assumed that the tumor is within
the duodenum.P A duodenotomy should be performed routinely in sporadic patients with ZES when the pancreatic
exploration is negative.'>"
Before this is performed, the duodenum should be carefully palpated from the pylorus to the level of the superior
mesenteric vein. However, fewer than half of sporadic
duodenal gastrinomas are palpable. Because a sporadic gastrinoma is singular, the duodenectomy can be placed for its
excision when it is palpable. In these cases, the neoplasm is
usually 0.5 em or larger and may locally infiltrate the submucosa. As a result, its excision with a full-thickness margin
of duodenal wall is required. 12,14When no tumor is palpable,
we make a 6- to 8-cm vertical duodenotomy centered in the
second portion of the duodenum. After inspection and gentle
finger palpation circumferentially, a small submucosal lesion
can usually be identified in the first, second, or proximal
third portion of the duodenum. When no tumor is initially
palpable, the duodenal wall, both proximally and distally,
is everted into the duodenotomy for further inspection and
palpation. Tumors as small as 1.5 mm can be detected by
these maneuvers. 12 Once identified, we place a stay stitch on
either side of the tumor, make an elliptical incision through
the mucosa around the tumor, and enucleate the tumor from
the underlying submucosa. If this cannot be easily accomplished, a full-thickness excision of the duodenal wall
around the tumor is performed. It has been our experience
that nearly all gastrinomas that are 0.5 em or smaller can be
enucleated. When a full-thickness excision has been performed, unless it is at the edge of the duodenotomy, two
separate closures are required. We prefer a two-layer closure
with a running full-thickness absorbable stitch followed by
an interrupted Lembert silk closure. Our duodenotomies are
closed vertically rather than in a transverse direction.
Regardless of a duodenal tumor's size, a regional lymph
node dissection is indicated. Gastrinomas as small as I mm
may be associated with one or more metastatic nodes.
We excise any visible nodes on both surfaces of the pancreatic head and those along the common bile duct and along
the common hepatic artery to the level of the celiac axis.
Pancreatic Surgeryfor Endocrine Tumors - - 739

When any of them are positive for metastatic disease, we
excise all of the lymph nodes in the porta hepatis as well.
A complete exploration of the pancreas and duodenum is
currently rarely negative. Although for a decade we routinely used percutaneous transhepatic selective venous sampling in localizing gastrinomas, we currently rely on EUS
after screening for hepatic metastases with a computed
tomographic (CT) scan.6,17,18 We also routinely obtain an
octreotide scan, primarily to identify any liver metastases or
otherwise occult distant metastases. Most gastrinomas 2 cm
or larger (either primary or metastatic) have sufficient
somatostatin receptors to be detectable with an octreotide
scan. Most primary duodenal gastrinomas are too small to
be identified by octreotide scans or any other localization
techniques, although their larger metastatic lymph nodes
may be detectable.
During the past 15 years, more than 70% of sporadic gastrinomas, in our experience have been duodenal in origin
with about 60% having associated metastatic lymph nodes
in the periduodenal or pancreatic region. Only one of these
patients had a liver metastasis 10%). During this time, we
recognized that tumors arising in the third or fourth portions
of the duodenum may also metastasize to lymph nodes
along the superior mesenteric vein and in the base of the
mesentery. These nodes are also now routinely resected for
primary tumors in these locations. Because of the likelihood
of recurrence in patients with malignant metastatic gastrinoma
and the possible future need for long acting somatostatin
therapy, we routinely perform a cholecystectomy as well.
If EUS is negative for a pancreatic tumor, it may be
assumed that a duodenal primary is present. Nevertheless, it
is reassuring to confirm regionalization with a selective arterial secretin stimulation test,19,20 In such cases, the liver not
only is palpated but also is examined by ultrasonography for
a rare primary hepatic gastrinoma. The distal duodenum and
proximal jejunum should also be evaluated as well as the
ovaries in a female patient.Although some have recommended
a blind Whipple procedure after a negative exploration in a
patient with proven localized gastrin hypersecretion in the
region of the head or duodenum, we do not favor that
approach. However, the possibility of re-exploration after
1 or 2 years should always be considered after a complete
re-evaluation in the patient with rising gastrin levels.
Other Sporadic Islet

Cell Tumors
Most other functional islet cell tumors such as glucagonomas,
vasoactive intestinal polypeptide tumors (VIPomas), and
somatostatinomas are too large at diagnosis to be amenable
to enucleation and require resection when feasible. 21-23 More
than half of these tumors are malignant with either local
invasion or hepatic metastases at the time of diagnosis.
Whenever feasible, debulking of tumors is desirable short of
Whipple's procedure even when hepatic metastases are present. When local invasion of the superior mesenteric vein is
the only apparent factor preventing complete tumor resection, the proximal portion of the vein and portal vein, if
uninvolved, can be mobilized and clamped and either an
autologous jugular vein or a ribbed Gore-Tex graft used for
replacement after the tumor has been resected. Another

option is the use of the distal right renal vein as a graft for
the resected superior mesenteric vein. Although we would
not usually perform superior mesenteric vein resection for
an adenocarcinoma of the pancreas, local venous involvement by an islet cell tumor may lead to portal hypertension
and mesenteric thrombosis in the absence of disseminated
disease. Every effort should be made to free the mesenteric
vessels of malignancy in patients without liver metastases.
When the superior mesenteric vein is locally invaded proximal to the confluence with the splenic vein, it may be possible to use the splenic vein as graft, swinging it down to the
proximal transected superior mesenteric vein and anastomosing it end to end (Fig. 81-2). We have used this simple
bypass on three occasions with success.
One lesson learned when there is complete occlusion of
the vein is that the superior mesenteric vein should be
shunted or bypassed to the portal vein with an elongated
graft over and around the tumor before resecting the pancreas. Incisions into the pancreas filled with venous collaterals in these cases can result in massive blood loss unless
decompressed by shunting. An elongated graft can be
clamped, divided, and shortened to an appropriate length
and anastomosed after the tumor has been excised. We have
not been as aggressive in resecting an involved superior
mesenteric artery, but we currently have several patients
without liver metastases in whom resection and bypassing
the artery are being considered because of the development
of visceral angina. In both cases, the only residual islet cell
tumor is in the superior mesenteric artery after an 85%
resection of the pancreas. In neither case was the aorta
invaded, although the superior mesenteric artery was
encased within 1 ern of its origin.
When functional islet cell tumors are associated with
liver metastases, we resect those that can be readily excised
and use radiofrequency ablation for those still remaining.
The occasional patient with a single large liver metastasis,
usually involving the right lobe, however, is a candidate for
a liver lobectomy. The effectiveness of somatostatin analogs
in the treatment of both metastatic glucagonoma and
VIPoma has lessened the need for more radical excisions of
metastatic deposits in the liver.24,25 Somatostatin analogs
may cause tumor regression in some VIPoma cases and can
control the secretion of VIP in nearly all cases. In patients
with progressive enlargement of liver metastases in both
liver lobes, we recommend hepatic arterial embolizations in
two stages, which may prove effective for 6 months to 1 year
or even longer. Because a somatostatin analog (octreotide)
is used eventually in the treatment of most incurable islet
cell tumors, cholecystectomy should always be considered
in the patient found to have liver metastases at exploration.
Long-term use of octreotide has been associated with a high
incidence of cholelithiasis and cholecystitis in those patients
with retained gallbladders.
Nonfunctional Sporadic Islet Cell Tumors

The general principles applied to the surgical treatment of nonfunctional islet cell tumors are essentially the same as those
identified for the treatment of tumors associated with clinical
syndromes. Most nonfunctional tumors are diagnosed after
FIGURE 81-2. A, Neuroendocrine tumor of head, neck, or

uncinate region encasing or invading the superior mesenteric vein
proximal to the confluence of the splenic and portal veins.
B, Distal splenic vein mobilized and clamped in preparation for
transposition as graft involvement. C, Proximal superior mesenteric
vein transection is oversewn, and splenic vein is transposed and
anastomosed end to end with proximal superior mesenteric vein.
A 95% pancreatectomy is performed. (A to C, From Thompson
NW, Eckhauser F. Malignant islet cell tumors of the pancreas.
World J Surg 1984;8:946.)
Pancreatic Surgery for Endocrine Tumors - -
they have attained a size large enough to cause local

symptoms. 21-23,26 These include jaundice, pancreatitis, steatorrhea, gastrointestinal bleeding, duodenal obstruction,
abdominal pain, and palpable abdominal mass. Most are
malignant, as manifest by local invasion, liver metastases,
or lymph node involvement. Nevertheless, even some of the
largest tumors are resectable for cure, and most can be
resected with expectation of palliation for extended periods.
Many of the nonfunctional tumors arise in the pancreatic
head, and a Whipple procedure is frequently feasible. This
operation should not be withheld because of local lymph
node metastases. An octreotide scan should be done preoperatively in all patients with suspected nonfunctional islet
cell tumors to confirm the diagnosis (when positive), for
staging, and to determine whether octreotide may be useful
as adjunctive therapy.
MEN 1
The most common functional islet cell tumor in MEN 1
patients is the gastrinoma. 22,27-34 MEN 1 patients account for
approximately 30% of all patients with the ZES, and, even
without a family history or other symptoms, all "sporadic"
ZES patients should be evaluated for the possibility of
MEN 1 and at least a serum calcium and prolactin level
obtained.
The surgical treatment of ZES in the MEN 1 patient has
remained controversial because of a previously high failure
rate in curing the disease. 28-31,35-39 Furthermore, with the use
of omeprazole, symptoms can be controlled or completely
alleviated in most patients. As a result, an operation designed
to excise the primary tumor has been deferred in many centers
until a pancreatic tumor has been imaged by CT or other
study.31.34 There are a number of obvious drawbacks to such
an approach. The first is that it ignores the potential malignancy of neuroendocrine tumors that arise in the pancreas
and the duodenum. It eliminates the possibility of cure and
concedes that the patient will require drug therapy for life. It
also potentially subjects these patients to the development of
enterochromaffin-like neuroendocrine tumors in the body of
the stomach." It appears that MEN 1 patients, in contrast
with those with sporadic gastrinoma, are genetically susceptible to the development of such tumors, and this possibility
may be enhanced by the long-term use of omeprazole in the
presence of high levels of serum gastrin.
A policy of delay until a tumor is imaged is based on the
presumption that MEN 1 patients have such diffuse functional
islet cell disease that eugastrinemia cannot be achieved without a total pancreatectomy. The evidence against this concept is that immunohistochemical staining of the MEN 1
pancreas in patients with ZES shows that the diffuse islet
cell dysplasia commonly found is not the source of gastrin
hypersecretion." Discrete tumors secrete gastrin, and most
of these are in the pancreatic head and the duodenum.
Furthermore, during the last decade, it has been shown that
duodenal tumors are present in most MEN 1 patients and
that most of these are associated with lymph node but not
liver metastases. IO,29,30.37.38,42-45 Complete excision of all
involved foci of disease can result in eugastrinemia in most
patients. 14,29.44
741
Our policy during the past 20 years has been to attempt

to cure all MEN 1 patients with ZES who do not have liver
metastases at presentation. The multifaceted approach we
currently use has evolved during this time and is based on
our previous experience and knowledge gained during
this time.
Although liver metastases are currently infrequent
(< 10%) in MEN 1 ZES patients at the time of diagnosis, a
CT or magnetic resonance and an octreotide scan is performed to exclude their presence with reasonable certainty.
These studies may also demonstrate one or more pancreatic
neuroendocrine neoplasms, although it is considered insensitive in detecting small tumors. The only other localization
study that we now consider useful is EUS, with attention
directed primarily to the head and uncinate process." EUS
may detect tumors as small as 0.5 em within the pancreatic
parenchyma that might not be detected intraoperatively by
palpation. During the past 10 years in which this procedure
has been routinely performed, duodenal tumors have also
been detected, in some cases during the preliminary endoscopic visualization of the duodenum/' However, the detection of small submucosal gastrinomas is the exception rather
than the rule, and a negative duodenal evaluation in no way
rules out the presence of such tumors.f
Our operative procedure is done through an upper abdominal transverse incision midway between the umbilicus and
the xiphoid process. After an initial careful bimanual exploration and ultrasonography of the liver for possible occult
metastases, the duodenum and pancreas are widely mobilized by extending the Kocher maneuver to the superior
mesenteric vein. Small venous branches on the lateral side
of the superior mesenteric vein entering the uncinate process
are divided between clips so that the entire uncinate may be
freed sufficiently that it can be bimanually palpated. Any
palpable nodules or those identified on EUS are exposed
after incising the pancreatic capsule and spreading the
parenchymal tissue with a fine-tip mosquito hemostat until
the capsule of the tumor has been identified. Any detectable
neoplasms in the head or uncinate are enucleated. When this
has been completed, the greater omentum is reflected from
the transverse colon by incising and reflecting its fusion
fascia, which allows entrance into the lesser omental space.
The splenic flexure is mobilized caudally away from the
inferior splenic pole. The retroperitoneum, from the superior
mesenteric vein to the spleen, is then incised sharply just
below the inferior border of the pancreas. The entire distal
pancreas is then mobilized by blunt dissection. When feasible, the small pancreatic branches from the splenic vessels
are isolated, clipped, and divided, freeing both the splenic
artery and vein from the body and tail to preserve the spleen.
In most patients, one or more neuroendocrine tumors is
readily identified in either the body or tail (Fig. 81-3). In
these cases, we include any lymphatics along the splenic
vessels and those around the celiac axis as well. The pancreas is mobilized so that the neck can be transected just to
the right of the superior mesenteric vein. The neck is then
oversewn with mattress sutures after separately ligating the
pancreatic duct. We prefer this technique to the use of either
a stapler or cross-clamping of the neck because there is no
crushed edge of tissue and the pancreatic duct can be seen
and securely ligated.
FIGURE 81-3. Multiple endocrine neoplasia type I pancreas with

islet cell tumors. Multiple neuroendocrine neoplasms are common.
After the pancreatic portions of the operation have been

completed, the duodenum is carefully palpated from the
pylorus to the superior mesenteric vein. A longitudinal duodenotomy centered in the second portion of the duodenum
allows excision of any palpable tumors in the anterior and
medial aspects of the duodenum. However, in many cases, no
tumors are palpable until the duodenotomy allows direct exposure of the mucosal surface. Both proximal and distal areas of
the duodenum must be everted into the incision and the
mucosa palpated circumferentially to rule out neuroendocrine
tumors as small as 1 mm in diameter. Tumors that are 0.5 em
or smaller can usually be enucleated from the submucosa
after an elliptical mucosal incision around the tumor. Most
larger tumors should be excised with a margin of fullthickness duodenal wall. One or more small excision sites
will require separate closure unless the tumor is close to the
original duodenotomy. Most MEN 1 patients with ZES have
one or more tumors in the first three parts of the duodenum.
One of our patients who had a previous Billroth II procedure
was found to have 29 separate tumors in the remaining
stump and second part of the duodenum proximal to the
ampulla of Vater. After local excision of the tumors distal to
the ampulla of Vater, the proximal duodenum was mobilized
from the pancreas and resected to a level just far enough
proximal to the ampulla that it could be safely closed at that
level. Most of our MEN 1 patients have had more than one
duodenal gastrinoma, although they were not always apparent until after a careful search has been made. The standard
duodenotomy is closed in two layers in a vertical direction
in which it was performed. When one or more duodenal
tumors has been found, all parapancreatic lymph nodes on
both surfaces of the pancreatic head are excised as are those
along the common bile duct, portal vein, and hepatic artery
to the celiac axis. On completion of these procedures, a
Jackson-Pratt drain is placed near the pancreatic stump and
brought out in the midline above the level of the transverse
incision (Fig. 81-4).
During the 17-year period from 1978 to 1995,25 MEN 1
patients with ZES without liver metastases underwent
FIGURE 81-4. Operation for multiple endocrine neoplasia

type l-Zollinger-Ellison syndrome: (1) distal pancreatectomy;
(2) enucleation of neuroendocrine (NE) tumors (head, uncinate);
(3) duodenotomy, excision ofNE tumors; (4) regional lymph node
dissection.
exploration with intent to "cure" their disease. The first

17 patients were reported elsewhere, with a follow-up ranging
from 2 to 16 years.f Sixty-five percent had normal basal
gastrin levels, were asymptomatic, and required no drug
therapy. The remaining 35% had a decrease in serum gastrin
levels, symptoms, and drug requirements. With longer
follow-up, the incidence of eugastrinemia has decreased to
about 30% with approximately half having been symptom
free for 10 years or longer and one for 25 years. Only one of
our MEN 1-ZES patients (n = 44) has developed a single
liver metastasis. This was recently treated by right liver
lobectomy and he is currently eugastrinemic. Several other
patients have been re-explored for recurrences in lymph
nodes or apparently new duodenal gastrinomas. No patient
has developed, as best as we can determine, either a local
recurrence in either the pancreatic head or duodenum after
an enucleation.
Gastrinomas were found in the duodenum in 76% of
patients and in both duodenum and pancreas in 35%.
Approximately half of the duodenal gastrinomas were
malignant, as proven by excision of peripancreatic metastatic lymph nodes. All patients were found to have at least
one microscopic neuroendocrine tumor involving the distal
pancreas, two of which were gastrinomas as determined by
immunohistochemical staining.
Insulinomas
Approximately 5% of all insulinomas occur in MEN 1
patients, and an estimated 10% to 15% of MEN 1 patients
acquire insulinomas as the only functional component of
their pancreatic disease.'2,22.27,30,42,47 Insulinomas in MEN 1
are commonly multiple or are associated with other pancreatic neuroendocrine tumors. Only by immunohistochemical
Pancreatic Surgery for Endocrine Tumors - - 743
staining subsequent to their excision can these tumors be

specifically classified. The only localization study we currently use in MEN 1 patients with a confirmed diagnosis of
insulinoma is EUS of the head and uncinate process of the
pancreas. A serum gastrin level is also obtained to rule out
concomitant preclinical gastrinoma and the possible need
for a duodenotomy. The operative procedure we now perform routinely is a distal pancreatectomy and enucleation of
any tumors in the head or uncinate process." At least two or
more insulinomas have been found in the eight MEN 1
patients with hypoglycemia that we have treated during a
20-year period. A duodenotomy is performed only when the
serum gastrin level is elevated and a secretin test is positive.
Extrapancreaticinsulinomas have not been reported in MEN 1
patients. A peripancreatic lymphatic dissection is performed
only in those patients with concomitant duodenal gastrinomas and in the rare patient with a malignant insulinoma arising from the pancreas. Only one of our patients, a 27-year-old
man, was found to have a 7-cm malignant insulinoma arising
from the neck of the pancreas as well as additional neuroendocrine tumors in the body and tail. Although one lymph node
contained a metastasis, there has been no evidence of recurrence during a 12-year follow-up. All other patients are also
euglycemic after follow-upperiods ranging from 6 to 20 years.
Nonfunctional Tumors
Most patients with functional tumors have other nonfunctional tumors or those secreting hormones that produce no
identifiable syndrome, most commonly arising in the distal
pancreas. Most of these are found before their malignant
potential is evident and before a functional syndrome has
developed. Their presence is one of the primary reasons for
recommending a distal pancreatectomy in all MEN l-ZES
and insulinoma patients. 30,44
Approximately 5% to 10% of MEN 1 patients acquire
neuroendocrine tumors, producing symptoms related
entirely to their size, local invasion, or hepatic metastases,
These patients may present with weight loss, abdominal
pain, jaundice, an abdominal mass, or gastrointestinal hemorrhage. In those with large tumors of the head but without
hepatic metastases, Whipple's procedure may be curative.
Even when the superior mesenteric vein is involved by a
neuroendocrine tumor, resection and vein replacement are
indicated whenever such involvement is the only factor preventing total excision of the tumor. Tumors localized to the
neck or uncinate involving the superior mesenteric vein or
artery may cause portal hypertension with bleeding varices
or visceral ischemia, respectively. Surgical resection and
revascularization may offer significant palliation, if not cure,
and should be considered. Finally, size alone does not
always imply local invasion or metastatic disease, and we
have resected three neuroendocrine tumors in MEN 1
patients that were 10 em or larger that showed no features of
malignancy or subsequent recurrence.
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insulinoma: Incidence, recurrence and long-term survival of patients:
A 60-year study. Mayo Clin Proc 1991;66:711.
3. Pasieka JL, McLeod MK, Thompson NW, Burney RE. Surgical
approach to insulinomas: Assessing the need for preoperative localization. Arch Surg 1992;127:442.
4. Udelsman R, Yeo CJ, Hruban RH, et al. Pancreaticoduodenectomy for
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1993;177:269.
5. Hamess JK, Geelhoed GW, Thompson NW, et al. Nesidioblastosis in
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6. Thompson NW, Czako PF, Fritts LL, et al. Role of endoscopic ultrasonography in the localization of insulinomas and gastrinomas.
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7. Doppman JL, Miller DL, Chang R, et al. Intraarterial calcium
stimulation test for detection of insulinoma. World J Surg 1993;17:439.
8. Norton JA, Cromack DT, Shawker TH, et al. Intraoperative ultrasonographic localization of islet-cell tumors: A prospective comparison to
palpation. Ann Surg 1988;207:160.
9. van Heerden JA, Grant CS, Czako P, et al. Occult functioning insulinomas: Which localizing studies are indicated? Surgery 1992;112:1010.
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aspects of gastrinomas in patients with Zollinger-Ellison syndrome
with and without multiple endocrine neoplasia type I. World J Surg
1993;17:481.
11. Delcore R, Herumreck AS, Friesen SR. Selective surgical management
of correctable hypergastrinemia. Surgery 1989;106:1094.
12. Thompson NW, Vinik AI, Eckhauser FE. Microgastrinomas of the
duodenum: A cause of failed operations for the Zollinger-Ellison
13. Sugg SL, Norton JA, Fraker DL, et al. A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann
Surg 1963;218:138.
14. Thompson NW, Pasieka J, Fukuuchi A. Duodenal gastrinomas, duodenotomy and duodenal exploration in the surgical management of
Zollinger-Ellison syndrome. World J Surg 1993;17:455.
15. Declore R Jr, Cheung LS, Friesen SR. Characteristics of duodenal wall
gastrinomas. Ann J Surg 1990;160:621.
16. Thorn AK, Norton JA, Axiotis CA, Jensen RT. Location, incidence, and
malignant potential of duodenal gastrinomas. Surgery 1991;110:1086.
17. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic
endocrine tumors by endoscopic ultrasound. N Engl J Med 1992;
326:1721.
18. Vinik AI, Moattari AR, Cho K, Thompson NW. Transhepatic portal
vein catheterization for localization of sporadic and MEN gastrinomas:
A ten-year experience. Surgery 1990;107:246.
19. Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the
Zollinger-Ellison syndrome. Ann Surg 1987;205:230.
20. Imamura M, Takahashi K, Isobe Y, et al. Curative resections of multiple
gastrinoma aided by selective arterial secretin injection test and intraoperative secretin test. Ann Surg 1989;210:710.
21. Grant CS. Surgical management of malignant islet cell tumors. World
J Surg 1993;17:498.
22. Norton JA. Neuroendocrine tumors of the pancreas and duodenum.
23. Thompson NW, Eckhauser FE. Malignant islet cell tumors of the pancreas. World J Surg 1984;8:1.
24. Lamberts SWJ, Krenning EP, Reubi Je. The role of somatostatin and its
analogs in the diagnosisand treatmentof tumors.Endocr Rev 1991;12:400.
25. Maton PN. Use of octreotide acetate for control of symptoms in
patients with islet cell tumors. World J Surg 1993;17:504.
26. Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malignant
neuroendocrine tumors of the pancreas. Surgery 1986;100:978.
27. Mignon M, Ruszniewski P, Podevin P, et al. Current approach to the
management of gastrinoma and insulinoma in adults with multiple
endocrine neoplasia type I. World J Surg 1993;17:489.
28. Shepherd J, Challis DR, Davies FF, et al. Multiple endocrine neoplasia,
type I: Gastrinoma, pancreatic neoplasms, microcarcinoids, ZollingerEllison syndrome, lymph nodes, and hepatic metastases. Arch Surg
1993;128:1133.
29. Thompson NW. The surgical treatment of the endocrine pancreas and
the Zollinger-Ellison syndrome in the MEN I syndrome. Henry Ford
Hospital Med J 1992;40:112.

30. Akerstrom G, Johansson H, Grama D. Surgical treatment of endocrine
pancreatic lesions in MEN I. Acta OncoI1991;30:542.
31. van Heerden JA, Smith SL, Miller L. Management of the ZollingerEllison syndrome in patients with multiple endocrine neoplasia type I.
Surgery 1986;100:871.
32. Tisell LE, Ahlman H, Jansson S, Grimelius L. Total pancreatectomy in
the MEN I syndrome. Br J Surg 1988;75:154.
33. Thompson NW, Bondeson AG, Bondeson L, Vinik AI. The surgical
treatment of gastrinoma in MEN I syndrome patients. Surgery 1989;
106:1081.
34. Sheppard BC, Norton JA, Doppmann JL, et al. Management of isletcell tumors in patients with multiple endocrine neoplasia: A prospective study. Surgery 1989;106:1108.
35. Norton JA. Advances in the management of Zollinger-Ellison syndrome. Adv Surg 1994;27:129.
36. Norton JA, Jensen RT. Unresolved surgical issues in the management
of patients with Zollinger-Ellison syndrome. World J Surg 1991;15:151.
37. Pipeleers-Marichal M, Somers G, Willems C, et al. Gastrinomas in the
duodenums of patients with multiple endocrine neoplasia type I and
the Zollinger-Ellison syndrome. N Engl J Med 1990;322:723.
38. Delcore R, Friesen SR. The role of pancreatic duodenectomy of
primary duodenal wall gastrinomas in patients with the Zollinger-Ellison
syndrome. Surgery 1992;112:1.
39. Cherevu JA, Sawyers JL. Benefits of resection of metastatic gastrinomas
in multiple endocrine neoplasia type I. Gastroenterology1992; 102:1049.
40. Solcia E, Capella C, Fiocca R, et al. Gastric argyrophilic carcinoidosis

in patients with Zollinger-Ellison syndrome due to type I multiple
endocrine neoplasia. Am J Surg PathoI1990;14:503.
41. Thompson NW, Lloyd RV, Nishiyama RH, et al. MEN I pancreas: A
histological and immunohistochemical study. World J Surg
1984;8:561.
42. Kloppel G, Willemer S, Stamm B, et al. Pancreatic lesions and hormonal profile of pancreatic tumors in multiple endocrine neoplasia
type I: An immunocytochemical study of nine patients. Cancer
1986;56:1824.
43. Donow C, Pipeleers-Marichal M, Schroder S. Surgical pathology of
gastrinoma: Site, size, multicentricity, association with multiple neoplasia type I and malignancy. Cancer 1991;68:1329.
44. Thompson NW. The surgical management of hyperparathyroidism and
endocrine disease of the pancreas in the multiple endocrine neoplasia
type I patient. J Intern Med 1995;238:1.
45. Imamura M, Kanda M, Takahashi K, et al. Clinicopathological characteristics of duodenal microgastrinomas. World J Surg 1992;16:702.
46. Zimmer T, Stolsel V, Bader M, et al. A duodenal gastrinoma in a patient
with diarrhea and normal serum gastrin concentrations. N Engl J Med
1995;333:634.
47. O'Riordain DS, O'Brien T, van Heerden JA, et al. Surgical management of insulinoma associated with multiple endocrine neoplasia
type I. World J Surg 1994;18:488.
Gastrinoma
Stuart D. Wilson, MD
A gastrinoma is an endocrine tumor that elaborates the

hormone gastrin. The consequences of the hypergastrinemia
are gastric acid hypersecretion and related complications.
Before the identification ofthe hormone gastrin as the gastric
secretagogue, the tumors were called "ulcerogenic tumors of
the pancreas."1,2 Zollinger-Ellison syndrome, or Z-E syndrome,
is used frequently in the medical literature in place of the
term gastrinoma.'
Gastrinoma patients should be classified as having either
sporadic or familial gastrinoma. This distinction is important
because the pathophysiology, natural history, and medical or
surgical management of sporadic and familial gastrinoma
patients are different. Sporadic gastrinomas are not inherited
and are only rarely associated with other endocrinopathies.
Familial gastrinomas are those that develop in individuals
who have inherited the genetic trait for multiple endocrine
neoplasia type 1 (MEN 1).4 The eponym for the MEN 1 syndrome is Wermer's syndrome.' The term multiple endocrine
adenopathy type 1 (MEA-I) is preferred to MEN 1 by some
authors.v' In this chapter sporadic gastrinomas are discussed,
Familial gastrinomas, occurring in patients with MEN I, are
discussed in Chapter 76.
peptic ulcerations of the jejunum associated with islet cell

tumors of the pancreas. They suggested a diagnostic triad
for a new clinical syndrome':
1. The presence of primary ulcerations in unusual locations, that is, second or third portions of the duodenum
or upper jejunum, or recurrent stomal ulcers after any
type of gastric surgery short of total gastrectomy (TG)
2. Gastric hypersecretion of gigantic proportions persisting despite adequate conventional medical, surgical,
or irradiation therapy
3. The identification of nonspecific islet cell tumors of
the pancreas (an "ulcerogenic tumor factor of pancreatic islet origin" was postulated)
The subsequent reports detailing the early descriptions of
patients with ulcerogenic tumors, the discovery of a potent
gastric secretagogue in the tumor tissue and the sera of
Z-E syndrome patients, the identification of gastrin as the
responsible hormone, and the development of radioimmunoassay (RIA) methods to measure physiologic and
supranormal gastrin concentrations all make fascinating
reading. This history has been recorded by Zollinger and
Coleman."
Brief History and Evolution

of the Zollinger-Ellison Syndrome
Pathophysiology and Symptoms
The history behind the identification and characterization of

the Z-E syndrome is fascinating. Four decades of investigating the pathophysiology and natural history, searching for
drugs to inhibit the marked gastric acid hypersecretion,
developing new technologies to diagnose and locate the
tumors, and searching for the preferred treatment for patients
with Z-E syndrome have captivated many physicianscientists, some of whom could appropriately be dubbed
"Z-E watchers." Some Z-E watchers have made the study of
this disease entity a focus of their research and clinical practice. Their contributionshave altered our approach to the diagnosis, management, and treatment of this disease. 1,7-28
In 1955, at the annual meeting of the American Surgical
Association, Robert M. Zollinger and Edwin H. Ellison
reported the clinical histories of two patients with primary
The altered physiology of patients with Z-E syndrome is due

to the effects of high concentrations of gastrin in the circulation. The primary effects of the hypergastrinemia are gastric
acid hypersecretion and parietal cell hyperplasia (Fig. 82-1).
Gastrin acts directly on specific receptors of the parietal cell
to promote gastric acid secretion. Because gastrin is also a
trophic hormone, chronic hypergastrinemia causes an absolute
increase in the number of parietal cells, thus increasing gastric
acid hypersecretion even more." Pancreatic volume and
bicarbonate output are similarly increased by a combination
of increased duodenal acid load and a direct trophic effect of
gastrin on pancreatic acinar cells."
The patient's response to the marked gastric acid hypersecretion is variable (see Fig. 82-1). Complications such as
bleeding, perforation, and outlet obstruction may occur.
Some patients with Z-E syndrome appear to have more than
745
746 - -
Endocrine Pancreas
EFFECTSOF HYPERGASTRINEMIA
1. gastric acid hypersecretion
2. parietal cell hyperplasia

3. pancreatic hypersecretion
PATIENTRESPONSE
TO ACID-VARIABLE
~bleed
gastric
}
hypersecretion
ulceratlon _
perforate
............ obstruction
/ ' " hypokalemia
FIGURE 82-1. Pathophysiology of the ZollingerEllison syndrome and tumor locations. Gastrinomas
may be (a) submucosal in duodenal wall; (b) pedunculated, arising from pancreatic surface; (c) in parapancreatic lymph nodes; (d) in pancreatic parenchyma;
(e) liver metastases. (From Wilson S. Gastrinoma. In:
Howard lM, Jordan GLJR, Reber HA reds], Surgical
Diseases of the Pancreas. Philadelphia, Lea & Febiger,
1987.)
' " diarrhee _electrolyte imbalance

............ steetorrhea
Tumor locations
the usual duodenal and gastric mucosal resistance to peptic

ulceration and initially may not experience peptic ulceration.
In these patients, the combination of the increased gastric and
pancreatic secretions may overwhelm the normal absorptive
capacity of the intestine, and a watery "overflow" diarrhea
may be the initial complaint." Erosive duodenitis and jejunitis
can usually be documented in these patients by endoscopy."
Seven diagnostic clues suggest the presence of a
gastrinoma:
1. Diarrhea in a patient with peptic ulcer disease
2. Peptic ulcers persisting after therapy with H2 receptor
antagonists or omeprazole
3. Recurrent ulcer after an adequate ulcer operation
4. Pathognomonic jejunal ulcers
5. Large gastric rugal folds, often associated with duodenitis, jejunitis, and rapid transit
6. Multiple atypical peptic ulcers
7. Marked gastric acid hypersecretion (>15 mEq/hour)
Although these clues suggest the presence of a gastrinoma, the clinician should remember that most patients with
Z-E syndrome present with signs and symptoms similar to
those seen in patients with ordinary acid peptic ulcer disease.
Most Z-E syndrome patients (approximately 70%) present
with pain related to acid peptic disease. Cramping pains
associated with diarrhea are not uncommon (20% to 30%),
and in some patients (about 10%) diarrhea may be the only
complaint. Symptoms have been present longer than a year in
four of five patients. Gastric acid hypersecretion can produce
a characteristic gastrointestinal radiologic picture (i.e., atypical
ulcers, large gastric folds, rapid transit, and flocculation of
barium); however, three of four patients exhibit ulceration
in the usual duodenal ulcer locations.v-" Nearly one third of
Z-E syndrome patients have had symptoms for 5 years before
presenting to a physician, and four of five patients have radiologic findings of an ordinary duodenal ulcer. 34 ,35
Pathology
Gastrinomas are composed of cells that resemble the
G cells of the gastric antrum and duodenum." Variability
in tumor histology, extrapancreatic sites, and multiplicity
of lesions are characteristics of Z-E syndrome (see
Fig, 82-1). Although first called pancreatic islet cell
tumors, many gastrinomas are located outside the pancreas,

with sites in the duodenal wall, stomach, jejunum, peri pancreatic tissue, ovaries, and liver. In some series, fewer
than 50% of Z-E syndrome patients have a histologically
documented pancreatic primary tumor. The existence of
primary (i.e., nonmetastatic) gastrinoma in a lymph node
as a cause of Z-E syndrome is controversial, but numerous
patients have been cured by removing one or more lymph
nodes. 37-39
At least 60% of gastrinomas are malignant. Even tumors
that appear histologically benign may be associated with
metastases. I consider all gastrinomas to be potentially malignant neoplasms. However, gastrinomas may have an indolent
course, and Z-E syndrome patients with proven lymph node
metastases may live for several decades without apparent
tumor progression.F'"
The first gastrinomas were described as "noninsulinproducing islet-cell tumors" by Zollinger and Ellison
because the tumors appeared to be islet cell lesions histologically, they produced a hormone, and conventional
staining techniques indicated an absence of beta granules
in the cytoplasm of the tumor cells. Islet cell tumor is a
misnomer because these gastrin-producing neuroendocrine
tumors probably do not develop from pancreatic islet cells
directly. Current theory is that these tumors develop from
pluripotential neuroendocrine stem cells located within
the duct epithelium of the exocrine pancreas and gastrointestinal tract. 4 1,42
The morphologic appearance of gastrinomas is similar
to that of carcinoid tumors and other neuroendocrine tumors
of the pancreas. The arrangement of the tumor cells is variable; the common patterns are ribbon, rosette, follicular, and
solid sheets of small, uniform, and usually well-differentiated
cells separated by trabeculae. Distinction between a benign
and a malignant tumor usually cannot be made on the basis
of histology alone. 43,44
Immunohistochemical staining techniques, using
specific antibodies, can identify gastrin granules within
cytoplasm of the gastrinoma cells. Chromogranin A,
neuron-specific enolase, and synaptophysin are proteins
that can also be found in gastrinomas by these techniques,
further characterizing these tumors as neuroendocrine
in nature."
Gastrinoma - -
Etiology of Sporadic Gastrinoma

Syndrome
The etiology of the sporadic gastrinoma syndrome has not
been defined, nor has a specific gene defect been identified.
Studies by 1. Thompson's group were unable to document
mutations of the p53 and ras genes in gastrinomas, but they
did find amplification of HER-2/neu, a protooncogene
related to the epidermal growth factor receptor." A gene
defect has been localized to the long arm of chromosome 11
in patients with MEN 1, some of whom acquire gastrinomas, but patients with sporadic gastrinomas do not appear to
have this defect."
Chronic alcohol abuse may be an important risk factor in
the genesis of some gastrinomas of the sporadic type. A history of excessive alcohol intake (>50 g/day) that antedated
the Z-E syndrome in 23 of 36 (64%) sporadic gastrinoma
patients admitted to our clinical research center could be
documented over a 30-year period. Gastrinomas in the duodenal wall and in lymph nodes were a common finding in
this group of patients, whereas primary pancreatic gastrinomas were rare. Death from progressive tumor growth has
been infrequent. These observations suggest that the Z-E
syndrome is not a single disease process but that several
subgroups exist."
Evaluation of Patients:
Suspected Zollinger-Ellison
Syndrome
The introduction of pharmacologic agents that inhibit gastric
acid hypersecretion now allows the luxury of a safe and
unhurried evaluation of patients, including diagnostic testing and tumor localization before an operation. Before the
introduction ofthe H 2 receptor antagonists in 1978 and more
recently the substituted benzimidazoles (omeprazole), most
Z-E syndrome patients suffered complications of gastric
acid hypersecretion before a surgeon was consulted. 18,49.50
Urgent operations, not planned elective procedures, were
the norm." More problematic was the surgeon's inability to
inhibit gastric acid hypersecretion after operating on a
Z-E syndrome patient. Indeed, from 1955 to 1965, the decade
after Zollinger and Ellison's historic presentation, nearly
one half of deaths of Z-E syndrome patients occurred within
30 days after an operation, usually because the surgeon had
not removed all of the gastrin-producing tumor or had not
performed a TG.52 The hospital can still be a dangerous
place for the gastrinoma patient. Great care should be taken
to ensure that the excessive gastric acid secretion is shut
down in patients during evaluation and testing periods.
Before any tumor-localizing studies or operation, the following steps are recommendedv:
1. Document pharmacologic control of gastric acid
hypersecretion. First, the dose of omeprazole required
to reduce acid secretion adequately may vary from 20 to
120 mg/day and needs to be titrated to the individual.P
Second, gastric acid secretion should be reduced to
less than 5 mEq/hour during the hour preceding the
747
next dose.53 Third, a somatostatin analogue (octreotide)

might be helpful to reduce acid secretion further in
difficult cases during the perioperative period when
intravenous infusion of H 2 antagonists is required.54-57
2. Document healing of peptic ulcers by endoscopy. The
absence of symptoms does not indicate the adequacy
of pharmacologic antisecretory control."
Diagnosis
The diagnosis of Z-E syndrome is established by documenting
gastric acid hypersecretion and hypergastrinemia. With rare
exception, a basal acid output (BAO) greater than 15 mEq/
hour and a fasting serum gastrin greater than 500 pg/mL are
diagnostic. There may be some overlap in the values of gastric
acid output in a few patients with ordinary peptic ulcer disease
and patients with gastrinoma, but when a fasting serum gastrin
is measured, the diagnosis is generally clear." If the fasting
serum gastrin is normal or in the equivocal range (100 to
500 pg/mL), a secretin injection test for gastrin response
should identify the patients who harbor a gastrinoma.t?
GASTRIC ANALYSIS
Marked gastric acid hypersecretion is the hallmark of the

Z-E syndrome. The following gastric acid secretory criteria
are characteristic:34.35.58.60.61
1. Nocturnal (12 hours) gastric acid secretion greater
than 1000 mL and 100 mEq of hydrochloric acid
2. One-hour BAO greater than 15 mEq
3. BAO greater than 60% maximal acid output (MAO)
(BAOIMAO ratio)
4. Basal acid concentration (BAC) greater than 60% of
the maximal acid concentration (MAC) (BACIMAC
ratio)
A gastric analysis documents a BAO of greater than
15 mEq/ hour in nearly every Z-E syndrome patient, and
more than 50% of Z-E patients have a BAO greater than
30 mEq/hour. The MAO and peak acid output (PAO) are
also greater in Z-E syndrome patients because of an increase
in parietal cells secondary to the trophic effect of gastrin.
The MAO and PAO are indirect measurements of parietal
cell mass. The BAOIMAO ratio is greater than 0.6 in most
Z-E syndrome patients because hypergastrinemia is stimulating the parietal cells to near-maximal output.
Evaluation of Hypergastrinemia
An understanding of gastrin physiology is necessary when
evaluating a patient with hypergastrinemia. Gastrin is a peptide
hormone, normally produced in the G cells of the antral
mucosa. Gastrin release is stimulated by food in the stomach,
and the amount of gastrin released is modulated by the surface
pH of the antral mucosa. Gastrin (from the antrum) and acid
(from the fundus) represent the positive and negative limbs
of a feedback loop. When gastrin is released into the blood,
the acid-producing parietal cells in the gastric fundus are
stimulated to secrete more acid; the pH of the antral mucosal
surface is lowered, and release of gastrin from the G cells is
inhibited. This negative feedback loop modulating system
maintains the serum gastrin in a normal physiologic range."
Z-E syndrome patients harbor a gastrinoma, which produces

excess gastrin, causing gastric acid hypersecretion. These
gastrinoma G cells are outside the negative feedback loop
and are not "turned off" by the excess gastric acid, resulting
in a chronic hypergastrinemic state.
Serum gastrin concentrations can be precisely measured
using RIA techniques.f Normal fasting serum gastrin averages between 10 and 150 pg/mL. Laboratories may use different assay methods, and normal values vary; interpretation
of serum gastrin should take into account these differences.
Hypergastrinemia can be caused by conditions other than
the Z-E syndrome.35,48,53 A complete history and gastric
analysis clarify the diagnosis in most situations (Table 82-1).
Antral G-cell hyperfunction can cause hypergastrinemia
and gastric acid hypersecretion. Antral G-cell hyperplasia
and pseudo-Z-E are other terms used for this condition.
BAO and serum gastrin are less than in gastrinoma patients,
but there may be some overlap in values. Short bowel syndrome, gastric outlet obstruction, renal failure, and
Helicobacter pylori gastritis can also be associated with an
increase in serum gastrin. The clinical picture and a secretin
provocative test rule out gastrinoma. A retained gastric
antrum, after Billroth II gastrectomy, can mimic Z-E syndrome. The G cells in the retained antrum are not exposed
to acid inhibition, so they release more gastrin than normal.
A secretin provocative test distinguishes a patient with a
retained antrum because gastrin release is not increased by
intravenous secretin as observed in Z-E syndrome patients.
Removal of the retained antrum returns the gastrin to normal
and cures the ulcer disease in these patients.
Patients with pernicious anemia or chronic gastritis have
been referred to our institution with a diagnosis of Z-E
syndrome because of an elevated serum gastrin, often
greater than 1000 pg/mL. Because of the achlorhydria or
hypochlorhydria inherent in these disorders, the usual acid
inhibition of antral gastrin release is diminished or lost.
Chronic atrophic gastritis and gastric ulcers can also be
associated with an elevated serum gastrin by a similar mechanism. A patient with a vagotomy may have an increase in
fasting serum gastrin, probably because of the loss of vagal
and acid inhibition of antral gastrin production. Even if a
gastric analysis cannot be obtained, an untreated gastric
content pH greater than 3.5 rules out acid hypersecretion,
and Z-E syndrome is excluded."
Provocative Diagnostic Tests

Three provocativetests have been used to clarify the diagnosis
of gastrinoma when the serum gastrin and gastric analysis
are not definitive. The current recommendation is to use
only the secretin injection test because of its simplicity, lack
of side effects, and better discrimination.
1. Standardized test meal: A patient with duodenal ulcer
or antral G-cell hyperplasia (pseudo-Z-E syndrome)
may show an augmented gastrin response to a test
meal, whereas the Z-E syndrome patient usually does
not have a significant increase over basal gastrin. 62,63
2. Calcium infusion: Intravenous calcium is a stimulus
for gastrin release from a gastrinoma as well as antral
G cells. The Z-E patient usually has a more immediate
and pronounced gastrin response than patients with
other hypergastrinemic conditions. 14,64
3. Secretin injection test (Fig. 82-2): Intravenous secretin
infusion produces a paradoxical increase in both
serum gastrin and gastric acid secretion." This paradoxical response is unique to the Z-E syndrome
patient. 59,66
Preoperative Tumor-Localizing
Techniques
Tumor-localizing techniques for gastrinoma have continued
to evolve since Zollinger and Ellison's first report.' Their
first two Z-E syndrome patients had only barium swallows,
demonstrating mucosal changes in the stomach and small
bowel related to excess acid. In Ellison's 1956 report, the
first reported "series" of ulcerogenic tumor patients, no
tumors were identified preoperatively by any imaging technique, and the concept of preoperative localizing was not
even mentioned. Abdominal plain films and barium studies
500
Secretin
400
~-5
.5
300
" 200
100
-5 -2.5
2.5
7.5
10 12.5
15
20
Minutes
FIGURE 82-2. Serum gastrin concentrations before and after the

intravenous injection of secretin (2 Ulkg body weight). The test
was performed before (circles) and after (triangles) resection of a
5-mrn submucosal duodenal wall gastrinoma from a patient with
near-normal serum gastrin concentration.
Gastrinoma - - 749
are not helpful unless there is a large, bulky tumor or

calcification in a pancreatic islet cell tumor. Sensitivities
for preoperative gastrinoma-localizing modalities are given
in Table 82-2. Practical steps for ordering preoperative
localizing studies are listed in Table 82-3.
Abdominal ultrasonography (US) has a low detection rate
(20% to 25%) for gastrinomas but is relatively inexpensive
and does not involve the risks associated with intravenous
contrast material and radiation exposure that accompany
computed tomography. Tumors smaller than I em are generally not detected, and only 15% of lesions I to 3 em in size
are detected. Tumors larger than 3 em are usually seen. 67
Despite its poor sensitivity, US may improve the overall sensitivity for detecting a tumor if it is used in conjunction with
other studies."
Computed tomography (CT) overshadowed abdominal

angiography during the 1980s and became a popular
gastrinoma-localizing technique. Early reports enthusiastically suggested that CT of the upper abdomen would detect
nearly 70% of islet cell tumors found at laparotomy.'"
However, even with the new-generation CT scanners and
improved techniques, most modem studies indicate that CT
identifies a gastrinoma in fewer than half of all Z-E patients."
CT rarely detects tumors smaller than 1 em and finds less
than 50% of 2-cm lesions. Preoperative CT has been important, however, to identify liver metastases. Two-phase helical
CT scans abdominal organs in both the arterial and parenchymal phase after intravenous contrast. In a 1995 report, 9 of
11 islet cell tumors were identified (82% sensitivity), including
a 4-mm gastrinorna.P This new technique could improve
detection of gastrinomas.
Magnetic resonance (MR) imaging has not demonstrated
great sensitivity for localizing primary gastrinomas.
Advantages of MR include the ability to obtain coronal and
sagittal images and to identify liver metastases. A 1993
study from the National Institutes of Health (NIH) group
that prospectively compared MR with US, CT, and angiography in 32 gastrinoma patients showed sensitivities of only
25%, 19%,28%, and 59%, respectively." However, for the
18 patients in the study with metastatic gastrinoma in
the liver, MR imaging had a sensitivity of 83%, whereas
the sensitivities of US, CT, and angiography were 50%,
56%, and 61%, respectively. The combination of MR, US,
and CT was the same as MR alone. They concluded that MR
is the imaging study of choice to assess metastatic pancreatic endocrine tumors in the liver. In contrast, the detection
of primary tumors by MR imaging had not improved; therefore, they also recommended that angiography remain the
study of choice for localizing primary tumors. MR imaging
technology is improving, and, with reduced scanning times,
image resolution may equal or exceed that of CT.
Somatostatin receptor scintigraphy (SRS) is a new technique to localize gastrointestinal endocrine tumors. Because
many of these tumors possess high-affinity somatostatin
receptors, it is possible with the stable indium-Ill-labeled
somatostatin analogue pentetreotide, which binds to these
receptors, to detect somatostatin receptor-positive tumors
scintigraphically. Several studies suggest that SRS is helpful
in the preoperative localization of gastrointestinal endocrine
tumors. n. 73 One study detected gastrinomas at a rate of
100% compared with 60% each for CT, MR, and percutaneous abdominal US.74
Endoscopic ultrasonography (EUS) has been shown to
image the pancreas accurately and to be highly sensitive
for small pancreatic adenocarcinomas." The University of
Michigan group reported that EUS correctly identified and
localized 7 of 10 insulinomas, all in the pancreas, but only 1
of 5 gastrinomas. Three "missed" gastrinomas, 3 to 6 mm,
were found at operation in the duodenal wall. They concluded that a negative EUS study in Z-E syndrome patients
excluded a pancreatic gastrinoma, indicating a small duodenal or extrapancreatic lesion." A subsequent prospective
study from Paris showed that EUS alone localized gastrinomas in 41 % of 22 Z-E syndrome patients." Sensitivity of
EUS was 50% for duodenal wall tumors (conventional
endoscopy, 40%), 75% for pancreatic tumors (CT scan,

25%), and 62.5% for tumoral lymph nodes (CT scan, 0%).
They concluded that EUS should be considered as a firstchoice imaging technique for preoperative detection of gastrinomas, and, although small duodenal gastrinomas are still
obviously difficult to detect, an accurate exploration of the
pancreatic area was provided by this technique. Both the
Michigan and Paris groups suggested that laparotomy could
be performed in most Z-E syndrome patients after only two
imaging studies: CT scan and EUS. Sensitivity of EUS is
related not only to tumor size but also to the experience of
the endoscopist and radiologist performing EUS. There is
a learning curve, and 100 cases may be needed to become
proficient. 76
Selective abdominal angiography was first used to detect
a pancreatic islet cell tumor (an insulinoma) in 1963.78
The sensitivity of angiography in detecting gastrinoma
has been considerably less than that for insulinoma, even
with the new ancillary techniques that improve sensitivity,
such as superselective vessel injection, magnification, and
digital subtraction angiography. Selective angiography has
proved to be the best imaging study to identify primary and
metastatic gastrinoma compared with US, CT, and MRI.28
However, in this study, angiography rarely identified duodenal wall tumor or lymph node metastases.
Portal venous sampling (PVS) is a fluoroscopically
guided, percutaneous transhepatic catheterization procedure
that obtains venous samples for gastrin from several different
veins draining the pancreas or other areas of interest.
Gradients in gastrin concentration "regionalize" the tumor
locatiou.?? This test requires considerable expertise and has
significant complications. PVS has now been replaced by
the selective arterial secretin injection (SASI) test because
the latter is more sensitive and patients experience fewer
cornplications.s"
The SASI test was developed by Imamura and colleagues
to localize preoperatively gastrinomas that could not be seen
by conventional imaging techniques." The principle of the
SASI test is based on the observation that secretin injection
induces a prompt release of gastrin from gastrinoma cells. 65
An arterial catheter is selectively inserted into one of three
peripancreatic arteries: gastroduodenal, superior mesenteric,
or splenic artery. The gastroduodenal artery feeds the upper
half of the pancreatic head and upper duodenum. The
splenic artery supplies the body and tail of the pancreas. The
superior mesenteric artery feeds the lower half of the pancreatic head and the lower duodenum. A second catheter
is placed in the right hepatic vein to collect venous samples
for gastrin. Secretin is injected into the selected artery, and
the hepatic venous blood samples are collected for gastrin
measurement before and then 20, 40, 60, 90, and 120 seconds after each secretin injection. Gastrin concentration in
the hepatic vein samples obtained after secretin injection
into the selected artery supplying the area of duodenum or
pancreas containing the gastrinoma peaks earlier and higher
than when injected into an artery feeding an area without
gastrinoma (Fig. 82-3). In a report by Imamura and
Takahashi, the SASI test localized gastrinomas in 12 of
12 Z-E syndrome patients studied, whereas CT and transhepatic PVS had a positive predictability of less than 10%.
Selective arteriography identified tumors in only 5 of
12 patients.P"?
5000
t
i
co.
4000
'a----~--
3000
SMA
2000
1000
: :
o+--~--~-~-~--~-~--
PRE
20
40
60
90
120
Seconds
FIGURE 82-3. Results of selective arterial secretin injection test

in a patient with Zollinger-Ellison syndrome with a gastrinoma in
the second portion of duodenum. The chart shows hepatic vein
serum gastrin concentrations after arterial secretin injection (25 U)
into three different arteries supplying the pancreas and duodenum.
A positive gradient occurred 20 seconds after injection into the
superior mesenteric artery (SMA). This vessel supplies the blood
to the second portion of the duodenum through the inferior pancreaticoduodenal arteries.
Medical Management
versus Operation
Optimum treatment recommendations for patients with Z-E
syndrome have undergone continuing change during the
40 years since Zollinger and Ellison reported on their first
two patients, both of whom required a TG to control the
complications of recurring peptic ulcer disease. These
changes in Z-E syndrome management have come with
a better understanding of the natural history and pathophysiology of Z-E syndrome, the RIA for gastrin, new imaging
technologies that preoperatively and intraoperatively localize
gastrinomas, and, perhaps most important, new drugs that
inhibit gastric acid secretion."
Medical Management
Inhibition of gastric acid secretion in many Z-E syndrome
patients was made possible with the introduction of the H2
receptor antagonist cimetidine." Previously, TG had been
necessary to achieve long-term survival of patients with Z-E
syndrome. After cimetidine became available in 1977, some
argued for medical management alone, claiming that the
mortality for TG was inordinately high and finding and
removing all gastrinoma tissue were unlikely.'" However,
there were failures of medical management and antiandrogen
side effects at high cimetidine doses (>4.8 g/day), such as
breast tenderness, gynecomastia, and impotence in men,
which continued to fuel the controversy. Some surgeons
still favored TG when not all tumor could be removed."
The introduction of two new H2 blockers, ranitidine and
famotidine, which inhibited gastric acid secretion more
effectively and did not have antiandrogen side effects, made
medical therapy even more attractive.
Gastrinoma - - 751
Then another important advance in medical therapy came
with the advent of a new class of antisecretory drugs: the
substituted benzimidazoles (omeprazolej.tv" The mechanism of action of these drugs is different from that of
the Hz receptor antagonists in that they bind to a unique
enzyme responsible for acid secretion at the apical (luminal)
aspect of the gastric parietal cell: the hydrogen-potassium
adenosine triphosphatase proton pump enzyme. In most
Z-E syndrome patients, gastric acid hypersecretion can be
treated effectively with a once-daily dose of omeprazole,
although about 10% to 25% of patients require a dose every
12 hours. 50,53 Tachyphylaxis does not occur, and the dose
can be decreased over time in some patients. The Z-E syndrome patient must continue to take omeprazole indefinitely
unless cured surgically. Repeated gastroduodenal endoscopy
is necessary to evaluate the dose of anti secretory medication
adequately.P>' There has been concern that long-term
complete acid inhibition with achlorhydria might increase
the risk of gastric carcinoids because these tumors can be
so induced in rats." However, studies report that in Z-E
syndrome patients there is no increase in occurrence of gastric carcinoids as a result of omeprazole."
Omeprazole is now the drug of choice for long-term antisecretory therapy in Z-E syndrome patients because of its
potency, long duration of action, and ease of use. Long-term
prospective studies of antisecretory therapy for the Z-E
syndrome by the group at the NIH outline the most effective
methods to control gastric acid hypersecretion.v-"
Operative Management: Sporadic

Gastrinoma
Laparotomy is now recommended for most patients with evidence of gastrinoma (sporadic type) to define the extent of
disease and then to achieve curative resection when possible.
The rationale for this approach is based on several factors.
First, although gastrinomas may have histologic characteristics that appear benign, most have malignant potential, and,
although frequently indolent in nature, these tumors can grow,
metastasize, and cause death. Second, using improved preoperative imaging modalities and aggressive exploratory
techniques to find the tumor, modem studies suggest that
20% to 50% of Z-E syndrome patients may be cured by
early exploration and excision of the gastrinoma.F''" Early
laparotomy and tumor extirpation, even with incomplete
excision of all gastrinoma tissue, appears to alter favorably
the natural history of this syndrome. 96.98
Operative Management: Familial

Gastrinoma
Controversy continues among Z-E watchers regarding
the advisability of early operation for the MEN I patient
with hypergastrinemia. Most MEN 1 patients present with
primary hyperparathyroidism before there is evidence of a
gastrinoma, and it is agreed that parathyroidectomy should
be performed before a laparotomy to explore for gastrinoma
because gastric acid hypersecretion and serum gastrin are
often reduced when parathyroidectomy returns serum calcium
to normal. The controversy centers on the question of whether
to explore the young, asymptomatic, hypergastrinemic
MEN I patient (acid secretion controlled) early or to wait

until a gastrinoma can be seen on an imaging study,zz.99
Surgeons from Ohio State University, NIH, Mayo Clinic,
and Paris reported few, if any, cures after exploration for
gastrinoma in MEN I patients. Z6,Z7,lOO,101 A cure is defined by
the return of serum gastrin to normal after removing one or
more gastrinomas.
Gastrinomas in MEN I patients are invariably multiple
and usually not large enough to be localized preoperatively,
so one is less likely to find and remove all gastrinoma tissue
than when one is operating for gastrinoma of the sporadic
type. IOZ.103 For these reasons, some authorities recommend
antisecretory therapy without surgery for the patient with
familial gastrinoma unless tumor can be identified on localizing studies. Z7,IOO,lOl,l04 However, Thompson's group at the
University of Michigan suggested that some MEN 1 patients
with gastrinomas can be cured if PVS is used to regionalize
the location of the gastrinomas. ZZ,79,99 The NIH group't" also
used the preoperative PVS technique but failed to cure any
patient even though each patient had an islet cell tumor
removed from the exact area of the pancreas implicated by
PVS. This topic of familial gastrinoma in the MEN I syndrome is discussed in more detail in Chapter 76.
Intraoperative Steps
to Find the Gastrinoma
Gastrinomas may be single or multiple and are often duodenal
and extrapancreatic. Frequently, the only gastrinoma found
is in paraduodenal-pancreatic lymph nodes, without a
primary site identified.P-" Gastrinomas in the duodenal
wall may be submucosal and smaller than 5 mm 95,106,107
(Figs. 82-4 and 82-5). Several intraoperative maneuvers
to find gastrinomas have been recommended for three
decades 35,48,108:
1. Perform a thorough abdominal exploration, including
search for tumor in the liver.
2. Open the lesser sac, inspect, and perform bimanual
palpation of the body and tail of the pancreas.
3. Perform a Kocher maneuver with inspection and palpation of the head of the pancreas; tumor nodes are
frequently found behind the uncinate portion of the
pancreas.
4. Look for small duodenal wall, submucosal tumors.
Palpation and inspection through a duodenotomy may
be necessary.
5. Multiple lymph node biopsies, with emphasis on

excision of paraduodenal and pancreatic capsule
"nodules," are most important. Histologic examination of several dozen lymph nodes and suspicious
duodenal wall nodes is often necessary to obtain a
tissue diagnosis.
6. Do not terminate the search after finding a single
positive node because numerous patients have been
"cured" only after removing several lymph nodes.
The routine use of duodenotomy as well as the newer
innovations of intraoperative US and endoscopic transillumination to search for duodenal wall tumors has resulted in
the detection of a gastrinoma in more than 90% of patients
explored.Tv'"
FIGURE 82-4. Intraoperative maneuvers to search for

gastrinomas. Endoscopy with transillumination, duodenotomy, and palpation for duodenal wall tumors
increase the surgeon's chances to find tumor.
Intraoperative ultrasonography of the mobilized pancreas helps to find pancreatic body and tail lesions.
A review of the pathology reports from "failed" Z-E syndrome operations (i.e., those in which a gastrinoma was not
found) usually shows that few biopsy specimens were taken
by the surgeon.'? The greater the number of lymph nodes
examined, the more likely it is that gastrinomas will be
found. A search in the area of the "gastrinoma triangle" can
be most rewarding. A gastrinoma can be found in 9 of
10 cases in this anatomic triangle, whose apices are the
cystic duct-common bile duct junction, the border of the
second and third portion of the duodenum, and the junction
of the neck and body of the pancreas."
Operative Procedure of Choice:

Sporadic Gastrinoma
The choice of operation depends on the character and extent
of the tumor identified by the surgeon. Ideally, all gastrinoma
FIGURE 82-5. Benign-appearing submucosal duodenal wall gastrinoma that was excised along with two adjacent lymph nodes
containing metastases. Immunocytochemically, all three lesions
stained positive for gastrin. The patient, now eugastrinemic, is presumably cured.
tissue should be removed to avoid the problems associated

with tumor growth as well as the excess gastric acid. TG is
rarely warranted now that gastric acid can be effectively
inhibited. Tumor staging can predict the biologic behavior
and long-term outcome, suggesting optimum operative
strategies.
1. Duodenal wall tumor: The most common disease
encountered by the surgeon during exploration of the
Z-E syndrome patient in modem series has been duodenal wall tumors, often with metastatic gastrinoma
in paraduodenal lymph nodes. The steps outlined
in intraoperative maneuvers should be carefully
followed.
2. Lymph nodes contain tumor and no apparent primary
tumor found: The surgeon should remove as many
lymph nodes as possible and search for primary and
liver metastases. Excision of only one or more lymph
nodes containing tumor has resulted in cure.
3. Liver metastases: Diffuse liver metastases indicate
that complete tumor excision is unlikely, and lifelong
antisecretory therapy is required. Single liver lesions
should be excised because cures have been reported,
even when a primary was not found.
4. Pancreatic tumors: Gastrinomas in the body and tail are
best managed by distal pancreatectomy. Some wellencapsulated lesions might be enucleated; however,
distal pancreatectomy is preferred because of the
concept that gastrinomas originating in the pancreas to
the left (splenic side) of the mesenteric vessels have a
more aggressive biologic behavior. 110 Pancreatic head
gastrinomas can be enucleated in some patients. For
large pancreatic head tumors not amenable to enucleation, pancreaticoduodenectomy is favored by some
authorities.92.94.111 Pancreaticoduodenectomy is usually
not advisable when not all gastrinoma tissue can be
excised.
5. Other extrapancreatic gastrinomas: Gastrinomas have
been reported in the ovary, stomach wall, small bowel
wall, omentum, and bowel mesentery, usually in
lymph nodes. Excision may cure or improve longterm survival.
Gastrinoma - - 753
6. Total gastrectomy: In special situations, TG may still
be the operation of choice. Z-E syndrome patients
who are noncompliant, do not take their omeprazole,
and have recurrent ulcer complications might benefit
from TG.
Assessment of Cure
and Follow-up
Several reports suggest that at least one half of all Z-E syndrome patients explored, with the expectation to extirpate
tumor and cure, continue to have hypergastrinemia postoperatively.84,96 Typically, a small duodenal gastrinoma or lymph
node containing tumor has been excised, but an elevated
serum gastrin level indicates that more tumor remains. A
follow-up plan is needed for such patients. Should such a
patient be re-explored or monitored? Should re-exploration
be done only when localizing studies indicate the site of
tumor? A prospective study by the NIH group to assess and
predict long-term cure in Z-E syndrome patients provides
insight into these questions.l'? Eighty-one consecutive Z-E
syndrome patients who had undergone surgical exploration
for gastrinoma resection were studied. Fasting gastrin and
secretin provocative tests were the first to become positive
in patients with recurrence, whereas the calcium provocative
test and imaging studies were less sensitive. Fifty-two
percent of the patients were disease free immediately after
surgery, 44% at 3 to 6 months, 42% at I year, and the
number of "cured" patients was down to 35% by 5 years.
This careful study indicates that in some Z-E syndrome
patients who have a normal serum gastrin level immediately
postoperatively and who appear to have been cured, hypergastrinemia recurs with time, indicating recurrent tumor.
After removal of a gastrinoma, I recommend a serum
gastrin measurement before the patient is discharged from
the hospital and then at 3-month intervals for the first year.
Hypergastrinemia indicates residual gastrinoma tissue. A
normal gastrin level may indicate a surgical cure, but a positive secretin provocative test for gastrin response unmasks
some patients who still harbor gastrinomas. A secretin
provocative test should be performed 3 months postoperatively and then annually for all normogastrinemic patients
who have undergone "curative" gastrinoma resection.
Patients previously operated on for gastrinoma but with
progression of hypergastrinemia should also be evaluated
periodically to search for a gastrinoma that might be
amenable to curative excision because these tumors can
grow and cause death. A CT scan and selective abdominal
angiography might be done at 1- to 2-year intervals in
selected patients. I have successfully excised a large extrapancreatic gastrinoma from a Z-E syndrome patient who
presented with a new abdominal mass and a serum gastrin
level of 1.5 million pg/mL 20 years after a TG. At the first
operation, a duodenal wall gastrinoma was removed along
with a TG, which was done to control bleeding ulcers,
The patient was in good health during the 20 years since her
TG until the discovery of an abdominal mass. After successful removal of the gastrinoma, the patient's serum gastrin
and secretin provocative tests have been normal for 5 years.
This case illustrates that some Z-E syndrome patients may
be cured by an operation, many years after incomplete

tumor excision. Lifelong follow-up is required.
Follow-up of Zollinger-Ellison Syndrome

Patients with Total Gastrectomy
Although TG is now done infrequently, there are numerous
living patients who have had TG. Some may have had
gastrinomas removed at the time of TG, but many still have
hypergastrinemia and residual tumor. Although these
patients are no longer at risk for complications of excess
gastric acid, they still need periodic evaluation to assess for
tumor progression as well as nutrition-related problems.
Evaluation of patients is recommended at 6-month intervals.
Vitamin B 12 injections are given monthly, and most patients
can administer their B 12 injections at home. Folic acid,
calcium, and iron supplements are advisable. Many Z-E
syndrome patients are noncompliant, particularly when
there is a history of alcohol abuse/" TG also places the
patient at risk for cholelithiasis. Nearly all Z-E syndrome
patients who have undergone TG acquire gallstones if they
live long enough.J':' I recommend that cholecystectomy be
done at the time of TG.33
Treatment of Metastatic
Gastrinoma
Appropriate treatment for unresectable metastatic gastrinoma
is not well defined, although there is general agreement
about certain groups of Z-E syndrome patients with metastatic
disease. For example, Z-E syndrome patients who have a duodenal wall tumor and a positive lymph node excised at operation and who still have hypergastrinemia postoperatively most
certainly have metastatic disease remaining. However, there
is no evidence that chemotherapy is indicated for these
patients. In fact, survival in this group of Z-E syndrome
patients is not significantly different from survival in patients
who are rendered eugastrinemic and presumably cured after
a similar operation. Survival is greater than 90% at
10 years. 93.98,114 On the other end of the spectrum is the
group of Z-E syndrome patients who present with liver
metastases; they have only a 20% 5-year survival rate. 37,93
Chemotherapy is not recommended for the Z-E syndrome patient with metastatic disease confined to regional
lymph nodes but is reserved for the patient with metastatic
disease in the liver or more distal sites. Tumor response
to chemotherapy regimens varies from 6% to 69%.115 The
combination of streptozocin and doxorubicin appears to be
more effective than streptozocin and 5-fluorouracil or
chlorozotocin alone (69% response versus 45% and 30%,
respectively) in terms of decreasing tumor size and also in
terms of survival.!"
Cytoreductive surgery for functioning unresectable gastrinoma may be helpful in selected cases. ll7,118 Treatment
with interferon has been disappointing. I 19 Somatostatin analogues decrease metastatic pancreatic endocrine tumor size
in about 10% of cases,54,55 but their usefulness for controlling tumor growth and prolonging survival is unproved.F?
Hepatic artery embolization, with or without chemotherapy,
has been tried in selected patients. Hepatic transplantation

has also been carried out in a few Z-E syndrome patients,
but improved survival has not been documented.!" The
reader is referred to Chapter 88 for detailed information
regarding chemotherapy.
Staging
A staging system has been proposed by Ellison 114 to develop
predictive survival curves. Analysis of Z-E syndrome
patients diagnosed at Ohio State University during a 40-year
period indicated three determinants of survival: primary
tumor size, presence of liver metastases, and complete
resection of tumor. Factors with no effect on survival were
age at diagnosis, sex, presence of lymph node metastases,
and associated MEN. The expected lO-year survival for
resected stage I tumors (primary < 2 em, no liver metastases)
was 94% to 96%; stage II (primary> 2 em, no liver metastases), 86% to 91%; and stage III (liver metastases), 65% to
90%. When tumor was not resected, survival for stage I was
68% to 82%; stage II, 40% to 55%; and stage III, 7% to 50%.
A report by the NIH group analyzing 185 consecutive
Z-E syndrome patients who were observed prospectively
showed that survival was determined primarily by the presence of liver metastases at the time of admission." Liver
metastases correlated with the size of the primary tumor and
occurred more often with pancreatic than duodenal tumors.
The lO-year survival rate was not significantly different
between patients with gastrinoma found only in lymph
nodes and patients with duodenal gastrinomas (100% and
94%, respectively); however, both groups had significantly
better survival than the 59% survival rate of all patients with
pancreatic gastrinomas. This report supports the concept
that there are two distinct clinical forms of gastrinoma:
benign and malignant.!"
Summary
Gastrinomas may be sporadic or familial and solitary or
multiple. A gastrinoma should be considered in patients with
(1) peptic ulcer disease and diarrhea, (2) persistent peptic
ulcer disease despite treatment with H2 receptor antagonists
or omeprazole, (3) recurrent ulcers after peptic ulcer surgery, (4) marked gastric hypersecretion (~15
mEq/L) ,
(5) multiple or jejunal ulcers, and (6) large gastric surgical
folds. The diagnosis is established by documenting hypergastrinemia in patients with gastric hypersecretion and by
a paradoxical rise in response to intravenous secretion.
Laparotomy is indicated for virtually all patients with sporadic gastrinoma, whereas controversy exists regarding the
surgical management of patients with familial disease.
Tumor size, liver metastases, and resectability influence
long-term survival.
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Multiple Endocrine
Neoplasia Type 2B
Craig A. Miller, MD E. Christopher Ellison, MD
Multiple endocrine neoplasia (MEN) includes three distinct

clinical entities characterized by patterns of hyperplastic,
adenomatous, or neoplastic change arising in functionally
and anatomically discrete endocrine tissues. MEN 1 and 2A
are discussed elsewhere in this text. MEN 2B is the focus of
the present chapter. Attention is directed at the pathogenesis,
clinical presentation, and surgical treatment of the manifestations of this syndrome.
MEN 2A and 2B are characterized by the presence of
medullary thyroid carcinoma and pheochromocytomas.
MEN 2B, however, is also distinguished by a characteristic
phenotype consisting of multiple mucosal neuromas and
a distinctive marfanoid body habitus. Skeletal and ophthalmic abnormalities as well as multiple gastrointestinal
ganglioneuromas may also be present. Parathyroid hyperplasia, a common finding in MEN 2A, is not a feature of
MEN2B.
MEN 2B is generally the most virulent of the MEN syndromes; the natural history of the disease is dominated by
the clinical course of an aggressive species of medullary
thyroid carcinoma. MEN 2B may arise de novo sporadically
or, more commonly, as a genetically transmitted syndrome
of autosomal dominant inheritance. Studies have begun to
elucidate the genetic derangements underlying the pathogenesis of this complex disorder.
Historical Considerations
Most endocrine tumors are solitary, occurring in single
organs without concomitant disease in other endocrine tissues. The first known report of neoplasia arising in multiple
endocrine organs in the same individual appeared in 1903,
when Erdheim described an acromegalic patient noted on
autopsy to have tumors of both the pituitary and parathyroid
glands. I Thereafter, only similar sporadic reports of multiple
endocrine tumors appeared in the literature until 1954, when

Wermer first described a familial clustering of anterior
pituitary, parathyroid, and pancreatic islet cell neoplasia,
which he termed endocrine adenomatosis? This report,
which described the pattern of endocrine tumors now known
as MEN 1, established the existence of heritable endocrine
tumor syndromes.
The presence of other related multiple endocrine adenomatoses became apparent over the next several years.
In 1959, medullary thyroid carcinoma was defined as a
histopathologically distinct tumor (characterized, unlike
other thyroid tumors, by the presence of stromal amyloid)
by Hazard and associates.' Subsequent studies in the 1960s
demonstrated the cell of origin of this tumor to be the thyroid parafollicular C cell, the source of calcitonin. In 1961,
Sipple" described an association between thyroid carcinoma
and pheochromocytoma, a concordance further defined
4 years later when Williams 5 and Schimke and colleagues"
noted that the involved thyroid tumor was medullary carcinoma. In 1968, Steiner and coworkers 7 coined the term
MEN 2, to describe the familial association of medullary
thyroid carcinoma, pheochromocytoma, and parathyroid
hyperplasia. The authors also suggested that the syndrome
described by Wermer be termed MEN 1.
In 1966, Williams and Pollack reported two patients
with concurrent medullary thyroid carcinoma, pheochromocytomas, and mucosal neuromas of the mouth and eyes,
describing an apparent variant of von Recklinghausen's
disease.! In 1968, both Gorlin.? Schimke.!? and their colleagues subsequently defined this pattern as a distinct
clinicopathologic syndrome of endocrine disease, and in
a 1975 review of medullary carcinoma of the thyroid,
Chong and coworkers!' applied the term MEN 2B to the
syndrome, which emphasized both the similarities and differences between this and the other more common MEN
syndromes.
757
Pathogenesis
The patterns of organ involvement and familial clustering of
the MEN syndromes suggest an autosomal dominant mode
of inherited transmission in each, with essentially complete
penetrance but a varying degree of expression.
In the 1960s, the observation that both thyroid parafollicular C cells (the cells of origin of medullary thyroid carcinoma) and cells of the adrenal medulla (which give rise
to pheochromocytomas) derive from the embryonic neural
crest and are of the amine precursor uptake and decarboxylation (APUD) variety of neuroendocrine cells led to speculation that a single defect in development of tissues of this
origin and nature might underlie the disease. Although
attractive at first glance, this hypothesis was understood to
be oversimplified in that it failed to adequately account for
both the clinicopathologic differences between the MEN
syndromes and, in particular, the derangements found in
these diseases among cells not possessing APUD characteristics and tissues not derived from the neural crest (e.g., the
parathyroid hyperplasia of MEN 2A). Nevertheless, the two
syndromes were clearly variations on a common theme of
genetic endocrine derangement.
In the late 1980s, several DNA concordance studies
definitively mapped the inherited defects of the MEN 2
syndromes (as well as a familial variant of medullary
thyroid carcinoma) to the pericentromeric region of chromosome 10.12, 13 Further work in the early 1990s making use
of the advancing DNA technology has shed considerable light
on the specific genetic alterations underlying the different
phenotypes of these related but distinct diseases.
The ret protooncogene is a segment of the human genome
on chromosome 10 that encodes a specific cell surface receptor
complex. This receptor, homologous to the well-characterized
epidermal growth factor receptor, possesses a large extracellular domain, a single membrane-spanning segment, and an
intracellular tyrosine kinase domain putatively involved in
signal transduction. Receptors of this kind are believed to play
a significant role in the regulation of cell growth and differentiation. The specific ligand and physiologic function of this
receptor are, however, unknown. It has been demonstrated
that mutations in the segment of the ret proto-oncogene
coding for the extracellular domain of the receptor protein are
responsible for producing the MEN 2A phenotype as well as
sporadic and familial cases of medullary thyroid carcinoma.
Studies by Hofstra, 14 Carlson," and their colleagues, in which
they used single-strand polymorphism analysis to examine
the DNA from MEN 2B patients, have clearly shown that a
single point mutation in the segment of ret encoding the intracellular tyrosine kinase catalytic domain of the protein product is responsible for MEN 2B (Figs. 83-1 and 83-2). This
mutation, which alters ret codon 918 from ATG to ACG and
thus results in a substitution of threonine for methionine in
the receptor catalytic segment, was found in both inherited and
sporadic cases of the syndrome. In addition, the mutation was
noted in the genetic material of all MEN 2B patients examined. It remains for further study to elucidate the mechanism
by which this specific mutation affects ligand binding or,
more likely, signal transduction to produce the MEN 2B
phenotype. Recent studies have characterized gene expression
induced by RET with MEN 2A or 2B mutation. Watanabe and
N= GTT AAA TGG ATG GCA ATT

Val Lys Trp Met Ala lie
918
M= GTT AAA TGG ACG GCA An
Thr
FIGURE 83-1. The point mutation in the tyrosine kinase domain ret
protooncogene, which gives rise to the multiple endocrine neoplasia (MEN) 2B phenotype, DNA sequence analysis of polymerase
chain reaction amplification products from genomic DNA of unaffected parents (unshaded square and circle) and daughter with
MEN 2B (half-shaded circle) from family-coded GK-7. DNA and
corresponding amino acid sequences appear beneath the sequencing
ladders, Both parents possess the normal sequence (ATG coding for
methionine) for each allele, whereas the daughter has one normal
and mutant allele, the mutation being a C for a T substitution at
position 918 (asterisk). This produces the codon ACG, which
replaces methionine with threonine. (From Carlson K, Dou S, Chi D,
et al. Single missense mutation in the tyrosine kinase catalytic
domain of the ret proto-oncogene is associated with multiple
endocrine neoplasia type 2B, Proc Nat! Sci USA 1994;91:1579.)
coworkers identified 10 genes induced by RET-MEN 2 or

RET-MEN 2B mutant proteins." The inducible genes
included cyclin D1, cathepsins Band L, and coflin-all
known to be involved with cell growth tumor progression and
invasion. The repressed genes included type I collagen, lysyl
oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3-all known to be implicated in tumor suppression.
The fact that MEN 2A and 2B arise from separate mutations
affecting different domains of a single receptor may also help
explain the observed similarities and differences between
these entities. Moreover, the observation that the ret protooncogene is expressed in the progenitors of parathyroid
cells may provide an explanation for the alterations found in
the MEN 2A phenotype among these cells, which are neither
of the APUD type nor derived from the neural crest.
Clinical and Pathologic

Characteristics
Although it may arise sporadically, MEN 2B more frequently
occurs as a familial disorder inherited in an autosomal
dominant fashion. MEN 2B is less common than MEN 2A.
Multiple Endocrine Neoplasia Type 2B - -
759
..
I IIIII11
LB
TM
1111
IIIUIIIJIIII- I
I I
I
1
CT
I
4
Arg.Asp.Leu.AI:.Ala.ArgAsnIIe.LeuVal.Ala.Glu.GIY.Arg.Lys.Me'.Lys.lle.ser.Asp.p:e.GIY.Leu.Ser'Arg)
CAsp.val'T;r'GIU'GIU'Asp.ser'T~r.val'Lys'Arg.ser'Gln.GlyArgl eProValLysTrpMetAlal eGlu
-----918--3
Thr
FIGURE 83-2. A diagram of the ret protooncogene demonstrating both highly conserved elements and sites of mutation known to be
responsible for sporadic and familial medullary thyroid carcinoma (MTC) as well as the multiple endocrine neoplasia (MEN) 2 syndromes.
Vertical bars within the diagram indicate sites of cysteine codons. Cysteine codon mutations in the juxtamembrane extracellular domain
(609, 611, 618, 620, 634) are responsible for familial MTC as well as the MEN 2A syndrome. Mutation at 630 (underlined) gives rise
to sporadic MTC. Segments 1 to 4 in the tyrosine kinase domain represent highly conserved elements, whereas asterisks denote possible
sites for tyrosine autophosphorylation. The substitution of threonine for methionine in position 918 produces the MEN 2B phenotype.
LB = ligand-binding segment; TM = transmembrane domain; TK = tyrosine kinase; CT = carboxyterminus; ATP = site of adenosine
triphosphate binding. (From Carlson K, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the ret
proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Sci USA 1994;91:1580.)
For example, a multicenter study by Modigliani and associates identified 300 MEN 2 patients with pheochromocytoma.
There were only 26 (<10%) with MEN 2BP Significantly,
disease that arises de novo is also subsequently transmitted
to descendant generations in an autosomal dominant fashion." Penetrance is believed to be nearly 100%, but expressivity is variable. As a result, all the manifestations of the
syndrome may not be present in a given afflicted patient.
Whereas medullary thyroid cancer, mucosal neuromas, and a
marfanoid habitus are essentially universal among MEN 2B
patients, pheochromocytoma is found in only about one
half. 19 The sexes are apparently affected equally.P Families
in which the diagnosis of MEN 2B has been made seldom
persist beyond a few generations, owing to the aggressive
nature of the neoplasia involved.
Although found most frequently in the gastrointestinal

tract, the neuromas of MEN 2B may be present in any organ
possessing a submucosa, including the bronchi and urinary
bladder. These neuromas have been described as hamartomatous proliferations of Schwann cells, nerve fibers, and,
less frequently, ganglion cells." When present in the gut,
they predispose the patient to significant gastrointestinal
symptoms, especially constipation or diarrhea, which may
constitute the presenting complaint.
Neuromas and Habitus

The outstanding clinical features of MEN 2B comprise the
near-pathognomonic physical appearance (Figs. 83-3 and
83-4). Patients afflicted with this syndrome possess a tall,
slender, "marfanoid" habitus with varying degrees of muscle
wasting. The face is generally elongated; neuromas cause
enlarged and nodular lips as well as thickened eyelids.
Slit-lamp examination may reveal thickening of corneal
nerves. Skeletal abnormalities are also characteristic and
may include genu valgum, pes cavus, and kyphoscoliosis.
Significantly, these characteristic physical features are often
recognizable in infancy or even at birth, affording the careful clinician the opportunity to diagnose the disorder before
the thyroid and adrenal neoplasia have become clinically
manifest.
FIGURE 83-3. Ganglioneuromatosis of the lips and tongue in a

patient afflicted with multiple endocrine neoplasm 2B. Note the
thickened lips as well as multiple submucosal nodules. (From
Dodd G. The radiologic features of multiple endocrine neoplasia
types 2A and 2B. Semin Roentgenol1985;20:79.)
FIGURE 83-4. Marfanoid habitus of a patient with multiple
endocrine neoplasia 2B. Note the disproportionately long limbs,

muscle wasting, and joint deformities. (FromDodd G. The radiologic features of multiple endocrine neoplasia types 2A and 2B.
SeminRoentgenol 1985;20:81.)

Medullary carcinoma of the thyroid, a tumor of the calcitoninproducing parafollicular C cells, is an invariable feature
of MEN 2B. If early diagnosis based on phenotype is not
made, this tumor is generally the ftrst abnormality discovered.
Classically, the clinical course of this tumor in the context of
MEN 2B has been characterized as being more virulent than
when it appears in MEN 2A or in an isolated form, with a
more ominous metastatic potential. This perception, however, is evolving. Studies have suggested that the natural
histories of these tumors in MEN 2A and 2B may, in fact, be
comparable. The major difference appears to be that medullary
thyroid cancer develops in MEN 2B at a signiftcantly earlier
age (in one study, diagnosis of medullary thyroid carcinoma
in MEN 2B occurred at a mean age of 22 years vs. a mean
age of 38 years in MEN 2A).22 However, a review of the
German Medullary Thyroid Carcinoma Registry demonstrated
a signiftcantly decreased survival rate in patients with this
disease in the context of MEN 2B in comparison to those
with the tumor in MEN 2A (survival rates in patients with
sporadic medullary thyroid cancer were similar to those in
MEN 2B patients) (see Fig. 83-6).23 A measure of the
aggressive nature of this neoplasm in MEN 2B may be
derived from a review of the syndrome in which 100% of
symptomatic patients had metastases at the time of surgery.-"
Medullary thyroid carcinoma in MEN 2A and 2B is
almost invariably bilateral and multicentric and is preceded
by a focal or diffuse proliferation of parafollicular calcitoninproducing cells termed C-cell hyperplasia. By contrast,
sporadically arising medullary thyroid cancer is typically
unilateral and, classically, is not preceded by a premalignant
proliferation. Therefore, bilateral disease, multicentricity,
and presence of C-cell hyperplasia have all been considered

to be evidence for familial rather than de novo disease.
However, several authors have described the presence of
C-cell hyperplasia in nonhereditary medullary thyroid
cancer as well as benign thyroid disease and, moreover,
its absence in medullary cancer in the setting of known
MEN 2A, suggesting that the identiftcation of this pathologic
entity may be of less value than previously thought. 25,26
In fact, aside from the suggestive evidence of multicentricity
and bilaterality, there are no microscopic differences between
sporadically arising and hereditary medullary thyroid cancer
that can be detected by histopathologic means at this time.
Medullary thyroid cancer is typically found in the superior portion of the gland, where the greatest concentration
of C cells exists. The tumor presents clinically as a thyroid
mass or nodule, most often noted incidentally on physical
examination, which may appear unilateral or bilateral to
palpation. Fine-needle aspiration biopsy may provide
cytologic evidence of the disease, which is subject to conftrmation by immunocytochemical staining for calcitonin.
The gross pathologic appearance is of whitish brown, wellcircumscribed nodules. Microscopically, the lesion appears
as nests of polygonal or round, uniform cells surrounded by
a ftbrous and vascular stroma in which material with the
staining properties of amyloid frequently resides (Fig. 83-5).
This material consists of a calcitonin prohormone secreted
by the tumor cells.
The tumor cells of medullary thyroid carcinoma actively
secrete a number of peptide hormone products. Foremost is
calcitonin, the serum level of which is markedly increased in
the presence of the tumor. Levels of calcitonin greater than
1000 pg/mL in the presence of elevated carcinoembryonic
antigen are said to be diagnostic of the disease, and persistently elevated calcitonin after surgical resection suggests
residual or recurrent tumor.F Provocative tests in which
FIGURE 83-5. The microscopic appearance of medullary thyroid

carcinoma. Compressed nestsof smallround and polygonal tumor
C cells amid stromal amyloid. Normal follicles are seen peripherally. (FromDodd G. The radiologic features of multiple endocrine
neoplasia types 2A and 2B. Semin Roentgenol 1985;20:81.)
pentagastrin (either alone or in combination with calcium) is

injected to stimulate calcitonin release (analogous to the
secretin stimulation test in gastrinoma diagnosis) have
also been advocated. Elevations of calcitonin higher than
300 pg/mL on provocation are considered diagnostic of C-cell
hyperplasia or medullary thyroid cancer," Other peptides
elaborated by the medullary thyroid cancer cells include
calcitonin gene-related peptide, somatostatin, corticotropin,
and chromogranin A.29 Paraneoplastic syndromes (particularly Cushing's syndrome from excessive corticotropin) occur
but are unusual. Diarrhea, presumably from an unidentified
humoral source, arises in approximately 30% of patients with
this tumor and is amenable to conservative therapy.
The most distinctive feature of medullary carcinoma of
the thyroid in the setting of MEN 2B is the ominous potential for early metastases. These appear first in the regional
cervical or mediastinal lymph nodes, with distant metastases
arising later in the lung, liver, and bone, Patients presenting
with advanced local disease may manifest hoarseness or
dysphagia, whereas distant metastases may be suggested by
symptoms referable to the systems involved.
Relatively little controversy attends the question of the
preferred method of treating medullary thyroid cancer.
Because this tumor is not responsive to present conventional
chemotherapeutic or radiologic treatment regimens, surgical
therapy is the only option. Most authorities recommend total
thyroidectomy once the diagnosis has been made, whether
this diagnosis is based on clinical evidence or biochemical
screening tests. Imaging studies are of little use because
localization of the tumor within the thyroid is of academic
interest only. Advocacy of total thyroidectomy is particularly sensible in the case of MEN 2B in light of the understanding that medullary thyroid cancer is frequently bilateral
as well as unusually aggressive in the setting of this syndrome.
Central neck compartment lymph nodes should be dissected
in all patients in an effort to achieve local control of disease.
Thyroid replacement therapy must, of course, be initiated in
the postoperative period.
Data from the German Medullary Thyroid Carcinoma
Registry indicate a 5-year (after diagnosis) survival rate of
82.5% in MEN 2B patients (Fig. 83-6). By 10 years after
diagnosis, the survival rate decreased to 66.0%.23The major
prognostic factor in this study appeared to be tumor stage at
diagnosis. Previous reports have noted improved survival in
patients whose thyroid tumors were detected by biochemical
means over those first diagnosed on the basis of clinical
grounds.P
Pheochromocytoma
Pheochromocytoma arises in approximately 50% of individuals with MEN 2B. The predisposition of pheochromocytoma in MEN 2 may be related to mutations in glial cell
line-derived neurotrophic factor (GDNF). Some studies
suggest that allelic variation at the GDNF locus may modify
the susceptibility to pheochromocytoma." Although its histologic appearance in this familial setting is indistinguishable
from that of the sporadically occurring tumor, bilateral
involvement (which is unusual in de novo disease) occurs in
more than half of MEN 2B patients.F These tumors are rarely
the initial presenting feature of MEN 2B; their presence is
761
80
~
~
.~
60
~MTConly
40
~MEN2a
20
-o-MEN 2b
--all
;j
CJ)
O............,...........,.....,"'T'"'....,.......'T""""...,..........,.........'T"'"~
12 24
36
48
60
.......
72 84 96 108 120
months
FIGURE 83-6. Comparison of survival rates between medullary
thyroid carcinoma (MTC) patients in whom the disease arose in
the absence of other endocrine neoplasias, as part of the multiple
endocrine neoplasia (MEN) 2A syndrome, and as part of the
MEN 2B syndrome. Data from 741 cases are entered in the German
Medullary Thyroid Carcinoma Registry. (From Raue F, FrankRaue K, Grauer A. Multiple endocrine neoplasia type 2: Clinical
features and screening. Endocrinol Metab Clin North Am
1994;23:137.)
most often detected either after the existence of medullary

thyroid carcinoma has been established or concurrently with
the diagnosis of thyroid involvement, when suspicion of
MEN 2B has been aroused. A multicenter center by
Modigliani and colleagues showed pheochromocytoma presented first in 25% of 300 cases (274 MEN 2A and 26
MEN 2B) after medullary thyroid cancer diagnosis in 40%
and in a synchronous manner in 35%.
Hyperplasia of the adrenal medulla precedes pheochromocytoma in MEN 2A and 2B. This hyperplasia is analogous to the C-cell hyperplasia that precedes medullary
thyroid cancer in these patients. As in the thyroid disease in
MEN 2, a spectrum of adrenal involvement may be encountered, including nodular or diffuse hyperplasia, multiple
small pheochromocytomas, and thickening of the entire
adrenal medulla. Most pheochromocytomas in this syndrome
are benign.
As with the sporadic form, pheochromocytoma in MEN 2B
may be either asymptomatic or associated with varying degrees
of symptomatology referable to the catecholamines produced
by these tumors. Symptoms include episodic diaphoresis,
headaches, anxiety, and palpitations. Hypertension may be
present and may be minimal or marked. The definitive diagnosis of pheochromocytoma may be made via biochemical
means (e.g., elevated amounts of urinary catecholamines),
abdominal computed tomographic (CT) or magnetic resonance imaging (MRI) scans, or metaiodobenzylguanidine
(MIBG) scintigraphy.
In MEN 2B, diagnosis of pheochromocytoma should
be followed by exploration and excision of the affected
tissue. Bilateral disease requires bilateral adrenalectomy.
Controversy has arisen, however, over the proper surgical
treatment of unilateral pheochromocytoma in this setting.
Some authorities maintain that bilateral adrenalectomy is
indicated owing to the likelihood of eventual contralateral
involvement. Others, however, have proposed that unilateral

excision with close follow-up is sufficient. Proponents of
the latter view note that this approach avoids both lifelong
glucocorticoid-mineralocorticoid replacement therapy and
the persistent risk of addisonian crisis.
If both medullary thyroid cancer and pheochromocytoma
exist concurrently, adrenalectomy must be performed first
followed by thyroidectomy. This order must be observed
to avoid the potential of intraoperative hypertensive crisis
during thyroid resection, and it underscores the importance
of screening for pheochromocytoma when MEN is suspected.
Screening and Diagnosis

Screening for MEN 2B should be reserved for a few welldefined populations: (1) family members of known MEN 2B
patients, (2) patients newly diagnosed with medullary thyroid carcinoma or pheochromocytoma, and (3) individuals
exhibiting the characteristic phenotype of marfanoid habitus
and mucosal neuromas. Screening is mandatory in these
patients to maximize the opportunity to perform curative
thyroidectomy or adrenalectomy, or both, before metastasis
of the endocrine tumors.
Screening of family members of affected individuals
should consist of biochemical tests of thyroid C cell and
adrenal medullary function as well as imaging studies where
indicated. A 1991 consensus statement of the European
Community Concerted Action: Medullary Thyroid Carcinoma
group recommended annual basal and pentagastrin- or
calcium-provoked serum calcitonin determinations in this
group of patients, beginning at age 3 years and continuing
until age 35 years, after which the frequency could be
decreased owing to greatly diminished yield.P The criteria
for diagnosis on the basis of serum calcitonin elevation were
discussed previously. Confusion may be noted in attempts to
diagnose medullary thyroid carcinoma biochemically in
children because serum calcitonin levels could be high in the
young in the absence of disease.l" Currently, individuals
suspected of MEN 2B are tested for zet mutation; if they
have the zet mutation, prophylactic total thyroidectomy is
recommended.v-" To detect pheochromocytomas, annual
assays of urinary catecholamines and catecholamine
metabolites (epinephrine, norepinephrine, vanillylmandelic
acid, and metanephrines) are also recommended. Some
authors advocate annual or semiannual abdominal imaging
studies, including MIBG, because these may detect
pheochromocytomas before elevation of urinary catecholamines. However, the wisdom of repetitive dosing with
ionizing radiation or radioiodinated compounds has been
called into question, especially in light of the generally
benign course of these tumors in MEN 2B. For screening
purposes, MRI may be preferable. With identification of
the genetic defect responsible for MEN 2B, in the future it
is likely that these biochemical, radiologic, and nuclear
screening tests will be reserved for those individuals known
to possess the mutant allele.
As noted, the characteristic facies and habitus of these
patients may be present from birth. In this setting, in the
absence of a family history, the phenotype may provide a
clue to the presence of the disorder before the tumors
become clinically manifest, allowing definitive surgical
therapy to be performed with excellent potential for cure.

Thus, children with multiple mucosal neuromas should also
undergo biochemical screening. These individuals may also
be tested for the presence of the MEN 2B ret mutation and
treated appropriately.
If, in de novo disease, the presence of neuromas is not
appreciated or the phenotype is incompletely expressed and
thus unremarkable, MEN 2B usually presents as a thyroid
mass incidentally identified on physical examination.
Histopathologic examination of tissue obtained by fineneedle aspiration biopsy then identifies the disease process
through appreciation of the characteristic tissue architecture
and amyloid as well as positive tumor cell staining for
calcitonin. The diagnosis of medullary thyroid carcinoma
should alert the physician to the possible presence of MEN 2A
or 2B and the potential for concurrent or metachronous
appearance of pheochromocytoma or (in MEN 2A) parathyroid disease, or both. Appropriate screening for these
entities should then proceed.
Occasionally, the catecholamine-induced symptomatology of pheochromocytoma may constitute the presenting
complaints in de novo MEN 2B. The presence of elevated
urinary catecholamines or characteristic abnormalities on
abdominal CT, MRI, or MIBG scans then confirms the presence of the tumor. The diagnosis of pheochromocytoma
should always arouse suspicion of the presence of a multiple
endocrine disease syndrome.
Summary
MEN 2B is a syndrome in which the phenotype of a marfanoid
body habitus with multiple mucosal neuromas is found in
combination with medullary carcinoma of the thyroid and,
frequently, pheochromocytomas. The syndrome may arise
sporadically but is more often genetically transmitted in an
autosomal dominant fashion.
The genetic defect appears to be a single missense mutation
in a segment of the ret protooncogene of chromosome 10.
The ret protooncogene encodes for a cell surface receptor,
the function of which is poorly characterized. The mutation
found in MEN 2B lies in a segment of ret that codes for the
intracellular tyrosine kinase domain of this receptor.
Although the exact mechanism by which this mutation
produces the MEN 2B phenotype is unknown, the receptor
encoded by ret bears considerable structural resemblance to
the epidermal growth factor receptor, which is involved in
transduction of signals regulating cellular growth and differentiation. Other well-characterized mutations in ret give rise
to the related MEN 2A syndrome.
The marfanoid habitus and multiple mucosal neuromas
present in MEN 2B produce a characteristic appearance and
symptomatology among affected patients. Large, nodular lips,
thickened eyelids, skeletal abnormalities, and constipation
or diarrhea from gastrointestinal ganglioneuromas are
common. These signs and symptoms may lead to diagnosis
of MEN 2B in the first years of life.
The clinical course of patients afflicted with MEN 2B is
largely dependent on intervention in the natural history of the
medullary thyroid carcinoma, which is invariably present.
In individuals with a positive family history, screening for zet
protooncogene mutation is indicated. If there is no family history, this cancer is most often found incidentally on physical
examination. The species of this neoplasm found in MEN 2B
is thought to be particularly aggressive, although this supposition has been called into question. The treatment is total thyroidectomy, with dissection of local lymph nodes. Patients
who have not undergone thyroidectomy before metastasis of
this tumor rarely survive beyond 40 years.
Pheochromocytomas are found in approximately 50% of
MEN 2B patients. They are generally bilateral and benign.
Rarely the source of the presenting complaint, they may be
clinically silent or frankly symptomatic. Bilateral adrenalectomy is advocated by many authorities when even unilateral involvement is established owing to the likelihood of
contralateral disease.
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Somatostatinoma and Rare

Pancreatic Endocrine Tumors
Jeffrey A. Norton, MD
General Comments
The overall prevalence of functional pancreatic endocrine
tumors is low, approximately I to 10 per million in the
population. I,2 Gastrinoma and insulinoma are the most
common functional neuroendocrine tumors and account for
approximately 70% to 90% of all functional pancreatic
neuroendocrine tumors.? Thus, somatostatinoma and other
functional neuroendocrine tumors are rare, and no endocrine
surgeon has vast experience with them. Patients with these
rare tumors present with either a specific syndrome or symptoms related to the malignant nature of the tumor. Therefore,
therapeutic strategies designed to treat these patients need to
control the tumoral process and ameliorate the syndrome
associated with it. Obviously, if the tumoral process can be
completely controlled by surgical resection, the characteristic syndrome resolves. However, in many individuals with
these rare tumors, the extent of the disease limits the effectiveness of surgery in completely controlling the tumor. For
these patients, effective medical treatments for controlling
symptoms may be available and must be considered. This
chapter also describes the medical therapy that may be
useful in preparing the patient for surgery or controlling
symptoms in the long term.
Pathology
Pancreatic endocrine tumors are commonly termed neuroendocrine tumors. However, some researchers indicate that
it is unclear whether these tumors originate from the pancreatic islets.' Pancreatic endocrine tumors may contain ductular structures; may produce hormones that are not produced
by the normal pancreas, including gastrin and vasoactive
intestinal polypeptide (VIP); and may produce more than one
hormone.t" These findings suggest that pancreatic endocrine
tumors originate from dedifferentiation of an immature
764
pancreatic stem cell. 4 The finding of ductular structures in

these tumors has led to the suggestion that these tumors are
ductular in origin." Further, these tumors may appear to be
papillary and cystic in structure."
It has also been proposed that pancreatic endocrine tumors
originate from cells that are part of the diffuse neuroendocrine system: amine precursor uptake and decarboxylation tumors (APUDomas).8-1O These tumor cells contain dense
secretory granules, may produce multiple peptides, and usually stain positive for neuron-specificenolase, chromograninA,
and synaptophysin.Vv! APUDomas comprise many neuroendocrine tumors, including carcinoids, medullary thyroid
carcinoma, and pbeochromocytomas.s!" Microscopically,
pancreatic endocrine tumors are composed of sheets of
small, round cells with uniform nuclei and cytoplasm
(Fig. 84-1). Mitotic figures are rare, and the precise determination of malignancy cannot be made on the basis of
histologic appearance.S'?
Studies suggest that there is an aggressive and a nonaggressive form of pancreatic neuroendocrine tumor. The
aggressive form comprises glucagonoma, somatostatinoma,
and most nonfunctional tumors. It is more common in patients
without multiple endocrine neoplasia type I (MEN I). It is
characterized by a short disease duration, large pancreatic
tumors, liver metastases, and a long-term survival rate as
low as 20% to 50%. This may also apply to liver metastases.
Some liver neuroendocrine tumors demonstrate slow growth
and progression, whereas others grow rapidly. Those with
rapid growth are associated with decreased survival.
Studies have shown a number of clinical and tumoral factors that are predictors of aggressive growth (Table 84-1).
These include liver metastases, lymph node metastases, local
invasion, large primary tumor size, nonfunctional tumor, and
incomplete tumor resection. The further definition of other
factors is likely to have a significant impact on the surgical
management of pancreatic neuroendocrine tumors; that is,
aggressive tumors will require more aggressive surgery.
Somatostatinoma and Rare Pancreatic Endocrine Tumors - -
FIGURE 84-1. Duodenal somatostatinoma. Sheets of uniformappearing, small, round cells with rare mitotic activity are present
within this tumor, which occurs in the submucosal layer of the
duodenum. This tumor stained positively for somatostatin by
immunocytochemistry. It was detected by palpation of the duodenum
at the time of cholecystectomy.
The molecular pathogenesis of pancreatic neuroendocrine

tumors is just being elucidated and holds promise for the identification of important parameters. Studies have demonstrated
that alterations in the tumor suppressor gene DPC4 located
on 18q21 are involved in tumorigenesis.P Unfortunately, at
present, no gene alteration sufficiently predicts aggressive
behavior to allow a different, more aggressive treatment
strategy to be implemented.
Determination of malignancy is best made by either radiographic or surgical pathologic documentation of metastases
to either regional lymph nodes or the liver.
765
Pancreatic endocrine tumors are classified according to

the functional syndrome they produce (Table 84-2). Every
type of pancreatic endocrine tumor may be associated with
MEN 1, and it is important to recognize this association
because these patients generally have multiple tumors and a
more indolent natural history. 14 Several studies suggest that,
in addition to MEN 1, pancreatic neuroendocrine tumors
are found in higher frequency in patients with von
Recklinghausen's disease, 15-17 von Hippel-Lindau disease,"
and tuberous sclerosis. 19 In patients with von Recklinghausen's
disease, duodenal somatostatinoma and gastrinoma have
been reported. 15-17 Of patients with von Hippel-Lindau disease, 17% had pancreatic endocrine tumors, including both
adenomas and carcinomas. However, it is unusual for these
tumors to be functional, and few patients have a clinical
hormonal syndrome. Patients with tuberous sclerosis may
have a higher incidence of insulinoma and nonfunctional
pancreatic neuroendocrine tumors.
Multiple Endocrine
Neoplasia Type 1
MEN 1 is a well-established inherited endocrine disorder
characterized by parathyroid hyperplasia, pituitary adenoma,
and pancreatic neuroendocrine tumors. Studies indicate that
the genetic defect in patients with MEN 1 is localized to the
long arm of chromosome 11 and linked to the skeletal
muscle glycogen phosphorylase gene. 20 21 Evidence from
these studies suggests that the development of endocrine
tumors in patients with MEN 1 conforms to Knudson's twohit model of neoplasm formation with an inherited mutation
in one chromosome unmasked by a somatic deletion or
mutation of the other normal chromosome, thereby removing the suppressor effects of the normal gene." In contrast,
in sporadic patients with pancreatic neuroendocrine tumors,

tumors do not appear to develop by homozygous inactivation of the same gene."
Furthermore, growth factors have been identified in the
plasma of patients with MEN I. A circulating blood factor
that was mitogenic for parathyroid cells in tissue culture has
been identified.P and a subsequent study demonstrated that
the factor was similar to fibroblast growth factor." In addition, patients with MEN 1 are susceptible to other tumors,
including bronchial, thymic, and intestinal carcinoid
tumors; thyroid adenomas; adrenal adenomas; and multiple
lipomas. 14 Thus, the complete pathogenesis of the multiple
endocrine tumors in MEN 1 patients is not completely
understood.
In patients with MEN I, primary hyperparathyroidism is the
most common clinical condition, occurring in approximately
95% of individuals. 14 Functional pancreatic neuroendocrine
tumors are the next most common condition, occurring in
approximately 80% of patients." Finally, approximately
35% of individuals with MEN 1 develop a pituitary adenoma, most commonly a prolactinoma.!" Gastrinoma and
insulinoma are the most common functional neuroendocrine
pancreatic tumors in MEN 1 patients, accounting for
approximately 50% and 20% of the neuroendocrine tumor
syndromes, respectively.P Nonfunctional pancreatic
endocrine tumors and pancreatic polypeptide (PP)-producing
tumors (PPomas) may be the most common pancreatic
neuroendocrine tumors in MEN 1 patients because these
tumors are almost always identified on careful histologic
studies of the pancreas.P-" Of the rare pancreatic neuroendocrine tumors, MEN 1 is present in approximately 3% of
patients with glucagonoma, 1% of patients with VIPoma,
33% of patients with tumors that secrete growth hormonereleasing factor (GRF) (GRFoma), and 5% of patients with
somatostatinoma.!" Essentially, any pancreatic neuroendocrine tumor may occur in individuals with MEN I; therefore,
when evaluating a patient with a known neuroendocrine
tumor, the possibility of unrecognized MEN 1 should be
considered. The best way to determine the presence of MEN I
is to question the patient carefully about family history,
search for lipomas, and measure serum levels of calcium,
gastrin, glucose, PP, and prolactin, If MEN 1 is present,
multiple neuroendocrine tumors are identified within the
pancreas.v-" and resection of the neuroendocrine tumor and
the portion of pancreas near it is indicated. Somatostatinomas
and other rare pancreatic neuroendocrine tumors, unlike
insulinomas, are almost always malignant.v>' Therefore, in
patients with localized, potentially curable disease, pancreatic resection--either Whipple's procedure for pancreatic
head tumors or subtotal pancreatectomy for pancreatic body
and tail tumors-is indicated,
Surgical Principles
The goal of the surgical operation in a patient with an islet
cell tumor is to identify accurately, stage, and remove the
tumor. The surgeon should remove all tumor in a manner
that allows the mortality and morbidity of surgery to be less
than those in the natural history of the tumor. The surgeon
needs to know the natural history and pathology of the neuroendocrine tumor, the expected outcome of the surgical
procedure, the expected survival with the tumor resected,

the immediate and long-term complication rate, and the
availability of alternative medical treatments to manage
the disease.F-"
Most experts recommend that patients with neuroendocrine tumors undergo surgery because any neuroendocrine
tumor may be malignant, medical management can only
control the signs and symptoms, and tumor resection is the
only potentially curative treatment. Therefore, each patient
with biochemical evidence of a neuroendocrine tumor
should undergo complete radiologic assessment of the
extent of disease to determine the feasibility of surgery.
During the radiologic evaluation, medical management
should be used to ameliorate symptoms secondary to excessive hormone secretion. It is clear that in some neuroendocrine tumors (such as VIPoma) advances in medical
control of the hormone production have improved the surgical outcome and reduced the operative complication rate. 34
Many variables associated with an individual patient
have an impact on the surgical outcome. These include the
extent of disease on preoperative imaging studies, whether
the primary tumor is within the pancreas or duodenum, the
exact area of the pancreas involved (head, body, or tail), the
presence of liver or other distant metastases and whether
they are resectable, the occurrence of the neuroendocrine
tumor in a familial or a sporadic setting, and the simultaneous occurrence of other medical conditions that may limit
the ability of a patient to undergo major surgery. Success
need not be defined as cure of the hormonal syndrome.
It may be a decreased medication requirement, decreased
symptoms, and increased length of survival. In each patient,
it is clear that neuroendocrine tumors may be malignant, that
surgery is an effective way of accurately staging the true
extent of disease, and that surgery may be curative, even in
the patient with metastatic neuroendocrine tumor. 34 -38
Somatostatinoma
Somatostatinomas are rare endocrine tumors of the pancreas
or duodenum that secrete excessive amounts of somatostatin.
Somatostatin excess causes a syndrome characterized by
steatorrhea, mild diabetes, and cholelithiasis, Somatostatin
is an inhibitory hormone originally discovered in the hypothalamus in 1973. It was discovered by its ability to inhibit
growth hormone and thus was called somatotropin
release-inhibiting hormone. In 1977, Lans-Inge Larsson
and P. O. Ganda and their colleagues reported the first two
cases of somatostatinoma.v-" Initially, the somatostatinoma
syndrome included diabetes, cholelithiasis, weight loss,
and anemia. Subsequently, diarrhea, steatorrhea, and
hypochlorhydria were added." Somatostatin inhibits the
release of most other hormones. It decreases many gastrointestinal functions, including acid secretion, pancreatic
enzyme secretion, and intestinal absorption. It reduces gut
motility and transit time.
Patients with pancreatic or intestinal somatostatinoma
are generally about 50 years old. There is an equal proportion of males and females." Initial symptoms are diabetes,
gallbladder disease, and steatorrhea (Table 84-3). Diabetes
mellitus and glucose intolerance are reported to occur in
Somatostatinoma and Rare Pancreatic Endocrine Tumors - - 767
60% of patients. Gallstones occur in 70% of patients. Diarrhea

and steatorrhea are reported in 30% to 68% of patients. In
some, the severity of the diarrhea and steatorrhea correlates
with the size and degree of metastatic spread of the tumor,
and it improves with tumor resection. Hypochlorhydria has
been found in approximately 33% to 53% of patients. It arises
more commonly with pancreatic somatostatinoma, occurring in 86% of patients with pancreatic somatostatinoma
and in 17% of patients with intestinal somatostatinoma. The
weight loss may be secondary to diarrhea and malabsorption.
In most instances, somatostatinomas have been found by
accident. The tumor is usually found at the time of cholecystectomy or during routine imaging studies. Imaging studies
have been performed because of abdominal pain, bleeding,
or diarrhea. Once discovered, the tumor is identified as
somatostatinoma either by a demonstration of elevated
tissue concentrations of somatostatin or by the documentation of increased plasma levels of somatostatin. The early
diagnosis of somatostatinoma may be possible with greater
awareness of its existence and reliable assays for the
determination of somatostatin in blood. Current assays
are complicated by the need for extraction of the plasma.
Most somatostatinomas are solitary and located within
the pancreatic head or duodenum. A high proportion of these
tumors are malignant. If the tumor is localized and not
widely metastatic, surgical resection is the treatment of
choice. This usually necessitates a Whipple pancreaticoduodenectomy. Surgical debulking of metastatic disease has
been advocated, but patients are few and clear benefits have
not been demonstrated. '
VIPoma
VIPomas are generally located within the pancreas. They
secrete excessive amounts of VIP, which causes a distinct
syndrome. Patients have a very large volume diarrhea,
severe hypokalemia with muscle weakness, hypercalcemia,
and hypochlorhydria (Table 84-4). VIPoma typically occurs
in adults. However, it has been reported in two children with
severe diarrhea.f It was originally called the Verner-Morrison
syndrome" because these two authors first described pancreatic cholera and the watery diarrhea, hypokalemia, and
achlorhydria syndrome in 1958.421\vo patients were described
who died from watery diarrhea, hypokalemia, and nephropathy associated with a non-insulin-secreting pancreatic
neuroendocrine tumor.P The diarrhea was so severe that
despite intravenous fluids both patients experienced renal
failure and death secondary to dehydration. The diarrhea is
characteristically large in volume (>5 L/day). It is secretory,
which means that it persists despite fasting.44,45 Hypokalemia
is present in nearly every patient and is caused by excessive
potassium losses in the diarrheal fluid. 46,47 The hypokalemia
causes severe muscle weakness, which is also a common
symptom in these patients, and some are bedridden.
Hypochlorhydria is found in 75% of patients with VIPoma
and is due to inhibition of gastric acid secretion by VIP.45,48
Flushing, which occurs in a minority of patients, is probably
caused by the vasodilatory effects of VIP.45 Hyperglycemia
occurs in 25% to 50% of patients and is caused by overconversion of glycogen to glucose. VIP is a glycogenolytic
hormone.f Hypercalcemia is present in a significant proportion of patients with VIPoma.
The diagnosis of VIPoma requires the triad of severe
secretory diarrhea, elevated fasting serum levels of VIP, and
the presence of a pancreatic neuroendocrine tumor. In most
patients, stool output is greater than 5 L/day, and the diagnosis is excluded when it is less than 700 mL/day. The
normal fasting plasma VIP concentration should be determined when diarrhea is present. The mean fasting plasma
level of VIP in 29 published patients with VIPoma was
956 pg/mL (range, 225 to 11,850 pg/mL).44,45
After the diagnosis has been established, all patients with
VIPoma need correction of dehydration, hypokalemia, and
other metabolic abnormalities (see Table 84-4). Before the
long-acting somatostatin analog octreotide was introduced,
complete correction of the electrolyte and volume derangements was impossible because the voluminous diarrhea
persisted. However, octreotide therapy dramatically reduces
serum levels of VIP; stops the diarrhea, dehydration, and
hypokalemia; and allows rapid restoration of total body
potassium (Fig. 84_2).49,50 Octreotide therapy has dramatically advanced the preoperative electrolyte management of
patients with VIPoma.
Patients with biochemical evidence of VIPoma should
undergo imaging studies to localize the tumor. Computed
tomographic (CT) scanning identifies tumor in nearly every
FIGURE 84-2. Use of octreotide in a patient with vasoactive intestinal polypeptide tumor (VIPoma). Serum potassium level, potassium replacement requirement, and stool output in patient with
VIPoma are shown. The patient had a low serum level of potassium, a high potassium replacement requirement, and a high stool
output. After initiating octreotide therapy at 150 ug subcutaneously
every 8 hours (450 Ilg/day), the serum level of potassium became
normal and the potassium replacement requirement and stool
output dramatically lessened. This drug is useful in preparing
patients with VIPoma for surgery.
patient with VIPoma. VIPomas can be well imaged by magnetic resonance imaging. Pancreatic masses are best shown on
a Tl-weighted fat-suppressed image as a low-signal-intensity
mass. Liver metastases from VIPoma show intense peripheral ring enhancement on postgadolinium spoiled gradient
echo images. 51,52 Octreoscan is useful in selected individuals
whose imaging studies are equivocal. After octreotide therapy
to restore circulating volume and potassium, all patients
who have localized tumors should undergo surgical exploration. Tumors may be malignant, and careful evaluation of
regional lymph nodes and the liver is necessary. In the case
of a malignant VIPoma with hepatic metastases, debulking
surgery may be indicated to decrease plasma VIP concentrations and facilitate medical management of the diarrhea. 53
Long-term management of the diarrhea in patients with
disseminated VIPoma has been successfully achieved with
octreotide. 49,50,54,55 However, not all patients respond to
octreotide, and patients who initially respond may become
refractory to it. An 86-year-old woman with a metastatic
VIPoma initially responded well to octreotide acetate
(Sandostatin LAR) but subsequently became refractory to it,
requiring higher and higher doses. Eventually, control was
impossible and she died from dehydration.56
Glucagonoma
Glucagonoma is an endocrine tumor of the pancreas that
secretes excessive amounts of glucagon and results in a
characteristic syndrome that includes a skin rash, diabetes
mellitus, malnutrition, weight loss, thrombophlebitis,
glossitis, and anemia (Table 84-5).57 Glucagon itself is

responsible for most of the signs and symptoms, and its
induction of hypoaminoacidemia is thought to be responsible for the skin rash. Liver disease and zinc deficiency may
also contribute in some cases." Unlike some other islet cell
tumors, glucagonomas are almost always malignant. Tumorrelated deaths occur in most patients after about 5 years of
follow-up. Unless the tumor can be removed surgically,
there is no other potentially curative treatment." In 1963,
Roger Unger first isolated glucagon by extraction from neuroendocrine tumors. McGavran and colleagues, in 1966,
first reported a patient with diabetes mellitus, a skin rash,
anemia, and a pancreatic carcinoma with liver metastases/"
Subsequently, the patient was found to have high plasma
levels of glucagon. Mallison and others associated
glucagonoma with a specific skin rash subsequently labeled
necrolytic migratory erythema and described a large series
of patients with dermatitis, diabetes mellitus, weight loss,
hypoarninoacidemia, anemia, and a glucagon-producing
tumor of the pancreas.57 We demonstrated that in one patient
the rash was due to markedly decreased plasma levels of
amino acid, which could be completely reversed with total
parenteral nutrition.f When the intravenous feeding corrected the hypoaminoacidemia, the rash completely resolved
(Fig. 84-3). However, others have reported that infusion of
peripheral amino acids did resolve the rash but not the serum
amino acid levels."
Patients with glucagonoma are between 50 and 60 years
of age. The skin rash is migratory, red, and scaling and
is associated with intense pruritus, It commonly occurs in
the groin and lower extremities. The rash is pathognomonic
of the tumor. 59,60,61 Hypoaminoacidemia occurs in most
p~tients,
and l~vels
vary with the plasma level of glucagon.
Diabetes mellitus and glucose intolerance are among the
most frequent findings in patients. However, some patients
(20%) do not have hyperglycemia.f Weight loss and cachexia
are common and may be profound. Thromboembolic symptoms occur more commonly in patients with glucagonoma.f
Both deep venous thrombosis and pulmonary emboli
may ultimately cause death. Patients have presented with
a dilated cardiomyopathy reversibly associated with
glucagonoma.v'
Diagnosis is made by measuring elevated plasma levels
of glucagon. In all patients with glucagonoma, the plasma
Somatostatinoma and Rare Pancreatic Endocrine Tumors - -
355
338
Baselinelevels
Levelsfollowing TPN
IITI Levelsfollowing aminoacid infusion
264
Z
238
o
~
cr::
I- en
Z...J
Ww
(
ZW
O...J
()...J
-::2:
()cr::
0
OZ
ZLL
~O
~
769
::2:
en
:sa..
200
180
160
140
120
100
80
60
40
20
OJ.J..l-.....L.IilO__L..IlIIL-J.......L....J-.J-.....L..Il_ _..L...IliI........
Ala
Gly
Leu
lieu
Val
Arg
Lys
His
Thr
Ser Phe
Pro
Tau Met
Tyr
Cit
Orn
FIGURE 84-3. Plasma concentrations of amino acids in a patient with glucagonoma and skin rash. Seventeen individual plasma amino
acid levels were determined in this patient. Normal levels are indicated by the dashed line (100%). Notice that each plasma amino acid
level is reduced. After peripheral amino acid infusion (3.5% amino acids), there was no change in plasma amino acid levels and no change
in the rash. After institution of total parenteral nutrition (TPN, 25% dextrose, 4.25% FreAmine II), there was a normalization of most
plasma amino acid levels and a complete resolution of the rash. Zinc was not added to the TPN solution, and zinc blood levels were
unchanged. When TPN was stopped, the rash recurred. This study suggested that the skin rash in this patient with glucagonoma (NME) is
caused by hypoaminoacidemia, which is corrected and ameliorated by TPN. (From Norton JA, Kahn CR, Schieberger R, et al. Amino acid
deficiency and skin rash associated with glucagonoma. Ann Intern Med 1979;91:213.)
glucagon concentration is elevated (>150 pg/mL). Plasma

levels of glucagon greater than 1000 pg/mL are diagnostic
of glucagonoma. Preoperative preparation of patients with
glucagonoma involves controlling the diabetes, treating any
complications of venous thrombosis, and improving the
nutritional status with total parenteral nutrition, which usually corrects and heals the rash (see Fig. 84-3). Octreotide
has been used, and it reduces plasma levels of glucagon,
improves nutritional status, and ameliorates the rash.>
Glucagonomas are usually found within the body and tail
of the pancreas and rarely in the pancreatic head.62,64
Glucagonomas are usually large, malignant neuroendocrine
tumors (>4 em) and are readily apparent on a CT scan.
Studies should also evaluate the liver because 70% of patients
with glucagonoma have liver metastases at diagnosis.
Surgical procedures are indicated to remove all tumor for
potential cure and to debulk tumor mass for improvement of
symptoms. Primary tumors within the pancreas are generally removed by resection (subtotal pancreatectomysplenectomy) because of the high probability of malignancy.
Resection may be used for liver metastases. Other options
include hepatic artery embolization, chemotherapy with
streptozotocin and 5-fluorouracil, long-term octreotide for
symptoms, and transplantation of the liver and pancreas.
Metastatic disease tends to progress slowly, and patients
may survive for years without treatment.f
GRFoma
GRFomas, first described in 1982,66,67 are neuroendocrine
tumors that secrete excessive amounts of GRF. Patients with
these tumors have acromegaly. GRF is a peptide that is similar to VIP.66.67 GRFomas can occur (in order of decreasing
frequency) in the lung (bronchus), pancreas, jejunum, adrenal,
and retroperitoneum.P" Patients with GRFoma commonly
have a large pancreatic neuroendocrine tumor (>6 em) that is
metastatic in one third of cases at diagnosis. Approximately
50% of patients with GRFomas also have Zollinger-Ellison
syndrome and 33% have MEN 1 (Table 84-6).
GRFoma is anticipated when a patient has acromegaly
and a pancreatic mass. Liver metastases and peptic ulcer
disease should also be considered. 66-68 The diagnosis can be
confirmed by performing a plasma assay for GRF and a CT
scan of the abdomen to identify a pancreatic or liver tumor.
Octreotide therapy can relieve the signs and symptoms of
acromegaly. Surgical resection should be attempted in these
patients because complete resection may be curative, and
debulking may decrease symptoms and prolong survival.
Corticotropin-Producing Tumor
Cushing's syndrome associated with a pancreatic neuroendocrine tumor that secretes corticotropin usually occurs in
patients with neuroendocrine tumors that secrete another
peptide and cause another syndrome." Malignant neuroendocrine tumors commonly secrete more than one peptide.
Excessive production of corticotropin by a pituitary tumor
may occur in patients with MEN 1 but is usually mild and
clinically insignificant." Cushing's syndrome has also been
reported in 5% of patients with Zollinger-Ellison syndrome.55
In these patients, Cushing's syndrome is severe, and they
usually have metastatic disease. Cushing's syndrome is due
to ectopic production of corticotropin by the neuroendocrine

tumor.s? These patients seldom respond to chemotherapy
and have a poor prognosis. In our experience, patients with
corticotropin-producing pancreatic neuroendocrine tumors
are usually unable to be rendered surgically free from disease. Medical management of the hypercortisolism in these
patients is usually inadequate. Therefore, either debulking
surgery or bilateral adrenalectomy may be indicated to control the severe signs and symptoms of hypercortisolism/"
Tumor Releasing Parathyroid

Severe hypercalcemia has been reported to be due to a pancreatic neuroendocrine tumor releasing parathyroid hormonerelated protein (PTHrP).70,71 Hypercalcemia associated with
pancreatic neuroendocrine tumors has also been reported to
be due to the release of other substances such as VIP. In
most cases, the pancreatic tumor is malignant and has spread
to the liver by the time of diagnosis,
Neurotensinoma
Pancreatic neuroendocrine tumors that secrete neurotensin
have been reported.F" Neurotensin is a peptide that is present in the brain and the gastrointestinal tract." Neurotensin
can cause hypotension, tachycardia, cyanosis, pancreatic
secretion, intestinal motility, and small intestinal secretion.F
Patients with neurotensinomas have diarrhea with
hypokalemia, weight loss, diabetes, cyanosis, hypotension,
and flushing. Patients may be cured by tumor resection, and
others have responded to chemotherapy. 72,73 Some have
questioned whether a separate neurotensinoma exists.
Patients with VIPoma and gastrinoma have been found to
have elevated plasma levels of neurotensin. At present, it is
unclear whether a separate syndrome exists.
Ghrelinoma
Ghrelin is a novel gastrointestinal hormone that exerts a
wide range of metabolic functions. It promotes growth hormone release. It is an important regulator of energy balance.
It has been demonstrated to increase appetite and food
intake and modulate insulin secretion. It has significant
homology with motilin and it stimulates gastric contractility
and acid secretion. A study demonstrated that one patient

with an apparently nonfunctional pancreatic neuroendocrine
tumor had markedly elevated serum levels of ghrelin.
Further, immunohistochemistry of tumor showed intense
focal cytoplasmic positivity for ghrelin. This study suggested
that the patient had a tumor that secreted ghrelin, a so-called
ghrelinoma. This had not been previously described. The
authors examined many other carcinoid and pancreatic neuroendocrine tumors and no other tumor had detectable levels
of ghrelin or stained positive for ghrelin."
PPoma and Nonfunctioning

Neuroendocrine Tumor
PPomas secrete pancreatic polypeptide, but this hormone does
not appear to cause symptoms in men and this tumor is considered nonfunctional. PPomas and nonfunctioning pancreatic
neuroendocrine tumors are tumors that have no functional syndrome. Dopamine agonists have been shown to decrease circulating levels of PP and chromogranin A in patients with large
unresectable islet cell tumors." PPomas produce symptoms
by tumor mass effects. This tumor is diagnosed because the
patient has cachexia, abdominal pain, intestinal bleeding,
blockage, or hepatomegaly. Patients with these tumors
have also presented with clinical signs and symptoms of
pancreatitis.v?? Patients commonly have locally advanced or
metastatic neuroendocrine tumor by the time of diagnosis.
Nonfunctioning pancreatic neuroendocrine tumors or
PPomas usually cannot be differentiated from other malignant tumors of the pancreas before biopsy. Preliminary studies suggested that plasma marker 7B2 may be a good
indicator of nonfunctional pancreatic neuroendocrine
tumors." However, this has not been the case, and serum
levels of chromogranin A or PP have been the best markers.
Tumors can be found incidentally during any operative
procedure.f Patients with a long survival (>5 years) and with
suspected metastatic pancreatic adenocarcinoma may have a
nonfunctioning neuroendocrine tumor or PPoma rather than
an exocrine carcinoma. Typically, these tumors are large
when diagnosed (>5 em), and almost all are malignant (70%
to 92%).80 Nonfunctioning pancreatic endocrine tumors are
differentiated from PPomas on the basis of results of the
serum PP assay. At present, there are no data that suggest
that PPomas or nonfunctioning pancreatic endocrine tumors
differ in biologic behavior from malignant functioning
neuroendocrine tumors. 81,82 However, recognizing that a
tumor is a PPoma may be clinically important in that serum
Somatostatinoma and RarePancreaticEndocrine Tumors - - 771

PP levels may be used to monitor the results of antitumor
therapies such as surgical resection or chemotherapy.
Summary
Unusual neuroendocrine tumors of the pancreas and duodenum as well as nonfunctional tumors are more typically
malignant than either gastrinoma or insulinoma. Despite this
fact, patients with these tumors may have a better prognosis
than those with other intra-abdominal solid malignancies.
Therefore, if the entire extent of tumor can be resected and
the patient is otherwise healthy, major operative procedures
(e.g., a Whipple pancreaticoduodenectomy, liver lobectomy,
subtotal pancreatectomy-splenectomy) may be indicated.v"
Furthermore, in patients with some rare tumors associated
with severe symptoms that are poorly controlled medically,
such as somatostatinoma, glucagonoma, PTHrP-releasing
tumor, and corticotropin-secreting tumor, major surgery to
debulk tumor or to remove end organs (adrenal in patients with
corticotropin-secreting tumor) may be necessary. Therefore,
aggressive surgery has an important role in the therapy of these
patients and is the only potentially curative treatment.
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4. Creutzfeldt W, Amold R, Creutzfeldt C, Track NS. Pathomorphological,
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Non-Multiple Endocrine
Neoplasia Endocrine
Syndromes
Gary B. Talpos, MD
Multiple endocrine neoplasia (MEN) type 1 (MEN 1) and

type 2 (MEN 2) syndromes have provided surgeons with most
of their knowledge about hereditary endocrine disorders.
Efficient screening, diagnostic, and postoperative surveillance
algorithms have been established and used to better evaluate
therapy. Less than 35 years after Sipple's initial description,
the specific genetic abnormality in the ret protooncogene
region of chromosome 10 has been identified in many
MEN 2 families and allows accurate genetic testing as the
sole diagnostic study before preemptive thyroidectomy. Ret
testing also simplifies screening of family members at risk
for familial medullary thyroid cancer,'
Although less well known, several other hereditary
syndromes involving the thyroid (Table 85-1), parathyroid,
adrenal (Table 85-2), or pancreas (Table 85-3) have been
described. Most syndromes, as in neurofibromatosis,
involve nonendocrine as well as endocrine abnormalities.
In some, such as the hereditary hyperparathyroidism-jaw
tumor syndrome, a specific location has been documented on
chromosome 1.1,2 In others, such as Li-Fraumeni syndrome,
even more is known about the mutation.' The tumor suppressor gene p53 at chromosome 17p13 appears to be the location
of the genetic abnormality.t-' Normally, this gene encodes a
protein that binds a specific DNA sequence or transcription
factor that blocks growth of abnormal cells in the G\ stage
of cell replication of the cell cycle using apoptosis or inhibition of angiogenesis." A mutation at this location allows propagation or avoidance of blockage of propagation of abnormal
genetic material, and one report indicated that the normal
gene inhibits angiogenesis.'
Frequently, clinical observations initiate a search using
molecular biology and other techniques to recognize hereditary endocrine syndromes and lead to identification of the
genetic abnormality. Thorough understanding of the mutation
eventually guides attempts to correct or treat the disorder and
even prevent the disorder through gene therapy in utero in
known kindreds. Most of the following clinical disorders

represent syndromes with involvement of endocrine organs
as well as nonendocrine tissue. Some represent discrete
mutations that appear to affect only one step in the normal
function of an endocrine organ if this defect has been recognized to be hereditary. Many defects that affect hormonal
biosynthesis have already been identified. An individual
need only consult testing algorithms for adrenal function
in a major text to appreciate the many enzyme defects that
have been well documented. Yet most abnormalities are
not recognized as hereditary with transmission of the defect
to subsequent generations. Undoubtedly, some of the
"nontransmissible" defects could also have a genetic basis
for the disorder with a recessive pattern of inheritance and
irregular penetrance and are not recognized to be hereditary.
Others are somatic mutations early in life, but not germline
mutations, which could be inherited by other family members.
Further study in this area will eventually illuminate the field
more effectively.
In this chapter I consider some of the more dramatic
syndromes that involve the endocrine glands as a major
component of the clinical disorder. In some instances,
endocrine gland involvement is the only recognized component of the clinical syndrome because multiorgan involvement
was not a criterion for inclusion in this chapter. Rather,
genetic transmission or a hereditary basis for the clinical
disorder was used as the major criterion for inclusion. This
chapter is not exhaustive because new information and associations appear regularly. It is merely a stepping stone that
delineates current knowledge and encourages the reader to
improve the related body of science.
Beckwith-Wiedemann syndrome is a disorder usually
recognized at birth and characterized by a variable constellation of findings, including hemihypertrophy, macroglossia,
gigantism, malrotation, and visceromegaly. 8 Islet cell
hyperplasia with associated hypoglycemia, Wilms' tumor,
773
adrenocortical abnormalities including carcinoma with

associated Cushing's syndrome, gonadal hyperplasia, and
liver abnormalities ranging from focal nodular hyperplasia
to hepatoblastoma have also been described. Mental retardation has been noted in several patients with this disorder as
well, although it is not clear whether it is related to the hypoglycemia associated with the nesidioblastosis and seen in
more than half of these patients. Beckwith first described these
patients in 1963 and pondered whether this was a discrete
syndrome." Wiedemann reported on additional families
shortly after and also suggested a new syndrome. to Irving
labeled this disorder the EMG syndrome, for exomphalos,
macroglossia, and gigantism. II Fraumeni and Miller also
referenced case reports dating from 1935 linking hemihypertrophy and adrenocortical tumors (five malignant, one
benign) in which the patients usually presented with precocious puberty (five) and Cushing's syndrome (twO).12.13
Undoubtedly, their review of 62 children with adrenocortical adenomas or carcinomas includes some children with the
Beckwith-Wiedemann syndrome and also some with what
has become known as the Li-Fraumeni syndrome.v-"
Clinically, patients with the Beckwith-Wiedemann

syndrome are recognized in the newborn period with hemihypertrophy, macroglossia, and the other somatic manifestations of this disease.P-'" Palpation or radiologic evaluation
of the abdomen frequently reveals a mass related to enlargement of the pancreas, adrenals, kidneys, or liver, which
requires prompt evaluation and treatment. More urgently,
however, normoglycemia needs to be ascertained in light
of associated nesidioblastosis. In selected cases, subtotal
pancreatectomy has proved essential in controlling the
serum glucose and preventing the sequelae of profound
hypoglycemia." It is also apparent that these children must
be committed to an aggressive surveillance program because
the development of adrenocortical abnormalities-usually
malignant-ean be delayed until at least age 17 years,
Genetic studies indicate an abnormality on chromosome
11 at the p l S locus in some patients with hemihypertrophy, 19
Eighty-five percent of these cases appear sporadic, although
variable expression and reduced penetrance could mask a
higher percentage of autosomal dominant transmission. This
genetic abnormality could act as a true oncogene. The
insulin-like growth factor (lGF2) gene is considered a
candidate gene in light of its proximity at 11p15 and the
hemihypertrophy and the fact that the product of the IGF2
gene is a fetal growth factor. Overexpression of the mutated
gene could then have an impact on any somatic mutation,
leading to multiple-organ involvement.'?
Familial hyperinsulinemia has an incidence of 1 to 5 per
100,000 and is sometimes called the familial hyperproinsulinemia syndrome. It involves autosomal dominant transmission of a point mutation at l lpl S, which results in reduced
insulin receptor binding and mild diabetes mellitus. It is rarely
recognized and is noted only to link it to the BeckwithWiedemann syndrome with its similar genetic location.
Treatment to reduce elevated insulin levels is not necessary
because these patients do not demonstrate hypoglycemia.P
The hereditary hyperparathyroidism-jaw tumor syndrome
has been described over the past 15 years." Typically, this
syndrome occurs in an autosomal dominant fashion, and
these patients present as teenagers with hypercalcemia
and are found to have single-gland parathyroid disease. The
abnormal parathyroid is characterized by an adenomatousappearing gland that frequently, but not invariably, is
cystic, Excision of this solitary gland and identification of
Non-Multiple Endocrine Neoplasia Endocrine Syndromes - -
normal-appearing glands usually result in a prompt return

of normocalcemia. However, at least two individuals in the
six described kindreds experienced recurrent single-gland
parathyroid disease several years after their initial operation.
At reoperation, only a single abnormal gland was found.
Parathyroid cancer has also been described in two kindreds
in younger individuals. This finding is supportive of
Knudsen's two-hit hypothesis in which the first "hit"
involves a germline mutation. The second hit represents
a somatic mutation. A third hit, or additional somatic
mutation, could then lead to development of a malignancy.
Usually, these hereditary tumors are multicentric and occur
in younger individuals. Jaw tumors associated with this
condition are distinct from osteitis fibrosa cystica and
"brown tumors." They have been characterized as ossifying
fibromas. Typically, they arise in an asymptomatic fashion
on dental radiographs or as tender intraoral nodules involving only the mandible or maxilla. In the six kindreds listed,
at least 10 of the 31 individuals with parathyroid disease did
not have jaw tumors at last report; thus, this feature of the
syndrome does not appear to have complete penetrance or
expressivity. Characteristically, these neoplasms occur much
earlier than the fourth or fifth decade, when sporadic jaw
tumors usually occur. Correction of the hypercalcemia also
appears to have no relationship to development or progression of the tumors. Some tumors have been monitored with
isotopic and plain film radiographs and appeared to stabilize
independent of development or redevelopment of the
clinical hyperparathyroidism.
Wilms' tumor has also been seen in a single individual in
three of the six known kindreds with hereditary hyperparathyroidism-jaw tumor syndrome, which suggests a striking coincidence or an unexplained genetic relationship.l,22,23
Extensive genetic studies have been performed on tissue
from members of five kindreds affected with the syndrome.
A candidate gene was mapped to chromosome Iq21-31
and labeled HRPT2. Furthermore, failure to identify loss
of heterozygosity in affected tissue from eight individuals
suggests that the responsible gene mutation for hereditary
hyperparathyroidism-jaw tumor syndrome is a protooncogene analogous to the ret protooncogene responsible for
MEN 2. An HRPT2 mutation has been identified in about
60% of sporadic parathyroid carcinomas.e' Currently, it is
unknown whether the six involved kindreds with hereditary
hyperparathyroidism-jaw tumor syndrome represent the true
incidence of this syndrome or whether the syndrome
involves more families but goes unrecognized.
Several hereditary thyroid syndromes have been described.
Most are associated with hypothyroidism and resultant
goiter formation, although at least one syndrome is associated with hyperthyroidism.
Pendred's syndrome is an autosomal recessive disorder
seen approximately once in every 15,000 births.i" It represents a defect in the peroxidase-generating system with
resultant hypothyroidism. Goiter usually results. Deafness
is also seen in these patients. Chromosomal studies have not
yet identified the specific mutation for this syndrome.
Separate and distinct unnamed hereditary disorders have
also been identified with iodide transport deficiency and
iodotyrosine deiodinase deficiency, both of which result in
hypothyroidism and goiter without other organ involvement.P
775
Both of these entities appear to be transmitted in an autosomal recessive fashion, although specific chromosomal
abnormalities have not yet been identified. Because only one
biochemical defect is noted in each disorder, these disorders
might be particularly amenable to gene therapy in the future.
Currently, thyroid replacement and thyroidectomy as necessary are indicated for Pendred's syndrome and patients with
the latter two disorders.
Hereditary hyperthyroidism is a rare disorder transmitted
in an autosomal dominant fashion in which increased stimulation of thyrocytes occurs with resultant thyromegaly and
autonomy" In some families, it has been thought mistakenly
to represent a hereditary form of Graves' disease. No trials
comparing therapy exist in this illness, although both radioiodine and surgery should be effective.
Von Hippel-Lindau disease has a long history. The classical eye findings were first described by Collins in 1894;
von Hippel recognized the familial pattern in 1904. Finally,
in 1926 Lindau saw that the retinal and cerebellar hemangioblastomas were part of the larger syndrome.P Von
Hippel-Lindau disease is now known to be an autosomal
dominant disorder because of a mutation at chromosome
3p25-26. 26 This appears to encode a tumor suppressor locus
and results in variable expression, with many organs potentially being affected. Classically, hemangioblastomas of the
brain stem, retina, or kidney are seen. Renal cell carcinoma;
pheochromocytoma, usually bilateral; epididymal cysts; and
pancreatic abnormalities are also found, although there are
marked interfamily differences with constant intrafamily
involvement.27.28
Depending on the method of diagnosis, pheochromocytoma is reported in 20% to 80% of patients found to have
von Rippel-Lindau disease, and it is usually the presenting
sign of the disorder.i? Lack of family screening programs
and the frequently dramatic occurrence of pheochromocytoma usually overshadow the more readily detectable retinal
findings evidenced on funduscopic examination. Bilaterality
of the pheochromocytomas has been seen but does not
appear to be as constant a finding as in MEN 2 syndrome.
When bilateral pheochromocytomas are detected, metachronous involvement seems to be the rule. It is not clear
whether this is a legitimate observation or a reflection of
diagnostic efforts. In addition, adrenal medullary hyperplasia has not been documented as a precursor lesion, although
medullary hyperplasia was thought to represent the initial
step in the development of pheochromocytoma in hereditary
cases. Finally, extra-adrenal pheochromocytomas or paragangliomas have been reported in approximately 10% of patients.
For this reason, transabdominal exploration is advocated for
surgery for pheochromocytoma in this disorder,"
Pancreatic lesions have also been seen in 56% of patients
with von Rippel-Lindau disease. Isolated pancreatic cysts
accounted for two thirds of these lesions, whereas approximately 15% of the abnormalities were found to be islet cell
tumors. Although immunoperoxidase staining occasionally
identified specific hormones stored in these tumors, no
clinical sequelae associated with the specific hormones
have been identified. The remainder of the pancreatic
lesions seen in von Hippel-Lindau disease were found to
be indeterminate pancreatic masses or combinations of the
just-mentioned syndromes.F-"
776 - -
Endocrine Pancreas
Although the genetic abnormality associated with von

Hippel-Lindau disease has been localized to chromosome
3p, widespread genetic testing for this disorder is not yet
available. A positive family history of pheochromocytoma
remains the single most important fact that identifies the
patient as having a hereditary disorder. Genetic testing and
calcitonin measurements can usually detect individuals with
pheochromocytomas associated with the MEN 2 syndrome.
The individuals with pheochromocytoma associated with a
phakomatosis can usually be identified by the cutaneous
manifestation of the disorder whether it is neurofibromatosis,
Sturge-Weber syndrome, or any other type of phakomatosis.
The remainder of hereditary cases involving pheochromocytoma appear to be found in kindreds with familial pheochromocytoma or von Hippel-Lindau disease. A detailed family
history searching for extra-adrenal manifestations of von
Hippel-Lindau disease and careful funduscopic examination
by an experienced ophthalmologist usually serve to distinguish these two disorders. Periodic screening of all individuals at risk in each kindred should also be performed because
survival is related to the stage of tumor at diagnosis.
Familial pheochromocytoma has also been reported in
different forms. Hereditary bilateral adrenal pheochromocytoma,29,30 extra-adrenal pheochromocytoma," and bilateral
multicentric pheochromocytoma associated with islet cell
tumors (unrelated to von Hippel-Lindau diseasej-' have all
been described as being transmitted in an autosomal dominant
fashion with incomplete penetrance. The genetic aberrations
in these disorders have yet to be determined, although each
disorder has been detected in multiple unrelated kindreds. It
is not known whether these distinct clinical entities represent
separate hereditary disorders or whether they are different
expressions of a common genetic mutation. A detailed
family history remains the best means of determining the
presence of a hereditary adrenal disorder. The increased incidence of multiple tumors, bilaterality with either synchronous
or metachronous involvement, adrenal medullary hyperplasia,
or an early age of onset should also heighten suspicion of
a pheochromocytoma-associated syndrome. If it is found,
regular screening should be instituted.
Carney's complex represents a variable constellation
of abnormalities, including myxomatous masses, spotty
pigmented lesions of the skin, endocrine disorders, and
psammomatous melanotic schwannomas.P'" The myxomas
occur in the heart (most important clinically), the skin, and
the breast. The pigmented skin lesions most commonly have
been termed lentigines or blue nevi, whereas the endocrine
disorders have consisted of a unique bilateral pigmented
nodular adrenocortical abnormality, testicular tumors, and a
growth hormone-producing pituitary adenoma. The characteristic schwannoma associated with Carney's complex is a
rare melanotic peripheral nerve tumor that is usually benign,
although malignancy has been seen and was fatal in 10%
of cases. Cushing's syndrome occurs early, with a mean age
of onset of 19 years. It is usually cured by bilateral adrenalectomy. Intraoperatively, the adrenal glands have been
noted to be studded with small, dark nodules. Interestingly,
Nelson's syndrome (postadrenalectomy pituitary tumor) has
yet to be reported in patients with Carney's complex.
Whether this is genuine or more a problem of recognition
remains to be seen.
Cardiac myxomas were seen in approximately 75% of

Carney's original series; more than half had multiple
myxomas. Excision, frequently in a staged fashion, is the
treatment of choice. Echocardiography remains the diagnostic
tool of choice. 34
Testicular tumors are also seen in Carney's complex,
affecting more than half of the male patients. They are
usually bilateral and multicentric, occurring at a mean age of
11 years. Metastasis has not yet been reported. Histologically,
the tumors have been characterized as large-cell calcifying
Sertoli cell tumors or as a steroid-type tumor (either a
Leydig cell tumor or a tumor of an adrenocortical rest).
Pituitary adenomas are also a major component of this
syndrome, affecting 10% of patients and usually occurring
in the teenage years. Growth hormone has invariably been
elevated. Hypophysectomy remains the treatment of choice.
Psammomatous melanotic schwannoma is an uncommon
tumor. Half of the cases have been reported in association
with Carney's complex. Typically, the tumor involves the
esophagus, stomach, or paravertebral sympathetic chains.
Although most tumors have been characterized as benign,
10% were malignant and fatal."
Patients with Carney's complex can usually be recognized by a positive family history and the spotty skin
changes. Multiple myxomatous tumors of the skin or breast
should also raise suspicion for this disorder." Screening
protocols for cardiac myxomas should be instituted early
because death from this entity has been reported as early as
4 years of age. Screening for adrenal abnormalities, pituitary
tumors, and testicular tumors should also be started
early because tumors were frequently seen before 10 years
of age." Early age of onset, multicentricity, bilaterality,
and familial tendency argue for a genetic mechanism for
this syndrome, although none has been determined to date.
Clinically, 32% of the patients reported by Carney were alive
and well, whereas 30% died, usually from a cardiac myxoma.
Another 30% were alive with sequelae of the syndrome, most
commonly myxoma-related embolism.
Gardner's syndrome, also termed familial adenomatous
polyposis, was first described in 1951. 38 This syndrome of
premalignant colonic polyposis, osteomas, and soft tissue
tumors is transmitted in an autosomal dominant fashion and
affects about 1 per million as opposed to just polyposis,
which affects 1 per 8000. In 1959 Turcot documented two
patients with familial adenomatous polyposis who also had
malignant brain tumors. Gardner's syndrome has been
traced to chromosome 5q21, as has adenomatous polyposis
coli. Epidermoid cysts are commonly seen, although
desmoid tumors are present in only about 10% of patients."
Typically, these occur in young women and can recur locally
after excision. Sulindac, tamoxifen, and interferon have
all been reported to cause regression in some instances.
Osteomas and pigmented eye lesions are also frequently
reported.
Malignant tumors are also seen in Gardner's syndrome."
Colon cancer eventually occurs in all patients, whereas periampullary carcinoma, the next most common malignancy, is
seen in 10% of cases." Papillary thyroid cancer is seen less
frequently (about 2%) but at a reported incidence of more
than 100 times the expected incidence in women younger
than 35 years in the general population.'? The cancer is
Non-Multiple Endocrine Neoplasia Endocrine Syndromes - - 777
usually multicentric and frequently bilobar. It appears to

be associated with both a germline APC mutation and a
ret/PTC somatic mutation. Histologically, the papillary thyroid
cancers have a unique cribriform pattern. Frequent physical
examinations of the neck combined with liberal fine-needle
aspiration of thyroid nodules should lead to curative total
thyroidectomy in these patients. Preemptive suppression of
thyroid function through the administration of oral thyroid
medication to prevent tumorigenesis remains an attractive
but unproven alternative.
Several isolated reports of adrenocortical adenomas and
adenocarcinomas complicating Gardner's syndrome also
exist.39 Recognizing the relative scarcity of adrenal neoplasms,
the coexistence of these with polyposis seems related. Only
detailed autopsy studies or better understanding of the
involved genetic mechanism is likely to explain this relationship. At this point, increased clinical awareness should
lead to earlier recognition of a symptomatic patient because
the incidence of adrenal tumors in Gardner's syndrome at
this time appears too low to justify screening programs.
Cowden's disease, also known as the multiple hamartoma syndrome, was named after Rachel Cowden, who, in
1963, was recognized as having a disorder involving mucocutaneous lesions and abnormalities of the breast and
thyroid. Ten years later she died of the breast cancer associated with this syndrome, as did her mother/" In retrospect,
patients presented by Costello in 1940 and by Witten and
Kopf in 1957 were found to share the same physical features
as well as the same histologic findings on biopsy." This genodermatosis is now recognized as an autosomal dominantly
inherited complex that has variable expressivity. Major criteria for diagnosis are cutaneous facial papules and oral
mucosal papillomatosis, whereas minor criteria are acral
and palmoplantar keratoses. A definitive diagnosis requires
(1) two major criteria, (2) one major and one minor criterion, (3) one major criterion and a positive family history, or
(4) two minor criteria and a positive family history. These
cutaneous lesions usually develop in the second or third
decade of life. Other characteristic lesions develop in the
breast in 76% of female patients. Aggressive fibrocystic
change, papillomas, and vaginal hypertrophy have all been
reported. Breast cancer is seen in approximately one third
of women with this disorder. In light of this increased
incidence, a more aggressive screening program for breast
cancer in women with a confmned diagnosis of Cowden's
disease is recommended.
Thyroid disease is also commonly seen; about two thirds
of both male and female patients are affected. Benign conditions predominate and include toxic as well as nontoxic
goiter, follicular adenomas, and less commonly carcinoma.f
These potential disorders should be sought and needle
biopsy performed for any thyroid nodules in patients with
Cowden's disease.
Gastrointestinal hamartomatous polyps are also seen,
although malignant degeneration is not thought to develop.
Hundreds and, on occasion, thousands of small polyps carpet
the entire gastrointestinal tract.f? Genitourinary, nervous
system, and skeletal abnormalities occur frequently as well
with varying degrees of disability. The major threats to the
involved patient, however, are the malignancies that develop
from the breast and thyroid disorders.
Noonan's syndrome has been recognized as a distinct

entity since 1963, although a male patient with features
compatible with this disorder was reported in 1883.43
The appearance is similar to that of Turner's syndrome
because a webbed neck, hypertelorism, low-set ears, and
short stature are seen in both. Turner's syndrome, however,
involves only females because it represents an absence or
an abnormality of the X chromosome. Noonan's syndrome
is seen in both sexes, and the underlying genetic defect
has been located on the long arm of chromosome 12.44
Autosomal dominant inheritance with variable expression is
noted in approximately one half; sporadic cases represent
the remainder. Most authors estimate the frequency to be
1 per 1000 to I per 2500 births. However, other estimates suggest a frequency of I per 1000 in the severely affected and
1 per 100 in the mildly affected patients." Neurofibromatosis
I has also been seen in association with Noonan's syndrome,
but genetic studies have not indicated any other abnormality
on chromosome 17, the neurofibromatosis I chromosome.f
Affected children have a typical facies, and 90% have a
chest deformity such as pectus excavatum or pectus carinatum. Hyperextensible joints are also seen. A variety of
cardiac defects have been noted in half of the patients with
this disorder, and right heart outflow anomalies are most
common.v Eye findings, including thickened corneal nerves,
have been documented in 63% in one series. Deafness also
occurs in about 40% of affected individuals. Undescended
testicles are seen in more than one half of males, which
results in decreased fertility. Pheochromocytomas have been
described as well. It is not certain, however, that these individuals did not have accompanying neurofibromatosis 1.47,48
Newborns affected with Noonan's syndrome have been
characterized as listless, poor feeders prone to episodes of
vomiting. Despite sharing these features as well as thickened corneal nerves and hyperextensible joints with the
MEN 2B syndrome, no genetic association has been identified between these two syndromes.
The phakomatoses represent a group of disorders characterized by neuroectodermal findings, including an increased
incidence of pheochromocytoma.
Neurofibromatosis is now recognized as two conditions.
Neurofibromatosis I includes von Recklinghausen's disease
and is associated with hereditary pheochromocytomas,
whereas neurofibromatosis II is considered the acoustic
neuroma syndrome. Neurofibromatosis I affects I in 3500
live births and appears to have an autosomal dominant
pattern of transmission. Criteria for diagnosis include two or
more of the following: cafe au lait spots, neurofibromas,
freckling in non-sun-exposed areas, optic glioma, Lisch
nodules, distinctive bone lesions, and a first-degree relative
with the disorder." A variety of mutations consisting primarily of deletions and insertions have been identified at chromosome 17q 11.2, which appears to cause disordered growth
through a tumor suppressor mechanism involving neurofibromin." This gene product appears to be involved with
regulation of cell proliferation and differentiation and is one
of the guanine triphosphatases (GTPases).50
The classical appearance of von Recklinghausen's
disease, or "elephant man's" disease, is usually seen.
Pheochromocytomas, however, are less commonly detected,
with a reported incidence of less than 1%.51 Whether this

reflects the true incidence is unclear because most screening
programs for neurofibromatosis do not prospectively screen
for adrenal abnormalities. Neurofibromatosis II does not
appear to be related to adrenal involvement, and its mutational site appears to be on chromosome 22.
Duodenal or periampullary carcinoids are also associated
with neurofibromatosis disease, although it has not yet been
determined whether they are seen in neurofibromatosis I, II,
or both. The incidence is probably less than that reported for
pheochromocytoma in this disorder.52
Tuberous sclerosis is an uncommon condition that is considered to be one of the phakomatoses or genodermatoses.
Several studies suggest a prevalence of 1 case per 6000 to
9000 individuals. Autosomal dominant transmission has
been recognized with variable penetrance and expressivity
and a high spontaneous mutation rate. Hamartomas as well
as true neoplasms are seen" Diagnostic criteria for tuberous
sclerosis involve combinations of primary, secondary, and
tertiary features. Multiple-organ involvement is usually
seen, with skin and retina typically affected. Cardiac rhabdomyomas are seen in approximately two thirds of patients,
as are renal cysts and angiomyolipomas. Brain involvement
is frequently seen and manifested by seizures and mental
retardation. Seen much less commonly are pulmonary
involvement, adrenal pheochromocytomas, and islet cell
tumors. 54.56 Survival is affected primarily by the cardiac
disease and, to a lesser intent, the pulmonary involvement,
which, although affecting only a small number of individuals, is usually fatal within 5 years. Two genetic variants of
tuberous sclerosis are recognized, although phenotypic
differences have not been seen. Tuberous sclerosis I (TSC 1)
appears to involve a mutation at chromosome 9q33.34,57
whereas TSC 2 involves a mutation at chromosome
16p13.3.56 The TSC 2 gene appears to be involved with
tuberin production and with polyadenylation affecting
the GTPase-activating protein (GAP) (or rap-l GAP).
Interestingly, neurofibromin, the product of the nfi gene,
is homologous to ras-GAP. The ras gene is one of a
group of GTPases that helps regulate all proliferation and
differentiation.
Birt-Hogg-Dube syndrome is a rare condition found in
one Canadian family and described in 1977.57 This is an
autosomal dominant condition consisting of multiple fibrofolliculomas with trichodiscomas and acrochordons, which
affected 15 of 25 adults studied in the kindred. Medullary
thyroid cancer was also found in 6 of 15 affected members.P
Summary
These syndromes as well as others waiting to be described
have endocrine features that require treatment. Earlier
recognition of the syndromes and better surveillance for the
different components of each syndrome should allow more
effective treatment algorithms. Surgeons should be aware of
these syndromes with endocrine involvement to better treat
each individual patient and also to participate in family
screening. Treating the preclinical stages of disease should
allow the best possible outcome. Endocrine surgeons must
remain involved if they are to keep intact their role as
physician-teacher-researcher.
The findings from the human genome project are providing much useful information regarding genotype-phenotype
relationships. These findings should lead to earlier diagnosis and more appropriate and effective therapies.
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53. Kim H, Kerr A, Morehouse R. The association between tuberous sclerosis and insulinoma. AJNR Am J Neuroradiol 1995;16:1543.
54. Davoren PM, Epstein MT. Insulinoma complicating tuberous sclerosis.
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Neuroendocrine Tumors
Laurent Brunaud, MD Hans-Dietrich Roeher, MD Dietmar Simon, MD
Neuroendocrine tumors (carcinoid tumors) are unusual, rare

tumors that can be localized in all organs originating from
the endoderm. They are derived from neoplastic proliferation
of cells of the diffuse neuroendocrine system. These cells
have been called enterochromaffin or Kulchitsky cells; they
are ubiquitous throughout the gastrointestinal tract, urogenital
tract, and bronchial epithelium and are considered to be the
largest endocrine organ of the human body.'? The neuroendocrine system has been described as a diffuse network of
nerve and endocrine cells with a common phenotype characterized by the simultaneous expression of general protein
markers and hormonal products specific to each neuroendocrine cell." The incidence of neuroendocrine tumors is
1 per 100,000 per year. The most frequent sites are the small
intestine (35%), the appendix (33%), the rectum (14%), and
the bronchial system (9%). However, a marked increase
in the percentage of lung-bronchial tumors and a decrease in
the percentage of appendiceal neuroendocrine tumors have
been reported.l In organs that rarely develop malignant
tumors, neuroendocrine tumors become the most frequent
tumors; thus, 34% of all small intestinal cancers and 77% of
all appendiceal tumors are neuroendocrine tumors. In organs
that develop tumors more frequently (e.g., the colon, stomach,
lung, and breast), neuroendocrine tumors make up only 1%
of the tumors. The overall prevalence of neuroendocrine
tumors is estimated at 0.5%.6
History
The first description of carcinoid tumors dates back to the
19th century, when Merling (1808), Langhans (1867), and
Beger (1882) identified appendiceal carcinoids as a unique
histologic entity. Lubarsh described multicentric small
tumors in the small intestine originating from the intestinal
glands (Lieberkuhn).? In 1907 Oberndorfer for the first time
used the term carcinoid to define the tumors as benign and
carcinoma-like." Between 1914 and 1928 Masson described
780
special staining techniques with silver impregnation

(Grimelius), which showed the carcinoid tumor cells to
be argentaffin.v'" Thus, these tumors were attributed to
the enterochromaffin cells named after Kulchitsky and were
postulated to be of endocrine origin." In 1938 Feyrter,
a German pathologist, described special cells and their
morphologic similarity to other neuroendocrine cells and
defined the diffuse endocrine system distributed throughout
the body.12 In 1953 serotonin was identified as the characteristic product of the carcinoid tumors. In 1954, Thorson,
coincidentally with Cassidy, Bjorck, Isler, Hedinger, and
Waldenstrom, defined the "carcinoid syndrome" with the
typical symptoms of flushing, diarrhea, and valvular heart
disease.
Williams and Sandler classified carcinoid tumors according
to their distribution in the foregut, midgut, and hindgut.'> In
1969 Pearse included carcinoid tumors in the amine precursor uptake and decarboxylation (APUD) system.lv"
However, their presumed common origin from the neural
crest holds true only for some of these cells. 16,17 In 1984,
Falkmer characterized carcinoid tumors by immunohistochemistry, showing a specific pattern of neurohormonal
peptides. It has become apparent, however, that the general
term carcinoid fails to describe the diverse spectrum of neoplasms with regard to functional state, localization, growth
pattem, degree of differentiation, expression of different
neuroendocrine marker molecules, and prognosis. A new
classification emerged in 1995 that includes not only the site
of origin but also variations in the histologic characteristics
of carcinoid tumors (Table 86_1).4,18 Using this system,
carcinoid tumors are classified as well-differentiated neuroendocrine tumors and well-differentiated (low-grade) and
poorly differentiated (high-grade) neuroendocrine carcinomas. The term carcinoid tumor should preferably be used for
classical midgut carcinoids, whereas other types of carcinoids
should be termed neuroendocrine tumor followed by their
primary location, for example, neuroendocrine thymic, gastric,
small bowel, or rectal tumor.
Neuroendocrine Tumors - - 781

Foregut
Midgut
Hindgut
Liver/pancreas
FIGURE 86-1. Carcinoid tumors of the primitive gut. (From
Simon D, Goretzki PE, BranscheidD, et al. Chirurgische Therapie

von intestinalen Karzinoidtumoren. AktuelChir 1992;27:8.)
Pathogenesis and
Pathophysiology
Although the histogenesis of neuroendocrine tumors is
incomplete and varies from organ to organ, it appears that
neuroendocrine tumors and naive endocrine cells arise
from the same progenitor cell. 3 ,19 Although controversial, it
appears that neuroendocrine tumors and low-grade neuroendocrine carcinomas arise from orthotopic neuroendocrine
cells of the epithelium of the respective organs, whereas
high-grade neuroendocrine carcinomas derive from a
putative stem cell rather than from neuroendocrine cells."
Microenvironmental or functional differentiation or dedifferentiation may lead the enterochromaffin cells to produce
and secrete neuroendocrine peptides. They also express
many cell surface peptide receptors that enable them to
respond to several growth factors. I The exact function of
Kulchitsky cells is not known, although they are presumed
to have endocrine and enzymatic functions. II The cells have
a characteristically uniform pattern and neurosecretory
granules. Neuroendocrine tumors are able to metabolize
biogenic amines and thus are called APUDomas. 14 ,15
Phylogenically, neuroendocrine tumors are divided into
those from the foregut, midgut, and hindgut. The foregut
includes the bronchus, thymus, stomach, duodenum, and
pancreas. The midgut includes the small bowel, appendix,
and right hemicolon. The hindgut includes the left colon,
rectum, and ovaries. 13 Each group of neuroendocrine tumors
has a typical clinical presentation and prognosis. Foregut
neuroendocrine tumors may stain for multiple hormones
with preferential production and secretion of 5-hydroxytryptophan. Hindgut tumors may also stain for multiple
hormones, but they usually do not secrete any hormone
(Fig. 86-1).
The exact cause of neuroendocrine tumors is not known.
The vast majority of cases are sporadic, although familial
cancer syndromes associated with an increased risk of
neuroendocrine tumors occur in multiple endocrine neoplasia type 1 (MEN 1), in MEN 2, and in von Recklinghausen's
disease (duodenum)." Moreover, studies of sporadic neuroendocrine tumors showed that a loss of heterozygosity at
the MEN 1 locus was present in 26% to 78% of these
tumors. Mutations were identified at this locus using other
techniques in 18% of cases. 22,23 Foregut tumors very often
show involvement of the MEN 1 gene.>' Links between
carcinogenesis (familial or sporadic tumors) and MEN 1 gene
could be explained by growth factor-related angiogenesis
(vascular endothelial growth factor, fibroblastic growth
factor, and transforming growth factor), but this relation is
difficult to confirm experimentally"
Gastric neuroendocrine tumors are frequently found in
patients with chronic atrophic gastritis (with or without
pernicious anemia) and Zollinger-Ellison syndrome, leading to the assumption that hypergastrinemia is one pathogenic factor. Experimental studies and clinicopathologic
results give strong evidence that omeprazole through
achlorhydria leads to hypergastrinemia and enterochromaffin-like (ECL) cell hyperplasia. Thus, ECL cell hyperplasia
may be the first step in the development of carcinoid
tumors. Loss of function of one allele of the MEN 1 gene is
probably required for progression to true neoplasia, and this
gene may function as a tumor suppressor gene for fundic
tumors in Zollinger-Ellison syndrome." However, the
problem may be more complex than was initially appreciated because gastric neuroendocrine tumors can occur in
MEN 1 patients without hypergastrinemia and the MEN 1
gene is not lost in some patients with gastric type II
lesions."
Gains of chromosomes 4, 5, and 19 and losses of

chromosome 18 by comparative genomic hybridization have
been associated with sporadic midgut carcinoids.Pv?
Hindgut tumors in general show rather low proliferation
capacity, and transforming growth factor-a or epidermal
growth factor receptor autocrine mechanism may playa role
in the tumor development." In contrast to a number of
nonendocrine tumors, neither common oncogenes (ras, src)
nor common tumor suppressor genes (P53) are generally
important in the molecular pathogenesis of neuroendocrine
tumors except for the more atypical forms."
782 - -
Endocrine Pancreas
Histopathology
Several specific staining techniques have been developed
for identifying neuroendocrine cells. The traditional ones
are the argentaffin and argyrophil reactions. The argentaffin
reaction as described by Masson characterizes endocrine
cells that can take up and reduce silver ions." Argentaffinpositive staining is typically found in midgut carcinoid
tumors and generally is assumed to be associated with the
presence of serotonin. For example, argyrophilic reaction
with the Grimelius technique is preferentially found in
foregut and appendiceal neuroendocrine tumors. An
argentaffin reaction is very specific for neuroendocrine cells,
whereas an argyrophilic reaction is much more sensitive.
Immunohistochemical techniques have greatly facilitated
the characterization of neuroendocrine tissues by using
monoclonal or polyclonal antibodies against neuron-specific
enolase, chromograninA, and synaptophysin." These markers
are important for the differential diagnosis and can also be
elevated in the serum and thus used as tumor markers for
follow-up. Diagnosis of well-differentiated neuroendocrine
tumors is usually easy because of their characteristic uniform
cell pattern with round nuclei and eosinophilic cytoplasm on
hematoxylin and eosin staining.P Discrimination of atypical
carcinoids and poorly differentiated or small cell neuroendocrine tumors may be difficult because they look like
metastatic tumors from the lungs or other sites. The same
applies for neuroendocrine carcinomas of the colon, which
may resemble poorly differentiated colon cancers or
lymphomas.
Typical neuroendocrine tumors have a yellow-grayish
color and can demonstrate various morphologic patterns,
such as insular growth with solid nests; trabecular growth;
glandular growth with alveolar, acinar, or pseudoglandular
pattern; and a mixed or undifferentiated growth.F Although
these different patterns can be seen in neuroendocrine tumors
from all sites, foregut and hindgut tumors show preferentially
a trabecular pattern arid midgut carcinoids show an insular
pattern. Foregut neuroendocrine tumors almost always stain
positively for thyroid transcription factor I (TTF-I),
whereas gastrointestinal carcinoids do not. Staining for
TTF-I can, therefore, help identify the site of origin when it
is not known. The various growth patterns do not affect the
prognosis, which is determined more by tumor location
(Fig. 86-2).
Clinical Syndrome
+
+
Biochemical evaluation
Endoscopy
Biopsy
Removal?
Serotonin, 5-HTP, 5-HIAA
Ultrasonogram
CTscan
+
+
Liver metastases?
~Barium examination
Stenosis?
Adhesions?
SMS scintigraphy
(MIBG scintigraphy)
Symptoms
FIGURE 86-2. A, Small, solid intramural carcinoid tumor of the

duodenum. B, Carcinoid tumor of small intestine is partially
obstructive. C, Diagnostic localization of carcinoid tumors.
CT = computed tomography; 5-HIAA = 5-hydroxyindoleaceticacid;
HTP = hydroxytryptophan; MmG = metaiodobenzylguanidine;
SMS = somatostatin.
The endocrine activity of neuroendocrine tumors is one of

their most characteristic features. They may secrete many
different hormones, neuropeptides, and neurotransmitters.
The best known is serotonin or its precursor, 5-hydroxytryptophan, which is predominantly secreted by gastric neuroendocrine tumors. Many other hormones (e.g., corticotropin,
corticotropin-releasing factor, catecholarnines, calcitonin,
somatostatin, substance P, pancreatic peptide, vasoactive
intestinal peptide, and ghrelin) and other neurohormonal
substances (e.g., bradykinin, tachykinin, neurokinin A,
neuropeptide K, and histamine) can be secreted from these

tumors. Not all of these substances produce clinical symptoms (Tables 86-2 and 86-3).
The classical carcinoid syndrome is assumed to be
caused by serotonin and bradykinin. Carcinoid syndrome is
defined by the presence of flushing, diarrhea, and endocardial or myocardial fibrosis with valvular heart disease."
Neuroendocrine Tumors - - 783
Carcinoid syndrome is found in 10% to 30% of the patients,

depending on the location of the primary tumor. In carcinoid
tumors of the gastrointestinal tract, the syndrome has been
described in 10% to 20% of the patients. The presence of
carcinoid syndrome should make one suspicious of metastases
or large mesenteric lymph node involvement, presumably
because of a lack of first-pass inactivation of the secreted
hormones by the liver. In contrast, neuroendocrine tumors of
the bronchus or the ovaries often arise with carcinoid syndrome in the absence of distant metastases (Table 86-4).33
Clinical observation shows various types of flushing that
may indicate the location of the primary neuroendocrine
tumor. A diffuse erythematous flushing affecting mainly the
face, neck, and upper chest and lasting for 2 to 30 minutes is
mostly associated with high urinary 5-hydroxyindoleacetic
acid (5-HIAA) and gastrointestinal carcinoids. In contrast,
long-lasting flushing (for hours or days) combined with
profuse lacrimation and suffused conjunctiva often indicates
a bronchial carcinoid"
Serotonin probably plays a role in mesenteric fibrosis as
well as in myocardial fibrosis, causing valvular heart disease.
Ten percent to 15% of the patients have evidence of carcinoid
heart disease; intra-abdominal fibrosis, including retroperitoneal fibrosis, occurs even more often and can cause bowel
obstruction. Intestinal obstruction is one of the most common
symptoms in gastrointestinal carcinoid tumors. It is caused
by mesenteric fibrosis, intraluminal growth, intussusception,
or intestinal infarction resulting from vascular compression

or adventitial fibrosis. Bleeding and chronic abdominal pain
are less frequent. In our experience, most patients with gastrointestinal carcinoid tumors present with acute symptoms
so that a complete biochemical evaluation and elective
operation are rare.
Typical symptoms of bronchial neuroendocrine tumors
are hemoptysis, recurrent pulmonary infections, coughing,
and wheezing. Bronchial neuroendocrine tumors are the
most frequent primary pulmonary neoplasms of childhood."
They most commonly arise with recurrent pneumonitis with
coughing, wheezing, and hemoptysis. Many bronchial neuroendocrine tumors are asymptomatic and are discovered by
routine x-ray films. They may cause bronchial constriction
and arise with a picture of bronchial asthma. Bronchial neuroendocrine tumors are typically associated with paraneoplastic syndromes; they may secrete corticotropin to
produce Cushing's syndrome or growth hormone to produce
acromegaly. Thymic neuroendocrine tumors may also cause
ectopic Cushing's syndrome. Both bronchial and thymic
neuroendocrine tumors may be associated with MEN 1.36
Diagnosis
A specific diagnosis based on clinical suspicion of a neuroendocrine tumor is rare and in our own experience has
been made in only 20% of the patients. The most important
examinations are the serum level of serotonin and the 24-hour
urine collection for 5-HIAA. Because the amount of
hormone secreted varies, multiple assessments may be necessary. When a gastric neuroendocrine tumor is suspected,
serum 5-hydroxytryptophan should be measured instead of
serotonin. In case of rare occasional flushing, pentagastrin
can be infused to prevent flushing and confirm the diagnosis.'?
Location of the neuroendocrine tumor determines whether
endoscopic or radiologic examination is more useful.
Endoscopic examination and biopsy are valuable in bronchial,
gastric, and rectal neuroendocrine tumors. Gastric and rectal
neuroendocrine tumors are often incidental findings when
endoscopy is performed for other reasons. Because neuroendocrine tumors may grow in submucous areas, they may
often be overlooked.
Primary midgut carcinoids are initially generally too
small to be diagnosed with conventional bowel contrast
studies, and localization of these tumors remains a problem.
When patients present with symptoms related to obstruction
or the carcinoid syndrome, the tumors are larger and unfortunately have usually metastasized to the mesenteric nodes
and liver. Computed tomography (CT) scanning is helpful in
FIGURE 86-4. Somatostatin receptor scintigraphy of large ileal

carcinoid tumor with extensive mesenteric infiltration and local
lymph node metastases.
the hormonal hypersecretion can be controlled by somatostatin

analogs (Fig. 86-4).41
Prognosis
FIGURE 86-3. A, Typical mesenteric fibrosis with isolated
structure. B, Typical multiple hepatic metastasis of varying size.
localizing the primary tumor in about 55% of cases.' The

presence of a mesenteric mass with radiating densities is
highly suggestive of mesenteric involvement of a midgut
carcinoid. CT scanning of larger tumors often helps determine
the size of the mesenteric tumor, its relation to the superior
mesenteric artery, and possible extension retroperitoneally
or above the pancreas. CT scanning is therefore recommended
for appropriate planning prior to surgery. For patients with
symptoms of intestinal obstruction, bowel contrast studies
are recommended (Fig. 86-3).38
Somatostatin receptor scintigraphy has an accuracy of
80% and a positive predictive value of 100%. Because of its
high sensitivity and ability to detect local and distant metastases, this examination is considered an essential imaging
procedure.l-" However, this localization study displays
images that are usually inadequate for precise anatomic
details to be of help preoperatively." Positron emission
tomography scanning is recommended for patients whose
neuroendocrine tumor fails to be identified with somatostatin
scanning. Preliminary studies comparing somatostatin
receptor scintigraphy and positron emission tomography
seem to show a higher sensitivity for the latter.v'?
Somatostatin receptor scintigraphy can also predict whether
Primary tumor location and tumor size are the most relevant
prognostic factors. Thus, appendiceal and rectal neuroendocrine tumors are mostly small tumors that almost never
metastasize.w" In contrast, thymus neuroendocrine tumors
arise with distant metastases in about 30%43,44 and gastric
and small intestinal carcinoids in up to 100%.45,46 In gastric
neuroendocrine tumors, pathogenesis also determines prognosis. The multiple carcinoid tumors found in the case of
hypergastrinemia with ECL cell hyperplasia (type I or II)
have a much better prognosis than solitary tumors unassociated with hypergastrinemia (type III).
Tumor size also predicts the risk of metastatic spread in
neuroendocrine tumors, whereas in other gastrointestinal
tumors the depth of tumor invasion is a better prognostic
factor.'? The appendiceal, colon, and rectal neuroendocrine
tumors are mostly small and usually do not metastasize.
Generally, tumors smaller than 1.5 or 2 em have a low risk
of metastatic spread. However, size is less predictive of
prognosis in small intestinal carcinoids. Even tumors smaller
than the critical size of 1.5 ern may have nodal or distant
metastases (Table 86-5).
Identifying molecular alterations or other factors that
categorize patients with aggressive tumors could be of great
clinical value, allowing more aggressive treatment.P In general, all cytosolic and granular markers are found in welldifferentiated endocrine tumors. In poorly differentiated
neuroendocrine carcinomas, however, only cytosolic markers
and synaptophysin are generally widely expressed." The
presence or type of somatic MEN 1 mutation has not been
correlated with disease phenotype and to date has no role
for neuroendocrine tumors in clinical prcgnosis/" Loss of
Neuroendocrine Tumors - -
neuropilin-2 expression in neuroendocrine cells has been

shown to accompany tumor progression in neuroendocrine
tumor.50 Moreover, MIB-l antibody reacts with the Ki-67
nuclear protein associated with cell proliferation and has
been used to profile tumor aggressiveness. Although studies
of Ki-67 have been helpful in assessing the malignant behavior of neuroendocrine tumors, multiparametric approaches
examining the full range of cyclins, cyclin inhibitors, factors
controlling apoptosis, oncogenes, and tumor suppressor
genes are essential to resolve this issue."
The overall survival in all groups of neuroendocrine
tumors is about 50% to 60% at 5 years, 30% to 40% at
10 years, and 25% at 15 years. Five-year survival rate in
patients with a distant metastases is about 20%. Thus,
neuroendocrine tumors have a moderately good prognosis,
and long-term survival is possible even in advanced stages.
Therapy
The predicted prognosis of patients with neuroendocrine
tumors influences therapy. Treatment modalities are numerous, including diverse surgical procedures, chemotherapy,
arterial embolization, hormone antagonists (somatostatin),
and cytokines (interferon-a). Surgery is the treatment of
choice in early-stage tumors to remove the primary tumors
and locoregionallymph nodes. Operations depend on tumor
location, tumor size, and multicentricity. Tumor location is
the most important factor and is strongly correlated with
tumor size. Therefore, the surgical procedures are discussed
according to the location of the tumors.
Besides the presence of lymph node involvement, tumor
histology determines the prognosis of bronchial neuroendocrine tumors. Atypical tumors have a worse prognosis.
The tumor histology and tumor grading are obtained in only
about 70% of tumors by bronchoscopy and bronchial lavage.
Magnetic resonance imaging and CT scanning are used to
identify these tumors as well as delineate tumor growth and
identify lymph node metastases. Because locoregional
tumor spread is encountered in one third of patients, radical
resection is mandatory. Tumor-free margins are essential,
and lymph node dissection should be performed. On the other
hand, surgery should save as much of parenchyma as possible. Therefore, lobectomy with or without bronchoplasty
785
should be the procedure of choice and pneumonectomy the

exception. Bronchoscopic removal with laser coagulation
should be reserved for unfit and high-risk patients. 1,26
Thymic neuroendocrine tumors are extremely rare
tumors and often arise with local invasion and paraneoplastic
syndromes. Thus, the aims of surgery are to resect the tumor
radically and to relieve paraneoplastic symptoms. Radical
resection should be performed even in the presence of
perithymic or vascular invasionfollowed by adjuvant radiation
therapy. For patients with MEN 1 and primary hyperparathyroidism, prophylactic upper thymectomy should be
done during neck exploration because supernumerary
parathyroid glands are found in 15% to 20% of these
patients and it also removes the site where thymus tumors
may develop (especially in men).52,53
In gastric neuroendocrine tumors, surgery may be indicated, depending on their pathogenesis, For solitary or
multiple gastric tumors in the presence of hypergastrinemia
and ECL cell hyperplasia, limited surgical procedures may
be justified. They include endoscopic removal of tumors or
antrectomy to remove the source of gastrin. There is, however,
a certain risk of tumor recurrence despite the return of serum
gastrin to normal. For other gastric neuroendocrine tumors,
radical resection with gastrectomy and lymphadenectomy
should be performed. 54
Duodenal neuroendocrine tumors are extremely rare
tumors that may contain and secrete calcitonin or somatostatin and are often found as polypoid tumors by endoscopy.
Endoscopic removal is justified because the tumors are
small and the depth of invasion can be assessed by endoluminal ultrasonography. Full-thickness wall excision or
resection is necessary for tumors over 4 em in diameter. The
management of these lesions is determined on a case-by-case
basis and dictated by presence of symptoms. 19
Small bowel carcinoid tumors are the most common
neuroendocrine tumors, with increasing frequency from the
jejunum to the ileum. The most important prognostic parameter is the presence of lymph node metastases. There is also
a good correlation of tumor size with locoregional tumor
spread, with a critical size of 1.5 to 2 em. Tumors of 1 em
in diameter or less, however, are capable of metastasis.
Therefore, segmental resection with lymph node dissection
is mandatory. Resection can relieve endocrine tumor symptoms even in the presence of distant metastases. The risk of
short bowel syndrome, which is difficult to manage in combination with the carcinoid syndrome, should always be kept
in mind by the surgeon. 19,38,45,55,56
Appendiceal neuroendocrine tumors are mostly incidental findings, usually smaller than 1.5 em in diameter.
Generally, the tumors are located at the apex and seldom at
the appendiceal base. As a rule, appendectomy is the standard
procedure. If the tumor is located proximally or larger than
2 em, additional partial resection of the cecum with lymph
node dissection may be necessary. For larger tumors or
suspicious lymph nodes, a right hemicolectomy is
indicated. 19,26,42
Neuroendocrine tumors of the colon show a decrease
in frequency from the right to the left colon. Tumor size
is strongly correlated with the incidence of lymph node
involvement, with a critical diameter of about 1.5 to 2 em.
Most of the tumors are larger, so lymphatic tumor spread is
786 - -
Endocrine Pancreas
to be expected. Surgical resection should include the lymphatic drainage similar to that for adenocarcinomas.Wt-"
Rectal neuroendocrine tumors are generally very small
and rarely metastasize. Good access by palpation and proctoscopy presumably leads to early diagnosis, so that in most
cases endoscopic removal or fulguration is sufficient. For
larger tumors between 1 and 2 em or those with deeper infiltration, a transanal excision should be performed, Transanal
endosonography may be particularly useful in this intermediate group to assess tumor extension. A more radical
approach (low anterior resection with total mesorectal excision
or abdominoperineal resection) is restricted to larger tumors
with a higher risk of metastasis. 19,58
Carcinoid Syndrome
Treatment of the carcinoid syndrome is more complicated
because it is often associated with hepatic metastases.
Carcinoid syndrome occurs with 5% of all neuroendocrine
tumors but occurs more often in patients with small bowel
. ids.59Many diifferent approaches, such as liver reseccarcmoi
tion, tumor debulking, radiofrequency ablation, chemoembolization, and liver transplantation, as well as treatment
with somatostatin analogs and interferon-a make it difficult
to choose the optimal therapy. Therapy should be guided by
whether curative or palliative therapy is possible and
whether the endocrine symptoms or the tumor burden is the
problem.
~es~ite
the development of potent drugs for controlling
carcinoid syndrome, surgery is still the treatment of choice
for possible cure. When liver metastases are resectable,
hepatectomy should be performed and the primary intestinal
tumor removed. 45 ,60 ,6 1 Even when hepatic metastases are
diffuse, operative intervention is critical in one or multiple
stages." Tumor debulking can control carcinoid syndrome
and reduce urinary 5-HIAA levels. The occurrence and
severity of the syndrome are clearly related to tumor bulk.
However, the tumor mass must be reduced to 10% to 20% to
control the symptoms when cytoreductive hepatic surgery is
performed.v With the advent of somatostatin analogs, the
role of surgical debulking may be restricted to low-risk
patients with one dominant tumor mass that did not respond
to somatostatin treatment. Liver transplantation for diffuse
hepatic metastases may be considered in selected patients
when extrahepatic metastases have been excluded. 26,63
Methods for in situ destruction of liver tumors (radiofrequency, cryotherapy, or laser ablation) are new alternative
regional treatment options. The long-term survival benefit of
these interventions is not yet known. 60,64 Neither systemic
chemotherapy nor hepatic dearterialization has been
effective in controlling tumor growth and symptoms. 1,65
Chemoembolization with superselective occlusion, however,
co~trols
the tumor burden and symptoms in up to 80% of the
patients for an average duration of 11 months. 66,67
Somatostatin has become the most important drug in the
medical treatment of neuroendocrine tumors. It alleviates
carcinoid syndrome symptoms in about 80% of patients at a
dosage of 200 to 600 ug/day, The duration of remission,
however, is short with a median of 8 to 12 months. Although
biochemical markers transiently decrease in about 70% of
Clinical Syndrome
No Symptoms
Biochemical evaluation
Incidental guiding
at operation
Diagnostic localization
Oncologic resection / "

(exceptions: duodenum,
appendix, rectum)
Hepatic metastases
.
+S,M;!
Hepatic resection
+SMS\
a-IFN + SMS?
Chemoembolization
Octreotide (SMS)
FIGURE 86-5. Therapy for carcinoid tumors, IFN = interferon'

,
SMS = somatostatin,
pati~nts,
tumor size reduction resulting from the antiproliferatrve effect of somatostatin analogs occurs in fewer than
10% of patients. Stabilization of tumor growth, however,
occurs in about 50% of patients with a median response of
about 18 months. 68,69 Somatostatin should be administered
before tumor manipulation, including all operative procedures and catheter embolization. Somatostatin reduces the
risk of severe flushing resulting from massive release of
hormones and kinins.?? Interferon-a inhibits tumor proliferation with short-term relief from the carcinoid syndrome,
Interferon-a alone or in combination with somatostatin
analogs and interferon in combination with fluorouracil may
result ~n a biochemical response in up to 50% of patients,
but evidence of tumor regression is reported in only 10%
to 20% of patients. 1,71 Thus, resection of hepatic metastases
c~ be performed with curative intention or for symptomatic
rehef. Another attractive option is cytoreduction by multimodal therapy (Fig. 86-5). Hepatic radioembolization and
somatostatin receptor-targeted radiotherapy are new
approaches to localized radiotherapy and are under clinical
evaluation."
Summary
Carcinoid tu~ors
are neuroendocrine tumors that frequently
produce vanous hormones and kinins that may cause
characteristic symptoms, including carcinoid syndrome. The
symptoms, treatments, and prognosis depend mostly on the
location and size of the tumor. Surgical resection can be
palliative even when there is metastatic tumor. Somatostatin
analogs can alleviate the symptoms of carcinoid syndrome,
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64. De Vries H, Verschueren RJC, Willemse PH, et aI. Diagnostic, surgical
and medical aspect of the midgut carcinoids. Cancer Treat Rev
2002;28:11.
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patients with advanced carcinoid tumors and islet cell carcinomas. Ann
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66. Therasse E, Breitmayer F, Roche A, et al. Transcatheter chemoembolization of progressive carcinoid liver metastases. Radiology
1993;189:541.
67. Proye C. Natural history of liver metastasis of gastroenteropancreiltic
neuroendocrine tumors: Place for chemoembolization. World J Surg
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gastroenteropancreatic tumors. Gut 1996;38:430.
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71. Oberg K. Chemotherapy and biotherapy in neuroendocrine tumors.
CUIT Opin Oncol 1993;5:110.
Endocrine Emergencies:
Hypoglycemic and
Silvio E. Inzucchi, MD Barbara K. Kinder, MD
Hypoglycemic and hyperglycemic crises are potentially

life-threatening events encountered with sufficient frequency in surgical patients to warrant a comprehensive
understanding of their causes and management. These aberrations of carbohydrate metabolism occur most commonly
in diabetic patients, who are hospitalized and undergo
surgery more frequently than the general population. I To
provide a framework for the understanding of the pathophysiology of these metabolic disorders, we first briefly
review the normal mechanisms of glucose homeostasis and
then discuss these emergencies individually, their clinical
presentations, pathogenesis, and recommended therapy. The
chapter concludes with our approach to the management of
diabetes in the surgical setting.
Overview of Glucose Metabolism

Physiology of Systemic Glucose
Homeostasis
Whole-body glucose homeostasis represents a balance
between glucose supply and glucose disposal (or utilization).
When the supply of glucose exceeds its disposal, blood
glucose concentration rises; when utilization exceeds supply,
glucose levels fall. In normal individuals, this balance is
intricately maintained so that blood glucose remains stable,
typically between 60 and 140 mg/dL, even in the setting of
such disparate stressors as the ingestion of a large, simple
carbohydrate load or a prolonged fast.' In contradistinction,
marked metabolic abnormalities occur when this balance is
perturbed, such as in diabetes mellitus or insulinoma. The
sources of blood glucose include gastrointestinal carbohydrate absorption and de novo hepatic production in the form
of glycogenolysis and gluconeogenesis. The major source
of glucose at any particular time depends on the phase of the
meal cycle. In the postprandial phase, hepatic glucose production is suppressed, with new glucose appearance primarily due
to absorption of digested carbohydrates. Glucose absorption
generally lasts for 2 to 5 hours after a meal, depending on
the caloric content and composition of the meal. The tissues
responsible for glucose utilization include those that require
insulin and those that are insulin independent. The brain is
the organ responsible for most of the insulin-independent
glucose utilization in the fasting state, with erythrocytes and
the renal medulla involved to a lesser extent.
In the postprandial phase, insulin-requiring glucose disposal occurs in many body tissues, most prominently in the
liver and muscle. After nutrient ingestion, insulin secretion
is stimulated directly by a rise in both plasma glucose and
amino acids and indirectly through the action of a variety of
incretins, or intestinal factors that promote insulin secretion.'
In liver and muscle, insulin stimulates storage of glucose
into glycogen and amino acids into protein. In adipose
tissue, insulin stimulates free fatty acid (FFA) incorporation
into triglycerides (TGs). Insulin action is balanced by the
effects of counter-regulatory hormones, most notably
glucagon and catecholamines.v' Both hormones stimulate
hepatic glycogenolysis and gluconeogenesis in the liver,
whereas catecholarnines have additional effects on the
pancreas to inhibit insulin release and on muscle to inhibit
insulin action. In the postabsorptive or fasting phase, the liver
becomes an organ of net glucose production; glycogenolysis
contributes approximately 40% of the new glucose supply
and gluconeogenesis contributes approximately 60%. As the
fast progresses, the percentage of gluconeogenesis contribution rises. By day 3, gluconeogenesis accounts for virtually
all glucose production.t Substrates for gluconeogenesis
include amino acids from catabolized muscle protein, lactate,
pyruvate, and glycerol. In general, the liver is the major
gluconeogenic organ in the body. However, under certain
789

circumstances such as prolonged fasting (lasting longer than
several weeks), the kidney can supply up to 40% of whole body
glucose production." In the postabsorptive phase, circulating
insulin levels are low. At this time, insulin-independent organs
consume about half of the body's glucose production,
whereas other tissues derive most of their energy needs from
fat oxidation (ketone bodies).
Hormonal Regulation of Glucose

Metabolism
The major hormones responsible for glucose homeostasis
are insulin and glucagon, both products of pancreatic islet
cells. Insulin, originally isolated from pancreatic tissue by
Banting and Best in 1921,7 is synthesized in the beta cells of
the islets. The insulin gene is located on the short arm of
chromosome 11. Because of the action of negative regulatory elements found in other tissues, insulin gene expression
and insulin biosynthesis are limited to beta cells as well as
to cells of the fetal yolk sac and liver," Glucose regulates
all aspects of insulin metabolism. In addition to directing
hormone exocytosis, glucose stimulates transcription of the
insulin gene 9 10 as well as certain post-transcriptional events.
The primary RNA transcript of the insulin gene encodes a
prepro sequence, alpha and beta chains, and an intervening
C peptide. Cleavage of the signal sequence on entry of the
nascent protein into the rough endoplasmic reticulum yields
proinsulin. II Although the pancreatic beta cell uses both
constitutive and regulated pathways to deliver its synthetic
products to their proper destinations, under normal circumstances proinsulin is sorted almost exclusively to the
regulated pathway.P Conversion of proinsulin to insulin and
C peptide occurs in the immature secretory granule during
intracellular transport. Proteolytic cleavage takes place in
two steps: first at the beta chain-C peptide junction and
second at the C peptide-alpha chain site. 13 This process of
conversion is accelerated when ambient glucose is elevated. 14
Despite the efficiency of targeting proinsulin to the regulated pathway and of its intragranular conversion, intact
proinsulin and conversion intermediates are detected in the
blood stream." Increased proinsulin-insulin ratios are commonly found in patients with type 2 diabetes mellitus
(T2DM; formerly, non-insulin-dependent diabetes mellitus)
and in some with type 1 diabetes mellitus (TlDM; formerly,
insulin-dependent diabetes mellitus). Although the exact
mechanisms are unknown, evidence supports both abnormalities of proinsulin conversion and rapid granule turnover,
preventing complete proteolysis." Increased proinsulininsulin ratios in patients with insulinoma may be due to
hormone release via constitutive rather than regulated pathways in these transformed cells. 17
The primary stimulants of insulin secretion are glucose
and other energy substrates, such as amino acids. Secondary
stimuli include glucagon, acetylcholine, and various gastrointestinal hormones, such as gastric inhibitory polypeptide
and glucagon-like peptide (GLP), that are capable of potentiating insulin secretion in the presence of a primary agent."
Glucose stimulation of insulin secretion requires the entry of
glucose into the beta cell and its metabolism. Glucose enters
the beta cell via GLUT-2 transporters, and its subsequent
aerobic glycolysis generates several adenosine triphosphate

(ATP)-dependent intracellular signals. Among these, closure
of ATP-sensitive potassium channels results in cell membrane depolarization and the influx of calcium via voltagedependent calcium channels.'? An increase in cytosolic
calcium, in tum, triggers exocytosis by a network of complex protein-protein and lipid-protein interactions similar to
those involved in neurotransmitter secretion and common
to all cellular membrane fusion events."
Glucagon was identified in 1923 as the hyperglycemic
component of canine pancreatic extracts.P The glucagon
gene is located on the long arm of chromosome 2 21 and is
expressed in pancreatic alpha cells, small intestinal L cells,
and certain hypothalamic cells.P Tissue-specific enzymes
permit cell-selective cleavage of preproglucagon into various
peptides such as glicentin (enteroglucagon), oxyntomodulin,
and GLP, but only alpha cells produce glucagon.P Glucagon
is the primary guarantor of cerebral fuel delivery and is
regulated by both glucose and insulin." In the human islet the
different endocrine cell types are arranged in a nonrandom
fashion, with the glucagon-producing alpha cells surrounding a beta-cell core." Glucose acts directly on alpha cells to
suppress glucagon release. In addition, insulin secreted into
the islet microcirculation from centrally located beta cells
potently inhibits glucagon secretion." Glucagon secretion is
also influenced by adrenergic, cholinergic, and peptidergic
innervation of the islets. For example, adrenergic stimulation initiated by exercise immediately stimulates secretion
of glucagon, preventing the development of exercise-related
hypoglycemia. During feeding, cholinergic and peptidergic
signals, amplified by the effects of various gastrointestinal
hormones, regulate the release of glucagon as nutrient
absorption begins.??
Despite circulating glucose levels in the low-normal range,
insulin secretion continues at a basal rate during fasting.
Within minutes of a carbohydrate meal, a prompt rise in
pancreatic insulin secretion, with a concomitant decline in
glucagon production, is observed. Postprandial (mixed-meal)
glucose excursions are thus maintained within a relatively
narrow window of +20 to 30 mg/dL. 28 By 180 minutes,
insulin levels have returned to baseline. Subsequent caloric
intake will result in similar fluctuations of these hormones,
depending on the size and nutrient composition of a particular meal. In patients with established TlDM, insulin is no
longer released to any significant degree. In T2DM, insulin
secretion is variable. However, because most of these
individuals demonstrate cellular insulin resistance, fasting
insulin levels are typically elevated early in the course of
disease." With carbohydrate challenge, insulin secretion is
further augmented, although the rise is comparatively delayed
and prolonged. As T2DM progresses, insulin secretory
capacity declines, although rarely to the extent demonstrated
in TlDM. In patients with postabsorptive hypoglycemia, as
occurs in insulinoma, inappropriate hyperinsulinemia is the
rule. A pathologically high degree of insulin secretion persists despite low ambient circulating glucose levels.'? In
addition, defective secretion of counter-regulatory hormones
has also been demonstrated in these patients." In those affected
by postprandial or reactive hypoglycemia, insulin secretion
may be inappropriately exuberant in response to meals,
although in the fasting state it is appropriately attenuated"
Endocrine Emergencies: Hypoglycemic and Hyperglycemic Crises - -
A mismatch between glucose supply and disposal leads to
clinical syndromes. Such defects in glucose homeostasis
occur because of alterations in nutrient absorption, storage,
or release.This may be a result of dysfunction of the pancreas,
gastrointestinal tract, liver, skeletal muscle, or endocrine
glands, such as the pituitary and adrenals, that is responsible
for the secretion of counter-regulatory hormones. In most
surgical patients, hyperglycemic or hypoglycemic crises are
primarily due to inadequate or excessive insulin secretion
or administration, accompanied by failure of compensatory
mechanisms. These medical emergencies and their treatment
in adult patients are reviewed.
Diabetic Ketoacidosis
CLINICAL PRESENTATION AND PATHOGENESIS
By definition, diabetic ketoacidosis (DKA) exists when the

plasma glucose level is higher than 250 mg/dL, whole blood
pH is 7.30 or less, serum bicarbonate is 18 mEq/L or less,
anion gap is greater than 12 mEq/L, and serum or urine
ketones are identified" Symptoms include polyuria, polydipsia, nausea, vomiting, abdominal pain, and alterations
in mental status. Physical signs include volume depletion
(hypotension, tachycardia, decreased skin turgor, dry
mucous membranes), ketosis (fruity odor to breath), and
metabolic acidosis (Kussmaul's respirations, ileus). This
potentially life-threatening condition results from severe
insulin deficiency or, rarely, from marked augmentation
of counter-regulation in an insulin-resistant patient. It is a
common presentation in individuals with TlDM. Other precipitating factors include omission of insulin administration
and the development of an intercurrent illness, such as a
superimposed viral or bacterial infection. DKA may also
occur in TIDM patients being treated with continuous
subcutaneous (SC) insulin infusion via an external insulin
pump." In this situation, because there is no SC depot of
intermediate- or long-acting insulin, plasma insulin levels
decrease quickly if pump delivery is interrupted for any
reason or if provision for increased delivery is not made in
the case of an intercurrent illness. DKA is uncommon in
individuals with T2DM, because these patients, although
frequently markedly hyperglycemic, typically produce
enough insulin to avoid this catabolic state. When DKA
occurs in T2DM, an underlying significant physical stress,
such as severe infection, fulminant pancreatitis, or myocardial infarction, is almost always involved.
Three factors are involved in the pathogenesis of DKA:
(1) failure of insulin release (or administration); (2) increase
in the secretion of counter-regulatory hormones; and
(3) superimposed dehydration. Determination of circulating
C-peptide levels (as a measure of insulin release) has confirmed decreased insulin secretion in patients with DKA
compared with those with hyperglycemic, hyperosmolar
syndrome (HHS) (see following discussion)." Although an
increase in the levels of counter-regulatory hormones is not
absolutely required for the development of DKA, these
do exacerbate the diabetic state by increasing glucose
production and contributing to negative nitrogen balance."
791
The third factor, dehydration, although more prominent in

HHS, also helps define the clinical picture of DKA.
In DKA, marked alterations occur in carbohydrate, lipid,
and protein metabolism, as shown in Figure 87-1. The
absolute or relative decrease in insulin availability and an
increase in counter-regulatory hormones result in a generalized catabolic state, with enhanced hepatic gluconeogenesis
and glycogenolysis, augmented lipolysis, and negative nitrogen balance. The proposed biochemical changes responsible
for the alterations of intermediary metabolism in DKA
are shown in Figure 87-2.33Both glucagon and catecholarnines
stimulate liver and muscle phosphorylases, initiating the
process of glycogenolysis. In the liver, increased gluconeogenesis occurs with activation of a series of rate-limiting
enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-biphosphatase, and glucose-6phosphatase (G-6-Pase). Activation of G-6-Pase by glucagon
facilitates conversion of glucose-6-phosphate (G-6-P) to
glucose. As a result, metabolism of G-6-P by glycolysis and
via the hexose monophosphate shunt is correspondingly
reduced. In adipose tissue, a lack of insulin and increased
circulating catecholamines combine to accelerate TG
metabolism into glycerol and FFAs. The former is a substrate for gluconeogenesis, and the latter are oxidized to
ketone bodies (~-hydroxybutyrate
and acetoacetate), which,
as unmeasured anions, result in the hallmark nonanion gap
metabolic acidosis.
Somewhat paradoxically, hypertriglyceridemia may be
seen in DKA36 because of new TG synthesis from increased
circulating substrates in the form of FFAs. In addition,
increased production of the TG-rich very-low-density
lipoproteins (VLDLs) by the liver and decreased VLDL
clearance as a result of decreased activity of lipoprotein
lipase are demonstrated. Negative nitrogen balance results
from decreased protein synthesis and increased proteolysis.
Metabolic acidosis results from the titration of protons
of ketoacids by bicarbonate." Once therapy is initiated, a
pure hyperchloremic metabolic acidosis may also develop,
resulting from extracellular space expansion with sodium
chloride (NaCI) and concurrent renal changes. In the hours
to days leading up to the marked metabolic changes of
DKA, significant water and electrolyte losses occur primarily because of osmotic diuresis. At presentation, total body
water, sodium, and potassium are depleted, with deficits in
some cases approaching 5 to 8 L, 400 to 700 mEq, and
250 to 700 mEq, respectively. This results in a contracted
intravascular space, decreased renal perfusion, a fall in
glomerular filtration rate, and reduced renal clearance of both
glucose and ketones. Both hyperglycemia and acidosis are
thus potentiated. In severe cases, hypotension and vascular
collapse may ensue-"
THERAPY
Once the diagnosis of DKA is confirmed, treatment is initiated as outlined in Figure 87-3. Because of the gravity of
this condition, treatment is best provided in a setting that
affords close and expeditious monitoring of the clinical
status, such as a medical intensive care unit. A loading dose
of 10 units of regular insulin is given intravenously (IV)
followed by a continuous IV drip of 5 to 10 units/hr. In mild
cases, frequent SC doses may be given, although more rapid
792 - -
Endocrine Pancreas
Glycogen
CG-1-P
4IG-6Jll1osphatase I
Glucose <II(
G-6-p--"IHMPshuntl
HK
- - - - - - - - - 7 ' ' - - -..... PFK
TG---.....;.-----i~
PK
Fatty
F-6-P ~
.-/
Triacylglycerol
(Hyperlipidemia)
IGlycolysis
PFK
F 1,6,bi~osPhate
... Keto enesis
2IPEPCKI~PEP~
Citrate
Synthetase
Triose P04
Oxaloac tate
Pyruvate
1 arbox las
Citrate
P ruvate Kinase
Pyruvate
~ ITCA Cycle
FIGURE 87-1. Proposed biochemical changes that occur during diabetic ketoacidosis. These alterations lead to increased gluconeogenesis and lipolysis and decreased glycolysis. Note that lipolysis occurs mainly in adipose tissue. Other events occur primarily in the liver
(except some gluconeogenesis in the kidney). ATP =adenosine triphosphate; CoA =co-enzyme A; FFA =free fatty acids; F-6-P =fructose6-phosphate; G-(X)-P = glucose-(X)-phosphate; HK = hexokinase; HMP = hexose monophosphate; PC = pyruvate carboxylase;
PFK =phosphofructokinase; PEP =phosphoenolpyruvate; PEPCK =PEP carboxykinase; PK =pyruvate kinase; TCA =tricarboxylic acid;
TG = triglycerides. (From Kitabchi AB, Fisher JN, Murphy MH, et al. Diabetic ketoacidosis and the hyperglycemic, hyperosmolar
nonketotic state. In: Kahn CR, Weir GC reds], Joslin's Diabetes Mellitus, 13th ed. Philadelphia, Lea & Febiger, 1994, p 738.)
and precise dosing is possible with the IV route. In the early

stages of DKA, if there is profound dehydration, absorption
from SC tissues may be unreliable. Rehydration with 0.9%
IV NaCI is begun as soon as possible. When the clinical
examination and laboratory indexes suggest repletion of the
intravascular space, or if hypernatremia develops, a solution
containing more free water, such as 0.45% NaCI, is used.
Glucose is measured hourly; electrolytes, arterial blood
gases, and serum ketones are measured every 2 to 4 hours
until stabilized. Once the blood glucose level falls to less
than 250 mg/dL, which typically occurs within the first
12 to 24 hours, the insulin dosage is lowered to I to 2 units/hr
and is given simultaneously with IV dextrose solution in
water (usual ratio, 5 g of dextrose to 1 unit of insulin) in
an effort to "clamp" the blood sugar in the low-200-mg/dL
range. This provides enough insulin to suppress lipolysis;
acidosis and ketonuria clear over the ensuing 24 to 36 hours.
Once this occurs, and the patient is tolerating oral feeding,
the insulin regimen is changed to the SC route. The recrudescence of acidosis and ketonuria is frequent after IV insulin
is discontinued. This results from relative insulinopenia
during the transition between rapidly cleared IV insulin and
the onset of action of the first SC injection. We therefore
recommend that the insulin drip be continued for several
hours after the initial SC dose, depending on its type
and amount. SC therapy is typically initiated with two daily

doses of intermediate-acting insulin (e.g., neutral protamine
Hagedorn [NPHD, with more frequent "coverage" with
short-acting regular (R) insulin or with one of the rapidacting insulin analogs (e.g., lispro, aspart). Coverage only
with short-acting insulins is not advised, since the use of
insulins with longer durations of action stabilizes blood
glucose levels to a greater degree. The total daily dose of
insulin should approximate 0.5 unitslkg. Two thirds of this
amount should be given as NPH, which is typically divided
as two thirds before breakfast and one third before the
evening meal or before sleep. The remainder should be
administered as R (or lispro or aspart) on a variable scale
based on the glucose reading, and injected three times a day
before meals; in those patients who are not yet eating, shortacting insulins are instead administered every 6 hours).
At this point, blood glucose is monitored 4 to 6 hours,
depending on the patient's status and response to therapy.
Once the glucose is reasonably well controlled 200 mg/dL),
the patient may continue this regimen or be transferred to a
more conventional and convenient "split-mixed" regimen to
be used at home (i.e., NPH and R before breakfast and supper).
More meticulous regimen, such as ones using the combination
of rapid-acting prandial insulins and long-acting basal insulin
analogs (e.g., glargine, detemir) (i.e., four injections per day)
793
FIGURE 87-2. Left. Substrate utilization

in the fed state showing the role of insulin
in the promotion of fuel storage. Right.
Metabolic alterations in diabetic ketoacidosis (DKA). Insulin deficiency and
elevation of counter-regulatory hormones
activate
ketogenic,
gluconeogenic,
glycogenolytic, and lipolytic pathways.
(Left and Right. From Kitabchi AE,
Fisher JN, Murphy MB, et al. Diabetic
ketoacidosis and the hyperglycemic,
hyperosmolar nonketotic state. In: Kahn
CR, Weir GC reds], Joslin's Diabetes
Mellitus, 13th ed. Philadelphia, Lea &
Febiger, 1994, p 738.)
or continuous SC insulin infusion (insulin pump) may also

be considered in highly motivated and compliant patients.
The ultimate goal is to maintain blood glucose at as near a
physiologic range as possible while avoiding hypoglycemia.
In certain patients, such as the very young and elderly, those
with significant cardiovascular or cerebrovascular disease,
and those with hypoglycemia unawareness, more conservative
goals are preferable.
Patients with DKA typically present with hyponatremia
because of dilution of the extracellular compartment from
intracellular water resulting from the osmotic effects of
hyperglycemia." This corrects with the administration of
insulin and isotonic solution. Hyperkalemia is common on
presentation despite the fact that most patients with DKA, as
previously noted, have a total body potassium (K+) deficit."
An initial osmotic diuresis promotes inappropriate urinary
K+ losses. K+ excretion may eventually become impaired,
however, in the setting of significant intravascular depletion.
In addition, acidemia results in an intracellular shift of
hydrogen ions, with a counterbalancing flux of K+ into the
extracellular space to maintain electrical neutrality. As the
acidosis is corrected, as plasma volume is expanded, and as
insulin is administered, serum K+ routinely falls. We do not
recommend providing Kt-containing solutions until the
serum K+ is in the normal range and adequate urine output
is secured. Bicarbonate should not be given except in
cases of severe acidosis (pH < 6.9 to 7.0) and then only to
partially correct the pH to greater than 7.0. 40 Finally,
hypophosphatemia is common after the first 24 to 48 hours

of treatment, although initial hyperphosphatemia may be
manifest." If the phosphate falls below normal, oral or IV
phosphorus replacement is required.
A search for an underlying illness that may have precipitated the DKA is important in all patients. This is best
performed with a careful physical examination and select
laboratory tests, such as routine chemistries, complete blood
count, urinalysis, and electrocardiogram. If the patient is
febrile, urine and blood cultures must be obtained, and
strong consideration should be given to empiric antibiotic
coverage pending results. Further testing should be directed
by physical or laboratory findings. Abdominal pain, often
severe and accompanied by ileus, is common. Good diagnostic skills, with measurement of hepatic and pancreatic
enzymes, are essential to rule out an underlying abdominal
catastrophe. An elevated amylase level is commonly noted
in DKA and may add to the confusion (lipase is usually normal
unless there is superimposed concomitant pancreatitisj.f
Hyperglycemic, Hyperosmolar Syndrome

CLINICAL PRESENTATION AND PATHOGENESIS
HHS is defined as severe hyperglycemia (blood glucose>

600 mg/dL), increased serum osmolality (effective serum
osmolality> 320 mOsm/kg H 20 ), and dehydration without
significant acidosis (serum bicarbonate> 15 mEqlL, anion

gap < 12 mEqlL, arterial pH > 7.30) or ketosis." Typically,
HHS occurs in elderly patients with a history of T2DM.
There is usually a more protracted history of polyuria, polydipsia, and blurring of vision and a gradual decline in overall status, occurring over days to weeks. Central nervous
system signs are more frequent in this syndrome than in
DKA, especially changes in mentation, lethargy, and, occasionally, frank coma. Dehydration is more severe, with
volume deficits in the 8- to IO-L range." As in DKA, the
volume depletion itself accentuates the hyperglycemia
because of alterations in renal clearance. Although epidemiologic studies are limited, data indicate that mortality is
increased in HHS compared with DKA.33 Whether this is
due to the more advanced age and worse health status of
patients with HHS or the intrinsic risk of more profound
volume depletion is unclear.
Several proposals have been made to explain the physiologic differences between HHS and DKA. First, some studies
have shown that higher levels of counter-regulatory hormones
and FFAs are found in DKA, although contrasting opinions
certainly exist. Second, the higher levels of insulin seen in

patients with HHS may be adequate to prevent lipolysis (and
ketogenesis) although not gluconeogenesis." Finally the
hyperosmolar state itself may prevent ketogenesis by
inhibiting lipolysis.
THERAPY
A treatment strategy for HHS is delineated in Figure 87-3.
As in DKA, patients with HHS are inherently unstable and
require close monitoring, sometimes in an intensive care
environment. Although these individuals have relatively
inadequate levels of insulin, the chief deficit is that of
volume. We recommend an initial administration of I to 2 L
of 0.9% NaCl followed by the administration of 5 to 10 units
of IV insulin.
If insulin is given before volume expansion, the resultant
intracellular glucose flux may further deplete the extracellular space, leading to further hypotension. An insulin drip
may be used, similar to that in the treatment of DKA,
although these patients, once volume is expanded, usually
Glucose> 600
Effective serum osmolality >320 mOsm/kg H2O
pH> 7.30
HCOa> 15
Ketones < 1:2
I DKA
Insulin I
10 U IVB
0.9% NaCI IV
@200-300 mUh
Insulin
5-10 U/h IV
Follow K+
and P, replete
IVor PO
Once BG < 250,

"clamp" at
200-250 w/insulin
1-2 U/h IV +
DsW 100-200 mUh
Once plasma
volume
expanded,
h.IV to
0.45% NaCI
to SC insulin after:
1. acidosis resolved,
2. ketones cleared, and
3. tolerating PO
~
Glucose> 250
pH:s; 7.30
HCOa:S;18
Ketones > 1:2
1000-2000 mL
0.9% NaCllVB
Hyperglycemic patient
NaCHOalV
if pH
< 6.9-7.0
I HHS I
0.9% NaCllVB
Follow K+
and P,
replete
IV or PO
Insulin
5-10 U/h IV
(or SC by
scale q6h)
0.9% NaCI IV
@100-200 mL/h
Once plasma
volume
expanded,
h.IVto
0.45% NaCI
Insulin
5-10 U IVB
1 1000-2000 mL I
~
to qd-bid insulin
(or oral agent) after:
1. volume repleted,
and
2. tolerating PO
FIGURE 87-3. Algorithm for the management of hyperglycemic crises.HC0 3 =bicarbonate radical; DKA =diabeticketoacidosis; HHS =
hyperglycemic, hyperosmolar syndrome; NaCI = sodium chloride; IYB = intravenous bolus; K+ = potassium; P = phosphorus; IV = intravenous; PO = by mouth; NaHC03 = sodium bicarbonate; SC = subcutaneous; BG = blood glucose; DsW = dextrose 5% in water; qd =
everyday; bid = twice a day.
795
do well with the frequent administration of SC short-acting

insulin. As in DKA, patients should be carefully examined
for clues of precipitating factors, such as infection. The
metabolic abnormalities are usually corrected within 24 to
48 hours, whereas the volume deficits may take longer to
normalize in elderly patients, who often have underlying
cardiovascular disease. Many of these individuals do best on
a similar split-mixed regimen, although in selected patients
more conservative approaches are possible, such as oral
antihyperglycemic agents (sulfonylureas or other insulin
secretagogues (i.e. meglitinides), biguanides, thiazolidinediones, or a-glucosidase inhibitors), one to two injections of
intermediate-acting insulin alone, or oral agents and insulin.
However, the development of HHS usually implies significant insulin deficiency, and, as a result, aggressive regimens
and close follow-up are typically necessary.
Hypoglycemic Crises
Hypoglycemia, defined as a blood glucose level less than
50 mg/dL, occurs in a wide variety of clinical settings."
This results from a failure of the normal homeostatic mechanisms previously discussed to achieve a balance in glucose
production and utilization.
In normal subjects, as plasma glucose decreases below
the physiologic range, the counter-regulatory hormones
epinephrine and glucagon are released followed by growth
hormone and, ultimately, cortisol. Signs and symptoms of
hypoglycemia are categorized as adrenergic and neuroglycopenic in origin." The glycemic threshold for epinephrine
release is higher than that for neuroglycopenic symptoms
and is reproducible for a given individual, although there is
considerable variability between subjects." The physical
sequelae of epinephrine release in response to hypoglycemia
include pallor, diaphoresis, tachycardia, nausea, and anxiety.
Because glucose is the preferred energy source for the central
nervous system, neuroglycopenic symptoms reflect cerebral
fuel deprivation. Symptoms include personality and behavioral changes, headache, lethargy, seizures, and coma. The
brain can also use ketone bodies as energy sources, but these
are usually in scarce supply in the fed state and do not rise
to significant levels until fasting has continued for many
hours. In addition, insulin decreases ketones by suppressing
lipolysis and promoting ketone utilization by peripheral
tissues. Because no alternative neural energy substrates are
available in hyperinsulinemic patients, the diabetic patient
who has taken too much insulin and the patient with an
insulin-secreting tumor are both at increased risk for hypoglycemic neurologic complications.f
From a practical standpoint, hypoglycemic disorders
are classified by the temporal setting: either postprandial or
fasting. A differential diagnosis is displayed in Table 87-1.
Because hypoglycemic symptoms are nonspecific, the first
goal is to document the presence of an abnormally low
blood glucose. Whipple's triad is defined as the presence of
symptoms consistent with hypoglycemia, documentation of
low glucose when symptoms occur, and resolution of symptoms with glucose repletion. Measurement of blood glucose
should specify whether the sample is whole blood or plasma.
In general, glucose should not be measured on serum because
of glucose consumption by erythrocytes. Samples for whole

blood or plasma glucose determination are collected in tubes
containing oxalate and fluoride, which inhibit glycolysis.
Frequently, capillary finger prick tests are used. However,
capillary glucose levels are 7% to 8% higher than in venous
blood, except in severely hypotensive patients, in whom they
may be lower, falsely suggesting hypoglycernia." Glucose
meters and reagent strips may yield falsely low glucose
values for technical reasons because they are intrinsically
more reliable in the hyperglycemic range. In general, these
convenient methods of glucose determination may be used
to exclude hypoglycemia, and low glucose readings should
be interpreted with caution."
Postprandial Hypoglycemia
Postprandial hypoglycemia occurs 1 to 5 hours after food
consumption and not during fasting. Normal blood glucose
in patients with postprandial symptoms implies a nonhypoglycemic disorder. The postprandial hypoglycemias include
alimentary hypoglycemia and reactive (idiopathic) hypoglycemia.
ALIMENTARY HYPOGLYCEMIA
Alimentary hypoglycemia typically occurs in postgastrectomy patients, approximately 30 to 60 minutes after eating,
and is manifested by both adrenergic and neuroglycopenic
symptoms. Its cause may be related to the loss of the reservoir
function of the stomach, with rapid absorption of glucose,
excess release of insulin, with a mismatched hypoglycemic
effect.t" Studies have raised the possibility of disordered secretion of insulin-stimulating gut peptides in this
syndrome." The diagnosis can be made in the appropriate
patient by measurement of blood glucose when symptoms
appear or by a glucose tolerance test. Because the symptoms
796 - -
Endocrine Pancreas
may be severe, the test must be carefully supervised and

terminated early if necessary. Alimentary hypoglycemia can
be effectively treated with multiple small feedings and
avoidance of concentrated sweets.
REACTIVE HYPOGLYCEMIA
Although a popular diagnosis in the past for a variety of

somatic complaints, from fatigue and depression to anxiety
and palpitations, reactive (or idiopathic) hypoglycemia is,
in fact, extremely uncommon.t" However, the use of the oral
glucose tolerance test to diagnose this disorder is controversial. Marked hypoglycemia (glucose < 45 mg/dL) occurring
2 to 5 hours after ingestion of a large glucose load (75 g)
that reliably reproduces symptoms may be helpful. However,
there is a great deal of variability in the response to this
stimulus in normal individuals. Indeed, when symptomatic
patients are tested rigorously, their symptoms often do not
correlate with decreases in blood glucose.F Thus, in many
patients, no definitive therapy exists. Abnormalities in circulating levels of neuroactive compounds have been described
in some patients with "postprandial syndromev'" although
the significance of this remains unclear. When it is reliably
diagnosed, true reactive hypoglycemia can be managed
by avoiding concentrated sweets and by frequent, small
feedings rich in complex carbohydrates and proteins.>'
Reactive hypoglycemia may also occur in patients predisposed to T2DM, possibly related to delayed and prolonged
insulin secretion from partially compromised beta cells.
Sometimes seen in patients years before the diagnosis of
diabetes, this syndrome may be an early indicator of islet
dysfunction.
Fasting Hypoglycemia
If evaluation confirms the presence of hypoglycemia during
fasting, different and generally more worrisome clinical
entities must be considered. It is first necessary to determine
whether the process is exogenous or endogenous in origin.
If endogenous, insulin-mediated and insulin-independent
processes must be distinguished. All the causes of fasting
hypoglycemia, when severe enough, may also be responsible for postprandial decreases in blood glucose.
Exogenous Causes
Diabetes mellitus accounts for most cases of hypoglycemia
seen in hospital emergency departments'" and is also the
most common cause in the surgical patient. Because diabetic
treatments such as insulin injections and oral insulin
secretagogues such as sulfonylureas result in an unregulated
increase in circulating insulin levels, patients so treated and
their physicians must ensure adequate and regular nutritional
intake to maintain glucose levels in a safe range. To complicate matters, many diabetic patients with recurrent hypoglycemia suffer from "hypoglycemia unawareness," resulting
from abnormal adrenergic response to a falling blood
glucose. 56 Insulin reactions related to diabetes therapy are
frequently seen in the hospitalized patient, when a patient's
insulin or oral agent dose is not adjusted to nutritional intake.
A common scenario is that of a diabetic patient who experiences a rapidly improved glycemic profile once placed on
a more regimented hospital diet. If medication dose is not

appropriately altered, hypoglycemia may ensue. In addition,
certain drugs that are highly protein bound when added to
a stable sulfonylurea regimen may promote increased free
levels of the hypoglycemic agent, with resultant decreases
in ambient glucose. Treatment-associated hypoglycemia is
frequently encountered in diabetic patients with renal failure, because of poor nutritional intake and decreased insulin
clearance.
In nondiabetics with hypoglycemia, it is important to
exclude the surreptitious use of insulin or an oral hypoglycemic agent. Exogenous insulin administration is best
confirmed by the simultaneous measurement of insulin,
glucose, and C-peptide levels as a measure of endogenous
insulin secretion. In the hypoglycemic patient receiving
exogenous insulin, the C-peptide level is discordantly IOW. 45
Abuse of sulfonylurea hypoglycemic agents can be detected
by the presence of circulating or urinary sulfonylurea
compounds.
In addition to insulin and the sulfonylureas, a variety of
drugs (see Table 87-1) are associated with the development
of hypoglycemia, especially in metabolically compromised
patients such as the very young and elderly, the malnourished, and those with hepatic or renal disease. 57 Among
the most important of these is alcohol. Alcohol-induced
hypoglycemia typically occurs in settings in which caloric
intake is otherwise restricted, during which time hepatic
glycogen stores may be depleted in 1 to 2 days. Maintenance
of blood glucose levels becomes wholly dependent on
gluconeogenesis, which is itself inhibited by alcohol, via
alterations of the hepatic cytosolic ratio of the reduced form
of nicotinamide-adenine dinucleotide to the whole form
of nicotinamide-adenine dinucleotide. In addition, alcohol
depresses hepatic uptake of lactate, alanine, and glycerol.
Other exogenous causes of hypoglycemia should be
excluded by a careful history and biochemical evaluation
when indicated.
Endogenous Causes
INSULIN MEDIATED
Fasting hypoglycemia in an otherwise healthy patient raises

the possibility of an insulin-secreting islet cell tumor. This
topic is discussed in detail elsewhere in this text. The biochemical diagnosis of insulinoma is made on the basis of
fasting hypoglycemia (glucose < 45 mg/dL) accompanied
by inappropriate hyperinsulinemia (insulin> 5 to 6IlU/mL).
Exogenous administration of hypoglycemic agents must
be excluded. Determination of plasma C-peptide levels
confirms an endogenous source of insulin production."
Nesidioblastosis, the diffuse proliferation of pancreatic islet
cells, has been implicated as a rare cause of hyperinsulinemic
hypoglycemia in adults." Optimal methods of diagnosis and
treatment remain controversial.
INSULIN INDEPENDENT
A variety of systemic illnesses are associated with hypoglycemia in the setting of appropriately suppressed circulating levels of insulin. Hypoglycemia may be encountered in
sepsis, severe hepatic dysfunction, renal insufficiency, and
severe and prolonged nutritional deficiency. 3DIt may also be
seen in a variety of endocrine disorders. Fasting hypoglycemia occurs in Addison's disease as a result of the
absence of cortisol, which has a key role in stimulating
hepatic glucose production. Hypopituitarism may lead to
hypoglycemia because of underproduction of both corticotropin and growth hormone. Hypoglycemia may also
occur in isolated growth hormone deficiency states
(although almost exclusively in the pediatric population).
Autoimmune hypoglycemia results from antibodies to
either the insulin receptor or to insulin itself." Insulin receptor antibodies cause hypoglycemia in some patients (receptor
activation) and insulin resistance in others (receptor blockade), possibly as a function of the titers of antibody produced. Insulin secretion is usually decreased, but circulating
levels may be increased as a result of failure of receptormediated endocytosis, an important mechanism of insulin
clearance.59 Antibodies to insulin may develop spontaneously,
particularly in patients with early insulin-dependent diabetes
mellitus or with other autoimmune diseases such as systemic lupus erythematosus and Graves' disease. In these
circumstances, C-peptide levels are not suppressed as they
are in patients with surreptitious insulin administration.
Hypoglycemia is usually reactive, reflecting the delayed
effect of insulin as it dissociates from the antibodies, but can
occur in fasting states.
Hypoglycemia occurs as a manifestation of some non-islet
cell tumors. The clinical presentation mimics that of insulinoma. Tumors are usually large, indolent, and of mesenchymal
origin. Research has determined that the mechanism of
hypoglycemia in most of these neoplasms involves the
secretion of insulin-like growth factor (IGF).60 IGF-II is
structurally homologous to insulin. It promotes glucose utilization and also inhibits growth hormone secretion, thus
decreasing hepatic glucose output (Fig. 87-4). Normal or
modestly elevated circulating IGF-II levels in the presence
Uncontrolled
Tumor Production
of IGF-II
Le ~ dS ~
Decreased Growth
Hormone secretion
Increased
Glucose
Utilization
~
,
Decreased:
Hepatic GlucoseOutput
IGF-I Production
Synthesisof IGF
Binding Proteins
Tumor-Induced
Hypoglycemia
FIGURE 87-4. Mechanism of tumor-induced hypoglycemia.

IGF = insulin-like growth factor.
797
of low plasma IGF-I levels in a patient with insulinindependent hypoglycemia suggests this diagnosis."
Hypoglycemia is also occasionally associated with other
tumors without elevated IGF-II levels. The origin of the
hypoglycemia is unclear in these cases but may be due, in
part, to increased glucose utilization by the neoplasm.
Treatment
In the patient presenting with coma or mental status changes
consistent with hypoglycemia, immediate administration
of IV glucose (50 mL of 50% dextrose solution or 25 g of
dextrose) is indicated pending results of plasma glucose
levels. (Intramuscular glucagon injection is often helpful
in unresponsive diabetic patients when IV access cannot be
secured, such as in the home setting.) Improvement in
mentation usually occurs within several minutes, although
occasionally a second bolus of dextrose is required. The
patient is then maintained on an IV drip of 5% to 10% dextrose in water and, when able, provided carbohydrates
orally. In patients with symptomatic hypoglycemia who are
cooperative with oral feeding, rapidly absorbed concentrated sweets containing 15 to 20 g of carbohydrates may be
administered. Those patients with reactive hypoglycemia
are typically initially helped by such treatment, although
rapidly absorbed simple sugars may set into motion another
cycle of insulin release followed by recurrent hypoglycemia.
In diabetic patients suffering from medication-induced
hypoglycemia, future doses of insulin or oral agents must be
appropriately adjusted.
The cause of proven hypoglycemia is determined when
the patient's acute condition is stabilized. In many patients
with fasting hypoglycemia secondary to endogenous hyperinsulinism, treatment with diazoxide suppresses insulin
secretion and normalizes blood glucose. This maneuver is
temporizing until more definitive therapy, such as resection
of the responsible insulinoma, is carried out. In certain
tumors that elaborate IGF-II, resulting in severe hypoglycemia, continuous feeding by IV or by nasogastric tube
may be necessary pending more definitive antitumor
therapy.
Perioperative Management of
the Diabetic Surgical Patient
Patients with diabetes undergo surgery more frequently than
the unaffected population. I The most common procedures
typically involve lengthy operative time and hospital stays,
such as cardiac and peripheral vascular surgery. In addition
the neuroendocrine stress response to surgery and anesthesia result in the secretion of counter-regulatory hormones
that lead to peripheral insulin resistance, hepatic glucose
production, decreased insulin secretion, and lipolysis and
proteolysis. Because of the inherent temporary alterations
in nutritional intake perioperatively and postoperatively,
judicious diabetes management is important. This becomes
of particular concern during lengthy surgeries that involve
general anesthesia because of the patient's unconscious
state. In addition, these patients may be more prone to postoperative infections, especially if ambient glucose is high.

In patients with TlDM, withholding insulin leads to the
development of ketosis, adding to the nutritional and electrolyte problems that often accompany surgical illness. In
these individuals, it is important to provide a certain amount
of insulin at all times, even during fasting. This is most
easily done with the IV coadministration of 5% dextrose in
water (l00 to 200 mLlhr) and R insulin (l to 2 unitslhr)
begun the evening before surgery. Ambient blood levels are
maintained between 100 and 150 mg/dL. Blood glucose is
monitored every 1 to 2 hours before surgery and hourly
during surgical anesthesia to optimize metabolic control.
More commonly used methods, such as providing one half
to two thirds of the usual intermediate insulin dose on the
morning of surgery, may be adequate. However, this method
results in a peak of insulin action, which will not necessarily
coincide with a planned meal. In addition, insulin absorption
from SC tissues may be altered during surgery because of
peripheral vasoconstriction. Thus, smoother glycemic
control is afforded with the IV technique. Postoperatively,
IV insulin is continued until the patient is eating, at which
time the preoperative regimen may be reinstituted. Blood
glucose monitoring should continue four times daily to coincide with meals and night-time snack, so that a variable dose
of R insulin can be administered as "coverage," thus
allowing for tighter control during this important time.
Postoperatively, the goal should be to maintain blood
glucose in the 90 to 130 mg/dL range preprandially and no
higher than 160 to 180 mg/dL postprandially. This minimizes the added risks of fluid and electrolyte shifts associated with hyperglycemia. In addition, euglycemia may
enhance wound healing and immune function, allowing
for shortened recovery time and decreased risk of nosocomial infection. 62 .63 A recent randomized trial in critically
ill postoperative patients showed that meticulous blood
glucose control (80 to 110 mg/dL) using IV insulin infusion
significantly reduced length of intensive care unit stay and
mortaliry.f
In T2DM patients, a less aggressive approach may be
successful. (Glucose targets should be the same, but,
because they are not absolutely insulin deficient, many
patients with T2DM are able to maintain euglycemia or
near-euglycemia when they are fasting.) With those patients
on oral agents, the medication is withheld on the day of
surgery. If there is a considerable wait before the procedure,
coverage with small amounts of R insulin will suffice, with a
continuous IV drip of 5% dextrose in water (50 to 100 mLIhr).
For those being treated with insulin, administering a fraction
(one half to two thirds) of the usual morning NPH dose
may be adequate, although the limitations of this custom, as
previously discussed, should be considered. Continuous
IV insulin may also be indicated for this group of patients,
particularly those with critical illness with stress hyperglycemia.
Summary
In most surgical patients, hyperglycemic or hypoglycemic
crises are due primarily to inadequate or excessive insulin
secretion or administration. Hyperglycemic crises may be
due to diabetic ketoacidosis or an HHS. IV rehydration with
normal saline and IV insulin is the initial therapy for both.

Hypoglycemic crises are classified as postprandial hypoglycemia (postgastrectomy or reactive hypoglycemia) and
fasting hypoglycemia. Fasting hypoglycemia can be due to
exogenous use of insulin or secretagogues or endogenous
unregulated secretion of insulin by an insulinoma or by
tumors that secrete IGF-II or consume glucose, or by lack of
counter-regulatory hormones. Acute treatment is IV glucose;
treatment depends on the specific cause. Patients with an
insulinoma have increased C-peptide levels as well as inappropriately high insulin levels when hypoglycemic. Diabetic
patients are at risk for hyperglycemic and hypoglycemic
crises, especially during illnesses and peri operatively.
Appropriate monitoring of glucose levels as well as management with IV saline, insulin, and glucose is the key to
treatment.
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Chemotherapy for
Unresectable Endocrine
Neoplasms
Anne C. Larkin, MD Kathryn L. Edmiston, MD
Nilima A. Patwardhan, MD
Neoplasms arising from endocrine organs are rare and have

unique clinical features. In contrast with most solid tumors,
symptoms from endocrine neoplasms may arise as a result
of the production of biologically active substances by the
tumor or invasion of surrounding structures and their ability
to metastasize. Tumors that are biologically active may
become clinically apparent as a result of endocrine hyperfunction, whereas those that do not produce active hormones
become apparent through local invasion and distant spread.
More sophisticated diagnostic tests have improved the
ability to recognize and characterize endocrine neoplasms.
The development of radioimmunoassays for circulating
peptides produced by endocrine neoplasms has revolutionized the recognition and diagnosis of hormone-secreting
tumors. Improved radiologic methods such as ultrasonography, endoscopic ultrasonography, computed tomography
(CT), magnetic resonance imaging, radionuclide scans, and
selective arteriography with selective venous sampling for
measurement of peptide concentration have improved diagnostic localization of endocrine neoplasms.
Most endocrine neoplasms have an indolent clinical
course. Survival after diagnosis is often measured in years and
decades. Because the morbidity associated with endocrine
tumors is often related to the metabolic and endocrine abnormalities caused by hormonal hypersecretion, the suppression
of tumor-related peptide secretion can produce relatively
long-lasting symptomatic and biochemical remission, even in
the absence of treatment directed at halting tumor growth.
Because most endocrine neoplasms are slowly progressive, surgery has been the mainstay of treatment, even in
cases of metastatic disease. 1.2 Hepatic resection for metastatic neuroendocrine tumors is safe, provides effective palliation, and prolongs survival. 3 Cytotoxic therapy is reserved
for patients with unresectable local or metastatic disease.t"
800
The efficacy of therapy for endocrine neoplasms is

judged not only by the effect of treatment on tumor size but
also by its effect on circulating levels of biologically active
substances produced by the tumor. The results of clinical
trials of chemotherapy for endocrine neoplasms are confounded by the rarity of these tumors and the variable criteria
for assessing response. A decrease in the production of
hormone mayor may not be accompanied by a decrease in
symptoms, shrinkage of the tumor, or prolongation of survival.
Islet Cell Tumors

Endocrine tumors of the pancreas are rare and arise from the
normal elements of the pancreatic islets. Insulinoma is
the most common islet cell tumor followed by gastrinoma.
As shown in Table 88-1, its primary symptom is hypoglycemia. Histologic criteria of malignancy, such as cytologic atypia, angioinvasion, and perineural invasion, are
often absent, even in metastatic islet cell tumors'? The only
universally agreed-on proof of malignancy is infiltration of
adjacent organs and spread to distant sites.' Only 10% to
15% of insulinomas are malignant." In contrast, 60% of islet
cell tumors producing gastrin 10 or vasoactive intestinal
polypeptide (VIP)ll are malignant. The characterization of
islet cell tumors by plasma or hormone production provides
important prognostic information.
Endocrine tumors of the pancreas may produce local
symptoms such as pain and jaundice as a result of involvement of the pancreas and compression of the common bile
duct or symptoms caused by involvement of the liver by
metastases. They may also exert profound systemic symptoms as a result of secretion of biologically active hormones.
The systemic symptoms usually dominate the clinical
Chemotherapy for Unreseetable Endocrine Neoplasms - -
picture and may be life threatening, even in patients with

a low tumor burden. Thus, a dual therapeutic strategy to eradicate the tumor and alleviate symptoms from the systemic
effects of hormone secretion is required to optimally
manage these patients.
The incidence of insulinoma is generally considered to be
I per 1,000,000 to 1,250,000 people, but it may be up to
4 patients per 1 million individuals per year. 12 Approximately
75% of insulin omas are solitary and benign, 10% to 15% are
malignant, and the remaining 10% to 15% are manifestations of multifocal disease of the pancreas, including islet
cell hyperplasia, microadenomatosis, or nesidioblastosis.?
Insulinomas are characterized by their ability to secrete
insulin and frequently produce hypoglycemia. The duration
of symptoms in patients with islet cell tumors may be as
short as 2 weeks or as long as 20 years." Symptoms are
common in patients with either benign or malignant
tumors, 14 The results of surgical resection for insulinoma are
good. Operative failures occur because of the inability to
locate the insulinoma or the presence of unresectable
metastatic disease, which occurs in 2% to 5% of patients."
Malignant insulinomas occur in an older age group, and
delay in diagnosis is a major problem. The liver is the most
frequent site of metastasis. Penetration of tumor through the
capsule and invasion of adjacent lymph nodes and blood
vessels are indicative of malignancy.v-"
Zollinger-Ellison syndrome (ZES) was originally
described as a combination of hypersecretion of gastric acid
and intractable and severe peptic ulceration as a result of a
pancreatic islet cell tumor." ZES accounts for two thirds of
pancreatic tumors found in patients with multiple endocrine
neoplasia (MEN) type 1.16 Gastrinomas are rarely found
among the general population. Many of the patients first
identified with gastrinoma had metastatic disease to the
lymph nodes." In spite of metastasis, patients may have a
long survival. Before the routine use of histamine receptor
antagonists, death was due to complications of peptic ulcer
disease. Currently, death is due to tumor growth." The
earliest signs and symptoms of ZES are indistinguishable
from those of uncomplicated peptic ulcer disease.
Abdominal pain is reported by most patients, and 18%
initially experience diarrhea. The major goal of therapy is to
801
identify and resect the primary tumor. Cytoreductive surgery

may be helpful in those with bulky nodal metastases in the
absence of hepatic involvement." Treatment with proton
pump inhibitors has become the mainstay of therapy in
patients with unresectable disease.'?
Glucagonomas are tumors that cause a distinct syndrome
composed of diabetes, dermatosis, diarrhea, and dementia.??
It is estimated that approximately 70% of patients with this
syndrome have malignant tumors. Fifty percent of patients
with malignant glucagonomas have hepatic metastases at
diagnosis. The cardinal feature is a rash that is a necrolytic
migratory erythema, which occurs in about 90% of cases.
By the time of diagnosis, glucagonomas are usually larger
than 3 em in diameter. Because of the high malignancy rate,
surgery is curative in less than 5% of patients with
glucagonoma. Palliative debulking can reduce hormone levels
and potentially improve survival." Radical excision of the
tumor with hepatic transplantation for improving survival,
disease-free interval, and control of endocrine-related
syndromes has been reported."
VIP-secreting tumor (VIPoma) results from the excess
secretion of vasoactive intestinal peptide. These tumors
cause a watery diarrhea, hypokalemia, and achlorhydria
syndrome. About 50% of the tumors are malignant, and 50%
will have metastasized at the time of diagnosis. The remaining
50% are benign and potentially curable. Therefore, when the
diagnosis is established but the tumor is not localized, "blind"
laparotomy is justifiable. Intraoperative localization may be
aided by the use of intraoperative ultrasonography. Surgery
may also be helpful in debulking metastatic disease.P
Nonfunctioning islet cell tumors are not associated with
a recognized hormonal syndrome. About 50% of all endocrine
tumors of the pancreas are nonfunctioning." As a result of the
advent of CT scans, the diagnosis of nonfunctioning tumors
has increased dramatically.V' Most tumors are malignant.P
and curative resection is possible in about 25% to 40%.8
Liver transplantation has been successfully done for metastatic nonfunctioning islet cell tumors.P
Surgery to remove all tumor should adequately treat both
local and systemic symptoms and offers the only chance of
cure for malignant endocrine neoplasms. Even with localized disease, complete surgical excision is not always possible.
Complete surgical resection rates range from 24% to 65%.
Criteria of inoperability include invasion of contiguous
structures (e.g., the superior mesenteric vein and portal vessels), extension into the porta hepatis, and portal hypertension or widespread involvement of the retroperitoneum.
Hepatic and other distant metastases or widespread lymphatic
involvement may render the tumor unresectable, although
surgical debulking of the primary and metastases can provide
palliation. 3,8.9,12 Up to half of patients who undergo noncurative resection demonstrate symptomatic improvement.
For patients with unresectable disease, chemotherapy is
indicated when there is significant morbidity because of
tumor bulk encroaching on normal structures or symptoms
resulting from hormone hypersecretion. Therapy is not
usually recommended for the asymptomatic patient with
advanced islet cell tumors unless the tumor manifests an
aggressive biologic behavior.P Patients who are considered
for chemotherapy must have adequate liver and kidney function and a good performance status at the time of treatment.

Studies of cytotoxic chemotherapy usually include
heterogeneous groups of patients because of the rarity of
these tumors and their indolent clinical course. Specific antihormonal therapy for the subtypes of islet cell tumors is
discussed separately in other chapters.
Streptozocin (STZ) is the most effective single chemotherapeutic agent for treating patients with advanced islet cell
tumors. The activity of STZ was first reported in 1968 by
Murray-Lyon and colleagues, who described a favorable
response in one patient with an advanced islet cell tumor.v
STZ is a naturally occurring nitrosourea that causes relatively selective destruction of the pancreatic beta cells. The
most common side effect is vomiting, although nephrotoxicity is frequently seen and may be dose limiting. Although
STZ was initially used as a single agent, it has more
recently been combined with doxorubicin (Adriamycin) or
5-fluorouracil (5-PU).
Combination therapy with 5-PU and STZ is the most
effective regimen for patients with advanced symptomatic
islet cell cancer and has become the standard of care. The
overall response rate and survival with this combination are
significantly better than with STZ alone: A doubling of
the response rate (63% vs. 36%) was seen in a prospective,
randomized trial comparing combination therapy with STZ
alone. Complete remissions occurred in 33% of the patients
receiving combination therapy but in only 12% of those
receiving STZ alone. The median duration of response was
17 months for all responders and 24 months for patients who
achieved a complete remisslon.'? The most common side
effects are gastrointestinal, but kidney, liver, and bone
marrow function need to be closely monitored.
More recently, the combination of STZ and 5-FU was
compared with STZ plus doxorubicin or chlorozotocin
alone. In this prospective trial, the addition of doxorubicin
was superior to 5-FU, with increased rates of tumor regression (69% vs. 45%) and median survival (2.2 vs. 1.4 years).
Chlorozotocin had similar results as the STZ/5-FU combination but with fewer side effects."
Dacarbazine (DTIC, dimethyl triazeno imidazole carboxamide) is an antitumor agent that inhibits DNA synthesis.
It has produced dramatic biochemical and objective tumor
responses in patients with islet cell tumors when used as
a single agent.t-'? In a recent study of 50 patients, DTIC
was administered at a dose of 850 mg/m- every 4 weeks.
It produced a response rate of 34% and a median survival of
19.3 months. The best results were noted in previously
untreated patients with advanced pancreatic islet cell tumors.'?
A number of agents have been identified for the treatment
of symptoms resulting from hormonal hypersecretion in
patients with functioning islet cell neoplasms. Somatostatin
occurs naturally throughout the gastrointestinal tract and
in the D cells of the pancreatic islets. Somatostatin has been
found to reduce the concentrations of marker hormones
effectively in patients with insulinoma, glucagonoma,
gastrinoma, and VIPoma, with a consequent improvement in
symptoms related to hypersecretion." Octreotide (SMS 201995) is a synthetic somatostatin analog with a longer half-life
than somatostatin. This has considerable advantages over
natural somatostatin, which must be administered by continuous intravenous infusion. Octreotide inhibits peptide secretion by islet cell tumors, resulting in marked improvement of
symptoms caused by hypersecretion. It appears to be helpful

in patients with VIPoma syndrome, glucagonoma syndrome,
ZES, and hyperfunctioning insulinomas.v-"
In the last several years, long-acting depot forms of octreotide have become available. Lanreotide is a slow-release
somatostatin analog, with activity for 10 to 14 days. Recent
studies have confirmed that the therapeutic efficacy and tolerability are similar to octreotide, but it is administered in the
amount of 30 mg every 2 weeks as opposed to three times
a day.34.35
Interferon a may be useful in the treatment of islet cell
tumors. In a phase II trial in seven patients with advanced
islet cell tumors, one patient had a partial response that
lasted 8 months and four had stable disease for a median of
13 months." However, the treatment was poorly tolerated,
requiring frequent dose reductions. Another report indicated
good symptomatic control of disease and tumor regression
when combined with 5_PU.37 The potential beneficial effects
of interferon need closer study, and combination regimens
with other cytotoxic agents should be evaluated.
Various other agents have been used for symptomatic
relief of patients with unresectable and metastatic insulinomas unresponsive to conventional chemotherapeutic measures. Diazoxide, calcium-channel blockers, propranolol, and
phenytoin all have been used with some success. Diazoxide
is a nondiuretic benzothiadiazine that suppresses insulin
release from the pancreas, resulting in increased blood sugar
levels. Calcium-channel blockers and ~-adrenergic
receptor
blockers are also theoretically capable of blocking insulin
secretion. Phenytoin inhibits in vitro release of insulin from
beta cells but has a less significant effect in vivo.
Carcinoid Tumors
Carcinoid tumors arise from Kulchitsky's or enterochromaffin cells and have been described in almost every organ in
the body. Carcinoid tumors occur most commonly in the
intestine. Carcinoids of the pancreas are rare and make up
less than 5% of all carcinoid tumors.t-" In contrast with
midgut carcinoids, they often secrete the serotonin analog
hydroxytryptophan. Episodic flushing and diarrhea are the
most common symptoms of the carcinoid syndrome and are
usually associated with metastases to the liver from a small
bowel carcinoid. Metastatic disease may require no treatment for months or even years if the patient is asymptomatic
or the symptoms are mild."
Numerous therapeutic options are available for the symptomatic patient, and it is important to consider the severity of
symptoms and select the appropriate therapy for the clinical
situation. Surgical resection is often curative for early-stage
disease, and it can prolong survival and provide significant
improvement in symptoms, even in patients with metastatic
disease." Potentially curative surgery should be considered in
all patients who can be rendered disease free with resection,
and palliative surgery should be offered to selected patients
because it improves symptoms and may delay or reduce the
need for chemotherapy.'? Selected patients not suitable for
hepatic resection for metastatic disease may benefit from
hepatic artery embolization." However, this may be associated
with significant side effects such as fever, nausea, and pain.
Chemotherapy for Unresectable Endocrine Neoplasms - -
Chemotherapy can be considered for patients with progressive, symptomatic, unresectable disease. STZ-based
regimens are helpful in the treatment of patients with carcinoid tumors of the pancreas.o? Etoposide and cisplatin have
been given to 27 patients with carcinoid syndrome; unfortunately, only two patients showed partial tumor regression.'?
In patients with aggressive variants of carcinoid tumor, the
same combination was administered and a 67% response rate
was noted. Patients with typical carcinoids did not respond in
this study.f? Octreotide is effective for treating symptoms in
patients with metastatic carcinoid and may result in disease
stabilization or even objective tumor regression."
Cyproheptadine (Periactin) is a serotonin and histamine
antagonist and is indicated for diarrhea caused by carcinoid
syndrome. Although it does not decrease circulating hormone
levels, it blocks the effects of these hormones in the bowel.
Most patients have significant relief of diarrhea. Interferon
has been used in patients with metastatic carcinoid with the
malignant carcinoid syndrome. Twenty percent of patients
had a measurable regression of tumor, 40% had a decrease in
hormone excretion, 65% had relief of flushing, and 33% were
relieved of diarrhea. Unfortunately, these results were transient.43 The addition of interferon to somatostatin analogs has
been helpful in patients resistant to octreotide alone."
Adrenocortical carcinoma is a rare malignant disease with
a dismal prognosis and an estimated incidence of 0.5 cases
per 1 million individuals per year," Patients with nonfunctioning tumors have manifestations attributable to a large
abdominal mass. Forty percent to 70% of adrenocortical
carcinomas are secretory.tv" and these patients usually
present with clinical features of hormone excess. The clinical features depend on the predominant excess steroid production: glucocorticoid-secreting tumors cause Cushing's
syndrome; androgen-secreting tumors lead to virilization;
mineralocorticoid-secreting tumors cause hypertension and
hypokalemia; and estrogen-secreting tumors result in
gynecomastia and testicular atrophy in men and menstrual
irregularities and precocious puberty in girls. 45.46 Diagnosis
is confirmed by elevated levels of urinary steroids. Eighty
percent of patients demonstrate a suprarenal mass on CT
scan. 45.46 Pooled data from several institutions confirm that
more than 60% of adrenal tumors are stage IV with local
invasion, positive lymph nodes, or distant metastasis at
initial diagnosis."
Complete surgical excision, which may include a
nephrectomy, is the only therapy that offers an opportunity of
cure, but recurrence rates are up to 73% and 5-year survival
may reach only 37%.48 Symptoms are largely proportional
to tumor bulk; therefore, resection of hepatic metastases
and excision of peritoneal and omental implants may be
indicated for symptom control.
Mitotane (o,p'-DDD) is an insecticide that causes necrosis of the adrenal cortex and has been used in the therapy of
adrenocortical carcinomas. Response to therapy can be
measured by objective decreases in tumor size or by changes
in the levels of circulating hormones. Biochemical response
rates are high but do not necessarily correlate with objective
803
decreases in tumor size." Treatment toxicity includes gastrointestinal and neuromuscular symptoms.
Experience with other chemotherapeutic agents is limited.
Antitumor responses have been reported in patients treated
with etoposide and cisplatin. One of 11 patients showed a
complete response and 2 of 11 showed partial responses with
1- and 2-year survival rates of 18% and 9%, respectively.'?
A subsequent phase II trial was unable to improve on these
results, with only a 13% response rare." The combination of
doxorubicin, vincristine, and etoposide with daily mitotane
yielded a response rate of 22%, but the authors noted that it
is uncertain whether this is superior to mitotane alone.>'
Malignant Pheochromocytomas
Pheochromocytomas are rare tumors of chromaffin tissue
that secrete catecholamines, either paroxysmally or continuously, producing hypertension. Diagnosis is made by measuring urinary concentrations of metanephrine, vanillylmandelic
acid, and free unconjugated catecholamines. When there is
increased excretion of urinary catecholarnines, CT scanning
or iodine-131-metaiodobenzylguanidine (MIBG) scan is used
to identify the location of the tumor.
Approximately 10% of pheochromocytomas are malignant. They are usually slow growing and may not cause
hypertension or symptoms. The tumors may spread locally
or may metastasize to the lungs, bones, and soft tissues.
Recurrent and metastatic pheochromocytomas should be
resected whenever possible. Palliation is achieved by excision of as much catecholamine-secreting tissue as possible.
Radioiodinated (1 231, 1311) MIBG, which is concentrated by
these tumors, has also been used for treatment. Brief
responses to therapeutic doses of 1311_MIBG have been
described. In one report, none of the nine patients showed
complete tumor regression and five patients showed symptomatic improvement. In addition, three complete hormonal
responses were observed. 1311_MIBG is believed to be a
useful therapeutic modality that provides temporary palliation but is rarely curative.V
Combination chemotherapy using cyclophosphamide,
vincristine, and dacarbazine in 14 patients produced complete
or partial responses in 8 patients (57%), with a mean duration of response of 21 months.P There has been a case
report of a patient with familial malignant pheochromocytoma who had an objective response lasting for 2 years with
cisplatin and 5_FU.54
Patients who are treated with chemotherapy may have
a hypertensive crisis and should be pretreated with a- and
~-adrenergic
blockers, vigorous hydration, and metyrosine,
which inhibit catecholamine secretion. Classic symptoms of
catecholamine excess from unresectable disease can be
treated with a-adrenergic blockade with phenoxybenzamine
or, if necessary, n-methylparatyrosine, Arrhythmias can be
controlled by ~ blockers such as propranolol.
Thyroid Cancer
Malignant thyroid neoplasms have a wide spectrum of
biologic behavior ranging from indolent growth of

well-differentiated neoplasms to the aggressive behavior of
anaplastic cancers, which can cause death in only a few
months. Management of papillary and follicular thyroid
carcinomas consists of surgery and radioactive iodine
(RAI). Medullary carcinomas of the thyroid arise from the
parafollicular C cells, which secrete calcitonin. Surgery is
the definitive treatment. Total thyroidectomy with a thorough central neck dissection as well as a modified lateral
neck lymph node dissection is recommended. RAI has little
value as an adjuvant to surgery in the management of
medullary thyroid cancer. External-beam radiation therapy
may be administered for remaining tumor that cannot be
excised. Anaplastic cancer of the thyroid is a rapidly fatal
tumor. Survival is not appreciably altered by treatment with
either radiation therapy or chemotherapy alone, and the
tumor often grows, even during treatment. In most patients
symptoms are caused by local tumor invasion. The median
survival after diagnosis is estimated to be 2 to 6 months, and
in only exceptional cases does survival exceed 12 months.P
Most chemotherapy trials involve heterogeneous groups
of patients with differentiated, medullary, and anaplastic
carcinomas. Experience with chemotherapy for differentiated thyroid cancer is limited because most recurrences are
treated with surgery or RAJ. The addition of lithium to RAI
in the treatment of well-differentiated thyroid has shown
some promise. 56 Combined chemotherapeutic regimens
appear to have a higher response rate (27%) than monotherapy (17%).57 However, a phase II trial indicated that the
combination of doxorubicin, cisplatin, and vindesine was
not superior to doxorubicin alone in patients with advanced
differentiated thyroid cancer." Patients whose tumors do
not concentrate 131 1 may benefit from retinoic acid, which is
thought to redifferentiate tumor cells. A small study indicated
some positive responses as evidenced by an increase in
serum thyroglobulin levels.59
The results of chemotherapy for the treatment of metastatic medullary thyroid carcinoma are disappointing. Twentythree patients who had metastatic thyroid cancer were
treated with various chemotherapeutic agents. The drugs
most often used were doxorubicin alone, doxorubicin plus
cisplatin, semustine (MeCCNU), and etoposide (VP-16). No
patient had a complete remission, and few had even partial
or minor responses." Although octreotide alone has not
been shown to be efficacious in the management of
advanced thyroid cancer," lanreotide has been combined
with interferon a2b in one small study. Clinical benefit was
obtained in six of seven patients, with decreases in flushing
and fatigue and increased performance status.F
Anaplastic tumors of the thyroid are highly resistant to any
form of therapy and are rarely cured. Surgery, chemotherapy,
and radiation therapy used separately have not been effective.
The best survival rates have been reported after combined
surgery, external-beam radiation, and chemotherapy. A clinical trial treated 20 patients with anaplastic cancer with
chemotherapy and radiation. Two types of chemotherapy
were used, depending on patients' ages. For those younger
than 65 years, a combination of doxorubicin (60 mg/m-)
and cisplatin (90 mg/m-) was given, and for older patients
mitoxantrone (14 mg/m-) was used. Radiation therapy was
administered to the neck and superior mediastinum. Three
patients survived for 20 months, and complete local tumor
response was observed in 5 patients. No response was

seen in distant metastasis, which was the cause of death in
14 patients." Protocols using paclitaxel and combinations
of doxorubicin and bleomycin have similarly
dismal responses.63.64 All authors agree that gross tumor resection should be performed whenever possible.55.65 However,
surgery should not delay commencement of the combinedmodality treatment with chemotherapy and radiation. There is
no consensus regarding the selection of chemotherapeutic
agents for the treatment of anaplastic thyroid cancer.
Summary
Chemotherapy for unresectable endocrine neoplasms is
usually palliative rather than curative. Palliative surgical
resection is indicated, especially for functioning tumors.
Octreotide or similar agents can be effective in controlling
symptoms in a variety of endocrine tumors. New agents or
combinations of agents need to be developed to treat
patients with these malignant endocrine neoplasms.
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62. Vitale G, Tagliaferri P, Caraglia M, et al. Slow-release lanreotide in
combination with interferon-a2b in the treatment of symptomatic
advanced medullary thyroid carcinoma. J Clin Endocrinol Metab
2000;85:983.
63. Busnardo B, Daniele 0, Pelizzo MR, et al. A multimodality therapeutic approach in anaplastic thyroid carcinoma: Study on 39 patients.
64. Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid
carcinoma with paclitaxel: Phase 2 trial using ninety-six-hour infusion.
Collaborative Anaplastic Thyroid Cancer Health Intervention Trials
(CATCHIT) Group. Thyroid 2000;10:587.
65. Mazzaferri EL. Undifferentiated thyroid carcinoma and unusual
thyroid malignancies. In: Mazzaferri EL, Samaan NA (eds), Endocrine
Tumors. Boston, Blackwell Scientific, 1993, p 334.
Index
Page numbers followed by the letter f refer to figures; those followed by the letter t refer to tables.
A
Abscess, in acute (suppurative) thyroiditis,
34,35
Accessory duct of Santorini, 669
Acetaminophen, for decompensation in thyroid
storm, 218
Acidosis, metabolic, in diabetic ketoacidosis,
791
Acquired immunodeficiency syndrome
(AIDS)
acute suppurative thyroiditis in, 34
Addison's disease in, 635
Actin, cytoskeletal, 296
Addison's disease, 634-639
adrenal autotransplantation for, 695
bilateral adrenal hemorrhage and, 637-639
causes of, 637t
CT scan of, 638, 638f
bilateral adrenal metastases and, 639
drugs causing, 639, 639t
exogenous steroid usage and, 635--636
hormone replacement therapy for, 695
in acquired immunodeficiency syndrome,
635
in autoimmune adrenalitis, 634
in polyglandular autoimmune syndromes,
634-635
in surgery, 635
in tuberculosis, 635
primary insufficiency in, 634-635
secondary insufficiency in, 635--636
stress-induced, 636
surgical, 635, 637
causes of, 634, 635t
Adenoma
adrenal. See Adrenal gland(s), adenoma of.
Hiirthle cell, 123, 124f, 228. See also
Hiirthle cell neoplasms.
chromosomal aberrations in, 348, 348f
mediastinal, arteriography of, 434, 434f
parathyroid. See Parathyroid gland(s),
adenoma of.
pituitary
corticotropin-secreting, Cushing's
syndrome from, 612
in Carney's complex, 776
in multiple endocrine neoplasia 1, 675,
675f
thyroid
follicular, 116, 116f
pathology of, 223-224
Adenomatosis, endocrine, 757
Adenosine monophosphate (AMP), cyclic

desensitization of, to thyroid-stimulating
hormone,273-274,273f
in pancreatic islet B cells, 703f, 707-708
in parathyroid hormone secretion, 374
in phosphorylation, 273
in thyroid regulation, 257t, 258, 258f
Adenosine triphosphate (ATP), from glucose,
707
Adenylase cyclase, response of, to
thyroid-stimulating hormone, 268, 268f
Adenylase cyclase-protein kinase A system,
in signal transduction, 266-269, 267f
Adhesion plaque, integrin-mediated,
297,297f
Adjuvant therapy
for adrenocortical carcinoma, 609-610, 610f
for papillary thyroid carcinoma, 107-108
for recurrent thyroid carcinoma, 183
Adrenal artery(ies), development of, 559
Adrenal carcinoma
Cushing's syndrome from, 618
fine-needle aspiration of, 590
imaging of, 581-582, 582f, 590, 591f
pathology of, 586, 587f
screening for, 589-590
tumor size in, 589-590, 590f
Adrenal cortex
aldosterone in, 571-572
physiologic effects of, 573
androgens in, physiologic effects of, 573
carcinoma of. See Adrenocortical carcinoma.
corticosteroids in
biosynthesis of, 571, 572f
cortisol in, 572-573
embryology of, 558, 558f
fetal (primitive), 558, 558f
microscopic anatomy of, 564, 565f
morphology of, 571, 572f
nerve supply to, 564
physiologyof,571-573
sex steroid secretion in, 573
zonation of, 564-565, 565f, 571, 572f
Adrenal gland(s), 557-569
accessory tissue in, 560
adenoma of, 587f
aldosterone-producing, hyperaldosteronism
from, 597-598
ACTH infusion and, 599
Adrenal gland(s) (Continued)

surgery for, hypertension after,
600-60 I, 60 It
venous sampling in, 599, 600t
Cushing's syndrome from, 618
frequency of, 586
imaging of, 582, 586
anatomic relations of, 560-562, 562f, 562t
anatomy of, 560-566
macroscopic aspect in, 560, 561
microscopic, 564-566, 565f
surgical,641-642
arterial supply to, 562-563, 563f
arteriography of, 577
autotransplantation of
animal experiments in, 695-697, 696f
for Addison's disease, 695
bilateral hemorrhage of, Addison's disease
from, 637-639
causes of, 637t
capsule of, 561
carcinoma of. See Adrenal carcinoma;
Adrenocortical carcinoma.
cortex of. See Adrenal cortex.
CT scan of, 562f, 566, 576, 577f
cyst in, 587f
embryology of, 558-560, 558f-559f
adrenal artery development in, 559
stereogenesis and, 559-560
fetal, 558, 558f, 560
Gerota's fascia of, 561
hereditary syndromes involving, 774t
historical background on, 557-558
hyperplasia of, Cushing's syndrome from, 618
imaging of, 562f, 566, 576-577, 577f
for adrenal adenoma, 582
for adrenocortical carcinoma, 581-582,
582f, 583, 583f
for hyperadrenocorticism, 577-579, 578f
for incidentaloma, 581-582, 582f, 583f
for metastatic disease, 582-583
for pheochromocytoma, 580-581,
580-581
for primary hyperaldosteronism, 579-580,
579f
incidentaloma of, 586-592. See also
Adrenaloma.
left, 561, 561, 562t
lymphatic drainage of, 563
mass in, clinically inapparent, 586. See also
Adrenaloma.
807
808 - - Index
Adrenal gland(s) (Continued)
medulla of. See Adrenal medulla.
metastases to, Addison's disease and, 639
MR imaging of, 562f, 566, 576
nerve supply to, 563-564
pheochromocytoma of. See
Pheochromocytoma.
physiology of, 571-575
right, 560-561, 561f, 562t
scintigraphy of, 566, 576-577
surgery on, 566-569, 641-646. See also
Adrenalectomy.
anterior approach to, 567t, 568-569,
642-646,642f-643f
flank approach to, 646
incision lines for, anatomic stratification
in, 567t-568t
lateral transthoracic approach to, 644-645,
645f
posterior approach to, 566-568, 567t,
645-646,645f
preparation for, 642
retroperitoneal laparoscopic approach to,
569
transabdominal approach to,
644-645, 644f-645f
laparoscopic, 569
ultrasonography of, 566, 577
venography of, 577
venous drainage of, 563
zona fasciculata of, 564, 565f
zona glomerulosa of, 564, 565f
zona reticularis of, 564, 565f
Zuckerkandl fascia of, 561-562
Adrenal insufficiency. See Addison's disease.
Adrenal medulla
catecholamines in
physiologic effects of, 574-575
release of, 574
chromaffin cells of, 565-566, 573, 574f
microscopic anatomy of, 565-566
nerve supply to, 563-564
transmitter mechanisms in, 573-574, 574f
Adrenal vein, dissection of, in laparoscopic
adrenalectomy, 650-651, 651f
Adrenalectomy
anterior approach to, 567t, 568-569,
642-646, 642f-643f
anticoagulation prophylaxis after, 616-617
bilateral, for Cushing's disease, 616-617
complications of, 617
steroid replacement therapy after, 6l7t
compensatory hypertrophy of remaining
gland after, 565
flank approach to, 646
incision lines for, anatomic stratification in,
567t-568t
indications for, 641
laparoscopic, 569, 647-660
as gold standard, 659
bilateral, 653, 659
indications for, 655t
care after, 654
choice of approach to, 658
complications of, 654-657, 656t
contraindication(s) to
malignancy as, 658-659
tumor size as, 659
cortical-sparing, 659-660
for adrenaloma, 648, 659
for Cushing's disease, 648
Adrenalectomy (Continued)
for Cushing's syndrome, 648
complications of, 656-657
for hyperaldosteronism, 600, 648
for pheochromocytoma, complications of,
656
indications for, 647-648, 655t
left-side
adrenal vein dissection in,
650-651, 65 If
dissection in, 649-650, 650f
extraction in, 651
patient positioning for, 649, 650f
retroperitoneal, 569
transabdominal, 569, 649-651,
649f-651f
operating room layout for, 649, 649f
outcome of, 654-657, 655t
for malignancy, 657
outpatient, 659
partial, 653-654
recent advances in, 659-660
results of, vs. open adrenalectomy, 658
retroperitoneal, 652-653
decubitus approach to, 653
prone jackknife approach to, 653
right-side
dissection in, 651-652, 652f
retroperitoneal, 569
transabdominal, 569, 651-652,
651f-652f
trocar sites for, 651, 651f
technique of, 649-654
laparoscopic ultrasonography in, 657
lateral transthoracic approach to,
644-645,645f
left,568
needlescopic, 654
Nelson's syndrome after, 617
posterior approach to, 566-568, 567t,
645-646,645f
results of, vs. laparoscopic adrenalectomy,
658
right, 568-569
transabdominal approach to, 644-645,
644f-645f
Adrenaline, 557. See also Epinephrine.
Adrenalitis, autoimmune, 634
Adrenaloma, 586-592
benign vs. malignant, 586, 587f
evaluation of, 588-590
screening for adrenal carcinoma in,
589-590, 590f-591f
screening for Cushing's syndrome in,
588-589
screening for pheochromocytoma in, 589
screening for primary aldosteronism in,
589
frequency of, 586
genetic studies of, 590
imaging of, 581-582, 582f
flow chart in, 583f
in adrenocortical carcinoma, 606-607
laparoscopic adrenalectomy for, 648, 659
management of, 591-592
surgical approach in, 592
pathology of, 586, 587f, 588
~-Adrenergic
receptor blockers, for thyroid
storm, 218
Adrenocortical carcinoma, 604-610
adjuvant therapy for, 609-610, 610f
adrenaloma in, 606-607
Adrenocortical carcinoma (Continued)

Anderson's syndrome in, 606, 607f
biochemical features of, 604
capsule of, 608
characteristics of, 604, 605t
chemotherapy for, 803
clinical features of, 604
clinical presentation of, 605-607, 606f-607f
hypersecretion in, 606
imaging of, 581-582, 582f, 583, 583f
preoperative, 607, 607f, 608
in childhood, 610
in multiple endocrine neoplasia I, 686
incidence of, 604
macroscopic venous invasion in, 608
malignant, criteria for, 604-605, 605t
mitotane for, 609-610
preoperative, 608
survival associated with, 6IOf
morphology of, 608
MR imaging of, 607
postoperative care in, 609
preoperative treatment of, 608
prognosis of, 609
recurrence of, 609
scintigraphy of, 607
staging of, 607-608, 608t
surgery for, 608-609
metastatic disease and, 609
results of, 609, 609f
survival rates for, 609, 609f, 6 !Of
tumor size and weight in, 605
Adrenocorticotropic hormone, infusion of, in
differentiation of aldosterone-producing
adenoma vs. hyperaldosteronism, 599
Aerodigestive tract, thyroid carcinoma invasion
of, 318-332. See also Thyroid carcinoma,
aerodigestive invasion by.
Age, effect of
on outcome of thyroid carcinoma, 250
on radiation-associated thyroid carcinoma,
241, 241f, 242t
AGES scoring system
for papillary thyroid carcinoma, 102, 110,
111, lIlt, 226
for thyroid carcinoma, 251
AIDS. See Acquired immunodeficiency
syndrome (AIDS).
Airway
obstruction of, intrathoracic goiter in, 309
thyroid carcinoma invasion of, 318-332. See
also Thyroid carcinoma, aerodigestive
invasion by.
Alcohol abuse
hypoglycemia from, 717, 796
in sporadic gastrinoma, 747
Aldosterone
in adrenal cortex, 571-572
plasma concentration of, in
hyperaldosteronism, 596-597.
See also Hyperaldosteronism.
subclinical, screening for, 589
Aldosterone-plasma renin ratio, 589
Aldosteronoma, 587f
imaging of, 580
Allotransplantation
of parathyroid tissue, 694-695
of thyroid tissue, 692
efficacy of, 693
rejection of, 693
prevention of, 692-693
Index - - 809
All-trans-retinoic acid, 335, 335f
Alpha cells, pancreatic, 666. See also
Pancreatic islets, A cells of.
AMES scoring system
for papillary thyroid carcinoma, 102, 104,
lIO, Ill, lilt
Amine precursor uptake and decarboxylation
(APUD)
chromaffin cells in, 560
in multiple endocrine neoplasia 2B, 758
Amine precursor uptake and decarboxylation
(APUD) tumor, 764
Amino acid concentrations, in glucagonoma,
768, 769f
Aminoglutethimide, for Cushing's
disease, 616
Amiodarone
hypothyroidism from, 45
thyroid disorders associated with, 25
AMP. See Adenosine monophosphate (AMP).
Ampulla of Vater, 669
Amylin, production of, by pancreatic islet
B cells, 703
Amyloid polypeptide, production of, by
pancreatic islet B cells, 703
Anaplastic thyroid carcinoma. See Thyroid
carcinoma, anaplastic.
Anderson's syndrome, in adrenocortical
carcinoma, 606, 607f
Androgens, adrenal, physiologic effects of, 573
Anemia
after parathyroidectomy, 515
in secondary hyperparathyroidism, 506
normochromic, normocytic, in chronic renal
failure, 506
Anesthesia
for parathyroidectomy, 442
local, for parathyroidectomy, 459
Angina, levothyroxine and, 71
Angiogenesis, 300
Angiography
of gastrinoma, 750
of insulinoma, 720, 721f
Ankle reflex, delayed, in hypothyroidism,
47-48,47t
Anticancer therapy. See also specific therapy,
e.g., Chemotherapy.
targeting tumor growth, invasion, and
angiogenesis, 30 I
Anti-CEA monoclonal antibodies, medullary
thyroid carcinoma imaging with, 148
Anticoagulation
in bilateral adrenal hemorrhage, 637--638
prophylactic, after adrenalectomy, for
Cushing's syndrome, 616-617
Antithyroid agents. See also specific drug.
for Graves' disease, 59--60, 60t
for Plummer's disease, 65
for thyroid storm, 217-218
prophylactic, 63-64
APe gene, 235, 292
Appendix, carcinoid tumors of, 780
treatment of, 785
APUD. See Amine precursor uptake and
decarboxylation (APUD) entries.
Aromatic fatty acids, in thyroid tumor growth
inhibition and redifferentiation, 336
Arrestin proteins, in desensitization, 273
Arteriography
of adrenal glands, 577
preoperative, for recurrent (persistent)
hyperparathyroidism, 434
Artery(ies), rupture of, from invasive thyroid

carcinoma surgery, 330
Askanazy cell(s), in Hashimoto's thyroiditis,
39
Askanazy cell tumors, 123. See also Hiirthle
cell neoplasms.
Aspiration biopsy, fine-needle. See Fine-needle
aspiration biopsy.
ATP (adenosine triphosphate), from glucose,
707
Autotransplantation
of adrenal cells
animal experiments in, 695-697, 696f
for Addison's disease, 695
of parathyroid tissue, 486-487, 514,
694-695,694f
cryopreservation with, 487, 523, 532-534
pocket storage in, 695
of thyroid tissue, 691-692
cryopreservation in, 691
for Graves' disease, 692
for multinodular goiter, 692
for postoperative hypothyroidism,
691-692,692f
long-term follow-up of, 691
B
Bacterial infection, in acute suppurative
thyroiditis, 34
Bayley's symptom complex, in thyroid storm,
216
B-celllymphoma, of thyroid, 174, 232, 233f.
See also Thyroid lymphoma.
Beckwith-Wiedemann syndrome, 773-774
Benign familial hypocalciuric hypercalcemia.
See Hypercalcemia, benign familial
hypocalciuric.
Benzimidazoles, for gastrinoma, 751
Beta cells, pancreatic, 666. See also Pancreatic
islets, B cells of.
~ Blockers
before pheochromocytoma surgery, 626
for thyroid storm, 218
Bexarotene, central hypothyroidism from, 47
Bioassays, of parathyroid hormone, 379
Biopsy
during parathyroid surgery, 443
fine-needle aspiration. See Fine-needle
aspiration biopsy.
lymph node, in gastrinoma, 751, 752f
Birt-Hogg-Dube syndrome, 778
Bisphosphonate agents
for hypercalcemia, 540
in parathyroid carcinoma, 552
for hypercalcemic crisis, 546
Bleeding. See Hemorrhage.
Blood collection, timing and processing of, for
intraoperative PTH assays, 474-475, 475f
Blood pressure, high. See Hypertension.
Body, distribution of calcium in, 424, 425f
Bone densitometry studies, of
hyperparathyroidism, 386, 398-399
Bone disease
in asymptomatic hyperparathyroidism, 419
in chronic renal failure, 505
in normocalcemic hyperparathyroidism, 422
in secondary hyperparathyroidism, 505-506
Bone loss, in primary hyperparathyroidism,
387,399
Bone marrow transplantation, allogeneic,
thyroid transplantation across major
histocompatibility complex barriers
using, 693
Bone metastases, surgical management of, 154,

154f-155f
Bone morphogenic protein, anaplastic thyroid
carcinoma and, 164
Bone resorption, inhibition of
Bone tumors, in primary hyperparathyroidism,
385
Bovine seminal ribonuclease, anaplastic
thyroid carcinoma and, 164
Brachioradialis muscle, transplantation of
cryopreserved thyroid tissue into,
691, 692f
BRAF mutations, in anaplastic thyroid
carcinoma, 164-165
Brain, metastases to, surgical management
of,I 54
Breathing, difficulty in, after thyroid surgery, 211
Bronchus, carcinoid tumors of, 783
Burch and Wartofsky's criteria, for diagnosis of
thyroid storm, 217t
c
C (parafollicular) cells, in medullary thyroid
carcinoma, 129, 13Of, 229
C peptide, 715, 790
in insulinoma
measurement of, 718
plasma concentration of, 719
CA4P, anaplastic thyroid carcinoma and, 164
Cadherins, in cell-cell interactions, 297-298,
298f
Caffeine, carcinogenic effect of, 246
Calcification, extraskeletal, in secondary
Calciphylaxis, in secondary
Calcitonin
in calcium homeostasis, 420
peripheral action of, 7
salmon
for hypercalcemic crisis, 546-547
secretion of, 7
C cells in, 129
in medullary thyroid carcinoma, 138, 138f
Calcitrol. See also 1,25-Dihydroxyvitamin D.
for hypoparathyroidism, 528
in secondary hyperparathyroidism
secretion of, 504
synthesis of, 503
preoperative, for parathyroidectomy, 511
Calcium
cytoplasmic, in pancreatic islet B cells, 709
elemental, for hypoparathyroidism, 528
homeostasis of, 424-425
in pancreatic islet B cells, 707, 708
in parathyroid hormone secretion, 372-374,
373f-374f
ionized, 425
metabolism of, after parathyroidectomy, 515
serum concentration of. See also
Hypercalcemia; Hypocalcemia.
body distribution of, 424, 425f
in primary hyperparathyroidism, 387,
397,397f
psychiatric symptoms associated with,
406
parathyroid hormone serum levels and,
372,373f
ultrafiltrable, 425
810 - - Index
Calcium channel blockers, before
pheochromocytoma surgery, 626
Calcium gluconate, for hypoparathyroidism,
528
Calcium infusion test
for gastrinoma, 748
for insulinoma, 719, 719f
Calcium sensor protein
in multiple endocrine neoplasia I-associated
on parathyroid cells, 375-376
Calcium-calmodulin-dependent protein kinase,
in thyroid growth regulation, 267f, 271
Carbohydrate metabolism, in primary
hyperparathyroidism, 408-409, 408t
Carcinoembryonic antigen, in anaplastic
thyroid carcinoma, 161
Carcinogenesis. See also Oncogenesis.
in thyroid tumors, 344, 345f
molecular, 245
Carcinoid syndrome, 786
classic, 782-783, 783t
definition of, 782
Carcinoid tumors, 780-786
appendiceal, 780
treatment of, 785
bronchial, 783
causes of, 781
chemotherapy for, 802-803
colonic, treatment of, 785-786
diagnosis of, 783-784, 784f
duodenal, 782f
treatment of, 785
gastric, 781
treatment of, 785
histopathology of, 782, 782f
history of, 780, 78lt
hormone secretion by, 782, 783t
in multiple endocrine neoplasia I, 686, 781
in multiple endocrine neoplasia 2, 781
in Zollinger-Ellison syndrome, 781
incidence of, 780
Kulchitsky cells in, 780
neurotransmitter secretion by, 782, 783t
nonfunctioning, 770-771
pathogenesis of, 781, 78lf
pathophysiology of, 781
prognosis of, 784-785, 785t
rectal,780
treatment of, 786
serotonin secretion by, 783
sites of, 780, 781
small bowel, 780
treatment of, 785
somatostatin receptor scintigraphy of,
784, 784f
surgery for, 739, 740f
symptoms of, 782-783, 783t
thymic, 783
treatment of, 785
treatment of, 785-786, 786f
Carcinoma. See specific type; under specific
organ.
Cardiovascular disease, in primary
hyperparathyroidism, 405-406
Carney's syndrome, 776
paraganglioma in, 629
pheochromocytoma in, 631
Carotid artery, rupture of, from invasive thyroid
CASR gene, in benign familial hypocalciuric
hypercalcemia, 386, 496
Catecholamines
in insulin secretion, 706
Catecholamines (Continued)
in pheochromocytoma, 621
physiologic effects of, 574-575
release of
determination of, 574
into systemic circulation, 564
synthesis of, in adrenal medulla, 573, 574f
~-Catenin
activation of, in anaplastic thyroid

carcinoma, 159
alterations of, in thyroid carcinoma, 298
Catheterization, venous, for medullary thyroid
carcinoma, 136
Cattell's maneuver, in adrenocortical carcinoma
surgery, 608
CD4+ T cells, in Hashimoto's thyroiditis,
38-39
CD8+ T cells, in Hashimoto's thyroiditis, 39
CDHI gene, in malignancies, 297-298
Cell biology
of pancreatic islet B cells, 703f, 707-708
of pancreatic islet non-B cells, 708
Cell-cell contacts, in cytoskeleton, 296-297
Cerebrospinal fluid concentrations, of calcium,
in primary hyperparathyroidism, 406-407
Cervicotomy, traditional
conversion of endoscopic parathyroidectomy
to, 470, 47lt
conversion of minimally invasive
parathyroidectomy to, 465, 465t
Chemoembolization, hepatic artery,
for insulinoma, 728
Chemotherapy. See also specific
chemotherapeutic agent.
for adrenocortical carcinoma, 803
for carcinoid tumors, 802-803
for insulinoma, 728
for islet cell tumors, 728, 800-802, 801t
for malignant pheochromocytoma, 803
for thyroid carcinoma, 803-804
anaplastic, 163
medullary, 135-136
for thyroid lymphoma, 176
Chest radiographs, of intrathoracic goiter, 310f,
311, 312f, 315f
Children. See also Neonates.
adrenocortical carcinoma in, 610
endemic goiter in, 20
thyroid carcinoma in, 93-99
acquired, 248-249, 249f
clinical presentation of, 96, 96t
cytogenic studies of, 94-95
etiology of, 93-95
follicular, 95, 95f
historical aspects of, 93
incidence of, 93-95, 94f
irradiation and, 94
long-term survival in, 99
medullary, 94
nodule and, 96
papillary, 95
pathology of, 95, 95f, 233
pulmonary metastases in, 252
radiation-associated, 240-242, 241f
radioiodine therapy for, 98-99, 98f-99f
complications of, 98t
recurrence of, 98, 98t
surgery for, 96-97
complications of, 97-98, 97t, 98t
treatment of, 96-99
Chlorpromazine, for decompensation in thyroid
storm, 218
Cholecystokinin immunoreactivity,
in pancreatic islet nerves, 706
Chondrocalcinosis
definition of, 409
in primary hyperparathyroidism, 409
Chromaffin bodies, 560
Chromaffin cells
in APUD system, 560
of adrenal medulla, 565-566, 573, 574f
Chromogranin A, in parathyroid tissue, 378
Chromosomal aberrations
in anaplastic thyroid carcinoma, 350, 350t,
351f,352t
in Hiirthle cell adenomas, 348, 348f
in Hiirthle cell neoplasms, 348-349, 348t, 3491
in medullary thyroid carcinoma, 351
in papillary thyroid carcinoma, 346-347, 347t
Chvostek's sign, in hypocalcemia, 528
Cimetidine, for gastrinoma, 750
Cisplatin
for anaplastic thyroid carcinoma, 162,804
for carcinoid tumors, 803
9-cis-retinoic acid, 335, 335f
13-cis-retinoic acid, 335
Clear cells, pancreatic, 666. See also Pancreatic
islets, F cells of.
Clodronate, for hypercalcemia, in parathyroid
carcinoma, 552
Col-3, inhibition of thyroid cancer cell invasion
by, 340
Colon, carcinoid tumors of, treatment of,
785-786
Columnar cell carcinoma, of thyroid, 171-172,
171f. See also Thyroid carcinoma.
Coma, myxedema. See Myxedema coma.
Comparative genomic hybridization
digital image acquisition and analysis in,
345-346,346f
DNA extraction in, 344
limitations and difficulties of, 351, 353
metaphase spreads in, 344, 345f
of anaplastic thyroid carcinoma, 349-351,
350t, 35lf-352f, 352t
of follicular thyroid carcinoma, 347
of Hiirthle cell neoplasms, 347-349, 348f,
348t,349t
of medullary thyroid carcinoma, 351
of papillary thyroid carcinoma, 346-347,
347t
technique of, 344-345, 345f
Compartmental syndromes, in recurrent goiter,
306
Computed tomography (CT)
of adrenal glands, 562f, 566, 576, 577f
of adrenocortical carcinoma, 607, 607f
of aldosterone-producing adenoma,
598,599f
of bilateral adrenal hemorrhage, in Addison's
disease, 638, 638f
of Cushing's syndrome, 614, 615f
of gastrinoma, 732-733, 733f, 734t, 749
of goiter, 28, 29f
of hyperadrenocorticism, 577-578, 578f
of insulin oma, 720, 72lf, 730-731, 73lt
of intrathoracic goiter, 31Of, 311-312, 315f
of liver, in MEN 2A, 137
of parathyroid adenoma, 482f
of pheochromocytoma, 580, 580f, 623,
623f,625f
of primary hyperaldosteronism, 579, 579f
Index - - 811
Confusion, mental, in primary
Contrast media, hypothyroidism caused by, 25
Coronary artery disease, in primary
Coronary bypass surgery, intravenous
triiodothyronine in, 50-51
Corticosteroids. See also Glucocorticoids.
Addison's disease from, 635-636
biosynthesis of, in adrenal cortex, 571, 572f
Corticotropin
corticotropin-releasing hormone and, in
Cushing's syndrome, 613, 613f
secretion of, diurnal variation in, 634
Corticotropin stimulation test, in Addison's
disease, 636
Corticotropin-producing tumor, 769-770
Corticotropin-releasing factor, secretion of,
diurnal variation in, 634
Corticotropin-releasing hormone, plasma
corticotropin response to, in Cushing's
syndrome, 613, 613f
Cortisol, 634
adrenal, 572-573
serum levels of, measurement of, 636
Cortisone acetate, replacement therapy with,
after bilateral adrenalectomy, 617t
Cowden's syndrome, 235, 777
Creatinine, serum levels of, in primary
Cretinism, endemic, iodine deficiency
in, 16, 20
Cross-talk
in malignant progression, 300-301
in signal transduction systems, 274
Cryopreservation
of parathyroid tissue
current technique in, 530-531
function of, 531-532, 532t, 533f, 533t
historical aspects in, 530
in autotransplantation, 487, 523, 530-534
indications for, 532-534
reoperation and, 523, 533
research on, 534, 534t
technical issues in, 530-531
thawing technique in, 531
variations of, 531, 532t
of thyroid tissue, in autotransplantation, 691
CT. See Computed tomography (CT).
Culture medium, for cryopreservation of tissue,
530-531
Cushing's disease, 612
bilateral adrenalectomy for, 61tHi 17, 617t
steroid replacement therapy after, 617t
irradiation for, 615
laparoscopic adrenalectomy for, 648
medical therapy for, 616
selective transsphenoidal microsurgery
for, 615
therapeutic approaches to, 617, 617f
treatment of, 614-617, 617t
Cushing's syndrome, 612-619
adrenal mass in, 588
clinical features of, 612-613, 613f-614f,
613t
corticotropin-dependent, 612
corticotropin-independent, 612
treatment of, 618
cutaneous striae in, 612, 613f
definition of, 588
Cushing's syndrome (Continued)

dexamethasone suppression test for,
588-589, 613
diagnosis of, 613, 614f
ectopic, 612
diagnosis of, 613
treatment of, 617-618
epidemiology of, 612
evaluation of, algorithm in, 614, 616f
facial appearances in, 614f
imaging of, 577-579, 578f, 613-614,
615f
complications of, 65tHi57
metabolic manifestations of, 613t
MR imaging of, 614, 615f
pathogenesis of, 612
pituitary-dependent, 612. See also Cushing's
disease.
therapeutic approaches to, 617, 617f
treatment of, 614-617, 617t
scintigraphy of, 614, 615f
subclinical, screening for, 588-589
results of, 618, 619t
venous sampling in, 577
Cyanoglucosides, 19
Cyclic adenosine monophosphate. See
Adenosine monophosphate (AMP), cyclic.
Cyproheptadine, for carcinoid tumors, 803
Cyst(s)
adrenal, 587f
thyroid, fine-needle aspiration of, 89
Cytokeratin, 296
expression of, in anaplastic thyroid
carcinoma, 165
Cytokines. See also specific cytokine.
associated with regulation, 356
hypothyroidism from, 45, 46
Cytoreductive surgery, for unresectable
gastrinoma, 753
Cytoskeleton
actin microfilaments of, 296
cadherins and catenins of, 297-298, 298f
cell-cell contacts in, 296-297
integrins of, 297, 297f
intermediate filaments of, 296
microtubu1es of, 295
structure of, 295-301
Cytotoxic agents, for thyroid carcinoma,
antitumor activity of, 338
D
Dacarbazine, for islet-cell tumors, 802
De Quervain's thyroiditis
clinical presentation of, 36
differential diagnosis of, 36
etiology and pathogenesis of, 35-36
histologic features of, 36, 36f
treatment of, 36-37
Death
after surgery for hyperparathyroidism,
415--416,416t
premature, after parathyroidectomy, 406
Dehiscence, anastomotic, from invasive thyroid
Dehydroepiandrosterone
in placental estrogen production, 559-560
synthesis of, 571
Deiodinase, 5
Deiodination, 5
Delirium, in primary hyperparathyroidism, 406
Delta cells, pancreatic, 666. See also Pancreatic

islets, D cells of.
Deoxyribonucleic acid. See DNA entries.
Depression, in primary hyperparathyroidism,
406,407t
Depsipeptide, increased NIS gene expression
with,358
Dermopathy, in Graves' disease, 57, 59f
Desensitization, in signal transduction,
273-274,273f
DEXA scans, for bone disease, in
normocalcemic hyperparathyroidism, 422
Dexamethasone suppression test, for Cushing's
syndrome,588-589,613,648
Diabetes mellitus
glucagonoma and, 768-769
hypoglycemia in, 796
islet cell transplantation for, 697-698, 698f
pancreatic transplantation for, 697
primary hyperparathyroidism in, 408--409,
408t
type I
diabetic ketoacidosis in, 791
surgery in, 797-798
type 2
diabetic ketoacidosis in, 791
endocrine pancreas and, 709, 709f
hyperglycemic, hyperosmolar syndrome
in, 794
surgery in, 798
Diabetic ketoacidosis
biochemical changes in, 791, 792f
definition of, 791
hyperkalemia in, 793
hypertriglyceridemia in, 791
hyponatremia in, 793
insulin for, 791-792, 793f
metabolic acidosis in, 791
pathogenesis of, 791
treatment of, 791-793, 793f
vs. hyperglycemic, hyperosmolar syndrome,
794
Diarrhea, in VIPoma patients, 767
Diathermy, in thyroidectomy, restricted use of,
189
Diazepam-binding inhibitor, production of, in
pancreatic islet D cells, 705
Diazoxide, for hypoglycemia in insulinoma,
727
Diet, influences of, on thyroid carcinoma,
245,245t
DiGeorge syndrome, 3
Digestive tract, thyroid carcinoma invasion of,
318-332. See also Thyroid carcinoma,
aerodigestive invasion by.
Digital image, acquisition and analysis of,
in comparative genomic hybridization,
345-346,346f
1,25-Dihydroxyvitamin D. See also
Calcitrol.
in calcium homeostasis, 425
in malignancy-associated hypercalcemia,
538-539
postoperative, for hypocalcemia, 388
Diiodotyrosine, synthesis of, 4f, 5
Diuretics, loop, for hypercalcemic crisis, 546
DMSO solution, in crypopreservation of tissue,
531
DNA, for hybridization
extraction of, 344
labeling of, 344
DNA assessments, in parathyroid carcinoma,
552
812 - - Index
DNA cytometry, of anaplastic thyroid
carcinoma, 160
Doxazosin, before pheochromocytoma surgery,
626
Doxorubicin, for anaplastic thyroid carcinoma,
162,804
DPC4 tumor suppressor gene, 765
Drug(s). See also specific drug or drug group.
causing Addison's disease, 639, 639t
Duodenotomy, in Zollinger-Ellison syndrome,
733, 738
Duodenum
carcinoid tumors of, 782f
treatment of, 785
somatostatinoma of, 765f
tumors of, in multiple endocrine neoplasia I,
681-682
Dysphagia, in intrathoracic goiter, 310
Dyspnea, after thyroid surgery, 211
E
Edema
in thyroid surgery, 208
periorbital, in hypothyroidism, 47, 47t
postoperative, in neck dissection, 203
Electroencephalopathy, preoperative, in
primary hyperparathyroidism, 407
Embryogenesis, of thyroid gland, 3, 4f
EMG syndrome, 774
En bloc resection
for aerodigestive invasive thyroid carcinoma,
327
thyroid carcinoma, aerodigestive invasion by,
surgery for, 327
Endocrine deficiency states, 692t
hormone replacement therapy for, 691
Endocrine glands. See also specific gland.
adenomatosis of, 757
autoimmune disorders of, in Hashimoto's
thyroiditis, 46
neoplasms of, chemotherapy for, 800-804
Endoscopy
for advanced thyroid cancer, in upper airway,
319,319f
in parathyroidectomy, 467-471. See also
Parathyroidectomy, endoscopic.
Endothelium-independent vasodilation, impaired,
Enoxaparin prophylaxis, after adrenalectomy,
Environment, effect of
on goiter, 25
on Hashimoto's thyroiditis, 39
Environmental radiation, exposure to, thyroid
carcinoma from, 243-245, 244f
Epidermal growth factor(s), 256
in invasive thyroid carcinoma, 299-300, 300f
in thyroid growth regulation, 77, 271-272,
272f
Epidermal growth factor receptor, 259
and neu/HER2/erb-B2 and c-met gene, 284
overexpression of, in thyroid carcinoma,
339
Epidermal growth factor-transforming growth
factor-a, in thyroid growth regulation,
258-259
Epinephrine, 557
degradation of, 574, 574f
ERB2 family, of tyrosine kinase receptors,
in thyroid carcinoma, 339
c-erb-Z oncogene, 290t, 291
epidermal growth factor receptor and, 284
overexpression of, in thyroid neoplasms,
284t
Esmolol
during pheochromocytoma surgery, 626
Esophagus
displacement of, in intrathoracic goiter, 310
thyroid carcinoma invasion of
papillary, 144-145
surgery for, 329
Etidronate, for hypercalcemia, in parathyroid
carcinoma, 552
Etoposide
for carcinoid tumors, 803
Euthyroidism, clinical, 19
Exercise
hyperglycemia and, 710
hypoglycemia after, 717
F
Facial nerve, marginal branch of, in neck
dissection, 200
Familial adenomatous polyposis, 776-777
thyroid carcinoma associated with, 235-236,
235f
Familial hyperinsulinemia, 774
Familial hyperparathyroidism. See
Hyperparathyroidism, familial.
Familial hypocalciuric hypercalcemia. See
Hypercalcemia, benign familial
hypocalciuric.
Familial non-MEN medullary thyroid
carcinoma, 129-130, 130t, 13It.
See also Thyroid carcinoma, medullary.
preventive surgery for, 134-135
Familial pheochromocytoma, 776. See also
Pheochromocytoma.
Family history, goiter recurrence associated
with, 305-306
Fasting, hypoglycemia after, 717, 795t,
796, 797
Fasting test, for insulinoma, 718, 718f
interpretation of, 718-719
Fatigue, in primary hyperparathyroidism, 407
Fatty acids, aromatic, in thyroid tumor growth
Fever, in thyroid storm, 218
Fibroblast growth factor(s), 256
in parathyroid cell growth regulation, 377
in thyroid growth regulation, 259, 259f
Fibroblast growth factor receptor, 259
Fibronectin receptor, 297
Fibro-osseous tumors, of jaw
in hereditary hyperparathyroidism, 774-775
in non-MEN familial hyperparathyroidism,
494
Fibrosis
postoperative, around recurrent goiter, 306
pulmonary, risk of, radioiodine therapy and,
157
Fine-needle aspiration biopsy
of acute suppurative thyroiditis, 35
of adrenal carcinoma, 590
of anaplastic thyroid carcinoma, 160
of follicular thyroid carcinoma, 118, 118f
of Htirthle cell neoplasms, 125
of papillary thyroid carcinoma, 104
of parathyroid hormone in tissue samples,
475
of parathyroid tumor, 434
of plasmacytoma, 168
of spontaneous nontoxic goiter, 29
of thyroid carcinoma, in children, 96
of thyroid cysts, 89
Fine-needle aspiration biopsy (Continued)

of thyroid lesions, interpretation of, 236
of thyroid lymphoma, 175
of thyroid nodules, 87-89, 295
cytologic features in, 88f-89f
showing Htirthle cells, 124f
Flavonoids, 19
Fluorhydrocortisone, replacement therapy with,
after bilateral adrenalectomy, 617t
Fluorodeoxyglucose positron emission
tomography
of adrenal carcinoma, 590, 591f
of advanced thyroid cancer, 320
of metastatic thyroid carcinoma, 148-149
5-Fluorouracil
for anaplastic thyroid carcinoma, 162
for medullary thyroid carcinoma, 135
5-Fluorouracillstreptozocin, for islet cell
tumors, 802
Focal adhesion kinase, 297
Follicular thyroid carcinoma. See Thyroid
carcinoma, follicular.
Food
intake of, endocrine pancreas after, 711
iodine in, 18-19
c-fos protooncogene, 285, 291-292
Fracture, risk of, in hyperparathyroidism,
421-422
G
G proteins. See Guanine nucleotide-regulatory
proteins.
Gagner procedure, for parathyroidectomy,
462, 463f
Ganglioneuroblastoma, 560
Ganglioneuroma, from sympathetic ganglion
cells,560
Ganglioneuromatosis, of lips and tongue, 759f
Gardner's syndrome, 776-777
thyroid carcinoma associated with, 235-236,
235f
Gastrectomy, for gastrinoma, 753
Gastric acid hypersecretion, 745, 746f
analysis of, 747
pharmacologic control of, 747
Gastric inhibitory polypeptide, in insulin
secretion, 707
Gastrin
physiology of, 745, 747-748
serum concentration of, after secretin
injection, 748, 748f
Gastrinoma, 745-754, 801
angiography of, 750
calcium infusion test for, 748
CT scan of, 732-733, 733f, 734t, 749
diagnosis of, 746, 748
familial, 745
surgery for. 751
gastrectomy for, 753
gastric acid hypersecretion in, 745, 747
gastrin secretion in, 745
liver metastases in, 753
localization studies for, 732-733, 732f-734f,
734t
preoperative, 748-750, 749t, 750f
recommendations in, 733
malignant, 746
medical management of, 750-751
vs. surgery, 750. See also Gastrinoma,
surgery for.
metastatic, treatment of, 753-754
morphology of, 746
Index - - 813
Gastrinoma (Continued)
MR imaging of, 749
pancreatic, 753
pathology of, 746
peptic ulcer in, 745, 747
portal venous sampling of, 750
provocative tests for, 748, 748f
SASI test for, 750, 750t
secretin injection test for, 748, 748f
selective arterial, 750, 750t
somatostatin receptor scintigraphy of, 733,
733f, 734t, 749
sporadic, 745
etiology of, 747
surgery for, 738-739, 751
procedure of choice in, 752-753
staging of, 754
standardized meal test for, 748
surgery for, 738-739, 751
assessment of cure after, 753
follow-up after, 753
in multiple endocrine neoplasia I,
741-742, 742f
intraoperative maneuvers in, 751-752,
752f
ultrasonography of, 732, 732f, 734t, 749
endoscopic, 749-750
intraoperative, 733, 734f
unresectable, cytoreductive surgery
for, 753
Gastrinoma triangle, 670f, 732
Gastrin-releasing polypeptide, 706
Gastritis, Helicobacter pylori, 748
Gastrointestinal tract
hamartomatous polyps of, 777
Geldanamycin, for thyroid carcinoma,
antitumor activity of, 338
Gemcitabine, for thyroid carcinoma, antitumor
activity of, 338
Gene(s). See also specific gene.
for parathyroid hormone, 373, 374
in thyroid carcinoma, 233-236
Gene therapy
for differentiated thyroid carcinoma,
336-338,338-339
Genetic factors
in Hashimoto's thyroiditis, 39
in sporadic nontoxic goiter, 24-25
Genetic testing, for hereditary medullary
Genomic hybridization, comparative.
See Comparative genomic hybridization.
Gerota's fascia, of adrenal glands, 561
Ghrelinoma, 770
Giant cells, in anaplastic thyroid carcinoma,
160, 160f, 23lf
Glucagon
production of, by pancreatic islet A cells,
704
secretion of, somatostatin inhibition in,
705
Glucagon test, for insulinoma, 719
Glucagonoma, 768-769, 769f
skin rash in, 738
surgery for, 739, 769, 80 I
Glucocorticoid response elements, 558
Glucocorticoids. See also Corticosteroids.
synthesis of, in adrenal glands, 634
Gluconeogenesis, in diabetic ketoacidosis,
791,792f
Glucose. See also Hyperglycemia;

Hypoglycemia.
blood levels of
in diabetic ketoacidosis, 792
in insulinoma, 717, 718f
preoperative management of, 724--725
GLUT-2 transport of, 707
homeostasis of, physiology of, 789-790
impaired tolerance to
in primary hyperparathyroidism, 408-409,
408t
metabolism of
hormonal regulation of, 790
overview of, 789-790
Glucose tolerance test, for insulinoma, 719
Glucose-dependent insulinotropic polypeptide,
GLUT-2, glucose transport by, 707
Glycolysis, in diabetic ketoacidosis, 791, 792f
Goiter(s). See also Thyroid nodule(s).
diffuse, in Graves' disease, 57, 58f
endemic, 16-22
classification of, 20, 20f
clinical presentation of, 20-21, 20f-2lf
cyanoglucosides and, 19
diagnosis of, 20-21
goitrogens and, 19
in children, 20
iodine deficiency in, 18-19, 18t, 19t, 26
large mechanical problems associated
with, 20, 21f
malignancies and, 20-21
malnutrition and, 19
morphologic changes in, 19-20
nodular, 20
prevalence of, 16-18, 17t, 18f
prevention of, 16
prophylaxis for, 21-22
radiation therapy for, 22
surgery for, 22
thyroxine therapy for, 22
total goiter rate in, 17-18, 18t
in Graves' disease, 57, 59f
intrathoracic, 308-316, 310, 311f
airway obstruction in, 309
case studies of, 309, 312, 313, 315
chest radiograph of, 31Of,311, 312f, 315f
clinical presentation of, 309-311, 309t,
31Of-31lf
CT scan of, 310f, 311-312, 315f
definition of, 308
esophageal displacement in, 310
hyperthyroidism in, 310-311
incidence of carcinoma in, 311, 311t
laryngeal nerve entrapment or distortion
in, 309
laryngoscopy of, 313
MR imaging of, 315f
preoperative imaging and assessment of,
311-313,312f
prevalence of, 308
removal of, 194
scintigraphy of, 312-313, 312f
cervical approach to, 313-314
complications after, 316
mediastinal approach to, 314--315
sternotomy in, 314, 314t
thoracotomy in, 315-316
thyroid function tests in, 313
Goiter(s) (Continued)
vocal cord paralysis in, 309-310
multinodular
dominant nodule within, 86f
thyrocyte regulation in, 73
thyroid tissue autotransplantation
for, 692
thyroid-stimulating hormone suppressive
therapy for, 73-74, 74t
toxic, 64-66. See also Plummer's disease.
nodular
formation of, 26, 26f
prevalence of, 68
therapy for, 73
toxic. See Graves' disease;
Hyperthyroidism.
recurrent, 304--308
after initial surgery, 306
case studies of, 306, 308
cause(s) of, 304--306
extent of initial surgical procedure as,
304-305
other factors as, 305-306
postoperative thyroxine
supplementation as, 305
compartmental syndromes in, 306
hyperthyroidism in, 306
preoperative assessment of, 306-307
prevalence of, 304
surgical approach to, 307-308
complications after, 308, 308t
sporadic nontoxic, 24--31
causes of, 24-25
clinical evaluation of, 27-28
environmentally induced, 25
genetic factors in, 24-25
growth of, 25-26
history of, 27-28
intervention vs. observation for, 26-27
management of patients with, 27
natural history of, 26
pathogenesis of, 25-26, 26f
physical examination of, 28
radioiodine ablation therapy for, 29, 30t
thyroidectomy for, 29-30, 30t
treatment options for, 30t
substernal. See Goiter(s), intrathoracic.
types of, 25t
Goitrogens, 19, 26
natural, 19
Graves' disease, 55-56, SSt
antithyroid drugs for, 59-60, 60t
clinical manifestations of, 57, 58f-59f
diagnosis of, 57-58, 59t
epidemiology of, 55, SSt, 57
historical aspects of, 54, 55f
pathogenesis of, 56f, 57
radioiodine therapy for, 60-61, 60t
surgery for, 60t, 61-64, 6lf, 63f
indications for, 6lt
thyroid tissue autotransplantation for, 692
treatment of, 58-64
adverse effects of, 60t
GRFoma (growth hormone-releasing factor
tumor), 769, 770t
Growth factor(s). See also specific growth
factor.
stimulatory and inhibitory, in thyroid cell
proliferation, 256, 257t
814 - - Index
Growth factor-tyrosine kinase, in thyroid
growth regulation, 271-272, 272f
Growth hormone-releasing factor tumor
(GRFoma), 769, 770t
gsp oncogene
in oncogenesis, 291
in thyroid neoplasms, 265, 282, 282f, 283t
Guanine nucleotide-regulatory proteins,
266-267,267f
in insulinomas, 715
mutations in, 281-282, 282f, 283t
Guanosine diphosphate, 266
Guanosine triphosphate, 266
Guanylyl nucleotide regulatory proteins,
266-267
GVASl gene, in pseudohypoparathyroidism,
528
H
Hamartoma(s)
multiple, 235, 777
parathyroid, 370
Hashimoto's thyroiditis
clinical course of, 40, 40f
clinical presentation of, 39-40
cytologic features of, 88f
diagnosis of, 40
hypothyroidism from, 44-46
prevalence of, 38
treatment of, 40
Heart disease, ischemic, thyroxine and, 71
Helicobacter pylori gastritis, 748
Hemithyroidectomy. See also Thyroidectomy.
for papillary thyroid carcinoma, 102-108
advantages and disadvantages of,
103-104, 100t
considerations in, 102-103, 103t
lymph node dissection with, 106-107,
107f-108f
postoperative adjuvant therapy with,
107-108
rationale and indications for, 104-106,
105f-l06f
survival rates in, 105t, 106
Hemorrhage
bilateral adrenal
Addison's disease related to, 637-639
causes of, 637t
in thyroid nodule growth, 26
control of, 189
Hemorrhagic stress, increased plasma glucose
during, 710
Henry procedure, for parathyroidectomy,
463,463f
Heparin, in bilateral adrenal hemorrhage,
637-638
Heparin prophylaxis, after adrenalectomy, for
Cushing's syndrome, 616
Hepatic artery chemoembolization, for
insulinoma, 728
Hepatocyte growth factor(s), 256
in thyroid growth regulation, 260
Hepatocyte growth factor receptor, 260
Hepatocyte growth factor/scatter factor, and
invasion in thyroid carcinoma, 300
HER (c-erb-Z) oncogene, 290t, 291
overexpression of, in thyroid neoplasms, 284t
Hereditary central hypothyroidism, 47

Hereditary hyperparathyroidism-jaw tumor
syndrome, 774-775
Hereditary hyperthyroidism, 775
Histone acetyltransferase, 358
Histone deacetylase, 358
Histone deacetylase inhibitor
as anticancer agent, 358
in thyroid tumor growth inhibition and
redifferentiation, 336, 337f
Hoarseness, postoperative, in thyroid surgery,
211
Honnone(s). See also specific hormone.
glucose metabolism regulation by, 790
secretion of, by carcinoid tumors, 782, 783t
Hospital lethality, in surgery for
aerodigestive invasive thyroid carcinoma,
329,329t
HRPT2 gene
mutation of, 775
Hiirthle cell(s), 123
in adenoma, 123, 124f, 228
in Hashimoto's thyroiditis, 39, 39f
in thyroid nodule, 123, 124f
Hiirthle cell neoplasms, 123-127
capsular invasion in, 125f
classification of, 123
clinical characteristics of, 123-124
comparative genomic hybridization in,
347-349, 348f, 348t, 349t
demographics of, 124
diagnosis of, 124-125
frozen section of, 125
histology of, 123-124, 124f
histopathology of, 124, 125f
historical background on, 123
origin of, 123
postoperative follow-up for, 127
prediction of malignancy in, tumor size as,
125, 125f
presentation of, 124
prognosis of, 127
radioiodine therapy for, 127
risk factors for, 124
surgery for, 126-127, 126f
vascular invasion in, 125f
Hiirtble cell nodule, 229
Hydrocarbons, carcinogenic effect of, 246
Hydrocortisone, replacement therapy with
after bilateral adrenalectomy, for Cushing's
disease, 617t
for decompensation in thyroid storm, 218
for myxedema coma, 221
preoperative, for hypothyroidism, 50
Hyperadrenocorticism. See Cushing's
syndrome.
Hyperaldosteronism, 595-602
aldosterone-producing adenoma and,
597-598
ACTH infusion and, 599
surgery for, hypertension after, 600-60 I,
60 It
venous sampling in, 599, 600t
biochemical studies of, 597-598
clinical characteristics of, 596
diagnosis of, 597
hyperparathyroidism in, 596
idiopathic, 597-598
laparoscopic adrenalectomy for, 600, 648
Hyperaldosteronism (Continued)
localization studies of, 598-599, 598f-599f,
600t
pathologic features of, 595, 596f
primary
imaging of, 579-580, 579f
subtypes of, 595
prolactinoma in, 596
screening for, 596-597
surgical treatment of, 599-600
persistent hypertension after, 600-60 I,
60 It
results of, 600-60 I
Hypercalcemia
benign familial hypocalciuric
CASR gene in, 386, 496
parathyroid hormone levels in, 386, 450
vs. non-MEN familial
vs. primary hyperparathyroidism, 386
calcium serum levels in, 394, 544
causes of, 534-544
differential diagnosis of, 385t, 544t
health survey screening for, 393-394
follow-up of, 394-395, 395f
in parathyroid hyperplasia, 482
in renal transplant recipients, 504
malignancy-associated, 384, 450, 536-540
biochemical characteristics of, 385t
clinical syndrome of, 536
differential diagnosis of, 539-540
1,25-dihydroxyvitamin Din, 538-539
osteolytic, 539
parathyroid hormone secretion in, 539
parathyroid hormone-related protein in,
536-538, 537f-538f, 538t
pathogenesis of, 536-539
prostaglandins in, 539
syndromes of, 543-544
treatment of, 540
tumor types in, 536, 537t
persistent, after renal transplantation,
510--511
prevalence of, 394, 394f
progression of
rapid, 397-398
risk of, 395
relapsing, after renal transplantation, 511
screening for, 393-394, 394f
subacute severe, after renal transplantation,
510
survival in, 394-395, 395f
transient, after renal transplantation, 510
Hypercalcemic crisis, 543-547
etiology of, 543-544
in pregnancy, 545
incidence of, 543
treatment of, 545-547, 546t, 547f
Hypercalcitoninemia, in medullary thyroid
carcinoma, 135
Hypercalciuria, in normocalcemic
Hypergastrinemia
differential diagnosis of, 748t
effects of, 745, 746f
evaluation of, 747-748
progression of, after gastrinoma surgery, 753
Hyperglycemia
exercise and, 710
hemorrhagic stress and, 710
in VlPoma patients, 767
Index - Hyperglycemia (Continued)

insulinoma resection and, 725
sepsis and, 710--711
Hyperglycemic, hyperosmolar syndrome
definition of, 793
algorithm for, 794f
Hyperglycemic crisis, 791-795. See also
Hyperglycemia; specific disorder,
e.g., Diabetic ketoacidosis.
Hyperinsulinemia, 408
familial, 774
Hyperinsulinism, ectopic (Anderson's
syndrome), 606, 607f
Hyperkalemia, in diabetic ketoacidosis, 793
Hyperlipidemia
Hyperparathyroidism
asymptomatic, 419-422
existence of, 419-420
historical perspective in, 419
osteitis fibrosa cystica in, 419
PAS scores in, 420-421, 421f-422f
quality of life (QOL) score in, 420
renal calculi in, 419
standardized health assessment tool
(SF-36) used in, 420
surgery for, NIH-sponsored guidelines for,
419,421,421f
utilization of outcome patient-based
instruments in, 420-421, 421f-422f
familial
489-491
in multiple endocrine neoplasia 2, 491
neonatal, 498
non-MEN,493-498
in hyperaldosteronism, 596
mediastinotomy for, 446
multiple endocrine neoplasia l-associated,
calcium sensor protein in, 377
neonatal, 483
non-MEN familial, 494t
age in, 493-494
clinical features of, 493-494, 495t
diseases associated with, 494
fibro-osseous tumors in, 494, 774-775
mechanism of inheritance of, 494
parathyroid cancer and, 497-498, 497t
persistent (recurrent) disease in, 495, 495f
surgery for, 495
thyroid disease with, 494
normocalcemic, 386,424-428
bone disease in, 427
calcium loading study of, 427-428, 428f
diagnostic studies of, 427-428, 428f
ionized calcium in, 425
renal calculi in, 425-427, 426f
ultrafiltrable calcium in, 425
parathyroid hormone secretion in, regulation
of,376-377
persistent. See Hyperparathyroidism,
recurrent (persistent).
primary
bone densitometry studies in, 386,
398-399
bone mass loss in, 387, 399
calcium concentrations in, 387, 397, 397f
Hyperparathyroidism (Continued)
carbohydrate metabolism in, 408-409,
408t
cardiovascular disease in, 405-406
chondrocalcinosis in, 409
classification of, 402, 403t
clinical findings in, 403t
clinical manifestations of, 384-385, 385t
confusion and delirious states in, 406
conservative management of, follow-up in,
395-398, 396t, 397f
creatinine levels in, 396
depression in, 406, 407t
diabetes mellitus in, 408-409, 408t
diagnosis of, 384-386, 450
epidemiology of, 393-394, 394f
etiology of, 449
fatigue in, 407
histopathologic varieties of, 456-457,
457f
hypercalcemia in, 393-394, 394f, 543
survival and, 394-395, 395f
hypertension in, 399, 402-405, 404t
hyperuricemia in, 409
in postmenopausal women, 393, 399
laboratory findings in, 385-386, 403t
lipoprotein metabolism in, 409
metabolic complications of, 402-410
severity of, 402, 403t
mild,450
multiple endocrine neoplasia I in, 673,
674t, 675--681
localization studies of, 676
management of, 676--677
surgical approach to, 677
muscle weakness in, 407
natural history of, 393-400
neuromuscular disease in, 407-408
nonsurgical approach to, Consensus
Development Conference guidelines
in, 387, 387t
osteitis fibrosa cystica in, 386, 398
parathyroid hormone concentration in,
385-386
parathyroidectomy for. See also
Parathyroidectomy.
benefits of, 450
bilateral approach to, 449-454
endoscopic,467-471
indications for, 386-387, 387t, 449
revised, 387
intraoperative PTH assay in, 472-479.
See also Parathyroid hormone
assay.
minimally invasive, 462-466
rationale for, 388, 388f-390f, 390
strategy in, 450-452, 45lt, 452f
unilateral approach to, 456-460
PAS scores in, 420-421, 421f-422f
physical examination of, 385
population screening for, 393-394
progression of, 395, 397, 398-399
pseudogout in, 409
psychiatric disorders in, 406-407, 407t
radiologic studies of, 386
renal calculi in, 396, 397
renal failure in, 399
renal function in, 396
standardized health assessment tool
(SF-36) used in, 420
causes of death from, 415-416, 416t
815
cure following, 413
long-term mortality after, 413-414,
414t,415t
natural history after, 413-417
postoperative mortality after, 413, 414t
risk factors associated with, 414-415,
415f,415t
symptoms and associated conditions in,
384,385t
Visual Analog Scale (VAS) questionnaire
for, 385
vs. benign familial hypocalciuric
hypercalcemia, 386
vs. malignancy-associated hypercalcemia,
384, 385t
recurrent (persistent), 430-436
after surgery, 518-519
arteriography of, 434
CT scan of, 431
677-679,678t,680f-68If
surgical approach to, 679-681,
679f-680f
results of, 681, 68lt
in non-MEN familial disease, 495, 495f
localization studies for, 430-435, 43lt
intraoperative, 435, 522-523
preoperative invasive, 433-435, 434f
preoperative noninvasive, 430-433,
43lf-433f, 434t, 521, 522f
sensitivity of, 435t
medical therapy for, 52 I
MR imaging of, 431 , 43 If
parathyroid hormone assay in, 434-435
radio-guided parathyroid surgery in, 435
reoperation for, 518-525. See also
Parathyroid gland(s), reoperation on.
technetium 99m sestamibi scintigraphy of,
432-433,432f-433f
thallium 20I-technetium 99m pertechnetate
scintigraphy of, 431-432
ultrasonography of, 430-431, 431f
intraoperative, 435
secondary
after renal transplantation, 504
clinical manifestations of, 507
anemia in, 506
before renal transplantation, 502-504
bone disease in, 505-506
bone resistance to parathyroid hormone in,
503-504
calciphylaxis in, 506
calcitrol secretion in, 504
calcitrol synthesis in, diminished, 503
clinical manifestations of, 505-507
extraskeletal calcification in, 506
hyperlipidemia in, 507
hypertension in, 506-507
hypocalcemia in, 502-503
impaired phagocytosis in, 507
insulin resistance in, 506
metabolic complications of, 502-507
parathyroid autonomy in, 504
parathyroid hormone in
nonsuppressible secretion of, 504
parathyroid gland involution and, 504
set-point changes and, 504
phosphate retention in, 503
pruritus in, 506
816 - - Index
renal,502
after renal transplantation, 510-511,
SIlt
anemia after, SIS
before renal transplantation, 510, SIlt
bone disease after, SIS
calcium metabolism after, SIS
care before, 511
clinical course of, 514-515
critical criteria in, 512
localization studies in, 511-512
selection of procedure in, 512-514,
513t
uremic osteodystrophy in, 505-506
Hyperphosphatemia, in chronic renal failure,
503
Hyperplasia
adrenal, Cushing's syndrome from, 618
parathyroid. See Parathyroid hyperplasia.
thyroid. See Thyroid hyperplasia.
Hypertension
after adrenalectomy, 600-601, 60 It
in pheochromocytoma, 621, 622
in primary hyperparathyroidism, 399,
402-405, 404t
Hyperthyroidism
hereditary, 775
in Graves' disease, 55, SSt. See also Graves'
disease.
pathogenesis of, 56f, 57
in intrathoracic goiter, 310-311
in Plummer's disease, SSt, 65
in recurrent goiter, 306
Jodbasedow. Zf
Hypertriglyceridemia, in diabetic ketoacidosis,
791
Hyperuricemia, in primary
Hypoacidemia, in glucagonoma, 768
Hypocalcemia
after parathyroidectomy
for hyperplasia and hyperparathyroidism,
486t
for secondary hyperparathyroidism, 514
1,25-dihydroxyvitamin D for, postoperative
use of, 388
postoperative, 444
in bilateral thyroidectomy, 213
transient, after parathyroidectomy, 514
Hypocalciuria, in benign familial hypocalciuric
hypercalcemia, 496
Hypochondria, in VIPoma patients, 767
Hypoglycemia
alcohol-induced, 717, 796
alimentary, 795-796
autoimmune, 797
definition of, 795
differential diagnosis of, 716-717, 717t, 795t
endocrine pancreas and, 710
endogenous causes of, 796-797
exogenous causes of, 796
fasting, 717, 795t, 796, 797
in insulinoma, 716-717
diazoxide for, 727
long-term therapy for, 727-728
Hypoglycemia (Continued)
somatostatin analogs for, 727
in myxedema coma, 220
insulin-independent, 796-797
insulin-mediated, 796
postprandial, 795-796, 795t
reactive, 796
treatment of, 797
tumor-induced, 797, 797f
Hypoglycemic crisis, 795-797. See also
Hypoglycemia.
Hyponatremia
in diabetic ketoacidosis, 793
Hypoparathyroidism
after thyroid surgery, 212-213
for recurrent goiter, 308
after thyroidectomy, for Graves'
disease, 62
permanent
after childhood thyroidectomy, 97, 97t
postsurgical, 413, 527-528, 528t
treatment of, 528
Hypophosphatemia, 408
Hypothermia, in myxedema coma, 220
Hypothyroidism, 44-51
after thyroid surgery, 213
amiodarone and, 45
autoimmune endocrine disorders and, 46
causes of, 44-47
central,47
cervical irradiation causing, 46
clinical features of, 44-47
congenital, 47
cytokines and, 46
drug-induced, 25
Hashimoto's thyroiditis causing, 44-46
increased thyroid hormone destruction
and,47
iodide-induced,47
iodination for, 51
iodine deficiency and, 46-47,51
iodine excess and, 45
iodine therapy causing, 46
laboratory evaluation of, 48
lithium and, 45-46
neonatal screening for, 51
postoperative
prevention of, 51
thyroid tissue autotransplantation for,
691-692,692f
pregnancy and, 45
prevalence of, 44
prevention of, 51
signs and symptoms of, 47-48, 47f, 47t
smoking and, 45
subclinical, 44
levothyroxine treatment and, 70, 71
subtotal thyroidectomy causing, 46
surgery for
approach to, 49-50
care in, 50, SOt
complications of, 50, SOt
thyroid hormone resistance and, 47
thyroid lymphoma and, 46
thyroxine therapy for, 48-49
adverse effects of, 49
maintenance dose of, 49
total thyroidectomy causing, 46
triiodothyronine therapy for, 48-49
coronary bypass surgery and, 50-51
Hypoventilation, in myxedema coma, 220
I
IGF2 gene, 774
Imamura method, for insulinoma localization,
732
Immunohistochemical staining, of recurrent
Immunometric assays, of parathyroid hormone,
379
Incidentaloma, adrenal, 586-592. See also
Adrenaloma.
Incretins, in insulin secretion, 707
Infection
bacterial, in acute suppurative thyroiditis, 34
wound
in neck dissection, 203
Innervation. See also specific nerve.
of adrenal glands, 563-564
of pancreas, 669-670
of pancreatic islets, 706
Innominate artery, rupture of, from invasive
thyroid carcinoma surgery, 330
Insular carcinoma, of thyroid, 170-171, 171f,
230. See also Thyroid carcinoma.
Insulin
deficiency of, diabetic ketoacidosis from,
791
exogenous administration of, hypoglycemia
from, 796
for diabetic ketoacidosis, 791-793, 793f
for hyperglycemic, hyperosmolar syndrome,
794-795,794f
perioperative administration of, for diabetic
patient, 798
plasma levels of, in insulinoma, 717, 718,
718f
production of, by pancreatic islet B cells,
702
resistance to, in secondary
secretion of. See also Insulinoma.
after food intake, 711
catecholamines in, 706
cell biologic processes in, 703f, 707-708
cholecystokinin in, 706
from pancreatic islet B cells, 703f, 716f
gastrin-releasing polypeptide in, 706
impaired, in chronic renal failure, 506
incretins in, 707
neuropeptide Yin, 706
pulsatility of, 708-709
somatostatin inhibition in, 705
vasoactive intestinal polypeptide in, 706
Insulin gene, RNA transcript of, 790
Insulin-glucose ratio, in insulinoma, 717
Insulin-like growth factor(s), 256
Insulin-like growth factor I, in thyroid growth
regulation, 271
Insulin-like growth factor receptor, 259
Insulinoma, 715-728
angiography of, 720, 72lf
arterial stimulation of, 720-722, 722f
C peptide measurement in, 718
calcium infusion test for, 719, 719f
clinical aspects of, 716-717
CTscanof, 720, 72lf, 730-731, 73lt
delays in, 716
differential diagnosis of, 717t
fasting test for, 718, 718f
interpretation of, 718-719
Index - -
Insulinoma (Continued)
glucagon test for, 719
glucose levels in, 717, 718f
glucose tolerance test for, 719
hepatic artery chemoembolization for, 728
hypoglycemia in, 716-717
diazoxide for, 727
long-term therapy for, 727-728
somatostatin analogs for, 727
in multiple endocrine neoplasia 1,715,
719,720f
insulin levels in, 717, 718f
insulin-glucose ratio in, 717
isotope-labeled somatostatin analysis of,
722, 723f, 723t
laparotomy for, 732
723t, 730-732, 731f, 73 It
benefits of, 724
recommendation in, 732
management of
intraoperative, 725
postoperative, 725
preoperative, 724-725
MR imaging of, 720, 731, 73 it
palpation of, intraoperative, 723
pathology of, 719, 720f
pathophysiology of, 715, 716f
percutaneous transhepatic portal venous
sampling of, 720, 721f, 731-732, 73 It
proinsulin measurement in, 718
provocative tests for, 719, 719f
serum glucose in, preoperative management
of,724-725
signs and symptoms of, 716, 716t
somatostatin receptors in, 722, 723t
surgery for, 725-727, 726f-727f, 737-738,
738f,742-743
care after, 725
care during, 725
failure of, 80 I
laparoscopic, 727
ultrasonography of, 720
endoscopic, 722-723, 724f, 730, 731t
intraoperative, 723, 724f-725f
venous sampling of, 720-722, 722f
Insulinotropic polypeptide, glucose-dependent,
Integrins, 296
malignancy and, 297, 297f
Interferon-a
for islet cell tumors, 802
hypothyroidism from, 45, 46
Interleukin(s), hypothyroidism from, 45, 46
Interleukin-Z, gene therapy using, for
differentiated thyroid carcinoma, 339
Interleukin-12, gene therapy using, for
differentiated thyroid carcinoma, 339
Intubation, of patient, with aerodigestive
invasive thyroid carcinoma, 322
Iodide
excess of, 25
metabolism of, 3-4
uptake of, 3-4, 4f
Iodide therapy, for thyroid storm, 217-218
Iodide transport deficiency, congenital,
mutations causing, 355, 357
Iodination
for goiter prophylaxis, 21
Iodination (Continued)
for hypothyroidism prophylaxis, 51
thyrotoxicosis from, 21
Iodine
deficiency of
endemic cretinism from, 16,20
endemic goiter from, 16,26
etiology of, 18-19, 18t, 19t
hypothyroidism from, 46-47
populations at risk for, 17, 17t, 18f
prevention of, implementation of salt
iodinization programs for, 21
severe, 19
spectrum of disorders in, 17t
dietary, 18
excess of, hypothyroidism from, 45
recommended daily intake of, 18t
Iodine therapy, radioactive. See Radioiodine
therapy; Scintigraphy, iodine 131.
Islet amyloid polypeptide, production of,
by pancreatic islet B cells, 703
Islet cells. See Pancreatic islets.
Islet cell tumors. See also Pancreatic tumors,
endocrine.
chemotherapy for, 728, 800-802, 80lt
enucleation of, 684f
sporadic, surgery for, 739, 741
Isotope scanning. See Scintigraphy.
Isthmectomy, 189
for follicular thyroid carcinoma, 119
for Hurthle cell neoplasms, 126
Isthmus, division of, for intrathoracic goiters,
194
J
Jaw, fibro-osseous tumors of
in hereditary hyperparathyroidism, 774-775
in non-MEN familial hyperparathyroidism,
494
Jodbasedow hyperthyroidism, 25
Jugular lymph nodes, metastases to, 197
Jugular vein, internal
bleeding of, in thyroid surgery, 208
in neck dissection, 200-201, 201f
intraoperative PTH assay sampling via,
475-476, 476f
c-jun protooncogene, 285, 291
K
Keratopathy, band, in primary
Ketoacidosis, diabetic. See Diabetic
ketoacidosis.
Ketoconazole, for Cushing's disease, 616
Kidney(s). See also Renal entries.
response of, to parathyroid hormone, 425
stones in. See Renal calculi.
Kocher maneuver
in adrenocortical carcinoma surgery, 608
in insulinoma surgery, 725, 726f
Kocher transverse collar incision, in modified
neck dissection, 200
Kulchitsky cells, in carcinoid tumors, 780
Kupffer cells, in parathyroid hormone
clearance by, 378
L
Langerhans tumors, 123. See also Hurthle cell
neoplasms.
Lanreotide, for islet cell tumors, 802
817
Laparoscopy
adrenalectomy with, 569, 647-660. See also
Adrenalectomy, laparoscopic.
diagnostic, of medullary thyroid carcinoma,
137, 137f
insulinoma resection via, 727
Laparotomy
for insulinoma, 732
for sporadic gastrinoma, 751
Laryngeal nerve
damage to, thyroidectomy causing, 97, 97t
entrapment or distortion of, intrathoracic
goiter and, 309
inferior, 13
recurrent, 12-13, 12f
in thyroid surgery, 62, 189-190, 191f
damage to, 208f-209f, 209-210
dissection of, 192-193, 193f
identification of, 210
protection of, 327
papillary thyroid carcinoma invasion of,
144
paralysis of, postoperative, 316
parathyroid glands and, 481, 482f
superior
in thyroid surgery
damage to, 211-212, 211f-212f
in thyroidectomy, 190-192, 191f
thyroid artery, 12, 12f
Laryngoscopy, of intrathoracic goiter, 313
Laryngotracheal resection, for
aerodigestive invasive thyroid
carcinoma, 324
types of, 324-327, 325f, 325t, 326f, 328f
Lethargy, in primary hyperparathyroidism, 406
Leukemia, risk of, radioiodine therapy and, 156
Levothyroxine. See also Thyroid-stimulating
hormone suppressive therapy;
Thyroxine (T4 ) .
angina and, 71
for benign goiters, 75-76
for diffuse goiter, 74-75, 75t
for multinodular goiter, 73-74
for thyroid carcinoma, 78-79, 79f
myocardial infarction and, 71
pharmacology of, 69
physiology of, 70
Lifestyle, effect of, on thyroid carcinoma,
245-246
Lipid metabolism, thyroxine and, 70-71
Lipoadenoma, parathyroid, 370
Lipoprotein
high-density/low-density, levothyroxine
effects on, 70
metabolism of, in primary
Lips, ganglioneuromatosis of, 759f
Lithium
causing hypothyroidism, 45-46
causing thyroid disorders, 25
Liver metastases
in endocrine pancreatic tumors, 764
in VIPoma, 768
in Zollinger-Ellison syndrome, 754
Lobectomy, thyroid, 189. See also
Thyroidectomy.
for follicular thyroid carcinoma, 119
for Hurthle cell neoplasms, 126
for multinodular goiter, goiter recurrence
after, 305
818 - -
Index
Lobectomy, thyroid (Continued)

for nodular disease, 90-91
for papillary thyroid carcinoma, 103,
l04t. 110
for Plummer's disease, 66
Lugol's solution, for thyroid storm, 218
Lungs
fibrosis of, risk of, radioiodine therapy
and, 157
metastases to
childhood thyroid carcinoma and, 96, 98,
98f,252
surgical management of, 154
Lymph nodes
biopsy of. in gastrinoma, 751, 752f
dissection of
hemithyroidectomy with, for papillary
thyroid carcinoma, 106-107,
107f-108f
in childhood thyroid carcinoma, 97
metastases to
bilateral intrathyroid tumors and,
133, l33t
childhood thyroid carcinoma and, 96
endocrine pancreatic tumors and, 764
insulinoma and, 726f
prognostic significance of, 198
neck dissection for, 198-200
technique of, 200-203, 201-202f
therapeutic strategy in, 203f, 204
regional recurrence of, 204
unilateral intrathyroid tumors and,
132t, 133
regional, surgical removal of, in medullary
thyroid carcinoma, 133-134, 133f
thyroidal, drainage of, 196
Lymphadenopathy, in childhood thyroid
carcinoma, 96
Lymphatic duct lesions, in thyroid surgery,
208-209,209f
Lymphoma, thyroid. See Thyroid lymphoma.
M
MACIS scoring system, for thyroid carcinoma,
251
papillary, 104
Magnetic resonance imaging (MRI)
of adrenal glands, 562f. 566, 576
of adrenocortical carcinoma, 607
of advanced thyroid cancer, in upper airway,
319,319f
of Cushing's syndrome, 6l4, 615f
of gastrinoma, 749
of insulinoma, 720, 731, 73lt
of intrathoracic goiter, 315f
of parathyroid gland adenoma, 431-432,
431
of pheochromocytoma, 581, 623, 623f-625f
of pituitary adenoma, 675f
hyperparathyroidism, 431, 431
Major histocompatibility complex (MHC)
barriers, thyroid transplantation across,
allogeneic bone marrow transplantation
in, 693
Malabsorption, thyroid-stimulating hormone
suppressive therapy in, 69, 70t
Malignancy. See also specific malignancy.
associated with Gardner's syndrome,
235-236,235~
776-777
hypercalcemia in, 536-540
Malignancy (Continued)
clinical syndrome of, 536
1,25-dihydroxyvitamin D and, 538-539
osteolysis and, 539
parathyroid hormone secretion and, 539
parathyroid hormone-related protein and,
536-538, 537f-538f, 538t
prostaglandins and, 539
treatment of, 540
tumor types in, 536, 537t
in endemic goiter, 20-21
in Hiirthle cell neoplasms, tumor size as
prediction of, l25, 125f
integrins and, 297, 297f
of adrenocortical tumors, criteria for,
604-605,605t
potential for, thyroid nodules and, 85, 86
progression of, molecular crosstalk in,
300-301
second, risk of, radioiodine therapy and, 157
Malnutrition, in endemic goiter, 19
Manumycinlpaclitaxel, for anaplastic thyroid
carcinoma, 163
Marafi6n's maneuver, in evaluation of goiter,
310
"Marfanoid" habitus, in multiple endocrine
neoplasia 2B, 759, 760f
Meal test, standardized, for gastrinoma, 748
Mediastinal tracheal resection, for
carcinoma, 327, 329
Mediastinotomy, 446
Mediastinum
adenoma of
arteriography of, 434, 434f
reoperation for, 525, 525f
exploration of, in parathyroid surgery, 522
goiter extension into. See Goiter(s),
intrathoracic.
goiters or thyroid tumors in, removal of, 194
lymph nodes of, metastases to, 197
Medullary thyroid carcinoma. See Thyroid
carcinoma, medullary.
MEN. See Multiple endocrine neoplasia
(MEN) entries.
MEN 1 gene, 673
mutations of, 673-674
menin gene, 399, 715
Menin protein, 673
Mental condition, of patient with
carcinoma, 32l
Meperidine, for decompensation in thyroid
storm, 218
Messenger RNA
for parathyroid hormone, 373-374
insulin, 702
MET oncogene, 290t, 291
Metabolic acidosis, in diabetic
ketoacidosis, 791
Metabolism
calcium, after parathyroidectomy, 515
carbohydrate, in primary
glucose
hormonal regulation of, 790
overview of, 789-790
iodide, 3-4
lipid, 70-71
lipoprotein, in primary hyperparathyroidism,
409
Metabolism (Continued)
parathyroid hormone, 378
thyroxine, 5
triiodothyronine, 5
Metalloproteinase(s)
antitumor effect of, 299
in malignancy, 298-299, 299t
enzymes implicated in, 299-300, 300f
overexpression of, in thyroid carcinoma, 339
Metalloproteinase inhibitors, for differentiated
thyroid carcinoma, 339-340
Metaphase spreads, preparation of, in
comparative genomic hybridization
analyses, 344, 345f
Metastasis. See also under specific cancer.
adrenal
bilateral, 639
imaging of, 582-583
distant
diagnostic procedures for, 152-153, 153f
location of, 152, 153t
prognosis of, 157
radioiodine therapy for. 154, 156-157,
156f
surgery for, 154, 154f-155f
thyroxine suppressive therapy for, 157
liver. See Liver metastases.
lymph node. See Lymph nodes, metastases to.
pulmonary. See Lungs, metastases to.
thyroid, 176-177, 176f
Methimazole
adverse effects of, 60, 60t
Metyrapone, for Cushing's disease, 616
Microcarcinoma, thyroid, 225
Microtubules, cytoskeletal, 295
Mifepristone, for Cushing's disease, 616
Minimally invasive parathyroid surgery,
462-466
advantages and disadvantages of, 464-465,
465f
results of, 465-466, 465t, 466t
techniques of, 462-463, 463f
Mitogen-active protein, 271
Mitogen-active protein kinase, 271, 272, 272f
Mitogenic pathways, in thyroid growth
regulation, 256-257, 258f
Mitotane
for adrenocortical carcinoma, 609-610, 803
preoperative, 608
survival associated with, 610f
Mitoxantrone, for anaplastic thyroid
carcinoma, 804
Molecular carcinogenesis, 245
Monoclonal antibody therapy. for differentiated
thyroid carcinoma, 339, 339f
Monoiodotyrosine, synthesis of, 4f, 5
MRI. See Magnetic resonance imaging (MRI).
MTS-l gene, 292
MTS-2 gene, 292
Mucoepidermoid carcinoma, of thyroid, 172.
See also Thyroid carcinoma.
Mucosa-associated lymphoid tissue (MALT)
lymphoma, of thyroid, 174-175,232.
See also Thyroid lymphoma.
Multimodality therapy, for anaplastic thyroid
carcinoma, 162-163
Multiple endocrine neoplasia I (MEN 1),
673-686
abnormal parathyroid glands in, 483
Index - Multiple endocrine neoplasia I (MEN I)

(Continued)
adenoma in, 675, 675f
carcinoid tumors in, 686, 781
endocrine pancreatic tumors in, 765-766
backgroundin,681-682,68If-682f
biochemical screening for, 682-683, 683t
imaging of, 683, 683f
incidence of, 770t
localization studies of, 733-735, 734f
surgery for, 683-684, 684t
epidemiology of, 673
familial hyperparathyroidism in, 489-491
clinical aspects of, 489
follow-up and screening for, 490-491
treatment of, 490
gastrinoma in, surgery for, 741-742, 742f
genetic counseling in, 674
genetic screening for, 674
hypercalcemia in, 496
hypoglycemic syndrome in, 684
insulinoma in, 715, 719, nOf
islet cell tumors in, 684
molecular biology of, 673-674
parathyroid cell proliferation in, 377
parathyroidectomy for, 452
pituitary tumors in, 674-675, 675f-676f
prevalence of, 673
primary hyperparathyroidism in, 673, 674t,
675-677
localization studies of, 676
surgery for, 677
recurrent (persistent) hyperparathyroidism
in, 677-679, 678t, 680f-681f
surgery for, 679-681, 679f-680f
results of, 681, 681t
vs. non-MEN familial hyperparathyroidism,
496-497
Zollinger-Ellison syndrome in, 734-735
surgery for, 684-686, 685f, 741-742,
742f
Multiple endocrine neoplasia 2 (MEN 2)
carcinoid tumors in, 781
familial hyperparathyroidism in, 491
gene carriers for, preventive surgery for,
134-135
in pheochromocytoma, 630-631
ret gene in, 491
497
Multiple endocrine neoplasia 2A (MEN 2A),
757
medullary thyroid carcinoma in, 129-130,
l30f-13lf, 130t, 13 It, 230
parathyroidectomy for, 452
ret mutations in, 134, 234
497
Multiple endocrine neoplasia 2B (MEN 2B),
757-763
amine precursor uptake and decarboxylation
in, 758
characteristics of, 757
clinical characteristics of, 758-762
diagnosis of, 762
historical considerations in, 757
"rnarfanoid" habitus in, 759, 760f
Multiple endocrine neoplasia 2B (MEN 28)

(Continued)
medullary thyroid carcinoma in, 129-130,
130f-131f, 130t, 13 It, 230, 760-761,
760f-76If
neuroma in, 759, 759f
pathogenesis of, 758, 758f-759f
pheochromocytoma in, 761-762
ret mutations in, 134,234,758, 758f-759f
screening for, 762
497
Multiple-gland disease, cryopreserved
parathyroid transplantation for, 533
Muscle weakness, in primary
c-myc protooncogene, 285
Myelolipoma, 587f
Myocardial infarction, levothyroxine and, 71
Myxedema, iodide-induced, 25
Myxedema coma, 219-221
cardiovascular complications in, 220
clinical manifestations of, 219-220
decreased mental function in, 220
diagnosis of, 220
hypoglycemia in, 220
hyponatremia in, 220
hypothermia in, 220
hypothyroidism in, 219
hypoventilation in, 220
metabolic complications of, 221
precipitants of, 217t
elimination of, 221
pulmonary complications in, 220
supportive care for, 221
thyroid hormone replacement therapy
for, 221
Myxoma, cardiac, in Carney's complex, 776
N
National Institutes of Health (NlH)-sponsored
guidelines, for parathyroidectomy, 419,
421,421f
Neck
exploration of, in parathyroid surgery,
521-522
irradiation of, hypothyroidism due to, 46
surgical anatomy of, 196-197
Neck dissection
lymph node metastases in, 199-200
surgical technique of, 200-203,
201f-202f
in parathyroidectomy, 442-443
incision in, 442
closure of, 444
radical, for Hiirthle cell neoplasms, 126,
126f
Needlescopic adrenalectomy, 654. See also
Adrenalectomy, laparoscopic.
Nelson's syndrome, after adrenalectomy, 617
Neonates. See also Children.
hyperparathyroidism in, 483
hypothyroidism screening in, 51
Neoplasms. See specific neoplasm.
Nephrolithiasis. See Renal calculi.
Nerve(s). See specific nerve, e.g., Laryngeal
nerve.
819
neu (c-erb-2) oncogene

overexpression of, in thyroid neoplasms,
284t
Neural crest, 9, 558
Neural tube, 558
Neuroblastoma, of primitive sympathogonia,
560
Neuroendocrine tumors, 780-786. See also
Carcinoid tumors.
Neurofibromatosis
Neurofibromatosis I, 777-778
Neurofibromatosis II, 777
Neuroglycopenia, 710
Neuroma, in multiple endocrine neoplasia 2B,
759, 759f
Neuromuscular disease, in primary
Neuropeptide(s), endocrine, 704t
Neuropeptide Y, as pancreatic neurotransmitter,
704, 706
Neurotensinoma, 770
Neurotransmitters
in pancreatic islets, 706
secretion of, by carcinoid tumors, 782, 783t
NIS gene
and thyroid carcinoma, 357-358
cloning of, 359
expression of
enhancement of, 358-359, 358f-359f
regulation of, 356
function of, regulation of, 356
molecular characterization of, 355-356, 357f
NIS gene therapy, for undifferentiated thyroid
carcinoma, 336-337
Nodule(s)
Hiirthle cell, 229
thyroid. See Thyroid nodule(s).
Non-islet cell tumors, hypoglycemia in, 797,
797f
Non-multiple endocrine neoplasia syndromes,
773-778. See also specific type,
e.g., Beckwith-Wiedemann syndrome.
Nonsteroidal anti-inflammatory drugs, for
subacute thyroiditis, 36
Nonthyroid illness, 48
Noonan's syndrome, 777
Norepinephrine, degradation of, 574, 574f
Nuclear explosions, radiation fallout from,
thyroid carcinoma and, 243-245, 244f
Nuclear oncogenes, 291-292
o
Octreotide
for VIPoma, 767, 768f
Oil iodination
Omeprazole
for gastric acid hypersecretion, 747
for gastrinoma, 751
Oncocytic adenoma, parathyroid, 370
Oncocytoma, 123. See also Hiirthle cell
neoplasms.
Oncogene(s). See also specific gene, e.g., gsp
oncogene.
activating G proteins in, 291
as growth hormone receptors, 283-285,
284t, 285t
dominant, 288
820 - - Index
Oncogene(s) (Continued)
in thyroid neoplasms, 280-286, 281f
nuclear, 285, 291-292
of thyroid-stimulating hormone, 280-283,
282f,283t
ras family of, 283, 284t
recessive, 288
tyrosine activity with, 283-285, 284t
Oncogene receptor protein, 288, 290t
Oncogenesis
genes involved in, 290t
multistep hypothesis of, 288, 289f
Ophthalmopathy, in Graves' disease, 57, 59f
Orphan Annie nuclei, in follicular variant of
papillary thyroid carcinoma, 117, 117f
Osteitis fibrosa cystica
in primary hyperparathyroidism, 386, 398,
419
Osteodystrophy, uremic, 505-506
Osteolysis, local, in hypercalcemia of
malignancy, 539
Osteoporosis, T score definition of, 427
Oxyphilic tumors, 123. See also Hiirthle cell
neoplasms.
P
p53 gene, 290t, 292
gene therapy with, for undifferentiated
in anaplastic thyroid carcinoma, 77, 159,
161, 161f, 162,232
Pain relief, for pancreatic cancer, 670
Painless thyroiditis, 37-38, 38f
Palliative procedures, for aerodigestive invasive
Palpation, intraoperative, of insulinoma, 723
Pamidronate
Pancreas
anatomy of, 665-670, 667f
arterial supply to, 667-668, 668f
anomalous, 668-669
body of, 667, 667f
cancer of. See also Pancreatic tumors;
specific tumor; e.g., Insulinoma.
chemotherapy for, 800-802, 801t
pain relief for, 670
divisions of, 666-667
ducts of, 669
ectopic, 665
endocrine
after food intake, 711
hypoglycemia and, 710
stress and, 710-711
type 2 diabetes and, 709, 709f
exocrine, 665-666
head of, 666-667, 667f
inflammation of, in kidney transplant
recipients, 507
islets of. See Pancreatic islets.
lymphatic drainage of, 668f, 669
neck of, 667, 667f
nerves of, 669-670
surgical exposure of, 670-671, 670f-671f
intraoperative assessment in, 671
Pancreas (Continued)
tail of, 667, 667f
transplantation of, 697
tumors of. See Pancreatic tumors.
uncinate process of, 667, 667f
ventral primordia of, 665, 666f
Pancreastatin, 378
production of, by pancreatic islet B cells,
703-704
Pancreatectomy
for gastrinomas, 752
for insulinomas, 726, 726f
laparoscopic, 727
Pancreatic accessory duct of Santorini, 669
Pancreatic cells, 665-666
Pancreatic duct of Wirsung, 669
Pancreatic islets
A cells of, 666, 701-702
glucagon production in, 704
peptide YY production in, 704
anatomy of, 701-702, 702f
B cells of, 666, 701, 702-704
biology of, 703f, 707-708
insulin production in, 702
insulin secretion in, 703f, 707-708
islet amyloid polypeptide production in,
703
neurosecretory granules of, 715, 716f
pancreastatin production in, 703-704
blood flow in, 705
catecholamine effects in, 706
cholecystokinin nerves in, 706
D cells of, 666, 701
diazepam-binding inhibitor production in,
705
somatostatin production in, 705
F cells of, 666, 701-702
pancreatic polypeptide production in, 705
function of, 701
hormone secretion in, 704t, 707
pulsatility of, 708-709
innervation of, 706
neurotransmitters of
parasympathetic effects of, 706
sympathetic effects of, 706
non-B cells of, biology of, 708
peptides and neuropeptides in, 704t
sensory nerves in, 707
transplantation of, 697-698, 698f
tumors of. See Pancreatic tumors, endocrine.
Pancreatic polypeptide, production of, in
pancreatic islet F cells, 705
Pancreatic polypeptide-producing tumor
(PPoma),770-771
Pancreatic tumors, endocrine, 764-771.
See also specific type, e.g., Insulinoma.
aggressive, characteristics of, 764-765, 765t
chemotherapy for, 728, 800-802, 80lt
classification of, 765, 765t
combination therapy for, 728
hepatic artery chemoembolization for, 728
in multiple endocrine neoplasia 1,673, 674t,
765-766
background of, 681-682, 681f-682f
biochemical screening for, 682-683, 683t
imaging of, 683, 683f
incidence of, 770t
localization studies for, 733-735, 734f
surgery for, 683-684, 684t, 741-742, 742f
734t
733-735,734f
Pancreatic tumors, endocrine (Continued)

nonfunctioning
localization studies for, 735
surgery for, 743
pathology of, 764-765, 765f
sporadic, surgery for, 737-739, 738f, 740f,
741
streptozocin for, 728
surgery for, 683-684, 684t, 737-743
principles in, 766
syndromes associated with, 765t
Pancreaticoduodenal artery, 667-668, 668f
Pancreaticoduodenal vein, 668, 668f
Pancreatitis, in kidney transplant recipients,
507
Pancytopenia, risk of, radioiodine therapy and,
156
Papillae, in papillary thyroid carcinoma, 224
Papillary thyroid carcinoma. See Thyroid
carcinoma, papillary.
Parafollicular (C) cells, in medullary thyroid
carcinoma, 129, l30f,229
Paraganglia, 560
Paraganglioma, 169, 170f,629-630
surgery for, 628
Paralysis. See under specific anatomic part.
Parathymus, 10
undescended, 481
Parathyroid artery, 441
Parathyroid carcinoma, 371, 371f, 549-553
biologic markers of, 550-551
DNA assessments in, 552
histopathologic characteristics of, 550,
55 If, 552t
hypercalcemia treatment in, 552
incidence of, 549, 550t
localization studies of, 549-550
non-MEN familial hyperparathyroidism
with, 497-498, 497t
prevalence of, 549
prognosis of, 552
recurrent, 552
vs. parathyromatosis, 552
Parathyroid cells
calcium sensor protein on, 375-376
proliferation of, 377
autocrine regulation of, 377-378
secretion of, autocrine regulation of, 377-378
Parathyroid gland(s). See also
Hyperparathyroidism;
Hypoparathyroidism.
adenoma of, 369-370, 369f-370f
CT scan of, 482f
MR imaging of, 431-432, 431f
PRADl oncogene in, 377, 399
reoperation for, 524-525, 524f-525f
scintigraphy of, 432-433, 432f-433f
surgery for, 451
ultrasonography of, 430, 43 If
variants of, 370
vs. hyperplasia, 370t, 453-454
allotransplantation of, 694-695
anatomy of, 11-15, 12f, 14f, 366-368,
367f-368f, 439-441, 440f-44lf, 481,
482f
arterial supply to, 14-15,368-369
autotransplantation of, 486-487, 514,
694-695,694f
cryopreservation in, 487, 523
Index - - 821
Parathyroid gland(s) (Continued)
pocket storage in, 695
biopsy of, during parathyroidectomy, 443
blood supply to, 441
carcinoma of. See Parathyroid carcinoma.
cryopreservation of, 487, 530-534
current technique in, 530-531
function of, 531-532, 532t, 533f, 533t
historical aspects in, 530
reoperation and, 523, 533-534
research on, 534, 534t
technical issues in, 530-531
thawing technique in, 531
variations of, 531, 532t
embryology of, 10-11, lOf, 365-366, 366f,
439,481
epithelial cells of, 369, 369f
gross features of, 441
hypercellular, 482, 483f
hyperplasia of. See Parathyroid hyperplasia.
identification of, in thyroid surgery, 213
inferior, 367, 367f
location of, 452, 452f
kissing-paired, 367
localization studies of, in recurrent
(persistent) hyperparathyroidism
intraoperative, 435
invasive preoperative, 43lt, 433-435,
434f,435t
noninvasive preoperative, 430-433,
43lf-433f, 431t, 434t
location of, 366, 367f, 440-441, 440f-44lf
lower, locations of, 441, 441f
management of, in medullary thyroid
carcinoma, 132-133
missing, troubleshooting for, 444-446,
444f-446f
morphology of, 481-482, 483f
pathology of, 369-371, 369f-37lf
preservation of, in thyroidectomy, 192, 192f
relationship between recurrent laryngeal
nerve and, 368
reoperation on, 518-525
anatomic site of disease at, 524t
approach to, 519-521
cervical exploration in, 521-522
cryopreservation in, 523, 533-534
diagnosis confirmation in, 519
failed initial explorations and, 518-519
illustrative cases of, 524-525, 524f-525f
in multiple endocrine neoplasia I patient,
679-681, 679f-680f
results of, 681, 68lt
intraoperative PTH assay in, 478, 681
localization tests before, 521, 52lt, 522f
localization tests during, 522-523
mediastinal exploration in, 522
medical alternatives to, 521
pathology review before, 520
results of, 523-524, 523t, 524t
risks in, 519-520, 520t
size, shape, and color of, 367-368, 441
stromal cells of, 369, 369f
superior, 366, 367f, 481, 482f
supernumerary, 439-440, 481
surgery on. See also Parathyroidectomy.
advantages and disadvanteages of,
464-465,465f
Parathyroid gland(s) (Continued)

results of, 465-466, 465t, 466t
techniques of, 462-463, 463f
radio-guided, in recurrent (persistent)
symmetry of, 367
tissue resection of, in parathyroidectomy,
443-444
tumors of
dissection of, 443-444
sites of, 440, 440f
upper, locations of, 440, 440f
vs. fat lobules, 368
weight of, 441
xenotransplantation of, 694
Parathyroid hormone, 372-380
assay of. See Parathyroid hormone assay.
bone resistance to, in secondary
gene for, 373, 374
immunometric assays of, 379
in calcium homeostasis, 419-420
in hypertension, 404-405
in pseudohypoparathyroidism, 528
messenger RNA levels for, 373-374
metabolism of, 378
radioimmunoassays of, 379
secretion of
autocrine regulation of, 377-378
calcium in, 372-374, 373f-374f, 419-420
calcium sensor proteins in, 375-376
cyclic adenosine monophosphate in, 374
G proteins in, 375
in fresh vs. cryopreserved tissue,
531, 533f
in malignancy-associated hypercalcemia,
539
in primary hyperparathyroidism, 376-377,
385-386
intracellular messengers in, 374-375,
374f-375f
parathyroid cell proliferation in, 377
physiologic regulation in, 372-374,
373f-374f
protein C kinase in, 375
set-point for, in secondary
Parathyroid hormone assay, 378-380
in differential diagnosis of hypercalcemia,
545
in parathyroidectomy
intraoperative, 435, 458-459, 459f
advantages of, 475-476
blood collection time and processing in,
474-475,475f
by fine-needle aspiration, 475
by internal jugular venous sampling,
475-476,476f
criterion accuracy in, 478
disadvantages of, 477
established criterion for evaluation of,
473-474, 473f, 474t
for sporadic primary
limitations of, 476-477
results of, 477-478
shorter operative time and cost savings
with, 476
technique of, 475
preoperative venous sampling for,
434-435
Parathyroid hormone receptor, 378

Parathyroid hormone-related protein, 378
in hypercalcemia, 545
in hypercalcemia of malignancy, 384,
536-538, 537f-538f, 538t
tumor-releasing, 770
Parathyroid hyperplasia, 370, 370f, 370t
etiology of, 482-483
hypercalcemia in, 482
hyperparathyroidism in, 483-484, 484f
multiple endocrine neoplasia and, 483
parathyroidectomy for, 481-487
autotransplantation and, 486-487
cryopreservation in, 487
indications for, 483-484, 484f
postoperative hypocalcemia after, 486t
results of, 487
technique of, 484-486, 485t, 486t
surgery for, 451
vs. adenoma, 370t, 451, 453-454
Parathyroid hypertensive factor, 405
Parathyroidectomy, 441-444. See also
Parathyroid gland(s), surgery on.
after renal transplantation, 510-511, 5llt
anemia after, 515
anesthesia for, 442
autotransplantation with, 486-487, 514
before renal transplantation, 510, 51lt
bilateral, 449-454
vs. unilateral, 452-454
biopsy during, 443
bone disease after, 515
calcium metabolism after, 515
care before, 511
dissection in, 442-443
endoscopic, 467-471
algorithm for surgical management in,
469f
contraindications to, 468-469, 470t
lateral approach to, 468, 468f, 470, 470t
pure, 467
results of, 469-470
for double adenoma, 451
for hyperplasia, 451, 481-487. See also
Parathyroid hyperplasia,
parathyroidectomy for.
for medullary thyroid carcinoma, 132-133
for multiple endocrine neoplasia, 452
for primary hyperparathyroidism, 388,
388f-390f, 390. See also
Hyperparathyroidism, primary,
parathyroidectomy for.
bilateral, 449-454
endoscopic,467-471
unilateral, 456-460
for single adenoma, 451
future aspects of, 460
hypertension control with, 405
incision in, 442
closure of, 444
indications for, in secondary
hyperparathyroidism, 510-512, 51lt
initial, intraoperative PTH assay in, 478
lateral approach to, 446
localization studies in, 511-512
minimally invasive
endoscopic, 462, 463f
lateral approach to, 463, 463f
video-assisted, 462-463, 463f, 467-468
results of, 465-466, 465t, 466t
neck exploration in, 442-443
822 - - Index
Parathyroidectomy (Continued)
NIH-sponsored guidelines for, 419, 421,
42lf
PAS scores and, 388, 39Of, 420-421,
42lf-422f
positioning of patient for, 442, 442f
premature death after, 406
recurrent (persistent) hyperparathyroidism
after
in multiple endocrine neoplasia I patients,
677-679, 678t
parathyroid hormone assay in, 434-435
selection of procedure in, 512-514, 513t
subtotal, 513
for MEN I in hyperparathyroidism, 677
results of, 678t
vs. autotransplantation trials, 513, 513t
surgical management of, 512
technique of, 441-444
tissue resection in, 443-444
total, autotransplantation with, 514
ultrasonography before, 458
unilateral, 456-460
advantages of, 460
in adenoma vs. hyperplasia, 453-454
intraoperative monitoring in, 458-459,
459f
local anesthesia for, 459
localization studies in, 453
preoperative, 458
minimal invasion in, 459-460
principle of, 456
rationale for, 452-453
results of, 457-458
vs. bilateral, 452-454
venous sampling before, 458
Parathyroidectomy Assessment of Symptoms
(PAS) scores, 388, 390f, 420-421,
42lf-422f
Parathyromatosis, 512
vs. parathyroid carcinoma, 552
Patient selection, for aerodigestive invasive
thyroid carcinoma surgery, 320-321
PAX8 gene therapy, for undifferentiated thyroid
carcinoma, 336
PAX8-PPAR:yl oncogene, 292
Pemberton's sign, in evaluation of goiter,
27,310
Pendred's syndrome, 5, 775
Peptic ulcer, in gastrinoma, 745, 747
Peptide(s), endocrine, 704t
Peptide YY, production of, by pancreatic islet
A cells, 704
Percutaneous transhepatic portal venous
sampling, of insulinoma, 720, 72lf,
731-732,73lt
Peroxisome proliferator-activated receptor y
agonist, in thyroid tumor growth inhibition and redifferentiation, 336
Personality changes, in primary
Phagocytosis, in secondary
Pharangeal pouches, parathyroid origin from,
365, 366f, 439
Pharynx, invasive thyroid carcinoma of,
surgery for, 329
Phenoxybenzamine, before pheochromocytoma
surgery,624,626,627
Phenylacetate, in thyroid tumor growth
Phenylbutyrate, in thyroid tumor growth
Pheochromocytoma, 621-631
catecholamines in, 621
clinical features of, 621-622, 622f
conditions associated with, 631
CT scan of, 623, 623f, 625f
diagnosis of, 622
extra-adrenal, 628, 629-630
familial, 776
hypertension in, 621, 622
imaging of, 580-581, 580f-58lf
flow chart in, 582f
in children, 631
in multiple endocrine neoplasia 2, 630-631
in multiple endocrine neoplasia 2B, 761-762
in pregnancy, 630
in von Rippel-Lindau disease, 775
incidence of, 621
localization studies of, 580-581, 580f-58 If,
623-624
malignant, 629, 630f
MR imaging of, 623, 623f-625f
pathology of, 586, 587f, 628-629, 629f
preoperative management of, 625, 626
scintigraphy of, 623-624, 624f-625f
size of, 622, 628
subclinical, screening for, 589
surgery for
anterior approach to, 627-628
~ blockers before, 626
calcium channel blockers before, 626
care after, 628
doxazosin before, 626
esmolol during, 626
laparoscopic, 626-627
left adrenal exposure in, 627-628
management during, 626
phenoxybenzarnine before, 624,
626,627
posterior approach to, 628, 628f
prazosin before, 626
propranolol before, 626
right adrenal exposure in, 627
sodium nitroprusside during, 626
venous sampling in, 581
Phorbol esters, tumor-promoting, 271
Phosphate, retention of, in secondary
Phosphatidylinositol-protein kinase C--<:alcium
pathway, in thyroid regulation, 257, 257t,
258f
Phosphoinositide turnover phospholipaseprotein kinase C, in thyroid growth
regulation, 270-271, 270f
Phospholipase
in signal transduction, 270
thyroid-stimulating hormone stimulation of,
270-271, 270f
Phrenic nerve, injury to, in neck dissection,
203
Physical condition, of patient with
carcinoma, 321
Physical exercise. See Exercise.
Pituitary adenylate cyclase activating
polypeptide, 706
Pituitary gland
adenoma of
corticotropin-secreting, Cushing's
syndrome from, 612
Pituitary gland (Continued)

in multiple endocrine neoplasia 1,675, 675f
irradiation of, for Cushing's disease, 615
selective transsphenoidal microsurgery of,
tumors of, in multiple endocrine neoplasia 1,
674-675,675f
treatment of, 675, 676f
Plasmacytoma, 168, l69f
Platelet-derived growth factor(s), 256
Platelet-derived growth factor receptor, 260
Plicamycin
for hypercalcemia, in parathyroid carcinoma,
552
Plummer's disease, 311
diagnosis of, 65
epidemiology of, 55t
historical aspects of, 54-55, 55f
pathogenesis of, 64-65, Mf
treatment of, 65-66
Polyglandular autoimmune syndromes,
Addison's disease in, 634-635
Polyps, gastrointestinal hamartomatous, 777
Portal venous sampling
of gastrinoma, 750
of insulin oma, 720, 72 If, 731-732, 73lt
Postpartum thyroiditis, 37, 38f
Potassium channels, APT-regulated, 703f, 707
Potassium iodide
for thyroid storm prophylaxis, 63
Potassium perchlorate, for Graves' disease,
59-60
PPoma (pancreatic polypeptide-producing
tumor),770-771
PRADl oncogene, in parathyroid adenoma,
377, 399, 449
Prazosin, before pheochromocytoma surgery,
626
Prednisone, for subacute thyroiditis, 36
Pregnancy
hypercalcemic crisis in, 545
hypothyroidism during, 45
thyroxine therapy in, 69, 70t, 76
Prethyroid fascia, 197
Proinsulin, in insulinoma, 718
Prolactinoma, in hyperaldosteronism, 596
Propranolol
before pheochromocytoma surgery, 626
for thyroid storm prophylaxis, 63-64
Propylthiouracil
adverse effects of, 60, 601
Prostaglandins, in malignancy-associated
hypercalcemia, 539
Protein kinase A
adenylase cyclase, in signal transduction,
266-269,267f
phosphorylation in, 273
Protein kinase C
calmodulin kinase and, 274
desensitization by, calmodulin kinase and,
273-274
elevation of, 376-377
in thyroid growth regulation, 270-271, 270f
inhibitors of, 271
Index - -
Protooncogene(s), 288. See also specific

protooncogene, e.g., ret protooncogene.
definition of, 280
Provocative tests, for insulinoma, 719, 719f
Pruritus, in secondary hyperparathyroidism,
506
Psammoma bodies, in papillary thyroid
carcinoma, 106, 106f, 224, 224f
Psammomatous melanotic schwannoma, in
Carney's complex, 776
Pseudogout, in primary hyperparathyroidism,
409
Pseudohypoparathyroidism, 528
classification of, 529t
Pseudopseudohypoparathyroidism, 528
Psychiatric disorders, in primary
Psychosis, in primary hyperparathyroidism,
406
PTEN gene, 235, 290t, 292
PTHrP gene, 537, 538
Q
Quality of life (QOL) score, in asymptomatic
R
Radiation
exposure to
anaplastic thyroid carcinoma from, 160
thyroid carcinoma from
carcinogenesis and, 245
environment and, 243-245, 244f
historical aspects of, 27, 240, 24lf
in childhood, 240-242, 24lf
medical therapy and, 242-243,
242t,243f
ionizing, thyroid tissue destruction with, 25
tumorigenic effects of, on child's thyroid, 94
Radiation dose, on radiation-associated thyroid
carcinoma, 242, 242t
Radiation therapy
for anaplastic thyroid carcinoma
palliative, 163
postoperative, 162, 162f
for bulky or minimal residual disease, in
advanced thyroid cancer patients, 330
for endemic goiter, 22
for plasmacytoma, 168
for thyroid carcinoma, recurrency prevention
with, 183-184
for thyroid lymphoma, 176
therapeutic, thyroid cancer caused by, 27,
242-243,242t, 243f
to neck, hypothyroidism due to, 46
Radioimmunoassays, of parathyroid
hormone,379
Radioimmunoguided surgery, for medullary
Radioiodine therapy
ablative
for sporadic nontoxic goiter, 29, 30t
postoperative, for papillary thyroid
carcinoma, 107-108
side effects of, 29
exposure to, risk of thyroid carcinoma and,
243, 243f
for bulky or minimal residual disease, in
advanced thyroid cancer
patients, 330
Radioiodine therapy (Continued)

for childhood thyroid carcinoma, 98-99,
98f-99f
complications of, 98t
for differentiated thyroid carcinoma,
251-252
for Graves' disease, 60-61, 60t
for Hiirthle cell neoplasms, 127
for metastatic thyroid carcinoma, 154, 156,
156f
side effects of, 156
for Plummer's disease, 65-66
for thyroid carcinoma, recurrency prevention
with, 183
Radionuclide scanning. See Scintigraphy.
ras oncogene, 283
in anaplastic thyroid carcinoma, 159, 162, 232
in oncogenesis, 291
in thyroid growth, 26
in thyroid neoplasms, 261, 265, 283, 284t
rb gene, 292
in thyroid neoplasms, 261-262
Rectum, carcinoid tumors of, 780
treatment of, 786
Redifferentiating agents, in restoration of
differentiated thyroid function, 334-336,
335f,337f
Renal calculi
in asymptomatic hyperparathyroidism, 419
in normocalcemic hyperparathyroidism,
425-427,426f
in primary hyperparathyroidism, 396, 397
in transplanted kidneys, 507
Renal failure
chronic, 502
bone disease in, 505
glucose intolerance in, 506
hyperlipidemia in, 507
hyperphosphatemia in, 503
hypertension in, 506-507
insulin secretion in, 506
normochromic, normocytic anemia in, 506
Renal graft, impaired function of, 504
Renal hyperparathyroidism, 502
Renal transplantation
secondary hyperparathyroidism after, 504
secondary hyperparathyroidism before,
502-504
simultaneous pancreas transplantation with,
697
ret protooncogene, 234
germline defects in, 134
in medullary thyroid carcinoma, 351
hereditary, 131, 13 It, 230
in multiple endocrine neoplasia 2,491,674,
758, 759f
in multiple endocrine neoplasia 2A, 134,234
in multiple endocrine neoplasia 2B, 134,
234, 758, 758f-759f
in papillary thyroid carcinoma, 226
in thyroid neoplasms, 285, 285t
RET receptor, 234
Retinoic acid, in enhancing NIS gene
expression, 358
Retinoic acid receptor, 334, 335f
Retinoid X receptor, 334, 335f
Retinoids, in thyroid tumor growth inhibition
and redifferentiation, 334-336, 335f, 337f
reVptconcogene,234-235,290-291,290t
rearrangements of, in carcinogenesis, 245
823
Ribonuclease, bovine seminal, anaplastic

Ribonucleic acid. See RNA entries.
Riedel's thyroiditis, 40-41
RNA, messenger
for parathyroid hormone, 373-374
insulin, 702
RNA transcript, of insulin gene, 790
RPMI-I640 culture medium, for
crypopreservation of tissue, 530-531
S
Salt iodination
Sarcoma, of thyroid, 169
SASI (selective arterial secretin injection) test,
for gastrinorna, 750, 750t
Scandinavian studies, on long-term mortality
after surgery for hyperparathyroidism,
413-415, 414t
Schmidt's syndrome, 46
Schwannoma, 587f
psammomatous melanotic, in Carney's
complex, 776
Scintigraphy
DMSA, of medullary thyroid carcinoma, 148
iodine 131
of adrenal glands, 566
of intrathoracic goiter, 312-313, 312f
of metastatic thyroid carcinoma, 153, 155f
145f
of recurrent thyroid carcinoma, 184-185
MillG
of adrenal glands, 566, 577
of medullary thyroid carcinoma, 147-148
of pheochromocytoma, 580-581, 58lf,
623-624, 624f-625f
of adrenal glands, 576-577
of adrenocortical carcinoma, 607
of aldosteromas, 580
of Cushing's syndrome, 614, 615f
of lungs, after childhood thyroidectomy, 98,
99f
of medullary thyroid carcinoma, 136-137
of thyroid nodules, 86-87, 87f
sestamibi, of parathyroid glands, 678-679,
679f-680f
somatostatin receptor
of carcinoid tumors, 784, 784f
of gastrinoma, 733, 733f, 734t, 749
of insulinoma, 722, 723f, 723t
technetium 99m sestarnibi
for recurrent (persistent)
hyperparathyroidism, 432-433,
432f-433f
146f3
thallium 201
146f
of recurrent thyroid carcinoma, 185
thallium 201-technetium 99m pertechnetate,
Sclerosis, tuberous, 778
Secretin injection test, for gastrinoma, 748,
748t
Selective arterial secretin injection (SASI) test,
for gastrinoma, 750, 750t
Sensory nerves, in pancreatic islets, 707
Sepsis, endocrine pancreas and, 710-711
824 - - Index
Serotonin secretion, by carcinoid tumors, 783
Severe combined immunodeficiency (SCID)
mice, transplantation of adrenocortical
cells into, 696-697, 696f
Sex hormone status, thyroid carcinoma and,
246
Sex steroids, synthesis of, 573
Sheenan's syndrome, 47
Signal transduction, 265-274
desensitization of, 273-274, 273f
system interaction (crosstalk) in, 274
system(s) for, 265-273, 266t
AC-PKA, 266-269, 267f, 268f
calcium-calmodulin-dependent protein
kinase, 271
growth factor-tyrosine kinase, 271-272,
272f
PI tumover-phospholipase-PKC,
270-271, 270f
Silent thyroiditis, 37
Skin lesions/rashes
in glucagonoma, 768
Small cell carcinoma, of thyroid, vs. anaplastic
thyroid carcinoma, 161,230-231
Smoking
carcinogenic effect of, 246
Sodium iodide, intravenous, for thyroid storm,
218
Sodium nitroprusside, during
pheochromocytoma surgery, 626
Sodium-iodide symporter (NIS) gene therapy.
See also NIS gene.
for undifferentiated thyroid carcinoma,
336-337
Somatostatin, 269
for hypoglycemia in insulinoma, 727
isotope-labeled analysis of, in insulinoma,
722, 723f, 723t
production of, in pancreatic islet D cells, 705
Somatostatin receptors, in neuroendocrine
tumors, 722, 723t
Somatostatinoma, 766-767
characteristics of, 767t
duodenal, 765f
surgery for, 739
Spinal accessory nerve, in neck dissection,
201-202
Spindle cells, in anaplastic thyroid carcinoma,
160, 16lf, 23lf
Splanchnic nerves, 669
Splenic arteries, 667, 668f
Squamous cell carcinoma, of thyroid, 170
Standardized meal test, for gastrinoma, 748
Sternocleidomastoid muscle, in neck
dissection, 200, 202
Sternohyoid muscle, 194
Sternothyroid muscle, 194
Sternotomy
in intrathoracic goiter surgery, 194, 314,
314t
Steroids. See also specific steroid.
exogenous, Addison's disease from, 635-636
Stomach. See also Gastric entries.
carcinoid tumors of, 781
treatment of, 785
Stones, kidney. See Renal calculi.
Strap muscles, division of, in intrathoracic
goiter removal, 194
Streptozocin
for insulinomas, 728
Stress
Addison's disease and, 636
endocrine pancreas and, 710-711
hemorrhagic, increased plasma glucose
during, 710
in bilateral adrenal hemorrhage, 637
Sturge-Weber syndrome, pheochromocytoma
in, 631
Suicide gene therapy, for differentiated thyroid
carcinoma, 338-339
Supportive care, for myxedema coma, 221
Suprarenal arteries, 562
branches of, 562-563
Suprarenal glands, 560
Suprarenal veins, 563
Surgery. See also specific procedure, e.g.,
Thyroidectomy; under specific disorder.
Addison's disease in, 635, 637
causes of, 634, 635t
conservative, for multinodular goiter, goiter
recurrence after, 304-305
Sympathogonia, primitive, neuroblastoma of,
560
T
T 3. See Triiodothyronine (T3)'
T4 See Thyroxine (T4) .
Tamoxifen, for Riedel's thyroiditis, 41
Teratoma, of thyroid, 170
Testicular tumors, in Carney's complex, 776
Thiocyanate, 25
Thoracic duct lesions, as complication in
thyroid surgery, 208-209, 209f
Thoracic inlet obstruction, large goiter with,
20, 2lf, 27
Thoracotomy, in intrathoracic goiter surgery,
315-316
Thymus, embryology of, 10-11, IOf
Thyrocytes
iodide uptake in, 355, 356f
regulation of, in multinodular goiter, 73
Thyroglobulin, serum levels of
in metastatic thyroid carcinoma, 152-153,
153f
in recurrent thyroid carcinoma, 184
Thyroglossal duct, 9
Thyroid artery
bleeding of, in thyroid surgery, 208
inferior, 12, 12f
in thyroidectomy, 189-190, 19lf
superior, 11-12, 12f
in thyroidectomy, 190-192, 191f
division of, 194
Thyroid carcinoma. See also Thyroid
neoplasms.
aerodigestive invasion by, 318-332
incidence of, 319t
local and distant disease in, preoperative
assessment of, 318-320, 319f-320f
physical and mental condition of patient
with, 321
additional treatment with, 330
cervical exploration in, 322, 322t
disease progression and, 321
en bloc resection in, 327
hospital lethality in, 329, 329t
incision in, 322
intraoperative frozen section in, safety
margins of, 327
laryngotracheal resection in, 324
types of, 324-327, 325f, 325t, 326f,
328f
Thyroid carcinoma (Continued)

local resectability and, 320-321, 320f
long-term results of, 330-331, 331t
mediastinal tracheal resection in, 327,
329
palliative local procedures in, 330
patient intubation in, 322
patient selection in, 320-321
pharyngoesophageal invasion and, 329
radical resection technique in, 322,
323f-326f, 324-327, 328f,
329-330
recurrent laryngeal and vagal nerve
protection in, 327
shaving procedures in, 327
window resection in, 327, 329t
tumor-invaded structures in, 322t
types of cancer in, 321t
aggressiveness of
clinical indicators of, 253-254
epidemiologic factors in, 248-249, 249f
pathology in, 249
predictors of, 248-254
risk group classification in, 250-251
anaplastic, 159-165
bone morphogenic protein and, 164
bovine seminal ribonuclease and, 164
BRAF mutations and, 164-165
CA4P and, 164
~-catenin
activation in, 159
chemotherapy for, 163,804
clinical course of, 232
349-351, 350t, 35lf-352f, 352t
cytokeratin 20 expression in, 165
diagnosis of, 160
gene therapy for, 165
giant cell, 160, 160f, 231f
metastatic, 160
multimodality therapy for, 162-163
p53 mutations in, 159, 161, 161f, 162,232
pathology of, 160f-162f, 231-232, 23lf
patient categorization in, 159
prognosis of, 164
radiation exposure and, 160
radiation for
palliative, 163
postoperative, 162, 162f
ras mutations in, 159, 162,232
recurrence of, 184, 184f
research investigation in, 164-165
spindle cell, 160, 161f, 231f
squamoid variant of, 160
surgery for, 162, 163
survival in, 164
after radiation with and without
chemotherapy, 164t
vs. lymphoma, 161
vs. small cell carcinoma, 161,230-231
benign nodular disease associated with, 246
changing presentation of, 252
childhood, 93-99. See also Children, thyroid
carcinoma in.
columnar cell, 171-172, I7lf
diagnosis of, role of thyroid iodide uptake in,
1,356f
dietary influences on, 245, 245t
familial adenomatous polyposis-associated,
235-236, 235f
Index - - 825
follicular
adenomatous, 116, 116f
adjuvant therapy for, 120
aggressiveness of, 250
capsular invasion in, 117, 117f, 227
347
fine-needle aspiration of, 118, 118f
incidence of, 115,227-228
localizations tests for, 142-147
lymph node metastases in
neck dissection for, 199
operative technique of, 200-203,
201-202f
therapeutic strategy in, 204
management of, 120-121, 121
pathologic features of, 116-118,
117f-118f, 226-228, 227f
prevalence of, 115, 227
prognosis of, 118, 119t
survival in, 119t
vascular invasion in, 117, 117f, 227
well-differentiated, 228
genes and protooncogenes in, 233-236
incidence of
in intrathoracic goiter, 311, 31lt
non-radiation factors affecting, 245, 246t
insular, 170-171, 171
intermediately differentiated, 170-174,
171-174f
invasion of, 295-301
epidermal growth factor in, 299-300, 300f
implications for clinical therapeutics
in, 301
metalloproteinases in, 298-299, 299t
molecular crosstalk in, 300-301
multistep process of, 295, 296f
proteases in, 298-300, 299t, 300f
regulators of, 300
urokinase plasminogen activator in, 299
iodide uptake in, 355
iodine 131 therapy for, recurrency
prevention with, 183
lifestyle factors in, 245-246
localization tests for, 142-149
lymph node dissection in, 196-197
lymph node metastases in, 197
incidence of, 197
localization of, 197
neck dissection for
choice of, 198-200
technique of, 200-203, 201-202f
recurrence of, 204
medullary, 129-139
anti-CEA monoclonal antibody imaging
of, 148
C (parafollicular) cells in, 129,
130f,229
calcification of, 147, 149
clinical presentation of, 129-132, 130t,
13lf,13lt
comparative genomic hybridization
in, 351
hereditary, 129, 131
genetic testing for, 134
ret mutations in, 131, 131t

hypercalcitoninemia in, persistent or
recurrent, 135
image diagnosis of, 147-148, 147f
in multiple endocrine neoplasia
2,129-130, 130f-I31, 130t, 13lt,
230, 760-761, 760f-761f
neck dissection for, 199-200
201-202f
metastatic disease in, 129, 130f
palpable disease in, surgery for, 132-134,
132t, 133f, 133t
persistent or recurrent
CT scan of, 136
diagnostic laparoscopy for, 137, 137f
localization of, 136-137
nuclear imaging studies of, 136-137
radiation therapy for, 135
selective venous catheterization
for, 136
ultrasonography of, 136
prognosis of, factors influencing, 132
reoperation for, 137-139
calcitonin levels after, 138, 138f
scintigraphy of
DMSA,148
MIBG, 147-148
surgery for, 132-134, 132t, 133t
parathyroid management in, 132-133
regional node management in, 133-134,
133f
ultrasonography of, 147, 147f
metastatic
diagnostic procedures for, 152-153
distant, 252-253
FDG-PET imaging of, 148-149
iodine 131 body scan in, 153
location of, 152, 153t
prognosis of, 157
radioiodine therapy for, 154, 156, 156f
side effects of, 156
serum thyroglobulin levels in, 152-153,
153f
surgery for, 154, 154f-155f
molecular carcinogenesis in, 245
mucoepidermoid, 172
new therapeutic approach(es) to, 334-338
cytotoxic agents in, 338
gene therapy in, 336-338, 338-339
metalloproteinase inhibitor in, 339-340
redifferentiating agents in, 334-336, 335f,
337f
tyrosine kinase receptors in, 339, 339f
vascular endothelial growth factor
inhibitors in, 340
NIS gene in, 357-358. See also NIS gene.
oncogenesis in, 288-293
papillary
AGES grading system of, 226
aggressiveness of, 250
346-347, 347t

diffuse sclerosing variant of, 172-173,
172f,226
follicular variant of, 117, 117f, 225
hemithyroidectomy for, 102-108
advantages and disadvantages of,
103-104, 104t
considerations in, 102-103, 103t
lymph node dissection with, 106-107,
107f-108f
postoperative adjuvant therapy with,
107-108
rationale and indications for, 104-106,
105f-106f
survival rates in, 104t, lOSt, 106
high-risk
classification of, 110, Ill, lIlt
treatment of, 108
histology of, 224, 224f
invasion of, to other organs, 144-146,
146f
lobectomy for, 110
low-risk, 104, 104t
classification of, 110, Ill, lIlt
neck dissection for, 199
201-202f
macrofollicular variant of, 226
minimal, 225
morphologic findings in, 224-225
papillae in, 224
psammomatous bodies in, 106, 106f,
224, 224f
recurrence of, 106
ret/pte oncogenes in, 226
scintigraphy of
radioiodine, 142-143, 145f
technetium 99m sestamibi, 143-144,
146f3
thallium 201, 143-144, 146f
solid/trabecular variant of, 173-174, 174f
tall cell variant of, 173, 173f, 225
total thyroidectomy for, 104, 104t,
106,108
benefits of, 112
rationale for, 110-112, lIlt
technique of, 112
ultrasonography of, 142, 143f-144f
preoperative recognition of, recurrency
prevention by, 181-182
radiation therapy for, 251-252
recurrency prevention with, 183-184
radiation-associated
carcinogenesis in, 245
environmental, 243-245, 244f
historical aspects of, 27, 240, 241f
in childhood, 240-242, 24lf
medical therapy in, 242-243, 242t, 243f
recurrent, 181-186,252
immunohistochemical staining of, 185
in lymph nodes, treatment of, 204
incidence of, 185-186
iodine 131 scintigraphy of, 184-185
local, 181
management of, 186
826 - - Index
metastases in, 185-186, 186f
MR imaging of, 184f
adjuvant iodine 131 therapy in, 183
preoperative recognition of malignancy
in, 181-182
radiation therapy in, 183-184
thyroid-stimulating hormone
suppression in, 182-183
total thyroidectomy in, 182
serum thyroglobulin levels in, 184
site of, 185
thallium 20 I scintigraphy of, 185
sex hormone status and, 246
squamous cell, 170
surgery for, 251. See also Lobectomy,
thyroid; Thyroidectomy, total.
thyroid growth factors and, 77, 77t
thyroidectomy for. See Thyroidectomy, total.
therapy for, 77-78
unusual types of, 168-174, 169t
Thyroid cork, 28
Thyroid crisis. See Thyroid storm.
Thyroid cysts, fine-needle aspiration of, 89
Thyroid function tests
after hemithyroidectomy, 103
preoperative, in intrathoracic goiter, 313
Thyroid gland. See also Hyperthyroidism;
Hypothyroidism.
aberrant tissue of, 10
adenoma of
follicular, 116, 116f
allografts of, 692--693
anatomy of, 11-15, 12f, 14f
surgical, 61--62, 6lf
autotransplantation of, 691--692, 692f
carcinoma of. See Thyroid carcinoma.
cyst of, fine-needle aspiration of, 89
diseases of
cryopreserved parathyroid transplantation
for, 533
non-MEN familial hyperparathyroidism
in, 494
embryogenesis of, 3, 4f
embryology of, 9-10, lOf
enlargement of. See Goiter(s).
function of
restoration of
gene therapy in, 336-338
redifferentiating agents in, 334-336,
335f,337f
treatments independent of, 338-340
cytotoxic agents in, 338
gene therapy in, 338-339
metalloproteinase inhibitor in, 339-340
tyrosine kinase receptors in, 339, 339f
vascular endothelial growth factor
inhibitors in, 340
growth regulation of
epidermal growth factor-transforming
growth factor-a in, 258-259
fibroblast growth factors in, 259, 259f
hepatocyte growth factors in, 260
insulin-like growth factors in, 259
mitogenic pathways in, 256-257, 258f
platelet-derived growth factors in, 260
stimulatory and inhibitory factors in, 256,
257t
thyrotropin in, 257-258
Thyroid gland (Continued)

homeostasis of, 256
Hiirthle cell neoplasms of, 123-127.
See also Hurthle cell neoplasms.
hyperplasia of, 260-261, 260f. See Thyroid
gland, growth regulation of.
somatic mutations in, 261, 26lf
intermediately differentiated carcinomas of,
170-174,17lf-174f
lymphatic drainage of, 13-14, 14f, 196
lymphoma of. See Thyroid lymphoma.
metastases to, 176-177, 176f
neoplasms of. See Thyroid neoplasms.
paraganglioma of, 169, 170f
physiology of, 3-7
plasmacytoma of, 168, 169f
sarcoma of, 169
squamous cell carcinoma of, 170
surgery on, 207-213. See also
Thyroidectomy.
bleeding in, 208
general, 208
specific, 208-213
dyspnea after, 211
edema in, 208
hoarseness after, 211
hypoparathyroidism after, 212-213
hypothyroidism after, 213
infection in, 208
lymphatic lesions in, 208-209, 209f
recurrent laryngeal nerve in
damage to, 208f-209f, 209-210
superior laryngeal nerve in, damage to,
211-212,211f-212f
vascular lesions in, 208
wound healing disorders in, 208
teratoma of, 170
xenografts of, 693
Thyroid growth factor(s), 77t
Thyroid growth-inhibiting factors, 77t, 260
Thyroid growth-promoting factors, 26, 77t
Thyroid growth-promoting immunoglobulin,
269
in endemic goiter, 19
in multinodular goiter, 73
Thyroid hormone. See also Calcitonin;
Thyroxine (T4) ; Triiodothyronine (T3) .
autoregulation of, 7
degradation of, hypothyroidism from, 47
for Hashimoto's thyroiditis, 40
peripheral action of, 5--6, 6f
physiology of, 3-7, 5
regulation of, 6-7, 6f
release of, 4, 4f
resistance to, hypothyroidism from, 47
synthesis of, 4-5, 4f-5f
transport of, 5
Thyroid hormone receptors, 6, 6f
Thyroid hormone replacement therapy, for
myxedema coma, 221
Thyroid hormone response element, 6
Thyroid hyperplasia, 260-261, 260f. See also
Thyroid gland, growth regulation of.
somatic mutations in, 261, 26lf
Thyroid lymphoma, 174-176
chemosensitive, 176
clinical features of, 174, 175f
diagnosis of, 175
in Hashimoto's thyroiditis, 46
marginal zone, 232
Thyroid lymphoma (Continued)

pathology of, 174-175,232-233, 233f, 249
radiosensitive, 176
stages of, 175
survival in, 176
Thyroid neoplasms. See also Thyroid
carcinoma.
benign, 261, 262f
bilateral, nodal metastasis in, 133t
comparative genomic hybridization in
digital image acquisition and analysis in,
345-346, 346f
DNA extraction in, 344
limitations and difficulties of, 351, 353
metaphase spreads in, 344, 345f
cytokines in, 269
factors predisposing to, 240-254. See also
specific factor, e.g., Radiation.
gsp gene mutations in, 265, 282,
282f,283t
multistep mutation theory of, 280, 28lf
oncogenes in, 280-286
ras mutations in, 261, 265, 283, 284t
rb mutations in, 261-262
signal transduction in, 265-274
desensitization of, 273-274, 273f
system interaction (crosstalk) in, 274
system(s) for, 265-273, 266t
AC-P~,
266-269, 267~ 268f
calcium-calmodulin-dependent protein
kinase, 267f, 271
growth factor-tyrosine kinase, 271-272,
272f
PI turnover-phospholipase-PKC,
270-271,270f
trk oncogene in, 265
tumor development in, 280, 28lf
unilateral, nodal metastasis in, 132t
Thyroid nodule(s), 85-91. See also Goiter(s).
autonomous (hot), 26
benign, associated with thyroid carcinoma,
246
benign colloid, 86, 88f
dominant, 86f
Hurthle cells in, 124f
in children, 96
prevalence of, 68
solitary, 86f
clinical evaluation of, 85-86, 86f, 86t
diagnosis of, 86-89
fine-needle aspiration of, 87-89
cytologic features in, 88f-89f
formation of, 26
incidence of cancer in, 85
malignant potential of, 86, 89
medical treatment of, 89-90
risk factors for, 86t
schematic of management of, 90f
scintigraphy of, 86-87, 87f
spontaneous resolution of, 5
indications for, 90
therapy for, 71, 72t
thyroxine for, 72-73, 72f
ultrasonography of, 87, 87f
Thyroid peroxidase, 4
antibodies to
in Hashimoto's thyroiditis, 40, 44
in painless thyroiditis, 37, 38
Thyroid rests, ectopic, midline, 9
Index - - 827
Thyroid storm, 63, 216-219
adrenergic depletion for, 218
antithyroid therapy for, 217-218
Bayley's symptom complex in, 216
~ blockers for, 218
coexisting illnes with, treatment of, 218,
219f
Burch and Wartofsky's criteria for, 217t
iodide therapy for, 217-218
precipitants of, 217t
prophylactic management of, 63-64
systemic decompensation in, 218
Thyroid transcription factor I, in carcinoid
tumors, 782
Thyroid vein, bleeding of, in thyroid surgery,
208
Thyroidectomy, 188-194. See also Thyroid
gland, surgery on.
access in, 188, 189, 189f-190f
accuracy of, 188
anatomic structures in, identification of,
188-189
bleeding control in, 189
completion
for follicular thyroid carcinoma, 119-120
for recurrent goiter, 307-308
complications of, 308, 308t
diathermy in, restricted use of, 189
fascia incision in, 190f
for anaplastic thyroid carcinoma, 162, 163
for Graves' disease, 61-64
anatomic considerations in, 61-62, 6lf
hypoparathyroidism after, 62
indications for, 6lt
for plasmacytoma, 168
for sporadic nontoxic goiter, 29-30, 30t
hemi-. See Hemithyroidectomy.
incisions in, 189f
isthmectomy in, 189. See also Isthmectomy.
isthmus in, division of, 194
laryngeal nerve in
recurrent, 189-190, 19lf
dissection of, 192-193, 193f
superi04 190-192, 191f
lobectomy in, 189. See also Lobectomy.
parathyroid gland preservation in, 192, 192f
principles of, 188-189
strap muscle division in, 194
subcutaneous fat division in, 190
subtotal
for Graves' disease, types of, 63, 63f
for hyperparathyroidism. See also
Hyperparathyroidism, surgery for.
for papillary thyroid carcinoma, 103, 104t
prevention of, 51
thyroid artery in
inferior, 189-190, 19lf
superior, 190-192, 19lf
division of, 194
therapy after, 75
therapy for, 79, 79f
T incision in, 194
total, 193
for childhood thyroid carcinoma, 96-97
complications of, 97-98, 97t
extent of disease at, 96t
Thyroidectomy (Continued)
for follicular thyroid carcinoma, 119-120
for Hiirthle cell neoplasms, 126
for papillary thyroid carcinoma, 104, 100t,
106,108
benefits of, 112
rationale for, 110-112, 11lt
technique of, 112
for thyroid carcinoma, recurrency
prevention with, 182
with central neck dissection, 200-201,
20lf
with lateral neck dissection, 201-203,
202f
wound closure in, 193
Thyroiditis, 34-41
acute (suppurative), 34-35, 35f
chronic, 38-41
classification of, 35t
definition of, 34
etiology of, 35t
granulomatous, 36, 36f
Hashimoto's. See Hashimoto's thyroiditis.
Riedel's, 40-41
subacute
painful (de Quervain's)
treatment of, 36-37
painless, 37-38
clinical course of, 38, 38f
variants of, 38
Thyroid-stimulating hormone, 6-7, 6f, 256
in endemic goiter, 19
in sporadic nontoxic goiter, 25-26
in thyroid growth regulation, 257, 257t,
258f, 267-268, 268f
Thyroid-stimulating hormone receptor,
267-268
in thyroid neoplasms, 257
mutations in, 280-281, 288, 290t
Thyroid-stimulating hormone suppressive
therapy, 68-79. See also Levothyroxine;
Thyroxine (T4 ) .
after thyroidectomy, 75
algorithm for, 79, 79f
for benign goiters, 75-76
for follicular thyroid carcinoma, 120, 121
for multinodular goiter, 73-74, 74t
for nodular goiter, 73
for papillary thyroid carcinoma, 103
postoperative, 108
for solitary thyroid nodule, 71, 72t, 89-90
history of, 68-69
in post-thyroidectomy patient, 75
lipid profile in, 70-71
physiologic goals of, 69-70
postoperative, recurrence of goiter from, 305
Thyroid-stimulating hormone test, for
hypothyroidism, 48
Thyroid-stimulating immunoglobulins, 269
Thyrotoxic crisis. See Thyroid storm.
Thyrotoxic storm. See Thyroid storm.
Thyrotoxicosis
after iodination, 21
in Plummer's disease, 65
Thyrotropin, 265, 296. See also

Thyroid-stimulating hormone.
in thyroid growth regulation, 257-258
Thyrotropin-releasing hormone, 6f, 7
Thyroxine (T4 ) . See also Levothyroxine;
Thyroid-stimulating hormone suppressive
therapy.
bioavailability and dosage of, factors
affecting, 69-70, 70t
for endemic goiter, 22
for hypothyroidism, 48-49
adverse effects of, 49
in neonates, 51
maintenance dose of, 49
for metastatic thyroid carcinoma, 157
for multinodular goiter, 73-74, 74t
nontoxic, 74
for solitary thyroid nodule, 72-73, 72f
for sporadic nontoxic goiter, 29, 30t
ischemic heart disease and, 71
lipid metabolism and, 70-71
metabolism of, 5
physiology of, 69
postoperative suppplementation with,
recurrent goiter after, 305
serum free, in hypothyroidism, 48
suppressive doses of, prior to intrathoracic
goiter surgery, 313
synthesis of, 4f, 5
T incision, in thyroidectomy, 194
Tissue thawing, in parathyroid
crypopreservation, 531
Tissue viability, in parathyroid
crypopreservation, 532t
TNM scoring system, for recurrent thyroid
carcinoma, 181
Tongue, ganglioneuromatosis of, 759f
Trachea
collapse of, after intrathoracic goiter
surgery, 316
papillary thyroid carcinoma invasion of,
145-146, 146f
Tracheomalacia, after intrathoracic goiter
surgery, 316
Transcription factors, in parathyroid and
thyroid development, 3
Transforming growth factor-a, 256
Transhepatic portal venous sampling,
percutaneous, of insulinoma, 720, 721f,
731-732,73lt
Transplantation. See also Allotransplantation;
Autotransplantation; Renal
transplantation; Xenotransplantation.
islet cell, 697-698, 698f
pancreas, 697
Transsphenoidal microsurgery, selective, for
Cushing's disease, 615
Trapezius muscle
in neck dissection, 201-202
paralysis of, 203
Trastuzumab,301
Trichostatin A, increased NIS gene expression
with, 358-359, 358f-359f
Triiodothyronine (T3)
for hypothyroidism, 48-49
coronary bypass surgery and, 50-51
metabolism of, 5
physiology of, 69
pituitary production of, 69
828 - - Index
Triiodothyronine (T3) (Continued)
synthesis of, 4f, 5
trk oncogene, 290t, 291
in thyroid neoplasms, 265, 285, 285t
Trousseau's sign, in hypocalcemia, 444, 528
ITF-I gene therapy, for undifferentiated
Tuberculosis, Addison's disease in, 635
Tuberous sclerosis, 778
Tubulin, 295
Tumor(s). See under anatomy; specific tumor.
Tumor necrosis factor, in thyroid growth
regulation, 269
Tumor suppressor genes, 290t, 292. See also
specific gene, e.g., p53 gene.
Tumorigenesis, multistep, proposed model of,
in thyroid carcinoma, 334, 335f
Tumor-promoting phorbol esters, 271
Tyrosine kinase receptor( s)
for differentiated thyroid carcinoma, 339, 339f
in thyroid regulation, 257, 257t, 258f
mutations in, 290-291, 290t
U
Ulcer, peptic, in gastrinoma, 745, 747
Ultrasonography
endoscopic
of gastrinoma, 749-750
of insulinoma, 722-723, 724f, 730, 731t
hyperparathyroidism
intraoperative, 435
preoperative, 430-431, 43 If
intraoperative
of gastrinoma, 733, 734f
of insulinoma, 723, 724f-725f
laparoscopic, in adrenalectomy, 657
of adrenal glands, 566, 577
of gastrinoma, 732, 732f, 734t, 749
of insulinoma, 720
of medullary thyroid carcinoma, 136, 147,
147f
of papillary thyroid carcinoma, 142,
143f-144f
of sporadic nontoxic goiter, 27
of subacute thyroiditis, 36, 37f
of thyroid nodules, 87, 87f
Uremic osteodystrophy, 505-506

Urokinase plasminogen activator, in invasive
Von Recklinghausen's disease, 777-778

variant of, 757. See also Multiple endocrine
neoplasia 28 (MEN 28).
V
Vagal nerve, protection of, in thyroid
Vanillylmandelic acid, in pheochromocytoma,
589
Vascular endothelial growth factor inhibitor(s),
for differentiated thyroid carcinoma, 340
Vascular lesions, in thyroid surgery, 208
Vasoactive intestinal polypeptide (VIP), 706
Vasoactive intestinal polypeptide tumor
(VIPoma), 767-768, 768f
surgery for, 739, 801
Venography, of adrenal glands, 577
Venous catheterization, for medullary thyroid
carcinoma, 136
Verner-Morrison syndrome, 767
VHL syndrome
Video-assisted parathyroidectomy, minimally
invasive, 462-463, 463f, 467-468
results of, 465-466, 465t, 466t
Vimentin, 296
VIP (vasoactive intestinal polypeptide), 706
VIPoma (vasoactive intestinal polypeptide
tumor), 767-768, 768f
surgery for, 739
Vitamin A, preoperative, adrenalectomy
and,642
Vitamin 8 12 injections, after total gastrectomy,
753
Vitamin D. See 1,25-Dihydroxyvitamin D.
Vocal cord paralysis
after surgery for recurrent goiter, 308, 308t
as manifestation of compartment syndrome,
306
intrathoracic goiter and, 309-310
Von Hippel-Lindau disease, pheochromocytoma
in, 775-776
W
Weiss criteria, for adrenocortical malignancy,
605t
Werrner's syndrome, 673, 745. See also
Multiple endocrine neoplasia I (MEN 1).
Whipple procedure, for insulinomas, 726
Whipple's triad, definition of, 795
Wilms' tumor, in hereditary
parathyroidism-jaw tumor syndrome, 775
Wolff-Chaikoff effect, 25, 356
World Health Organization (WHO)
classification, of endemic goiter, 20, 20f
Wound closure, in thyroidectomy, 193
Wound infections
X
Xenotransplantation, 691
of parathyroid tissue, 694
of thyroid tissue, 693
Z
ZDl839 (Iressa), 301
Zollinger-Ellison syndrome. See also
Gastrinoma.
diagnosis of, 747
duodenotomy in, 733, 738
evaluation of patients with, 747-748
gastrectomy in, follow-up after, 753
gastric carcinoid tumors in, 781
history and evolution of, 745
liver metastases in, 754
multiple endocrine neoplasia 1 in,
734-735
surgery for, 684-686, 685f, 741-742,
742f
pathophysiology of, 745-746, 746f
Zona fasciculata, 564, 565f
Zona glomerulosa, 564, 565f
Zona reticularis, 564, 565f
Zuckerkandl fascia, of adrenal glands,
561-562

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ELSEVIER

Copyright 2005, 1997 Elsevier Inc.

Textbook of endocrine surgery / [edited by] Orlo H. Clark, Quan-Yang Duh,

Acquisitions Editor: Judith Fletcher

Printed in the United States of America

Claudette Abela-Forman EK, MD

Anders O. J. Bergenfelz, MD, PhD

John R. Frandon, BSc, MD, FRCSt

Miguel F. Herrera, MD, PhD

Job Kievit, MD, PhD

George L. Irvin III, MD

Chung Yau Lo, MB BS(HK), MS(HK),

Raducu Mihai, MD, PhD, MRCS

Peter Ridefelt, MD, PhD

Irving B. Rosen, MD, FRCS(C)

J. A. Roukema, MD, PhD

Maria Sorhede-Winzell, PhD

John A. van Heerden, MB, ChB, MS(Surg) (Minn),

Andrew P. Zbar, MB, BS

Since the first edition of the Textbook of Endocrine Surgery

associated with ret/PTC rearrangements and other papillary

Quan- Yang Duh, MD

Surgical anatomy and embryology of the thyroid and parathyroid

Medical and surgical treatment of endemic goiter

Sporadic nontoxic goiter

Graves' and Plummer's diseases : medical and surgical management

Use and abuse of thyroid-stimulating hormone suppressive therapy in

Approach to thyroid nodules

Childhood thyroid carcinoma

Papillary thyroid carcinoma : rationale for hemithyroidectomy

Papillary thyroid carcinoma : rationale for total thyroidectomy

Follicular neoplasms of the thyroid

Hurthle cell adenoma and carcinoma

Medullary thyroid carcinoma

Localization tests in patients with thyroid cancer

Papillary and follicular carcinoma : surgical and radioiodine treatment

Anaplastic carcinoma of the thyroid gland

Unusual thyroid cancers, lymphoma, and metastases to the thyroid

Recurrent thyroid cancer

Management of regional lymph nodes in papillary, follicular, and

Occurrence and prevention of complications in thyroid surgery

Thyroid emergencies : thyroid storm and myxedema coma

Pathology of tumors of the thyroid gland

Factors that predispose to thyroid neoplasia

Predictors of thyroid tumor aggressiveness

Growth factor, thyroid hyperplasia, and neoplasia

Signal transduction in thyroid neoplasms

Oncogenes in thyroid tumors

Mechanisms and regulation of invasion in thyroid cancer

Surgical management of recurrent and intrathoracic goiters

Surgical management of advanced thyroid cancer invading the

Potentially new therapies in thyroid cancer

Comparative genomic hybridization in thyroid neoplasms

Sodium-iodide symporter and radioactive iodine therapy

Parathyroid embryology, anatomy, and pathology

Parathyroid hormone : regulation of secretion and laboratory

Diagnosis of primary hyperparathyroidism and indications for

Natural history of untreated primary hyperparathyroidism

Metabolic complications of primary hyperparathyroidism

Natural history of treated primary hyperparathyroidism

Asymptomatic primary hyperparathyroidism

Localization studies in persistent or recurrent hyperparathyroidism

Surgical approach to primary hyperparathyroidism (bilateral

Surgical approach to primary hyperparathyroidism (unilateral