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Nosé
SECOND EDITION
ii
Second Edition
Vania Nosé, MD, PhD

Associate Chief of Pathology
Director of Anatomic and Molecular Pathology
Massachusetts General Hospital
Professor of Pathology
Harvard Medical School
Boston, Massachusetts
iii
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
DIAGNOSTIC PATHOLOGY: FAMILIAL CANCER SYNDROMES, SECOND EDITION ISBN: 978-0-323-71204-0

Inkling: 978-0-323-71206-4
Copyright © 2020 by Elsevier. All rights reserved.
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds or experiments described herein.
Because of rapid advances in the medical sciences, in particular, independent verification of
diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is
assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or
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any methods, products, instructions, or ideas contained in the material herein.
Previous edition copyrighted 2013.
Library of Congress Control Number: 2019956687
Printed in Canada by Friesens, Altona, Manitoba, Canada
Last digit is the print number: 9 8 7 6 5 4 3 2 1
iv
Dedication
Developing a comprehensive book like this could only be accomplished with
high levels of amazing teamwork. I would like to acknowledge and thank so
many remarkable people for their support and contributions to this book. I will
start with my parents, Dalva and Antonio Nosé, for their support, invaluable
teaching and guidance, and for being my life examples. To my wonderful sons
and best friends, Gustave, Erick, and Phillip, and their wives, Carla, Suzana,
and Bianca, and to my grandsons, Nicolas, Leonardo, and Lucas Antonio, you
all make my life so lovely and complete. To my brothers, Dalton and Walton,
and their families for their love and continuous support. To the outstanding
and dedicated contributing authors of this book for their hard work and
contributions to this unique project. To the wonderful Elsevier team for their
extraordinary work in making this book a reality. My final thanks are to all my
family, friends, residents, fellows, colleagues, and everyone who shares our
love and commitment to a better understanding of familial cancer diseases.
VN
v
Contributing Authors
Ying-Hsia Chu, MD Jochen K. Lennerz, MD, PhD
Clinical Fellow Medical Director
Department of Pathology Center for Integrated Diagnostics
Massachusetts General Hospital Associate Chief, Department of Pathology
Boston, Massachusetts Massachusetts General Hospital
Associate Professor
Daniel C. Chung, MD Harvard Medical School
Medical Co-Director, Center for Cancer Risk Assessment Boston, Massachusetts
MGH Cancer Center and Division of Gastroenterology
Director, High-Risk GI Cancer Clinic Susan C. Lester, MD, PhD
Associate Professor of Medicine Associate Pathologist
Harvard Medical School Breast Pathology Services
Boston, Massachusetts Brigham and Women’s Hospital
Assistant Professor
Vikram Deshpande, MD Harvard Medical School
Pathologist Boston, Massachusetts
Department of Pathology
Massachusetts General Hospital Alexander Craig MacKinnon, MD, PhD
Professor of Pathology Director
Harvard Medical School Division of Genomics, Diagnostics, and Bioinformatics
Boston, Massachusetts Professor
Department of Pathology
Alexander J. Gallan, MD University of Alabama at Birmingham
Renal and Genitourinary Pathologist Birmingham, Alabama
Assistant Professor
Department of Pathology Fabiola Medeiros, MD
Medical College of Wisconsin Director of Gynecologic, Placental and
Milwaukee, Wisconsin Perinatal Pathology
Department of Pathology and Laboratory Medicine
David G. Hicks, MD Cedars-Sinai Medical Center
Professor and Director of IHC-ISH Laboratory and Los Angeles, California
Breast Subspecialty Service
University of Rochester Medical Center Mari Mino-Kenudson, MD
Rochester, New York Pathologist, Department of Pathology
Director, Pulmonary Pathology
Mai P. Hoang, MD Massachusetts General Hospital
Professor of Pathology Professor of Pathology
Harvard Medical School Harvard Medical School
Director, Dermatopathology Services Boston, Massachusetts
Boston, Massachusetts Michelle Menon Miyake, MD
Otolaryngologist
Yin Rex Hung, MD, PhD Research Fellow
Assistant in Pathology Department of Otolaryngology
Department of Pathology Massachusetts Eye and Ear Infirmary
Massachusetts General Hospital Harvard Medical School
Boston, Massachusetts Boston, Massachusetts
vi
Valentina Nardi, MD
Assistant Professor of Pathology
Additional Contributing
Assistant in Pathology
Authors
Carla Martins Alberti, MD
Lori A. Erickson, MD
G. Petur Nielsen, MD Larissa V. Furtado, MD
Harvard Medical School Joel K. Greenson, MD
Pathologist, Department of Pathology
Director of Bone & Soft Tissue Pathology
Julie Guilmette, MD
Director of Electron Microscopy Unit Gregory Y. Lauwers, MD
M. Beatriz S. Lopes, MD, PhD
Alexandros D. Polydorides, MD, PhD
Patricia Nogueira de Sa, MD Von Samedi, MD, PhD
Internal Medicine Residency Program
Rochester General Hospital Karen S. Thompson, MD
Rochester, New York
Arthur S. Tischler, MD
Gladell P. Paner, MD, (BS) MT
Associate Professor of Pathology and Surgery,
Section of Urology
Director of Genitourinary Pathology Fellowship
Director of Point of Care Testing
Associate Director UC Medlabs
The University of Chicago Medical Center
Chicago, Illinois
Fausto J. Rodríguez, MD
Associate Professor of Pathology, Oncology and
Ophthalmology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Amitabh Srivastava, MD
Associate Professor of Pathology
Chief, GI Pathology
Associate Director, Surgical Pathology
Director, Surgical Pathology Fellowship Program
Brigham and Women’s Hospital
vii
viii
Preface
Welcome to the second edition of Diagnostic Pathology: Familial Cancer Syndromes!
The expanding use of gene sequencing (as NGS) technologies and our insight in neoplasm-
predisposing genes has greatly impacted our understanding of cancer initiation and progression.
Neoplasms that were formerly considered sporadic have been now redefined as part of novel
hereditary cancer predisposition syndromes. The proportion of tumors with a hereditary background,
and the list of hereditary cancer syndromes and cancer-predisposing genes, has been steadily
increasing. Presently, at least 10% of all tumors develop in the setting of germline predispositions.
Diagnostic Pathology: Familial Cancer Syndromes, second edition, features a comprehensive review
of the top inherited tumor syndromes. It is becoming increasingly well recognized that a given
familial tumor syndrome may be very heterogeneous in clinical appearance, where patients may
present initially with an apparently isolated tumor. It is crucial for clinicians, oncologists, and
surgical pathologists to be aware of the specific clinical and morphological findings that suggest a
possible syndromic association. A significant number of the hereditary neoplasms have distinct and
reproducible morphological and immunophenotypic, as well as molecular, findings.
Written by clinicians, molecular pathologists, and subspecialty pathology experts focused on familial
diseases, this book’s 166 chapters will help clinicians, oncologists, surgical pathologists, fellows, and
residents understand the critical aspects of diagnosing familial tumors and differentiating these
from their sporadic counterparts.
The book is organized into three parts. The first part, “Diagnoses Associated With Syndromes
by Organ,” discusses in detail the diseases encompassing the syndromes, highlighting the
characteristics of the tumors in each organ across the different syndromes. The book points out
some of the distinct characteristics of tumors found in inherited tumor syndromes that distinguish
these tumors from tumors in a sporadic setting. This part also contains tables that can be used as
a quick tumor classification reference.
The second part, “Overview of Syndromes,” has detailed descriptions of the major syndromes,
including genes involved, associated tumors, and diagnostic criteria. We have also included several
newly defined cancer syndromes.
Finally, the third part, “Reference,” offers a detailed index of each gene referenced in the book and
in which chapters each gene appears.
We hope that this second edition of Diagnostic Pathology: Familial Cancer Syndromes will guide you
to master diagnostic criteria when diagnosing tumors associated with inherited tumor syndromes.

Associate Chief of Pathology
Director of Anatomic and Molecular Pathology
ix
x
Acknowledgments
LEAD EDITOR
Arthur G. Gelsinger, MA
TEXT EDITORS
Nina I. Bennett, BA
Rebecca L. Bluth, BA
Terry W. Ferrell, MS
Megg Morin, BA
Kathryn Watkins, BA
IMAGE EDITORS
Jeffrey J. Marmorstone, BS
Lisa A. M. Steadman, BS
MEDICAL EDITORS
Daniel C. Chung, MD
Jochen K. Lennerz, MD, PhD
Alexander Craig MacKinnon, MD, PhD
ILLUSTRATIONS
Richard Coombs, MS
Lane R. Bennion, MS
Laura C. Wissler, MA
ART DIRECTION AND DESIGN

Tom M. Olson, BA
PRODUCTION COORDINATORS
Emily C. Fassett, BA
John Pecorelli, BS
xi
xii
Sections
PART I: Diagnoses Associated With Syndromes by Organ
SECTION 1: Blood and Bone Marrow
SECTION 2: Bone and Soft Tissue
SECTION 3: Breast
SECTION 4: Endocrine
SECTION 5: Gastrointestinal
SECTION 6: Genitourinary
SECTION 7: Gynecology
SECTION 8: Head and Neck
SECTION 9: Nervous System
SECTION 10: Pulmonary
SECTION 11: Skin
PART II: Overview of Syndromes

SECTION 1: Introduction
SECTION 2: Syndromes
PART III: Reference

SECTION 1: Molecular Factors
xiii
TABLE OF CONTENTS
Part I: Diagnoses Associated With ADRENAL MEDULLA AND PARAGANGLIA

Syndromes by Organ 88 Adrenal Medullary Hyperplasia
92 Neuroblastic Tumors of Adrenal Gland
SECTION 1: BLOOD AND BONE MARROW
4 Acute Lymphoblastic Leukemia and Non-Hodgkin 104 Pheochromocytoma and Paraganglioma
Lymphoma Vania Nosé, MD, PhD and Arthur S. Tischler, MD
Valentina Nardi, MD 114 Adrenal Medulla and Paraganglia Table
6 Blood and Bone Marrow Table Vania Nosé, MD, PhD
Valentina Nardi, MD
PANCREAS
SECTION 2: BONE AND SOFT TISSUE 118 Pancreatic Neuroendocrine Neoplasms
10 Chondrosarcoma Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 128 Endocrine Pancreas Table
14 Chordoma Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
18 Malignant Peripheral Nerve Sheath Tumor PARATHYROID
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 130 Parathyroid Adenoma
22 Osteosarcoma Vania Nosé, MD, PhD and Lori A. Erickson, MD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 136 Parathyroid Carcinoma
28 Rhabdomyosarcoma Vania Nosé, MD, PhD and Lori A. Erickson, MD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 142 Primary Parathyroid Hyperplasia
32 Schwannoma Lori A. Erickson, MD and Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD 152 Parathyroid Table
36 Bone and Soft Tissue Table Vania Nosé, MD, PhD
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
PITUITARY
SECTION 3: BREAST
158 Pituitary Adenoma
46 Breast Carcinoma M. Beatriz S. Lopes, MD, PhD and Vania Nosé, MD, PhD
Susan C. Lester, MD, PhD and David G. Hicks, MD 164 Pituitary Hyperplasia
54 Breast Table M. Beatriz S. Lopes, MD, PhD
David G. Hicks, MD and Susan C. Lester, MD, PhD 166 Pituitary Table
SECTION 4: ENDOCRINE
ADRENAL CORTEX THYROID, MEDULLARY
170 C-Cell Hyperplasia
58 Adrenal Cortical Adenoma
176 Medullary Thyroid Carcinoma
62 Adrenal Cortical Carcinoma
Vania Nosé, MD, PhD and Julie Guilmette, MD
186 Thyroid, Medullary Carcinoma Table
70 Adrenal Cortical Neoplasms in Children
78 Primary Pigmented Nodular Adrenocortical Disease THYROID, NONMEDULLARY
84 Adrenal Cortex Table 188 Familial Thyroid Carcinoma
Vania Nosé, MD, PhD Vania Nosé, MD, PhD
200 Follicular Thyroid Carcinoma
xiv
TABLE OF CONTENTS
208 Thyroid, Nonmedullary Carcinoma Table 308 Succinate Dehydrogenase-Deficient Renal Cell
Vania Nosé, MD, PhD Carcinoma
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS)
SECTION 5: GASTROINTESTINAL MT
312 Wilms Tumor
HEPATOBILIARY AND PANCREAS
212 Hepatoblastoma MT
Larissa V. Furtado, MD and Karen S. Thompson, MD 320 Kidney Table
218 Hepatocellular Carcinoma Gladell P. Paner, MD, (BS) MT
222 Pancreatic Adenocarcinoma PROSTATE
Amitabh Srivastava, MD and Von Samedi, MD, PhD 326 Prostate Carcinoma
226 Biliary Tract/Liver/Pancreas Table Gladell P. Paner, MD, (BS) MT
Amitabh Srivastava, MD 338 Prostate Table
TUBULAR GUT
228 Colonic Adenomas RENAL PELVIS AND URETER
Ying-Hsia Chu, MD and Vikram Deshpande, MD 344 Renal Urothelial Carcinoma
234 Esophageal Adenocarcinoma Gladell P. Paner, MD, (BS) MT
Ying-Hsia Chu, MD and Vikram Deshpande, MD 348 Ureter Urothelial Carcinoma
236 Esophageal Squamous Cell Carcinoma Gladell P. Paner, MD, (BS) MT
Ying-Hsia Chu, MD and Vikram Deshpande, MD 350 Renal Pelvis and Ureter Table
238 Gastric Adenocarcinoma Gladell P. Paner, MD, (BS) MT
Ying-Hsia Chu, MD and Vikram Deshpande, MD
244 Gastrointestinal Stromal Tumor TESTICLE
352 Germ Cell Tumor
252 Hamartomatous Polyposis Syndromes
Vania Nosé, MD, PhD and Amitabh Srivastava, MD
358 Sertoli Cell Neoplasms
262 Small Bowel Adenocarcinoma
362 Testicle Table
268 Colon/Rectum Table
Joel K. Greenson, MD and Amitabh Srivastava, MD
270 Esophagus/Stomach/Small Bowel Table SECTION 7: GYNECOLOGY
370 Cervical Carcinoma
SECTION 6: GENITOURINARY Fabiola Medeiros, MD
372 Fallopian Tube Carcinoma
BLADDER Fabiola Medeiros, MD
274 Bladder Urothelial Carcinoma 374 Ovarian Tumors
Gladell P. Paner, MD, (BS) MT Fabiola Medeiros, MD
282 Bladder Table 380 Endometrial Carcinoma
Gladell P. Paner, MD, (BS) MT Fabiola Medeiros, MD
384 Gynecologic Tumors
KIDNEY Fabiola Medeiros, MD
286 Angiomyolipoma SECTION 8: HEAD AND NECK
290 Clear Cell Renal Cell Carcinoma 390 Endolymphatic Sac Tumor
Gladell P. Paner, MD, (BS) MT Vania Nosé, MD, PhD
294 Cystic Nephroma 394 Head and Neck Squamous Cell Carcinoma
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) Vania Nosé, MD, PhD
MT 400 Head and Neck Table
296 HLRCC Syndrome-Associated Renal Cell Carcinoma Vania Nosé, MD, PhD
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) 404 Salivary Glands Table
MT Vania Nosé, MD, PhD
300 Papillary Renal Cell Carcinoma
SECTION 9: NERVOUS SYSTEM
304 Renal Oncocytoma, Chromophobe, and Hybrid 412 Central Nervous System
Tumors Fausto J. Rodríguez, MD
xv
TABLE OF CONTENTS
416 Eye 522 Bloom Syndrome
Fausto J. Rodríguez, MD Valentina Nardi, MD
420 Peripheral Nervous System 524 Brooke-Spiegler Syndrome
Fausto J. Rodríguez, MD Mai P. Hoang, MD
528 Carney Complex
SECTION 10: PULMONARY Vania Nosé, MD, PhD
426 Adenocarcinoma, Lung 536 Colonic Carcinoma Syndromes
Mari Mino-Kenudson, MD Joel K. Greenson, MD and Amitabh Srivastava, MD
432 Adenocarcinoma With Lepidic (Bronchioloalveolar) 540 Costello Syndrome
Predominant Pattern Mai P. Hoang, MD
Mari Mino-Kenudson, MD 542 Denys-Drash Syndrome
434 Lymphangioleiomyomatosis Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS)
Mari Mino-Kenudson, MD MT
438 Neuroendocrine Tumor, Lung 546 Diamond-Blackfan Anemia
Mari Mino-Kenudson, MD and Yin Rex Hung, MD, PhD Valentina Nardi, MD
442 Pleuropulmonary Blastoma 548 DICER1 Syndrome
Mari Mino-Kenudson, MD and Yin Rex Hung, MD, PhD Vania Nosé, MD, PhD and Michelle Menon Miyake, MD
444 Lung Table 556 Down Syndrome
Mari Mino-Kenudson, MD Valentina Nardi, MD
560 Dyskeratosis Congenita
SECTION 11: SKIN Mai P. Hoang, MD
564 Familial Acute Myeloid Leukemia and
448 BAP1-Inactivated Melanocytic Tumor
Mai P. Hoang, MD Myelodysplastic Syndrome
450 Basal Cell Carcinoma Valentina Nardi, MD
Mai P. Hoang, MD 568 Familial Adenomatous Polyposis
456 Cutaneous Melanoma Alexandros D. Polydorides, MD, PhD and Vania Nosé, MD,
Mai P. Hoang, MD PhD
460 Cutaneous Squamous Cell Carcinoma 576 Familial Chordoma
Mai P. Hoang, MD G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
466 Sebaceous Carcinoma 578 Familial Gastrointestinal Stromal Tumor
Mai P. Hoang, MD Vania Nosé, MD, PhD and Daniel C. Chung, MD
472 Skin Table 584 Familial Infantile Myofibromatosis
Mai P. Hoang, MD G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
586 Familial Isolated Hyperparathyroidism
Part II: Overview of Syndromes 590 Familial Nonmedullary Thyroid Carcinoma
SECTION 1: INTRODUCTION 596 Familial Paraganglioma Pheochromocytoma
476 Pathology of Familial Tumor Syndromes Syndrome
Vania Nosé, MD, PhD Vania Nosé, MD, PhD and Arthur S. Tischler, MD
484 Clinical Diagnosis and Management of 600 Familial Testicular Tumor
Familial/Hereditary Tumor Syndromes
602 Familial Uveal Melanoma
Vania Nosé, MD, PhD and Daniel C. Chung, MD
494 Molecular Aspects of Familial/Hereditary Tumor
604 Familial Wilms Tumor
Syndromes
Alexander Craig Mackinnon, MD, PhD
MT
SECTION 2: SYNDROMES 606 Fanconi Anemia
Valentina Nardi, MD
502 Ataxia Telangiectasia 608 Glucagon Cell Hyperplasia and Neoplasia
Fausto J. Rodríguez, MD Vania Nosé, MD, PhD
504 BAP1 Tumor Predisposition Syndrome 610 Breast/Ovarian Cancer Syndrome: BRCA1
Mai P. Hoang, MD Susan C. Lester, MD, PhD and David G. Hicks, MD
506 Basal Cell Nevus Syndrome/Gorlin Syndrome 616 Breast/Ovarian Cancer Syndrome: BRCA2
Mai P. Hoang, MD David G. Hicks, MD and Susan C. Lester, MD, PhD
510 Beckwith-Wiedemann Syndrome 620 Hereditary Diffuse Gastric Cancer
Vania Nosé, MD, PhD and Patricia Nogueira de Sa, MD Joel K. Greenson, MD and Daniel C. Chung, MD
518 Birt-Hogg-Dubé Syndrome
Mai P. Hoang, MD
xvi
TABLE OF CONTENTS
624 Hereditary Leiomyomatosis and Renal Cell 744 Hamartomatous Polyps, Peutz-Jeghers
Carcinoma Syndrome Gregory Y. Lauwers, MD and Amitabh Srivastava, MD
Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS) 750 PTEN-Hamartoma Tumor Syndromes
MT Vania Nosé, MD, PhD
628 Hereditary Mixed Polyposis Syndrome 758 RASopathies: Noonan Syndrome
Joel K. Greenson, MD Valentina Nardi, MD
630 Multiple Osteochondromas 762 Rhabdoid Predisposition Syndrome
G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD Fausto J. Rodríguez, MD
632 Hereditary Neuroblastoma 766 Schwannomatosis
Vania Nosé, MD, PhD Fausto J. Rodríguez, MD
636 Hereditary Pancreatic Cancer Syndrome 770 Shwachman-Diamond Syndrome
Daniel C. Chung, MD and Vania Nosé, MD, PhD Valentina Nardi, MD
640 Hereditary Papillary Renal Cell Carcinoma 772 Steatocystoma Multiplex
Gladell P. Paner, MD, (BS) MT Mai P. Hoang, MD
642 Hereditary Paraganglioma/Pheochromocytoma 774 Tuberous Sclerosis Complex
Syndromes Fausto J. Rodríguez, MD
Vania Nosé, MD, PhD 780 Tumor Syndromes Predisposing to Osteosarcoma
650 Hereditary Prostate Cancer G. Petur Nielsen, MD and Yin Rex Hung, MD, PhD
Gladell P. Paner, MD, (BS) MT 782 von Hippel-Lindau Syndrome
652 Hereditary Renal Epithelial Tumors, Others Vania Nosé, MD, PhD and Carla Martins Alberti, MD
Gladell P. Paner, MD, (BS) MT 790 Werner Syndrome/Progeria
656 Hereditary Retinoblastoma Mai P. Hoang, MD
Fausto J. Rodríguez, MD 794 Wilms Tumor-Associated Syndromes
658 Hereditary SWI/SNF Complex Deficiency Syndromes Alexander J. Gallan, MD and Gladell P. Paner, MD, (BS)
Fausto J. Rodríguez, MD MT
660 Howel-Evans Syndrome/Keratosis Palmares and 796 Wiskott-Aldrich Syndrome
Plantares With Esophageal Cancer Valentina Nardi, MD
Mai P. Hoang, MD 798 Xeroderma Pigmentosum
662 Hyperparathyroidism-Jaw Tumor Syndrome Mai P. Hoang, MD
668 Juvenile Polyposis Syndrome
Daniel C. Chung, MD, Gregory Y. Lauwers, MD, and
Part III: Reference
674 Li-Fraumeni Syndrome
SECTION 1: MOLECULAR FACTORS
David G. Hicks, MD and Susan C. Lester, MD, PhD 804 Molecular Factors Index
680 Lynch Syndrome Vania Nosé, MD, PhD
Joel K. Greenson, MD, Daniel C. Chung, MD, and Vania
Nosé, MD, PhD
686 McCune-Albright Syndrome
692 Melanoma/Pancreatic Carcinoma Syndrome
Mai P. Hoang, MD
696 Multiple Endocrine Neoplasia Type 1 (MEN1)
Vania Nosé, MD, PhD and Michelle Menon Miyake, MD
718 MUTYH-Associated Polyposis
720 Neurofibromatosis Type 1
728 Neurofibromatosis Type 2
734 Nijmegen Breakage Syndrome
Valentina Nardi, MD
736 Pancreatic Neuroendocrine Tumor Syndromes
xvii
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Nosé
SECOND EDITION
PART I
SECTION 1
Blood and Bone Marrow
Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma 4

Blood and Bone Marrow Table 6
Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma
KEY FACTS
Diagnoses Associated With Syndromes by Organ:
CLINICAL ISSUES ○ Germline IKZF1 mutations

• Acute lymphoblastic leukemia (ALL) • ALL as manifestations of genetic syndromes
○ Not exclusively sporadic disease ○ Li-Fraumeni syndrome
○ Risk of developing B-acute lymphoblastic leukemia (B- ○ Down syndrome
ALL) is 2-4x increased among siblings of affected children ○ Wiskott-Aldrich syndrome
• Number of genetic alterations that predispose individuals ○ Bloom syndrome
to development of ALL is growing ○ Ataxia telangiectasia syndrome
• Children with ALL should have thorough history and ○ Constitutional mismatch repair syndrome
focused physical exam or be referred to screen for ○ Nijmegen breakage syndrome
potential familial syndrome ○ Familial platelet disorder due to RUNX1 mutations
• Implications for preimplantation genetic diagnosis, ○ Fanconi anemia
management of patient and relatives, screening of related ○ Neurofibromatosis type 1
stem cell donors ○ Noonan syndrome
DIAGNOSTIC CHECKLIST • Genetic predisposition to lymphoma
○ No known syndromes predisposing exclusively to
• Familial B-ALL due to
lymphomas
○ Germline PAX5 mutations
○ Syndromes leading to immunodeficiency can predispose
○ Germline ETV6 mutations or deletions
to NHL
○ Germline SH2B3 mutations
B-ALL/Lymphoma in Bone Marrow B-ALL/Lymphoma Morphology

(Left) Bone marrow is 100%
cellular. Hematopoietic
marrow is replaced by blasts
with high nuclear:cytoplasmic
ratio conferring the blue
appearance at low power.
(Right) Lymphoid blasts can
have irregular nuclear
contours mimicking myeloid
blasts. The chromatin is
vesicular, and distinct nucleoli
can be seen.
B-ALL/Lymphoma in Bone Marrow Aspirate B-ALL/Lymphoma in Lymph Node

(Left) High-power view shows
bone marrow involved by B-
ALL. The cellularity consists of
sheets of small- to medium-
sized blasts, with scant
cytoplasm, slightly indented,
irregular nuclei, fine
chromatin, and occasional
distinct nucleoli. (Right) Sheets
of immature cells with open
chromatin and distinct nucleoli
consistent with blasts are
filling the sinuses and
replacing the parenchyma.
4
Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma

• 25-30% of patients with germline ETV6 mutations will
TERMINOLOGY develop B-ALL; in addition some may develop solid tumors
Abbreviations &/or myeloid malignancies
• Acute lymphoblastic leukemia (ALL) Familial B-ALL Due to Germline SH2B3 Mutations
• Non-Hodgkin lymphoma (NHL)
• SH2B adaptor protein 3 (SH2B3) gene (a.k.a. LNK) encodes
negative regulator of cytokine signaling and tyrosine
ETIOLOGY/PATHOGENESIS kinases
ALL as Manifestation of Genetic Syndromes • SH2B3 plays critical role in development and function of
• Li-Fraumeni (pediatric hypodiploid B-ALL) hematopoietic stem cells and lymphoid progenitors
• Down syndrome (often characterized by somatic CRLF2 • Biallelic germline loss of function mutations in SH2B3 are
rearrangements) associated with familial developmental delay,
• Wiskott-Aldrich syndrome autoimmunity, and B-ALL
• Bloom syndrome • ALL with sporadic or germline SH2B3 mutations, may be
• Ataxia telangiectasia: T-ALL > B-ALL sensitive to kinase inhibitors or agents inhibiting activated
JAK-STAT pathway
• Constitutional mismatch repair syndrome
• Nijmegen breakage syndrome: T-ALL > B-ALL Familial B-ALL Due to Germline IKZF1 Mutations
• Familial platelet disorder with predisposition to myeloid • IKZF1 encodes zinc finger transcription factor IKAROS,
malignancy due to RUNX1 mutations (T-ALL) critical regulator of lymphoid development
• Fanconi anemia • ~ 0.9% of presumed sporadic pediatric B-ALL will have
• Neurofibromatosis type I germline IKZF1 variants
• Noonan syndrome • Germline IKZF1 variants tend to cluster outside known
annotated functional domains
Familial B-ALL Secondary to Germline Mutations in
• Germline IKZF1 alterations predispose to ALL, with variable
Genes Somatically Mutated in ALL
penetrance, and potentially reduce response to
• PAX5 chemotherapy and kinase inhibitors
• ETV6 • Some patients with germline IKZF1 variants have B
• SH2B3 lymphopenia
• IKZF1
Genetic Predisposition to Lymphoma MICROSCOPIC
• Currently no known syndromes predisposing exclusively to Histologic Features
lymphomas (mostly NHL) • Histologically indistinguishable from pediatric sporadic
• Syndromes leading to immunodeficiency can predispose to acute lymphoblastic leukemia/lymphoma and from
NHL sporadic Hodgkin and non-Hodgkin lymphomas
○ Ataxia telangiectasia (also at risk for Hodgkin lymphoma)
○ Bloom syndrome ANCILLARY TESTS
○ Nijmegen breakage syndrome Genetic Testing
○ Wiskott Aldrich syndrome
• Targeted gene sequencing to detect point mutations,
○ Constitutional mismatch repair syndrome insertions and deletions
• Microarrays, multiplex ligation-dependent probe
CLINICAL ISSUES amplification-based (MLPA), or next-generation sequencing
Familial B-ALL Due to Germline PAX5 Mutations assays to detect large-scale genomic
• B-cell transcription factor paired box protein PAX5 is rearrangements &/or deletions
essential for normal B-cell development • Preferred tissue for germline genetic testing in patients
• PAX5 is somatically deleted, rearranged, or otherwise with hematologic malignancy are cultured skin fibroblasts
mutated in ~ 30% of sporadic B-ALL
• Heterozygous hypomorph germline mutations (i.e., SELECTED REFERENCES
p.Gly183Ser) need somatic loss of wild-type PAX5 allele to 1. Pui CH et al: Somatic and germline genomics in paediatric acute
be leukemogenic lymphoblastic leukaemia. Nat Rev Clin Oncol. 16(4):227-40, 2019
2. Rampersaud E et al: Germline deletion of ETV6 in familial acute
Familial B-ALL Due to Germline ETV6 Mutations or lymphoblastic leukemia. Blood Adv. 3(7):1039-46, 2019
3. Churchman ML et al: Germline genetic IKZF1 variation and predisposition to
Deletions childhood acute lymphoblastic leukemia. Cancer Cell. 33(5):937-48.e8, 2018
• ETV6 is ETS family transcriptional repressor essential for 4. Auer F et al: Inherited susceptibility to pre B-ALL caused by germline
bone marrow haematopoiesis transmission of PAX5 c.547G>A. Leukemia. 28(5):1136-8, 2014
5. Perez-Garcia A et al: Genetic loss of SH2B3 in acute lymphoblastic leukemia.
• Many germline ETV6 variants have dominant negative Blood. 122(14):2425-32, 2013
effect on transcriptional repression mediated by wild-type
protein
• Heterozygous germline mutations in ETV6 are associated
with thrombocytopenia and predisposition to B-ALL with
hyperdiploid karyotype
5
Diagnoses Associated With Syndromes by Organ: Blood and Bone Marrow Table
Germline Mutations and Conditions Associated With Increased Risk of Hematological

Malignancies
Disorder Genes Inheritance Hematologic Nonhematological Additional Clinical
Malignancy Malignancies Findings
Fanconi anemia FANCA, FANCB*, AR MDS, AML, [ALL Squamous cell Short stature, skin
FANCC, FANCD1 * X-linked with FANCD1 carcinomas of head and pigmentation, skeletal and
(BRCA2), FANCD2, ** AD (BRCA2)] neck, vulva, GI tract; liver thumb abnormalities,
FANCE, FANCF, tumors; brain tumors facial dysmorphisms,
FANCG, FANCI, FANCJ and Wilms tumor renal, gonadal, cardiac, GI,
(BRIP1/BACH1), [FANCD1 (BRCA2)] and CNS abnormalities
FANCL, FANCM,
FANCN (PALB2),
FANCO (RAD51C),
FANCP (SLX4), FANCQ
(ERCC4), FANCR
(RAD51)**, FANCS
(BRCA1), FANCT
(UBE2T), FANCU
(XRCC2), FANCV
(MAD2L2/REV7)
Diamond-Blackfan anemia RPL5, RPL11, RPL15, AD MDS, AML Osteosarcoma, soft Macrocytic anemia, short
RPL23, RPL 26, RPL27, tissue sarcomas stature, thumb
RPL31, RPL35A, abnormalities, facial
RPL36, RPS7, RPS10, dysmorphisms, cleft
RPS15, RPS17, RPS19, lip/palate, Pierre Robin
RPS24, RPS26, RPS27, syndrome, cardiac and
RPS27A, RPS28, genitourinary
RPS29, abnormalities
GATA1
TSR2
X-linked
X-linked
Dyskeratosis congenita DKC1 X-linked MDS, AML, AA Squamous cell Nail dystrophy, rash,
TERC AD carcinomas of head and leukoplakia, short stature,
TERT AD, AR neck, GI tract pulmonary fibrosis,
NOLA3/NOP10 AR vascular anomalies, early
NOLA2/NHP2 AR graying of hair, hair loss;
TINF2 AD dental, CNS, GI and GU
WRAP53/TCAB1 AR abnormalities
CTC1 AR
RTEL1 AD, AR
ACD/TPP1 AD, AR
PARN AD, AR
NAF1 AD
STN1 AD
Shwachman-Diamond syndrome SBDS AR MDS, AML - Short stature, steatorrhea,
metaphyseal dysostosis
Severe congenital neutropenia ELANE AD MDS, AML - Neurological
HAX1 AR abnormalities
Familial MDS/AML with mutated GATA2 AD MDS, AML, - Warts, atypical
GATA2 CMML mycobacteria,
lymphedema, deafness,
pulmonary alveolar
proteinosis, arteriovenous
malformations
MIRAGE syndrome SAMD9 AD MDS, AML - Short stature, adrenal
hypoplasia, infections;
CNS, GI, GU, and skeletal
abnormalities
Ataxia-pancytopenia syndrome SAMD9L AD MDS, AML - Ataxia (variable)
Myeloid neoplasm with mutated SRP72 AD MDS - Sensorineural hearing loss
6
Blood and Bone Marrow Table

Germline Mutations and Conditions Associated With Increased Risk of Hematological
Malignancies (Continued)
Disorder Genes Inheritance Hematologic Nonhematological Additional Clinical
Malignancy Malignancies Findings
SRP72
Familial MDS/AML with mutated DDX41 AD MDS, AML - -
DDX41
Familial platelet disorder RUNX1 AD MDS, AML, ALL - Thrombocytopenia and
with propensity to abnormal platelet
myeloid malignancy function
Thrombocytopenia 2 ANKRD26 AD MDS, AML - Thrombocytopenia and
abnormal platelet
function
Thrombocytopenia 5 ETV6 AD ALL, MDS, AML - Thrombocytopenia and
abnormal platelet
function
Familial AML with CEBPA CEBPA AD AML - -
mutation
Li-Fraumeni TP53 AD ALL, MDS, AML Breast, soft tissue -
sarcomas, brain,
adrenocortical
carcinoma, lung, colon,
pancreas, Wilms,
prostate
Susceptibility to ALL3 PAX5 AD ALL - -
Constitutional mismatch MLH1 AR Lymphoma, CNS, GI tract, other Café au lait spots, axillary
repair deficiency PMS2 AR ALL, AML freckling, Lisch nodules,
syndrome MSH2 AR neurofibromas, intestinal
MSH6 AR adenomas
Wiskott Aldrich WAS X-linked Lymphoma, Thrombocytopenia,
leukemia neutropenia, eczema,
infections, autoimmune
disorders
Nijmegen breakage syndrome NBN AR Lymphoma Gliomas, Severe microcephaly,
rhabdomyosarcoma, abnormal facies, other
medulloblastoma malformations
Bloom syndrome BLM AR Lymphoma, Colon, skin cancer, Facial rash with butterfly
MDS, ALL squamous cell distribution, other
carcinomas of head and dermatologic
neck, Wilms tumor, and manifestations, chronic
others, at early age obstructive lung disease,
endocrine abnormalities
Ataxia telangiectasia ATM AR Lymphoma, Solid tumors -
leukemia
Noonan syndrome PTPN11, SOS1, RAF1, AD JMML Rhabdomyosarcoma, Short stature,
KRAS, NRAS, BRAF, neuroblastoma macrocephaly, feeding
MAP2K1 difficulty, cardiac defects,
other
AD = autosomal dominant; AR = autosomal recessive; A<L = acute myeloid leukemia: ALL = acute lymphoblastic leukemia; JMML = juvenile
myelomonocytic leukemia; MDS = myelodysplasic syndrome.
Godley LA et al: Genetic predisposition to hematologic malignancies: management and surveillance. Blood, 130(4):424-432), 2017.
7
PART I
SECTION 2
Bone and Soft Tissue
Chondrosarcoma 10
Chordoma 14
Malignant Peripheral Nerve Sheath Tumor 18
Osteosarcoma 22
Rhabdomyosarcoma 28
Schwannoma 32
Bone and Soft Tissue Table 36
Chondrosarcoma
KEY FACTS
TERMINOLOGY – Ollier disease and Maffucci syndrome: Somatic

• Malignant cartilaginous matrix-producing tumor postzygotic mutation in IDH1/IDH2
• Secondary chondrosarcoma arises in association with – Metachondromatosis: Germline mutation in PTPN11
preexisting benign tumor or diseased bone ○ Hereditary multiple exostoses/osteochondromatosis:
• Atypical cartilaginous tumor is used for tumor arising in Germline mutation in EXT1/EXT2
appendicular skeleton with microscopic appearance CLINICAL ISSUES
identical to grade 1 chondrosarcoma
• Conventional central chondrosarcoma accounts for > 90%
• Dedifferentiated chondrosarcoma contains high-grade of all chondrosarcomas
nonchondrogenic sarcoma juxtaposed to low-grade
• Atypical cartilaginous tumor can be treated conservatively
cartilaginous tumor
with curettage
ETIOLOGY/PATHOGENESIS MACROSCOPIC
• > 90% of cases sporadic
• Permeation of medullary cavity, scalloping of endosteal
○ Somatic mutations in IDH1/IDH2 in 50-60% and COL2A1 surface, cortical thickening
in 20-40% of tumors
• Secondary cases associated with MICROSCOPIC
enchondromatosis/osteochondromatosis • Infiltration of preexisting trabecular bone is single most
○ Enchondromatosis important histologic criterion
• Histologic grading (grades 1, 2, and 3) is prognostic
Pelvic Chondrosarcoma Pelvic Chondrosarcoma

(Left) Axial CT shows a large
chondrosarcoma ﬊ arising
from the left iliac wing with
scattered ring and arc
mineralization ﬆ. (Right)
Gross photograph shows pelvic
chondrosarcoma in the same
patient. The tumor is
lobulated with a blue-gray cut
surface ﬅ; adjacent residual
normal bone can be seen ﬇.
Conventional Chondrosarcoma in Proximal

Chondrosarcoma Tibia
(Left) Radiograph shows a
chondrosarcoma in the
proximal tibia with ill-defined
border and characteristic ring
and arc mineralization ﬉.
(Right) Gross photograph
shows conventional
chondrosarcoma with a blue-
gray cut surface in the same
patient.
10
Chondrosarcoma

• Most commonly pelvis (especially ilium), followed by
TERMINOLOGY proximal/distal femur, proximal humerus, and ribs
Definitions ○ In long bones, chondrosarcoma usually involves
• Malignant cartilaginous matrix-producing tumor of bone metaphysis or diaphysis
○ Primary chondrosarcoma: Arises in medullary cavity • Rarely (< 1%) develops in small bones of hands and feet
(conventional type) or on bone surface • Chondrosarcomas of cranium usually involve skull base
(periosteal/juxtacortical type) • Secondary chondrosarcomas: Arise in association with
○ Secondary chondrosarcoma: Arises from preexisting preexisting osteochondromas/enchondromas
benign tumor (e.g., enchondroma, osteochondroma) or
Presentation
diseased bone (e.g., radiation, Paget disease)
○ Atypical cartilaginous tumor: Low-grade cartilaginous • Pain, enlarging mass, &/or pathologic fracture
tumor in appendicular skeleton with microscopic • Skull-based tumors: Headache, cranial nerve palsies
appearance identical to grade 1 chondrosarcoma • Abrupt mass enlargement and worsening of clinical
○ Dedifferentiated chondrosarcoma: High-grade symptoms in preexisting osteochondromas/enchondromas
nonchondrogenic sarcoma juxtaposed to areas of low- Treatment
grade cartilaginous tumor
• Curettage for atypical cartilaginous tumor
• Wide surgical resection for grade 1 chondrosarcomas
ETIOLOGY/PATHOGENESIS
arising in axial skeleton and high-grade chondrosarcoma
Sporadic • Adjuvant chemotherapy considered in dedifferentiated
• > 90% of cases chondrosarcomas
• Rarely arise associated with solitary sporadic/nonsyndromic • Radiation considered in surgically unresectable tumors
osteochondroma Prognosis
• 50-60% of cases harbor somatic mutations in isocitrate
dehydrogenase IDH1 or IDH2 • Histologic grade is single most important prognostic factor
• 20-40% of cases harbor somatic mutations in major • Atypical cartilaginous tumors show excellent prognosis
cartilage collagen gene COL2A1 with conservative surgical curettage treatment
• Grade 1 chondrosarcomas are locally aggressive
Hereditary Multiple Exostosis/Osteochondromatosis ○ 5-year survival ~ 80-85%
• Autosomal dominant • Grades 2-3 chondrosarcomas show worse prognosis
○ Mutations in EXT1 (8q24) or EXT2 (11p11) ○ 5-year survival ~ 50%
○ As part of trichorhinophalangeal syndrome type 2 • Dismal prognosis in dedifferentiated chondrosarcomas
(Langer-Giedion syndrome) ○ Median survival < 1-2 years, frequent metastases
– Disruption/microdeletion of genes including EXT1
○ As part of Potocki-Schaffer syndrome IMAGING
– Disruption/microdeletion of genes including EXT2 Radiographic Findings
• Develop multiple exostoses/osteochondromas often by
• Lytic with irregular spiculations and radiodensities caused
2nd decade of life
by matrix calcification
• Risk of malignant transformation 2-25%
• Densities often in "rings and arcs" configuration indicative
Enchondromatosis of endochondral ossification and reactive bone formation
• Sporadic (Ollier disease, Maffucci syndrome) or familial • Low-grade tumors often show mineralization, bone
(metachondromatosis) expansion, endosteal scalloping, and thickening of cortex
○ Ollier disease and Maffucci syndrome • High-grade tumors often show large radiolucency, cortical
– Somatic postzygotic mutation in isocitrate destruction/permeation, frequently accompanied by soft
dehydrogenase genes IDH1 or IDH2 tissue extension
– Maffucci syndrome differs from Ollier disease with MR Findings
additional development of vascular tumors (spindle
• Helpful in visualizing tumor extent, particularly in soft tissue
cell hemangiomas)
• Dark on T1WI
– Risk of malignant transformation up to 35-40%
• Bright on T2WI
○ Metachondromatosis
• Cartilage cap of > 2 cm in osteochondroma may raise
– Autosomal dominant
concern for malignant transformation but not entirely
– Develops multiple enchondromas and
sufficient
osteochondromas
• Contrast enhancement may aid in distinguishing secondary
– Germline PTPN11 loss-of-function mutation
chondrosarcoma from preexisting
– Risk of malignant transformation unclear osteochondroma/enchondroma
CLINICAL ISSUES CT Findings

Site • Unmineralized and mineralized components of tumor
delineated in medullary or cortical lesion
• Arise in bone derived from endochondral ossification
11
Diagnoses Associated With Syndromes by Organ: Chondrosarcoma
• Recurrent GRM1 gene rearrangement in subset of tumors

MACROSCOPIC
General Features Chondroid Chordoma
• Usually arises in skull base
• Low-grade tumors permeate medullary cavity, scallop
endosteal surface, and produce cortical thickening • Can be difficult to differentiate from low-grade
chondrosarcoma
• High-grade tumors destroy cortex and extend into soft
tissue, frequently associated with elevated periosteum • Expresses both keratin and T-brachyury (not expressed by
chondrosarcoma)
• Neoplastic hyaline cartilage appears gray-blue and
glistening Chondroblastic Osteosarcoma
• Mineralized matrix appears as punctate, chalk-like deposits • Osteoid deposition
• Myxoid matrix appears translucent, gray, mucoid-to-watery • Chondrogenic component is typically high grade
• Chondrosarcoma arising in osteochondroma shows thick • Lacks mutations in IDH1/IDH2 (whereas 50-60% of
cartilage cap and frequent cystic changes chondrosarcomas harbor IDH1/IDH2 mutations)
• Areas of dedifferentiation appear firm and fleshy
Fracture Callus
MICROSCOPIC • Small nodules of cartilages often with pronounced
endochondral ossification
Histologic Features
• May simulate malignancy based on histologic appearance
• Infiltrative growth pattern encasing preexisting trabecular • Correlation with radiologic features aids recognition
bone is single most important diagnostic criterion
• Diverse histologic subtypes: Conventional (hyaline or SELECTED REFERENCES
myxoid), clear cell, dedifferentiated, mesenchymal
1. de Andrea CE et al: Integrating morphology and genetics in the diagnosis of
• Conventional hyaline type cartilage tumors. Surg Pathol Clin. 10(3):537-52, 2017
○ Hyaline cartilaginous matrix: Homogeneous, pink 2. Andreou D et al: Metastatic potential of grade I chondrosarcoma of bone:
○ Neoplastic chondrocytes vary in size with moderate results of a multi-institutional study. Ann Surg Oncol. 23(1):120-5, 2016
eosinophilic-to-vacuolated cytoplasm in lacunar spaces 3. DeLaney TF et al: Long-term results of Phase II study of high dose
photon/proton radiotherapy in the management of spine chordomas,
• Conventional myxoid type chondrosarcomas, and other sarcomas. J Surg Oncol. 110(2):115-22, 2014
○ Myxoid cartilaginous matrix frothy, bubbly, basophilic 4. Nord KH et al: GRM1 is upregulated through gene fusion and promoter
swapping in chondromyxoid fibroma. Nat Genet. 46(5):474-7, 2014
○ Bipolar-to-stellate cells singly or in cords and strands
5. Kerr DA et al: Molecular distinction of chondrosarcoma from chondroblastic
• Clear cell osteosarcoma through IDH1/2 mutations. Am J Surg Pathol. 37(6):787-95,
○ Low-grade subtype, abundant clear cytoplasm 2013
6. Tarpey PS et al: Frequent mutation of the major cartilage collagen gene
• Mesenchymal COL2A1 in chondrosarcoma. Nat Genet. 45(8):923-6, 2013
○ Sheets of round to spindled cells with scant cytoplasm 7. Vanel D et al: Enchondroma vs. chondrosarcoma: a simple, easy-to-use, new
admixed with nodules of hyaline cartilage magnetic resonance sign. Eur J Radiol. 82(12):2154-60, 2013
○ Recurrent HEY1-NCOA2 fusion 8. Yang W et al: Ptpn11 deletion in a novel progenitor causes
metachondromatosis by inducing hedgehog signalling. Nature.
• Dedifferentiated 499(7459):491-5, 2013
○ Transition from typically low-grade cartilaginous tumor 9. de Andrea CE et al: Interobserver reliability in the histopathological diagnosis
to high-grade nonchondrogenic sarcoma of cartilaginous tumors in patients with multiple osteochondromas. Mod
Pathol. 25(9):1275-83, 2012
• Infiltration of preexisting bony trabeculae most helpful clue 10. Amary MF et al: IDH1 and IDH2 mutations are frequent events in central
in recognizing malignant transformation chondrosarcoma and central and periosteal chondromas but not in other
• Histologic grading (grades 1, 2, and 3) important prognostic mesenchymal tumours. J Pathol. 224(3):334-43, 2011
11. Amary MF et al: Ollier disease and Maffucci syndrome are caused by somatic
factor mosaic mutations of IDH1 and IDH2. Nat Genet. 43(12):1262-5, 2011
○ Based on cellularity and degree of cytologic atypia 12. Pansuriya TC et al: Somatic mosaic IDH1 and IDH2 mutations are associated
with enchondroma and spindle cell hemangioma in Ollier disease and
Maffucci syndrome. Nat Genet. 43(12):1256-61, 2011
DIFFERENTIAL DIAGNOSIS 13. Verdegaal SH et al: Incidence, predictive factors, and prognosis of
Enchondroma chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an
international multicenter study of 161 patients. Oncologist. 16(12):1771-9,
• No infiltrative pattern or extension into soft tissue 2011
• Relatively paucicellular and lacks significant cytologic atypia 14. Lin PP et al: Secondary chondrosarcoma. J Am Acad Orthop Surg.
18(10):608-15, 2010
Osteochondroma 15. Eefting D et al: Assessment of interobserver variability and histologic
parameters to improve reliability in classification and grading of central
• No infiltrative pattern or extension into soft tissue cartilaginous tumors. Am J Surg Pathol. 33(1):50-7, 2009
• Characteristic stalk with cortical and medullary continuity 16. Porter DE et al: Severity of disease and risk of malignant change in hereditary
multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br.
• Thin cartilaginous cap, typically < 2 cm 86(7):1041-6, 2004
Chondromyxoid Fibroma 17. Bovée JV et al: Chondrosarcoma of the phalanx: a locally aggressive lesion
with minimal metastatic potential: a report of 35 cases and a review of the
• Radiographically and histologically nonaggressive and well- literature. Cancer. 86(9):1724-32, 1999
circumscribed 18. Rosenberg AE et al: Chondrosarcoma of the base of the skull: a
clinicopathologic study of 200 cases with emphasis on its distinction from
• Fibromyxoid stroma with conspicuous small staghorn blood chordoma. Am J Surg Pathol. 23:1370-8, 1999
vessels
• Spindled-shaped cells and frequent osteoclast-type giant
cells
12
Chondrosarcoma

Chondrosarcoma Arising in Association
Chondrosarcoma With Enchondromatosis With Enchondromatosis
(Left) Radiograph shows the
proximal femur in a patient
with Ollier disease, with
multiple intramedullary
cartilaginous lesions in the
form of ring and arc
mineralization ﬅ, associated
with an adjacent large
chondrosarcoma ﬇. (Right)
Gross photograph of proximal
femur in the same patient
shows multiple blue-gray
intramedullary nodules ﬆ,
consistent with Ollier disease.
An expansile, fleshy
chondrosarcoma ﬊ is also
present.
Chondrosarcoma With Permeative Pattern Clear Cell Chondrosarcoma

(Left) A helpful histologic clue
to the diagnosis of
chondrosarcoma is the
presence of permeation.
Chondrosarcoma shows
infiltration of normal
trabecular bone ﬊. (Right)
Clear cell chondrosarcoma is a
histologic subtype with
prominent clear-cell changes
with abundant clear
cytoplasm and variably
hyperchromatic nuclei.
Dedifferentiated Chondrosarcoma Mesenchymal Chondrosarcoma

(Left) Dedifferentiated
chondrosarcoma comprises a
high-grade sarcoma ﬊
juxtaposed to a low-grade
cartilaginous tumor ﬆ. Here,
both components infiltrate
among preexisting bony
trabeculae ﬈. (Right)
Mesenchymal chondrosarcoma
characteristically shows
sheets-to-nodules of small
blue cells ﬅ intermixed with
small aggregates of
cartilaginous nodules ﬊.
13
Chordoma
KEY FACTS
TERMINOLOGY IMAGING
• Primary malignant tumor of bone that shows notochordal • Destructive lytic lesion
differentiation and usually arises within axial skeleton • Invariably extends into soft tissues
ETIOLOGY/PATHOGENESIS MACROSCOPIC
• Benign notochordal cell tumor (BNCT) thought to be • Gelatinous, lobulated, and well delineated
precursor lesion to chordoma • Solid and fish flesh-like in dedifferentiated chordomas
• Mutation in TBXT implicated in both somatic and familial
chordomas MICROSCOPIC
• Histologically classified into 4 groups: Conventional,
CLINICAL ISSUES chondroid, dedifferentiated, and poorly differentiated
• Accounts for ~ 1-3% of primary malignant bone tumors • Conventional chordomas show epithelioid cells with
• Usually diagnosed in patients 30-70 years old, rarely vacuolated bubbly "physaliferous" cells in myxoid stroma
children or infants • Chondroid chordomas have areas that mimic hyaline-type
• Primarily involves axial skeleton with soft tissue extension chondrosarcomas
• Treated by surgery &/or radiotherapy, generally with • Dedifferentiated chordomas contain areas of high-grade
limited role for chemotherapy sarcoma and portend worst prognosis
• Median overall survival 5-7 years for most chordomas but < • Poorly differentiated chordomas defined by loss of
1 year for dedifferentiated chordomas SMARCB1/INI1 expression
Sacrococcygeal Chordoma Sacrococcygeal Chordoma

(Left) Chordomas most
commonly involve the
sacrococcygeal region ﬇ in
the distal coccyx with
considerable soft tissue
extension. (Right) Sagittal
section of the same tumor in
the distal coccyx demonstrates
a well-circumscribed,
gelatinous mass with
multinodular architecture and
a patchy red-brown area,
consistent with hemorrhage.
Conventional Chordoma With

Physaliferous Cells T-Brachyury Expression in Chordoma
(Left) Tumor cells in
conventional chordoma often
show prominent
intracytoplasmic, pale to clear
vacuoles, which give rise to a
bubbly appearance (so-called
physaliferous cells). (Right)
Chordomas express T-
brachyury, a transcription
factor involved in notochord
development and regulation.
While nuclear staining ﬈ is
seen in chordoma cells,
background inflammatory and
endothelial cells are negative
﬊.
14
Chordoma

○ Mobile spine: Pain, neurologic symptoms, compression
TERMINOLOGY fracture
Definitions ○ Sacrum: Pain, constipation, incontinence, bladder
• Chordoma: Primary malignant tumor of bone showing dysfunction
notochordal differentiation and arising usually in axial Treatment
skeleton
• Surgery and preoperative/postoperative radiotherapy
• Chondroid chordoma: Showing areas of hyaline matrix,
resembling low-grade hyaline-type chondrosarcoma • No established role for chemotherapy in conventional or
chondroid chordomas
• Dedifferentiated chordoma: Showing areas of high-grade
sarcoma juxtaposed to conventional chordoma ○ Chemotherapy may be used in managing
dedifferentiated or poorly differentiated chordomas
• Poorly differentiated chordoma: Showing loss of
SMARCB1/INI1 expression Prognosis
• Depends on histology
ETIOLOGY/PATHOGENESIS ○ Best prognosis in conventional and chondroid
Sporadic chordomas
• Thought to arise from notochordal remnants – Median overall survival 5-7 years
• Benign notochordal cell tumor (BNCT) may be precursor ○ Poorly differentiated chordomas show median survival
lesion to chordoma of 4.4 years
• Associated with somatic TBXT duplication &/or mutations in ○ Worst prognosis in dedifferentiated chordoma
growth factor signaling pathways – Median overall survival < 1 year, usually rapidly fatal
• Poorly differentiated chordoma with SMARCB1 deletion with disseminated disease
&/or mutation • Depends on tumor location, size, and resectability
○ Best prognosis seen in sacral chordomas with complete
Familial resection and negative margin
• Associated with germline TBXT duplication • Metastatic chordoma seen in < 5-40% of patients
• Chordoma of childhood/infancy reported in tuberous ○ Commonly to lung, skin, and bone
sclerosis complex (germline mutations in TSC1/TSC2)
• Germline mutations in DNA repair machinery BRCA2, NBN, IMAGING
or CHEK2
Radiographic Findings
CLINICAL ISSUES • Lytic and destructive
• Extends into adjacent soft tissue
Epidemiology
• Calcifications may be seen
• Incidence • In sacrococcygeal chordomas, soft tissue component is
○ < 1 per 1 million usually anterior
○ 1-3% of primary malignant bone tumors ○ May displace rectum and extend along sacral nerve roots
• Age into sciatic notch
○ Median 60 years, range usually 30-70 years
MR Findings
○ Earlier in familial chordomas (30-50 years)
○ 5% of chordomas seen in patients < 20 years • Bright, lobulated-appearing on T2WI
○ Chordomas in children/infancy often in skull base, • Foci of calcification are frequent
occasionally in setting of tuberous sclerosis complex • Soft tissue extension is better delineated
• Sex CT Findings
○ Slight male predominance for sacral chordoma
• Destructive and radiolucent bone lesion
○ Slight female predominance for skull base chordoma
• Calcifications may be seen
Site
• Primarily arises within axial skeleton MACROSCOPIC
○ ~ 60% in sacrococcygeal region General Features
○ ~ 30% in skull base • Soft, lobulated, tan-gray, gelatinous to mucoid
○ ~ 10% in cervical, lumbar, or thoracic spine • Well delineated from surrounding tissues
○ Rarely reported outside axial skeleton • Dedifferentiated chordoma appears variegated with solid,
• Chondroid chordoma predominantly in skull base fish flesh-like appearance similar to soft tissue sarcomas
• Dedifferentiated chordoma usually in sacrococcygeal • Poorly differentiated chordoma lacks mucoid areas but
region instead often shows hemorrhage and necrosis
• Poorly differentiated chordoma most often in skull base
Size
Presentation • Skull-base tumors typically small (< 5 cm)
• Depends on tumor site • Sacrococcygeal tumors often large (up to > 20 cm)
○ Skull base: Headache, diplopia, cranial nerve defects
15
Diagnoses Associated With Syndromes by Organ: Chordoma
○ T-brachyury expression absent in high-grade component

MICROSCOPIC of dedifferentiated chordoma
Histologic Features • Poorly differentiated chordoma shows loss of
• 4 histologic types: Conventional, chondroid, SMARCB1/INI1 expression in addition
dedifferentiated, and poorly differentiated
○ Similar histologic appearance in familial and sporadic DIFFERENTIAL DIAGNOSIS
chordomas Metastatic Adenocarcinoma
• Conventional chordoma shows lobular pattern, infiltrates
• Mucinous adenocarcinoma mimic chordoma on small
marrow space, encases preexisting bony trabeculae, and
biopsy sample
usually breaches cortex, forming demarcated soft tissue
• Mucinous adenocarcinoma is negative for T-brachyury and
mass
S100 protein; these markers are positive in chordoma
○ Composed of large epithelioid cells arranged in cohesive
nests and cords Chondrosarcoma
○ Nuclei are of moderate size and may contain small • Distinction between chordoma and chondrosarcoma can
nucleolus or pseudoinclusions be difficult on small biopsies, especially from skull base
○ Moderate eosinophilic to clear cytoplasm • Chondrosarcoma is negative for T-brachyury and
○ Physaliferous cells with numerous small, cytokeratins; these markers are positive in chordoma
intracytoplasmic vacuoles that impart bubbly
appearance Benign Notochordal Cell Tumor
– Physaliferous cells not pathognomonic of chordoma, • Generally confined to bone with no soft tissue involvement
as other tumor types may have similar-appearing cells • Radiographically sclerotic with no contrast enhancement;
and some chordomas lack them whereas chordoma appears lytic
○ One tumor cell may wrap or "hug" another • Lacks extracellular myxoid matrix, which is present in
○ Pleomorphism and spindling of tumor cells may be conventional chordoma
present • Cells with abundant clear (adipocyte-like) to eosinophilic
○ Basophilic and myxoid extracellular matrix cytoplasm
○ Mitotic activity usually limited • Identical immunohistochemical profile as chordoma
○ Foci of necrosis common, especially in large tumors Ecchordosis Physaliphora
• Chondroid chordoma contains chondroid component and
• Proliferation of fetal notochordal remnants
areas of conventional chordoma
• Circumscribed, generally < 3 cm, mostly in retroclival region
○ Chondroid component composed of hyaline matrix, with
• Shows epithelioid vacuolated cells and myxoid stroma,
similar appearance to hyaline cartilage, containing
microscopically almost identical to chordoma
neoplastic cells in lacunar-like spaces
• Identical immunohistochemical profile as chordoma
○ Chondroid component abruptly abuts or merges with
conventional component • Distinction relies on radiologic correlation
○ Quantity of chondroid component variable
– Chondroid areas may predominate in some
SELECTED REFERENCES
chordomas, thus difficult to distinguish from 1. Gröschel S et al: Defective homologous recombination DNA repair as
therapeutic target in advanced chordoma. Nat Commun. 10(1):1635, 2019
chondrosarcomas
2. Shih AR et al: Clinicopathologic characteristics of poorly differentiated
• Dedifferentiated chordoma shows biphasic appearance chordoma. Mod Pathol. 31(8):1237-45, 2018
with high-grade sarcoma juxtaposed to conventional 3. Tarpey PS et al: The driver landscape of sporadic chordoma. Nat Commun.
chordoma 8(1):890, 2017
4. Rotondo RL et al: High-dose proton-based radiation therapy in the
○ High-grade sarcoma may show diverse histology: management of spine chordomas: outcomes and clinicopathological
Pleomorphic, osteosarcomatous, prognostic factors. J Neurosurg Spine. 23(6):788-97, 2015
rhabdomyosarcomatous, or fibrosarcoma-like 5. Choy E et al: Genotyping cancer-associated genes in chordoma identifies
• Poorly differentiated chordoma shows epithelioid tumor mutations in oncogenes and areas of chromosomal loss involving CDKN2A,
PTEN, and SMARCB1. PLoS One. 9(7):e101283, 2014
cells with eccentric nuclei 6. Le LP et al: Recurrent chromosomal copy number alterations in sporadic
○ Myxoid matrix is absent chordomas. PLoS One. 6(5):e18846, 2011
○ Lack of SMARCB1/INI1 expression with presence of 7. Yang XR et al: T (brachyury) gene duplication confers major susceptibility to
familial chordoma. Nat Genet. 41(11):1176-8, 2009
brachyury expression is diagnostic
8. Deshpande V et al: Intraosseous benign notochord cell tumors (BNCT):
• BNCT may be seen adjacent to chordoma, suggesting further evidence supporting a relationship to chordoma. Am J Surg Pathol.
malignant transformation 31(10):1573-7, 2007
9. Vujovic S et al: Brachyury, a crucial regulator of notochordal development, is
a novel biomarker for chordomas. J Pathol. 209(2):157-65, 2006
ANCILLARY TESTS 10. Rosenberg AE et al: Chondrosarcoma of the base of the skull: a
clinicopathologic study of 200 cases with emphasis on its distinction from
Immunohistochemistry chordoma. Am J Surg Pathol. 23:1370-8, 1999
• Consistent expression of cytokeratins and epithelial 11. O'Connell JX et al: Base of skull chordoma. A correlative study of histologic
membrane antigen and clinical features of 62 cases. Cancer. 74(8):2261-7, 1994
12. Coffin CM et al: Chordoma in childhood and adolescence. A clinicopathologic
• Variable expression of S100 protein analysis of 12 cases. Arch Pathol Lab Med. 117(9):927-33, 1993
• Consistent expression of T-brachyury 13. Meis JM et al: "Dedifferentiated" chordoma. A clinicopathologic and
immunohistochemical study of three cases. Am J Surg Pathol. 11(7):516-25,
1987
16
Chordoma

Skull Base Chordoma Conventional Chordoma
(Left) Chordomas generally
involve midline bony
structures. A typical location
for chordoma (~ 30% of cases)
is at the base of skull in the
region of clivus ﬊. (Right) On
low power, conventional
chordoma shows a lobulated
growth pattern, with fibrous
band ﬊ and epithelioid tumor
cells amidst prominent myxoid
stroma ﬊.
Chondroid Chordoma Dedifferentiated Chordoma

(Left) Chondroid chordoma
most often arises in the skull
base and shows areas of
hyaline-type chondroid matrix,
which can be a histologic
mimic of chondrosarcoma.
(Right) Dedifferentiated
chordoma, characterized by a
high-grade sarcoma ﬊
juxtaposed to areas of
conventional chordoma ﬊, is
highly aggressive.
Loss of INI1 Expression in Poorly

Poorly Differentiated Chordoma Differentiated Chordoma
(Left) Poorly differentiated
chordoma shows sheets of
epithelioid cells with abundant
cytoplasm. Necrosis is often
present ﬈. Unlike
conventional chordoma,
myxoid stroma is not a
feature. Poorly differentiated
chordoma expresses T-
brachyury (not shown). (Right)
Poorly differentiated
chordoma characteristically
shows loss of INI1 expression
with lack of nuclear staining in
the tumor cells ﬊, whereas
intact expression can be seen
in the control stromal and
inflammatory cells ﬈.
17
Malignant Peripheral Nerve Sheath Tumor
KEY FACTS
TERMINOLOGY ○ Alternating hypercellular/hypocellular areas ("marbled")

• Sarcoma arising from nerve or benign nerve sheath tumor ○ Fascicles of spindle cells, variable pleomorphism
or showing nerve sheath cellular differentiation ○ Perivascular accentuation of tumor cells around vessels
• Heterologous differentiation (15%)
ETIOLOGY/PATHOGENESIS • Epithelioid MPNST (5%)
• 50% associated with neurofibromatosis type 1 (NF1)
• 10% associated with radiation ANCILLARY TESTS
• Mutations in polycomb complex (EED, SUZ12) or tumor • Immunohistochemistry: Focal S100, SOX10, GFAP
suppressors (CDKN2A, TP53) • Loss of H3K27Me3 in ~ 50% of conventional MPNST
• Loss of SMARCB1 in ~ 70% of epithelioid MPNST
CLINICAL ISSUES
• Mostly adults, younger in NF1-associated cases TOP DIFFERENTIAL DIAGNOSES
• Most arise in major nerve trunks • Synovial sarcoma
• 5-year survival 15-40% • Malignant melanoma
• Local recurrence > 40% • Clear cell sarcoma
• Metastasis 30-60%, commonly to lungs and bones • Cellular schwannoma
• Atypical neurofibroma
MICROSCOPIC
• Atypical neurofibromatous neoplasm of uncertain biologic
• Spindle-cell MPNST (80%) potential
MPNST Arising in Plexiform Neurofibroma Radiation-Associated MPNST

(Left) Grossly, malignant
peripheral nerve sheath tumor
(MPNST) shows a yellow-tan,
fleshy cut surface, often with
necrosis and hemorrhage ﬉.
This MPNST arises in a
plexiform neurofibroma ﬅ in
a patient with
neurofibromatosis type 1
(NF1). (Right) About 10% of
MPNST arises in patients with
history of prior therapeutic
radiation. This radiation-
associated MPNST involves
the sciatic nerve ﬇.
MPNST With "Marbled" Pattern Spindle Cells in Conventional MPNST

(Left) MPNST often shows
fascicles of spindle cells in
alternating hypercellular and
hypocellular areas within the
tumor, giving a "marbled"
histologic appearance. (Right)
MPNST typically shows
fascicles of spindle cells with
variably hyperchromatic nuclei
in a myxoid-to-collagenous
stromal background.
Conspicuous mitoses may be
seen.
18

TERMINOLOGY Treatment
• Surgical approaches
Abbreviations ○ Wide excision/resection or amputation
• Malignant peripheral nerve sheath tumor (MPNST) • Adjuvant therapy
Synonyms ○ Radiation
• Neurofibrosarcoma, neurogenic sarcoma, malignant ○ Chemotherapy, though generally less effective
schwannoma Prognosis
Definitions • Depends on age, tumor location, size, and histologic grade
• Diagnostic criteria (1 of following) ○ Superior survival in pediatric and intracranial MPNST
○ Sarcoma arising from nerve or benign nerve sheath ○ Worse survival in central and head/neck MPNST (more
tumor (e.g., neurofibroma) common in NF1 patients)
○ Sarcoma with histologic features of nerve sheath • 5-year overall survival 15-40%
differentiation in patients with neurofibromatosis type 1 • Local recurrence > 40%
(NF1) • Metastasis 30-60%
○ Sarcoma with histologic and immunophenotypic or ○ Most commonly to lungs, bones, &/or pleura
ultrastructural evidence of nerve sheath differentiation
in patients without NF1 IMAGING
General Features
ETIOLOGY/PATHOGENESIS
• Large, heterogeneous, fusiform mass associated with major
Genetic Predisposition nerve trunk
• 50% of tumors associated with NF1 • Tumor necrosis seen on MR suggests MPNST rather than
○ Lifetime incidence of MPNST in NF1 patients: 8-15% neurofibroma in NF1 patients
• 40% of tumors sporadic
MACROSCOPIC
Environmental Exposure
General Features
• 10% of tumors associated with radiation exposure
• Fusiform or eccentric mass associated with major nerve or
Molecular Pathogenesis nerve trunk
• NF1 characterized by germline mutation in NF1 • Color/consistency similar to other soft tissue sarcomas
○ MPNST tumorigenesis accelerated by somatic loss of ○ Gray-tan, firm to fleshy
2nd NF1 allele ○ Necrosis and hemorrhage common
• Recurrent mutations in polycomb repressive complex 2
(PRC2) components: EED or SUZ12
Size
○ Subsequent loss of histone 3 lysine 27 trimethylation • Usually > 5 cm, sometimes massive > 20 cm
marks (H3K27Me3)
• Recurrent mutations in tumor suppressors CDKN2A (p16) MICROSCOPIC
&/or TP53 (p53) Histologic Features
• Inactivating mutation in SMARCB1 in ~ 70% of epithelioid • Mostly high grade, < 20% low grade
MPNST
• Some arising from preexisting benign nerve sheath tumor
○ Most commonly from neurofibroma (usually NF1
CLINICAL ISSUES patients), rarely schwannoma, ganglioneuroma, and
Epidemiology others
• Rare, 3-10% of soft tissue sarcomas • Histologic types: Conventional/spindle cell (80%),
• Mostly adults heterologous differentiation (15%), and epithelioid (5%)
○ Wide age range: ~ 10-70 years ○ Conventional/spindle-cell MPNST
○ Average age in NF1 patients: ~ 30 years (vs. ~ 40 years in – Alternating hypercellular and hypocellular areas
sporadic cases) ("marbled" pattern)
• No sex predilection – Fascicles of spindle cells, variable pleomorphism
– Perivascular accentuation of tumor cells around small
Site vessels
• Most commonly deep-seated soft tissue: Thigh, buttock, – Extensive necrosis common, mitoses frequent
trunk, upper extremities, followed by retroperitoneum, ○ MPNST with heterologous differentiation
head and neck – Rhabdomyosarcomatous (malignant triton tumor)
• Most arise in major nerves: Sciatic nerve, followed by – Osteosarcomatous, chondrosarcomatous,
brachial plexus, sacral plexus, and paraspinal nerves angiosarcomatous, etc.
Presentation ○ Epithelioid MPNST
• Painful mass – Lobules of large epithelioid cells with eosinophilic
cytoplasm, vesicular nuclei, prominent nucleoli
• Neurological deficit
19
Diagnoses Associated With Syndromes by Organ: Malignant Peripheral Nerve Sheath Tumor
– Associated with schwannomatosis and germline Atypical Neurofibromatous Neoplasm of Uncertain

SMARCB1 mutation Biologic Potential
• Schwann cell neoplasm with at least 2 of following
ANCILLARY TESTS ○ Cytologic atypia
Immunohistochemistry ○ Loss of neurofibroma architecture
• Conventional MPNST ○ Hypercellularity
○ Positive for S100, typically focal, in 20-60% of cases ○ Mitotic activity > 1/50 HPF to < 3/10 HPF
○ Positive for SOX10 &/or GFAP in 20-60% of cases
○ Complete loss of H3K27Me3 in ~ 50% of cases SELECTED REFERENCES
• Epithelioid MPNST 1. Martin E et al: Treatment and survival differences across tumor sites in
○ Diffusely positive for S100 in all cases malignant peripheral nerve sheath tumors: a SEER database analysis and
review of the literature. Neurooncol Pract. 6(2):134-43, 2019
○ Complete loss of SMARCB1/INI1 nuclear staining in ~ 2. Schwabe M et al: How effective are noninvasive tests for diagnosing
70% of cases malignant peripheral nerve sheath tumors in patients with
neurofibromatosis type 1? Diagnosing MPNST in NF1 patients. Sarcoma.
2019:4627521, 2019
DIFFERENTIAL DIAGNOSIS 3. Yan P et al: Nomograms for predicting the overall and cause-specific survival
in patients with malignant peripheral nerve sheath tumor: a population-
Synovial Sarcoma based study. J Neurooncol. 143(3):495-503, 2019
• Usually uniformly hypercellular (rather than "marbled" 4. Makise N et al: Clarifying the distinction between malignant peripheral nerve
pattern with alternations of cellularity in MPNST) sheath tumor and dedifferentiated liposarcoma: a critical reappraisal of the
diagnostic utility of MDM2 and H3K27me3 Status. Am J Surg Pathol.
• Immunohistochemistry 42(5):656-64, 2018
○ Usually positive for cytokeratin, EMA, and TLE1 5. Le Guellec S et al: Loss of H3K27 trimethylation is not suitable for
distinguishing malignant peripheral nerve sheath tumor from melanoma: a
○ Generally negative for S100 and SOX10 study of 387 cases including mimicking lesions. Mod Pathol. 30(12):1677-87,
• Gene fusion between SS18 (formerly SYT) and SSX1, SSX2, 2017
or SSX4 in nearly all cases 6. Miettinen MM et al: Histopathologic evaluation of atypical
neurofibromatous tumors and their transformation into malignant
Malignant Melanoma peripheral nerve sheath tumor in neurofibromatosis 1 patients - a consensus
overview. Hum Pathol. 67:1-10, 2017
• Typically superficial dermal tumors 7. Pekmezci M et al: Significance of H3K27me3 loss in the diagnosis of
○ Sometimes metastasize/involve deep-seated locations malignant peripheral nerve sheath tumors. Mod Pathol. 30(12):1710-9, 2017
• Presence of melanoma in situ component or melanin 8. Cleven AH et al: Loss of H3K27 tri-methylation is a diagnostic marker for
malignant peripheral nerve sheath tumors and an indicator for an inferior
pigments can be helpful clues survival. Mod Pathol. 29(6):582-90, 2016
• Immunohistochemistry 9. Le Guellec S et al: Malignant peripheral nerve sheath tumor is a challenging
○ Diffusely positive for S100 diagnosis: a systematic pathology review, immunohistochemistry, and
molecular analysis in 160 patients from the French Sarcoma Group
○ Positive for melanocytic markers HMB45, Melan-A, and Database. Am J Surg Pathol. 40(7):896-908, 2016
MiTF 10. Prieto-Granada CN et al: Loss of H3K27me3 expression is a highly sensitive
marker for sporadic and radiation-induced MPNST. Am J Surg Pathol.
• BRAF V600E mutation in some cases 40(4):479-89, 2016
Clear Cell Sarcoma 11. Röhrich M et al: Methylation-based classification of benign and malignant
peripheral nerve sheath tumors. Acta Neuropathol. 131(6):877-87, 2016
• Predilection for acral sites 12. Schaefer IM et al: Loss of H3K27 trimethylation distinguishes malignant
• Nests of uniform epithelioid-to-spindly cells, prominent peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 29(1):4-
13, 2016
nucleoli, rare scattered multinucleated giant cells
13. Jo VY et al: Epithelioid malignant peripheral nerve sheath tumor:
• Immunohistochemistry clinicopathologic analysis of 63 cases. Am J Surg Pathol. 39(5):673-82, 2015
○ Diffusely positive for S100 14. Lee W et al: PRC2 is recurrently inactivated through EED or SUZ12 loss in
malignant peripheral nerve sheath tumors. Nat Genet. 46(11):1227-32, 2014
○ Positive for HMB45
15. Zhang M et al: Somatic mutations of SUZ12 in malignant peripheral nerve
• EWSR1-ATF1 or EWSR1-CREB1 gene fusion in most cases sheath tumors. Nat Genet. 46(11):1170-2, 2014
16. Rahrmann EP et al: Forward genetic screen for malignant peripheral nerve
Cellular Schwannoma sheath tumor formation identifies new genes and pathways driving
• Common locations: Retroperitoneum, pelvis, posterior tumorigenesis. Nat Genet. 45(7):756-66, 2013
17. Carter JM et al: Epithelioid malignant peripheral nerve sheath tumor arising
mediastinum, or gastrointestinal tract in a schwannoma, in a patient with "neuroblastoma-like" schwannomatosis
• Dominated by Antoni A (cellular) areas and a novel germline SMARCB1 mutation. Am J Surg Pathol. 36(1):154-60,
• May show focal necrosis, mitosis, &/or degenerative atypia 2012
18. Terry J et al: TLE1 as a Diagnostic immunohistochemical marker for synovial
with smudgy nuclei sarcoma emerging from gene expression profiling studies. Am J Surg Pathol.
• Immunohistochemistry 31(2):240-6, 2007
○ Diffusely positive for S100 and SOX10 19. Birindelli S et al: Rb and TP53 pathway alterations in sporadic and NF1-
related malignant peripheral nerve sheath tumors. Lab Invest. 81(6):833-44,
Atypical Neurofibroma 2001
20. Perry A et al: NF1 deletions in S-100 protein-positive and negative cells of
• Cytologic atypia ("ancient neurofibroma") or sporadic and neurofibromatosis 1 (NF1)-associated plexiform neurofibromas
hypercellularity and malignant peripheral nerve sheath tumors. Am J Pathol. 159(1):57-61,
2001
• Retain neurofibroma architecture with characteristic
collagen bundles ("shredded carrots" pattern)
20

Focal S100 Expression in Conventional
Spindle Cells in Conventional MPNST MPNST
(Left) The tumor cells in
conventional MPNST show
spindle morphology and
tapered nuclei, suggestive of
neural differentiation. (Right)
S100 expression is often focal
in conventional MPNST and is
only seen in 20-60% of cases.
This is in contrast to
schwannoma, which shows
strong, diffuse nuclear
staining for S100 in all cases.
Rhabdomyoblasts in Malignant Triton

MPNST With Heterologous Differentiation Tumor
(Left) MPNST can show
heterologous elements, such
as this example with
osteosarcomatous and
chondrosarcomatous
differentiation. (Right) A
subset of MPNSTs harbors
heterologous elements such as
rhabdomyoblasts, which are
tumor cells with abundant
eosinophilic cytoplasm
showing skeletal muscle
differentiation; these are
known as malignant triton
tumors.
Epithelioid MPNST Loss of INI1 in Epithelioid MPNST

(Left) Epithelioid MPNST
shows nodules to sheets of
epithelioid tumor cells with
prominent nucleoli. Diffuse
S100 expression (not shown) is
seen in epithelioid MPNST but
not in most conventional
MPNST. (Right) Epithelioid
MPNST shows loss of
SMARCB1/INI1 expression in
70% of cases. This example
shows loss of INI1 nuclear
staining in the tumor cells,
whereas the stromal and
inflammatory cells retain INI1
expression.
21
Osteosarcoma
KEY FACTS
TERMINOLOGY CLINICAL ISSUES

• High-grade malignant tumor in which neoplastic cells • Most patients are young, between 10 and 20 years
produce bone • Distal femur > proximal tibia > proximal humerus
ETIOLOGY/PATHOGENESIS MICROSCOPIC
• Primary osteosarcomas arise de novo without known • Admixture of 2 elements in varying proportions
predisposing condition ○ High-grade sarcoma with epithelioid, plasmacytoid,
• Secondary osteosarcomas arise within diseased bone fusiform, ovoid, small-round, spindle, or clear cells;
○ Paget disease of bone sometimes with multinucleated giant cells
○ Radiation exposure ○ Bone produced directly by tumor cells
○ Chemotherapy • Conventional osteosarcoma
○ Trauma ○ Histologic variants: Osteoblastic, chondroblastic,
○ Foreign body fibroblastic, telangiectatic, giant cell, small cell,
• Hereditary syndromes osteoblastoma-like, chondroblastoma-like,
○ Hereditary retinoblastoma: RB1 mutation chondromyxoid fibroma-like
○ Li-Fraumeni syndrome: TP53 mutation • Other variants with distinct biological/clinical behavior
○ Rothmund-Thomson syndrome: RECQL4 mutation ○ Parosteal osteosarcoma, periosteal osteosarcoma, well-
○ Bloom syndrome: BLM mutation differentiated intramedullary osteosarcoma,
○ Werner syndrome: WRN mutation osteosarcoma of craniofacial bones
Osteosarcoma in Distal Femur Osteosarcoma in Distal Femur
Osteosarcoma commonly arises in the region of the knee. Gross photograph of the same patient shows a tan-yellow,
Radiograph of an osteosarcoma in the distal femur fleshy mass involving the distal femur and adjacent soft
demonstrates a destructive, bone-forming tumor ﬇ tissue. A pathologic fracture is apparent ﬅ.
associated with pathologic fracture ﬅ.
22
Osteosarcoma

TERMINOLOGY Presentation
• Progressively enlarging, painful mass
Synonyms ○ Pain deep-seated and frequently noted months prior
• Osteogenic sarcoma ○ Pain intensity increases over time, eventually unremitting
Definitions • May appear as visible and palpable mass
• High-grade malignant tumor in which tumor cells produce • Overlying skin may be warm, erythematous, edematous,
bone and cartographed by prominent, engorged veins
○ Skin ulceration secondary to pressure ischemia can occur
ETIOLOGY/PATHOGENESIS • Restricted range of motion in those with large tumors
• Joint effusions when tumor involves epiphysis or
Neoplastic Process periarticular structures
• Primary osteosarcomas arise de novo without known • Weight loss and cachexia in patients with advanced disease
predisposing condition • Pathologic fracture as heralding event in 5-10% of cases
• Secondary osteosarcomas arise within diseased bone
○ Paget disease of bone
Laboratory Tests
○ Radiation exposure • Elevated serum alkaline phosphatase
○ Chemotherapy Treatment
○ Trauma • Surgical approaches
○ Foreign body (e.g., orthopedic implants) ○ Limb salvage; complete excision with wide negative
Genetic Susceptibility margins is optimal
• Hereditary retinoblastoma: Germline mutation in RB1 – Biopsy tract often removed with tumor
• Li-Fraumeni syndrome: Germline mutation in TP53 ○ Amputation necessary if major vessels and nerves
• Rothmund-Thomson syndrome: Germline mutation in compromised, if tumor involves region that cannot be
RECQL4 reconstructed, or if large volumes of tissue
contaminated by fracture or prior surgical intervention
• Bloom syndrome: Germline mutation in BLM
• Adjuvant therapy
• Werner syndrome: Germline mutation in WRN
○ Neoadjuvant &/or adjuvant chemotherapy often
Molecular Pathogenesis administered
• Frequent TP53 mutations – Tumor may diminish in size
• Subsets harbor amplification of PDGFRA, KDR, or VEGFA – Tumor often undergoes extensive mineralization and
• Subsets harbor mutations in cell cycle/DNA repair develops pseudocapsule facilitating excision
regulators: RB1, BRCA2, or BAP1 – Chemotherapeutic efficacy determined by histologic
• Genomic instability signature reminiscent of BRCA1/BRCA2- assessment of amount of induced tumor necrosis
deficient tumors □ Induced tumor necrosis of ≥ 90% considered good
response, important prognostic indicator
CLINICAL ISSUES • Drugs
○ High-dose methotrexate, doxorubicin, and cisplatin, &/or
Epidemiology
others
• Incidence • Radiation
○ Most common primary malignant tumor of bone, ○ Used for unresectable tumors because of size &/or site
exclusive of hematopoietic malignancies ○ Used in patients considered incurable with widely
– Accounts for ~ 20% of primary bone sarcomas metastatic disease
○ ~ 800 cases each year in USA ○ Adjuvant radiation if excision associated with positive
• Age margins
○ Most patients are young, between 10 and 20 years
– Females usually younger than males, probably due to Prognosis
earlier skeletal development • Relapse-free survival rates 50-80% (median ~ 70%)
○ 2nd peak occurs in patients > 50 years (often secondary • May vary by subtypes of conventional osteosarcoma
osteosarcoma) ○ Chondroblastic variant associated with poor response to
• Sex chemotherapy
○ M:F = 1.3:1.0
IMAGING
Site
Radiographic Findings
• Most commonly arises in long tubular bones
○ Distal femur > proximal tibia > proximal humerus • Permeative and destructive
– 50% of cases located in knee region • Centered around metaphysis of long bones
• In older individuals, pelvis and axial skeleton are most ○ < 10% diaphyseal
common locations ○ Rarely epiphyseal
• < 10% occur in mandible and craniofacial bones • Poorly defined, lack of sclerotic rim
• Mixed lytic and blastic mass transgressing cortex and
forming large soft tissue components
23
Diagnoses Associated With Syndromes by Organ: Osteosarcoma
○ 90% extend into soft issue • Skip metastases appear as intramedullary firm, ovoid, tan-
• Matrix visible in 90% of cases white nodules located adjacent to or far from main mass
○ Periphery usually less mineralized than central area • Variants of osteosarcoma confined to surface of bone
• Soft tissue components may have fine "cloud-like" pattern uncommon
of radiodensity
• Entirely lytic or sclerotic in some instances MICROSCOPIC
○ Entirely lytic appearance characteristic of telangiectatic Histologic Features
variant
• Admixture of 2 elements in varying proportions
• Lower grade lesions tend to be more mineralized
○ High-grade sarcoma with epithelioid, plasmacytoid,
• Periosteal reaction fusiform, ovoid, small-round, spindle, or clear cells;
○ Appears as multiple layers (onion skin) or radiating sometimes with multinucleated giant cells
(sunburst) appearance ○ Bone matrix produced directly by tumor
○ Codman triangle: Periosteal reaction at diaphyseal end • Nuclei hyperchromatic, central or eccentric in position
of tumor at angle created by cortex and elevated
○ Brisk mitotic activity, prominent nucleoli
periosteum
○ Degree of atypia variable but frequently severe
• Rarely, imaging appears deceptively benign
○ Numerous mitoses, including atypical forms
MR Findings • Eosinophilic cytoplasm, variable in volume
• Heterogeneous metaphyseal mass • Tumor cells intimately related to surface of neoplastic bone
• Osteoid shows low signal on all sequences ○ Tumor cells diminish in size and appear less atypical as
• Helpful in detecting skip lesions in same or adjacent bone they are surrounded and imprisoned by matrix
• T1WI: Nonosteoid portions of tumor near isointense to – In heavily mineralized portions, tumor cells lack atypia
skeletal muscle – This phenomenon is referred to as normalization
• Fluid-sensitive sequences: Appears heterogeneous • Neoplastic bone varies in quantity
○ Deposited as primitive disorganized trabeculae
CT Findings
producing coarse lace-like pattern, or broad large sheets
• Useful in defining bone matrix ○ Frequently mineralized
• Useful in delineating tumor extent and surgical planning ○ Neoplastic lamellar bone is very rare
Bone Scan ○ Preexisting bony trabeculae function as scaffold for
tumor growth in some cases
• Increased activity in primary tumor and metastasis
• Bone is eosinophilic or basophilic and may have pagetoid
appearance caused by haphazardly deposited cement lines
MACROSCOPIC
• Histologic variants
General Features ○ Osteoblastic osteosarcoma
• Intramedullary ○ Chondroblastic osteosarcoma
• Usually centered in metaphysis, but can involve any portion – Neoplastic cartilage is usually hyaline, but may be
of bone myxoid, particularly in tumors arising in jaw bones
• Tumors with abundant mineralized bone are tan-white and – Malignant chondrocytes demonstrate severe
hard cytologic atypia
• Nonmineralized components are glistening and gray ○ Fibroblastic osteosarcoma
○ May be mucinous if matrix is myxoid, or more rubbery if ○ Telangiectatic osteosarcoma
hyaline in nature ○ Giant cell-rich osteosarcoma
• Areas of hemorrhage and cystic change ○ Small-cell osteosarcoma
○ Can be extensive and produce friable, bloody, and ○ Osteoblastoma-like osteosarcoma
spongy mass (telangiectatic osteosarcoma) ○ Chondroblastoma-like osteosarcoma
• Usually destroys overlying cortex and forms eccentric or ○ Chondromyxoid fibroma-like osteosarcoma
circumferential soft tissue component displacing
periosteum peripherally DIFFERENTIAL DIAGNOSIS
• Dislodged periosteum becomes sharp interface between
mass and bordering skeletal muscle and fat Fracture Callus
• Layer of reactive bone at proximal and distal regions where • Bone rimmed by osteoblasts
periosteum lifted from cortex • Distribution zonal rather than haphazard
• May grow into joint space • Fracture site shows fibrocartilage, finding not seen in either
○ Growth may occur through synovium, via extension osteosarcoma or chondrosarcoma
along cortical surface, or through tendoligamentous and • Atypical mitotic figures not seen
joint capsule insertion sites • Radiographic correlation essential
• Open growth plates often function as effective barriers to
Osteoblastoma
advancing tumors
○ Penetration of physis and invasion through epiphysis to • Shows interconnecting trabeculae of tumor bone lined by
base of articular surface occurs in some cases plump osteoblasts
24
Osteosarcoma

• Distinction between osteoblastoma-like osteosarcoma and
aggressive osteoblastoma can be challenging
DIAGNOSTIC CHECKLIST
○ Radiographic correlation essential Pathologic Interpretation Pearls
○ Features supporting diagnosis of osteosarcoma • Delicate lace-like deposition of unmineralized eosinophilic
– Infiltration of preexisting bony trabeculae matrix (osteoid)
– Large size (> 5 cm) • At least focal bone production by malignant cells is
– Atypical mitotic figures necessary to render diagnosis of osteosarcoma
– Prominent abundant lace-like bone deposition • Ancillary tests do not help in identifying bone
Myositis Ossificans Assessment of Chemotherapy Effect
• Both soft tissue and parosteal myositis ossificans may be • Complete or near-complete response (> 90% necrosis)
mistaken for osteosarcoma associated with better survival
• Distinct zonal pattern characteristic of myositis ossificans • Assessment of necrosis should be performed by
and not seen in osteosarcoma histologically evaluating central slice of tumor and sampling
○ Radiologically and grossly, center lacks mineralization, remaining halves
whereas periphery is mineralized • Extent of necrosis on preoperative chemotherapy may be
○ Microscopically, center shows granulation tissue/nodular used to alter postoperative regimen
fasciitis-like appearance, whereas periphery shows
woven bone lined by osteoblasts with outermost layer of SELECTED REFERENCES
lamellar bone in mature lesions 1. Baumhoer D et al: An update of molecular pathology of bone tumors.
• Recently described to harbor USP6 rearrangement Lessons learned from investigating samples by next generation sequencing.
Genes Chromosomes Cancer. 58(2):88-99, 2019
Aneurysmal Bone Cyst 2. Suehara Y et al: Clinical genomic sequencing of pediatric and adult
osteosarcoma reveals distinct molecular subsets with potentially targetable
• May mimic telangiectatic osteosarcoma alterations. Clin Cancer Res. ePub, 2019
• Cells in cyst wall not severely atypical 3. Švajdler M et al: Fibro-osseous pseudotumor of digits and myositis ossificans
• Presence of USP6 rearrangements may support aneurysmal show consistent COL1A1-USP6 rearrangement: a clinicopathological and
genetic study of 27 cases. Hum Pathol. 88:39-47, 2019
bone cyst 4. Hameed M et al: Tumor syndromes predisposing to osteosarcoma. Adv Anat
Pathol. 25(4):217-22, 2018
Giant Cell Tumor of Bone
5. Kovac M et al: Exome sequencing of osteosarcoma reveals mutation
• May show reactive woven bone formation in periphery signatures reminiscent of BRCA deficiency. Nat Commun. 6:8940, 2015
• Bone lined by osteoblasts and not atypical tumor cells as in 6. Behjati S et al: Distinct H3F3A and H3F3B driver mutations define
chondroblastoma and giant cell tumor of bone. Nat Genet. 2013
osteosarcoma Dec;45(12):1479-82. Epub 2013 Oct 27. Erratum in: Nat Genet. 46(3):316,
• Most harbor histone H3F3A/H3F3B G34W mutation 2014
7. Perry JA et al: Complementary genomic approaches highlight the
Chondrosarcoma PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl
Acad Sci U S A. 111(51):E5564-73, 2014
• Distinction from chondroblastic osteosarcoma can be 8. Kerr DA et al: Molecular distinction of chondrosarcoma from chondroblastic
challenging osteosarcoma through IDH1/2 mutations. Am J Surg Pathol. 37(6):787-95,
○ Bone may be scarce in chondroblastic osteosarcomas 2013
and some gnathic osteosarcomas 9. Deyrup AT et al: Sarcomas arising in Paget disease of bone: a
clinicopathologic analysis of 70 cases. Arch Pathol Lab Med. 131(6):942-6,
○ Extensive sampling may reveal diagnostic foci of osteoid 2007
deposition or immature bone for osteosarcoma 10. Mankin HJ et al: Survival data for 648 patients with osteosarcoma treated at
one institution. Clin Orthop Relat Res. (429):286-91, 2004
○ Cartilaginous tumor with marked atypia, particularly in
11. Ozaki T et al: Genetic imbalances revealed by comparative genomic
2nd-3rd decades of life, is suspicious for osteosarcoma hybridization in osteosarcomas. Int J Cancer. 102(4):355-65, 2002
• Presence of IDH1 or IDH2 mutations favors 12. Bridge JA et al: Cytogenetic findings in 73 osteosarcoma specimens and a
chondrosarcoma rather than osteosarcoma review of the literature. Cancer Genet Cytogenet. 95(1):74-87, 1997
13. Chow LT et al: Chondromyxoid fibroma-like osteosarcoma: a distinct variant
Dedifferentiated Chondrosarcoma of low-grade osteosarcoma. Histopathology. 29(5):429-36, 1996
14. Glasser DB et al: Survival, prognosis, and therapeutic response in osteogenic
• Characterized by low-grade cartilage juxtaposed to high- sarcoma. The Memorial Hospital experience. Cancer. 69(3):698-708, 1992
grade sarcoma (dedifferentiated component) 15. Unni KK et al: Osteosarcoma: pathology and classification. Semin
○ Dedifferentiated component may be osteosarcoma Roentgenol. 24(3):143-52, 1989
• Presence of IDH1 or IDH2 mutations favors 16. Rosen G et al: Primary osteogenic sarcoma: eight-year experience with
adjuvant chemotherapy. J Cancer Res Clin Oncol. 106 Suppl:55-67, 1983
chondrosarcoma rather than osteosarcoma 17. Dahlin DC et al: Osteosarcoma of bone and its important recognizable
varieties. Am J Surg Pathol. 1(1):61-72, 1977
Ewing Sarcoma
• Small cell variant of osteosarcoma mimic Ewing sarcoma
• Presence of EWSR1 rearrangements (present in ~ 95% of
cases) supports Ewing sarcoma
Metastatic Carcinoma
• Metastatic carcinoma from breast or prostate may evoke
robust osteoblastic reaction, mimicking osteosarcoma
25
Diagnoses Associated With Syndromes by Organ: Osteosarcoma
Osteosarcoma in Proximal Humerus Osteosarcoma

(Left) Radiograph of an
osteosarcoma in the proximal
humerus illustrates ill-defined
central densities ﬅ
corresponding to the
calcifications present in this
tumor. Codman triangle ﬇
indicative of a prominent
periosteal reaction and soft
tissue extension by tumor is
present. (Right) Axial STIR MR
in the same osteosarcoma in
the proximal humerus
illustrates a tumor forming a
circumferential soft tissue
mass.
Osteosarcoma in Proximal Humerus Treated Osteosarcoma With Necrosis

(Left) Gross photograph shows
osteosarcoma involving the
proximal humerus in the same
patient. The raised periosteum
﬇ corresponds to the
radiographic findings of the
Codman triangle. (Right) After
treatment, this osteosarcoma
in the proximal femur shows
residual bone ﬊. The tumor
demonstrates an infiltrative
growth pattern, encasing
preexisting bony trabeculae
ﬅ. Treatment effect is
present, with extensive tumor
necrosis ﬉.
Sclerotic Osteosarcoma With Permeative

Osteosarcoma Encasing Preexisting Bone Growth Pattern
(Left) In osteosarcoma, tumor
cells occasionally grow in
sheets ﬆ, infiltrating among
preexisting trabecular bone
﬊. (Right) In osteosarcoma,
neoplastic bone ﬆ can
sometimes be seen being built
along preexisting native
trabecular bone ﬊ as
scaffolds, giving rise to the
permeative pattern.
26
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microscope. On blood serum and potato it forms a grayish white
layer.
Pathogenesis. The bacillus is inoculable on other pigeons and as
it usually appears in the young birds in the nest, still fed by the
parent bird, it is probable that no inflammation nor abrasion is
necessary to make it take. Pure cultures inoculated in the mouth gave
rise to the usual local type of the disease. When inoculated subcutem
it caused a local necrotic inflammation.
In mice subcutaneous injections proved fatal in five days with
general dissemination of the bacillus. There are congested and
hemorrhagic spots on the lungs, enlarged spleen, and the liver is
marbled by numerous necrotic white masses, in the centre of which
the capillaries are found to be blocked with the bacilli. This is so
pathognomonic that Löffler looks on the inoculation of mice as the
best means of diagnosis.
Inoculated rabbits showed inflammation in the seat of
inoculation and sometimes fibrinous peritonitis and enlarged spleen.
Inoculation on the cornea produced a false membrane.
In Guinea pigs induration and ulceration occurred in the seat of
inoculation but recovery followed in 14 days.
Sparrows inoculated in the pectoral muscles died in three days
with yellowish necrotic tissue highly charged with bacilli.
Inoculation of the chicken by Löffler and Megnin produced a
circumscribed redness which soon disappeared. On the other hand
Krajewski, Colin, Loir and Ducloux seem to have inoculated chickens
successfully, and Cadeac says that the cultures are infecting for
sparrows, pigeons, turkeys, chickens and ducks. It rests
uncertain therefore whether the pseudomembranous pharyngitis of
hens is a distinct disease as alleged by Löffler and Megnin or if the
chickens used by these observers were not already immune by reason
of a prior attack.
Löffler’s experiments showed that dogs and rats were immune.
Loir and Ducloux failed to infect cattle.
In infected dove-cots a comparative immunity is attained by the
older pigeons, which continue to harbor the germ, but do not suffer
materially from its presence. They however communicate it to the
susceptible young in the milky secretion produced in the crop and
with which they feed them, and these accordingly perish in large
numbers. Thus pigeons that are themselves in fine condition become
the propagators of the bacillus to the more impressible.
Sparrows and other small birds are also held to be common
propagators of the germ, and if they too can secure an individual
immunity and yet harbor the bacillus, their passage from yard to
yard may be attended with great danger. The grains soiled by their
bills and not swallowed are common media of transmission.
Loir and Ducloux found the affection transmissible between man
and pigeon. The identity of the bacillus with that of genuine
diphtheria in man appears to have been thoroughly disproved by the
observations of Roux and Yersin.
The following differential characters have been noted:
Bacillus Diphtheriæ (Klebs- Bacillus Diphtheriæ

Löffler). Columbarum
1. In gelatine cultures grows only 1. In gelatine cultures grows at 15–

above 23°C. 17°C.
2. Kills Guinea-pig and dog. 2. Guinea-pig and dog nearly
immune.
3. Mice immune. 3. Mice usually die with hepatic
necrosis.
4. Does not grow on potatoe. 4. Grows luxuriantly on potatoe.
It may be accepted as demonstrated that the common diphtheria

of birds is essentially distinct from the genuine diphtheria of man,
and that when such diphtheria of the bird is conveyed to man as has
been often alleged (Richter, Gips, Bonig, Gerhart, etc.), it is one of
the forms of pseudo diphtheria that is produced, and not that which
is caused by the Klebs-Löffler bacillus. Dr. V. A. Moore, who has
cultivated specimens of the bacillus diphtheriæ Columbarum
obtained from Germany, considers the germ as belonging to the
group of the bacillus coli communis, and as not the cause of the
chicken diphtheria in America. Further investigation must settle
whether the bacillus diphtheriæ Columbarum is the one cause of this
affection in Europe, and what is the microbian cause or causes of the
disease in America.
Incubation. This is very variable. False membranes may form in
twenty-four hours in some cases; in other cases they may be delayed
from four to fourteen days (Colin, Babes, Puscarin, Marinescu).
Symptoms. There is dullness, prostration, sunken head, ruffled
feathers, altered hoarse voice, drooping wings, wheezing breathing,
difficult deglutition, sneezing, and patches of dark red congestion in
the fauces covered with a thin film, at first translucent, but soon
becoming dense, adherent, opaque, whitish or yellowish. As it
becomes older this deposit becomes granular, wrinkled, dry and
friable. It is more adherent in chickens than in pigeons and causes
bleeding when detached. Necrotic changes may take place in the
mucosa leading to considerable loss of tissue, and even to
perforations of the soft palate, pharynx or œsophagus. It may remain
circumscribed by the region of the mouth and end in an early
recovery, or it may extend to the organs of the chest and abdomen, or
the germs may proliferate largely in the blood and induce fatal
results. On the other hand it may become subacute or even chronic,
and, as already noted in the case of the parent pigeons, it may persist
as an infecting disease without materially injuring the general health
of a comparatively immune animal.
The affected nasal passages become filled by frothy liquid and
blocked by false membranes, so that the bird is driven to breath
through the open mouth. The skin around the nares, and eyelids and
the cavity beneath the eye may be covered with the false membrane,
by the increase of this product the bones may be driven out of place,
so that the palatines press downward, the eyeball is pressed outward
and the root of the beak may seem swollen. The false membranes
that form on the skin or reach the surface are soft, creamy, cheesy, or
dry, granular and friable.
When the eye is specially affected there are swelling of the lids,
profuse lachrymation, closure of the lids by adhesion, and formation
around their borders or on their inner surface and on the membrana
nictitans of false membranes which press the lids outward more or
less unevenly, and may be easily recognized when the lid is everted.
The cornea and even the interior of the eye may suffer, leading to
perforation, internal tension, and in some cases atrophy, with
permanent blindness.
The tongue may suffer on the tip as in pip, or on its dorsum, from
which the disease extends to the larynx, trachea and even the air
sacks, which become filled with false membranes, that are coughed
up, and decomposing in the mouth, add to the infection and fœtor.
Dyspnœa and cyanosis of comb and wattles are marked features.
The extension may take place downward along the alimentary
track, the false membranes forming on the gullet or crop and
interfering with swallowing or digestion, or on the intestine and
determining a fœtid, often greenish or bloody diarrhœa with
indications of false membranes. Vomiting may be a marked
symptom.
The skin is usually attacked secondarily around the margin of the
beak, the eyelids, the nares, the ears, the comb, the wattles, the anus,
but it may develop at any point where the infecting material has
touched an abraded surface.
Trinchera found that in acute cases the acme was reached in
fifteen days after which improvement might be looked for. A chronic
form affecting the gullet might however persist indefinitely in
pigeons without proving incompatible with good health.
Paralysis of the wings or limbs may remain after the healing of the
local lesions.
Mortality. Prognosis. The disease is very fatal to both pigeons and
chickens, 50, 70 or even 100 per cent. perishing when a flock is
attacked for the first time. In flocks that have previously suffered, on
the other hand, a large number are practically immune, and even if
they contract the disease it assumes a mild form, and they survive
but may retain the germ and continue to communicate it to others.
Even the young of such immune flocks suffer less severely, coming as
they probably do from less susceptible and therefore surviving birds,
or having already perhaps contracted a mild (non-fatal) type of the
disease from their parents.
Differential Diagnosis. From psorospermosis (coccidiosis) it is
distinguished by its origin on the mucous membranes, and not on
the skin, the skin lesion being a secondary one. In psorospermosis
the primary lesion is usually on the skin, from which it extends to the
mouth and especially along its floor. In psorospermosis the morbid
deposit assumes the form of rounded warty-like masses, on comb or
wattles; is easily propagated by inoculation, is promptly checked by
antiseptics, does not tend to produce internal extension nor
generalization, and on microscopic examination shows numerous
spheroidal coccidia intermingled with the epidermic cells and
possessing amœboid movement. By virtue of this automatic
movement they make their way between and into the epidermic cells
in which they multiply.
From the croupous angina of Rivolta it is distinguished by the
absence of the infusoria (monocercomonas gallinæ) to which he,
Delprato and Pfeiffer attributed that affection. The monocercomonas
is a flagellate organism 14 μ to 25 μ in length and 5 μ to 7 μ in
breadth. Its rounded end bears one flagellum as long as the body,
and its acute end three flagella which give it active motions. These
are found in the yellowish white swellings of the mucosa, which vary
in size from a millet seed to a pea, covering a hyperæmic spot and
composed of epithelial cells, blood globules—white and red,—
leucocytes, granules and the infusoria. The false membrane is
remarkable for its lack of consistency and its tendency to invade the
mouth and gullet rather than the air passages. These infusoria are
not colored by picrocarminate of ammonia, but stain by methyl-
violet and then appear as round or slightly irregular hyaline bodies.
From aspergillus disease of pigeons, by the absence of the
characteristic, miliary, white nodule of that disease showing caseated
contents intermixed with an abundant mycelium of aspergillus
fumigatus. The aspergillus disease attacks especially the mouth but
may also implicate the gullet, lungs, liver, intestine and kidneys. The
microscopic examination of the exudate is conclusive, by reason of
the presence of the bacillus diphtheriæ columbarum, and the
comparative absence of the filamentous mycelium.
Treatment. This is mainly prophylactic. The first step must be to
separate the sick and healthy, destroying the former, or shutting
them up in a special enclosure apart from all other birds. In the case
of valuable chickens, their eggs may be set under other hens and the
young raised apart from the suspected flock. This may even be
attempted in pigeons, the common eggs being removed and the
valuable ones put in their place under a healthy sitting dove. In the
case of pigeons that have been recently through the disease they
should be kept strictly by themselves, even though they may appear
to have regained perfect health. The dead bodies must be burned or
deeply buried. Sparrows and even rabbits dying in the vicinity must
be similarly disposed of, and where the disease prevails sparrows and
small birds may be exterminated as probable bearers of infection.
The purchase of strange birds must be carefully guarded, none
being taken that show weeping eyes, nasal discharge, labored or
wheezing breathing, and all new birds should be placed by
themselves in quarantine for ten to fifteen days. Finally a thorough
disinfection of the place where the sick have been is of first
importance. Thorough cleaning of the poultry house, followed by a
coat of white-wash, every gallon of which contains four ounces of
chloride of lime, or one drachm of mercuric chloride will usually
prove effective. The poultry runs should be liberally sprinkled with a
solution of sulphuric or hydrochloric acid, one part to 1000. The
same may be used on the building, which may further be fumigated
by burning sulphur.
Poultry shows should be kept under the most rigorous sanitary
supervision.
Curative treatment is only profitable in the case of specially
valuable birds, and even then only, as a rule, when the disease is
confined to the nose, mouth, larynx and pharynx. The affected parts
may be brushed with a solution of chloride of iron (1 dr. of the
tincture to 1 oz. water), nitrate of silver (2 grs. to 1 oz. water),
sulphide of calcium (½ dr. to 1 oz. water), tannin (10 grs. to 1 oz.).
Tincture of iodine may be applied direct, or a solution of carbolic
acid or of creosote or creolin (1 part to 50) will often succeed.
Thomassen recommends the removal of the false membranes and
the application of boric acid followed by dry sulphur. Benoist says
the majority recover when made to inhale the fumes of oil of
turpentine evaporated at a gentle heat twice a day.
As internal medication, or to correct the intestinal affection,
sulphate of iron may be dissolved in the drinking water, or salicylic
acid may be given in pill form with molasses.
CHRONIC PHARYNGITIS.
Sequel of acute: or subacute from the first. Due to œstrus, in cattle to summer
catarrh, tubercle or actinomycosis. Lymphatic horses predisposed; attends chronic
indigestion; in swine tonsilitis. Symptoms: chronic cough, easily roused, wheezy or
mucous; nasal discharge; low condition; lack of spirit. Lesions: congestion;
softenings; erosions; cicatrices; tonsilitis; abscesses; specific deposits. Treatment:
hygienic; antiparasitic; astringent; antiseptic; derivative; counter-irritant; tonic
inhalations and electuaries. Bitters. Iron.
Causes and Nature. Chronic pharyngitis in animals may be a
simple continuation of the acute, in a milder form, or it may assume
a subacute or chronic type from the first and never rise to the
intensity that would characterize the acute. It may be a simple
catarrhal affection or it may become more or less follicular or
glandular. Again in horses it is not infrequently a result of the
hibernation form of the œstrus (bots) attached to the delicate
pharyngeal mucosa, and in cattle from the extension of the chronic
summer catarrh, or from the local development of tubercle or
actinomycosis in the walls of the pharynx or in the adjacent lymph
glands. Horses of a soft, lymphatic constitution, with a heavy coat,
confined in close warm stalls, and which perspire abundantly are
especially liable to the affection. It may also be an accompaniment
and result of chronic gastric indigestion. In swine the affection is
commonly associated with tonsilitis.
Symptoms. In many cases the main symptom is a chronic cough
which is aroused by any cause of irritation, feed, especially dry or
fibrous fodder, cold drinking water, sudden passing from the hot
stable to the cold outer air, reining in, pressure on the throat, or
sudden active exertion. If the cartilages are calcified it may be
impossible to rouse the cough by pressure. The cough is often dry
and wheezy, rather than soft and gurgling as in the second stage of
acute pharyngitis, and is repeated several times paroxysmally. In the
intervals there is more or less stertor or wheezing, or a distinct rattle
especially when the neck is curved by drawing the nose inward.
Deglutition may be interfered with but this shows most with the first
swallow, which in the case of liquids may be returned through the
nose, whereas those that follow go down without difficulty. A lateral
swelling of the parts above the larynx or a bulging of the parotids is
not uncommon. Discharge from the nose of a mucopurulent
character is usually present, but often so scanty as to be overlooked.
There is usually loss of flesh and lack of vigor even if the subject is
well fed.
Lesions. In the simple catarrhal form the mucous membrane of the
lateral pharyngeal walls, the posterior pillars of the palate and the
back of the soft palate, is red, congested, with arborescent vessels,
thickening, and puckering into rugæ. The epithelium has lost its
translucency, become opaque and granular, and its desquamation in
spots and patches may leave erosions, ulcers more or less deep, and
white drawn cicatrices. When the follicles and mucous crypts are
involved (follicular) they stand out like millet seed, peas or beans,
and may show ulceration or minute abscess. In pigs especially,
tonsilitis is liable to be present, and the tonsillar follicles are filled
and distended with tenacious mucous, a caseous granular debris, or
even a cretaceous material. In the vicinity of the tonsils, minute
abscesses may exist in or beneath the mucosa.
Ulceration may be the result of tubercle, glanders, actinomycosis,
aspergillus, sarcoma, or some local infection, and attendant
symptoms of one or other of these diseases will guide the diagnosis.
Thus in tubercle there will be the implication of the adjacent lymph
glands and usually of distant ones; in glanders the deposits in the
nose, submaxillary lymph glands and lungs will enable one to
diagnosticate; in actinomycosis the hardness of the neoplasm and
the presence of the yellowish tufts which present under the
microscope the concentrically arranged club-shaped elements, will
show its nature; and in sarcoma or carcinoma the structure of the
new tissue will decide its character. The pharyngeal muscles are the
seat of granular or fatty degeneration or of fibroid change.
Friedenreich speaks of a fold from the vault of the pharynx which
had nearly closed the passage and had killed the horse by inability to
swallow.
Treatment. Chronic pharyngitis is usually a very obstinate
affection and demands careful hygienic as well as medicinal
treatment. Hot, foul stables, unduly thick coats, unwholesome food,
irregular feeding, excessive meals at long intervals, overwork, undue
exposure to cold and wet, lack of sunshine or of grooming are to be
corrected. Next, the removal of mechanical irritants such as
pharyngeal bots, actinomycosis growths, etc., will be in order. Then
the use of astringents and antiseptics internally and of derivatives
externally will be demanded. An occasional embrocation of mustard,
or the application of ammonia and oil, will often serve a good
purpose, and in obstinate cases the hot iron in points will sometimes
prove effective.
Internally the inhalation of the fumes of tar, carbolic acid, creolin,
oil of turpentine, or of burning sulphur kept up continually or
frequently repeated. Giving all drink in the form of tar water will
often have a good effect. Electuaries made with boric acid, salicylate
of soda, ammonium chloride or iodide, borax, with honey, molasses,
liquorice, Iceland moss, or gum arabic will often prove beneficial.
Agents that stimulate the mucosa may follow, such as balsams of
Peru or Tolu, copaiba, cubebs, pilocarpin, wild cherry bark, or these
may be combined with the former. Finally a course of tonics are
usually of the first importance; iron sulphate, copper sulphate,
arsenious acid, arsenite of strychnia may furnish examples.
DEPRAVED APPETITE. STUMP SUCKING.
PICA. LICKING DISEASE.
Common features of group. Ruminants; depraved appetite; objects swallowed:
hair balls. Sheep eating wool in winter. Pigs eat bristles. Puppies swallow marbles,
etc., wantonly. Solipeds swallow hair, plaster, earth, sand, and lick manger or rack.
Fowls eat their feathers. Causes: soil exhaustion, lack of lime, soda, potash,
phosphorous; relation to osteo malacia; granitic or sandy soils, peat, muck,
causative; digestive disorder; faulty food; yearly breeding and heavy milking;
constant stabling; dry seasons. Course: chronic. Lesions; emaciation; anæmia;
serous exudate; catarrh of the bowels. Treatment: soil; good fodder; salts of soda,
potash and lime, phosphates; tonics; apomorphine. Wool eating; example:
digestive disorders; emaciation. Treatment: open air; good fodder; salts of the
bones and soft tissues; clip nurses; apomorphine.
Definition. We have here a class of morbid habits, which cannot be
referred to any constant lesion or group of lesions, and which appear
in certain cases to result from example and to constitute nothing
more than a bad habit.
Symptoms. Ruminants without any appreciable cause, lick the
clothes of their care-takers, chew and swallow articles of clothing of
all kinds, bones, old shoes, gloves, socks, cuffs, collars, small forks,
pocket-knives, nails, wires, needles, coins, stones, lumps of clay, hair,
which may give rise to secondary troubles of a more or less serious
kind. Pregnant cows are especially subject to this infirmity. The small
pointed objects like pins, needles, ends of wires, etc., which are
mostly taken by accident with the food are especially apt to be
entangled in the alveoli of the reticulum and make their way to the
heart, with fatal effect, or through the abdominal walls creating a
fistula. Hair aggregates with saliva, mucus and phosphates, to form
balls in the first two or three stomachs. Other indigestible objects
may also become encrusted and prove sources of irritation. Licking
the skin of another animal is doubtless at times encouraged by the
taste of the salts of perspiration, but in other cases it has all the
appearance of a mutual kind service as the cow with itching head will
walk up and present it to its fellow which rarely fails to respond to
the invitation. Stump licking is not uncommon.
Sheep shut up in the winter get in the habit of chewing each
other’s wool, thus virtually depilating their fellows and accumulating
wool balls in their stomachs.
Pigs when running at large eat human fæces often infecting
themselves with the cysticercus cellulosa, and devour their own or
their fellows’ bristles, which form ovoid and irritating aggregations in
the stomach.
Puppies are proverbial for swallowing every small object that
comes in their way, coal, pebbles, marbles, leather, hair, etc., with
the result of inducing nausea and vomiting, or more seriously,
wounds of the stomach, gastritis and enteritis. In older dogs the
habit is more likely to imply rabies.
Solipeds will lick and swallow each others hair, eat off the hair
from each other’s tails and manes, eat their clothing, lick the wall
plaster, earth or sand, and even the manger or rack. The last named
habits are usually connected with disease.
Fowls can digest almost anything they swallow, but if they take to
picking their feathers, they create serious injury to the skin and
indirectly to the general health.
Causes and Nature. In general terms it may be said that the causes
of depraved appetite are very numerous, so that the trouble must be
looked upon as a symptom of many morbid conditions in place of a
disease sui generis.
Heredity has been invoked as a cause, mainly, it would appear,
because the disease appears enzootically on certain exhausted soils,
or in herds kept in the same unhygienic conditions. In such cases the
real cause is usually to be found in faulty conditions of soil, water,
buildings, food, etc., on the correction of which the trouble
disappears. When, however, from a long continuance of unhygienic
conditions, a weakness of constitution is transmitted from parent to
offspring, such hereditary debility may be accepted as a predisposing
factor.
An exhausted soil, lacking especially the elements of lime and
phosphorus, is a common cause, though by no means the only one.
Nessler who analyzed the hay and water, furnished to cattle suffering
from this disease in the Black Forest found a notable absence of the
soda salts. In others in which osteo malacia was the prominent
symptom the lack was in phosphate of lime as well. In the nature of
things the soil that has been continuously cropped to exhaustion is
robbed of both earthy and alkaline salts, and the animals fed on its
exclusive products suffer not only as regards the nutrition of the
bone, but also of the soft parts. Hence Trasbot says that in osteo
malacia, pica is never absent. Roloff and Röll hold that it is the first
symptom of osteomalacia. In South Africa where the land has been
cropped with oats year after year without manure and as long as it
will bear, the disease became prevalent in the street car horses fed on
the oats, and was corrected by the addition of phosphates, or
phosphate bearing food, to the ration. In the older dairying farms of
New York which have been kept under grass for a great length of
time, and all the milk products sold off, depraved appetite in all its
forms is quite frequent. Where the land is originally light and sandy
and naturally deficient in lime, osteo malacia is often a concurrent
disorder. The two conditions may however occur independently of
each other, and especially may pica appear alone, in keeping with the
greater solubility of the soda and potash salts and the readiness with
which these can be washed out of the soil, while the less soluble lime
salts in part remain.
Lemcke, Haubner and Siedamgrotzky attribute the disease to a
nervous disorder. Lemcke indeed traces the disorder to a lack of
phosphorus, and claims that osteomalacia only supervenes where the
rheumatic diathesis is also present.
It may be shortly stated that the disease prevails especially on
granitic or sandy soils, or on those which are mainly composed of
organic debris (peat, muck). Limestone soils and those which contain
any considerable proportion of potash or soda are usually exempt.
Digestive disorder though starting from a different point may tend
to the same end. A hyperacidity of the stomach has been observed to
coincide with the malady, and by interfering with easy and normal
digestion, it may stand in the way of such assimilation as is necessary
to vigorous health.
Faulty food operates in a similar manner. The exhausted soils, and
their products deficient in alkaline and earthy salts have been
already referred to; we must also note the evil effect of fibrous
fodders, the main nutritive elements of which have been washed out
by intemperate weather after they were cut, the rank aqueous
products of wet or swampy soils, the fibrous and siliceous plants
(rushes, carex, equisetums, etc.) which grow on poor, wet or soured
soils, the innutritious and fermented products of beet sugar factories,
and generally the spoilt food which has undergone fermentation.
Yearly breeding and constant milking, by undermining the
general health, predisposes so strongly that in many cases the
affection is seen in dairy cows, while oxen and young cattle escape.
The last period of gestation when the demands for the growing calf
are greatest, is the period of especial danger.
Permanent stabling which denies the invigorating influence of
sun, exercise and pure air contributes toward the general debility
and therefore, in animals that are closely stabled for the winter the
spring is especially to be feared, when compulsory inactivity, poor
feeding, gestation and milking have combined to reduce the system.
Dry seasons have been noticed to increase the affection manifestly
by reducing the supply of food.
Course. The affection is chronic and unless arrested by the
supervention of more favorable conditions, may last for a year or
more. Spontaneous recovery may set in when turned out to
pasturage and open air life, and especially if a rich grain feeding is
added. Without change in the conditions however, the tendency is to
a fatal result.
Lesions. The victims of the disorder are emaciated, the fatty tissue
contains a yellow serum, there is little blood, and that is thin and
watery and coagulates loosely, the muscles are pale and flabby, and
the gastro-intestinal mucous membrane is the seat of catarrh.
Treatment. To treat rationally and successfully we must adapt the
measures to the obvious causes. When the soil has been scourged
and exhausted, a change of pasture, and of land used for hay or
soiling crops is the first consideration. If these cannot be secured
then grain and seeds rich in protein, and alkaline and earthy salts
should be added to the ration. Wheat bran, middlings, peas, beans,
cotton seed meal, linseed meal, rapecake may be named among
available resorts, or in their absence, daily doses of phosphate of
lime, and sodium chloride or bicarbonate, or potash salts may be
allowed, or even bone dust.
If imperfect digestion is a manifest factor, sodium chloride, or
potassium chloride, calcium phosphate, iron and bitters will serve a
good end. In hyperacidity, limewater, chalk, or magnesia may be
given. If the digestion is torpid, hydrochloric acid with bitters may be
resorted to.
Feser and especially Lemcke strongly recommend apomorphia. It
is used hypodermically in doses of 2 grains for horse or cow repeated
daily for three days.
Secondary Symptoms in Wool-eating Lambs. Lambs from
two to six weeks old especially such as suck ewes with woolly udders
(merino, Cotswold) first swallow the wool inadvertently, and then
acquire a liking for the saline matters in the abundant yolk (merino),
till finally the accumulating wool balls produce digestive and nervous
disorder and a craving for the indulgence. Thus the breed must be
considered in estimating the symptoms. For the same reason the
wool about the hips or elsewhere soiled with salts of the urine or
liquid fæces prove attractive to the victim. The proximity of other
wool eaters is another cause which starts others to follow the bad
example. The general conditions of debility, exhausted soil, and the
absence of alkaline and earthy salts must be borne in mind. So too
with prolonged confinement indoors in winter, the absence of
invigorating exercise and the restriction of the animals (dams) to
food which is deficient in saline matters.
Beyond the mere eating of the wool and the destruction of fleeces,
the lambs do not usually suffer seriously. But if the consumption of
wool is excessive the accumulating balls of the size of marbles in the
stomach, and the blocking of the pylorus and small intestine, may
give rise to intermittent constipations and diarrhœas, deranged
digestion, muco-enteritis, mucous covered stools, loss of condition,
emaciation and retarded development.
Treatment consists first in the securing of a more healthy regimen.
This is but one of the evils of the close winter confinement of an
animal preëminently adapted to freedom and exercise. Turning out
in a wide range, especially if pasture is available, is a prime
consideration. The separation from the flock, of the first wool eaters,
will check the propagation of the vice by imitation. Food that is
defective in one or more constituents must be supplemented by that
which will correct the deficiency. Salt, potassic salts and above all
phosphate of lime or bone meal will sometimes benefit. May
recommends the separation of the lambs from the ewes except when
nursing, three times a day. Finally Lemcke claims for apomorphia
the same curative effect as in other animals. The dose is 2 grains,
subcutem, as in the cow and may be repeated three days in
succession.
LACERATION OF THE PHARYNX.
Trauma of pharynx from objects swallowed; from whip or other instrument in
choking; lesions. Symptoms: swelling; rapidly extending; dysphagia; salivation;
retching; dyspnœa; roaring; asphyxia. Treatment: as for pharyngitis; open pouch,
suture laceration; use antiseptics; liquid diet.
Laceration of the velum palati has been already referred to, and
the remaining walls of the pharynx sometimes suffer in the same way
and from identical causes. Pins, needles, and other sharp pointed
bodies taken with the food sometimes perforate the walls and
determine an advancing ulceration which furnishes a way for their
escape externally in the region of the throat. In other cases a rigid
staff, a whip, or even a probang introduced to overcome choking, is
forced through the walls of the pharynx forming a pouch for the
accumulation and septic fermentation of ingesta, and extensive
ulcerative and gangrenous lesions.
Lesions and Symptoms. These depend mainly on the extent of the
laceration. If there is a mere abrasion, superficial laceration or prick
of the mucosa, it determines a prompt inflammation, with exudation
which covers or closes the wound and a speedy healing may ensue.
When, however, the whole thickness of the mucosa has been
extensively lacerated and a pouch has been formed beneath it, it
becomes filled with decomposing mucus and ingesta, and the
resulting septic products determine ulceration, abscess, or gangrene.
The result is too often a general and fatal septic infection.
In the milder forms there are only the common indications of a
moderate pharyngitis. In the more severe form, the throat swells at
first on the lacerated side and later all around. This swelling soon
fills the intermaxillary space and extends over the face and the entire
head. From the first, deglutition is extremely difficult or impossible,
liquids are returned through the nose and saliva flows abundantly
from the mouth. Retching is not uncommon and saliva mixed with
alimentary matters is discharged by the nose (solipeds) or mouth
(other animals). The swelling of throat and head has a doughy,
œdematous feeling, it is very tender, and soon causes rattling,
wheezing breathing, roaring, dyspnœa and asphyxia.
Necropsy shows the general œdematous exudate, the laceration of
the pharyngeal walls, and the collection of debris and pus in the
lacerated cavity. The pus may have extended between the muscles
following the course of the gullet and trachea as far as the chest.
Extensive patches of necrosis may also be shown. Treatment. In the
slighter cases the ordinary treatment for catarrhal pharyngitis is
demanded. In the more severe the lesions are so redoubtable and
their progress so rapid that a fatal result is virtually inevitable. As a
desperate resort the septic pouch may be opened from without, its
contents removed, the pharyngeal wound sutured if possible, and a
thorough irrigation with antiseptics (acetate of aluminium solution)
employed at frequent intervals to check if possible the septic process.
The animal should be fed with well boiled milk or other liquid which
will not add to the fermentation, and this may be given through a
stomach tube, or by the rectum when deglutition is impossible.
PARALYSIS OF THE PHARYNX
From nervous bulbar lesion, or toxic from the pathogenic bacteria. Transient or
permanent and fatal. Symptoms: dysphagia: liquids expelled by nose or enter
lungs. Inhalation pneumonia. Facial palsy. Roaring, laryngeal thrill. Atrophy.
Gangrene. Treatment: remove cause: combat bulbar hyperæmia and cephalic
congestion: cold: derivatives, electricity: blisters: antiseptics.
This has been described as a rare affection, yet it is often a marked

symptom of cerebro spinal meningitis, and has been observed in
infectious pneumonia, and influenza of the horse (Cadeac, Palat) as
well as in rabies, and traumatic injuries of the brain.
The existence of the condition usually implies disease of the bulb
at the roots of the vagus and glossopharyngeal nerves, or swellings
affecting these nerves or the sympathetic along its course. The
morbid condition may be transient in which case a speedy recovery
may follow, or it may be permanent and end fatally.
Symptoms. Swallowing is impossible and the animal refuses food
and drink or if the latter is forced on him it is rejected by the nose or
mouth when the head is lowered or still worse, it enters the larynx
and descends into the lungs. The larynx innervated by the same
trunks is usually involved and the alimentary solids and liquids
determine gangrenous bronchitis and pneumonia, with labored
breathing, fœtid breath and violent dyspnœa. In other cases the
facial nerve is involved, the nostrils and lips are flaccid on one or
both sides, and the eyelids and ears may droop. There may be
snuffling breathing from the closure of the alæ nasi, or roaring from
the approximation of the arytenoids and vocal cords. If the affection
is unilateral the difficulty of breathing is greatly diminished and even
deglutition may be effected with some effort. There is usually,
however, the obvious unilateral paralysis of the face, and especially
of the larynx, with the distinct thrill, during inspiration, conveyed to
the finger placed on the larynx.
Complications in the form of gangrene and atrophy of parts
supplied by the same nerves, or those adjoining the pharynx, have
been recognized in different cases.
Treatment. This must depend on the obvious cause of the
affection. If due to an infectious disease the first attention must be
given to that. If due to tumors or abscesses pressing on the nerves
they may be removed. If there is bulbar hyperæmia or effusion
attention must be devoted to derivation and other means of
combating that. Cephalic congestion and heat may be met by cold
applications. Derivation toward the bowels may be secured by
eserine, pilocarpin or physostigmine administered subcutem.
Reabsorption of exudate may be sought by pilocarpin, or diuretics—
the latter administered by the rectum. Electricity in weak current
may be tried when the acute febrile symptoms have moderated,
accompanied by hypodermic injection of strychnia (2 grs.). Frictions
around the throat with essential oils or even a cantharides blister
may be used to advantage. Antiseptic washes may be injected into
the mouth,—vinegar, boric acid, borax, sulphite of soda. Finally the
animal must be nourished by rich gruels and soups given by the
rectum, or in the smaller animals by the stomach tube.
TUMORS OF THE PHARYNX.
Varieties of neoplasms. Malignant invade adjacent and distant parts. Symptoms:
sore throat; stertor; dyspnœea; dysphagia. In cattle, lymphadenoma, tubercle,
actinomycosis. Cause cough, ptyalism, discharge, fœtor, dysphagia. Dogs and pigs
vomit. Treatment: medical; surgical.
Tumors of the pharynx are not common in the horse yet they
occasionally appear as either primary or secondary neoplasms. They
are of various kinds, as, epithelioma (Labat, Mathis), carcinoma
(Casper, Dupuy, Mathis), sarcoma (Siedamgrotzky, Johne), lipoma
(Fricker), cystoma (Degive) and melicerous (Lesbre). The malignant
forms tend to invade the surrounding tissues and spread widely into
the nose, palate, tongue, pharyngeal glands, and, secondarily, into
the small intestines. The simple tumors like the lipomata and
fibromata tend to detach themselves and hang by a pedicle (see
pharyngeal polypi). The same is true of the melicerous cyst which
originating in an obstructed mucous or salivary duct projects as a
mass as large as a hen’s or pigeon’s egg into the fauces or pharynx.
Symptoms. There are symptoms of intense sore throat with stertor
continuous or intermittent, increasing to dyspnœa at intervals or on
exertion. In case of pediculated tumors these attacks correspond to
the displacement of the tumor into the glottis. Deglutition is difficult
or impossible, liquids or even solids returning through the nose,
mixed with mucus and at times tinged with blood. Nasal discharge
and ptyalism are present.
In cattle pharyngeal tumors may be of the same nature as
mentioned for the horse, but they are far more frequently
lymphadenoma, and above all tubercle or actinomycosis. Zimmer
found that of seventy-three such tumors fifty-four were
actinomycosis.
The symptoms are wheezing breathing, cough, nasal discharge,
ptyalism, bleeding from the nose, fœtid breath, difficult deglutition
attended by cough and rejection of the ingesta through the nose, and
the presence of a solid body in or on the pharynx which may be
manipulated from without or within and tends to increase in size.

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Diagnostic Pathology: Familial Cancer

Syndromes - eBook PDF

Vania Nosé, MD, PhD

DIAGNOSTIC PATHOLOGY: FAMILIAL CANCER SYNDROMES, SECOND EDITION ISBN: 978-0-323-71204-0

Previous edition copyrighted 2013.

Library of Congress Control Number: 2019956687

Printed in Canada by Friesens, Altona, Manitoba, Canada

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Vania Nosé, MD, PhD

ART DIRECTION AND DESIGN

PART II: Overview of Syndromes

PART III: Reference

Part I: Diagnoses Associated With ADRENAL MEDULLA AND PARAGANGLIA

Blood and Bone Marrow

Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma 4

CLINICAL ISSUES ○ Germline IKZF1 mutations

B-ALL/Lymphoma in Bone Marrow B-ALL/Lymphoma Morphology

B-ALL/Lymphoma in Bone Marrow Aspirate B-ALL/Lymphoma in Lymph Node

Blood and Bone Marrow

Germline Mutations and Conditions Associated With Increased Risk of Hematological

Blood and Bone Marrow

Bone and Soft Tissue

TERMINOLOGY – Ollier disease and Maffucci syndrome: Somatic

Pelvic Chondrosarcoma Pelvic Chondrosarcoma

Conventional Chondrosarcoma in Proximal

Bone and Soft Tissue

CLINICAL ISSUES CT Findings

• Recurrent GRM1 gene rearrangement in subset of tumors

Bone and Soft Tissue

Chondrosarcoma With Permeative Pattern Clear Cell Chondrosarcoma

Dedifferentiated Chondrosarcoma Mesenchymal Chondrosarcoma

Sacrococcygeal Chordoma Sacrococcygeal Chordoma

Conventional Chordoma With

Bone and Soft Tissue

○ T-brachyury expression absent in high-grade component

Bone and Soft Tissue

Chondroid Chordoma Dedifferentiated Chordoma

Loss of INI1 Expression in Poorly

TERMINOLOGY ○ Alternating hypercellular/hypocellular areas ("marbled")

MPNST Arising in Plexiform Neurofibroma Radiation-Associated MPNST

MPNST With "Marbled" Pattern Spindle Cells in Conventional MPNST

Bone and Soft Tissue

– Associated with schwannomatosis and germline Atypical Neurofibromatous Neoplasm of Uncertain

Bone and Soft Tissue

Rhabdomyoblasts in Malignant Triton

Epithelioid MPNST Loss of INI1 in Epithelioid MPNST

TERMINOLOGY CLINICAL ISSUES

Osteosarcoma in Distal Femur Osteosarcoma in Distal Femur

Bone and Soft Tissue

Bone and Soft Tissue

Osteosarcoma in Proximal Humerus Osteosarcoma

Osteosarcoma in Proximal Humerus Treated Osteosarcoma With Necrosis

Sclerotic Osteosarcoma With Permeative

Bacillus Diphtheriæ (Klebs- Bacillus Diphtheriæ

1. In gelatine cultures grows only 1. In gelatine cultures grows at 15–

It may be accepted as demonstrated that the common diphtheria

This has been described as a rare affection, yet it is often a marked

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