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BARNHILL'S DERMATOPATHOLOGY
FOURTH EDITION

Editor In Chief
Raymond L. Barnhill, MD
Professor of Pathology
lnstitut Curie
University of Paris Descartes
Paris, France

Auocfatw Edlton
A. Neil Crowson, MD
Clinical Professor of Dermatology, Pathology and Surgery
Director of Dermatopathology
University of Oklahoma
President
Pathology Laboratory Associates
Tulsa, Oklahoma

Cynthia M. Magro, MD
Distinguished Professor of Pathology and Laboratory Medicine
Weill Cornell Medicine
New York., New York

Michael W. Piepkorn, MD
Clinical Professor of Dermatology
Department of Medicine, University of Washington School of Medicine
Seattle, Washington

Heinz Kutzner, PD Dr Med

Dermatopatholog ie Friedrichshafen
Friedrichshafen, Germany

Garrett T. Desman, MD
Associate Program Director, Pathology Residency Program
Attending Pathologist, Dermatopathology Division
Assistant Professor of Pathology, Molecular and Cell-Based Medicine
Assistant Professor of Dermatology
Icahn School of Medicine at Mount Sinai
NewYork, NewYork

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To Claire
Contents

Contributors vii PART2

Foreword xiii Predominantly Nonfnflammatory
Prefac:.e to the Fourth Edition xv Conditions 417
Preface to the First Edition xvi
Table ofAcronyms and Ab'llrtviations xvii 14 Alterations of the Stratum
Corneum and Epidermis 419
PART1 Michael W. Piepkorn
Inflammatory Reactions in the Skin 1 15 Disorders of Pigmentation 448
A. Neil Crowson, Cynthia M. Magro,
1 Introduction to Microscopic Interpretation 3
Anne Janin, and Raymond L. Barnhill
Raymond L. Barnhill, Daniel M. Jones. and
Almut BOe.r-Auer 16 Deposition Disorders 477
Franco Rongioletti and Raymond L. Barnhill
2 Spongiotic Dermatitis 20
Preeti fhorar, Michael Murphy. and 17 Alterations of Collagen and Elastin 504
Jane M. Grant-Keis Garrett T. Desman and Raymond L. Barnhill
3 Interface Dermatitis 42 18 Ectopic Tissue 537
Thomas D. Horn and Jacqueline M. Junlcins-Hopkins
Jacqueline M. Junlcins-Hopkins
4 Psoriasiform Dermatitis 76 PART3
Isabella Fried and Raymond L. Barnhill Infections 551
5 Superficial and Deep Perfvascular Dermatitis 97 19 Bacterial Infections 553
A. Neil Crowson Ronald P. Rapini
6 Nodular and Diffuse Cutaneous Infiltrates 118 20 Treponemal and Rickettsial Diseases 581
Garrett T. Desman, Jeff D. Harveli and A. Neil Crowson, Cynthia M. Magro,
Raymond L. Barnhill J. Stephen Dumler, and Raymond L. Barnhlll
7 lntraepidermal Vesiculopustular Diseases 166 21 Fungal Infections 596
Cynthia M. Magro. A. Neil Crowson, and Alexandre Alanio, Matthew W. McCarthy,
'.lerence /. Harrist Thomas J. Walsh, Catherine Lisa Kauffman. and
Raymond L. Barnhill
8 Subepidermal Blistering Diseases 191
A. Neil Crowson and Cynthia M. Magro 22 Viral Infections 642
Garrett T. Desman, Clay J. Cochrdl, and
9 Vasculttis and Related Disorders 224 James/. Lyons
Sarah K. Barksdale and Raymond L. Barnhill
23 Protozoa! and Algal Infections 669
10 Disorders of Cutaneous Appendages 273 Eileen M. Burd, Lan F. Westblade, and
Lynne]. Goldberg and Sarah K. Barksdale
Paul Hofman
11 Panniculitis 315 24 Helminthic Diseases 686
Almut BOe.r-Auer. Birgitta Schmidt, and
Blaine A. Mathison and Raymond L. Barnhill
Raymond L. Barnhill
•12 Cutaneous Drug Eruptions 374 PART4
A. Neil Crowson and Cynthia M. Magro Proliferations-Hamartom as, Hyperplasias,
13 Cutaneous Reactions to Exogenous Agents 402 and Neoplasias 699
A. Neil Crowson and Cynthia M. Magro 25 Cutaneous Cysts and Related Lesions 701
Glynis A. Scott
vl CONTENTS

26 Tumors of the Epidermis 714 PARTS

AlanS. Boyd Disorders of the Nail Apparatus, the Oral
27 Tumors of Melanocytes 786 Mucosa, the Genital Mucosa, and
Raymond L. Barnhill, Michael W. Piepkorn, the Conjunctiva (Tumors) 1267
Armita Bahrami, Almut Boer-Auer,
36 Disorders of the Nail Apparatus 1269
Artur Zembowicz, and Thomas Wiesner
Aldo Gonzalez-Serva
28 Tumors with Hair Follicle and
37 Disorders of the Oral Mucosa 1311
Sebaceous Differentiation 896
Mark A. Lerman and Sook-Bin Woo
Maxime Battistella, Mark R. Wick,
Heinz Kutzner, and Raymond L. Barnhill *38 Disorders of the Genital Mucosa 1336
29 Sweat Gland Tumors 939 Russell A. Bait Katherine M. Bait and
Maxime Battistella, Mark R. Wick, Kelly L. West
Heinz Kutzner, and Raymond L. Barnhill 39 Conjunctiva! Tumors 1362
30 Fibrous and Fibrohistiocytic Tumors 989 Artur Zembowicz, Jakub Khzouz,
Scott C. Bresler, Stefan Kraft, Sarah E. Coupland, Nathalie Cassoux, and
Jason L. Hornick, and Scott R. Granter Raymond L. Barnhill
Appendix 1: Laboratory Methods 1389
31 Vascular Tumors and Vascular
Garrett T. Desman, Klaus J. Busam, Heinz Kutzner, and
Malformations 1038
Heinz Kutzner, Hansgeorg Muller, Raymond L. Barnhill
Michel Wassef, Steven J. Hunt, Appendix 2: Current and Emerging Molecular
Daniel J. Santa Cruz, and Raymond L. Barnhill Technologies in Dermatopathology 1399
Garrett T. Desman and Michael Donovan
32 Tumors of Adipose Tissue, Muscle,
Cartilage, and Bone 1119 Appendix 3: Molecular Biologic Techniques
Kristen M. Paral and Thomas Krausz for the Diagnosis of Cutaneous Lymphomas 1412
Garrett T. Desman, Gary S. Wood, Heinz Kutzner, and
33 Neural and Neuroendocrine Tumors 1151 Shafinaz Hussein
Zsolt B. Argenyi and Chris H. Jokinen
*Appendix 4: The Future of Dermatopathology
34 Lymphoid, Leukemic, and Garrett T. Desman, Brandon Veremis, Michael Donovan,
Other Cellular Infiltrates 1176 and Carlos Cordon-Cardo
Werner Kempf, Guenter Burg,
Cesare Massone, Lorenzo Cerroni, Index 1421
Melissa Pulitzer, A. Neil Crowson, and
Cynthia M. Magro
35 Cutaneous Metastases 1240
Ghadah Al Sannaa and Alexander J. Lazar

•Additional content for Chapters 12 and 38 along with the full text for Appendix 4 can be found at: mhprofessional.com/
barnhillsdermatopathology4e.
Contributors

Glwlab Al Sannaa. MBBS Raymond L BemhilL MD

Dermatopathology Fellow Professor of Pathology
The University ofTens Medical Branch lnstitut Curie
Galveston, Te:u.s University of Paris Descartes
Chapter 35. Cutaneous Metastases Paris, France
Chapter 1. Introduction to Microscopic Interpretation
Aleundre Alanio, MD, PhD Chapter 4. Psoriasiform Dermatitis
Inatitut Pasteur Chapter 6. Nodular and Diffuse Cutaneous Infiltrates
National Reference Center for Invasive Mycoses and Chapter 9. Vasculitis and Related Disorders
Anti.fungals Chapter 11. Panniculiti.s
Molecular Mycology Unit, CNRS UMR2000 Chapter 15. Disorders of Pigmentation
Parasitology-Mycology Laboratory Chapter 16. Deposition Diaord.ers
LariboiliUe. Saint-Louis Chapter 17. Alterations ofCollagen and Elastin
Fernand Widal. Hospitals Chapter 20. Treponemal and Rickettsial Diseases
Assistance Publique-HOpitaux de Paris (AP-HP) Chapter 21. Fungal Infections
Universite de Paris Chapter 24. Helminthic Diseases
Paris, France Chapter 27. Tumors ofMelanocytes
Chapter 21. Fungal Infections Chapter 28. Tumors with Hair Follicle and Sebaceous
Differentiation
Zaolt B. Argenyi, MD Chapter 29. Sweat Gland Tumors
Professor of Pathology and Dermatology Chapter 31. Vascular Tumors and Vascular Malformations
University of Washington Medical Center Chapter 36. Disorders of the Nail Apparatus
Seattle, W uhington Chapter 39. Conjunctiwl Twnors
Chapter 33. Neural and Neuroendocrine Tum.ors Appendix 1. Laboratory Methods
Armlta Bahrami, MD Mai.me Battiltella, MD, PbD
Associate Professor Assistant Professor of Pathology
St. Jude Children's Research Hospital Pathology Deparbnent
Memphis, Tennessee H!lpital Saint Louis, Assistance Publique-H!lpitaux de Paris
Chapter 27. Tumors of Melanocytes Paris, France
Chapter 28. Tumors with Hair Follicle and Sebaceous
Katherine M . Ball. BS
Differentiation
Director ofEducational Outreach
Chapter 29. Sweat Gland Tumors
Ball Dennpath, PA
Greensboro, North Carolina
Alm.ut Btier-Auer, MD
Chapter 38. Disorders of the Genital Mucosa
Lecturer in Dermatology
Ruaell A. Ball, MD University of Munster
Founder and Medical Director Department of Dermatology
Ball Dermpath, PA Munster, Germany
Greensboro, North Carolina Dermatologist/Dermatopathologist
Chapter 38. Disorders of the Genital Mucosa Director of Academics
Dermatologikum Hamburg
Sarah K. Barbdale, MD Hamburg. Germany
Senior Dermatopathologist Chapter 1. Introduction to Microscopic Interpretation
MyLab Chapter 11. Panniculitis
Brisbane, Australia Chapter 27. Tumors of Melanocytes
Chapter 9. Vasculitis and Related Disorders
Chapter 10. Disorders of Cutaneous Appendages
viii CONTRIBUTORS

Alan S. Boyd, MD Carlos Cordon-Cudo, MD, PhD

Professor of Dermatology and Pathology Irene Heinz Given and John LaPorte Given Professor
Vanderbilt University Medical Center and Chairman
Nashville, Tennessee Department of Pathology
Chapter 26. Tumors of the Epidermis Icahn School of Medicine at Mount Sinai
New York, New York
Scott C. Bresler, MD, PhD Appendix 4. The Future of Dermatopathology
Assistant Professor of Pathology and Dermatology
University of Michigan Sarah E. Coupland, MBBS, PhD
Ann Arbor, Michigan George Holt Chair of Pathology, University ofLiverpool
Chapter 30. Fibrous and Fibrohistiocytic Tumors Consultant Histopathologist, Royal Liverpool University
Hospital
Eileen M. Burd, PhD, D(ABMM) Liverpool, England, UK
Professor, Department of Pathology and Laboratory Medicine Chapter 39. Conjunctiva! Tumors
Emory University School of Medicine
Atlanta, Georgia A. Neil Crowson, MD
Chapter 23. Protozoa! and Algal Infections Clinical Professor of Dermatology, Pathology and Surgery
Director of Dermatopathology
Guenter Burg, MD University of Oklahoma
Professor and Chairman Emeritus of Dermatology President
University of Zurich Pathology Laboratory Associates
Zurich, Switzerland Tulsa, Oklahoma
Chapter 34. Lymphoid, Leukemic, and Other Cellular Chapter 5. Superficial and Deep Perivascular Dermatitis
Infiltrates Chapter 7. Intraepidermal Vesiculopustular Diseases
Chapter 8. Subepidermal Blistering Diseases
Klaus J. Busam, MD Chapter 12. Cutaneous Drug Eruptions
Professor Chapter 13. Cutaneous Reactions to Exogenous Agents
Department of Pathology Chapter 15. Disorders of Pigmentation
Memorial Sloan-Kettering Cancer Center Chapter 20. Treponemal and Rickettsial Diseases
New York, New York Chapter 34. Lymphoid, Leukemic, and Other Cellular
Appendix 1. Laboratory Methods Infiltrates

Nathalie Cassoux, MD, PhD Garrett T. Desman, MD

Professor of Ophthalmology Associate Program Director, Pathology Residency Program
Head of Department of Surgical Oncology Attending Pathologist, Dermatopathology Division
lnstitut Curie Assistant Professor of Pathology, Molecular and Cell-Based
University of Paris Descartes Medicine
Paris, France Assistant Professor of Dermatology
Chapter 39. Conjunctiva! Tumors Icahn School of Medicine at Mount Sinai
New York, New York
Lorenzo Cerroni, MD Chapter 6. Nodular and Diffuse Cutaneous Infiltrates
Associate Professor of Dermatology Chapter 17. Alterations of Collagen and Elastin
Department of Dermatology Chapter 22. Viral Infections
Medical University of Graz Appendix 1. Laboratory Methods
Graz, Austria Appendix 2. Current and Emerging Molecular Technologies in
Chapter 34. Lymphoid, Leukemic, and Other Cellular Dermatopathology
Infiltrates Appendix 3. Molecular Biologic Techniques for the Diagnosis
of Cutaneous Lymphomas
Clay J. Cockerell, MD Appendix 4. The Future of Dermatopathology
Clinical Professor of Dermatology and Pathology
University of Texas Southwestern Medical Center Michael Donovan, MD, PhD
Cockerell Dermatopathology Research Professor
Dallas, Texas Department of Pathology
Chapter 22. Viral Infections Icahn School of Medicine at Mount Sinai
New York, New York
Appendix 2. Current and Emerging Molecular Technologies in
Dermatopathology
Appendix 4. The Future of Dermatopathology
 CONTRIBUTORS ix

J. Stephen Dumler, MD Jeff D. Harvell, MD

Professor and Chair Dermatopathology Section Head
Joint Department of Pathology Department of Surgical Pathology
Uniformed Services University of the Health Sciences Inova Fairfax Hospital
Walter Reed National Military Medical Center Falls Church, Virginia
Joint Pathology Center Chapter 6. Nodular and Diffuse Cutaneous Infiltrates
Bethesda, Maryland
Chapter 20. Treponemal and Rickettsial Diseases Paul Hofman, MD, PhD
Professor of Pathology
Isabella Fried, MD Laboratory of Clinical and Experimental Pathology
Department of Dermatology Louis Pasteur Hospital
Medical University of Graz University COte d'Azur
Graz, Austria Nice, France
Chapter 4. Psoriasiform Dermatitis Chapter 23. Protozoa! and Algal Infections

Lynne J. Goldberg, MD Thomas D. Hom, MD, MBA

Jag Bhawan Professor of Dermatology and Pathology and
Laboratory Medicine
Boston University Medical Center
Boston, Massachusetts
Chapter 10. Disorders of Cutaneous Appendages
Clinical Professor of Dermatology and Pathology
Harvard Medical School
Massachusetts General Hospital
Boston, Massachusetts
Chapter 3. Interface Dermatitis

Aldo Gonzaiez-Serva, MD Jason L. Hornick, MD, PhD

Senior Dennatopathologist Director of Surgical Pathology and Immunohistochemistry
Quantum Pathology Brigham and Women's Hospital
Waltham, Massachusetts Professor of Pathology
Chapter 36. Disorders of the Nail Apparatus Harvard Medical School
Boston, Massachusetts
Scott R. Granter, MD Chapter 30. Fibrous and Fibrohistiocytic Tumors
Former Associate Professor of Pathology
Harvard Medical School Steven J. Hunt, MD
Boston, Massachusetts Northern Pathology Laboratory
Chapter 30. Fibrous and Fibrohistiocytic Tumors Iron Mountain, Michigan
Chapter 31. Vascular Tumors and Vascular Malformations
Jane M. Grant-Keis, MD, FAAD
Founding Chair, Emeritus, Department of Dermatology Shafinaz Hussein, MD
Founding Director, Emeritus, UCONN Dermatopathology Assistant Professor of Pathology
Laboratory and Dermatology Residency Icahn School of Medicine at Mount Sinai
Founding Director, Cutaneous Oncology Center and New York, New York
Melanoma Program Appendix 3. Molecular Biologic Techniques for
Professor of Dermatology, Pathology and Pediatrics the Diagnosis of Cutaneous Lymphomas
Vice Chair, Department of Dermatology
University of Connecticut School of Medicine Anne Janin, MD, PhD
Farmington, Connecticut Dermatologist
Adjunct Professor of Dermatology, University of Florida Professor of Pathology
College of Medicine University Paris Diderot
Gainesville, Florida Paris, France
Chapter 2. Spongiotic Dermatitis Chapter 15. Disorders of Pigmentation

Terence J, Harrist, MD Preeti Jhorar, MD

Dermatopathologist Dermatology Chief Resident
Winchester Hospital and Strata Department of Dermatology
Diagnostics University of Connecticut
Winchester and Waltham, Massachusetts Farmington, Connecticut
Chapter 7. Intraepidermal Vesiculopustular Diseases Chapter 2. Spongiotic Dermatitis
x CONTRIBUTORS

Chris H. Jokinen, MD Heinz Kutzner, PD Dr Med

Essentia Health - SMDC Dermatopathologie Friedrichshafen
Department of Pathology Friedrichshafen, Germany
Duluth, Minnesota Chapter 28. Tumors with Hair Follicle and Sebaceous
Chapter 33. Neural and Neuroendocrine Tumors Differentiation
Chapter 29. Sweat Gland Tumors
Daniel M. Jones, MD, PhD Chapter 31. Vascular Tumors and Vascular Malformations
Professor and Vice Chair of Pathology Appendix 1. Laboratory Methods
The Ohio State University Appendix 3. Molecular Biologic Techniques for the Diagnosis
Columbus, Ohio of Cutaneous Lymphomas
Chapter 1. Introduction to Microscopic Interpretation
Alexander J. Lazar, MD, PhD
Jacqueline M. Junkins-Hopkins, MD Professor
Dermatologist, Dermatopathologist, Cutaneous Departments of Pathology, Genomic Medicine, Dermatology,
Lymphoma Consultant and Translational Molecular Pathology
Department of Dermatology The University of Texas MD Anderson Cancer Center
Department of Pathology Houston, Texas
Geisinger Medical Center Chapter 35. Cutaneous Metastases
Danville, PA
Chapter 3. Interface Dermatitis Mark A. Lennan, DMD
Chapter 18. Ectopic Tissue Associate Professor of Diagnostic Sciences
Division of Oral and Maxillofacial Pathology
Catharine Lisa Kauffman, MD, FACP Tufts University School of Dental Medicine
Georgetown Dermatology Boston, Massachusetts
Washington, DC Chapter 37. Disorders of Oral Mucosa
Chapter 21. Fungal Infections
James J. Lyons, MD
Professor of Pathology and Family Medicine
Werner Kempf, MD
Alabama College of Osteopathic Medicine
Kempf und Pfaltz Histologische Diagnostik
Dothan, Alabama
Department of Dermatology, University Hospital Zurich
Chapter 22. Viral Infections
Zurich, Switzerland
Chapter 34. Lymphoid, Leukemic, and Other Cellular Cynthia M. Magro, MD
Infiltrates Distinguished Professor of Pathology and Laboratory
Medicine
Jakub Khzouz, MBBS Weill Cornell Medicine
Consultant Pathologist New York, New York
King Hussein Cancer Center Chapter 7. Intraepidermal Vesiculopustular Diseases
Amman, Jordan Chapter 8. Subepidermal Blistering Diseases
Chapter 39. Conjunctiva! Tumors Chapter 12. Cutaneous Drug Eruptions
Chapter 13. Cutaneous Reactions to Exogenous Agents
Stefan Kraft, MD Chapter 15. Disorders of Pigmentation
Dermatopathologist Chapter 20. Treponemal and Rickettsial Diseases
Center for Dermatopathology Chapter 34. Lymphoid, Leukemic, and Other Cellular Infiltrates
Freiburg, Germany
Chapter 30. Fibrous and Fibrohistiocytic Tumors Cesare Massone, MD
Medical Director
Thomas Krausz, MD, FRCPath Dermatology Unit
Professor and Vice Chair of Pathology Ospedali Galliera
Director of Anatomic and Surgical Pathology Genoa, Italy
University of Chicago Chapter 34. Lymphoid, Leukemic, and Other Cellular Infiltrates
Chicago, Illinois
Chapter 32. Tumors of Adipose Tissue, Muscle, Blaine A. Mathison, BS, M(ASCP)
Cartilage, and Bone Scientist
Institute for Clinical and Experimental Pathology
ARUP Laboratories
Salt Lake City, Utah
Chapter 24. Helminthic Diseases
 CONTRIBUTORS xl

Matthew W. McCarthy, MD Daniel J. Santa Cruz, MD

Assistant Professor of Medicine Cutaneous Pathology
Weill Cornell Medicine Maryland Heights, Missouri
New York, New York Chapter 31. Vascular Tumors and Vascular Malformations
Chapter 21. Fungal Infections
Birgitta Schmidt, MD
Hansgeorg Mueller, MD Assistant Professor
Dermatohistologie am Stachus Department of Pathology
Munich, Germany Boston Children's Hospital
Chapter 31. Vascular Tumors and Vascular Malformations Harvard Medical School
Boston, Massachusetts
Michael Murphy, MD Chapter 11. Panniculitis
Professor of Dermatopathology
Department of Dermatology Glynis A. Scott, MD
UConn Health Professor of Dermatology and Pathology
Farmington, Connecticut University of Rochester School of Medicine
Chapter 2. Spongiotic Dermatitis Rochester, New York
Chapter 25. Cutaneous Cysts and Related Lesions
Kristen M. Para!, MD
Assistant Professor of Pathology Brandon Veremis, DDS
Duke University Medical Center Senior Scientist
Durham, North Carolina The Mount Sinai Hospital
Chapter 32. Tumors of Adipose Tissue, Muscle, New York, New York
Cartilage, and Bone Appendix 4. The Future of Dermatopathology

Michael W. Piepkorn, MD Thomas J. Walsh, MD, PhD (Hon), FIDSA, FAAM, FECMM
Clinical Professor of Dermatology Founding Director, Transplantation-Oncology Infectious
Department of Medicine, University of Washington Diseases Program
School of Medicine Chief, Infectious Diseases Translational Research Laboratory
Seattle, Washington Professor of Medicine, Pediatrics, and Microbiology and
Chapter 14. Alterations of the Stratum Corneum and Immunology
Epidermis Weill Cornell Medicine of Cornell University,
Chapter 27. Tumors of Melanocytes New York Presbyterian Hospital, and Hospital for Special
Surgery
Melissa Pulitzer, MD Henry Schueler Foundation Scholar
Associate Attending Pathologist Investigator of Emerging Infectious Diseases of the Save Our
Memorial Sloan Kettering Cancer Center Sick Kids Foundation
Assistant Professor Adjunct Professor of Pathology, Johns Hopkins University
Weill Medical College of Cornell University School of Medicine
New York, New York Adjunct Professor of Medicine, University of Maryland School
Chapter 34. Lymphoid, Leukemic, and Other Cellular of Medicine
Infiltrates Visiting Professor, National and Kapodistrian University of
Athens Medical Schoo~ Athens, Greece
Ronald P. Rapini, MD Chapter 21. Fungal Infections
Professor and Chernosky Distinguished Chair
Department of Dermatology Michel Wassef, MD
Professor of Pathology Associate Professor of Pathology
University of Texas McGovern Medical School at Houston Hopital Lariboisiere
MD Anderson Cancer Center Universite Paris Diderot-Assistance Publique H6pitaux
Houston, Texas de Paris
Chapter 19. Bacterial Infections Paris, France
Chapter 31. Vascular Tumors and Vascular Malformations
Franco Rongioletti, MD
Full Professor and Chairman Kelly L. West, MD, PhD
Unit of Dermatology Director of Research and Education
University of Cagliari Ball Derrnpath, PA
Cagliari, Italy Greensboro, North Carolina
Chapter 16. Deposition Disorders Chapter 38. Disorders of the Genital Mucosa
xii CONTRIBUTORS

Lars F. Westblade, PhD, D(ABMM) Gary S. Wood, MD

Associate Professor of Pathology and Laboratory Medicine Geneva F. and Store Johnson Professor Emeritus
Department of Pathology and Laboratory Medicine University of Wisconsin
Weill Cornell Medicine Department of Dermatology
New York, New York Madison, Wisconsin
Chapter 23. Protozoa! and Algal Infections Appendix 3. Molecular Biologic Techniques for the Diagnosis
of Cutaneous Lymphomas
Mark R. Wick, MD
Professor of Pathology Artur Zembowicz, MD, PhD
University of Virginia Medical Center Professor of Anatomic and Clinical Pathology
Charlottesville, Virginia Tufts Medical School
Chapter 28. Tumors with Hair Follicle and Sebaceous Boston, Massachusetts
Differentiation Senior Staff, Lahey Clinic
Chapter 29. Sweat Gland Tumors Burlington, Massachusetts
Founder and Medical Director, Dermatopathology
Thomas Wiesner, MD Consultations LLC
Department of Dermatology Needham, Massachusetts
Medical University of Vienna Chapter 27. Tumors ofMelanocytes
Vienna, Austria Chapter 39. Conjunctiva! Tumors
Chapter 27. Tumors of Melanocytes

Sook-Bin Woo, DMD, FDSRCS (Edin)

Associate Professor
Department of Oral Medicine, Infection, and Immunity
Harvard School of Dental Medicine
Boston, Massachusetts
Chapter 37. Disorders of Oral Mucosa
Foreword
As senior editor of this new Textbook of Dermatopathology,
Dr. Raymond Barnhill brings to the task years of experience as a
dermatopathologist, clinical dermatologist, clinical investigator,
and author. This has given him an unparalleled understanding
of inflammatory and neoplastic diseases of the skin and the
ability to teach others. As director of dermatopathology at the
Brigham and Women's Hospital and the Children's Hospital
in Boston, he has had contact with both pediatric and adult
dermatologic conditions, and as a member of the Combined
Harvard DermatopathologyTraining Program, he has developed
the knowledge and skills to interact with pathologists, derma-
tologists, trainees, and students. The success of his monograph
on melanocytic lesions of the skin speaks to the effectiveness of
his writing and teaching approaches.
For this book, Dr. Barnhill has assembled a stellar roster of
authors from various disciplines and has appropriately included
both established leaders in the field as well as the cream of our
younger generation of dermatopathologists. He himself has
coauthored one-third of the chapters of the book. and I know
firsthand that he has spent a great deal of effort meticulously
editing all chapters for consistency, style, and accuracy. His
associate editor, Dr. Neil Crowson, has been instrumental in
providing the high-quality micrographs for many of the entities
in the book, and two young. energetic assistant editors, Ors.
Klaus Busam and Scott Granter, contributed heavily to the
book.
I look forward to the publication of this text and wish it the
success it truly deserves.
Ramzi. S. C.Otran, MD, 1998
This page intentionally left blank
Preface to the Fourth Edition
The editor and publisher are extremely enthusiastic to offer a
fourth edition of this book to physicians and others in the fields
of dermatopathology, dermatology, and allied specialties. It is
the express wish of the editors, contributors, and the publisher
that the information compiled in this work greatly aids phy-
sicians and other health care workers in facilitating the best
patient care possible. The editor is deeply appreciative of the
prodigious work of the associate editors Neil Crowson, Cynthia
Magro, Michael Piepkom, Heinz Kutzner, and Garrett Des.man
and the many eminent contributors in producing an accessible
and scholarly book.
The fourth edition has been revised with the same goals as
the previous editions-that is, to provide "descriptive histopa-
thology and differential diagnosis, critical analysis, balanced
perspectives on what is known and what is not, clarity of writ-
ing, the use of tables to summarize the key features of major
entities, and color photomicrographs" and also to maintain a
uniform style.
In the course of revising the book. a significant effort has
been made to improve the overall quality of photographs in
the book. The latter has been accomplished by replacing the
existing black and white and many color images, increasing
the overall number of photographs, and finally including
new clinical images. All chapters and the appendices have
been superbly revised, and much new information has been
included with respect to various inflammatory conditions,
infections, melanocytic. lymphoid, vascular, and other neo-
plastic conditions. Two entirely new superlative chapters
concerning disorders of the genital mucosa and tumors of
the conjunctiva have been included. Newly described entities
have been added to the book where appropriate, and many
new color photomicrographs have been incorporated into the
fourth edition.
As before, I aclcnowledge the tremendous efforts of the many
people involved in this fourth edition, without which it would
not have been possible. I am especially indebted to all the con-
tributors and to the staff at McGraw-Hill who have made the
fourth edition a reality. I sincerely hope that the information
contained in this book may contribute to improved and more
enlightened patient care.
Ra')'DlOnd L Barnhill, MD
Preface to the First Edition
The question might be posed, "Why another textbook of der-
matopathology?" since a number of books are currently avail-
able and would seem to do justice to the subject. Quite simply,
I have perceived the need for another book. Following on the
success of a monograph on melanocytic lesions of the skin,
The Pathology of Melanocytic Nevi and Malignant Mel.anoma,
I believe that there is indeed a need for a general text on dermato-
pathology emphasizing the same format as the aforementioned
monograph: descriptive histopathology and differential diag-
nosis, critical analysis, balanced perspectives on what is known
and what is not, clarity of writing. the use of tables to summarize
the key features of major entities, and color photomicrographs.
At the same time it must be acknowledged that the scope of
such a book goes well beyond that of a monograph on melano-
cytic lesions. As a result, I have engaged a scholarly group of
individuals to help in writing such a book in a timely fashion.
Nonetheless, one of my major goals has been to maintain a uni-
form style in keeping with the philosophy of the book.
In recent years I have been impressed with the need to pro-
vide some orientation for beginning the process oflearning der-
matopathology. Thus, the first chapter of this book is devoted
to the approach to diagnosis at the microscope. Daniel Jones,
MD, PhD, also discusses succinctly the scientific basis of pat-
tern recognition as a prologue to algorithms and the description
of the major patterns of inflammation of the skin. Christopher
French, MD, has, in addition, designed schematic color figures
that enhance the recognition of patterns of inflammation of
the skin. Another major feature is that associate editor Neil
Crowson. MD, has taken high-quality photomicrographs for
most of the entities in the book. This is another characteristic
that provides a uniform style to the book. I am deeply grateful
to Dr. Crowson for this enormous undertaking.
Although all major entities have been covered in an eru-
dite fashion in the book, a number of unique features must
be mentioned. The chapter on disorders of the skin append-
ages provides new quantitative information on the alopecias
and describes the use of transverse sections in the diagnosis of
alopecia. Dr. Crowson has written a comprehensive chapter on
drug eruptions and included lists of medications implicated in
these eruptions. Critical chapters on controversial and difficult
topics such as vasculitis, panniculitis, disorders of pigmenta-
tion, and melanocytic lesions will provide greater insight and
aid to the pathologist dealing with these conditions. Finally,
there are more detailed chapters on disorders of the nails and
the oral mucosa than are currently available in most other texts.
Another modification has been the inclusion of a scholarly
section on normal skin histology, laboratory methods, immu-
nohistochemistry, and the molecular biology ofcutaneous lym-
phoid infiltrates in an appendix rather than in the text itself.
It will become evident to the reader that there is occasion-
ally some overlap or duplication of some conditions among the
various chapters, since no method of classification is entirely
consistent. My intention has been to allow some duplication
since this provides different perspectives on a disease process.
Finally and most importantly, I would like to acknowledge
the tremendous efforts of many friends and colleagues with-
out whose advice, encouragement, and help this book would
not have been possible. First of all, I would like to thank
Neil Crowson for his enormous contn"butions in photography
and writing and for bis unflagging encouragement and support
throughout the project. I am also indebted to my former fellows
Klaus Busam and Scott Granter for their commitment and hard
work on the book, and I am most appreciative of my secretaries
Robin McCarthy (who has since departed for an undoubtedly
easier job!) and Maria Palaima. and the staff at McGraw-Hill
for their dedication and efforts in bringing the book to closure.
Lastly, I am most grateful to all the contributors who have sac-
rificed so much of their time and energy to make the book not
only possible but a learned work that will have an impact on
the field.
Raymond L. Barnhill, MD
Table of Acronyms and
Abbreviations
A BCI.2: B-cell lymphoma 2 protein
AA: acne aeativalWaggrelllive angiomyxomal
alopecia areata, 1econdary amyloid A
AAD: acroangiodennatitis
AATD: alpha-1-antitrypsin deficiency
ACC: adenoid cystic carcinoma
ACD: allergic contact dermatitis/
angiokeratoma corporis diffu.sum
AEPS: acquired elastoail perforaru
serpiginosa
AFH: angiomatoid fibrous histiocytoma
AFX: aaal fibromyxoma/atypical
fibroxanthoma
AGEP: acute generalized exanthematoua
puatulosi.s
AHE: acute infantile hemorrhagic edema
AIDS: acquired lmmunodeftdency syndrome
AITL: angioimmunoblastic T-c:ell lymphoma
AJCC: American Joint Commission on
Cancer
AK: actinic keratosis
ALM: acral lentlginoul melanoma
AM: alopeda muclnosa
AMFH: angiomatoid malignant fibrous
bistiocytoma
AML: acute myeloidJmyelogenous leukemiaJ
angiomyolipoma
AMMoL: acute myelomonocytlc leukemia
APC: acquired perforating collagenosis
APL: acquired progressive }ymphangioma
APLEXSCT: atypical ple:Dform spindle c:ell
tumor
APSCT: atypical pigmented spindle cell tumor
ARCI: autosomal recessive congenital
ichthyosis
ARMS: alveolar rhabdomyosarcoma
ASF: actinic superficial folliculitis
AST: angi.omato&is ofsoft tissue/atypical Spitz
tumor
ATLL: adult T-cell leukemia/lymphoma
AVL: atypical vascular lesion
AVM: arteriovenous malformation
B combined with high-throughput
BA: bacillary angiomatosis
BADAS: bowel-usodated dermatosi&-
arthritis syndrome
BAP: benign atrophic papulosis
BAPl: BRCAl (breast cancer 1) associated
protein 1
BCI.6: B-cell lymphoma 6 protein
B-CLL: chronic lymphocytic leukemia, B--cell
types
BEC: blood vessel endothelial c:ell
BFH: basaloid follicular hamartoma
BLAP: benign lymphangiomatow papule
after radiotherapy
BMG: benign migratory glossitis
BMM: benign mudnous metaplasia
BMZ: basement membrane zone
BP: bullous pempbigoid
BPAGI: bullous pemphigold antigen 1
BPAG2: bullous pempbigoid antigen 2
BPDCN: blastic plasmacytoid dendrltlc cell
neoplasm
BRBNS: blue rubber bleb nevua syndrome
c DADA2: deficiency of adenosine deaminase 2
CALM: cafe-au-lait macule
CAMPS: CARD14-mediated psoriasis
CANDLE: chronic atypical neutrophilic
dermatosil with lipodystrophy and elevated
temperature
CAPS: cryopyrin-associated periodic
syndrome
CAT: cutaneovisceral angiomatosis with
thrombocytopenla
CBCL: cutaneous B-cell lymphoma
CBN: cellular blue nevus
CCA: cl.ear cell acanthoma
CCCA: central centrifugal cicatricial alopecia
CD30+ LPD: CD30 positive
lytnphoproliferative disorder
CEAN: cutaneous epithelioid angiomatous
nodule
CG: cheilitis glandularis
CGD-TCL: cutaneous y/6+ T-cell lymphoma
CGH: comparative genomic hybridization
CH: composite hemangioendothelioma
CHILD syndrome: congenital b.emidy&plasia,
lchthyoslform erythroderma. llmb defects
ChIP-seq: chromatin immunopm:ipitation
sequencing
CL: cutaneous lymphoma
CM: capillary malformation/conjunctival
melanoma/cutaneous mastocytosis
CM-AVM: capillary malformation-
arteriovenous malformation
C-MIN: conjunctiva! melanocytic
lntraeplthelial neoplasia
CML: chronic myeloid leula:mia
CMMoL: chronic myelomonocytic leukemia
CMN: congenital melanocytlc nevi
CMTC: cutis marmorata telangiectatica
congenita
CMV: cytomegalovirus
COA: condyloma acuminata
CP: clcatrlcial pempbigoid
CSIN: conjunctival squamous intraepithelial
neoplasia
CTCL: cutaneous T-cell lymphomas
ctDNA: circulating free tumor DNA
CUA: calcific uremic arteriolopathy
CVV: cutaneous collagenous vasculopathy
D
DCM: diffuse cutaneoua mastocytosis/
melano1i&
DCS: dissecting cellulitis of the scalp
DDA: diffuse dermal angtomatosll
DDD: Dowling-Degoa disease
DDL: dedifferentiated liposarcoma
DEB: dominant epiderm.olysis bullosa
dystrophica
DFSP: dermatofibrosarcoma protuberans
DGGE: denaturing gradient gel
electrophoresis
DH: dermatitis herpetifnrmis
DIF: direct immunotl.uorescence
DIRA: defidency of interleukin 1 antagonist
DLE: discoid lupus erythematosus
DLSO: di&tal lateral subungual
onychomycosis
DM: desmoplastic melanoma
DNIEMD: de novo intraepidermal eplthelioid
melanocytic dyspluia
DPA: digital papillary adenocarcinoma
dPIN: differentiated penile intraepithelial
neoplasia
DPN: deep-penetrating nevus
DPW: dilated pore of Winer
DRESS syndrome: drug rash with
eoslnophilia and syatemlc symptoms
DTE: desmoplastic bichoepithelioma
DTGCT: diffuse-type giant cell tumor
dVIN: diffe.re:ntiated vulvar intraepithelial
neoplasia
xvlll TABLE OF ACRONYMS AND ABBREVIATIONS
E HPS: Hermansky-Pudlak syndrome
EAC: erythema annulare centrifugurn
EAH: eccrine angiomatous hamartoma
EBA: epidermolysis bullosa acquisita
EBV: Epstein-Barr virus
EC: epidermoid cyst
ECD: Erdheim-Chester disease
EF: eosinophilic folliculitis
EGPA: eosinophilic granulomatosis with
polyangiitis
EH: epithelioid hemangioma
EHE: epithelioid hemangioendothelioma
EMPD: extramammary Paget disease
EM: erythema multiforme
EMPSGC: endocrine mucin-producing sweat
gland carcinoma
EMA: epithelial membrane antigen
EVHC: eruptive vellus hair cyst
F IFAP: follicular ichthyosis with atrichia and
FCH: folliculosebaceous cystic hamartoma
FDE: fixed drug eruption
FISH: fluorescence in situ hybridization
FITC: fluorescein isothiocyanate
FM: follicular mucinosis
FMF: familial Mediterranean fever/
folliculotropic mycosis fungoides
FOPT: fibre-osseous pseudotumor
FR: fibroblastic rheumatism
F-RM: fetal rhabdomyoma
G KA: keratoacanthoma
GA: granuloma annulare
GCA: giant cell arteritis/giant condylomata
acuminata
GEH: generalized eruptive histiocytosis
GH: glomeruloid hemangioma
GMCSF: granulocyte-macrophage
colony-stimulating factor
GMS: Gomori methanamine silver
GPA: granulomatosis with polyangiitis
GVHD: graft-versus-host disease
GVM: glomuvenous malformation
H LE: lupus erythematosus
HBID: hereditary benign intraepithelial
dyskeratosis
HCL: hairy cell leukemia
HE: hand eczema
H&:E: hematoxylin and eosin
HHD: hyperkeratotic hand dermatitis
HHT: hereditary hemorrhagic telangiectasia
HHV-4: human herpesvirus 4
HHV-6: human herpesvirus 6
HHV-7: human herpesvirus 7
HHV-8: human herpesvirus 8
HID: hystrix-like ichthyosis with deafness
HIHS: drug-induced hypersensitivity
syndrome
HIVI AIDS: humanimmunodeficiency virus/
acquired immunodeficiency syndrome
HLH: hemophagocytic lymphohistiocytosis
HMB45: human melanoma black (gplOO)
HPC: hemangiopericytoma
HPV: human papillomavirus
HPV-OED: human papillomavirus-associated
oral epithelial dysplasia
HS: hidradenitis suppurativa
HSV: herpes simplex virus
HTLV-1: human T-cell leukemia virus type I
HUV: hypocomplementemic urticarial
vasculitis
HV: hydroa vacciniforme
HAK: hypertrophic actinic keratosis
I MCTD: mixed connective tissue disease
IB: infectious balanoposthitis
ICAM-1: intracellular adhesion molecule 1
ICD: irritant contact dermatitis
IEE: intraepidermal/intraepithelial
epithelioma of Borst-Jadassohn
IF: indirect immunofluorescence
photophobia syndrome
lg: immunoglobulin
ILVEN: inflammatory linear verrucous
epidermal nevus
IPEH: intravascular papillary endothelial
hyperplasia
J MPNST: malignant peripheral nerve sheath
JXG: juvenile xanthogranuloma
K MSC: metaplastic synovial cyst
KD: Kawasaki disease/Kyrle disease
KH: kaposifonn hemangioendothelioma
KID: keratitis, ichthyosis-like hyperkeratosis,
and deafness
KMS: Kasabach-Merritt syndrome
KS: Kaposi sarcoma
L NAME: nevi-atrial myxomas-myxoid
LAD: linear IgA disease
LBT: lupus band test
LCH: Langerhans cell histiocytosis
LCV: leukocytoclastic vasculitis
LEC: lymphatic vessel endothelial cell
LELC: lymphoepithelioma-like carcinoma
LGFMS: low-grade fibromyxoid sarcoma
LGV: lymphogranuloma venereum
LI: lamellar ichthyosis
LJSGH: localized juvenile spongiotic gingival
hyperplasia
LM: lymphatic malformation
LMM: lentigo maligna melanoma
LP: lichen planus
LPK: lichen planus-like keratosis
LPD: lymphoproliferative disorder
LPP: lichen planopilarisnichen planus
pemphigoides
LS: lichen sclerosus
LSC: lichen simplex chronicus
LTGCT: localized tenosynovial giant cell
tumor
LyP: lymphomatoid papulosis
M
MAC: microcystic adnexal carcinoma
MADISH: metabolizing acquired
dioxin-inducedskinhamartoma
MANIAC: melanocytic acral nevus with
intraepidermal ascent of cells
MAP: malignant atrophic papulosis
MBAIT: melanocytic BAPI-mutated atypical
intradermal tumor
MBN: melanoma arising in blue nevus/
malignant blue nevus
MC: mucinous carcinoma
MDS: myelodysplastic syndrome
Melan-A/MART-1: melanoma antigen
recognized by T-cells
MF: mycosis fungoides
MFH: malignant fibrous histiocytoma
MiTF: Melanocyte inducing transcription
factor
MLT: multifocal lymphangioendotheliomatosis
MMMT: malignant mixed Mfillerian tumor
MPA: microscopic polyangiitis
MPC: myopericytoma
MPCM/UP: maculopapular cutaneous
mastocytosis/urticaria pigmentosa
MPD: mammary Paget disease
tumor
MRH: multicentric reticulohistiocytosis
MT: mixed tumor of the skin
MTS: Muir-Torre syndrome
MUP: melanomas of unknown primary
MVH: microvenular hemangioma
MZL: marginal zone B-cell lymphoma
N
NAE: necrolytic acral erythema
neurofibromas [cutaneous
myxomas]-ephelides
NEH: neutrophilic eccrine hidradenitis
NET: neutrophil extracellular trap
NF: necrotizing fasciitis/neurofibroma
NGS: next generation sequencing
NHL: non-Hodgkin lymphoma
NICH: noninvoluting congenital
hemangioma
NK cell: natural killer cell
NL: necrobiosis lipoidica
NM: nevoid melanoma/nodular
melanoma
NME: necrolytic migratory erythema
NOS: not otherwise specified
NPB: nail plate biopsy
NS: nevus sebaceus
NSF: nephrogenic systemic fibrosis
NUD: neutrophilic urticarial dermatosis
NXG: necrobiotic xanthogranuloma
0
QIN: oral intraepithelial neoplasia
OLP: oral lichen planus

p PSRHC: primary signet ring cell/histiocytoid
PAM: primary acquired melanosis
PAM/C-MIN: conjunc:tival primary acquired
melanosis/melanoc:ytic intraepithelial
neoplasia
PAMS: paraneoplastic autoimmune
multiorgan syndrome
PAN: polyarteritis nodosa
PAPA: pyogenic arthritis, pyoderma
gangrenoswn and ac:ne syndrome
PAPASH: pyogenic arthritis, pyoderma
gangrenoswn and ac:ne syndrome with
hidradenitis suppurativa
PAS: periodic acid-Schiff
pc:ALCL: primary cutaneous anaplastic large
cell lymphoma
PCH: penile cutaneous horn
PCM: plasma cell mucositis
PCR: polymerase chain reaction
PEC: proliferating epithelial cyst
PEH: pseudoepitheliomatous hyperplasia
PEM: pigmented epithelioid
melanocytoma
PEP: polymorphic eruption of pregnancy
PF: perforating folliculitis
PFAPA: periodic fever, adenitis, pharyngitis,
aphthae
PG: pyogenic granuloma
PH: papillary hemangioma
PHE: pseudomyogenic
hemangioendothelioma
PILA: papillary intralymphatic
angioendothelioma
PKMB: pseudoepitheliomatous, keratotic, and
micaceous balanitis
PLAID: PLC gamma 2-associated antibody
deficiency and immune dysregulation
PLC: pityriasis lichenoides chronica
PLEVA: pityriasis lichenoides et varioliformis
acuta
PLEXSCN: plexiform spindle cell nevus
PM: pediatric melanoma/pilomatricoma
PNECS: primary neuroendocrine carcinoma
of the skin
PNH: progressive nodular histiocytoma
PNP: paraneoplastic: pemphigus
PP: palmar psoriasis
PPD: pigmented purpuric dermatosis
PPP: pearly penile papule
PR: pagetoid reticulosis
PRP: pityriasis rubra pilaris
PSA: pilar sheath acanthoma
PSCC: penile squamous cell carcinoma
PSCN: pigmented spindle cell nevus
PSL: pseudolymphoma
PSO: proximal subungual onychomycosis
TABLE OF ACRONYMS AND ABBREVIATIONS
carcinoma of the skin
PTL: primary cutaneous peripheral T-cell
lymphoma
PTT: proliferating tricholemmal tumor/cyst
PUPPP: pruritic urticarial papules and
plaques of pregnancy
PUVA: psoralen and ultraviolet A
photochemotherapy
PVPN: pseudoverrucous papules and nodules
of infancy
PWSO: proximal white subungual
onychomycosis
Q SR: solitary reticulohistiocytoma
qPCR: quantitative polymerase chain reaction
R polymorphism
RA: reactive arthritis
RAE: reactive angioendotheliomatosis
RAPK: reticulate acropigmentation of
Kitamura
RASD: reticulated acanthoma with sebaceous
differentiation
REM: reticular erythematous mucinosis
RH: retiform hemangioendothelioma
RICH: rapidly involuting congenital
hemangioma
RLH: reactive lymphoid hyperplasia
RMS: rhabdomyosarcoma
RMSF: Rocky Mountain Spotted Fever
RS: Reed-Sternberg
RT-PCR: real-time polymerase chain
reaction/reverse transcription polymerase
chain reaction
RXLI: X-linked recessive ichthyosis
s syndrome
SA: sebaceous adenoma
SADDAN: severe achondroplasia with
developmental delay and acanthosis
nigricans
SALP: stasis-associated lipomembranous
panniculitis
SAP: serum amyloid P
SAVI: sting associated vasculopathy with
onset in infancy
SC: sebaceous carcinoma
SCC: squamous cell carcinoma
SCH: spindle cell hemangioma
SCLE: subacute cutaneous lupus
erythematosus
SCL/PL: spindle cell/pleomorphic lipoma
SCSCC: spindle cell squamous cell carcinoma
SDM: solitary dermal melanoma
SEDC: squamoid eccrine ductal carcinoma
xix
SFT: soft tissue tumor/solitary fibrous tumor
SH: sebaceous hyperplasia
SIN: squamous intraepithelial neoplasia
SJS: Stevens-Johnson syndrome
SL: solar lentigo
SLE: systemic lupus erythematosus
SM: systemic mastocytosis
SMA: smooth muscle actin
SNP: single nucleotide polymorphism
SOXlO: SRY-related HMG-box 10
SP: squamous papilloma
SPP: small-plaque parapsoriasis
SPTCL: subcutaneous panniculitis-like T-cell
lymphoma
SS: Sezary syndrome
SSCP: single-strand DNA conformational
SSM: superficial spreading melanoma
SSSS: staphylococcal scalded-skin syndrome
SVV: small-vessel vasculitis
T
TA: tufted angioma
TB: tuberculosis
TCR: T-cell receptor
TdT: terminal deoxynucleotidyl transferase
TEN: toxic epidermal nec:rolysis
TFI: tumor of the follicular infundibulwn
TGGE: temperature gradient gel
electrophoresis
TGU: telogen germinal unit
THH: targetoid hemosiderotic hemangioma
TMEP: telangiectasia macularis eruptiva
perstans
T-PLL: T-cell prolymphocytic leukemia
TRAPS: TNF receptor-associated periodic
TSS: toxic shock syndrome
TTM: trichotillomania
TUG: traumatic ulcerative granuloma
u
uPeIN: usual penile intraepithelial neoplasia
uVeIN: usual vulvar intraepithelial neoplasia
v
VH: verrucous hemangioma
VP: vestibular papillomatosis
VSCC: vulvar squamous cell carcinoma
V'ZV: varicella-zoster virus
w
WCD: Weber-Christian disease
WDL: well-differentiated liposarcoma
WSO: white superficial onychomycosis
This page intentionally left blank
PART 1
Inflammatory Reactions
in the Skin
This page intentionally left blank
Introduction
to Microscopic
Interpretation
Raymond L. Barnhill • Daniel M. Jones • Almut Boer-Auer
INTRODUCTION
Perhaps in no other area of pathology does one encounter
such diverse disease processes and bewildering terminology as
in dermatopathology. The approach to learning dermatopa-
thology, as in many other areas of medicine, had traditionally
been disease oriented, a style not easily mastered by beginners
or even more advanced students. However, in recent years,
there has been greater emphasis on using a systematic or algo-
rithmic approach for initial training,1 proceeding to more
sophisticated and intuitive pattern recognition with experi-
ence, particularly for melanocytic lesions and inflammatory
conditions.2 ·5
The objectives of this chapter are (1) to outline a practical
step-by-step method for interpreting a microslide and formu-
lating a differential diagnosis using a systematic approach and
(2) to highlight the limitations and pitfalls most commonly
encountered. We close with a briefdiscussion of the commonly
used adjuvant techniques and some emerging technologies that
may supplement dermatopathology diagnoses.
Interpretation of the sllde
The diagnostic approach of this textbook. is to implement a
systematic method to diagnosis of skin lesions. The chapter
organization reflects this explicit algorithmic process, with an
emphasis in the chapter on a step-by-step approach to microslide
review (see Fig. 1-1).
Although the correct diagnosis of common skin tumors
often can be made by inspection of the microslide with the
naked eye or at the lowest scanning magnification, the per-
ceptual processes involved in diagnosis are quite complex.
They can be schematized by the simplllied algorithm that
follows.
1. "Reading• the slide (ie, visual perception/attention)
2. Processing the acquired visual information
3. Arriving at a tentative diagnosis (ie, model building)
4. Testing the preliminary diagnosis with further examination
5. Connrming the diagnosis
6. Attending to secondary features (eg. status of margins,
tumor grade)
7. Correlating available clinical information
8. Finalizing the diagnosis
CHAPTER 1
Initial examination of the slide with
the naked eye
The histopathologist should first inspect the microslide with the
naked eye in order to gain some appreciation of the size, num-
ber, and nature of the histologic sections on the slide. Often one
can make certain deductions from this gross examination alone.
For example, a small specimen may be a curetting, a shave, or
a punch biopsy and connotes particular pathologic processes.
(In contrast, a large specimen generally indicates an excision.)
Often it is possible to establish the process as epidermal, dermal,
or subcutaneous by this examination. The tinctorial properties
(histochemical staining) also may provide clues to diagnosis;
for example, bluish cellular aggregates or nodules suggest high
nuclear-to-cytoplasmic ratios because of basophilic staining of
nuclei and, as a result, processes such as basal cell carcinoma,
small cell carcinoma, and infiltrates of small lymphocytes or
calcium deposition.
Examination of the mlcrosllde at
scanning (2x or 4x) magnification
The microslide next should be viewed at scanning magniflca-
tion-that is, with a 2x or 4x objective. Although a 2x objective
may prove optimal for the initial examination of many spec-
imens, particularly large specimens, many microscopes are
equipped only with 4x objectives. However, the 4x objective
is a reasonable alternative, and additional information gener-
ally can be obtained at this magnification. If possible, the spec-
imen always should be studied initially without the knowledge
of age, gender, or other clinical information in order to gather
information objectively and formulate a differential diagnosis.
Although the experienced pathologist often does not need to
resort to such a method unless a diagnosis is not immediately
apparent, the beginner should systematically study a slide with
specific goals in mind.
1. First of all, the pathologist should attempt to identify the
type of specimen submitted; that is, is it a curettage, punch,
shave, or excisional specimen? Determination of the type
of specimen is important because it often provides some
clue to the type of disease process suspected by the sub-
mitting clinician. For example, curettage specimens often
are taken for neoplastic processes such as actinic or seb-
orrheic keratoses or basal cell carcinoma. Shave biopsies
4 DERMATOPATHOLOGY
Principally Proliferative/
inflammatory neoplastic
Epidermal Epidermis
Epidermis
alteration normal
FIGURE 1-1 Algorithmic approach to diagnosis.
usually are obtained for diagnosis of keratoses or basal or
squamous cell carcinoma. In general, punch biopsies are
submitted for diagnosis of either neoplastic or inflamma-
tory conditions. In some instances they are used to "excise"
a proliferation or tumor, and thus margins may need to be
assessed. By and large, skin ellipses (excisions) are submit-
ted for suspected tumors but also on occasion for inflam-
matory processes such as vasculitis or panniculitis.
2. Next, the pathologist should inspect the specimen with the
idea of determining in general terms from what anatomic
site the tissue was taken. In general, based on character-
istics such as prominence of sebaceous follicles, relative
paucity of hair follicles, thickness of the reticular dermis,
and thickness of the stratum corneum, one can recognize
the following general regions of the integument: (a) head
and neck, (b) trunk and proximal extremities, and (c) acral
(including frictional) surfaces. It is evident that many dis-
eases have characteristic site distributions, and knowledge
of the particular localization of the lesion or eruption is
useful in formulating one's differential diagnosis.
3. The entire specimen (ie, epidermis, dermis, or subcutis)
should be scanned for the principal site of involvement
by a disease process, if any, and the nature of the pro-
cess, whether inflammatory, proliferative, inflammatory
and proliferative, or noninflammatory. Although in most
instances the site of involvement is obvious, it is impor-
tant that the specimen is examined systematically when the
process is not so obvious. In general, the specimen should
be scrutinized in a sequential fashion, for example, begin-
ning with the stratum corneum and then proceeding to the
epidennis, dermis, subcutis, and fascia. At scanning mag-
nification, one should be able to appreciate many aspects
of the disease process without going into greater magnifi-
cation. If an inflammatory process is present, one should
attempt to recognize the nature of epidermal involve-
ment, for example, spongiosis, interface vacuolopathy,
psoriasiform epidermal hyperplasia, or vesicle, blister, or
pustule formation; the pattern of the inflammatory infil-
trate, whether bandlike (cell-poor or cell-rich/lichenoid),
perivascular, interstitial, periadnexal, nodular, or diffuse
(pandermal); the depth of the infiltrate, for example, super-
ficial only or superficial and deep; possibly the presence of
vascular damage; the cellular composition of an infiltrate-
that is, whether it is comprised of mononuclear cells, sug-
gesting small lymphocytes or larger cells; and alterations of
the dermis, for example, by fibrosis or sclerosis resulting in
,___ __, Noninflammatory ,___ __, ''Normal skin"
Dermis and/or
subcutis
a "square" punch biopsy versus the typical inverted cone
configuration, thickening, or atrophy of the dermis or
deposition of material such as calcium. A primary prolif-
erative or neoplastic condition also should be obvious in
most instances at scanning magnification.
After the completion of this exercise, the pathologist is often
able to establish the basic nature and localization of the disease
process and possibly to develop a preliminary differential diag-
nosis if he or she has not already arrived at a specific diagnosis.
In many instances, this may not be possible at scanning mag-
nification because the changes are too subtle for diagnosis at
this or perhaps any magnification or there has been a sampling
error. At this point, the pathologist must go to greater magnifi-
cation in order to confirm an impression or to gain more infor-
mation that is only possible at increased magnification.
Examination at intermediate magnification
It cannot be overemphasized that, in general, most information
about a pathologic process is obtained at scanning magnifi-
cation. The tendency to go to higher magnification too soon
should be resisted because one often will overlook a crucial fea-
ture, and thus, in effect, one "cannot see the forest for the trees."
The reasons for closer inspection of the specimen (with 1Ox and
20x objectives) are to confirm particular features of pathologic
processes, for example, parakeratosis, spongiosis, fibrinoid
necrosis, or mucin deposition, and for identification of spe-
cific cell types, such as lymphocytes or granulocytes. However,
in some instances, greater magnification may be needed in
order to identify a morphologic feature not recognizable at low
magnification, such as hyphal elements in the cornified layer,
epidermal basal layer vacuolopathy, amyloid deposits in the
papillary dermis, or mucinosis in the reticular dermis.
Examination at high magnification
As mentioned for intermediate magnification, use of the high-
power objective also should be reserved for specific indications.
Such examination is necessary in order to study the cytologic
details of cells, such as the nuclear contours oflymphocytes or
nuclear atypia in general, to confirm the nature of infectious
organisms, and to confirm other findings.
Integration of all information
During the preceding exercise of examining the microslide, the
histopathologist should take the perspective that he or she is
objectively gathering information that can be integrated with
other (clinical and laboratory) information to arrive at some
 Chapter 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION
conclusion about the disease process and not necessarily to
arrive at a single diagnosis. One should, at all times, try to avoid
reaching a conclusion too quickly and failing to observe other
pertinent findings in the specimen. The pathologist always
should try to think expansively of every potential pathologic
process that might explain the histologic findings. One should
continuously weigh the various points that argue for or against
a particular pathologic condition.
After completing the preceding examination and reaching
some tentative impression (or lack of conclusion) about the
specimen without knowledge of clinical parameters, it is then
necessary to consider the clinical context of the specimen. Even
if the histopathologic diagnosis appears straightforward, such
as, for example, basal cell carcinoma, the pathologist always
should have certain clinical information before finalizing the
case: age, gender, anatomic site, an accurate clinical descrip-
tion of the lesion(s) or eruption, pertinent brief clinical history
if relevant. and clinical differential diagnosis. If at all possible,
clinical photographs should be provided by clinicians. With-
out such information, the pathologist is much more prone to
blatant errors, such as rnislabeled specimens or misdiagnosis."
For many conditions, particularly inflammatory processes
and melanocytic lesions, detailed clinical information concern-
ing the onset. evolution, distribution, and specific character of
the skin lesions is essential in order to arrive at a diagnosis or
to formulate a differential diagnosis. Many inflammatory reac-
tion patterns are not specific and may be secondary to several
processes. Thus an accurate clinical history is needed to estab-
lish the most likely condition or group of conditions that might
explain the histologic findings. The pathologist is encouraged
to communicate directly with the clinician in order to achieve
optimal clinicopathologic correlation.
Finally the histopathologist must recognize the limitations
of histopathological interpretation: in some instances specific
diagnosis is not possible including because histological find-
ings are nonspecific and diagnosis rests in the clinical domain,
current knowledge about the disease process is inadequate, the
FIGURE 1-2 DJstlngulshlng benfgn from malignant neoplasms by low-power microscopic features. Well circumscribed
epithelial proliferation with characteristic acan1hosis, hyperkeratosis, and keratin pseudocyst formation in seborrheic keratosis
(left). Asymmetric epithelial proliferation with infiltrating growth pattem and formation of parakeratotic cysts in cutaneous
squamous cell carcinoma (right).
5
biopsy specimen is inadequate, or sampling error has occurred.
In this case, inclusion of pertinent negative findings may be
helpful in guiding the next step in the workup.7
PATIERN RECOGNITION IN
DERMATOPATHOLOGY
Accurate perception of the findings on a microslide is obviously
the initial step in accurate diagnosis. Many, perhaps most, seri-
ous errors in diagnosis are related to a failure to attend to or
notice critical histologic findings rather than a misinterpreta-
tion of these features. A trivial but common reason for misdiag-
nosis is simply a failure to examine a relevant tissue fragment or
level Poor tissue preservation and histologic detail or substan-
dard tissue sectioning also can contribute greatly to problems in
accurate perception. The visual fatigue and information over-
load that occur after examining many cases also contributes to
perceptual mistakes.
As outlined in Fig. 1-1, the initial decision one must make
is whether a process is predominantly inflammatory, predom-
inantly proliferative/neoplastic, both inflammatory and pro-
liferative, or noninflamm.atory/nonproliferative. This is not
always possible, but, in general, the vast majority of pathologic
processes can be categorized into one of these groups. Thus one
is able to proceed along one of the decision trees.
Features of benign venus malignant tumors
Although it may appear intuitive and instantaneous, recogni-
tion ofcutaneous tumors is a highly complex perceptual process
that involves more than simple "wallpaper matching." Particu-
larly in the diagnosis of cutaneous tum.ors, the low-power pat-
tern (tumor silhcnutte) often can be at least as important if not
definitive for diagnosis as high-power cytologic findings.,
Certain tumor growth patterns appear to be intrinsically
more readily recognizable and often are the first to be mas-
tered by the student of dermatopathology. Easy recognition
of some benign skin tum.ors (Fig. 1-2, eg, seborrheic keratosis,
6 OERMATOPATHOLOGY

FIGURE 1..3 Examples of poorly-circumscribed dennal prollferat.tons that are more dlfftcult to recognize. A sclerosing blue
nevus {left) and a desmoplastic melanoma (right). Prominent and irregular involvement of the subcutaneous tissue and patchy
lyrnphocytic infiltrates seen at scanning magnification provide support for desmoplastic melanoma {right).

ke.ramacanthoma. or cylindroma) in contrast to others (Pig. 1-3,
eg. a sclerosing melanocytic nevus or desmoplastic me1anoma)1
is due in part to the visual impact of their particular growth
patterns evident at low magnmcation.
Similarly, the presence of ancillary features such as inflam-
matory infiltrate can be an instantly recognizable clue to search
for evidence of twnor invasion. As a pathologist gains experi-
ence with twnors in dermatopathology, the distinction of the
range of benign versus malignant growth patterns becomes
easier.
Features of inflammatory and reactive lesions
Although it also involves pattern recognition, the diagnosis
of inflammatory lesions presents a much different challenge.
Instead of rendering a definitive diagnosis, the usual approach
is descriptive (ie, what kinds of epidermal alterations and
inflammatory cells are present and where they are located). In
the absence ofadequate clinical information, a range ofpossible
diagnoses usually is provided. This is a different perceptual task
where the goal is not simply to match a precise stored visual
image but to compare the features of a lesion with the clinical
entity to which it is (statistically) most similar.
Inflammatory lesions are grouped initially into general cate-
gories (see Pigs. 1-4 to 1-8), and then specific features are sought
to narrow (or prioritize) the diagnoses. For instance, once the
pattern of vacuolar interface dermatitis has been identified,
visual search for viral inclusions or apoptotic bodies could sup-
port the diagnoses ofa viral exanthem or erythema multiforme.
Combining the available information on the gross appear-
ance and the clinical differential diagnosis with the histologic

Vesicle/ Spongiotic Interface Psoriaaiform

bliate.r/ dermatitis dermatitis dermatitis
papule Chap.2 Chap.3 Chap.4

i !
Intraepidermal Subepidermal Vacuolar Licbenoid
Chap. 7 Chap.8 type type

!
Iunctional Dermolytic

.. ! ! ! !
Subcomeal
lnlnalratum Suprabuilar, Conventional Bosinophilic Neutrophilic Follicular Miliarial
11Ub91ratu.m
spinosum intrabasilar spongiosis spongiosia spongiosis spongiosis spongiosis
granulosum

FIGURE 1-4 Inflammatory conditions with epidermal alteration.

 Chapter 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION 7

No vascular damage 1 - - - - - - - - - - - - - - - - - 1 Vascular damage

Perivascular Disorders of Nodular Diffuse Panniculitis

infiltrates skin appendages infiltrates infiltrates fasciitis
Chap. 5 Chap.10 Chap. 6 Chap. 6 Chap.11

Hair follicle, folliculitis, Sweat glands, Vasculopathy Vasculitis

perifolliculitis, alopecia miliaria, hidradenitis Chap. 9 Chap. 9

FIGURE 1-5 Inflammatory conditions of the dermis and/or subcutis without epidermal alterations and with and without
vascular injury.

Granulomas/granulomatous inflammation
Chap.6

Sarcoidal Tuberculoid Foreign

Suppurative Elastolytic
epithelioid cell caseating body

FIGURE 1-6 Inflammatory infiltrates with granulomas/granulomatous inflammation.

I Alterations of stratwn comewn and epidermis I

Chap.14

~
Hyperkeratosis
Alteration of
with parakeratosis Hyperorthokeratosis
basal layer melanin
focal or diffuse

l l
Normal granular
Hypogranulosis layer or
hypergranulosis

l l
Hypopigmentation, Hyperpigmentation,
focal or diffuse focal or diffuse
Chap.15 Chap. 15

FIGURE 1-7 Noninflammatory disorders with alterations of stratum corneum and epidermis.
I OERMATOPATHOLOGY
Papillaly dermal alteration
vs
Reticular dermal alt.eration
I
! !
Deposition
Atrophy of material
Chap.16
FIGURE 1·8 Noninflammatory disorders with dennal alteration.
diagnosis is the vitally important penultimate stage prior to
rendering a final diagnosis. The close linkage in training and
expertize between dermatologist and dermatopathologist often
makes this process easier because the histopathologist becomes
more familiar with the clinical appearance of the lesions in the
differential diagnosis. This synergistic effect is most obvious in
the rare cases where the biopsy specimen is being diagnosed by
the person who has actually examined the patient. However, in
all cases, the differential diagnosis provided by the submitting
dermatologist may force a reexamination of the mic:roscopic
features, and as a result, this book provides detailed descrip-
tions of both the histological features and clinical appearance
of each entity.
There are also added complexities to diagnosis of inflam-
matory lesions in the skin that are related to the nature of the
immune responses producing these lesions. These include:
1. The temporal phase of a lesion. Many dermatitis reactions
have acute, subacute, and chronic phases with fairly spe-
ciflc histologic correlates (Fig. 1-9). Therefore, it is impor-
tant to consider the varying histologic appearances that
can occur ove.r the life span of a skin lesion.
2. The severity of the reaction. For inflammatory lesions incited
by external or internal antigenic reaction, there is a spectrum
of responses ranging from mild to severe (Fig. 1-10).
FIGURE 1·9 Spongiotic dermatitis, acute versus chronic changes. Spongiosis with incipient spongiotic vesiculation in early
lesions of allergic contact dermatitis (left) and spongiosis combined with irregular acanthosis, scale-crust, hypergranulosis, and
dermal fibrosis in longer standing lesions of the same disease (right).
!
Hypertrophy
!
Pigmentary
fibrosis alterations
Chap.17 Chap.15
3. Etiological relationships between disease entities. For
example, cutaneous T-cell lymphomas may evolve from a
preceding atopic dermatitis. Therefore, there can be over-
lap in the histologic features requiring careful attention to
lymphocyte atypia at high magnification.5
Full maturation of expertize in dermatopathology thus
requires not only a "library" of stored visual images of inflam-
matory skin lesions that correlate with. clinical syndromes but
also knowledge of the time-course and spectrum. of changes
seen for each particular entity. As discussed below, the stepwise
approach to learning to diagnose inflammatory lesions in skin
emphasizes the importance of mastering the differential diag-
nosis for each inflammatory pattern.
Major inflammatory reaction pattems in the skin
Since the pathogenesis of most inflammatory dermatitides is
unknown, one must, of necessity, use morphologic criteria for
classification at present. Although most inflammatory condi-
tions can be categorized into one of the major reaction patterns,
there are inevitable dermatitides that show overlapping features
and some that defy classification. Some inflammatory condi-
tions may be sampled either too early or too late in their evolu-
tion to be diagnostic. Inflammatory diseases are dynamic, and
knowledge of the point in time when the dermatitis is sampled
 Chapter 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION
FIGURE 1-10 Interface dermatrtrs, mild to severe. Erythema multiforme in an early lesion shows vacuolar alteration in the basal
layer with few necrotic keratinocytes and few intraepidermal lymphocytes (left). A fully developed or severe expression of the
disease shows numerous necrotic keratinocytes and, eventually ful I thickness necrosis of the epidermis (right).
is critical to optimal microscopic interpretation. The histopa-
thologist should strive to assess specimens with the "fourth
dimension" of time always kept in mind.
As mentioned previously, one initially attempts to ascertain
whether the epidermis shows one of the following major reac-
tion patterns or is uninvolved by the inflammatory process.
Inflammatory Reaction Patterns of the Epidermis
Sponglotlc Dermatitis. "Spongiotic dermatitis'" refers specifi-
cally to the presence of spongiosis or intercellular edema that
stretches apart keratinocytes and sometimes results in the for-
mation of intraepidermal vesicles. Spongiosis is often variable,
multifocal, and accompanied by intracellular edema and exo-
cytosis of inflammatory cells. The disease process is dynamic
and in general has been categorized according to morphologic
features correlating with the stages of its life history: (1) acute,
(2) subacute, and (3) chronic (Fig.1-9). Other alterations, such
as granulocyte infiltration of the epidermis (eg, eosinophilic or
neutrophilic spongiosis) or involvement of skin appendages
(eg, follicular spongiosls). may be observed.
Spongiosis is a relatively nonspeclfic morphologic altera-
tion observed in a wide variety of conditions (see Table 1-1).
It is perhaps the most characteristic of the group of conditions
referred to as "eczematous dermatitis." These disorders include
endogenous or atopic dermatitis, contact allergic and irritant
dermatitis, and nummular dermatitis. Other common dermati-
tides showing spongiosis include seborrheic dermatitis, spongi-
otic drug eruptions, and some primary bullous conditions.
Interface Dermatitis. "'Interface dermatitis"' refers to a mor-
phologic alteration at the junction or interface between the epi-
dermis (or epithelium) and dermis. Spedfically, one observes
vacuolization (vacuoles or discrete clear spaces) either within
basilar keratinocytes or within the basement membrane zone.
This reaction pattern is often accompanied by a number of
other alterations present to variable extent: individually dysker-
atotic keratinocytes (which are probably apoptotic cells), dis-
ruption of orderly keratinocytic maturation to the surface, and
clefts resulting from coalescence of vacuoles.
9
Interface dermatitides may be further $Ubclassified
according to the density and pattern of the inflammatory
cell infiltrate in the papillary denni$ a$ (1) the vacuolar or
cell-poor type, based on perivascular or patchy infiltrates in
the papillary dermis or (2) the lichenoid or cell-rich type,
which shows a dense bandlike infiltrate that fills the papil-
lary dermis (Table 1-2). As with all inflammatory processes,
interface dermatitides also may be characterized according
to their severity (Fig. 1-10, illustrating erythema multiforme)
or their stage of evolution as acute or early stage, subacute or
developed, or chronic or late stage. Certain diseases are pro-
totypic of the two patterns of interface dermatitis mentioned
earlier. Erythema multiforme, many drug eruptions, viral
exanthems, and connective tissue diseases result in a vacuo-
lar pattern of interface dermatitis. On the other hand, lichen
planus, lichenoid drug eruptions, lichen planus-like kerato-
sis, and "halo" nevus are associated with lichenoid patterns
of inflammation.
Psoriasiform Dermatitis. "Psoriasiform. dermatitis" refers to
a characteristic pattern of epidermal hyperplasia typified by
elongation of the epidermal rete ridges (Fig. 1-11). In general,
the topography of the epidermal surface is unaffected-ie,
it remains essentially flat-topped. This pattern of epidermal
alteration may be further described as either regular or irregu-
lar. Regular psoriasiform hyperplasia, as the name suggests,
indicates elongated epidermal rete ridges of fairly uniform
length and thickness and is typical of psoriasis in a well-developed
stage. This morphologic feature is accompanied by a num-
ber of other histologic alterations notable in psoriasis: broad
zones of parakeratosis, absence of the granular layer, exo-
cytosis of neutrophils, pallor of keratinocytes (intracellular
edema), thinning of the epidermis above the dermal papillae,
prominent dilated and tortuOU$ papillary dermal microves-
sels, and papillary dermal edema. Irregular psoriasiform epi-
dermal hyperplasia may be observed in psoriasis but typifies
other processes more commonly, such as chronic eczematous
dermatitis, lichen simplex chronicus (Fig. 1-11), or mycosis
fungoides (Table 1-3).
10 DERMATOPATHOLOGY

TABLE 1-1 Spongiotic Dermatitis TABLE 1-2 Interface Dermatitis

Conventional Spongiotic Dermatitis Vacuolar Interlace Dermatitis

Allergic contact dermatitis Erythema multiforme
Irritant contact dermatitis Fixed drug eruption
Atopic (endogenous) dermatitis Drug eruptions
Nummular dermatitis Viral xanthems
Dyshidrotic eczema (pompholyx) HIV interface dermatitis
Id reaction Connective tissue disease
Seborrheic dermatitis
Lupus erythematosus
Stasis dermatitis
Dermatomyositis
Spongiotic drug eruption
Graft-versus-host reaction
Erythroderma
Pityriasis lichenoides
Pityriasis rosea
Pityriasis alba Poikiloderma congenitale
Photoallergic contact dermatitis Bloom syndrome
Polymorphous light eruption Vitiligo
Arthropod bites Pigmented purpuric dermatitis
Gyrate/figurate erythemas Lichenoid Interlace Dermatitis
Dermatophyte infection Lichen planus and variants
Transient acantholytic dermatosis
Lichenoid drug eruption
Pigmented purpuric dermatitis
Lichenoid keratosis
Papular and urticarial eruptions of pregnancy
Lichen striatus
Eosinophilic Spongiosis
Lichen nitidus
Pemphigus group
Lichenoid purpura
Bullous pemphigoid
Porokeratosis
Allergic contact dermatitis
Histologic regression of many tumors
Spongiotic drug eruptions
Infestations
Cutaneous larva migrans
Arthropod bites
Other conditions that exhibit this reaction in addition to
lncontinentia pigmenti
those already mentioned are psoriasiform drug eruptions,
Eosinophilic folliculitis
lamellar ichthyosis, and secondary syphilis.
Neutrophilic Spongiosis
Vesicular and Bullous Dermatitis. This reaction pattern refers
Psoriasis to the formation of tissue clefts or spaces that may or may
Reactive arthritis not be accompanied by cellular infiltrates such as eosino-
Seborrheic dermatitis phils, neutrophils, or lymphocytes. In general, these disorders
Irritant contact dermatitis are classified according to whether the level of cleavage is (1)
Phototoxic dermatitis intraepidermal or (2) subepidermal (Figs. 1-4, 1-12; see also
Tables 1-4 and 1-5). Intraepidermal blisters may include, for
Pemphigus variants (particularly lgA pemphigus)
example, subcomeal or intragranular layer cleavage or cleavage
Follicular Spongiosis through the superficial layer or suprabasal layer of the epider-
Atopic dermatitis mis. Subepidermal blisters may be further delineated as cleav-
Pityriasis alba age through the lamina lucida of the basement membrane zone
Contact dermatitis or through the superficial dermis.
lnfundibulofolliculitis Blistering dermatitides may then be characterized as predom-
inantly inflammatory or noninflammatory. If inflammatory,
Eosinophilic folliculitis
the composition of the infiltrate and possibly immunofluo-
Follicular mucinosis rescence and serological studies will further aid classification.
Fox-Fordyce disease Finally, one may be able to recognize the mechanism ofvesicle/
Miliarial Spongiosis blister formation as spongiotic, acantholytic, ballooning degen-
Miliaria eration, or resulting from prominent basal layer vacuolization
or subepidermal edema.
 Chaptu 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION 11

FIGURE 1·11 Psoriasiform dermatitis. Psoriasis shows hypericeratosis with thinned granular layer and elongation of the rete
ridges (left) together with parakeratosis that contains neutrophils in staggered fashion. Irregular psoriasiform hyperplasia
can be seen due to mechanical irritation in lichen simplex chronicus (right), here combined with hypergranulosis, compact
orthokeratosis, and vertically oriented thickened collagen bundles in the papillary dermis.

Overlapping and Distinctive Patterns. When two or more of epidermal hyperplasia. and variable spongi.otic and inter-
the patterns of epidermal alteration are noted, the predominant face alteration. Depending on which of these features might
reaction pattern generally should be used as the basis for cate- predominate, various dermatitides in this group also might be
gorization, or one of the variants below ifclinically compatible. classified as a subacute spongiotic, psoriasifonn, or interface
dermatitis, as below.
Pityriosiform Dermatitis. A small but important group of
These conditions generally include pity.riasis rosea. pityriasis
inflammatory dermatitides shows a constellation of epider-
lichenoides, sebo.rrheic dermatitis, eruptive or guttate psoriasis,
mal changes that include focal or spotty parakeratosis. slight
pre- or early mycosis fungoides lesions (parapsoriasis), some
drug eruptions, subacute eczematous dermatitis, pityriasis
rub.ra pilaris, and superfi.dal fungal infections.
TABLE 1-3 Psoriasiform Dermatitis
Overlapping Reaction Pattems. The four patterns listed below
Psoriasis emphasize the prominence of two or more morphologic altera-
Reactive arthritis tions. Particular patterns often correlate with particular disease
Subacute to chronic eczematous dermatitis processes. For example. spongiotic psoriasiform dermatitis is
a typical pattern associated with chronic active eczematous
Seborrheic dermatitis
dermatitis.
Lichen simplex chronicus
1. Spongiotic psoriasiform dermatitis
Pityriasis rubra pilaris
2. Spongiotic interface dermatitis
Pa rapsoriasis 3. Spongiotic psoriasiform. interface dermatitis
Mycosis fungoides 4. Psoriasiform. interface dermatitis
Psoriasiform drug eruption
Characterization of the Inflammatory Process in the Dermis
Erythroderma
After one has examined the epidermis for morphologic altera-
Candidiasis
tion, one proceeds to evaluate the inflammatory process in the
Secondary syphilis dermis (and subcutis and fascia, as the case may be). A highly
Inflammatory linear verrucous epidermal nevus (ILVEN) signiflcant clue to pathogenesis is whether recognizable vascu-
Scabies lar injury is present or absent.
Lamellar ichthyosis Absence of Vascular Injury. The pattern, depth, density, and
Clear cell acanthoma composition of the inflammatory cell infiltrate are assessed,
with patterns classified as lichenoid, perivascular (Fig. 1-13),
Pellagra
periadnenl, interstitial (infiltrating collagen bundles). nod-
Acrodermatitis enteropathica ular (Fig. 1-14). or diffuse, when occupying the entire der-
Migratory necrolytic erythema mis (Fig. 1-15. Fig. 1-16 and Table 1-6). Regarding depth of
Bazex syndrome infiltration. drug eruptions and viral exanthems often show
superficial perivascular involvement only, whereas conditions
12 DERMATOPATHOLOGY

FIGURE 1-12 Vesfcular and bullous dermatitis. lntraepidennal vesiculation in herpes virus infection (upper left) shows
acantholysis, necrosis, and ballooning of keratinocytes and some multinucleated epithelial cells with steel gray nuclei (upper
right). Bullous pemphigoid is a subepidermal blistering disease (lower left) with numerous eosinophils in the dermal infiltrate and
in the blister (lower right).

such as lupus erythematosus, polymorphous light eruption,
and se<:<>ndary syphilis are prone to involvement of the deep
dermal vascular plexus (ie, a superficial and deep perivascular
pattern). Deep infiltrates also may be indicative of a systemic
disease process, as in lupus or secondary syphilis. Infiltrate
density is usually assessed in rather subjective terms, such as
sparse, moderate, or dense. However, recognizing the density of
an infiltrate has relevance for particular disease processes, such
as acute urtlcaria (which is sparse), figurate erytb.ema (which
is moderately dense), and cutaneous lymphoid hyperplasia or
lymphoma (which tends to be dense).
The cellular infiltrates in the dermis commonly are com-
posed of lymphocytes, possibly with varying admixtures of
other cell types, including monocytes/macrophages (histiocytes),
eosinophils, neutrophils. plasma cells, and mast cells. The par-
ticular cellular composition often has diagnostic significance,
particularly when integrated with infiltrate pattern, depth, and
density. Thus a sparse superficial perivascular infiltrate con-
taining lymphocytes and eosinophils (and often neutrophils)
would suggest urticaria. Infiltrates showing the same cell types
but having moderate density nt the broad category of allergic
hypersensitivity reactions. Whereas circumscribed superficial
and deep perivascular aggregates of epithelioid macrophages
would suggest the sarcoidal granulomatous reaction pattern
(see Granulomatous Reaction Patterns, Fig. 1-16).
Presence of vascular injury. •vascular injwY° refers to a spec-
trum. of morphologic alterations ranging from endothelial
perturbation or activation to frank ftbrinoid necrosis and the
presence of inflammation for an interpretation of vasculitis
(Table 1-7, Fig. 1-17). These changes may be primary or se<:-
ondary (a distinction not always easily made). In assessing
vascular injury, a number of parameters must be considered.
and these include caliber and type of vessels involved. degree
of vascular injury (as already mentioned), the composition and
density of the cellular infiltrate, and the presence or absence of
such factors as antineutrophil cytoplasmic antibodies (ANCA).
Granulomatous Reaction Patterns. The essential definition of
a granuloma is a drcwnsaibed aggregate of macrophages. The
cytologic characteristics of such cells vary from mononuclear
cells with abundant pale, vacuolated, or lipi.dized cytoplasm to
cells with plentiful pink cytoplasm, resembling epithelial cells
and hence the term •epitb.elioid" cells (Fig. 1-6). Multinucle-
ated giant cells are commonly present and are generally one of
two types: foreign-body and Langhans giant cells. Granulomas
often contain a variable admixture of other cell types, such as
 Chapter 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION 13

TABLE 1-4 lntraepidermal Vesicular and Pustular TABLE 1-5 Subepidermal Vesicular Dermatitis
Dermatitis
Subepidermal Blisters with Little Inflammation
lntracorneal and Subcorneal Vesicles and Pustules Epidermolysis bullosa
Impetigo Porphyria
Staphylococcal "scalded skin" syndrome Pseudoporphyria
Superficial fungal infection Bullous pemphigoid (cell-poor type)
Pemphigus foliaceus Burns
Pemphigus erythematosus Toxic epidermal necrolysis
Subcorneal pustular dermatosis Bullae associated with diabetes
Infantile acropustulosis Blisters overlying scars
Erythema toxicum Bullous amyloidosis
Transient neonatal pustular melanosis
Subepidermal Blisters with Lymphocytes
Miliaria crystallina
Erythema multiforme
lntraepidermal Vesicles and Pustules
Fixed drug eruption
Spongiotic vesicles Lichen planus pemphigoides
Viral vesicles Polymorphous light eruption
Palmoplantar pustulosis Bullous mycosis fungoides
Friction blister Bullous fungal infections
Epidermolysis bullosa
Subepidermal Blisters with Eosinophils
Bullous pemphigoid
lymphocytes, plasma cells, neutrophils, and mast cells. Poorly Epidermolysis bullosa acquisita
defined granulomatous infiltrates often are referred to as "gran- Pemphigoid gestationis
ulomatous inflammation." Granulomas may be classified in a
Arthropod bites
number of ways, such as infectious or noninfectious or by mor-
phologic features, acknowledging that there is considerable Drug reactions
overlap among many of these entities. A generally accepted Subepidermal Blisters with Neutrophils
scheme is as follows (Fig. 1-16): (1) sarcoidal or epithelioid
cell granulomas, (2) tuberculoid or caseating granulomas, Dermatitis herpetiformis
(3) foreign-body granulomas, (4) suppurative granulomas, (5) Linear lgA bullous dermatosis
palisading/necrobiotic granulomas, and (6) xanthogranulomas. Cicatricial pemphigoid and localized
In general, these reaction patterns are nonspecific and should cicatricial pemphigoid
prompt a differential diagnosis and systematic evaluation, as
Pustular vasculitis
discussed in more detail in Chap. 6 (see Fig. 1-6}.
Bullous lupus erythematosus
Disorders of Skin Appendages. The skin appendages, princi-
pally the hair follicle and the eccrine sweat apparatus, may show Sweet syndrome
primary inflammatory involvement. Epidermolysis bullosa acquisita
Disorders of the Hair Follicle. Folliculitis is categorized as to Erysipelas
whether it is infectious or noninfectious and according to Bullous urticaria
its depth: superficial only or superficial and deep. Acne is an Subepidermal Blisters with Mast Cells
extremely common form of folliculitis that has a multifactorial
basis, for example. The hair follicle also may show a peculiar Bullous mastocytosis
reaction-follicular mucinosis-which may be associated with a Miscellaneous Blistering Diseases
number ofprocesses, including mycosis fungoides and inflamma-
tory conditions such as arthropod bites and lupus erythematosus. Drug-overdose-related bullae
"Alopecia" histologically refers to an overall reduction in PUVA•-induced bulla
the number of terminal anagen hair follicles, which may be Etretinate-induced bullae
reversible or irreversible. Operationally (and perhaps simplis-
tically), alopecia may be classified as nonscarring or scarring. •Psoralen (P) and ultraviolet A (UVA) therapy.
Nonscarring alopecias may result from any number of factors
interrupting the hair growth cycle, whether inflammatory, as in
the case of alopecia areata, or noninflammatory, as in androge-
netic alopecia or telogen effluvium. Scarring alopecia follows
14 DERMATOPATHOLOGY

FIGURE 1·13 Perivascular (and interstitial) dermatitis without epidermal changes. Relatively nonspecific features of a mild
perivascular lymphocytic infiltrate only (upper left) with few plasma cells (upper right) in early cutaneous borreliosis (erythema
migrans). Infiltrates are not only perivascular but also interstitial in erysipelas (lower left), interstitial neutrophils and extravasated
erythrocytes are numerous (lower right).

FIGURE 1·14 Nodular dennal infiltrate due to ruptgre of a folliculitis in rosacea (left). Infiltrates show a mixture of
neutrophils, lymphocytes, and macrophages indicating a granulomatous variant of rosacea.
 Chaptu 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION 15

FIGURE 1·15 Diffuse dennal infiltrate {left) with mixed composition {right) induding neutrophils, nudear dust of
neutrophils, eosinophils, lymphocytes and plasma cells in granuloma faciale.

FIGURE 1-16 Different types of granulornu. Tuberculoid granuloma (upper left}: Aggregations of macrophages with
lymphocytic infiltrate$ at the periphery in cutaneou$ leishmaniasis; Insert shows amastigotes within macrophages. Sarcoidal
granuloma (upper right): Aggregations of macrophages with very few lymphocytes at the periphery in sarcoidosis. Suppurative
granuloma (lower left): Aggregation of neutrophils surrounded by macrophages in atypical mycobacteriosis; Insert shows acid
fast bacilli with Ziehl-Neelson stain. Xanthogranuloma (lower right): Diffuse granulomatous infitrates with scattered vacuolated
("foamy"} macrophages in necrobiotic xanthogranuloma: Insert shows foamy macrophages, some multinucleate dose up.
16 DERMATOPATHOLOGY

TABLE 1-6 Dermal Inflammatory Infiltrates without TABLE 1-7 Vasculitis and Related Disorders
Vascular Injury
Vasculopathy
Superficial or Superficial and Deep Perivascular
Small-Vessel Vasculitis
Infiltrates*
Neutroph ilidleukocytoclastic vascu Iitis
Urticaria
Lymphocytic vasculitis
Urticarial reactions
Granulomatous vasculitis
Viral exanthems
Medium-Sized Vessel Vasculitis
Drug eruptions
Gyrate/figurate erythemas
Lupus erythematosus factitial disease, or physical injury. Adequate sampling and the
Polymorphous light eruption stage of disease when the biopsy is taken will influence the mor-
Photosensitive eruptions phologic findings observed. The reaction pattern of adipose tis-
sue to injury is rather limited. Initially one observes an influx of
Chilblains/perniosis
neutrophils (erythema nodosum pattern, Fig. 1-18), followed
Leprosy (indeterminate) by mononuclear cells (lymphocytes and macrophages), and
Syphilis finally, reparative fibrosis, depending on the nature and sever-
Borreliosis ity of the insult.
Leukemia
Proliferative or neoplastic conditions
Urticaria pigmentosa
A large category of conditions encompasses hyperplasias,
Nodular Infiltrates* hamartomas, and benign and malignant neoplasms involving
Arthropod bite reactions the epidermis, melanocytes, skin appendages, dermis, subcutis,
and hematopoietic cells in the skin.
Cutaneous lymphoid hyperplasia
Histiocytic infiltrates Noninflammatory conditions
Neutrophilic dermatoses In the absence of an obvious inflammatory dermatitis or pro-
Lymphoma liferative/neoplastic process, one must proceed along the algo-
rithm considering noninflammatory conditions. Histologic
Diffuse Infiltrates*
alterations may suggest "normal skinn and may include the
Reactive infiltrates so-called invisible dermatoses (Table 1-8).8 As already out-
Leukemia lined earlier, one generally must resort to systematic study of
Lymphoma the specimen beginning with the stratum corneum or perhaps
with the subcutis in the reverse order. It goes without saying
Histiocytic infiltrates
that the histopathologist should have some understanding of
Mast cell infiltrates the regional microanatomy and age-related variations of skin
in order to know what is within normal limits.
•Further classified according to cell types present, such as
lymphocytes, eosinophils, neutrophils, and so on.
Alterations of Stratum Corneum and Epidermis
The stratum corneum is studied for subtle abnormalities
a wide variety of processes, such as infective folliculitis, lupus such as parakeratosis, hyperkeratosis, and fungal elements.
erythematosus, lichen planus, or traumatic injury. The epidermis is inspected for acanthosis, atrophy, subtle
Disorders of the Sweat Apparatus. The eccrine duct may be alterations suggesting an inflammatory or vesicular reaction,
involved primarily in an inflammatory reaction termed "miliarian alterations of the granular layer as in ichthyosiform dermati-
and categorized according to depth of involvement as (superfi- tides, peculiar processes such as epidermolytic hyperkeratosis,
cial) miliaria crystallina, miliaria rubra, and miliaria profunda. and finally, pigmentary alterations associated with hypo- and
Hidradenitis refers to an inflammatory disorder involving the hyperpigmentation.
sweat coil as in neutrophilic eccrine hidradenitis, which may be
Alterations of Papillary Dermis
infectious or noninfectious.
The papillary dermis is then studied for alterations such as
Panniculitis. The primary focus of inflammation may be in the deposition of amyloid, hyalinization of vessels as in porphyria,
subcutaneous fat, fascia, or both. Although traditionally pan- and incontinence of melanin (melanin-laden macrophages in
niculitis has been classified as septal or lobular, in fact, in most papillary dermis).
instances the inflammatory process is both septal and lobular,
often spreading from the septae. Particular factors that should Alterations of Reticular Dermis
be considered when evaluating panniculitis include presence The reticular dermis is examined systematically for alterations of
or absence of infection, vascular injury, cold-related injury, collagen as in morphealscleroderma or scleredema, thickening
 Chaptu 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION 17

FIGURE 1-17 Vascular injury. Fibrin in the vessel wall of a small vessel together with infiltrates of neutrophils and nuclear
dust in leukocytoclastic vasculitis (upper left). Thrombus in 1he lumen of a small vessel in the subcutis in a coagulopathy (upper
right). Fibrin and inflammatory infiltrates in the vessel wall of a medium-sized artery in polyarteritis nodosa (lower left). Calcium
deposition in a vessel wall in calciphylaxis (lower left).

FIGURE 1-18 Panniculitia. Prominent alteration of the subcutaneous fat in erythema nodosum. Rbrosis of the septae and
infiltrates of macrophages with multinucleated giant cells, lymphocytes and neutrophils are present in the broadened septae.
18 DERMATOPATHOLOGY

TABLE 1-8 Differential Diagnosis of "Normal Skin"

Superficial Fungal Infection
Dermatophytosis and tinea versicolor Hyphae and spores in stratum corneum
Porokeratosis Cornoid lamella
lchthyosis Slight hyperkeratosis, diminished or absent granular layer
Hypopigmentation Diminished or absent basal layer melanin, melanocytes
Vitiligo
Piebaldism
Chemical leukoderma
Nevus depigmentosus
Hyperpigmentation Increased basilar melanin and possibly melanocytes
Cafe-au-lait macule
Freckle
Melasma
Lentigo
Macular amyloidosis Pink amorphous globules in papillary dermis
Pigment incontinence
Onchocerciasis Microfilaria in superficial dermis
Dermal melanocytosis Dendritic melanocytes in dermis
Urticaria pigmentosa Increased numbers of mast cells in dermis
Argyria Deposition of silver granules in basement membranes, particularly
surrounding eccrine sweat coils
Urticaria Sparse perivascular infiltrate
Edem a
Anhidrotic ectodermal dysplasia Absence of eccrine sweat glands
Anetoderma Focal or diffuse absence of elastic tissue
Inflammation present or absent
Cutis laxa Absence of elastic fibers
Connective tissue nevus Increased or decreased collagen and/or elastin
Abnormal connective tissue
Dermal mucinosis Increased dermal mucin
Myxedema
Scleromyxedema
Atrophoderma Decreased thickness of dermis
Lipoatrophy Fat lobules diminished in size

or atrophy of the reticular dermis, alterations of elastic fibers, inflammatory cell type) due to the incorporation of automated
and deposition of materials such as mucin or amyloid. feature detection algorithms.

Effed of digital pathology Adjuvant marker studies for tumor diagnosis

The introduction of whole slide imaging and its reliance on a
fields-of-view approach may subtly change the practice pat-
terns in dermatopathology.9 Initial studies on the accuracy
of diagnosis with digital imaging have shown acceptable per-
formance for most lesions.10 As digital slide imaging becomes
more common in routine diagnostic histopathology, it may
result in a more formalized approach to enumerating diag-
nostic elements (eg, recording the location and density of each
In most cases, pattern recognition skills gained with expertize
are sufficient to diagnose common skin neoplasms without
additional studies. However, recent advances in new biomark-
ers, genetics, and genomics have had a great impact in the
diagnosis of melanocytic lesions. The techniques increasingly
helpful in delineating atypical melanocytic nevi from mela-
noma are array comparative genomic hybridization 11 and pan-
els of proliferation/cell cycle immunomarkers,12 with genomic
 Chapter 1 INTRODUCTION TO MICROSCOPIC INTERPRETATION
signatures13 and next-generation sequencing methods14 show-
ing promise.
Techniques to further characterize
inflammatory infiltrates
As described above, patterns of infiltration can help in defining
the differential diagnosis(es) based on morphology alone. The
introduction of digital slide imaging and feature analysis may
lead over time to more precise enumeration of inflammatory
cell types/ but currently routine histology is sufficient to gener-
ate the appropriate differential diagnosis.
Adjunct immunohistochemical characterization is most
useful for dense dermal lymphoid infiltrates, with CD20+
B-cell-rich infiltrates warranting consideration of B-cell lym-
phoma (versus cutaneous lymphoid hyperplasia) whereas
mixed or predominantly CD3+ T-cell infiltrates may support
autoimmune or infectious causes or reactive conditions such as
arthropod bite reaction.
With superficial lymphoid infiltrates showing epidermal or
adnexal infiltration, CD4 and CDS immunostains can often
assist in classification. A predominance of CD4+ T cells sug-
gests spongiotic dermatitis or early cutaneous T -cell lym phoma5
whereas CDS-rich infiltrates are more common in psoriasis and
drug reactions. Molecular diagnostics, particularly T -cell and
B-cell PCR studies to assess for clonality, are useful whenever
infiltrates harbor atypical lymphoid cells since immunostaining
is not definitive for lymphoma.
As immunotherapies play an increasingly important role
in treatment of autoimmune disorders and cancer, more pre-
cise multianalytic profiling oflymphocyte subsets may become
important to classify drug reactions. These investigational
techniques include improved digital image analysis algorithms
( eg, automated, continuous, and quantitative analysis of tissue
microarrays) for typing the activation state of specific lymphoid
populations 15 and multiparameter phenotyping by mass cytom-
etry employing time-of-flight (CyTOF) methods. 16
REFERENCES
1. Ackerman A, Boer A, Bennin B. Gottlieb G. Histologic Diagnosis of
Inflammatory Skin Diseases: A Method of Pattern Analysis. 3rd ed.
Philadelphia, PA: Lea & Febiger; 2005.
19
2. Duncan LM, Berwick M, Bruijn JA, et al. Histopathologic recognition
and grading of dysplastic melanocytic nevi: an interobserver agree-
ment study. J Invest DermatoL 1993;100(3):S318-21.
3. Ackerman AB. Differentiation of benign from malignant neoplasms
by silliouette. Am J Dermatopathol. 1989;11 (4) :297-300.
4. Vyas NS, Markow M, Prieto-Granada C, et al. Comparing whole slide
digital images versus traditional glass slides in the detection of com-
mon microscopic features seen in dermatitis. I Pathol Informatics.
2016;7:30.
5. Ferrara G, Di Blasi A, Zalaudek I, et al Regarding the algorithm for
the diagnosis of early mycosis fungoides proposed by the International
Society for Cutaneous Lymphomas: suggestions from routine histopa-
thology practice. JCutaneous Pathol. 2008;35(6):549-553.
6. Wong C, Peters M, Tilburt J, et al. Dermatopathologists' opinions
about the quality of clinical information in the skin biopsy requisition
form and the skin biopsy care process: a semiqualitative assessment
American J Clinic Pathol. 2015; 143(4):593-597.
7. Trotter MJ, Au S, Naert KA. Practical strategies to improve the clin-
ical utility of the dermatopathology report Archiv Path & Lab Med.
2016;140(8):759-765.
8. Brownstein MH, Rabinowitz AD. The invisible dermatoses. J Am Acad
Dermatol. 1983;8(4):579-588.
9. Onega T, Reisch LM, Frederick PD, et al. Use of digital whole slide
imaging in dermatopathology. J Digital Imaging. 2016;29(2):243-253.
10. Kent MN, Olsen TG, Feeser TA, et al. Diagnostic accuracy of virtual
pathology vs traditional microscopy in a large dennatopathology
study. JAMA Dermatol. 2017;153(12):1285-1291.
11. Wang L, Rao M, Fang Y, et al. A genome-wide high-resolution array-
CGH analysis of cutaneous melanoma and comparison of array-CGH
to FISH in diagnostic evaluation. JMol Diagn. 2013;15(5):581-591.
12. Cho-Vega JH. A diagnostic algorithm for atypical spitzoid tumors:
guidelines for immunohistochemical and molecular assessment. Mod
Pathol. 2016;29(7):656.
13. Clarke LE, Flake DD, Busam K, et al An independent validation of a
gene expression signature to differentiate malignant melanoma from
benign melanocytic nevi. Cancer. 2017; 123(4):617-628.
14. Wiesner T, Kutzner H, Cerroni L, et al. Genomic aberrations in spit-
zoid melanocytic tumours and their implications for diagnosis, prog-
nosis and therapy. Pathology. 2016;48(2):113-131.
15. Kluger HM, Zito CR. Barr ML, et al. Characterization ofPD-Ll expres-
sion and associated T-cell infiltrates in metastatic melanoma samples
from variable anatomic sites. Clin Cancer Res. 2015;21(13):3052-3060.
16. Yao Y, Liu R. Shin MS, et al. CyTOF supports efficient detection
of immune cell subsets from small samples. J Immunol Methods.
2014;415;1-5.
Spongiotic
Dermatitis
Preeti Jhorar • Michael Murphy • Jane M. Grant-Keis
INTRODUCTION
The term "spongiotic dermatitis• refers to a large group of
inflammatory disorders that share the histopathologic find-
ing of spongiosis, characterized by impairment of cohesion
between epidermal keratinocytes and intercellular edema
(Fig. 2-1 and Table 2-1). Spongiosis is the hallmark of ecze-
matous dermatitides but can be seen in a variety of other skin
conditions (Table 2-2). Both T lymphocytes and keratinocytes
are thought to play major roles in the pathogenesis of spongi-
otic dermatitis. 1.i Skin-infiltrating T cells damage the epidermis
by releasing pro-inflammatory cytokines and induce keratino-
cyte apoptosis through "killer molecules.•i.i There is subse-
quent cleavage of adhesion molecules, including E-cadherin,
on keratinocytes.1.i Accumulation of extracellular fluid results
in widening of the spaces between keratinocytes, causing the
epidermis to resemble a sponge histologically.1.z
Other terms used to refer to these diseases include "eczema;
"eczematous dermatitis; and simply "'dermatitis." The clinical
appearance of the spongiotic dermatoses can vary significantly,
depending on the duration, etiology, and location of the lesions,
the presence ofsuperimposed secondary changes such as excori-
ation, and prior/concurrent therapy. However, the salient clin-
ical finding is that of epidermal alteration. These primary and
secondary epidermal changes may include vesiculation, scaling,
crusting, lichenification, hyperpigrnentation, excoriation, ooz-
ing, erosions, or fissures. Most lesions of spongiotic dermatitis
are poorly demarcated clinically, with the notable exceptions of
numm.ular dermatitis (round. well-defined, coin-shaped plaques)
and some lesions of contact dermatitis. Collectively, the spongi-
otic dermatoses are among the most common cutaneous disor-
ders presenting to dermatologists and primary care providers.
Spongiotic dermatitis is conventionally divided into acute,
subacute, and chronic stages (Table 2-3). A single lesion may
evolve through these three stages; however, not all lesions do
this. The c:lassic example of acute spongiotic ekrmatitis is acute
allergic contact dermatitis, such as that caused by exposure to
poison ivy. Acute spongiotic dermatitis is characterized histo-
Iogically by significant intercellular edema with formation of
spongiotic microvesicles or even macrovesicles (that can be
seen clinically) (Figs. 2-2 and 2-3). An associated superficial
perivascular inflammatory infiltrate composed oflymphocytes,
histioc:ytes, some eosinophils, and occasionally extravasated red
blood cells is noted. Papillary dermal edema may also be prom-
inenl The stratum c:orneum may still be normally c:ornified
CHAPTER 2
without parakeratosis. The clinical lesion reflects these histo-
logic features, appearing as edematous, inflamed, oozing pap-
ules and plaques, often with visible vesicles. A lesion ofsubacute
spongiotic ekrmatitis usually demonstrates spongiosis with
formation of some microvesicles and overlying parakeratosis
(Figs. 2-4 to 2-6). Mild epidermal uanthosis may be a feature.
A superficial perivascular inflammatory infiltrate composed of
lymphocytes, histiocytes, with or without eosinophils is present
in the dermis, but papillary dermal edema is not a prominent
feature. Good examples of subacute spongiotic dermatitis are
lesions of atopic dermatitis and nummular dermatitis present
for several weeks. Clinically, these lesions are scaling, pink.-to-
red papules and plaques, often with secondary changes such
as excoriation. Many lesions of subacute spongiotic derma-
titis become chronic (such as atopic dermatitis) (Figs. 2-7 to
2-9). Chronic spongiotic dermatitis describes lesions that have
been present for some time and demonstrate changes of repair
and/or secondary features, in addition to spongiosis. Chronic
spongiotic dermatitis can show compact hyperkeratosis,
acanthosis with hypergranulosis, spongiosis, and sometimes
papillary dermal fibrosis due to chronic rubbing (Fig. 2-10).
Spongiosis is usually minimal and only focal in chronic lesions.
These lesions present as lichenified, firm papules and plaques
with accentuation of skin lines and often with postinfiamma-
tory pigmentary changes (hyperpigmentation more commonly
than hypopigmentation).
The most common inflammatory cells identified in the
spongiotic epidermis are lymphocytes, often in association
with Langerhans cell microvesicles (Fig. 2-11 ), but as discussed
later in this chapter, other cells may predominate, including
eosinophils and/or neutrophils, resulting in changes of eosin-
ophilic spongiosis and neutrophilic spongiosis, respectively. A
PAS (and/orGMS) stain to excludedennatophytoses should be
performed in all biopsies showing spongiosis, particularly those
associated with neutrophil e:xocytosis (Fig. 2-12).
SECONDARY CHANGES
Because spongiotic dermatoses are often pruritic, secondary
changes are common. The most frequently identified second-
ary changes seen in association with spongiosis include (a)
superimposed infection; (b) lichenification/lichen simplex
cluonicus, secondary to chronic rubbing (Fig. 2-13 and 2-14);
(c) prurlgo nodularis, secondary to chronic picking (Fig. 2-15);
and (d) erosion or ulceration, secondary to excoriation.
 Chapter 2 SPONGIOTIC DERMATITIS 21

Spongiotic Dermatitis

1
Proliferation of the
mpetficial vascular
plexus, thickCIJai
vessel walls, variable
amount of lymphocytic
infiltrate, hemorrhage,
and hcmosiderin-laden
macrophages:
Chronic Italia dermatitis
Acromiiodermatitis
1
Superficial perivascular
l~ocylic infiltrate with
hcmmrhagc md/or
bemosiderin-
Wien IIlllCrophages:
Pigmentm purpuric
dc:rmatosis (eczematous
variant ofDollC8S and
Kapetanalris)
1
Supedicial and deep Wedge-llhapc4
1 1
Supedicial perivascular
perivascular lymphoid infiltrate, superficial and deep lympbtlid infiltrate and
tightly cuffed "ccat-slcc:vc" perivascular lymphoid inlnepidamal or intra-
around ves11el: infiltrates with eosinophilll: corneal neutrophils:
Figurate erytbemas Hypenenaitivity reaction Seborrbeic dermatitis
to arthropod assaults Early or trcatm psoriasis
Dyskcratotic cells:
Sneddon-Wtlldnaon
Polymorphous light rcactioo disease
Photodrugn:action
Contact dermatitia
Many dyskttatotic cells and
(esp. irritant)
kttatinocytic atypia:
Phototoxic reaction

1
Superficial perivascular
lymphoid infiltrate with
or without cosinopbils
and large, well-formed
intniepidennal vesicles:
Pompholyx
Allergic contact dermatilis
Dyllllidrotic ccuma
l
Superficial perivascular
l
Superficial perivascular lymphoid
l
With intracomeal hypbal fOIIDll:
lymphocytic infiltrate infiltrate with or without eosinophils: Dennatophytosis
without eosinophih: Drug hypersemitivity rcactioo
With intracomeal gram-positive
Pityriaaia lichenoi.dcs chrooica Atopic dermatitis cocx:i:
Polymorphous eruption of pn!gnmcy Nummular dermatitis Impetigo
Gianotti-Crosti 1yndrome Pityriaaia rosea (eapecially inllllllllillllory variant) With plasma cells and
Early myc01il fungoide& Grover's dUeasc: (spongiotic variant) endothelial cell swelling:
Idn:action Secondary syphilil

Hypenenaitivity reaction ID arthropod assault

FIGURE 2-1 Algorithm for spongiotic dermatitis.

Patients chronically rub itchy spongiotic dermatoses. As a CONTACT DERMATITIS

result, the skin clinically becomes thickened and papular with
accentuation of normal skin markings, hyperpigmentation, and
scaliness (Table 2-4).
Superimposed infection or secondary impetiginization is
not an infrequent complication. This change is secondary to the
scratching of these often intensdy pruritic eruptions. The resul-
tant bacterial infection overlying the changes of the spongiotic
dermatitis results in abundant scale-crust laden with bacteria
that can be identified on routine staining and highlighted with a
Gram stain. In more severe cases, vesiculopustules may be iden-
tified. Eczema herpeticum (Kaposi varicelliform eruption) is an
extensive cutaneous vesicular eruption that can arise in patients
with pre-existing spongiotic/eczematous dermatoses, usually
atopic dermatitis. It is caused by a viral infection, typically her-
pes simplex virus (HSV).
EOSINOPHILIC SPONGIOSIS
Eosinophilic spongiosis describes a reaction pattern in which
there is exocytosis of eosinophils associated with changes of
spongiosis (Figs. 2-16 and 2-17).3~ These changes can be seen
in a variety of inflammatory dermatoses, described in other
chapters (Table 2-5).
NEUTROPHILIC SPONGIOSIS
A heterogeneous group of dermatoses can demonstrate neu-
trophilic spongiosis {Figs. 2-12, 2-18, and 2-19), described as
the presence of neutrophil exocytosis with epidermal spongi-
osis (Table 2-6).4•7•8 Occasionally, neutrophils can form collec-
tions within the epidermis (ie, spongiform pustules).
Contact dermatitis describes an inflammatory skin reaction to an
exogenous agent Two variants have been described: (1) allergic
contact dermatitis and (2) irritant contact dermatitis (ICD).9- 16
Allergic contact dermatitis (ACD) is a delayed type N hypersensi-
tivity reaction in the skin of a patient who has been previously sen-
sitized to an allergen. Common allergens include nickel, urushiol
(poison ivy), and topical medications, including local anesthetics
and topical antibiotics. ICD is due to exposure to chemical or
physical agents that induce direct (nonimmunologically medi-
ated) damage to the skin. Common offending agents include
detergents, soaps, some sunscreens, acids, and alkalis. ICD is the
most common mechanism of occupational hand dermatitis. Irri-
tant contact dermatitis occurs more quickly after exposure, tends
to resolve more quickly, and is more common than ACD, but it
may be difficult to distinguish allergic and irritant contact der-
matitis from each other or from other spongiotic dermatitides on
the basis of clinical or histopathologic features. In addition, some
agents may act as both an irritant and an allergen.
Allergic contact dermatitis
Clinical Features
The skin changes are often localized, with the distribution of
the lesions providing clues to the diagnosis and potential etio-
logical agent(s) (Table 2-7).
Patients usually have a history of contact with an allergen
prior to the cutaneous eruption. Clinical lesions vary depending
on the nature and concentration of the allergen and duration of
contact. Mild skin erythema, erythematous scaly papules and
plaques, vesiculobullous lesions, or any combination of these
changes can be seen (Fig. 2-20A).
22 DERMATOPATHOLOGY

TABLE 2-1 Differential Diagnosis of Spongiotic Dermatoses

ENTITY DISTINGUISHING H1STOLOGIC FINDING

Allergic contact dermatitis Eosinophilic spongiosis

Irritant contact dermatitis
Photoallergic contact dermatitis
Phototoxic dermatitis
Dermal/protein contact dermatitis
Atopic dermatitis
Fox-Fordyce disease
Nummular dermatitis
Pompholyx
Seborrheic dermatitis
Id reaction
Asteatotic eczema
Sulzberger-Garbe syndrome
Pityriasis rosea
Exfoliative erythroderma
Stasis dermatitis
Spongiotic drug eruptions
Pityriasis alba
Gianotti-Crosti syndrome
Polymorphic eruption of pregnancy
lncontinentia pigmenti
Miliaria
Spongiotic micro- and macrovesiculation
Collections of intraepidermal Langerhans cells
Follicular spongiosis and exocytosis of lymphocytes into the
follicular infundibulum
Neutrophils
Ballooning
Necrosis
Eosinophilic spongiosis
Necrotic keratinocytes
Sunburn (necrotic) keratinocytes
Pallor of keratinocytes
Neutrophils
Prominent papillary dermal edema
Epidermal acanthosis
Prominent vasculature
Secondary changes of lichen simplex chronicus
Follicular infundibular spongiosis
None
Vesiculopustules
Parakeratosis at lips of follicular ostia
None
None
Genital skin
Mounds of parakeratosis
Extravasated red blood cells
Depends on underlying disease
Lobular capillary proliferations
Extravasated red blood cells
Hemosiderin deposition
Fibrosis
Spongiotic ± interface changes
Necrotic keratinocytes
Eosinophils
Follicular spongiosis
Perifollicular parakeratosis
Decreased melanization in basal layer
Reduction in basal melanocytes
Melanophages
Spongiotic ±interface changes
Lymphocyte exocytosis
Papillary dermal edema
None
Eosinophilic spongiosis
Dyskeratotic squamous cells
Involvement of eccrine duct
 Chapter 2 SPONGIOTIC DERMATITIS 23

be present in the stratum corneum. With time, the pathol-

TABLE 2-2 Skin Diseases in which Spongiosis May
Be Seen (Other than Eczematous Dermatoses)
Dermatophytosis
Erythema neonatorum
Grover's disease, spongiotic variant
Gyrate erythemas
Lichen striatus
Mycosis fungoides
Para psoriasis
Pigmented purpuric dermatoses
Pityriasis lichenoides
Polymorphous light eruption
Primary syphilis
Psoriasis, early or treated
Reaction to arthropod assault
The rash may become generalized if autoeczematization
(id reaction) occurs. Long-standing lesions usually show skin
thickening with scaling and accentuation of skin markings
(lichenification). The diagnosis can be confirmed by patch test-
ing, and lesions typically resolve with avoidance of allergens.
Histopathological Features
ACD is the prototypic spongiotic reaction pattern. Acute,
subacute, and chronic stages of disease can be seen, depend-
ing on the duration of contact with the offending allergen and
correlating with the clinical features. The earliest changes are
seen in the superficial dermis, with a perivascular lymphohis-
tiocytic and sometimes eosinophilic inflammatory infiltrate
and papillary dermal edema. This is followed by exocytosis of
inflammatory cells into the epidermis with varying degrees of
intercellular edema, often associated with spongiotic microve-
siculation (Figs. 2-20 and 2-21). Intraepidermal collections
of Langerhans cells may be prominent in ACD (Fig. 2-11).17
Parakeratosis with inflammatory cell debris and serum may
ogy reflects a progressive reduction in epidermal spongiosis,
with irregular (nonpsoriasiform) epidermal hyperplasia and
fibroplasia of the superficial dermis.
Irritant contact dermatitis
Clinical Features
In addition to bum-type reactions, necrosis, and ballooning
(intracellular edema), all three spongiotic (acute, subacute, and
chronic) patterns can be seen. Similar to ACD, skin lesions are
typically localized but may become generalized. Lesions may
be prevented if the irritant is identified and avoided or contact
reduced.
Histopathological Features
If the irritant is applied in sufficient concentration, the epidermis
will show ballooning degeneration of keratinocytes with necro-
sis in addition to changes ofkeratinocyte regeneration. At lower
irritant concentrations, acute, subacute, and chronic spongiotic
patterns can be seen, depending on the duration of exposure.
Histologic clues to distinguishing ACD from ICD are:
1. Variable presence of aggregates ofintraepidermal Langer-
hans cells17 and/or eosinophils and predominance of
spongiosis in ACD. The presence of collections of Langer-
hans cells favors ACD (Fig. 2-11).
2. Follicular spongiosis and exocytosis of lymphocytes into
follicular infundibulurn favor ACD over ICD but raise dif-
ferential diagnosis of follicular atopic dermatitis.18
3. Variable presence of neutrophils and ballooning in ICD
(Fig. 2-19).
Hand dermatitis
Hand dermatitis is one of the most common presenting com-
plaints among patients attending dermatology clinics. 19 "Hand
dermatitis" is a term loosely used to encompass palmar psoria-
sis (PP), hand eczema (HE), and hyperkeratotic hand dermatitis
(HHD). All these entities can be very disabling and negatively
affect a patient's quality of life. Therefore, it is important to
make the correct diagnosis in order to initiate the appropriate

TABLE 2-3 Histopathologic Features in Spongiotic Dermatitis

5UBACUTE 5PONGIOTIC CHRONIC 5PONGIOTIC

ACUTE SPONGIOTIC DERMATITIS DERMATITIS DERMATTTIS

Stratum corneum Often normal; sometimes Parakeratosis and Compact

parakeratosis, scale-crust scale-crust hyperkeratosis
Epidermal acanthosis None to minimal Mild to moderate Moderate to marked
Spongiosis Mild to marked Mild to moderate Minimal to absent
lntraepidermal microvesicles Yes Yes No
± macrovesicles
Dermal perivascular Lymphocytes and Lymphocytes and Lymphocytes and
inflammation eosinophils eosinophils histiocytes
Papillary dermal edema Minimal to marked Minimal No
Papillary dermal thickening No No Yes
to fibrosis
24 DERMATOPATHOLOGY
FIGURE 2-Z Acute spongiotic dermatitis. Marked epidermal
intercellular edema with spongiotic microvesicles and
superficial perivascular lymphocytic infiltrate. The stratum
comeum shows normal basket weave pattern.
FIGURE 2..3 Acute sponglotrc dennatrtrs. Marked epidermal
intercellular edema, micro and macrovesicles, and superficial
perivascular lymphocytic and eosinophilic infiltrate. There is
focal parakeratosis.
FIGURE 2-4 Subacute spongiotic dermatitis. Parakeratosis,
slight epidermal acanthosis, minimal spongiosis, and
occasional lymphocyte exocytosis.
FIGURE 2-S Subacute spongiotic dermatitis. Mounds
of parakeratosis, slight epidermal acanthosis, spongiosis
with Langerhans microvesicle, and superficial perivascular
lymphocytic infiltrate.
FIGURE 2-6 Subacvte spongfotlc dermatitis. Parakeratosis,
scale crust, slight epidermal acanthosis, intercellular
spongiosis, and superficial perivascular lymphohistiocytic
infiltrate.
FIGURE 2-7 Chronfc sponglotlc dennattds. Compact
hyperkeratosis, parakeratosis, slight hypergranulosis,
epidermal acanthosis, and spongiosis.
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have a perfect right to do as they please in such matters. You must
not take it up personally.”
The speech was not judicious. Cicely raised her head proudly;
there came an unusual light into the soft eyes, the lines about the
gentle mouth grew hard.
“A perfect right,” she repeated. “Yes, of course they have a perfect
right to give a ball whenever they please. But they have no right to
expect me to go to it. I am engaged to their son certainly, but if they
disregard my feelings and consider me no more than a stranger, it
leaves me free to behave like one. How could I wish to go to a ball?
Think of what sorrow we have had so lately—think of my father’s
state oh! mother, it is most inconsiderate.”
“My dear, you are hardly reasonable,” said Mrs. Methvyn. “You
are very honest, Cicely,” she went on. “Tell me, dear, is it not partly
that you are hurt at not having been consulted about it at all, at not
having been asked if the idea of such a thing was pleasant to you?”
Cicely was silent for a little. Then she said slowly, “Yes, I think it is
partly that. But I don’t think it is from any small or mean feeling of
vexation at not being consulted. It is that it seems to me that Trevor
is different.”
“Wait till to-morrow,” said Mrs. Methvyn sagely. What she had said
had done some good. It inclined Cicely to restrain her first
vehemence of feeling, to receive more gently Mr. Fawcett’s
explanation of what had led to this unexpected piece of dissipation. It
sounded simple enough when, as Cicely expected, he came the next
morning to talk it over with her. They had been speaking about balls,
he said, one evening at Eastbourne, and Geneviève, who (though in
some mysterious manner she had learnt to dance) had never been
at any entertainment of so “wholly worldly” a kind, had expressed
with girlish eagerness her intense wish to assister at a real ball. Half
in joke, half in earnest, the idea had been mooted; Sir Thomas, who
Trevor declared had altogether lost his heart to his pretty visitor, had
taken it up and promised to open the ball with her himself, “and,”
said Mr. Fawcett in conclusion, “the day was fixed for the twentieth of
October, my birthday, you know, Cicely.”
 “Yes,” said Cicely, “I remember.”
Her tone of voice aroused Trevor’s misgivings.
“Don’t you like the idea of a ball, Cicely?” he asked. “I am sure
you used to like dancing, especially in the country. And I thought you
would have been glad for Geneviève to be pleased.”
“Her notions of pleasure and mine differ,” said Cicely coldly, “if she
can find it in amusing herself in a way her parents would disapprove
of.”
“Rubbish,” said Mr. Fawcett. “What can they know about it? They
would not expect Geneviève to behave differently from other people.
She is ‘at Rome’ now, and they must take the consequences of
sending her there.”
“I am not dictating anything to Geneviève,” said Cicely more
gently; “she must judge for herself. As to my own feeling about it, I
confess to you, Trevor, I would have much preferred not taking part
in anything of the kind at present, but—”
“But what?” said Mr. Fawcett.
“If you wish it, I will try to dismiss the feeling I have,” she
answered.
“If I wish it. Cicely, you speak as if I were an unfeeling tyrant. It is
not fair to me, upon my soul it isn’t,” said Trevor, working himself up
into vexation. “No one felt more for you than I did last spring, but you
cannot shut yourself up for ever.”
“It is not only that,” said Cicely. “I have other feelings—my father’s
state of health, my having to leave him so soon—all these things
make me sad. But I dare say it is wrong to feel so. Dear Trevor, don’t
be vexed with me. I will try and enter into it cheerfully. If I had been
with you and could have talked it over with you and your mother
before, it would have been all right.”
“I wish you had been with us when it was first proposed. You don’t
know how I wished for you at Eastbourne, Cicely,” exclaimed Trevor.
 Cicely looked up at him affectionately. For the moment their old,
happy relations seemed to have returned—the vague, painful feeling
“that Trevor was different,” which of late had so often troubled her,
melted away. And for the rest of that day Cicely’s brow looked clear,
and her eyes had a smile in them.
But Geneviève’s brilliant spirits seemed already to have received
a check. She was tired, she told Cicely, she thought one always felt
so the day after a railway journey more than at the time.
“Are you too tired to talk about what you will wear at the Lingthurst
ball?” said Cicely brightly. “Mother wants us to have very pretty
dresses, and I am going to order them from town; so we must have a
grand consultation, Geneviève.”
Geneviève looked up in amazement.
“I thought you were angry about it—I almost thought you would
say you would not go,” she exclaimed.
Cicely was silent for a moment. Then she said quietly,—“It is true I
was surprised, and not pleased at the idea of it last night. But I think
it was unreasonable of me, and I am sorry for having chilled your
pleasure in it.”
“You are very good, Cicely,” said Geneviève. “I wish I were as
good as you.”
She sighed. Cicely looked at her with some surprise.
“You are not to go off into a fit of low spirits, Geneviève,” she said,
in a rallying tone. “I am not good when I am cross—the least I can do
is to say I am sorry, isn’t it? But if you look miserable it will be like a
reproach to me. I was so pleased to see you so bright and merry last
night. Now tell me about your dress. What would you like it to be?”
“White,” said Geneviève decidedly. “It is as it were my first ball,
you see, my cousin.”
“Yes,” said Cicely drily. “I suppose you did not go to balls at
Hivèritz?”
 “No,” replied Geneviève, in the most matter-of-fact tone. “Papa
being a pasteur, you understand, it would hardly have been
convenable that I should go to balls there.”
“And what will your parents say to your going here?” inquired
Cicely.
“Oh! I don’t think I shall say anything about it,” answered
Geneviève carelessly. “Not that I think mamma would object—she
has placed me under the care of my aunt—it is not for me to dictate
to your mother, Cicely.”
Cicely did not contradict her, and Geneviève proceeded to
discuss the important question of her dress. She warmed into
enthusiasm on the subject, quite astonishing her cousin by her
display of millinery lore and perfect acquaintance with the
requirements of the occasion.
“I can hardly believe you have never been at balls, and all sorts of
things of the kind, Geneviève,” she exclaimed at last. “Where did you
learn to dance?”
“There was a class at the pension where I went. I used to watch
them and then try by myself afterwards,” said Geneviève. “It is quite
simple. Mr. Fawcett says I dance very well.”
“Trevor!” exclaimed Cicely. “How does he know?”
“Oh! we only tried once—là-bas—at Eastbourne, I mean, when
the band was playing a waltz before our windows,” said Geneviève
hastily. “Tell me, Cicely,” she went on quickly, “who will there be at
the Lingthurst ball that I shall know. Will Mr. Guildford be there?”
“No, I am sure he will not,” replied Cicely. “He has other things to
do.”
“But he comes here very often. He can not be very busy,” pursued
Geneviève. “My aunt tells me he has been here three—four times in
the week.”
“He doesn’t come here for pleasure—it is perfectly different,”
answered Cicely coldly.
 “Is it? Ah! yes, I see. He comes here but as my uncle’s doctor,”
said Geneviève so innocently that Cicely felt ashamed of the slight
feeling of annoyance which her cousin’s remarks aroused in her.
“I wonder if she has heard Trevor speak of Mr. Guildford in that
foolish way,” she thought to herself. “Trevor should be careful.
Geneviève does not understand—she will be treating Mr. Guildford
as if he were beneath her.”
But her fears were misplaced. When Mr. Guildford came the next
day, Geneviève made herself as charming as ever. She smiled and
blushed more than she talked, it is true; but once or twice Cicely
caught Mr. Guildford’s eyes resting upon her in a way which awoke a
new feeling in her mind. “Does he really care for her?” she said to
herself uneasily. “He, so clever and good. Is she worthy of it?”
She felt more than ever that she could not understand Geneviève.
There were times at which it seemed to her that a creature more
artless and ingenuous could not exist—that the feeling of
bewilderment about her must arise entirely from her own in ability to
be carelessly, childishly transparent like this sunny little fairy. Then
again a sudden glimpse of something very like calculating
selfishness on Geneviève’s part would startle her into perplexity
again, and then would follow a fit of disgust at her own
suspiciousness.
“Do you understand Geneviève, Trevor?” she asked Mr. Fawcett
one day. It was the very day before the ball. They had been at
luncheon at Lingthurst, discussing and admiring the all but
completed arrangements, and Trevor had walked home with Cicely.
Geneviève had been invited to come with them, but for some reason
that Cicely was at a loss to explain, had refused to do so, and had
driven home with her aunt.
“Do you understand her?” Miss Methvyn repeated, for Mr. Fawcett
had not seemed to hear her question the first time.
Trevor started. “What are you saying, Cicely?” he exclaimed. “Do I
understand Geneviève? Of course, I do. You are always diving into
unknown depths or soaring into the clouds, my dear child. Please
remember that other people find it fatiguing. You must be at a loss
for a subject of speculation if you are going to make one of poor
Geneviève—she is just a sweet, simple little creature, very
affectionate, and not very wise, and perhaps a little vain; which is
certainly excusable. There is not much to understand about her.”
“Is that it?” said Cicely thoughtfully. She had listened attentively to
what Trevor said, looking up into his face with a questioning,
somewhat anxious expression in her eyes. Somehow it annoyed
Trevor. He began kicking the pebbles on the path impatiently. But
just for the moment, Cicely was too intent on what she was saying to
observe his irritation.
“I wonder if it is so,” she repeated consideringly. “Sometimes I feel
as if she were perfectly artless and sweet and unselfish. And then
she says and does things that I don’t like, or rather that I don’t
understand. To-day for instance.”
“What did she do to-day?” said Trevor sharply. “I declare Cicely
you are just as bad as other women after all—everlastingly picking
holes in each other—especially if “each other” has the misfortune to
be bewitchingly pretty!”
The sneering tone as well as the unkindness of the speech
wounded Cicely to the quick. She turned her face away, and walked
on without speaking.
“Cicely,” said Mr. Fawcett in a minute or two.
No answer.
“Cicely,” he repeated.
“What, Trevor?” she said gently. Her tone was sad, but nothing
more.
“What are you offended at?” he asked. “I did not in the least mean
to vex you—you might know that—but you take up things so hastily
now. You, who used to be so sweet-tempered.”
His words touched her. Cicely’s conscience was very tender.
 “Am I ill-tempered?” she said anxiously. “You never used to think
me so, but perhaps it is true. I don’t understand myself now, it seems
to me, so I should not be hard upon Geneviève.”
“That’s just it,” said Trevor. “You are hard upon her, Cicely, and I
have always thought so. What was it that she did to vex you to-day?”
“I would much rather not speak about it any more,” said Cicely. “It
only makes you think me unkind, and perhaps I am fanciful.”
“No, I won’t think you unkind. Do tell me. I want to know what it
was.”
“It was when we were talking about to-morrow. Something was
said about your dancing first with me, and you said I must certainly
keep half-a-dozen dances for you, as it was so long since we had
had any, Don’t you remember?”
“Well? Yes, I think I do.”
“Geneviève was beside me at the time. When I turned round to
speak to her, she would not answer me. Then all of a sudden she
muttered something about wishing she had never come here. And
when you went away, and I asked her what was the matter, she
began to cry, and accused me of unkindness and selfishness and all
sorts of things. She was just offended at not being made first in
everything. And I have tried to make her happy, Trevor.”
“She is a spoilt child,” said Trevor carelessly, “but you need not
trouble yourself so much about her. When we are married, Cicely,
and she has it all to herself at Greystone, she will be all right, you will
see.”
“Then you do think she dislikes me, Trevor?” said Cicely quickly.
“That is the feeling I don’t understand. She almost seems—I don’t
like saying so—but she almost seems jealous of me.”
Trevor laughed, but his laugh was not hearty.
“Really, Cicely, you must not take things up so seriously,” he said.
His tone was not unkind this time, however. They were close to the
Abbey grounds, and Trevor stopped as if about to turn back.
 “I must go home again now, I think,” he said. “Good-bye, Cicely.
You will give me the first dance to-morrow, and half-a-dozen others,
even if Mademoiselle Geneviève is offended, won’t you?”
Cicely smiled. “I think I can brave her displeasure,” she said.
“Good night, Trevor; you won’t come in?”
“I can’t,” he replied. “My mother begged me to come back soon.
Miss Winter and I will be kept at work all the evening, I expect, for
my mother is never satisfied with anything till it has been undone and
then put back again as it was originally. Good night.”
He strode away. Cicely stood watching him for a minute, then
taking the key from her pocket, she unlocked the little door near
which she was standing, and passed through into the park. How
many times she had done so in her life; how far from her thoughts it
was just then that this might be the last time she would pass through
that little old doorway; how seldom any of us think that to even the
commonest and most familiar actions of our daily lives there must
come a “last time!” A last time in many cases not known to be such,
till looked back upon from the other side of some sudden crisis in life,
or sometimes, it must be, from the farther shore of the dark river
itself. And it is well that it should be so. We could make no progress
in our journey were we constantly to realise the infinite pathos
attending every step; we should sink fainting by the way did we
suspect the mines of tragic possibilities over which we are ever
treading.
When Cicely entered the hall she met Geneviève, who was
crossing it on her way to the library.
“Have you come back alone?” she said quickly, when she saw
that there was no one with her cousin.
“Oh! no; Trevor came to the park door with me,” replied Cicely.
“He had to hurry back again. Have you and mother been home
long?”
“Yes, a good while. You have missed some one,” said Geneviève,
“Mr. Guildford has been here.”
 “Oh! I am so sorry; I wanted to see him!” exclaimed Cicely. “Why
would he not stay?”
“He saw my uncle,” said Geneviève shortly. “That was what he
came for. I told him where you were; he left no message.”
“I didn’t expect any message,” said Cicely, not quite
understanding Geneviève’s curious tone.
“Yes, you did,” answered the girl bitterly, “or you expected him to
wait for the chance of seeing you. You think you are to be queen of
all—if you are there no one must have a word, a glance! I have said I
loved you, that you were good; but I think not so now. I love you not.
You are cold and proud, and know not what love means, yet you
gain all! And I—I am miserable and alone, and who cares?”
“Geneviève, you must be mad! I do not know, and I do not wish to
know, what you mean. You have yielded to-day to temper till you
have completely lost your reason, that is the only excuse I can make
for you.”
Then Cicely walked quietly across the hall and down the passage
to the library, leaving her cousin standing alone. Geneviève did not
follow her. When Cicely had gone, she ran upstairs to her own room
and threw herself down upon the bed, sobbing bitterly.
Miss Methvyn found her mother in the library.
“Mr. Guildford has been here, Cicely,” said Mrs. Methvyn as she
came in.
“Yes, I know; Geneviève has just told me. I wish I had seen him. I
think he might have waited a few minutes.”
“He said he would; he seemed to want to see you,” said Mrs.
Methvyn. “I told him you would not be out long, and he seemed in no
hurry, and went out into the garden with Geneviève. Then, to my
surprise, in about a quarter of an hour he came in again suddenly
and told me he had just remembered an engagement at Sothernbay,
and that he could not possibly wait any longer. But he is coming
again to-morrow.”
 “To-morrow,” repeated Cicely. “Why should he come so soon
again!”
“I don’t quite know,” said her mother. “Cicely,” she went on
tremulously, “I am afraid he does not think your father quite so well.”
“Do you think so, dear mother?” said Cicely. “I hope not. You get
nervous. I wish I had been in.”
“So do I,” said Mrs. Methvyn. “I fancied from his manner that he
would have spoken more openly to you.”
“What did he say? Tell me exactly, mother,” said Cicely. Her voice
sounded calm, but inwardly a sort of icy tremor seemed to have
seized her. She would not tell her mother that even to her eyes a
slight change had been visible in her father for the last day or two;
she had tried to persuade herself that it was “only her fancy;” but she
had longed for Mr Guildford’s next visit with intense though
concealed anxiety. “Do tell me all he said,” she repeated.
“He did not say much. It was before he had seen Geneviève,”
replied Mrs. Methvyn. “After he had been with your father, he came
down here and asked when you would be in. Then he said he
thought your father rather “low” to-day, and that he had been trying
to persuade him not do so much—to get a proper man of business to
manage things, and not to worry himself. I think it is true, and I told
Mr. Guildford I agreed with him. I know Phillip has been annoyed the
last few days by some letters he got.”
“What letters? He never told me about them,” said Cicely.
“You would not have understood them. I do not. I only know they
were about money matters,” replied Mrs. Methvyn vaguely.
“Money matters,” said Cicely. “Oh! he really should not trouble
himself about things of that kind.”
She spoke more cheerfully. There was a certain relief in being
able to name a cause for her father’s depression. And to her happy
experience the expression “money matters” bore no terrible
significance. She was only thankful that his anxiety arose from no
more important cause.
 “No; I wish he would not,” sighed Mrs. Methvyn.
“Well, Mr. Guildford will be here to-morrow, and then we can talk it
over with him, and make papa do what we tell him,” said Cicely
brightly.
She was leaving the room when her mother recalled her.
“Cicely,” she said mysteriously, “do you know that there was
something very odd in that young man’s manner this afternoon?”
“How? what do you mean, mother?” replied Cicely. “You speak as
if he were going out of his mind.”
“Nonsense, my dear, you know quite well what I mean,” said Mrs.
Methvyn. “I really do believe he has got something in his head about
Geneviève. It was after he had seen her in the garden that he came
in and said he must go home at once.”
“But why should seeing Geneviève in the garden have made him
say so?” inquired Cicely.
“My dear, how can I tell? When people are in love, there is no
accounting for what they will do. Geneviève may have been cold to
him, or—he is a very modest young man—he may think we should
not approve of it, and may have been afraid of being tempted to say
something. Who can say? I only say that I feel sure he has got
something of the kind in his head.”
Cicely looked grave. “Perhaps he has,” she replied. To herself she
said, “I wonder why, if it is so, it should have made Geneviève so
desperately cross.”—“Mamma,” she added, after a little silence, “I
wish you would do something to oblige me.”
“What, my dear,” said Mrs. Methvyn in surprise.
“Please don’t call Mr. Guildford ‘a very modest young man.’”
CHAPTER X.
 FORGIVE ME, AND GOOD-BYE.

“Yet I will but say what mere friends say,

Or only a thought stronger; I will hold your hand but as long as all may,
Or so very little longer!”
R. Browning

IT was the day of the Lingthurst ball. Cicely woke early, and tried to
believe that she was in good spirits, and that her anxiety of the
evening before had been exaggerated and uncalled for. And when
her mother met her with the good news that Colonel Methvyn had
had a calm and undisturbed night, and seemed wonderfully
refreshed by it, the make-believe seemed something very like reality,
and Cicely’s face looked bright enough when she met her cousin in
the breakfast-room to satisfy Geneviève that her ebullition of the
previous day had been forgiven, if not forgotten, or that at least it
was to be tacitly ignored.
Geneviève was excited, but not happy. Some closeness of
observation is, however, required to discriminate between the two
conditions, and this neither of her companions was this morning
sufficiently at leisure to bestow upon her. So, “poor Geneviève is full
of her ball. I hope she will enjoy it,” thought Mrs. Methvyn; and
“Geneviève cannot have meant what she said yesterday. It must just
have been one of her childish little fits of temper, not worth noticing,”
was the decision Cicely arrived at.
“Your father is very anxious for his letters this morning,” said Mrs.
Methvyn, as they were sitting at breakfast. “I hope there will be
nothing wrong in them—nothing to upset him, when he seems so
much better.”
Just as she spoke the letter-bag was brought in. Mrs. Methvyn
opened it.
“Two for you, Cicely,” she said, as she distributed the budget; “one
for Geneviève, three for your father, all business letters I fear.” She
looked at them anxiously. “I wish we could keep them till Mr.
Guildford comes.”
“It would be no use. Papa would be sure to ask for them,” said
Cicely decidedly. “Give them to me, mother; I will take them up to
him myself.”
“Is Mr. Guildford coming to-day?” said Geneviève in surprise, as
her cousin left the room.
“Yes,” said Mrs. Methvyn; “he promised yesterday, when he had
to leave in such a hurry, that he would come again to-day.”
“Oh!” said Geneviève. Then, fancying her aunt looked at her
curiously, “I thought that he was so very busy,” she added
confusedly.
Cicely meanwhile was knocking at her father’s door. Her first tap
was unnoticed. She repeated it.
“Come in,” said Colonel Methvyn’s voice. To Cicely it sounded
very weak and feeble. “Oh! is it you, my dear?” he exclaimed when
he saw her. “I thought it was Barry with the letters.”
“I have brought them, papa,” said Cicely. “But I do so wish you
would not read them yet. They look like business letters, and they
always tire you so.”
She stooped and kissed him. He had had a good night Mrs.
Methvyn had said, but to Cicely’s eyes he looked sadly white and
frail this morning; his voice was tremulous, his hand shook as he
held it out for the letters.
“Give them to me, my dear child. I shall be more comfortable
when I have read them.”
He opened two of them and tossed them aside with indifference.
The third was a longer letter. Colonel Methvyn read it through once—
twice—then folded it up again and put it back carefully into its
envelope with a little sigh. Cicely watched him anxiously.
“Is it all right, papa?” she said. “Nothing to vex you, I mean?”
“Oh! no, it is all right enough,” he answered rather absently.
“Cicely,” he went on, after a little pause, “there will probably be a
telegram for me some time to-day. Don’t think of keeping it from me,
my dear. It would annoy me inexpressibly if you did so. Let it be
brought up at once. Tell your mother so.”
“Very well, papa,” replied Cicely. She leant over him and kissed
him again, then she went quietly downstairs.
Her mother looked up quickly as she re-entered the room.
“I don’t think there is anything particular in papa’s letters,” said
Cicely, in answer to her mother’s unspoken question. “But he says
there may be a telegram some time to-day, and he wishes it taken to
him at once.”
“I hope it won’t come,” said Mrs. Methvyn. “I don’t feel easy about
your father. He is doing far too much. How do you think he is looking
this morning, Cicely?”
“Pretty well,” replied Cicely. “What time do you think Mr. Guildford
will be here, mother?”
“Early—before luncheon, I fancy,” said Mrs. Methvyn. “You will not
be out today when he comes, my dear?”
 “Oh! no,” said Cicely. “I wish I knew what time he will be coming,”
she thought to herself, “I would walk part of the way to meet him.”
For since seeing her father her fears had revived. She felt certain
that Mr. Guildford must have thought unfavourably of him the day
before, otherwise he would not be coming again so soon; she felt
restless and unhappy, and longed with intense longing to express
her fears to the only person who could soothe or allay them; the
thought of the ball at Lingthurst grew hourly more distasteful to her.
“If only Geneviève could go alone,” she thought, “and mother and
I stay at home. But, of course, it would give offence—I must go.”
She could settle to none of her usual occupations, and at last she
determined to set off to meet Mr. Guildford. She looked in at the door
of her cousin’s room before going. Geneviève was laying out
betimes her costume for the evening, apparently perfectly happy in
the occupation; she looked up with a bright smile at the sound of
Cicely’s voice.
“Is not the effect of these flowers on the skirt beautiful, my
cousin?” she exclaimed, pointing to the mass of snowy clouds of
gauze that lay on the bed. “I only wish it were time to dress. I am all
impatience to put it on.”
“It is very pretty,” said Cicely kindly. “I am sure it will suit you
beautifully, Geneviève. I am going out for a little,” she went on,
“please tell mamma so if you hear her asking for me. I cannot disturb
her just now. She is in papa’s room. You don’t want to come out this
morning?”
“Oh! no, thank you,” said Geneviève, “I have twenty things to do. I
don’t like the bows they have put on my boots, they make the foot so
broad. I am going to arrange them again.”
“Well, good-bye then,” said Cicely, turning to go. Just then there
came a ring at the front-door bell. It sounded sharp and loud through
the quiet house.
“Who can that be?” exclaimed Geneviève.
“The telegram,” said Cicely. “I must go and see if it is.”
 “Stay a moment. I can tell you,” said Geneviève.
One of the windows of the room looked to the front, but the sill
was high and narrow. She drew a chair forward and stepped up on to
it. Cicely watched her in astonishment.
“What are you doing, Geneviève?” she exclaimed. “You can’t see
anything from there. You forget the porch.”
“Ah! but I can,” replied Geneviève triumphantly. She was by this
time mounted on the sill, craning her neck round in a peculiar
fashion. “You forget there is a window in the side of the porch. From
here, when I put my head so, I can see who stands at the door—
voilà! I found this out the first days I was here. Now I see. No, Cicely,
it is not the boy from the station. It is a tall figure, a gentleman. Can it
be Mr. Fawcett?”
She turned round with eager inquiry.
“No,” replied Cicely, “I don’t expect him to-day. Do come down,
Geneviève. It would look so strange if any of them saw you climbing
up there.”
She spoke rather coldly. Geneviève’s conduct jarred upon her.
She only waited till the little lady had accomplished her descent in
safety, and then went downstairs, to satisfy herself of the correctness
of her cousin’s information.
She was not long left in doubt. Parker was coming in search of
her—Mr. Guildford was in the library and had asked for her.
“How kind of him to come so early,” thought Cicely, trying to
believe that no thing but kindness was the motive for such prompt
fulfilment of his promise. “If he were really uneasy about papa, he
would certainly have waited to see me last night,” she said to herself,
as she entered the room; but, nevertheless, she looked strangely
pale, and the tremor in her voice was not quite imperceptible when
Mr. Guildford came forward to meet her. He shook hands somewhat
abruptly. Cicely glanced at his face. He too seemed discomposed;
he looked worn and tired, as if he had not slept all night. A terror
seized Cicely. “Has he come to break it to me? Does he think the
very worst?” were the thoughts that flashed through her mind. She
felt herself beginning to tremble so much that she sat down on the
nearest chair without attempting to speak.
Mr. Guildford did not seem to notice her agitation; he did not look
at her, but kept his eyes fixed upon the table beside which he was
standing.
“He is afraid of looking at me—he cannot make up his mind how
to tell me what he must,” thought Cicely, with a sort of shiver. But the
silent waiting at last grew unendurable; she felt that it must be
broken.
“It is very kind of you to have come so early,” she began. “I cannot
tell you how kind I think it.”
Mr. Guildford turned suddenly. “I came early on purpose,” he said.
“I was so afraid of missing you. But how ill you look, Miss Methvyn,”
he went on hastily. “Is there anything wrong? You look so dreadfully
pale. I am afraid I should not have asked to see you.”
Cicely’s pale lips quivered. “I am quite well,” she whispered.
“There is nothing wrong with me. I shall be all right again directly—
but, Mr. Guildford, I—I know why you have come this morning I know
what you have to tell me. Please don’t hesitate—it is better not. I
shall not be silly—you will see.”
She tried to smile, but hardly succeeded. Mr. Guildford looked at
her in amazement. “You know why I wanted to see you this morning,
Miss Methvyn?” he repeated. “You cannot. It is impossible that—that
you should suspect,” he stopped in confusion.
“I have thought him much less well the last few days,” said Cicely.
“Of course I cannot judge as you can, but still I almost expected you
to tell me you were beginning to lose hope. I knew you would tell me
first.”
“Are you speaking about your father?” said Mr. Guildford. “Did you
think it was on his account I wanted to see you?”
“Yes, of course,” replied Cicely wonderingly. “Is it not so? Do you
not think him much worse?”
 “No,” said Mr. Guildford. “I have not thought so. I do not think
Colonel Methvyn quite as well as he was some time ago—he is more
nervous, more easily upset than he used to be; but I see no
important change in him. There is no reason why he should not
remain as well as he is—or even gain ground a little—for years to
come, provided always his mind is kept tranquil. I could not take
upon myself to say how he would stand any severe shock.”
Cicely gazed at him as if she could hardly believe him.
“That is just what you said some months ago,” she exclaimed.
“And you really don’t think him much worse?
“Certainly not. What made you think so?”
“I don’t know. I have not thought him quite well. I fear he has been
worried and troubled, and I have let my fears get the better of me, I
suppose. I felt quite certain that you had come this morning to
prepare me for something dreadful.”
She smiled, but faintly still—the revulsion from terror to renewed
hope was almost too much for her. Mr. Guildford smiled too, but in
his smile there was even less sunshine than in Cicely’s, and in his
voice there was even a touch of bitterness as he replied,
“Something dreadful! Far from it. You will believe me when you
hear what it really is that I want to say to you this morning—” he
paused and took a step or two away from where he had been
standing. Then he came back again to the table, and, lifting a book
that was lying upon it, turned the leaves over idly with his fingers. “I
want you to release me from a promise, Miss Methvyn,” he said at
last.
Cicely looked up in surprise. “What promise? I don’t understand,”
she replied.
“Don’t you remember,” he went on, speaking slowly, but without
looking at her, “don’t you remember that some time ago I promised
you—tacitly or directly I am not sure which, and it does not matter,
the promise was given—that I would not leave this neighbourhood as
long as Colonel Methvyn required me—as long as I felt that I could
be of use to him?”
 “Yes,” said Cicely, “I have always depended upon your not doing
so. I don’t remember the exact words, but I felt satisfied that you had
perfectly re-assured me about it, at the time I was afraid of your
going.”
“Yes. I did promise as I said. There is no doubt I did,” said Mr.
Guildford, and it is from this promise I want you to release me.”
“You want to go away! You have got some better position in
prospect!” exclaimed Cicely. “Oh! how unfortunate—can you not
defer going, even for a few months? Papa may be stronger, or Dr.
Farmer may be back; of course, we cannot expect you to sacrifice
your future to us, but I cannot help telling you I am dreadfully sorry. I
was so thankful to hear you say that you do not think papa much
worse, and now, I shall just feel more anxious about him than ever.”
She turned her head away, but Mr. Guildford felt that there were
tears in her eyes.
“You need not—you must not think I would act without regard to
Colonel Methvyn,” said Mr. Guildford hurriedly. “I have heard from Dr.
Farmer—he is not likely to be away very much longer—and in the
meantime I can assure you that the medical man I should
recommend to your father is thoroughly deserving of your
confidence.
“I dare say he is,” said Cicely impatiently. “It is not that that I am
thinking of. I don’t believe any doctor can do much for my father. It is
not doctoring he needs as much as cheering and interesting. That is
what you have done for him—far better than poor old Dr. Farmer
could do. And he will miss you after a while even more than now;
there are reasons—” she hesitated. “Oh! I am dreadfully sorry,” she
repeated, “but of course we cannot expect you to sacrifice your
future. We are only too grateful for what you have done. Forgive me
for seeming so selfish.”
Mr. Guildford did not appear to notice her last words. “You mistake
me a little,” he said. “My reasons for wishing—for thinking it best I
should go away, have nothing to do with my prospects—nothing
whatever. At this moment I have not the faintest notion where I shall