Practical Skin Pathology: A Diagnostic Approach E-Book
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1608 pages
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Description

Practical Skin Pathology is the only dermatopathology reference that uses a systematic pattern recognition approach to help you achieve more accurate diagnoses of both neoplastic and non-neoplastic skin diseases. This volume in the Pattern Recognition Series helps you to efficiently and confidently evaluate even the most challenging skin diseases and lesions.

  • Identify challenging types of skin cancer, including cutaneous lymphomas and melanocytic lesions, as well as non-neoplastic skin diseases such as panniculitis; drug eruptions, including reactions to newer chemotherapeutic agents; infectious diseases; and many more, with the only dermatopathology reference that uses a pattern recognition approach.
  • Progress logically from the histologic pattern, through the appropriate workup, around the pitfalls, to the best diagnosis.
  • Compare your clinical findings to more than 1,400 full-color, high-quality photos that capture the characteristic presentation of a full range of dermatopathology specimens.

Sujets

Ebooks
Savoirs
Medecine
Reticulohistiocytoma
Subcutaneous granuloma annulare
Cutaneous small-vessel vasculitis
Mucinosis
Factitial panniculitis
Septal panniculitis
Nevi and melanomas
Trichoepithelioma
Oncology
Alopecia mucinosa
Folliculitis nares perforans
Systemic lupus erythematosus
Systemic vasculitis
Metastatic carcinoma
Elastosis perforans serpiginosa
Spongiosis
Kaposi's sarcoma
Photocopier
Lichenoid eruption
Chickenpox
Acne
Lupus erythematosus
The Only Son
Benignity
Cicatricial pemphigoid
Histiocytosis
Pulmonary pathology
Blue nevus
Juvenile xanthogranuloma
Types of volcanic eruptions
Papular mucinosis
Schwannoma
Necrolytic migratory erythema
Granuloma annulare
Necrobiosis
Angiokeratoma
Pretibial myxedema
Pyogenic granuloma
T-cell lymphoma
Necrobiosis lipoidica
Pseudoxanthoma elasticum
Erythema nodosum
Bullous pemphigoid
Merkel cell carcinoma
In Debt
Dermatitis
Connective tissue disease
Neuropathology
Langerhans cell histiocytosis
Hyperkeratosis
Photosensitivity
Dermatopathology
Mycosis fungoides
Epidermoid cyst
Neoplasm
Benign fibrous histiocytoma
Seborrheic keratosis
Dermatofibrosarcoma protuberans
Inborn error of metabolism
Hyperpigmentation
Digestive disease
Dermatomyositis
Degenerative disease
Nevus
Plasma cell
Differential diagnosis
Urticaria
Lichen planus
Hemangioma
Orthopedics
Enthusiasm
Melanoma
Histopathology
Basal cell carcinoma
Panniculitis
Vasculitis
Ichthyosis vulgaris
Ichthyosis
Pulmonology
Amyloidosis
Erythema
Nutrition disorder
Xanthoma
Physician assistant
Itch
Fibrous connective tissue
Folliculitis
Weight loss
Arthralgia
Pellagra
Biopsy
Lesion
Archive
Carcinoma
Multiple myeloma
Mast cell
Tetralogy of Fallot
Connective tissue
Internal medicine
Alopecia
List of human parasitic diseases
Cytopathology
Cyst
Médecine
Acné rosacea
Mucocele
Herpes zóster
Editorial
Actinic elastosis
Hodgkin's lymphoma
Desmoplastic trichoepithelioma
Scleredema
Alopecia areata
Mastocytosis
Atkins diet
Porphyria
Dermatology
Non-Hodgkin lymphoma
Skin neoplasm
Crohn's disease
Melanocyte
Philadelphia
Melanocytic nevus
Melanin
Keratin
Infection
Unconsciousness
Data storage device
Radiation therapy
Mechanics
Magnetic resonance imaging
Infectious disease
Genetic disorder
Chemotherapy
Collagen
Perforation
Wick
Calcification
Pathology
Immunofluorescence
Pemphigus
Clay
Adipocyte
Blister
Vitiligo
Macule
Pustule
Fatigue
Electronic
Contact
Papule
Psoriasis
Son
Copyright

Informations

Publié par
Date de parution 07 mai 2013
Nombre de lectures 0
EAN13 9781455738274
Langue English
Poids de l'ouvrage 17 Mo

Informations légales : prix de location à la page 0,0717€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Practical Skin Pathology
A Diagnostic Approach

James W. Patterson, MD
Professor of Pathology and Dermatology, Director of Dermatopathology, University of Virginia Health System, Charlottesville, Virginia
Table of Contents
Cover image
Title page
Series page
Copyright
Dedication
Contributors
Series Preface
Preface
Acknowledgments
Pattern-Based Approach to Diagnosis
Chapter 1: Spongiotic Dermatitis
Forms of Eczematous Dermatitis
Other Manifestations of Spongiotic (Eczematous) Dermatitis
Other Conditions for which Spongiosis Is a Microscopic Hallmark
Chapter 2: Erythemas with Perivascular Inflammation
Urticaria and Its Variants
Papular Urticaria
Urticarial Dermatitis
Annular Erythemas
Other Erythemas
Chapter 3: Psoriasiform and Lichenoid Dermatitis
Psoriasiform Dermatitis
Lichenoid Dermatitis
Chapter 4: Vesiculobullous and Selected Pustular Disorders
Immunobullous Disorders
Inherited Blistering Diseases
Selected Pustular Disorders
Traumatic Blisters
Chapter 5: Vascular Disorders
Conditions Associated with Vessel Occlusion
Vasculitis
Other Conditions Associated with Vessel Injury
Chapter 6: Nutritional Deficiency and Gastrointestinal Disease
Selected Nutritional Deficiency Disorders
Cutaneous Manifestations of Selected Gastrointestinal Diseases
Chapter 7: Panniculitis
Septal Panniculitis
Lobular or Mixed Septal-Lobular Panniculitis
Malignancy and Panniculitis or Panniculitis-like Subcutaneous Infiltration
Other Considerations in the Diagnosis of Panniculitis
Chapter 8: Connective Tissue Disorders
Lupus Erythematosus
Dermatomyositis
Sclerosing Conditions of the Skin
Rheumatoid Arthritis
Chapter 9: Metabolic Diseases
Amyloidosis
Colloid Milium
Porphyrias
Calcinosis Cutis
Oxalosis
Gout
Ochronosis
Acanthosis Nigricans
Xanthomas and Selected Lipid Storage Diseases
Chapter 10: Degenerative Diseases
Disorders of Transepidermal Elimination
Elastic Tissue Abnormalities
Other Degenerative Diseases
Chapter 11: Mucinoses
Traumatic or Degenerative Conditions
Metabolic Conditions
Mucinosis with Paraproteinemia
Other Forms of Cutaneous Mucinosis
Chapter 12: Drugs and Physical Agents
Exanthems Caused by Drugs
Interface Dermatitis
Neutrophilic Eccrine Hidradenitis
Selected Reactions to Recombinant Cytokines
Phototoxic and Photoallergic Drug Reactions
Pigmentary Changes Caused by Drugs
Selected Pustular Drug Eruptions
Selected Reactions to Metals
Drug-Induced Pseudolymphoma
Dermatoses Caused by Physical Agents
Chapter 13: Noninfectious Granulomas
Necrobiotic Granulomas
Other Noninfectious Granulomas
Chapter 14: Non-neoplastic Diseases of Appendages
Acneiform Dermatoses
Nonscarring Alopecias
Scarring Alopecias
Apocrine and Eccrine-Related Inflammatory Lesions
Chapter 15: Pigmentation Disorders
Reticulated Pigment Anomalies
Melasma
Addison Disease
Peutz-Jeghers Syndrome
Laugier-Hunziker Syndrome
Postinflammatory Pigment Anomalies
Phytophotodermatitis
Chemical Leukoderma
Idiopathic Guttate Hypomelanosis
Psoralen and Ultraviolet A–Induced Pigment Alterations
Albinism
Chédiak-Higashi Syndrome
Piebaldism
Vitiligo
Ash Leaf Macules of Tuberous Sclerosis
Nevus Depigmentosus
Nevus Anemicus
Hypomelanosis of Ito
Chapter 16: Disorders of Epidermal Maturation, Keratinization, and Connective Tissues
Disorders of Epidermal Maturation and Keratinization
Selected Disorders of Connective Tissues
Chapter 17: Infectious Diseases, Including Infestations and Parasitic Diseases
Bacterial Diseases
Fungal Diseases
Viral Diseases
Parasitic Diseases and Arthropod Reactions
Protozoal and Other Infectious Diseases
Chapter 18: Epidermal Cysts and Tumors
Epithelial Cysts
Benign Epidermal Tumors or Malformations
Premalignant and Malignant Epidermal Tumors
Chapter 19: Cutaneous Appendageal Tumors
Tumors with Hair Follicle Differentiation
Sebaceous Tumors
Sweat Gland Tumors
Chapter 20: Metastatic Tumors in the Skin
Clinical Considerations
Histologic Nuances and Differential Diagnosis
Histologic Diagnosis of Metastatic Carcinomas: A Pattern-Based Approach
Primary Nonadnexal Skin Tumors That May Resemble Metastatic Lesions
Other Metastatic Neoplasms
Chapter 21: Fibrous Tissue Tumors
Benign Fibrous Tissue Tumors
Fibrous Tissue Tumors of Intermediate Malignancy
Malignant Fibrous Tissue Tumors
Chapter 22: Vascular and Perivascular Proliferations of the Skin
Vascular Nevi
Benign Vascular Neoplasms
Borderline Endothelial Tumors
Malignant Endothelial Neoplasms
Tumefactive Non-neoplastic Vascular Proliferations
Glomus Tumor and Glomangiopericytoma
Perivascular Epithelioid Cell Tumors
Chapter 23: Tumors and Tumor-like Conditions Showing Neural, Nerve Sheath, and Adipocytic Differentiation
Patterns of Growth in Neural Proliferations of the Skin
Cutaneous Neural Proliferations
Pseudotumors of the Skin Related to the Nervous System
Patterns of Growth in Cutaneous Adipocytic Proliferations
Superficial Liposarcomas
Adipocytic Pseudotumors
Chapter 24: Tumors of Muscle, Cartilage, and Bone
Smooth Muscle Tumors
Striated Muscle Tumors and Rhabdoid Tumor
Cartilaginous Tumors and Parachordoma
Calcifying and Ossifying Tumors
Chapter 25: Histiocytic Proliferations
Non–Langerhans Cell Histiocytic Infiltrates
Malignant Histiocytosis
Langerhans Cell Histiocytoses and Indeterminate Cell Histiocytosis
Chapter 26: Disorders of Mast Cells and Plasma Cells
Disorders of Mast Cells
Disorders of Plasma Cells
Chapter 27: Lymphoid Infiltrates, Lymphoma, and Hematopoietic Proliferations Involving the Skin
Mature B-Cell Neoplasms
Mature T-Cell and Natural Killer Cell Neoplasms
Immature Hematopoietic Malignancies
Hodgkin Lymphoma
Lymphocytoma Cutis (Reactive Lymphoid Infiltrates, Cutaneous Lymphoid Hyperplasia, Pseudolymphoma, Lymphadenosis Benigna Cutis)
Mature B-Cell Neoplasms
T-Cell and Natural Killer Cell Neoplasms
Other T-Cell and Natural Killer Cell Lymphomas Involving the Skin
Hodgkin Disease (Hodgkin Lymphoma)
Leukemia Cutis
Extramedullary Hematopoiesis
Chapter 28: Melanocytic Tumors
Non-neoplastic Hyperpigmented Lesions
Benign Melanocytic Tumors
Malignant Melanocytic Tumors
Index
Series page
Pattern Recognition Series
Series editors: Kevin O. Leslie and Mark R. Wick
Practical Breast Pathology
Edited by Kristen A. Atkins and Christina S. Kong
Practical Cytopathology
Edited by Matthew Zarka and Barbara Centeno
Practical Skin Pathology
Written by James W. Patterson
Practical Hepatic Pathology
Edited by Romil Saxena
Practical Orthopedic Pathology
Edited by Andrea T. Deyrup and Gene P. Siegal
Practical Pulmonary Pathology, Second Edition
Edited by Kevin O. Leslie and Mark R. Wick
Practical Renal Pathology
Edited by Donna J. Lager and Neil A. Abrahams
Practical Soft Tissue Pathology
Edited by Jason L. Hornick
Practical Surgical Neuropathology
Edited by Arie Perry and Daniel J. Brat
Copyright

1600 John F. Kennedy Blvd.
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Philadelphia, PA 19103-2899
PRACTICAL SKIN PATHOLOGY: A DIAGNOSTIC APPROACH ISBN 978-1-4377-1996-3
Copyright © 2013 by Saunders, an imprint of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions .
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
Practical skin pathology : a diagnostic approach / James W. Patterson.
  p. ; cm.—(Pattern recognition series)
 Includes bibliographical references and index.
 ISBN 978-1-4377-1996-3 (hardcover : alk. paper)
 I. Title. II. Series: Pattern recognition series.
 [DNLM: 1. Skin—pathology. 2. Skin Diseases—diagnosis. 3. Skin Diseases—pathology. WR 105]
 616.5’071—dc23
 2012045987
Acquisitions Editor: William R. Schmitt
Publishing Services Manager: Pat Joiner
Designer: Lou Forgione
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
This book is dedicated to my wife, Julie, and our son, Wyatt, who fully support my efforts and show great tolerance when I try to finish “just one more page” on the computer while at home and officially off duty. I also wish to express my gratitude to a wonderful mentor and friend, the late Dr. James H. Graham.
Contributors

Smitha S. Kuppalli, MD , Chief Resident Department of Dermatology University of Virginia School of Medicine Charlottesville, Virginia

Michael Marchetti, MD , Chief Resident Department of Dermatology University of Virginia School of Medicine Charlottesville, Virginia

Mark R. Wick, MD , Professor of Pathology Division of Surgical Pathology University of Virginia Medical Center Charlottesville, Virginia
Series Preface


It is often stated that anatomic pathologists come in two forms: “Gestalt”-based individuals, who recognize visual scenes as a whole, matching them unconsciously with memorialized archives; and criterion-oriented people, who work through images systematically in segments, tabulating the results—internally, mentally, and quickly—as they go along in examining a visual target. These approaches can be equally effective, and they are probably not as dissimilar as their descriptions would suggest. In reality, even “Gestaltists” subliminally examine details of an image, and, if asked specifically about particular features of it, they are able to say whether one characteristic or another is important diagnostically.
In accordance with these concepts, in 2004 we published a textbook entitled Practical Pulmonary Pathology: A Diagnostic Approach (PPPDA). That monograph was designed around a pattern-based method, wherein diseases of the lung were divided into six categories on the basis of their general image profiles. Using that technique, one can successfully segregate pathologic conditions into diagnostically and clinically useful groupings.
The merits of such a procedure have been validated empirically by the enthusiastic feedback we have received from users of our book. In addition, following the old adage that “imitation is the sincerest form of flattery,” since our book came out other publications and presentations have appeared in our specialty with the same approach.
After publication of the PPPDA text, representatives at Elsevier, most notably William Schmitt, were enthusiastic about building a series of texts around pattern-based diagnosis in pathology. To this end we have recruited a distinguished group of authors and editors to accomplish that task. Because a panoply of patterns is difficult to approach mentally from a practical perspective, we have asked our contributors to be complete and yet to discuss only principal interpretative images. Our goal is eventually to provide a series of monographs which, in combination with one another, will allow trainees and practitioners in pathology to use salient morphological patterns to reach with confidence final diagnoses in all organ systems.
As stated in the introduction to the PPPDA text, the evaluation of dominant patterns is aided secondarily by the analysis of cellular composition and other distinctive findings. Therefore, within the context of each pattern, editors have been asked to use such data to refer the reader to appropriate specific chapters in their respective texts.
We have also stated previously that some overlap is expected between pathologic patterns in any given anatomic site; in addition, specific disease states may potentially manifest themselves with more than one pattern. At first, those facts may seem to militate against the value of pattern-based interpretation. However, pragmatically, they do not. One often can narrow diagnostic possibilities to a very few entities using the pattern method, and sometimes a single interpretation will be obvious. Both of those outcomes are useful to clinical physicians caring for a given patient.
It is hoped that the expertise of our authors and editors, together with the high quality of morphologic images they present in this Elsevier series, will be beneficial to our reader-colleagues.

Kevin O. Leslie, MD

Mark R. Wick, MD
Preface


I am very pleased to make this contribution to the outstanding Pattern Recognition Series in pathology. Cutaneous pathology occupies an important place within the surgical pathology firmament, and it is certainly a field that lends itself to the type of pattern analysis for which this series has become justly famous.
There are a number of pattern recognition approaches to dermatopathology, the most notable being the groundbreaking work of the late Dr. A. Bernard Ackerman. It has been a challenge to produce a pattern analysis that is somewhat novel while at the same time considerably more condensed than previous efforts. Acknowledging a great debt to all the previous workers in this area, I have proposed in this book eight different patterns: five of them based on anatomic location (epidermocentric, adnexocentric, dermocentric-noninflammatory, dermocentric-inflammatory, and panniculocentric) and three representing special categories of histopathologic abnormality (nearly normal skin, cystic change, and bullous/pustular dermatosis). As has been the case in other volumes in this series, a list of examples of each pattern is provided, including both specific entities and broad categories of disease. The tables that follow the list give additional findings in each pattern, the diagnoses associated with each additional finding, and the chapter and page in the text where these diagnoses are discussed.
The text itself is divided into more traditional chapter groupings, variably defined by morphology and etiology. The discussion of most disease entities is organized according to Clinical Features, Microscopic Findings, and Differential Diagnosis. I have tried to emphasize differential diagnosis throughout the book, with the hope that these discussions, together with pattern analysis, will enable the reader to gain facility first in accurately categorizing the disease process and then in distinguishing among disorders within a category. All chapters include many illustrations—critical to such a visual specialty. The reference lists are reasonably generous but not exhaustive and hopefully are sufficient to provide more detailed information for the interested reader.
I have not included introductory chapters on basic cutaneous microanatomy and histopathology. There are numerous references that provide this information, a review of which would certainly be an important first step for senior medical students and beginning dermatology and pathology residents. I would particularly recommend Chapter 0 in Dermatology , 3rd edition, edited by Bolognia and colleagues. * Armed with this information, the beginning student should be able to tackle the material in this book with confidence. Also, I have not included every entity known to exist in dermatopathology; nor have I exhaustively reviewed every clinical variation or detailed basic science aspects of the diseases covered here.
However, the book represents a compendium of conditions that I have seen in practice over a period of 36 years, and I have made an assumption that all of these are “fair game” for a dermatopathologist during the course of his or her career. It is my hope that this will truly be a “practical” guide that can be kept by the microscope and relied upon, when needed, to make the challenging process of dermato pathologic diagnosis just a bit easier, and perhaps even a bit more fun!

James W. Patterson, MD


* Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology . 3rd ed. Philadelphia: Saunders; 2012:1–43.
Acknowledgments
I am grateful to Dr. Mark R. Wick for his chapters on Metastatic Tumors in the Skin, Vascular and Perivascular Proliferations of the Skin, and Tumors and Tumor-like Conditions Showing Neural, Nerve Sheath, and Adipocytic Differentiation. I am also indebted to Dr. Smitha Kuppalli for her outline of Pigmentation Disorders and to Dr. Michael Marchetti for his outline of Melanocytic Tumors. In both cases, their contributions made the organization and writing of these chapters a much more fluid process. A special thank you goes to Peggy Gordon and Clay Cansler at P. M. Gordon Associates for their editorial and production expertise and to our editor, William Schmitt of Elsevier, for his patience and encouragement during the preparation of this book.

James W. Patterson, MD
Pattern-Based Approach to Diagnosis
Pattern Diseases to Be Considered Nearly normal skin (including polypoid/pedunculated skin) Pityriasis alba Urticaria Macular amyloidosis Solar elastosis (uncomplicated) Anetoderma (on hematoxylin and eosin [H&E]–stained sections) Papillary dermal and mid-dermal elastolysis (on H&E-stained sections) Chronic telogen effluvium Miliaria crystallina Pigmentation disorders (on H&E-stained sections) Ichthyosis vulgaris (some examples) Acquired ichthyosis (some examples) Ectodermal dysplasias Ehlers-Danlos syndrome (secondary changes may provide a clue) Cutis laxa (on H&E-stained sections) Tinea versicolor Fibroepithelial polyp Connective tissue nevus Some vascular nevi (nevus flammeus and telangiectasias) Telangiectasia macularis eruptiva perstans Ephelides Some lentigines Dermal melanocytoses (e.g., nevus of Ota but excluding neurocristic hamartoma) Epidermocentric change Forms of spongiotic and eczematous dermatitis Psoriasiform dermatitis Lichenoid dermatitis Nutritional deficiency disorders Acrodermatitis enteropathica and zinc deficiency  Necrolytic migratory erythema  Necrolytic acral erythema  Pellagra Lupus erythematosus Dermatomyositis Acanthosis nigricans Disorders of transepidermal elimination Chondrodermatitis nodularis chronica helicis Reactions to antineoplastic agents Halogen eruptions  Bromoderma  Iododerma Acute generalized exanthematous pustulosis Hydroa vacciniforme Calcaneal petechiae Ichthyosis Keratosis palmaris et plantaris Acral keratodermas Other disorders of keratinization Staphylococcal scalded skin syndrome Pitted keratolysis Erythrasma Dermatophytosis Tinea nigra Candidiasis Chromomycosis “Deep” fungal infections  North American blastomycosis  South American blastomycosis  Coccidioidomycosis (some examples)  Cryptococcosis (some examples)  Sporotrichosis (some examples) Molluscum contagiosum Orf and milker nodules Human papillomavirus infections Oral hairy leukoplakia Scabies Larva migrans Tungiasis Benign epidermal tumors Premalignant and malignant epidermal tumors Certain cutaneous appendageal tumors  Trichilemmoma  Tumor of the follicular infundibulum  Trichilemmal carcinoma  Nevus sebaceus  Poroma and hidroacanthoma simplex  Syringofibroadenoma  Syringocystadenoma papilliferum Paget disease and extramammary Paget disease T-cell lymphomas  Adult T-cell leukemia/lymphoma  Mycosis fungoides  Pagetoid reticulosis  Sézary syndrome Melanocytic lesions  Reticulated pigment anomalies Mucosal melanosis (labial melanotic macule)  Café-au-lait spot and nevus spilus  Becker nevus  Lentigo  Junctional nevi  Atypical (dysplastic) nevi  Melanoma in situ Adnexocentric change Spongiotic folliculitis (follicular eczema) Scurvy Lupus erythematosus (discoid) Lymphocytic infiltrate of Jessner Perforating folliculitis Squamous syringometaplasia Neutrophilic eccrine hidradenitis Diseases of appendages  Acneiform dermatoses  Alopecias Fox-Fordyce disease Syringolymphoid hyperplasia Miliaria Infectious folliculitis Pigmented follicular cyst Hair follicle nevus and nevus comedonicus Trichodiscoma, fibrofolliculoma, and perifollicular fibroma Folliculotropic T-cell lymphoma Pilar neurocristic hamartoma Cystic change Gout Mucocele Digital mucous cyst Conglobate acne Hidradenitis suppurativa and “Fox den disease” Dissecting cellulitis Pilonidal sinus Onchocerciasis (onchocercoma) Cysts of epidermal and follicular origin/differentiation Ciliated cysts Metaplastic synovial cyst Median raphe cyst Omphalomesenteric duct polyp Dilated pore of Winer Pilar sheath acanthoma Trichoadenoma Proliferating trichilemmal cyst/tumor Trichofolliculoma Pilomatricoma Folliculosebaceous cystic hamartoma Eccrine hidrocystoma Apocrine hidrocystoma and cystadenoma Cystic hygroma Cavernous hemangioma Bullous and pustular dermatosis Acute spongiotic dermatitis Immunobullous disorders Inherited blistering diseases Selected pustular disorders Traumatic blisters Acantholytic dermatosis of the genitocrural region Porphyria, especially porphyria cutanea tarda Fixed drug eruption Halogen eruptions Acute generalized exanthematous pustulosis Burns Eosinophilic pustular folliculitis Epidermolytic hyperkeratosis Darier disease (bullous variant) Grover disease (some examples) Incontinentia pigmenti (first stage) Selected infectious diseases  Impetigo (bullous)  Staphylococcal scalded skin syndrome  Anthrax  Dermatophytosis and candidiasis (bullous tinea, pustular lesions)  Herpes simplex, varicella, and herpes zoster infections Dermocentric change (noninflammatory, or with minor inflammatory component) Coagulopathies (thrombi) Other conditions associated with vessel occlusion Infiltrate-poor connective tissue diseases  Tumid lupus erythematosus  Dermatomyositis Sclerosing conditions of the skin Metabolic diseases and lipidoses (excluding acanthosis nigricans) Elastic tissue abnormalities Myospherulosis Mucinoses Pigmentary changes due to drugs Reactions to metals Erythema ab igne Radiation dermatitis Focal dermal hypoplasia (Goltz syndrome) Pseudoxanthoma elasticum Lipoid proteinosis Ehlers-Danlos syndrome Malignant epidermal tumors  Squamous cell carcinoma  Adenosquamous carcinoma  Carcinosarcoma  Lymphoepithelioma-like carcinoma  Basal cell carcinoma Nevoid follicular tumors Trichoepithelioma Trichoblastic tumors Neoplasms with differentiation toward follicular mesenchyme Malignant proliferating trichilemmal tumor Pilomatrix carcinoma Sebaceous tumors other than nevus sebaceus and folliculosebaceous cystic hamartoma Eccrine and apocrine nevi Syringometaplasia Benign sweat gland tumors (poroma, syringofibroadenoma, and syringocystadenoma papilliferum included under epidermocentric) Malignant sweat gland tumors (other than Paget and extramammary Paget disease) Metastatic carcinomas Benign fibrous tissue tumors (other than fibroepithelial polyp) Fibrous tissue tumors of low-grade malignancy Malignant fibrous tissue tumors Vascular tumors and pseudotumors (cavernous hemangiomas and lymphangiomas listed under “cystic” lesions; Kimura disease, angiolymphoid hyperplasia with eosinophilia, and early Kaposi sarcoma all have significant inflammatory components) Tumors showing neural, nerve sheath, neuroendocrine, and lipomatous differentiation Tumors of muscle, cartilage, and bone Benign melanocytic tumors with prominent intradermal component Malignant melanocytic tumors other than in situ lesions Dermocentric change (inflammatory or neoplastic with relationship to/derivation from inflammatory elements) Erythemas with perivascular inflammation (urticaria also listed under nearly normal skin) Vasculitis Other conditions associated with vessel injury  Sweet syndrome  Rheumatoid neutrophilic dermatosis  Pyoderma gangrenosum  Behçet syndrome Cutaneous manifestations of Crohn disease, ulcerative colitis Connective tissue disorders  Lupus erythematosus  Dermatomyositis  Manifestations of rheumatoid arthritis Drug reactions  Drug exanthems  Recombinant cytokine reactions  Phototoxic and photoallergic reactions  Drug-induced pseudolymphoma  Polymorphic light eruption  Actinic prurigo  Chronic actinic dermatitis/actinic reticuloid Noninfectious granulomas Bacterial diseases other than bullous impetigo and staphylococcal scalded skin syndrome Fungal infections other than dermatophytosis, tinea versicolor, and tinea nigra (many of the fungal infections have both prominent epidermal and dermal components; Candida sepsis is predominantly dermal/subcutaneous) Cytomegalovirus infection Some Epstein-Barr virus infections (play role in several lymphomas and some examples of hydroa vacciniforme) Onchocerciasis Dermal myiasis Arthropod reactions Protozoal and other infectious diseases Histiocytic proliferations Disorders of mast cells and plasma cells Nonepidermocentric lymphomas, leukemias, extramedullary hematopoiesis Panniculocentric change Forms of panniculitis Eosinophilic fasciitis Amyloidosis (systemic) Calcinosis cutis (tumoral calcinosis, calciphylaxis) Necrobiotic granulomas  Subcutaneous granuloma annulare  Necrobiosis lipoidica  Rheumatoid nodule Sarcoidosis (some examples) Fibrous hamartoma of infancy Some examples of dermatofibroma (fibrous histiocytoma) Fibromatosis Nodular fasciitis  Proliferative fasciitis Subcutaneous panniculitis-like T-cell lymphoma γ/δ T-cell lymphoma Neurocristic hamartoma


Pattern 1 Nearly Normal Skin


Elements of the pattern:
This pattern includes those lesions that show minimal discernible abnormality in routinely H&E-stained sections, particularly at low magnification. Accurate diagnosis requires good clinical information, high-power inspection (organisms in the stratum corneum in tinea versicolor), special staining (Verhoeff–van Gieson stain to appreciate elastic fiber loss in anetoderma), or sometimes ultrastructural study (distinction among forms of hypomelanosis). The image shows uncomplicated solar elastosis.

Pattern 1
Nearly Normal Skin


Pattern 2 Epidermocentric Change


Elements of the pattern:
In epidermocentric lesions, the microscopic changes are focused on or about the epidermis. This pattern is most clearly represented by abnormalities of keratinocytes and their products (e.g., psoriasiform dermatitis, premalignant and malignant epidermal tumors). However, it also includes material occupying the epidermis (blood, in the case of calcaneal petechiae; organisms, in the case of erythrasma or dermatophytosis), cells that accumulate immediately beneath the epidermis (lichen planus), and cells that infiltrate the epidermis (lymphocytes in mycosis fungoides; melanocytes in pagetoid melanoma). The image shows lichen simplex chronicus.

Pattern 2
Epidermocentric Change



Pattern 3 Adnexocentric Change


Elements of the pattern:
In adnexocentric change, abnormalities are concentrated in the area of cutaneous appendageal structures, including hair follicles, apocrine glands, and eccrine sweat glands. Examples of this pattern include structural abnormalities (scurvy and squamous syringometaplasia), alterations in the normal hair cycle (alopecia areata), inflammation (lupus erythematosus and lichen planopilaris), infection (furunculosis and Majocchi granuloma), nevoid conditions (nevus comedonicus), and neoplastic infiltrates (folliculotropic T-cell lymphoma and syringolymphoid hyperplasia). The image shows lichen planopilaris.

Pattern 3
Adnexocentric Change

* Some experts consider lymphocytic infiltration of Jessner to be the same disorder as tumid lupus erythematosus.

Pattern 4 Cystic Change


Elements of the pattern:
This pattern consists of aggregates of material (or what appear to be empty spaces) in tissue sections, often but not invariably lined by different types of epithelium. Cysts may be lined by stratified squamous epithelium (epidermal or infundibular cyst; pilar or trichilemmal cyst), apocrine epithelium (apocrine hidrocystoma), urothelium (median raphe cyst) or ciliated epithelium (bronchogenic cyst). Some may arise from follicular dilatation (vellus hair cyst) or as a type of adnexal tumor (folliculosebaceous cystic hamartoma). Other cysts form through accumulations of material without a cyst lining (digital mucous cyst; gout) or through tissue metaplasia (metaplastic synovial cyst). Markedly dilated vascular structures lined by endothelium can also produce the clinical or microscopic appearance of a cyst (cystic hygroma; cavernous hemangioma). The image shows a vellus hair cyst.

Pattern 4
Cystic Change


Pattern 5 Bullous and Pustular Dermatosis


Elements of the pattern:
The pattern of bullous dermatosis is defined by formation of a fluid-filled cavity, generally within or just beneath the epidermis. Bullae are often classified by the level at which they occur (intragranular—pemphigus foliaceus; upper epidermal—friction blister; through the lamina lucida—junctional epidermolysis bullosa), by the presence or lack of inflammation (respectively, dermatitis herpetiformis, traumatic blisters), or by mechanism (autoimmune—pemphigus; metabolic—porphyria cutanea tarda; infection—herpes simplex). Pustules have characteristics of blisters but also contain inflammatory cells, particularly neutrophils (impetigo) or eosinophils (incontinentia pigmenti, first stage). The image shows bullous pemphigoid.

Pattern 5
Bullous and Pustular Dermatosis


Pattern 6 Dermocentric Change (Noninflammatory)


Elements of the pattern:
This dermocentric pattern includes all those noninflammatory processes that can occur within the dermis. A wide variety of processes fall into this category, including vascular occlusive disease (coagulopathies), dermal sclerosis due to autoimmune connective tissue disorders (morphea) or physical agents (burns, radiation injury), elastic tissue abnormalities (pseudoxanthoma elasticum), deposition of pigments or metals (minocycline pigmentation, argyria), and the vast array of nonlymphoid tumors. This image is an example of morphea.

Pattern 6
Dermocentric Change (Noninflammatory)



Jenkins J, Babu K, Hsu-Hung E, et al. ANCA-positive necrotizing vasculitis and thrombotic vasculopathy induced by levamisole-adulterated cocaine: a distinctive clinicopathologic presentation. J Am Acad Dermatol. 2011;65:e14-e6.

Pattern 7 Dermocentric Change (Inflammatory, or Neoplastic with Relationship to/Derivation from Inflammatory Elements)


Elements of the pattern:
This dermocentric pattern encompasses dermal infiltrates due to either inflammation or neoplasia composed of lymphoid or other cell types. These can be grouped in three ways. One is by their location within the dermis: superficial (viral exanthems), or superficial and deep (lupus erythematosus). Two is by their predominant cell type (lymphocytes—polymorphic light eruption; eosinophils—arthropod bites; neutrophils—Sweet syndrome; granulomas—sarcoidosis; fibroblast-like cells—scleromyxedema). Three is by a combination of cell type and neoplastic category (macrophages—juvenile xanthogranuloma; Langerhans cells—Langerhans cell histiocytosis; mast cells—urticaria pigmentosa; plasma cells—extraosseous plasmacytoma; lymphomas and leukemias [chronic lymphocytic leukemia/small cell lymphoma]). This image shows perniosis.

Pattern 7
Dermocentric Change (Inflammatory, or Neoplastic with Relationship to/Derivation from Inflammatory Elements)



Pattern 8 Panniculocentric Change


Elements of the pattern:
The panniculocentric pattern encompasses conditions that are centered in the subcutis, although there may be some involvement of the dermis as well. Forms of fasciitis are arbitrarily included in this category. Subtypes of panniculitis are grouped by their predominant location in the subcutis (e.g., septal [erythema nodosum], presence of medium-vessel vasculitis [nodular vasculitis], predominance of neutrophils [alpha-1 antitrypsin deficiency panniculitis], or lymphocytes and plasma cells [lupus panniculitis], and other specific findings [needle-shaped clefts within lipocytes—subcutaneous fat necrosis of the newborn; crystalline deposits—gouty panniculitis]). Panniculocentric change also includes some ordinarily dermal processes that are occasionally located in the subcutis (sarcoidosis) as well as tumors derived from stromal elements (nodular fasciitis), lymphoid cells (subcutaneous panniculitis-like T-cell lymphoma), or melanocytes (neurocristic hamartoma). This image is an example of erythema nodosum.

Pattern 8
Panniculocentric Change
1
Spongiotic Dermatitis


Forms of Eczematous Dermatitis 

Contact Dermatitis 
Atopic Dermatitis 
Seborrheic Dermatitis 
Stasis Dermatitis 
Other Manifestations of Spongiotic (Eczematous) Dermatitis 

Photoallergic Dermatitis 
Pityriasis Alba 
Pompholyx 
Autoeczematization (Id) Reactions 
Exfoliative Dermatitis (Erythroderma) 
Prurigo Simplex, Lichen Simplex Chronicus, and Prurigo Nodularis 
Other Conditions for which Spongiosis Is a Microscopic Hallmark 

Miliaria 
Small Plaque Parapsoriasis (Guttate Parapsoriasis, Digitate Dermatosis, Chronic Superficial Dermatitis, Xanthoerythrodermia Perstans) 
Pityriasis Rosea 
Polymorphic Eruption of Pregnancy (Pruritic Urticarial Papules and Plaques of Pregnancy) 
Spongiotic dermatitis is one of the key patterns of inflammatory skin disease. The fundamental change is that of intercellular edema, producing a separation between keratinocytes. The term spongiosis is most often applied to changes within the epidermis, but there may also be spongiotic folliculitis, spongiosis resulting from rupture of an apocrine duct, and spongiosis involving the intraepidermal portions of eccrine sweat ducts. In early or limited spongiosis, the microscopic findings may be rather subtle, often consisting of a vertical orientation (“stretching”) of keratinocytes with slightly increased prominence of the spinous processes ( Fig. 1-1 ). With progression, exaggerated spaces between keratinocytes may be evident, even on low-power inspection. With increasing intercellular edema, keratinocytes may separate from one another, producing microvesicles or clinically apparent intraepidermal blisters; the prototype condition showing the latter change is acute allergic contact dermatitis, as seen, for example, in rhus (poison ivy) dermatitis ( Fig. 1-2 ). In chronic forms of spongiotic dermatitis, lesions may demonstrate significant acanthosis, with vertically oriented rete ridges producing a resemblance to psoriasis. At this stage, actual spongiotic changes in a given lesion may be subtle or nonexistent ( Fig. 1-3 ).


Figure 1-1 Early or mild spongiotic dermatitis. There is mild intercellular edema, giving a somewhat pale appearance to portions of the epidermis. Slight vertical “stretching” of keratinocytes can also be seen.


Figure 1-2 Vesicle formation in spongiotic dermatitis. In this example from a patient with allergic contact dermatitis, marked spongiosis has led to the formation of intraepidermal vesicles that were clinically apparent. There has also been exocytosis of inflammatory cells, which have accumulated within the vesicles.


Figure 1-3 Chronic spongiotic dermatitis. This lesion shows marked acanthosis. There is still evidence of disease activity, as exemplified by the parakeratosis, focal erosion, persistent spongiosis, and exocytosis.
Spongiosis is the hallmark of a category of diseases known as eczematous dermatitis (eczema is derived from a Greek word meaning “boiling over”). Sometimes the term dermatitis alone is used to refer to these disorders, but it has been used for numerous inflammatory skin diseases that may or may not be spongiotic and, therefore, should probably only be used with an appropriate modifier. Clinical conditions in the eczematous category include atopic dermatitis, contact dermatitis, seborrheic dermatitis, stasis dermatitis, and some forms of exfoliative dermatitis (erythroderma). Lichen simplex chronicus is often regarded as a chronic form of spongiotic (eczematous) dermatitis. However, spongiosis can be observed to various degrees in a number of other conditions not usually recognized as eczematous dermatoses. Examples include pityriasis rosea, small plaque parapsoriasis, arthropod reactions, miliaria (heat rash), drug reactions, and viral exanthems. In the latter conditions, spongiosis may not be of central importance, and other changes may factor into the diagnosis. This chapter will consider the major forms of spongiotic dermatitis, but spongiosis will be mentioned as a microscopic feature in a number of other conditions, described in other chapters in this book.

Forms of Eczematous Dermatitis

Contact Dermatitis

Clinical Features
Contact dermatitis is probably the best understood form of spongiotic (eczematous) dermatitis, mainly because it is the most amenable to controlled studies. It can be experimentally induced and its progress timed rather accurately. Thus, it has served as a model for understanding eczematous processes in general.
Contact dermatitis is divided into two categories: allergic and irritant contact dermatitis. Allergic contact dermatitis is a type IV, T-cell–mediated response in an individual who has been sensitized by contact with a particular antigen. These antigens consist of low-molecular-weight substances, called haptens , which combine with host protein to form complete antigens. Epidermal Langerhans cells transport antigen to regional lymph nodes via afferent lymphatics. There, naive T lymphocytes are sensitized, multiply, and circulate through the blood as memory T cells. Later, they may be recruited to the skin via cell surface molecules. 1 Cytokines released by lymphocytes largely account for the changes noted clinically and histopathologically. 2 There is a significant increase in expression of the cytotoxic granule proteins perforin and granzyme B in dermal infiltrates of allergic contact dermatitis when compared with normal skin and psoriasis. 3 A recent study suggests that mast cell production of interleukin-10 may limit the tissue damage associated with contact dermatitis, a finding that is counterintuitive given the known production of proinflammatory mediators by these cells. 4
The effects of irritants on the skin are more direct, are not manifestations of cell-mediated immunity, and are more dependent on the type and concentration of the substance involved. 5 Generally, skin biopsies are not helpful in distinguishing between irritant and allergic contact dermatitis, because these are typically obtained more than 2 days after the onset of the condition, at which point the microscopic changes are indistinguishable. 6 , 7 However, during the first 24 to 48 hours of response to a contactant, differences between the two reactions may be exploited for purposes of diagnosis under ideal conditions (see later discussion).
In contact dermatitis, pruritus is accompanied by a polymorphous eruption of macules, papules, and/or vesicles. Edema, oozing, and crusting are often present in early lesions. With chronicity, lesions may become dry, scaly, and thickened or lichenified. Moisture and maceration of lesions may be seen in intertriginous areas, and secondary infection sometimes occurs.
Dermatitis produced by irritants is confined to the area exposed to a particular substance, whereas allergic contact dermatitis may involve surfaces not in the immediate area of contact. 1 A pattern of dermatitis is sometimes discernible, suggesting the manner in which contact dermatitis occurred and sometimes providing a clue as to the specific etiology. The linear vesicles of rhus (e.g., poison ivy) dermatitis provide one example of this. Chronic forms of contact dermatitis take on the clinical characteristics of lichen simplex chronicus and may be difficult to distinguish from other forms of chronic spongiotic dermatitis. Although topical and systemic corticosteroids are capable of suppressing contact dermatitis reactions and improving existing lesions, identification and removal of the contactant is the key to treating this form of spongiotic dermatitis.

Microscopic Findings
The histopathologic findings of contact dermatitis and, in fact, all the primary forms of spongiotic (eczematous) dermatitis are often subdivided into acute, subacute, and chronic spongiotic stages. 8 In the acute phase, intercellular edema within the epidermis results in the development of intraepidermal vesicles and bullae (see Fig. 1-2 ). Some intracellular edema (ballooning) of keratinocytes is apparent, but this is typically not as pronounced as the intercellular edema and certainly not as striking as in herpesvirus infections, where intracellular edema predominates. Varying degrees of parakeratosis and serous transudation are noted at the epidermal surface. The superficial dermis features edema, vasodilatation, and a perivascular infiltrate comprised mainly of mononucleated cells, especially lymphocytes, but also macrophages and Langerhans cells. Eosinophils are often present but may not be numerous and at times are difficult to demonstrate; the author does not consider their identification necessary to make a diagnosis of contact dermatitis. Lymphocytes extend into the epidermis (exocytosis), and this feature may be particularly pronounced in allergic contact dermatitis ( Fig. 1-4 ). When eosinophils are involved in this process, the term eosinophilic spongiosis is used. The author associates the latter change somewhat more with atopic dermatitis, but it does not have the same diagnostic importance as is the case in immunobullous diseases. In the subacute phase, spongiotic changes are readily apparent but somewhat less pronounced, with formation of microvesicles rather than larger intraepidermal vesicles or bullae. A moderate degree of acanthosis is present, and there may be parakeratosis and a surface crust containing some neutrophils. In the chronic phase, the dermatitis is characterized by marked acanthosis, often associated with hyperkeratosis and hypergranulosis. Thickening of papillary dermal collagen is often noted, with vertical streaking of collagen within the papillae. Spongiosis may be present but is often inconspicuous. Lesions with these features often receive the designation lichen simplex chronicus , a term used for lesions that have been subjected to long-term rubbing or scratching.


Figure 1-4 Allergic contact dermatitis. Exocytosis is often a prominent feature.
It should be pointed out that some authorities do not use the term subacute , preferring to divide the stages of spongiotic dermatitis into acute and chronic types. This results, in part, from the considerable overlap of microscopic findings in dermatitis that has progressed beyond the acute phase.
As discussed previously, a microscopic distinction between irritant and allergic contact dermatitis is usually difficult or impossible—and, certainly, lesions of allergic contact dermatitis can also be irritated! However, some differences between the two may be discerned in biopsies of lesions less than 48 hours old. Strong irritants tend to produce ballooning of superficial keratinocytes, with varying degrees of epidermal necrosis ( Fig. 1-5 ). 8 , 9 According to one study, early biopsies of allergic contact dermatitis were more likely to show follicular spongiosis. 10 There may also be differences in dermal fibrin deposition patterns between allergic and irritant contact dermatitis, in that perivascular fibrin deposition in the papillary and reticular dermis is associated with allergic contact dermatitis. 11 A new technique called in vivo reflectance confocal microscopy indicates that irritant reactions demonstrate more prominent parakeratosis and greater disruption of the stratum corneum than is the case for allergic reactions. 12


Figure 1-5 Irritant contact dermatitis. This case occurred from exposure to ethylene oxide. A, Necrotic epidermis forms a surface crust over re-epithelialized epidermis. B, Detail of the necrotic surface, showing “mummified” epidermis that resulted from the ethylene oxide burn. Scattered lymphocytes are also present.

Differential Diagnosis
Contact dermatitis is microscopically difficult, if not impossible, to distinguish from other forms of spongiotic dermatitis, and clinical information is often essential. In working up such cases, special stains for fungal organisms may be useful, in that spongiotic dermatitis is one of the microscopic configurations that accompany dermatophytosis ( Fig. 1-6 ) and candidiasis. Cases with extensive exocytosis may be difficult to separate from mycosis fungoides, particularly because the activated T lymphocytes in chronic contact reactions may demonstrate convoluted nuclei. Aiding in this distinction are the use of published criteria for mycosis fungoides when diagnosing such lesions, such as those proposed by Guitart and colleagues, 13 immunohistochemical staining to assess for dropout of selected pan–T-cell antigens, and in some circumstances T-cell receptor gene rearrangement studies. However, it must be realized that false-positive gene rearrangement studies may sometimes occur in reactive processes. Forms of chronic spongiotic dermatitis (lichen simplex chronicus) can resemble psoriasis ( Fig. 1-7 ), because the configuration of acanthosis may be quite similar. However, psoriasis is more likely than chronic spongiotic dermatitis to have neutrophilic aggregates in the stratum corneum (Munro microabscesses) or spongiform pustulation in the superficial viable epidermis, thinning of suprapapillary plates, and edematous dermal papillae with tortuous capillaries. In one study comparing nonpustular palmoplantar psoriasis with eczematous dermatitis, the most useful discriminating diagnostic feature favoring psoriasis was the presence of vertically oriented alternating orthokeratosis and parakeratosis. 14


Figure 1-6 Spongiotic dermatitis due to dermatophyte infection. Numerous hyphae are evident in the stratum corneum.


Figure 1-7 Psoriasis with spongiosis. Spongiotic changes predominate in the lower half of the epidermis. However, there are also confluent parakeratosis with layers of neutrophils, spongiform pustulation of the viable surface epidermis, and dilated papillary dermal vessels—all characteristic features of psoriasis.

Atopic Dermatitis

Clinical Features
This form of dermatitis is inherited, although the inheritance pattern is not strictly along mendelian lines. It is often seen in families where there is a history of dermatitis, hay fever, and/or sinusitis. There is clearly an increased risk of atopic dermatitis in children of affected parents, and the majority of cases of atopic dermatitis begin in early childhood.
Criteria for the diagnosis have been developed; among these are the ones reported in a consensus conference on pediatric atopic dermatitis produced by the American Academy of Dermatology. 15 Patients must have 3 of 4 major criteria (pruritus, typical morphology and distribution of dermatitis, chronic or chronically relapsing dermatitis, and/or a personal or family history of atopy) and 3 of 22 minor criteria (e.g., elevated serum immunoglobulin E [IgE], early age of onset, Dennie-Morgan infraorbital folds). Erythematous, scaly, papular, and exudative lesions develop over the scalp, neck, and extensor extremities of infants. With advancing age, lesions develop over the face and flexural folds of extremities, and adults often manifest with chronic hand eczema or localized, sometimes coin-shaped lesions (nummular dermatitis). Papular lesions may be folliculocentric. More chronic lesions become thickened with exaggerated skin markings (“lichenified”) and are sometimes designated lichen simplex chronicus . In heavily pigmented patients, lesions may bear a close clinical resemblance to lichen planus. 16 Dermatitis is less common in patients who are past middle age. Bacteria, particularly Staphylococcus aureus , may colonize eczematous lesions and contribute to their pathogenesis; some of these strains demonstrate production of exfoliative B toxin. 17
Treatments include preventive measures (emollients, avoiding temperature extremes, and sometimes avoidance of selected foods) and therapy with topical corticosteroids and calcineurin inhibitors, antihistamines, and short courses of antibiotics. In more severe cases, systemic corticosteroids, cyclosporine, azathioprine, or phototherapy may be useful.

Microscopic Findings
Biopsy changes in active lesions include hyperkeratosis, acanthosis, focal erosions, and surface accumulation of neutrophils with staphylococcal colonization (features associated with infectious eczematoid dermatitis [not confined to atopic individuals]). Follicular spongiosis may also be present. In more chronic lesions, psoriasiform acanthosis, prominent thick-walled dermal vessels, and fibrosis of cutaneous nerves are apparent. 18 Hurwitz and DeTrana found that lesions of atopic dermatitis show a characteristic evolution from a perivascular and interstitial spongiotic dermatitis, to a psoriasiform microvesicular configuration, and finally to psoriasiform dermatitis. 19 Eosinophils may be present but are usually not prominent. However, the eosinophil product, major basic protein, can be found in lesions and is particularly abundant among those with a history of respiratory atopy. 20

Differential Diagnosis
The differential diagnosis given for contact dermatitis pertains also to atopic dermatitis. The clinical history, evolution, and distribution of lesions are strongly supportive of the diagnosis of atopic dermatitis. However, this information is not always available, and a microscopic distinction from other forms of spongiotic dermatitis may be difficult or impossible. Nevertheless, atopic dermatitis does differ somewhat from allergic contact dermatitis. In particular, the prominent vesiculation seen in acute allergic contact dermatitis is not generally characteristic of atopic dermatitis, and eosinophils and basophils are more prominent in contact dermatitis.

Seborrheic Dermatitis

Clinical Features
Clinically, seborrheic dermatitis consists of erythema with yellow, greasy scale, concentrated in the scalp, eyebrows and eyelids, nasolabial folds, and behind the ears. Similar lesions can form in the presternal region, axillae, umbilicus, and groin. It is typical in teenagers and adults, but infants can develop at least two conditions that are considered to be closely related: scalp disease, referred to as cradle cap , and a form of generalized exfoliative dermatitis, referred to as Leiner disease . Seborrheic dermatitis can be particularly severe and show an atypical distribution in acquired immunodeficiency syndrome, and it can accompany neurologic disorders such as Parkinson disease and stroke. 21 Certain drugs, including arsenic, gold, haloperidol, and cimetidine, have been associated with seborrheic dermatitis–like eruptions. A role for Malassezia organisms in the development of seborrheic dermatitis has been postulated, but specific mechanisms have yet to be worked out.
Treatments include topical corticosteroids, antifungal agents, and calcineurin inhibitors. 22

Microscopic Findings
Seborrheic dermatitis evolves through the stages of acute, subacute, and chronic spongiotic dermatitis, although the degree of intraepidermal vesiculation seen in acute contact dermatitis is generally not observed. Fully developed lesions tend to display acanthosis that is typically psoriasiform. 23 It is possible to identify parakeratosis and scattered neutrophils in the stratum corneum, 24 particularly in the vicinity of follicular ostia, as well as spongiosis and lymphocyte exocytosis ( Fig. 1-8 ).


Figure 1-8 Seborrheic dermatitis. Parakeratosis and neutrophils are apparent in the stratum corneum, features also seen in psoriasis. But no spongiform pustulation is noted, the suprapapillary plates are not thinned, and both spongiosis and lymphocyte exocytosis are visible.

Differential Diagnosis
The chief differential diagnostic problem in seborrheic dermatitis is its distinction from psoriasis. This is not necessarily a difficult task when acanthosis is irregular, suprapapillary plates are not thinned, spongiosis and exocytosis are readily demonstrable, and no spongiform pustules are noted. However, psoriasis that has been traumatized or secondarily eczematized can show considerable histopathologic overlap with seborrheic dermatitis. In such instances, clinical correlation and repeat biopsies may be necessary. Other conditions that can bear a close clinical resemblance to seborrheic dermatitis include dermatophytosis, Norwegian scabies, or Langerhans cell histiocytosis of the Letterer-Siwi type. However, these can be distinguished microscopically by the finding in tissue sections of fungal hyphae, numerous scabetic organisms, or neoplastic Langerhans cells, respectively.

Stasis Dermatitis

Clinical Features
This form of dermatitis appears most often over the lower legs as varying combinations of erythema, induration, scale, and bronze pigmentation. It is particularly prominent medially, superior to the medial malleolus. Presumably, the dermatitis results from a kind of localized nutritional deficiency that results from venous insufficiency. Stasis dermatitis is often complicated by external trauma—rubbing and scratching of pruritic skin—or superimposed allergic contact dermatitis from applications of topical agents. Papular or plaquelike lesions do occur, probably reflecting degrees of vessel proliferation that can be encountered in some cases.

Microscopic Findings
Microscopically, varying stages of spongiotic dermatitis are superimposed on dermal changes that include fibrosis and proliferations of thick-walled vessels throughout the dermis and in the subcutis ( Figs. 1-9 and 1-10 ). Pigment-containing macrophages are readily identified within the dermis; these contain hemosiderin and melanin, as can be demonstrated with stains for iron (Perls, Prussian blue) and melanin (Fontana). Research has recently shown that macrophages can demonstrate nonselective phagocytosis of both hemosiderin and melanin pigments. 25


Figure 1-9 Stasis dermatitis. Spongiosis involving the lower half of the epidermis is apparent. Fibrosis, proliferative blood vessels, and extravasated erythrocytes are present in the underlying dermis, consistent with venous stasis.


Figure 1-10 Chronic stasis dermatitis. In this more chronic example of stasis dermatitis, orthokeratosis, marked hypergranulosis, and acanthosis are present. Clusters of thick-walled vessels and fibrosis are evident in the superficial dermis.

Differential Diagnosis
Stasis dermatitis is distinguished from other forms of spongiotic dermatitis by the vascular and connective tissue changes. Proliferations of thick-walled vessels can predominate to such a degree that there is the suggestion of a vascular tumor (i.e., acroangiodermatitis of the Mali type, so-called pseudo-Kaposi sarcoma).

Other Manifestations of Spongiotic (Eczematous) Dermatitis

Photoallergic Dermatitis
This type IV cell-mediated immune reaction is induced by applied substances (photoallergic contact dermatitis) or by systemically administered medications. Examples of the former include sunscreen agents such as benzophenones and certain plants (ragweed), whereas examples of the latter include griseofulvin, sulfonamides, and chlorpromazine. In fact, certain medications can produce both phototoxic and photoallergic reactions. Dermatitis develops in areas of contact with a topical agent that are also exposed to ultraviolet light, or, in the case of systemic agents, in more generalized fashion in all sun-exposed areas. In distinction to phototoxic reactions, photoallergic reactions may spread beyond the area (areas) exposed to ultraviolet light. The lesions themselves are pruritic, sometimes papular, and eczematous. Microscopically, the features are quite similar to those of allergic contact dermatitis, although there may be somewhat deeper dermal extension of the inflammatory infiltrate (see Chapter 12 for further information). 26

Pityriasis Alba
This condition consists of hypopigmented, dry patches, often in exposed areas such as the cheeks, shoulders, or upper trunk. This dermatitis is typically more pronounced in dark-skinned individuals. It tends to become more prominent in late summer or fall and may become less pronounced in other seasons of the year. The pigment alteration is a hypopigmenting rather than a depigmenting one, as can be seen with Wood light examination or staining for melanocytes. Lesions often improve with emollients or mild topical corticosteroids. Biopsy changes are often minimal but usually include slight spongiosis, particularly involving hair follicles, a minimal perivascular round cell infiltrate, and occasional lymphocyte exocytosis. 27 , 28 The findings therefore range from slight spongiosis to those of nearly normal skin ( Fig. 1-11 ).


Figure 1-11 Pityriasis alba. The epidermal changes in this specimen are minimal. There is a slight perivascular lymphocytic infiltrate in the papillary dermis.

Pompholyx
Pompholyx is typified by the formation of numerous small vesicles that form on the palms, soles, and sides of fingers and toes. Due to the thick stratum corneum in these locations, the vesicles often have a deep-seated appearance, and some observers have likened them to frog spawn or tapioca. Patients may be atopic or have demonstrable contact hypersensitivity, and clinicians have even suspected ingestion of nickel in some cases. Some cases may actually represent autoeczematization (id) reactions (see subsequent discussion). Microscopically, the findings are those of spongiotic dermatitis with intraepidermal vesicle formation. The acrosyringia are not directly involved in the process, as had been implied by the earlier term for this condition— dyshidrosis . 29 Later accumulation of neutrophils can produce the changes of pustulosis palmaris and lead to a differential that includes localized forms of pustular psoriasis or dermatophytosis. In the workup of these cases, special staining is advised to exclude the possibility of dermatophyte infection.

Autoeczematization (Id) Reactions
These reactions compose perhaps one of the least understood phenomena in clinical dermatology. In this reactions, papules or vesicles develop in sites distant (sometimes remote) from an area of inflammation or infection. Classic examples are vesicular eruptions on the sides of the fingers in patients with inflammatory tinea pedis and papular or papulovesicular lesions following allergic contact dermatitis superimposed on stasis dermatitis. The author has also observed papular eruptions in patients with extensive rhus contact dermatitis who have been treated with inadequate tapered courses of systemic corticosteroids.
Commonly called id reactions, these lesions are frequently named for the underlying infection or other condition from which they derive; thus, there are dermatophytids, bacterids, pintids, eczematids, and even leukemids. When derived from a distant focus of infection, ids are culture negative (whereas the primary source of infection is positive), have no organisms demonstrable on special staining, and resolve with treatment of the primary infection. Presumably, ids are T-cell–mediated disorders, and some data support this assertion. 30 On biopsy, vesicular ids show spongiosis with intraepidermal vesicle formation, thus meeting criteria for acute spongiotic dermatitis ( Fig. 1-12 ). 31 Usually a degree of papillary dermal edema and a superficial perivascular round cell infiltrate, composed mainly of lymphocytes, are present. Papular ids typically show a lesser degree of spongiosis, and therefore the microscopic features are rather nonspecific, falling into a differential diagnosis that can range from forms of urticaria to drug reactions, viral exanthems, and arthropod reactions ( Fig. 1-13 ). A purpuric variant also displays extravasated erythrocytes, although without changes of true vasculitis.


Figure 1-12 Id reaction. This is a typical vesicular id located on an acral surface. It has the characteristics of an acute spongiotic dermatitis.


Figure 1-13 Id reaction, papular lesion. Spongiosis is present but less pronounced. There is a mild perivascular lymphocytic infiltrate with some erythrocyte extravasation.

Exfoliative Dermatitis (Erythroderma)

Clinical Features
Erythroderma and exfoliative dermatitis are terms that are often used interchangeably. Most examples of erythroderma are associated with increased scale and exfoliation, but there are examples of erythroderma in which scale is not a prominent feature, including the “red man syndrome” due to vancomycin or other drugs or sometimes associated with lymphoma. There are also conditions with widespread scaling in which erythema is not pronounced, such as some of the ichthyoses. Exfoliative dermatitis can develop as a systemic response (e.g., to a drug or lymphoma [most noteworthy, in the form of Sézary syndrome]), can be idiopathic, or can result from generalization of a primary cutaneous disease. Thus, psoriasis, pityriasis rubra pilaris, seborrheic dermatitis, or even allergic contact dermatitis have been associated with an exfoliative dermatitis, and congenital ichthyosiform erythroderma is an inherited form of ichthyosis that is virtually by definition an exfoliative dermatitis.
Treatment is directed toward the underlying cause of exfoliation, including, when relevant, the underlying primary dermatosis.

Microscopic Findings
Most cases show a relative hypokeratosis with parakeratosis, a diminished granular layer, acanthosis that is often psoriasiform (even in those cases not due to psoriasis), and some degree of spongiosis. Vasodilatation and a perivascular round cell infiltrate are often observed. This image unfortunately provides few clues as to the specific diagnosis. However, occasionally specific features may point to an underlying dermatosis, such as alternating orthokeratosis and parakeratosis (pityriasis rubra pilaris), spongiform pustules (psoriasis), or atypical lymphoid cells with epidermotropism or Pautrier microabscesses (Sézary syndrome). 32 Unfortunately, eosinophils can be found in exfoliative cases unrelated to drugs (even in some examples of Sézary syndrome). The author has seen lichenoid tissue changes in examples of exfoliative dermatitis, and a number of these cases have proven to be drug-related (see Chapter 3 , Psoriasiform and Lichenoid Dermatitis) ( Fig. 1-14 ). 33


Figure 1-14 Exfoliative dermatitis. This example is associated with reaction to medication. Findings include hypokeratosis with parakeratosis, spongiosis, and marked acanthosis. The dermal infiltrate is rather prominent, and exocytosis of lymphocytes and prominent apoptosis are present.

Differential Diagnosis
As mentioned, the major challenge in these cases is to find a specific primary dermatosis that might underlie the exfoliative dermatitis. Otherwise, the features often resemble other forms of spongiotic (eczematous) dermatitis. Those examples showing a lichenoid tissue reaction can closely resemble erythema multiforme, and therefore clinical data are essential in such cases.

Prurigo Simplex, Lichen Simplex Chronicus, and Prurigo Nodularis

Clinical Features
To varying degrees, three conditions represent a cutaneous response to pruritus. Prurigo simplex , the least specific of the three, is manifested by erythematous papules, sometimes papulovesicles, located over the trunk and extensor surfaces of extremities. Often there is an eroded surface, usually the consequence of excoriation. The cause is frequently difficult to determine, but reaction to arthropod or papular forms of spongiotic dermatitis (papular eczema) are among the possibilities. Lichen simplex chronicus is a change that results from chronic rubbing or other forms of irritation to the skin, resulting in thickening of the epidermis and superficial dermis. Clinically, the lesions are often well demarcated and show exaggerations of normal skin markings; hyperpigmentation often accompanies the process. A variety of forms of spongiotic dermatitis may underlie this change. Typical locations include wrists, ankles, and posterior neck. In individuals with atopic dermatitis, lichenification can be found in other flexural areas, such as antecubital fossae, with a degree of bilateral symmetry. Prurigo nodularis is characterized by the development of discrete nodules, sometimes in linear fashion, and particularly over the extremities. Lesions are often hyperpigmented. They are association with paroxysms of pruritus, which can be particularly elicited by stress.
The mainstays of treatment are topical corticosteroids and oral antihistamines. Psoralen plus ultraviolet A (PUVA) therapy has been used in prurigo simplex and prurigo nodularis, and agents such as cyclosporine and thalidomide have been used in recalcitrant cases of prurigo nodularis.

Microscopic Findings
The histopathology of prurigo simplex is nonspecific, and it includes spongiosis, with or without surface erosion, as well as a perivascular lymphocytic infiltrate, usually with eosinophils. Follicular and perifollicular spongiosis have predominated in some studies. 34 The microscopic features of lichen simplex chronicus include orthokeratosis, often with formation of a stratum lucidum—a horizontal, pale blue zone of stratum corneum immediately above the granular cell layer. This phospholipid-rich zone generally occurs only in the palms and soles, and its appearance elsewhere is a good presumptive clue to lichen simplex chronicus ( Fig. 1-15 ). The granular cell layer is typically prominent. There is vertically oriented acanthosis with exaggeration of the rete ridge pattern, often mimicking psoriasis, although the acanthosis may be quite irregular. Vertically oriented thickening of papillary dermal collagen (“vertical streaking”) is usually observed, and there is a perivascular round cell infiltrate of varying intensity in the superficial dermis. 35 Lichen simplex chronicus may be the only finding on biopsy, or it may coexist with another dermatosis, in which case its features may intermingle with or be found adjacent to the lesion. For example, changes of lichen simplex chronicus are often associated with verrucae or squamous cell carcinomas, the latter finding being particularly common on the dorsa of the hands or over the lower legs. Prurigo nodularis displays pseudoepitheliomatous hyperplasia, superficially resembling squamous cell carcinoma but without significant keratinocyte atypia ( Fig. 1-16 ). This may be accompanied by varying degrees of erosion or scale crusting (although only orthokeratosis may be seen in many cases), thickening of papillary dermal collagen, and lymphocytic perivascular inflammation ( Fig. 1-17 ). Changes of lichen simplex chronicus are sometimes identified at the periphery of foci of pseudoepitheliomatous hyperplasia. Hyperplasia of dermal nerves has been emphasized as an essential feature of prurigo nodularis and can be demonstrated with antibodies to S-100 protein and other neural stains. 36 , 37


Figure 1-15 Lichen simplex chronicus. Orthokeratosis is associated with stratum lucidum formation. Hypergranulosis, marked acanthosis, vertical streaking of papillary dermal collagen, and vasodilatation with a perivascular round cell infiltrate are also apparent. This particular example also shows a degree of papillomatosis.


Figure 1-16 Prurigo nodularis. Marked pseudoepitheliomatous hyperplasia without significant keratinocyte atypia.


Figure 1-17 Prurigo nodularis. This lesion shows more “activity” in the form of erosion, hemorrhage, inflammation, and exocytosis. Vertical streaking of papillary dermal collagen is also evident.

Differential Diagnosis
Prurigo simplex can be readily distinguished from dermatitis herpetiformis (a clinical mimic) by its lack of papillary neutrophilic microabscesses and negative or nonspecific direct immunofluorescence findings. Among other somewhat similar clinical conditions, pityriasis lichenoides et varioliformis acuta (PLEVA) shows combinations of vacuolar alteration of the basilar layer, exocytosis with keratinocyte necrosis, and/or an underlying wedge-shaped dermal inflammatory infiltrate. In addition, Grover disease (transient acantholytic dermatosis) displays epidermal acantholysis, often with the features of focal acantholytic dyskeratosis. The microscopic differential diagnosis of lichen simplex chronicus often includes psoriasis, and at times a distinction can be quite difficult. A typical plaque of psoriasis should show parakeratosis, accumulations of neutrophils in the stratum corneum (Munro microabscesses) or in the superficial spinous layer (spongiform pustules), thinning of suprapapillary plates, and edematous dermal papillae containing “tortuous” capillaries—changes not seen in lichen simplex chronicus. However, biopsied lesions of psoriasis may have been partly treated or become secondarily lichenified, in which case classic changes may be subtle or entirely absent. Pathologists should request that, whenever possible, biopsies to rule out psoriasis be obtained from lesions that show minimal secondary change or are located in hard-to-reach areas. In addition to well-differentiated squamous cell carcinoma, prurigo nodularis should be distinguished from keratoacanthoma, but the latter lesions have a well-developed keratin-filled crater with a buttressing arrangement of the adjacent epidermis, glassy-appearing cytoplasm, and often intraepidermal neutrophilic abscesses. Other forms of pseudoepitheliomatous hyperplasia that can be mimics include halogen reactions (bromoderma, iododerma), although these often show pronounced dermal edema and a neutrophilic infiltrate that may be folliculocentric, or a group of chronic cutaneous infections, the prototype of which is North American blastomycosis. Lesions that show pseudoepitheliomatous hyperplasia together with suppuration and/or granulomatous inflammation should raise suspicions for infection, and special staining for organisms is in order.

Other Conditions for which Spongiosis Is a Microscopic Hallmark

Miliaria

Clinical Features
Miliaria , the medical term for heat rash, results from obstruction of eccrine sweat ducts at varying levels and to varying degrees. Two forms are of common importance histopathologically: miliaria crystallina and miliaria rubra. In miliaria crystallina, there is either occlusion or disruption of the intracorneal (superficial) portion of the eccrine sweat duct, resulting in the formation of small, clear vesicles near the epidermal surface. 38 These particularly arise in the setting of febrile illnesses or following sunburn. Due to the superficial nature of the condition, the vesicles rupture easily, and resolution is quick once the cause has been removed. In miliaria rubra, the occlusion or disruption has occurred in deeper levels of the epidermis, resulting in the formation of itchy red papules; pustules can develop later in these lesions (miliaria pustulosa). Sweating with prolonged occlusion is usually the precipitating cause, and lesions may be seen on the back in truck drivers or under sweat bands.

Microscopic Findings
Biopsies are rarely obtained of these lesions, because the diagnosis is usually apparent clinically. However, sometimes changes of miliaria are found incidentally in biopsies obtained for other reasons. An intracorneal or subcorneal vesicle overlying the intraepidermal sweat duct is evident in miliaria crystallina ( Fig. 1-18 ), 39 whereas spongiotic intraepidermal vesicles that, on levels, appear to be associated with deeper portions of intraepidermal sweat ducts are characteristic of miliaria rubra. Exocytosis of inflammatory cells is apparent, especially in pustular lesions ( Fig. 1-19 ). 40 Papillary dermal edema and subepidermal vesiculation under these circumstances would indicate a more profound degree of sweat gland occlusion—hence the term miliaria profunda .


Figure 1-18 Miliaria crystallina. There is an intracorneal separation overlying the intraepidermal portion of an eccrine sweat duct.


Figure 1-19 Miliaria rubra/pustulosa. There is spongiosis involving the intraepidermal and superficial dermal portion of an eccrine sweat duct. Exocytosis of neutrophils has resulted in the formation of a pustule.

Differential Diagnosis
The targeting of acrosyringia in the various forms of miliaria makes the microscopic findings rather distinctive, but when miliaria coexists with other dermatoses, recognizing its changes can be a challenge. Fox-Fordyce disease (apocrine miliaria) differs in that the apocrine duct is part of the primary epithelial germ apparatus, and therefore follicular plugging and spongiosis are often the predominant microscopic features.

Small Plaque Parapsoriasis (Guttate Parapsoriasis, Digitate Dermatosis, Chronic Superficial Dermatitis, Xanthoerythrodermia Perstans)

Clinical Features
This is a troublesome diagnostic entity because of the wide variety of clinical terms (reflecting the variability in clinical appearance of the lesions), the nonspecific microscopic changes, and the opinion (held by some) that this may be an abortive or precursor lesion of mycosis fungoides. Clinically, there are discrete, reddish brown to yellow patches, with fine scale distributed over the trunk and proximal extremities. These patches may take the form of drop-shaped (guttate) lesions; small plaques; or elongated, finger-shaped lesions. Researchers have found that they tend to be persistent but relatively asymptomatic and have described the occurrence of spontaneous regression. 41 Others have detected T-cell receptor gene rearrangements in some cases, raising the aforementioned possibility of lymphoma, 42 and in fact evolution to mycosis fungoides reportedly occurs in lesions termed small plaque parapsoriasis . However, it is not clear whether these cases might have represented parapsoriasis en plaque (a known precursor—or early stage—of mycosis fungoides) with smaller lesions. 43 In the author’s view, the ultimate categorization of this group of lesions vis-à-vis lymphoma remains in doubt.

Microscopic Findings
Microscopically, changes are mild and nonspecific but include parakeratosis, 44 which may be confluent along the length of the biopsy specimen ( Fig. 1-20 ); mild to moderate acanthosis; spongiosis; and a slight perivascular inflammatory infiltrate composed of lymphocytes and a few macrophages. These features are difficult to distinguish from other mild forms of spongiotic dermatitis, 45 but they are distinct from true psoriasis and do not meet microscopic criteria for mycosis fungoides.


Figure 1-20 Small plaque parapsoriasis (digitate dermatosis). There is a confluent band of parakeratosis. The underlying epidermis is only slightly acanthotic, and a trace of spongiosis is suggested by vertical orientation of the nuclei in the left side of the figure. There is also a mild perivascular lymphocytic infiltrate.

Differential Diagnosis
In the author’s experience, an accurate diagnosis of the “small plaque parapsoriasis” group of disorders relies heavily on clinicopathologic correlation. The microscopic features alone can closely resemble low-grade forms of spongiotic dermatitis or pityriasis rosea (see later discussion).

Pityriasis Rosea

Clinical Features
This is a classic dermatologic disease, seen predominantly in younger individuals, with a distinctive clinical presentation and a histopathologic image that is characteristic, if not pathognomonic. It consists of an eruption of oval, salmon-colored, sometimes pruritic patches with “cigarette paper” wrinkling and a collarette of scale, which is usually distributed over the trunk and proximal extremities, although “inverse” distributions are sometimes reported. The eruption often begins with the development of a single lesion that may prove to be larger than subsequent ones, called a herald patch . Lesions last for up to 6 to 8 weeks and then resolve. Uncommonly (in about 2% of patients), there can be recurrences. 46 The manner of evolution of this disease has long suggested a viral etiology. This has not yet been proven, although a role for human herpesviruses 6 and 7 has been proposed, and in a recent study 7 of 34 skin specimens were positive for human herpesvirus 8 DNA sequences using polymerase chain reaction methods. 47 Pityriasis rosea–like drug eruptions have been reported with agents such as gold, captopril, and clonidine.
Treatments have included emollients and antipruritic lotions and ultraviolet therapy.

Microscopic Findings
The microscopic features include acanthosis that is typically mild to moderate, with focal spongiosis ( Fig. 1-21 ). Uncommonly, spongiotic vesicles can develop, and a rare “vesicular” pityriasis rosea has been reported. Parakeratosis tends to occur in discrete foci, called parakeratotic mounds ( Fig. 1-22 ). There is a mild lymphocytic infiltrate around papillary dermal vessels, and extravasated erythrocytes can be identified in the dermal papillae ( Fig. 1-23 ). Apoptotic keratinocytes are sometimes observed in older lesions.


Figure 1-21 Pityriasis rosea. There is definite spongiosis with mild irregular acanthosis and a perivascular and interstitial lymphocytic infiltrate.


Figure 1-22 Pityriasis rosea. This view shows a typical mound of parakeratosis.


Figure 1-23 Pityriasis rosea. Extravasated erythrocytes can be seen in the dermal papillae.

Differential Diagnosis
A specific diagnosis of pityriasis rosea is sometimes possible, even in the absence of a clinical history, if all the characteristic microscopic features are present, but otherwise the changes could suggest a variety of mild forms of spongiotic dermatitis. The author agrees with the view of Ackerman that the superficial variant of erythema annulare centrifugum can have a close microscopic resemblance to pityriasis rosea, and even a clinical resemblance, at least in terms of the individual lesions. The finding of plasma cells should prompt a consideration of syphilis (a definite clinical mimic), and special staining and/or serologic studies may be advisable.

Polymorphic Eruption of Pregnancy (Pruritic Urticarial Papules and Plaques of Pregnancy)

Clinical Features
Some authors prefer the term polymorphic eruption of pregnancy (PEP) for this and other conditions that historically have been classified separately but share the combination of a pruritic eruption and pregnancy. 48 In this disorder, urticarial papules and plaques develop, particularly over the abdomen and proximal lower extremities, and involvement of striae is common. Lesions on distal extremities are not typical but may occur. The eruption begins in the third trimester, most often during the first pregnancy, and only uncommonly recurs. Although it usually resolves with delivery, the author has occasionally seen late-onset disease that has continued several weeks after a pregnancy. The eruption has no adverse long-term effect on mother or fetus, but the pruritus can be extremely troubling, and of course treatment options are limited to antihistamines such as diphenhydramine or antipruritic lotions.

Microscopic Findings
On biopsy, PEP often shows a superficial perivascular infiltrate comprised of lymphocytes, macrophages, and usually some eosinophils. There may be minimal if any acanthosis or spongiosis ( Fig. 1-24 ), but occasionally spongiotic changes are sufficiently pronounced to produce clinically apparent vesicles ( Fig. 1-25 ). 49 , 50 Within the context of a pregnancy, this can actually prove to be a reasonably diagnostic constellation of findings. 51 , 52


Figure 1-24 Pruritic urticarial papules and plaques of pregnancy. This example shows no spongiosis and a perivascular dermal infiltrate that includes lymphocytes and scattered eosinophils.


Figure 1-25 Pruritic urticarial papules and plaques of pregnancy. This example shows spongiosis and intraepidermal vesicle formation. In this particular lesion, neutrophils have accumulated in some of the superficial vesicles.

Differential Diagnosis
The most significant differential diagnostic consideration is pemphigoid gestationis , which tends to occur late in pregnancy; this condition occurs as urticarial lesions and is quite pruritic. However, pemphigoid gestationis begins during the second trimester, often presents with bullae (vesicles may occur in PEP, but these are small and form on the basis of spongiosis), may continue following delivery (the author has seen pemphigoid gestationis continue for up to a year following parturition), and recurs with succeeding pregnancies.
Typically, papillary dermal edema and subepidermal blister formation, along with the spongiosis, also occur. Direct immunofluorescent studies are particularly helpful in this situation, because pemphigoid gestationis shows linear C3 and, sometimes, IgG deposition at the dermal-epidermal junction, whereas the changes in PEP are negative or nonspecific.

References

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25. Rivera, MR, Ishihara, M, Mihara, M. A case of non-selective phagocytosis of hemosiderin and melanin of dermal histiocytes in stasis dermatitis. Arch Dermatol Res . 2003;295:19–23.
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2
Erythemas with Perivascular Inflammation


Urticaria and Its Variants 
Papular Urticaria 
Urticarial Dermatitis 
Annular Erythemas 

Erythema Annulare Centrifugum 
Erythema (Chronicum) Migrans 
Erythema Gyratum Repens 
Other Erythemas 

Wells Syndrome (Eosinophilic Cellulitis) 
Drug-Induced Exanthems, Dermal Contact Dermatitis, Infectious (Viral) Exanthems, and Papular Id Reactions 
This chapter will consider dermatoses clinically presenting with erythema, either circumscribed or widespread, often with an edematous appearance. These lesions are often described as urticarial, and they may take the form of macules, papules, or plaques. Many conditions, of diverse etiology, share these features. They also share the microscopic features: dermal edema and a perivascular inflammatory infiltrate without overt changes of vasculitis. Inflammation may be restricted to the superficial vascular plexus or be found around both superficial and deep dermal vessels. Because of the marked clinical and microscopic overlap of these diverse conditions, dermatologists and dermatopathologists tend to use mnemonics as a way of remembering the differential diagnosis of these entities. One of the more familiar is the “5L” group of conditions: lupus erythematosus (LE), luetic disease (syphilis—particularly, secondary syphilis), light eruptions (e.g., polymorphic light eruption), lymphoma or pseudolymphoma, and lymphocytic infiltration of Jessner. 1 , 2
Unfortunately, this list is not complete, and it is necessary to include a number of other entities, including (but not limited to) annular erythemas, urticaria and its variants, drug eruptions, viral exanthems, arthropod reactions, dermal contact dermatitis, and those id reactions that lack significant epidermal involvement. Common classification systems necessitate that some of these entities be grouped in other categories; for example, LE and lymphocytic infiltration of Jessner are considered connective tissue diseases, whereas syphilis and some viral exanthems are grouped with other infectious diseases. Those erythemas with perivascular inflammation that do not fit “comfortably” in other sections are included here, but all of them are linked by their common histopathologic characteristics.

Urticaria and Its Variants


Clinical Features
Urticaria (commonly called “hives”) is characterized by erythema and edema—the typical wheal-and-flare phenomenon. It is typically pruritic, but deeper forms of urticaria may be painful. A wide variety of triggering factors has been reported, including foods, medications, infectious agents, and inhalant allergens. A form known as contact urticaria can be elicited by exposure to topical agents, including foods (fruits, raw vegetables), antibiotics, and vehicles used in topical medications. This may occur on an allergic or nonallergic basis. There is also a group of physical urticarias, such as those caused by ultraviolet light, heat, cold, water, and pressure. Cholinergic urticaria is characterized by small wheals that can be elicited by exercising or exposure to hot showers.
Frequently, urticaria is often transient. Hence, biopsies are often not performed. However, urticaria is sometimes more persistent; by definition, so-called chronic urticaria lasts 6 weeks or more. In these circumstances, or when a degree of purpura accompanies the process, there is concern about urticarial vasculitis , in which there is usually evidence of leukocytoclastic vasculitis (see Chapter 5 ). Some of these cases may simply represent small-vessel vasculitis with an urticarial component, but others may involve hypocomplementemic vasculitis, a distinctive syndrome that includes arthritis, arthralgias, and gastrointestinal or genitourinary symptoms. Hypocomplementemic vasculitis may be associated with underlying disorders such as LE or hepatitis C.

Microscopic Findings
Microscopic features of ordinary urticaria include dermal edema (which may be subtle) and a sparse perivascular infiltrate, sometimes both superficial and deep, containing mainly lymphocytes but sometimes also a few eosinophils ( Fig. 2-1 ). 2 These changes may produce a first impression of nearly normal skin. However, chronic urticaria can occasionally display a more substantial perivascular infiltrate, again with a predominance of lymphocytes and a few eosinophils. 3 Some urticarias have a neutrophilic component. These cells may be found in or around vessels in early lesions, and sometimes, in other examples, in a more diffuse distribution in the dermis. Physical urticarias, including pressure urticaria, may show a predominance of neutrophils around vessels, but without other changes associated with vasculitis ( Fig. 2-2 ). 4 , 5


Figure 2-1 Urticaria. Findings include dermal edema and a sparse perivascular infiltrate that in this case is composed mainly of lymphocytes.


Figure 2-2 Neutrophilic urticaria. The perivascular infiltrate shows a predominance of neutrophils. A, Low-power view. B, High-power view. Note the lack of leukocytoclasia. Extravasated erythrocytes are observed only at the edge of the specimen.

Differential Diagnosis
When urticarial lesions show perivascular lymphocytic infiltrates, the differential diagnosis is quite broad and includes polymorphic light eruption, drug-induced exanthem, arthropod reaction, viral exanthem, and id reaction. Although the presence of eosinophils often narrows the focus somewhat to drug or arthropod reaction, clearly eosinophils appear in urticaria due to other factors, and they may be entirely absent in reactions to arthropod or drug. The finding of diffuse neutrophils with mild perivascular inflammation also raises the possibility of cellulitis or erysipelas, and it must be remembered that bacteria are difficult to identify in tissue sections of those lesions. Neutrophilic urticarias usually lack the other features commonly associated with true vasculitis: endothelial swelling, leukocytoclasis, extravasated erythrocytes, and fibrin deposition. If those features are found, in varying combinations, one should suspect urticarial vasculitis. Direct immunofluorescence may then be helpful, in that vasculitic lesions show immunoglobulin and complement deposition in vessel walls. A recently described group of disorders termed neutrophilic urticarial dermatosis can also display leukocytoclasia; disorders showing these changes include systemic LE, Still disease (juvenile rheumatoid arthritis) and Schnitzler syndrome (chronic urticaria associated with fever, bone pain, arthralgia/arthritis, and monoclonal immunoglobulin M [IgM] gammopathy). 6 Spongiotic changes should argue against a diagnosis of urticaria, unless another process can be invoked (e.g., superimposed allergic contact dermatitis, or secondary eczematization of an urticarial lesion). The condition papular urticaria may also show spongiosis (see later discussion). It should also be recognized that a variety of dermatoses can probably have an urticarial dermal component and yet not represent a primary form of urticaria.

Papular Urticaria


Clinical Features
This condition is considered to represent a reaction to various arthropods, including fleas and bedbugs. It is most common in children. These pruritic lesions may arise in crops, and they consist of edematous papules that often have an overlying crust that has resulted from scratching.

Microscopic Findings
Microscopically, spongiosis, with or without surface erosion or shallow ulceration, overlies a superficial and deep perivascular lymphocytic and eosinophilic infiltrate. The infiltrates are heavier than those usually seen in conventional urticaria ( Fig. 2-3 ). 7 Varying degrees of dermal edema may be appreciated.


Figure 2-3 Papular urticaria. Note spongiosis, dermal edema, and a perivascular lymphocytic and eosinophilic infiltrate.

Differential Diagnosis
The epidermal changes and density of inflammation distinguish this condition from other forms of urticaria. As a practical matter, the finding of numerous eosinophils in this context usually creates the impression of a reaction to arthropod.

Urticarial Dermatitis
This is a condition defined by Kossard in 2006. 8 It includes a group of cutaneous lesions that are often loosely referred to clinically as hypersensitivity dermatitis . In this study, the clinical differential of these cases often included pemphigoid, dermatitis herpetiformis, dermatitis, drug reaction, or urticarial vasculitis. Microscopic findings included dermal edema and a superficial and deep perivascular inflammatory infiltrate that contained lymphocytes and eosinophils ( Fig. 2-4 ). There appeared to be good correlation between the clinical impression and the microscopic findings, and with time, clinicians became familiar with these lesions and often rendered a correct diagnosis of “urticarial dermatitis” prior to biopsy! This category may prove useful in providing a name for cases that have the properties of hypersensitivity but otherwise lack specific features. Hopefully, a clinical study will be able to relate these changes to a specific set of triggering factors.


Figure 2-4 Urticarial dermatitis. There is a superficial and deep perivascular dermal infiltrate. In this view, lymphocytes predominate, but eosinophils may also be observed.

Annular Erythemas
Annular erythema is a feature shared by a number of cutaneous diseases. Examples are as diverse as LE (especially subacute cutaneous LE) and dermatophytosis. However, there are three major annular erythemas that do not clearly fit into other categories: erythema annulare centrifugum, erythema (chronicum) migrans, and erythema gyratum repens. Of these, the first has fairly characteristic microscopic findings; the second has somewhat typical findings but also offers the possibility of detecting organisms; and the third is actually quite nonspecific.

Erythema Annulare Centrifugum

Clinical Features
Erythema annulare centrifugum is perhaps the best known of the annular erythemas. As the name implies, lesions have an annular, arcuate, or serpiginous border and may enlarge over time. One form of the disease consists mainly of erythema and induration, whereas another is more superficial, featuring a trailing edge of scale behind the advancing front of erythema. The cause is frequently unknown, but some cases can be related to foods (e.g., cheese mold) or medications. A relation to malignancy has been reported, suggesting a link with another annular erythema, erythema gyratum repens (see subsequent section).

Microscopic Findings
Two fairly characteristic histopathologic features have been described. The superficial variant includes focal parakeratosis, spongiosis, and a mild superficial perivascular infiltrate composed mainly of lymphocytes ( Fig. 2-5 ). Ackerman has noted the similarity of this image to pityriasis rosea, and in this connection it is worth pointing out that the clinical features of pityriasis rosea lesions often bear a striking resemblance to those of superficial erythema annulare centrifugum, the main difference being the smaller size of pityriasis rosea lesions. 9 The superficial and deep variant of erythema annular centrifugum shows essentially no epidermal change and a superficial and deep perivascular lymphocytic infiltrate ( Fig. 2-6 ). Inflammatory cells are typically tightly packed around the vessels, giving a “coat-sleeved” appearance, although scattered lymphocytes may be identified in the interstitium. 10


Figure 2-5 Erythema annulare centrifugum, superficial type. Focal parakeratosis, irregular acanthosis, spongiosis, a superficial perivascular lymphocytic infiltrate, and occasional extravasated erythrocytes are observed. The constellation of findings is quite similar to that of pityriasis rosea.


Figure 2-6 Erythema annulare centrifugum, superficial and deep types. A, There is a “coat-sleeved” perivascular lymphocytic infiltrate. B, In this example of erythema annulare centrifugum of long duration, eosinophils are also evident.

Differential Diagnosis
The microscopic findings of superficial erythema annulare centrifugum not only resemble those of pityriasis rosea but, at times, other forms of spongiotic dermatitis. Often, clinical information is necessary to make the distinction. In larger biopsies, a more or less discrete focus of parakeratosis may suggest a trailing edge of scale in cross-section. Special stains (especially periodic acid–Schiff and methenamine silver) can be obtained to exclude dermatophytosis. When fully developed, the deep form of erythema annulare centrifugum can produce a rather classic microscopic image, but earlier lesions, or those with lesser degrees of inflammation, may be difficult to distinguish from other “5L” diseases. A lack of periadnexal involvement and interstitial mucin deposition argues against LE or lymphocytic infiltration of Jessner, and the normal epidermal findings provide further evidence against LE. Polymorphic light eruption has overlapping features but often displays papillary dermal edema and may have epidermal changes such as spongiosis. Eosinophils are not common in erythema annulare centrifugum, and their presence may suggest reaction to arthropods. However, the author has seen at least one long-standing case of recurrent erythema annulare centrifugum that did display eosinophils in some of the specimens. Finally, dense perivascular lymphocytic infiltrates could raise the specter of angiocentric lymphoma, but lymphocyte atypia is minimal and gene rearrangement studies are negative in erythema annulare centrifugum.

Erythema (Chronicum) Migrans

Clinical Features
Erythema migrans is the best-known cutaneous manifestation of Lyme disease. This disorder is tick-borne and due to infection with a variety of species of Borrelia . In the United States, the best known causative agent is Borrelia burgdorferi , but Borrelia lonestari causes a similar condition in the southern part of the country. Borrelia garinii is the principal cause in Europe. An expanding erythematous ring develops around the site of the tick bite. Multiple secondary lesions form in some cases. These lesions fade in a month or so but may recur. Other findings include fever, malaise, headaches, stiff neck, and arthralgia and, later, chronic arthritis, atrioventricular block, or neurologic symptoms.
Antimicrobial therapy, particularly with doxycycline (or amoxicillin in young children) is effective, especially if used in earlier stages.

Microscopic Findings
These include a superficial and deep, perivascular and interstitial infiltrate composed of lymphocytes, plasma cells, and variable numbers of eosinophils ( Figs. 2-7 and 2-8 ). 11 Eosinophils are more numerous if biopsies are taken from the site of the tick bite. Borrelia organisms are best seen when biopsies are obtained from the annular border of a lesion. These thin structures are present in the papillary dermis, ranging from 10 to 35 microns long and 0.2 to 0.3 microns wide, and they are wavy and not coiled, as in the case of Treponema pallidum of syphilis. They may be visible with silver stains, particularly the Warthin-Starry stain. 12 However, in the author’s experience, it is extremely difficult to find convincing organisms with this method, because there is often background staining that may give the false impression of the presence of organisms. A better approach is specific immunoperoxidase staining using antibodies to various components of the Borrelia organism. 13 There is reportedly some cross-reactivity with stains for treponemal antigens, but the author has not yet had success using this method. Depending on availability, polymerase chain reaction testing is also highly specific. 14 Serologic testing is used to confirm the diagnosis of Lyme disease, although false-positive results can occur with other treponemal diseases.


Figure 2-7 Erythema chronicum migrans. There is a perivascular and interstitial dermal infiltrate. Lymphocytes predominate in this example.


Figure 2-8 Erythema chronicum migrans. Detail from another biopsy. Lymphocytes, macrophages, and eosinophils are present. Plasma cells are difficult to identify in this case.

Differential Diagnosis
From a histopathologic point of view, the author has found the diagnosis of erythema migrans, and Lyme disease, to be difficult, because the microscopic features (in the absence of identifiable organisms with special staining) are rather nonspecific. Thus, this diagnosis requires close clinicopathologic correlation. Even when a presumptive diagnosis is made, the lack of follow-up information is frustrating. Successes are no doubt more frequent in endemic areas or when specific antibodies are available for diagnosis.

Erythema Gyratum Repens

Clinical Features
This gyrate erythema is included here for completeness. It is rarely seen, and its microscopic features are nonspecific. However, its great importance lies in the strong association with internal malignancy. It is certainly one of the most dramatic clinical presentations in dermatology. In this condition, arcuate erythematous bands, sometimes with a trailing edge of scale, migrate over the skin surface. This may produce intricate patterns resembling the grain of wood. 15 , 16 Involvement is concentrated over the trunk and proximal extremities. This condition has a strong association with lung, breast, and undifferentiated carcinomas. However, similar changes have accompanied non-neoplastic conditions such as cystic hypertrophy of the breast and pulmonary tuberculosis, and they have arisen in apparently normal individuals. When associated with malignancy, the eruption has been reported to occur either before or after detection of the cancer. Erythema gyratum repens may result from lymphokines secreted by the tumors such as epidermal growth factor.

Microscopic Findings
These include foci of parakeratosis and spongiosis and a moderately intense, perivascular infiltrate concentrated around vessels of the superficial to mid-dermis, composed of lymphocytes and macrophages. 16 , 17 In some reports, the infiltrates have been more diffuse or contained eosinophils. 15 , 18 On direct immunofluorescence, granular IgG and C3 deposition have been seen along the dermal-epidermal junction, but the significance of these findings is not entirely clear.

Differential Diagnosis
As previously mentioned, the histopathologic image of this entity is quite nonspecific. Basically, a diagnosis of erythema gyratum repens depends on the clinical presentation, which as mentioned is usually quite striking. However, the microscopic findings can be supportive of the diagnosis. The combination of focal parakeratosis, spongiosis, and a superficial perivascular lymphocytic and macrophagic infiltrate can also be seen in the superficial variant of erythema annulare centrifugum, and it should be noted that in some case reports, erythema gyratum repens has begun as a more localized annular erythema with clinical features that do resemble erythema annulare centrifugum. Histopathologic evaluation can be important in excluding other annular erythemas that might clinically mimic erythema gyratum repens, such as dermatophyte infection (organisms should be detectable in the stratum corneum with periodic acid–Schiff or silver methenamine stains) or subacute cutaneous LE (interface rather than spongiotic dermatitis, often with dermal mucin deposition).

Other Erythemas

Wells Syndrome (Eosinophilic Cellulitis)

Clinical Features
This condition consists of erythematous plaques with a resemblance to cellulitis that tend to be persistent. 19 They can arise at any age, and recurrences are common. Reaction to an arthropod is usually most strongly suspected, but other possible triggering factors include parasitosis, viral infections, or reaction to medications. It has not been determined whether Wells syndrome is a specific disease entity or a reaction pattern to a number of antigenic stimuli.

Microscopic Findings
Histopathologic changes are characteristic, and they include dermal edema and a perivascular and interstitial infiltrate comprised of a variety of cell types but, most prominently, of eosinophils ( Fig. 2-9 ). The best-known features are the flame figures, bright red streaks within the connective tissue that result from deposition of eosinophil major basic protein on collagen bundles. 20 These structures may show some basophilia at their periphery. Eventually, small granulomas can surround these flame figures ( Fig. 2-10 ). The process occasionally is concentrated in the subcutis, where it may be termed eosinophilic panniculitis .


Figure 2-9 Wells syndrome (eosinophilic cellulitis). There is a perivascular and interstitial dermal infiltrate containing large numbers of eosinophils. Several flame figures are evident.


Figure 2-10 Wells syndrome with flame figures. A, Early flame figure, showing degranulation of eosinophils with deposits of granules on collagen bundles. B, Macrophage formation around cross-sectional profiles of collagen-containing eosinophil granules. C, Fully formed flame figure, surrounded by granulomatous inflammation.

Differential Diagnosis
Flame figures are a hallmark of Wells syndrome, but they are not always present or obvious (particularly in early lesions). In addition, they can be identified in other dermatoses characterized by numerous eosinophils, including dermatophytosis, bullous pemphigoid, and eczematous disorders . 21 , 22 Therefore, histopathologic suspicion of Wells syndrome should be correlated with clinical findings for confirmation. However, it has also been the author’s experience that well-formed and/or numerous flame figures are generally evident in situations where Wells syndrome is the leading clinical diagnosis.

Drug-Induced Exanthems, Dermal Contact Dermatitis, Infectious (Viral) Exanthems, and Papular Id Reactions
Drug-induced exanthems with maculopapular clinical morphology often show superficial perivascular infiltrates composed of lymphocytes and some eosinophils, with few other specific changes ( Fig. 2-11 ). When given a strong clinical suspicion, a list of the patient’s medications, and information about the timing of those medications, it is sometimes possible to identify the most likely inciting agents.


Figure 2-11 Drug-induced exanthem. Mild acanthosis with spongiosis and a perivascular lymphocytic and eosinophilic dermal infiltrate are present.
Dermal contact dermatitis can be extremely difficult to diagnose without a clinical history, but the distribution of the dermatitis and history of exposure to certain agents can be decisive. For example, inflammatory lesions without scale on the upper lateral thigh, in the area of a pocket where change is kept, might suggest a reaction to nickel, a known cause of the dermal variant of contact dermatitis. Other causes of this reaction include gold, neomycin, formaldehyde, and ragweed. Dermal edema and a superficial perivascular lymphocytic infiltrate, sometimes with eosinophils, with minimal overlying epidermal change, typify this type of reaction ( Fig. 2-12 ), but it is clear from this description that clinical information is essential.


Figure 2-12 Dermal contact dermatitis. There are dermal edema and a perivascular lymphocytic infiltrate. Epidermal changes are minimal. Nickel, gold, neomycin, formaldehyde, and ragweed are known causes of this variant of contact dermatitis.
Viral exanthems often show a nonspecific microscopic image, including a superficial perivascular lymphocytic infiltrate with or without recognizable edema. Suspicion for this cause tends to be particularly high in children with a negative history of drug or arthropod exposure ( Fig. 2-13 ).


Figure 2-13 Viral exanthem. This lesion shows spongiosis and a superficial perivascular lymphocytic infiltrate.
Papular id reactions may not show obvious spongiosis on biopsy, and therefore microscopic features tend to be nonspecific, essentially consisting of superficial dermal patchy perivascular lymphocytic infiltrates. The purpuric variant also displays extravasated erythrocytes, without evidence of true vasculitis. A history of a distant focus of inflammation or infection supports the diagnosis of id reaction (see Chapter 1 ).

References

1. Lever, WF, Schaumburg-Lever, G. Connective tissue diseases. Histopathology of the Skin , 7th ed. Philadelphia: JB Lippincott; 1990. [497].
2. Synkowski, DR, Levine, MI, Rabin, BS, et al. Urticaria. An immunofluorescence and histopathology study. Arch Dermatol . 1979;115:1192–1194.
3. Stewart, GE, II. Histopathology of chronic urticaria. Clin Rev Allergy Immunol . 2002;23:195–200.
4. Winkelmann, RK. Cholinergic urticaria shows neutrophilic inflammation. Acta Derm Venereol . 1985;65:432–434.
5. Peters, MS, Winkelmann, RK. Neutrophilic urticaria. Br J Dermatol . 1985;113:25–30.
6. Kieffer, C, Cribier, B, Lipsker, D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature. Medicine (Baltimore) . 2009;88:23–31.
7. Jordaan, HF, Schneider, JW. Papular urticaria: a histopathologic study of 30 patients. Am J Dermatopathol . 1997;19:119–126.
8. Kossard, S, Hamann, I, Wilkinson, B. Defining urticarial dermatitis: a subset of dermal hypersensitivity reaction pattern. Arch Dermatol . 2006;142:29–34.
9. Bressler, GS, Jones, RE, Jr. Erythema annulare centrifugum. J Am Acad Dermatol . 1981;4:597–602.
10. Ellis, FA, Friedman, AA. Erythema annulare centrifugum (Darier’s): clinical and histologic study. AMA Arch Derm Syphilol . 1954;70:496–507.
11. Berger, BW, Clemmensen, OJ, Ackerman, AB. Lyme disease is a spirochetosis. A review of the disease and evidence for its cause. Am J Dermatopathol . 1983;5:111–124.
12. Berger, BW. Erythema chronicum migrans of Lyme disease. Arch Dermatol . 1984;120:1017–1021.
13. Eisendle, K, Grabner, T, Zelger, B. Focus floating microscopy: “gold standard” for cutaneous borreliosis? Am J Clin Pathol . 2007;127:213–222.
14. Zore, A, Ruzic-Sabljic, E, Maraspin, V, et al. Sensitivity of culture and polymerase chain reaction for the etiologic diagnosis of erythema migrans. Wien Klin Wochenschr . 2002;114:606–609.
15. Leavell, UW, Jr., Winternitz, WW, Black, JH. Erythema gyratum repens and undifferentiated carcinoma. Arch Dermatol . 1967;95:69–72.
16. Gammel, JA. Erythema gyratum repens: skin manifestations in patient with carcinoma of breast. AMA Arch Derm Syphilol . 1952;66:494–505.
17. Holt, PJ, Davies, MG. Erythema gyratum repens—an immunologically mediated dermatosis? Br J Dermatol . 1977;96:343–347.
18. Skolnick, M, Mainman, ER. Erythema gyratum repens with metastatic adenocarcinoma. Arch Dermatol . 1975;111:227–229.
19. Wells, GC, Smith, NP. Eosinophilic cellulitis. Br J Dermatol . 1979;100:101–109.
20. Brehmer-Andersson, E, Kaaman, T, Skog, E, et al. The histopathogenesis of the flame figure in Wells’ syndrome based on five cases. Acta Derm Venereol . 1986;66:213–219.
21. Wood, C, Miller, AC, Jacobs, A, et al. Eosinophilic infiltration with flame figures. A distinctive tissue reaction seen in Wells’ syndrome and other diseases. Am J Dermatopathol . 1986;8:186–193.
22. Lee, S, Park, J, Kim, D, et al. Flame figures in molluscum contagiosum. Am J Dermatopathol . 2004;26:441–442.
3
Psoriasiform and Lichenoid Dermatitis


Psoriasiform Dermatitis 

Psoriasis and Variants 
Reiter Syndrome 
Pityriasis Rubra Pilaris 
Lichenoid Dermatitis 

Lichen Planus 
Lichenoid Keratosis (Benign) 
Lichenoid Drug Eruption 
Lichenoid and Granulomatous Dermatitis 
Lichen Nitidus 
Lichen Sclerosis (et Atrophicus) 
Erythema Dyschromicum Perstans 
Keratosis Lichenoides Chronica 
Lichen Striatus 
Pityriasis Lichenoides 
Poikiloderma Atrophicans Vasculare 
Graft-versus-Host Disease 
Eruption of Lymphocyte Recovery 
Two important epidermocentric patterns are represented by psoriasiform and lichenoid dermatitis. Both display acanthosis. In psoriasiform dermatitis, this often takes the form of markedly elongated rete ridges (vertical acanthosis) with preservation of the basilar layer. Parakeratosis frequently accompanies these conditions, a reflection of rapid epithelial turnover. Neutrophils comprise a fundamental inflammatory cell type and can be of great diagnostic importance. In lichenoid dermatitis, acanthosis tends to be broad, often with loss of identifiable rete ridges (horizontal acanthosis). The basilar layer shows evidence of vacuolization (vacuolar alteration of the basilar layer), and necrotic or apoptotic keratinocytes are easily identifiable. In contrast to psoriasiform change, the stratum corneum tends to be compact and orthokeratotic, and the granular layer is prominent, an indicator of slower epithelial turnover.
These microscopic changes are among the most recognizable in dermatopathology. Although the prototypical lesions showing these changes are psoriasis and lichen planus, there are groups of conditions, not readily assignable to other categories, that can mimic both of these entities. Examples include pityriasis rubra pilaris and Reiter syndrome (resembling psoriasis) or keratosis lichenoides chronica and lichen striatus (resembling lichen planus). Moreover, lesions in other categories can closely mimic these disorders, such as chronic spongiotic dermatitis or lichen simplex chronicus (resembling psoriasis) or lichenoid drug eruption (resembling lichen planus). Therefore, differential diagnosis becomes an important exercise when attempting to diagnose these disorders.

Psoriasiform Dermatitis

Psoriasis and Variants

Clinical Features
Psoriasis is one of the most distinctive of cutaneous diseases, and its diagnosis and management have been a central concern among practitioners of dermatology. It can be classified as a hyperproliferative disorder of epidermis that is best known for producing erythematous, hyperkeratotic plaques, although it may assume a variety of forms. In addition to plaque-type psoriasis , which involves particularly the scalp, portions of the trunk, and extensor surfaces of the extremities, the following clinical types are frequently encountered:

•  Guttate psoriasis: This type of psoriasis consists of an eruption of small, drop-shaped lesions. It typically follows infections (especially streptococcal pharyngitis), and investigators have reported an association with glomerulonephritis in this context. 1
•  Pustular psoriasis: This category includes pustules involving plaques and generalized (von Zumbusch) pustular psoriasis. In the latter condition, patients are typically quite ill with fever, hypocalcemia, and sometimes respiratory distress syndrome or congestive heart failure.
•  Localized pustular disease: There are several pustular eruptions that are generally confined to the hands and feet. These include acrodermatitis continua of Hallopeau (or dermatitis repens), a pustular eruption that typically involves a single digit—often resulting in loss of the affected nail—or shows an asymmetrical distribution; pustular bacterid of Andrews, a bilaterally symmetrical eruption involving palms and soles, possibly related to a distant focus of infection; and pustulosis palmaris et plantaris, a problematic disorder whose relation to psoriasis is sometimes disputed. Some examples are associated with sternoclavicular hyperostosis, forming part of a syndrome defined by the acronym SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis); there is an increased prevalence of human leukocyte antigen (HLA)-B27 in these patients. 2 , 3
•  Erythrodermic psoriasis: This form can resemble, and be difficult to differentiate from, exfoliative erythroderma of other etiologies. See Chapter 1 for further details.
•  Psoriatic arthritis: Psoriasis can be accompanied by arthritis of varying types and degrees, ranging from arthritis mutilans to ankylosing spondylitis. A significant percentage of these patients are positive for HLA-B27. Knowledge about the existence of arthritis in a particular patient with suspicious cutaneous lesions can raise awareness of the possibility of psoriasis.
The etiology and pathogenesis of psoriasis appear to be multifactorial. There is a complex inheritance pattern, and a link with certain HLA types and an increase in the cutaneous expression of certain genes are well established. Certain cytokines, particularly the interleukins, and a predominance of certain T-cell populations are important in the disease. Bacteria, particularly streptococci, may lead to flare-ups of psoriasis, and certain drugs, including antimalarials, beta blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, and lipid-lowering agents, may induce it or make it worse. Pregnancy generally has a salutary effect on psoriasis, but the condition known as impetigo herpetiformis , basically a form of generalized pustular psoriasis, is specifically associated with pregnancy.
Topical or intralesional corticosteroids are of therapeutic benefit, but systemic corticosteroids should be avoided, due to the risk of rebound flares of the disease or the induction of pustular psoriasis. 4 , 5 Other topical treatments include tars, retinoids, calcineurin inhibitors, and calcipotriene. Ultraviolet light, including psoralen and ultraviolet A (PUVA) therapy, is particularly effective, but long-term risks of squamous cell carcinoma or melanoma are definite concerns. Systemic agents include methotrexate, cyclosporine, or the newer biologic agents. Antibiotics can be helpful to address the superantigen effects of bacterial exotoxins. 6

Microscopic Findings
In classic, plaque-type psoriasis , there is marked acanthosis, characterized by pronounced and often quite regular elongation of rete ridges ( Fig. 3-1 ). These ridges often display club-shaped tips. The intervening suprapapillary plates are thinned, a finding that is best demonstrated when tissue sections are completely vertical. The stratum corneum is parakeratotic, and confluent parakeratosis is common. As might be expected in conditions showing rapid epithelial turnover, the granular cell layer is reciprocally diminished or absent. However, lesions of psoriasis are often episodic or partly treated, so coexistence of a prominent granular cell layer with parakeratosis is sometimes seen. Of great diagnostic importance are neutrophils, which migrate through the epidermis, forming aggregates within the stratum corneum (Munro microabscesses), or collecting in the distal portion of the stratum spinosum, where they are surrounded by spongiotic spaces. The latter finding is termed spongiform pustulation (the spongiform pustule of Kogoj) ( Fig. 3-2 ). These arrangements of neutrophils, particularly in the absence of serous transudation or scale-crust formation, can often allow for a definitive diagnosis. Within the dermal papillae are tortuous, dilated capillaries ( Fig. 3-3 ). The bleeding points that are often observed clinically when scale is removed from lesions (Auspitz sign) result from disruption of these vessels. Within the dermis is a mixed perivascular and interstitial inflammatory infiltrate containing lymphocytes and some neutrophils.


Figure 3-1 Psoriasis, plaque lesion. Note regular acanthosis, slight clubbing of rete ridges, and thinned suprapapillary plates.


Figure 3-2 Psoriasis, plaque lesion. There are confluent parakeratosis and spongiform pustulation.


Figure 3-3 Psoriasis, plaque lesion. Papillary dermal capillaries are dilated and tortuous.
The changes in guttate psoriasis are more subtle, because the lesions rapidly evolve and therefore do not display the same degree of acanthosis. However, even in these lesions, surface collections of neutrophils, forming Munro microabscesses or spongiform pustules, can often be identified ( Fig. 3-4 ).


Figure 3-4 Guttate psoriasis. A small spongiform pustule can be seen on the right side of the figure.
In pustular psoriasis , including localized and generalized forms, spongiform pustules become quite large, dominating the histopathologic image ( Fig. 3-5 ). In pustulosis palmaris et plantaris, an initial influx of lymphocytes into the epidermis is eventually replaced by neutrophils, forming a unilocular intraepidermal pustule ( Fig. 3-6 ). Spongiotic change is often noted in the adjacent epidermis, and the presence of scattered neutrophils in these foci produces the appearance of spongiform pustulation. The configuration of these lesions has suggested to some that pustulosis palmaris et plantaris is a different disease from psoriasis, representing perhaps secondary pustule formation in what would otherwise be considered a form of spongiotic dermatitis. Possible clinical examples include pompholyx or vesicular id reactions with secondary pustule formation. This issue has not been completely resolved.


Figure 3-5 Pustular psoriasis. The microscopic image is dominated by spongiform pustulation.


Figure 3-6 Pustulosis palmaris et plantaris. There is a unilocular intraepidermal pustule.
Some, but not all, examples of erythrodermic psoriasis may display the typical neutrophilic components of psoriasis. In other instances, the changes may be nonspecific, resembling other forms of erythroderma.
The need for a specific diagnosis of psoriasis places a premium on lesion selection. It is essential that the clinician try to choose a lesion that does not display evidence of secondary change, such as erosion or surface crusting. In addition, partial treatment of psoriatic lesions can alter the microscopic image by obscuring or obliterating the most helpful morphologic findings. Therefore, patches that are relatively new or exist in hard-to-reach areas may display the most diagnostic features.

Differential Diagnosis
Several conditions fall into the differential diagnosis of psoriasis. Chronic forms of spongiotic dermatitis are perhaps the most troublesome, sometimes displaying a pattern of acanthosis that is almost identical to that of psoriasis. Spongiosis is certainly a major differentiating feature, but spongiosis can be seen in lesions of psoriasis ( Fig. 3-7 ), especially if they have been traumatized. In a recent study comparing the microscopic features of nonpustular palmoplantar psoriasis and eczematous dermatitis, the only difference that achieved statistical significance was the presence of multiple vertically oriented parakeratotic foci alternating with orthokeratosis; interestingly, spongiotic vesicles were seen in most of the psoriatic lesions. 7 When identified in the epidermis of patients with spongiotic (eczematous) lesions, neutrophils are typically associated with serous transudation or scale-crusting; therefore the finding of pure neutrophilic aggregates within parakeratotic stratum corneum is a finding favoring psoriasis.


Figure 3-7 Psoriasis with spongiosis. In addition to confluent parakeratosis, Munro microabscesses, and spongiform pustulation, there is also significant spongiosis involving the lower half of the epidermis.
Spongiform pustules can be identified in several other conditions. Two of these, Reiter syndrome and geographic tongue, are likely to be closely related to psoriasis, and as previously mentioned, impetigo herpetiformis is generally regarded to be pustular psoriasis of pregnancy. Lesions of candidiasis can display spongiform pustulation, and dermatophytosis may show neutrophils within the stratum corneum. However, unlike psoriasis, the stratum corneum in dermatophytosis often consists of compact orthokeratosis or basket-woven keratin, and in both conditions, organisms can frequently be identified by special staining. Necrolytic migratory erythema, a disorder usually associated with glucagonoma, has been reported to show spongiform pustulation, but often there is vacuolization of the surface epidermis, a finding typical of nutritional deficiency disorders but not characteristic of psoriasis. Subcorneal pustular dermatosis shows a discrete subcorneal pustule without formation of Munro microabscesses and with minimal if any evidence for spongiform pustulation; psoriasiform acanthosis is not observed. Those examples that display intercellular immunoglobulin A (IgA) deposition on direct immunofluorescence represent examples of IgA pemphigus. Other conditions that can display psoriasiform acanthosis, such as parapsoriasis (digitate dermatosis; see Chapter 1 ) or pityriasis rubra pilaris (see subsequent discussion), lack the characteristic neutrophilic aggregates and usually fail to display the degree of acanthosis seen in fully developed lesions of psoriasis.

Reiter Syndrome

Clinical Features
This syndrome consists of a triad of urethritis, arthritis, and conjunctivitis. A fourth component, skin lesions, can often be identified. These take the form of hyperkeratotic, pustular lesions involving particularly the soles of the feet (termed “mountain range” hyperkeratosis or keratoderma blenorrhagicum ), keratotic lesions in other areas of skin with a “rupioid” appearance (pustular lesions that accumulate thick scale), balanitis circinata sicca, and mucosal erosions. The condition typically occurs following a bout of urethritis or diarrhea, often in an individual who is HLA-B27 positive. Among the organisms implicated are Chlamydia and Ureaplasma . 8
Treatment for Reiter syndrome includes antibiotics and methotrexate.

Microscopic Findings and Differential Diagnosis
Microscopically, the lesions closely resemble those of psoriasis, especially pustular psoriasis ( Fig. 3-8 ). However, some of them, particularly the rupioid lesions or those of keratoderma blenorrhagicum, show an exaggerated degree of hyperkeratosis and parakeratosis, with more profound neutrophilic infiltration and spongiform pustulation ( Fig. 3-9 ).


Figure 3-8 Reiter syndrome. The image is similar to that of pustular psoriasis, although spongiform pustulation is not evident in this particular lesion.


Figure 3-9 Reiter syndrome. This lesion shows an exaggerated degree of hyperkeratosis and parakeratosis with spongiform pustulation, as is often seen on the soles of the feet.

Pityriasis Rubra Pilaris

Clinical Features
Pityriasis rubra pilaris (PRP) is a hyperkeratotic condition that often initially manifests as conical follicular papules with keratotic centers and sometimes pierced by a hair shaft. Patches of erythema with scale occur particularly over the scalp (resembling seborrheic dermatitis), neck, trunk, and extensor extremities. Palmoplantar keratoderma often occurs. Lesions may remain localized, particularly in one juvenile variant, 9 or may become widespread, producing an erythroderma but with characteristic “islands of sparing.” The erythema has a distinctly salmon color. The cause of this disorder is unknown.
Treatments include systemic retinoids and methotrexate.

Microscopic Findings
Biopsies of PRP lesions demonstrate hyperkeratosis and acanthosis that tends to be mild to moderate ( Fig. 3-10 ). Foci of parakeratosis are evident, and one of the most characteristic findings is alternating orthokeratosis and parakeratosis, in both horizontal and vertical directions, sometimes producing a “checkerboard” configuration ( Fig. 3-11 ). 10 When follicular units are included in the biopsy specimen, follicular hyperkeratosis with adjacent “shoulders” of parakeratosis can be identified ( Fig. 3-12 ). 11 Studies have described acantholytic foci, but these are not seen in all cases ( Fig. 3-13 ). 11 , 12 Inflammation tends to be slight and nondiagnostic.


Figure 3-10 Pityriasis rubra pilaris. In this low-power view, hyperkeratosis, involving both epidermis and follicular units, and a typical degree of acanthosis are apparent.


Figure 3-11 Pityriasis rubra pilaris. Two examples ( A and B ) of alternating orthokeratosis and parakeratosis, in both horizontal and vertical directions.


Figure 3-12 Pityriasis rubra pilaris, follicular hyperkeratosis. Shoulders of parakeratosis are present but rather faint in this example.


Figure 3-13 Pityriasis rubra pilaris. A focus of acantholysis.

Differential Diagnosis
The microscopic differential diagnosis may include psoriasis, but PRP tends to show modest degrees of acanthosis while lacking the thinning of suprapapillary plates or the neutrophilic infiltration expected in psoriasis. Although psoriasis can show vertically oriented parakeratosis alternating with orthokeratosis, the “checkerboard” configuration of PRP is not observed. When present, acantholysis would argue against psoriasis, which does not display that feature. PRP can also resemble other lesions showing modest acanthosis, including chronic spongiotic dermatitis or parapsoriasis (digitate dermatosis). Spongiosis is generally not observed in PRP, but when lesions in the “spongiotic” category lack significant spongiotic change on microscopic examination, differentiation may be quite difficult. Horizontal and vertical alternating orthokeratosis and parakeratosis would not be expected in conditions other than PRP. Unfortunately, this feature is not always present, but extra levels from the paraffin block are sometimes useful to demonstrate the finding. The presence of follicular hyperkeratosis with shouldered parakeratosis may be an additional feature pointing to a diagnosis of PRP, but this feature could potentially be mimicked in individuals with atopic dermatitis with follicular involvement or in patients with coincidental keratosis pilaris.

Lichenoid Dermatitis
This group of dermatoses is characterized by vacuolar alteration of the basilar layer of the epidermis, apoptotic (necrotic) keratinocytes, and upper dermal infiltrates of varying intensity. It derives its name from the prototypical disorder, lichen planus. Variations in microscopic configuration have led to the alternative term interface dermatitis and the use of subcategories such as lichenoid, poikilodermatous, and pigmented dermatosis.
The possible mechanisms leading to lichen planus and other lichenoid dermatoses have long been of interest to investigators. It had been believed that lichen planus was a disorder of slow epithelial turnover, suggesting a shift of cells away from proliferating basilar cells towards more mature granular and keratinized cells. However, both increased labeling index and increased rate of corneocyte layer formation have been detected, suggesting continuous erosion and repopulation of the epidermis following microinjury. 13 Changes in basal keratinocytes are associated with altered fibronectin distribution, or fibronectin loss, in several lichenoid disorders, including lichen planus, lupus erythematosus (LE), and lichen sclerosus et atrophicus. A T-lymphocyte attack on the epidermis is important in lichen planus and related disorders and may be the principal event in lichenoid tissue reactions. These cells may be attracted by T-cell growth factors or interleukin-3, and their adhesion to keratinocytes mediated by lymphocyte function-associated antigen on lymphocytes and intercellular adhesion molecule-1 (ICAM-1) on keratinocytes. Apoptosis is a hallmark of lichenoid tissue reactions, and T lymphocytes again may be involved in this process.
A listing of the major lichenoid disorders is provided in Box 1-1 . Certain entities are discussed in this chapter, and others are discussed elsewhere.

Box 1-1    Major Disorders Characterized by Lichenoid Tissue Reaction

Lichen Planus–Like

Lichen planus *
Lupus erythematosus (see Chapter 8 )
Lichen nitidus *
Lichenoid keratosis *
Lichenoid drug eruption *
Lichenoid actinic keratosis (see also Chapter 18 )
Lichen sclerosus et atrophicus *
Lichen amyloidosus (see Chapter 9 )
Erythema dyschromicum perstans *

Poikiloderma

Poikiloderma atrophicans vasculare *
Parapsoriasis with poikiloderma (see also Chapter 27 )
Lupus erythematosus (see Chapter 8 )
Dermatomyositis (see Chapter 8 )

Lichenoid Disorders with Lymphocytic “Vasculitis”

Erythema multiforme (see Chapter 4 )
Fixed drug eruption (see Chapter 12 )
Toxic epidermal necrolysis (see Chapter 4 )
Secondary syphilis (see Chapter 17 )
Pityriasis lichenoides *
Mycosis fungoides (see Chapter 27 )
Lymphomatoid papulosis (see Chapter 27 )

Regressing Lesions

Seborrheic keratosis, basal cell carcinoma, porokeratosis (see Chapter 18 )
Verrucae (see Chapter 17 )

Drugs and Physical Agents

High-dose radiotherapy, subacute radiation dermatitis (see Chapter 12 )
Phototoxic dermatitis/photosensitivity disorders (see Chapter 12 )
Chemotherapy for malignancy, morbilliform drug eruptions (see Chapter 12 )
Reactions to red tattoos (see Chapter 11 )

Other Dermatoses and Disease Associations

Graft-versus-host disease *
Eruption of lymphocyte recovery *
Keratosis lichenoides chronica *
Lichen striatus *
Lentigo maligna (see Chapter 28 )
Herpes simplex lesions (see Chapter 17 )
Exfoliative dermatitis *
* These entities are discussed in this chapter, whereas others, primarily because of their pathogenesis, are discussed in other chapters, as indicated in parentheses.

Lichen Planus

Clinical Features
Lichen planus is an extremely pruritic condition characterized by the eruption of violaceous, flat-topped, angulated papules with a predilection for flexural areas of the wrists and forearms, lower legs, genitalia, and oral mucosa. The etiology is unclear; studies have proposed that hepatitis C infection may play a role, particularly in oral lichen planus. 14 – 16 Mucous membrane lesions may be erosive and painful. On the buccal mucosa, they often form reticulated, lacelike, white lines. White streaks running through the cutaneous lesions are termed Wickham striae . New lesions develop in linear array in areas of superficial trauma, and this arrangement is known as the Koebner phenomenon . Lesions located particularly on the lower legs may become hypertrophic and can both clinically and microscopically resemble squamous cell carcinoma. Various forms of nail dystrophy can develop, including some examples of so-called “twenty-nail dystrophy.” Lichen planus targeting follicular units is termed lichen planopilaris . It most often presents as a form of alopecia; therefore, it will be discussed in depth in Chapter 14 . However, lesions of lichen planopilaris can develop on glabrous skin, where it produces conical rather than flat-topped, angulated papules. On occasion, this variant can also involve the eyebrows, axillae, and pubic areas in addition to the scalp; this constitutes the Graham-Little syndrome. 17
In the author’s experience, true lichen planus is uncommon, and I tend to see many more cases that prove to be lichenoid keratoses or lichenoid drug eruption (see later discussion). In addition, a bullous eruption develops in some patients with lichen planus, termed lichen planus pemphigoides . These bullae do not arise in the more typical lichen planus lesions and have characteristics in common with bullous pemphigoid. This condition is discussed in Chapter 4 .

Microscopic Findings
Microscopically, the changes are quite recognizable. They include compact hyperkeratosis (orthokeratosis), hypergranulosis that is often wedge-shaped, broad acanthosis with obscuring of the usual rete ridge pattern, vacuolar alteration of the basilar layer with formation of numerous apoptotic (necrotic) keratinocytes, and a bandlike dermal infiltrate composed mainly of lymphocytes and macrophages ( Fig. 3-14 ). Plasma cells are typically absent, except in some mucous membrane lesions. However, the author has been struck by the frequent scarcity of plasma cells in lichen planus, even in mucosal lesions ( Fig. 3-15 ). The vacuolar alteration results in loss of the normally palisaded basilar keratinocytes, so that the base of the epidermis has a sharp, toothlike appearance (“saw toothing” of the epidermal base). Cleftlike spaces form between the altered basilar epidermis and the underlying dermis; these are termed Max-Joseph clefts. These can occasionally be sufficiently extensive to produce a clinically apparent subepidermal bulla ( Fig. 3-16 ). Typically, the dermal infiltrate is heavy and bandlike, but early lesions may show milder, more patchy inflammation involving the superficial dermal vascular plexus, whereas older or partly treated lesions may display diminished inflammation. Although the epidermis is usually acanthotic, atrophic variants also occur (see Fig. 3-16 ), and hypertrophic variants display pseudoepitheliomatous hyperplasia ( Fig. 3-17 ). The latter can be a particular challenge, in part because of a resemblance to squamous cell carcinoma, 18 in part because the characteristic basilar changes and inflammation may not be readily apparent. In addition, there have been reports of squamous cell carcinoma arising from hypertrophic lichen planus ( Fig. 3-18 ). 19 Lichen planopilaris shows, in addition to (or instead of) the typical epidermal changes, dense lymphocytic infiltrates around follicular units with vacuolar alteration of outer root sheath epithelium ( Fig. 3-19 ).


Figure 3-14 Lichen planus. Features include hyperkeratosis; hypergranulosis with a somewhat wedge-shaped configuration; evidence for vacuolar alteration of the basilar layer with pigmentary incontinence; and a bandlike, predominantly lymphocytic upper dermal infiltrate partly obscuring the dermal-epidermal interface.


Figure 3-15 Lichen planus of the tongue. A, Typical low-power configuration of lichen planus. B, On high-power examination, plasma cells are difficult to identify.


Figure 3-16 Lichen planus. This is an example of atrophic lichen planus. Loss of cohesion at the dermal-epidermal junction has led to formation of a subepidermal bulla.


Figure 3-17 Lichen planus, hypertrophic type.


Figure 3-18 Lichen planus and squamous cell carcinoma. In addition to changes of lichen planus, squamous cell carcinoma can be identified on the right side of the figure.


Figure 3-19 Lichen planopilaris. In this example, the epidermis adjacent to the involved hair follicle is spared.
Direct immunofluorescence shows several characteristic changes, including staining of numerous apoptotic bodies (also termed necrotic keratinocytes or Civatte bodies ) near the dermal-epidermal interface, most prominently for IgM but usually also for IgA and C3, and a band of fibrin deposition along the junctional zone.

Differential Diagnosis
The distinction of most concern is that between lichen planus and LE. This can be a particular problem with scalp lesions, where the infiltrates of lichen planopilaris can closely resemble the follicular involvement of LE, or with lupus lesions that display dense superficial dermal infiltrates. Atrophic lichen planus can bear a resemblance to poikilodermatous lesions of LE, and hypertrophic lesions of discoid LE can resemble their hypertrophic lichen planus counterpart. In contrast to lichen planus, LE most often shows epidermal atrophy, persistent vacuolar change of the basilar layer rather than basal keratinocyte loss (with flattening or “saw toothing” of the epidermal base), basement membrane zone thickening (especially in lesions of at least 6 months’ duration), a deep as well as superficial dermal infiltrate that involves vessels and sweat glands as well as follicles, and often interstitial dermal mucin deposition. In addition, a degree of panniculitis is seen in a significant number of lupus cases, consisting of mild patchy lymphocytic infiltrates, mucin deposition, or lipoatrophy. These changes are not seen in lichen planus.
The most common problems in differential diagnosis arise with lichenoid keratoses and lichenoid drug eruptions. These entities will be further discussed subsequently. Most of the other lichenoid dermatoses discussed in this chapter lack the full constellation of findings of lichen planus. Lichenoid actinic keratosis, or actinic cheilitis, shows basilar keratinocyte atypia that is disproportionate to that expected as a response to inflammation alone, and often the atypical changes extend laterally beyond the zone of most intense dermal inflammation. Fully developed lichen sclerosus is quite distinctive, but early disease may show a bandlike superficial infiltrate partly obscuring the dermal-epidermal interface. Together with vacuolar alteration of the basilar layer, this can produce an image somewhat reminiscent of lichen planus. However, the loss of basilar keratinocytes with “saw toothing” or flattening of the epidermal base is often not a feature in lichen sclerosus, and dermal edema or early homogenization of papillary collagen may be evident even in early stages of the disease. Poikilodermatous mycosis fungoides with a heavy, bandlike infiltrate, could be confused with the atrophic variety of lichen planus, but atypical lymphocytes, “lining up” of singly dispersed lymphocytes along the basilar layer, and wiry papillary dermal collagen may be identified—findings not expected in lichen planus. In erythema multiforme and fixed drug eruption, dense, bandlike infiltrates obscuring the dermal-epidermal interface would be unusual. The rapid onset of these conditions usually means that the epidermis is of approximately normal thickness, and an ordinary-appearing, basket-woven stratum corneum is often preserved. Furthermore, apoptotic keratinocytes in lichen planus are usually observed at the basilar layer or within the papillary dermis, where they are often arranged in clusters; in erythema multiforme and fixed drug eruption, apoptotic keratinocytes are usually found widely scattered throughout all levels of the epidermis. Keratosis lichenoides chronica and lichen striatus often show dermal infiltrates in patchy distribution, with involvement of the mid to deep dermis and sometimes perieccrine lymphocytic infiltration.
Direct immunofluorescence can sometimes be helpful in differential diagnosis. The combination of junctional apoptotic bodies staining for IgM and a fibrin band along the dermal-epidermal junction is characteristic of lichen planus. Although it can be mimicked by other lichenoid dermatoses, these features differ from LE, which when positive shows particulate, “thick linear,” or occasionally linear deposition of immunoglobulin, C3 complement, or fibrin along the dermal-epidermal junction. Therefore, this procedure can be helpful in those cases of lichen planus–LE overlap. Immunofluorescent study can also be useful when evaluating mucous membrane biopsies, where the differential diagnosis includes both lichen planus and cicatricial pemphigoid (e.g., the condition known as desquamative gingivitis , which can be a manifestation of either disease). In contrast to lichen planus, cicatricial pemphigoid shows linear deposition of immunoglobulin and/or C3 complement along the epithelial-stromal interface (see Chapter 4 ).

Lichenoid Keratosis (Benign)

Clinical Features
This is a particularly common lesion, and in the author’s practice it is much more frequently encountered than lichen planus. Lesions are often solitary. However, sometimes several occur, and when that occurs they may become apparent to the patient at about the same time. 20 These flat-topped, red or violaceous to brown papules develop on the upper trunk, arms, or dorsa of the hands in middle-aged individuals. An experienced dermatologist can often make the correct diagnosis, but the most frequent alternative interpretation is basal cell carcinoma. There is some evidence that these lesions arise in preexisting solar lentigines or seborrheic keratoses. 21 Biopsy is often curative, and in addition, these lesions respond well to cryotherapy.

Microscopic Findings
Biopsy findings may be virtually identical to lichen planus, in which case clinical information may be necessary to make the correct diagnosis. However, there are sometimes recognizable differences. These include parakeratosis or foci of spongiosis ( Fig. 3-20 ). The superficial dermal infiltrate may be sparse or variable in intensity, and it often includes plasma cells and/or eosinophils. Within or adjacent to the lesion, there are frequently changes suggesting a preexisting solar lentigo or flat seborrheic keratosis. Investigators have described bullous and atrophic variants. 20


Figure 3-20 Lichenoid keratosis. This lesion features parakeratosis, serous transudation, and focal diminution to absence of the granular cell layer—features not expected in ordinary lichen planus.

Differential Diagnosis
With regard to the features usually cited as differentiating points between lichenoid keratosis and lichen planus, the author has occasionally seen eosinophils in true lichen planus ( Fig. 3-21 ). In the author’s experience, these are most often encountered in rapidly evolving, widespread disease. However, plasma cells in cutaneous lesions of lichen planus are extremely uncommon, and their finding is of greater differential diagnostic importance. Lichenoid actinic keratosis bears a definite resemblance to benign lichenoid keratosis, but there is a greater degree of basilar keratinocyte atypia, often extending laterally from the zone of most intense dermal inflammation. Lichenoid drug eruption shows many of the same microscopic features as lichenoid keratosis, so a distinction may depend on clinical information. A solitary lesion in a typical location obviously favors lichenoid keratosis, but in situations where there are several lesions, differentiation may be more difficult. Finding changes of solar lentigo or seborrheic keratosis on biopsy also supports the diagnosis of lichenoid keratosis.


Figure 3-21 Lichen planus with eosinophils. Although eosinophils are usually considered a differentiating feature between lichenoid keratosis/lichenoid drug eruption and true lichen planus, the author has seen eosinophils in examples of lichen planus, particularly in rapidly evolving disease.

Lichenoid Drug Eruption

Clinical Features
An eruption of lichenoid papules can be triggered by a wide array of medications. Lesions may remain discrete or coalesce into plaques. Occasionally, extensive confluence can evolve into a picture of exfoliative erythroderma. Onset may occur several months after initiating drug therapy, and even after discontinuing the drug, it may take several months for lesions to resolve. Implicated agents include gold, antimalarials, beta blockers, angiotensin-converting enzyme inhibitors, proton pump inhibitors, nonsteroidal anti-inflammatory compounds, and hepatitis B vaccines. 22 In addition, a photolichenoid eruption may be triggered by certain agents, including hydrochlorothiazide, tetracyclines, and the anticancer agent docetaxel. 23 The eruption then is concentrated over extensor surfaces of the extremities and dorsa of the hands.

Microscopic Findings
The biopsy findings in lichenoid drug eruption are quite similar to those in lichenoid keratosis (except for the lack of an association with solar lentigo or seborrheic keratosis). As is the case in the latter disorder, parakeratosis, eosinophils, and/or plasma cells may be identified. The dermal inflammatory infiltrate may be less intense than in a fully developed example of lichen planus ( Fig. 3-22 ). In the author’s experience, lichenoid eruptions evolving into exfoliative dermatitis have features more in common with erythema multiforme, including apoptotic keratinocytes at all levels of the epidermis, vacuolar alteration of the basilar layer, and a mild superficial perivascular lymphocytic infiltrate in the dermis ( Fig. 3-23 ).


Figure 3-22 Lichenoid drug eruption. Note eosinophils and relatively sparse dermal infiltrate.


Figure 3-23 Lichenoid exfoliative dermatitis. Apoptotic keratinocytes at all levels of the epidermis, focal vacuolar alteration of the basilar layer, and a mild superficial dermal lymphocytic infiltrate are present.

Differential Diagnosis
The same differential diagnostic comments made for lichenoid keratosis are pertinent here. Eosinophils certainly provide a clue to the diagnosis of lichenoid drug eruption, but they may also be seen in lichenoid keratosis and, rarely, in true lichen planus.

Lichenoid and Granulomatous Dermatitis

Clinical Features
In 2000, Magro and Crowson reported a group of 40 patients with what they described as a lichenoid and granulomatous dermatitis. 24 Since that time, the author has seen a number of examples of this condition in his practice. Lesions present as a lichenoid eruption or erythroderma but can also be linear, annular, or vasculitis-like. One fifth of the lesions described by Magro and Crowson were idiopathic, but the investigators suspected drugs in about one third of these cases. 24 Many of the implicated agents, including antibiotics, anti-inflammatory agents, antimalarials, and angiotensin-converting enzyme inhibitors, also produce conventional lichenoid drug eruptions. Other disease associations include rheumatoid arthritis, inflammatory bowel disease, diabetes mellitus, thyroiditis, infectious agents (including hepatitis C), and cutaneous T-cell lymphoma. In a subsequent study, Breza and Magro reported three cases associated with primary cutaneous atypical mycobacterial infections. 25

Microscopic Findings
Five microscopic patterns have been reported based largely on the distribution of macrophages: in a loose arrangement, in more cohesive fashion ( Fig. 3-24 ), in a diffuse interstitial pattern, in the form of scattered giant cells, or as granulomatous vasculitis. As might be expected, investigators have identified atypical lymphocytes in cutaneous T-cell lymphoma. These infiltrates may be superficial or associated with bandlike lymphocytic inflammation. The authors have suggested that lymphocytic eccrine hidradenitis is a feature in patients with drug eruptions. 24 Refinements in the definition of this disorder are likely to occur over time, but lichenoid and granulomatous dermatitis appears to be a definite reaction pattern that may lead to better understanding of a puzzling array of dermatoses.


Figure 3-24 Lichenoid and granulomatous dermatitis. This example shows cohesive macrophages, many of them epithelioid in type, within the papillary dermis.

Differential Diagnosis
Occasionally, other defined granulomatous processes, such as sarcoidosis (particularly ichthyosiform sarcoid) and lupus vulgaris (a manifestation of secondary tuberculosis), can show granulomas concentrated in the superficial dermis with a somewhat lichenoid configuration. Sarcoidal granulomas consist of typical naked tubercles, but lupus vulgaris may show a greater admixture of lymphocytes and smaller macrophages. Organisms are rarely identified with the usual staining methods. Clinical data may be necessary to exclude these conditions.

Lichen Nitidus

Clinical Features
This rare dermatosis consists of multiple flat-topped, light-colored or whitish papules that concentrate over the abdomen, penis, inner thighs, and flexor forearms and wrists. Coalescence into plaques has been reported, but the author has not observed this change in lichen nitidus. Pruritus is not a distinctive feature of these lesions. The small papular lesions are chronic, but spontaneous clearing does occur. The cause of this disorder is unknown, although there are rare familial cases. 26 It is generally considered a condition distinct from lichen planus. Coexistence of the two has been reported, but there are also small papular lesions of lichen planus. The latter could be confused with lichen nitidus, at least initially, but they probably evolve differently.

Microscopic Findings
There is a dense but discrete inflammatory infiltrate concentrated in, and expanding, a single dermal papilla; however, extension to adjacent papillae can occur. The epidermis sometimes appears to partly surround the infiltrate in a “ball in claw” configuration. There is overlying vacuolar alteration of the basilar layer; in fact, the basilar layer may be lost, as it is in lichen planus. The inflammatory infiltrate consists mainly of lymphocytes and some macrophages, and multinucleated giant cells are occasionally seen ( Fig. 3-25 ).


Figure 3-25 Lichen nitidus. A dense infiltrate composed of lymphocytes and macrophages occupies a single dermal papilla.

Differential Diagnosis
These changes are sufficiently distinctive that they are rarely confused with other disorders, with the possible exception of smaller papular lesions of lichen planus that only involve several dermal papillae ( Fig. 3-26 ). Occasionally, one encounters other lesions—arthropod reactions come to mind—characterized by discrete, superficial dermal infiltrates, but they almost always lack the classic features (vacuolar alteration of the overlying basilar layer, confinement to a single dermal papilla, “ball in claw” configuration) or show more widely distributed inflammation with different cellular components. The pathologist should also remember that the diagnostic changes can easily be absent in a given tissue section; therefore, serial sections may then be necessary to find these tiny lesions.


Figure 3-26 Small papular lichen planus. These lesions can closely resemble lichen nitidus, but there may be other, larger lesions more typical of lichen planus.

Lichen Sclerosus (et Atrophicus)

Clinical Features
This chronic disease occurs in both sexes and in children as well as adults. Although best known as a genital disease, lichen sclerosis may also be manifested as extragenital lesions, either in discrete or disseminated form. Lesions begin as white, flat-topped papules and coalesce into plaques, surrounded by violaceous borders. Wrinkling occurs in some lesions due to epidermal atrophy. Comedonal plugs are sometimes observed. Lichen sclerosus sometimes forms an “hourglass” configuration when present on female genitalia, and in males, phimosis or paraphimosis may occur. Indurated lesions can resemble morphea, and the author has seen linear lesions on the scalp that mimic the en coup de sabre configuration of linear scleroderma. Bullae can develop in lichen sclerosus lesions, probably the result of trauma in lesions that feature vacuolar alteration of the basilar layer. Squamous cell carcinoma can develop in these lesions. Although this usually occurs in lesions of long-standing, the author has seen at least one case that arose only 2 years after the initial diagnosis of lichen sclerosus. Some have described a relationship to morphea. Clearly, there are lesions of morphea with changes resembling lichen sclerosus, but the author has seen, and others have reported, patients who appear to have both disorders. 27 In fact, one of the author’s patients had widespread lesions, some of which had the clinical and microscopic features of lichen sclerosus, morphea, or eosinophilic fasciitis.
The etiology of lichen sclerosus is unclear. Some have described a relationship with autoimmune diseases (vitiligo, alopecia areata). In Europe, there have been reports of cases due to Borrelia species, with apparent response to antimicrobial agents 28 ; in the United States, this so far does not appear to be the situation. 29

Microscopic Findings
The classic histopathologic changes in well-developed lesions of lichen sclerosus are hyperkeratosis; follicular plugging (explaining the comedonal openings noted clinically); epidermal atrophy; vacuolar alteration of the basilar layer; edema and homogenization of the upper dermis; and a mid-dermal, bandlike infiltrate composed of lymphocytes and macrophages ( Figs. 3-27 and 3-28 ). In early lesions, the dermal infiltrate may be concentrated in the superficial dermis, partly obscuring the dermal-epidermal interface ( Fig. 3-29 ). 30 It is believed that the connective tissue changes in the superficial dermis eventually displace the infiltrate until in occupies a mid-dermal location. The epidermis (or epithelium, in the case of mucosal lesions) may not always be atrophic, and in fact, irregular acanthosis is frequently identified ( Fig. 3-30 ). With chronicity, there may be sclerosis of collagen in the mid-to-lower dermis. Bullae that are often hemorrhagic develop as the result of the combination of vacuolar alteration of the basilar layer; underlying connective tissue changes; and, probably, external trauma.


Figure 3-27 Lichen sclerosus. This lesion shows hyperkeratosis with follicular plugging, epidermal atrophy, edema and homogenization of upper dermal connective tissue, and a mid-dermal, bandlike infiltrate.


Figure 3-28 Lichen sclerosus. In this example, there is pronounced, eosinophilic homogenization of papillary dermal connective tissue. Note the vacuolar alteration of the basilar layer and pigmentary incontinence.


Figure 3-29 Early lichen sclerosus. The dermal infiltrate extends to the dermal-epidermal interface, especially on the left side of the figure, but homogenization of papillary dermal connective tissue has begun.


Figure 3-30 Lichen sclerosus. This example (diagnosed as kraurosis vulvae) shows marked irregular acanthosis.

Differential Diagnosis
The edema and/or homogenization of superficial dermal collagen are the distinctive changes that allow a diagnosis of lichen sclerosus in most instances. Lichen planus does not show these changes. As noted in the previous discussion, early lichen sclerosus does have a resemblance to lichen planus, but the degree of basal keratinocyte destruction seen in that disorder is generally not observed in lichen sclerosus. The more sclerotic lesions can closely resemble morphea, whereas the latter can sometimes show a suggestion of homogenization of superficial dermal collagen. However, morphea lacks follicular plugging or vacuolar alteration of the basilar layer, and at the same time it often displays evidence for a septal panniculitis, with a lymphoplasmacytic infiltrate concentrated at the dermal-subcutaneous junction, septal sclerosis, sometimes lymphoid follicle formation, and, in more chronic stages, lipoatrophy. Elastic tissue stains, such as Verhoeff–van Gieson, can be helpful in this situation, because elastic fibers are absent within the zones of edematous/homogenized upper dermal collagen in lichen sclerosus ( Fig. 3-31 ), but these are still preserved in morphea. 31


Figure 3-31 Lichen sclerosus. This lesion was stained for elastic fibers using the Verhoeff–van Gieson method. Note the absence of elastic fibers in the homogenized zone of the upper dermis.
When reading the histopathologic description of a classic example of lichen sclerosus, one is struck by the similarity to chronic cutaneous or discoid LE. Both have follicular plugging, epidermal atrophy, and vacuolar alteration of the basilar layer, and they can have an edematous papillary dermis. Strangely, however, this differential is rarely a problem, in part because of the frequent location of lichen sclerosus on the genitalia, but also because the upper dermal connective tissue changes of lichen sclerosus are usually so distinctive. Furthermore, in contrast to lichen sclerosus, LE is prone to show periadnexal inflammation and interstitial dermal mucin deposition.

Erythema Dyschromicum Perstans

Clinical Features
This condition is also known as ashy dermatosis , and patients in South America are known as los cenicientos —the ashen ones. Lesions tend to begin in young adults, who present with generalized, symmetrical, gray macules. Some have an inflammatory border. 32
Treatment of the inflammatory phase of the disease is similar to therapy for lichen planus (e.g., topical or intralesional corticosteroids). Clofazimine has been reported to be effective, 33 although this agent also produces a reddish brown pigmentation that can be a significant complication of therapy.

Microscopic Findings
Biopsies of active lesions show vacuolar alteration of the basilar layer and a superficial dermal perivascular infiltrate composed of lymphocytes and macrophages, with the configuration of a lichenoid dermatosis ( Fig. 3-32 ). 34 Pigmentary incontinence can be recognized at this stage. However, biopsies of later stage lesions, or older portions of lesions, show only marked dermal pigment deposition, which has been mostly ingested by macrophages (melanophages). This accounts for the distinctive color of the lesions noted clinically ( Fig. 3-33 ).


Figure 3-32 Erythema dyschromicum perstans, active lesion. Findings include vacuolar alteration of the basilar layer and a superficial dermal perivascular infiltrate composed of lymphocytes and macrophages.


Figure 3-33 Erythema dyschromicum perstans, late-stage lesion. Pigmentary incontinence is apparent, but basilar vacuolar change is resolved and inflammation is sparse.

Differential Diagnosis
Inflammatory lesions have elements in common with other lichenoid disorders, and researchers have suggested that erythema dyschromicum perstans may be the same entity as lichen planus pigmentosus. 34 The pigmentary incontinence seen in late-stage lesions is quite nonspecific, showing overlap with melasma, third-stage incontinentia pigmenti, and numerous other conditions. At this point, clinical information is needed to make a correct diagnosis.

Keratosis Lichenoides Chronica

Clinical Features
This unusual but distinctive dermatosis is also termed morbus moniliformis or lichen ruber moniliformis . It begins in childhood and consists of hyperkeratotic papular to nodular lesions, particularly over the arms, legs, and buttocks. The lesions form linear or reticulated arrangements, mimicking the growth patterns of Candida ( Monilia ) in culture. 35 There may also be hyperkeratosis of the palms and soles or seborrheic dermatitis–like changes on the face. Nail changes have been identified.
Treatments have included PUVA, oral retinoids, or topical calcipotriol.

Microscopic Findings
On biopsy, the epidermis may show foci of both atrophy and acanthosis. Findings include focal parakeratosis, vacuolar alteration of the basilar layer with Civatte body formation, telangiectasia, and a patchy perivascular and periadnexal infiltrate composed of lymphocytes and plasma cells ( Fig. 3-34 ). Perieccrine infiltration may be associated with squamous metaplasia of the acrosyringium ( Fig. 3-35 ); Kossard and Lee have described this finding as lichen planoporitis. 36


Figure 3-34 Keratosis lichenoides chronica. This lesion shows hyperkeratosis with parakeratosis, variable atrophy, and a patchy lichenoid infiltrate.


Figure 3-35 Keratosis lichenoides chronica. In the same lesion shown in Figure 3-34 , there is a perieccrine lymphocytic infiltrate.

Differential Diagnosis
The rarity of keratosis lichenoides chronica means that it can be easily confused with other lichenoid dermatoses. However, it does not generally show the classic features of lichen planus. The parakeratosis, the variable atrophy and acanthosis seen in some lesions, and the deeper dermal perivascular and periadnexal infiltrates are reasonably distinctive.

Lichen Striatus

Clinical Features
Lichen striatus is seen most frequently in children, but adults can also develop the condition. It consists of erythematous to hypopigmented papules that form linear arrays over the extremities or trunk. Nail changes can be seen in those cases extending to the digits. The lesions last for about 1 year or so and eventually resolve, without scarring, although pigmentary changes may persist. 37 , 38

Microscopic Findings
The microscopic findings can include spongiosis or intracellular edema and a superficial and deep perivascular and perieccrine infiltrate ( Fig. 3-36 ), composed mainly of lymphocytes. However, in some examples a bandlike infiltrate resembling lichen planus can occur, and apoptotic bodies may be visible ( Fig. 3-37 ). 39 So-called dyskeratotic cells can sometimes be found near the epidermal surface. Investigators have sometimes described these as resembling corps ronds ( Fig. 3-38 ). 40 , 41 In the author’s experience, this form of dyskeratosis is rarely identified in lichen striatus, and classic corps ronds are unusual, although eosinophilic bodies consistent with apoptotic keratinocytes certainly occur.


Figure 3-36 Lichen striatus. As is the case in keratosis lichenoides chronica, there is a perieccrine dermal infiltrate.


Figure 3-37 Lichen striatus. This lesion has a distinctly lichenoid configuration.


Figure 3-38 Lichen striatus. In this example, there is evidence of dyskeratosis in the region of the granular cell layer.

Differential Diagnosis
Lichen striatus is often not biopsied, because its appearance and clinical history are so distinctive. However, the biopsy changes are usually not confused with lichen planus; the epidermal changes are dissimilar, and the deeper, perieccrine infiltrates are not seen in lichen planus. The findings are actually similar to those in keratosis lichenoides chronica, particularly in terms of the perieccrine infiltration, but the latter lesion is more likely to show epidermal acanthosis, or variable acanthosis and atrophy. Lichen striatus is linear; therefore, it has clinical resemblances to inflammatory linear verrucous epidermal nevus, other epidermal nevi, or linear lichen planus or psoriasis. However, all of those lesions show acanthosis and often degrees of papillomatosis, which are not features of lichen striatus.

Pityriasis Lichenoides

Clinical Features
This condition has two forms: pityriasis lichenoides et varioliformis acuta (PLEVA), also known as Mucha-Habermann disease, and pityriasis lichenoides chronica. Pityriasis lichenoides is frequently classified as a form of lymphocytic vasculitis, but one with distinct epidermal changes. At one time it was grouped with the parapsoriases, but is now generally considered to be a separate category of disease. 42 Pityriasis lichenoides usually begins in childhood or young adult life. It can certainly occur in middle age, but in the author’s experience, occurrence in the elderly is distinctly uncommon. In PLEVA, there is an eruption of erythematous papules or papulovesicles, in crops, particularly over the trunk. Lesions tend to heal, although new ones develop. The resulting clinical image approaches that of varicella. Often, the condition resolves over several years. 43 Patients are asymptomatic, but there is a severe form characterized by fever and ulceronecrotic lesions. 44 , 45 Pityriasis lichenoides chronica consists of eruptions of flat, scaly papules and macules that resolve after several months. 46
PLEVA often responds to systemic antibiotics or phototherapy. The ulceronecrotic form may require systemic corticosteroids or methotrexate. Pityriasis lichenoides chronica also responds to phototherapy.
The etiology of pityriasis lichenoides is unclear. Both forms have shown clonal T-cell receptor gene rearrangements, suggesting they could represent a form of T-cell dyscrasia. 47 For this reason, they warrant close follow-up. Evolution to true cutaneous T-cell lymphoma is a rarity, reported in some examples of pityriasis lichenoides chronica. PLEVA can have a close clinical resemblance to lymphomatoid papulosis, but it lacks the degree of cytologic atypia of that disease (see Chapter 27 ).

Microscopic Findings
Microscopically, PLEVA shows a somewhat wedge-shaped dermal infiltrate, patchy and perivascular in the mid-dermis, and more confluent (the base of the wedge) in the upper dermis ( Fig. 3-39 ). This consists of perivascular lymphocytes that encroach on vessel walls and are associated with erythrocyte extravasation, constituting lymphocytic vasculitis. There are vacuolar alteration of the basilar layer, exocytosis of inflammatory cells, erythrocytes within the epidermis, varying degrees of keratinocyte necrosis, and overlying parakeratosis ( Fig. 3-40 ). Some examples bear a close resemblance to erythema multiforme, with scattered apoptotic bodies at all levels of the epidermis and vacuolar alteration of the basilar layer but limited exocytosis. The intensity of these changes is clearly affected by the duration of the lesion at the time of biopsy; epidermal changes are particularly severe in the ulceronecrotic form of the disease ( Fig. 3-41 ). The changes in pityriasis lichenoides chronica are similar but milder. These differences are the chief means of distinguishing between the two forms of the disease ( Fig. 3-42 ). 48 , 49


Figure 3-39 Pityriasis lichenoides et varioliformis acuta (PLEVA). Interface dermatitis and a somewhat wedge-shaped dermal infiltrate.


Figure 3-40 PLEVA. Findings include vacuolar alteration of the basilar layer, parakeratosis, and apoptotic keratinocytes at all levels of the epidermis. Extravasated erythrocytes can be identified in the dermal papillae, with a rare erythrocyte in the epidermis.


Figure 3-41 PLEVA. This lesion was obtained from a patient with the ulceronecrotic form of the disease.


Figure 3-42 Pityriasis lichenoides chronica. The findings are similar to, but of lesser degree than, those of PLEVA. Note the parakeratosis, focal vacuolar alteration of the basilar layer, extravasated erythrocytes, and sparse perivascular inflammation.

Differential Diagnosis
When all the classic findings of PLEVA are present, they are sufficiently characteristic to enable a microscopic diagnosis, even when there is minimal clinical information. When the changes mimic erythema multiforme, excluding that disease can be quite difficult. Helpful findings favoring PLEVA include significant exocytosis and deep as well as superficial perivascular dermal infiltrates with lymphocytic vasculitis. There can be some microscopic as well as clinical resemblance to lymphomatoid papulosis; in fact, some authors initially described the latter as pityriasis lichenoides with atypia. Generally, the degree of cytologic atypia among lymphoid cells in lesions of lymphomatoid papulosis is quite striking—more severe and extensive than would be expected in pityriasis lichenoides acuta. However, there may be a problematic degree of atypia in the severe ulceronecrotic variant of pityriasis lichenoides, and, as noted, positive T-cell receptor gene rearrangements have occurred in PLEVA. This could potentially create diagnostic issues but also suggests that these conditions may fall within different points of a spectrum of T-cell lymphoid dyscrasias.
The problem in pityriasis lichenoides chronica is often that the changes are quite mild, and thus a wide array of dermatoses—including forms of spongiotic dermatitis, drug reactions, or digitate dermatosis—is often part of the differential diagnosis. Under these circumstances, it is helpful to look for the more diagnostic findings of PLEVA in such lesions (e.g., subtle lymphocytic vasculitis, occasional apoptotic keratinocytes, erythrocytes within the epidermis); they are often present, but to a lesser degree.

Poikiloderma Atrophicans Vasculare
This term emphasizes the variegated erythema and pigmentation that characterize this particular lesion, accompanied by epidermal atrophy and vasodilatation. This is actually a microscopic pattern rather than a disease that can be seen in a variety of inherited, congenital, and acquired conditions. However, acquired lesions showing poikiloderma atrophicans vasculare that are of the greatest diagnostic significance can be grouped into two categories: connective tissue disease (LE and dermatomyositis) and early cutaneous T-cell lymphoma.
These disorders will be discussed in greater detail in Chapters 8 and 27 . However, the tissue reaction pattern is discussed here because it is a subtype of lichenoid dermatitis, although it has distinctive features. The microscopic findings include epidermal atrophy, vacuolar alteration of the basilar layer with apoptotic body formation, pigmentary incontinence, telangiectasia, and a superficial dermal infiltrate that varies in intensity and may be either bandlike or perivascular ( Figs. 3-43 and 3-44 ). Clues to the underlying disorder include dermal mucin deposition and possibly subtle periadnexal inflammation, pointing toward connective tissue disease, or cytologic atypia among lymphocytes, seen in some examples of patch stage mycosis fungoides. In most instances, this constellation of features is distinctive and not readily confused with lichen planus or other forms of lichenoid dermatitis.


Figure 3-43 Poikiloderma atrophicans vasculare. This is an active lesion. Epidermal atrophy, vacuolar alteration of the basilar layer, vasodilatation, and bandlike inflammation are present.


Figure 3-44 Poikiloderma atrophicans vasculare, late-stage lesion. Inflammation is sparse, but epidermal atrophy and telangiectasia are apparent.

Graft-versus-Host Disease

Clinical Features
The best-known form of graft-versus-host disease (GVHD) occurs following allogeneic bone marrow transplantation in the treatment of leukemia or other disorders, but it can also occur in the immunodeficient fetus as a result of maternal-fetal blood transfusion and in other circumstances in which immunocompetent donor lymphocytes are administered to individuals with a depressed immune system. The sequence of events is best studied in the setting of bone marrow transplantation. Acute GVHD begins about 1 to 3 weeks following the transplant. It is characterized by fever, diarrhea, hepatic dysfunction, and a macular erythema, sometimes with the development of follicular papules. The erythema may be sufficiently severe to manifest with bullae and a picture resembling toxic epidermal necrolysis. A chronic phase begins several months to a year later, usually following an identifiable acute phase. In the early part of this chronic phase, patients develop cutaneous and oral lesions that closely resemble lichen planus. Later, poikilodermatous changes develop, along with dermal sclerosis that mimics scleroderma. GVHD represents an attack of donor T-lymphocytes directed toward host histocompatibility antigens. Langerhans cells and basilar keratinocytes appear to be particular targets. 50

Microscopic Findings
Biopsy of early lesions shows basilar vacuolization and a sparse superficial dermal infiltrate of lymphocytes, with epidermal exocytosis. Degenerated eosinophilic keratinocytes, resembling Civatte bodies or apoptotic bodies, can be identified in the epidermis ( Fig. 3-45 ), and in some instances lymphocytes can be found juxtaposed to these cells, a phenomenon termed satellite cell necrosis. 51 Severe acute reactions can closely resemble toxic epidermal necrolysis, showing not only a sparse superficial dermal infiltrate but also full-thickness necrosis of the epidermis. Early chronic lesions can closely resemble lichen planus, with basilar vacuolar alteration 52 and necrosis, although the superficial dermal infiltrate tends not to be as densely bandlike. Follicular involvement is commonly apparent, mainly involving the portion of the follicle superficial to the sebaceous duct; in fact, a follicular variant of GVHD has this change as its most striking microscopic feature ( Fig. 3-46 ). 53 In later stages, the epidermis assumes the appearance of poikilodermatous lesions; that is, epidermal atrophy, vacuolar alteration of the basilar layer, and pigmentary incontinence are evident. At this point, dermal sclerosis may be identified. In some cases, this may be most pronounced in the upper to mid-dermis, but in others, there is sclerosis of the entire dermis, extending into subcutaneous septa and resulting in appendageal atrophy ( Fig. 3-47 ). 54


Figure 3-45 Graft-versus-host disease, early lesion. Findings include vacuolar alteration of the basilar layer, a superficial dermal infiltrate with exocytosis, and apoptotic bodies within the epidermis.


Figure 3-46 Graft-versus-host disease, early chronic lesion. A, Well-developed lichenoid epidermal changes are present, and epidermal-dermal separation has led to bulla formation. B, Follicular involvement is apparent.


Figure 3-47 Graft-versus-host disease, chronic lesion. A, Lichenoid tissue changes persist. B, There is marked sclerosis of collagen involving the entire dermis and extending into subcutaneous septa.
Studies by Horn and colleagues using an allogeneic rat model have shown that dermal lymphocytic infiltration is a significant feature of GVHD, and low levels of dyskeratotic cells are commonly present due to preparative regimens and, in isolation, are not sufficient to diagnose GVHD. 55 Involvement of the superficial portions of follicles is accompanied by dendritic cells that are limited to this region, possibly due to the inability of lower follicular epithelium to upregulate major histocompatibility complex class II antigens. 55

Differential Diagnosis
The changes outlined in the preceding discussion, in the context of immunosuppression and bone marrow transplantation or the administration of blood products, make a strong case for GVHD. Acute phase lesions showing full-thickness epidermal necrosis closely resemble toxic epidermal necrolysis, and therefore a careful analysis of all clinical information is warranted, including a review of medications known to trigger the latter disorder. As noted, the dermal infiltrates of GVHD tend not to be as heavy as in a fully developed lesion of lichen planus, but there is sufficient overlap to make distinction difficult in the absence of clinical data. Late-stage lesions resemble morphea or scleroderma, but the latter conditions are not associated with poikilodermatous surface changes. The only possible exception would be an “overlap” connective tissue disease, combining the features of poikilodermatous LE or dermatomyositis with scleroderma. Looked at another way, a biopsy showing poikiloderma atrophicans vasculare with significant dermal sclerosis should always raise the question of late-stage GVHD.
A greater diagnostic problem is the distinction of GVHD from reaction to medications. The finding of eosinophils does not necessarily clinch a diagnosis of drug reaction: eosinophils have been identified in GVHD. 56 The eruption of lymphocyte recovery, brought about as a consequence of cytoreductive chemotherapy, can closely resemble GVHD and may even be responsible for some of its manifestations (see subsequent discussion). 57 Another issue is so-called “maturation arrest” or keratinocyte dysmaturation resulting from certain therapeutic agents used in treating leukemias and solid tumors, including alkylating agents such as cyclophosphamide, busulfan, and thiotepa and antimetabolites such as cytarabine and etoposide. A similar phenomenon results from the use of pegylated doxorubicin. 58 The microscopic findings produced by these agents include hyperkeratosis, epidermal atrophy, keratinocyte necrosis with scattered apoptotic keratinocytes, vacuolar alteration of the basilar layer, and superficial dermal inflammation, all features of GVHD. Another finding of diagnostic importance is the formation of enlarged keratinocytes with irregularly shaped nuclei and large acidophilic nucleoli; these changes also involve eccrine sweat duct epithelium. This keratinocyte atypia is thought to result from the effects of these drugs on nucleic acids or on normal regulatory functions of the underlying dermis. Due to the overlap in microscopic appearance, Horn has recommended avoiding areas of identifiable chemotherapy effect when considering a biopsy to rule out GVHD. 59 It should be noted that substantial microscopic changes due to chemotherapy may be found even in the face of minimal clinical disease. Clearly, cytologic atypia and loss of orderly surface maturation are not criteria for GVHD. When these findings occur, they are suggestive of epidermal dysmaturation due to chemotherapy; nevertheless, the possible coexistence of the two phenomena cannot be completely ruled out.

Eruption of Lymphocyte Recovery
A maculopapular eruption can occur at the time of recovery of the bone marrow from cytoreductive therapy, as lymphocytes reenter the circulation. This event occurs 2 to 3 weeks following therapy, and is found in both transplanted and nontransplanted patients. In fact, it has been theorized that the eruption known as GVHD that follows autologous bone marrow transplantation may actually represent the eruption of lymphocyte recovery. 57 This eruption resolves spontaneously, unless of course the patient also develops true GVHD in the course of transplantation of immunocompetent lymphocytes. Microscopically, the findings include occasional apoptotic keratinocytes, sometimes with satellite cell necrosis, and a mild upper dermal perivascular lymphocytic infiltrate with epidermal exocytosis ( Fig. 3-48 ). This constellation of features mimics that of early or mild GVHD and requires clinical data for accurate diagnosis.


Figure 3-48 Eruption of lymphocyte recovery. Note subtle vacuolar alteration of the basilar layer, occasional apoptotic keratinocytes, and mild upper dermal perivascular lymphocytic infiltrate.

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4
Vesiculobullous and Selected Pustular Disorders


Immunobullous Disorders 

Pemphigus 
Bullous Pemphigoid 
Lichen Planus Pemphigoides 
Pemphigoid (Herpes) Gestationis 
Cicatricial Pemphigoid (Mucous Membrane Pemphigoid) 
Epidermolysis Bullosa Acquisita 
Bullous Lupus Erythematosus 
Dermatitis Herpetiformis 
Linear Immunoglobulin A Disease 
Erythema Multiforme and Toxic Epidermal Necrolysis 
Inherited Blistering Diseases 

Hailey-Hailey Disease 
Bullous Darier Disease 
Hereditary Epidermolysis Bullosa 
Selected Pustular Disorders 

Pustular Dermatoses of Infancy 
Subcorneal Pustular Dermatosis 
Traumatic Blisters 
The focus of this chapter is a group of conditions that result in vesicle or bulla formation. Not all bullous disorders are included here; some are listed according to etiology. Thus, intraepidermal vesicles due to spongiosis are discussed in Chapter 1 , viral vesicles (particularly those due to herpesvirus infections) are discussed in Chapter 17 , and bullae of porphyria cutanea tarda are included in Chapter 9 .
Vesicles and bullae can arise at various levels within the skin, from the stratum corneum to the superficial dermis. Many of them develop in or near the basement membrane zone, a complex structure (as defined ultrastructurally and by antibody studies) that is located between the epidermis and papillary dermis. The major components of this zone, moving from basal keratinocytes toward the dermis, are the hemidesmosome, composed of tonofilaments that insert into an attachment plaque; the lamina lucida, within which can be found a subdesmosomal dense plate and anchoring filaments; the lamina densa; collagen rootlets; and anchoring fibrils. Abnormalities of these structures, whether resulting from genetically determined alterations, mechanical factors, or autoimmune attack, can lead to a separation that appears to be subepidermal, and the level at which separation occurs can be crucial in determining diagnosis, therapeutic options, and prognosis. Diagnosis can often be made on routine light microscopy, with an assist from direct or indirect immunofluorescence, but on occasion, particularly when attempting to determine subtypes of epidermolysis bullosa, ultrastructural evaluation and more sophisticated mapping studies may be necessary.
A significant portion of this chapter will consider a group of autoimmune diseases, often referred to as immunobullous disorders. In addition, topics of discussion will include some pustular eruptions of infancy and adult life, heritable forms of epidermolysis bullosa, inherited and acquired abnormalities of cell-to-cell adhesion, and traumatically induced blisters.

Immunobullous Disorders

Pemphigus

Clinical Features
The term pemphigus defines a groups of disorders characterized by the formation of acantholytic blisters that leave denuded areas and involve both skin and mucous membranes. Blisters result from an autoimmune attack on target antigens that are related to components of desmosomes within epithelia—epidermis, mucosa, and adnexal epithelium. The prototype condition of this group, pemphigus vulgaris , shows extensive flaccid blistering of trunk, groin, axillae, and scalp, as well as erosions of mucous membranes. The target antigen is desmoglein 3. 1 Blisters have the property of spreading following trauma, such as pressure or twisting; this phenomenon is variably known as the Nikolsky or Asboe-Hansen sign. Extensive loss of fluid and electrolytes and secondary infection can accompany this often severe and persistent disease. Other variants of pemphigus include

•  Pemphigus vegetans: a rare variant of pemphigus vulgaris in which vegetative plaques develop over intertriginous areas. Most often, this form is a phase that occurs during the course of pemphigus vulgaris.
•  Pemphigus foliaceus: an often sporadic form of the disease that is endemic in parts of South America, where it is referred to as fogo selvagem or Brazilian pemphigus . 2 It produces shallow erosions and crusted plaques but can undergo transition to pemphigus vulgaris. Oral lesions are rarely observed. The target antigen is desmoglein 1, which is concentrated in desmosomes of the more superficial epidermis. 3
•  Herpetiform pemphigus: considered a variant of pemphigus foliaceus, although sometimes antibodies to desmoglein 3 (as found in pemphigus vulgaris) can be demonstrated. 4 This variant features grouped blisters; this arrangement mimics that seen in herpes viral vesicles.
•  Pemphigus erythematosus (Senear-Usher disease): features erythematous, erosive lesions, often involving the malar areas of the face. It shares that clinical feature as well as some immunofluorescent and serologic characteristics with lupus erythematosus (LE). 5 , 6
•  Paraneoplastic pemphigus: consists of erosions of the lips and oropharynx, pseudomembranous conjunctivitis, and pruritic skin lesions with blisters and erosions, some of which have a target-like configuration reminiscent of erythema multiforme. There are multiple desmosomal target antigens in this disease, including desmoplakin I (250 kD), the major bullous pemphigoid antigen (230 kD), envoplakin (210 kD), and periplakin (190 kD). 7 , 8 Paraneoplastic pemphigus has a strong association with lymphoproliferative disorders, including T-cell and B-cell lymphomas, thymoma, chronic lymphocytic leukemia, and Castleman disease. 9
•  Immunoglobulin A (IgA) pemphigus: presents in two forms—one resembles subcorneal pustular dermatosis, 10 and the other, called intraepidermal neutrophilic IgA dermatosis, has herpetiform lesions. 11 In the subcorneal pustular dermatosis variant, desmocollins are often the target antigens, 12 whereas in the intraepidermal neutrophilic IgA dermatosis variant, antibodies to desmogleins 1 and 3 are found. 13 The subcorneal pustular dermatosis type may be associated with a monoclonal IgA gammopathy.
Treatment for pemphigus vulgaris, and sometimes the other variants, includes corticosteroids and other immunosuppressive agents. Systemic corticosteroids are sometimes used as the initial approach, followed by other agents, such as azathioprine or mycophenolate mofetil, used for their steroid-sparing therapeutic properties.

Microscopic Findings
On biopsy, pemphigus vulgaris may show intraepidermal vesicles with eosinophilic spongiosis ( Fig. 4-1 ) in early stages, 14 but eventually suprabasilar acantholysis can be identified ( Fig. 4-2 ). The basilar keratinocytes remain attached to the floor of the separation but appear to separate from one another, producing the so-called “row of tombstones” appearance ( Fig. 4-3 ). A few acantholytic cells are identified within the blister. 15 The process involves adnexal structures in the vicinity of the lesions, and at times, extensive acantholysis of follicular epithelia is apparent ( Fig. 4-4 ). The dermal infiltrate contains a mixture of inflammatory cells, but often a few eosinophils are identified.


Figure 4-1 Pemphigus vulgaris. Eosinophilic spongiosis in early disease.


Figure 4-2 Pemphigus vulgaris. Fully developed lesion, showing suprabasilar acantholysis. Only a few acantholytic cells are seen in the blister cavity.


Figure 4-3 Pemphigus vulgaris. The basilar keratinocytes separate from one another, producing the appearance of a “row of tombstones.”


Figure 4-4 Pemphigus vulgaris. This lesion shows extensive acantholytic changes in follicular units. This is in marked contrast to Hailey-Hailey disease, in which follicular sparing is the rule.
In variants of pemphigus, other microscopic findings occur. Pemphigus vegetans is characterized by hyperkeratosis, papillomatosis, and acanthosis with intraepidermal collections of eosinophils ( Fig. 4-5 ); acantholytic foci are not always demonstrable. 16 Pemphigus foliaceus shows an intraepidermal vesicle with separation occurring in or near the granular cell layer ( Fig. 4-6 ). At times, the picture is more an erosive than a bullous one, and acantholysis may be subtle, seen best at the edge of the specimen or near follicular ostia. Eosinophilic spongiosis may be present. Pemphigus erythematosus microscopically resembles pemphigus foliaceus ( Fig. 4-7 ). In contrast to other forms of pemphigus, paraneoplastic pemphigus often shows a lichenoid tissue reaction that somewhat resembles erythema multiforme, and acantholysis may or may not be identified ( Fig. 4-8 ). In the two forms of IgA pemphigus, one resembles subcorneal pustular dermatosis (see later discussion), whereas the other, intraepidermal neutrophilic IgA dermatosis, consists of intraepidermal pustules ( Fig. 4-9 ). Slight acantholysis can be seen in the subcorneal pustular dermatosis variant.


Figure 4-5 Pemphigus vegetans. Intraepidermal collections of eosinophils. In this example, acantholysis is inapparent.


Figure 4-6 Pemphigus foliaceus. There is separation in the region of the granular cell layer.


Figure 4-7 Pemphigus erythematosus. Acantholysis has occurred in the superficial portion of the epidermis.


Figure 4-8 Paraneoplastic pemphigus. Vacuolar alteration of the basilar layer is seen on the right side of the figure, whereas acantholysis leading to suprabasilar separation has occurred on the left.


Figure 4-9 Immunoglobulin A (IgA) pemphigus. Intraepidermal pustules have formed in this variant, known as intraepidermal neutrophilic IgA dermatosis.
Immunofluorescence (IF) studies, particularly direct IF but to a lesser extent indirect IF, play an important role in the diagnosis of pemphigus. On direct IF, pemphigus vulgaris, pemphigus vegetans, and paraneoplastic pemphigus show intercellular IgG and C3 deposition involving the full thickness of epidermis ( Fig. 4-10 ), although sometimes staining of upper layers of the epidermis may be diminished. This staining may be linear (producing the so-called “chicken wire” appearance) or particulate. In pemphigus foliaceus, intercellular staining for IgG and C3 is sometimes restricted to superficial portions of the epidermis, 17 reflecting the primary location of the target antigen, desmoglein 1. However, in some cases staining of the full thickness of epidermis is seen, in the manner of pemphigus vulgaris. In fact, the majority of the author’s cases of pemphigus foliaceus have shown the latter staining pattern. Pemphigus erythematosus may show staining of the basement membrane zone, resembling a “lupus band,” in addition to intercellular epidermal fluorescence. 18 This IF finding may occur even in the absence of clinical or serologic evidence suggesting LE. Similar direct IF findings can be seen as well in paraneoplastic pemphigus. Intercellular IgA deposition is seen in cases of IgA pemphigus ( Fig. 4-11 ).


Figure 4-10 Pemphigus vulgaris, direct immunofluorescence. Intercellular immunoglobulin G deposition involves most of the epidermis.


Figure 4-11 IgA pemphigus, direct immunofluorescence. This specimen shows intercellular deposits of IgA.
Indirect IF has been commonly used in the diagnosis of pemphigus, particularly pemphigus vulgaris, but it also has been used as a means of following the course of the disease. The procedure involves layering of various dilutions of patient sera on an epithelial substrate, staining with anti-human IgG antibodies, and determining the antibody titer by finding at what dilution intercellular fluorescence can no longer be detected in the substrate. It is known that antibody titers reflect disease activity. However, they do not always predict disease activity, and therefore many consider clinical evaluation of the patient a better means of assessment. 19 Regarding the diagnostic uses of indirect IF in pemphigus, there has been some controversy about whether direct or indirect IF methods are more reliable. Advocates of indirect IF argue that the statistics favor this method when the proper substrate is used, and the best substrate is considered to be monkey esophagus. There are certainly selected situations in which indirect IF might be preferable (e.g., in patients who have only mucous membrane disease, where blood drawing might be a technically easier procedure, or very young or elderly patients who might tolerate obtaining of a blood sample better than a skin biopsy). False-positive pemphigus-like antibodies can be encountered in patients with extensive burns, penicillin-associated drug eruptions, or high-titer blood group antibodies. 20 Usually, however, these antibodies are only seen in low dilutions. Indirect IF studies are also not invariably positive; this is particularly true in some patients with pemphigus foliaceus, and they are also positive in only 50% of cases of IgA pemphigus. Indirect IF also can assume great diagnostic importance in cases of paraneoplastic pemphigus, because (unlike other forms of pemphigus), intercellular fluorescence can be found when murine bladder epithelium is used as the substrate.

Differential Diagnosis
Pemphigus vulgaris can be potentially confused with other acantholytic disorders, particularly Hailey-Hailey disease (familial benign chronic pemphigus), an inherited acantholytic disorder, and a similar but localized disorder that appears to be acquired, acantholytic dermatosis of the genitocrural region. However, those conditions usually show much more extensive suprabasilar acantholysis, with separation of keratinocytes in the spinous layer producing the appearance of a “dilapidated brick wall.” Some dyskeratosis can be seen in Hailey-Hailey disease, a feature not seen to the same extent in pemphigus. Importantly, the acantholysis in Hailey-Hailey disease “respects” the hair follicles; that is, follicular epithelia in acantholytic lesions tend to be spared. This is not the case in pemphigus. Dermal infiltrates containing eosinophils are common in pemphigus, and eosinophilic spongiosis may be seen in early disease. This cell type is less common in Hailey-Hailey disease, but eosinophils can occasionally be seen in that disease. Hailey-Hailey disease is not associated with eosinophilic spongiosis. Examples of focal acantholytic dyskeratosis, particularly transient acantholytic dermatosis (Grover disease), can have a pemphigus vulgaris–like configuration, but often some dyskeratosis can be identified. Actinic keratoses with marked acantholysis might occasionally mimic a lesion of pemphigus vulgaris, but some basilar keratinocyte atypia can usually be identified, and the clinical presentation would be quite different from that of pemphigus. IF studies would be definitive, because none of these other conditions shows positive intercellular fluorescence.
The diagnosis of other forms of pemphigus may be difficult. Pemphigus vegetans may bear a superficial resemblance to blastomycosis-like pyoderma, which had previously been termed pyoderma vegetante of Hallopeau or, misleadingly, the Hallopeau variant of pemphigus vegetans. However, that lesion does not show acantholysis, produces negative IF findings, and actually more closely resembles North American blastomycosis microscopically than it does true pemphigus vegetans. In addition, eosinophils are particularly prominent in pemphigus vegetans. Pemphigus foliaceus can be confused with bullous impetigo and subcorneal pustular dermatosis because of the level of splitting—subcorneal, often through the granular cell layer. Pemphigus foliaceus tends to be less pustular than those two diseases, with occasional exceptions, such as some cases of herpetiform pemphigus. Acantholysis is usually, but not always, more evident in pemphigus foliaceus, and occasionally, suprabasilar acantholysis can also be observed. Direct IF can permit a definitive diagnosis; in these diseases, positive intercellular IgG and C3 staining is seen only in pemphigus foliaceus. The same superficial epidermal acantholysis is also characteristic of pemphigus erythematosus, and this permits separation from LE, which pemphigus can resemble both clinically and, partially, on direct IF, since a “lupus band” may be observed. Paraneoplastic pemphigus shows changes resembling erythema multiforme, but most often there are at least foci of suprabasilar acantholysis, and intercellular staining on direct IF is confirmatory of the diagnosis. The morphologic findings of the subcorneal pustular dermatosis–like variant of IgA pemphigus can be virtually identical to those of the disease it resembles. In fact, subcorneal pustular dermatosis may be undergoing redefinition as an entity (see subsequent discussion). However, there are clearly examples of a subcorneal pustular eruption that lack positive intercellular IgA deposition on direct IF study. It would appear that, for this variant of pemphigus, IF studies are essential.

Bullous Pemphigoid

Clinical Features
In the early 1950s, Lever distinguished this condition, sometimes simply referred to as pemphigoid , from pemphigus and established it as a separate entity. It is most common among elderly adults, but it can clearly also occur in younger age groups. Although often arising for no apparent reason, it has been associated with certain drugs, including penicillins, sulfur-containing agents, and beta blockers. 21 Ultraviolet light exposure has been known to trigger pemphigoid; this has been noticed with the use of ultraviolet therapy and has even been exploited in the experimental elicitation of pemphigoid lesions. 22 It also appears that other conditions that can affect the dermal-epidermal junction, such as lichenoid dermatoses or erythema multiforme, can lead to secondary development of pemphigoid due to a phenomenon called epitope spreading . 23 , 24
Most often, tense bullae form over the trunk and intertriginous areas as well as extremities. Blisters can develop in either normal or erythematous skin, and urticarial lesions can sometimes be an early manifestation of the disease. Mucous membrane lesions occur, and disease localized to the lower extremities is occasionally evident. The target antigen of pemphigoid is a 230-kD protein, known as the major pemphigoid antigen, along with a 180-kD protein, known as the minor pemphigoid antigen. These are components of the hemidesmosome complex of the basement membrane zone, the area where subepidermal separation occurs. There are also variants of pemphigoid, whose target antigens reside in the lower portion of the lamina lucida, with molecular weights of 105 kD and 200 kD.
Treatment includes topical and systemic corticosteroids. Tetracycline and niacinamide, dapsone, immunosuppressive therapy, and plasmapheresis may also be useful.

Microscopic Findings
The essential biopsy finding of a fully developed lesion is subepidermal separation. Eosinophilic spongiosis may be an early change in pemphigoid, just as is the case with some examples of pemphigus ( Fig. 4-12 ). Lesions can be sorted into two basic histopathologic configurations: “infiltrate-poor,” in which there may be only a few inflammatory cells, including eosinophils around dermal vessels 25 ( Fig. 4-13 ), and “infiltrate-rich,” showing edema and a prominent perivascular and periadnexal infiltrate that usually includes numerous eosinophils ( Fig. 4-14 ). At times, papillary neutrophilic or eosinophilic microabscesses may be present. 26 The changes in very early lesions may be quite subtle, resembling ordinary urticaria, whereas in late, resolving lesions, re-epithelialization may obscure the most diagnostic finding, that of subepidermal separation.


Figure 4-12 Bullous pemphigoid. This lesion shows eosinophilic spongiosis. A few eosinophils can be found within this intraepidermal vesicle.


Figure 4-13 Bullous pemphigoid, infiltrate-poor type.


Figure 4-14 Bullous pemphigoid, infiltrate-rich type. Numerous eosinophils are seen within the blister cavity.
Direct IF study shows linear deposition of IgG and C3 along the dermal-epidermal junction of perilesional skin 27 ( Fig. 4-15 ). There may be a continuous band or a discontinuous staining pattern, resembling a “hash line” and often called the interrupted linear pattern of immunofluorescence ( Fig. 4-16 ). The latter emphasizes the hemidesmosomal focus of the immune attack in this disease. IgG is positive in most cases, but not infrequently linear C3 deposition is either the only finding or is much more pronounced than IgG deposition. Other immunoglobulins, particularly IgA, may also be positive, but they are typically weaker than IgG, an important diagnostic clue. The author has occasionally observed examples of pemphigoid in which basement membrane zone fluorescence includes an intercellular component among basilar keratinocytes. False-negative IF studies may occur in up to one third of cases of pemphigoid when biopsies are obtained from the lower extremities. 28 The selection of perilesional skin for IF study is important, because biopsies containing only blistered skin may be negative or nonspecific. Indirect IF, using monkey esophagus substrate, shows linear basement membrane zone fluorescence in about 70% of cases. Unlike pemphigus, antibody titers performed by indirect IF do not correlate with disease activity.


Figure 4-15 Bullous pemphigoid, direct immunofluorescence. There is linear immunoglobulin G deposition along the dermal-epidermal junction.


Figure 4-16 Bullous pemphigoid, direct immunofluorescence. Subepidermal separation has occurred in this specimen. Note the interrupted linear pattern of immunoglobulin G deposition along the roof of the separation.

Differential Diagnosis
At the early stage of eosinophilic spongiosis, pemphigoid and pemphigus vulgaris can certainly resemble one another. However, direct IF allows clear separation of the two, and the acantholytic appearance that defines classic pemphigus is not confused with the subepidermal separation of pemphigoid. Reliable differentiation from cicatricial pemphigoid with cutaneous involvement, or pemphigoid (herpes) gestationis, may not be possible, and they are widely considered variants of the same disease. However, cicatricial pemphigoid may actually be a complex of diseases that includes the mucosal variant of linear IgA disease and epidermolysis bullosa acquisita as well as pemphigoid. This may allow differentiation based on direct IF methods (see later discussion). In addition, cicatricial pemphigoid tends to show more neutrophils than eosinophils and a greater degree of scarring than ordinary pemphigoid.
A significant differential diagnostic problem can arise in differentiating pemphigoid from epidermolysis bullosa acquisita, because there can be overlapping clinical as well as microscopic features (see subsequent discussion). Both conditions can show linear IgG and C3 deposition along the dermal-epidermal junction. However, the target antigens differ. In epidermolysis bullosa acquisita, antibody binds to type VII collagen, a component of anchoring fibrils that are found below the lamina densa of the basement membrane zone. In pemphigoid, the target antigen is the hemidesmosome complex, above the lamina densa. This difference can be exploited by a procedure known as saline splitting. Tissues incubated in normal saline separate through the lamina lucida of the basement membrane zone. If the separated tissues are stained with antibodies to IgG, linear fluorescence is seen at the floor of the separation in epidermolysis bullosa acquisita, whereas bullous pemphigoid shows linear staining along the roof of the separation, or sometimes along both the roof and the floor. Only rarely is staining in pemphigoid found only along the floor of the separation; these are probably examples of the rare anti-p200 pemphigoid, whose target antigen resides in the lower lamina lucida of the basement membrane zone. 29 Saline splitting can be performed either as part of a direct or indirect IF procedure. The author has most often used this method in direct IF, with very reliable results.
Pemphigoid gestationis shows considerable microscopic overlap with pemphigoid, although there may be pronounced edema of dermal papillae (“teardrop-shaped” papillae). On direct IF, pemphigoid gestationis is more apt than pemphigoid to show only linear C3 deposition along the junctional zone, and indirect IF studies are typically negative unless a complement-enhanced procedure is performed (see later discussion). A major distinction is that pemphigoid, in the author’s experience, is distinctly unusual in young adults. This is highlighted by a recent case in a woman in the third decade of life, who had a bullous disease, deposition of linear basement membrane zone IgG and C3, and no known history of pregnancy. Further investigation showed that she had an “aborted” pregnancy several months earlier, markedly elevated human chorionic gonadotropin levels, and, in addition, an undetected choriocarcinoma. Linear IgA disease can closely resemble pemphigoid and on biopsy can show papillary neutrophilic microabscesses. However, elicitation by drug (e.g., vancomycin) can often be shown, and the positive linear IgA deposition that defines the disease is regularly found on direct IF study. Similarly, papillary neutrophilic microabscesses are a hallmark of dermatitis herpetiformis, but direct IF study shows granular IgA deposition (often accompanied by C3 and fibrin) along the basement membrane zone, often concentrated at tips of dermal papillae. Erythema multiforme has a distinct set of microscopic changes (vacuolar alteration of the basilar layer, apoptotic body formation at all levels of the epidermis, and a mild upper dermal perivascular lymphocytic infiltrate) and shows negative or nonspecific findings on direct IF study. However, the author has seen examples of erythema multiforme evolving into bullous pemphigoid, probably as a result of epitope spreading.

Lichen Planus Pemphigoides
This is an unusual bullous eruption occurring in patients with lichen planus. It does not represent blistering in a lesion of lichen planus due to extensive vacuolar alteration of the basilar layer, although that phenomenon also occurs (see Chapter 3 ). Tense bullae develop in areas of skin not directly involved with lichen planus lesions but can also occasionally incorporate these lesions. Despite a close resemblance to pemphigoid, lichen planus pemphigoides has a different target antigen 30 : a 200-kD protein, as well as the minor 180-kD pemphigoid antigen. 31 Microscopically, there is a subepidermal bulla with a mild perivascular infiltrate that may be composed of lymphocytes, eosinophils, and/or neutrophils ( Fig. 4-17 ). More typical lichenoid tissue changes can sometimes be identified. With direct IF, linear IgG and C3 deposition are identified along the dermal-epidermal junction, and linear staining is also visible on indirect IF. 32 Using the saline splitting procedure, staining of the roof of the resulting separation occurs, in a manner similar to pemphigoid.


Figure 4-17 Lichen planus pemphigoides. There is subepidermal separation with a mild superficial dermal infiltrate that contains lymphocytes and a few neutrophils.

Pemphigoid (Herpes) Gestationis

Clinical Features
Pemphigoid gestationis, formerly known as herpes gestationis, is an eruption of pregnancy that typically begins in the second or third trimester as urticarial plaques with the evolution of blisters over the trunk and extremities. It usually subsides shortly after parturition, but it may develop progressively earlier with succeeding pregnancies, and it may continue to flare, following a pregnancy, with menses, or on oral contraceptives. 33 Reportedly, an association with choriocarcinoma has occurred on a number of occasions. 34 Transplacental transfer to the infant also can occur, but it is apparently not associated with an increased risk of fetal mortality, as had been believed in the past. 35 , 36 The target antigen is the 180-kD minor bullous pemphigoid antigen, believed to be a component of type XVII collagen.

Microscopic Findings
On biopsy, there is papillary dermal edema, sometimes producing “teardrop-shaped” dermal papillae ( Fig. 4-18 ). Subepidermal separation may ensue, associated with basal cell degeneration. A perivascular lymphocytic and eosinophilic infiltrate is also present. 37 As in bullous pemphigoid, eosinophilic spongiosis can occur, particularly in early lesions. 14 Direct IF regularly shows linear C3 deposition along the dermal-epidermal junction ( Fig. 4-19 ), and IgG staining is less frequent (much less frequent, in the author’s experience). 38 Saline splitting shows staining of the roof of the separation, as in bullous pemphigoid. Indirect IF is usually negative when performed in the usual way, but a procedure known as complement-enhanced indirect IF can show basement membrane zone complement deposition. This technique involves adding a source of complement (such as normal human serum) to the indirect IF protocol and then staining the treated substrate with anticomplement antibody. 39 This phenomenon occurs because the circulating immunoglobulin (IgG 1 class) is difficult to detect directly but avidly binds complement, and the addition of a complement source thereby enhances the sensitivity of indirect IF testing.


Figure 4-18 Pemphigoid gestationis. This lesion shows marked papillary dermal edema, producing “teardrop-shaped” dermal papillae.


Figure 4-19 Pemphigoid gestationis, direct immunofluorescence. There is linear deposition of C3 complement along the basement membrane zone.

Differential Diagnosis
The microscopic differential diagnosis in early stages can include either urticaria or other conditions characterized by eosinophilic spongiosis. Fully developed blisters are difficult to distinguish from bullous pemphigoid. In the presence of papillary neutrophilic and/or eosinophilic microabscesses, consideration is also given to epidermolysis bullosa acquisita, dermatitis herpetiformis, linear IgA disease, or bullous LE. The clinical history, usually that of a young woman who is or has recently been pregnant, would heavily favor pemphigoid gestationis, and IF findings would provide strong support. In the author’s experience, bullous pemphigoid is extremely unusual in young persons. Epidermolysis bullosa acquisita also favors middle-aged to older adults, and an immunofluorescent procedure with saline splitting would show staining of the floor, rather than the roof, of the subepidermal separation. Dermatitis herpetiformis and linear IgA disease would show, respectively, granular or linear basement membrane zone IgA deposits on direct IF. Bullous LE could certainly occur in a young woman and possibly during pregnancy, and both conditions would show linear IgG and/or C3 basement membrane zone deposition. However, the majority of patients with bullous LE have other clinical or serologic evidence of LE, and again, saline splitting in that disease would show positivity along the floor, rather than the roof, of the subepidermal separation.

Cicatricial Pemphigoid (Mucous Membrane Pemphigoid)

Clinical Features
Formerly and somewhat unfortunately called “benign” mucous membrane pemphigoid, cicatricial pemphigoid shows blistering of ocular, oral, or other mucosal surfaces, with resultant scarring. 40 Blindness can result in up to 20% of the cases with conjunctival involvement. Cicatricial pemphigoid is also a cause of desquamative gingivitis. Skin lesions can develop in one third of cases, and dermatologic involvement varies from a widespread, nonscarring bullous eruption to intermittent, eruptive disease of the head and neck, particularly the scalp, with atrophic scarring, the so-called Brunsting-Perry variant. Although previously considered a single disease entity, cicatricial pemphigoid may represent a complex of disorders, 41 including classic cicatricial pemphigoid (essentially, a mucous membrane variant of bullous pemphigoid), mucosal linear IgA disease, and mucosal epidermolysis bullosa acquisita. The target antigens include the major and minor bullous pemphigoid antigens, epiligrin, or laminin 5 (one component of which is a 100-kD protein), and the β4 subunit of α6β4 integrin, although others have been identified in individual cases.

Microscopic Findings
Microscopic features include a subepithelial bulla and an inflammatory infiltrate that includes lymphocytes and neutrophils with variable numbers of eosinophils; in fact, eosinophils may well be inconspicuous. Subepithelial fibrosis and/or scarring are also evident ( Fig. 4-20 ). Direct IF shows linear basement membrane zone deposition, usually consisting of IgG and/or C3, in perilesional skin or mucosa ( Fig. 4-21 ). Occasionally, linear IgA deposition is encountered, either together with other immunoglobulins or, more rarely, as an isolated finding. Indirect IF may or may not show linear IgG or IgA along the basement membrane zone; the titers may correlate with disease activity. Results of saline splitting procedures vary, depending on the subtype of cicatricial pemphigoid; the bullous pemphigoid–like cases show staining of the roof of the subepidermal separation, whereas the antiepiligrin or laminin 5 cases show staining along the floor of the separation. 42 , 43


Figure 4-20 Cicatricial pemphigoid. This cutaneous lesion was present on the scalp. Note the extensive subepidermal separation and dermal scarring.


Figure 4-21 Cicatricial pemphigoid, direct immunofluorescence. There is linear immunoglobulin G deposition along the dermal-epidermal junction.

Differential Diagnosis
The microscopic differential diagnosis includes many of the subepidermal immunobullous diseases, but the primarily mucosal location of most examples can usually lead to the correct diagnosis. In fact, it may be that cicatricial pemphigoid can represent a “mucosal” subtype of bullous pemphigoid, linear IgA disease, or epidermolysis bullosa acquisita, and direct IF studies can help clarify this relationship. However, it is important to point out that the target antigens of IgA cicatricial pemphigoid may differ from those of cutaneous linear IgA disease, and the same can be said of cicatricial pemphigoid with staining of the floor of a saline split preparation, when compared with epidermolysis bullosa acquisita.
In the author’s experience, a more common diagnostic problem is the categorization of a case of conjunctivitis or desquamative gingivitis as either cicatricial pemphigoid or mucosal lichen planus. There can be considerable overlap in the clinical presentations of these two diseases. The microscopic task is made more difficult by the technical problems inherent in biopsy of these two sites, especially in the case of friable tissue. However, bandlike subepithelial lymphocytic inflammation clearly favors lichen planus, whereas a more mixed inflammatory reaction and scarring tend to favor cicatricial pemphigoid. In this situation, assuming that an intact specimen is submitted, direct IF can be immensely helpful, in that positive linear basement membrane zone IgG, C3, or IgA deposition favors cicatricial pemphigoid, whereas IgM-positive Civatte bodies and a shaggy fibrin band are characteristic of lichen planus.

Epidermolysis Bullosa Acquisita

Clinical Features
Epidermolysis bullosa acquisita is an acquired immunobullous disease with clinical and, sometimes, histopathologic resemblances to hereditary forms of epidermolysis bullosa. However, it tends to occur frequently in middle-aged to older adults. Acral skin (usually) displays increased fragility and noninflammatory bullae, and scarring and milia formation ensue. 44 The lesions can mimic those of pemphigoid, or there can be cicatricial pemphigoid-like mucosal lesions. The target antigen is type VII collagen, a component of anchoring fibrils, and has a molecular weight of 290 kD.
Treatment includes systemic corticosteroids, azathioprine, dapsone, and a variety of other agents.

Microscopic Findings
Microscopically, there is typically an infiltrate-poor subepidermal bulla ( Fig. 4-22 ), but inflammatory lesions contain lymphocytes, neutrophils, and eosinophils. Occasionally, some examples display papillary neutrophilic microabscesses ( Fig. 4-23 ). Direct IF shows linear IgG, C3, and sometimes other immunoglobulins along the dermal-epidermal junction. Indirect IF can also show circulating anti–basement membrane zone antibodies. The saline splitting procedure, used in conjunction with either direct or indirect IF methods, usually shows staining of the floor, rather than the roof, of the resulting subepidermal separation. 45


Figure 4-22 Epidermolysis bullosa acquisita. This lesion shows an infiltrate-poor subepidermal bulla.


Figure 4-23 Epidermolysis bullosa acquisita. Occasional examples contain papillary neutrophilic microabscesses, resembling dermatitis herpetiformis and a limited group of subepidermal blistering disorders.

Differential Diagnosis
On routine light microscopy, noninflammatory lesions of epidermolysis bullosa acquisita can closely resemble hereditary forms of epidermolysis bullosa, particularly the junctional or dermolytic types. However, heritable forms of epidermolysis bullosa typically begin in infancy and childhood, and IF studies are negative.
The major problem in differential diagnosis is the distinction between epidermolysis bullosa acquisita and bullous pemphigoid of either the infiltrate-poor or infiltrate-rich types. Eosinophils are usually a hallmark of pemphigoid, whereas this is not the case for epidermolysis bullosa acquisita; however, exceptions can occur. IF findings are also quite similar. In the author’s experience, the “interrupted” linear pattern of junctional staining, when present, is generally indicative of pemphigoid, because it reflects the hemidesmosomal location of the target antigen. In situations where continuous linear basement membrane zone fluorescence occurs, the saline splitting procedure is most useful, in that IgG staining is generally visible in the floor of the separation in epidermolysis bullosa acquisita but most often in the roof of the separation in pemphigoid. The same can be said for pemphigoid gestationis although usually the clinical history is decisive. However, pemphigoid can occasionally show staining only in the floor of a saline split preparation; some of these may be examples of anti-p200 pemphigoid. Pang and colleagues emphasized this issue and suggested using invertebrate skin in an indirect IF procedure. Toad skin apparently possesses the bullous pemphigoid and not the epidermolysis bullosa acquisita antigen, and therefore a positive indirect IF procedure using this substrate and patient serum is indicative of pemphigoid. 46 An additional theoretical problem is that IF staining of the roof of a subepidermal separation in epidermolysis bullosa acquisita could occur as a consequence of epitope spreading.
It is also possible to confuse examples of epidermolysis bullosa acquisita with papillary neutrophilic microabscesses with dermatitis herpetiformis, linear IgA disease, or bullous LE. IgA staining of the basement membrane zone, in a granular or linear pattern, favors one of the first two diagnoses. In the occasional situation where epidermolysis bullosa acquisita also displays linear IgA deposition, invariably IgG is also present and is typically expressed more strongly than IgA. Both bullous LE and epidermolysis bullosa acquisita can show deposits of multiple immunoglobulins in linear fashion along the dermal-epidermal junction, and in both cases their target antigens are components of type VII collagen, found in the anchoring fibrils of the sublamina densa zone. 47 , 48 Therefore, the results of saline splitting may be identical in both, showing staining of the floor of the resulting separation. Clinical data supporting the diagnosis of LE would obviously be important, but there are previous reported examples of a bullous disease resembling epidermolysis bullosa acquisita in patients with LE. Therefore, authorities have suggested that the two conditions are closely related or variants of the same process. One additional finding that would point toward a diagnosis of LE in such circumstances is the finding of an antinuclear antibody, along with basement membrane zone fluorescence, on either direct IF or indirect IF testing (see subsequent discussion).

Bullous Lupus Erythematosus

Clinical Features
Patients with bullous LE present with asymmetric, nonpruritic, photodistributed bullae. These lesions may occur singly or may be grouped. Patients usually have established systemic LE, 49 but skin lesions more typical of LE may not be present, and American College of Rheumatology criteria for the disease may not be met. 50 The target antigens are the 290-kD and 145-kD components of type VII collagen, which as previously mentioned is a constituent of the anchoring fibrils of the sublamina densa basement membrane zone.
The lesions are often, but not invariably, 51 responsive to dapsone, a drug also used in the management of dermatitis herpetiformis.

Microscopic Findings
The lesions of bullous LE do not display many of the characteristics of typical LE skin lesions but instead show papillary dermal neutrophilic microabscesses and subepidermal separation 49 ( Figs. 4-24 and 4-25 ). However, dermal mucin deposition may be detected. This is clearly not the picture one would expect when blisters arise in ordinary lesions of cutaneous LE, in which case separation occurs in the context of extensive vacuolar alteration of the basilar layer and may be accompanied by hyperkeratosis, follicular plugging, epidermal atrophy, and perivascular and periadnexal lymphocytic inflammation. Direct IF shows linear or granular IgG, C3, or other immunoglobulins along the dermal-epidermal junction ( Fig. 4-26 ). On indirect IF, basement membrane zone deposits are rarely found, but when present, suggest a link with epidermolysis bullosa acquisita. An antinuclear antibody can be detected in keratinocyte nuclei on either direct or indirect IF ( Fig. 4-27 ). In a few cases, bullous LE has been associated with antiphospholipid antibodies. 52


Figure 4-24 Bullous lupus erythematosus (LE). There is a subepidermal separation with accumulations of inflammatory cells—mostly neutrophils—at the base.


Figure 4-25 Bullous LE. Some examples show papillary neutrophilic microabscesses.


Figure 4-26 Bullous LE, direct immunofluorescence. This case shows linear immunoglobulin G deposition along the dermal-epidermal junction.


Figure 4-27 Bullous LE, direct immunofluorescence, saline-splitting procedure. Linear immunoglobulin G deposition is evident along the floor of the resulting subepidermal separation. This outcome would be expected in LE and would also be seen in epidermolysis bullosa acquisita. In addition, antinuclear antibody staining can be seen in keratinocyte nuclei. It is possible that intranuclear binding sites were unmasked during incubation in 1 molar NaCl.

Differential Diagnosis
As previously mentioned, the microscopic features are not those of typical LE, making the diagnosis difficult in the absence of clinical and serologic data. Uncommonly, patients with LE may develop a nonbullous neutrophilic dermatosis. Such lesions consist of pruritic papules and plaques, and they show a superficial dermal neutrophilic infiltrate with leukocytoclasis in the absence of vasculitis. 53 The differential diagnosis of subepidermal blisters with papillary neutrophilic microabscesses includes dermatitis herpetiformis, linear IgA disease, some examples of bullous pemphigoid, and epidermolysis bullosa acquisita. Direct or indirect IF studies may be essential in establishing the diagnosis in each of these disorders. When granular IgA deposition is seen in bullous LE, other immunoglobulins are likely to be present as well, and staining for these is typically at least as intense, or more so, as it is for IgA. The same can be said when there is linear IgA deposition in bullous LE. Saline splitting can be helpful in ruling out pemphigoid, because immunoglobulins in bullous LE would be expected to stain the floor, rather than the roof, of the subepidermal separation. The difficulties in separating bullous LE from epidermolysis bullosa acquisita have been discussed in the previous section. This is particularly the case when linear staining with multiple immunoglobulins is present. Saline splitting is not helpful in this instance, because the target antigens in the two conditions are similar. Again, detection of an antinuclear antibody in epidermal keratinocytes is supportive of the diagnosis of bullous LE. It should also be mentioned that a prozone phenomenon rarely occurs in antinuclear antibody testing 54 ; in at least one such case, performance of a saline splitting procedure unmasked an antinuclear antibody that had been negative by more traditional laboratory methods.

Dermatitis Herpetiformis

Clinical Features
Dermatitis herpetiformis presents as a symmetrical eruption involving extensor surfaces, consisting of grouped, tense, extremely pruritic vesicles on erythematous bases. This grouping is reminiscent of that associated with infections by herpes simplex and varicella-zoster viruses—hence, the diagnostic terminology. As a result of pruritus, lesions are often excoriated, and sometimes it is difficult to demonstrate intact vesicles. 55 , 56 Spruelike changes can be found when jejunal biopsies are performed, and there is a high frequency of the human leukocyte antigens (HLAs) B8, DR3, and Dqw2. Investigators believe that IgA antibodies, perhaps formed in the gut, bind to bundles of microfibrils in the papillary dermis, followed by complement deposition and recruitment of neutrophils. 57 , 58
Dermatitis herpetiformis is a chronic, relapsing disease that can be well controlled, but not cured, by the drugs dapsone and sulfapyridine. A strict gluten-free diet can also be helpful, resulting in decreased dosages or even discontinuation of these agents. Malignancy has been reported in dermatitis herpetiformis, particularly enteropathy-associated non-Hodgkin lymphoma. However, recent studies appear to indicate only a slightly increased risk of malignancy in these patients, and in fact there may actually be a decrease in mortality. 59 , 60 A gluten-free diet may serve a protective role. 61

Microscopic Findings
The hallmark of the histopathology in dermatitis herpetiformis is the formation of papillary dermal neutrophilic microabscesses ( Fig. 4-28 ). Cleftlike spaces develop over these microabscesses, which can coalesce to form clinically apparent vesicles. 62 Eosinophils are sometimes visible and are said to be more prominent in older lesions. There is also an underlying perivascular dermal infiltrate that includes neutrophils, lymphocytes, and eosinophils in varying combinations. Leukocytoclasis is sometimes observed, and this may create an impression of vasculitis in some cases. Direct IF is of great help in diagnosis, because it shows granular to particulate IgA deposition along the dermal-epidermal junction, frequently concentrated at the tips of dermal papillae ( Fig. 4-29 ). 63 C3 complement and/or fibrin are often, but not invariably, found in the same vicinity. Indirect IF studies are negative, except that diagnostic antiendomysial IgA antibodies can be found with some substrates.


Figure 4-28 Dermatitis herpetiformis. The characteristic papillary neutrophilic microabscesses are illustrated in this example.


Figure 4-29 Dermatitis herpetiformis, direct immunofluorescence. Granular-particulate immunoglobulin A staining is seen in the junctional zone, concentrated at the tips of dermal papillae.

Differential Diagnosis
Dermatitis herpetiformis is the prototype disorder showing papillary neutrophilic microabscesses, sometimes including eosinophils. However, as mentioned previously, similar changes can be seen in a number of the immunobullous diseases, including bullous pemphigoid (and the variant disorders cicatricial pemphigoid and pemphigoid gestationis), epidermolysis bullosa acquisita, bullous LE, and linear IgA disease. Distinction among these disorders depends largely on direct IF studies. The only one of these disorders that might create confusion on IF study would be bullous LE with granular IgA deposition along the junctional zone. However, as mentioned previously, other immunoglobulins would also be present, of at least equal or greater intensity. Other conditions that feature neutrophils in the dermis can occasionally show accumulation of these cells in the dermal papillae and therefore resemble dermatitis herpetiformis to a degree. A common example is florid leukocytoclastic vasculitis. In that particular example, unequivocal vasculitis is identified, and direct IF study shows granular deposition of immunoglobulins and complement around vessels; the junctional zone is typically spared, with the possible exception of some granular C3 or fibrin deposition.
One caveat regarding dermatitis herpetiformis—routinely performed biopsy specimens may not always show diagnostic changes, but the classic direct IF findings can still be seen. In a recent example in the author’s laboratory, the clinician sent biopsy specimens to rule out dermatitis herpetiformis. Both the hematoxylin and eosin–stained sections and the IF sections showed only the morphologic features of verruca plana, and yet the direct IF findings were diagnostic for dermatitis herpetiformis.

Linear Immunoglobulin A Disease

Clinical Features
This designation describes several different clinical disorders, including an eruption of childhood that features polycyclic lesions ringed by blisters that occur periorally and over the trunk (chronic recurrent bullous dermatosis of childhood), 64 a widespread bullous eruption in adults, 65 and the previously mentioned mucous membrane lesions that may comprise a subtype of cicatricial pemphigoid. The adult type has a strong association with certain drugs, including vancomycin (particularly common, in the author’s experience), captopril, furosemide, ibuprofen, lithium, naproxen, and trimethoprim. 66 Although once considered a variant of dermatitis herpetiformis, linear IgA disease has different HLA types, and affected patients are usually only partly responsive to dapsone therapy. The involved target antigens vary considerably. They include 97-kD and 120-kD proteins, degradation products of the minor 180-kD bullous pemphigoid antigen, 67 as well as a lamina densa protein that may be a component of type VII collagen. 68

Microscopic Findings
The histopathology of linear IgA disease is similar to that of dermatitis herpetiformis in that papillary neutrophilic microabscesses are present. However, papillary neutrophils are sometimes continuous along the junctional zone, producing larger areas of separation than normally encountered in dermatitis herpetiformis ( Fig. 4-30 ), and organization into discrete microabscesses may not be as well developed. Direct IF shows linear IgA deposition, with or without C3 deposition, along the dermal-epidermal junction ( Fig. 4-31 ). 69 Indirect IF occasionally shows linear IgA deposits.


Figure 4-30 IgA disease. Papillary neutrophilic collections become confluent and are associated with a large subepidermal separation.


Figure 4-31 IgA disease, direct immunofluorescence. Linear IgA deposition is present along the dermal-epidermal junction.

Differential Diagnosis
Despite the previously stated microscopic resemblance to other immunobullous diseases, of which dermatitis herpetiformis is the prototype, the direct IF findings in linear IgA disease are quite striking and almost always diagnostic. However, in a minority of cases of linear IgA disease, linear deposition of other immunoglobulins is seen in addition to IgA. This can create confusion with examples of bullous LE, bullous pemphigoid, or cicatricial pemphigoid that include IgA among other immunoglobulins showing linear basement membrane zone deposits. Saline splitting may not provide additional help in this regard. Typically in linear IgA disease, IgA staining is stronger than for other immunoglobulins, whereas the reverse is the case in other immunobullous diseases. Nevertheless, correlation with other clinical and laboratory findings may be necessary.

Erythema Multiforme and Toxic Epidermal Necrolysis

Clinical Features
Erythema multiforme is a blistering disorder that can demonstrate varying degrees of severity. Although urticaria-like or papular lesions may occur, particularly in early stages, the hallmark is the iris, or target lesion that shows a central necrotic bulla. Numerous triggering factors are known, but among the best established are herpes simplex infection, a common cause of erythema multiforme in younger individuals, and certain medications, frequently encountered in older individuals. Recurrent bouts of erythema multiforme may occur in patients who develop recurrent herpesvirus infections, whereas drug-induced erythema multiforme in older individuals may last for longer periods of time, up to 3 to 4 weeks or more. 70 Erythema multiforme is believed to represent a cell-mediated response to the various etiologic agents that can trigger the disease. The Stevens-Johnson variant , a more extensive form of erythema multiforme that is typically accompanied by prominent mucous membrane involvement, is often related to drug ingestion.
Toxic epidermal necrolysis , characterized by widespread erythema and exfoliation, is considered by some to represent a severe variant of erythema multiforme. It is also most often associated with drugs, particularly trimethoprim-sulfamethoxazole and other antibiotics, allopurinol, and anticonvulsants. Loss of fluid and electrolytes and infection are among the complications of this disorder.
Treatment of erythema multiforme includes removing the underlying cause (e.g., antiviral therapy or discontinuation of the offending medication) and symptomatic treatment. Management of toxic epidermal necrolysis involves intravenous immunoglobulin and replacement of fluid and electrolytes.

Microscopic Findings
Classic erythema multiforme consists of a triad of findings: vacuolar alteration of the basilar layer, apoptotic keratinocytes that can be found at all levels of the involved epidermis, and a relatively sparse superficial perivascular dermal infiltrate composed mainly of lymphocytes ( Fig. 4-32 ). 71 Papillary dermal edema may be the predominant feature when biopsies are obtained from the border of a lesion, whereas keratinocyte apoptosis (necrosis) may be the chief finding when specimens are obtained from the center of a necrotic blister. The epidermis is often of approximately normal thickness, and the stratum corneum may retain its normal basket-weave appearance, a reflection of the rapidity of lesional development. Blisters result from the extensive basilar vacuolar change with resulting cleft formation. The dermal infiltrate is often surprisingly mild. Although lymphocytes predominate, eosinophils are not infrequently found, and they can be numerous (>3/high-power field) in drug-induced cases. 70 The epidermal changes are more severe in Stevens-Johnson syndrome ( Fig. 4-33 ). Direct IF is often performed to rule out other blistering disorders—in particular, immunobullous diseases. The results are usually negative, although sometimes apoptotic (Civatte) bodies stain for IgM, and there may be granular C3 deposition in papillary dermal vessels or along the dermal-epidermal junction. Indirect IF studies are negative in this disease. Toxic epidermal necrolysis shows full-thickness epidermal necrosis ( Fig. 4-34 ); however, early lesions may show extensive apoptosis. Dermal inflammation is notably sparse in many cases.


Figure 4-32 Erythema multiforme. There is vacuolar alteration of the basilar layer leading to subepidermal separation, along with numerous apoptotic keratinocytes and a relatively modest perivascular lymphocytic infiltrate.


Figure 4-33 Stevens-Johnson syndrome. There is more extensive keratinocyte necrosis. Re-epithelialization has begun along the blister base.


Figure 4-34 Toxic epidermal necrolysis. The epidermis is completely necrotic. There is a mild lymphocytic infiltrate in the underlying dermis.

Differential Diagnosis
The constellation of features in erythema multiforme is quite characteristic, if not pathognomonic, and allows a diagnosis in most instances. Early papular or urticarial lesions may be the most problematic due to their nonspecific features. Most immunobullous diseases look quite different from erythema multiforme and can easily be excluded on a routine biopsy, with or without supplementation by direct IF. One possible exception is paraneoplastic pemphigus, which can closely mimic erythema multiforme microscopically, but shows different direct IF findings (intercellular and, sometimes, basement membrane zone fluorescence). Other differential diagnostic considerations included fixed drug eruption and pityriasis lichenoides acuta. Fixed drug eruption is limited to one or a few clinical locations and is exemplified by a discrete zone of recurrent erythema following ingestion of a particular agent. Biopsies show epidermal changes closely mimicking erythema multiforme, but there is a superficial and deep perivascular dermal infiltrate in fixed drug eruption, and neutrophils may be more evident. The author has seen rare examples of a spongiotic variant of fixed drug with prominent eosinophils and neutrophils, and this form would be readily distinguishable from erythema multiforme (see Chapter 12 ). Pityriasis lichenoides acuta can closely mimic erythema multiforme microscopically. However, usually there is a greater degree of parakeratosis and exocytosis of inflammatory cells in the former, and the dermal infiltrate may be more wedge-shaped and show evidence for lymphocytic vasculitis. Two other conditions that can resemble erythema multiforme microscopically but have substantially different clinical presentations are graft-versus-host disease and occasional examples of exfoliative dermatitis due to drugs, underlying neoplasm, or distant focus of infection.
An important clinical differential consideration for toxic epidermal necrolysis is staphylococcal scalded skin syndrome, a primarily childhood disease due to the effects of exfoliative exotoxins types A and B. However, the latter disease typically has a much better prognosis and microscopically shows only superficial rather than full-thickness epidermal necrosis. This can be determined not only on routine biopsy specimens but also in a rapid procedure performed on frozen sections of separated skin.

Inherited Blistering Diseases

Hailey-Hailey Disease

Clinical Features
Initially described by the Hailey brothers, this autosomal dominant disease is probably best designated by the eponym rather than its other name, familial benign chronic pemphigus . Hailey-Hailey disease features erythematous plaques with flaccid bullae that rupture and produce crusting and erosions. It commonly occurs in intertriginous areas. The chief finding, a loss of cohesion among epidermal keratinocytes, results from an abnormality of adherens junctions. The involved gene, ATP2CI, encodes a calcium pump (ATPase) that may be important in the maintenance of epidermal integrity. 72 This is not an immune-mediated disease.
Treatment is largely supportive, including antibiotics for infection, dermabrasion, and grafting. However, clinicians have used a variety of other agents, such as photodynamic therapy and topical calcineurin inhibitors.

Microscopic Findings
On biopsy, lesions show extensive suprabasilar acantholysis involving epidermal keratinocytes, so much so that the resulting changes have been likened to a “dilapidated brick wall” ( Fig. 4-35 ). At the base of a lesion, a single row of basilar keratinocytes lines the dermal papillae, producing structures called villi, and narrow strands of keratinocytes protrude into the underlying dermis. Follicular epithelia in the vicinity of lesions are spared (see Fig. 4-35 ). On occasion, some dyskeratosis can be identified, manifesting as cells with pyknotic nuclei surrounded by clear halos (corps ronds) or displaying elongated, pyknotic nuclei (grains) ( Fig. 4-36 ). 73 Dermal inflammation is variable and usually attracts little attention; the author has seen at least one case in which eosinophils were prominent. Direct and indirect IF studies are negative in this disease.


Figure 4-35 Hailey-Hailey disease. There is extensive suprabasilar acantholysis, producing the resemblance to a “dilapidated brick wall.” Note that the deeper portions of the follicular unit are spared by the process.


Figure 4-36 Hailey-Hailey disease. This example shows dyskeratosis, with corps rond formation, in the superficial epidermis.

Differential Diagnosis
The differential diagnosis of Hailey-Hailey disease includes other acantholytic dermatoses. The most important of these is pemphigus. Although both disorders show suprabasilar acantholysis, the degree of acantholysis tends to be much greater in Hailey-Hailey disease, whereas in pemphigus, often only a few acantholytic cells are evident in the blister cavity. It is possible to observe dyskeratosis, at least focally, in Hailey-Hailey disease, and this is not a common feature of pemphigus. Eosinophilic spongiosis is not a feature of Hailey-Hailey disease, but on the other hand, eosinophils are often prominent in the dermal infiltrate of pemphigus lesions, and eosinophilic spongiosis may be identified in early lesions. Dermal eosinophils are not usually conspicuous but can be; the author has seen this on several occasions. One other major differentiating feature is follicular involvement. Although follicles are spared in Hailey-Hailey disease, they are typically involved in pemphigus and in fact may constitute a prominent feature in some examples of the latter disease. Direct IF study is often decisive, because positive intercellular IgG and C3 deposits are not evident in Hailey-Hailey disease but are seen in the epidermis in pemphigus.
Other acantholytic dermatoses must be ruled out. Darier disease (keratosis follicularis), another genodermatosis combining acantholysis with dyskeratosis, may show overlapping features with Hailey-Hailey disease, and for a time, the latter was considered a possible blistering variant of Darier disease. However, in most instances, Darier disease displays microscopic clefts rather than bullae, and dyskeratosis is much more prominent than in Hailey-Hailey disease (see later discussion). The same considerations would apply to other, acquired conditions showing focal acantholytic dyskeratosis, particularly Grover disease (transient acantholytic dermatosis). The latter tends to occur in middle-aged patients as scaly papules, particularly over the trunk. That scenario is often decisive. Microscopically, Grover disease can have at least five microscopic configurations associated with acantholysis: pemphigus-like, Hailey-Hailey–like, spongiotic, Darier-like, or pemphigus foliaceus–like. Obviously the greatest difficulty vis-à-vis this particular differential is created by the forms of Grover disease resembling pemphigus or Hailey-Hailey disease. However, the small, self-limited nature of the lesions would ordinarily allow a confident diagnosis. A further consideration is the entity acantholytic dermatosis of the genitocrural region (papular acantholytic dyskeratosis). These papular lesions often have histopathologic changes identical to those of Hailey-Hailey disease ( Fig. 4-37 ), but they are localized and lack the familial history of the latter. As in Hailey-Hailey disease, direct IF studies are negative.


Figure 4-37 Acantholytic dermatosis of the genitocrural region. The findings can be virtually identical to those of Hailey-Hailey disease, but the clinical presentation is different, consisting of papular lesions in the aforementioned location, in the absence of a family history.

Bullous Darier Disease
The preceding discussion delineates the microscopic differences between Hailey-Hailey disease and Darier disease (see Chapter 16 ). However, rare examples of bullous Darier disease do occur. 74 , 75 Occasionally, lesions of Grover disease (transient acantholytic dermatosis—an acquired disorder featuring focal acantholytic dyskeratosis) may also form bullae. These appear to result from an exaggeration of the suprabasilar clefting that is a hallmark of the disease ( Fig. 4-38 ). In one such case, other subtle findings—particularly nail changes—facilitated the diagnosis, even though in other respects the cutaneous findings were atypical. The marked degree of dyskeratosis, with well-formed corps ronds and grains, enables a correct diagnosis, and direct IF studies would be negative.


Figure 4-38 Bullous Darier disease. A, Suprabasilar separation has occurred, in the vicinity of a follicular unit. This is basically an exaggeration of the less extensive clefting that usually develops in this disease. B, Detail of the blister roof, showing prominent dyskeratosis with corps rond formation.

Hereditary Epidermolysis Bullosa

Clinical Features
The term epidermolysis bullosa refers to an extensive grouping of disorders that produce blistering either within the epidermis or at various levels of the basement membrane zone. Although numerous clinical varieties have been described, these disorders can generally be divided into intraepidermal, junctional, or dermolytic types.
The major intraepidermal types include the dominantly inherited epidermolysis bullosa simplex and Weber-Cockayne disease, also known as “recurrent bullous eruption of the hands and feet.” Epidermolysis bullosa simplex consists of vesicles and bullae that tend to occur with trauma to acral surfaces, especially the elbows, knees, lower legs, and feet. The condition usually begins shortly after birth. Fortunately, other complications are rare, and although troubling, this is considered one of the milder forms of epidermolysis bullosa. Weber-Cockayne disease manifests in the first several years of life but may not become apparent until adolescence, when it initially is often believed to be an exaggeration of normal friction blistering. Both of these disorders involve mutations of the keratin 5 and/or 14 genes. 76 , 77
Junctional epidermolysis bullosa is an autosomal recessive disorder that includes a severe variant, often lethal in infancy, termed Herlitz disease , 78 as well as several more benign forms with better prognosis. 79 In Herlitz disease, there is extensive blistering and denudation of skin and mucous membranes that may be present at birth. Death may result from the complications of laryngeal or bronchial involvement, although survival past infancy has reportedly occurred. This form of the disease is associated with mutations of genes coding for polypeptide subunits of laminin 5: specifically, LAMA3, LAMB3, and LAMC2. 80 Other rare forms include junctional epidermolysis bullosa with pyloric atresia, a severe form that may also be lethal at birth; cicatricial junctional epidermolysis bullosa, which produces syndactyly and joint contractures; generalized atrophic benign epidermolysis bullosa, in which patients can survive to adult life; and localized (pretibial) and inverse (truncal rather than acral involvement) atrophic forms. The genetic defects in these disorders, in some cases, have been shown to differ from those of Herlitz disease.
Dermolytic forms of epidermolysis bullosa result in varying degrees of scarring, because separation occurs in the sublamina densa zone. 81 Those types with autosomal dominant inheritance are most often associated with blistering early in life, accompanied by scarring and milia formation. Hypertrophic scars develop in the Cockayne-Touraine variant, whereas pale to flesh-colored albopapuloid lesions are typical of the Pasini type. A rare pretibial variant first develops more typically in later childhood or early adult life. Type VII collagen, the important component of anchoring fibrils in the sublamina densa zone, is often abnormal in these dominant varieties of the disease, and this in turn is linked to abnormalities of the COL7A1 gene on chromosome 3. 82 The major recessively inherited forms of dystrophic epidermolysis bullosa include a localized type and two generalized variants: (1) the mild, or mitis, type and (2) the better known, severe, Hallopeau-Siemens type. In the latter, mucocutaneous blistering is present at birth, causing (as one of the most distinctive features) fusion of the digits and producing a mitten-like deformity of the hands and feet. Growth retardation, joint contractures, and anemia are present, and development of squamous cell carcinomas takes place in older patients in areas of repeated blistering and scarring. Again, these forms of the disease result from mutations in the COL7A1 gene that encodes type VII collagen, a component of anchoring fibrils in the sublamina densa zone of the basement membrane.

Microscopic Findings
In epidermolysis bullosa simplex, fully developed lesions have the appearance of an infiltrate-poor subepidermal bulla, but in reality the initial change involves degeneration of the infranuclear portions of basilar keratinocytes. 83 Observation of this feature is best at the edge of a blister, or in subclinical lesions purposely created with a pencil eraser or other device; then, degeneration of basilar keratinocytes is evident, with the impression that the infranuclear portions of these cells are “pulling away” from the underling dermis ( Fig. 4-39 ). In fully developed blisters, fragments of keratinocyte cytoplasm attached to the floor of what appears to be a “subepidermal” split are apparent. This produces a fringelike arrangement that can often be seen in routinely stained sections ( Fig. 4-40 ) but may stand out with cytokeratin staining or on electron microscopy. In Weber-Cockayne disease, the area of separation appears to involve the mid or upper epidermis. Because purposely induced blisters in this variant of the disease form in the basilar layer, as is true in epidermolysis bullosa simplex, a “two hit” theory has been proposed to explain the usual microscopic appearance of separation in upper levels of the epidermis. Initial injury to germinative basilar keratinocytes ( Fig. 4-41 ) is presumably followed by later injury to altered cells that, at the time of biopsy, have migrated to a more superficial epidermal location ( Fig. 4-42 ).


Figure 4-39 Epidermolysis bullosa simplex. This change was induced by a pencil eraser. Note the infranuclear degeneration of basilar keratinocytes with early separation from underlying tissues.


Figure 4-40 Epidermolysis bullosa simplex. At low magnification, this lesion appeared to be a subepidermal blister. At higher magnification, it can be seen that the base is composed of basal keratinocyte cytoplasmic fragments attached to the dermal side of the split.


Figure 4-41 Epidermolysis bullosa simplex, Weber-Cockayne type. Early changes include infranuclear degeneration with basilar vacuolization.


Figure 4-42 Epidermolysis bullosa simplex, Weber-Cockayne type. A fully developed blister shows keratinocyte degeneration and separation occurring through the superficial portion of the viable epidermis.
In junctional types of epidermolysis bullosa, separation occurs through the lamina lucida of the basement membrane zone, giving the low-power appearance of an infiltrate-poor subepidermal bulla ( Fig. 4-43 ). Immunostaining shows laminin and type IV collagen at the floor of the separation, distinguishing this group of disorders from the dystrophic forms of epidermolysis bullosa. 84 On electron microscopy, absence or hypoplasia of hemidesmosomes can be demonstrated. 85


Figure 4-43 Junctional epidermolysis bullosa. This section shows a “clean” subepidermal separation, with no scarring and minimal inflammation. Ultrastructural examination shows hypoplasia or absence of hemidesmosomes.
All forms of dermolytic (dystrophic) epidermolysis bullosa show infiltrate-poor subepidermal blistering with varying degrees of scar formation. Milder scarring and milia formation are particularly seen in the dominant forms ( Fig. 4-44 ), whereas scarring is more extensive in the recessive variants ( Fig. 4-45 ). The albopapuloid lesions of the Pasini type of dominant dystrophic epidermolysis bullosa show hyperkeratosis, epidermal atrophy, and dermal fibrosis, some of which is perifollicular. 86 The level of separation can be demonstrated with staining for laminin and type IV collagen, which exists in the roof of the blister in dystrophic variants. If available, staining for antibodies to type VII collagen is used, and weak or absent staining is apparent in the recessive dystrophic forms. Ultrastructural studies confirm the level of separation beneath the lamina densa in these disorders and show diminished (dominant forms) or absent (recessive forms) anchoring fibrils. 85


Figure 4-44 Dominant dystrophic epidermolysis bullosa. Findings include subepidermal separation, scar, and milia formation.


Figure 4-45 Recessive dystrophic epidermolysis bullosa. Findings include extensive subepidermal separation and scarring.

Differential Diagnosis
For all types of epidermolysis bullosa, knowledge of the hereditary nature of the disease can be decisive in properly categorizing the disorder, and direct IF studies can further exclude those immunobullous diseases that are potential microscopic mimics. In epidermolysis bullosa simplex, fully developed blisters appear to be subepidermal, but as previously noted, careful inspection of the junctional zone lateral to the blister often shows degeneration of infranuclear portions of basilar keratinocytes. The history of childhood disease, usual absence of a significant inflammatory component, and negative routine direct IF studies help distinguish junctional forms of epidermolysis bullosa from immunobullous disorders such as bullous pemphigoid. The ultrastructural finding of hypoplastic hemidesmosomes substantiates the diagnosis. Microscopic examination in cases of dermolytic epidermolysis bullosa are often said to be of little value. However, with use of immunostains, including direct IF, this group of entities can often be diagnosed with reasonable certainty, at least to the point where they can be distinguished from infiltrate-poor immunobullous disorders such as epidermolysis bullosa acquisita and some examples of pemphigoid. A distinction from epidermolysis bullosa simplex and junctional epidermolysis bullosa is also possible, although electron microscopy is most useful in this regard. Specialized antibody studies are available at some institutions to allow more precise categorization among the subtypes of epidermolysis bullosa.

Selected Pustular Disorders

Pustular Dermatoses of Infancy

Clinical Features
The development of pustules in infancy is characteristic of three conditions. Erythema toxicum neonatorum , which occurs during the first few days of life, consists of patchy erythema involving the face, trunk, and proximal extremities. Papules and pustules that appear to be follicular-based are also evident. This self-limited dermatosis typically disappears within a week or so. Dermatologists are often not consulted about this common disorder, and biopsies are rarely obtained. Acropustulosis of infancy , in which pruritic vesicopustules develop over the extremities, 87 typically begins in the first few months of life and may persist or recur over a period of several years. Lesions can mimic those of scabies, and a relationship to that disorder or to atopy has been described. Transient neonatal pustular melanosis , a similar condition, is somewhat more widespread in distribution. It is characterized by vesicopustules that rupture to leave hyperpigmented macules, often with scaly edges. These lesions resolve after a few days, although the associated pigmentation fades more gradually. 88

Microscopic Findings
On biopsy, erythema toxicum neonatorum shows eosinophils within the outer root sheath and infundibulum of hair follicles as well as scattered within the superficial dermis ( Fig. 4-46A ). In fully formed lesions, eosinophils accumulate in a subcorneal location adjacent to follicular ostia (see Fig. 4-46B ). 89 In acropustulosis of infancy, there is formation of intraepidermal pustules that eventually reach a subcorneal location ( Fig. 4-47 ). Neutrophils tend to predominate, but eosinophils may occur. 90 The findings in transient neonatal pustular melanosis are similar to those in acropustulosis of infancy, although the pigmented macules display basilar hypermelanosis. 91


Figure 4-46 Erythema toxicum neonatorum. A, There is eosinophilic spongiosis, with an intraepidermal vesicle forming in the infundibulum of a hair follicle. Note portion of hair shaft at the top of the figure. B, In this fully formed lesion, a large intraepidermal eosinophilic abscess has formed.


Figure 4-47 Acropustulosis of infancy. There is an intracorneal pustule comprised of neutrophils. The findings are similar to those in transient neonatal pustular melanosis, but in the latter disorder there is also basilar hyperpigmentation.

Differential Diagnosis
Erythema toxicum neonatorum can resemble other dermatoses characterized by eosinophilic microabscess formation in the epidermis. The most significant problem would arise in distinguishing this disorder from the early “bullous” phase of the X-linked dominant disorder incontinentia pigmenti, which also arises early in life. However, erythema toxicum neonatorum is more transient, and its chief clinical finding, in contrast to the linear vesicles of incontinentia pigmenti, is actually macular erythema. The papules and pustules of erythema toxicum neonatorum are clearly folliculocentric, unlike in incontinentia pigmenti, in which eosinophilic spongiosis and intraepidermal microabscess formation are most prominent. Acropustulosis of infancy and transient neonatal pustular melanosis may be difficult to distinguish from one another, particularly when the former disease occurs in individuals with dark complexions, and clinical information would then be required. Two other conditions that could mimic these two disorders microscopically are bullous/pustular impetigo and subcorneal pustular dermatosis (including the subcorneal pustular dermatosis variant of IgA pemphigus). The first of these may be difficult to distinguish in the absence of clinical information, but the latter is a primarily a condition of adults (a few children have been reported with the disease). Direct IF would be useful in the unlikely event that IgA pemphigus were a serious clinical consideration.

Subcorneal Pustular Dermatosis

Clinical Features
Sneddon and Wilkinson first described this chronic, relapsing condition in 1956. 92 It occurs mainly in middle age and particularly in women, although some children reportedly have the disorder. Pustules, some forming annular configurations, develop, especially over the trunk and in intertriginous areas. It is a problematic dermatosis in that some cases, including those with IgA monoclonal gammopathy, have proven to be IgA pemphigus, 93 and others show a distinct overlap with generalized pustular psoriasis. 94 , 95 It remains to be seen if subcorneal pustular dermatosis persists as a defined clinicopathologic entity, but it is still important in terms of differential diagnosis.
Sulfapyridine and dapsone are mainstays of treatment. However, various other therapies have been used.

Microscopic Findings
The disease name well describes the essential histopathologic change: the formation of subcorneal pustules with minimal acantholysis and, at least classically, the absence of spongiform pustulation ( Fig. 4-48 ). 96 A mixed superficial dermal infiltrate often includes neutrophils. Direct IF is negative; those examples with intercellular IgA deposition are now classified as the subcorneal pustular dermatosis variant of IgA pemphigus.


Figure 4-48 Subcorneal pustular dermatosis. This subcorneal pustule lacks significant acantholysis or spongiform pustulation.

Differential Diagnosis
The differential diagnosis of subcorneal pustular dermatosis includes the full spectrum of pustular diseases, most of which can be ruled out on clinical grounds. Although bullous impetigo can appear virtually identical, normally it would not have as florid a clinical presentation and could be distinguished by culture studies. Pemphigus foliaceus tends not to produce such discrete pustules, and acantholysis is much more evident. IgA pemphigus can have identical histopathologic findings but is recognized by direct IF due to the intercellular deposition of IgA within the epidermis. Pustular psoriasis is a major consideration, and some cases originally reported as subcorneal pustular dermatosis eventually proved to be examples of pustular psoriasis. However, pustular psoriasis is typified by spongiform pustulation, in which neutrophils are found within spongiotic spaces in the superficial spinous layer; this should not be the case in subcorneal pustular dermatosis, and in the author’s view such a finding would be prima facie evidence for pustular psoriasis or a small group of related conditions (candidiasis, geographic tongue, Reiter syndrome). Drug-related cases mimicking subcorneal pustular dermatosis may actually represent acute generalized exanthematous pustulosis. However, in contrast to subcorneal pustular dermatosis, that condition features intraepidermal pustules with slight spongiform pustulation, apoptotic keratinocytes, eosinophils, and sometimes leukocytoclastic vasculitis.

Traumatic Blisters
Various forms of superficial injury to the skin can produce bullae, and these have characteristic microscopic changes. In purest form, they are all infiltrate-poor, although inflammation can be seen in long-standing, infected, or additionally traumatized lesions. Friction blisters show a cleavage plane high in the epidermis, just beneath the granular cell layer. These are difficult or impossible to distinguish from the lesions of Weber-Cockayne disease. Suction blisters are located subepidermally. Thermal burns and cryotherapy both produce subepidermal bullae ( Fig. 4-49 ). Similarly, electrical injury produces subepidermal separation. In the realm of dermatopathology, this is most frequently encountered in electrodesiccation injury or when cutting current is used in the excision of large specimens. These blisters show vertical “stretching” of the overlying degenerated basilar keratinocytes and an intensely eosinophilic to basophilic, amorphous appearance of superficial dermal collagen bundles. Coma blisters are found at pressure sites and believed to result from pressure, ischemia, and local tissue hypoxia. They are associated with ingestion of certain drugs, especially barbiturates, but are also seen in conjunction with certain infections or metabolic abnormalities. Microscopic findings include subepidermal blisters with both epidermal and sweat gland necrosis ( Fig. 4-50 ) and minimal inflammation. Re-epithelialization can be seen in later stages (see Fig. 4-50A ). Subepidermal separation also commonly occurs overlying dermal scars. This is usually an incidental finding and not associated with the clinical appearance of a blister; it probably results from trauma related to tissue handling, particularly when involving scars with a recently re-epithelialized surface.


Figure 4-49 Blister due to thermal burn. Findings include subepidermal separation and foci of keratinocyte necrosis.


Figure 4-50 Coma bulla. A, There is complete epidermal necrosis, with foci of epithelial regeneration. The underlying dermis has a degenerative appearance. B, Sweat gland necrosis is also apparent in this lesion.

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5
Vascular Disorders


Conditions Associated with Vessel Occlusion 

Coagulopathies 
Livedo Reticularis 
Atrophie Blanche (Segmental Hyalinizing Vasculopathy, Livedoid Vasculopathy) 
Embolic Disease 
Degos Disease (Malignant Atrophic Papulosis) 
Vasculitis 

Leukocytoclastic Vasculitis 
Large-Vessel Vasculitis: Polyarteritis Nodosa 
Large-Vessel Vasculitis: Thrombophlebitis 
Eosinophilic Vasculitis 
Lymphocytic Vasculitis 
Granulomatous Vasculitis 
Vasculitis Accompanied by Other Unique Microscopic Changes: Granuloma Faciale 
Vasculitis Accompanied by Other Unique Microscopic Changes: Erythema Elevatum Diutinum 
Other Conditions Associated with Vessel Injury 

Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis) 
Rheumatoid Neutrophilic Dermatosis 
Pyoderma Gangrenosum 
Behçet Syndrome 
Abnormalities involving the cutaneous and subcutaneous vasculature include inflammatory and non-neoplastic changes of the vessels, inflammatory conditions in which vessel involvement is a significant factor, vascular malformations, and vascular tumors. The latter two conditions will be considered in Chapter 22 .
Inflammatory and non-neoplastic changes of the vessels with significant cutaneous abnormalities include thrombotic conditions and vasculitis in its varying manifestations: leukocytoclastic (particularly neutrophilic, less commonly eosinophilic), lymphocytic, and granulomatous. In a few conditions, vessel injury likely plays an important role, but this may be obscured or overridden by other tissue changes; examples include Sweet syndrome, rheumatoid neutrophilic dermatitis, pyoderma gangrenosum, and Behçet syndrome. In these instances, an argument can certainly be made for a different grouping or chapter assignment, but by tradition this group of conditions is often included under the umbrella of inflammatory diseases of the vessels.
When evaluating skin biopsies, the low-power impression is often that of a predominantly angiocentric process. Next, the practitioner should determine whether the process is predominantly inflammatory or one in which little or no inflammation of the vessels is apparent. When inflammation appears to be dominant, it is necessary to assess whether there is true vessel injury (i.e., vasculitis) or simply a perivascular infiltrate, such as is often observed in cutaneous lupus erythematosus (LE), forms of photodermatitis, annular erythemas, or numerous other disorders. Some hints to aid in this determination are provided in this chapter. Disruption of the integrity of the vessel wall is generally indicative of vasculitis, but when this feature is apparent, one must also consider the possibility of a neoplastic angiocentric process, particularly when the infiltrate is predominantly lymphocytic and shows evidence of cytologic atypia. Examples of neoplastic angiocentric conditions include B-cell lymphomas with inflammatory elements, such as lymphomatoid granulomatosis, and angiocentric T-cell lymphomas, such as natural killer cell T-cell lymphoma (sinonasal type). If there is little or no inflammation, one should consider thrombosis due to various coagulopathies (cryoglobulinemia, disseminated intravascular coagulation), hyalinizing vasculopathy (atrophie blanche), Degos disease, or metabolic disorders (calciphylaxis). Vessel involvement that may be more or less identifiable, depending on the intensity of inflammation, often accompanies heavy neutrophilic dermal infiltrates, as in Sweet syndrome, rheumatoid neutrophilic dermatosis, or pyoderma gangrenosum. In addition, the physician should remember that thrombosis and changes resembling primary leukocytoclastic vasculitis frequently occur at the base of ulcers due to various causes. Therefore, caution is advised in assigning the underlying cause of an ulcer to these changes, and a careful inspection of vessels at some distance from the ulcer bed is necessary.

Conditions Associated with Vessel Occlusion

Coagulopathies
Disorders resulting in thrombosis of dermal and subcutaneous vessels arise from an assortment of coagulopathies, and the first clue to these may be provided by cutaneous findings. There is considerable morphologic overlap of these conditions; thus, they will be considered as a group.


Clinical Features:

Antiphospholipid Antibody Syndrome: This syndrome is associated with arterial and venous thrombosis, spontaneous abortions, and thrombocytopenia. The term antiphospholipid antibodies encompasses the so-called lupus anticoagulant and anticardiolipin antibodies. 1 Between 20% and 50% of patients with LE have these antibodies, although not all manifest signs or symptoms directly attributable to the antibodies. 2 Several cases with thrombotic lesions have been seen in the context of bullous LE. 3 The syndrome can also be seen in association with other connective tissue diseases (rheumatoid arthritis), certain drugs (antibiotics, hydralazine, procainamide, quinine), infections (HIV, pneumonia, hepatitis C), or as an idiopathic event (primary antiphospholipid antibody syndrome). Cutaneous lesions include livedo reticularis, infarctive lesions with purpura and ulceration, Raynaud phenomenon, and the occasional development of nodules.
Sneddon syndrome is defined as livedo reticularis associated with hypertension and cerebrovascular infarcts. Occlusion of vessels occurs through a rather complex process, as described by Zelger and colleagues. 4 An association with the antiphospholipid antibody syndrome reportedly has occurred in some cases.

Cryoglobulinemia: This condition is characterized by the presence of serum proteins that precipitate at low temperatures and dissolve on rewarming. It is divided into three types, based on the composition of cryoproteins. Type I cryoglobulinemia is the monoclonal type, consisting of immunoglobulin M (IgM), IgG, or light chains (Bence Jones protein). This type is most commonly seen in association with multiple myeloma or macroglobulinemia of Waldenström, and produces acrocyanosis, purpura, or ulcerations. 5 Types II and III are mixed types, comprised of immunoglobulin (usually IgM, or rheumatoid factor) complexed with the Fc portion of polyclonal IgG. The rheumatoid factor is monoclonal in type II and polyclonal in type III. 6 Mixed cryoglobulinemia has a strong association with hepatitis C infection but may also occur with hepatitis B, connective tissue diseases (LE and Sjögren’s syndrome, as well as rheumatoid arthritis), lymphomas, and thyroid disorders. Mixed cryoglobulinemia is associated with vasculitic signs and symptoms, including fatigue, purpuric macules and papules, arthralgias, renal disease, and sensory or motor neuropathy. This discussion will concentrate on type I (monoclonal) cryoglobulinemia, which features mainly changes due to thrombosis, and the discussion of vasculitis will again mention mixed cryoglobulinemia.

Factor V Leiden: Factor V Leiden, a variant of clotting factor V, is inherited as an autosomal dominant trait. It is responsible for the most common hypercoagulable condition in Europeans. Factor V normally activates thrombin, which in turn cleaves fibrinogen to fibrin, responsible for the development of effective clotting. Activated protein C cleaves and degrades factor V, thereby inactivating factor V. In this disorder, a mutation in the gene that encodes the protein prevents normal inactivation of factor V by activated protein C. The result is hypercoagulability, which may be associated with deep venous thrombosis and some examples of purpura fulminans. 7 Investigators have recently reported this purpura in cases of livedoid vasculopathy 8 (see later discussion).

Protein C and S Deficiency: This important phenomenon underlies several specific cutaneous disorders. Synthesis of protein C occurs in the liver, and it becomes activated by its conversion to a two-chain, serine protease–like enzyme. Activated protein C binds to a cell surface anticoagulant factor, protein S, and the resulting complex proteolyses clotting factors VIII and V (as mentioned previously). This in turn retards the formation of fibrin. Deficiencies in these proteins can result in thrombosis with its attendant complications. The most severe manifestations, as might be expected, occur in hereditary forms of the disease in individuals who are homozygous or compound heterozygous for the genetic defects responsible for the deficiency. Conditions associated with the acquired forms of the disease include warfarin (Coumadin) therapy, 9 hormonal therapy, pregnancy, liver disease, or chronic infections.
A number of syndromes with cutaneous manifestations are associated with protein C and/or S deficiency. Disseminated intravascular coagulation may frequently occur, accompanied by changes ranging from petechiae and ecchymoses to hemorrhagic bullae and gangrene. Triggers of disseminated intravascular coagulation include certain infections, malignancies, burns, other forms of trauma, or vasculitis. Thrombi in the microcirculation are also associated with hemorrhagic diatheses, resulting from consumption of platelets, fibrinogen, and other clotting factors, as well as the generation of fibrin split products such as D-dimer. Coumarin (warfarin) necrosis occasionally occurs in patients who are receiving loading doses of these agents. Between the third and tenth days of initial therapy, ecchymoses develop that may be accompanied by necrosis and/or bulla formation. These patients may have a hereditary or (more commonly) acquired deficiency of protein C or protein S, although researchers also have detected factor V Leiden mutation or antiphospholipid antibody syndrome in some cases. 10 The reaction can be fatal but is reversible with discontinuation of coumarin and administration of vitamin K or purified protein C. Heparin necrosis also occurs but through a different mechanism: the development of antiplatelet antibodies. Purpura fulminans is a severe condition characterized by extensive cutaneous hemorrhage and necrosis, with associated fever and hypotension. Although it is most frequent in children with infections, particularly due to gram-negative organisms (e.g., meningococci), it may occasionally develop in adults. Disseminated intravascular coagulation is responsible for the hemorrhagic and necrotic lesions. Investigators have demonstrated that these patients most often have profound protein C deficiency, 11 although they have also reported occurrence of an idiopathic form of the disease.
Treatment includes antibiotics, wound care, attention to fluid and electrolyte balance, and (as in coumarin necrosis) administration of vitamin K or purified protein C.

Thrombotic Thrombocytopenic Purpura: Thrombotic thrombocytopenic purpura (TTP) is a syndrome consisting of fever, neurologic symptoms, renal failure, thrombocytopenic purpura, and microangiopathic hemolytic anemia. Cutaneous petechiae and purpura often occur. The cause is the collection of platelets and activation of the clotting system within small vessels. There are three types. Idiopathic TTP results from antibodies that inhibit the metalloproteinase ADAMTS13, an enzyme that normally breaks down von Willebrand factor. 12 Secondary TTP is associated with malignancy, 13 bone marrow transplantation, pregnancy, HIV disease, or certain medications (cyclosporine, 14 interferon alpha); a mechanism other than inhibition of ADAMTS13 may be involved in these cases. However, it should also be pointed out that disseminated malignancy has been known to mimic, and therefore been misdiagnosed as, TTP. 15 In the Upshaw-Schulman syndrome, 16 , 17 there are inherited mutations and resulting deficiency in ADAMTS13 18 ; manifestations can be mild, but TTP develops in conditions, such as infection, that are prone to increase von Willebrand factor. Treatment for TTP includes plasmapheresis and immunosuppressive agents.

Microscopic Findings: All of the previously mentioned conditions are characterized by thrombosis of cutaneous vessels of varying calibers. Hemorrhage is also common, especially in those disorders associated with consumption coagulopathy. Thrombi are variably described as “hyaline” or “amorphous and eosinophilic” in antiphospholipid antibody syndrome associated with LE, monoclonal cryoglobulinemia, and thrombotic thrombocytopenic purpura and as “platelet-fibrin” thrombi in disorders associated with protein C and S deficiency ( Figs. 5-1 to 5-4 ). However, this may reflect the age of the lesion selected for biopsy rather than an intrinsic difference in the nature of the thrombus, and the terminology used has been of little practical diagnostic benefit in the author’s laboratory. In lesions of longer duration, it is possible to identify recanalization of organized thrombi, increasing prominence of endothelium, and vessel proliferation in the adventitia of vessels or the surrounding connective tissue.


Figure 5-1 Small-vessel thrombi in antiphospholipid antibody syndrome. This patient had systemic lupus erythematosus with bullous lesions.


Figure 5-2 Thrombi in monoclonal cryoglobulinemia.


Figure 5-3 Thrombi in a patient with disseminated intravascular coagulation. This disease is often associated with protein C or S deficiencies.


Figure 5-4 Early, partial thrombus formation in a case of heparin necrosis. Heparin necrosis occurs due to the development of antiplatelet antibodies. In contrast, coumarin necrosis is most closely associated with protein C or S deficiency, although factor V Leiden mutation or antiphospholipid antibody syndrome has been detected in some cases.
Zelger and colleagues have provided a detailed description of the vessel changes in Sneddon syndrome. In their experience, adequate evaluation requires a substantial biopsy obtained from white, or apparently uninvolved skin, in the center of livedoid areas. Such specimens show involvement restricted to small to medium-sized arteries at the dermal-subcutaneous junction. 4 Initial detachment of some endothelial cells, with adherent mononucleated cells and fibrin, proceeds to formation of a thrombus comprised of erythrocytes, inflammatory cells, and fibrin, and eventually progresses to subendothelial cell proliferation and changes of arterial fibrosis and atrophy. 4 , 19 Occasionally, a few neutrophils are identified around vessels in cryoglobulinemia, insufficient to warrant a diagnosis of true leukocytoclastic vasculitis; otherwise, inflammation in these lesions tends to be sparse. Thrombosis of cutaneous vessels is often accompanied by varying degrees of epithelial necrosis, particularly involving epidermis and eccrine sweat glands. As part of this process, the epidermis may separate from the underlying dermis, producing the appearance of an infiltrate-poor subepidermal bulla, and homogenization and basophilia of dermal and subcutaneous connective tissue may also occur. These changes are common to ischemia due to a variety of causes.

Differential Diagnosis: As a practical matter, differentiation among these thrombosis-producing diseases based on histopathology of skin alone is difficult, and correlation with other clinical and laboratory studies is necessary. In the author’s experience, thrombosis associated with vascular or perivascular neutrophilic infiltration is quite suggestive of cryoglobulinemia; the other situation in which this combination of features occurs is septic vasculitis, particularly when associated with gonococci or meningococci. The ischemic changes associated with thrombotic diseases are quite similar to those seen in pressure necrosis, barbiturate intoxication, or calciphylaxis, and therefore careful inspection of the vessels is warranted in such cases (see Chapters 9 and 12 ).

Livedo Reticularis


Clinical Features: This term refers to a netlike pattern of red-blue mottling of the skin, which encloses white-appearing areas. The author has already mentioned livedo reticularis in the context of Sneddon syndrome (associated with hypertension, cerebrovascular infarcts, and sometimes antiphospholipid antibodies [see earlier discussion]). Livedo reticularis can also be idiopathic, or associated with other disorders (connective tissue disease—especially LE, cutaneous polyarteritis nodosa, cholesterol embolism, or atrophie blanche [see later discussion]).

Microscopic Findings: The microscopic findings are somewhat dependent on the cause or underlying condition. Thus, in cutaneous polyarteritis nodosa, vasculitis involving cutaneous arteries occurs, whereas in Sneddon syndrome, detachment of endothelial cells and arterial thrombi take place. In a recent study of livedo due to several different causes, In and associates found the following variable vessel abnormalities: thrombi, erythrocyte aggregates, arterial obliteration, and inflammation. 20 As noted previously, the work of Zelger and colleagues indicated that, at least in the case of livedo due to Sneddon syndrome, the best areas to biopsy are the white areas between the areas of mottled erythema. 4 However, In and associates found no significant differences in vessel abnormalities between blanched and erythematous areas in their series of cases. 20

Atrophie Blanche (Segmental Hyalinizing Vasculopathy, Livedoid Vasculopathy)


Clinical Features: Atrophie blanche is a small-vessel vasculopathy characterized by the formation of fibrin thrombi and hyalinization of vessels. It most commonly affects middle-aged individuals. Purpuric macules, papules, and plaques develop most frequently on the lower legs, especially the ankles and dorsa of the feet. Changes of livedo reticularis are also evident. Ulcers form in the purpuric areas, and these eventually heal to form the white, atrophic, stellate scars that give the disease one of its names. 21 It is possible to demonstrate a decrease in fibrinolytic activity, and some researchers have found an association with anticardiolipin antibodies, the lupus anticoagulant, protein C deficiency, factor V Leiden mutation, and other disorders. 22 , 23 Not surprisingly, disease associations include LE and other connective tissue diseases.
Treatment has included aspirin, dipyridamole, and pentoxifylline.

Microscopic Findings: There are thrombi of small vessels in the dermis, which may have a hyaline or fibrinous appearance. This material is periodic acid–Schiff-positive and diastase-resistant. It is possibly to identify infarctive changes in affected skin, including an amorphous appearance of dermal collagen and epidermal necrosis. Over time, thickening and hyalinization of vessel walls may occur ( Fig. 5-5 ), in addition to fibrinous occlusion of vessels and dermal scarring. 24 Direct immunofluorescence (IF) of early lesions shows fibrin deposition around vessels, whereas later-stage lesions may show immunoglobulin and/or C3 deposition in these areas. This result suggests that the latter components nonspecifically accumulate around vessels and are not indicative of immune complex vasculitis. 25 , 26


Figure 5-5 Atrophie blanche. This image shows marked thickening and hyalinization of vessel walls.

Differential Diagnosis: The combination of fibrin thrombi and hyalinization of vessel walls, in the absence of vasculitis, is quite supportive of the diagnosis of atrophie blanche. However, early lesions that only show fibrin thrombi can resemble those caused by specific clotting disorders. Similar alterations of vessels (including both thrombi and hyalinization of vessel walls) can be seen immediately beneath ulcers due to a variety of causes, so it is important to inspect dermal vessels located at a distance from an ulcer to be certain the changes are specific; ideally, biopsies should be generous enough to make such a thorough inspection possible. In chronic venous stasis with ulceration, a condition that could well have overlapping clinical features with atrophie blanche, fibrinous and hyalinizing changes are again most prominent immediately beneath the ulcer. Larger vessels also show significant changes, and clustering of thick-walled vessels in the dermis often provides a clue to underlying chronic venous stasis.

Embolic Disease


Clinical Features: Occlusion of vessels due to emboli of various types can variably produce livedo reticularis or purpura with necrosis, ulceration, or gangrene, the result of infarction of tissues. Cholesterol emboli result from dislodgement from atheromatous plaques, either spontaneously or due to therapeutic procedures. Changes most often involve the lower legs, feet, and toes. Tumor emboli can produce similar changes, and quite a variety of tumors may be responsible. In fact, cutaneous changes may occasionally provide the first clue of an underlying neoplasm. The author has seen an example of angiosarcoma arising in the abdominal aorta, first manifesting as a necrotic lesion of the leg due to tumor embolism. 27 In another case, biopsy of small erythematous papules on the fingers and hands revealed mucinous material in small arterioles that proved to have arisen from an atrial myxoma. Similar cutaneous changes can also indicate the presence of intravascular large B-cell lymphoma.

Microscopic Findings and Differential Diagnosis: Diagnosis of embolic disease requires a certain index of suspicion, as well as careful inspection of dermal and subcutaneous vessels. Vessel involvement is typically focal, and therefore multiple levels or serial sections may be necessary. In some cases, the nature of the embolic material may become immediately apparent: for example, needle-shaped crystals in cholesterol emboli ( Fig. 5-6 ), mucin in the case of atrial myxoma ( Fig. 5-7 ), 28 , 29 or organisms in some septic emboli ( Fig. 5-8 ). In others, special stains, including stains for microorganisms and immunohistochemistry, are necessary to determine the source of the embolus.


Figure 5-6 Cholesterol embolus. Cholesterol clefts are apparent in the lumen of this vessel.


Figure 5-7 Embolus from atrial myxoma. A, Hematoxylin and eosin–stained section showing mucinous material and scattered mesenchymal cells within a vessel lumen. B, Colloidal iron–stained section of the same material.


Figure 5-8 Septic embolus. In this case, bacteria are readily visible within the embolic material on routine staining.

Degos Disease (Malignant Atrophic Papulosis)


Clinical Features: This disorder most commonly affects individuals in the third and fourth decades of life. It is characterized by the development of discrete red papules that develop white centers, which are often described as “porcelain-like.” They arise in crops, but typically only a few at a time, concentrated over the trunk and proximal portions of the extremities. Some time after the development of cutaneous lesions, there may be episodes of fever and abdominal pain, and death may ensue from the peritonitis that results from multiple intestinal perforations. Cerebral infarctions constitute a less common cause of death. 30 Although the disease course may be fulminant, chronic variants are also known to occur.
The cause has been the subject of debate. There may be occlusion of small arteries and arterioles, resulting either from an endothelial defect and/or hypercoagulable state. Investigators have identified defects in platelet aggregation and fibrinolytic activity in Degos disease 31 and detected anticardiolipin antibodies. 32 The antibodies are of particular interest, because researchers have shown that patients with LE who develop similar clinical lesions may have antiphospholipid antibodies. 33 A lymphocyte-mediated necrotizing vasculitis has also been suggested. 34
Treatment may include aspirin, dipyridamole, and heparin. Sometimes fibrinolytic therapy with recombinant plasminogen activators may be useful.

Microscopic Findings: On biopsy, there is a wedge-shaped zone of connective tissue degeneration, the base of the wedge being found in the superficial dermis, displaying a smudged appearance of the involved dermal collagen ( Fig. 5-9 ). This is often associated with significant mucin deposition that may be appreciated in sections stained with hematoxylin and eosin ( Fig. 5-10 ) but can be shown more clearly with mucin stains such as colloidal iron. The epidermis overlying the wedge is often markedly atrophic and sometimes necrotic, displaying, at times, vacuolar alteration of the basilar layer and overlying hyperkeratosis ( Fig. 5-11 ). At the base of the wedge, in the deep dermis or subcutis, vessels may show endothelial swelling, thrombi, and perivascular fibrin deposition. However, the finding of a single thrombosed arteriole underlying the wedge-shaped zone of infarction is surprisingly uncommon. 35 A perivascular lymphocytic infiltrate is seen at the periphery of the “wedge,” and the author has also encountered perifollicular and perieccrine inflammation in the same vicinity ( Fig. 5-12 ).


Figure 5-9 Degos disease. There is a wedge-shaped zone of connective tissue degeneration. Note the marked thinning of the overlying epidermis.


Figure 5-10 Degos disease. Interstitial mucin deposition is apparent in this example, even in hematoxylin and eosin–stained sections.


Figure 5-11 Degos disease. Epidermal atrophy with vacuolar alteration of the basilar layer and clefting is evident.


Figure 5-12 Degos disease. Changes at the periphery of a lesion are visible, showing perivascular and perieccrine inflammation.

Differential Diagnosis: Degos disease is a rare entity, and when all of the chief microscopic characteristics are present, it is not difficult to diagnose. However, the histopathologic features show some overlap with LE, dermatomyositis, and lichen sclerosus et atrophicus. These features include hyperkeratosis, epidermal atrophy, vacuolar alteration of the basilar layer, and an amorphous and/or mucinous appearance to the papillary dermal collagen. Therefore, biopsies should be of sufficient size to show the wedge-shaped configuration of the epidermal and dermal changes. The resemblance to LE can be especially striking if periadnexal inflammation and perivascular inflammation are apparent in the vicinity of the lesion. This is especially problematic, because patients with LE are known to sometimes develop “Degos-like” clinical lesions, and both may have antiphospholipid antibodies. Careful assessment of the clinical features and serologic studies may then be necessary to distinguish between the two disorders; for example, “Degos-like” lesions in LE tend to be larger and more irregular in shape than those of true Degos disease.

Vasculitis
Perivascular infiltrates are common in a wide variety of dermatoses, but it is important to distinguish these from conditions that show targeted vessel injury, thereby representing examples of vasculitis. In vasculitis, there are varying combinations of endothelial swelling, permeation of the vessel walls by inflammatory cells, extravasated erythrocytes, often leukocytoclasis, and eventually deposits of fibrin in and around the involved vessel. As might be expected, the recognition of vasculitis is fairly straightforward when these changes are florid and well developed but may be quite a challenge in early or otherwise subtle lesions.
The most familiar form of vasculitis, often termed leukocytoclastic vasculitis, shows neutrophilic infiltration of vessels. However, other cell types are sometimes involved, and thus there are examples of eosinophilic, lymphocytic, or granulomatous vasculitis. Different vessel types may be the principal targets; thus, in polyarteritis nodosa, arteries are primarily or exclusively involved, whereas in traditional leukocytoclastic vasculitis, postcapillary venules are the main targets. A number of clinical syndromes that feature vasculitis as a major component are sufficiently unique that they receive separate treatment; examples include urticarial vasculitis, purpura hyperglobulinemica, and Wegener granulomatosis. Finally, neoplastic infiltrates of cutaneous vessels sometimes occur, technically meeting the microscopic criteria for vasculitis but constituting malignancy. These include some examples of leukemia and angiocentric lymphomas such as lymphomatoid granulomatosis.

Leukocytoclastic Vasculitis


Clinical Features: This term defines vasculitis in which neutrophils predominate and nuclear fragmentation is frequently identified. 36 Clinically, it is typified by the finding of palpable purpura, in contrast to the flat purpura seen with simple bruising or noninflammatory, hemorrhagic conditions. Lesions are most prevalent over the lower legs and ankles (dependent areas) but may be seen elsewhere, including the arms. They may start out as pink to red papules that become progressively more purpuric. Vesicles, pustules, and ulcerations can develop. Circulating immune complexes are responsible for vessel injury. In some cases, the cause of the process is unknown. However, the most common and prototypical form of leukocytoclastic vasculitis, Henoch-Schönlein purpura , may follow an upper respiratory infection, and in at least some of the cases is believed to be triggered by a preceding viral or bacterial infection. 37 Lesions may develop in crops. The process often lasts for 1 to 2 months, but chronic/recurrent variants also occur, historically known as Gougerot-Ruiter vasculitis. 38 Other underlying causes of leukocytoclastic vasculitis include drugs (penicillins, hydrochlorothiazide), associated connective tissue diseases (rheumatoid arthritis, LE) and, uncommonly, malignancies (lymphoma, multiple myeloma, and solid tumors). Mixed cryoglobulinemia is associated with leukocytoclastic vasculitis, in contrast to monoclonal cryoglobulinemia, whose changes are chiefly those of thrombosis. Elements of leukocytoclastic vasculitis can be seen in a number of other disorders that, because of their unique combinations of clinical and microscopic features, are discussed separately in this chapter; these include polyarteritis nodosa, granuloma faciale, and erythema elevatum diutinum. Leukocytoclastic vasculitis is also commonly seen in cutaneous lesions of Wegener granulomatosis, and in fact is more frequently encountered in that disease than is vasculitis with granulomas.
Treatment includes eliminating the causative antigen (if possible), rest, leg elevation, and nonsteroidal anti-inflammatory agents. In more severe cases, use of systemic corticosteroids and/or other immunosuppressive agents is necessary.
Several specific syndromes associated with leukocytoclastic vasculitis merit separate discussion. Henoch-Schönlein purpura, which has already been mentioned, mainly occurs in children but can also develop in adults. Some cases are associated with fever, headache, arthralgia, and abdominal pain. Hematuria reportedly occurs in up to one fourth of patients. Recovery is often good, but renal failure associated with progressive glomerulonephritis may occur. Acute hemorrhagic edema is a disease of infancy that follows upper respiratory infection and/or antibiotic therapy. 39 Large, annular lesions involve the head and neck and extremities, and ascending acral edema may be a feature. Other than low-grade fever, systemic symptoms are uncommon, and the condition often resolves within 2 to 3 weeks. Microscopic polyangiitis is a subset of small-vessel vasculitis distinguished from the other small vessel vasculitides by the laboratory finding of positive antineutrophil cytoplasmic antibodies (ANCA), usually perinuclear-ANCA (p-ANCA), resulting from antibodies to myeloperoxidase, and by microscopic evidence of involvement of arterioles as well as capillaries and postcapillary venules. 40 There is a high incidence of renal (glomerulonephritis) and pulmonary involvement. Purpura hyperglobulinemica of Waldenström 41 manifests as petechial and purpuric lesions that occur most commonly in women and particularly target the lower extremities. It may be idiopathic or associated with other disorders, including connective tissue diseases (Sjögren’s syndrome, rheumatoid arthritis), hepatitis C, or multiple myeloma. Laboratory studies show an elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia, rheumatoid factor, and antibodies to Ro antigen. Among biopsies of inflammatory dermatoses submitted to the author’s laboratory, urticarial vasculitis 42 is frequently included in the differential diagnosis. Urticarial lesions that are chronic, fixed, and/or show a slight degree of purpura should raise suspicions of this diagnosis. However, only a small minority of patients with persistent urticarial lesions have urticarial vasculitis on biopsy. Triggering factors or associated conditions include drug, connective tissue disease, or viral infection (hepatitis B and C, mononucleosis). Although patients with normal complement levels tend to have self-limited disease, some patients are hypocomplementemic, with clinical findings that include joint signs and symptoms as well as pulmonary, gastrointestinal, or renal involvement. Laboratory studies include evaluation of CH50, C3, C4, and detection of antibodies to C1q. The presence of those antibodies has an increased association with angioedema, glomerulonephritis, and ocular or pulmonary findings. Urticarial vasculitis with hypocomplementemia may be associated with LE and/or positive ANCA. 43
Treatments have included nonsteroidal anti-inflammatory agents, antihistamines, colchicines, dapsone, or corticosteroids with or without steroid-sparing immunosuppressive agents.

Microscopic Findings: Biopsies of the various forms of leukocytoclastic vasculitis show dermal edema, endothelial swelling, permeation of the vessel walls by inflammatory cells, extravasated erythrocytes, leukocytoclasis, and, eventually, fibrin deposition in and around the involved vessels ( Fig. 5-13 ). 44 Classic forms of leukocytoclastic vasculitis target postcapillary venules. Early lesions may display subtle or focal findings, and additional levels may be necessary to find diagnostic changes. In florid disease, neutrophils aggregate in dermal papillae (see Fig. 5-13B ), subepidermal separation may occur, and epidermal necrosis may be evident. With chronicity, lymphocytes may be more numerous, either obscuring the more diagnostic features of leukocytoclastic vasculitis or producing the image of a “lymphocytic vasculitis” ( Fig. 5-14 ) 45 (see later discussion). It may be difficult to distinguish among the various clinical subtypes of leukocytoclastic vasculitis on biopsy alone, but biopsies of cryoglobulinemia and vasculitis directly due to infection (septic vasculitis) often show thrombosis accompanying the other typical features of leukocytoclastic vasculitis. When vasculitis and granulomas (either angiocentric or extravascular) are identified, Wegener granulomatosis or Churg-Strauss syndrome should be considered. As previously mentioned, microscopic polyangiitis shows arteriolar involvement, and in addition, some lesions may show a deep dermal, mixed inflammatory infiltrate. Some cases of purpura hyperglobulinemica show only a perivascular lymphocytic or round cell infiltrate. Eosinophils are not uncommonly found in biopsies of leukocytoclastic vasculitis and do not necessarily provide an indication of the underlying cause. Some studies suggest that lymphocytic vasculitis, with variable numbers of eosinophils, predominates in cases of urticarial vasculitis. 46 , 47


Figure 5-13 Leukocytoclastic vasculitis. A, Involved vessels show endothelial swelling, marked erythrocyte extravasation, and leukocytoclasis. B, As lesions progress, fibrin deposition becomes apparent. In this example, there is also subepidermal neutrophilic aggregation.


Figure 5-14 Leukocytoclastic vasculitis, late stage. Lymphocytes predominate, but neutrophils, leukocytoclasis, and erythrocyte extravasation can also be identified.
Direct IF, when used appropriately, can be most helpful in confirming a diagnosis of leukocytoclastic (immune complex–mediated) vasculitis, especially when routine light microscopic features are equivocal. A key to the use of direct IF is that the sampled lesion needs to be less than 48 hours old, because lesions of longer duration may yield negative or equivocal findings due to phagocytosis of immune reactants. Patients can sometimes assist in pointing out an early lesion, which is usually consistent with the appearance of other lesions but less purpuric. Another method is to use the histamine trap test, in which 50 µL of a 0.1 mg/mL solution of histamine is injected intradermally and biopsy is then performed 3 to 4 hours later. This produces “endothelial gaps” that entrap immune complexes and are likely to yield a positive direct IF result. However, in the author’s experience, the histamine trap test is rarely used. Positive direct IF findings include deposition of immunoglobulins, complement (C3), and fibrin in vessel walls. Typically, immunoglobulins and complement are present in a granular or particulate configuration, whereas fibrin deposition is often heavier and confluent. Considering all cases of vasculitis, in the author’s experience, immunoglobulin A (IgA) deposition is most common ( Fig. 5-15 ). IgA is the immunoglobulin typically seen in Henoch-Schönlein purpura, but it is also found in urticarial (hypocomplementemic) vasculitis and mixed cryoglobulinemia. IgM deposition is next most common, with IgG third. Occasionally, two or three immunoglobulin classes are identified; examples include vasculitis accompanying mixed cryoglobulinemia or connective tissue diseases. Some biopsies show only C3 or fibrin deposition without immunoglobulin deposits. This result can certainly be found in leukocytoclastic vasculitis, but C3 and/or fibrin can sometimes be identified in dermatoses that do not represent immune complex–mediated vasculitis and therefore, in our opinion, do not have the same level of specificity as when immunoglobulins are present.


Figure 5-15 Leukocytoclastic vasculitis, direct immunofluorescence. There is strongly positive IgA deposition in walls of papillary dermal vessels. This is from a case of Henoch-Schönlein purpura.

Differential Diagnosis: The chief differential diagnostic problem is the recognition of leukocytoclastic vasculitis when changes are subtle, obscured by dense inflammation, or mimicked (to an extent) by neutrophilic perivascular infiltrates. Diagnosis therefore requires careful inspection of vessel changes, facilitated at times by multiple levels and direct IF study. One must also be aware of the phenomenon of “secondary vasculitis,” as seen, for example, at the base of ulcers or in heavy neutrophilic dermal infiltrates. In such circumstances, it is worthwhile to evaluate those vessels that are not in the immediate vicinity of an ulcer and to examine for evidence of true vessel injury. Some examples of neutrophilic urticaria, a potential clinical mimic of urticarial vasculitis, can create considerable diagnostic difficulty. This form of urticaria consists of long-standing lesions that are accompanied by pain rather than pruritus. Included are a number of the physical urticarias: cholinergic, cold, and delayed pressure urticarias. Neutrophils aggregate around dermal vessels, but leukocytoclasis is inapparent, and evidence of endothelial injury or fibrin deposition is not observed.

Large-Vessel Vasculitis: Polyarteritis Nodosa


Clinical Features: Polyarteritis nodosa, a necrotizing arteritis involving small and medium-sized arteries, presents in two forms: systemic and cutaneous. Systemic polyarteritis nodosa is generally seen in middle age, with men being more commonly affected than women. It particularly involves arteries of the kidneys and gastrointestinal tract. Patients develop fever, edema, hypertension, cardiac abnormalities, and peripheral neuropathy. The skin is frequently involved, approaching 50% of cases, with findings that include subcutaneous nodules, purpura, bullae, ulcers, and changes of livedo reticularis. The legs are most frequently affected. There may be leukocytosis, thrombocytosis, and anemia. Disease associations include hepatitis B and C, streptococcal infections, inflammatory bowel disease, and LE. Death occurs due to renal failure or intestinal bleeding or perforation. Enhanced understanding of systemic vasculitic syndromes has led to calls for use of a revised classification scheme for those disorders that had previously been labeled systemic polyarteritis nodosa. 48 Treatment includes corticosteroids and cyclophosphamide for idiopathic forms of the disease and antiviral therapy (and preventive vaccination) for those cases associated with hepatitis B. 49 , 50
Cutaneous polyarteritis nodosa involves changes that are usually limited to the skin, although peripheral neuropathy or arthralgia may accompany the disease. The most common findings are subcutaneous nodules and livedo reticularis, the latter often having a “starburst” configuration. 51 When ulcers develop in association with livedo, this may create an image closely resembling atrophie blanche (livedoid vasculopathy). Disease associations are similar to those of systemic polyarteritis nodosa, and include hepatitis B and C, streptococcal infections, and inflammatory bowel disease. In contrast to the systemic disease, cutaneous polyarteritis nodosa follows a long-term, relapsing but otherwise benign clinical course. Treatment includes aspirin or nonsteroidal anti-inflammatory agents, although corticosteroids are sometimes used.

Microscopic Findings: Both forms of the disease show vasculitis involving small arteries (but prominent, by cutaneous standards) of the subcutis. The changes are focal, which means that additional levels of tissue may be necessary for diagnosis. The findings include neutrophilic infiltration of the vessel wall with leukocytoclasis, destruction of external and internal elastic laminae, necrosis of the vessel wall with fibrin deposition, and eventually intimal proliferation and thrombosis ( Fig. 5-16 ). The latter change leads to infarction of tissue. Lymphocytes and macrophages may be more common in older lesions.


Figure 5-16 Polyarteritis nodosa. Changes of leukocytoclastic vasculitis involve a small artery in the subcutis.

Differential Diagnosis: The microscopic differential diagnosis includes thrombophlebitis and its variants. Both conditions show neutrophilic infiltration of a prominent subcutaneous vessel. However, in the author’s experience, biopsies of thrombophlebitis are more prone to show a mixed inflammatory infiltrate involving the vessel, including macrophages and even multinucleated giant cells. This in part probably reflects the relative duration of the lesions prior to biopsy, but different inflammatory mechanisms might also explain the differences. Traditionally, the presence or absence of an internal elastic lamina has been considered decisive in determining whether the involved vessel is an artery or a vein (the presence of an internal elastic lamina indicating that the vessel is most likely an artery). However, internal elastic laminae are also found in larger veins. A recent publication by Dalton and coworkers indicates that a better way to distinguish between the two types of vessels is to examine the smooth muscle pattern of the vessel wall; veins show a “checkerboard” arrangement of muscle intermingled with collagen, whereas arteries demonstrate a more concentric pattern of smooth muscle ( Fig. 5-17 ). Combining assessments of both internal elastic lamina and smooth muscle pattern enhances the accuracy of determining whether an involved vessel is an artery or a vein. 52 Microscopic polyangiitis can also show vasculitis involving arterioles, but capillaries and postcapillary venules are also involved. In contrast to polyarteritis nodosa, microscopic polyangiitis is an ANCA-positive disease (most often, p-ANCA) that features pulmonary involvement but not hypertension.


Figure 5-17 Distinguishing polyarteritis nodosa from thrombophlebitis. A, A small artery from a later stage lesion of polyarteritis nodosa. Note the concentric pattern of smooth muscle in the arterial wall. B, A vein in a case of thrombophlebitis. Note the “checkerboard” arrangement of smooth muscle. Dalton and colleagues have pointed out this difference. 52

Large-Vessel Vasculitis: Thrombophlebitis


Clinical Features: Superficial forms of thrombophlebitis fall within the purview of dermatopathology. Specific disease examples include Buerger disease , or thromboangiitis obliterans, prone to occur in younger men with a history of tobacco use, which frequently involves the arms; Mondor disease , most common in women, which involves vessels of the anterior-lateral chest wall and often follows some form of trauma; and superficial migratory thrombophlebitis , in which nodules or cords appear on the lower legs or elsewhere with the impression of migration. Trousseau first described an association with malignancy in 1865, and therefore health care professionals sometimes use the eponym Trousseau syndrome. 53 The underlying malignancies involve the pancreas, lung, stomach, prostate, or hematopoietic system. It is likely that the hypercoagulable state accompanying these malignancies promotes development of the syndrome. 54 , 55

Microscopic Findings: A vein at the dermal-subcutaneous interface shows thrombosis with an inflammatory infiltrate composed initially of neutrophils, followed by lymphocytes and macrophages (see Fig. 5-17B ; Fig. 5-18 ). The infiltrating cells are concentrated in the immediate vicinity of the vessel. 56 Recanalization of the thrombus eventually occurs.


Figure 5-18 Thrombophlebitis. Inflammatory cells surround the lumen of a vessel and permeate the surrounding smooth muscle.

Differential Diagnosis: The intense involvement of a subcutaneous vessel raises the differential diagnostic consideration of polyarteritis nodosa; this may be a significant problem in early lesions, where neutrophils predominate. However, as mentioned earlier, thrombophlebitis often shows a more mixed inflammatory infiltrate, sometimes including multinucleated giant cells, and the vessel can be identified as a vein by the “cobblestoned” smooth muscle pattern of its wall and the (sometimes) absent internal elastic lamina. 52

Eosinophilic Vasculitis
This form of vasculitis sometimes occurs in biopsy specimens, involving small vessels of the dermis and subcutis, but it should probably be regarded as a phenomenon, or variant form of vasculitis, rather than a specific disease entity ( Fig. 5-19 ). The cutaneous findings are often nonspecific, but studies have reported associations with hypereosinophilic syndrome, rheumatoid arthritis, or other connective tissue diseases. 57 , 58 The author has encountered an example of eosinophilic vasculitis accompanying lesions of dermatitis herpetiformis. In this instance, eosinophils were also prominent within the dermal papillae, and typical direct IF findings were observed.


Figure 5-19 Eosinophilic vasculitis. These changes can be seen in a variety of circumstances, including hypereosinophilic syndrome, rheumatoid arthritis, and other connective tissue diseases.

Lymphocytic Vasculitis
This term is controversial, mainly because it is difficult to define precisely, and experts differ on the degree of vessel change necessary to qualify for this designation. Furthermore, perivascular lymphocytic infiltrates are so common in dermatopathology that distinguishing between a perivascular infiltrate and vasculitis can become quite difficult. Presumably, vasculitis requires some degree of endothelial swelling, involvement of the wall of the vessel as well as the perivascular space by lymphocytes, and perhaps evidence for erythrocyte extravasation. Leukocytoclasis is not common in lymphocytic infiltrates, and fibrin deposition seldom occurs. The major consideration is the impact that the term “vasculitis” has for most clinicians; overuse may render the term useless (“he or she calls everything vasculitis”) or, on the other hand, prompt more aggressive therapy than is called for by the nature of the associated disease. The author’s list of lymphocytic vasculitides is therefore limited to a few conditions about which there is at least a reasonable degree of agreement: connective tissue disease, particularly LE; pityriasis lichenoides ( Fig. 5-20 ); forms of pigmented purpura; perniosis; and certain infectious exanthems, particularly rickettsial disease (Rocky Mountain spotted fever). It is also widely recognized that lymphocytes predominate in late-stage leukocytoclastic vasculitis. This section will discuss pigmented purpuric eruptions and perniosis; other sections of the book will consider the remaining entities.


Figure 5-20 Lymphocytic vasculitis—pityriasis lichenoides. In this example of pityriasis lichenoides acuta, changes of lymphocytic vasculitis can be seen in dermal vessels, forming the so-called wedge-shaped infiltrate.

Pigmented Purpuric Eruptions

Clinical Features: This term is applied to a small group of lesions that probably have the same or closely related histopathogenesis but display different clinical features. 59 The best known and prototypical eruption in this group is purpura pigmentosa chronica or progressive pigmentary purpura of Schamberg, characterized by small petechiae associated with yellow-brown hemosiderin pigmentation. Purpura annularis telangiectodes of Majocchi presents as annular lesions composed of petechiae and telangiectasia, again with hemosiderin deposits. Eczematid-like purpura of Doucas and Kapetanakis combines the telangiectasia-hemosiderin combination with eczematous patches. Two other forms of the disease have lichenoid components. Pigmented purpuric lichenoid dermatitis of Gougerot and Blum features small lichenoid papules that sometimes coalesce to form plaques. Lichen aureus is composed of one or several larger, flat-topped papules or plaques with a characteristic golden hue, a result of erythrocyte extravasation combined with hemosiderin deposition. 60 These lesions tend to arise over the lower legs, ankles, and dorsa of feet but can also involve the thighs, abdomen, or occasionally the arms. However, lesions of lichen aureus are prone to arise almost anywhere on the body surface. Incompetent perforator veins have been implicated in some forms of the disease, 61 and the tendency for lesions to develop over the lower legs may reflect this as well as a preferential unmasking of damage to small vessels in dependent locations.
The inflammation that accompanies these eruptions is believed to represent a delayed hypersensitivity response to self-antigens generated through repeated injury to small vessels resulting from various toxins or hydrostatic stress. In some cases, a specific antigenic source for the eruption can be determined: examples include drugs, contactants (allergic contact dermatitis), or distant focus of infection. Not surprisingly, risk factors tending to promote pigmented purpura include conditions associated with microangiopathy, such as diabetes mellitus and rheumatoid arthritis.
Treatments include use of support hose, topical corticosteroids, and agents such as pentoxifylline.

Microscopic Findings: On biopsy, all forms of pigmented purpura show numerous capillaries, some of them dilated, within the papillary dermis, associated with endothelial swelling, extravasated erythrocytes, and hemosiderin deposition. In the author’s experience, hemosiderin deposits are often not evident or are subtle, although stains for iron, such as Perls or Prussian blue, can demonstrate them. This experience probably results from the clinician having sampled lesions in early stages. Varying degrees of lymphocytic inflammation are noted, surrounding and permeating vessels walls—hence the categorization “lymphocytic vasculitis” ( Fig. 5-21 ). Denser, bandlike inflammation occurs in lichenoid forms of pigmented purpura. Often, the bandlike infiltrate is separated from the overlying epidermis by a thin grenz zone of uninvolved (or largely uninvolved) connective tissue, and vacuolar alteration of the basilar layer may or may not be apparent. Spongiotic changes of the epidermis occur in eczematid-like purpura.


Figure 5-21 Lymphocytic vasculitis—pigmented purpuric eruption. Note lymphocytic infiltration of papillary dermal vessels and erythrocyte extravasation.

Differential Diagnosis: Diagnosis is generally not difficult, although in early lesions the microscopic changes can be disproportionately subtle when compared with fairly obvious clinical disease. Some degree of small vessel proliferation in the superficial dermis is often encountered in biopsies of the lower extremities of adults; this often represents merely background change and is frequently a clue to that particular anatomic location. Patients with chronic venous stasis or stasis dermatitis often show superficial dermal changes of pigmented purpura. In addition, they have significant epidermal (acanthosis, ulceration) or dermal (sclerosis, aggregations of thick-walled vessels in the mid-to-deep dermis) changes.
A major diagnostic issue is the distinction of certain cases of pigmented purpura from cutaneous T-cell lymphoma (mycosis fungoides). There is overlap in both the clinical and microscopic appearance, and this is particularly the case in lichenoid forms of pigmented purpura. As in lichenoid pigmented purpura, early lesions of mycosis fungoides also show a bandlike lymphocytic dermal infiltrate, separated from the epidermis by a sometimes incomplete grenz zone of uninvolved or sparsely involved sclerotic collagen. There can even be overlapping degrees of nuclear atypia among lymphocytes. In some cases, T-cell receptor gene rearrangements are found in cases resembling pigmented purpura. 62 In one study, monoclonal cases were characterized by extensive disease and more common involvement of sites other than the lower extremities. 63 This has led some authors to propose that pigmented purpura is itself a form of T-cell lymphoid dyscrasia. 63 Careful assessment of the nuclear details of lymphocytes, marker studies, and correlation with clinical findings are essential in evaluating difficult cases, and several biopsies over time may be necessary to determine a possible diagnosis of T-cell lymphoma.

Perniosis

Clinical Features: Perniosis describes localized erythema, often with a livid hue, and edema occurring as a result of cold exposure. Acral areas, particularly the toes but also the fingers and earlobes, are common locations. 64 Lesions also occur on the thighs, especially in equestrians, clinically resembling a probably related condition termed equestrian cold panniculitis. 65 Similar lesions can develop in patients with LE and a few other disorders. It is important that the terminology for pernio in LE not be confused with another condition known as lupus pernio , a different disorder representing a manifestation of facial sarcoidosis. Perniosis is prone to occur in young, relatively thin individuals exposed to cold, damp climates. Warming of the body and use of vasodilators are helpful in this condition.

Microscopic Findings: These include marked superficial dermal edema and a prominent perivascular lymphocytic infiltrate that cuffs the vessels of the superficial and mid-dermis. Thickening of the involved vessel walls has been described as “fluffy edema.” 66 There may be infiltration of the vessel wall by lymphocytes (hence the designation “lymphocytic vasculitis”), but leukocytoclasis is not a feature, and fibrin deposition is uncommonly noted ( Fig. 5-22 ).


Figure 5-22 Lymphocytic vasculitis—perniosis. Thickening of vessel walls, surrounding dense lymphocytic inflammation, and focal infiltration of vessel walls are evident.

Differential Diagnosis: Fully developed changes are rather characteristic of perniosis, but lesser degrees of perivascular inflammation could be confused with a variety of dermatoses that show this type of infiltrate. Some focal vacuolar alteration of the basilar layer overlying the dermal changes can be seen in ordinary perniosis and does not necessarily indicate a diagnosis of LE. However, extensive interface changes should raise the possibility of the latter disorder, and correlation with other clinical and laboratory findings may be necessary.

Granulomatous Vasculitis
Granulomatous vasculitis can be associated with a variety of conditions, ranging from arthritis, gastrointestinal disease, and sarcoidosis to lymphoproliferative disorders. The patients with systemic vasculitis or lymphoproliferative disease tend to have a particularly poor prognosis. 67 Two conditions frequently associated with granulomatous vasculitis are particularly important in dermatopathology: Wegener granulomatosis and Churg-Strauss syndrome (allergic granulomatosis).

Wegener Granulomatosis

Clinical Features: Wegener granulomatosis is a necrotizing granulomatous disease involving both the upper and lower respiratory tract and the kidneys, producing focal necrotizing glomerulitis and interstitial disease. 68 A limited form of Wegener granulomatosis that features only respiratory and cutaneous lesions but lacks renal findings has a better prognosis. Manifestations of the disease include fever, weight loss, and nasal lesions. Skin involvement occurs in between 40% and 50% of cases and includes nodules, ulcers, and petechial or purpuric eruptions. Wegener granulomatosis is an ANCA-associated disease, and most patients are positive for cytoplasmic ANCA (c-ANCA), directed toward proteinase 3. Cyclophosphamide therapy has had a dramatic impact on the prognosis of this disease.

Microscopic Findings: In the author’s practice, biopsies to rule out Wegener granulomatosis have been uncommon. The most frequent finding is leukocytoclastic vasculitis, often indistinguishable from leukocytoclastic vasculitis due to other causes, although it is possible to observe a more necrotizing form of vasculitis, with a tendency to involve larger or deeper dermal vessels ( Fig. 5-23 ). 69 Patients with this finding tend to have more widespread and rapidly progressive disease than do those who lack skin lesions or present with granulomatous changes on biopsy. 70 The diagnosis can be difficult if ulcers are sampled, because “secondary vasculitis” is frequently evident in the base of ulcers due to a variety of causes. The more classic form of the disease, with granulomatous vasculitis ( Fig. 5-24 ) and/or extravascular granulomas surrounding central zones of necrosis, occurs in a minority of cases, particularly if samples come from nodular lesions ( Fig. 5-25 ). The necrotic foci within extravascular granulomas often contain degranulated neutrophils. 71 , 72


Figure 5-23 Wegener granulomatosis. Necrotizing vasculitis is evident with thrombosis and leukocytoclasis.


Figure 5-24 Wegener granulomatosis. Vasculitis containing macrophages as well as neutrophils, thereby displaying an element of granulomatous vasculitis.


Figure 5-25 Wegener granulomatosis. A and B, Examples of extravascular granulomas.

Differential Diagnosis: Changes in cutaneous ulcers are often nonspecific; therefore, when obtaining a biopsy, it is important that the clinician either avoid ulcerative lesions or obtain generous portions of surrounding tissue when an ulcer biopsy cannot be avoided. Fully developed granulomas with necrotizing vasculitis strongly support the diagnosis, but changes limited to leukocytoclastic vasculitis cannot be distinguished from similar vasculitis due to other causes. Positive serologic studies for ANCA, particularly c-ANCA, can then be decisive in the appropriate clinical context. The extravascular granulomas of Churg-Strauss disease usually contain eosinophils instead of neutrophils. However, the author has encountered at least one case presenting as classic Wegener granulomatosis that did show a predominance of eosinophils in one skin biopsy. Two other conditions that authorities once classified as granulomatous vasculitides, lymphomatoid granulomatosis and lethal midline granuloma, are now considered lymphomas (lymphomatoid granulomatosis is a lymphoma of large B cells with substantial numbers of reactive T cells, and “lethal midline granuloma” is now a natural killer cell–T-cell lymphoma, sinonasal type). Both are angiocentric processes but otherwise bear little microscopic resemblance to Wegener granulomatosis.

Churg-Strauss Syndrome
This discussion includes Churg-Strauss–like cutaneous disease due to inhalant therapy.

Clinical Features: Churg-Strauss syndrome, also known as allergic granulomatosis, presents with asthma and allergic rhinitis, followed (sometimes after many years) by fever, eosinophilia, pulmonary infiltration, and angiitis involving numerous organs. The majority of patients also develop skin lesions, including lesions resembling typical leukocytoclastic vasculitis and cutaneous nodules, especially on the extremities and scalp. Reports have also described urticaria and livedo reticularis. 73 Triggers of the vasculitic manifestations include certain drugs, such as leukotriene inhibitors, and rapid discontinuation of corticosteroids. Deaths are likely to occur in untreated patients, most often due to congestive heart failure. Positive ANCA studies are common, most commonly for p-ANCA but occasionally for c-ANCA. Treatment has included corticosteroids, cyclophosphamide, methotrexate, and the newer biologic agents. 74
In recent years, there have been a number of reports of a Churg-Strauss–like syndrome in asthmatic patients who receive inhalants containing leukotriene receptor antagonists, especially montelukast. The author has seen a similar syndrome in a patient using a fluticasone-salmeterol inhalant, representing a combination of corticosteroid and a β 2 -adrenergic receptor agonist. 75 These patients may have a syndrome closely resembling, if not the same as, traditional Churg-Strauss syndrome, but occasionally skin lesions are the principal findings. The patient who received fluticasone-salmeterol therapy developed ulcerated nodules on the palms and fingers. Treatment includes withdrawal of the inhalant and corticosteroid therapy.

Microscopic Findings: Biopsy findings consist mainly of vasculitis, which may resemble leukocytoclastic vasculitis but often involves deep as well as superficial dermal vessels, including arterioles and venules ( Fig. 5-26 ). 73 Widespread dermal infiltration often includes numerous eosinophils. The vessel changes can result in epidermal necrosis. Extravascular granulomas surrounding central zones of necrosis may sometimes occur, and they often contain degranulated eosinophils; these are referred to as Churg-Strauss granulomas ( Fig. 5-27 ). 76


Figure 5-26 Churg-Strauss disease. Small-vessel vasculitis containing lymphocytes, macrophages, and eosinophils.


Figure 5-27 Churg-Strauss disease. Extravascular granuloma surrounded by dense inflammation, including eosinophils.

Differential Diagnosis: The microscopic image of Churg-Strauss lesions can be quite unique, and the combination of necrotizing vasculitis and numerous eosinophils is certainly suggestive. However, as noted previously, more than a few eosinophils may sometimes occur in vasculitis due to other causes. Investigators have identified Churg-Strauss granulomas from time to time in non–Churg-Strauss conditions. 77 One of these, mentioned previously, is Wegener granulomatosis. Others include connective tissue diseases (LE, rheumatoid arthritis), polyarteritis nodosa, and lymphoma. Careful evaluation of accompanying microscopic changes and the clinical and laboratory findings may be necessary to exclude these other diseases.

Vasculitis Accompanied by Other Unique Microscopic Changes: Granuloma Faciale


Clinical Features: This disorder consists of nodules or plaques, usually solitary but occasionally multiple, occurring predominantly on the face. Middle-aged men are most often affected. Lesions are reddish-brown in color and display more intense erythema when subjected to heat or stress. The cause is unclear, but authorities widely consider it a manifestation of small-vessel vasculitis. Occasionally, lesions may be associated with dermatophyte infection. 78 A variety of treatment methods have been used with varying success, including topical corticosteroids, cryotherapy, and laser therapy.

Microscopic Findings: The histopathologic features are quite characteristic. 79 There is a dense dermal infiltrate, separated from the overlying epidermis and adnexal structures in the vicinity by a grenz zone of uninvolved collagen ( Fig. 5-28 ). The infiltrate is polymorphous, usually containing eosinophils or neutrophils as well as lymphocytes and plasma cells. Eosinophils are often considered the hallmark of the disorder, but they may be sparse or absent; in such cases, neutrophils can still be identified, often arranged around small vessels and accompanied by nuclear dust ( Fig. 5-29 ). The author has seen a rare example consisting mostly of plasma cells. Foci of fibrosis can be identified in some lesions. With direct IF, immunoglobulin and complement can be identified in vessel walls, and perivascular fibrin deposition is often evident.


Figure 5-28 Granuloma faciale. There is a dense dermal infiltrate, separated from the overlying epidermis and adnexal structures by a grenz zone of uninvolved collagen.


Figure 5-29 Granuloma faciale. A dense infiltrate that includes not only lymphocytes and eosinophils but also fairly numerous neutrophils largely obscures a vessel.

Differential Diagnosis: There is some microscopic resemblance to a condition many consider to be related, erythema elevatum diutinum. However, the latter lesions occur most commonly over extensor extremities, lack a grenz zone on biopsy, and show a predominance of neutrophils; eosinophils are typically sparse to absent (see subsequent discussion). In late stages, erythema elevatum diutinum typically displays profound fibrosis, but concentric perivascular fibrosis has also been described in granuloma faciale, suggesting a link between these two disorders. 80 In fact, lesions with some microscopic elements of granuloma faciale or erythema elevatum diutinum but with more varied histopathologic features can present in a variety of clinical locations, and some authorities have grouped these under the term localized chronic fibrosing vasculitis . 81

Vasculitis Accompanied by Other Unique Microscopic Changes: Erythema Elevatum Diutinum


Clinical Features: Another form of chronic leukocytoclastic vasculitis, erythema elevatum diutinum, features brownish-red to yellow papules and nodules over the extensor surfaces of the extremities, including the dorsa of hands and feet. 82 With time, the lesions progressively harden. Otherwise, patients are usually asymptomatic, although an association with keratitis may reportedly occur. Researchers have described occurrence of erythema elevatum diutinum with HIV infection. It is likely that the condition termed papular neutrophilic xanthoma , a facial eruption also described in HIV-positive patients, is either the same or a closely related entity. 83 The cutaneous lesions are quite persistent, but they may respond to dapsone therapy, particularly in early stages.

Microscopic Findings: There is a dense, neutrophil-rich dermal infiltrate with angiocentricity, and it is possible to identify changes of leukocytoclastic vasculitis ( Fig. 5-30 ). A grenz zone separating the infiltrate from the adjacent epidermis or adnexal structures is not evident, and eosinophils are difficult to detect. 84 With time, granulation tissue and fibrosis develop, and in late stages, lesions take on a distinctly fibrotic appearance, with intracellular or extracellular lipid deposits. 85 Even at this stage, focal aggregates of neutrophils are apparent ( Fig. 5-31 ). With direct IF, it is possible to detect immunoglobulins and complement in affected vessels, especially in earlier stages of the disease.


Figure 5-30 Erythema elevatum diutinum. Angiocentric neutrophilic infiltrate with leukocytoclasis.


Figure 5-31 Erythema elevatum diutinum. Late-stage lesion, showing fibrosis and extracellular cholesterol clefts. Neutrophils with leukocytoclasis are also apparent.

Differential Diagnosis: To determine how to distinguish this condition from granuloma faciale, see the previous section on Differential Diagnosis. The late, fibrotic stage of erythema elevatum diutinum, uncommonly seen in recent years, can be difficult to recognize, especially in the absence of clinical information, but it is necessary to consider this if the history indicates a nodule of long duration on the extensor portion of an extremity. The additional microscopic findings of lipid deposits and scattered neutrophils would then be quite suggestive of the diagnosis. The latter findings have also been described in papular neutrophilic xanthoma involving the face in HIV-positive patients ( Fig. 5-32 ).


Figure 5-32 Papular neutrophilic xanthoma. The combination of neutrophils (with leukocytoclasis) and lipid deposits (in this case, in the form of foamy macrophages) is also seen in erythema elevatum diutinum.

Other Conditions Associated with Vessel Injury

Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)


Clinical Features: In this disorder, there are one or more rapidly evolving, tender, sharply marginated, erythematous plaques or nodules, most commonly seen on the head and neck, extremities, or upper trunk. Vesicles can develop on occasion. Patients often also have fever, arthritis, or conjunctivitis. In addition, leukocytosis is common. Sporadic reports have identified numerous disease associations, but among the most common is a preceding upper respiratory infection. Hematologic malignancy accompanies Sweet syndrome in 10% to 15% of cases, most often myelomonocytic leukemia. There is evidence that Sweet syndrome occurring in the setting of CD34+ acute myelogenous leukemia treated with granulocyte colony-stimulating-factor may reflect differentiation in a clonal neutrophilic dermatosis. 86 Other associated conditions include inflammatory bowel disease. Similarities to pyoderma gangrenosum have been emphasized in the literature (see subsequent discussion for further comments on this issue).
The lesions of Sweet syndrome are often exquisitely responsive to prednisone therapy, resulting in rapid resolution of fever and skin lesions. However, it is necessary to make an effort to address any underlying diseases, especially leukemia or inflammatory bowel disease. 87

Microscopic Findings: Sweet syndrome forms a characteristic image. There is pronounced papillary dermal edema and a dense, usually mid-dermal infiltrate composed mainly of neutrophils ( Fig. 5-33A ). There is extensive leukocytoclasis, but true vasculitis is often difficult to identify (see Fig. 5-33B ). Researchers have described a “histiocytoid” variant of Sweet syndrome, but in reality these variants contain not macrophages but immature neutrophils, including band forms. 88 The term Marshall syndrome applies to Sweet-like skin lesions followed by the development of cutis laxa.


Figure 5-33 Sweet syndrome. A, Low-power view shows papillary edema and a dense neutrophilic infiltrate in the upper to mid-dermis. B, On higher magnification, leukocytoclasis is evident, but true vasculitis is difficult to identify.

Differential Diagnosis: Despite the frequently diagnostic image of Sweet syndrome, several disorders can produce overlapping changes. Two leading ones are rheumatoid neutrophilic dermatosis and pyoderma gangrenosum. Besides its disease association, rheumatoid neutrophilic dermatosis often shows denser, more deeply extending neutrophilic infiltrate than is typical of Sweet syndrome, and leukocytoclasis may not be prominent. We have identified several examples of rheumatoid neutrophilic dermatosis overlying changes of interstitial granulomatous dermatitis. 89 Pyoderma gangrenosum is obviously prone to ulcerate. Early lesions may show dermal edema and a dense neutrophilic infiltrate. However, it is more common for early lesions of pyoderma gangrenosum to show pustular folliculitis with abscess formation. Erythema elevatum diutinum in early stages also shows a dense neutrophilic infiltrate, but changes of leukocytoclastic vasculitis and perivascular fibrin deposition are features that are difficult to identify in lesions of Sweet syndrome.

Rheumatoid Neutrophilic Dermatosis
Rheumatoid neutrophilic dermatosis is an uncommon condition that accompanies well-established rheumatoid arthritis. 90 Clinically, the lesions resemble urticarial plaques and are seen on the trunk or extremities. As previously noted, microscopic findings include a dense, often superficial and deep, dermal neutrophilic infiltrate ( Fig. 5-34 ). 91 Leukocytoclasis may be visible but is often less pronounced and obvious than it is in Sweet syndrome. Careful inspection of some cases may show an underlying, interstitial infiltrate of macrophages with a dusky, degenerative appearance to “entrapped” collagen bundles, consistent with interstitial granulomatous dermatitis ( Fig. 5-35 ). 92 This type of dermatitis itself may be associated with rheumatoid arthritis, and typically those interstitial granulomatous dermatitis cases accompanying systemic diseases have neutrophilic infiltrates, although ordinarily to a lesser degree than in rheumatoid neutrophilic dermatosis.


Figure 5-34 Rheumatoid neutrophilic dermatosis. There is again a dense neutrophilic infiltrate, in this case admixed with other cell types.


Figure 5-35 Rheumatoid neutrophilic dermatosis. At the base of the neutrophilic infiltrate in the lesion shown in Figure 5-34 , changes of interstitial granulomatous dermatitis are evident.

Pyoderma Gangrenosum


Clinical Features: Pyoderma gangrenosum often begins as a pustule or, less commonly, a nodule that breaks down and ulcerates. The ulcer enlarges, surrounded by a dusky, undermined margin of skin. The ulcers spread when subjected to trauma—hence the “surgical stress test.” A less destructive bullous variant bears resemblances to Sweet syndrome and sometimes shares the association with leukemia. Superficial granulomatous pyoderma is most often solitary and characterized by superficial ulceration, and it may respond to topical therapy. Many examples appear to be idiopathic, but there are known associations with inflammatory bowel disease (both ulcerative colitis and Crohn disease), rheumatoid arthritis, leukemia, or monoclonal gammopathy. 93 , 94
Treatment is directed toward any underlying disease. For ulcerative lesions, hyperbaric oxygen, systemic corticosteroids, azathioprine, cyclosporine, and the newer biologic agents have been used successfully. 95

Microscopic Findings: Early changes include neutrophilic folliculitis with follicular rupture ( Figs. 5-36 and 5-37 ), dermal edema with dense dermal and subcutaneous inflammation, and subepidermal edema in the vicinity of the undermined epidermal border. 96 Lesions are pustular, with subcorneal pustules containing dense dermal neutrophilic infiltrates ( Fig. 5-38 ). Leukocytoclastic vasculitis is evident, but in most, if not all, cases, this likely represents “secondary vasculitis” in the immediate vicinity of the ulcer ( Fig. 5-39 ). In superficial granulomatous pyoderma ( Fig. 5-40 ), there are necrotizing granulomas with palisades of macrophages and overlying pseudoepitheliomatous hyperplasia. 97


Figure 5-36 Pyoderma gangrenosum. An early lesion shows a neutrophilic folliculitis.


Figure 5-37 Pyoderma gangrenosum. In this lesion, there is rupture of a follicular-derived, epithelial-lined sinus, with neutrophilic infiltration and adjacent ulcer.


Figure 5-38 Pyoderma gangrenosum. A pustule has formed beneath the stratum corneum.


Figure 5-39 Pyoderma gangrenosum. This image was obtained from the base of a long-standing ulcer. There is marked small vessel proliferation with neutrophil infiltration and some leukocytoclasis. Changes such as these can be interpreted as “secondary vasculitis.”


Figure 5-40 Pyoderma gangrenosum—superficial granulomatous pyoderma. Granulomas in the superficial dermis are apparent.

Differential Diagnosis: Fully developed ulcerative lesions are difficult, if not impossible, to distinguish from ulcers due to a variety of causes—a widely experienced source of frustration for both clinician and pathologist. Convincing leukocytoclastic vasculitis is not observed in these specimens, at least in the author’s experience. The best chance for a specific diagnosis occurs in early lesions, when neutrophilic folliculitis occurs in the context of a supportive clinical history. Superficial granulomatous pyoderma is fairly characteristic. Although it has some overlapping features with blastomycosis-like pyoderma, organized palisading granulomas are not a feature of the latter condition.

Behçet Syndrome


Clinical Features: In Behçet syndrome, oral aphthous ulcers (aphthae) are associated with recurrent genital ulcers, eye lesions (especially uveitis), and cutaneous findings. Arthritis and meningoencephalitis can also occur. Cutaneous lesions include papulopustular lesions, erythema nodosum, and a phenomenon known as pathergy , in which a pustule develops in the site of a needle prick injury. Behçet syndrome is prevalent in Mediterranean countries, where it occurs most commonly in young adult men; however, this pattern may vary somewhat according to geographic location. 98 , 99 There is a strong association with HLA types Bw51 and B12. The etiology appears to be complex, although authorities have long suspected that the syndrome is due to a defect in the immune system. It is known that intermittent flares of the disease occur, and potentially devastating complications include vascular abnormalities (thrombosis, aneurysm formation), central nervous system effects, and blindness.
Treatment has included colchicine, dapsone, and thalidomide in selected circumstances.

Microscopic Findings: The essential microscopic process in Behçet syndrome is said to be a leukocytoclastic vasculitis, but in the author’s experience this is often difficult to demonstrate—probably because its detection requires biopsy of an early lesion. Sampling of oral or genital ulcers often yields nonspecific findings, including fibrin and neutrophilic accumulation at the base of the ulcers, varying degrees of edema, and a mixed dermal infiltrate that includes lymphocytes and macrophages as well as neutrophils ( Fig. 5-41 ). A trend toward angiocentricity of the infiltrate can be seen and endothelial swelling can often be detected, but convincing leukocytoclastic vasculitis is typically not apparent. 100 Folliculitis-type lesions show evidence of a neutrophilic or granulomatous folliculitis, and the vessels in the vicinity of the affected follicle show a neutrophilic vascular reaction that can sometimes have the characteristics of a leukocytoclastic vasculitis; Magro and Crowson have described this constellation of features as sterile neutrophilic folliculitis with perifollicular vasculopathy. 101 Erythema nodosum–type lesions show lymphocytes and sometimes neutrophils around vessels in subcutaneous septa, with varying degrees of infiltration of vessel walls and endothelial swelling. Thrombophlebitis or lobular involvement can also be seen in these lesions. Significant lobular panniculitis can also be seen in erythema nodosum with other disease associations, particularly in early or initial biopsies, but later sampling tends to show the more classic “septal” panniculitis (see Chapter 7 for further information). However, findings of thrombophlebitis would be unusual in erythema nodosum, and their recognition should prompt consideration of Behçet syndrome. 102 Findings in pathergic lesions vary somewhat. An intraepidermal and/or subepidermal pustule is often evident ( Fig. 5-42 ), but dermal changes can include both a heavy perivascular neutrophilic infiltrate and a superficial and deep perivascular and periappendageal round cell infiltrate. 103


Figure 5-41 Behçet syndrome. Typical mucosal ulcer, showing a mixed dermal infiltrate, vascular proliferation, and in this case significant adjacent acanthosis.


Figure 5-42 Behçet syndrome—pathergy. There is a neutrophilic pustule with an underlying mixed perivascular inflammatory infiltrate.

Differential Diagnosis: A specific microscopic determination that a lesion is due to Behçet disease is difficult, if not impossible, in the absence of clinical information. The most characteristic changes occur in pathergic lesions and in those examples of erythema nodosum that also feature thrombophlebitis. Pathergy is not always demonstrable in Behçet syndrome, whereas it is evident in patients with pyoderma gangrenosum, Sweet syndrome, inflammatory bowel disease, and some forms of leukemia. Superficial migratory thrombophlebitis has other disease associations, but microscopically inflammation is confined to the immediate vicinity of the involved vessel; additional changes of erythema nodosum would not be expected, and therefore this combination would favor Behçet syndrome. Sterile neutrophilic folliculitis with perifollicular vasculopathy is not unique to Behçet syndrome, and has also been found in inflammatory bowel disease, Reiter syndrome, hepatitis B, mixed connective tissue disease, rheumatoid arthritis, scrofuloderma, and hematologic disorders. 101 In the author’s experience, the findings in biopsies of oral or genital ulcers are nonspecific, and it is not possible to distinguish these ulcers from ordinary aphthous ulcers. Genital aphthae sometimes receive the designation Lipschütz ulcers.

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6
Nutritional Deficiency and Gastrointestinal Disease


Selected Nutritional Deficiency Disorders 

Acrodermatitis Enteropathica and Zinc Deficiency 
Necrolytic Migratory Erythema 
Pellagra 
Vitamin C deficiency (Scurvy) 
Cutaneous Manifestations of Selected Gastrointestinal Diseases 

Crohn Disease 
Ulcerative Colitis 
This chapter will consider a few select nutritional deficiency disorders that are commonly encountered in dermatopathology and have reasonably characteristic microscopic changes. There are definite microscopic resemblances in several of these: necrolytic migratory erythema; acrodermatitis enteropathica/zinc deficiency; and, according to some descriptions, pellagra. Each can show parakeratosis with loss of the granular cell layer and, sometimes, pallor of superficial keratinocytes. This chapter also provides a brief summary of the cutaneous findings in Crohn disease and ulcerative colitis.

Selected Nutritional Deficiency Disorders

Acrodermatitis Enteropathica and Zinc Deficiency

Clinical Features
Acrodermatitis enteropathica is an autosomal recessive disorder presenting in infancy with diarrhea; alopecia; retardation of growth; and an erythematous, scaly, sometimes pustular and bullous eruption. The latter is characteristically acral and periorificial in distribution. Nail dystrophy may be a feature. 1 , 2 Authorities discovered that acrodermatitis enteropathica, a somewhat mysterious disorder in the not-too-distant past, was due to zinc deficiency, resulting in part from abnormalities of gastrointestinal absorption. Onset is often, but not invariably, associated with weaning, because breast milk typically provides adequate quantities of zinc. Investigators have now traced this disease to the SLC39A4 gene, which encodes a zinc transporter protein, Zip4. 3 Other causes of zinc deficiency in children or adults include parenteral nutrition without zinc supplementation, 4 gastrointestinal surgery, and inflammatory bowel disease. 5 In addition to obtaining zinc levels, determination of alkaline phosphatase, a zinc-dependent enzyme, can be of value in selected circumstances where laboratory results are equivocal.
Zinc supplementation is the treatment of choice. It is also important to consider secondary causes of zinc deficiency, such as inflammatory bowel disease.

Microscopic Findings
The key microscopic features are evident in both acrodermatitis enteropathica and acquired zinc deficiency. They include pallor or vacuolization of superficial portions of the epidermis, with diminished or absent granular cell layer and overlying parakeratosis that is often confluent. 6 , 7 Vesicles and bullae result from extensive vacuolization; neutrophils may accumulate in these areas ( Fig. 6-1 ). 1 , 8 The dermis features vasodilatation and perivascular inflammation. With chronicity, varying degrees of epidermal necrosis may be visible, associated with acanthosis ( Fig. 6-2 ).


Figure 6-1 Acrodermatitis enteropathica. There are confluent parakeratosis, vacuolization in the superficial portion of the epidermis, and neutrophils in the stratum corneum.


Figure 6-2 Acrodermatitis enteropathica, older lesion. This lesion shows significant acanthosis and focal keratinocyte necrosis (apoptosis). Confluent parakeratosis and cleft formation are still apparent.

Differential Diagnosis
The microscopic findings in zinc deficiency are quite similar to those in necrolytic migratory erythema, and differentiation requires correlation with other clinical and laboratory studies. Pustular variants can resemble candidiasis, and in fact Candida infection not infrequently coexists with acrodermatitis enteropathica. Therefore, detection of organisms with periodic acid–Schiff or silver methenamine stains would by itself not exclude the possibility of zinc deficiency. The cutaneous histopathologic findings of biotin deficiency are not well delineated, although there is certainly overlap of the clinical findings, and a patient with both deficiencies has been reported. 9 Pellagra can have some microscopic features in common. In fact, some descriptions of pellagra emphasize pallor and vacuolization in keratinocytes in superficial portions of the epidermis. In addition, both pellagra and late-stage zinc deficiency show prominent parakeratosis. However, unlike zinc deficiency, pellagra features prominent dermal edema, it may produce subepidermal bullae, and it often displays basilar hypermelanosis. Late-stage lesions of zinc deficiency show fewer diagnostic changes and can resemble other forms of chronic spongiotic dermatitis.

Necrolytic Migratory Erythema

Clinical Features
This syndrome features anemia, weight loss, glossitis, and adult-onset diabetes mellitus. The essential cutaneous feature is a migrating annular erythema with erosions and crusting. This erythema is concentrated in intertriginous areas of the trunk, groin, buttocks, and thighs, and perioral lesions may occur. 10 , 11 Necrolytic migratory erythema is most often associated with a glucagon-secreting islet cell tumor of the pancreas. In a typical case, elevated glucagon levels and reduced plasma amino acids are detected. Other conditions in which glucagons are sometimes elevated, including neuroendocrine hepatic tumors and hepatic cirrhosis, can produce similar cutaneous findings. 12 , 13 Furthermore, changes of necrolytic migratory erythema can accompany jejunal and rectal adenocarcinoma, myelodysplastic syndrome, inflammatory bowel disease, pancreatitis, and malabsorption disorders. The occurrence of necrolytic migratory erythema in the absence of a pancreatic tumor is sometimes called the “pseudoglucagonoma syndrome.” 14 There appears to be no clear consensus regarding the pathogenesis of necrolytic migratory erythema, but amino acid deficiency due to the catabolic effects of elevated glucagon levels, other nutritional deficiencies (such as zinc and fatty acids), and the effects of certain inflammatory mediators, including arachidonic acid, may all play a role. 14 , 15 Skin lesions resolve with treatment of the underlying tumor and/or correction of nutritional deficiencies.

Microscopic Findings
There is often some degree of acanthosis, which may range from mild to marked and psoriasiform. Confluent parakeratosis overlies distinctly vacuolated keratinocytes in the upper portion of the epidermis ( Fig. 6-3 ). 16 Necrosis may ensue, with coalescence of vacuoles and neutrophil accumulation, at times producing spongiform pustulation. Subcorneal pustules occasionally form and may be the principal histopathologic finding. 17 Within the superficial to mid-dermis, there is a perivascular infiltrate composed mainly of lymphocytes but sometimes including neutrophils.


Figure 6-3 Necrolytic migratory erythema. Pallor and vacuolization of the surface epidermis are features common to several nutritional deficiency disorders, and they frequently occur in acrodermatitis enteropathica and pellagra as well as necrolytic migratory erythema. Note also the overlying confluent parakeratosis.

Differential Diagnosis
The presence of confluent parakeratosis overlying vacuolated superficial keratinocytes is quite characteristic of necrolytic migratory erythema and should raise suspicions for that diagnosis. However, as mentioned, zinc deficiency (acrodermatitis enteropathica) can have overlapping microscopic features. In general, biopsies showing parakeratosis and pallor or vacuolization of superficial keratinocytes should suggest a nutritional deficiency disorder and prompt investigations in this regard. The clinical presentations of biotin deficiency, pellagra, and childhood acrodermatitis enteropathica are often distinctive, although overlapping features exist. 18 , 19 In addition, adult-onset zinc deficiency can be difficult to distinguish from necrolytic migratory erythema in the absence of laboratory data. Another condition resembling necrolytic migratory erythema but occurring in an acral distribution, particularly on the legs, is termed necrolytic acral erythema . This entity is virtually indistinguishable histopathologically from necrolytic migratory erythema of the glucagonoma syndrome but has a strong association with hepatitis C infection. In this instance, knowledge of the clinical distribution of the lesions is important, and laboratory studies are essential.
Psoriasiform varieties of necrolytic migratory erythema may be difficult to distinguish from true psoriasis. Vacuolization of superficial keratinocytes is not typical of psoriasis in the absence of spongiform pustulation (spongiotic change in superficial portions of the epidermis associated with accumulations of neutrophils), but the latter change can occur in both conditions. Among the other dermatoses characterized by spongiform pustulation, candidiasis would be expected to show organisms at the surface epidermis with periodic acid–Schiff or silver methenamine stains. Unfortunately, coexistence of necrolytic migratory erythema and candidiasis has been reported, so the diagnosis of the former cannot be entirely excluded if organisms are found. 20 The occasional case presenting with purely subcorneal pustules would be quite difficult to distinguish from subcorneal pustular dermatosis. However, the variant of immunoglobulin A (IgA) pemphigus manifesting as subcorneal pustules could be recognized through direct immunofluorescence study; in that case, intraepidermal intercellular IgA deposition would be detected.

Pellagra

Clinical Features
Classic pellagra develops due to a dietary deficiency of niacin and occurs in patients who eat a diet of “meat (meaning fatback pork), maize, and molasses.” However, the situation is somewhat more complicated, in that individuals deficient in niacin often have additional vitamin deficiencies, which in turn may have deleterious effects on the conversion of tryptophan to niacin. Meanwhile, some otherwise at-risk populations are protected by consumption of other foods rich in niacin or methods of preparation of maize (corn) that successfully release niacin from its bound form. 21 , 22
The conversion of tryptophan to niacin is an important source of the vitamin; therefore, other conditions that alter this pathway can produce a similar clinical picture, resulting in a “secondary” form of pellagra. Examples are the autosomal recessive disorder Hartnup disease , in which absorption of tryptophan is impaired, 23 or carcinoid , in which the tumor diverts tryptophan to the production of serotonin. 24 In addition, certain drugs can interfere with niacin biosynthesis and promote the signs and symptoms of pellagra, including antituberculous drugs (isoniazid, pyrazinamide) and 5-fluorouracil. 25 , 26
Clinical features of pellagra include depression, weakness, abdominal pain, and diarrhea. The chief cutaneous finding is photosensitivity, producing erythema and, eventually thickening, scaling, and hyperpigmentation involving the skin of the face, neck, extensor forearms and dorsa of the hands. Lesions on the neck and chest produce the characteristic Casal necklace . Scale and follicular plugging involving the nose, sometimes termed dyssebacia , produces a roughened appearance.
Treatment includes dietary management and niacin supplementation, in addition to correction of other associated nutritional deficiencies. Management of any underlying disorders, such as alcoholism or potential secondary causes of pellagra, may also be important.

Microscopic Findings
The microscopic descriptions of pellagra vary somewhat, depending on the source. Several authors emphasize early dermal edema and chronic perivascular inflammation. Hyperkeratosis, parakeratosis, and basilar hypermelanosis are apparent, particularly in older lesions. Bullae may arise either subepidermally, related to the marked dermal edema, or intraepidermally. Researchers have described pallor and vacuolization of upper layers of the epidermis, probably the source of intraepidermal blistering. In addition, they have observed sebaceous gland prominence and follicular plugging, especially in biopsies of the nose or central face. 18 , 27 , 28

Differential Diagnosis
When lesions display pallor or vacuolization of the surface epidermis, they can closely resemble zinc deficiency and necrolytic migratory erythema. 29 In fact, these deficiency disorders have often been grouped together, at least conceptually. It must also be kept in mind that some individuals with pellagra may have multiple nutritional deficiencies, and the possibility that vacuolization is actually due to deficiencies in zinc, biotin, or other amino acids should be kept in mind. It has even been proposed that the manifestations of acrodermatitis enteropathica and pellagra stem from a common deficiency of picolinic acid, which like nicotinic acid derives from tryptophan. 19 However, subepidermal bullae and basilar hypermelanosis in this setting are certainly suggestive of pellagra. Follicular plugging can also be seen in vitamin C deficiency (see later discussion), but the formation of “corkscrew hairs” is a feature of the latter disorder.

Vitamin C Deficiency (Scurvy)

Clinical Features
Ascorbic acid deficiency is encountered in alcoholic patients and individuals on restricted diets, with reduced intake of fruits and vegetables. It is an important factor in normal collagen biosynthesis and thereby contributes to the integrity of small vessels. Humans and some other species are incapable of synthesizing the vitamin and therefore are dependent on external sources. Mucocutaneous manifestations are common and include petechiae, perifollicular hemorrhages, ecchymoses, bleeding gums, and “woody edema” of the lower extremities. Hyperkeratosis of hair follicles is associated with coiling of hair shafts, the so-called “corkscrew hairs.” 30

Microscopic Findings
Extravasated erythrocytes are common, and hemosiderin deposition occurs. Perifollicular hemorrhages are characteristic ( Fig. 6-4 ). Follicular hyperkeratosis is associated with coiling of the entrapped hair shafts. 31 , 32


Figure 6-4 Scurvy. Perifollicular hemorrhage and mild perivascular inflammation are apparent. There is also a cross-sectional profile of a distorted hair shaft within the follicular lumen.

Differential Diagnosis
Dermal hemorrhages can be due to a variety of causes. Thus, this change in isolation is nonspecific. However, the follicular alterations are quite characteristic and can even occasionally suggest the diagnosis when it has not been suspected clinically.

Cutaneous Manifestations of Selected Gastrointestinal Diseases

Crohn Disease

Clinical Features
Crohn disease, including granulomatous colitis, can be associated with perianal abscesses, sinuses, fistulae, episcleritis and uveitis, aphthous stomatitis, periorificial ulcers with formation of “cobblestoned papules,” erythema nodosum, and pyoderma gangrenosum. 33 Granulomas in perianal skin tags can provide an important clue to the diagnosis of Crohn disease. 34 Examples of polyarteritis nodosa in Crohn disease have also been described, 35 and the author has seen at least one example of this association. Cutaneous involvement in areas widely separated from the gastrointestinal tract is commonly termed metastatic Crohn disease. These lesions can consist of erythematous nodules or ulcers and can involve the face, trunk (especially flexural areas), and extremities. 36 , 37

Microscopic Findings
Many of these lesions have nonspecific histopathologic findings, although the clinical setting (e.g., perianal abscesses and fistulae) can be quite suggestive of Crohn disease. The most characteristic feature is granulomatous inflammation, which may be seen in the perianal, perioral, and cutaneous “metastatic” lesions. The typical finding is a noncaseating granuloma, associated with a few scattered lymphocytes or small macrophages ( Fig. 6-5 ). 38 Lesions clinically resembling erythema nodosum can either show classic findings of erythema nodosum or granulomatous elements, including granulomatous vasculitis.


Figure 6-5 Crohn disease. This figure shows a dermal granuloma located in a cutaneous “metastatic” lesion.

Differential Diagnosis
The noncaseating granulomas of Crohn disease closely resemble those of sarcoidosis. This distinction can be particularly difficult in examples of metastatic Crohn disease when lesions are sampled at sites other than the perianal or perioral regions. For correct classification, additional clinical information may be necessary.

Ulcerative Colitis

Clinical Features
Cutaneous findings develop in ulcerative colitis in up to 34% of reported cases. A number of these develop in both Crohn disease and ulcerative colitis, including aphthous stomatitis, erythema nodosum, and pyoderma gangrenosum. Erythema nodosum, pyoderma gangrenosum, and acute toxic arthritis are associated with active bowel disease and most often respond to surgical resection of the involved bowel. Pustular disease is particularly prone to occur in ulcerative colitis; its manifestations include discrete, small pustular lesions; pustules that evolve into pyoderma gangrenosum 39 ; and pyoderma vegetans of Hallopeau , which consists of vegetative plaques with elevated borders. Some authorities consider this to be the same disorder as blastomycosis-like pyoderma , and at one time it was erroneously classified with pemphigus vegetans. Similar vegetative lesions of the oral cavity are called pyostomatitis vegetans. 40 , 41

Microscopic Findings
Lesions of pyoderma vegetans show pseudoepitheliomatous hyperplasia and intraepidermal abscesses, usually composed of neutrophils but sometimes including eosinophils ( Fig. 6-6 ). 42 There is a rather heavy, mixed dermal inflammatory infiltrate. Bacterial cultures may demonstrate Staphylococcus aureus , but this may in fact be a secondary invader rather than the etiologic agent for this disorder.


Figure 6-6 Pyoderma vegetans. This lesion shows pseudoepitheliomatous hyperplasia and diffuse neutrophils in the surface epidermis. These lesions are also termed blastomycosis-like pyoderma .

Differential Diagnosis
As previously mentioned, the changes of pyoderma vegetans were at one time linked to pemphigus vegetans, which is also characterized by irregular acanthosis and intraepidermal abscesses. However, in pemphigus vegetans, the intraepidermal abscesses are usually composed of eosinophils, foci of acantholysis can sometimes be found, and direct immunofluorescence shows intercellular epidermal fluorescence with antibodies to IgG. Acantholysis is not a feature of pyoderma vegetans, and direct immunofluorescence studies are negative. Microscopically, the epidermal changes of pyoderma vegetans may reach pseudoepitheliomatous hyperplasia proportions. Together with intraepidermal neutrophilic abscesses, these findings may also resemble “deep” fungal infections (i.e., North American blastomycosis, South American blastomycosis, some examples of cryptococcosis and coccidioidomycosis) as well as in some atypical mycobacterial infections and protothecosis. Therefore, special stains for these organisms and/or culture studies may be necessary.

References

1. Jensen, SL, McCuaig, C, Zembowicz, A, et al. Bullous lesions in acrodermatitis enteropathica delaying diagnosis of zinc deficiency: a report of two cases and review of the literature. J Cutan Pathol . 2008;35(suppl 1):1–13.
2. Perafan-Riveros, C, Franca, LF, Alves, AC, et al. Acrodermatitis enteropathica: case report and review of the literature. Pediatr Dermatol . 2002;19:426–431.
3. Maverakis, E, Fung, MA, Lynch, PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol . 2007;56:116–124.
4. Ferrandiz, C, Henkes, J, Peyri, J, et al. Acquired zinc deficiency syndrome during total parenteral alimentation. Clinical and histopathological findings. Dermatologica . 1981;163:255–266.
5. Krasovec, M, Frenk, E. Acrodermatitis enteropathica secondary to Crohn’s disease. Dermatology . 1996;193:361–363.
6. Niemi, KM, Anttila, PH, Kanerva, L, et al. Histopathological study of transient acrodermatitis enteropathica due to decreased zinc in breast milk. J Cutan Pathol . 1989;16:382–387.
7. Gonzalez, JR, Botet, MV, Sanchez, JL. The histopathology of acrodermatitis enteropathica. Am J Dermatopathol . 1982;4:303–311.
8. Borroni, G, Brazzelli, V, Vignati, G, et al. Bullous lesions in acrodermatitis enteropathica. Histopathologic findings regarding two patients. Am J Dermatopathol . 1992;14:304–309.
9. Lagier, P, Bimar, P, Seriat-Gautier, S, et al. [Zinc and biotin deficiency during prolonged parenteral nutrition in the infant]. Presse Med . 1987;16:1795–1797. [[in French]].
10. Leichter, SB. Clinical and metabolic aspects of glucagonoma. Medicine (Baltimore) . 1980;59:100–113.
11. Vandersteen, PR, Scheithauer, BW. Glucagonoma syndrome. A clinicopathologic, immunocytochemical, and ultrastructural study. J Am Acad Dermatol . 1985;12:1032–1039.
12. Technau, K, Renkl, A, Norgauer, J, et al. Necrolytic migratory erythema with myelodysplastic syndrome without glucagonoma. Eur J Dermatol . 2005;15:110–112.
13. Marko, PB, Miljkovic, J, Zemljic, TG. Necrolytic migratory erythema associated with hyperglucagonemia and neuroendocrine hepatic tumors. Acta Dermatovenerol Alp Panonica Adriat . 2005;14:161–164. [166].
14. Tierney, EP, Badger, J. Etiology and pathogenesis of necrolytic migratory erythema: review of the literature. MedGenMed . 2004;6:4.
15. Peterson, LL, Shaw, JC, Acott, KM, et al. Glucagonoma syndrome: in vitro evidence that glucagon increases epidermal arachidonic acid. J Am Acad Dermatol . 1984;11:468–473.
16. Franchimont, C, Pierard, GE, Luyckx, AS, et al. Angioplastic necrolytic migratory erythema. Unique association of necrolytic migratory erythema, extensive angioplasia, and high molecular weight glucagon-like polypeptide. Am J Dermatopathol . 1982;4:485–495.
17. Kheir, SM, Omura, EF, Grizzle, WE, et al. Histologic variation in the skin lesions of the glucagonoma syndrome. Am J Surg Pathol . 1986;10:445–453.
18. Hendricks, WM. Pellagra and pellagralike dermatoses: etiology, differential diagnosis, dermatopathology, and treatment. Semin Dermatol . 1991;10:282–292.
19. Krieger, IE. Acrodermatitis enteropathica and the relation to pellagra. Med Hypotheses . 1981;7:539–547.
20. Katz, R, Fischmann, AB, Galotto, J, et al. Necrolytic migratory erythema, presenting as candidiasis, due to a pancreatic glucagonoma. Cancer . 1979;44:558–563.
21. Karthikeyan, K, Thappa, DM. Pellagra and skin. Int J Dermatol . 2002;41:476–481.
22. Jagielska, G, Tomaszewicz-Libudzic, EC, Brzozowska, A. Pellagra: a rare complication of anorexia nervosa. Eur Child Adolesc Psychiatry . 2007;16:417–420.
23. Seyhan, ME, Selimoglu, MA, Ertekin, V, et al. Acrodermatitis enteropathica-like eruptions in a child with Hartnup disease. Pediatr Dermatol . 2006;23:262–265.
24. Castiello, RJ, Lynch, PJ. Pellagra and the carcinoid syndrome. Arch Dermatol . 1972;105:574–577.
25. Darvay, A, Basarab, T, McGregor, JM, et al. Isoniazid induced pellagra despite pyridoxine supplementation. Clin Exp Dermatol . 1999;24:167–169.
26. Stevens, HP, Ostlere, LS, Begent, RH, et al. Pellagra secondary to 5-fluorouracil. Br J Dermatol . 1993;128:578–580.
27. Findlay, GH, Rein, L, Mitchell, D. Reactions to light on the normal and pellagrous Bantu skin. Br J Dermatol . 1969;81:345–351.
28. Moore, RA, Spies, TD, Cooper, ZK. Histopathology of the skin in pellagra. Arch Dermatol Syphilol . 1942;46:106–111.
29. van Beek, AP, de Haas, ER, van Vloten, WA, et al. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol . 2004;151:531–537.
30. Hirschmann, JV, Raugi, GJ. Adult scurvy. J Am Acad Dermatol . 1999;41:895–906. [quiz 907-910].
31. Walker, A. Chronic scurvy. Br J Dermatol . 1968;80:625–630.
32. Ellis, CN, Vanderveen, EE, Rasmussen, JE. Scurvy. A case caused by peculiar dietary habits. Arch Dermatol . 1984;120:1212–1214.
33. Schoetz, DJ, Jr., Coller, JA, Veidenheimer, MC. Pyoderma gangrenosum and Crohn’s disease. Eight cases and a review of the literature. Dis Colon Rectum . 1983;26:155–158.
34. Taylor, BA, Williams, GT, Hughes, LE, et al. The histology of anal skin tags in Crohn’s disease: an aid to confirmation of the diagnosis. Int J Colorectal Dis . 1989;4:197–199.
35. Kahn, EI, Daum, F, Aiges, HW, et al. Cutaneous polyarteritis nodosa associated with Crohn’s disease. Dis Colon Rectum . 1980;23:258–262.
36. Lebwohl, M, Fleischmajer, R, Janowitz, H, et al. Metastatic Crohn’s disease. J Am Acad Dermatol . 1984;10:33–38.
37. Goh, M, Tekchandani, AH, Wojno, KJ, et al. Metastatic Crohn’s disease involving penile skin. J Urol . 1998;159:506–507.
38. Witkowski, JA, Parish, LC, Lewis, JE. Crohn’s disease—non-caseating granulomas on the legs. Acta Derm Venereol . 1977;57:181–183.
39. Salmon, P, Rademaker, M, Edwards, L. A continuum of neutrophilic disease occurring in a patient with ulcerative colitis. Australas J Dermatol . 1998;39:116–118.
40. Markiewicz, M, Suresh, L, Margarone, J, III., et al. Pyostomatitis vegetans: a clinical marker of silent ulcerative colitis. J Oral Maxillofac Surg . 2007;65:346–348.
41. Kitayama, A, Misago, N, Okawa, T, et al. Pyodermatitis-pyostomatitis vegetans after subtotal colectomy for ulcerative colitis. J Dermatol . 2010;37:714–717.
42. Bianchi, L, Carrozzo, AM, Orlandi, A, et al. Pyoderma vegetans and ulcerative colitis. Br J Dermatol . 2001;144:1224–1227.
7
Panniculitis


Septal Panniculitis 

Erythema Nodosum 
Subacute Nodular Migratory Panniculitis 
Morphea/Scleroderma Panniculitis 
α 1 -Antitrypsin Deficiency Panniculitis 94
Lobular or Mixed Septal-Lobular Panniculitis 

Erythema Induratum and Nodular Vasculitis 
Pancreatic Panniculitis 
Sclerema Neonatorum, Subcutaneous Fat Necrosis of the Newborn, and Poststeroid Panniculitis 
Lupus Erythematosus Panniculitis (Lupus Profundus) 
Panniculitis of Dermatomyositis 
Traumatic Panniculitis 
Lipodermatosclerosis 
Infection-Induced Panniculitis 
Malignancy and Panniculitis or Panniculitis-like Subcutaneous Infiltration 

Cytophagic Histiocytic Panniculitis 
Malignant Subcutaneous Infiltrates 
Other Considerations in the Diagnosis of Panniculitis 
Panniculitis is a diagnostically challenging category for dermatologists and pathologists. Terminology is difficult, partly because various names have been applied to the same disorder (e.g., nodular vasculitis and erythema induratum, pancreatic fat necrosis and enzymic panniculitis) and partly because new discoveries have resulted in the abandonment of some terms. For example, cases that were classified as Weber-Christian disease in the past may now be categorized as α 1 -antitrypsin deficiency panniculitis, lupus panniculitis, or pancreatic panniculitis. Clinically, many of the panniculitides resemble one another, because they usually present as tender erythematous subcutaneous nodules. Several forms of panniculitis, particularly erythema nodosum, are actually manifestations of a variety of different disease processes, and clinical and laboratory investigations are often required to determine an underlying etiology. In addition, the subcutaneous fat responds to a variety of different insults in a limited number of ways, and therefore histopathologic differences among the various forms of panniculitis may be subtle. This chapter will emphasize the distinctive clinical and histopathologic characteristics of the major forms of panniculitis.
When performing a biopsy in a case of panniculitis, it is absolutely critical that the specimen include a generous portion of subcutaneous fat. Therefore, excisional biopsies carried through the subcutis, or narrow incisional biopsies that incorporate a broad expanse of subcutaneous fat, are generally preferable to punch biopsies. Regarding the classification scheme for panniculitis, it is based partly on etiology (e.g., traumatic or infection-induced panniculitis); partly on the disease category associated with a particular form of panniculitis (e.g., panniculitides associated with connective tissue diseases, including morphea/scleroderma panniculitis, panniculitis in dermatomyositis, and lupus panniculitis); and partly on microscopic characteristics (e.g., panniculitis displaying needle-shaped clefts among lipocytes or septal versus lobular panniculitis). Regarding septal versus lobular panniculitis, these are largely artificial groupings, because there is actually no purely septal or purely lobular panniculitis. However, some forms of panniculitis do show either predominantly septal or predominantly lobular involvement, and so this finding can provide one useful clue to diagnosis when combined with other clinical and histopathologic features.

Septal Panniculitis

Erythema Nodosum


Clinical Features: Erythema nodosum is probably the best known of the forms of panniculitis, as well as the most common. It typically presents as an acute eruption of erythematous, tender subcutaneous nodules over the pretibial areas bilaterally. Authorities widely regarded it as a delayed hypersensitivity response to a variety of antigenic challenges, although the mechanisms of its development are probably more complex. 1 Erythema nodosum can occur at any age regardless of gender, but it is most common in young women. It occurs with especially high frequency during the second through fourth decades of life. 2 This condition is not limited to any particular geographic region. However, the prevalence of erythema nodosum when caused by certain disorders may vary according to location (e.g., in areas where coccidioidomycosis or Behçet disease are endemic).
The bilateral nodules of erythema nodosum occur in crops, and the most common site by far is the shins. However, other locations are occasionally involved, particularly the thighs and forearms. 3 Occasional systemic symptoms include arthritis, arthralgia, fever, and malaise. Erythema nodosum is an important skin sign of systemic disease. Its development may precede an attack or accompany a flare of colitis. It may also have some value as a prognostic indicator; for example, erythema nodosum may have a protective effect against disseminated disease in patients with coccidioidomycosis, and it is closely associated with a more benign and self-limited form of sarcoidosis. 1 However, up to one third of cases have no known disease association, even when followed for 1 year or more. 4 Lesions usually last a few days or weeks and then slowly involute, without scar formation. Discoloration suggestive of a bruise (“erythema contusiformis”) may be seen as the erythema subsides. However, more chronic examples also occur, some of which show a tendency toward migration or centrifugal spread; the latter have been termed subacute nodular migratory panniculitis or erythema nodosum migrans (see later discussion).
Up to one third of cases of erythema nodosum recur. Management of any underlying disorder is helpful. Treatments specifically directed toward the subcutaneous nodules include bed rest, salicylates or nonsteroidal anti-inflammatory agents, and potassium iodide.

Microscopic Findings: Erythema nodosum is the prototypical septal panniculitis, but the histopathologic changes are not entirely confined to subcutaneous septa ( Fig. 7-1 ). Biopsies of early lesions tend to show edematous septa and mild lymphocytic infiltrates. Neutrophils may predominate in early lesions, 5 and reportedly, a variant with predominance of eosinophils has occurred. 6 True vasculitis of the type seen in leukocytoclastic vasculitis is not demonstrable, and erythema nodosum is not generally regarded as a vasculitic process. However, “secondary” vasculitis may be observed in lesions containing relatively heavy, mixed, or neutrophil-rich inflammatory infiltrates. In early lesions, one may also find Miescher microgranulomas, a characteristic if not pathognomonic feature of erythema nodosum. These are small collections of histiocytes (macrophages), found within septa or at a septal-lobular interface, that tend to surround neutrophils or small cleftlike spaces. 7 Miescher microgranulomas can also be apparent in older lesions, at which point the constituent cells have evolved into the appearance of epithelioid and multinucleated giant cells ( Fig. 7-2 ).


Figure 7-1 Erythema nodosum. There is septal sclerosis, but a lacelike infiltration of adjacent fat lobules is also apparent, most prominently at the septal-lobular interface.


Figure 7-2 Erythema nodosum, chronic lesion. A, Widening and infiltration of septa is apparent. There are clusters of macrophages near septal-lobular junctions, representing Miescher microgranulomas. B, This view shows that the cells comprising the granulomas surround cleftlike spaces within the septum.
As lesions progress, the septa become widened and contain a mixed, partly granulomatous infiltrate. These cells infiltrate the periphery of fat lobules in a lacelike configuration. Not surprisingly, the extent of lobular involvement can vary, and no doubt in some cases this can be relatively prominent. 8 Nevertheless, in the case of a lobular panniculitis without the characteristic septal changes, a diagnosis of erythema nodosum requires caution. There is also frequently a mild to moderate perivascular lymphocytic infiltrate in the overlying dermis. In later stages, the septa become fibrotic, partly replacing the fat lobules. Residual granulomas and lipophages are apparent, and a degree of vascular proliferation may be present. Over the long term, a remodeling process takes place, which usually results in minimal residual scarring.

Differential Diagnosis: Histopathologically, the picture of a predominantly septal panniculitis usually limits the differential diagnosis and tends to exclude those conditions that are chiefly lobular or mixed. Pancreatic panniculitis may show predominantly septal changes in its earliest stages, 9 but eventually these lesions exhibit the characteristic fat necrosis, with saponification and “ghost cell” formation. Infection-induced panniculitis can sometimes mimic erythema nodosum, but there are often more extensive neutrophilic infiltrates, cellular necrosis (including sweat gland necrosis), vascular proliferation, and hemorrhage. 10 Special staining for organisms and microbiologic studies may be helpful if infection is a serious consideration. Two other septal panniculitides differ in other respects: morphea panniculitis is accompanied by dermal sclerosis and atrophy of appendages, whereas α 1 -antitrypsin deficiency panniculitis features, among other things, liquefactive necrosis of fat lobules and early splaying of reticular dermal collagen by neutrophils.

Subacute Nodular Migratory Panniculitis


Clinical Features: Bafverstedt first described this condition in 1954, and Vilanova and Pinol Aguade named it subacute nodular migratory panniculitis in 1956. 11 Sometimes referred to as Vilanova disease , it has some clinical and microscopic characteristics that are similar to chronic erythema nodosum. Many believe it to represent a variant of the latter 12 ; however, others consider it to be a separate disorder. 13 Subacute nodular migratory panniculitis is seen predominantly in women, is often unilateral, and is characterized by nodules that migrate or expand in a centrifugal manner, with central clearing. Lesions tend to be less tender than those of classic erythema nodosum. There may be few, if any, associated systemic symptoms, 12 although arthralgias have been reported. Most cases are idiopathic, but some are associated with streptococcal infection or thyroid disease.
Untreated, subacute nodular migratory panniculitis can last for months or years. However, treatment with potassium iodide is effective, often resulting in clearing of lesions within several weeks. 14

Microscopic Findings and Differential Diagnosis: The changes are those of a chronic septal panniculitis ( Fig. 7-3 ). 14 However, in contrast to more classic forms of chronic erythema nodosum, subacute nodular migratory panniculitis shows greater septal thickening, more prominent granulomatous inflammation along the borders of widened subcutaneous septa, absence of phlebitis, and rare hemorrhage. 13 The differential diagnosis includes the other conditions with predominantly septal inflammation discussed under erythema nodosum, and the same considerations apply.


Figure 7-3 Subacute nodular migratory panniculitis. There is a septal panniculitis, in this case primarily consisting of lymphocytes.

Morphea/Scleroderma Panniculitis


Clinical Features: Both morphea and scleroderma are characterized by subcutaneous inflammation. These changes are particularly well developed in morphea profunda. 15 Subcutaneous involvement has also been reported in such variants as acral pansclerosis of childhood, generalized morphea, and linear scleroderma. Eosinophilic fasciitis can also extend into the subcutis. 16 Associations with peripheral eosinophilia, polyclonal gammopathy, and serologic abnormalities may occur. Fleischmajer and colleagues have proposed that the sclerosing process in scleroderma is initiated by inflammatory changes that take place in the subcutis. 17

Microscopic Findings: Morphea and scleroderma show predominantly septal panniculitis, with widening of subcutaneous septa and mucin deposition ( Fig. 7-4 ). Inflammation is especially concentrated at the dermal-subcutaneous interface ( Fig. 7-5 ). Lymphocytes and plasma cells predominate, 16 although macrophages and eosinophils may be present. In some cases, the number of plasma cells is striking. 18 In late stages of morphea, the subcutis is largely replaced by hyalinized connective tissue, quite often accompanied by changes of lipoatrophy. These inflammatory changes are generally of a lesser degree in systemic scleroderma, in which lymphoid follicles typically do not occur. 19


Figure 7-4 Morphea panniculitis. There is marked thickening of subcutaneous septa. This is an example of morphea profunda.


Figure 7-5 Morphea profunda. Inflammation tends to concentrate at the dermal-subcutaneous interface.

Differential Diagnosis: The combination of septal panniculitis with lymphoplasmacytic predominance and dermal and subcutaneous sclerosis is unique, and it helps separate morphea/scleroderma panniculitis from other septal forms of panniculitis. Differentiation among the several varieties of these sclerosing disorders is more difficult and may require clinical data for accurate classification. Sclerosis with lesser degrees of subcutaneous inflammation characterizes scleroderma, whereas a predominance of fascial involvement with extension into the subcutis would be more typical of eosinophilic fasciitis.

α 1 -Antitrypsin Deficiency Panniculitis


Clinical Features: α 1 -Antitrypsin deficiency is a well-established but infrequently diagnosed cause of panniculitis. The most severely affected individuals, with markedly decreased levels of the protease inhibitor, develop a severe ulcerating panniculitis. Recognition of the disorder is important for proper management, addressing of other manifestations of the deficiency, and appropriate genetic counseling.
α 1 -Antitrypsin is the most important protease inhibitor. It acts on a wide range of proteolytic enzymes that play a direct role in degradation of tissues, including trypsin, collagenase, and elastase, 20 and has important effects on immune function.
The most common protease inhibitor (Pi) genotype is MM (homozygous for the M allele), which is associated with normal serum levels of α 1 -antitrypsin. Heterozygotes with one copy of the S and Z alleles have moderate deficiencies of the inhibitors (PiMS and PiMZ), whereas patients who are homozygous for the Z allele (PiZZ) have severe α 1 -antitrypsin deficiency, with serum levels in the range of 0.187 to 0.385 g/L. Conditions associated with severe α 1 -antitrypsin deficiency include chronic liver disease with cirrhosis (resulting from retention of the molecule in the liver), emphysema, pancreatitis, membranoproliferative glomerulonephritis, rheumatoid arthritis, cutaneous vasculitis, and angioedema. 21
The initiating event in individuals who develop panniculitis is not always clear, but trauma appears to play a role in some cases. Absence of the protease inhibitor results in activation of lymphocytes and macrophages, lack of restraint on the complement cascade, release of chemotactic factors, accumulation of neutrophils with release of their proteolytic enzymes, and consequent attack on fat and nearby connective tissues. The subcutis is thought to be particularly vulnerable to this process, because fatty acids make nearby elastin more susceptible to proteolytic degradation. 22
Large, erythematous to purpuric, tender nodules or plaques appear in a variety of sites, especially the lower trunk and proximal extremities (flanks, buttocks, and thighs). 20 Ulcers develop that may be deep and necrotic, accompanied by an oily discharge. A history of antecedent trauma can be elicited in approximately one third of cases. Some patients with panniculitis also have fever, pleural effusions, and pulmonary embolism. 21
The clinical course of the panniculitis is often prolonged, and lesions are resistant to therapy. Doxycycline and dapsone may be helpful in mild cases. Other successful therapies have included plasma exchange 23 ; liver transplantation 24 ; and, especially, replacement of α 1 -antitrypsin via intravenous infusions.

Microscopic Findings: Descriptions of the pathology of α 1 -antitrypsin deficiency panniculitis have varied considerably. However, in early stages there appears to be a neutrophilic panniculitis, followed rapidly by necrosis and destruction of fat lobules. 20 Splaying of neutrophils between collagen bundles in the reticular dermis has been described as an early clue to the diagnosis. 25 Dissolution of dermal collagen, with resultant liquefactive necrosis and separation of fat lobules from adjacent septa, is encountered in most cases. 26 Another characteristic feature is the presence of ‘skip areas’ of normal fat adjacent to foci of severe necrotizing panniculitis. 20 Chronic inflammation and hemorrhage may be present at the periphery of areas of involvement. Although there are descriptions of small-vessel vasculitis, most authors have not found evidence of “primary” leukocytoclastic vasculitis. However, researchers have noted “secondary” vasculitis in areas of heavy neutrophilic infiltration and phlebothrombosis. 20 In individuals with intermediate levels of protease inhibitor deficiency, lipophage and giant cell accumulation may be more prominent. Lesions heal with scarring and obliteration of fat lobules.

Differential Diagnosis: Su and associates have extensively reviewed the microscopic differential diagnosis for this disorder. 20 Entities that are of particular importance for consideration include traumatic (factitial) panniculitis, infection-induced panniculitis, pancreatic (enzymic) panniculitis, and erythema induratum (nodular vasculitis). Each of these may be associated with infiltrates that include neutrophils and varying degrees of necrosis. Findings that would tend to exclude α 1 -antitrypsin deficiency panniculitis include foreign material or large “swiss cheese–like” vacuolated spaces (traumatic panniculitis); microorganisms identified with special staining (infection-induced panniculitis); “ghost cells” and saponification of fat (pancreatic panniculitis); or vasculitis involving a medium-sized subcutaneous vessel, sometimes with caseous necrosis (erythema induratum).

Lobular or Mixed Septal-Lobular Panniculitis

Erythema Induratum and Nodular Vasculitis


Clinical Features: Erythema induratum is characterized by nodules on the lower extremities that may ulcerate and drain. Classically regarded as a tuberculid, its relationship to tuberculosis has now been substantiated by the detection of mycobacterial DNA in skin lesions by polymerase chain reaction techniques. 27 , 28 Sequencing analysis of polymerase chain reaction products can now distinguish Mycobacterium tuberculosis complex DNA from that of other mycobacterial pathogens. 29 However, there are also lesions with similar clinical and histopathologic features but without an identifiable relationship to M. tuberculosis ; these have been designated “nodular vasculitis.” At various times, different authors have considered the vasculitis either different from, or synonymous with, traditional erythema induratum. It may be best to regard erythema induratum as a subtype of nodular vasculitis associated with tuberculosis.
Erythema induratum and nodular vasculitis show a strong female predominance. They are characterized by tender, erythematous nodules that sometimes ulcerate, most often located on the lower legs but occasionally elsewhere. 30 Lesions are persistent and prone to recurrence. In erythema induratum associated with M. tuberculosis , there may be clinical and radiographic evidence of active tuberculosis and positive skin tests for purified protein derivative (PPD), but in other respects, clinical differences between tuberculous and nontuberculous cases are minor. Most investigators believe that the process represents a type IV, cell-mediated response to a particular antigenic stimulus. 31
Treatment should be directed at the underlying cause, if found. This includes antituberculous therapy for those cases associated with M. tuberculosis and other antimicrobial agents for those cases due to different infectious organisms. In cases not due to infection, possible inciting medications should be discontinued. Other helpful therapies in these instances have included corticosteroids, nonsteroidal anti-inflammatory drugs, and potassium iodide.

Microscopic Findings: Erythema induratum is a lobular or mixed septal-lobular panniculitis ( Fig. 7-6 ). Inflammatory cells include neutrophils, lymphocytes, macrophages, and multinucleated giant cells. Vasculitis is present and can involve small or medium-sized vessels ( Fig. 7-7 ). It may be predominantly neutrophilic, 32 lymphocytic, 33 or granulomatous. At times, multiple levels may be necessary to find the involved vessel, which may be obscured by dense surrounding inflammation. Necrosis with a caseous appearance may be present, sometimes with palisading granulomas ( Fig. 7-8 ). 32 Although researchers have described necrosis in both tuberculous and nontuberculous cases, the incidence and degree of necrosis are greater in those cases that are positive for M. tuberculosis DNA by polymerase chain reaction methods. 28 Nevertheless, necrosis is absent in more than one half of cases.


Figure 7-6 Erythema induratum (nodular vasculitis). This is a predominantly lobular panniculitis.


Figure 7-7 Erythema induratum (nodular vasculitis). There is vasculitis involving a medium-sized vessel in the subcutis. In this case, the vessel appears to be a small artery.


Figure 7-8 Erythema induratum (nodular vasculitis). There is a zone of “caseous” necrosis, bordered by a palisading granuloma.

Differential Diagnosis: Regarding differential diagnosis, early erythema nodosum may show lobular involvement, particularly in early stages, but it generally evolves into a picture of predominantly septal panniculitis; true vasculitis is uncommonly encountered, and caseous necrosis is not a feature. Perniosis can be difficult to distinguish from erythema induratum, but there is typically a history of cold exposure, and on microscopic examination the vessels often show “fluffy edema” of their walls. Infection-induced panniculitis tends to demonstrate a more prominent neutrophilic component, granular basophilic necrosis, sweat gland necrosis, and proliferations of small vessels, and organisms may be identifiable on special staining. Lupus panniculitis is typically less granulomatous, has a prominent lymphoplasmacellular infiltrate, shows mucinous deposits, and sometimes (in almost one half of cases) has overlying epidermal and dermal changes typical of lupus erythematosus. Both polyarteritis nodosa and thrombophlebitis tend to show inflammation limited to the immediate perivascular zone, in contrast to the extensive lobular panniculitis often encountered in erythema induratum.

Pancreatic Panniculitis


Clinical Features: Pancreatic panniculitis is an uncommonly reported complication of pancreatic disease. Its main importance is as a sign of a significant systemic disorder, particularly because the panniculitis may be recognized prior to detection of the underlying pancreatic disease. In this condition, subcutaneous nodules develop in association with acute or chronic pancreatitis, pancreatic carcinoma (particularly acinar cell carcinoma), pancreatic pseudocysts, or traumatic pancreatitis. 34 , 35 Panniculitis may precede the detection of pancreatic disease by several months, and in the case of pancreatic carcinoma, its onset may signal the presence of metastatic disease. 34 , 36 Subcutaneous nodules develop most often on the legs but also on the abdomen, chest, arms, and scalp. These erythematous, edematous, and sometimes painful lesions occur singly or in crops, and they can migrate. They may become fluctuant and ulcerate, discharging an oily material. 34 Panniculitis may also involve visceral fat, including the omentum and peritoneum. Associated findings include fever, abdominal pain, inflammatory polyarthritis, ascites, and pleural effusions. 34 Lesions may involute within a period of weeks, leaving hyperpigmented scars. There is considerable evidence that the enzymes lipase, amylase, and trypsin are involved in producing the lesions of pancreatic fat necrosis. 37 However, enzyme levels may not completely explain the changes of pancreatic panniculitis, 38 and it is likely that immunologic factors also play a role.
In acute pancreatitis, the panniculitis resolves as the acute inflammatory phase has passed. However, lesions may also persist and expand until the underlying pancreatic abnormality has been treated. Effective management of pancreatic panniculitis depends on treatment of the underlying pancreatic disease.

Microscopic Findings: Although pancreatic panniculitis may begin as a septal panniculitis, 9 with progression the lesion takes on the appearance of a lobular or mixed septal-lobular process. Even in early stages, fat necrosis with liquefaction and microcyst formation is apparent. 37 , 38 Lipocytes lose their nuclei and develop thick, shadowy walls, forming the characteristic “ghost cells” ( Fig. 7-9 ). Saponification of fat by calcium salts results in deposition of granular or homogeneous basophilic material ( Fig. 7-10 ). Neutrophils, occasional eosinophils, macrophages, and multinucleated giant cells are sometimes present and may encroach on the septa. Fibrosis and lipoatrophy are seen in late stages as the process resolves.


Figure 7-9 Pancreatic panniculitis. Note fat necrosis, formation of “ghost cells” with thick, shadowy walls, and adjacent neutrophilic inflammation.


Figure 7-10 Pancreatic panniculitis. Saponification of fat has resulted in deposition of homogeneous, basophilic material.

Differential Diagnosis: The histopathologic differential diagnosis includes erythema nodosum (in early stages), erythema induratum, traumatic panniculitis, infection-induced panniculitis, α 1 -antitrypsin deficiency panniculitis, and lupus panniculitis, but “ghost cell” formation or saponification of fat are not observed in those conditions. Lupus panniculitis is predominantly lymphoplasmacytic, may feature mucin deposition or overlying epidermal/dermal changes of lupus erythematosus, and shows eosinophilic hyaline necrosis that differs from the granular or homogeneous basophilic necrosis typical of pancreatic panniculitis.

Sclerema Neonatorum, Subcutaneous Fat Necrosis of the Newborn, and Poststeroid Panniculitis
Three dermatoses—sclerema neonatorum, subcutaneous fat necrosis of the newborn, and poststeroid panniculitis—are characterized by formation of needle-shaped clefts within lipocytes. The subcutaneous fat of infants, in contrast to that of adults, is prone to crystal formation because of a higher content of saturated fatty acids, including palmitic and stearic acids, and a relatively lower content of unsaturated fatty acids, such as oleic acid. 39 This increased saturated-to-unsaturated fatty acid ratio results in a higher melting point for stored fat and promotes crystallization under certain conditions. Microsized crystals (type A) apparently do not produce an inflammatory response, and they are actually common (in widely dispersed form) in healthy infants 6 months of age or younger but are numerous in sclerema neonatorum. Larger crystals (type B) that tend to be arranged in rosettes are capable of eliciting a granulomatous response; these crystal types are most often seen in subcutaneous fat necrosis of the newborn and poststeroid panniculitis. 39 , 40 Crystallization and defects in fat mobilization account for the clinical findings in these disorders.

Sclerema Neonatorum

Clinical Features: This disorder presents most often in premature infants, usually during the first week of life. There is a slight male predominance, with no substantial difference in death rates between the sexes. 41 The skin tends to be cold, pale, and waxy in consistency, with a livid, mottled discoloration. Virtually the entire body surface is involved except for the palms, soles, and genitalia. 42 Underlying conditions include hypothermia, respiratory difficulties, congestive heart failure, diarrhea, and intestinal obstruction. Death, often from septicemia, occurs in approximately three fourths of cases.
Low admission weight and temperature as well as hemorrhagic phenomena indicate a particularly poor prognosis. 41 Attempts to treat this disorder have generally been disappointing.

Microscopic Findings: Needle-shaped clefts occur within lipocytes in the subcutis; these structures are not as common within multinucleated giant cells. 42 Inflammation is usually sparse, but occasionally a few inflammatory cells may be evident ( Fig. 7-11 ). Some investigators have found no significant microscopic changes save for thickened connective tissue bands, 42 although this could be the result of either sampling error or variations in the timing of biopsies. The dermis may have an edematous appearance, and mucin deposition may be apparent. 39


Figure 7-11 Sclerema neonatorum. There are needle-shaped clefts within lipocytes. Only minimal inflammation is present.

Differential Diagnosis: In contrast to sclerema neonatorum, subcutaneous fat necrosis of the newborn is a more localized process with a generally favorable prognosis. Lesions of subcutaneous fat necrosis show a more prominent inflammatory infiltrate, and needle-shaped crystals in radial array are frequently evident within giant cells, whereas in biopsies of sclerema neonatorum, the dermis appears edematous, with increased amounts of mucin deposition.

Subcutaneous Fat Necrosis of the Newborn

Clinical Features: Subcutaneous fat necrosis occurs in newborn infants, often 2 to 3 weeks after birth. Smooth, circumscribed, mobile, red to violaceous, subcutaneous nodules or plaques develop, sometimes in symmetrical fashion. 39 , 43 Some cases are associated with hypercalcemia and may develop 1 to 4 months after the onset of the skin lesions. 44 Other cases may be associated with thrombocytopenia. It is believed that a variety of stresses imposed on fetal fat, with its high ratio of saturated to unsaturated fatty acid, can result in crystallization, adipocyte injury, and granulomatous inflammation. Hypothermia is one possible eliciting factor. The possible role of birth trauma has been questioned, because a number of cases have occurred in infants delivered by cesarean section. 43
It is believed that the hypercalcemia results from extrarenal mechanisms. 45 The mechanism for thrombocytopenia may be local sequestration of platelets in the subcutis, because studies have shown normal bone marrow findings and resolution of the platelet abnormality as the inflammatory process resolves. 46 Spontaneous resolution of lesions is the rule, sometimes leaving changes of lipoatrophy; however, some deaths have been reported. Many lesions resolve spontaneously; thus, the emphasis is on supportive care.

Microscopic Findings: There is a predominantly lobular panniculitis, with varying numbers of neutrophils, lymphocytes, macrophages, and multinucleated giant cells. Needle-shaped clefts, often in radial array, may be present both within lipocytes and in giant cells ( Fig. 7-12 ). The crystals are doubly refractile and stain with oil red O. Sometimes, needle-shaped clefts are absent in otherwise typical cases. Foci of calcification and areas of hemorrhage are also apparent. Eosinophilic granules sometimes occur within multinucleated giant cells; their origin is not entirely certain, but they may derive from degranulating eosinophils. 47 , 48


Figure 7-12 Subcutaneous fat necrosis of the newborn. There is a lobular panniculitis. Needle-shaped clefts can be identified in lipocytes and within multinucleated giant cells. The findings are quite similar in poststeroid panniculitis.

Differential Diagnosis: The extensive cutaneous involvement in sclerema neonatorum is usually distinguishable from the localized, self-limited process of subcutaneous fat necrosis, and, on biopsy, inflammation in sclerema is minimal. Poststeroid panniculitis is microscopically indistinguishable from subcutaneous fat necrosis, but it arises in a distinctive clinical setting (see subsequent discussion).

Poststeroid Panniculitis

Clinical Features: Patients who have developed poststeroid panniculitis have received corticosteroid therapy for a variety of conditions, including acute rheumatic fever. 49 This form of panniculitis occurs following rapid withdrawal of systemic corticosteroids, although the precise mechanism of is not known. Lesions develop within 1 to 40 days after corticosteroids are suddenly discontinued. 50 These subcutaneous nodules, which frequently form on the cheeks, arms, or trunk, may be small and discrete or large and confluent. Pruritus may be marked, as was the case in the original reported series, but lesions may also be tender or asymptomatic. The plaques disappear spontaneously over a period of months to a year. 50 , 51
Treatment is unnecessary, because spontaneous resolution is the rule. Surprisingly, lesions continue to resolve with readministration of corticosteroids. However, they can reappear if corticosteroids are again withdrawn too rapidly. 51

Microscopic Findings: Changes include a lobular panniculitis composed of lymphocytes, macrophages, and multinucleated giant cells. 50 Needle-shaped clefts, some with a “starburst” pattern, can be identified within lipocytes or giant cells.

Differential Diagnosis: Cold panniculitis (Haxthausen disease), including popsicle panniculitis, may have both clinical and microscopic similarities, but the history of cold exposure and the lack of needle-shaped clefts on biopsy permits distinction. The microscopic changes of poststeroid panniculitis are virtually identical to those of subcutaneous fat necrosis of the newborn. However, the clinical history should be decisive. In the absence of a history, findings such as calcification or hemorrhage are more suggestive of subcutaneous fat necrosis of the newborn.

Lupus Erythematosus Panniculitis (Lupus Profundus)


Clinical Features: Lupus panniculitis affects a small subset of all patients with lupus erythematosus. The condition predominates in adults but may also develop in younger patients. There is a predominance in women. 52 , 53 Lupus panniculitis consists of tender subcutaneous nodules and plaques that sometimes occur in crops. They tend to develop on the face, upper arms, or trunk; in fact, the lack of involvement of distal extremities is noteworthy. 53 The overlying skin varies from a pink-red color to the appearance of chronic cutaneous lupus erythematosus (CCLE) and may appear to be “tethered” to the subcutaneous nodule or plaque, creating a surface depression. Patients may have a history of trauma. The lesions have a chronic, relapsing clinical course.
Although lupus panniculitis often occurs prior to other manifestations of lupus erythematosus or in the absence of other inflammatory autoimmune diseases, manifestations of CCLE or systemic lupus erythematosus (SLE) can also occur before, or at the same time as, the panniculitis. 52 There appears to be a closer relationship of lupus panniculitis to CCLE than to SLE.
Clinical changes of CCLE can be identified in the skin overlying the panniculitis in about one third of cases 54 ; these include scaling, follicular plugging, atrophy, dyspigmentation, telangiectasias, and ulceration. A few patients meet the criteria for SLE, but most have less severe systemic manifestations, usually consisting of arthralgias or Raynaud phenomenon. It is common for patients to have low-titer antinuclear antibodies; they can also have other circulating autoantibodies (e.g., to double-stranded DNA or extractable nuclear antigen), leukopenia, hypocomplementemia, and elevated erythrocyte sedimentation rates. 55 , 56
In addition to potent topical and intralesional corticosteroids, antimalarials are frequently used to treat lupus panniculitis, resulting in improvement in most cases.

Microscopic Findings: Lupus panniculitis is a predominantly lobular process. It features an inflammatory infiltrate that can be sparse, patchy, or heavy. As in other forms of panniculitis associated with connective tissue disease, there is a marked predominance of lymphocytes, often with admixed or surrounding plasma cells ( Fig. 7-13 ). Nuclear dust is often prominent and some believe it can be diagnostically useful. 54 , 57 Nodular aggregates of lymphocytes are common ( Fig. 7-14 ), and well-formed lymphoid follicles with germinal centers are sometimes apparent. Granulomas can occur and tend to encroach on the septa, but they are usually not prominent. Other features include lymphocytic vasculitis, deposits of mucin or calcium, 55 and hyaline necrosis of fat lobules that sometimes extends into the septa. The subcutaneous findings alone are considered sufficiently characteristic to permit a diagnosis of lupus panniculitis in many instances. However, overlying epidermal or dermal changes of CCLE occur in half to two thirds of cases ( Fig. 7-15 ). 54 , 58 With direct immunofluorescence, it is possible to identify a positive lupus band in the overlying skin in a high percentage of cases, even in those where the epidermal-dermal histopathologic changes are nonspecific. 58


Figure 7-13 Lupus panniculitis. The subcutaneous infiltrate is composed mainly of lymphocytes and plasma cells. Cytologic atypia is minimal.


Figure 7-14 Lupus panniculitis. Nodular aggregate of lymphocytes is visible. Hyaline necrosis of fat lobules is also apparent.


Figure 7-15 Lupus panniculitis. In this case, there are overlying epidermal and dermal changes of lupus erythematosus, including epidermal atrophy and periappendageal infiltrates.

Differential Diagnosis: Lupus panniculitis most closely resembles morphea or dermatomyositis panniculitis, traumatic panniculitis, and localized lipoatrophy. Both morphea and lupus panniculitis can have lymphoid follicles, but these are more common in lupus panniculitis, and hyaline necrosis is not a feature of morphea panniculitis. 59 Traumatic panniculitis may show foreign material, a central nidus of subcutaneous inflammation, or “swiss cheese–like” vacuolated spaces or other evidence of extrinsic injury. Lipoatrophy can be an end stage of a variety of forms of panniculitis, including lupus panniculitis, but hyaline necrosis, lymphoplasmacytic predominance, and lymphoid follicle formation would be unusual in those cases not related to lupus. Overlying epidermal or dermal changes of lupus erythematosus, when present, can also be of great help in excluding other forms of panniculitis. The greatest concern in the differential diagnosis is the distinction of lupus panniculitis from subcutaneous panniculitis-like T-cell lymphoma (SPTCL); see later discussions on cytophagic histiocytic panniculitis and malignant subcutaneous infiltrates.

Panniculitis of Dermatomyositis


Clinical Features: Panniculitis is a rare but established clinical manifestation of dermatomyositis. However, microscopic involvement of subcutaneous fat without overt clinical features of panniculitis may be more common than generally recognized. Typically, these lesions manifest as indurated, painful plaques and nodules. Ulceration and lipodystrophy (lipoatrophy) may occur. 60 Spontaneous regression is uncommon. The plaques and nodules can arise in the setting of established dermatomyositis or can precede or follow other manifestations of the disease. 61
There is nothing particularly unique with regard to the other clinical and laboratory manifestations of dermatomyositis in patients who also have panniculitis, and the incidence of malignancy thus far is comparable to that for dermatomyositis without panniculitis. 60 Treatments include prednisone, methotrexate, azathioprine, cyclosporine A, and intravenous immunoglobulin. 60 , 62 , 63

Microscopic Findings: The panniculitis of dermatomyositis is usually of lobular or mixed septal-lobular type. Lymphocytes and plasma cells predominate, as in other forms of connective tissue panniculitis ( Fig. 7-16 ), and sometimes nodular lymphocytic aggregates may occur. Researchers have described lymphocytic vasculitis, and several reports have noted the existence of fat necrosis. 60 , 63 Membranocystic changes are evident in some cases (see discussion of Lipodermatosclerosis). Calcification is not always apparent, 64 , 65 but it would be an expected finding in those cases of dermatomyositis associated with calcinosis of deep soft tissues and skeletal muscle. 16 Reportedly, vacuolar alteration of the basilar layer of the overlying epidermis occurs, and the dermis may be edematous or mucinous, with perivascular lymphocytic inflammation. 66 Investigators have found that direct immunofluorescence is negative for deposits along the dermal-epidermal junction, although they have detected immunoreactants in vessel walls. 66


Figure 7-16 Panniculitis of dermatomyositis. There is a mixed septal-lobular panniculitis, composed mainly of lymphocytes.

Differential Diagnosis: Lupus panniculitis is more likely to show hyaline necrosis and lymphoid nodules, but to make a distinction, clinical and laboratory findings may be necessary. Overlying poikilodermatous changes can occur in both diseases, and both often show interstitial dermal mucin deposition. However, lupus is more likely to show appendageal involvement and is associated with positive basement membrane zone fluorescence on direct immunofluorescence.

Traumatic Panniculitis


Clinical Features: Extrinsic injury of varying types can produce panniculitis. Four broad categories represent the major causes of panniculitis due to trauma: cold panniculitis, sclerosing lipogranuloma, panniculitis due to injectable substances or other therapies, and panniculitis due to blunt trauma.
Infants and small children are most at risk for cold panniculitis. This is due in part to the higher ratio of saturated to unsaturated fatty acids, resulting in a higher solidification point of infantile fat. 67 Cold injury is also related to fluctuations in blood flow that occur with declining temperatures (the “hunting phenomenon”), ice crystal formation, and the changes that occur with thawing. 68 Also, a form of the disease occurs on the legs of young adult women who are equestrians. 69 Injections of oils (and their impurities) are known to produce subcutaneous inflammation. Substances include mineral oil (paraffin), camphor, cottonseed, and sesame oils. Medical-grade silicone may contain impurities, and, because encapsulation of this material is desirable when used for cosmetic purposes, fibrosis-inducing substances such as olive oil or castor oil are often added. 70 Sclerosing lipogranuloma of the male genitalia is seen mostly in young adults. 71 Panniculitis due to injections of other substances or blunt trauma can occur in persons of a wide range of ages and geographic locations. Panniculitis has been produced by numerous therapeutic agents, such as meperidine (pethidine), morphine, tetanus antitoxoid, pentazocine, phytonadione (phytomenadione), 72 povidone, 73 aurothioglucose, 74 interleukin-2, 75 and bovine collagen. 76 In forms of blunt trauma, granulomas contain material that may have been derived from breakdown of erythrocyte membranes. 77
In cold panniculitis, erythematous, firm nodules develop, particularly over the cheeks and chin. Lesions with a similar appearance occur in popsicle panniculitis. 67 , 68 In equestrian cold panniculitis, erythematous to violaceous, tender plaques arise on the thighs, following exposure to cold while wearing tight-fitting clothing. 69 In lipogranuloma, nodular, granulomatous, and sometimes migratory lesions can develop, accompanied by varying degrees of swelling, inflammation, abscess formation, lymphangitic spread, and fibrosis. 70 Sclerosing lipogranuloma often refers to lesions arising on the male genitalia, which are believed to result most often from self-injection of oily materials. There has also been a report of sclerosing lipogranuloma that apparently resulted from topical application of a vitamin E cream. 78 Patients with sclerosing lipogranuloma frequently deny injecting sites in the genital region, making diagnosis difficult. Another variant of lipogranuloma is the grease gun granuloma, which results from accidental firing of the grease gun used especially by mechanics. This leads to formation of a verrucous nodule that often involves the dorsum of the hand. 79 Inflamed nodules with varying degrees of pain and fibrosis are apparent in other forms of panniculitis due to injection, with the distribution of lesions sometimes providing a clue to their cause. One example is Texier disease, a panniculitis due to phytonadione (vitamin K) injection. In this disorder, sclerotic lesions with lilac-colored borders form around the buttocks and thighs, producing a resemblance to a “cowboy gunbelt and holster.” 72 A complication of a different form of therapy, radiation recall dermatitis, may present with infiltrative plaques in prior sites of radiation when patients have received forms of chemotherapy. Lesions due to blunt trauma often have an ecchymotic character and involve locations such as the arm or hand. 77
Treatment of all types of traumatic panniculitis mainly involves removal of the inciting agent, be it cold, an injectable substance, a therapeutic agent, or blunt trauma. Intralesional or systemic corticosteroids can be helpful in controlling inflammatory manifestations of these disorders. Surgery may also be an option for treatment of sclerosing lipogranuloma. 70

Microscopic Findings: Cold panniculitis consists of septal-lobular inflammation, especially along the dermal-subcutaneous junction and around adnexa. Cell types include neutrophils, lymphocytes, foamy macrophages, and poorly developed granulomas. Mucin deposition, fat cell necrosis, and microcyst formation are also apparent. In sclerosing lipogranuloma, nodular aggregates of lymphocytes, plasma cells, eosinophils, macrophages, or giant cells are often evident, but the most diagnostically significant findings are the numerous round or oval vacuoles of various sizes in the dermis and subcutis that produce a “swiss cheese–like” appearance ( Fig. 7-17 ). 71 It is possible to determine the presence of exogenous oils in these vacuoles using special stains. Grease gun granulomas often combine these features with overlying pseudoepitheliomatous hyperplasia. Panniculitis due to injection often displays a “central nidus” of subcutaneous inflammation ( Fig. 7-18 ), but in other respects the changes may vary depending on the nature of the injected substance. Phytonadione injections are accompanied by dermal-subcutaneous sclerosis and infiltration by lymphocytes and mast cells. Pentazocine injury features marked dermal and subcutaneous fibrosis, lipid-containing vacuoles, fat necrosis with foam cell formation, thrombosis of small vessels, and endarteritis. 80 Meperidine panniculitis shows patchy septal and lobular inflammation with necrosis and fibrosis, but massive granuloma formation or vasculitis is not observed. Povidone panniculitis shows focal hemorrhage, necrosis, and gray-blue material within macrophages on routine staining. 73 Lesions due to repeated blunt trauma demonstrate focal granulomas in addition to the expected blood breakdown products. 77 Postirradiation or radiation recall reactions show deep fibrosis and mixed inflammation that may include lymphocytes, plasma cells, histiocytes, or eosinophils. 81 , 82


Figure 7-17 Sclerosing lipogranuloma. Numerous vacuolated spaces accompany nodular aggregates of lymphocytes and macrophages.


Figure 7-18 Panniculitis due to an injectable substance. There is a central nidus of subcutaneous inflammation.

Differential Diagnosis: In cold panniculitis, the absence of needle-shaped clefts in lipocytes and location of the most intense inflammation near the dermal-subcutaneous interface help distinguish this condition from subcutaneous fat necrosis of the newborn. In sclerosing lipogranuloma and related lipogranulomas, the large vacuoles found in the dermis and subcutis are distinctive. If necessary, one can use special stains for exogenous lipids on frozen sections. Radiographs are sometimes useful for distinguishing lipogranulomas from silicone granulomas, because, of the two, only the latter are radio-opaque. 83 Infrared spectrophotometry identifies mineral oil in nonprocessed tissue. 79 It is possible to distinguish panniculitis due to injectable substances from primary forms of panniculitis by the presence in the former of significant dermal involvement or of foreign material that can be identified (often) by polarization microscopy. Cases with acute inflammation and necrosis may resemble infection-induced panniculitis, and, in fact, infection may accompany injection panniculitis; special stains and cultures for organisms are useful in this regard. Sclerosing traumatic panniculitis (e.g., due to phytonadione or pentazocine) may resemble morphea but would not be expected to present as a septal panniculitis. Finding organizing hematomas with deposition of iron pigments should raise the possibility of blunt trauma.

Lipodermatosclerosis


Clinical Features: Erythema, induration, and pigmentary changes have been known for many years to be associated with venous insufficiency. Because of the variety of clinical appearances and histopathologic findings that can occur at different stages of the disease process, investigators have introduced different diagnostic terms to explain the changes. In recent years, as the evolution of the disorder has become better understood, the various manifestations of this panniculitis have been consolidated under the headings of lipodermatosclerosis or sclerosing panniculitis. Most patients are women older than 40 years of age. In the acute phase of the disorder, pain, warmth, erythema, scale, and some induration occur, most often located over the medial lower leg above the malleolus. At this point, the changes are relatively diffuse. 84 In the chronic phase, marked sclerosis of the dermis and subcutis results in induration that is sharply demarcated from the adjacent normal skin. Hyperpigmentation due to hemosiderin deposition may also be present. These features give the affected leg the appearance of an inverted wine bottle. 85
In addition to chronic venous insufficiency, other contributing factors to lipodermatosclerosis include protein C and S deficiencies 86 and local stimulation of collagen synthesis. 84 Researchers have reported good therapeutic results in early disease with the anabolic steroid stanozolol. 87 Compression therapy is also helpful and may enhance the benefits of stanozolol. 84 Other suggested treatments include ultrasound, pentoxifylline, fasciotomy, and phlebectomy. Traditional anti-inflammatory therapies tend not to be effective. 88

Microscopic Findings: Early lesions show mid-lobular ischemic necrosis, a lymphocytic infiltrate in the septa that rims the fat lobules, degrees of capillary congestion and thrombosis, and hemorrhage with hemosiderin deposition. As the lesion progresses, septal thickening, hyaline sclerosis involving lipocytes, lipophage formation, and mixed inflammatory cell infiltrates occur. 88 Advanced lesions show marked septal sclerosis and membranocystic change in the face of markedly reduced inflammation. Membranocystic change, emphasized as a key feature in lipodermatosclerosis, 89 consists of thickened, undulating membranes that form cysts and papillary configurations ( Fig. 7-19 ). The membranes are believed to result from degenerated cell membranes of lipocytes and/or macrophages. The material making up the membranes is ceroid, an oxidation product of unsaturated fatty acids. 90 Researchers have demonstrated pericapillary fibrin in lesions of lipodermatosclerosis with phosphotungstic acid–hematoxylin stain or with immunofluorescent methods. 91 Dermal changes associated with chronic venous stasis are also evident. These include fibrosis, tortuous thick-walled veins, and superficial and deep perivascular inflammation ( Fig. 7-20 ). 88


Figure 7-19 Lipodermatosclerosis with membranocystic changes. Thickened membranes forming papillary projections are evident within cleftlike spaces in the subcutis.


Figure 7-20 Lipodermatosclerosis. This low-power view shows dermal sclerosis and perivascular inflammation.

Differential Diagnosis: As induration develops and progresses, differentiation from morphea and scleroderma may be necessary. In morphea, subcutaneous involvement is predominantly septal, and lipophagic and lipodystrophic changes are not as prominent as they are in lipodermatosclerosis. Membranocystic changes, when present, can be of great diagnostic help. However, readers should recognize that these findings can occur in a variety of other conditions, including lupus and dermatomyositis panniculitis, liposarcoma, erythema nodosum, and the pretibial pigmented patches of diabetes mellitus.

Infection-Induced Panniculitis


Clinical Features: It is well known that, on an immunologic basis, panniculitis can result from a distant focus of infection, a classic example being erythema nodosum. In addition, it is necessary to recognize that panniculitis can be directly induced by an infectious agent. This produces a variety of clinical and microscopic appearances, although there are some features that infection-induced lesions have in common, regardless of the etiologic agent. There appears to be no age, sex, or racial predilection in cases of infection-induced panniculitis. Many of these patients are immunosuppressed 10 , 92 or have a possible predisposing medical condition (e.g., diabetes mellitus). 93 Patients with panniculitis due to direct infection develop local swelling and erythema. One or more fluctuant nodules may ulcerate and drain. Lesions on the legs and feet are common, but sites of involvement may also include the gluteal region, abdomen, axillary area, arm, or hand. Underlying conditions have included diabetes mellitus, leukemias or solid tumors, connective tissue disease, acquired immunodeficiency syndrome, and organ transplantation. In this group of disorders, authorities consider infectious agents to be directly responsible for the panniculitis. Some of the reported microorganisms include gram-positive and gram-negative bacteria, 94 – 96 mycobacteria, 10 , 97 and fungi. The latter include dermatophytes, 98 “deep fungi,” 93 opportunistic fungi, 92 , 99 and Candida. 10 , 100 Involvement of the subcutis can result from direct inoculation or septicemia. Other potential modes of spread include transfascial from an enteric source, in the case of abdominal panniculitis, or through “persorption,” a mechanism by which Candida can migrate across intact endothelium from the gut to a subcutaneous site. 100 Immunosuppression is common, but not invariable, in individuals with infection-induced panniculitis, and it may explain a predisposition to this form of infection; however, there are clearly cases that appear to have occurred in immunocompetent individuals. 96
Treatment with appropriate antimicrobial therapy is indicated in cases of infection-induced panniculitis. Surgery may be indicated for isolated lesions caused by grain-forming bacteria or fungi, such as mycetoma or botryomycosis. 98

Microscopic Findings: Individual cases can mimic other primary forms of panniculitis. However, common changes include a frequently mixed septal-lobular panniculitis, neutrophilic infiltration, vascular proliferation, hemorrhage, and necrosis that involves lipocytes, inflammatory cells, and eccrine sweat coils ( Fig. 7-21 ). 10 In the rickettsial disease Q fever, there may be a “doughnut” granulomatous lobular panniculitis, in which fibrin and inflammatory cells form a ring around a central clear space; similar changes have been found in the liver and bone marrow in patients with Q fever. 101


Figure 7-21 Infection-induced panniculitis. In this example of bacterial panniculitis, there is mixed septal-lobular inflammation composed mainly of neutrophils. Vascular proliferation and hemorrhage are apparent.

Differential Diagnosis: The presence of fluctuant, ulcerating lesions may suggest pancreatic panniculitis, traumatic panniculitis, or α 1 -antitrypsin deficiency panniculitis. Clinical and laboratory data usually permit distinction. Traumatic panniculitis may also be accompanied by infection. Infection-induced panniculitis with predominantly septal involvement or with large-vessel vasculitis could be confused with acute erythema nodosum or erythema induratum, respectively. Special stains for organisms and cultures are keys to the diagnosis. One study found that special stains were positive for organisms in 14 of 15 cases. 10

Malignancy and Panniculitis or Panniculitis-like Subcutaneous Infiltration

Cytophagic Histiocytic Panniculitis


Clinical Features: Not surprisingly, initial reports of cytophagic histiocytic panniculitis (CHP) focused on the cytophagic activity demonstrated by large macrophages and on a possible relationship to forms of “malignant histiocytosis.” With the evolution of immunophenotyping and genetic techniques, it has become apparent that many cases are associated with lymphoma, particularly T-cell lymphoma. In fact, CHP may be part of a spectrum of disease that includes SPTCL. 102 , 103 At the same time, “benign” forms of CHP and fatal cases in which a diagnosis of lymphoma cannot be proven suggest that under certain circumstances, other factors may be capable of producing the lesions of cytophagic panniculitis. The diagnosis of CHP is currently in evolution.
CHP primarily affects young to middle-aged adults. 102 , 104 Patients develop flesh-colored to erythematous, sometimes painful subcutaneous nodules, or diffuse, ill-defined hemorrhagic plaques on the extremities and trunk. Ulceration or persistent drainage following biopsy can occur. 105 There may be few associated symptoms in those with benign forms of the disease (other than swelling and transient fever), and these cases tend to follow a chronic course. More fulminant forms of the disease are associated with persistent fever, hepatosplenomegaly, mucosal ulcers, serosal effusions, pancytopenia, intravascular coagulation, and liver failure. Hemorrhagic diathesis and death may ensue. 106
Accumulating evidence indicates that many patients with CHP have T-cell lymphoma. The relationship is particularly close with SPTCL, which has been listed as a unique type of cutaneous T-cell lymphoma by the World Health Organization–European Organization for Research and Treatment of Cancer. 107 These lymphomas have had either α/β or γ/δ phenotypes, although recently, researchers have grouped the latter with nonpanniculitic forms of γ/δ T-cell lymphoma as a single entity. 108 Morphologically similar tumors have expressed natural killer cell (CD56) phenotypes or have proven to be B-cell lymphomas. 103
Research has shown that other examples of CHP, both fatal and nonfatal, are not lymphomas. 109 , 110 Investigators have detected latent Epstein-Barr virus infection in SPTCL with hemophagocytosis but not in fatal or nonfatal cases of CHP without lymphoma. 111 Whatever the origin in a particular case, the cytophagic activity probably results from generation of cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-1β.
Treatment for CHP includes prednisone, cyclosporine A, dapsone, and combination chemotherapy. 102

Microscopic Findings: In CHP, there is a mixed septal-lobular panniculitis, sometimes with foci of fat necrosis. Lymphocytes tend to predominate, but there are also macrophages, neutrophils, and plasma cells. 105 , 112 Macrophages, some of them enlarged but not otherwise atypical, contain erythrocytes, lymphocytes, or karyorrhectic debris. These are often described as “bean bag cells” ( Fig. 7-22 ). 112 Atypical lymphoid cells are apparent in those cases associated with SPTCL ( Fig. 7-23 ), and immunophenotyping or gene rearrangement studies support a diagnosis of lymphoma. In rapidly progressive or fatal cases, cytophagic changes may be visible in other organs, including lymph nodes, spleen, liver, and bone marrow; changes in the bone marrow lead to pancytopenia. 112


Figure 7-22 Cytophagic histiocytic panniculitis. Large macrophages contain fragments of lymphocytes.


Figure 7-23 Panniculitic T-cell lymphoma. There are atypical lymphocytes, some of which appear to “rim” lipocytes and fat microcysts.

Differential Diagnosis: Biopsy is usually definitive, because of the characteristic feature of cytophagocytosis. More problematic is the question of whether a given patient with CHP has a lymphoma or a non-neoplastic disorder. Immunophenotyping and genotypic studies are helpful in this regard, but even in the face of negative results, an evolving lymphoma is still possible. 113

Malignant Subcutaneous Infiltrates
Malignant infiltrates may involve the subcutis, mimicking the clinical and microscopic appearance of panniculitis. The best known of these is SPTCL, where some, but not all, of them may demonstrate cytophagic features. As mentioned above, studies have also reported examples of subcutaneous B-cell lymphoma 114 and lymphoma with a natural killer cell phenotype. 115 , 116 Other lymphomas, leukemias, and metastatic solid tumors can sometimes infiltrate the subcutis. An unusual recent example is a case of melanophagic panniculitis that obscured foci of metastatic melanoma. 117 Detailed clinical information is obviously crucial in such cases. Histopathologic clues include the recognition of significant pleomorphism or monotony among infiltrating cells in the subcutis ( Fig. 7-24 ), infiltration between collagen bundles of the dermis or around adnexal structures, and supporting immunohistochemical studies. The diagnosis of SPTCL can be elusive. Researchers report examples that initially presented as nonspecific panniculitis with lipomembranous changes 118 or with interface dermatitis and other features suggesting lupus panniculitis . 119 A number of recent papers have emphasized the resemblance to lupus panniculitis, which is a significant diagnostic trap. Because panniculitic T-cell lymphoma has been accompanied by interface dermatitis, dermal mucin deposition, and even lupus-like direct immunofluorescence findings, differentiation requires careful attention to the histopathologic features (especially to cytologic atypia among infiltrating lymphocytes), correlation with other clinical and serologic findings, and gene rearrangement studies. 120 – 122 Even then, close monitoring of patients with apparent lupus panniculitis may be necessary to determine the course of the disease. 122


Figure 7-24 Lymphoma involving the subcutis, mimicking panniculitis. High-power examination shows that the infiltrate is primarily composed of markedly atypical lymphoid cells.

Other Considerations in the Diagnosis of Panniculitis
In the 1920s, Weber, Christian, and others described Weber-Christian disease , also known as “relapsing febrile nonsuppurative panniculitis.” Reportedly, it consists of recurrent subcutaneous nodules that heal with depression of the overlying skin. Involvement of perivisceral fat and systemic symptoms occur, sometimes with a fatal outcome. Microscopically, there are three phases, consisting of an acute neutrophilic lobular panniculitis, subacute adipocyte necrosis and foam cell formation, and chronic fibrosis. Unfortunately, these changes are recapitulated in a wide variety of forms of panniculitis and, therefore, must be considered nonspecific.
At least as early as the 1960s, some experts raised doubts about the existence of Weber-Christian disease as a specific nosologic entity. Subsequent studies, in which cases initially bearing this designation have subsequently been reclassified as erythema nodosum, lipodermatosclerosis, traumatic panniculitis, CHP, α 1 -antitrypsin deficiency panniculitis, or lupus panniculitis, support this view. 37 , 123 Although the term Weber-Christian disease is definitely of historic interest, most authorities recommend that it be abandoned in favor of more specific diagnostic entities.
In recent years, there have been reports of painful erythematous nodules occurring on the plantar surfaces of the feet, but also occasionally on the palms. 124 These lesions, designated plantar panniculitis (painful plantar erythema), are prone to occur in otherwise healthy children. Recurrences are common, but the disorder is self-limited and tends to respond to conservative therapies. Most reported examples show the microscopic features of neutrophilic eccrine hidradenitis, with aggregates of neutrophils around eccrine sweat coils, particularly the coiled portions of eccrine sweat ducts. 125 , 126 However, in contrast to chemotherapy-associated neutrophilic eccrine hidradenitis, syringosquamous metaplasia is not a feature in these cases. 125 Other tender plantar nodules have shown septal and lobular panniculitis with vasculitis. It is apparent that painful plantar erythema can be a manifestation of several forms of panniculitis (erythema nodosum, traumatic panniculitis, cold panniculitis) as well as vasculitis, urticaria, or neutrophilic eccrine hidradenitis.
Several crystal deposition diseases are associated with panniculitis. In calciphylaxis, calcium is deposited in small vessels of the subcutis (of arteriolar or lesser size), in association with fat necrosis and varying degrees of inflammation. In hyperuricemia (gout), sodium urate crystals can be deposited in the subcutis. Oxalosis (hyperoxaluria) occurs both as an autosomal recessive disorder, resulting from deficiency of one of two enzymes (alanine-glyoxylate aminotransferase or D-glycerate dehydrogenase), or as a secondary condition caused by chronic renal failure or long-term hemodialysis. 127 As a result, insoluble calcium oxalate is deposited in kidneys and other organs, including the skin. Cutaneous involvement presents in two ways: as miliary deposits on the fingers or palmar surfaces and as livedo reticularis with acrocyanosis. The latter is classically associated with primary oxalosis, but the author has observed livedo reticularis in secondary disease as well. Microscopically, deposits of birefringent crystals occur in the walls of subcutaneous vessels. Calcium oxalate crystals stain with alizarin red at pH 7.0 but not at pH 4.2, in contrast with calcium apatite and calcium carbonate, which stain at both pH levels. 127

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122. Pincus, LB, LeBoit, PE, McCalmont, TH, et al. Subcutaneous panniculitis-like T-cell lymphoma with overlapping clinicopathologic features of lupus erythematosus: coexistence of 2 entities? Am J Dermatopathol . 2009;31:520–526.
123. White, JW, Jr., Winkelmann, RK. Weber-Christian panniculitis: a review of 30 cases with this diagnosis. J Am Acad Dermatol . 1998;39:56–62.
124. Buezo, GF, Requena, L, Fraga Fernandez, J, et al. Idiopathic palmoplantar hidradenitis. Am J Dermatopathol . 1996;18:413–416.
125. Stahr, BJ, Cooper, PH, Caputo, RV. Idiopathic plantar hidradenitis: a neutrophilic eccrine hidradenitis occurring primarily in children. J Cutan Pathol . 1994;21:289–296.
126. Bartolo, E, Anes, I, Capitao-Mor, M, et al. Idiopathic plantar hidradenitis. J Eur Acad Dermatol Venereol . 1998;10:257–261.
127. Ohtake, N, Uchiyama, H, Furue, M, et al. Secondary cutaneous oxalosis: cutaneous deposition of calcium oxalate dihydrate after long-term hemodialysis. J Am Acad Dermatol . 1994;31:368–372.
8
Connective Tissue Disorders


Lupus Erythematosus 
Dermatomyositis 
Sclerosing Conditions of the Skin 

Morphea and Scleroderma 
Atrophoderma of Pasini and Pierini 
Eosinophilic Fasciitis 
Nephrogenic Systemic Fibrosis 
Rheumatoid Arthritis 
As used in this chapter, the term connective tissue disorders refers to a set of diseases that are characterized by autoimmune phenomena affecting connective tissues—specifically, collagen and mucopolysaccharides (glycosaminoglycans). However, several of these conditions, particularly lupus erythematosus (LE) and dermatomyositis, can also have a significant impact on the epidermis or adnexal epithelia.
Among the entities to be discussed, LE and its variants are considered most frequently in the day-to-day practice of dermatopathology, probably because their protean histopathologic manifestations are capable of mimicking a wide variety of inflammatory conditions. This situation has been exacerbated to some extent by the recognition of a “tumid” form of LE (its relationship to lymphocytic infiltration of Jessner is discussed later in this chapter) and by the increasing number of cases of drug-induced LE involving the skin. Morphea is the other disorder in this group that commonly arises in discussions of differential diagnosis, because thickening or sclerosis of dermal collagen can result from a variety of unrelated conditions. The differential diagnosis of morphea also includes two other conditions: scleroderma and a cutaneous enigma, atrophoderma of Pasini and Pierini. Dermatomyositis can bear a close resemblance to LE and can share with it the constellation of findings known as poikiloderma atrophicans vasculare. Mixed connective tissue disease is well-defined immunologically but can have overlapping features of LE, dermatomyositis, and scleroderma; at the same time, there are less well-defined overlap connective tissue disorders that defy accurate classification. Although rheumatoid arthritis is generally considered to reside within the province of rheumatology, it has substantial cutaneous findings that deserve separate treatment.
It should also be mentioned that some unique manifestations of these disorders are discussed in other chapters: for example, bullous LE, lupus panniculitis, and interstitial granulomatous dermatitis. The latter form of dermatitis, a manifestation particularly of rheumatoid arthritis, may be associated with other systemic disorders and certain medications.

Lupus Erythematosus


Clinical Features
Cutaneous involvement with LE can show wide morphologic variability. Skin findings can certainly be found in systemic and neonatal LE but are also encountered in more limited forms of the disease, particularly discoid LE (including hypertrophic varieties) and subacute cutaneous LE. Bullous LE is usually associated with systemic disease, whereas lupus panniculitis is often either unassociated with other manifestations of the disorder or found together with discoid LE. See Chapters 4 and 7 for details about these forms of the disease. Vascular complications of LE manifest as perniosis or as thrombotic lesions in the antiphospholipid antibody syndrome; these conditions are discussed further in Chapter 5 . Tumid lupus is a problematic category that will be considered separately. Finally, consideration will be given to the important category of drug-induced LE.
Discoid LE in many ways constitutes the prototypical lesion of cutaneous LE and often serves as the basis of comparison for potential LE lesions, both clinically and microscopically. Many patients develop only localized discoid lesions, particularly over the scalp, face, and ears (especially the concha and external auditory canals). However, generalized lesions of discoid LE can occur, and patients so affected are more likely to have serologic abnormalities than those with localized disease. Discoid lesions can also develop in patients with systemic LE, but progression from strictly cutaneous disease to systemic LE is quite uncommon. The lesions show varying degrees of erythema, sometimes with perifollicular accentuation and hyperkeratosis. When peeling the scale, keratotic spines representing follicular hyperkeratosis can be seen on the undersurface of the scale, the so-called “carpet tacking” sign. Eventually, lesions develop scarring and dyspigmentation. Scalp involvement can result in significant alopecia. Some lesions of discoid LE have hypertrophic characteristics, producing a resemblance to verrucae or hypertrophic lichen planus. Squamous cell carcinomas can develop in lesions of long duration.
Described by Sontheimer and colleagues in 1979, 1 subacute cutaneous LE is seen most frequently in young women. It occurs as erythematous, scaly, annular or polycyclic lesions that most often arise on the head and neck, trunk, and arms. A photosensitive component is usually evident. Although joint symptoms and sometimes leukopenia are noted, severe systemic disease (including central nervous system or renal disease) is uncommon. Antinuclear antibodies and antibodies to Ro/SSA and/or LA/SSB are frequently positive. Deficiencies of C4 and C2 are accompanied by disease closely resembling, if not identical to, subacute cutaneous LE. Treatments include antimalarial therapy and rigorous sun protection. Drug-induced LE with clinical characteristics of subacute cutaneous LE is encountered with increasing frequency (see subsequent discussion).
Systemic LE, often seen in young women, can include thrombotic complications, myocarditis, renal involvement that can lead to chronic renal insufficiency, or central nervous system complications. Initiation or flare of the disease can follow intense ultraviolet (sunlight) exposure. The American College of Rheumatology criteria for systemic LE, slightly modified, are listed in Table 8-1 . The presence of four or more of these criteria, simultaneously or serially, support the diagnosis.

Table 8-1
The American College of Rheumatology Criteria for Systemic Lupus Erythematosus 1 Malar rash Fixed, flat, or raised erythema 2 Discoid rash Erythematous patches with keratotic scale, follicular plugging, possible scarring 3 Photosensitivity Exposure to ultraviolet light causes rash 4 Oral ulcers Includes nasopharyngeal ulcers 5 Arthritis Nonerosive; two or more peripheral joints 6 Serositis Pleuritis or pericarditis 7 Renal disorder Proteinuria >0.5 g/day or casts 8 Neurologic disorder Seizures; psychosis 9 Hematologic disorder Hemolytic anemia, leukopenia, thrombocytopenia 10 Immunologic disorder Antibodies: anti-dsDNA, anti-Sm, antiphospholipid 11 Antinuclear antibody Abnormal titer; not explainable by drug
Modified from Petri M. Review of classification criteria for systemic lupus erythematosus. Rheum Dis Clin North Am . 2005;31(2):245-254.
The importance of cutaneous involvement in the diagnosis is underscored by the fact that the first four of these criteria involve mucocutaneous findings. Erythematous patches, including the well-known malar erythema, constitute the “unique” cutaneous lesions of systemic LE. However, a significant proportion of patients may have typical discoid lesions, and a similar proportion may have no skin lesions at all. Homozygous C4A and C4B deficiency can also be accompanied by cutaneous and renal manifestations of systemic LE. Neonatal LE can present with annular, telangiectatic, erythematous lesions that eventually develop atrophy and variegated pigmentation. Congenital heart block is among the major complications, and antibodies to Ro/SSA are frequent.
Annular lesions resembling those of erythema multiforme can occur in LE, especially (but not exclusively) in the setting of systemic disease. Occasionally, there may be significant epidermal necrosis, producing changes resembling the Stevens-Johnson variant of toxic epidermal necrolysis. 2 This phenomenon has been termed Rowell syndrome , and it is associated with speckled antinuclear antibodies, anti-La antibodies, and positive rheumatoid factor. 3 , 4
Tumid LE typically consists of erythematous plaques over the head and neck and upper trunk. This variant sometimes accompanies discoid or systemic LE, but it may occur without other obvious cutaneous or systemic changes of LE and may lack serologic abnormalities. Therefore, diagnosis can be particularly challenging (see differential diagnosis). Mucinous papules and nodules also occur, often in the setting of chronic cutaneous disease, and some consider these to represent a variant form of tumid LE. Lymphocytic infiltration of Jessner has long been problematic in that for quite some time it retained the status of a distinct entity while suspicion remained that it may be a variant form of LE. Now, the prevailing view is that it is indeed a form of LE, probably fitting within the tumid LE spectrum. Lesions consist of persistent erythematous papules and plaques that predominately involve the face and upper trunk. Other clinical or serologic evidence of LE is typically lacking. However, much like more typical forms of cutaneous LE, lesions are often responsive to antimalarial therapy. A similarly problematic condition is called reticular erythematous mucinosis. This disorder also shows considerable overlap with, and may represent another clinical form of, tumid lupus. It is a photosensitive disorder that presents with erythematous papules and plaques, most commonly (but not exclusively) on the trunk, sometimes producing a reticulated configuration. Lesions are responsive to antimalarial therapy.
Drug-induced LE was formerly associated most closely with systemic disease—fever, arthralgia, pleuritis, and pericarditis—but uncommonly with cutaneous lesions, a combination seen with hydralazine, procainamide, and isoniazid. However, in recent years, there have been numerous cases of drug-induced LE with the clinical features of subacute cutaneous LE. Inciting agents include hydrochlorothiazide, calcium channel blockers, angiotensin-converting enzyme inhibitors, anticonvulsants, penicillamine, and statin agents. The tumor necrosis factor receptor antagonist etanercept has been associated with both classic drug-induced LE and the variant resembling subacute cutaneous LE. Discontinuation of the drug in question is the definitive treatment, but often this must be supplemented by sunlight avoidance, topical corticosteroids, or antimalarial therapy. Patients with drug-induced LE may have positive antinuclear, antihistone, and anti–single-stranded DNA antibodies, and those cases associated with subacute cutaneous LE lesions may also have antibodies to Ro/SSA.
Mixed connective tissue disease is a disorder that combines features of scleroderma, systemic LE, and dermatomyositis, and it is associated with high-titer antiribonucleoprotein (anti-RNP) antibodies and a particulate antinuclear antibody pattern. The principal clinical features include arthralgia and nondeforming arthritis, Raynaud phenomenon, esophageal dysmotility, polymyositis, and restrictive lung disease. There is a low incidence of central nervous system or renal disease. Cutaneous findings have included focal and diffuse nonscarring alopecia, pigmentation abnormalities, swollen hands, and changes of chronic cutaneous (or discoid) LE. 5 , 6 Mixed connective tissue disease tends to be fully responsive to corticosteroid therapy.

Microscopic Findings
Discoid LE typically shows a constellation of features that includes hyperkeratosis, follicular plugging, epidermal atrophy, vacuolar alteration of the basilar layer with formation of apoptotic bodies (Civatte bodies), thickening of the basement membrane zone, a perivascular and periappendageal infiltrate composed mainly of lymphocytes, vasodilatation, and dermal edema or interstitial mucin deposition ( Fig. 8-1 ). As might be expected, these findings are not always present and may be expressed in varying degrees or not at all. To some extent, their appearance depends on the age of the lesion and where the biopsy is obtained. Hyperkeratosis is usually compact and of the orthokeratotic type; parakeratosis tends not to be a prominent feature. When present, hyperkeratosis extends into dilated follicular orifices—the microscopic equivalent of the “carpet tacking” sign ( Fig. 8-2 ). Epidermal atrophy may be extreme or subtle and focal. At times, marked acanthosis can occur in hypertrophic lesions of LE. Basement membrane zone thickening is most apparent in lesions of 6 months’ duration or more. It presents as thick, eosinophilic subepidermal deposits that have a cuticular or shaggy appearance. Perivascular, perifollicular, and perieccrine infiltrates are usually evident. The intensity of these infiltrates can vary, but at times there is a sufficiently heavy and deeply extending infiltrate to raise concerns about cutaneous lymphoma. Involved follicular units typically show vacuolar alteration of the basilar layer of their outer root sheaths, and there may be thinning of lateral follicular walls, analogous to the epidermal atrophy (see Fig. 8-2 ). Perieccrine infiltrates can assume particular diagnostic importance ( Fig. 8-3 ), because numerous disorders show perifollicular inflammation but the number of disorders that demonstrate targeted perieccrine infiltrates is limited. Dermal infiltrates are composed mainly of lymphocytes with a few macrophages. Some experts have denied the presence of plasma cells in these lesions, but in the author’s experience, plasma cells can definitely be identified in some cases, and they are certainly present in those discoid lesions associated with underlying lupus panniculitis. Dermal edema can be present, but the apparent edema is usually accompanied by interstitial mucin deposition. Dermal scarring may develop in long-standing lesions. Special stains that can be helpful include periodic acid–Schiff, which can highlight basement membrane zone thickening, and mucin stains such as colloidal iron or Alcian blue, which show increased amounts of interstitial dermal mucin.


Figure 8-1 Discoid lupus erythematosus. This low-power view of a punch biopsy shows follicular plugging, epidermal atrophy, and a moderately intense perivascular and periappendageal infiltrate.


Figure 8-2 Discoid lupus erythematosus. Hyperkeratosis with follicular plugging, epidermal atrophy, vacuolar alteration of the basilar layer, and patchy dermal inflammation is present. Thinning of the lateral follicular wall is evident, and some basement membrane zone thickening can be seen on the left side of the figure. There is parakeratosis in this particular example.


Figure 8-3 Discoid lupus erythematosus. Perieccrine infiltrates have particular diagnostic importance in this disorder.
The microscopic findings in subacute cutaneous LE are quite similar to those of discoid LE. In an early study comparing the histopathologic characteristics of the two lesions, discrimination was possible in 82% of cases. 7 In that study, discoid lesions tended to have greater degrees of hyperkeratosis, follicular plugging, basement membrane zone thickening, and deep inflammation, whereas subacute cutaneous LE lesions tended to show more epidermal atrophy ( Fig. 8-4 ). David-Bajar and associates also noted that dermal infiltrates tended to be denser and deeper in discoid LE. 8 On the other hand, Jerdan and coworkers emphasized the significant histopathologic overlap of the two lesions, making discrimination on purely microscopic grounds quite difficult. Furthermore, with multivariate regression analysis of the various histologic variables, only pilosebaceous atrophy proved to be a significant predictor of discoid LE over subacute cutaneous LE. 9


Figure 8-4 Subacute cutaneous lupus erythematosus. Epidermal atrophy and a perivascular lymphocytic infiltrate are present. The degree of hyperkeratosis and follicular plugging expected in discoid lesions is generally not seen in this form of the disease, and dermal inflammatory infiltrates tend to be less dense and not as deep. The intense basophilia of the dermis apparent in this case is mainly due to marked solar elastosis.
The microscopic changes in nondiscoid lesions of systemic LE—that is, the erythematous patches—can be particularly subtle, and they typically include vacuolar alteration of the basilar layer; edema and/or mucin deposition in the dermis; a mild perivascular lymphocytic infiltrate in the superficial dermis; and fibrin deposits on collagen bundles, around some vessels, and in the basement membrane zone. Persistent lesions can assume the features of poikiloderma atrophicans vasculare ( Fig. 8-5 ). Neonatal LE has findings that closely resemble systemic LE or some examples of subacute cutaneous LE in adults ( Fig. 8-6 ). The microscopic findings in lesions of Rowell syndrome can closely resemble those of erythema multiforme, often yielding the latter diagnosis in the absence of clinical data ( Fig. 8-7 ).


Figure 8-5 Cutaneous lesion of systemic lupus erythematosus. Note marked epidermal atrophy, vacuolar alteration of the basilar layer with formation of apoptotic bodies, dermal edema, and subtle fibrin deposits around small papillary dermal vessels.


Figure 8-6 Neonatal lupus erythematosus. This example shows changes resembling subacute cutaneous and discoid lupus erythematosus, in that there are epidermal atrophy, follicular plugging, and thinning of lateral follicular walls.


Figure 8-7 Rowell syndrome. Apoptotic keratinocytes are evident at all levels of the epidermis in the left portion of the image, and confluent keratinocyte necrosis is present in the right side of the image. Vacuolar alteration of the basilar layer has led to subepidermal separation, and there is only a sparse superficial dermal inflammatory infiltrate. These changes are suggestive of a severe variant of erythema multiforme.
Tumid LE, including both the papulonodular and plaque varieties, shows considerable dermal edema and interstitial mucin deposition, confirmatory with mucin stains such as colloidal iron, and perivascular and periadnexal dermal infiltrates of varying intensity. Epidermal changes are minimal ( Fig. 8-8 ), and because serologic abnormalities may not be detected in this variant, differential diagnosis may be extremely difficult. This microscopic description also applies to lesions that have been designated lymphocytic infiltration of Jessner ( Fig. 8-9 ). Some advocates for maintaining lymphocytic infiltration of Jessner as a distinct entity refer to a study in which most cases of the latter showed a predominance of CD8-positive, cytotoxic (although polyclonal) T cells, 10 in contrast to tumid lupus, which has shown a predominance of CD4-positive helper T cells. 11 Here the operative word is most ; most, but not all, cases of lymphocytic infiltration of Jessner showed CD8 predominance. Furthermore, it is not clear that any attempt was made to differentiate between the two when selecting cases for inclusion in these studies. Microscopic findings of reticular erythematous mucinosis include an essentially normal epidermis, interstitial dermal mucin deposition, and a superficial to mid-dermal perivascular infiltrate that may be found adjacent to follicles and eccrine sweat glands ( Fig. 8-10 ). Serologic studies suggesting LE are typically negative, but reportedly a few cases evolve into a picture of LE.


Figure 8-8 Tumid lupus erythematosus. A, The epidermis is essentially normal, although with a slight hint of follicular plugging. Extensive dermal mucin deposition is evident, but inflammation is slight. B, In this example, mucin deposition is again evident, but there is also more substantial perivascular inflammation. Perieccrine inflammation can also be seen around a segment of duct and a secretory coil in the lower left portion of the figure.


Figure 8-9 Lymphocytic infiltration of Jessner. Again, there are dermal mucin deposition and perivascular as well as periappendageal infiltrates. The intensity of inflammation can vary in these lesions. A clear-cut microscopic distinction from tumid lupus erythematosus is not possible.


Figure 8-10 Reticular erythematous mucinosis. Findings include a normal epidermis, dermal mucin deposition, and a superficial to mid-dermal inflammatory infiltrate around vessels and appendages.
Lesions of drug-induced LE often have microscopic as well as clinical characteristics of subacute cutaneous LE. Eosinophils can be present in drug-induced lesions, but in the author’s experience they are not always found in drug-induced cases, while at the same time they can occasionally be encountered in examples of LE not associated with drugs.
Lupus-like lesions that occur in mixed connective tissue disease have the microscopic features of either discoid or subacute cutaneous LE but may also show vasculopathic alterations resembling those of dermatomyositis; these include reduced vascularity, vasodilatation, and or/thromboses in the superficial vascular plexus. 12 Edema and/or sclerodermoid changes may be apparent both in biopsies of swollen digits and in lupus-like cutaneous lesions. 12 , 13
Cutaneous manifestations associated with LE that are not listed here are discussed in other chapters. These include immune complex vasculitis (see Chapter 5 ), thrombotic complications associated with antiphospholipid antibody syndrome (see Chapter 5 ), lupus panniculitis (lupus profundus) (see Chapter 7 ), bullous LE (to be distinguished from the occasional instance of a subepidermal bulla arising in a preexisting lesion of cutaneous LE, related to extensive vacuolar alteration of the basilar layer) (see Chapter 4 ), and palisaded neutrophilic and granulomatous dermatitis (interstitial granulomatous dermatitis) (see Chapter 13 ). 14 – 16
Direct immunofluorescence (IF) study can often be helpful in establishing a diagnosis of LE. Positive results consist of a band of one or more immunoglobulins, sometimes combined with C3 complement and/or fibrin deposition, along the dermal-epidermal junction. These bands may be linear (thin or thick), granular, or shaggy ( Fig. 8-11 ). Thin linear bands resemble those of bullous pemphigoid and are often seen in association with bullous LE (see Chapter 4 , Fig. 4-26 ). Immunoglobulin M (IgM) deposition is most common but also of low specificity, particularly when found in isolation. IgG deposits are more specific and often found together with IgM. Specimens obtained from lesional skin have the highest yield of positive results and are therefore used for establishing the diagnosis of cutaneous LE. Biopsies from normal sun-exposed skin (e.g., forearm skin) have a lower yield but when positive are suggestive of systemic disease. This is technically the “lupus band” test often requested by internal medicine or rheumatology services. The specimen with the lowest yield is that obtained from normal non–sun-exposed skin, but a positive result in this case not only indicates systemic disease but also has an association with more severe forms of LE—for example, those with significant renal involvement. When performing a biopsy of lesional skin in an attempt to establish the diagnosis of LE, sampling of the active erythematous border of the lesion produces the best results; biopsy of a very early lesion, or on the other hand of an older, scarred lesion, is likely to produce a negative result. There may also be a high false-negative rate for IF biopsies obtained from lesions on the trunk. 17 A “lupus band” is typically not identified in forms of tumid LE, including those cases labeled lymphocytic infiltration of Jessner.


Figure 8-11 Lupus erythematosus, direct immunofluorescence, from a case of discoid lupus erythematosus. There are lumpy-bumpy (“shaggy”) deposits of immunoglobulin M along the basement membrane zone.
Some IF biopsies display an antinuclear antibody via staining of keratinocyte nuclei with antibody to IgG; this finding can be seen on indirect IF study, but occasionally also with direct IF (see Chapter 4 , Fig. 4-27 ). In mixed connective tissue disease, direct IF characteristically shows speckled staining of keratinocyte nuclei with anti-IgG; in addition, a “lupus band” can sometimes be identified along the dermal-epidermal junction. 5

Differential Diagnosis
A major consideration in the differential diagnosis is lichen planus. Ordinary lichen planus has a distinctive set of findings, which often make the diagnosis straightforward; these include hyperkeratosis, hypergranulosis that is often wedge-shaped, broad acanthosis, vacuolar alteration of the basilar layer producing a “saw-toothed” appearance of the epidermal base, numerous apoptotic keratinocytes near the junctional zone, and a bandlike infiltrate that appears to “hug” the epidermis and obscures the dermal-epidermal junction. However, a number of these features are also identified in LE: in particular, hyperkeratosis, vacuolar alteration of the basilar layer, and formation of apoptotic keratinocytes. Occasional examples of LE show a hypertrophic epidermis, which combined with the other changes can create a close resemblance to hypertrophic lichen planus. Lesions of lichen planopilaris, particularly in scalp biopsies, can be even more problematic, because they may display follicular plugging, a dense perifollicular infiltrate, and in later stages marked thinning of lateral follicular walls. Some cases with mixed features of lichen planus and cutaneous LE cannot be readily categorized and may require serial biopsies and long-term follow-up for accurate categorization. However, features that would tend to favor cutaneous LE include epidermal atrophy, a patchy and sometimes superficial and deep perivascular and periappendageal infiltrate, inflammation involving eccrine sweat coils, significant dermal mucin deposition, and sometimes evidence of panniculitis not directly associated with perifollicular inflammation. Direct IF study can be helpful, too, in that a “lupus band” is not identified in lichen planus, but instead there is a combination of clustered Civatte bodies in the papillary dermis staining positively for IgM and fibrin deposition along the dermal-epidermal junction. The finding of an elevated antinuclear antibody titer on routine testing, or of a positive antinuclear antibody with direct cutaneous IF, lends further support to the diagnosis of cutaneous LE.
LE can resemble other connective tissue diseases, particularly dermatomyositis and morphea and/or scleroderma. Systemic LE and (sometimes) subacute cutaneous LE can bear a particularly close microscopic resemblance to dermatomyositis. Both can show epidermal atrophy, vacuolar alteration of the basilar layer, and significant interstitial mucin deposition. Later, a bandlike subepidermal infiltrate can develop, producing the image of poikiloderma atrophicans vasculare. Hints of hyperkeratosis, follicular plugging, or a periadnexal component to the dermal infiltrate would tend to favor LE. Ordinarily, direct IF would be considered decisive, because only LE would be expected to have a band of immunoglobulin along the dermal-epidermal junction. However, false-negative studies are not unusual in LE, whereas according to one study, a small proportion of dermatomyositis cases can show a positive band test with staining for IgM, IgG, or C3. 18 The significance of the latter finding, however, could be questioned, because granular IgM and/or C3 deposition can be found in normal sun-exposed skin, particularly facial skin. Recent studies have suggested that plasmacytoid dendritic cells may play a role in the pathogenesis of both LE and dermatomyositis. McNiff and Kaplan 19 found that distribution of these cells, labeled by CD123, is different in the two disorders; the cells are preferentially located within the epidermis in dermatomyositis, but they are mainly in the dermis in LE. It is possible that the differing localization of these cells might be useful in the microscopic differential diagnosis of these two conditions. The histopathologist should consider several possible scenarios when faced with such a problematic biopsy: the lesion may represent only LE, or only dermatomyositis, or mixed connective tissue disease, or a less well-defined overlapping connective tissue disorder. Lesions of LE with overlapping features of morphea and/or scleroderma are not as common but have been reported, particularly in an unusual linear variant of LE. 20
The changes of poikiloderma atrophicans vasculare can also create diagnostic dilemmas. With onset early in life, lesions of congenital LE could show a close microscopic resemblance to those of poikiloderma congenitale (Rothmund-Thomson syndrome) or congenital telangiectatic erythema (Bloom syndrome). Other clinical and serologic findings and direct IF studies are key to ruling out these other uncommon syndromes. As an acquired dermatosis, changes of poikiloderma atrophicans vasculare can be seen in early, patch stage mycosis fungoides as well as in LE and dermatomyositis. Clinical information is essential, because the distribution of lesions would ordinarily be quite different in poikilodermatous mycosis fungoides, particularly when compared with poikilodermatous LE, which tends to appear in sun-exposed sites. Unfortunately, cytologic atypia of lymphocytes is often minimal in this stage of mycosis fungoides; however, finding lymphocytes with cerebriform nuclei, lining up along the basilar layer or migrating into the epidermis in the absence of spongiosis (“exocytosis without spongiosis”) would raise concern for mycosis fungoides, whereas interstitial dermal mucin deposition and superficial and deep perivascular and periadnexal inflammation would favor a diagnosis of LE.
LE also falls into the same differential diagnosis as a miscellaneous group of disorders characterized by superficial and deep dermal infiltrates. These are often grouped together mnemonically as the “5 Ls” (the letter “L” figures prominently in their names): l uetic disease (syphilis), polymorphic l ight eruption, l ymphoma or “pseudo l ymphoma” (lymphocytoma cutis, lymphadenosis benigna cutis), and l ymphocytic infiltrate of Jessner. As mentioned previously, the latter lesion is probably now best considered a form of tumid LE. Therefore, the chief diagnostic difficulty now lies in determining whether these tumid lesions truly fit in the LE spectrum.
A lichenoid tissue reaction pattern can certainly occur in syphilis, especially in secondary disease. In addition, perifollicular infiltrates can be identified and may even be a prominent finding in syphilitic alopecia (moth-eaten alopecia). On the other hand, plasma cells are more likely to be present than in LE, and certainly numerous plasma cells would be unexpected in LE. Inflammatory infiltrates in syphilis often tightly surround dermal vessels (“coat-sleeving” of vessels), while at the same time perieccrine inflammation is not a hallmark of this disease. Increased interstitial mucin deposition is also a helpful discriminating feature; this would be more commonly encountered in LE. Definitive diagnosis is made possible by the finding of spirochetes in tissue with silver stains (e.g., Warthin-Starry or Steiner and Steiner stains) or with immunohistochemistry using newer monoclonal antibodies. Direct IF with positive basement membrane immunoglobulin deposition would obviously favor LE. Serologic methods would be of additional help, as long as one remains aware of the possibility of biologic false-positive Venereal Disease Research Laboratory (VDRL) or fluorescent treponemal antibody, absorbed (FTA-ABS) studies in some cases of LE.
As is the case in LE, polymorphic light eruption is a photosensitive disorder that often first manifests in the spring of the year, with some diminution of intensity as the summer wears on. As the name implies, the clinical and microscopic findings can vary. However, in the author’s experience, interface dermatitis, with significant vacuolar alteration of the basilar layer, is not a feature of polymorphic light eruption, and the hyperkeratosis, follicular plugging, and basement membrane zone thickening apparent in some forms of LE do not occur. Pronounced dermal edema is often seen in polymorphic light eruption, but this is not generally accompanied by significant mucin deposition. Inflammatory infiltrates are primarily targeted toward vessels; inflammation adjacent to adnexa may be evident, but, in contrast to LE, infiltration of these structures is not observed and vacuolar alteration of basilar outer root sheath epithelium is not a feature. Direct IF study and serologic testing can be definitive in difficult cases.
Dense, superficial and deep dermal infiltrates may be apparent in discoid LE but also in lymphoma and lymphocytoma cutis. In some instances, cutaneous LE can also feature lymphoid follicle-like structures with germinal center formation, whereas interstitial dermal mucin can sometimes occur in cutaneous lymphomas. However, the typical epidermal changes of LE are not evident in these other disorders. Adnexal infiltration is not a feature of B-cell lymphomas. A folliculotropic T-cell lymphoma exists, but infiltration involving the full thickness of follicular epithelia is usually observed, sometimes with intrafollicular Pautrier microabscess formation or changes of follicular mucinosis. In LE, infiltrates are usually confined to the follicular-stromal interface and associated with vacuolar alteration of basilar outer root sheath epithelium and often with thinning of lateral follicular walls. Researchers have reported secondary follicular mucinosis in LE, but it is distinctly uncommon.
Lesions of tumid lupus, including those that may have received the designation lymphocytic infiltrate of Jessner or reticular erythematous mucinosis, typically lack the epidermal changes ordinarily associated with LE. Therefore, the varying combinations of atrophy, vacuolar alteration of the basilar layer, hyperkeratosis, and follicular plugging expected in other forms of LE are not evident. One is generally dependent on the constellation of dermal findings: perivascular and periadnexal lymphocytic infiltrates and interstitial dermal mucin deposition. The differential diagnosis of such lesions includes some conditions already mentioned, including polymorphic light eruption and, occasionally, lymphoma or lymphocytoma cutis. Additional disorders that might be considered include erythema annulare centrifugum, featuring superficial and deep, “coat-sleeved” inflammatory infiltrates; chronic urticaria, characterized by edema and a superficial and deep perivascular infiltrate of mild to moderate intensity; and scleredema, in which there is marked thickening of the dermis due to interstitial deposits of mucin. However, erythema annulare centrifugum lacks mucin deposition or periadnexal inflammation and may show some degree of overlying parakeratosis and spongiosis. Chronic urticaria is edematous but not mucinous, and targeted periadnexal inflammation is not a feature (occasionally, perivascular inflammation involving vessels near appendages may be confused with true periadnexal infiltration). Scleredema does show significant mucin deposition, but inflammation is typically sparse.
Finally, the marked acanthosis seen in some examples of hypertrophic LE can raise concerns for squamous cell carcinoma, and in fact carcinoma can develop in long-standing lesions of cutaneous LE. As in other similar circumstances, careful evaluation for malignant features (infiltration of connective tissue stroma, nuclear pleomorphism, cell necrosis, bizarre mitotic figures) is essential in distinguishing true squamous cell carcinoma from pseudoepitheliomatous hyperplasia. This may be a difficult task when small biopsies with sectioning or staining artifacts are submitted for evaluation; under such circumstances, submission of a larger specimen may provide the best solution.

Dermatomyositis


Clinical Features
Dermatomyositis combines the features of inflammatory disease of striated muscle with selected cutaneous findings. The same disorder of muscle in the absence of skin findings is termed polymyositis. There is also a group of patients who have characteristic cutaneous disease but lack skeletal muscle findings; the latter condition is termed dermatomyositis sine myositis . Furthermore, there may be elements of dermatomyositis in mixed connective tissue disease and other, less well-defined forms of overlapping connective tissue disease.
The etiology of this disorder is not completely understood but is thought to involve autoimmune phenomena. Microvascular injury occurs in the disease and may play a pathogenetic role. 21 IF studies have shown deposition of the membrane attack complex, C5b-9, in vessels and along the dermal-epidermal junction in skin lesions of dermatomyositis, 21 and increased serum levels of soluble vascular cell adhesion molecule-1 have been detected. 22 A causative role for infection by the endotheliotropic virus parvovirus B19 has been proposed in adults with dermatomyositis, and the B19 genome has been found in skin biopsy material from these patients. Drugs, such as terbinafine and hydroxyurea, have been associated with a dermatomyositis syndrome 23 , 24 ; these may play a role through their effects on endothelial cells or cytokines. 23 An association between dermatomyositis and malignancy has been reported in 15% to 25% of cases, 25 generally in older individuals. The neoplasms may precede, develop concurrently with, or follow the onset of dermatomyositis, and their frequency tends to mirror that of the general population. 26
The classic diagnostic criteria for dermatomyositis were set out by Bohan and Peter in 1975. 27 , 28 These are listed here in modified form:

1.  Symmetrical weakness of limb girdle muscles and anterior neck flexors, progressing over time with or without dysphagia or respiratory muscle involvement.
2.  Muscle biopsy evidence of necrosis of type 1 and 2 fibers, phagocytosis, regeneration with basophilia, large vesicular sarcolemmal nuclei and prominent nucleoli, atrophy in a perifascial distribution, and variation in fiber size and inflammatory exudate, often perivascular.
3.  Elevated muscle enzymes, especially creatine phosphokinase, aldolase, and lactate dehydrogenase.
4.  A triad of findings on electromyography: small polyphasic action potentials, positive sharp waves and insertional irritability, and bizarre high-frequency repetitive discharges.
5.  Dermatologic component: heliotrope eyelids with periorbital edema; scaly dermatitis over the dorsum of the hands, especially the proximal interphalangeal joints (Gottron papules); and involvement of the knees, elbows, medial malleoli, face, and upper torso.
A definite diagnosis of dermatomyositis is feasible when dermatitis is combined with three or four of the other criteria, probable when combined with two criteria, and possible when combined with one criterion. In addition, a rather unique set of autoantibodies occurs in patients with dermatomyositis. These may include one of the anti–aminoacyl-tRNA synthetases, the best known of which is anti-Jo-1 (histidyl-tRNA synthetase). This antibody has a high association with interstitial lung disease. 29
The major cutaneous manifestations include violaceous erythema and scale, sometimes accompanied by variegated pigmentation, telangiectasia, and atrophy; “heliotrope” eyelids; papules over the interphalangeal joints (Gottron papules); nail fold telangiectasias; and ragged-appearing cuticles (Samitz sign). Photosensitivity, with painful burning sensations, is frequently noted, and calcified plaques may occur. Panniculitis also occurs, either accompanying other inflammatory manifestations or independently; see Chapter 7 for details.
Treatments of dermatomyositis include prednisone and steroid-sparing agents, such as methotrexate, azathioprine, or mycophenolate mofetil. Cutaneous lesions are sometimes but not invariably improved with systemic therapy. Sunlight avoidance, liberal use of sunscreens, and antimalarial therapy can be useful in addressing cutaneous manifestations of the disease.

Microscopic Findings
The most typical presentation is that of a lichenoid tissue reaction, particularly with changes of poikiloderma atrophicans vasculare. Accordingly, the features include epidermal atrophy, vacuolar alteration of the basilar layer, vasodilatation, and pigmentary incontinence ( Fig. 8-12 ). Basement membrane zone thickening may also be evident. A superficial dermal perivascular lymphocytic infiltrate typically occurs but is usually mild. Dermal mucin deposition is often identified and may be extensive; this can be highlighted with various mucin stains, particularly colloidal iron and Alcian blue ( Fig. 8-13 ). 30 The dermal changes are quite similar in biopsies of Gottron papules. However, acanthosis or papillomatosis is common, and epidermal atrophy is rare ( Fig. 8-14 ). 31 Calcification can be observed in some lesions of dermatomyositis ( Fig. 8-15 ). Direct IF is usually negative for immunoglobulin deposition along the dermal-epidermal junction, although positive staining has occasionally occurred. 18 Generally, only scattered Civatte bodies stain positively for IgM or C3. However, staining of vessels or the dermal-epidermal junction for the membrane attack complex, C5b-9, is a characteristic feature of dermatomyositis. 21


Figure 8-12 Dermatomyositis. Vacuolar alteration of the basilar layer, dermal mucin deposition, and a perivascular (and, in this example, interstitial) lymphocytic infiltrate are evident.


Figure 8-13 Dermatomyositis. Alcian blue stain shows significant dermal mucin deposition. Vacuolar alteration of the basilar layer with pigmentary incontinence is evident.


Figure 8-14 Dermatomyositis, Gottron papule. The dermal findings are similar to other examples of dermatomyositis, but with hyperkeratosis and irregular acanthosis (appropriate for the location but somewhat exaggerated).


Figure 8-15 Dermatomyositis. Subcutaneous calcification has occurred in this example of dermatomyositis panniculitis.

Differential Diagnosis
The microscopic resemblance of poikilodermatous lesions of dermatomyositis to those of LE has been discussed previously. It must be acknowledged that the lesions can be sufficiently similar that distinction on histopathologic grounds may be impossible; then, to reach a correct diagnosis, additional clinical and serologic data are essential. It should further be pointed out that combinations of both conditions can be encountered in mixed connective tissue disease and other, less well-defined overlap disorders. When present, hyperkeratosis, follicular plugging, periadnexal infiltrates, and vacuolar alteration of outer root sheath epithelia with thinning of lateral follicular walls point to a diagnosis of LE. Direct IF study can be helpful, in that findings of a “lupus band” strongly favor LE, whereas deposition of C5b-9 (the membrane attack complex) in vessels and along the dermal-epidermal junction is most characteristic of dermatomyositis. In the study by Magro and Crowson, the best statistical predictor of dermatomyositis is the combination of a negative “lupus band” test; vascular C5b-9 deposition; and serologic studies showing negative antibodies to Ro, La, Sm (Smith antigen), and RNP. 21

Sclerosing Conditions of the Skin

Morphea and Scleroderma

Clinical Features
Both morphea and scleroderma are characterized by the formation of hardened, hidebound skin.
Morphea may develop in children or adults. It generally occurs as macules, plaques, linear bands, or guttate lesions, which may appear on the trunk or extremities. Lesions may be pink to violaceous at first, but as sclerosis develops they take on a white or ivory color and are surrounded by a lilac-colored border. In a given individual, lesions may remain localized or be disseminated. When sclerosis extends deep in the subcutis or involves fascia, the term morphea profunda is used. An uncommon bullous form of morphea has been described, and this has been linked to morphea profunda in several cases. 32 Even more extensive sclerosis may involve fascia, muscle, and sometimes underlying bone; this is known as pansclerotic morphea . Linear lesions are found in the extremities or frontal scalp and forehead; the latter is descriptively termed en coup de sabre . The effects of morphea are typically limited to the skin, although depending on the location and depth of involvement, the disorder may be accompanied by hemiatrophy or thickening of bone resembling “dripping candle wax” (melorheostosis). True transitions from morphea to systemic scleroderma are very rare; however, the two conditions can coexist in the same patient. 33 The cause of morphea is not completely understood. There is evidence for an association with Borrelia infection, particularly in material from Europe, but this has not proved to be the case in the United States. 34 , 35 Cytokines released by inflammatory cells promote collagen synthesis, 36 and inflammation near the dermal-subcutaneous interface is typical in early morphea. Fleischmajer and Nedwich actually suggested this mechanism a number of years ago. 37 Treatments for morphea have included calcitriol, topical calcipotriene, and psoralen and ultraviolet A (PUVA) therapy. El-Mofty and colleagues have explored the mechanism for phototherapy in this disease. 38
Scleroderma occurs in two forms. The CREST syndrome, characterized by calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectases with a matlike clinical appearance, occurring particularly over the digits, shows limited systemic involvement. In progressive systemic sclerosis, cutaneous sclerosis, sometimes with “salt and pepper” skin pigmentation, is associated with varying degrees of systemic involvement and affects the lungs (bilateral basilar pulmonary fibrosis), heart, or kidneys. Additional systemic therapies include calcium channel blockers and other vasodilating agents, cyclophosphamide, and methotrexate.

Microscopic Findings
In morphea and scleroderma, the microscopic changes are similar. In early examples of both lesions, there is a perivascular and interstitial lymphoplasmacytic infiltrate at the dermal-subcutaneous interface. This infiltrate tends to be heavier in morphea than in scleroderma. Lymphocytic inflammation, with variable numbers of plasma cells, is also evident between dermal collagen bundles and around vessels ( Fig. 8-16 ). Collagen bundles thicken and assume a hyalinized, smudged appearance. This results in punch biopsies having a distinctive “squared off” appearance. As noted in the chapter on panniculitis (see Chapter 7 ), there is often a septal panniculitis with thickening of subcutaneous septa due to inflammation and deposition of new collagen. Lymphoplasmacytic infiltrates in the subcutis may be fairly dense in morphea, and lymphoid follicles with germinal center formation can be apparent. As inflammation subsides, collagen in the dermis and subcutis becomes increasingly thickened and amorphous. Adnexal structures lose their surrounding adipose tissue, become encased (“entrapped”) in collagen, and eventually display atrophy. Eccrine sweat coils appear to be located higher in the dermis than usual ( Fig. 8-17 ). In late stages, follicular units may be lost. Changes of lipoatrophy are often identified in the subcutis. Sclerosis may extend from the septa into the superficial fascia in examples of morphea profunda. Papillary dermal edema is sometimes encountered, producing a resemblance to lichen sclerosus ( Fig. 8-18 ). A superficial variant of morphea also occurs, in which the sclerotic changes are concentrated in the upper reticular dermis; this too can create an image somewhat resembling lichen sclerosus. In scleroderma, inflammation tends to be milder in earlier lesions ( Fig. 8-19 ). In later stages, there may be thickening and hyalinization of vessel walls with partial luminal occlusion ( Fig. 8-20 ). 39 Direct IF study is typically negative in morphea. In scleroderma, an antinuclear antibody may be found in the keratinocytes in the face of antinucleolar or anticentromere antibodies, and basement membrane zone fluorescence is sometimes identified with antibodies to IgM. 40


Figure 8-16 Early morphea. There are perivascular and interstitial dermal inflammation, composed mainly of lymphocytes and a few plasma cells.


Figure 8-17 Morphea, advanced lesion. The dermal collagen is particularly thick and amorphous. Sweat coils are atrophic, encased in collagen, and appear to be located higher in the dermis than usual.


Figure 8-18 Morphea. In this example, there is pronounced papillary dermal edema, resembling lichen sclerosus, but there is also marked dermal thickening with atrophic, “entrapped” eccrine sweat coils (lower left of image). In contrast to lichen sclerosus, elastic tissue stains usually show preservation of elastic fibers in the edematous papillary dermal zone.


Figure 8-19 Scleroderma. This biopsy was obtained from a patient with systemic disease. Dermal sclerosis is evident, but inflammation is sparse. Note irregular dermal pigment deposition; dyspigmentation is common in these lesions.


Figure 8-20 Scleroderma. In this late-stage lesion, there is thickening of the wall of a subcutaneous vessel with narrowing of its lumen.

Differential Diagnosis
Virtually any situation associated with thickening of dermal collagen could create confusion with morphea or scleroderma. Apparent “smudging” of dermal collagen can be seen as “normal” background change in tissue sections from certain laboratories, probably an artifact of fixation or tissue handling. In this case, it is often clear from the history that a sclerosing condition is not a clinical concern. Dermis often appears thickened in biopsies obtained from the trunk—especially the back and abdomen—or from skin overlying large joints, such as the shoulders and hips. Knowledge of the site of biopsy is then important, and a search for characteristic inflammatory features or sweat gland “entrapment” is useful. Morphea and scleroderma can be difficult to distinguish from hypertrophic scar or keloid. Surgical scars tend to be well demarcated, with normal-appearing connective tissue outside the immediate scarred site. A lymphoplasmacellular infiltrate at the dermal-subcutaneous junction, a homogeneous appearance to the affected collagen, and the apparent “entrapment” of eccrine sweat coils would be features expected in morphea or scleroderma rather than scar. However, it should be pointed out that changes of keloid and hypertrophic scar can occur in morphea or scleroderma, in some cases manifesting as nodular lesions. 41 , 42 Other clinical or laboratory information may then be necessary to determine if scarring or keloidal changes are occurring in the setting of one of these disorders. Mizutani and colleagues have observed that tenascin expression in involved skin of morphea is at an intermediate level and tends to be long-lasting, whereas scarred lesions show marked but short-lived tenascin expression. 43 Late-stage radiation dermatitis can show swollen, hyalinized collagen bundles and loss of follicles, producing a resemblance to morphea. Changes that may suggest radiation injury include hyperkeratosis; variable acanthosis; and (sometimes) atypical keratinocyte nuclei, thick-walled vessels, with occlusion of their lumina, and bizarre radiation fibroblasts. Ischemic changes due to vessel occlusion, calciphylaxis, prolonged pressure, and/or ingestion of drugs such as barbiturates can result in a degenerated, amorphous appearance of dermal collagen, raising the possibility of morphea. In such cases, evidence of vessel occlusion and/or calcification, or necrosis of epidermis or eccrine sweat glands, should provide a clue to the true diagnosis. Lichen sclerosus can be mimicked by morphea; this is particularly the case when there is papillary dermal edema—or in examples of superficial morphea. However, only lichen sclerosus is likely to show hyperkeratosis, follicular plugging, or epidermal atrophy with vacuolar alteration of the basilar layer; often there is a mid-dermal, bandlike infiltrate. Elastic tissue stains (e.g., Verhoeff-van Gieson) can also provide a useful differentiating feature, in that elastic fibers are preserved in morphea, particularly in the papillary dermis, whereas they are diminished to absent in lichen sclerosus. 44 , 45 Nephrogenic systemic fibrosis is discussed in more detail subsequently. A history of chronic renal failure and hemodialysis is obtained in most cases. This condition also shows significant dermal thickening. However, rather than displaying homogeneous, smudged, amorphous collagen, these lesions show numerous spindled cells within the dermis and superficial subcutis, and there is often accompanying interstitial mucin; the image is therefore closer to lichen myxedematosus (scleromyxedema) than to morphea. In addition, prominent CD34-positive cells are observed in lesions of nephrogenic systemic fibrosis, whereas an absence of CD34 cells is typically noted in the involved foci in morphea. 45

Atrophoderma of Pasini and Pierini

Clinical Features
Atrophoderma of Pasini and Pierini is a problem disorder in that it is uncommonly observed, and although it has a fairly characteristic clinical appearance, it often shows nonspecific microscopic changes. Lesions are brown-gray in color, vary in size from small macules to larger patches, and are typically located on the trunk. They may be somewhat irregular in shape but are sharply demarcated from the adjacent, normal skin. This appearance creates an optical illusion that the lesions are depressed (the so-called “cliff drop” border), and in fact there may be a slight degree of true depression due to dermal atrophy. Atrophoderma is widely considered to be a variant of morphea, because the lesions bear some clinical resemblance to morphea, particularly in late stages, and are often seen in patients who have typical lesions of morphea elsewhere. A further link to morphea is the finding of serum antibodies to Borrelia burgdorferi in some patients with atrophoderma. 46 , 47

Microscopic Findings
The microscopic changes in atrophoderma are usually subtle, and a full appreciation requires comparison with adjacent normal skin. This can be accomplished either by an elliptical biopsy obtained through the edge of the lesion, with inking or placement of a suture to indicate which portion of the specimen represents “normal” tissue, or by two separate biopsies from involved and uninvolved skin. All biopsies should include subcutaneous fat. The epidermis is usually normal in appearance, but often basilar hypermelanosis and pigmentary incontinence are present. In early lesions, there is a superficial dermal, perivascular, and interstitial infiltrate composed mainly of lymphocytes, with macrophages and sometimes a few plasma cells. A heavier, deep dermal perivascular infiltrate may sometimes be visible. At this early stage, there is only slight thickening of collagen bundles in the mid to deep dermis, but in later stage lesions there is more pronounced thickening and homogenization of collagen in the deep dermis, and the overall thickness measurement of the dermis may be less than that of adjacent, uninvolved skin ( Fig. 8-21 ). The appendages are largely unaffected, and atrophy or “entrapment” of eccrine sweat coils is not observed. With elastic tissue stains, elastic fibers generally appear normal, although focal diminution, fragmentation, or clumping of these fibers may be evident. The author has not found assessments of elastic tissue changes or analysis of cell populations by immunohistochemistry to be helpful in the diagnosis of this disorder.


Figure 8-21 Atrophoderma of Pasini and Pierini. An elliptical specimen was obtained that encompassed both involved and uninvolved skin. A, The involved skin shows thickening and homogenization of dermal collagen. B, Homogenization of collagen is not apparent in the adjacent normal skin. The base of the photomicrograph is at the same level for parts A and B ; it is apparent that the subcutis is not yet visible in part B , reflecting the fact that the measurable dermal thickness is slightly greater in the uninvolved tissue.

Differential Diagnosis
Clinical correlation is essential in the diagnosis of atrophoderma; in its absence, the microscopic interpretation can be extremely difficult, especially in early disease, where the changes are quite mild and nonspecific. The slight degree of deep dermal sclerosis may be interpreted as a variant of normal or attributed to the usual truncal location of these lesions. A diagnosis of atrophoderma, or perhaps early morphea, may be suspected when normal adjacent skin is provided for comparison. However, the author has not seen changes or read descriptions of a septal lymphoplasmacytic panniculitis in atrophoderma—a frequent finding in early morphea. Serum antibodies to Borrelia are found in a minority of patients and are more likely to be found in Europe than in the United States.

Eosinophilic Fasciitis

Clinical Features
First described by Shulman, 48 this disorder can develop spontaneously or follow strenuous physical activity. Pain and swelling of the extremities is followed by marked induration. The affected limb often has a dimpled appearance, and linear grooves following the course of vessels can be identified. These changes are accompanied by peripheral eosinophilia and hypergammaglobulinemia. An association with morphea and scleroderma has been described, suggesting a relationship to those disorders. Nevertheless, changes of Raynaud phenomenon are infrequent, and other systemic signs and symptoms are usually not evident, although investigators have reported associations with disparate disorders such as polycythemia, 49 multiple myeloma, 50 and T-cell lymphoma. 51 , 52 Cases of eosinophilic fasciitis have accompanied so-called toxic oil syndrome, 53 and, in epidemic proportions, they occurred as a result of ingestion of contaminated L-tryptophan. 54 A characteristic of this disease is that it is often (but not invariably) exquisitely responsive to systemic corticosteroids.

Microscopic Findings
Diagnosis requires a sufficiently deep biopsy to include fascia. Despite this seemingly obvious fact, it is amazing how frequently biopsy material is submitted that is too superficial for full evaluation. The findings include edema or thickening of fascial connective tissue, accompanied by a patchy or diffuse lymphocytic, macrophagic, and plasmacytic inflammatory infiltrate. Eosinophils are not always readily evident and do not have to be present in order to make a diagnosis. Nevertheless, it has been the author’s experience that they are usually present, if not always in large numbers ( Fig. 8-22 ). It is possible that direct IF for major basic protein may reveal their presence even when they are not apparent on routine microscopy. Thickening of the overlying subcutaneous septa can also be observed, and this may extend to the level of the dermis. Immunohistochemical studies have shown a predominance of cytotoxic, CD8-positive T cells among the lymphocytes in the inflammatory infiltrates. 55


Figure 8-22 Eosinophilic fasciitis. There is thickening of fascial connective tissue. The inflammatory infiltrate includes lymphocytes, macrophages, and plasma cells. Eosinophils are numerous in this particular example.

Differential Diagnosis
The major considerations in the microscopic differential diagnosis are morphea or systemic scleroderma. The sclerosis of deep dermis and subcutaneous septa seen in eosinophilic fasciitis may also be present in morphea profunda or pansclerotic morphea. 56 Differentiation then depends on a determination of the “center of gravity” of the sclerotic changes and subcutaneous inflammatory infiltrates. Changes concentrated in the fascia, with extension superficially, favor eosinophilic fasciitis, whereas sclerosis focused in the deep dermis and subcutis, without significant fascial inflammation, would point toward a diagnosis of morphea.

Nephrogenic Systemic Fibrosis

Clinical Features
Nephrogenic systemic fibrosis (NSF), formerly known as “nephrogenic fibrosing dermopathy,” was first reported in The Lancet by Cowper and associates in 2000. 57 It is a sclerosing condition of the skin seen in patients with renal insufficiency, most, but not all, of whom have undergone hemodialysis. Thickening of the skin with formation of papules and plaques develops on both trunk and extremities, producing a clinical resemblance to the disease scleromyxedema. Underlying calcification sometimes occurs. 58 Reports of fibrosis of muscle, renal tubules, and rete testes indicate that NSF may be a systemic disease. 59 There is a strong association between the administration of gadolinium-containing contrast agents in the course of magnetic resonance contrast studies and the development of NSF; in fact, in some studies, no individuals developed the disease unless they had been exposed to this class of agents. 60 Several gadolinium-containing agents have been implicated, with gadodiamide being among the most common. 60 Presumably, dechelation of the administered contrast agent is likely to be associated with the induction of this disease, and therefore the choice of more stable agents might reduce the risk of NSF development. 60 Treatments that have worked include plasmapheresis, 61 photopheresis, 62 and intravenous immunoglobulin. 63

Microscopic Findings
There is marked thickening of the dermis, with thickened collagen bundles and interstitial mucin deposition. At low magnification, the dermis has a “busy” appearance because there are numerous spindled to dendritic cells ( Fig. 8-23 ). The changes extend into the subcutaneous septa ( Fig. 8-24 ). Interstitial mucin deposition can be demonstrated with special stains such as colloidal iron ( Fig. 8-25 ). CD34-positive cells are numerous, and their prominent dendritic processes align with or appear to surround collagen bundles ( Fig. 8-26 ). There are also numerous factor XIIIa–positive dendrocytes and CD68-positive macrophages. Subcutaneous calcification, either in diffuse distribution or in the walls of subcutaneous vessels, may sometimes be apparent. 58


Figure 8-23 Nephrogenic systemic fibrosis. The thickened dermis has a “busy” appearance due to the numerous spindled to dendritic cells. The bluish cast to the tissue has resulted from the presence of mucin.


Figure 8-24 Nephrogenic systemic fibrosis. Involvement of subcutaneous septa is apparent. The deeper dermal-subcutaneous involvement helps distinguish this condition microscopically from scleromyxedema, which it otherwise closely resembles.


Figure 8-25 Nephrogenic systemic fibrosis. Interstitial mucin deposition is demonstrable with colloidal iron staining.


Figure 8-26 Nephrogenic systemic fibrosis. Numerous CD34-positive dendritic cells appear to align with collagen bundles.

Differential Diagnosis
The microscopic features of NSF closely resemble those of scleromyxedema (see Chapter 11 for details). No truly reliable means of distinguishing these by traditional microscopy has yet been found, 64 although the connective tissue changes extend deeper into the dermis and subcutis in NSF than is usually the case in scleromyxedema. 65 The mucin deposition and prominent cellularity of NSF lesions create an image different from that of morphea. In addition, CD34-positive cells are diminished or absent in lesions of morphea and scleroderma 45 but are particularly prominent in NSF. Gadolinium can be detected and even quantified in the skin of NSF patients using a field emission scanning electron microscope equipped with energy-dispersive spectroscopy. 66 , 67

Rheumatoid Arthritis
Rheumatoid arthritis can have a variety of cutaneous manifestations, although it does not truly have a set of microscopic features that uniquely characterize the disease, as is the case, for example, for LE. Nevertheless, two particular changes feature prominently in rheumatoid skin lesions: presence of neutrophils and necrobiotic changes. Accordingly, cutaneous lesions of particular interest are leukocytoclastic vasculitis, rheumatoid neutrophilic dermatosis, interstitial granulomatous dermatitis (which combines neutrophilic infiltrates with degenerative changes of connective tissue), rheumatoid papules and nodules, and superficial ulcerating rheumatoid necrobiosis. Detailed information on these dermatoses appears in Chapters 5 and 13 .

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40. Kulthanan, K, Jiamton, S, Taiyaitiang, C, et al. Direct immunofluorescence study in Thai patients with scleroderma. J Med Assoc Thai . 2006;89:1670–1676.
41. Ling, TC, Herrick, AL, Andrew, SM, et al. Keloidal scleroderma. Clin Exp Dermatol . 2003;28:171–173.
42. Barzilai, A, Lyakhovitsky, A, Horowitz, A, et al. Keloid-like scleroderma. Am J Dermatopathol . 2003;25:327–330.
43. Mizutani, H, Taniguchi, H, Sakakura, T, et al. Nodular scleroderma: focally increased tenascin expression differing from that in the surrounding scleroderma skin. J Dermatol . 1995;22:267–271.
44. Rahbari, H. Histochemical differentiation of localized morphea-scleroderma and lichen sclerosus et atrophicus. J Cutan Pathol . 1989;16:342–347.
45. McNiff, JM, Glusac, EJ, Lazova, RZ, et al. Morphea limited to the superficial reticular dermis: an underrecognized histologic phenomenon. Am J Dermatopathol . 1999;21:315–319.
46. Wojas-Pelc, A, Wielowieyska-Szybinska, D, Kieltyka, A. [Presence of the antinuclear antibodies and antibodies to Borrelia burgdorferi among patients with morphea en plaque, deep linear scleroderma and atrophoderma Pasini-Pierini]. Przegl Lek . 2002;59:898–902. [[in Polish]].
47. Buechner, SA, Rufli, T. Atrophoderma of Pasini and Pierini. Clinical and histopathologic findings and antibodies to Borrelia burgdorferi in thirty-four patients. J Am Acad Dermatol . 1994;30:441–446.
48. Shulman, LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol . 1984;11:569–570.
49. Jacob, SE, Lodha, R, Cohen, JJ, Romanelli, P, Kirsner, RS. Paraneoplastic eosinophilic fasciitis: a case report. Rheumatol Int . 2003;23:262–264.
50. Khanna, D, Verity, A, Grossman, JM. Eosinophilic fasciitis with multiple myeloma: a new haematological association. Ann Rheum Dis . 2002;61:1111–1112.
51. Chan, LS, Hanson, CA, Cooper, KD. Concurrent eosinophilic fasciitis and cutaneous T-cell lymphoma. Eosinophilic fasciitis as a paraneoplastic syndrome of T-cell malignant neoplasms? Arch Dermatol . 1991;127:862–865.
52. Eklund, KK, Anttila, P, Leirisalo-Repo, M. Eosinophilic fasciitis, myositis and arthritis as early manifestations of peripheral T-cell lymphoma. Scand J Rheumatol . 2003;32:376–377.
53. Posada de la Paz, M, Alonso Gordo, JM, Castro Garcia, M, et al. Toxic oil syndrome, scleroderma, and eosinophilic fasciitis. Arthritis Rheum . 1984;27:1200.
54. Blackburn, WD, Jr. Eosinophilia myalgia syndrome. Semin Arthritis Rheum . 1997;26:788–793.
55. Toquet, C, Hamidou, MA, Renaudin, K, et al. In situ immunophenotype of the inflammatory infiltrate in eosinophilic fasciitis. J Rheumatol . 2003;30:1811–1815.
56. Doyle, JA, Ginsburg, WW. Eosinophilic fasciitis. Med Clin North Am . 1989;73:1157–1166.
57. Cowper, SE, Robin, HS, Steinberg, SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet . 2000;356:1000–1001.
58. Edsall, LC, English, JC, III., Teague, MW, et al. Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy. J Cutan Pathol . 2004;31:247–253.
59. Ting, WW, Stone, MS, Madison, KC, et al. Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol . 2003;139:903–906.
60. Cowper, SE. Gadolinium—is it to blame? J Cutan Pathol . 2008;35:520–522.
61. Baron, PW, Cantos, K, Hillebrand, DJ, et al. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol . 2003;25:204–209.
62. Mathur, K, Morris, S, Deighan, C, et al. Extracorporeal photopheresis improves nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: three case reports and review of literature. J Clin Apher . 2008;23:144–150.
63. Weiss, AS, Lucia, MS, Teitelbaum, I. A case of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Nat Clin Pract Nephrol . 2007;3:111–115.
64. Kucher, C, Xu, X, Pasha, T, et al. Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol . 2005;32:484–490.
65. Satter, EK, Metcalf, JS, Maize, JC. Can scleromyxedema be differentiated from nephrogenic fibrosing dermatopathy by the distribution of the infiltrate? J Cutan Pathol . 2006;33:756–759.
66. High, WA, Ayers, RA, Cowper, SE. Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol . 2007;56:710–712.
67. High, WA, Ayers, RA, Chandler, J, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol . 2007;56:21–26.
9
Metabolic Diseases


Amyloidosis 
Colloid Milium 
Porphyrias 
Calcinosis Cutis 
Oxalosis 
Gout 
Ochronosis 
Acanthosis Nigricans 
Xanthomas and Selected Lipid Storage Diseases 

Xanthomas 
Selected Lipid Storage Diseases 
Most of the conditions included in this chapter on metabolic diseases can be considered “deposition diseases,” because they are characterized by dermal deposits of substances that accumulate as the result of metabolic abnormalities. This certainly applies to amyloid, the periodic acid–Schiff (PAS)–positive basement membrane material in porphyria, calcium, sodium urate, calcium oxalate, and homogentisic acid. However, not all of these depositions result from systemic abnormalities; local changes in skin can promote some of these deposits in the absence of a generalized metabolic disorder. Examples include primary cutaneous amyloidosis, colloid milium, some forms of calcinosis cutis, and exogenous ochronosis. Each of these circumstances will be considered here. Acanthosis nigricans is one exception in which there are no cutaneous deposits, but instead metabolic changes promote epidermal growth that mimics the findings in epidermal nevi.

Amyloidosis


Clinical Features
Amyloidosis represents a group of conditions that have in common the deposition in tissue of an amorphous, eosinophilic material characterized by a cross–beta-pleated sheet structure. 1 , 2 This material gives the substance some of its characteristic staining properties. Amyloid (the term is actually based on an early, mistaken observation suggesting that it was a starchlike substance) is composed of a variety of precursor proteins that take on a fibrillar configuration, together with a glycoprotein known as amyloid P component, glycosaminoglycans, and apoE lipoprotein. 3 , 4 Thus, in primary systemic amyloidosis, the amyloid protein is AL, derived from immunoglobulin light chain. In secondary systemic amyloidosis, AA is derived from (apo) serum AA, an amyloid-associated protein synthesized by the liver. The amyloid associated with Alzheimer disease is Aβ, derived from Aβ precursor protein. 3 It is believed that in superficial forms of cutaneous amyloidosis, the amyloid is generally derived either from keratinocyte tonofilaments or other proteins secreted by basal keratinocytes, possibly combined with components of the epidermal basement membrane. 5 , 6 Although there can be cutaneous amyloid deposits in primary systemic amyloidosis, there is also a localized form of nodular cutaneous amyloidosis, in which the material is derived from locally produced (rather than systemically derived) immunoglobulin light chains. There is some evidence that macrophages and/or fibroblasts may be involved in localized amyloid formation. 7
Cutaneous amyloid deposition is encountered in several different situations: (1) as a primary localized disorder, either derived from keratinocytes (macular amyloidosis, lichen amyloidosus) or light chains (nodular amyloidosis); (2) as an incidental change occurring in keratinocyte-derived tumors, such as basal cell carcinoma ( Fig. 9-1 ), seborrheic keratosis, and trichoepithelioma (secondary localized cutaneous amyloidosis) 8 , 9 ; (3) or in connection with primary systemic amyloidosis, either as a clinical manifestation of the disease or as clinically inapparent deposits that can be exploited in establishing the diagnosis of primary systemic disease. Amyloidosis can also accompany chronic inflammatory diseases involving the skin (e.g., hidradenitis suppurativa) or rare heredofamilial disorders with cutaneous manifestations (e.g., urticaria, deafness, and amyloidosis—Muckle-Wells syndrome). An unusual condition characterized by deposition of amyloid material on elastic fibers was reported by Winkelmann and colleagues as amyloid elastosis 10 ; the author of this chapter also saw ultrastructural evidence for amyloid production, apparently derived from elastotic material, in a case he reported as nodular colloid degeneration. 11


Figure 9-1 Amyloid deposition within a nodule of basal cell carcinoma.
Macular amyloidosis presents as hyperpigmented macules, most commonly in the interscapular regions, although other portions of the trunk and extremities can be involved. The pigmentation is usually described as rippled in appearance, 12 but mottling 13 or swirling in the manner of incontinentia pigmenti 14 have also been described. There is typically a history of pruritus, and much evidence supports a role for rubbing and scratching, 15 although not all studies have been able to demonstrate this. 16 The common location of these lesions on the upper back, together with a history of dysesthesia accompanied by friction has suggested a relationship to notalgia paresthetica. 17 , 18 These lesions are persistent, although there has been some reported success in reducing the pigmentation through use of the Q-switched neodymium:yttrium aluminum garnet (Nd:YAG) laser. 19
In the condition lichen amyloidosus, there is also often a history of pruritus with chronic rubbing. Numerous close-set lichenoid papules develop, particularly in the pretibial areas, although these lesions can also form elsewhere on the extremities or the upper back. There may be some geographic variation in incidence; for example, lichen amyloidosis is relatively common in Taiwan. 20 There have been several reports of an association with Kimura disease. 21 A close link with macular amyloidosus has been proposed, 22 and it may well be that this condition consists of papillary dermal amyloid deposits accompanied by superimposed changes of lichen simplex chronicus. Treatments that are occasionally effective include narrow-band ultraviolet B, topical corticosteroids, 23 and acitretin. 24
Nodular amyloidosis, uncommonly encountered in clinical practice, consists of single or multiple nodules that tend to involve acral surfaces, although numerous other sites have been reported, including the face. The amyloid in this case is AL, derived from locally produced immunoglobulin light chains. There are numerous single case reports of an association with Sjögren sydrome. 25 Some studies have shown monoclonality of the infiltrating plasma cells. 26 , 27 Progression to systemic amyloidosis has been reported but appears to occur at a low rate, approximately 7%. 28 Surgical treatment is most commonly used, but other therapies include dermabrasion 29 and use of a pulsed dye laser. 30
Primary systemic amyloidosis, particularly associated with multiple myeloma, produces cutaneous manifestations in a substantial percentage of patients. Involvement of the heart, tongue, and gastrointestinal tract is particularly common in this form of amyloidosis. Skin lesions most often consist of waxy, flat-topped to dome-shaped papules that evolve into nodules and plaques. Lesions may have the appearance of blisters due to their translucent quality, and in addition, true bullous lesions do occur. The eyelids, nose, mouth, and mucocutaneous junctions are common locations. Purpura develops following trauma, and “pinch purpura” is a frequently cited cutaneous finding. Glossitis with macroglossia may also occur. Systemic findings include peripheral neuropathy, arthropathy, and cardiac arrhythmias. The amyloid material is derived from light chains, often of the lambda subtype, and in most cases light chains can be identified in the urine or serum. Prognosis is generally poor, and treatments include systemic chemotherapy and stem cell transplantation. 31 – 33

Microscopic Findings
Findings are similar in macular amyloidosis and lichen amyloidosis, in that both show amorphous, eosinophilic, and sometimes fissured deposits of amyloid in the dermal papillae. 22 The amount of deposition is variable in both conditions, but deposits are often smaller and usually more subtle in macular amyloidosis. Apoptotic (necrotic) keratinocytes can be seen in the vicinity, and the amyloid deposits are often associated with pigment incontinence. The findings in macular amyloidosis are so subtle that they can be easily missed; hence, this condition is often included among the microscopic “invisible dermatoses” ( Fig. 9-2 ). Lichen amyloidosis lesions differ by showing additional changes of hyperkeratosis and acanthosis, sometimes resembling lichen simplex chronicus ( Fig. 9-3 ).


Figure 9-2 Macular amyloidosis. A, On low-power inspection, changes are minimal, consisting of a slightly amorphous appearance of the papillary dermis. This subtle change explains why macular amyloidosis is often included among the microscopic “invisible dermatoses.” B, On higher magnification, the amorphous papillary dermal deposits are somewhat more apparent. These may have a globular configuration, and sometimes, small clefts or fissures can be identified.


Figure 9-3 Lichen amyloidosus. The epidermis is papillomatous and acanthotic. Amyloid deposits can be seen in the papillary dermis.
In nodular amyloidosis, large masses of amyloid are found in the dermis and subcutis beneath an atrophic epidermis. These are accompanied by a chronic inflammatory infiltrate that includes lymphocytes and fairly numerous plasma cells 34 ( Fig. 9-4 ). Lesions of primary systemic amyloidosis show similar dermal amyloid deposits, but inflammation tends to be sparse. 35 Involvement of vessel walls, the basement membrane zone of eccrine sweat glands, and adipocytes (the latter forming so-called amyloid rings) is also apparent ( Fig. 9-5 ). For diagnosis of systemic amyloidosis, abdominal fat pad aspiration biopsy has long been recommended as the method of choice. Recent studies show that this is indeed a technique with excellent specificity and positive predictive value, but unfortunately its sensitivity is low and inadequate sampling is fairly frequent. 36 Skin biopsy has been recommended as a more effective method, because subcutaneous amyloid deposits are not always found. Also, careful selection of biopsy site (included areas suspicious for amyloid-altered skin) increases sensitivity by permitting the detection of dermal, vascular, and periappendageal as well as subcutaneous deposits. 37


Figure 9-4 Nodular amyloidosis. Large amyloid deposits are seen in the dermis. Note the adjacent plugged follicle with adjacent inflammation; this consists of lymphocytes and plasma cells.


Figure 9-5 Primary systemic amyloidosis. This skin biopsy showed extensive deposits of amyloid in the subcutis, both around adipocytes (“amyloid rings”) and vessels.
The classic stain for amyloid is Congo red, which stains amyloid pink but shows characteristic green birefringence under polarized light ( Fig. 9-6 ). However, green birefringence is not always observed, and depending on the optical conditions, other colors may be identified. 38 It is also the author’s experience that tiny deposits of amyloid, such as are sometimes observed in macular amyloidosis, often fail to show green birefringence. Clinically apparent skin involvement is not seen in secondary systemic amyloidosis (which may accompany rheumatoid arthritis, osteomyelitis, lepromatous leprosy, and other conditions), but there may be detectable amyloid deposits in the subcutaneous fat. These amyloid deposits, which contain amyloid A protein, can be distinguished from those of primary systemic disease by treatment of biopsy material with potassium permanganate prior to staining with Congo red. Affinity for Congo red is lost in the case of secondary systemic amyloidosis. 39 Reliable staining results are obtained with crystal violet, which produces red-violet metachromasia. 40 Although it is said that this method is best performed on unfixed, frozen sections, the author has obtained very good results in paraffin-embedded material ( Fig. 9-7 ). Because crystal violet fades rather quickly, slides should be reviewed as soon after preparation as possible. Cotton dyes such as pagoda red have been recommended as being more specific for amyloid than Congo red. 41 Immunofluorescence of thioflavin (T or S)-stained, paraffin-embedded sections has also been used, although false positive results do occur. 42 The advent of immunohistochemistry now permits specific antibody staining of amyloid components, including amyloid P component (found in all forms of amyloidosis), light chains (in the case of systemic or nodular cutaneous amyloidosis), and keratins (in macular and lichenoid amyloidosis). On electron microscopy, amyloid filaments are straight, nonbranching, often tightly packed, and they measure approximately 7 nm in diameter. 43


Figure 9-6 Congo red staining of amyloid. A, The characteristic pink stain of amyloid with Congo red. This stain was performed on a case of amyloidosis involving the kidneys. B, Polarization of larger amyloid deposits stained with Congo red. Note the apple green birefringence.


Figure 9-7 Crystal violet staining of amyloid deposits, producing red metachromasia.

Differential Diagnosis
Amyloid deposits have a resemblance to the colloid material seen in adult and juvenile colloid milium. Colloid should not be positive for Congo red, 44 although this has been reported, and adult colloid milium has a close relationship to solar elastosis; a link between amyloid deposition and elastic tissue has only rarely been reported. 10 , 45 Juvenile colloid milium is derived from keratins and stains for keratins; this is also true of macular and lichenoid forms of amyloidosis, but deposits in the latter also stain positively with crystal violet, Congo red, and for amyloid P component. A variant histochemical stain, the van Gieson stain (without the component for elastic fibers), can also be helpful, in that amyloid stains pink and colloid stains yellow. If needed, electron microscopy can be useful in distinguishing between the two deposits, in that filaments of juvenile colloid milium are wavy or whorled with a diameter of 8 to 10 nm, 46 whereas those of adult colloid milium are smaller in diameter and show a close relationship with degenerated elastic fibers. 47 There may also be some resemblance to amyloid in two other conditions characterized by the dermal deposition of amorphous, eosinophilic material: erythropoietic protoporphyria and the rare autosomal recessive disorder lipoid proteinosis. In both of these conditions, there is ultrastructural evidence for reduplication of basal lamina material, and in lipoid proteinosis, there are also dermal deposits of granular material interspersed with fine collagen fibrils. 48 These features are quite different from those of amyloid. Staining shows neutral mucopolysaccharide, variable amounts of lipid, and (by immunohistochemistry) collagen—including type IV collagen; stains for amyloid are negative, although occasional reports of weak Congo red positivity have been published.

Colloid Milium


Clinical Features
There are two forms of colloid milium: juvenile and adult. Clinical variations on the adult form include small, translucent papules and larger nodules and plaques, sometimes called nodular colloid degeneration. The adult form is derived from elastotic material; this variety is discussed in Chapter 10 . Juvenile colloid milium is relatively rare. It consists of translucent to flesh-colored papules that form on the face, neck, and hands. There is a relationship to sun exposure, 44 including documented outbreaks following severe sunburn. 46 Sometimes there is a family history of the disorder, and a genetic component has been postulated. 44 , 49 This is further supported by several reports of an association with two other conditions: ligneous conjunctivitis and ligneous periodontitis . 50 – 52 The latter disorders are defined by the development of pseudomembranes composed largely of fibrinogen, and they are believed to result from a defect of fibrinolysis due to plasminogen deficiency. 53 Immunohistochemical and ultrastructural evidence indicates that the colloid material in juvenile colloid milium derives from apoptotic keratinocytes. 46 , 49

Microscopic Findings
In fully developed lesions, there are fissured masses of pale eosinophilic amorphous material that fill the papillary dermis ( Fig. 9-8 ). The rete ridges of the overlying epidermis are effaced, but it is usually possible to identify apoptotic bodies originating from the epidermis. Hashimoto and associates showed that these apoptotic keratinocytes form filamentous whorls that appear to be the origin of the thin, wavy filaments characteristic of colloid milium. Amyloid-type filaments are also observed, 46 but the colloid material lacks the staining properties of amyloid, and Congo red staining is usually negative. The material does stain with antibodies to keratin.


Figure 9-8 Juvenile colloid milium. Low ( A ) and high ( B ) magnification show amorphous deposits in the papillary dermis.

Differential Diagnosis
Although on routine staining, the material deposited in juvenile colloid milium resembles that of adult colloid milium, the latter derives from elastic tissue. Therefore, in adult colloid milium, an association with elastic fibers is observed on both hematoxylin and eosin (H&E)–stained sections and in tissues stained with the Verhoeff–van Gieson method ( Fig. 9-9 ), and the colloid is negative for keratin. As previously noted, keratin positivity also characterizes the deposits in macular and lichenoid amyloidosis. However, stains for amyloid are usually negative in juvenile colloid milium; weak Congo red positivity has been described, but immunostaining for amyloid P substance is negative.


Figure 9-9 Adult colloid milium. Large amorphous deposits are seen in the dermis. At the base of these deposits, some intermingling with elastotic fibers can be seen.

Porphyrias
The porphyrias represent a group of disorders associated with various enzyme deficiencies in the metabolic pathway of heme biosynthesis. Numerous textbooks and review articles detail the metabolic abnormalities that accompany this set of disorders. 54 , 55 The following discussion emphasizes the features of those porphyrias commonly encountered in dermatopathology.


Clinical Features
Porphyria cutanea tarda (PCT) is the most common form of porphyria seen in clinical practice. As in other forms of porphyria, PCT features photosensitivity due to the absorption by porphyrins of ultraviolet light in the 400- to 410-nm range—the Soret band. This is accompanied by skin fragility and the development of blisters, particularly over the hands and forearms but also on the face, legs, and dorsal feet. Bullae heal with scars and milia formation. Other changes include hyperpigmentation, hypertrichosis of the facial region, and focal sclerodermoid changes. The familial type (autosomal dominant inheritance) is infrequently encountered; tends to present at an early age; and is associated with profound deficiency of the responsible enzyme, uroporphyrinogen decarboxylase. The sporadic, nonfamilial form is by far the most common, begins somewhat later in life, and is associated with decreased uroporphyrinogen decarboxylase activity restricted to the liver. 56 Elevated uroporphyrin III is identified in the urine, which fluoresces pink under Wood light. Factors that are associated with this disease and often implicated in sporadic cases include hepatitis C viral infection, alcohol, estrogens, and iron. 57 Iron overload in some cases is related to gene mutations associated with hemochromatosis, particularly those involving C282Y and H63D. 56 , 58 Disease associations with lupus erythematosus and HIV infection have also been reported. The name hepatoerythropoietic porphyria has been applied to the severe homozygous form of PCT. These patients have severe blistering with scarring, but they also have red fluorescence of teeth under Wood light. In addition to elevated uroporphyrins in the urine, these patients also have elevated coproporphyrins in the feces and elevated erythrocyte protoporphyrins. 59
Two other conditions should be described here. The first, pseudoporphyria, almost exactly mimics the skin fragility and blistering of PCT but lacks its other cutaneous manifestations (i.e., hypertrichosis, sclerodermoid change). With regard to specimens submitted to his laboratory, the author sees more cases of pseudoporphyria than true PCT. The former is most often associated with medications, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), furosemide, and nalidixic acid. Of the NSAIDs, pseudoporphyria is especially associated with naproxen, nabumetone, and oxaprozin. 60 , 61 Use of tanning beds has also been associated with pseudoporphyria, although some of these patients have also received pseudoporphyria-producing drugs such as naproxen and nalidixic acid. 62 , 63 Bullous dermatosis of hemodialysis has also been considered a form of pseudoporphyria, but some affected patients can be shown to have true PCT through careful laboratory evaluation of serum and fecal porphyrins. 64
Erythropoietic protoporphyria (EPP) usually occurs as an autosomal dominant disorder, but an autosomal recessive variant has also been reported. 65 It results from a deficiency of the enzyme ferrochelatase, resulting in the accumulation of protoporphyrin IX in liver, erythrocytes, and skin. Protoporphyrin IX absorbs light in the Soret band and in the visible spectrum, and a characteristic symptom is burning sensation of skin on direct sun exposure and through window glass. Erythema and urticaria resembling solar urticaria may develop, and, especially in childhood, vesiculonecrotic lesions resembling hydroa vacciniforme occur over the face and upper extremities. With chronicity, the skin shows thickening with formation of waxy papules. Abnormal liver function tests are not uncommon in EPP, and fatal hepatic failure may occur in about 5% of patients due to various toxic effects of accumulated protoporphyrins. 66 The risk of more severe liver disease is higher in patients with recessively inherited disease. 67 Microcytic anemia can also occur. Elevated fecal protoporphyrins are found, and protoporphyrins are also found in erythrocytes, producing transient fluorescence (see later discussion). Photoprotection is a key in clinical management. Beta-carotene is also effective; it increases ultraviolet tolerance by several possible mechanisms, including scavenging of free radicals, singlet oxygen quenching, and/or absorption of 400 nm light. 68
Other forms of porphyria may have significant cutaneous manifestations. Variegate porphyria is an autosomal dominant disorder that combines the cutaneous lesions of porphyria cutanea tarda with the gastrointestinal and neuropsychiatric symptoms of acute intermittent porphyria. During the attacks of acute intermittent porphyria, urinary delta aminolevulinic acid and porphobilinogen as well as fecal protoporphyrin and coproporphyrin are elevated. 55 Erythrocytes are negative for porphyrins. Hereditary coproporphyria, another autosomal dominant disorder, involves a deficiency of coproporphyrinogen oxidase, which results in the accumulation of fecal coproporphyrins. These patients can develop blisters similar to those of PCT and variegate porphyria, and, as is the case in the latter disorder, they can also have attacks with neurologic and gastrointestinal symptoms similar to those in acute intermittent porphyria, accompanied by increases in urinary delta aminolevulinic acid, porphobilinogen, and (uniquely in this setting) coproporphyrin. 69 , 70 Erythropoietic porphyria is a rare but particularly severe form of porphyria inherited as an autosomal recessive trait. Affected patients have a homozygous defect of the enzyme uroporphyrinogen III synthase. Uroporphyrin I and coproporphyrin I are present in urine, feces, and erythrocytes. Symptoms and signs include severe photosensitivity with bullae and scarring, red fluorescence of teeth, and red or dark urine. Hemolytic anemia is a significant feature. Erythrocyte fluorescence occurs, as in EPP, but is stable rather than transient. Management of these individuals includes strict sunlight avoidance; packed red cell transfusions; and, when possible, stem cell transplantation. 71 , 72

Microscopic Findings
The fundamental microscopic changes associated with the porphyrias can be well illustrated by the findings in porphyria cutanea tarda and erythropoietic protoporphyria. In PCT, biopsies of blisters reveal an infiltrate-poor subepidermal bulla ( Fig. 9-10 ). The PAS-positive portion of the basement membrane zone has been variously detected at the floor 73 or the roof 74 of the subepidermal separation. It has been suggested that the lamina lucida is the preferred site of separation but that separation at the sublamina densa is more prone to occur in severe disease. 75 The dermal papillae retain their shape at the blister floor, a feature known as “festooning” ( Fig. 9-11 ). At the roof of the blister, globules of eosinophilic material may connect to form so-called caterpillar bodies 76 ( Fig. 9-12 ). Immunohistochemically and ultrastructurally, these bodies have been shown to contain basement membrane material 76 , 77 as well as degenerating keratinocytes and “colloid bodies” (whorled masses of probable keratin filaments). 77 Papillary dermal vessels walls are particularly thickened (see Fig. 9-11 ), with a homogeneous, eosinophilic appearance demonstrated well with routine H&E staining but emphasized with the PAS method. On electron microscopy, there is prominent, concentric reduplication of the basement membrane material around these vessels, surrounded by amorphous and filamentous material. 78 Direct immunofluorescence shows deposition of immunoglobulins (especially immunoglobulin G [IgG]) and complement with a smudged appearance along the dermal-epidermal junction and around blood vessels. This has been considered to represent entrapment of immunoglobulins and complement within laminated and filamentous basement membranes. Inflammation is slight to virtually absent in fresh lesions, but in older blisters a mixture of inflammatory cells can be identified in the dermis, including occasional eosinophils. The findings in bullous dermatosis of hemodialysis and pseudoporphyria are virtually identical to those in PCT ( Fig. 9-13 ). Although initial studies suggested that vessel wall thickening was not as prominent in pseudoporphyria, the differences, if any, are not sufficient to be diagnostically useful. In EPP, blister formation is less common. 79 Areas of waxy, thickened skin show prominent deposits of hyaline material ( Fig. 9-14A ). This PAS-positive material (see Fig. 9-14B ) is found in the superficial dermis, concentrated around vessels. The hyaline material contains type IV collagen, and reduplication of vascular basal lamina material is again seen ultrastructurally. 80 Blood smears examined with a fluorescent microscope show a transient pink-red fluorescence, a characteristic finding in this disease. Screening for porphyrins in plasma using a fluorometric method is a useful means of diagnosing and categorizing certain types of porphyrias; a number of these disorders have characteristic maximum emission spectra. For example, a maximum fluorescence emission of 634 to 636 nm is characteristic of EPP, 618 to 620 nm is found in a group of porphyrias that includes PCT, and 625 to 627 nm is present in variegate porphyria. 81


Figure 9-10 Porphyria cutanea tarda. There is an infiltrate-poor subepidermal bulla. However, these lesions are not necessarily devoid of inflammation, particularly when biopsies are obtained at a later stage of development. Note the retention of the shape of the dermal papillae at the blister floor (“festooning”).


Figure 9-11 Porphyria cutanea tarda, with “festooning” of the blister base. Note the marked thickening of papillary dermal vessel walls.


Figure 9-12 Porphyria cutanea tarda. Globular basement membrane material can be seen in roof of blister, forming so-called “caterpillar bodies.”


Figure 9-13 Lesions resembling porphyria cutanea tarda (PCT). A, Bullous dermatosis of hemodialysis, showing subepidermal separation (a portion of the separated epidermis was removed during processing) and thick-walled papillary dermal vessels. Some of these cases can be shown to represent true PCT. B, Pseudoporphyria due to oxaprozin. The findings are essentially identical to those of PCT.


Figure 9-14 Erythropoietic protoporphyria. A, Amorphous, hyaline deposits are identified in the superficial dermis, concentrated around vessels. B, This material is positive with periodic acid–Schiff stain.

Differential Diagnosis
The constellation of microscopic features enumerated earlier is characteristic of the various types of porphyria. The differential diagnosis for bullous lesions includes the group of infiltrate-poor subepidermal blistering disorders: hereditary epidermolysis bullosa; bullosis diabeticorum; infiltrate-poor pemphigoid; and some blisters due to extrinsic injury, such as suction or cryotherapy bullae. “Festooning” at the blister base can occur in a number of these disorders, particularly epidermolysis bullosa and infiltrate-poor pemphigoid. However, the thickened basement membrane material at the dermal-epidermal junction and around vessels seen in forms of porphyria is not encountered in those disorders. Direct immunofluorescence findings can be helpful, in that the smudged-appearing basement membrane zone and perivascular fluorescence (particularly for IgG) of porphyrias is not encountered in these other disorders. It has been suggested that bullosis diabeticorum may be a variant of porphyria or pseudoporphyria, particularly in those cases associated with renal failure. This requires further investigation. Some reported examples of bullosis diabeticorum show intraepidermal rather than subepidermal separation, but this could have been the result of epidermal regeneration at the blister base. 82 , 83 The hyaline material seen in skin biopsies of EPP can bear a resemblance to amyloid, the material seen in colloid milium, or the deposits of the rare condition, lipoid proteinosis. The perivascular distribution and type IV collagen content of the deposits in EPP differ from those of primary cutaneous amyloidosis and colloid milium. EPP deposits do not have the staining properties of amyloid and do not show either the relationship with elastic fibers of adult colloid milium or the derivation from apoptotic keratinocytes of juvenile colloid milium. In lipoid proteinosis, the hyaline material surrounds follicles and sweat glands as well as vessels, 84 contains hyaluronic acid and variable amounts of lipid, 85 and fails to show reduplication of basal laminae ultrastructurally. 86 In difficult cases, other clinical and laboratory data can be decisive in distinguishing among these disorders.

Calcinosis Cutis


Clinical Features
Calcium deposition in skin is one of the most common findings in dermatopathology. It is most often encountered in the form of dystrophic calcification in areas subjected to inflammation or trauma, or as secondary deposits in a variety of epithelial tumors (e.g., basal cell carcinoma, pilomatricoma), usually in foci of keratinization. These forms of calcification are usually not apparent clinically and are found only on biopsy, but more profound forms of dystrophic calcification with very obvious and significant cutaneous manifestations can be encountered in dermatomyositis and scleroderma. 87 , 88 Calcium is found in miliary osteomas of the skin, which present as stony-hard papules on the face; they may be idiopathic or follow outbreaks of acne vulgaris or dermabrasion. Tumoral calcinosis is seen in several settings: in the rare autosomal recessive familial hyperphosphatemia; as a secondary phenomenon occurring in diseases known to be associated with soft tissue calcification, such as dermatomyositis; or in normophosphatemic patients who have no known predisposing condition. 89 These deposits are often found in periarticular soft tissues. 90 Researchers have found loss-of-function mutations of the GALNT3 gene associated with familial hyperphosphatemic tumoral calcinosis, which may promote increased expression of proteins implicated in ectopic calcification. 91 These same investigators have found mutations in the SAMD9 gene in families with a rare form of normophosphatemic tumoral calcinosis, a condition associated with severe pain, skin infections, and calcifications in areas subjected to repeated injury. Calcification in these individuals may result from a link between mutations of this gene and the tumor necrosis factor-alpha signaling pathway. 92
Two localized forms of cutaneous calcification that deserve separate consideration are subepidermal calcified nodule and idiopathic calcinosis of the scrotum. Subepidermal calcified nodule most often presents as a solitary hard nodule on the face of a child. Idiopathic scrotal calcinosis consists of multiple nodules that are usually encountered in young adults. A vulvar equivalent has also been described. 93
A final, but most important, form of calcinosis cutis is the deep dermal and subcutaneous calcification associated with abnormalities of calcium and phosphate metabolism. This has been termed metastatic calcification , and it can present as the previously mentioned tumoral calcinosis, as calcifying panniculitis, or as a calcification of vessel walls. The most common scenario occurs in association with chronic renal failure as well as with elevated phosphate and secondary (sometimes tertiary) hyperparathyroidism. However, other conditions associated with hypercalcemia can lead to metastatic calcification, including hypervitaminosis D, milk-alkali syndrome, and Paget disease of bone. Calcification of deep vessel walls, with or without an elevated calcium-phosphate product, is known as calciphylaxis . This condition presents as livedoid to violaceous patches that progress to firm, black, necrotic eschars. 94 Classically, calciphylaxis requires a sensitization factor and an eliciting factor. Background “sensitization” is most commonly related to chronic renal failure, and “elicitation” can occur through trauma, infection, or numerous other factors. However, there are examples of the condition arising in the absence of renal failure, often (but not invariably) related to hyperparathyroidism. 95 Recent work on the etiology of calciphylaxis has focused on the pathway involving nuclear factor κ–light chain enhancer of activated B cells, or NF-κB, which acts through a receptor activator, RANK, and its ligand, RANKL. There is also an antagonist of RANKL known as osteoprotegerin. These elements are involved in normal bone development. 96 Increased NF-κB activity results in demineralization of bone and vascular calcium deposition. Interestingly, treatment with bisphosphonates (which increase osteoprotegerin expression and inhibit expression of RANKL) has resulted in healing of calciphylaxis ulcers. 97

Microscopic Findings
Calcium deposits in skin (most of which represent calcium phosphate) are usually readily recognizable as amorphous, basophilic (blue-gray) deposits in tissue. They are common findings in forms of dystrophic calcification in areas of injury or chronic inflammation; in keratinizing lesions such as ruptured epidermal (infundibular) or trichilemmal cysts ( Fig. 9-15 ), the horn cysts that accompany trichoepitheliomas; or in basal cell carcinomas and pilomatricomas. Small foci of calcification are seen in miliary osteomas ( Fig. 9-16 ), whereas larger masses can be observed in such divergent conditions as familial hyperphosphatemia, dermatomyositis, or the metastatic calcification accompanying abnormal calcium-phosphate metabolism. In subepidermal calcified nodules, calcium is arranged mainly as dermal aggregates of small globules; these may in turn arise from larger calcific masses 98 ( Fig. 9-17 ). Granulomatous inflammation may surround these larger masses of calcium. 99 Transepidermal elimination of calcium has been observed in some cases. 100 The origin of this lesion is not fully understood, although an association with hair follicles 100 or sweat glands 101 has been suggested. Idiopathic scrotal calcinosis shows calcific masses, some surrounded by granulomas ( Fig. 9-18 ). Although in a given case, the cause of calcification may be inapparent, often there is evidence of a partial epithelial lining around some calcium deposits or unequivocal epidermal cysts in the vicinity, leading many investigators to conclude that this condition represents dystrophic calcification of scrotal epithelial cysts.

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