Dermatopathology

W. Kempf ] M. Hantschke ] H. Kutzner ] W. H. C. Burgdorf

Dermatopathology

W. Kempf M. Hantschke H. Kutzner W. H. C. Burgdorf

Dermatopathology With 242 Color Figures

12

Werner Kempf MD Kempf und Pfaltz Histologische Diagnostik Schaffhauserplatz 3 8042 Zürich Switzerland Lecturer and Consultant Physician Department of Dermatology University of Zürich Gloria Str. 31 8091 Zürich Switzerland

Markus Hantschke MD Dermatopathology Friedrichshafen Siemens Str. 6/1 88048 Friedrichshafen Germany Heinz Kutzner MD Dermatopathology Friedrichshafen Siemens Str. 6/1 88048 Friedrichshafen Germany Walter H. C. Burgdorf MD Traubinger Str. 45A 82327 Tutzing Germany

ISBN 978-3-7985-1839-1 Steinkopff Verlag Bibliographic information published by Die Deutsche Nationalbibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at http://dnb.d-nb.de. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Steinkopff Verlag. Violations are liable for prosecution under the German Copyright Law. Steinkopff Verlag a member of Springer Science+Business Media www.steinkopff.com © Steinkopff Verlag 2008 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book. In every individual case the user must check such information by consulting the relevant literature. Medical Editors: Dr. med. Gertrud Volkert, Petra Elster Production: Klemens Schwind Cover design: Erich Kirchner, Heidelberg Typesetting: K+V Fotosatz GmbH, Beerfelden Printing and binding: Stürtz GmbH, Würzburg SPIN 12327249

105/7231 – 5 4 3 2 1 0 – Printed on acid-free paper

We dedicate this book to our families

Preface A basic knowledge of dermatopathology is essential for the diagnosis of both inflammatory and neoplastic skin diseases. Our goal in writing this book is to provide a structured well-illustrated introduction to dermatopathology for beginners, not to replace any of the existing standard textbooks. Since the German version was published in the spring of 2007, many positive comments suggest that we may have come close to achieving this goal. Thus we are especially happy to now be able to offer an English version, designed to reach a new group of readers. We would like to thank Gertrud Volkert MD of Steinkopff Verlag for her support and advice in planning and producing both editions. Michael Hertl MD reviewed the information on the diagnosis of blistering diseases. We have limited ourselves to the most common and important diseases in order to make the initial study of dermatopathology as simple and painless as possible. Each disease is presented in a structured fashion, with clinical description, histologic features, special stains, differential diagnostic considerations and comments accompanied by two representative photomicrographs with all of the important diagnostic features labeled with pointers. We have tried to pick representative sections so that the book is useful for the age-old learning tradition of matching pictures to what one sees under the microscope. Especially in the case of inflammatory skin diseases, the clinicopathologic correlation is often the key to the diagnosis. We have tried to mention essential points in the comments section. Similarly, the differential diagnostic possibilities are considered for each individual disease, leading sometimes to repetition, but hopefully enhanced learning and less page turning. We do read the literature but have deliberately not cited any references. Both the Internet and standard dermatopathology textbooks can provide as much directed reading material as anyone could possibly want. Our true hope for this book is that it succeeds in transferring our fascination and love of dermatopathology to at least a few members of the upcoming generations in our specialty. Summer 2008

Werner Kempf Markus Hantschke Heinz Kutzner Walter H. C. Burgdorf

Contents I

Basic Principles

1.1

Principles of diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

1.2

The skin biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

1.3 1.3.1 1.3.2 1.3.3 1.3.4

Histopathological techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunohistochemical stains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunofluorescence studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular biological procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7 7 9 11 12

1.4

Dermatopathologic glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15

II

Inflammatory and Infectious Dermatoses

2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6 2.1.7 2.1.8

Epidermis – Spongiosis, acanthosis and hyperparakeratosis . . . . . . Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prurigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pustular psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pityriasis rosea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cutaneous fungal infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Viral papillomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molluscum contagiosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19 20 22 24 26 28 30 32 34

2.2 2.2.1 2.2.2 2.2.3

Epidermis – Acantholysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Darier disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hailey-Hailey disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Herpes virus infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37 38 40 42

2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5

Bullous diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pemphigus foliaceus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pemphigus vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bullous pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dermatitis herpetiformis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Porphyria cutanea tarda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45 46 48 50 52 54

2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6

Interface dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Erythema multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pityriasis lichenoides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pigmented purpuric dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57 58 60 62 64 66 68

X ]

Contents

2.5 2.5.1 2.5.2 2.5.3 2.5.4

Dermis – Vascular disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leukocytoclastic vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Granuloma faciale and erythema elevatum et diutinum . . . . . . . . . . Polyarteritis nodosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cryoglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71 72 74 76 78

2.6 2.6.1 2.6.2 2.6.3 2.6.4 2.6.5 2.6.6 2.6.7

Dermis – Granulomatous inflammation . . . . . . . . . . . . . . . . . . . . . . Granuloma annulare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Necrobiosis lipoidica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Foreign body granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mycobacterial infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81 82 84 86 88 90 92 94

2.7 2.7.1 2.7.2

Dermis – Interstitial inflammation . . . . . . . . . . . . . . . . . . . . . . . . . Borreliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97 98 100

2.8 2.8.1 2.8.2 2.8.3 2.8.4

Dermis – Diffuse mixed inflammatory infiltrates . . . . . . . . . . . . . . Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute febrile neutrophilic dermatosis . . . . . . . . . . . . . . . . . . . . . . . . Eosinophilic cellulitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arthropod assault reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

103 104 106 108 110

2.9 2.9.1 2.9.2 2.9.3

Dermis – Degenerative and metabolic disorders . . . . . . . . . . . . . . . Chondrodermatitis helicis nodularis chronica . . . . . . . . . . . . . . . . . . Pseudoxanthoma elasticum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

113 114 116 118

2.10 2.10.1 2.10.2 2.10.3 2.10.4

Dermis – Inflammation of adnexal structures . . . . . . . . . . . . . . . . . Folliculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alopecia areata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lupus erythematosus of scalp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Folliculitis decalvans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

121 122 124 126 128

2.11 Subcutaneous fat – Panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.11.1 Erythema nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.11.2 Lupus panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

131 132 134

2.12

Drug reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

136

2.13

Artifactual damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

140

III

Cysts

3.1 3.1.1 3.1.2 3.1.3

Epithelial cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidermoid cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trichilemmal cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steatocystoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

145 146 148 150

3.2 3.2.1

Pseudocysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Digital mucous cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

153 154

Contents ]

IV

Hamartomas and Neoplasms

4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.1.7 4.1.8 4.1.9

Epidermal hamartomas and neoplasms . . . . . . . . . . . . . . . . . . . . . . . Epidermal nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nevus sebaceus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Seborrheic keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clear cell acanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Porokeratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Actinic keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bowen disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Squamous cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Keratoacanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

159 160 162 164 166 168 170 172 174 176

4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.7 4.2.8 4.2.9 4.2.10 4.2.11 4.2.12 4.2.13

Melanocytic lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mucosal melanotic macule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lentigo simplex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melanocytic nevi – junctional and compound types . . . . . . . . . . . . . Melanocytic nevi – dermal and congenital types . . . . . . . . . . . . . . . . Halo nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blue nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dysplastic melanocytic nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spitz nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lentigo maligna and lentigo maligna melanoma . . . . . . . . . . . . . . . . Superficial spreading melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nodular melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acrolentiginous melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Desmoplastic melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

179 180 182 184 186 188 190 192 194 196 198 200 202 204

4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.7 4.3.8 4.3.9 4.3.10 4.3.11 4.3.12 4.3.13

Adnexal tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sebaceous hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pilomatricoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Syringoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Syringocystadenoma papilliferum . . . . . . . . . . . . . . . . . . . . . . . . . . . Poroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hidradenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spiradenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cylindroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paget disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trichoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Desmoplastic trichoepithelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basal cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fibroepithelioma of Pinkus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

207 208 210 212 214 216 218 220 222 224 226 228 230 232

4.4 4.4.1 4.4.2 4.4.3 4.4.4 4.4.5 4.4.6 4.4.7 4.4.8 4.4.9 4.4.10 4.4.11 4.4.12

Soft tissue proliferations and neoplasms . . . . . . . . . . . . . . . . . . . . . . Scar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertrophic scar and keloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Skin tag . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dermatofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dermatofibrosarcoma protuberans . . . . . . . . . . . . . . . . . . . . . . . . . . . Atypical fibroxanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leiomyoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nevus lipomatosus superficialis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Merkel cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

235 236 238 240 242 244 246 248 250 252 254 256 258

XI

XII

] Contents

4.5 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5

Vascular tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyogenic granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiokeratoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kaposi sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

261 262 264 266 268 270

4.6 4.6.1 4.6.2 4.6.3 4.6.4

Lymphomas and pseudolymphomas . . . . . . . . . . . . . . . . . . . . . . . . . Mycosis fungoides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary cutaneous CD30-positive lymphoproliferative diseases . . . . Primary cutaneous follicle center B-cell lymphoma . . . . . . . . . . . . . Cutaneous B-cell pseudolymphoma . . . . . . . . . . . . . . . . . . . . . . . . . .

273 274 276 278 280

4.7 4.7.1 4.7.2 4.7.3

Histiocytoses and mastocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . Langerhans cell histiocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Juvenile xanthogranuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cutaneous mastocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

283 284 286 288

4.8.

Cutaneous metastases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

290

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

293

I Basic Principles

1.1 Principles of diagnosis When starting, the simplest approach is to examine the epidermis, then the dermis and finally the subcutaneous fat. This approach reduces the likelihood of overlooking something. For this reason, we have arranged this book, starting with epidermal changes and moving down through dermal and subcutaneous lesions. Inflammatory dermatoses are best approached by identifying first the pattern of inflammation (superficial vs. superficial and deep vs. subcutaneous; with and without epidermal involvement) and studying the cellular composition (lymphocytes, macrophages, neutrophils, eosinophils, and mast cells). Cutaneous tumors are approached just like all other tumors considering the pattern (symmetry, circumscription, level of invasion) and cytomorphology (nuclear pleomorphism and mitotic activity). Increasingly the final answer is based on the expres-

sion of a pattern of specific tumor antigens (immunohistochemical profile). Clinicopathologic correlation: This is the crux and beauty of dermatopathology; no other branch of medicine has so many different names for the appearance of an organ and in many cases, each of the peculiar names has a histological correlate. On the other hand, the skin can only react in so many ways, so that some patterns such as “superficial lymphocytic perivascular infiltrate with sparse admixture of eosinophils” can be associated with many different diagnoses ranging from viral exanthem to drug reaction to bullous pemphigoid. The digital age has made it convenient to provide the dermatopathologist not only with a detailed clinical history but also with clinical pictures (e.g., digital images), both of which increase the chances of the clinician receiving a helpful diagnosis.

1.2 Skin biopsy ] Biopsy techniques

] Fixation

There are several ways of obtaining a skin biopsy; each has advantages and disadvantages.

Skin biopsies are routinely fixed in a buffered 10% formalin solution (about 4% formaldehyde in water) for at least 6–12 hours, being sure that the ratio of fixative to biopsy volume exceeds 20 : 1. Specimens for immunofluorescent examination should be flash-frozen or transported in Michel solution. Specimens for electron microscopic examination require fixation in paraformaldehyde and glutaraldehyde in a cacodylate buffer.

Excision. An excision is preferred when removing skin tumors as it allows an adequate evaluation of the margins to determine completeness of excision. An excisional biopsy is required for deep inflammatory processes, especially panniculitis, and is ideal for studying a disease process at all levels of the skin. Punch biopsy. Punch biopsies usually 3–4 mm in diameter produce a cylindrical plug. They can be done rapidly, heal satisfactory without suturing and are thus efficient; their downside is the risk of sampling error, especially for larger lesions. Shave biopsy. The shave biopsy is the quickest way to sample or remove a lesion but never allows adequate study of the depths of the lesion and often results in an incomplete lateral excision as well. The shave biopsy is perfect for small protuberant or papillomatous lesions but otherwise causes more trouble than the time savings it brings. Curettage biopsy. Superficial lesions like actinic keratoses and seborrheic keratoses are often curetted. The resulting fragments can be diagnosed, but in the event the actinic keratosis is a squamous cell carcinoma, it is impossible to comment on the extension of the tumor to the depth and the adequacy of excision. Special sites. Biopsies on the scalp should be done parallel to the direction of the hair follicles and deep enough to sample the hairs in the subcutaneous fat. Many prefer to obtain two deep punch biopsies for alopecia; one is processed transversely (horizontal sections) and the other in the traditional fashion (vertical sections). Biopsies from the lower aspects of the legs always feature thickened vessels and stasis changes in adults, while those from the elbow have pressure and rubbing changes.

] Embedding and sectioning Excision specimens usually require special handling. The traditional method of bread-loafing the specimen – that is, multiple slices perpendicular to the long axis of an ellipse – is the most widely accepted method for determining the adequacy of the excision and in our opinion the best approach for smaller tumors. A variety of other methods are available for micrographic control of the tumor margins. These techniques, whether it is the Mohs method or the Tübinger Torte in Europe, result in an almost complete three-dimensional control of the excision margins, allowing possible maximum preservation of tissue while best insuring complete excision. The operating physician generally decides if micrographic control is necessary or not. Ideally consultation with the dermatopathologist should occur prior to the specimen appearing in the laboratory if there are special issues. Some indications for this more time-consuming process include: ] Tumors with unclear clinical borders, locallydestructive behavior or potential to metastasize (sclerotic basal cell carcinoma, Merkel cell carcinoma) ] Recurrent tumors, especially in the head and neck region ] Tumors with perineural growth patterns.

1.3 Histopathological techniques 1.3.1 Staining The tissues are embedded in paraffin, cut into 3–6 micron sections, placed on glass microscopic slides and stained. The standard stain in dermatopathology is hematoxylin and eosin (H & E stain) which stains the nuclei blue and the cytoplasm pink. A variety of special stains serve to better visualize a wide variety of cellular and extracellular structures. The most common additional stain is the periodic acid-Schiff (PAS stain) which colors sugars and polysaccharides violet. It is used to identify fungal elements, better visualize the basement membrane, and identify deposits of glycogen as in some sweat gland or epithelial proliferations. Acid glycosamines in mucin are best seen with the alcian blue stain. Congo red is used to identify amyloid, which also has a green color when the specimen is polarized; in addition, the Pagoda stain imparts an orange color. Elastic fibers are stained black with a variety of stains, usually acid orcein or van Gieson; the latter also stains collagen pink and muscles yellow. Areas of calcification are stained by the von Kossa stain which colors calcium salts black. Melanin appears black in the Masson-Fontana stain. Hemosiderin colors blue with the iron (or Prussian blue) stains. Thus these two comment pigments which both appear yellow-brown

on H&E stain can be accurately separated with special stains. Exogenous dyes such as tattoos often retain their intrinsic color in histological sections. Gram stain is the usual method for identifying bacteria, while mycobacteria are best seen with the Ziehl-Neelsen stain and Mycobacterium leprae with the Fite-Faraco stain. A more sensitive alternative approach is to use the anti-M. bovis BCG antibody which stains a wide range of microbes (fungi, bacteria). The Giemsa stain is preferred for leishmania. Fungi can also be better visualized with silver stains such as the Grocott stain. Some prefer the Giemsa stain for studying nuclear detail, especially in the diagnosis of lymphomas. Mast cells are usually identified with toluidine blue or Giemsa stains, while the chloroacetate esterase (Leder) stain marks both neutrophils and mast cells. Early myeloid cells are best seen with the myeloperoxidase stain. Extravasates of erythrocytes stain brilliant orange with the Goldner stain, while the collagen fibers are marked green. Lipids can be stained in frozen sections with Sudan orange. Routine processing removes the lipids but may leave behind distinctive empty spaces.

8 ]

Histopathological techniques

Stain

Structures identified

Color

Acid orcein

Elastic fibers

Black

Alcian blue

Acid glycosaminoglycans

Blue

Chloroacetate esterase (Leder)

Neutrophils, mast cells (myeloid cells)

Red

Congo red

Amyloid

Red; green in polarized light

Fite-Faraco

Mycobacterium leprae

Red

Giemsa

Nuclei

Blue

Eosinophil granules

Red

Mast cell granules

Purple

Leishmania

Blue

Gram-positive bacteria

Blue

Gram-negative bacteria

Red

Erythrocytes

Orange

Collagen, mucus

Green

Grocott silver

Fungi

Black

Iron (Prussian blue)

Hemosiderin

Blue

Masson-Fontana

Melanin

Black

Myeloperoxidase

Immature myeloid cells

Orange

Pagoda

Amyloid

Orange

Periodic acid-Schiff (PAS)

Glycogen

Red

Fungi

Red

Fibrin

Red

Sudan

Lipids (on frozen section)

Orange

Toluidine blue

Mast cell granules

Blue

Van Gieson

Collagen

Red

Elastic fibers

Black

Muscle fibers

Yellow

Von Kossa

Calcium salts

Black

Warthin-Starry

Spirochetes

Black

Fungi

Black

Acid-fast bacteria

Red

Gram

Goldner trichrome

Ziehl-Neelsen

Immunohistochemical stains

1.3.2 Immunohistochemical stains Immunohistochemical stains are essential for modern and accurate dermatopathologic diagnosis. They are most important in diagnosing tumors and identifying specific organisms. Most of the relevant antibodies today can be employed on formalin-fixed, paraffin-embedded tissue. Almost all antibodies stain more than a single cell type of tumor. Thus a panel of antibodies should always be employed, also to provide some internal control, and the final diagnosis should balance the clinical history, histological diagnosis and immunohistochemical panel.

Immunohistochemical stains incorporate either monoclonal or polyclonal antibodies. Some antigens are relatively inaccessible after routine processing, so that antigen retrieval with enzymatic digestion or heating may be required prior to applying the antibodies to the tissue. The antigen-antibody complex can then be identified with different detection systems producing various colors. A sampling of the important antibodies and their antigens as used in most dermatopathology practices is given below. The information is incomplete but many other paper and electronic references are available.

] Epithelial tumors Carcinoembryonic antigen (CEA) CAM5.2 CK7 EMA (epithelial membrane antigen) GCDFP-15 (gross cystic disease fluid protein-15) HER2 (ErbB2) Pancytokeratin AE1/AE3, MNF 116

Oncogene involved in carcinoma of breast Many cytokeratins

] Melanocytic tumors HMB-45 Melan-A p75 S-100

Melanocytes Melanocytes Neurotropin Melanocytes

] Merkel cell carcinoma Chromogranin CK20 Neurofilament Synaptophysin TTF-1 (thyroid transcription factor-1)

Neuroendocrine granules Cytokeratin 20 Neural intermediate filaments Neuroendocrine granules Small cell lung carcinoma; not Merkel cell carcinoma

] Soft tissue tumors CD31 CD34 Desmin Factor XIIIA HHV8-LNA

Eccrine and apocrine sweat glands Cytokeratins 8, 18 Cytokeratin 7 Many epithelia Apocrine glands; some breast tumors

Endothelial cells (also stains macrophages) Endothelial cells, stem cells, fibroblasts (dermatofibrosarcoma protuberans) Intermediate filaments; marker for smooth and striated muscle cells Dermal dendrocytes Human herpes virus 8 latent nuclear antigen (Kaposi sarcoma)

] 9

10 ] Histopathological techniques Neurofilament Podoplanin S-100 SMA (smooth muscle actin) Vimentin ] Lymphomas ALK Bcl-2 Bcl-6 CD3 CD4 CD7 CD8 CD20 CD21 CD30 CD79a LCA (leukocyte common antigen) MUM1 (multiple myeloma oncogene-1) TIA-1

Neural intermediate filaments Lymphatic endothelial cells Schwann cells, Langerhans cells, adipocytes, chondrocytes, melanocytes Smooth muscle cells, pericytes, myofibroblasts Intermediate filaments; marker for all mesenchymal cells and tumors Anaplastic lymphoma kinase Anti-apoptosis factor (B and T cells) Germinal centers (B cells) T cells (pan T-cell marker) Helper T cells, Langerhans cells, macrophages T cells – expression often lost in mycosis fungoides Cytotoxic T cells B cells (except for plasma cells) Follicular dendritic cells Activated T and B cells, tumor cells in some lymphomas (lymphomatoid papulosis) B cells (pan B-cell marker including plasma cells) White blood cell lines Germinal center B cells, activated T cells, plasma cells Cytotoxic capacity (T, NK/T cells)

] Histiocytic neoplasms CD1a CD68 CD207 (langerin) S-100

Langerhans cells, other dendritic cells Macrophages Langerhans cells Langerhans cells, activated macrophages

] Mast cell neoplasms CD117 Mast cell tryptase

c-Kit Tryptase, especially in granules

] Metastases CDX2 (caudal-type homeobox) PSA (prostate-specific antigen) Uroplakin ] Microorganisms M. bovis (BCG) M. tuberculosis In text only M. bovis (BCG) is mentioned. ] Proliferation marker Ki-67

Gastrointestinal and carcinoid tumors Prostate carcinomas Bladder carcinomas Mycobacteria (bacteria, fungi) Mycobacteria

Proliferating cells

Cave! No marker is completely specific for a tumor. Both histological findings and immunohistochemical profile must be combined to make a diagnosis.

Immunofluorescence studies ] 11

1.3.3 Immunofluorescence studies 1.3.3.1 Direct immunofluorescence

1.3.3.2 Indirect immunofluorescence

Direct immunofluorescence examination (DIF) serves to identify immunoglobulins, complement factors or fibrinogen in the patient’s tissues. A biopsy is taken, then either flash-frozen or transported in Michel medium, and then analyzed. Fluorescence-labeled antibodies are applied to sections and allowed to incubate. Then using a special microscope, the sites of attachment of the labeled antibodies in the skin can be identified. Typically antibodies against IgG, IgM, IgA, C3 and fibrin are used. The most important indications are the autoimmune bullous dermatoses, which were first classified in a reproducible manner after the introduction of DIF. In addition collagen-vascular disorders (lupus erythematosus and dermatomyositis) and immune complex vasculitides also have characteristic findings. The site of the biopsy is important; generally perilesional skin adjacent to a fresh blister is preferred for bullous diseases. Biopsies from a blister may have non-specific deposits or because of degradation of immunoglobulins be false-negative. In analyzing patients with lupus erythematosus, biopsies can be taken from lesional skin as well as non-sun-exposed skin (usually buttocks); the lupus band test is no longer widely used because of increased sensitivity and specificity of serologic tests for diagnosing the disorder. For vasculitides, DIF may be essential to differentiate immune complex vasculitides (especially Henoch-Schönlein purpura with IgA deposits) from pauci-immune (usually ANCA-positive) disorders; the latter have a much more severe course.

Indirect immunofluorescence (IIF) uses the patient’s serum which is applied to a substrate such as monkey esophagus, rat bladder, human skin or HEp-2 cells. Antibodies in the serum attach to tissue antigens. After rinsing, a second labeling anti-immunoglobulin antibody is applied, identifying the sites of attachment of antibodies from the patient. The response can be titrated and for several disorders the titers correlate with the clinical course and can sometimes predict flares. Anti-nuclear antibodies (ANA) are detected in the same way using substrate such as HEp-2 cells. Circulating antibodies can also be identified by ELISA and immunoblot techniques.

1.3.3.3 Salt-split skin When skin is incubated in 1 M NaCl solution, separation occurs in the lamina lucida. When indirect immunofluorescence is then performed using the patient’s serum, sera from bullous pemphigoid patients preferentially stain the roof of blister while those from epidermolysis bullosa acquisita patients label the floor of the blister. Often the two diseases are identical clinically, histologically and on routine immunofluorescence studies. Sera from patients with mucous membrane pemphigoid sometimes show reactivity with the roof and floor (laminin332-positive pemphigoid).

12 ] Histopathological techniques Disease

Pattern

Antigens

] Pemphigus foliaceus

IgG, C3 – intercellular deposits in epidermis

Desmoglein 1

] Pemphigus vulgaris

IgG, C3 – intercellular deposits in epidermis, mucosa Desmogleins 3 and 1, less often desmoglein 4 or non-desmosomal antigens

] Bullous pemphigoid

C3, IgG – linear deposits at DEJ; in early stages, IgM BP 180, BP 230

Autoimmune bullous diseases

] Mucous membrane pemphigoid IgG, C3 – linear deposits at DEJ; occasionally IgA

BP 180, laminin 332 (formerly laminin 5 or epiligrin), a6b4 integrin

] Pemphigoid gestationis

C3, IgG – linear deposits at DEJ

BP 180 (BP 230)

] Epidermolysis bullosa acquisita

IgG, C3 – linear deposits at DEJ, occasionally IgA

Collagen type VII

] Dermatitis herpetiformis

IgA – granular deposits in papillary tips; rarely C3

Epidermal transglutaminase

] Linear IgA disease

IgA and C3 – linear at DEJ

BP 180 (BP 230)

] Leukocytoclastic vasculitis

IgM, IgG, C3, fibrinogen around venules primarily in superficial dermis

Unclear

] Henoch-Schönlein purpura

IgA in same pattern

Unclear

Vasculitis

Lupus erythematosus ] Chronic discoid LE

IgG, IgM, IgA, C3 – linear or granular deposits at DEJ in lesional skin; no deposits in unaffected, non-sun-exposed skin

] Subacute cutaneous LE

IgG, IgM, IgA, C3 – linear or granular deposits at DEJ in lesional skin; no deposits in unaffected, non-sun-exposed skin

] Systemic LE

IgG, IgM, IgA, C3 – linear or granular deposits at DEJ in lesional skin and unaffected, non-sun-exposed skin (lupus band test) Keratinocyte nuclei fluoresce in normal, non-sun-exposed skin (in vivo ANA)

DEJ = dermal-epidermal junction

1.3.4 Molecular biological procedures Molecular biological methods are used in dermatopathology primarily in tumor diagnosis and for identifying microbes. The most common investigations include in situ hybridization, fluorescence in situ hybridization and polymer-

ase chain reaction. Most studies can be performed on formalin-fixed, paraffin-embedded tissue. All three techniques depend on the binding of specific oligonucleotides (probes) to complementary DNA or RNA target sequences.

Molecular biological procedures ] 13

1.3.3.1 In situ hybridization (ISH) ] Principle:

Specific oligonucleotide probes bind to complementary RNA or DNA sequences in tissue (hybridization). Then they are visualized using enzymatic color reactions.

] Advantages:

Labeling of target sequence in tissue, allowing one to identify which cells are involved.

] Disadvantages: Less sensitive than PCR because there is no amplification of target sequences. ] Indications:

– Identification of microorganisms, especially viruses (for example, HPV using type-specific or common sequences). – Demonstration of clonality in B-cell lymphomas by determining mRNA expression of immunoglobulin kappa and lambda light chains.

1.3.3.2 Fluorescence in situ hybridization (FISH) ] Principle:

Same as ISH, but the probes are fluorescence-labeled allowing the hybrid sequences to be visualized with fluorescence microscopy.

] Advantages:

Labeling of target sequence in tissue, allowing one to identify which cells are involved.

] Disadvantages: Harder to interpret than ISH because fluorescent signals may not be visualized in all planes of sectioning. ] Indications:

– Identification of chromosomal aberrations in soft tissue tumors (for example, dermatofibrosarcoma protuberans)

1.3.3.3 Polymerase chain reaction (PCR) ] Principle:

After extraction of DNA from the tissue, specific oligonucleotide primers are added and attached to target sequences. The hybrid product is sequentially multiplied using cyclic temperature-dependent enzymatic amplification over a period of hours. The amplification product is identified using gel electrophoresis.

] Advantages:

Very sensitive because target sequences are amplified, so that trace amounts of DNA or RNA can be identified.

] Disadvantages: The DNA or RNA sequences cannot be localized in tissue. Because of the extreme sensitivity, false-positive results are a major concern. ] Indications:

– Identification of microorganisms: Viruses (human papilloma virus, herpes viruses), bacteria (Borrelia burgdorferi, atypical mycobacteria) and parasites (leishmania). – Identification of monoclonality of T-cell receptor gamma genes in T-cell lymphomas and of immunoglobulin heavy chain genes in B-cell lymphomas. – Identification of mutations in oncogenes or tumor suppressor genes in tumors and in structural proteins in ichthyoses.

1.4 Dermatopathologic glossary Acanthosis: Thickening of the spinous layer. One can distinguish between broad-based acanthosis as in chronic dermatitis and psoriasiform acanthosis with elongated rete ridges as in psoriasis. Acantholysis: Separation of keratinocytes because of disruption of desmosomes (intercellular bridges) leading to intraepidermal blisters (for example herpes infections, pemphigus vulgaris).

Giant cells: Macrophages with multiple nuclei as a result of ingestion and fusion, seen in foreign body and inflammatory granulomatous processes (sarcoidosis, xanthogranuloma). Main types are foreign body (nuclei scattered), Langhans (nuclei arranged as horseshoe) and Touton (wreath of nuclei surrounding lipids). Hemorrhage: Extravasates of erythrocytes either within epidermis or dermis, usually traumatic or associated with vasculitis.

Ballooning degeneration: Destruction of cells because of increased intracellular fluid in response to cell injury (often seen with herpes virus infections).

Histiocyte: Tissue macrophage; term avoided in this book because of confusion with Langerhans cell histiocytosis which is a disease of dendritic Langerhans cells, not tissue macrophages.

Basement membrane: Thin amorphous zone upon which the epidermal rests and through which it is bound to dermis; exact molecular structures are known but not visible on routine microscopy.

Hypergranulosis: Thickened granular layer, especially common in inflammatory disorders (lichen planus) and in human papilloma virus infections.

Cornoid lamella: Column of parakeratosis overlying defect in spinous and granular layer; defining feature of porokeratosis. Dyskeratosis: Apoptosis with premature keratinization of individual keratinocytes with condensation of cytoplasmic and nuclear proteins (Darier disease) or after sun damage (sunburn cells). Epidermal or epithelial giant cells: Multinucleated keratinocytes seen in herpes virus infections, often identified in blisters with Tzanck smear. Epithelioid cell: Cell rich in cytoplasm with vesicular nucleus; in inflammatory infiltrates usually a macrophage.

Hyperkeratosis: Thickening of the cornified layer, either with retained nuclei (hyperparakeratosis) or without (orthohyperkeratosis). Inclusions, cytoplasmic: Collections of proteins or other material in the cytoplasm, often seen with viral infections (molluscum bodies). Inclusions, nuclear: Collections of cellular proteins within the nucleus. Incontinence of pigment: Deposition of melanin in upper dermis after inflammation or other damage to dermal-epidermal junction; it may remain free in tissue or be taken up by macrophages.

Erosion: Superficial epithelial defect in which the basal layer is not destroyed.

Interface dermatitis: Vacuolar changes in the cells of the basal layer often with apoptotic cells and a lymphocytic infiltrate at the dermal-epidermal junction (typical in lichen planus and lupus erythematosus).

Flame figure: Degenerated collagen fibers surrounded by eosinophils and their products.

Kogoj pustule: Collection of neutrophils in spinous layer in psoriasis.

16 ] Dermatopathologic glossary Leukocytoclasia: Nuclear dust (karyorrhexis) from neutrophils, most often seen in leukocytoclastic vasculitis or infections. Lichenoid infiltrate: Band-like infiltrate of lymphocytes at dermal-epidermal junction, usually associated with interface dermatitis; prototype is lichen planus. Macrophage: Bone-marrow derived cell active in phagocytosis; when tissue-bound, also known as histiocyte. Source of epithelioid and giant cells. Metachromasia: Situation where a given stain imparts a variety of colors to different structures. Microabscess: Small collection of neutrophils in cornified layer in psoriasis (Munro microabscess); also used incorrectly for collections of atypical lymphocytes in epidermis in mycosis fungoides (Pautrier microabscess). Papillary abscess: Accumulation of neutrophils in papillary tip, as seen primarily in dermatitis herpetiformis. Papillomatosis: Enlargement of the dermal papillae leading to finger-like projections of epidermis and papillary dermis (also called church spires), most common in verrucae. Pautrier microabscess: Intraepidermal collections of atypical lymphocytes (and Langerhans cells). Misnomer, since it is not an abscess (accumulation of neutrophils and necrosis).

Perivascular infiltrate: Collection of lymphocytes and macrophages around vessel; most common finding in many inflammatory dermatoses. Pustule: Intraepidermal collection of neutrophils or eosinophils. Satellite cell necrosis: Necrotic keratinocytes in association with cytotoxic T cell. Spongiosis: Separation of spinous layer because of increased fluid in epidermis secondary to inflammation. Excessive spongiosis can lead to intraepidermal vesicles. Ulcer: Tissue defect extending into the dermis or subcutis. Vacuolar degeneration: Cell damage by the formation of intercellular vacuoles, most common in cells of basal layer with inflammation at dermal-epidermal junction, usually followed by cell death. Vasculitis: Damage to a blood vessel with swelling of endothelial cells and penetration of wall by inflammatory cells; most common variant is leukocytoclastic vasculitis with accumulations of neutrophils with nuclear dust and leakage of erythrocytes, but little vessel occlusion. Lymphocytic vasculitis features dense accumulations of lymphocytes, little exocytosis or nuclear dust, but often thrombi and vessel occlusion.

II Inflammatory and Infectious Dermatoses

2.1 Epidermis Spongiosis, acanthosis and hyperparakeratosis 2.1.1 Dermatitis 2.1.2 Prurigo 2.1.3 Psoriasis 2.1.4 Pustular psoriasis 2.1.5 Pityriasis rosea 2.1.6 Cutaneous fungal infections 2.1.7 Viral papillomas 2.1.8 Molluscum contagiosum

2.1.1 Dermatitis Definition

Allergic or toxic-irritant reaction with various clinical and histological stages and patterns; eczema is a synonym

Clinic

. Acute and subacute dermatitis: Inflamed erythematous skin with vesicles and crusts . Chronic dermatitis: Erythematous scaly lesions, sometimes lichenified . Atopic dermatitis, contact dermatitis, seborrheic dermatitis, nummular dermatitis

Variants

Histopathology Acute and subacute dermatitis  Slight parakeratosis with tiny exudate inclusions  Spongiosis with intraepidermal vesicles  Exocytosis of lymphocytes and occasional neutrophils  Perivascular lymphocytic infiltrate, sometimes with eosinophils, in upper dermis

Variant  Seborrheic dermatitis: Subacute pattern with parakeratotic keratinization around the hair follicle openings

Differential diagnoses ] Tinea

Neutrophils and fungal elements seen in cornified layer

] Scabies

Acute or subacute pattern. Infiltrate rich in eosinophils. Diagnosis confirmed by finding mite, eggs or feces in epidermis

] Pityriasis rosea Subacute pattern with spongiosis and focal parakeratosis. Superficial perivascular infiltrate without neutrophils. Widened dermal papillae, erythrocyte exocytosis ] PLEVA

Focal vacuolar change at junction, spongiosis, exocytosis of lymphocytes, apoptotic keratinocytes. Above these areas focal hyperparakeratosis with inclusions of fibrinous exudate and neutrophils. Wedge-shaped dermal lymphocytic infiltrate with CD8+ cells. Erythrocyte extravasation

Histopathology Chronic dermatitis . Hyperparakeratosis . Broad-based acanthosis with markedly thickened rete ridges . Little spongiosis . Superficial lymphocytic perivascular infiltrate with possible occasional eosinophils . Excoriations in pruritic forms

Differential diagnoses ] Psoriasis vulgaris Psoriasiform acanthosis, intra- and subcorneal collections of neutrophils, broad hyperparakeratosis, minimal or no spongiosis ] Mycosis fungoides (early stage) Psoriasiform or broad-based acanthosis, little or no spongiosis but epidermotropism of lymphocytes, many of which are atypical

Comment Distinguishing between chronic dermatitis and psoriasis may be impossible microscopically, especially for palmoplantar, irritated or treated lesions. Tinea and dermatitis are so similar histologically that a PAS stain should always be performed to exclude the presence of fungal elements.

Dermatitis ] 21

parakeratosis

acanthotic epidermis

lymphocytic perivascular infiltrate

parakeratosis with serum crusts

spongiosis with lymphocytes

2.1.2 Prurigo Definition Reaction pattern secondary to chronic exogenous irritation through scratching and rubbing. Multiple causes (arthropod assault, infestation, metabolic disease, artifact)

Clinic

Flat nodule with central excoriation or crust, found on areas which can be manipulated, such as forearms. Marked pruritus. Often lichenification of adjacent skin

Variant

Prurigo nodularis with larger nodules

Histopathology  Hyperparakeratosis with inclusion of fibrinous-hemorrhagic exudate  Crescendo-like acanthosis, sometimes with pseudo-carcinomatous hyperplasia of epidermis with thickened granular layer, little or no spongiosis  Scattered apoptotic keratinocytes, intraepidermal erythrocytes  Circumscribed epidermal defect (erosion, ulceration) possible  Fibrotic vertically-arranged collagen bundles in the elongated dermal papillae  Moderate lymphocytic perivascular infiltrate with occasional eosinophils

Differential diagnoses ] Scabies ] ] ] ]

Chronic lesions have prurigo changes but still a persistent infiltrate usually with eosinophils. Definitive diagnosis by identifying mite, eggs or feces Reactive perforating collagenosis Sharply-bordered flat ulceration, collagen at base is damaged with basophilic collagen remnants in crust Psoriasis Hyperparakeratosis with accumulations of neutrophils, psoriasiform acanthosis with elongated rete ridges and dermal papillae Verrucous lichen planus Interface dermatitis with vacuolar change especially at tips of rete ridges. Wedgeshaped hypergranulosis. Acanthosis Verrucous carcinoma Pushing or invasive broad strands of well-differentiated squamous epithelium with moderate atypia

Prurigo ] 23

Prurigo nodularis crescendo-like epidermal hyperplasia

thickened granular layer

discrete spongiosis

hyperparakeratosis

lymphocyte infiltrate with admixed macrophages

fibrosis

Scabies excoriation

inflammatory infiltrate

mite

infiltrate with neutrophils

2.1.3 Psoriasis Definition Inflammatory dermatosis with genetic predisposition, characteristic morphology (scales or pustules on erythematous base), sites of predilection and a chronic-recurrent course

Clinic

Circumscribed erythematous patches and plaques with silvery scales, favoring knees, elbows, gluteal cleft and scalp. Pustular variant most common on palms and soles

Histopathology  Hyperparakeratosis  Collections of neutrophils in tiny unicellular pustules (Kogoj pustule) and larger confluent abscesses (Munro microabscess); in both spinous and cornified layers  Focal loss of granular layer, pale-staining epidermis with suprapapillary thinning (thinned epidermis) over elongated dermal papillae  Uniform acanthosis with elongated rete ridges (psoriasiform acanthosis)  Ectatic capillaries in the elongated dermal papillae  Superficial lymphocytic perivascular infiltrate with admixture of occasional neutrophils Variants  Pustular psoriasis (Sec. 2.1.4): Exocytosis of numerous neutrophils forming larger microabscesses or pustules in the upper epidermis, along with spongiosis  Guttate psoriasis: Acute form with mild spongiosis, exocytosis of neutrophils with microabscesses and overlying parakeratotic caps

Differential diagnoses ] Dermatitis

Subacute and chronic dermatitis with broad-based acanthosis, with widened rete ridges, spongiosis, and retained granular layer ] Tinea Exocytosis of neutrophils with presence of fungal elements in cornified layer with PAS stain ] Pityriasis rubra pilaris Horizontal and vertical pattern of changing ortho- and parakeratosis (chessboard pattern). Discrete acanthosis, sparse lymphocytic infiltrate ] Drug eruptions Sometimes psoriasiform, for example with b-blockers and lithium. Eosinophils may be present

Comment It may be impossible to separate psoriasis from subacute and chronic dermatitis, especially if the lesions have been irritated or treated. Always do PAS stain to exclude tinea.

Psoriasis ] 25

hyperparakeratosis

acanthosis with elongated rete ridges

neutrophils in stratum spinosum neutrophils

absent stratum granulosum

dilated elongated capillaries

2.1.4 Pustular psoriasis Definition Pustular variant of psoriasis Clinic

Pustules on erythematous base; most commonly found on palms and soles

Histopathology     

Moderate hyperparakeratosis Exocytosis and primarily subcorneal collections of neutrophils in spinous layer Focal loss of granular layer with pale-staining epidermis Broad-based acanthosis and modest spongiosis in areas of exocytosis Superficial lymphocytic perivascular infiltration with admixture of neutrophils

Differential diagnoses ] Subcorneal pustulosis Subcorneal collection of neutrophils (see comment) ] Impetiginized dermatitis Broad-based acanthosis, spongiosis. Inclusions of exudate and neutrophils in cornified layer ] Pustular tinea Exocytosis of neutrophils with pustules but presence of fungal elements in cornified layer with PAS stain ] Impetigo Subcorneal acantholysis with exudate and numerous neutrophils in cornified layer. Clefting with acantholysis mostly beneath cornified layer, producing subcorneal blisters ] Pustular drug eruption Focal discrete spongiosis with subcorneal pustules, occasionally including eosinophils. Usually histologically identical to pustular psoriasis

Comment Pustular psoriasis, impetigo and subcorneal pustulosis are often impossible to separate histologically. Subcorneal pustulosis may be a presenting feature of IgA pemphigus. When pustules are present, always do a PAS stain to exclude a pustular tinea.

Pustular psoriasis ] 27

parakeratosis

psoriasiform acanthosis

spongiform pustule

neutrophils

2.1.5 Pityriasis rosea Definition Inflammatory dermatosis of unknown, but perhaps viral, etiology Clinic

Initial lesion is scaly erythematous plaque (target lesion); it is followed by numerous smaller oval slightly scaly patches along the skin lines (Christmas tree pattern). Spontaneous resolution over weeks to months

Histopathology    

Focal hyperkeratosis Slight acanthosis with widened rete ridges Discrete spongiosis with exocytosis of lymphocytes and occasionally a parakeratotic cap Lymphocytic infiltrates with occasional eosinophils in upper dermis, especially in widened dermal papillae  Extravasation of erythrocytes and occasional intraepidermal erythrocytes

Differential diagnoses ] Subacute dermatitis Acanthosis, spongiosis, exocytosis of lymphocytes. Superficial lymphocytic perivascular infiltrate, often with eosinophils ] Erythema annulare centrifugum Minimal epidermal changes and superficial lymphocytic perivascular infiltrate, identical to pityriasis rosea. Clinical information is needed to separate the two entities

Comment Acute to subacute dermatitis, pityriasis rosea and erythema annulare centrifugum share many features. The clinical pictures are usually quite different. The main histological clues are more epidermal changes in dermatitis and a dense infiltrate with less prominent epidermal change in erythema annulare centrifugum.

Pityriasis rosea ] 29

focal parakeratosis

slight lymphocytic perivascular infiltrate with exocytosis of erythrocytes

discrete spongiosis

lymphocytes

erythrocytes outside of vessel

modest acanthosis

2.1.6 Cutaneous fungal infections Definition Cutaneous or mucocutaneous infections caused by dermatophytes, yeasts or molds Clinic

Annular, erythematous lesions with peripheral scale; sometimes pustular especially in children. In intertriginous areas, maceration and erythema; in hair-bearing areas, pustular and folliculitic lesions. Mucosal involvement with yeasts usually with white easily-removed plaques or atrophic erythematous patches

Histopathology Tinea corporis, manuum et pedum  Epidermis with mild acanthosis, focal spongiosis and parakeratosis  Exocytosis of neutrophils with small collections in cornified layer  Fungal hyphae in cornified layer especially at border between ortho- and parakeratosis  Superficial lymphocytic perivascular infiltrate with occasional neutrophils or eosinophils Tinea capitis  Hair follicle is infiltrated by inflammatory cells, edematous, acanthotic and focally destroyed, producing abscess  Perifollicular dense mixed infiltrate with neutrophils, eosinophils and plasma cells  Fungal hyphae in or around the hair shaft and occasionally in the interfollicular cornified layer

Additional studies Hyphae and spores can be stained with PAS or Grocott stains. Fungi can also be identified immunohistochemically with an anti-M. bovis (BCG) antibody

Differential diagnoses ] Acute and subacute dermatitis Acanthosis, spongiosis, exocytosis of lymphocytes and neutrophils. Superficial lymphocytic perivascular infiltrate sometimes with eosinophils ] Psoriasis Psoriasiform acanthosis of rete ridges. Collections of neutrophils in areas with hyperparakeratosis ] Impetigo Subcorneal acantholysis and clefts containing neutrophils ] Folliculitis Follicular inflammation with bacteria identified with Gram or Giemsa staining

Comment Dermatophyte infections can mimic many inflammatory dermatoses; thus PAS or Grocott staining of all dermatitic or psoriatic lesions is wise. Sometimes the spores and hyphae are seen on H&E but usually the PAS or Grocott stains are required. In tinea versicolor, there is little inflammation and a cornified layer full of hyphae and spores. Pityrosporon are often found in hair follicles but usually not clinically relevant (exception is massive follicular damage with many organisms and inflammation). In contrast fungal hyphae in follicles are always pathogenic.

Cutaneous fungal infections ] 31

Tinea parakeratosis

acanthotic epidermis

fungal elements in stratum corneum (right side PAS stain)

Candidiasis parakeratosis

acanthotic mucosal epithelium

yeast elements (right side PAS stain)

2.1.7 Viral papillomas Definition Benign epithelial tumors caused by human papilloma virus (HPV) Clinic

Variants

. Verruca vulgaris: hyperkeratotic papules with dark inclusions (inclusions of hemorrhagic exudate in hyperparakeratotic cornified layer). Typical sites include hands, palms and soles . Verruca plana: polygonal flat papules without marked hyperkeratosis . Condyloma acuminatum: hyperpigmented or skin-colored papule without hyperkeratosis in anogenital area

Histopathology Verruca vulgaris  Focal acanthosis and papillomatosis with confluence of elongated rete ridges  Hyperparakeratosis with focal parakeratosis and hemorrhage over the papillary tips  Koilocytes with clear cytoplasm, condensed nuclei in granular layer  Ectatic capillaries in papillae  Variable lymphocytic infiltrate Condyloma acuminatum  Broad-based acanthosis, papillomatosis, no hyperkeratosis  Focal parakeratosis  Few koilocytes, sparse infiltrate

Differential diagnoses ] Seborrheic keratosis Broad-based localized acanthosis, intraepithelial horn cysts. No confluence of elongated rete ridges ] Palmoplantar keratoderma Hyperkeratosis, thickened or otherwise altered (for example in epidermolytic hyperkeratosis) granular layer ] Epidermal nevus Many histological variants; some with only papillomatosis and hyperkeratosis, thus very similar to seborrheic keratosis but latter usually has horn pseudocysts; others with persistent inflammation and parakeratosis (ILVEN = inflammatory linear verrucous epidermal nevus); yet others show epidermolytic hyperkeratosis with abnormal granular layer ] Bowenoid papulosis Condyloma-like papules with multiple mitoses and marked pleomorphism in keratinocytes in all epidermal layers, sometimes increased melanin

Comment In anogenital area seborrheic keratosis and condyloma acuminatum can be histologically identical. The age of patient helps most. HPV antigens or DNA can be identified with immunohistochemical staining or PCR.

Viral papillomas ] 33

Verruca vulgaris columns of hyperparakeratosis orthohyperkeratosis filiform hyperplastic epidermis

koilocytes

parakeratosis

koilocytes

Condyloma acuminatum hyperplastic epithelium

vessel-rich stroma

koilocytes

2.1.8 Molluscum contagiosum Definition Benign epithelial tumor caused by infection with molluscum contagiosum virus, a DNA virus in the poxvirus group

Clinic

Usually multiple grouped, dome-shaped papules with a central dell. Smaller lesions often lack dell. More common in children, especially those with atopic dermatitis. In adults usually anogenital

Histopathology  Circumscribed multilobular epithelial proliferation with central keratinization  Intracytoplasmic inclusions, at the periphery eosinophilic and towards the center of the tumor more basophilic  Associated mixed or lymphocytic infiltrate  Occasionally lymphocytes are activated and enlarged Variant  Molluscum contagiosum folliculitis: Involvement of follicular epithelia with inclusion bodies and associated mixed infiltrate

Differential diagnoses The histological changes are pathognomonic. When the inflammation is intense or in folliculitis, the inclusion bodies may initially be masked and the infiltrate mistaken for a lymphoma until deeper sections unearth the classic changes.

Molluscum contagiosum ] 35

central crater

cystic tumor with acanthotic epithelium

eosinophilic inclusion bodies (molluscum bodies)

2.2 Epidermis Acantholysis 2.2.1 Darier disease 2.2.2 Hailey-Hailey disease 2.2.3 Herpes virus infections

2.2.1 Darier disease Definition Common genodermatosis inherited in an autosomal dominant fashion Clinic

Hyperkeratotic, often crusted papules usually on the trunk favoring the seborrheic areas. Chronic course with pruritus, secondary infections and inability to handle herpes viruses. Oral hyperkeratosis (cobblestones) and nail dystrophies

Histopathology  Focal hyperparakeratosis  Focal suprabasal acantholysis  Dyskeratotic keratinocytes with cytoplasmic clearing (corps ronds) and pyknotic nuclei (grains) in areas of acantholysis  Superficial lymphocytic perivascular infiltrate

Additional studies IF studies do not reveal antibodies against epidermal components

Differential diagnoses ] Grover disease (transient acantholytic dermatosis) Intensely pruritic tiny papules on trunk, usually in men > 50 years of age. Focal suprabasal acantholysis with dyskeratosis and hyperkeratosis. Occasionally fibrinous exudate in cornified layer ] Hailey-Hailey disease Suprabasal acantholysis involving all epidermal layers, dyskeratotic keratinocytes, crusts with secondary bacterial infection. IF examinations negative ] Pemphigus vulgaris Extensive suprabasal acantholysis extending into hair follicles; no dyskeratosis. Infiltrate often contains eosinophils. IF: Epidermal intercellular deposits of IgG and C3 directed against desmogleins, components of the hemidesmosome; circulating antibodies are present ] Warty dyskeratoma Solitary benign epithelial tumor with epidermal invagination, suprabasal acantholysis and dyskeratotic cells; often involves hair follicle

Comment Grover disease may exactly mimic Darier disease, Hailey-Hailey disease or pemphigus vulgaris. The clinical picture usually provides the answer.

Darier disease ] 39

focal hyperparakeratosis

suprabasal acantholysis

dyskeratotic keratinocytes

acantholysis

lymphocytic infiltrate

2.2.2 Hailey-Hailey disease Definition Genodermatosis with classic predilection sites inherited in an autosomal dominant fashion

Clinic

Circumscribed erythematous eroded or crusted patches and plaques usually in the axillae, groin and nape. Chronic-recurrent course with frequent secondary infections

Histopathology    

Hyperparakeratosis with inclusions of fibrinous exudate, neutrophils and bacteria Broad-based transepidermal acantholysis (dilapidated brick wall) Scattered dyskeratotic keratinocytes Superficial perivascular lymphocytic infiltrate

Additional studies IF studies do not reveal antibodies against epidermal components

Differential diagnoses ] Darier disease and Grover disease Focal suprabasal acantholysis; many dyskeratotic keratinocytes (corps ronds and grains) with hyperparakeratosis. IF examinations negative ] Pemphigus vulgaris Extensive suprabasal acantholysis extending into hair follicles; no dyskeratosis. Infiltrate often contains eosinophils. IF: Epidermal intercellular deposits of IgG and C3 directed against desmogleins, components of the hemidesmosome; circulating antibodies are present ] Warty dyskeratoma Solitary benign epithelial tumor with epidermal invagination, suprabasal acantholysis and dyskeratotic cells; often involves hair follicles

Comment The histological findings in pemphigus vulgaris can overlap with Hailey-Hailey disease, leading to the confusing name of benign familial pemphigus. Under the microscope pemphigus vulgaris is more likely to have suprabasal acantholysis while Hailey-Hailey disease shows full-thickness acantholysis. The distinction is best made with direct immunofluorescence studies, as Hailey-Hailey disease is invariably negative

Hailey-Hailey disease ] 41

parakeratosis

acanthosis with acantholysis

acantholysis in all layers of epidermis

lymphocytic infiltrate

2.2.3 Herpes virus infections Definition Infection of the skin or mucosa by herpes simplex virus (HSV) type 1 or 2, or by varicella zoster virus (VZV)

Clinic Variants

Grouped blisters on erythematous base . Herpes folliculitis, VZV vasculitis . Hyperkeratotic ulcerated chronic lesions in immunosuppressed patients

Histopathology  Acantholysis with intraepidermal vesicles  Epithelial cells with ballooning degeneration, steel gray nuclei, multinucleate syncytial epithelial giant cells  Superficial and deep lymphocytic perivascular infiltrate often with neutrophils and plasma cells  With VZV infection often focal vasculitis with nuclear dust Variant

 “Herpes incognito” with dense dermal lymphocytic infiltrate and necrotic adnexal structures (usually hair follicles)

Additional studies Viral antigens or DNA can be identified with immunohistochemical stains, in situ hybridization or polymerase chain reaction (PCR). DIF is negative

Differential diagnoses ] Pemphigus vulgaris Extensive suprabasal acantholysis extending into hair follicles; no dyskeratotic cells. Infiltrate often contains eosinophils. No ballooning degeneration or multinucleate giant cells. IF: Epidermal intercellular deposits of IgG and C3 directed against desmogleins, components of the hemidesmosome; circulating antibodies are present ] Darier disease and Grover disease Focal suprabasal acantholysis; many dyskeratotic keratinocytes (corps ronds and grains) with hyperparakeratosis. IF examinations negative ] Orf and milker’s nodule Pale keratinocytes with ballooning degeneration, no acantholysis or blisters. Tricolor sign – red cornified layer, pale (white) necrotic epidermis, blue (basophilic) dermal infiltrate (red, white and blue – the three colors of the French flag)

Comments HSV and VZV infections cannot be separated histologically. VZV does tend to have deeper and denser infiltrates.

Herpes virus infections ] 43

intraepidermal blister with acantholysis

balloon cells

acantholytic cells

lymphocytes and neutrophils

2.3 Bullous diseases 2.3.1 Pemphigus foliaceus 2.3.2 Pemphigus vulgaris 2.3.3 Bullous pemphigoid 2.3.4 Dermatitis herpetiformis 2.3.5 Porphyria cutanea tarda

2.3.1 Pemphigus foliaceus Definition Autoimmune bullous dermatosis with acantholysis mediated by antibodies directed against desmoglein 1. Some cases are drug-induced Variant

Endemic pemphigus foliaceus (fogo selvagem) in Amazon Basin likely has infectious trigger

Clinic

Erythematous scaly lesions on head and trunk favoring seborrheic areas. Flaccid unstable blisters soon evolve into erosions with crusts

Histopathology    

Separation or loss of cornified and granular layer (naked epidermis) Denuded epidermis covered with exudate and neutrophils Acantholysis at level of granular layer Superficial lymphocytic perivascular infiltrate with neutrophils and eosinophils

Additional studies . DIF: Intercellular deposits of IgG and C3 in the upper levels of epidermis . IIF: Circulating autoantibodies against desmoglein 1

Differential diagnoses ] Impetigo Toxin-mediated acantholysis at the level of the granular layer. Mixed infiltrate with neutrophils and plasma cells ] Pemphigus vulgaris Extensive suprabasal acantholysis extending into hair follicles; no dyskeratosis. Infiltrate often contains eosinophils. IF: Epidermal intercellular deposits of IgG and C3 directed against desmogleins, components of desmosomes, circulating anti-desmosomal antibodies are present

Comment Pemphigus foliaceus and impetigo are often histologically indistinguishable. Clinical findings and immunofluorescent examinations may help establish the diagnosis of pemphigus foliaceus; identification of staphylococci in an intact blister suggests impetigo but bacteria may reflect secondary contamination.

Pemphigus foliaceus ] 47

subcorneal blister

acantholysis

2.3.2 Pemphigus vulgaris Definition Autoimmune bullous dermatosis with suprabasal acantholysis mediated by antibodies directed against desmoglein 3 and 1

Clinic

Flaccid unstable blisters which develop on seemingly normal skin. Blisters can be induced by rubbing or enlarged by gentle pressure (Nikolsky phenomenon). 80% of patients have oral involvement, which may be initial site

Histopathology Pre-bullous phase  Epidermis with spongiosis and exocytosis of eosinophils (eosinophilic spongiosis)  Superficial mixed interstitial and perivascular infiltrate rich in eosinophils Bullous phase  Broad suprabasal acantholysis with separation of overlying epidermal layers; hair follicles involved  Blister lumen contains acantholytic keratinocytes, fibrin, and eosinophils. No dyskeratotic cells  Superficial mixed interstitial and perivascular infiltrate rich in eosinophils Variant  IgA pemphigus: Intercellular IgA and C3 deposits. Marked exocytosis of neutrophils with frequent pustules; overlaps with subcorneal pustulosis

Additional studies . DIF: Epidermal intercellular deposits of IgG (100%), C3 (90%) and rarely IgM . IIF: Circulating -autoantibodies against desmoglein 3 and 1; titers mostly correlate with disease activity Always biopsy perilesional skin for the DIF. Biopsies from blistered skin may give false-negative results

Differential diagnoses ] Pemphigus foliaceus Acantholysis in granular layer with separation or loss of cornified and granular layer (naked epidermis). Surface contains exudates and neutrophils, IgG against desmoglein 1 only ] Hailey-Hailey disease Suprabasal acantholysis involving all epidermal layers, dyskeratotic keratinocytes, crusts with secondary bacterial infection. IF examinations negative ] Darier disease and Grover disease Focal suprabasal acantholysis; many dyskeratotic keratinocytes (corps ronds and grains) with hyperparakeratosis. IF examinations negative ] Bullous impetigo Subcorneal loss of adhesion with many neutrophils (caused by clearage of desmoglein 1 by bacterial exotoxin) ] Herpes virus infections Acantholysis with ballooning degeneration of keratinocytes with steel gray nuclei; multinucleate syncytial giant cells

Pemphigus vulgaris ] 49

broad suprabasal acantholysis

acantholytic keratinocytes

involvement of adnexa

lymphocytes and granulocytes

2.3.3 Bullous pemphigoid Definition

Autoimmune bullous dermatosis with subepidermal blister formation mediated by antibodies directed against the hemidesmosomal proteins BP180 and BP230

Clinic

Dense stable blisters on an erythematous base; often urticarial precursor lesions. Disease of the elderly (60–80 years)

Variant

Mucous membrane pemphigoid: favors mucosa (conjunctiva, mouth, genitalia) with scarring and synechiae. DIF: Linear deposits of IgG, IgA and C3 at dermal-epidermal junction (DEJ). IIF: Circulating antibodies directed against BP180, laminin 332, a6b4 integrin

Histopathology Pre-bullous phase  Epidermis with spongiosis and exocytosis of eosinophils. Mixed infiltrate rich in eosinophils and edema in upper and mid-dermis Bullous phase  Subepidermal blister with separation of entire epidermis. Blister lumen contains eosinophils, neutrophils, and fibrin. In upper dermis mixed infiltrate rich in eosinophils with occasional neutrophils

Additional studies . DIF: Linear deposits of IgG and C3 and IgA (40%) at the DEJ. In salt-split skin, IgG antibodies on the roof of blister. Immunohistochemistry: type IV and type VII collagen at base of blister . IIF: Circulating IgG autoantibodies against BP 180 and BP230. Immunoserology: titers of antibodies against NC16A correlate with disease course

Differential diagnoses ] Epidermolysis bullosa acquisita Autoimmune bullous dermatosis with subepidermal blisters mediated by antibodies directed against collagen VII. Clinically and histologically may resemble bullous pemphigoid or porphyria cutanea tarda. Usually sparse infiltrate with subepidermal neutrophils and few eosinophils. DIF: Linear IgG (less often C3 or IgA) at DEJ. With salt-split skin, immunoglobulin IgG (and rarely IgA) deposits at base of blister. IIF: Circulating antibodies against type VII collagen. Immunohistochemistry: Type IV collagen at the roof of the blister ] Epidermolysis bullosa Congenital mechanobullous disorder with many forms. Intra- or subepidermal blisters. Blisters usually with minimal infiltrate; often scarring. IF examination negative ] Pemphigoid gestationis Pemphigoid during 3rd trimester of pregnancy. Clinically blisters less pronounced but histologically identical. IF more likely to reveal C3 than IgG at DEJ ] Dermatitis herpetiformis Subepidermal blister with neutrophils in dermal papillae. DIF: Granular or linear deposits of IgA at DEJ ] Linear IgA bullous dermatosis (chronic bullous disease of childhood) Subepidermal blisters with neutrophilic infiltrate. DIF: Linear deposits of IgA and C3 (ca. 50%) at the DEJ. IIF: In 50% IgA reacting with the epidermal site of salt-split skin. Autoantigens: splice variant of BP180 ectodomain, BP230 ] Porphyria cutanea tarda Subepidermal blister, retained dermal papillae (naked papillae), scarring; PAS-positive basement fragments in vessels and blister roof (caterpillar bodies). Sparse infiltrate ] Bullous arthropod assault reaction Subepidermal edema leading to mechanical blister. Deep wedge-shaped infiltrate with numerous eosinophils ] Bullous systemic lupus erythematosus Subepidermal blister with band-like arrangement of neutrophils beneath basement membrane. DIF: Linear or granular deposits of IgG and C3 at the DEJ. Autoantigen is type VII collagen

Comment Clinical data, DIF, IIF immunohistochemistry and often salt-split skin or more specialized techniques are needed to sort out subepidermal blisters. Always biopsy perilesional skin for IF studies.

Bullous pemphigoid ] 51

subepidermal blister

fibrin in blister lumen

neutrophils and eosinophils in blister lumen

mixed dermal infiltrate with neutrophils and eosinophils

eosinophils

spongiosis

neutrophils

edema

2.3.4 Dermatitis herpetiformis Definition Autoimmune bullous dermatosis with subepidermal blister associated with IgA antibodies directed against epidermal transglutaminase; obligatory association with gluten-sensitive enteropathy (autoantigen is tissue transglutaminase)

Clinic

Grouped papulovesicles, usually excoriated; most common on knees, elbows and sacrum. Intense pruritus

Histopathology  Focal subepidermal blisters with collections of neutrophils in dermal papillae  Papillary dermal edema  Superficial mixed perivascular infiltrate with neutrophils

Additional studies DIF: Granular deposits of IgA in dermal papillae of non-lesional skin; rarely linear and granular deposits. Cross-reactive IgA antibodies against tissue transglutaminase and endomysial antigens (on monkey esophagus)

Differential diagnoses ] Linear IgA dermatosis (chronic bullons disease of childhood) Clinically usually affects children, more likely to have grouped blisters in rosette fashion; histology similar but fewer changes in papillae. DIF: Linear deposits of IgA (and C3) at DEJ. Autoantigens: splice variant of soluble BP180 ectodomain, BP230 ] Bullous pemphigoid and epidermolysis bullosa acquisita Broad-based subepidermal blister. No papillary abscesses. Linear deposits of IgG and C3 at DEJ ] Subacute cutaneous lupus erythematosus Vacuolar changes at DEJ, occasionally leading to subepidermal separation. Lymphocytic infiltrate with occasional neutrophils. DIF: Lupus band positive (60%). Very rarely systemic bullous lupus erythematosus overlaps with epidermolysis bullosa acquisita with IgG autoantibodies to type VII collagen ] Epidermolysis bullosa Congenital mechanobullous disorder with many forms. Intra- or subepidermal blisters. Blisters usually with minimal infiltrate; often scarring. IF examination negative

Comment Dermatitis herpetiformis is best separated from other diseases with subepidermal blisters by history and IF examination. When confronted with poorly understood pruritic or burning excoriated lesions, always consider dermatitis herpetiformis and perform DIF examinations of non-lesional skin.

Dermatitis herpetiformis ] 53

subepidermal blister

enlarged papillary bodies with neutrophils

discrete lymphocytic perivascular inflitrate with scattered neutrophils

discrete spongiosis

collections of neutrophils and occasional eosinophils

edema with inflammatory cells

2.3.5 Porphyria cutanea tarda Definition Metabolic disorder with disturbed hemoglobin synthesis and accumulation of phototoxic metabolites (porphyrins)

Clinic

Increase photosensitivity with dense blisters, milia and scars in sun-exposed areas, especially backs of hands

Histopathology    

Subepidermal blister with little inflammation Retained dermal papillae which extend into blister lumen (festooning, naked papillae) Deposits of eosinophilic PAS-positive material around small vessels in superficial dermis Apoptotic keratinocytes. Accumulations of degenerated basement membrane type IV collagen in the spinous layer (caterpillar bodies)

Additional studies DIF: IgG (rarely IgM and C3) are trapped at DEJ and around papillary dermal vessels. Type VII collagen at base of blister, type IV on roof. Diagnosis confirmed by elevated urine porphyrins, blood examinations, genetic and enzymatic studies

Differential diagnoses ] Bullous pemphigoid and epidermolysis bullosa acquisita Broad-based subepidermal blister. Usually infiltrate with eosinophils in bullous pemphigoid, but cell-poor types exist. EBA can be histologically identical to PCT and only be separated with biochemical studies. DIF: Deposits of IgG and C3 at DEJ ] Epidermolysis bullosa Congenital mechanobullous disorder with many forms. EB simplex forms have degeneration in basal layer and blisters but no scarring. Junctional and dystrophic forms have subepidermal blisters. Blisters usually with minimal infiltrate; often scarring. IF examination negative ] Bullous disease of diabetes Subepidermal blister with little infiltrate. No apoptotic epidermal keratinocytes

Comments Erythropoietic protoporphyria (EPP) features marked photosensitivity early in life and distinctive facial scarring. Biopsy reveals more massive deposits of eosinophilic PAS-positive material in dermal papillae and around dermal vessels

Porphyria cutanea tarda ] 55

subepidermal blister naked papillary bodies

almost no infiltrate

naked papillary bodies

almost no infiltrate

caterpillar bodies – collagen IV-positive basement membrane fragments

PAS-positive, thickened vessel walls

2.4 Interface dermatoses 2.4.1 Erythema multiforme 2.4.2 Pityriasis lichenoides 2.4.3 Lichen planus 2.4.4 Lichen sclerosus 2.4.5 Lupus erythematosus 2.4.6 Pigmented purpuric dermatoses

2.4.1 Erythema multiforme Definition Immunologic-allergic reaction usually triggered by herpes simplex virus or medications. When medications are involved, progression to more severe skin reactions such as Stevens-Johnson syndrome possible

Clinic

Targetoid annular lesions with central epidermal necrosis (iris lesions). Sites of predilection: Backs of hands, palms, soles

Histopathology  Orthokeratosis  Apoptotic keratinocytes, exocytosis of lymphocytes, satellite cell necrosis (necrotic keratinocyte accompanied by lymphocyte)  Over time, epidermal necrosis in central part of lesion  Edema in upper dermis, sometimes producing subepidermal blisters  Superficial lymphocytic perivascular infiltrate, sometimes with eosinophils  Exocytosis of erythrocytes

Differential diagnoses ] Toxic epidermal necrolysis Widespread epidermal necrosis with separation or loss of entire epidermis. At periphery apoptotic keratinocytes. Minimal lymphocytic infiltrate ] Phytophototoxic reaction Apoptotic keratinocytes and epidermal necrosis. Marked edema with subepidermal blisters. Minimal infiltrate ] Acute graft-versus-host reaction Apoptotic keratinocytes, satellite cell necrosis, vacuolar change at DEJ, sparse lichenoid infiltrate, occasional eosinophils, no edema ] Fixed drug eruption Incontinence of pigment. Apoptotic keratinocytes, satellite cell necrosis, vacuolar changes at DEJ, superficial lymphocytic perivascular infiltrate with eosinophils and neutrophils. No edema ] Porphyria cutanea tarda Subepidermal blister, scarring fibrosis in upper dermis. Deposits of eosinophilic PAS-positive material in and around vessels of superficial dermis

Comment Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and graft-versushost disease share many histological features. The clinical findings and history determine the diagnosis – not the histology

Erythema multiforme ] 59

orthokeratosis

lichenoid inflammation with necrotic keratinocytes lymphocytic infiltrate in upper dermis

orthokeratosis

necrotic keratinocytes

lymphocyte

edema

lymphocytic infiltrate

2.4.2 Pityriasis lichenoides Definition Inflammatory dermatosis with broad clinical spectrum in which acute and chronic forms with frequent overlap are distinguished. Acute cases may have infectious cause

Clinic

. Acute form: Pityriasis lichenoides et varioliformis acuta (PLEVA): Disseminated erythematous crusted and later scaly hemorrhagic papules . Chronic form: Pityriasis lichenoides chronica (PLC): Slightly erythematous papules and plaques with thick sheet of scale

Histopathology PLEVA  Focal hyperparakeratosis with inclusions of neutrophils  Foci with vacuolar change at DEJ, spongiosis, apoptotic keratinocytes and exocytosis of lymphocytes  Varying degrees of epidermal necrosis  Wedge-shaped superficial and deep lymphocytic infiltrate more prominent around vessels. Occasionally activated, enlarged atypical lymphocytes present. Cytotoxic infiltrate of CD8+, TIA-1 lymphocytes  Exocytosis of erythrocytes with dermal and epidermal accumulations PLC  Epidermis with minimal spongiosis and parakeratosis. No necrosis  Superficial band-like or scattered lymphocytic infiltrate

Differential diagnoses ] Acute and subacute dermatitis Spongiosis, less hyperparakeratosis, eosinophils ] Pityriasis rosea Focal spongiosis, parakeratotic caps, no apoptotic keratinocytes, enlarged dermal papillae with sparse lymphocytic infiltrate ] Acute graft-vs-host reaction Apoptotic keratinocytes, satellite cell necrosis, vacuolar change at DEJ, superficial infiltrate ] Fixed drug eruption Incontinence of pigment. Apoptotic keratinocytes, satellite cell necrosis, vacuolar changes at DEJ, superficial lymphocytic perivascular infiltrate with eosinophils and neutrophils. No edema ] Cutaneous T-cell lymphoma Lining up of atypical lymphocytes along DEJ, epidermotropism without spongiosis. Necrotic keratinocytes variable, depending on lymphoma subtype ] Guttate psoriasis No apoptotic keratinocytes. Parakeratotic caps with neutrophils in upper parts of epidermis and in hyperkeratotic parts of cornified layer. No cytotoxic infiltrate

Comment PLEVA and PLC overlap. In PLEVA the presence of atypical lymphocytes with epidermotropism can mimic lymphomatoid papulosis. Sometimes clonality can be proven, but this does not equate with a lymphoma. The clinical picture then determines the diagnosis

Pityriasis lichenoides ] 61

broad-based parakeratosis orthokeratosis

wedge-shaped lymphocytic perivascular infiltrate

necrotic keratinocyte intraepidermal lymphocytes

exocytosis of erythrocytes

2.4.3 Lichen planus Definition Inflammatory dermatosis with damage of basal keratinocytes by cytotoxic T cells Clinic

Pruritic polygonal violet papules, especially likely to affect volar surface of wrist. Possible involvement of mucosa with Wickham striae, hair (cicatricial alopecia) and nails (pterygium)

Histopathology       

Focal hyperkeratosis Wedge-shaped thickening of granular layer Acanthosis with saw-tooth pattern to rete ridges Interface dermatitis with vacuolar change at DEJ and apoptotic keratinocytes (Civatte bodies) Exocytosis of lymphocytes into lower 1/3 of epidermis Subepidermal band-like lymphocytic infiltrate with occasional eosinophils Incontinence of pigment in upper dermis with melanophages

Differential diagnoses ] Lichenoid drug reaction Very similar but usually more eosinophils and apoptotic keratinocytes, occasionally parakeratosis ] Acute graft-vs-host reaction Apoptotic keratinocytes, satellite cell necrosis, vacuolar change at DEJ, less intense lymphocytic infiltrate ] Fixed drug eruption Incontinence of pigment. Apoptotic keratinocytes, satellite cell necrosis, vacuolar changes at DEJ, superficial lymphocytic perivascular infiltrate with eosinophils and neutrophils ] Mycosis fungoides Lining up of atypical lymphocytes along DEJ, epidermotropism without spongiosis. Infiltrate may be band-like but rarely damages keratinocytes ] Lichen sclerosus Initially lichenoid infiltrate very similar to lichen planus; later epidermal atrophy, pale sclerotic upper dermis with band-like infiltrate located deeper ] Lichenoid keratosis Can be histologically identical to lichen planus but a solitary lesion, often an irritated flat seborrheic keratosis on neck or upper trunk

Lichen planus ] 63

hyperkeratosis hypergranulosis

lichenoid lymphocytic infiltrate

apoptotic keratinocytes

saw tooth rete ridges

2.4.4 Lichen sclerosus Definition Inflammatory dermatitis with interface dermatitis (early stage) and sclerotic collagen in upper dermis (late stage)

Clinic

Initially erythematous patches, later thin white porcelain-like patches and plaques with an erythematous rim. Site of predilection: genitalia

Histopathology Early stage  Interface dermatitis with vacuolar change at the DEJ and band-like lymphocytic infiltrate (lichenoid pattern) Late stage  Epidermal atrophy with hyperkeratosis  Focal vacuolar change at DEJ; subepidermal separation possible  Sclerotic pale-staining collagen in upper dermis with telangiectases and often exocytosis of erythrocytes. Pigment incontinence  Diffuse or band-like lymphocytic infiltrate in mid-dermis beneath sclerotic zone

Differential diagnoses ] Lichen planus Interface dermatitis with band-like lymphocytic infiltrate and vacuolar change. No sclerosis in upper dermis ] Acute graft-vs-host reaction Apoptotic keratinocytes, satellite cell necrosis, vacuolar change at DEJ, less intense lymphocytic infiltrate ] Mycosis fungoides Lining up of atypical lymphocytes along DEJ, epidermotropism without spongiosis. Infiltrate may be band-like but rarely damages keratinocytes. Fibrotic changes, but no sclerosis in upper dermis

Comment Early lesions and the active border of lichen sclerosus cannot always be separated from lichen planus. In some cases the early dense lymphocytic infiltrate of lichen sclerosus can be confused with an epidermotropic lymphoma. Melanocytic nevi arising in lichen sclerosus often show striking atypia and are difficult to interpret.

Lichen sclerosus ] 65

epidermal atrophy focal hyperkeratosis

edema

lymphocytic infiltrate

vacuolar degeneration of basal keratinocytes

pale sclerotic dermis

blister with hemorrhage

2.4.5 Lupus erythematosus Definition

Autoimmune disease with cutaneous, mixed or systemic involvement

Clinic

Chronic cutaneous or discoid LE and subacute-cutaneous LE have erythematous scaly patches and plaques, often with central atrophy. Subacute LE may be strikingly annular or psoriasiform. Systemic LE often features acute symmetrical facial erythema (butterfly rash) as most common sign of photosensitivity. Sometimes juicy often facial nodules (lupus tumidus) or panniculitis

Histopathology Chronic and subacute cutaneous LE  Hyperparakeratosis with follicular plugs  Epidermal atrophy with apoptotic keratinocytes in basal layer (“sick epidermis”)  Interface dermatitis with vacuolar change at DEJ, apoptotic keratinocytes  Thickened (PAS-positive) basement membrane zone  Tight perivascular and periadnexal lymphocytic infiltrate, sometimes with plasma cells  Mucin deposits through dermis between strands of collagen  Telangiectases in upper dermis Systemic LE Interface dermatitis with vacuolar changes at DEJ and epidermal atrophy. Sometimes leukocytoclastic vasculitis with neutrophils Lupus tumidus Little or no epidermal change Massive mucin deposits with perivascular and periadnexal lymphocytic infiltrates Lupus panniculitis Lobular panniculitis with dense lymphocytic infiltrate, karyorrhexis of lymphocytes (not neutrophils), and plasma cells (Sec. 2.11.2)

Additional studies . DIF: Immunoglobulins and C3 deposited at DEJ in lesional skin of cutaneous LE and even non-involved, sun-protected skin of systemic LE (lupus band test) . Immunohistochemical stains: The lymphocytic infiltrate contains primarily T cells with admixture of B cells and plasma cells

Differential diagnoses Chronic and subacute cutaneous LE

] Dermatomyositis Interface dermatitis with mucin but much less of a subepidermal infiltrate ] Acute graft-vs-host reaction Apoptotic keratinocytes, satellite cell necrosis, vacuolar change at DEJ, less intense lymphocytic infiltrate. No mucin

Systemic LE

] Leukocytoclastic vasculitis Vessel changes similar but no epidermal changes except necrosis possible with severe involvement ] Drug reaction Vacuolar change at DEJ; superficial lymphocytic perivascular infiltrate with eosinophils

Lupus tumidus Both lymphocytic infiltrate of Jessner-Kanof and reticular erythematous mucinosis (REM syndrome) are variants. In one case the lymphocytic infiltrate dominates; in the other mucin ] Myxedema No epidermal changes. Less intense lymphocytic perivascular infiltrate. Usually lakes of mucin, especially for pre-tibial myxedema

Comment Always consider LE when confronted by mucin deposits.

Lupus erythematosus ] 67

follicular plugs

lymphocytic perivascular and periadnexal infiltrate

vacuolar degeneration of basal keratinocytes

thickened basal membrane

edema telangiectasis

lymphocytic infiltrate

actinic elastosis

2.4.6 Pigmented purpuric dermatoses Definition Spectrum of inflammatory dermatoses, characterized by red-brown lesions of varying size and pattern

Clinic

Red-brown purpuric macules, favoring legs below knees. May be speckled (Schamberg), annular (Majocchi), lichenoid (Gougerot-Blum), or eczematoid (Doucas-Kapetanakis)

Histopathology    

Dermal lymphocytic infiltrate either perivascular or lichenoid Dense band-like infiltrate in Gougerot-Blum form. Spongiosis in eczematoid form Exocytosis of erythrocytes with hemosiderin deposits No true vasculitis as leukocytoclasia, fibrin deposits and nuclear dust are absent. Some designate the lymphocytic perivascular infiltrate as lymphocytic vasculitis, but true vessel damage is rare

Differential diagnoses ] Fixed drug eruption Incontinence of pigment. Apoptotic keratinocytes, satellite cell necrosis, vacuolar changes at DEJ, superficial lymphocytic perivascular infiltrate with eosinophils and neutrophils. No exocytosis of erythrocytes or hemosiderin deposits ] Acute graft-vs-host reaction Apoptotic keratinocytes, satellite cell necrosis, vacuolar change at DEJ, less intense lymphocytic infiltrate, no exocytosis of erythrocytes or hemosiderin deposits ] Mycosis fungoides Lining up of atypical lymphocytes along DEJ, epidermotropism without spongiosis. Infiltrate may be band-like but rarely damages keratinocytes. Purpuric mycosis fungoides may be impossible to distinguish from a cell-rich pigmented purpura initially

Comments The many patterns of pigmented purpura cause clinical confusion but the microscopic picture is more uniform. Whether there is simply vessel leakage or true vessel damage remains controversial. Hemosiderin deposits may not be found in early disease stages.

Pigmented purpuric dermatoses ] 69

lichenoid lymphocytic infiltrate

exocytosis of erythrocytes

lymphocytes

siderophages (right iron stain marks siderophages blue)

2.5 Dermis Vascular disorders 2.5.1 Leukocytoclastic vasculitis 2.5.2 Granuloma faciale and erythema elevatum et diutinum 2.5.3 Polyarteritis nodosa 2.5.4 Cryoglobulinemia

2.5.1 Leukocytoclastic vasculitis Definition Destruction of small post-capillary venules by immunologic reaction often triggered by infectious agents or drugs

Clinic

Petechiae, purpura and especially palpable purpura, usually favoring the shins. Other forms may be urticarial, pustular, bullous, papulonecrotic or ulcerated. HenochSchönlein purpura is leukocytoclastic vasculitis in children with abdominal or joint pain

Histopathology  Epidermis usually unaffected, occasionally exocytosis of neutrophils, pustules and necrosis  Mixed perivascular infiltrate dominated by neutrophils but also containing lymphocytes and eosinophils around small vessels of upper dermis  Destruction of vessel wall by migrating neutrophils with nuclear dust (leukocytoclasia) in adjacent dermis  Fibrin in vessel wall  Exocytosis of erythrocytes

Additional studies DIF: Non-specific deposits of complement and fibrinogen as sign of vessel damage. In HenochSchönlein purpura, deposits of IgA, which may also affect kidney; occasionally IgG or IgM found. Immunoglobulins often only present in early lesions

Differential diagnoses ] Lymphocytic vasculitis Lymphocytic perivascular infiltrate, with lymphocytes in vessel wall, sometimes with fibrin deposits, but no leukocytoclasia ] Cryoglobulinemia Leukocytoclastic vasculitis with fibrin plugs and often mild superficial necrosis ] Granuloma faciale and erythema elevatum et diutinum Persistent form of leukocytoclastic vasculitis with red-brown nodules. Histologically more diffuse infiltrates with eosinophils (especially in granuloma faciale) and plasma cells. Slight exocytosis of erythrocytes. Lamellar fibrosis (cut-onion pattern) around infiltrates in chronic lesions ] Septic vasculitis Leukocytoclastic vasculitis, often papulonecrotic or pustular, with fibrin thrombi and fibrin in vessel walls or necrosis of vessel walls. Bacteria also present in destroyed vessels ] Polyarteritis nodosa Fibrin thrombi and vessel wall involvement of deeper mid-sized vessels but often associated with typical leukocytoclastic vasculitis in superficial dermis ] Wegener granulomatosis Granulomatous vasculitis with involvement of mid-sized vessels especially in upper airways, lungs and kidneys. Classically ANCA-positive. Most common skin presentation is leukocytoclastic vasculitis

Leukocytoclastic vasculitis ] 73

exocytosis of erythrocytes

spongiosis and early epidermal necrosis

vessel walls invaded and destroyed by neutrophils

eosinophil

neutrophils

leukocytoclasia

2.5.2 Granuloma faciale and erythema elevatum et diutinum Definition Inflammatory dermatoses of unknown etiology with chronic fibrosing leukocytoclastic vasculitis

Clinic

. Granuloma faciale: Red-brown nodules and plaques usually on face . Erythema elevatum et diutinum: Red-brown papules and nodules favoring extensor aspects of forearms

Histopathology  Vessel walls in upper and mid-dermis infiltrated by lymphocytes and neutrophils. Admixture of eosinophils (especially in granuloma faciale) and plasma cells. Leukocytoclasia.  In later lesions (especially erythema elevatum et diutinum) striking sclerosis, resembling face of cut onion, with plasma cells and occasionally residual foci of leukocytoclastic vasculitis Variant  Granulomatous form with infiltrates of macrophages, neutrophils and plasma cells

Differential diagnoses ] Leukocytoclastic vasculitis Other types have less infiltrate and more erythrocyte extravasation ] Sweet syndrome (acute febrile neutrophilic dermatosis) Diffuse or nodular infiltrates of neutrophils, usually without leukocytoclastic vasculitis, although vessel damage occasionally seen ] Eosinophilic cellulitis (Wells syndrome) Diffuse infiltrate of eosinophils with flame figures and no vasculitis ] Cutaneous pseudolymphomas B-cell pseudolymphoma has lymphoid follicles with tingible bodies (also a type of nuclear dust) but no vessel changes. T-cell pseudolymphoma has nodular lymphocytic infiltrates, perhaps with eosinophils, but no vessel changes ] Dermatofibroma Late fibrotic stages of erythema elevatum diutinum can mimic a dermatofibroma. The latter usually have epithelial hyperplasia and peripheral entrapment of collagen, but lack vessel changes

Comment Although granuloma faciale and erythema elevatum diutinum are clinically quite different, they share so many histological features that some consider them a single entity.

Granuloma faciale and erythema elevatum et diutinum ] 75

Granuloma faciale mixed granulomatous infiltrate with lymphocytes, plasma cells, eosinophils and neutrophils infiltrate in vessel wall

plasma cells

Erythema elevatum et diutinum (late stage) thinned epidermis

concentric fibrosis and sclerosis

neutrophils and leukocytoclasia as residual signs of vasculitis fibrosis and sclerosis

2.5.3 Polyarteritis nodosa Definition Systemic disease with involvement of small and mid-sized arteries. Variants with only cutaneous involvement occur. Overlaps with ANCA-positive vasculitides

Clinic

Livedo racemosa with subcutaneous nodules and sometimes ulcers

Histopathology  Epidermal necrosis and ulceration possible  Walls of mid-sized vessels in dermis and subcutis infiltrated by neutrophils and with fibrin deposits  Leukocytoclastic vasculitis often presents in superficial dermis; infiltrate may contain eosinophils as well as neutrophils, leukocytoclasia and exocytosis of erythrocytes  Little involvement of underlying fat

Differential diagnoses ] Leukocytoclastic vasculitis Clinically palpable purpura; histologically similar superficial vessel destruction but no involvement of deeper vessels ] Cryoglobulinemia Fibrin plugs in superficial vessels and often leukocytoclastic vasculitis with fibrin and PAS-positive cryoglobulin plugs and often superficial necrosis ] Wegener granulomatosis Granulomatous vasculitis with involvement of mid-sized vessels especially in upper airways, lungs and kidneys. Classically ANCA-positive. Many present with superficial leukocytoclastic vasculitis ] Churg-Strauss syndrome Granulomatous vasculitis with eosinophilia and asthma. Cutaneous lesions features eosinophilic granulomatous vasculitis of mid-sized vessels in deep dermis with palisading granulomas, also often rich in eosinophils ] Thrombophlebitis Large vein in the subcutaneous fat with thrombotic occlusion and mixed cellular infiltrate within the vessel wall ] Nodular vasculitis Mostly lobular panniculitis with leukocytoclastic vasculitis of subcutaneous vessels

Polyarteritis nodosa ] 77

focal inflammatory reaction around mid-sized artery at the dermissubcutis border

normal fat

vessel wall necrosis, fibrin deposits and inflammation of adjacent fat

2.5.4 Cryoglobulinemia Definition Elevated levels of cold-sensitive immunoglobulins cause hypercoagulability on cold exposure with thrombotic closure of superficial dermal vessels. Type I disease features monoclonal IgG or IgM proteins and may be associated with lymphoproliferative processes. Types II and III feature mixed polyclonal proteins and are more likely to be associated with collagen-vascular disorders or hepatitis C infection

Clinic

Hemorrhagic crusted superficial painful ulcers, often with jagged edges; usually around ankles. Adjacent skin with livedo racemosa and palpable purpura

Histopathology Variable histological manifestations depending somewhat on underlying cause:  Type I usually has thrombotic occlusion of vessels at all levels of dermis by PAS-positive plugs of immunoglobulin. Usually no inflammation; modest extravasation of erythrocytes  Type II and III present as leukocytoclastic vasculitis with marked inflammation, vessel damage and prominent exocytosis of erythrocytes. Plugged vessels are less likely to be seen

Additional studies PAS stain enhances fibrin thrombi. DIF: Deposits of IgG, IgM C3 or fibrinogen in vessel walls. Diagnosis confirmed by identifying serum cryoglobulins

Differential diagnoses ] Disseminated intravascular coagulation (DIC) In initial stage widespread fibrin thrombi in capillaries and venules. Little infiltrate. No history of cold trigger. Later more extensive thrombosis with infiltrates and necrosis ] Septic vasculitis Leukocytoclastic vasculitis, often papulonecrotic or pustular, with fibrin thrombi and fibrin in vessel walls. Bacteria also present in destroyed vessels ] Cutaneous cholesterol emboli Thrombi with distinctive slits (representing dissolved cholesterol crystals) in arterioles and small arteries, sometimes with necrosis. Usually history of trauma or intravascular procedures. Often subtle and only seen on serial sections ] Livedo vasculopathy Fibrin thrombi and fibrin deposition in vessel wall (thrombi and rings) without significant vasculitis. Extravasation of erythrocytes ] Leukocytoclastic vasculitis and polyarteritis nodosa Damage to small and mid-sized vessels with mixed infiltrates, leukocytoclasia, and erythrocyte extravasation. No history of cold exposure. No thrombi

Cryoglobulinemia ] 79

thrombosed vessels

thrombi

PAS-positive thrombi

2.6 Dermis Granulomatous inflammation 2.6.1 Granuloma annulare 2.6.2 Necrobiosis lipoidica 2.6.3 Sarcoidosis 2.6.4 Foreign body granuloma 2.6.5 Mycobacterial infections 2.6.6 Syphilis 2.6.7 Leishmaniasis

2.6.1 Granuloma annulare Definition Inflammatory dermatosis of unknown etiology. Multiple lesions perhaps associated with diabetes mellitus

Clinic

Multiple small skin-colored or lilac papules, often arranged in annular pattern. Typically over the distal extremities, often near joints. Subcutaneous form may be on scalp or palmoplantar. Disseminated form may have numerous small papules without annular pattern

Histopathology  Epidermis normal  Dermis features necrobiosis with basophilic collagen bundles, nuclear debris and mucin deposits  Necrobiotic zone surrounding by palisading macrophages admixed with rare giant cells, lymphocytes and sometimes eosinophils but few or no plasma cells Variant  Interstitial granuloma annulare: Diffuse infiltrate of macrophages with little or no necrobiosis. Instead eosinophilic free-floating collagen bundles are dotted with macrophages

Additional studies Alcian blue or Hale stain indicates presence of mucin

Differential diagnoses ] Necrobiosis lipoidica More extensive and confluent necrobiotic zones. Plasma cells usually present ] Rheumatoid nodule Subcutaneous necrobiotic nodule, often with more eosinophilic hues, with palisading macrophages. Cannot be separated from subcutaneous granuloma annulare ] Mycobacterial infection Granuloma with caseation necrosis, multinucleated giant cells; often with peripheral neutrophilic and lymphocytic infiltrate. Presence of mycobacteria (Ziehl-Neelsen stain, anti-M. bovis (BCG) immunostain, PCR) ] Sarcoidosis Naked granulomas with epithelioid and multinucleate cells but no peripheral lymphocytic cuff and no necrobiosis ] Interstitial granulomatous dermatitis Diffuse infiltrate of macrophages between collagen bundles, sometimes in pseudo-rosette pattern. Diffuse interstitial mucin deposits; often clinically cords or strands in patients with rheumatoid arthritis. Microscopically similar to interstitial granuloma annulare

Comments Granuloma annulare cannot always be separated with certainty histologically from necrobiosis lipoidica and rheumatoid nodule. The clinical diagnosis is crucial. If plasma cells are present, early borreliosis should be excluded as it may occasionally mimic interstitial granuloma annulare with extensive mucin.

Granuloma annulare ] 83

necrobiotic area surrounded by palisading macrophages

lymphocytic infiltrate

necrobiosis of collagen with mucin

lymphocytes

palisading macrophages

2.6.2 Necrobiosis lipoidica Definition Inflammatory dermatosis of unknown etiology; about half of cases are associated with diabetes mellitus

Clinic

Solitary or multiple red-brown plaques with central atrophic red-yellow zone, almost always on shins

Histopathology     

Normal epidermis, occasionally with atrophy Extensive and confluent zones of necrobiosis in mid and deep dermis Within the necrobiosis prominent nuclear debris Palisading infiltrate of macrophages around necrobiotic zone Infiltrate contains lymphocytes and plasma cells; may also be perivascular

Additional studies Alcian blue or Hale stain reveals sparse or no mucin

Differential diagnoses ] Granuloma annulare No confluence of necrobiotic zones. No plasma cells and almost always mucin ] Interstitial granulomatous dermatitis Diffuse infiltrate of macrophages between collagen bundles, sometimes in pseudo-rosette pattern. Diffuse interstitial mucin deposits; often clinically cords or strands in patients with rheumatoid arthritis. Microscopically very similar to interstitial granuloma annulare ] Mycobacterial infection Granuloma with caseation necrosis, multinucleated giant cells; often with peripheral neutrophilic and lymphocytic infiltrate. Presence of mycobacteria (Ziehl-Neelsen stain, anti-M. bovis (BCG) immunostain, PCR) ] Elastolytic granuloma Band-like macrophage-rich infiltrate in the upper dermis with elastophagocytosis by giant cells

Necrobiosis lipoidica ] 85

full-thickness dermal involvement

horizontal zones of necrobiosis throughout specimen

granulomatous infiltrate with lymphocytes, macrophages and plasma cells

necrobiosis

multi-nucleated giant cells

2.6.3 Sarcoidosis Definition Inflammatory systemic disorder with typically pulmonary involvement but can affect Variants

almost any organ. Etiology is unknown but infectious cause long suspected . Lupus pernio describes sarcoidosis involving the nose . Scar sarcoidosis develops in areas of trauma

Clinic

Red-brown papules, nodules or plaques

Histopathology    

Epidermis normal Epithelioid cell granulomas without necrosis Sparse or no peripheral lymphocytic infiltrate (naked granulomas) Langhans and foreign body giant cells with star-shaped (asteroid) or lamellated (Schaumann) cytoplasmic inclusion bodies  No mucin Variants  Lupus pernio has a denser lymphocytic infiltrate  Scar sarcoidosis is associated with dermal fibrosis and sometimes foreign bodies

Additional studies Elastic stain reveals dense network of elastic fibers around granulomas. Polarization microscopy must be performed; some foreign body granulomas are sarcoidal

Differential diagnoses ] Mycobacterial infection Granuloma with caseation necrosis, multinucleated giant cells; often with peripheral neutrophilic and lymphocytic infiltrate. Presence of mycobacteria (Ziehl-Neelsen stain, anti-M. bovis (BCG) immunostain, PCR) ] Granuloma annulare Palisading of macrophages around necrobiotic zones. No plasma cells and almost always mucin

Comments When a cutaneous sarcoidal granuloma is identified, the patient must be evaluated to exclude systemic sarcoidosis. Even the presence of a foreign body in a sarcoidal granuloma does not exclude the possibility of systemic disease, as patients with sarcoidosis are more likely to react to foreign bodies.

Sarcoidosis ] 87

epithelioid cell granulomas without central necrosis

granulomas with epithelioid macrophages without necrosis

lymphocytes

2.6.4 Foreign body granuloma Definition Inflammatory reaction to exogenous foreign bodies or endogenous materials which are poorly degraded and misinterpreted by immune response as foreign

Clinic

Usually skin-colored to red-brown nodule, sometimes inflamed and tender. History is crucial

Histopathology  Epidermis normal  Mixed diffuse dermal infiltrate, rich in macrophages but also containing neutrophils and giant cells. May extend into subcutis. Occasionally abscess or necrosis  Fibrosis between infiltrates  Multinucleated foreign body giant cells  Fragments of hairs, cyst contents or foreign bodies (glass fragments, splinters, thorns, suture material) may be within infiltrate or inside of giant cells  Many, but by no means all, foreign bodies can be better visualized with polarized light Variants  Sarcoidal foreign body granuloma: Epithelioid naked granulomas induced by foreign bodies with fibrosis (Sec. 2.6.3)  Ruptured epithelioid cyst: Rich in neutrophils, often with abscesses and extensive macrophage reaction. Presence of keratin scales within giant cells (corn flake sign) is almost pathognomonic

Differential diagnoses ] Mycobacterial infection Granuloma with caseation necrosis, multinucleated giant cells; often with peripheral neutrophilic and lymphocytic infiltrate. Presence of mycobacteria (Ziehl-Neelsen stain, anti-M. bovis (BCG) immunostain, PCR) ] Sarcoidosis Naked granulomas with epithelioid and multinucleate cells but subtle peripheral lymphocytic cuff and no necrobiosis ] Granuloma annulare Palisading of macrophages around necrobiotic zones. No plasma cells and almost always mucin

Foreign body granuloma ] 89

acanthotic epidermis

diffuse mixed inflammatory infiltrate

hair shaft outside follicle serves as foreign body

abscess formation with neutrophils

granulomatous inflammation with multi-nucleated giant cells

2.6.5 Mycobacterial infections Definition Infection with Mycobacterium tuberculosis or atypical mycobacteria. Cutaneous involvement via inoculation, local spread, lymphatic or hematogenous dissemination, or may induce allergic reaction at distant sites (id reaction)

Clinic

Tuberculosis: Lupus vulgaris is typically a red-brown plaque which acquires an apple jelly color on diascopy and is likely to have atrophy, ulceration and scarring. Inoculation tuberculosis is usually verrucous, while papulonecrotic tuberculid features widespread necrotic papules Atypical mycobacterial infection: Swimming pool granuloma is most common example, presenting as an infiltrated nodule or plaque, usually on hands or knees, sometimes ulcerated. Caused by M. marinum

Histopathology Lupus vulgaris  Epidermis with both acanthosis and atrophy, often ulcerated  Diffuse dense infiltrate rich in lymphocytes and histiocytes  Tuberculoid granuloma with epithelioid cells and multinucleated giant cells (Langhans type)  Central caseation necrosis (not always present!) Atypical mycobacterial infection  Epidermis with acanthosis, occasionally ulcerated, and may have exocytosis of neutrophils  Initially mixed infiltrate rich in neutrophils, sometimes extending into subcutis; occasionally necrosis  Later granuloma formation with epithelioid cells, multinucleated giant cells and plasma cells

Additional studies Ziehl-Neelsen stain identifies acid-fast bacilli. Anti-Mycobacterium bovis (BCG) or anti-M. tuberculosis antibodies identify all mycobacteria with high sensitivity. PCR and tissue culture also employed

Differential diagnoses ] Sarcoidosis Naked granulomas with epithelioid and multinucleate cells but subtle peripheral lymphocytic cuff and no necrobiosis. Lymphocyte-rich form (lupus pernio) hard to separate from mycobacterial infection without necrosis ] Foreign body granuloma Foreign body identified (always use polarization!). Necrosis uncommon ] Deep fungal infections Pseudo-carcinomatous hyperplasia of epidermis. Mixed infiltrate with abscesses and occasionally granulomas. Fungal elements identified with PAS or Grocott stains ] Leprosy Granulomatous infiltrate with multinucleated giant cells (foreign body or Langhans type) in tuberculoid leprosy; foamy macrophages in lepromatous leprosy. Perineural infiltrates with plasma cells. M. leprae identified in lepromatous leprosy with FiteFaraco stain; also labels with anti-M. bovis (BCG) antibody

Mycobacterial infections ] 91

mixed granulomatous and neutrophilic inflammation

neutrophils

macrophages and plasma cells

mycobacteria as acid-fast rods (Ziehl-Neelsen stain)

plasma cells

2.6.6 Syphilis Definition Sexually transmitted disease caused by Treponema pallidum Clinic

Three stages: . Stage I: Hard painless ulcer (chancre) usually on genitalia . Stage II: Many features; classic is disseminated maculopapular psoriasiform exanthem, often involving palms and soles. Also mucosal lesions and condylomata lata . Stage III: Ulcerated plaques and nodules (gummata) and systemic disease

Histopathology Stage I  Ulceration  Diffuse mixed deep infiltrate with neutrophils and plasma cells Stage II  Epidermis with psoriasiform acanthosis and focal spongiosis  Exocytosis of neutrophils  Interface dermatitis with apoptotic keratinocytes  Band-like pale infiltrate rich in plasma cells, often perivascular, and with focal epithelioid granulomas Stage III  Extensive mixed infiltrate with tuberculoid granulomas, fewer plasma cells and marked necrosis

Additional studies T. pallidum is difficult to stain; standard is Warthin-Starry silver stain, but not very sensitive. The most sensitive tissue approaches are immunohistochemistry and PCR for T. pallidum DNA

Differential diagnoses (syphilis stage II) ] Psoriasis Similar epidermal changes but no plasma cells, perivascular infiltrates or granulomas ] Lichen planus More vacuolar change, thickened granular layer, no plasma cells ] Acrodermatitis chronica atrophicans Epidermal atrophy. Dermal thinning with numerous dilated vessels and plasma cells ] Dermatophyte infection No plasma cells; PAS or Grocott stains identify fungal elements

Comment The diagnosis of syphilis is confirmed with serological studies. The histology can serve to alert the clinician to the possibility of the diagnosis. In some situations, organisms can be found even when serology is negative, as in HIV-associated lues maligna.

Syphilis ] 93

psoriasiform epidermis

lichenoid and perivascular granulomatous infiltrate

treponema identified with immunohistochemical stain

plasma cells

2.6.7 Leishmaniasis Definition Infection with Leishmania, a protozoon which is transferred by sand flies Clinic

After the sand fly assault, in immunocompetent hosts a single papulonodular lesion develops, typically on face, increases in size, then resolves spontaneously with characteristic scarring

Histopathology  Epidermis with pseudo-carcinomatous hyperplasia and ulceration  Dense granulomatous infiltrate rich in histiocytes, neutrophils, lymphocytes and plasma cells; focal pale areas with organism-laden macrophages  Amastigote form of leishmania (diameter 2–4 lm) in cytoplasm of macrophages, especially in the subepidermal component of infiltrate in the middle of lesion

Additional studies Sometimes the organisms are better seen with Giemsa stain than with H&E. Leishmania DNA can be identified with PCR. Tissue culture possible

Differential diagnoses ] Cutaneous B-cell pseudolymphoma Nodular infiltrates with reactive germinal centers with blasts and tingible body macrophages. Usually associated with Borrelia ] Lupus vulgaris Tuberculoid granuloma with necrosis (often caseation). Rare acid-fast bacilli identified with Ziehl-Neelsen stain or anti-M. bovis (BCG) antibodies ] Histoplasmosis Granolomatous infiltrate with PAS-positive spores with surrounding halo

Comments Before diagnosing B-cell lymphoma or pseudolymphoma as a solitary lesion on exposed surface, always exclude leishmaniasis.

Leishmaniasis ] 95

serum crust

acanthosis

granulomatous inflammation

plasma cell

amastigotes of leishmania

2.7 Dermis Interstitial inflammation 2.7.1 Borreliosis 2.7.2 Morphea

2.7.1 Borreliosis Definition

Tick-borne infection caused by borrelial spirochetes (B. burgdorferi, B. afzelii, B. garinii) with both cutaneous and systemic manifestations; also known as Lyme disease

Clinic

Four cutaneous findings: . Erythema migrans . Acrodermatitis chronica atrophicans . Lymphadenosis cutis benigna (B-cell pseudolymphoma) . Juxta-articular nodules

Histopathology Erythema migrans  Perivascular lymphocytic infiltrate with plasma cells at all levels of dermis; admixture of eosinophils and macrophages Acrodermatitis chronica atrophicans  Atrophy of epidermis, dermis and subcutis  Ectatic capillaries in upper dermis  Perivascular lymphocytic infiltrate rich in plasma cells, sometimes also band-like at DEJ  Loss of elastic fibers Lymphadenosis cutis benigna (Sec. 4.6.4) Interstitial granulomatous inflammatory pattern  Collagen fibers surrounded by macrophages, sometimes in pseudo-rosette pattern around “free floating” fibers  Interstitial mucin deposits  Seen classically with rheumatoid arthritis, but also other autoimmune disorders, early borreliosis, drug reactions Juxta-articular (or fibrinoid) nodules Striking areas of fibrosis with thickened collagen fibers arranged in cut-onion pattern and lymphocytic perivascular infiltrate rich in plasma cells

Additional studies Borrelia are best identified with PCR which can be performed on formalin-fixed, paraffin-embedded tissue. Warthin-Starry stain and immunohistochemistry are also possible but have low yield

Differential diagnoses ] Erythema migrans . Erythema annulare centrifugum: Focal spongiosis and perivascular infiltrate, sometimes with eosinophils but no plasma cells . Drug reaction: Superficial lymphocytic perivascular infiltrate with eosinophils but no plasma cells . Syphilis stage II: Interface dermatitis with psoriasiform acanthosis, granulomatous perivascular infiltrates rich in plasma cells and macrophages ] Acrodermatitis chronica atrophicans . Morphea: Thickening of dermal connective tissue. Adnexal structures appear entrapped and elevated. No loss of elastic fibers. Sometimes sparse infiltrates of lymphocytes and plasma cells

Comment In erythema migrans, the serology may be negative, so PCR can help confirm diagnosis, but negative PCR does not exclude borreliosis if clinical and histological pictures fit. In acrodermatitis chronica atrophicans the organisms may not be detectable by PCR Always think of these diseases when confronted by an infiltrate with plasma cells – Six “L” rule 1) Lues (syphilis) 2) Leprosy 3) Lyme disease (borreliosis) 4) Leishmaniasis 5) Lupus vulgaris 6) Lymphoma

Borreliosis ] 99

band-like and perivascular infiltrate

lymphocytes

plasma cells

2.7.2 Morphea Definition Chronic inflammatory dermatosis with sclerosis of dermal connective tissue Clinic

Solitary or multiple plaques with lilac border and central hypopigmented sclerosis

Variant

Linear morphea involving limb, coup de sabre with forehead scarring

Histopathology Early stage Superficial and deep lymphocytic perivascular and interstitial infiltrates with plasma cells, less often neutrophils or eosinophils Late stage  Lymphocytic perivascular infiltrate with occasional cells throughout dermis  Thickened connective tissue with widened, eosinophilic collagen bundles, which surround the adnexal structures. Sweat glands appear to be pushed up higher into dermis, while hair follicles are often destroyed, leaving naked arrector pili muscles  Subcutaneous fat septa thickened with lymphocytic infiltrate  No retraction of sides of biopsy during fixation (square biopsy)

Additional studies Acid orcein elastic stain reveals intact elastic network No mucin seen with Alcian blue

Differential diagnoses ] Lichen sclerosus Subepidermal connective tissue sclerotic with loss of elastic fibers ] Lupus tumidus Tight perivascular and perifollicular lymphocytic infiltrate. Generous deposits of mucin between collagen fibers ] Scar

Horizontally-arranged collagen fibers with vertically-oriented capillary vessels. Loss of elastic fibers

] Connective tissue nevus Irregularly arranged thickened collagen fibers in mid-dermis without inflammatory infiltrate. Elastic fibers usually normal or even increased

Comment Morphea cannot be separated histologically from the skin changes seen in systemic sclerosis. Lichen sclerosus and morphea may also have overlapping clinical and histological features making a distinction impossible.

Morphea ] 101

lymphocytic perivascular infiltrate

trapped eccrine glands

widened fat septa

lymphocytic infiltrate

sclerotic collagen bundles

2.8 Dermis Diffuse mixed inflammatory infiltrates 2.8.1 Urticaria 2.8.2 Acute febrile neutrophilic dermatosis 2.8.3 Eosinophilic cellulitis 2.8.4 Arthropod assault reaction

2.8.1 Urticaria Definition Urticaria is a disease featuring multiple, usually pruritic, hives triggered by IgEmediated immediate allergic reactions, as well as a variety of other triggers (mast cell degranulating agents, dietary histamines, physical triggers)

Clinic

Hives are pruritic plaques which result from fluid leakage into the dermis via dilated vessels, producing erythema, blanching and swelling. They resolve over hours, but are often recurrent

Variant

Urticarial vasculitis: When individual hives persist for longer than 24 hours, one should consider possibility of urticarial vasculitis which is classically associated with arthritis and hypocomplementemia

Histopathology    

Epidermis normal Interstitial edema in upper and mid-dermis Mixed perivascular infiltrate with scattered interstitial eosinophils and neutrophils Neutrophils in vessel lumens but no leukocytoclastic vasculitis

Variant  Urticarial vasculitis: Same findings, but also has leukocytoclastic vasculitis

Differential diagnoses ] Drug eruption, viral exanthem Superficial lymphocytic perivascular infiltrate with admixed eosinophils. No intravascular neutrophils ] Acute febrile neutrophilic dermatosis (Sweet syndrome) Diffuse dermal infiltrates of neutrophils, sometimes favoring perivascular region but no leukocytoclastic vasculitis ] Eosinophilic cellulitis (Wells syndrome) Diffuse dermal infiltrates of eosinophils with flame figures ] Arthropod assault reaction Often epidermal damage at site of assault (bite or sting) with spongiosis. Wedgeshaped mixed infiltrate rich in eosinophils ] Erythema annulare centrifugum Focal spongiosis and lymphocytic perivascular infiltrates, sometimes with eosinophils

Urticaria ] 105

normal epidermis

edema

sparse perivascular infiltrate with lymphocytes and eosinophils

interstitial edema

lymphocytes

eosinophils

2.8.2 Acute febrile neutrophilic dermatosis Synonym: Sweet syndrome Definition Inflammatory dermatosis of unknown etiology, which may be associated with infections, inflammatory bowel disease or even leukemia

Clinic

Painful succulent red-brown plaques favoring face, shoulders and arms; accompanied by fever, malaise and leukocytosis

Histopathology  Epidermis normal  Subepidermal edema, in some cases advancing to subepidermal blisters  Dense diffuse or band-like neutrophilic infiltrate in upper and mid-dermis, sometimes extending into subcutis  Swollen vessel walls, sometimes with perivascular accentuation of infiltrates. Few lymphocytes. Leukocytoclastic vasculitis not seen Variants  Histiocytoid Sweet syndrome: Diffuse infiltrate of immature neutrophils with non-segmented nuclei (promyelocytes) which appear mononuclear  Bullous Sweet syndrome: Extensive edema in the upper dermis leading to blisters

Additional studies In histiocytoid Sweet syndrome the immature neutrophils (promyelocytes) are strongly positive for myeloperoxidase

Differential diagnoses ] Pyoderma gangrenosum Ulceration and abscess formation with dense neutrophilic infiltrates and secondary vessel damage ] Urticaria Sparse perivascular and interstitial infiltrate with lymphocytes, neutrophils and eosinophils in upper and mid-dermis ] Erysipelas Moderate diffuse and interstitial infiltrate of neutrophils in upper and mid-dermis. Dilated lymphatics and edema in upper dermis ] Eosinophilic cellulitis (Wells syndrome) Diffuse dermal infiltrates of eosinophils with flame figures

Comment Sweet syndrome can be a marker for myeloid leukemia, so an underlying hematological malignancy should always be excluded.

Acute febrile neutrophilic dermatosis ] 107

subepidermal edema

neutrophilic infiltrate (shown at bottom in higher magnification)

2.8.3 Eosinophilic cellulitis Synonym: Wells syndrome Definition Inflammatory dermatosis usually of unknown cause but in some cases associated with arthropod assault

Clinic

Initially edematous infiltrated plaques with erythematous border which may be persistent or recurrent. Occasionally bullous. Later more sclerotic lesions but with eventual spontaneous resolution. Most common on trunk and extremities

Histopathology     

Epidermis normal Papillary dermal edema (initial phase) Perivascular and interstitial infiltrate rich in eosinophils with admixture of neutrophils Numerous flame figures Vessels occasionally edematous or damaged, but no leukocytoclastic vasculitis

Differential diagnoses ] Acute febrile neutrophilic dermatosis (Sweet syndrome) Diffuse dermal infiltrates of neutrophils, sometimes favoring perivascular region, but no leukocytoclastic vasculitis. No flame figures ] Urticaria Sparse mixed perivascular infiltrates with eosinophils, no flame figures ] Urticarial vasculitis Leukocytoclastic vasculitis of small vessels in the upper and mid dermis ] Hypereosinophilic syndrome Superficial and deep perivascular infiltrates rich in eosinophils, sometimes with admixed plasma cells. Eosinophilia in peripheral blood ] Arthropod assault reaction Often epidermal damage at site of assault (bite or sting) with spongiosis and vesicle. Wedge-shaped mixed infiltrate rich in eosinophils, sometimes with flame figures ] Drug eruption, viral exanthem Superficial lymphocytic perivascular infiltrate with admixed eosinophils. ] Urticarial stage of bullous pemphigoid Diffuse eosinophilic infiltrates with admixed plasma cells in upper dermis. No blisters

Comment Flame figures are areas of collagen damaged by degranulation of eosinophils with release of major basic protein. They are not specific for eosinophilic cellulitis but can be seen in any condition with eosinophilic infiltrates, such as arthropod assault, infestations and bullous pemphigoid.

Eosinophilic cellulitis ] 109

flame figure

eosinophils

flame figure (damaged collagen fibers)

2.8.4 Arthropod assault reaction Definition Inflammatory reaction triggered by bite or sting of arthropod Clinic

Pruritic urticarial papules or nodules

Histopathology  Epidermis with localized spongiosis, vesicle and loss of substance at site of assault, acanthosis and parakeratosis; ulceration via excoriation possible  Subepidermal edema  Wedge-shaped irregular mixed infiltrate with lymphocytes, eosinophils and neutrophils, occasionally plasma cells  In center of infiltrate hypereosinophilic, sometimes thickened collagen bundles with occasional flame figures  Lymphocytes often activated with enlarged dense nuclei and mitotic activity

Differential diagnoses ] Eosinophilic cellulitis (Wells syndrome) Diffuse dermal infiltrates of eosinophils with flame figures ] Urticarial vasculitis Superficial infiltrate with neutrophils and eosinophils as well as leukocytoclastic vasculitis ] Infestation (for example scabies) Spongiosis, superficial perivascular infiltrate with eosinophils, sometimes organisms in cornified layer ] Cutaneous pseudolymphoma Dense nodular or band-like lymphocytic infiltrate often with eosinophils. In B-cell variant, often reactive lymphoid follicles ] Lymphomatoid papulosis (type A) Mixed wedge-shaped lymphocytic infiltrate containing large anaplastic CD30+ cells

Comment The shape and nature of the infiltrate offer no clues as to the responsible arthropod. Sometimes the infiltrate is so extensive that a cutaneous pseudolymphoma is diagnosed. Insect bite reaction is a common synonym, but incorrect as many of the attacking species are not insects, and many bite instead of stinging.

Arthropod assault reaction ] 111

edema

wedge-shaped lymphocytic infiltrate

flame figure

vesicle with neutrophils and eosinophils (site of bite/sting)

edema

infiltrate with neutrophils and eosinophils

flame figure (damaged collagen fibers)

2.9 Dermis Degenerative and metabolic disorders 2.9.1 Chondrodermatitis helicis nodularis chronica 2.9.2 Pseudoxanthoma elasticum 2.9.3 Xanthoma

2.9.1 Chondrodermatitis helicis nodularis chronica Definition Reactive disorder on the ear helix with both epidermal damage and degenerative changes in dermis and underlying cartilage

Clinic

Painful often crusted nodule on helix

Histopathology  Hyperparakeratosis with inclusions of exudate  Acanthosis with widened rete ridges or pseudo-carcinomatous hyperplasia, usually with central dell or ulcer  Sparse lymphocytic infiltrate in sun-damaged upper dermis  Subepidermal fibrin deposits  Fibrosis, often with increased fibroblasts  Numerous superficial dilated capillaries  Degeneration or necrosis of the underlying superficial cartilage, often with connection to epidermal defect

Differential diagnoses ] Squamous cell carcinoma Epidermal atypia with clusters or strands of abnormal keratinocytes cells invading dermis ] Relapsing polychondritis Marked neutrophilic destruction of cartilage without overlying epidermal changes. Patients usually are systemically ill ] Elastotic nodule Clinically similar but only massive actinic elastosis without ulcer or cartilage damage ] Gouty tophus Dermal accumulation of crystalline material with clefts

Comment Often the diagnosis can be made based on the classic central dell even when the biopsy is not deep enough to sample cartilage.

Chondrodermatitis helicis nodularis chronica ] 115

hyperparakeratosis

acanthosis

ulceration

fibrinoid necrosis

damaged cartilage

fibrosis with inflammatory infiltrate

2.9.2 Pseudoxanthoma elasticum Definition Genodermatosis inherited in an autosomal dominant fashion with degeneration and calcification of elastic fibers, leading to cutaneous, ocular and cardiovascular disease

Clinic

. Patches studded by yellow papules (chicken skin). Sites of predilection are neck, axillae, groin, umbilicus, popliteal and antecubital flexures. Prominent transverse chin creases . Visual defects include angioid streaks (breaks in Bruch membrane) and visual loss secondary to retinal hemorrhage and chorioretinitis . Cerebrovascular infarcts, gastrointestinal bleeding and hypertension

Histopathology    

Epidermis normal Thickened, fragmented calcified elastic fibers (sometimes fancifully compared to ball of yarn) Sometimes larger clumps of calcified fibers No inflammatory infiltrate

Variant  Perforating pseudoxanthoma elasticum most common around umbilicus, features extrusion of calcified masses, often in obese individuals without systemic disease

Additional studies The abnormal elastic fibers are easily seen with H&E but can be enhanced with an elastic stain or calcium salt stain (von Kossa)

Differential diagnoses ] Actinic elastosis Diffuse amorphous steel gray band of abnormal thickened collagen which stains positively with elastic stains. Papillary dermis often appears spared (Grenz zone) because of regeneration by basement membrane zone fibroblasts ] Elastosis perforans serpiginosa Grouped papules, often on neck, most common in Down syndrome and other congenital connective tissue disorders. Focal pseudo-carcinomatous hyperplasia. Epidermal perforation with hyperkeratosis, cell debris and neutrophils. Basophilic degeneration of underlying collagen. Elastic stains positive. No calcification ] Calcinosis cutis Focal calcification of damaged connective tissue may be seen in all connective tissue disorders but especially CREST variant of systemic sclerosis. Trauma, such as needle sticks, EEG electrodes, may also cause focal calcification. No diffuse connective tissue changes

Pseudoxanthoma elasticum ] 117

clumped and fragmental elastic fibers

calcification

2.9.3 Xanthoma Definition Localized collection of lipid-laden macrophages, often a marker of an underlying defect in lipid metabolism

Clinic

Classification based on clinical appearance, site and underlying disorder: . Eruptive xanthoma: Multiple tiny yellow papules which appear suddenly, often palmoplantar . Tuberous xanthoma: Large nodules often on extensor surfaces of limbs or over tendons . Xanthelasma: Flat yellow plaques on eyelids – common but only associated with lipid defects in 50% of cases

Histopathology Eruptive and tuberous xanthomas  In early stages patchy perivascular infiltrates with neutrophils, lymphocytes and macrophages  Later macrophages with foamy cytoplasm predominate  Extracellular lipid deposits  Increased fibroblasts with dermal fibrosis Xanthelasma  Macrophages with foamy cytoplasm  Little or no extracellular lipids  Usually no associated inflammatory infiltrate  Location-specific changes for eyelids including very thin skin and superficial striated muscles

Additional studies The lipids in foamy cells are dissolved by usual fixation and tissue preparation methods so one just sees their histological “shadows” (empty spaces). On frozen sections, the lipids can be stained with Sudan stain, but this is usually not needed. Macrophages are CD68+

Differential diagnoses ] Granuloma annulare Palisading of macrophages around necrobiotic zones. No plasma cells and almost always mucin. No foam cells ] Granular cell tumor Neural tumor with granular cytoplasm, cells are S-100+; no foam cells

Comment Patients with histological evidence for xanthomas should be evaluated for disturbances in lipid metabolism, thyroid disease and diabetes mellitus (the latter are common co-factors). If no lipid abnormalities are present, then consider causes of normolipidemic xanthomas (phytosterol disorders, rare apolipoprotein defects, papular xanthoma as variant of non-Langerhans cell histiocytosis).

Xanthoma ] 119

foamy macrophages

extra-cellular lipids

2.10 Dermis Inflammation of adnexal structures 2.10.1 Folliculitis 2.10.2 Alopecia areata 2.10.3 Lupus erythematosus of scalp 2.10.4 Folliculitis decalvans

2.10.1 Folliculitis Definition Inflammation of hair follicle and adjacent connective tissue, caused by variety of infections, as well as by irritants

Clinic

Erythematous papules and pustules centered on hair follicles

Histopathology  Mixed infiltrate with numerous neutrophils and eosinophils, as well as plasma cells, in and around hair follicle  Spongiosis with distention or destruction of follicular epithelium  Occasionally abscess formation  Chronic variants have perifollicular fibrosis Variants  Ostiofolliculitis: Pustule formation involves upper reaches (ostium) of follicle with numerous neutrophils and adjacent superficial mixed perivascular infiltrate  Pityrosporon and Demodex folliculitis: Fungal spores or Demodex mites in the follicular ostium or isthmus with associated inflammation and damage to follicle epithelium. In advanced cases spores or mites within dermal infiltrate

Additional studies Fungal elements should be excluded with PAS stain; Gram stain may help find bacteria

Differential diagnoses ] Eosinophilic folliculitis Folliculitis and perivascular lymphocytic infiltrate with numerous eosinophils. Two forms – Ofuji with dense plaques and HIV/AIDS-associated with intensely pruritic papules ] Rosacea

Lymphocytic perivascular and interfollicular infiltrates with admixture of neutrophils. Edema, dilated lymphatics, telangiectases. Sometimes increased numbers of enlarged sebaceous glands. Granulomatous infiltrates possible

] Trichophyton infection Perifollicular dense mixed infiltrate with destruction of hair follicle. Presence of hyphae or spores within the hair follicle or hair shaft

Comment The cause of folliculitis can only be definitively diagnosed with microbiological studies.

Folliculitis ] 123

widened follicle ostium with hyperkeratosis

abscess formation with neutrophils

destroyed follicular epithelium

neutrophils

hairshaft

2.10.2 Alopecia areata Definition Inflammatory reversible alopecia without scarring Clinic

Circular patches of alopecia with broken-off terminal hairs at periphery (exclamation point hairs), follicle openings are retained. Association with atopy, vitiligo and autoimmune thyroiditis possible

Histopathology    

Deep peribulbar lymphocytic infiltrates (swarm of bees), sometimes with eosinophils Discrete lymphocytic perivascular infiltrate in upper dermis Hair follicles in same stage with increased numbers of catagen and telogen follicles In later stages, reduced numbers of hair follicles with residual vertical fibrotic tracts and melanin

Differential diagnoses ] Androgenetic alopecia Rarefaction and miniaturization of hair follicles. Prominent sebaceous glands. No fibrosis. Little or no lymphocytic perivascular or perifollicular infiltrates ] Trichotillomania Dilated hair follicle with twisted and fragmented hair shafts (trichomalacia) which contain melanin. Little or no lymphocytic perivascular or perifollicular infiltrates ] Telogen effluvium Increased number of hairs in telogen. Vertical fibrotic tracts. Little or no lymphocytic perivascular or perifollicular infiltrates ] Inflammatory scarring alopecia More extensive infiltrate both at DEJ and around hair follicle; most common causes are lupus erythematosus (Sec. 2.10.3) and lichen planus. In end stages fibrosis and loss of follicles (pseudopelade)

Comment The histological picture of alopecia areata varies widely depending on the acuity of the disease.

Alopecia areata ] 125

fibrous tracks

catagen hair follicle

melanin

lymphocytic peribulbar infiltrate

2.10.3 Lupus erythematosus of scalp Definition Scalp involvement with inflammation and then scarring alopecia in the form of chronic cutaneous lupus erythematosus

Clinic

Erythematous infiltrated patches and plaques with peripheral erythema, central atrophy, adherent scales, loss of pigment and alopecia

Histopathology  Hyperparakeratotic plugging of follicular ostia  Vacuolar change at transition zone between interfollicular epithelium and basal follicular epithelium. Apoptotic follicular keratinocytes  Thickened basement membrane  Perifollicular and perivascular sharply circumscribed lymphocytic infiltrate with exocytosis into follicular epithelium  Mucin deposits between strands of collagen  In late stage, fibrosis with loss of hair follicles and loss of elastic fibers

Additional studies DIF: Linear or granular deposits of C3 along the DEJ. PAS stain: Thickened PAS-positive basement membrane. Elastic stain: Loss of elastic fibers in zones of fibrosis. Immunohistochemical stains: T-cell infiltrate with admixture of B cells and plasma cells

Differential diagnoses ] Lichen planopilaris Hypergranulosis in follicular ostia. Band-like lymphocytic interface infiltrate favoring perifollicular areas, often sparing interfollicular epidermis. Lamellar perifollicular fibrosis with lichenoid infiltrate. In later stages, loss of hair follicles and marked fibrosis ] Folliculitis decalvans Perifollicular infiltrate rich in neutrophils extending into follicle wall. Confluence of hair follicles. In later stages, numerous plasma cells, loss of hair follicles and fibrosis. Infiltrate often contains hair shafts

Comments Scarring alopecia is only diagnosed early and by studying the upper dermis – lupus erythematosus involves the follicles and intervening epidermis while lichen planopilaris is primarily follicular. The combination of fibrosis with loss of hair follicles and often a discrete non-specific inflammatory infiltrate is often termed pseudopelade, as clues to the initial inflammatory condition are no longer present.

Lupus erythematosus of scalp ] 127

lymphocytic infiltrate

loss of hair follicles

epidermal atrophy with vacuolar degeneration of basal keratinocytes

hyperkeratosis

fibrosis

mucin

lymphocytic infiltrate

2.10.4 Folliculitis decalvans Definition Pustular folliculitis of scalp with scarring alopecia. Bacterial infections with staphylococci are possible co-factor

Clinic

Pustular follicles on scalp with erythema, scale and bundles of hairs (paint brush sign). Later scarring alopecia

Histopathology    

Initial follicular and perifollicular infiltrates of neutrophils which penetrate the follicle Pustules Confluence of hair follicles Later numerous plasma cells, loss of follicles and scarring

Additional studies Admixture of CD79a-positive B cells and plasma cells. Loss of elastic fibers in the fibrotic areas

Differential diagnoses ] Lichen planopilaris Hypergranulosis in follicular ostia. Band-like lymphocytic interface infiltrate hugging the follicle but sparing of interfollicular epidermis. Lamellar perifollicular fibrosis with lichenoid inflammation. In later stages, loss of hair follicles and marked fibrosis ] Lupus erythematosus Hyperparakeratotic keratin plugs of follicular ostia. Apoptotic follicular keratinocytes. Lymphocytic infiltrate with interface changes affects follicles and intervening epidermis. Also perivascular infiltrates. Mucin deposits between strands of collagen. In late stages, fibrosis with loss of hair follicles

Folliculitis decalvans ] 129

hyperkeratosis with serum crust

widened follicle ostium with abscess fibrosis and loss of hair follicles

neutrophils

destruction of follicle

infiltrate rich in plasma cells

2.11 Subcutaneous fat Panniculitis 2.11.1 Erythema nodosum 2.11.2 Lupus panniculitis

2.11.1 Erythema nodosum Definition Most common inflammatory panniculitis. Most cases idiopathic; common triggers include drugs, pregnancy, underlying infections (often gastrointestinal) and sarcoidosis

Clinic

Painful infiltrated plaques and nodules usually over shins. No ulceration. Early lesions mistaken for bruises

Histopathology Early stage  Slight lymphocytic perivascular infiltrate in dermis  In fat, septal and paraseptal infiltrate of neutrophils  Thickening of septa through edema Fully-developed stage  In deep dermis perivascular, and in fat, almost exclusively septal mixed infiltrate with lymphocytes, macrophages, giant cells, and neutrophils  Fibrotic thickened septa  Characteristic paraseptal granuloma with multinucleated giant cells (Miescher radial nodule)  No vasculitis

Differential diagnoses ] Nodular vasculitis Mixed infiltrate of neutrophils, lymphocytes and plasma cells around arteries in deep dermis and near septa. Fat necrosis and abscesses in the lobules, often with ulceration. When associated with tuberculosis, known as erythema induratum of Bazin, a type of tuberculid ] Post-traumatic panniculitis Lobular infiltrate of foamy macrophages surrounding spaces left behind by confluent necrotic adipocytes (micropseudocysts). Erythrocyte extravasates ] Sarcoidosis Epithelioid cell granulomas in dermis and fat lobules ] Infectious panniculitis Septal and lobular neutrophil-rich infiltrates with abscess formation. Microorganisms identified with additional studies (Gram- and Ziehl-Neelsen stains, anti-M. bovis (BCG) immunostain) ] Ruptured epidermoid cyst Cyst often lie deep in dermis; when the rupture, the associated inflammation frequently extends into the fat

Comment In sharp contrast to other forms of panniculitis, erythema nodosum frequently involves the lower half of the dermis.

Erythema nodosum ] 133

extravasation of erythrocytes

widened fat septa

granuloma

inflammation spreading to fat lobules

Miescher nodule (multinucleated giant cells with clefts, surrounded by macrophages)

widened fat septa

granuloma with multinucleated giant cells

2.11.2 Lupus panniculitis Definition Variant of lupus erythematosus with involvement of fat. In 1/3 of cases associated with overlying chronic cutaneous (discoid) lupus erythematosus

Clinic

Livid-erythematous plaques and ulcerated nodules with predilection for the proximal aspects of limbs. Typically painful ulcers with scarring

Histopathology  Dense lobular lymphocytic infiltrates surrounding adipocytes (rimming). Admixture of plasma cells  Paraseptal reactive lymphoid follicles  Lymphocytic nuclear debris without vasculitis; no neutrophils  In late stage, dense infiltrates also rich in macrophages

Additional studies The infiltrate is dominated by T cells admixed with B cells and plasma cells; follicles may be found. In late stages, often CD68-positive macrophages dominate

Differential diagnoses ] Subcutaneous panniculitis-like T-cell lymphoma Lobular infiltrate of pleomorphic T cells around adipocytes. Cells of varying sizes with nuclear pleomorphism and nuclear debris. Cytotoxic immunotyping profile ] Subcutaneous B-cell pseudolymphoma Paraseptal and lobular lymphocytic infiltrate with reactive follicles. Occasionally granulomas with necrosis secondary to injections (for example, from allergy shots) ] Erythema nodosum Initial neutrophil-rich deep dermal and primarily septal infiltrates, later with admixture of macrophages and granulomas ] Nodular vasculitis Primary lobular mixed infiltrate with neutrophils and plasma cells, as well as vasculitis of deep dermis and septal arteries ] Artifactual panniculitis Necrotic adipocytes of varying sizes (micropseudocysts), erythrocyte extravasates. In initial stage, neutrophils primarily in lobular fashion; later macrophages with foamy cells. Occasionally presence of injected foreign bodies

Comment Accumulations of lymphocytes lining adipocytes like a string of pearls (rimming) can be seen in lupus panniculitis and in subcutaneous panniculitis-like T-cell lymphoma. It is not disease-specific.

Lupus panniculitis ] 135

mucin

lymphocytic infiltrate (resembling lymph node follicle)

advanced lobular panniculitis

necrotic adipocytes and fibrosis

2.12 Drug reactions Definition Cutaneous manifestations of intolerance reactions to medications; mechanism may be toxic or immunologic; wide spectrum of clinical and histological variants

Specific forms Fixed drug reaction Red, red-brown or violet patches which recur in exactly the same site upon repeated exposure to causative agent. Interface band-like dermatitis with vacuolar change, apoptotic keratinocytes, exocytosis of lymphocytes. Superficial lymphocytic infiltrate with admixture of neutrophils and eosinophils. Melanophages

Differential diagnoses ] Acute graft-versus-host reaction Interface dermis, lymphocytic infiltrate with apoptotic keratinocytes at all levels of epidermis. Involvement of hair follicles and sweat glands ] Erythema multiforme Orthokeratosis, necrotic keratinocytes or epidermal necrosis. Subepidermal edema with rare scattered eosinophils

Toxic epidermal necrolysis Widespread epidermal necrosis. Subepidermal blisters. Little or no perivascular infiltrate; occasionally scattered eosinophils

Differential diagnoses ] Phototoxic reaction Solitary necrotic keratinocytes (sunburn cells) or focal epidermal necrosis with subepidermal blisters. Little infiltrate ] Staphylococcal scalded skin syndrome (SSSS) Subcorneal split with little epidermal necrosis. Acantholytic keratinocytes in upper spinous layer. Initially sparse perivascular infiltrate with neutrophils

Drug reactions ] 137

Fixed drug reaction

orthokeratosis

edema

lichenoid and perivascular lymphocytic inflammation

necrotic keratinocytes

spongiosis

melanophages

neutrophils and eosinophils

Nonspecific forms Maculopapular drug reaction Most common problem in hospitalized patients. Two helpful features are vacuolar interface changes and superficial infiltrate containing eosinophils and sometimes neutrophils

Differential diagnoses ] Urticaria Dermal edema, both perivascular and interstitial eosinophils ] Viral exanthem Usually no or only focal interface changes, rare eosinophils; often identical

Lichenoid drug reaction Acanthosis, hypergranulosis, hyperparakeratosis. Interface dermatitis with vacuolar change, apoptotic keratinocytes and exocytosis of lymphocytes. Subepidermal band-like infiltrates with occasional eosinophils

Differential diagnoses ] Lichen planus Identical, but almost never has eosinophils

Comment If one encounters an inflammatory infiltrate which does not fit into any known pattern, one should always think of a possible drug reaction

Drug reactions ] 139

Toxic epidermal necrolysis

necrotic epidermis

blister

complete epidermal necrosis

almost no inflammation in dermis

2.13 Artifactual damage Definition Self-inflicted damage to skin from exogenous mechanical or toxic factors. A variety of clinicopathologic patterns can be observed

Excoriation Localized small superficial ulcer with fibrinous-hemorrhagic exudate, neutrophils and sometimes bacteria. Subepidermal fibrin deposits with sparse or modest mixed perivascular infiltrates

Differential diagnosis ] Reactive perforating collagenosis Sharply bordered but larger ulcer with basophilic necrosis of crust caused by extrusion of collagen fibers and numerous neutrophils in the crust

Toxic damage Reversal of staining of epidermis with cornified layer unaffected, early necrosis in upper reaches of spinous layer and basal layer pale staining (outside-in phenomenon). Little or no dermal infiltrate

Differential diagnosis ] Zinc deficiency (acrodermatitis enteropathica) Psoriasiform pattern with pale-staining upper part of epidermis

Artifactual damage ] 141

Excoriation

serum crust with inflammation

superficial ulceration

neutrophilic infiltrate

III Cysts

3.1 Epithelial cysts 3.1.1 Epidermoid cyst 3.1.2 Trichilemmal cyst 3.1.3 Steatocystoma

3.1.1 Epidermoid cyst Definition Epithelial cyst with epidermal type of keratinization, arising either from infundibular follicular epithelium or through post-traumatic deposit of epidermal fragments in dermis

Clinic

Firm rubbery dermal nodules almost always with central follicular opening (pore). Most common on face and trunk. Multiple lesions can be marker for Gardner syndrome. Traumatic epidermal inclusion cysts more common on hands

Histopathology  Cyst with stratified squamous epithelium, granular layer and epidermal pattern of keratinization  Pore (residual follicle) may be seen; often multiple sections required  Cyst contains layers of moderately compacted horn  Larger cysts often have pressure atrophy of cyst wall  If the cyst has been ruptured, there is often a foreign body reaction with neutrophils, macrophages and multinucleated giant cells, sometimes with inclusions of scales (corn flakes sign)  Acute ruptured cysts often have abscesses, while later lesions show fibrosis Variants  Milium: Small epidermoid cyst in upper dermis. More common with superficial damage either from blistering dermatoses (porphyria cutanea tarda, some forms of epidermolysis bullosa) or trauma (burns)  Proliferating epidermoid cyst: Proliferation of epithelium into lumen of cyst with cyclic swirling areas of keratinization  Hybrid cyst: Areas of both epithelial and trichilemmal keratinization in same cysts

Differential diagnoses ] Trichilemmal cyst Epithelial cyst with compact amorphous keratinization and no granular layer ] Steatocystoma Epithelial cyst with crenellated cuticle-like lining and focal areas with sebaceous glands included in cyst wall

Comment Epidermoid cysts with focal areas of pilomatricoma-like keratinization (Sec. 4.3.2) suggest Gardner syndrome.

Epidermoid cyst ] 147

epidermis

cyst wall

epidermis

stratum granulosum in cyst wall

layers of keratin

3.1.2 Trichilemmal cyst Definition Epithelial cyst with trichilemmal keratinization mimicking changes in hair follicle isthmus (also known as isthmus-catagen or pilar cyst)

Clinic

Firm sharply defined dermal cyst, most common on the scalp; easily shell out during excision and usually submitted intact

Histopathology  Dermal cyst usually without pore  Epithelial cells of cyst wall are not flattened, show no granular layer change and interdigitate with amorphous keratin masses  Amorphous dense pink masses of keratin  Calcification common; rupture unlikely but then accompanied by granulomatous inflammation and later fibrosis Variants  Proliferating trichilemmal cyst: Sharp outer boundary retained but inwards towards lumen proliferation of atypical keratinocytes in pattern of squamous cell carcinoma with individual cell keratinization and mitoses. If the lesion is > 5 cm, it should be considered a squamous cell carcinoma with metastatic potential  Hybrid cyst: Areas of both epithelial and trichilemmal keratinization in same cyst

Differential diagnoses ] Epidermoid cyst Epithelial cyst with epidermal pattern of keratinization including granular layer. Cyst contains loosely-aggregated masses of horn scale ] Steatocystoma Epithelial cyst with crenellated cuticle-like lining and focal areas with sebaceous glands included in cyst wall

Trichilemmal cyst ] 149

epidermis

granulomatous inflammation from previous trauma

cyst wall

homogenous eosinophilic keratin

stratified squamous epithelium

trichilemmal keratinization without stratum granulosum

homogenous eosinophilic keratin

3.1.3 Steatocystoma Definition Epithelial cyst arising at level of infundibulum where the sebaceous duct enters the hair follicle

Clinic

Soft compressible cysts most commonly on anterior chest or less often back

Variant

Steatocystoma multiplex. Multiple steatocystomas, usually on chest and back. In some patients, mutation in keratin 17 which also causes pachyonychia congenita

Histopathology  Multi-layered epithelial lining without granular layer  Narrow eosinophilic zone with compact keratinization (cuticle) and zigzag pattern (crenellated lining)  Cyst usually collapsed; contains very loose horn  Sebaceous lobules in wall of cyst

Differential diagnoses ] Epidermoid cyst Epithelial cyst with epidermal pattern of keratinization including granular layer. Cyst contains loosely-aggregated keratin scales ] Trichilemmal cyst Epithelial cyst with compact amorphous keratinization and no granular layer ] Vellus hair cyst Small epithelial cysts with variable keratinization pattern, usually collapsed, often have sebaceous glands but also have numerous vellus hairs (bundles of 10–15) ] Hidrocystoma Dermal cyst with 2-layered epithelial lining in either apocrine or eccrine pattern. Most common around eyes. Eccrine form may be reactive, reflecting occlusion of eccrine ducts

Steatocystoma ] 151

sebaceous gland in cyst wall

crenellated cuticle

cyst wall without stratum granulosum

3.2 Pseudocysts 3.2.1 Digital mucous cyst

3.2.1 Digital mucous cyst Definition Post-traumatic or idiopathic collection of mucin in the dermis, usually on digits; not a true cyst but pseudocyst

Clinic

Skin-colored or translucent domed-shaped papule, usually on distal digit of finger, either at nail fold with nail dystrophy or over distal interphalangeal joint

Histopathology  Acanthotic localization-specific epidermis, sometimes with central pressure-induced flattening  Localized but irregularly bordered deposits of mucin in upper and mid-dermis  No epithelial cyst wall; sometime pseudocapsule formed by macrophages, other inflammatory cells and fibrosis

Additional studies The mucin is mesenchymal, manufactured by fibroblasts and not glandular epithelium. It is usually generous and obvious, but can be confirmed with Alcian blue stain

Differential diagnoses ] Ganglion Larger deeper lakes of mucin, usually with focal remnants of synovial cells. Surrounding fibrotic pseudocapsule with strands of mucin ] Epidermoid cyst Epithelial cyst with epidermal pattern of keratinization including granular layer. Cyst contains loosely-aggregated masses of horn ] Myxoid neurothekeoma Sharply circumscribed proliferation of S-100-positive basaloid tumor cells with deposits of mucin

Comment Digit mucous cysts do not have a true cyst wall and are thus pseudocysts. Nonetheless, detailed studies suggest that both ganglions and at least some digital mucoid cysts arise from the synovial lining of joints and may start out as a true cyst. Thus some consider the two to be variants of the same process.

Digital mucous cyst ] 155

pseudocyst with mucin

acanthotic epidermis

fibrotic connective tissue without cyst wall

epidermis

fibrotic connective tissue without cyst wall

mucin

IV Hamartomas and Neoplasms

4.1 Epidermal hamartomas and neoplasms 4.1.1

Epidermal nevus

4.1.2

Nevus sebaceus

4.1.3

Seborrheic keratosis

4.1.4

Clear cell acanthoma

4.1.5

Porokeratosis

4.1.6

Actinic keratosis

4.1.7

Bowen disease

4.1.8

Squamous cell carcinoma

4.1.9

Keratoacanthoma

4.1.1 Epidermal nevus Definition Area of permanent aberrant cutaneous differentiation caused by genetic mosaicism, usually following lines of Blaschko

Clinic

The classic epidermal nevus (EN) is a sharply defined patch or plaque in linear pattern; typically hyperkeratotic and papillomatous, usually hyperpigmented. There is a bewildering array of clinical and histological variants

Histopathology    

Focal acanthosis and papillomatosis with sharp base and distinct lateral margins Orthohyperkeratosis Focally increased basal layer pigmentation No inflammatory infiltrate

Variants  Inflammatory linear verrucous EN (ILVEN): Linear hyperkeratotic plaque with erythema. Histologically parakeratosis, and subepidermal band-like lymphocytic infiltrate, often psoriasiform pattern  Epidermolytic EN: Acanthosis, papillomatosis and focal distinct dyskeratosis at level of granular layer, known as epidermolytic hyperkeratosis  Nevus comedonicus: Almost rectangular horn-filled epidermal invaginations; clinically lesions resemble comedones, but there is not follicular involvement  Nevus sebaceus: Organoid nevus with acanthosis, papillomatosis, and increased numbers of sebaceous, eccrine and apocrine glands. Often decreased number of follicles

Differential diagnoses ] Seborrheic keratosis Histologically identical to classic epidermal nevus but age of patient and clinical description determine diagnosis. Much more likely to have horn pseudocysts ] Verruca vulgaris Papillomatosis with basal confluence of elongated rete ridges, hyperparakeratosis with hemorrhage, ectatic capillaries ] Becker nevus Hyperpigmented unilateral patch often with increase in terminal hairs. Epidermis is hyperpigmented with flattened rete ridges and no increase in melanocytes. Something underlying smooth muscle hamartoma

Epidermal nevus ] 161

acanthosis and papillomatosis

epidermolytic changes in stratum granulosum (in epidermolytic epidermal nevus)

hyperkeratosis

4.1.2 Nevus sebaceus Definition Organoid nevus with both epidermal and adnexal permanent differentiation abnormalities caused by genetic mosaicism, mostly solitary

Clinic

Usually on scalp. Presents in infancy as patch of alopecia. Later develops into yellowbrown plaque

Histopathology    

Focal acanthosis and papillomatosis with sharp base and distinct lateral margins Enlarged sebaceous glands Increased numbers of apocrine and eccrine glands Few or no hair follicles

Differential diagnoses ] Epidermal nevus Similar epidermal changes but normal dermis without excessive adnexal structures ] Sebaceous hyperplasia Small papule on face of adult with increased sebaceous glands centered on single follicle

Comment Biopsies from nevus sebaceus in infancy are difficult to interpret. The sebaceous hyperplasia is usually absent and only the hypoplastic hair follicles may be a clue to the diagnosis. In about 2% of patients, adnexal tumors (trichoblastoma, syringocystadenoma papilliferum) develop within nevus sebaceus. Trichoblastomas were formerly routinely misinterpreted as basal cell carcinomas and the standing recommendation was to excise nevus sebaceus as a pre-malignant lesion. This is incorrect: any surgical decision should be based solely on cosmetic considerations or to rule out above mentioned adnexal tumors. Organoid nevi are somewhat more likely than epidermal nevus to be associated with underlying systemic problems, such as ocular and CNS abnormalities.

Nevus sebaceus ] 163

sebaceous glands high in dermis

acanthosis and papillomatosis

dilated sweat gland ducts

trichoblastoma arising in nevus sebaceus

trichoblastoma

4.1.3 Seborrheic keratosis Definition

Common benign tumor of adults; some variants related to mutations in fibroblast growth factor receptor 3 (FGFR3)

Clinic

Waxy tan-brown-black papillomatous or verrucous tumor which appears “stuck on” to the skin surface (drop of wax sign) Stucco keratosis: Small white verrucous papules, usually on distal limbs and multiple Dermatosis papulosa nigra: Tiny black papules on cheeks of blacks

Variants

Histopathology    

Focal acanthosis and papillomatosis with sharp usually flat base and distinct lateral margins Intraepithelial horn pseudocysts Monotonous basaloid tumor cells without atypia Often increased melanin

Variants

   

Adenoid or reticular: Rich in horn pseudocysts and basaloid strands, often 2–3 cells thick, forming a network Acanthotic: Marked acanthosis Papillomatous: Prominent church spire effect Melanoacanthoma: Acanthotic seborrheic keratosis with marked increase in melanin, sometimes striking dendritic melanocytes  Irritated seborrheic keratosis: Features dermal inflammatory infiltrate and squamous eddies (areas with keratinocytes in swirled pattern). Flat irritated seborrheic keratoses with lichenoid infiltrate (lichenoid keratosis) may represent a stage of involution rather than of irritation  Clonal (Borst-Jadassohn) seborrheic keratosis: Intraepithelial proliferations of distinctive basaloid cells which are sharply distinguished from surrounding monotonous cells, either by size or staining properties. Not an indication of malignancy  Inverted follicular keratosis: Sharply circumscribed endophytic verrucous proliferation with prominent squamous eddies

Differential diagnoses ] Epidermal nevus Histologically identical. Age and clinical picture often determine diagnosis ] Verruca vulgaris Papillomatosis with basal confluence of elongated rete ridges, hyperparakeratosis with hemorrhage, ectatic capillaries ] Condyloma acuminatum Same silhouette as seborrheic keratosis with less cornified layer and no horn pseudocyst. Usually has focal parakeratosis and may have koilocytes ] Hidroacanthoma Intraepidermal “cannon-ball-like” proliferation of poroid cells centered on eccrine ducts or their remnants. Eosinophilic cytoplasm, no horn pseudocysts ] Clear cell acanthoma Circumscribed psoriasiform acanthosis with clear-cell change, PAS-positive, often neutrophils ] Bowen disease Acanthosis with full-thickness epidermal dysplasia, atypical mitoses, crowded nuclei ] Paget disease Pagetoid (scattered, like pattern of shot gun) distribution of clear tumor cells in epidermis; CAM5.2 and CK7 are best immunostains

Seborrheic keratosis ] 165

acanthosis and papillomatosis

horn pseudocysts

increased melanin

4.1.4 Clear cell acanthoma Definition Benign epithelial tumor of unknown etiology with distinctive histological picture Clinic

Sharply bordered, usually skin-colored or sometimes erythematous papule or nodule, usually on shin

Histopathology     

Sharply-bordered psoriasiform focal acanthosis Keratinocytes of spinous layer are strikingly pale with abrupt transition at edge Basal layer keratinocytes unchanged No mitoses or nuclear atypia Exocytosis of neutrophils

Additional studies PAS stain identifies abundant glycogen in the pale keratinocytes

Differential diagnoses ] Bowen disease, clear cell variant Intraepidermal carcinoma with nuclear atypia and mitoses. Abundant intraepidermal clear cells, but often more scattered ] Seborrheic keratosis Usually numerous horn pseudocysts, increased pigment, rare clear-cell change but other features retained ] Psoriasis Elongated rete ridges. Numerous neutrophils in spiny and cornified layer. Clinically multiple lesions

Clear cell acanthoma ] 167

hyperparakeratosis

sharp transition between clear and normal epidermal cells

4.1.5 Porokeratosis Definition Very focal disturbance in keratinization; two main factors appear to be genetic changes and UV damage to keratinocytes

Clinic

Many different clinical variants with two most common a solitary annular lesion (parakeratosis of Mibelli) and disseminated irregular but sharply bordered patches on sun-exposed skin (disseminated superficial actinic porokeratosis). Unifying clinical feature is distinct hyperkeratotic border. Central atrophy and erythema also common

Histopathology  At both edges, inward-bent slender columns of parakeratosis with abnormal granular layer (cornoid lamella)  Epidermis between cornoid lamellae often thinned; may show premature keratinization and mild nuclear atypia  Underneath is band-like and perivascular lymphocytic infiltrate similar to lupus erythematosus

Additional studies PAS stain shows punctate glycogen inclusions within cornoid lamella, helping to distinguish from parakeratotic columns in actinic keratoses

Differential diagnoses ] Actinic keratosis Atypical keratinocytes especially in basal layer. Alternating horizontal areas of orthokeratosis and parakeratosis (pink and blue pattern) ] Lupus erythematosus Epidermal atrophy, perivascular and periadnexal lymphocytic infiltrates. Sometimes focal, usually follicular, hyperkeratosis. No cornoid lamella

Comment Porokeratosis requires a biopsy which can be oriented and ideally demands a thin ellipse perpendicular to annular border with instructions to the laboratory that porokeratosis is suspected. Otherwise, even multiple sections may miss diagnostic finding. The central area can easily be confused with atrophic chronic cutaneous (discoid) lupus erythematosus.

Porokeratosis ] 169

columns of parakeratosis (cornoid lamellae)

cornoid lamella

glycogen inclusions (PAS)

4.1.6 Actinic keratosis Definition Intraepidermal neoplasm with atypia of keratinocytes (squamous cell carcinoma in situ). Potential for transformation to invasive tumor; greater risk in elderly and immunosuppressed and on mucosal surfaces

Clinic

Erythematous usually hyperkeratotic papules and plaques on sun-exposed skin. Sometimes markedly hyperkeratotic or pigmented; often easier to feel than to see. Field effect means solitary lesions uncommon

Histopathology  Horizontal alternation of parakeratotic and orthokeratotic hyperkeratosis (pink and blue sign). Follicular ostia usually orthokeratotic (follicular sparing)  Epidermis ranges from atrophic to acanthotic  Neoplastic keratinocytes especially in basal layer with increased cellularity, nuclear pleomorphism and scattered mitoses  Superficial lymphocytic infiltrate, either lichenoid or perivascular, often with admixed plasma cells  Actinic elastosis Variants  Acantholytic actinic keratosis: Suprabasal acantholysis producing clefts  Pigmented actinic keratosis: Focal increase in melanin primarily in basal keratinocytes, but melanocytes may also be increased

Differential diagnoses ] Bowen disease Acanthosis with full-thickness epidermal maturation defects, atypical mitoses, clumped nuclei ] Flat seborrheic keratosis No atypical keratinocytes. No alternating hyper- and parakeratosis

Comment Bowen disease and bowenoid actinic keratosis are clinically different but histologically similar with identical epidermal changes. Bowenoid actinic keratosis is more likely to having solar elastosis.

Actinic keratosis ] 171

hyperparakeratosis

mixed inflammatory infiltrate

abnormal epidermal maturation, atypical keratinocytes

orthokeratosis

4.1.7 Bowen disease Definition Intraepidermal carcinoma with atypia of keratinocytes at all levels of epidermis (squamous cell carcinoma in situ)

Clinic

Circumscribed, often erythematous plaque with psoriasiform or dermatitic appearance. Variants may be hyperkeratotic, nodular or pigmented

Histopathology  Parakeratosis and often hyperkeratosis  Epidermis may be flat or acanthotic; latter often with bulbous rete ridges  Entire epidermis shows disordered maturation with atypical keratinocytes, individual cell keratinization, pleomorphic nuclei, atypical mitoses and multi-nucleated tumor cells  Often intact basal layer (eyeliner sign)  In some cases pagetoid keratinocytes; in others, more extensive clear cell change  Lymphocytic perivascular or lichenoid infiltrate, often with admixed plasma cells

Additional studies Sometimes in pigmented forms without significant sun damage, human papilloma viruses (especially HPV 16 and 18) can be identified. S100, HMB-45 and Melan A, as well as cytokeratin stains, may be used to exclude melanoma

Differential diagnoses ] Erythroplasia of Queyrat Bowen disease on mucosa; histologically identical ] Paget disease Pagetoid (scattered, like pattern of shot gun) distribution of clear tumor cells in epidermis; CAM5.2 and CK7 are best immunostains ] Bowenoid papulosis Genital HPV infection with atypical keratinocytes and mitoses identical microscopically to Bowen disease ] Superficial spreading melanoma (SSM) Pagetoid spread through epidermis of S-100-positive melanocytes, usually more concentrated in basal layer. Both solitary cells and nests ] Irritated seborrheic keratosis No significant keratinocyte atypia. Squamous eddies and mitoses reflect marked irritation

Bowen disease ] 173

hyperparakeratosis

abnormal epidermal maturation

lymphocytic infiltrate actinic elastosis

parakeratosis

individual cell dyskeratosis

atypical keratinocytes

mitosis

eyeliner sign (intact basal layer)

4.1.8 Squamous cell carcinoma Definition Epithelial neoplasm of atypical keratinocytes with locally destructive growth and potential for metastasis. Main causes are UV damage and in genital area, HPV infection

Clinic

Nodular, erythematous tumors often ulcerated. Typically found in sun-exposed areas on forearm, ears, dorsal aspects of hands and arms; also lower lip and genitalia

Histopathology  Invasive epithelial tumor with broad buds and strands of atypical and dyskeratotic keratinocytes  Hyperchromatic, pleomorphic nuclei with mitoses  Well-differentiated tumors typically have horn pearls and single cell keratinization; less differentiated ones lack keratinization and have numerous atypical mitoses  Several growth patterns can be seen; desmoplastic (marked fibrotic stroma), neurotropic (perineural spread), and acantholytic (small tumor strands, individual free-floating cells)  Tumors often accompanied by lymphocytic and particularly plasma cell infiltrate

Differential diagnoses ] Metastasis from internal squamous cell carcinoma Nodular proliferation of epithelial tumor cells without connection to epidermis; often in sites without sun damage ] Adnexal carcinoma May have squamous differentiation but also hints of adnexal features; usually without connection to epidermis ] Inverted follicular keratosis Sharply circumscribed endophytic symmetrical epithelial tumor with squamous eddies but no nuclear atypia

Squamous cell carcinoma ] 175

invasive strands of atypical keratinocytes

atypical keratinocytes

mitosis

pleomorphic hyperchromatic nuclei

4.1.9 Keratoacanthoma Definition Epithelial neoplasm with squamous differentiation, rapid growth and tendency to spontaneous resolution. Some consider keratoacanthoma a specific entity; others regard it as a variant of squamous cell carcinoma

Clinic Variants

Nodular usually erythematous tumor with central crater filled with horn plug. Typically on face, less often extremities . Keratoacanthoma centrifugum marginatum: Giant keratoacanthoma with striking centrifugal spread in superficial and mid-dermis . Multiple keratoacanthomas: Occasionally eruptive, may be marker for Muir-Torre syndrome (multiple keratoacanthomas, unusual sebaceous tumors, wide variety of underlying malignancies)

Histopathology       

Symmetrical relatively sharply circumscribed proliferation of keratinocytes Central horn plug, sometimes first seen on serial sections At the periphery, epidermis extends over tumor (cupping) Pale ground-glass-like keratinocytes with uniform differentiation Minimal nuclear pleomorphism and mitoses Collections of neutrophils within the squamous masses (intratumoral microabscesses) Rich lymphocytic and neutrophilic peritumoral infiltrates

Differential diagnoses ] Squamous cell carcinoma Classic squamous cell carcinoma invades with an irregular pushing margin and displays wide pattern of cell differentiation

Comment There is no certain way to separate a keratoacanthoma from a squamous cell carcinoma. Often changes at the base of the keratoacanthoma fulfill criteria for a squamous cell carcinoma. Even lesions with a classic history, clinical appearance and microscopic pattern may occasionally recur or even metastasize. We consider keratoacanthoma as a highly differentiated squamous cell carcinoma which only rarely escapes intrinsic tumor surveillance.

Keratoacanthoma ] 177

central keratotic plug

symmetrical epithelial tumor with central crater

peripheral epidermal cuffs

uniform keratinocytes with ground glass cytoplasm

necrotic keratinocytes as sign of early regression

mixed inflammatory infiltrate

4.2 Melanocytic lesions 4.2.1

Mucosal melanotic macule

4.2.2

Lentigo simplex

4.2.3

Melanocytic nevi – junctional and compound types

4.2.4

Melanocytic nevi – dermal and papillomatous types

4.2.5

Halo nevus

4.2.6

Blue nevus

4.2.7

Dysplastic melanocytic nevus

4.2.8

Spitz nevus

4.2.9

Lentigo maligna and lentigo maligna melanoma

4.2.10 Superficial spreading melanoma 4.2.11 Nodular melanoma 4.2.12 Acrolentiginous melanoma 4.2.13 Desmoplastic melanoma

4.2.1 Mucosal melanotic macule Definition Focal increase in melanin in basal layer epithelial cells secondary to increased melanin production and transfer, but without significant increase in number of melanocytes

Clinic

Circumscribed brown macules on lips or genital mucosa; often multiple

Histopathology    

Normal mucosa Focal increased basal layer pigmentation No or minimal increase in melanocytes without nests In superficial lamina propria, incontinence of pigment with melanin-laden macrophages

Additional studies Masson-Fontana stain shows focal increase in melanin in basal layer. S-100 and HMB-45 stains show no increase in melanocytes

Differential diagnoses ] Lentigo maligna Neoplastic proliferation of atypical melanocytes with hyperchromatic nuclei and elongated dendrites within epidermis and follicular epithelium ] Pigmented actinic keratosis Atypical hyperpigmented keratinocytes. Little or no increase in melanocytes and no atypical melanocytes. Horizontal alternation of ortho- and parakeratosis. Actinic elastosis

Comment Solitary labial macules are sporadic and not associated with underlying disease. Multiple pigmented labial lesions may be a marker for Peutz-Jeghers or Carney complex. It is often wise to biopsy several sites in larger irregular pigmented mucosal macules to reduce the risk of a sampling error. S-100, HMB-45 and Melan A immunostains help to identify subtle melanocytic proliferations.

Mucosal melanotic macule ] 181

mucosal epithelium

increased basal layer melanin without increased melanocytes

4.2.2 Lentigo simplex Definition Increased basal layer melanin accompanied by few melanocytes without nests. When melanocytes are prominent, also called nevus incipiens

Clinic

Sharply circumscribed brown-black macules

Histopathology  Increased melanin in basal layer with few basal melanocytes but no nests

Additional studies Masson-Fontana stain confirms presence of melanin. S-100, HMB-45 and Melan A immunostains reveal slight or no increase in melanocytes

Differential diagnoses ] Solar or senile lentigo Macule or patch usually on sun-exposed skin of face or distal arms. Histologically elongated rete ridges with marked increase in melanin at tips (dirty feet) but no increase in melanocytes ] Flat pigmented seborrheic keratosis Very similar but with more acanthosis, horn pseudocysts, and more diffuse pigmentation. Some view solar lentigo as very early flat variant of seborrheic keratosis ] Lentigo maligna Neoplastic proliferation of atypical melanocytes with hyperchromatic nuclei and elongated dendrites within epidermis and follicular epithelium ] Pigmented actinic keratosis Atypical hyperpigmented keratinocytes. Little or no increase in melanocytes and no atypical melanocytes. Horizontal alternation of ortho- and parakeratosis. Actinic elastosis ] Becker nevus Clinically completely different as large often hairy pigmented plaque. Histologically increased pigment in flattened bases of elongated rete ridges without increase in melanocytes. Hairs and dermal smooth muscle and lack of solar elastosis additional clues

Lentigo simplex ] 183

hyperpigmentation of rete ridges

increased basal layer melanin with discrete individual melanocytes but no nests

4.2.3 Melanocytic nevi – junctional and compound types Definition Benign melanocytic neoplasms which can appear at any age Clinic

Tan-brown macule or papule, usually sharply circumscribed. Can occur in any body region

Histopathology         

Symmetrical architecture with sharp lateral borders Uniform nests of monomorphous melanocytes at junction and in upper dermis Scattered solitary melanocytes in basal layer Melanocytes have round or oval nuclei with dense chromatin and varying degrees of cytoplasmic melanin. No nuclear atypia or mitoses. These melanocytes have been called nevocytes or nevomelanocytes, but they are melanocytes and we will only use that term Characteristic maturation of melanocytes towards the depths, as they become smaller Incontinence of pigment and associated lymphocytic infiltrate possible When irritated, melanin inclusions may wind up horny layer Junctional nevus: Melanocytes singly and in nests only in the junctional zone, most often at tips of the rete ridges Compound nevus: Melanocytes both at the junction and in nests in the dermis

Additional studies The melanocytes express S-100, HMB-45, and Melan A to varying degrees. The junctional melanocytes express HMB-45 while those in the dermis usually do not

Differential diagnoses ] Lentigo simplex Slight increase in junctional melanocytes without nests ] Dysplastic melanocytic nevus Variant of junctional/compound nevus with varying degrees of melanocytic atypia, bridging between nests, shoulders (epidermal spread of melanocytes lateral to the dermal borders), lamellar fibrosis around the nests, sparse dermal lymphocytic infiltrates ] Spitz nevus Dome-shaped red-brown nodule, more common in children and young adults. Sharp lateral borders, epidermis often hyperplastic. Nests and strands of spindle and epithelioid melanocytes. Clefts around junctional nests. Intraepidermal eosinophilic globules (Kamino bodies) ] Malignant melanoma Asymmetrical over-all pattern, poor lateral circumscription, atypical melanocytes with transepidermal migration and impaired maturation towards the base

Comment Most melanocytic nevi are not hamartomas but instead neoplastic proliferations of melanocytes whose growth is halted by oncogen-induced senescence and other growth control mechanisms.

Melanocytic nevi – junctional and compound types ] 185

Junctional melanocytic nevus melanin granules in stratum corneum

junctional nests of uniform melanocytes

melanophages

Compound melanocytic nevus

junctional and dermal nests of melanocytes with maturation towards the base

4.2.4 Melanocytic nevi – dermal and congenital types Definition Benign melanocytic neoplasm in which the melanocytes are primarily or exclusively in the dermis

Clinic

Skin-colored to brown soft dome-shaped or polypoid nodules. Sites of predilection are head and trunk. Congenital lesions may be larger, often contain hairs

Histopathology    

Polypoid tumor with sharp lateral circumscription Nests and strands of monomorphous melanocytes predominantly in dermis Maturation of melanocytes towards depths Scattered often larger melanocytes at junction; most congenital nevi have junctional melanocytes during infancy and childhood  Spread of melanocytes along hair follicles into deep dermis in older congenital nevi  No nuclear atypia or mitoses Variants  Miescher nevus: Exo- and endophytic dermal melanocytic nevus, usually on face, dome-shaped with a wedge-like collection of melanocytes extending into deep dermis  Unna nevus: Exophytic papillomatous melanocytic nevus  Duperrat nevus: Dermal melanocytic nevus combined with epidermoid cyst; usually facial and more common in women. Inflammation of cyst may be mistaken for change in nevus  Nanta nevus: Dermal melanocytic nevus, almost always facial, with cutaneous osteoma  Clonal nevus: Nests of heavily-pigmented epithelioid melanocytes, often surrounded by melanophages, lying within an otherwise banal dermal melanocytic nevus

Differential diagnoses ] Dermal Spitz nevus Wedge-shaped or flat-bottomed pattern, dominated by nests and strands of epithelioid and spindle-shaped melanocytes, sometimes with increased stromal fibrosis (desmoplastic Spitz nevus) ] Cellular blue nevus Strands and bundles of densely-packed epithelioid or neuroid variably-pigmented dermal melanocytes, sometimes combined with areas of dendritic melanocytes; no nuclear atypia and rare mitoses ] Nodular melanoma Dermal accumulation of atypical melanocytes with nuclear pleomorphism and mitoses; no maturation to base. At periphery, transepidermal migration of atypical melanocytes. Overlying epidermis atrophic or ulcerated ] Fibrous papule Small dome-shaped papule with fibrosis, stellate multinucleated fibroblasts, and telangiectases

Comment Congenital melanocytic nevi examined during newborn period and infancy often have junctional changes including transepidermal migration, atypical junctional nests and proliferative nodules (nodules of epithelioid heavily pigmented melanocytes). Sometimes without a clinical history, biopsies from such lesions cannot be separated with certainty from melanoma.

Melanocytic nevi – dermal and congenital types ] 187

Congenital melanocytic nevus

melanocytes extend along adnexal structures and vessels

melanocytes mature at base

4.2.5 Halo nevus Synonym: Sutton nevus Definition Benign melanocytic neoplasm with marked lymphocytic host response which often leads to regression of nevus

Clinic

Irregular tan-brown nevus surrounded by erythematous or hypopigmented ring (halo). Sometimes no such changes are appreciated clinically, but the host response is seen histologically. In other instances, no residual nevus is seen clinically and the lesion is interpreted as a type of hypopigmentation

Histopathology    

Elevated melanocytic lesion with nests of melanocytes showing varying degrees of pigmentation Sometimes bridging of nests Modest nuclear pleomorphism, but no mitoses Dense subepidermal band-like lymphocytic infiltrate with interspersed melanocytic nests (cloudy pattern)  Incontinence of pigment  On occasion, only inflammatory infiltrate without certain signs of previous melanocytic proliferation

Additional studies Melan A stain is better than S-100 or HMB-45 for helping visualize residual melanocytes within the dense infiltrate

Differential diagnoses ] Melanoma Asymmetrical architecture, transepidermal migration of atypical melanocytes, epidermis often thinned and displaced by malignant cells (consumption), usually patchy lymphocytic infiltrate with plasma cells ] Dysplastic melanocytic nevus Variant of junctional/compound nevus with varying degrees of melanocytic atypia, bridging between nests, shoulders (epidermal spread of melanocytes lateral to the dermal borders), lamellar fibrosis around the nests, sparse dermal lymphocytic infiltrates

Halo nevus ] 189

melanocytes obscured by dense lymphocytic infiltrate

melan A stains the melanocytes red

melanocytes

lymphocytes

4.2.6 Blue nevus Definition Dermal melanocytic neoplasm usually consisting of dendritic melanocytes Clinic

Circumscribed blue-gray macule or papule, often on extremities

Histopathology     

Focal collection of spindle-shaped dendritic melanocytes in upper and mid-dermis, but no nests Melanocytes with elongated nuclei and melanin-rich cytoplasm No nuclear atypia or mitoses Numerous melanophages between the spindled and dendritic melanocytes Varying amounts of interspersed collagenous stroma

Variants  Cellular blue nevus: Strands and bundles of densely-packed epithelioid or neuroid variably-pigmented dermal melanocytes, sometimes combined with areas of dendritic melanocytes; no nuclear atypia and rare mitoses  Deep penetrating blue nevus: Multiple strands of dermal melanocytes of varying morphology extending into deep dermis or even subcutaneous fat; some are usually dendritic, other may be epithelioid and rich in pale or dusty cytoplasm. Often large interspersed melanophages (fishnet pattern)  Epithelioid blue nevus: Large round or cuboidal melanocytes. Few dendritic cells. Usually sporadic, but potential marker for Carney complex

Additional studies The melanocytes express S-100, HMB-45, and Melan A to varying degrees

Differential diagnosis ] Dermal melanocytosis Scattered often very subtle hyperpigmented dendritic melanocytes in all levels of dermis. No nests; no epithelioid cells Diagnosis is clinical based on age (Mongolian spot) and location (nevus of Ota in first branch of trigeminal nevus, nevus of Ito on shoulder) ] Desmoplastic melanoma Asymmetrical architecture, dermal proliferation of spindle cells with nuclear atypia, often little melanin, embedded in a collagenous stroma with myofibroblasts. Patchy inflammatory infiltrate. Extends into deep dermis, subcutis, often with perineural involvement. Marked desmoplasia (fibrosis). Often associated with overlying lentigo maligna. Tumor cells express S-100 and p75; other melanocytic markers usually negative

Blue nevus ] 191

bundles of spindled melanocytes

melanophages

thick bundles of spindled melanocytes

4.2.7 Dysplastic melanocytic nevus Synonym: Clark nevus Definition Benign melanocytic neoplasm which is separated from common melanocytic nevus because of both architectural and cytological features

Clinic

Irregularly-pigmented (shades of red, tan, brown and black) macules or papules; often central papule with surrounding pigmented macule (fried egg sign)

Histopathology  Asymmetrical and poorly circumscribed lesion  Shoulders (junctional melanocytic nests extend laterally past the underlying dermal component)  Bridging (confluence of melanocytic nests at the tips of adjacent rete ridges)  Lamellar fibrosis around junctional nests  Moderate pleomorphism of hyperchromatic nuclei  Occasional junctional and rare dermal mitoses  Cytoplasm of melanocytes has fine granular dusty melanin  Maturation of melanocytes toward depth  No or minimal transepidermal migration of melanocytes  Incontinence of pigment and dermal lymphocytic infiltrate

Additional studies The melanocytes express S-100, HMB-45, and Melan A to varying degrees; the dermal cells are usually HMB-45 negative

Differential diagnosis ] Melanoma Asymmetrical architecture, transepidermal migration of atypical melanocytes, epidermis often thinned and displaced by malignant cells (consumption), usually patchy lymphocytic infiltrate with plasma cells

Comment There are many problems with the concept of dysplastic or atypical nevus. First there are no reproducible clinical or histological features for diagnosis. Second, whether the lesions are unusual nevi, melanoma precursors, or melanoma markers is still unclear. Third, most individuals have one or a few such flat unusual nevi without any consequences. Patients with multiple atypical nevi (dysplastic nevus syndrome, B-K mole syndrome) do have an increased risk of melanoma. Some prefer to use the term “atypical nevus” for the clinical presentation and reserve “dysplastic nevus” for a histological diagnosis. Unfortunately there is little correlation between clinically atypical nevi and those with histological features of dysplasia.

Dysplastic melanocytic nevus ] 193

shoulders (junctional melanocytes extend lateral to dermal component)

atypical melanocytes with pleomorphic nuclei (sometimes suprabasal)

irregular nests with bridges lamellar fibroplasia

maturation of melanocytes at base

4.2.8 Spitz nevus Definition Benign melanocytic tumor with characteristic histological pattern Clinic

Sharply circumscribed dome-shaped, usually red-brown, papule or nodule; more common in children and young adults; often with history of rapid growths

Variant

Pigmented spindle cell nevus (Reed nevus): Typically dark brown-black flat macule

Histopathology  Symmetrical overall pattern with sharp lateral and deep borders  Melanocytes primarily in nests at junction and in dermis  Melanocytes have epithelioid or spindle cell morphology with central vesicular nucleus and pale eosinophilic cytoplasm  Cytoplasm usually eosinophilic but occasionally dusty  Maturation of melanocytes to depth  Clefting between junctional nests and overlying epidermis  Transepidermal migration of isolated melanocytes  Epidermis with acanthosis, prominent granular layer and characteristic PAS-positive homogenous globules (Kamino bodies)  While mitoses may occur, those in deeper parts of the tumor should be viewed with suspicion Variants  Dermal Spitz nevus: Wedge-shaped dermal infiltrate of epithelioid and spindle-shaped melanocytes without typical junctional involvement  Desmoplastic Spitz nevus: Marked stromal reaction to predominantly dermal Spitz nevus. Often single or few epithelioid melanocytes in fibrous stroma. Numerous small vessels  Reed nevus: Superficial, purely spindle-cell variant of Spitz nevus with marked pigmentation of melanocytes at junction with striking often horizontally-elongated nests in superficial dermis

Additional studies The melanocytes express S-100, HMB-45, and Melan A to varying degrees

Differential diagnosis ] Melanoma Asymmetrical architecture, transepidermal migration of atypical melanocytes, epidermis often thinned and displaced by malignant cells (consumption), usually patchy lymphocytic infiltrate with plasma cells

Comment The distinction between Spitz nevus and melanoma can be problematic, especially in adults with asymmetrical lesions. Molecular biological studies indicate that Spitz nevi have a different pattern of mutations than do melanomas, a potential tool for future diagnosis. Some use the term atypical Spitz tumor for those borderline lesions where an increased number of mitoses may be found, but with current techniques a clear distinction is impossible.

Spitz nevus ] 195

symmetrical melanocytic tumor with uniform acanthosis

melanocytes primarily in nests

acanthotic epidermis

nests of spindled and epithelioid melanocytes

Kamino body

4.2.9 Lentigo maligna and lentigo maligna melanoma Definition Lentigo maligna is a malignant intraepithelial or in situ melanocytic tumor; the invasive form is known as lentigo maligna melanoma

Clinic

Slowly growing irregular pigmented brown-black macule or patch on sun-exposed skin. When a nodule develops, invasive melanoma is likely

Histopathology  Atrophic epidermis, marked actinic elastosis  Atypical melanocytes with enlarged, hyperchromatic atypical nuclei and clear cytoplasm, initially and primarily in basal layer  Melanocytes are irregularly distributed, often increased in number and grouped along basal layer (back-to-back proliferation) or in nests of varying size and shape  Focal transepidermal migration of melanocytes  Spread of tumor cells along follicular epithelium  No dermal tumor cells

Additional studies Often only weak expression of S-100 and HMB-45. Melan A usually clearly positive although atypical keratinocytes can also express Melan A. (See Sec. 4.2.12 for information on reporting)

Differential diagnoses ] Lentigo maligna melanoma All the features of lentigo maligna, but also dermal invasion ] Follicular melanoma Atypical melanocytes extend downward along the follicular epithelium and permeate parts of the follicle as well as the adjacent dermis. Usually smaller than 0.5 cm but grow more rapidly than lentigo maligna ] Other types of melanoma Superficial spreading melanoma shows more transepidermal spread of atypical melanocytes with less epidermal atrophy and often no actinic elastosis. Acrolentiginous melanoma can also have scattered atypical junctional melanocytes but overlying epidermis is acanthotic and no actinic elastosis ] Solar lentigo Elongated hyperpigmented rete ridges (dirty feet) or more continuous basal layer hyperpigmentation with epidermal atrophy; little or no increase in melanocytes ] Pigmented actinic keratosis Atypical hyperpigmented keratinocytes. No increase in melanocytes and no atypical melanocytes. Horizontal alternation of ortho- and parakeratosis. Actinic elastosis

Comment While we have chosen to discuss the classic clinicopathologic variants of melanoma separately, others have correctly pointed out that there are frequent overlaps and individual tumors may show several patterns. The subtype is not of prognostic significance. Genetic studies favor a completely different division into sun-exposed, non-sun-exposed and intermediate types of melanomas.

Lentigo maligna and lentigo maligna melanoma ] 197

atypical melanocytes, most prominent in stratum basale

actinic elastosis

atypical melanocytes with pleomorphic nuclei scattered in epidermis

4.2.10 Superficial spreading melanoma Definition Malignant melanocytic tumor with initially primarily horizontal or radial growth and marked transepidermal migration of tumor cells

Clinic

Asymmetrical, poorly circumscribed irregular brown-black patch or nodule. Depending on vascularity, regression and dermal melanin, may have red, white and blue areas. Advanced lesions may be nodular or ulcerated

Histopathology  Asymmetrical architecture with poorly defined lateral border  Atypical melanocytes with irregular hyperchromatic nuclei and clear cytoplasm both singly and in nests at junction  Transepidermal migration of melanocytes with pagetoid pattern in epidermis  Lack of maturation of dermal melanocytes towards base  Occasional mitoses  Focally thinned epidermis as tumor cells and nests replace normal structures (consumption of epidermis) and are separated by clefts  Focal fibrosis, incontinence of pigment, and increased vascularity in dermis; lymphocytic infiltrates, sometimes with plasma cells

Additional studies Melanocytes express S-100, HMB-45 and Melan A to varying degrees. (See Sec. 4.2.12 for information on reporting)

Differential diagnoses ] Dysplastic melanocytic nevus Variant of junctional/compound nevus with varying degrees of melanocytic atypia, bridging between nests, shoulders (epidermal spread of melanocytes lateral to the dermal borders), lamellar fibrosis around the nests, sparse dermal lymphocytic infiltrates. The hardest differential diagnosis in dermatopathology – in comparison to melanomas, dysplastic nevi are more symmetrical, have fewer mitoses, less transepidermal spread, and more maturation towards the base ] Halo nevus Melanocytic nevus usually with slight central elevation. No transepidermal migration of melanocytes. Marked band-like lymphocytic infiltrate in papillary dermis ] Lentigo maligna melanoma Epidermal atrophy, actinic elastosis; primarily junctional melanocytes with more discrete transepidermal migration ] Paget disease Intraepidermal pagetoid spread of epithelial tumor cells which express CK7, CAM5.2 (CK 8/18) and EMA ] Pagetoid reticulosis Localized form of mycosis fungoides (Sec. 4.6.1) with atypical lymphocytes with clear cytoplasmic rim in pagetoid epidermal pattern ] Bowen disease Full-thickness distorted epidermal differentiation. Intraepithelial clear keratinocytes which express cytokeratins. Sometimes increased melanin

Superficial spreading melanoma ] 199

asymmetrical tumor

consumption (epidermal thinning by tumor cells)

various populations of melanocytes

no maturation of melanocytes at base

atypical melanocytes throughout epidermis and adnexal structures

4.2.11 Nodular melanoma Definition Malignant melanocytic neoplasm with dominant vertical growth phase, leading to primarily nodular pattern

Clinic

Usually rapidly-growing red-brown to dark-brown-black tumors which tend to ulcerate. Classic tumor has only slight macular component at periphery, but nodular melanomas may evolve out of the other forms

Variant

Amelanotic melanoma: Skin-colored to pink nodule; tumor cells de-differentiate and fail to produce melanin. Often not recognized clinically

Histopathology  Nodular protuberant proliferation of atypical melanocytes  Nests and bundles of relatively cohesive tumor cells of varying sizes. Nuclear pleomorphism and abundant cytoplasm with varying degrees of melanin. Mitoses common, also at depth of lesion  Epidermis often atrophic or ulcerated  At the periphery, transepidermal migration of melanocytes and other changes similar to superficial spreading melanoma  Usually peritumoral lymphocytic infiltrate, often rich in plasma cells, and incontinence of pigment

Additional studies The melanocytes express S-100, HMB-45, and Melan A to varying degrees. (See Sec. 4.2.12 for information on reporting)

Differential diagnoses ] Spitz nevus Symmetrical architecture, melanocytes mature towards depth ] Cellular blue nevus Strands and bundles of densely-packed epithelioid or neuroid variably-pigmented dermal melanocytes, sometimes combined with areas of dendritic melanocytes; no nuclear atypia and rare mitoses ] Anaplastic large-cell lymphoma Nodular proliferation of tumor cells which express lymphocytic markers, in some cases CD30 ] Other poorly differentiated anaplastic tumors Tumors such as Merkel cell carcinoma or atypical fibroxanthoma often only identified with certainty using immunostaining

Nodular melanoma ] 201

nodular tumor composed of atypical melanocytes Breslow thickness 3.8 mm

adjacent epidermis normal

consumption (epidermal thinning by tumor cells)

polymorphic atypical tumor cells

adnexal structures infiltrated by melanocytes

4.2.12 Acrolentiginous melanoma Definition Malignant melanocytic tumors usually found on the palms and soles Clinic

Irregularly pigmented tan-brown-black initially macular lesion with poorly defined border

Variant

Verrucous acrolentiginous melanoma: Marked hyperkeratosis often with little pigment. Frequently mistaken for verruca vulgaris with dramatic consequences. May also be subungual with just nail discoloration; at least one-third are amelanotic

Histopathology  Acanthosis and hyperparakeratosis (sometimes with melanin in horny layer)  Asymmetrical lesion with poorly-defined lateral borders  Initially individual atypical melanocytes with nuclear pleomorphism and scattered mitoses (lentiginous pattern). May be grouped together along basal layer (back-to-back proliferation) or form nests  Melanocytes often have striking elongated dendrites  Transepidermal migration of atypical melanocytes  Lymphocytic infiltrate, often with plasma cells; incontinence of pigment

Additional studies Melan A and melanin stains are very useful in early lesions for identifying the atypical melanocytes with elongated dendrites which extend into the upper reaches of spinous layer – a typical finding for this form of melanoma

Differential diagnoses ] Acral melanocytic nevus Symmetrical architecture with sharp lateral border and nests tending to dominate over individual cells. Bland cytomorphology. Transepidermal migration of small nests possible in palmoplantar nevi. MANIAC = melanocytic acral nevus with intraepidermal ascent of cells

The pathology report should include 1) Tumor thickness (Breslow depth): the distance in mm between granular layer and the deepest intradermal tumor cell 2) Clark level: the anatomic depth of the tumor including five levels – I (in situ), II (papillary dermis), III (into reticular dermis), IV (filling reticular dermis) and V (subcutis) 3) Presence or absence of ulceration All three parameters provide prognostic information

Acrolentiginous melanoma ] 203

lateral border not sharp

epidermis infiltrated at all levels by atypical melanocytes

4.2.13 Desmoplastic melanoma Definition Uncommon malignant melanocytic neoplasm in which dermal fibrosis dominates over the epidermal changes

Clinic

Skin-colored or tan firm dermal nodule, resembling keloid. Very difficult clinical diagnosis; often history of pre-existing macular pigmented lesion. May occur in younger patients

Histopathology  Isolated atypical melanocytes in basal layer (similar to lentigo maligna)  Asymmetrical wedge-shaped dermal proliferation of spindle-shaped melanocytes whose nuclei are slightly hyperchromatic and pleomorphic, with little or no cytoplasmic melanin, occasional mitoses  Fibrotic dermal response often surrounds or even masks the atypical melanocytes, presenting as an asymmetrical scar; many stromal myofibroblasts  Perineural spread of tumor cells common  Patchy lymphocytic infiltrate

Additional studies Prior to the advent of immunohistochemical stains, desmoplastic melanomas were only rarely correctly diagnosed. While the expression is variable, p75 and S-100 are most reliable. All other melanocytic markers may be negative. (See Sec. 4.2.12 for information on reporting)

Differential diagnoses ] Scar

Dense collagen bundles and bands, usually parallel to skin surface

] Dermatofibrosarcoma protuberans Cohesive bands of monomorphous tumor cells with hyperchromatic nuclei which often extend into fat septa and express CD34 ] Dermal sarcoma (malignant fibrous histiocytoma type) Cohesive tumor bundles with striking nuclear pleomorphism and multi-nucleated tumor cells (monster cells). Negative for S-100 and p75 ] Poorly-differentiated squamous cell carcinoma Irregular tumor, usually with epidermal connection found on multiple sections. May be heavily spindled or pleomorphic. Cytokeratin markers commonly positive

Comment Desmoplastic melanoma often develops from a pre-existing lentigo maligna. Thus whenever, a lentigo maligna or lentigo maligna melanoma is diagnosed, the dermis should be studied for desmoplasia and patchy infiltrates which may be masking a deeper involvement. Immunohistochemical stains are mandatory. In addition, when ever confronted with an asymmetrical scar in sundamaged skin, one should think of a desmoplastic melanoma, checking the current specimen carefully for dermal tumor cells and reviewing any prior specimens from the same site.

Desmoplastic melanoma ] 205

dermis is thickened and dense (desmoplastic)

lymphocytic infiltrates

atypical pleomorphic cells abnormal cells express S100 and are melanocytes

4.3 Adnexal tumors 4.3.1

Sebaceous hyperplasia

4.3.2

Pilomatricoma

4.3.3

Syringoma

4.3.4

Syringocystadenoma papilliferum

4.3.5

Poroma

4.3.6

Hidradenoma

4.3.7

Spiradenoma

4.3.8

Cylindroma

4.3.9

Paget disease

4.3.10 Trichoblastoma 4.3.11 Desmoplastic trichoepithelioma 4.3.12 Basal cell carcinoma 4.3.13 Fibroepithelioma of Pinkus

4.3.1 Sebaceous hyperplasia Definition Benign proliferation of enlarged sebaceous glands Clinic

Small yellow papule with central dell or pore, usually on face. Predisposing factors include genetic predisposition, seborrhea, and immunosuppression. Usually biopsied to exclude basal cell carcinoma

Histopathology  Enlarged regularly-structure sebaceous glands arranged around a central hair follicle  Normal peripheral rim of basaloid germinative cells Variant  Montgomery tubercle: Ectopic subepithelial sebaceous glands with central opening on nipple

Differential diagnoses ] Sebaceous adenoma Larger, irregular accumulation of sebaceous glands; basophilic rim of germinative cells usually thicker, not uniform; may have cystic areas in the center. Often ulcerated or crusted ] Cystic sebaceous tumor Cystic variant of sebaceous adenoma which is often a marker for Muir-Torre syndrome which displays defects in DNA mismatch repair gene expression. Patients may have multiple keratoacanthomas and systemic malignancies ] Sebaceoma Circumscribed basaloid tumor with areas of sebaceous differentiation

Sebaceous hyperplasia ] 209

central dilated hair follicle

increased numbers of normal but enlarged sebaceous glands

4.3.2 Pilomatricoma Synonym: Calcifying epithelioma of Malherbe Definition Benign adnexal tumor with follicular differentiation and tendency towards calcification

Clinic

Solitary firm dermal nodule usually in head and neck region. More common in children and adolescents

Histopathology    

Circumscribed nodular epithelial lesion in the deep dermis Basaloid tumor cells, with transition to pale-straining or necrobiotic central area (shadow cells) Deposits of calcium salts and even foci of ossification in the central portion Reactive inflammatory infiltrate with multinucleated giant cells throughout and around tumor

Differential diagnoses ] Basal cell carcinoma No shadow cells, clefting between basaloid tumor cells and stroma ] Trichoblastoma Basaloid tumor nodules with foci of hair germ differentiation. No calcification or shadow cells; cell-rich tumor stroma ] Osteoma cutis Ossification without hints of residual pilomatricoma (shadow cells, basaloid tumor cells)

Comment In older lesions, the basaloid tumor cells may be hard to find, so the picture is dominated by shadow cells. Pilomatricoma is one of the most common precursors for solitary osteoma cutis, so when confronted with cutaneous bone, always look for residual signs of this lesion. Pilomatrical carcinoma should be suspected when there are numerous mitoses or true necrosis.

Pilomatricoma ] 211

epidermis

matrix cells

shadow cells

granulomatous inflammation

matrix cells

matrical keratinization

shadow cells

4.3.3 Syringoma Definition Benign adnexal tumor with eccrine differentiation and many small ductal structures Clinic

Multiple yellow-white papules, most commonly on lids and cheeks

Histopathology  Proliferation of small ductal structures with 1–2 layers of cuboidal lining epithelium limited to upper and mid-dermis  Characteristic tadpole shape with eccentric proliferation of epithelial cells with eosinophilic cytoplasm  No cellular atypia  Occasionally dense stroma Variant  Clear-cell syringoma has PAS-positive glycogen in cytoplasm

Differential diagnoses ] Desmoplastic trichoepithelioma Tumor in upper and mid-dermis with strands of epithelial cells, small horn-filled cysts and a dense fibrous (desmoplastic) stroma ] Microcystic adnexal carcinoma Asymmetrical deep epithelial tumor with small horn-filled microcysts in the superficial component, proliferation of strands and basaloid and squamous ductal epithelial cells with bland cytologic appearance (no nuclear atypia or mitoses) extending into deep dermis and subcutis often with perineural infiltration. Deep dermis is dense and often sclerotic

Syringoma ] 213

dense fibrotic stroma

eccrine ductal structures with cuboidal epithelium, sometimes dilated to give tadpole form

strands of basaloid cells

4.3.4 Syringocystadenoma papilliferum Definition Benign adnexal tumor with apocrine differentiation Clinic

Nodule often in head and neck region, especially scalp; about 1/3 arise in a nevus sebaceus

Histopathology  Circumscribed epithelial invagination of tubular structures arising from epidermis with twolayered apocrine differentiation and focal squamous changes. Frequent anastomosis of ductal structures  Papillomatous protrusions into lumen (intraluminal pseudopapillae)  Two-layered epithelium; on the luminal side cuboidal apocrine epithelium, on the outer side cylindrical epithelium  Stroma with dense inflammatory infiltrate rich in plasma cells  When associated with nevus sebaceus, ectatic widened eccrine and apocrine ducts as well as enlarged sebaceous glands may be found beneath the syringocystadenoma

Differential diagnoses ] Hidradenoma papilliferum Circumscribed glandular proliferation in anogenital region with similar epithelial structures, including pseudopapillae and a two-layered apocrine pattern. Dermal tumor with no epidermal connection and little inflammation. Plasma cells not prominent ] Metastasis of adenocarcinoma Usually asymmetrical tumor with tubular structures, nuclear pleomorphism, and mitoses. No epidermal connection

Syringocystadenoma papilliferum ] 215

hyperplastic epidermis

cystic tumor lined by epithelium

papillomatous protrusions

cuboidal and cylindrical epithelium

infiltrate with plasma cells

4.3.5 Poroma Definition Group of benign adnexal tumors with eccrine ductal differentiation including hidroacanthoma simplex, eccrine poroma and dermal duct tumor

Clinic

. Hidroacanthoma simplex: Raised often verrucous papule or plaque, usually acral . Poroma and dermal duct tumor: Erythematous papule or nodule; usually acral or on scalp

Histopathology All three variants contain small basaloid tumor cells with little cytoplasm (poroid cells) admixed with larger cells with eosinophilic cytoplasm (cuticular cells).  Hidroacanthoma simplex: Circumscribed intraepidermal nodular proliferation of cuboidal poroid cell  Poroma: Proliferation of densely-packed cuboidal poroid cells with connection to epidermis; centrally cuticular cells around ducts. Characteristic necrosis (necrose en masse) usually in center of tumor nodules  Dermal duct tumor: Identical to poroma but without epidermal connections

Differential diagnoses Hidroacanthoma simplex ] Seborrheic keratosis The clonal form with Borst-Jadassohn phenomenon has intraepidermal nests of keratinocytes. Horn cysts usually present ] Bowen disease Intraepidermal tumor cells with full-thickness maturation defects, atypical mitoses, clumped nuclei ] Paget disease Pagetoid (scattered, like pattern of shot gun) distribution of clear tumor cells in epidermis; CAM5.2 and CK7 are best immunostains

Poroma and dermal duct tumor ] Basal cell carcinoma Asymmetrical architecture, palisading of peripheral tumor cells with clefting between them and stroma ] Porocarcinoma Similar but likely to be asymmetrical and larger; diagnosis based on atypical mitoses and nuclear pleomorphism, as well as broad clefts between tumor nests and stroma

Poroma ] 217

basaloid tumor arising from epidermis

proliferation of monomorphic basaloid and cuboidal cells forming ductal and cystic structures

4.3.6 Hidradenoma Synonyms: Nodular hidradenoma, clear cell hidradenoma Definition Benign adnexal tumor of apocrine differentiation with more glandular and less ductal elements than a poroma

Clinic

Solitary, sometimes painful, skin-colored to red-brown nodule, usually on head or extremities. May arise within nevus sebaceus

Histopathology  Intradermal circumscribed nodular proliferation with several types of tumor cells: Eosinophilic epithelioid cells rich in cytoplasm, sometimes polygonal with squamous differentiation and vesicular nuclei  Clear cells with pale cytoplasm rich in glycogen (PAS-positive)  Focal areas of duct formation  Cystic areas  Characteristic sclerotic stroma with dilated capillaries Variant  Clear cell hidradenoma with predominance of PAS-positive clear cells

Differential diagnoses ] Spiradenoma Similar but with two distinct cell types, numerous intratumoral lymphocytes (salt and pepper pattern), and infrequent ductal structures ] Cylindroma “Jig saw puzzle” pattern of nests of basaloid tumor cells surrounded by prominent dense PAS-positive membrane. Focal tubular structures ] Poroma or dermal duct tumor Circumscribed proliferation of poroid and occasional cuticular cells. Ductal structures with focal cystic change. Typical necrose en masse ] Basal cell carcinoma Basaloid tumor cells with peripheral palisading and clefting between tumor cells and stroma

Hidradenoma ] 219

circumscribed epithelial tumor in dermis

fibrous stroma

polygonal cells with eosinophilic and sometimes clear cytoplasm

ductal structures

4.3.7 Spiradenoma Definition Benign adnexal tumor with apocrine differentiation typically with two cell types Clinic

Solitary often painful skin-colored to red-brown nodules usually on face. When multiple, inherited in an autosomal dominant fashion and often associated with cylindromas and trichoblastomas (Brooke-Spiegler syndrome)

Histopathology  Circumscribed dermal nodule with epithelial proliferation containing two cell types: Small basaloid cells with dense nuclei and little cytoplasm Larger cuboidal cells with eosinophilic cytoplasm and less-condensed nuclei  Numerous dispersed intratumoral lymphocytes  No capsule  Ductal structures uncommon; cystic areas occasionally seen

Additional studies Intratumoral T cells can be identified with immunohistochemistry

Differential diagnoses ] Cylindroma “Jig saw puzzle” pattern of nests of basaloid tumor cells surrounded by prominent PAS-positive eosinophilic membrane. Focal tubular structures ] Basal cell carcinoma Basaloid tumor cells with peripheral palisading and clefting between tumor cells and stroma. No intratumoral lymphocytes ] Poroma or dermal duct tumor Circumscribed proliferation of poroid and occasional cuticular cells. Ductal structures with focal cystic change. Typical necrose en masse

Comment Although this tumor has long been known as eccrine spiradenoma, latest studies show that it has apocrine differentiation.

Spiradenoma ] 221

circumscribed epithelial tumor in dermis

small basaloid cells with dense nuclei admixed with large clear cells with pale nuclei, as well as scattered lymphocytes

4.3.8 Cylindroma Definition Benign adnexal tumor with apocrine or eccrine differentiation and characteristic pattern

Clinic

Solitary or more often multiple smooth pink-red nodules usually on scalp. When numerous and packed together, described as turban tumor. When multiple, inherited in an autosomal dominant fashion and often associated with spiradenomas and trichoblastomas (Brooke-Spiegler syndrome)

Histopathology  Circumscribed proliferation of nests of epithelial tumor cells arranged in “jig saw puzzle” pattern  Two types of tumor cells: Peripheral basaloid cells with hyperchromatic nuclei Central cuboidal cells with pale nuclei  Few mitoses  Nests surrounded by prominent PAS-positive membrane  Eosinophilic PAS-positive globular inclusions within the tumor islands  Focal tubular structures  Small number of intra- and peritumoral lymphocytes

Additional studies Membranes and globular inclusions within tumor islets are strikingly PAS-positive

Differential diagnoses ] Spiradenoma No “jig saw puzzle” pattern, numerous tumoral lymphocytes ] Basal cell carcinoma No prominent membrane around tumor islands; instead peripheral palisading and clefting. Usually asymmetrical

Comment Overlaps between cylindroma and spiradenoma are common; they have been called spiradenocylindroma or cylindrospiradenoma.

Cylindroma ] 223

circumscribed nests of basaloid epithelial cells

peripheral palisading of basaloid cells

pale cells in centers of nests

prominent membranes

4.3.9 Paget disease Definition . Mammary Paget disease: Intraepidermal spread of an underlying, usually intraductal, carcinoma of the breast . Extramammary Paget disease: Intraepidermal spread of cutaneous adnexal carcinomas or of a metastatic carcinoma (colon, prostate, bladder)

Clinic

Erythematous plaque, sometimes eroded, present either on nipple or in axillae, groin or anogenital region for the extramammary variant. Often clinically mistaken for dermatitis or candidiasis in groin

Histopathology  Pagetoid (scattered, like pattern of shot gun) distribution of solitary or nested epithelial tumor cells in often acanthotic epidermis  Tumor cells typically with pale basophilic cytoplasm, enlarged pleomorphic nuclei and prominent nucleoli  Lymphocytic infiltrate in upper dermis

Additional studies The tumor cells are usually PAS-positive but immunohistochemical studies are mandatory. The tumor cells react with CAM5.2, CK7, EMA and gross cystic disease fluid protein-15. HER2 (ErbB2) is a sensitive marker of tumor activity which can be expressed in all forms of Paget disease, not just those associated with breast carcinoma. Markers in extramammary Paget disease depend on underlying tumor (CDX2 for colon, PSA for prostate and uroplakin for bladder carcinomas)

Differential diagnoses ] Melanoma (superficial spreading type) Epidermis features atypical, sometimes clear melanocytes both singly and in nests, usually more prominent in basal layer, and positive for S-100, HMB-45 or Melan A ] Bowen disease and Bowenoid papulosis Acanthosis with full-thickness epidermal maturation defects, atypical mitoses, clumped nuclei ] Pagetoid reticulosis Localized form of mycosis fungoides (Sec. 4.6.1) with atypical clear lymphocytes in pagetoid intraepidermal pattern ] Periorbital sebaceous carcinoma Sebaceous carcinomas of the eyelid usually have replacement of epidermis by pale sebaceous cells with abundant cytoplasm

Comment Most cases of extramammary Paget disease are primary apocrine adnexal carcinomas. In about 15% of patients an underlying carcinoma (colon, prostate, bladder) has metastasized to epidermis.

Paget disease ] 225

serum and crusts (not always seen)

somewhat acanthotic epidermis laced with Paget cells

non-specific inflammatory infiltrate

epidermis

balloon-like Paget cells with pale cytoplasm and pleomorphic nuclei

Right side: Paget cells express cytokeratin 7

lymphocytes in inflammatory infiltrate

4.3.10 Trichoblastoma Definition Benign adnexal tumor with trichogenic differentiation Clinic

Solitary skin-colored to red-brown nodule, usually on scalp or head and neck. Occasionally ulcerated. Most common tumor found in nevus sebaceus. When multiple, inherited in an autosomal dominant fashion and often associated with cylindromas and spiradenomas (Brooke-Spiegler syndrome)

Histopathology  Circumscribed dermal nodule with proliferation of basaloid epithelial tumor cells  Peritumoral stroma is circumscribed and dense  No clefting between tumor islands and stroma – instead between peritumoral stroma and normal connective tissue  Rudimentary hair germs with epithelial strands enclosing primitive mesenchyme (“papillary mesenchymal bodies”)  Tumor cells are monomorphous, basophilic and have dense uniform nuclei  Increased melanocytes and melanin in tumor islands  Several different patterns of growth: nodular, retiform, cribriform (more common when multiple) and admixed with dense lymphocytic infiltrate (lymphadenoma) Variant  Trichoepithelioma: Superficial form with horn cysts

Differential diagnoses ] Basal cell carcinoma Very similar, but asymmetrical, no primitive hair germs, and clefting between tumor cells and stroma. Peripheral palisading more prominent in basal cell carcinoma but seen in both. Trichoblastomas have a more distinct stroma ] Pilomatricoma Basophilic epithelial tumor cells and shadow cells, usually calcified ] Trichofolliculoma Multiple small, often immature hair follicles arranged around dilated follicular ostium

Trichoblastoma ] 227

circumscribed dermal tumor with follicular differentiation

fibrotic tumor-associated stroma with artifactual separation from rest of dermis

basaloid tumor islands with follicular differentiation

4.3.11 Desmoplastic trichoepithelioma Definition Benign adnexal tumor with trichogenic differentiation, microcysts, and prominent fibrous stroma

Clinic

Usually a firm flat-topped or depressed tumor on the face of young adults. Clinically resembles a sclerosing basal cell carcinoma

Histopathology  Overview usually reveals central depression  Epithelial tumor in upper and mid-dermis consisting of poorly circumscribed strands of pale basaloid epithelial cells  Horn-filled microcysts primarily in superficial component. Sometimes ductal epithelial structures resembling syringoma  Stroma is sclerotic (thickened, relatively cell-poor) and not circumscribed (as in trichoblastoma)  Small foreign body granulomas

Differential diagnoses ] Sclerosing basal cell carcinoma Asymmetrical invasive tumor with basaloid tumor cells, no microcysts, and dense stroma but usually with clefting between tumor strands and stroma ] Microcystic adnexal carcinoma Asymmetrical deep epithelial tumor with small horn-filled microcysts in the superficial component, strands of basaloid and squamous ductal epithelial cells with bland cytologic appearance (no nuclear atypia or mitoses) extending into deep dermis and subcutis often with perineural infiltration. Deep dermis is dense and often sclerotic ] Syringoma Upper dermis features epithelial tumor cells with ductal differentiation and tadpolelike structures

Comment Desmoplastic trichoepithelioma is also grouped with trichoblastoma by some groups. One should be extremely reluctant to diagnose desmoplastic trichoepithelioma or syringoma when the tumor extends to the depths of the specimen. The superficial portions of both may easily be confused with microcystic adnexal carcinoma.

Desmoplastic trichoepithelioma ] 229

poorly circumscribed tumor limited to upper and mid-dermis

foreign body granuloma after ruptured cyst

horn cysts

strands of basaloid cells

dense fibrous (desmoplastic) stroma

4.3.12 Basal cell carcinoma Definition Basaloid adnexal tumor with many clinical variants and locally destructive growth pattern but almost no metastatic potential

Clinic

Three important clinical-pathological subtypes: . Superficial basal cell carcinoma: Erythematous patch or plaque, sometimes focally pigmented, usually on trunk. Frequently multiple. Often mistaken for chronic dermatitis . Solid-nodular basal cell carcinoma: Glassy or erythematous nodule, usually with telangiectases and sometimes central ulceration . Sclerosing (or morpheiform) basal cell carcinoma: Firm white scar-like lesion with infiltrated periphery. When confronted by “spontaneous scar”, always consider this diagnosis

Histopathology  All forms show a proliferation of strands or islands of basaloid tumor cells with dense nuclei embedded in a stroma. Usually peripheral palisading of tumor cells resembling basal layer. Clefting between tumor masses and stroma common. Apoptotic cells common; mitoses variable. Calcification occurs  Superficial type: Small epithelial buds arise from epidermis and extend into superficial dermis, mimicking hair germs. May be widely spaced and easily missed  Solid-nodular type: Asymmetrical nodular proliferation with typical clefting, stroma, reaction and usually inflammation  Sclerosing type: Narrow tumor bands (2–3 cells thick) with dense cell-rich stroma. Strikingly asymmetrical with indistinct borders

Differential diagnoses ] Trichoblastoma Symmetrical tumor with uniform basaloid tumor islands, primary hair germs, distinct tumor stroma separated from normal connective tissue by clefting. No connection with epidermis ] Merkel cell carcinoma Diffuse or trabecular basophilic tumor with medium-sized tumor cells with round somewhat dense vesicular nuclei and little cytoplasm. Apoptotic cells and mitoses common. Express cytokeratins, especially CK20 with perinuclear punctate pattern. Also neurofilament, synaptophysin, chromogranin and CD56 ] Desmoplastic trichoepithelioma Symmetrical, centrally-depressed basaloid tumor with cells in strands and forming horn-filled microcysts; does not extend beneath mid-dermis ] Microcystic adnexal carcinoma Asymmetrical deep epithelial tumor with small horn-filled microcysts in the superficial component, strands of basaloid and squamous ductal epithelial cells with bland cytologic appearance (no nuclear atypia or mitoses) extending into deep dermis and subcutis often with perineural infiltration. Deep dermis is dense and often sclerotic

Comment The histogenesis of basal cell carcinoma has long been controversial. The likely sources are primitive epithelial stem cells which differentiate in a trichogenic pattern. The basal layer budding of the superficial type is often taken as proof of origin from the basal layer, but also shows similarities with hair germs.

Basal cell carcinoma ] 231

ulceration

circumscribed nodular basaloid tumor

cleft between tumor and stroma

peripheral palisading of basaloid cells

necrosis

4.3.13 Fibroepithelioma of Pinkus Definition Variant of basal cell carcinoma with unique histological pattern Clinic

Skin-colored or pink nodule or plaque, usually on back

Histopathology  Circumscribed net-like proliferation of fine epithelial tumor strands with basaloid differentiation  Stroma between strands of tumor mimics exaggerated version of hair papillae; rich in vessels and fibroblasts. Little clefting  Rudimentary hair germs and small ductal structures with tumor strands  May contain areas of typical basal cell carcinoma

Differential diagnoses ] Trichoblastoma Basaloid tumor strands and islands with distinct stroma; clefting between tumor stroma and normal connective tissue; primitive hair germs present. Often horn-filled microcysts in trichoepithelioma variant. Cribriform (sieve-like) variant is most similar ] Mixed tumor of skin Nodular proliferation arising from epidermis with complex pattern of basaloid and poroid cells forming tubular structures. Stroma variable with myxoid and chondroid areas. May calcify

Comment Since fibroepithelioma, trichoblastoma and basal cell carcinoma all are primarily trichogenic in differentiation, it is not surprising that they share many features and can sometimes be impossible to distinguish with certainty.

Fibroepithelioma of Pinkus ] 233

net-like proliferation of basaloid tumor strands arising from epidermis

cellular and vascular stroma

4.4 Soft tissue proliferations and neoplasms 4.4.1

Scar

4.4.2

Hypertrophic scar and keloid

4.4.3

Dermatofibroma

4.4.4

Skin tag

4.4.5

Dermatofibrosarcoma protuberans

4.4.6

Atypical fibroxanthoma

4.4.7

Leiomyoma

4.4.8

Nevus lipomatosus superficialis

4.4.9

Lipoma

4.4.10 Neurofibroma 4.4.11 Schwannoma 4.4.12 Merkel cell carcinoma

4.4.1 Scar Definition Physiologic repair mechanism in which damaged dermis (and other tissues) is replaced by fibrosis

Clinic

Appearance depends on age; initially erythematous, later skin-colored, hyper- or hypopigmented; may be elevated, depressed or almost flat

Histopathology Initial stage  Acanthotic epidermis  Loose fine collagen fibers  Increased fibroblasts, myofibroblasts and capillaries  Mixed infiltrate Late stage  Atrophic epidermis, sometimes with subepidermal clefting  Collagen fibers parallel to skin surface  Increased numbers of fibroblasts  Vertically-oriented capillaries  Discrete predominantly lymphocytic infiltrates

Differential diagnoses ] Hypertrophic scar and keloid Focal nodular proliferation of fibroblasts with thickened hypereosinophilic and sclerotic collagen bundles ] Dermatofibroma Acanthosis often with basal layer hyperpigmentation. Dermal infiltrate of (myo-) fibroblasts and macrophages extending peripherally and entrapping eosinophilic collagen bundles. Sometimes increased vessels and hemosiderin deposits ] Dermatomyofibroma Dermal plaque consisting of horizontally arranged bundles of myofibroblasts, also increased elastic fibers

Scar ] 237

normal dermis

scar tissue which is cellular and rich in vessels

proliferation of fibroblasts collagen vessels

4.4.2 Hypertrophic scar and keloid Definition Scars with increased activity of fibroblasts and excessive amounts of collagen production

Clinic

A hypertrophic scar is confined to the original boundaries of the injury, while a keloid expands beyond the limits of the injury site. Keloids are more common in blacks and in the upper half of the body; typical sites include ear lobes (after piercing), nape, sternum, shoulder girdle and ankles

Histopathology  Localized nodular proliferation of fibroblasts, myofibroblasts and capillaries  Thickened eosinophilic collagen bundles  In keloid, strikingly thickened sclerotic collagen bundles

Additional studies The fibroblasts express vimentin, while the myofibroblasts also express smooth muscle actin (SMA). No expression of CD34

Differential diagnoses ] Dermatofibroma Acanthosis often with basal layer hyperpigmentation. Dermal infiltrate of (myo-) fibroblasts and macrophages extending peripherally and entrapping eosinophilic collagen bundles. Sometimes increased vessels ] Dermatofibrosarcoma protuberans Monomorphic proliferation of cells with slightly wavy nuclei, often infiltrating subcutaneous fat; CD34-positive ] Dermatomyofibroma Dermal plaque consisting of horizontally arranged bundles of myofibroblasts with increased elastic fibers ] Desmoplastic melanoma Asymmetrical architecture, dermal proliferation of spindle cells with nuclear atypia, often little melanin, embedded in a collagenous stroma with myofibroblasts. Patchy inflammatory infiltrate. Extends into deep dermis, subcutis, often with perineural involvement. Marked desmoplasia (fibrosis). Often associated with overlying lentigo maligna. Tumor cells express S-100 and p75; other melanocytic markers usually negative

Comment Whenever a scar is associated with a previously excised melanocytic lesion, especially in sundamaged skin, think of a desmoplastic melanoma (S-100 and p75 stains, review original slides).

Hypertrophic scar and keloid ] 239

thin epidermis

nodular fibrous proliferation

thickened sclerotic bundles of collagen

4.4.3 Skin tag Synonym: Fibroma molle Definition Benign polypoid lesion with increased collagen Clinic

Skin-colored or slightly hyperpigmented polypoid or stalked tumors, usually multiple; commonly on neck, axillae and groin; more common in obese individuals

Histopathology     

Polypoid lesion, hard to orient for sectioning so many views possible Epidermal acanthosis and often papillomatosis Acellular stroma with loosely structured collagen bundles No adnexal structures Occasionally adipocytes

Differential diagnoses ] Pedunculated melanocytic nevus Identical to skin tag, but with melanocytes in nests in dermis and sometimes at junction ] Pedunculated seborrheic keratosis Broad-based acanthosis and often papillomatosis; horn pseudocysts ] Condyloma acuminatum Polypoid lesion but broad-based with acanthosis, focal parakeratosis and koilocytes ] Epidermal nevus Similar epidermal changes (acanthosis, papillomatosis) but much larger lesion and not polypoid ] Nevus lipomatosus superficialis Similar epidermal changes (acanthosis, papillomatosis) but dermis widely replaced by adipocytes; larger lesion and not polypoid ] Neurofibroma Overall architecture similar, but stroma consists of fine spindle cells which are S100-positive and have wavy nuclei. Increased numbers of mast cells ] Irritation fibroma Intraoral reactive process with broad-based acanthosis and parakeratosis; thickening of lamina propria (connective tissue)

Comment A small pedunculated seborrheic keratosis is identical to a skin tag and one can choose whichever diagnosis is preferred.

Skin tag ] 241

papillomatosis

loose vascular dermis

Scattered inflammatory cells after irritation

4.4.4 Dermatofibroma Definition Hyperplastic reactive process with proliferation of fibroblasts, myofibroblasts and macrophages, sometimes following trauma or arthropod assault; also known as histiocytoma

Clinic

Slightly raised firm tan-brown nodule, often with increased pigment at periphery. Most common on legs

Histopathology    

Radial proliferation of fibroblasts with entrapment of sclerotic collagen bundles at periphery Centrally, foam cells, giant cells, hemorrhage, hemosiderin and increased vessels Cytologic features unremarkable with few mitoses and little nuclear pleomorphism Acanthotic overlying epidermis often with induction of basaloid cells, follicles and sebaceous glands

Variants  Cellular dermatofibroma: Very cellular, sometimes increased mitoses, swirling pattern with little entrapment, tends to extend to subcutaneous fat and recur after incomplete excision  Sclerotic dermatofibroma: Cell-poor with thickened collagen bundles  Hemosiderotic dermatofibroma: Marked deposition of hemosiderin  Aneurysmal dermatofibroma: Hemorrhage and dilated pseudo-vascular spaces  Dermatofibroma with monster cells: Stroma contains multinucleated giant cells, some with striking nuclear pleomorphism

Additional studies Fibroblasts express vimentin and factor XIIIa; myofibroblasts express SMA. At the periphery of cellular lesions, focal CD34 positivity is possible

Differential diagnoses ] Dermatofibrosarcoma protuberans Monomorphic proliferation of cells with slightly wavy nuclei, often infiltrating subcutaneous fat along septa; CD34-positive ] Dermal sarcoma (malignant fibrous histiocytoma) Asymmetrical spindle cell tumor with marked nuclear pleomorphism, mitoses common, infiltration of subcutaneous fat ] Xanthogranuloma Symmetrical dome-shaped proliferation of epithelioid macrophages, foam cells and Touton giant cells, as well as neutrophils and eosinophils ] Leiomyosarcoma Asymmetrical tumor with fascicles of pleomorphic spindle cells with cigar-shaped nuclei and mitoses; smooth muscle actin- and desmin-positive ] Kaposi sarcoma (nodular stage) Proliferation of small densely packed spindle cells and erythrocyte-filled clefts. Tumor cells express vascular markers (CD31, CD34, podoplanin). Human herpes virus 8 detectable by immunohistochemistry (nuclei express HHV8-LNA) or PCR

Comment Most consider dermatofibroma a reactive process, but some regard it is a benign mesenchymal tumor of fibroblasts, myofibroblasts or even dermal dendritic cells.

Dermatofibroma ] 243

acanthotic epidermis with increased basal layer pigmentation

poorly circumscribed proliferation of fibroblasts

swirled pattern of fibroblasts

entrapment of collagen at periphery

4.4.5 Dermatofibrosarcoma protuberans Definition Malignant mesenchymal tumor of fibroblastic origin with locally destructive growth but low metastatic potential

Clinic

Skin-colored or red-tan-brown firm plaque or nodule, often several centimeters in size. Clinically confused with scar. Favors shoulder girdle or trunk. Tumor of young adults, but also affects infants and children

Histopathology  Poorly circumscribed proliferation of monomorphic spindle cells in deep dermis  Initially extends along fat septa; later diffuse infiltration of subcutaneous fat producing honeycomb pattern  Storiform (swirled and interwoven) arrangement of tumor cells  Cells have spindled or wavy nuclei and little cytoplasm; few mitoses  Usually minimal inflammatory infiltrate Variant  Pigmented dermatofibrosarcoma protuberans (Bednar tumor): Presence of scattered melanocytes within tumor

Additional studies Characteristic positivity for CD34. Negative for S-100 (except Bednar tumor), CD31 and smooth muscle actin (SMA). Cytogenetics shows a ring chromosome 2 with t(17;22) leading to COL1A1PDGFR-B fusion gene whose protein induces over-expression of growth factor receptors

Differential diagnoses ] Cellular dermatofibroma Radial proliferation of cells with monotonous large nuclei. Often hemosiderin deposits or increased vessels. Positive for Factor XIIIa and SMA; central parts negative for CD34 ] Dermal sarcoma (malignant fibrous histiocytoma) Asymmetrical spindle cell tumor with marked nuclear pleomorphism, mitoses common, infiltration of subcutaneous fat ] Leiomyosarcoma Asymmetrical tumor with fascicles of pleomorphic spindle cells with cigar-shaped nuclei and mitoses; smooth muscle actin- and desmin-positive ] Desmoplastic melanoma Asymmetrical tumor with fibrosis, as well as S-100- and p75-positive tumor cells. Focal lymphocytic infiltrates ] Neurofibroma Symmetrical nodular lesion of S-100-positive spindle cells with wavy uniform nuclei, admixed mast cells

Comment Dermatofibrosarcoma protuberans frequently recurs; both the clinical and histological borders are frequently indistinct. Wide local excision or micrographic surgery is indicated.

Dermatofibrosarcoma protuberans ] 245

dense proliferation at spindle cells infiltrating fat

4.4.6 Atypical fibroxanthoma Definition Low-grade cutaneous malignancy with striking histological features but unclear histogenesis

Clinic

Irregular nodule, usually less than 2 cm, in sun-damaged skin. Favors head and neck region of elderly. Usually diagnosed as squamous cell carcinoma or basal cell carcinoma

Histopathology  Focal proliferation of atypical epithelioid or spindled cells with pleomorphic nuclei and common mitoses  Multinucleated tumor giant cells (monster cells)  Usually limited to upper and mid-dermis  Little necrosis, but occasionally ulceration  Adjacent skin shows actinic damage with epidermal atrophy and marked elastosis Variant  Dermal sarcoma (malignant fibrous histiocytoma): Same cytomorphology, but asymmetrical and extends deeper

Additional studies Tumor cells express vimentin, CD68 and often SMA. No expression of keratinocytic or melanocyte markers

Differential diagnoses ] Poorly differentiated squamous cell carcinoma Symmetrical tumor arising from epidermis; positive for cytokeratins ] Nodular melanoma Tumor cells express melanocytic markers. At periphery often nests or transepidermal spread of atypical melanocytes ] Cellular dermatofibroma Radial proliferation of cells with monotonous large nuclei. Often hemosiderin deposits or increased vessels. Positive for Factor XIIIa and SMA; central parts negative for CD34

Comment The nature of the atypical fibroxanthoma is controversial. It probably represents a superficial lowgrade sarcoma.

Atypical fibroxanthoma ] 247

localized dermal proliferation of atypical cells

actinic elastosis

atypical mitosis

multinucleated cell

4.4.7 Leiomyoma Definition Benign mesenchymal tumor with smooth muscle differentiation Clinic

Red-brown dermal nodule, often painful or tender. Typically on extremities and multiple when it arises from arrector pili muscles; usually solitary when associated with vascular smooth muscle, or that of genitalia or nipples. Multiple tumors on occasion associated with uterine leiomyomas (fibroids) and renal carcinomas

Histopathology  Circumscribed dermal nodule  Tangential and transversely sectioned bundles of spindle cells with cigar-shaped nuclei  No nuclear pleomorphism, rare mitoses Variant  Angiomyolipoma: Proliferation of smooth muscle in association with vessel

Additional studies Tumor cells express SMA and desmin

Differential diagnoses ] Leiomyosarcoma Similar pattern, but typically asymmetrical, extends deeper and has atypical cells with pleomorphic sometimes hyperchromatic nuclei and increased number of mitoses ] Dermatofibroma Acanthosis often with basal layer hyperpigmentation. Dermal infiltrate of macrophages extending peripherally and entrapping eosinophilic collagen bundles. Sometimes increased vessels ] Dermatomyofibroma Dermal plaque consisting of horizontally arranged bundles of myofibroblasts with increased elastic fibers ] Dermatofibrosarcoma protuberans Monomorphic proliferation of cells with slightly wavy nuclei, often infiltrating subcutaneous fat along septa; CD34-positive ] Neurofibroma Symmetrical nodular lesion of S-100-positive spindle cells with wavy uniform nuclei, admixed mast cells

Comment When dealing with a large lesion with smooth muscle differentiation, always search for mitoses and other hints for leiomyosarcoma.

Leiomyoma ] 249

thin epidermis

spared sebaceous glands

circumscribed bundle of smooth muscle cells in dermis

smooth muscle cells with cigar-shaped nuclei

4.4.8 Nevus lipomatosus superficialis Definition Hamartoma with adipocytes extending into higher parts of the dermis Clinic

Usually present at birth or identified early in life, but sometimes first becomes clinically apparent in adolescence. Skin-colored to tan soft polypoid nodule or plaque, usually on buttocks, thighs or flank. Sometimes inherited in an autosomal dominant fashion with deletion on chromosome 11

Histopathology  Bands and collections of fat cells between collagen fibers in all levels of the dermis, replacing this layer and making it thinner. No capsule  Adipocytes without nuclear pleomorphism or mitoses

Differential diagnoses ] Fibrolipoma Variant of larger skin tag with high dermal adipocytes. Usually smaller collections of fatty tissue. Appearance first in adult life ] Atypical lipomatous tumor Irregular proliferation of adipocytes varying in size and shape (beer foam pattern) with occasional lipoblasts with wedge-shaped, indented nuclei ] Focal dermal hypoplasia Identical picture because of loss of dermis so that normal fatty tissue lies very high. Lesions usually follow Blaschko lines; patients are girls with ocular and skeletal defects

Nevus lipomatosus superficialis ] 251

lobules of fat in the dermis

collagen fibers

4.4.9 Lipoma Definition Benign proliferation of adipocytes Clinic

Subcutaneous soft or rubbery nodule often movable; size varies greatly. Solitary or multiple; later may be inherited in an autosomal dominant fashion. Angiolipomas are often tender

Histopathology  Circumscribed subcutaneous collection of adipocytes surrounded by fine fibrous capsule  No nuclear pleomorphism, mitoses, or lipoblasts  Often shelled out, so only tumor is available for examination Variants  Angiolipoma: Increased numbers of small capillaries in fat lobules, often with microthrombi  Spindle cell lipoma: Usually on forearm or nape of young men. Adipocytes accompanied by CD34-positive spindle cells and basophilic, mucin-rich stroma  Intramuscular lipoma: Poorly circumscribed tumor infiltrating striated muscle, favoring thigh and trunk; 20% recurrence rate with incomplete excision

Differential diagnoses ] Nevus lipomatosus superficialis and fibrolipoma Collections of adipocytes between bundles of collagen in dermis. No capsule ] Atypical lipomatous tumor Irregular proliferation of adipocytes varying in size and shape (beer foam pattern) with occasional lipoblasts with wedge-shaped, indented nuclei ] Liposarcoma Nuclear pleomorphism, mitoses, cellular areas ] Hibernoma Benign tumor of brown fat. Large adipocytes with vacuolated or honeycomb cytoplasm. Even though brown fat is normal in infancy, tumor is not typically seen in children

Comment When encountering recurrent lipoma, exclude well-differentiated liposarcoma (grade 1).

Lipoma ] 253

Lipoma

fibrous capsule

Angiolipoma

increased numbers of capillaries, many with thrombi

lobules of fat

4.4.10 Neurofibroma Definition Common benign mesenchymal tumor with neurogenic differentiation Clinic

Soft skin-colored papule or nodule; when solitary usually mistaken for skin tag or pedunculated melanocytic nevus. Multiple lesions are marker for neurofibromatosis type 1 (von Recklinghausen disease) with café-au-lait macules and axillary freckling, as well as systemic signs and symptoms. Patients have mutation in neurofibromin at 17q11.2

Variants

Diffuse neurofibroma: Superficial plaque with diffuse swelling Plexiform neurofibroma: Large deep tumor with palpable bundles of Schwann cells giving “bag of worms” phenomenon

Histopathology  Circumscribed proliferation of spindle cells in superficial and mid-dermis, occasionally extending to subcutis  Tumor cells with elongated wavy monomorphous dark nuclei  No nuclear pleomorphism or mitoses  Numerous mast cells in tumor stroma  Capsule Variants  Myxoid neurofibroma: Marked deposits of mucin dominate picture, pushing aside tumor cells  Plexiform neurofibroma: Bundles of cells with wavy nuclei often admixed with typical more diffuse pattern

Additional studies Tumor cells are positive for S-100 and neurofilament; capsule is positive for EMA

Differential diagnoses ] Malignant peripheral nerve sheath tumor (neurofibrosarcoma) Deeper tumor, often with plexiform elements; marked nuclear pleomorphism and mitoses, including atypical mitoses ] Dermatofibrosarcoma protuberans Monomorphic proliferation of cells with slightly wavy nuclei, often infiltrating subcutaneous fat along septa; CD34-positive and S-100 negative ] Traumatic neuroma (Morton neuroma) Fascicles with cells with neurogenic differentiation embedded in fibrous stroma or scar ] Schwannoma Encapsulated neural tumor with both spindle-cell (Antoni A) and myxoid areas (Antoni B). Palisading nuclei parallel to one another (Verocay bodies) ] Solitary circumscribed neuroma Sharply circumscribed dermal nodule with fascicles of Schwann cells with embedded axons

Comment If patients are identified with multiple neurofibromas, then appropriate specialty evaluation should be undertaken to exclude neurofibromatosis. Mucosal neuromas suggest multiple endocrine neoplasia syndrome 2b and patients should be screened for medullary thyroid carcinoma and pheochromocytoma

Neurofibroma ] 255

circumscribed proliferation of spindle cells in dermis

mast cells

spindle cells with wavy nuclei

4.4.11 Schwannoma Synonym: Neurilemmoma Definition Benign mesenchymal tumor with distinctive complex neurogenic differentiation Clinic

Skin-colored firm nodules, usually on legs. Multiple lesions are rare but suggest neurofibromatosis type 2 (schwannomatosis) with acoustic neuromas and mutation in merlin at 22q12.2

Histopathology    

Circumscribed nodule with fibrous capsule Proliferation of spindle cells with dense nuclei Cell-rich areas with fascicles (Antoni A) and cell-poor loose myxoid areas (Antoni B) Areas with palisading of nuclei which run parallel to one another (Verocay bodies)

Variant  Ancient schwannoma: Nuclei with degenerative changes. Small vessels in tumor stroma often with thick walls

Additional studies Tumor cells are S-100 positive; capsule is positive for EMA. Minimal or no expression of neurofilament

Differential diagnoses ] Neurofibroma Symmetrical nodular lesion of S-100-positive spindle cells with wavy uniform nuclei, admixed mast cells. No fibrous capsule ] Traumatic neuroma (Morton neuroma) Fascicles with cells with neurogenic differentiation embedded in fibrous stroma or scar ] Solitary circumscribed neuroma Sharply circumscribed dermal nodule with fascicles of Schwann cells ] Perineuroma Circumscribed tumor without capsule; spindle cells arranged in cut onion pattern. EMA-positive ] Nerve sheath myxoma (myxoid neurothekeoma) Circumscribed tumor with spindle cells and thicker S-100-positive cells in nests and strands in a mucin-rich stroma

Schwannoma ] 257

fibrous capsule

Verocay bodies

4.4.12 Merkel cell carcinoma Definition Malignant cutaneous tumor of epithelial and neuroendocrine differentiation, presumably differentiating from cutaneous Merkel cell

Clinic

Solitary pink-red to blue-purple nodule which grows rapidly. Most common on head, neck and extremities of elderly patients. Dismal prognosis

Histopathology  Deeply basophilic highly cellular tumor with small to medium-sized tumor cells with dense round nuclei  Cytoplasm sparse and hard to appreciate; cell outlines appear blurred despite proper techniques (“murky sign”)  Tumor cells arranged in diffuse, trabecular or nested pattern, usually extend into subcutis; occasional intraepidermal pagetoid spread  Apoptotic tumor cells with mitoses; larger tumors may be necrotic

Additional studies Tumor cells express neurofilament, CAM5.2, pancytokeratin and cytokeratin 20 (characteristic perinuclear punctate pattern); also positive for neuroendocrine granule markers synaptophysin and chromogranin. Negative for S-100 and LCA

Differential diagnoses ] B-cell lymphoma Express CD20 and other B-cell markers. No intraepidermal component ] Nodular melanoma Usually has intraepidermal component with transepidermal migration of atypical melanocytes. Expresses melanocyte markers (S-100, HMB-45, Melan A) ] Metastases Metastases of small cell carcinoma of the lung, neuroendocrine carcinoma and neuroblastoma are very similar. Identification of the primary tumor is the best method of diagnosis. Small cell lung carcinoma cells express TTF-1 which is not expressed by Merkel cells ] Basal cell carcinoma Asymmetrical architecture, palisading of peripheral tumor cells with clefting between them and stroma

Merkel cell carcinoma ] 259

actinic elastosis

nodular and diffuse infiltrate of basaloid cells

lymphocytic infiltrate

mitoses

medium-sized tumor cells with round and oval dense nuclei

4.5 Vascular tumors 4.5.1

Hemangioma

4.5.2

Pyogenic granuloma

4.5.3

Angiokeratoma

4.5.4

Kaposi sarcoma

4.5.5

Angiosarcoma

4.5.1 Hemangioma Definition Benign vascular proliferation consisting primarily of capillaries Clinic

Red-blue nodules varying in size from just a few mm to several cm

Histopathology  Circumscribed lesion in upper and mid-dermis, occasionally extending into deep dermis or subcutis  Conglomerate of capillaries, some with dilated lumina  Endothelial cells without nuclear pleomorphism. Mitoses present  Peripheral layer of pericytes  Thromboses possible Variants  Venous hemangioma: Venous component with thick-walled vessels with large lumina  Sinusoidal hemangioma: Large thin-walled lacunae with endothelial septa

Additional studies Organoid pattern typical with CD31-positive endothelial cells surrounded by pericytes positive for smooth muscle actin. No expression of lymphatic endothelial markers such as podoplanin

Differential diagnoses ] Pyogenic granuloma Polypoid capillary hemangioma with inflammatory infiltrates and usually ulceration ] Lymphangioma Bizarre thin-walled vessels in upper and mid-dermis, sometimes with inflammatory infiltrate. Endothelial cells express podoplanin; no pericytes ] Kaposi sarcoma Initially bizarre vascular spaces in mid and lower dermis without endothelial atypia. Later predominantly spindled tumor cells. Expression of CD34 and podoplanin. Human herpes virus 8 can also be identified by immunohistochemistry (HHV8-LNA positive nuclei) and PCR ] Angiosarcoma Malignant vascular neoplasm with irregular dissecting vascular spaces and atypical endothelial cells with nuclear pleomorphism and mitoses

Comment There are many clinical and histological variants of hemangioma. Hemangiomas are vascular tumors, and especially in infants must be distinguished from vascular malformations, such as port wine stains. The unifying feature of all hemangiomas is the organoid pattern of small capillaries with CD31-positive endothelial cells surrounded by smooth muscle actin-positive pericytes.

Hemangioma ] 263

circumscribed tumor in dermis

thickened capillaries

erythrocytes

4.5.2 Pyogenic granuloma Definition Reactive rapidly growing polypoid capillary hemangioma Clinic

Rapidly growing red-blue nodule, often ulcerated on surface

Histopathology      

Symmetrical polypoid lesion with superficial ulceration and epidermal collarette Lobular proliferation of thick-walled capillaries with connective tissue septa Numerous mitoses in endothelial cells, but no nuclear pleomorphism or atypical mitoses At the base often a larger thick-walled feeding vessel Mixed infiltrate with numerous neutrophils and macrophages In later stages, fibrosis and less inflammation

Variant  Intravascular pyogenic granuloma: Lobular proliferation of capillaries within lumen of vessel, usually in vein after trauma

Additional studies Organoid vessels with CD31-positive endothelial cells and smooth muscle actin-positive pericytes

Differential diagnoses ] Capillary hemangioma Similar lobular vascular stroma with many capillaries. No ulceration, no associated inflammation and no prominent septa ] Bacillary angiomatosis Diffuse neutrophil-rich infiltrate admixed with capillaries. In mid and lower reaches, perivascular eosinophilic globules (colonies of bacteria). Causative organism (Bartonella henselae) identified with Warthin-Starry stain or immunohistochemistry ] Angiosarcoma Malignant vascular neoplasm with irregular dissecting vascular spaces and atypical endothelial cells with nuclear pleomorphism and mitoses

Comment Pyogenic granuloma is a variant of capillary hemangioma, often triggered by infection or trauma. It overlaps with proud flesh (vascular granulation tissue). The term lobular capillary hemangioma is also used, but the lobular pattern is simply a recapitulation of how all new vessels arise from vascular islands (lobules) in the embryonic mesenchyme. The same pattern is seen in many vascular tumors.

Pyogenic granuloma ] 265

ulcerated tumor in acral skin

neutrophils

dense proliferation of small capillaries with pericytes

4.5.3 Angiokeratoma Definition Superficial vascular proliferation with characteristic epidermal hyperplasia Clinic

Angiokeratomas can be solitary, grouped or serve as a marker for metabolic disorders . Angiokeratoma Mibelli: Hyperkeratotic usually solitary lesion, often on limb . Angiokeratoma Fordyce: Multiple lesions on scrotum or labia majora . Angiokeratoma circumscriptum: Segmental grouping of many dark tumors on limb . Angiokeratoma corporis diffusum: Multiple tiny telangiectases (not true angiokeratomas because of lack of epidermal change) as marker for Fabry disease, fucosidosis and other metabolic disturbances

Histopathology    

Circumscribed thin-walled vessels in papillary dermis Overlying epidermis acanthotic and hyperkeratotic Thrombosis common The dermis which separates the vessels from the epidermis is often so thin that the vessel walls appear to impinge on the epidermis

Differential diagnoses ] Verrucous hemangioma Similar interaction between vessels and epidermis with acanthosis and hyperkeratosis, but larger, thicker-walled vessels which extend into mid dermis ] Telangiectases Thin-walled capillaries in upper dermis without epidermal changes ] Lymphangioma Bizarre thin-walled vessels in upper and mid-dermis, sometimes with inflammatory infiltrate. Endothelial cells express podoplanin; no pericytes

Angiokeratoma ] 267

hyperkeratosis

acanthosis

thin convoluted vessels with erythrocytes

thin vessel with erythrocytes

vessel impinges on epidermis

early thrombosis

4.5.4 Kaposi sarcoma Definition Vascular tumor of lymphatic differentiation, caused by human herpes virus 8 (HHV8) with a variety of clinical and histological forms

Clinic

. Types: Classic-sporadic, immunosuppression-induced, HIV-associated, African-endemic . Patch stage: Oval red-brown macules often following skin lines . Plaque and tumor stages: Expanding red-brown and blue-violet plaques and nodules . Classic form almost limited to distal legs. Immunosuppressed form usually with disseminated lesions. Mucosal involvement most common in HIV infection. African types can involve lymph nodes (in children) or be larger and ulcerated

Histopathology Patch stage  Irregular bizarre vascular spaces dissecting between collagen fibers in the mid and deep dermis  Tiny subtle clefts found along adnexal structures and vessels (promontory sign)  Monomorphous endothelial cells with dense nuclei without mitoses  Associated infiltrate with plasma cells and hemosiderin-laden macrophages Plaque stage  Vascular clefts filled with erythrocytes  Spindled tumor cells  PAS-positive globules in tumor cells  Hemosiderin deposits Tumor stage  Nodular proliferation of primarily spindle cells without nuclear pleomorphism  Very small vascular clefts between tumor cells Variants  Lymphangioma-like Kaposi sarcoma: Bizarre large lacunae  Pyogenic granuloma-like Kaposi sarcoma: Polypoid lesion

Additional studies Tumor cells express CD31, CD34 and lymphatic endothelial markers (podoplanin). Immunohistochemical or molecular biological identification of HHV-8 antigens, such as latent nuclear antigen (HHV8-LNA) or DNA

Differential diagnoses ] Lymphangioendothelioma Bizarre lymphatic vessels in upper and mid-dermis, dissecting between strands of collagen. No spindle tumor cells. No association with HHV-8 ] Angiosarcoma Malignant vascular neoplasm with irregular dissecting vascular spaces and atypical endothelial cells with nuclear pleomorphism and mitoses. No association with HHV-8 ] Dermatofibroma with hemosiderin deposits Dense mixed stroma with fibroblasts and macrophages, as well as multinucleate giant cells and hemosiderin-laden macrophages. Hemorrhage not confined to slits. Overlying epidermal changes. Cells express CD68 and factor XIII a

Comment Kaposi sarcoma can be differentiated from all other vascular neoplasms by its association with human herpes virus 8.

Kaposi sarcoma ] 269

entire dermis filled with diffuse proliferation of fascicular spindle cells

vascular slits with erythrocytes

4.5.5 Angiosarcoma Definition Malignant vascular neoplasm with poor prognosis Clinic

Variants

Initially poorly defined blue-red macule which gradually expands and becomes nodular; often ulcerated. Tumor invariably extends far beyond clinical margin. Favors head and neck region of elderly . Post-radiation angiosarcoma on irradiated skin, especially after irradiated breast carcinoma . Stewart-Treves syndrome: Angiosarcoma developing in area of chronic lymphadema

Histopathology      

Ectatic bizarre vessels in upper dermis (may be only feature in rosacea-like form) Characteristic dissecting growth pattern with lightning strike-like vascular clefts Endothelial cells protrude into lumina; have nuclear pleomorphism and atypical mitoses Piling up of atypical endothelial cells in lumina (pseudopapillae) In deeper parts often cohesive bundles of spindle or epithelioid tumor cells At periphery, lobular capillary proliferations and accompanying inflammatory infiltrate

Additional studies Tumor cells express vascular markers (CD31, CD34, podoplanin) in varying degrees. Smooth muscle actin-positive pericytes usually absent. Epithelioid angiosarcomas are cytokeratin-positive in 50% of cases. Ki67 expression increased in endothelial cells, even in subtle peripheral areas

Differential diagnoses ] Kaposi sarcoma Spindle cell tumor with vascular slits and hemosiderin deposits; in advanced stage more circumscribed than angiosarcoma. Association with HHV-8 ] Epithelioid hemangioma Symmetrical polypoid lesion with lobular capillary vessels. Epithelioid endothelial cells without nuclear pleomorphism or atypical mitoses ] Poorly differentiated squamous cell carcinoma Asymmetrical proliferation of epithelial cells which express cytokeratins but no endothelial markers ] Nodular melanoma Atypical dermal tumor cells express melanocytic markers; usually residual evidence of junctional or intra-epidermal melanocytes

Comment The unifying feature of angiosarcoma is atypical endothelial cells which protrude into or pile up in the lumen and often have atypical mitoses. At the periphery of an angiosarcoma, the microscopic findings can be subtle and banal, leading to misdiagnosis of telangiectasis or pyogenic granuloma. Thus a full-thickness biopsy is essential.

Angiosarcoma ] 271

diffuse dissecting tumor growth with vascular spaces

neoplastic vascular spaces with nuclear atypia and piling up of endothelial cells

4.6 Lymphomas and pseudolymphomas 4.6.1

Mycosis fungoides

4.6.2

Primary cutaneous CD30-positive lymphoproliferative diseases

4.6.3

Primary cutaneous follicle center B-cell lymphoma

4.6.4

Cutaneous B-cell pseudolymphoma

4.6.1 Mycosis fungoides Definition Most common cutaneous T-cell lymphoma with characteristic clinical and histological features

Clinic

Three stages . Patch stage: Circumscribed erythematous macules and patches, sometimes wrinkled surface, usually on trunk . Plaque stage: Infiltrated thicker lesions . Tumor stages: Nodules frequently ulcerated . Numerous variants including hyper- and hypopigmented, granulomatous and folliculotropic forms

Histopathology Patch and plaque stages  Epidermis with focal parakeratosis, discrete acanthosis  Exocytosis (epidermotropism) of atypical lymphocytes with little spongiosis  Lymphocytes with atypical cerebriform nuclei and scant eosinophilic cytoplasm  Intraepidermal lymphocytes larger than dermal lymphocytes  Accumulation of the several (>4–5) atypical lymphocytes in spinous layer (Pautrier microabscess) and palisading of atypical lymphocytes along dermal-epidermal junction (lining up)  In superficial dermis, fibrosis and band-like lymphocytic infiltrate with scattered eosinophils Tumor stage Nodular infiltrate of medium- to large lymphocytes with nuclear pleomorphism. Loss of epidermotropism may occur, ulceration possible

Additional studies Intraepidermal lymphocytes express CD3, CD4; often with loss of CD7. Transformation may be associated with expression of CD30. Cases with CD8+ tumor cells are rare. Using PCR a clonal Tcell population can be identified in 50% of patch-stage and >90% of plaque- and tumor-stage MF

Differential diagnoses ] Dermatitis Spongiosis with vesicles, acanthosis and exocytosis in spongiotic areas. Lymphocytes without nuclear atypia ] Pityriasis lichenoides Focal vacuolar change at DEJ, spongiosis and parakeratosis, apoptotic keratinocytes. Activated lymphocytes may exhibit enlarged nuclei

Comments Patch-stage mycosis fungoides is extremely difficult to separate from mild dermatitis. The final diagnosis must always be based on both the clinical and histological findings. Large-patch parapsoriasis is synonymous with patch-stage MF; small-patch parapsoriasis can also be similar histologically but has a different course and usually does not progress to MF.

Mycosis fungoides ] 275

Pautrier microabscesses

lining up of atypical lymphocytes at dermal-epidermal junction

fibrosis

4.6.2 Primary cutaneous CD30-positive lymphoproliferative diseases Definition Low-grade T-cell lymphomas characterized by anaplastic lymphocytes which express CD30. The second most common form of cutaneous lymphoma

Clinic

. Lymphomatoid papulosis (LyP): Recurrent erythematous to red-brown papules and nodules with spontaneous regression over weeks, sometimes heal with scarring . Primary cutaneous anaplastic large cell lymphoma (ALCL): Rapidly growing often ulcerated nodules, solitary or grouped

Histopathology Lymphomatoid papulosis  Type A: Wedge-shaped infiltrate of solitary or small clusters of anaplastic lymphocytes with marked nuclear pleomorphism and mitoses. Admixture of numerous neutrophils and eosinophils  Type B: Band-like epidermotropic infiltrate in upper dermis of small atypical lymphocytes with dense nuclei  Type C: Cohesive nodular collections of anaplastic lymphocytes. Little reactive infiltrate Primary cutaneous anaplastic large cell lymphoma (ALCL)  Nodular infiltrate of anaplastic, pleomorphic or immunoblastic lymphocytes  Minimal reactive infiltrate of small lymphocytes and eosinophils. Ulceration common

Additional studies Tumor cells express CD30, CD4 and often TIA-1. Loss of T-cell markers (such as CD3) possible, especially in primary cutaneous ALCL

Differential diagnoses ] Mycosis fungoides Pleomorphic tumor cells expressing CD30 may be present in tumor stage. Thus LyP type B cannot be separated with certainty from MF ] Hodgkin lymphoma Primary cutaneous disease almost unheard of. Tumor cells express CD30 ] Secondary skin involvement from primary nodal CD30-positive ALCL Histology identical to primary cutaneous form, but tumor cells may express ALK and EMA

Comment Since there is histological overlap with tumor-stage MF and primary and secondary forms of CD30-positive lymphomas cannot be separated with certainty, the final diagnosis is always a clinicopathological one combined with staging. Finding CD30-positive atypical lymphocytes is not sufficient for the diagnosis of LyP, since medium-sized CD30-positive lymphocytes can be seen in a variety of infectious and inflammatory dermatoses (verruca vulgaris, molluscum contagiosum, orf, scabies, PLEVA and others).

Primary cutaneous CD30-positive lymphoproliferative diseases ] 277

Lymphomatoid papulosis wedge-shaped lymphocytic infiltrate

atypical lymphocytes

eosinophils

lower panel: CD30positive tumor cells

4.6.3 Primary cutaneous follicle center B-cell lymphoma Definition Low-grade cutaneous B-cell lymphoma with follicle center cell differentiation Clinic

Red-brown to blue-red nodules often with plaques. Sites of predilection are head, neck and trunk

Histopathology  Normal epidermis with Grenz zone (area of sparing) in superficial dermis  Nodular and sometimes confluent lymphocytic infiltrate with cohesive groups of follicle center cells (primarily centrocytes) with indented nuclei with varying chromatin density, often extending into deep dermis or subcutis  Admixture of small lymphocytes with dense nuclei, in some cases eosinophils and plasma cells also present Three patterns  Follicular: Large neoplastic follicles containing cells with centrocytic differentiation, usually without tingible body macrophages  Mixed (follicular-diffuse)  Diffuse: Diffuse sheets of centrocytic cells without follicular structures

Additional studies Tumor cells express B-cell markers (CD20, CD79a) and bcl-6, but are usually negative for bcl-2. In some cases restringent monoclonal expression of immunoglobulin lambda or kappa light chains. Up to 80% show monoclonal rearrangement of immunoglobulin heavy chain with PCR

Differential diagnoses ] Primary cutaneous marginal zone B-cell lymphoma Proliferation of interfollicular compartment with monocytoid or lymphoplasmacytoid poorly differentiated tumor cells which express bcl-2 but are negative for bcl-6. Remnants of reactive germinal centers. Often monoclonal immunoglobulin light chains ] Cutaneous B-cell pseudolymphoma (lymphadenosis cutis benigna) More uniform germinal centers with tingible body macrophages and small B-cells with dense nuclei. Plasma cells and eosinophils present. No clonality present ] Diffuse large-cell B-cell lymphoma, leg type Diffuse cohesive sheets of centroblasts or immunoblasts. Marked expression of bcl-2 and MUM1

Comment In some cases Borrelia can be found in primary cutaneous B-cell lymphomas, including follicle center and marginal zone B-cell lymphomas.

Primary cutaneous follicle center B-cell lymphoma ] 279

Grenz zone

follicular pattern with large neoplastic follicles

tumor cells primarily centrocytic follicle center cells

4.6.4 Cutaneous B-cell pseudolymphoma Synonyms: Lymphocytoma cutis, lymphadenosis cutis benigna when caused by borrelial infections Definition Lymphoid hyperplasia in response to a variety of triggers including Borrelia, arthropod assaults (especially scabies), molluscum, drugs or additives, and vaccines

Clinic

Red-brown to blue-red nodule without ulceration; when Borrelia-associated, typical sites are ear lobe, nipple and scrotum

Histopathology    

Normal epidermis with Grenz zone (area of sparing) in papillary dermis Circumscribed infiltrates of lymphocytes with follicle formation in upper and mid-dermis Tingle body macrophages in follicular structures At the periphery small lymphocytes with dense nuclei, plasma cells and eosinophils

Additional studies Tumor cells express B-cell markers and have a regular network of CD21-positive follicular dendritic cells. No monoclonal expression of immunoglobulin light chains kappa or lambda and no monoclonal rearrangement of immunoglobulin heavy chain genes

Differential diagnoses ] Primary cutaneous follicle center B-cell lymphoma Nodular infiltrate usually extending into deep dermis or subcutis. Irregular accumulations of B-cells with primarily centrocytic differentiation. Monoclonal expression of immunoglobulin light chains ] Primary cutaneous marginal zone B-cell lymphoma Proliferation of interfollicular compartment with monocytoid or lymphoplasmacytoid poorly differentiated tumor cells which express bcl-2 but are negative for bcl-6. Remnants of reactive germinal centers. Often monoclonal expression of immunoglobulin light chains ] Lupus tumidus Variant of lupus erythematosus with marked mucin deposition. Lymphocytic perivascular and periadnexal infiltration, predominantly T cells, involving entire dermis

Comment Primary cutaneous marginal zone B-cell lymphoma and cutaneous B-cell pseudolymphoma can often not be separated with certainty histologically. The clinical history is always required, as well as a search for Borrelia.

Cutaneous B-cell pseudolymphoma ] 281

lymphocytic infiltrate with reactive follicles in dermis

germinal center with tingible body macrophages

4.7 Histiocytoses and mastocytoses 4.7.1

Langerhans cell histiocytosis

4.7.2

Juvenile xanthogranuloma

4.7.3

Cutaneous mastocytoses

4.7.1 Langerhans cell histiocytoses Definition Neoplastic proliferation of Langerhans cells in the skin and other organs Clinic

Four clinical forms . Letterer-Siwe disease: infants, children, diffuse skin disease with systemic involvement . Hand-Schüller-Christian disease: often diabetes insipidus secondary to pituitary involvement, other bone disease . Eosinophilic granuloma: Solitary tumor . Congenital self-healing reticulohistiocytosis: Neonatal papules and nodules; usually self-healing Two types of skin lesions . Hemorrhagic tiny papules, usually with scale; favor scalp and flexures; most often seen in Letterer-Siwe disease . Nodular infiltrates in skin, bone or other organs (eosinophilic granuloma)

Histopathology  Infiltrate of Langerhans cells with large kidney-shaped nuclei and pale eosinophilic cytoplasm. Papular lesions show marked epidermotropism of tumor cells with hemorrhage. Nodules show clusters of Langerhans cells admixed with eosinophils

Additional studies Langerhans cells express CD1a, S-100 and langerin (CD207), as well as containing Birbeck granules when studied with electron microscopy (not required for diagnosis)

Differential diagnoses ] Dermatitis Acanthosis, spongiosis, exocytosis from lymphocytes. Occasionally increased numbers or clusters of Langerhans cells seen in dermatitis and other inflammatory disorders (scabies) ] Mycosis fungoides Intraepidermal collections of T-cells (Pautrier microabscess) which usually contain scattered Langerhans cells ] Superficial spreading melanoma Buckshot scatter of atypical melanocytes in epidermis; tumor cells express melanocytic markers (S-100, Melan A) ] Paget disease Pagetoid (scattered, like pattern of shot gun) distribution of clear tumor cells in epidermis; CAM5.2 and CK7 are best immunostains

Comment If the clinician does not warn the dermatopathologist about the possibility of Langerhans cell disease, it is easy to overlook the key cells on routine sections. Confirmation of their identity with immunohistochemical stains is mandatory. Always stain cases of dermatitis with purpura in children when answer is not clear.

Langerhans cell histiocytoses ] 285

epidermotropic tumor cells

Langerhans cells

Right panel: Langerhans cells express CD1a

4.7.2 Juvenile xanthogranuloma Definition Localized benign proliferation of macrophages with admixture of foamy cells and giant cells

Clinic

Solitary or multiple asymptomatic yellow-brown nodules. Most common in children; usually favor scalp and trunk

Histopathology  Dome-shaped nodular infiltrate in upper and mid-dermis, usually filling dermal papillae  In early lesions monomorphic infiltrate of macrophages with abundant pale eosinophilic cytoplasm  In later stages macrophages with lipid-laden cytoplasm (foam cells), multinucleated giant cells (Touton type) with wreath of nuclei surrounding pale center, and eosinophils Variants  Reticulohistiocytoma: Numerous multinucleated giant cells with ground glass cytoplasm  Papular xanthoma: Numerous foam cells in papules in normolipemic patients  Spindle cell xanthogranuloma: Nodules dominated by spindled macrophages, easily mistaken for dermatofibroma

Additional studies Langerhans cells and macrophages are derived from related bone marrow monocyte populations. Langerhans cell express CD1a and strongly express langerin. Macrophages express CD68 and do not express CD1a or langerin. Occasionally a few macrophages may be S-100 positive

Differential diagnoses ] Foreign body granuloma Granuloma with multinucleated giant cells with irregular arrangement of nuclei and demonstration of foreign body (polarization) ] Dermatofibroma Proliferation of macrophages and fibroblasts extending lateral and entrapping bundles of collagen; overlying epidermis usually acanthotic, sometimes with hair germs or basaloid buds ] Anaplastic large cell lymphoma Pleomorphic or anaplastic cells which express lymphocytic markers. On occasional Langerhans cell histiocytosis has anaplastic infiltrates and can be confused

Comment A solitary reticulohistiocytoma is a variant of xanthogranuloma and requires no further investigation; patients with multiple lesions have multicentric reticulohistiocytosis, a systemic multi-organ disease with disabling arthritis.

Juvenile xanthogranuloma ] 287

nodular infiltrate pushing on epidermis

Touton giant cells

4.7.3 Cutaneous mastocytoses Definition Localized or diffuse cutaneous proliferations of mast cells, sometimes associated with systemic disease

Clinic

. Mastocytoma: Single or several red-brown papules or nodules, usually in children . Urticaria pigmentosa (UP): Numerous symmetrical macular, papular or plaquelike, usually red-brown lesions . Telangiectasia macularis eruptiva perstans (TMEP): Disseminated small tan macules admixed with telangiectases All of these lesions may urticate after mechanical irritation (Darier sign)

Histopathology Mastocytoma  Dense circumscribed infiltrate of mast cells in upper and mid-dermis  Mast cells have round nuclei and basophilic cytoplasmic granules if not degranulated UP/TMEP  Epidermis with increased basal layer melanin  Discrete lymphocytic perivascular infiltrate in upper dermis with increased numbers of perivascular mast cells and admixed eosinophils  Ectatic capillaries

Additional studies Metachromatic granules seen better with Giemsa or toluidine blue stain. Mast cells stain with chloroacetate esterase (Leder stain), CD117 (c-kit), and mast cell tryptase

Differential diagnoses ] Mastocytoma . Lymphoproliferative disorders: No granular cytoplasm, no c-kit reactivity. Expression of lymphocytic markers . Granular cell tumor: Tumor cells are S100-positive and granules are not Giemsapositive . ] UP/TMEP Urticaria: More eosinophils, also found between collagen bundles and in capillaries . Drug reaction: Lymphocytes and eosinophils, but fewer mast cells

Comment In UP/TMEP mast cells are very hard to see in H&E sections, especially if degranulated by manipulation or biopsy technique. There is no absolute number of mast cells per high-power field required for the diagnosis – numbers between 6 and 10 have been proposed. When diffuse clusters of mast cells are associated with basal layer hyperpigmentation, eosinophils or telangiectases, mast cell disease is likely.

Cutaneous mastocytoses ] 289

Mastocytoma dense nodules of monomorphous mast cells

polygonal mast cells with wide cytoplasmic rim

Right panel: mast cell granules with Giemsa stain

Urticaria pigmentosa increased basal layer melanin

discrete papillary dermal infiltrate

mast cells

Right panel: mast cell granules with Giemsa stain

occasional eosinophils

4.8 Cutaneous metastases Definition Spread of systemic malignancy to skin via blood or lymphatics. Most common sources are breast, colon and bronchial carcinomas, as well as metastatic melanoma

Clinic

Erythematous to blue-red rapidly growing papules and nodules. Sometimes diffuse infiltration (erysipelas-like)

Histopathology  Epidermis usually uninvolved  Nodular proliferation of malignant epithelial cells with squamous or glandular (tubular, ductal) differentiation  Atypical mitoses and nuclear pleomorphism  In center may be necrosis or hemorrhage  Both inflammatory and stromal reaction is sparse to absent  Sometimes single tumor cells between strands of collagen (Indian filing) Variant  Lymphangiosis carcinomatosa: Bizarre tumors cells with nuclear pleomorphism and mitoses in ectatic lymphatics of upper dermis. Minimal lymphocytic infiltrate

Additional studies Battery of immunohistochemical stains usually needed to identify likely primary tumor. Squamous tumor cells usually positive for cytokeratin 7; adenocarcinomas are also positive for CAM5.2. Prostate-specific antigen positivity points to prostate carcinoma and uroplakin indicates prostate carcinoma, while CDX2 suggests colon carcinoma. Always exclude metastatic melanoma with S-100, Melan A or HMB45

Differential diagnoses ] Squamous cell carcinoma Connections to overlying epidermis and actinic damage to surrounding skin ] Cutaneous adnexal carcinomas Nodular proliferations with ductal or glandular pattern, usually has peritumoral infiltrate. Sometimes indistinguishable from adenocarcinoma metastasis except by history and detailed examination ] Merkel cell carcinoma Basophilic cellular tumor without keratinization or tubular/glandular differentiation. Punctate perinuclear expression of CK20 and neurofilament

Comment In very rare instances, a metastasis is present and even after complete screening examination no primary tumor is found. In such instances, histochemical patterns can help refine the search for the underlying tumor.

Cutaneous metastases ] 291

Lymphangiosis carcinomatosa

atypical cells in dermal lymphatics

Diffuse metastases

diffuse dermal involvement with fibrosis secondary to metastatic breast carcinoma right panels: tumor cells stain with MNF116, an anti-keratin stain

Subject Index A acantholysis 15 acanthoma, clear cell 166 acanthosis 15 acid orcein stain 6 acrodermatitis chronica atrophicans 98 acrodermatitis enteropathica 140 acrolentiginous melanoma 202 actinic elastosis 116 actinic keratosis 170 acute febrile neutrophilic dermatosis 106 adenoma, sebaceous 208 alcian blue stain 6 alopecia areata 124 alopecia, androgenetic 124 anaplastic large cell lymphoma 276 ancient schwannoma 256 androgenetic alopecia 124 angiokeratoma 266 angiolipoma 252 angiomatosis, bacillary 264 angiomyolipoma 248 angiosarcoma 270 Antoni areas 256 arthropod assault reaction 110 artifactual damage 140 artifactual panniculitis 134 asteroid body 86 atypical fibroxanthoma 246 atypical lipomatous tumor 252 atypical mycobacteria 90 B bacillary angiomatosis 264 ball of yarn 116 ballooning degeneration 15 band-like infiltrate 16 basal cell carcinoma 230 basement membrane 15 Bazin disease 132 B-cell lymphoma 278 B-cell pseudolymphoma 280 BCG antibody 10 Bcl-2 10 Bcl-6 10 Becker nevus 160 Bednar tumor 244 beer foam pattern 252 biopsy 5 – square 100 Birbeck granule 284 blue nevus 190 borreliosis 98

Bowen disease 172 bowenoid papulosis 172 Breslow depth 202 brick wall, dilapidated 40 bullous disease – childhood 52 – of diabetes 54 bullous lupus erythematodes 50 bullous pemphigoid 50 bullous Sweet syndrome 106 C calcifying epithelioma 210 calcinosis cutis 116 CAM5.2 9 candidiasis 30 capillary hemangioma 264 carcinoembryonic antigen (CEA) 9 carcinoma – basal cell 230 – Merkel cell 258 – microcystic adnexal 228 – squamous cell 174 – verrucous 22 caseation necrosis 90 caterpillar bodies 54 CD1a 10 CD3 10 CD4 10 CD7 10 CD8 10 CD20 10 CD21 10 CD30 10 CD30-positive lymphoproliferative disease 276 CD31 9 CD34 9 CD68 10 CD79a 10 CD117 10 CD207 10 CDX2 10 cellular blue nevus 190 cellulitis, eosinophilic 108 chancre 92 chloroacetate esterase stain 6 cholesterol emboli 78 chondrodermatitis helicis nodularis chronica chromogranin 9 chronic bullous disease of childhood 52 church spires 16 Churg-Strauss syndrome 76

114

294 ] Subject Index CK7 9 CK20 9 Clark level 202 Clark nevus 192 clear cell acanthoma 166 clear cell hidradenoma 218 clonal nevus 186 clonal seborrheic keratosis 164 coagulation, disseminated intravascular 78 collagenosis, reactive perforating 140 compound nevus 184 condyloma acuminatum 32 condyloma latum 92 congenital nevus 186 congenital self-healing reticulohistiocytosis 284 Congo red stain 6 connective tissue nevus 100 consumption of epidermis 198 corn flake sign 88 cornoid lamella 15, 168 corps ronds 38 cryoglobulinemia 78 curettage biopsy 5 cylindroma 222 cyst 145 – digital mucous 154 – epidermoid 146 – hybrid 146 – isthmus-catagen 148 – pilar 148 – trichilemmal 148 – – proliferating 148 – vellus hair 150 cystic sebaceous tumor 208 D Darier disease 38 deep fungal infections 90 deep penetrating blue nevus 190 degeneration – ballooning 15 – vacuolar 16 dermal duct tumor 216 dermal melanocytosis 190 dermal nevus 186 dermal sarcoma 246 dermatitis herpetiformis 52 dermatitis – acute 20 – chronic 20 – interface 15 – interstitial granulomatous 82 dermatofibroma 242 dermatofibrosarcoma protuberans 244 dermatomyofibroma 248 dermatomyositis 66 dermatophytosis 30 dermatoses, pigmented purpuric 68 dermatosis papulosa nigra 164

dermatosis – acute febrile neutrophilic 106 – linear IgA 52 – transient acantholytic 38 desmin 9 desmoplastic melanoma 204 desmoplastic trichoepithelioma 228 DIC 78 DIF 11 digital mucous cyst 154 dilapidated brick wall 40 direct immunofluorescence 11 disseminated intravascular coagulation 78 disseminated superficial actinic porokeratosis Doucas-Kapetanakis purpura 68 drug reaction 136 – fixed 136 – lichenoid 138 – maculopapular 138 Duperrat nevus 186 dust, nuclear 16 dyskeratoma, warty 38 dyskeratosis 15 dysplastic melanocytic nevus 192 E elastolytic granuloma 84 elastosis perforans serpiginosa 116 elastosis, actinic 116 elastotic nodule 114 EMA 9 emboli, cholesterol 78 eosinophilic cellulitis 108 eosinophilic folliculitis 122 eosinophilic granuloma 284 eosinophilic spongiosis 48 epidermal nevus 160 epidermis, naked 46 epidermoid cyst 146 epidermolysis bullosa 54 epidermolysis bullosa acquisita 50 epidermolytic epidermal nevus 160 epithelioid cell 15 epithelioid hemangioma 270 epithelioma – calcifying 210 – Malherbe 210 erosion 15 erysipelas 106 erythema annulare centrifugum 28 erythema elevatum et diutinum 74 erythema induratum 132 erythema migrans 98 erythema multiforme 58 erythema nodosum 132 erythroplasia of Queyrat 172 erythropoietic protoporphyria 54 exanthem, viral 138 extramammary Paget disease 224 eyeliner sign 168

168

Subject Index ] 295 F factor XIIIA 9 fibroepithelioma of Pinkus 232 fibrolipoma 250 fibroma molle 240 fibroma, irritation 240 fibrous papule 186 fibroxanthoma, atypical 246 FISH 13 Fite-Faraco stain 6 fixation 5 fixed drug reaction 136 flame figure 15, 108 fluorescent in situ hybridization 13 focal dermal hypoplasia 250 fogo selvagem 46 follicular melanoma 196 folliculitis 122 folliculitis decalvans 128 Fordyce angiokeratoma 266 foreign body giant cell 15 foreign body granuloma 88 fungal infections 30 G ganglion 154 GCDFP-15 9 giant cells 15 Giemsa stain 6 Goldner stain 6 Gougerot-Blum disease 68 gouty tophus 114 graft-versus-host reaction 58 grains 38 Gram stain 6 giant cell – foreign body 15 – Langhans 15 – Touton 15 granular cell tumor 118 granuloma annulare 82 granuloma faciale 74 granuloma – elastolytic 84 – eosinophilic 284 – foreign body 88 – pyogenic 264 granulomatosis, Wegener 72 Grocott stain 6 Grover disease 38 guttate psoriasis 24 H Hailey-Hailey disease 40 halo nevus 188 Hand-Schüller-Christian disease 284 hemangioma 262 – capillary 264

– epithelioid 270 – verrucous 266 hematoxylin and eosin stain 6 hemorrhage 15 Henoch-Schönlein purpura 72 HER2 9 herpes simplex virus 42 HHV8-LNA 9 hibernoma 252 hidradenoma 218 hidradenoma papilliferum 214 hidradenoma – clear cell 218 – nodular 218 hidroacanthoma simplex 216 hidrocystoma 150 histiocyte 15 histiocytoid Sweet syndrome 106 histiocytoma 242 – malignant fibrous 246 histiocytosis, Langerhans cell 284 histoplasmosis 94 HMB-45 9 Hodgkin lymphoma 276 hybrid cyst 146 hybridization – fluorescent in situ 13 – in situ 13 hypereosinophilic syndrome 108 hypergranulosis 15 hyperkeratosis 15 hyperplasia, sebaceous 208 hypertrophic scar 238 hypoplasia, focal dermal 250 I IIF 11 ILVEN 160 immunofluorescence – direct 11 – indirect 11 – table 12 immunohistochemical stains 9 impetigo 26 in situ hybridization 13 inclusion 15 incontinence of pigment 15 indirect immunofluorescence 11 infection, deep fungal 90 infiltrate – band-like 16 – lichenoid 16 – perivascular 16 inflammatory epidermal nevus 160 insect bite reaction 110 interface dermatitis 15 interstitial granulomatous dermatitis inverted follicular keratosis 164 iris lesions 58 iron stain 6

82

296 ] Subject Index irritation fibroma 240 isthmus-catagen cyst 148 Ito nevus 190 J Jessner-Kanof disease 66 jig saw puzzle 222 junctional nevus 184 juvenile xanthogranuloma 286 juxta-articular nodule 98 K Kamino body 194 Kaposi sarcoma 268 karyorrhexis 16 keloid 238 keratoacanthoma 176 keratosis – actinic 170 – inverted follicular 164 – lichenoid 62 – seborrheic 164 – stucco 164 Ki-67 10 Kogoj pustule 15 L lamella, cornoid 15, 168 Langerhans cell histiocytosis 284 langerin 10 Langhans giant cell 15 LCA 10 leiomyoma 248 leiomyosarcoma 248 leishmaniasis 94 lentigo maligna 196 lentigo maligna melanoma 196 lentigo simplex 182 lentigo – senile 182 – solar 182 leprosy 90 Letterer-Siwe disease 284 leukocytoclasia 16 leukocytoclastic vasculitis 72 lichen planopilaris 126 lichen planus 62 – scalp 126 – verrucous 22 lichen sclerosus 64 lichenoid drug reaction 138 lichenoid infiltrate 16 lichenoid keratosis 62 linear IgA dermatosis 52 lipoma 252 lipomatous tumor, atypical 252 liposarcoma 252 livedo vasculopathy 78

lupus erythematosus 66 – bullous 50 – scalp 126 lupus panniculitis 134 lupus pernio 86 lupus tumidus 66 lupus vulgaris 90 lymphadenosis cutis benigna 280 lymphangioendothelioma 268 lymphangioma 262 lymphangiosis carcinomatosa 290 lymphocytic infiltrate Jessner-Kanof 66 lymphocytic vasculitis 72 lymphocytoma cutis 280 lymphoma – anaplastic large cell (ALCL) 276 – B-cell 278 – follicle center B-cell 278 – panniculitis-like 134 – T-cell 274 lymphomatoid papulosis 276 M M. bovis antibody 10 M. tuberculosis antibody 10 macrophage 16 – tingle body 280 macule, mucosal melanotic 180 maculopapular drug reaction 138 Majocchi disease 68 Malherbe epithelioma 210 malignant fibrous histiocytoma 246 malignant peripheral nerve sheath tumor 254 mammary Paget disease 224 MANIAC 202 marginal zone B-cell lymphoma 278 Masson-Fontana stain 6 mast cell tryptase 10 mastocytoma 288 melan-A 9 melanoacanthoma 164 melanocytic nevus 184 – compound 184 – congenital 186 – dermal 186 – dysplastic 192 – junctional 184 melanocytosis, dermal 190 melanoma – acrolentiginous 202 – desmoplastic 204 – follicular 196 – lentigo maligna 196 – nodular 200 – superficial spreading 198 melanotic macule 180 membrane, basement 15 Merkel cell carcinoma 258 metachromasia 16 metastases 290

Subject Index ] 297 Mibelli angiokeratoma 266 Mibelli porokeratosis 168 Michel medium 11 microabscess 16 – Munro 16 – Pautrier 16 microcystic adnexal carcinoma 228 Miescher nevus 186 milium 146 milker’s nodule 42 mixed tumor of skin 232 molluscum contagiosum 34 Mongolian spot 190 morphea 100 Morton neuroma 254 mucinosis, reticular erythematous 66 mucosal melanotic macule 180 mucous membrane pemphigoid 50 multicentric reticulohistiocytosis 286 MUM1 10 Munro microabscess 16 murky sign 258 mycobacteria, atypical 90 mycobacterial infections 90 Mycobacterium marinum 90 Mycobacterium tuberculosis 90 mycosis fungoides 274 myeloperoxidase stain 6 myxedema 66 myxoma, nerve sheath 256 N naked epidermis 46 Nanta nevus 186 necrobiosis lipoidica 84 necrosis – caseation 90 – satellite cell 16 nerve sheath myxoma 256 neurilemmoma 256 neurofibroma 254 neurofibrosarcoma 254 neurofilament 9 neuroma – Morton 254 – solitary circumscribed 254 – traumatic 254 neurothekeoma 256 nevus comedonicus 160 nevus incipiens 182 nevus lipomatosus superficialis nevus of Ito 190 nevus of Ota 190 nevus sebaceus 162 nevus – Becker 160 – blue 190 – Clark 192 – clonal 186 – compound 184

– congenital 186 – connective tissue 100 – dermal 186 – Duperrat 186 – dysplastic 192 – epidermal 160 – halo 188 – junctional 184 – melanocytic 184 – Miescher 186 – Nanta 186 – Reed 192 – Spitz 192 – Sutton 188 – Unna 186 Nikolsky phenomenon 48 nodular hidradenoma 218 nodular melanoma 200 nodular vasculitis 132 nodule – elastotic 114 – juxta-articular 98 – rheumatoid 82 normolipemic xanthoma 118 nuclear dust 16 O Ofuji folliculitis 122 orf 42 osteoma cutis 210 ostiofolliculitis 122 Ota nevus 190 P

250

p75 9 Paget disease 224 Pagoda stain 6 palmoplantar keratoderma 32 panniculitis 132 panniculitis-like lymphoma 134 papilloma, viral 32 papillomatosis 16 papule, fibrous 186 papulosis – bowenoid 172 – lymphomatoid 276 PAS stain 6 Pautrier microabscess 16 PCR 13 pemphigoid gestationis 50 pemphigoid – bullous 50 – mucous membrane 50 pemphigus foliaceus 46 pemphigus vulgaris 48 perineuroma 256 periodic acid-Schiff stain 6 peripheral nerve sheath tumor, malignant 254 perivascular infiltrate 16

298 ] Subject Index phototoxic reaction 136 phytophototoxic reaction 58 pigment, incontinence 15 pigmented purpuric dermatoses 68 pilar cyst 148 pilomatricoma 210 pink and blue sign 168 Pinkus fibroepithelioma 232 pityriasis lichenoides 60 pityriasis lichenoides chronica 60 pityriasis lichenoides et varioliformis acuta 60 pityriasis rosea 28 pityriasis rubra pilaris 24 pityrosporon folliculitis 122 PLEVA 60 PLC 60 polyarteritis nodosa 76 polychondritis, relapsing 114 polymerase chain reaction 13 porocarcinoma 216 porokeratosis 168 poroma 216 porphyria cutanea tarda 54 proliferating trichilemmal cyst 148 prostate-specific antigen 10 protoporphyria, erythropoietic 54 prurigo 22 prurigo nodularis 22 Prussian blue stain 6 PSA 10 pseudocyst 154 pseudolymphoma, B-cell 280 pseudoxanthoma elasticum 116 psoriasis 24 – guttate 24 – pustular 26 punch biopsy 5 purpura, Henoch-Schönlein 72 pustular psoriasis 26 pustule 16 – Kogoj 15 pustulosis, subcorneal 26 pyoderma gangrenosum 106 pyogenic granuloma 264 Q Queyrat erythroplasia 172 R reaction – arthropod assault 110 – insect bite 110 – phototoxic 136 reactive perforating collagenosis 140 Reed nevus 194 relapsing polychondritis 114 REM syndrome 66 reticular erythematous mucinosis 66 reticulohistiocytoma 286 reticulohistiocytosis

– congenital self-healing 284 – multicentric 286 rheumatoid nodule 82 rosacea 122 S S-100 10 salt-split skin 11 sarcoidosis 86 sarcoma – dermal 246 – Kaposi 268 satellite cell necrosis 16 saw-tooth pattern 62 scar 236 – hypertrophic 238 Schamberg disease 68 Schaumann body 86 schwannoma 256 sebaceoma 208 sebaceous adenoma 208 sebaceous carcinoma, periorbital 224 sebaceous hyperplasia 208 sebaceous tumor, cystic 208 seborrheic keratosis 164 sectioning 5 senile lentigo 182 septic vasculitis 72 shave biopsy 5 six “L’s” 98 skin biopsy 5 skin tag 240 SMA 10 smooth muscle actin 10 solar, lentigo 182 solitary circumscribed neuroma 254 special stains, table 7 spiradenoma 220 Spitz nevus 194 spongiosis 16 – eosinophilic 48 squamous cell carcinoma 174 square biopsy 100 staining 6 stains – immunohistochemical 9 – special 7 staphylococcal scalded skin syndrome 136 steatocystoma 150 Stewart-Treves syndrome 270 stucco keratosis 164 subcorneal pustulosis 26 Sudan orange stain 6 superficial spreading melanoma 198 Sutton nevus 188 swarm of bees 124 Sweet syndrome 106 synaptophysin 9 syphilis 92 syringocystadenoma papilliferum 214 syringoma 212

Subject Index ] 299 T tadpole 212 tag, skin 240 T-cell lymphoma, mycosis fungoides 274 T-cell lymphoma, CD30-positive 276 telangiectases 266 telangiectasia macularis eruptiva perstans 288 telogen effluvium 124 thrombophlebitis 76 TIA-1 10 tinea 30 – versicolor 30 tingle body macrophage 280 toluidine blue stain 6 tophus, gouty 114 Touton giant cell 15 toxic epidermal necrolysis 136 transient acantholytic dermatosis 38 traumatic neuroma 254 Treponema pallidum 92 trichilemmal cyst 148 trichoblastoma 226 trichoepithelioma, desmoplastic 228 trichofolliculoma 226 trichotillomania 124 tricolor sign 42 tryptase, mast cell 10 TTF-1 9 tumor – dermal duct 216 – granular cell 118 – mixed 232 U ulcer 16 Unna nevus 186 uroplakin 10 urticaria 104 urticaria pigmentosa 288

V vacuolar degeneration 16 van Gieson stain 6 varicella zoster virus (VZV) 42 vasculitis – leukocytoclastic 72 – lymphocytic 72 – nodular 132 – septic 72 vasculopathy, livedo 78 vellus hair cyst 150 Verocay body 256 verruca vulgaris 32 verrucous carcinoma 22 verrucous hemangioma 266 vimentin 10 viral exanthem 138 viral papilloma 32 von Kossa stain 6 W wart 32 warty dyskeratoma 38 Wegener granulomatosis Wells syndrome 108 X xanthelasma 118 xanthogranuloma 286 xanthoma 118 Z Ziehl-Neelsen stain 6 zinc deficiency 140

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