Pathology of Pigmented Skin Lesions Jose A. Plaza Victor G. Prieto 123 Pathology of Pigmented Skin Lesions Jose A. Plaza • Victor G. Prieto Pathology of Pigmented Skin Lesions Jose A. Plaza Victor G. Prieto Division of Dermatopathology MD Anderson Cancer Center Miraca Life Sciences University of Texas Dallas, TX, USA Houston, TX, USA ISBN 978-3-662-52719-1 ISBN 978-3-662-52721-4 (eBook) DOI 10.1007/978-3-662-52721-4 Library of Congress Control Number: 2016950573 © Springer-Verlag Berlin Heidelberg 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer-Verlag GmbH Germany The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany Preface The histomorphologic study of pigmented lesions of the skin constitutes the majority of our daily dermatopathology practice. In this book, we have compiled our experience in regard to pigmented lesions of the skin and have illustrated not only stereotypical examples of pig- mented lesions but also unusual variants and a wide spectrum of variations that can be observed in such lesions. Our goal in this book is to illustrate thoroughly the most difficult topics in melanocytic tumors and to describe our view on how to diagnose these lesions. The opinions stated in this book represent our personal views on the topics. As with other topics in the field of pathology, the reader should consider the information provided and assimilate it to her/his own experience. The histological diagnosis of melanocytic lesions is one of the most difficult areas in pathol- ogy, given the subjectivity and histologic variations that some of such entities may depict. In the last decade, there have been major advances in terms of diagnosis and prognosis of such lesions. It is well known that a number of these lesions cannot be precisely and reproducibly classified as either entirely benign or malignant just by using conventional histologic and immunohistochemical techniques. New understandings of molecular pathogenesis of melano- cytic proliferations have revealed genetic differences between nevi and melanoma that can be used as targets for developing molecular diagnostic tests. FISH has emerged as a preferred molecular technique to interrogate chromosomal abnormalities, with proven utility as a diag- nostic adjunct in lymphoid lesions and solid tumors and that has been recently validated for the diagnosis of melanocytic lesions. In this book, in addition to special mention to immunohisto- chemistry, we cover also the utility of adjunct molecular studies applied to the diagnosis of certain melanocytic lesions that are exceedingly difficult to diagnose on pure histomorpho- logic grounds. We are in debt with our teachers, colleagues, and students who have guided and challenged us over the years. We also are thankful to many pathologists who have shared their challenging cases with us on consultation, and we have learned from them. The major sources of material used in book are from the dermatopathology divisions of Medical College of Wisconsin, University of Texas MD Anderson Center, and Miraca Life Sciences. And last, but not least, we are much in debt with our families who have supported us during all these years. Dallas, TX, USA Jose A. Plaza Houston, TX, USA Victor G. Prieto v Contents 1 Lentigines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Ephelides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Lentigo Simplex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Actinic Lentigo (Pigmented Early Actinic Keratosis, Solar Lentigo) . . . . . . . . . . . . 3 Ink-Spot Lentigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Large Cell Acanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Melanotic Macules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 PUVA Lentigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Becker Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Café-au-lait Macule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2 Dermal Melanocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Nevus of Ota and Ito . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 “Mongolian” Blue Spot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Nevus of Sun and Nevus of Hori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Histologic Variants of Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Combined Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Compound Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Amelanotic Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Desmoplastic (Sclerosing) Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Blue Nevus with Atypical Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Epithelioid Blue Nevus (Pigmented Epithelioid Melanocytomas) . . . . . . . . . . . . . 45 Cellular Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Variants of Cellular Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Amelanotic Cellular Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Plaque-Type Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Atypical Cellular Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Blue Nevus-Like Melanoma (Malignant Blue Nevus) . . . . . . . . . . . . . . . . . . . . . . . . 82 Deep Penetrating Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Cutaneous Neurocristic Hamartoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 3 Acquired Melanocytic Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Common Acquired Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Histologic Features of Melanocytes in Common Acquired Melanocytic Nevi . . . . . . 99 Melanocytic Nevi Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Unna Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Miescher Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Meyerson Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 vii viii Contents Cockarde Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Spilus Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Inverted Type A Melanocytic Nevi (Clonal Nevi) . . . . . . . . . . . . . . . . . . . . . . . . . 108 “Ancient” Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Balloon Cell Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Neurotized Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Melanocytic Nevi with Adipose Metaplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Melanocytic Nevi with Pseudovascular Spaces . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Melanocytic Nevi with Dermal Mitotic Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Traumatized Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Combined Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Halo Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Nevi in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Recurrent/Persistent Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Acral Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Genital Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 4 Spitz Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Intraepidermal/Junctional Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 Compound Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Intradermal Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Spitz Nevi Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Pigmented Spindle Cell Nevus of Reed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Atypical Pigmented Spindle Cell Nevus of Reed . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Spitz Nevus with Dysplastic (Clark) Features (“Spark”) . . . . . . . . . . . . . . . . . . . . . . 241 Desmoplastic Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Angiomatoid Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 Hyalinizing Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Spitz Nevus with Halo Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 Polypoid Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 Plexiform Spitz Nevus (See Section of Spitz Nevi with ALK Fusion) . . . . . . . . . . . 264 Pagetoid Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 Recurrent/Persistent Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 Spitzoid Lesions with BAP-1 Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 Spitz Nevi with HRAS Mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Spitz Nevi with ALK Fusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Atypical Spitz Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Immunohistochemistry and Molecular Studies Advances in Atypical Spitz Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 5 Dysplastic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Dysplastic Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Dysplastic Nevi as a Risk Factor and Precursor of Melanoma . . . . . . . . . . . . . . . . . . 292 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Dysplastic Nevi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Histologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Grading Dysplastic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 Dysplastic Nevi Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 Contents ix “Spark” Melanocytic Nevus with Features of Both Spitz and Clark (See Spitz Nevi Section) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 Differential Diagnosis of Dysplastic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 6 Congenital Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Congenital Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Melanoma Associated with Congenital Melanocytic Nevus . . . . . . . . . . . . . . . . . . . 329 Congenital Nevus with Neurofibromatosis- like Features . . . . . . . . . . . . . . . . . . . . . . 331 Congenital Blue Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Congenital Spitz Nevus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Congenital Nevus with Dysplastic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Proliferative Nodules in Congenital Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 7 Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Histologic Parameters Reported in Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 Breslow Thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 Clark Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 Radial and Vertical Growth Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 Mitotic Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 Ulceration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Regression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Lymphovascular Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Perineural Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Microscopic Satellitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Tumor-Infiltrating Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Subtypes of Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Lentigo Maligna . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Superficial Spreading Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 Acral Lentiginous Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Genetics of Acral Lentiginous Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Nodular Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 Desmoplastic Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457 Role of Immunohistochemistry in Desmoplastic Melanoma . . . . . . . . . . . . . . . . . . . 458 Nevoid Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Mucosal Melanoma (Oral Cavity, Vulva, and Penis) . . . . . . . . . . . . . . . . . . . . . . . . . 482 Lentiginous Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 Primary Dermal Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Metastatic Cutaneous Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 Melanoma of Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 Spitzoid Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501 Melanocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Blue Nevus-Like Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Comparative Genomic Hybridization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Fluorescence In Situ Hybridization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Lentigines 1 Differential Diagnosis Ephelides The clinical differential diagnosis of ephelides includes Clinical Features lentigo simplex and café au lait spot. The diagnosis of café au lait spot will rely on the identification of giant melano- Ephelides (freckles) are common, uniformly pigmented, somes and mild increased number of melanocytes. Lentigo multiple macules (1–5 mm in size) mainly limited to body simplex (as explained in detail below) will show elongated regions above the waist. These macules are more numerous rete ridges with hyperpigmentation of basal keratinocytes on sun-exposed areas (face, shoulders, and upper back) and (some authors accept also mild increased in numbers of usually fade and become smaller in the winter season. melanocytes) (Fig. 1.1a–c). Ephelides appear early in childhood and partly disappear with age and are closely related to pigmentary host charac- teristics such as fair skin and/or red hair. Only rarely epheli- Lentigo Simplex des are seen in individuals with dark skin. Ephelides may manifest an autosomal dominant pattern of inheritance Clinical Features (appearing in sequential generations). High levels of freck- ling may indicate a raised susceptibility to the development Lentigo simplex is a very common, benign, pigmented lesion of melanoma. In contrast to solar lentigines, ephelides are that can be found anywhere on the body surface and is pref- not strongly associated with age [1–4]. There is a strong rela- erentially observed in young people, although it may occur tion between variants in the gene encoding the melanocortin- at any age. They usually appear early in life and are typically 1 receptor (MC1R) and ephelides in childhood suggesting not associated with sun exposure. Clinically, lesions present the MC1R gene is the major ephelide gene [5]. as non-palpable, relatively symmetric, uniform, homoge- neous, light-brown to black macules, on the trunk, extremi- ties, genitals, and mucosa surfaces, usually measuring less Histopathology than 5 mm in size (in certain anatomic sites such as the palms, soles, genitalia, and mucosal membranes, they can be The epidermis appears normal in structure. The basal cells in the larger). It is rare for a lentigo simplex to be asymmetrical or affected areas are more heavily pigmented with melanin than to have irregular borders. Lentigo simplex may occur as sin- those in the surrounding skin, and there is usually sharp delimi- gle or multiple lesions. It has been proposed that lentigo sim- tation of the abnormal from the normal areas. There are normal plex may evolve into a lentiginous/junctional melanocytic and sometimes decreased numbers of melanocytes within epi- nevus when melanocytes start proliferating and aggregating dermis; however, the melanosomes in those cells are larger than to form small nests in the junctional zone. On the other hand, those in the surrounding skin and can sometimes be seen with a recent study has shown that absence of BRAF, FGFR3, and the microscope as dark, large, intracytoplasmic granules PIK3CA mutations can clearly differentiate lentigo simplex (macromelanosomes). The adnexal structures are not involved. from melanocytic nevi and solar lentigo. These results fur- By electron microscopy studies, the melanocytes contain thermore indicate that lentigo simplex has a distinct yet enlarged spherical granular melanosomes as opposed to the stri- unknown genetic basis, which does not necessarily exclude ated ellipsoid forms seen in normal skin [3, 6, 7] (Fig. 1.1a–c). the proposed lentigo-nevus sequence [8]. © Springer-Verlag Berlin Heidelberg 2017 1 J.A. Plaza, V.G. Prieto, Pathology of Pigmented Skin Lesions, DOI 10.1007/978-3-662-52721-4_1 2 1 Lentigines a b c Fig. 1.1 Ephelides. Note the pigmented basal keratinocytes and the decreased number of melanocytes within epidermis (a). Higher magnification showing melanocytes with rare melanosomes (b). Observe the lack of melanocytes (c)