Ebook Pathology of challenging melanocytic neoplasms - Diagnosis and management: Part 1

(BQ) Part 1 book Pathology of challenging melanocytic neoplasms - Diagnosis and management presents the following contents: Gross prosection of melanocytic lesions, clinicopathologic correlation in melanocytic lesions, applications of additional techniques to melanocytic pathology, histopathologic staging and reporting of melanocytic lesions,....

Christopher R Shea Jon A Reed Victor G Prieto Editors Pathology of Challenging Melanocytic Neoplasms Diagnosis and Management 123 Pathology of Challenging Melanocytic Neoplasms Christopher R Shea • Jon A Reed Victor G Prieto Editors Pathology of Challenging Melanocytic Neoplasms Diagnosis and Management Editors Christopher R Shea Section of Dermatology University of Chicago Medicine Chicago, IL, USA Victor G Prieto Department of Pathology University of Texas MD Anderson Cancer Houston, TX, USA Jon A Reed, M.D Department of Pathology Baylor College of Medicine Houston, TX, USA CellNetix Pathology Seattle, WA, USA ISBN 978-1-4939-1443-2 ISBN 978-1-4939-1444-9 (eBook) DOI 10.1007/978-1-4939-1444-9 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2014948771 © Springer Science+Business Media New York 2015 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 Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer Permissions for use may be obtained through RightsLink at the Copyright Clearance Center Violations are liable to prosecution under the respective Copyright Law The use of general descriptive names, registered names, trademarks, service marks, 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 While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made The publisher makes no warranty, express or implied, with respect to the material contained herein Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) The editors wish to thank our master teacher, Prof N Scott McNutt, M.D., who imparted to us his ideals in pathology: a scientific approach to diagnostic problems, clear communication, dedication, and professionalism We also wish to express to our wives Kuri (Shea), Nobuko (Reed), and Eugenia (Prieto) our deepest gratitude, love, and appreciation for their endless patience and support Christopher R Shea, M.D Jon A Reed, M.D Victor G Prieto, M.D., Ph.D Contents Part I Introductory Chapters Gross Prosection of Melanocytic Lesions Jon A Reed, Victor G Prieto, and Christopher R Shea Histopathologic Staging and Reporting of Melanocytic Lesions Eduardo K Moioli, Jon A Reed, Victor G Prieto, and Christopher R Shea Clinicopathologic Correlation in Melanocytic Lesions Juliana L Basko-Plluska, Victor G Prieto, Jon A Reed, and Christopher R Shea Anathema or Useful? Application of Immunohistochemistry to the Diagnosis of Melanocytic Lesions Victor G Prieto, Christopher R Shea, and Jon A Reed 35 Applications of Additional Techniques to Melanocytic Pathology Victor G Prieto, Christopher R Shea, and Jon A Reed 43 Part II 23 Diagnostic Challenges Spitz Nevus Versus Spitzoid Melanoma Victor G Prieto, Christopher R Shea, and Jon A Reed 49 Halo Nevus Versus Melanoma with Regression Penvadee Pattanaprichakul, Christopher R Shea, Jon A Reed, and Victor G Prieto 55 Nevoid Malignant Melanoma vs Melanocytic Nevus Jon A Reed, Victor G Prieto, and Christopher R Shea 63 Dysplastic Nevi Versus Melanoma Adaobi I Nwaneshiudu, Jon A Reed, Victor G Prieto, and Christopher R Shea 73 10 Blue Nevus Versus Pigmented Epithelioid Melanocytoma Jon A Reed, Victor G Prieto, and Christopher R Shea 93 vii Contents viii 11 Recurrent Melanocytic Nevus Versus Melanoma 105 Alexander D Means, Victor G Prieto, Jon A Reed, and Christopher R Shea 12 Neurothekeoma Versus Melanoma 115 Kristen M Paral, Jon A Reed, Victor G Prieto, and Christopher R Shea 13 Melanoma In Situ Versus Paget’s Disease 133 Jon A Reed, Christopher R Shea, and Victor G Prieto 14 Desmoplastic Nevus Versus Desmoplastic Melanoma 145 Victor G Prieto, Penvadee Pattanaprichakul, Christopher R Shea, and Jon A Reed 15 Cutaneous Metastatic Melanoma Versus Primary Cutaneous Melanoma 151 Jamie L Steinmetz, Victor G Prieto, Jon A Reed, and Christopher R Shea 16 Acral Nevus Versus Acral Melanoma 157 Penvadee Pattanaprichakul, Christopher R Shea, Jon A Reed, and Victor G Prieto 17 Capsular (Nodal) Nevus Versus Metastatic Melanoma 169 Victor G Prieto, Christopher R Shea, and Jon A Reed Index 175 Contributors Juliana L Basko-Plluska, M.D University of Chicago Medicine, Chicago, IL, USA Alexander D Means University of Chicago Medicine, Chicago, IL, USA Eduardo K Moioli University of Chicago Medicine, Chicago, IL, USA Adaobi I Nwaneshiudu University of Chicago Medicine, Chicago, IL, USA Kristen M Paral University of Chicago Medicine, Chicago, IL, USA Penvadee Pattanaprichakul Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Victor G Prieto, M.D., Ph.D MD Anderson Cancer Center, University of Houston, Houston, TX, USA Jon A Reed, M.S., M.D CellNEtix Pathology & Laboratories, Seattle, WA, USA Christopher R Shea, M.D University of Chicago Medicine, Chicago, IL, USA Jamie L Steinmetz University of Chicago Medicine, Chicago, IL, USA ix J.L Basko-Plluska et al 30 The proliferative activity was absent week after treatment Because of the aforementioned histopathologic changes, UV-irradiated nevus may simulate malignant melanoma This becomes a diagnostic pitfall especially when a pathologist examines pigmented lesions soon after an intense sun exposure without the appropriate clinical history Although the presence of parakeratosis above a regular basket-weave stratum corneum and the superficial inflammatory infiltrate in the dermis may be clue to the diagnosis of irritated nevus changes, these are not always present In this case, the erroneous diagnosis of malignant melanoma may be easily rendered, followed by unnecessary treatment Dermoscopic/PhotographicPathologic Correlation Over the last several years, there has been a substantial increase in the use of dermoscopy and digital photography in the evaluation of melanocytic lesions by dermatologists Dermoscopy is a noninvasive in vivo technique that can clinically enhance the ability to accurately diagnose melanocytic lesions Dermoscopic features of melanocytic lesions result from specific histopathologic changes [66] For example, the blue-white veil seen on dermoscopy correlates with aggregation of heavily pigmented melanoma cells or melanophages in the dermis combined with overlying compact orthokeratosis Likewise, radial streaming on dermoscopy corresponds to the radial growth phase of melanoma In challenging or equivocal cases, the diagnostic accuracy of the histopathologic examination may be enhanced by considering dermoscopic features [67–70] Dermoscopy is considered as the conceptual and practical link between clinical dermatology (macrocosm) and dermatopathology (microcosm) [71] Like clinical dermatology, dermoscopy works parallel to the skin surface and provides information on a third dimension—the horizontal spread—which is not evident to the pathologist However, like histopathology, dermoscopy allows visualization of structures which could not be discernable by the naked eye Therefore, dermoscopy draws the histopathologist’s attention to the suspicious area in a melanocytic lesion, thus orienting the macroscopic sampling and/or suggesting the need of step-sectioning the paraffin block(s) to obtain representative sections In case of an inconsistency between the dermoscopic and histopathologic diagnoses, it may be advisable to re-evaluate the specimen for the safety of the patient In addition to dermoscopy, digital photography can provide the pathologist with additional clues which can assist with a more definite histopathologic diagnosis Photographic surveillance adds the fourth dimension—time—which can demonstrate subtle changes in lesions which might have otherwise gone unnoticed Similar to dermoscopy, digital photographs may alert the practicing pathologist to specifically look at the evolving areas and possibly diagnose an early, subtle melanoma [72] Summary Clinicopathologic correlation is an important step in the diagnosis of melanocytic lesions The clinical context, such as the age of the patient, anatomic location of the lesion, presence of an underlying skin disease, history of trauma or ultraviolet irradiation, should be always taken into account in order to make an accurate diagnosis Certain benign melanocytic lesions may show features that we often associate with malignant melanoma; however, knowledge and recognition of the clinical context may prevent the practicing pathologist from making the wrong diagnosis References Huynh PM, Grant-Kels JM, Grin CM Childhood melanoma: update and treatment Int J Dermatol 2005;44:715–23 Dulon M, Weichenthal M, Blettner M, Breibart M, Hetzer M, Greinert R, et al Sun exposure and number of nevi in 5- to 6-year old European children J Clin Epidemiol 2002;55:1075–81 Zayour M, Lazova R Congenital nevi Clin Lab Med 2011;31:267–80 Clinicopathologic Correlation in Melanocytic Lesions Barnhill RL, Fleischli M Histopathologic features of congenital melanocytic nevi in infants year of age or younger J Am Acad Dermatol 1995;33(5 Pt 1): 780–5 Tannous ZS, Mihm MC, Sober AJ, Duncan LM Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma and clinical management J Am Acad Dermatol 2005;52:197–203 Barnhill RL Congenital melanocytic nevi and associated neoplasms, congenital and childhood melanoma In: Barnhill R, editor Pathology of melanocytic nevi and malignant melanoma Boston: ButterworthHeinemann; 1995 p 65–96 Clark WH, Reimer RR, Greene MH, Ainsworth AM, Mastrangelo MJ Origin of familial malignant melanomas from heritable melanocytic lesions: ‘the B-K mole syndrome’ Arch Dermatol 1978;114:732–8 Tucker MA, Greene MH, Clark WH, Kraemer KH, Fraser MC, Elder DE Dysplastic nevi on the scalp of pre-pubertal children from melanoma-prone families J Pediatr 1983;103:65–9 Bonifazi E, Bilancia M, Berloco A, Ciampo L, De Roma MR Malignant melanoma in children aged 0–12 Review of 289 cases of the literature Eur J Pediatr Dermatol 2001;11:157–75 10 Ferrari A, Bono A, Baldi M, Collini P, Casanova M, Pennacchioli E, Terenziani M, Marcon I, Santinami M, Bartoli C Does melanoma behave differently in younger children than in adults? A retrospective study of 33 cases of childhood melanoma from a single institution Pediatrics 2005;115:649–54 11 Leman JA, Evans A, Mooi W, MacKie RM Outcomes and pathological review of a cohort of children with melanoma Br J Dermatol 2005;152(6):1321–3 12 Kossard S, Commens C, Symons M, Doyle J Lentiginous dysplastic naevi in the elderly: a potential precursor for malignant melanoma Australas J Dermatol 1991;32:27–37 13 Agusti-Mejias A, Badia FM, Ruiz RG, Martinez VO Alegre de Miquel V Atypical lentiginous nevus: a clinical and histopathologic study of 14 cases Actas Dermosifiliogr 2012;103(5):394–400 14 King R, Page RN, Googe PB, Mihm Jr MC Lentiginous melanoma: a histopathologic pattern of melanoma to be distinguished from lentiginous nevus Mod Pathol 2005;18:1397–401 15 Davis T, Zembowicz A Histopathologic evolution of lentiginous melanoma: a report of five new cases J Cutan Pathol 2007;34:296–300 16 Ferrara G, Zalaudek I, Argenziano G Lentiginous melanoma: a distinctive clinicopathologic entity Histopathology 2008;52:523–5 17 Weedon D Lentiginous melanoma J Cutan Pathol 2009;36:1232 18 Kossard S Atypical lentiginous junctional nevi of the elderly and melanoma Australas J Dermatol 2002; 43:93–101 19 Kossard S, Wilkinson B Small cell (nevoid) melanoma: a clinicopathologic study of 131 cases Australas J Dermatol 1997;38:54–8 31 20 King R Lentiginous melanoma Arch Pathol Lab Med 2011;135:337–41 21 Hosler GA, Moresi JM, Barrett TL Nevi with siterelated atypia: a review of melanocytic nevi with atypical histopathologic features based on anatomic site J Cutan Pathol 2008;35:889–98 22 MacKie RM, English J, Atchison TC, Fitzsimons CP, Wilson P The number and distribution of benign pigmented moles (melanocytic nevi) in a healthy British population Br J Dermatol 1985;113:167 23 Kopf AW Pigmented lesions of the palms and soles Med Rec Ann 1964;57:511 24 Cook DL Melanocytic nevi of special sites Diagn Histopathol 2010;16(7):309–16 25 Boyd A, Rapini R Acral melanocytic neoplasms: a histopathologic analysis of 158 lesions J Am Acad Dermatol 1994;31:740–5 26 Cheung WL, Smoller BR Dermatopathology updates on melanocytic lesions Dermatol Clin 2012;20: 617–22 27 Clark WH, Hood AF, Tucker MA, Jampel RM Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia Hum Pathol 1998;29:S1 28 Christensen WN, Friedman KJ, Woodruff JD, Hood AE Histopathologic characteristics of vulvar nevocellular nevi J Cutan Pathol 1987;14:87–91 29 Gleason BC, Hirsch MS, Nucci MR, Schmidt BA, Zembowicz A, Mihm MC, McKee PH, Brenn T Atypical genital nevi: a clinicopathologic analysis of 56 cases Am J Surg Pathol 2008;32:51–7 30 Dunton CJ, Kautzy M, Hanau C Malignant melanoma of the vulva: a review Obstet Gynecol Surv 1995;50:739–46 31 Alexander A, Harris RM, Grossman D, Bruggers CS, Leachman SA Vulvar melanoma: diffuse melanosis and metastasis to the placenta J Am Acad Dermatol 2004;50:293–8 32 Ronglioletti F, Urso C, Batolo D, Chimenti S, Fanti PA, Filotico R, Gianotti R, Innocenzi D, Lentini M, Tomasini C, Pippione M, Rebora A Melanocytic nevi of the breast: a histopathologic case-control study J Cutan Pathol 2004;31:137–40 33 Ronglioletti F, Ball RA, Marcus R, Barnhill RL Histopathological features of flexural melanocytic nevi: a study of 40 cases J Cutan Pathol 2000;27:215–7 34 Saad AG, Patel S, Mutasim DF Melanocytic nevi of the auricular region: histopathologic characteristics and diagnostic difficulties Am J Dermatopathol 2005;27:111–5 35 Lazova R, Lester B, Glusac RJ, Handerson T, McNiff J The characteristic histopathologic features of nevi on and around the ear J Cutan Pathol 2005;32:40–4 36 Fabrizi G, Pagliarello C, Parente P, Massi G Atypical nevi of the scalp in adolescence J Cutan Pathol 2007;34:365–9 37 Lanschuetzer CM, Emberger M, Laimer M, Diem A, Bauer JW, Soyer HP, Hintner H Epidermolysis J.L Basko-Plluska et al 32 38 39 40 41 42 43 44 45 46 47 48 49 50 51 bullosa nevi reveal distinctive dermoscopic pattern Br J Dermatol 2005;153(1):97–102 Cash SH, Dever TT, Hyde P, Lee J Epidermolysis bullosa nevus: an exception to the clinical and dermoscopic criteria for melanoma Arch Dermatol 2007;143(9):1164–7 Bauer JW, Schaeppi H, Kaserer C, Hantich B, Hintner H Large melanocytic nevi in hereditary epidermolysis bullosa J Am Acad Dermatol 2001;44(4): 577–84 Soltani K, Pepper MC, Simjee S, Apatoff BR Large acquired nevocytic nevus induced by the Koebner phenomenon J Cutan Pathol 1984;11(4):296–9 Hoss DM, McNutt NS, Carter DM, Rothaus KO, Kenet BJ, Lin AN Atypical melanocytic lesions in epidermolysis bullosa J Cutan Pathol 1994;21(2): 164–9 Stavrianeas NG, Katoulis AC, Moussatou V, Bozi E, Petropoulou H, Limas C, Georgala S Eruptive large melanocytic nevus in a patient with hereditary epidermolysis bullosa simplex Dermatology 2003;207(4): 402–4 Gallardo F, Toll A, Malvehy J, Mascaro-Gally JM, Lloreta J, Barranco C, Pujol R Large atypical melanocytic nevi in recessive dystrophic epidermolysis bullosa: clinicopathological, ultrastructural, and dermoscopic study Pediatr Dermatol 2005;22(4):338–43 Carlson JA, Wu XC, Slominski A, Weismann K, Crowson AN, Malfetano J, Prieto V, Mihm MC Melanocytic proliferations associated with lichen sclerosus Arch Dermatol 2002;138:77–87 Weinstock MA Malignant melanoma of the vulva and vagina in the United States: patterns of incidence and population-based estimates of survival Am J Obstet Gynecol 1994;171:1225–30 Tasseron EW, van der Esch EP, Hart AA, Brutel de la Riviere G, Aatsen EJ A clinicopathologic study of 30 melanomas of the vulva Gynecol Oncol 1992;46: 170–5 Raber G, Mempel V, Jackisch C, Hundeiker M, Heinecke A, Kürzl R, Glaubitz M, Rompel R, Schneider HP Malignant melanoma of the vulva: report of 89 patients Cancer 1996;78:2353–8 Ragnarsson-Olding BK, Kanter-Lewensohn LR, Lagerlof B, Nilsson BR, Ringborg UK Malignant melanoma of the vulva in a nationwide, 25-year study of 219 Swedish females: clinical observations and histopathologic features Cancer 1999;86:1273–84 Creasman WT, Philips JL, Menck HR A survey of hospital management practices for vulvar melanoma J Am Coll Surg 1999;188:670–5 Bragdate MG, Rollason TP, McConkey CC, Powell J Malignant melanoma of the vulva: a clinicopathological study of 50 women Br J Obstet Gynaecol 1990;97:124–33 Piura B, Egan M, Lopes A, Monaghan JM Malignant melanoma of the vulva: a clinicopathologic study of 18 cases J Surg Oncol 1992;50:234–40 52 Winton GB, Lewis CW Dermatoses of pregnancy J Am Acad Dermatol 1982;6:977–98 53 Pamley T, O’Brien TJ Skin changes during pregnancy Clin Obstet Gynecol 1990;33:713–7 54 Pennoyer JW, Grin CM, Driscoll MS, Dry SM, Walsh SJ, Gelineau JP, Grant-Kels JM Changes in size of melanocytic nevi during pregnancy J Am Acad Dermatol 1997;36(3 Pt 1):378–82 55 Grin CM, Rojas AI, Grant-Kels JM Does pregnancy alter melanocytic nevi? J Cutan Pathol 2001;28: 389–92 56 Sanchez JL, Figueroa LD, Rodriguez E Behavior of melanocytic nevi during pregnancy Am J Dermatopathol 1984;6:89–91 57 Foucar E, Bentley TJ, Laube DW, Rosai J A histopathologic evaluation of nevocellular nevi during pregnancy Arch Dermatol 1985;121:350–4 58 Chan MP, Chan MM, Tahan SR Melanocytic nevi in pregnancy: histopathologic features and Ki-67 proliferation index J Cutan Pathol 2010;37:843–51 59 Leleux TM, Prieto VG, Diwan AH Aberrant expression of HMB-45 in traumatized melanocytic nevi J Am Acad Dermatol 2012;67(3):446–50 60 Selim MA, Vollmer RT, Herman CM, Pham TTN, Turner JW Melanocytic nevi with nonsurgical trauma: a histopathologic study Am J Dermatopathol 2007;29:134–6 61 Adeniran AJ, Prieto VG, Chon S, Duvic M, Diwan AH Atypical histopathologic and immunohistochemical findings in melanocytic nevi after liquid nitrogen cryotherapy J Am Acad Dermatol 2009; 61(2):341–5 62 Dummer R, Kempf W, Burg G Pseudo-melanoma after laser therapy Dermatology 1998;197:71–3 63 Lee HW, Ahn SJ, Lee MW, Choi JH, Moon KC, Koh JK Pseudomelanoma following laser therapy J Eur Acad Dermatol Venereol 2006;20:342–4 64 Tronnier M, Wolff HH UV-irradiated melanocytic nevi simulating melanoma in situ Am J Dermatopathol 1995;17(1):1–6 65 Tronnier M, Smolle J, Wolff HH Ultraviolet irradiation induces acute changes in melanocytic nevi J Invest Dermatol 1995;104:475–8 66 Crotty KA, Menzies SW Dermoscopy and its role in diagnosing melanocytic lesions: a guide for pathologists Pathology 2004;36(5):470–7 67 Nardone B, Martini M, Busam K, Marghoob A, West D, Gerami P Integrating clinical/dermoscopic findings and fluorescence in situ hybridization in diagnosing melanocytic neoplasms with less than definitive histopathologic features J Am Acad Dermatol 2012; 66:917–22 68 Ferrara G, Argenziano G, Giorgio CM, Zalaudek I, Kittler H Dermoscopic-pathologic correlation: apropos of six equivocal cases Semin Cutan Med Surg 2009;28:157–64 69 Bauer J, Metzler G, Rassner G, Garbe C, Blum A Dermatoscopy turns histopathologist’s attention to Clinicopathologic Correlation in Melanocytic Lesions the suspicious area in melanocytic lesions Arch Dermatol 2001;137:1338–40 70 Ferrara G, Argenyi Z, Argenziano G, Cerio R, Cerroni L, Di Blasi A, et al The influence of clinical information in the histopathologic diagnosis of melanocytic skin neoplasms PLoS One 2009;4(4):e5375 71 Argenziano G, Puig S, Zalaudek I, Sera F, Corona R, Alsina M, et al Dermoscopy improves accuracy of 33 primary care physicians to triage lesions suggestive of skin cancer J Clin Oncol 2006;24:1877–82 72 Salerni G, Carrera C, Lovatto L, Marti-Laborda RM, Isern G, Palou J, Alos L, Puig S, Malvehy J Characterization of 1152 lesions excised over 10 years using total-body photography and digital dermatoscopy in the surveillance of patients at high risk for melanoma J Am Acad Dermatol 2012;67:836–45 Anathema or Useful? Application of Immunohistochemistry to the Diagnosis of Melanocytic Lesions Victor G Prieto, Christopher R Shea, and Jon A Reed Antibodies Commonly Used in Dermatopathology S-100 protein: S100 proteins constitute a family of acidic calcium-binding proteins that are important in intracellular calcium metabolism but some of them are secreted and thus are likely involved in cell–cell interactions S100 protein was originally extracted from the brain and contains two polypeptide chains, S100a and S100b These polypeptides can present in three possible combinations: S100aa, S100ab, and S100bb S100aa proteins are mostly expressed in macrophages [1] and therefore macrophages are usually nonreactive with the “standard” anti-S100 antibodies (this antibody mainly reacts with cells containing S100B polypeptide chains) Subsequently, monoclonal antibodies were developed that mainly react with several variants of the S100a chains More than 95 % of melanomas cells in primary V.G Prieto, M.D., Ph.D (*) MD Anderson Cancer Center, University of Houston, 1515 Holcombe Blvd., Unit 85, Houston, TX 77030, USA e-mail: vprieto@mdanderson.org C.R Shea University of Chicago Medicine, 5841 S Maryland Ave., MC 5067, L502, Chicago, IL 60637, USA J.A Reed CellNEtix Pathology & Laboratories, 1124 Columbia St., Suite 200, Seattle, WA 98117, USA cutaneous melanomas react with the standard poly- or monoclonal anti-S100 antibody, and show both a cytoplasmic and nuclear pattern However, several situations may affect its expression, such as too much or too little fixation time, previously frozen tissue, and excessive enzymatic pretreatment (e.g., with trypsin) [2] Of the several antigens detected by anti-S100, A6 is expressed in a differential manner by standard nevi, Spitz nevi, and melanoma Spitz nevi show strong expression of S100 A6 in both junctional and dermal components while standard nevi and melanoma are usually negative in the junctional component and weakly or negative in the dermal component [3] In addition, detection of S100 A6 is a very helpful marker in the differential diagnosis of neurothekeomas [1, 4] gp100 (as detected with the antibody HMB-45): This is a fairly specific antibody for melanocytic differentiation Although other lesions express this marker (angiomyolipoma, sugar cell tumor of the lung, and so-called “pecoma”), they not usually enter in the differential diagnosis of cutaneous lesions We use HMB-45 because it is particularly helpful in detecting the pattern of “maturation” of nevi It is well known that benign melanocytes change their morphology according to their distance from epithelia Thus, superficial, type-A melanocytes (epithelioid shape, intraepidermal or close to the epithelium, and mostly pigmented) express neuronal markers and gp100 while the deeply located type-C melanocytes C.R Shea et al (eds.), Pathology of Challenging Melanocytic Neoplasms: Diagnosis and Management, DOI 10.1007/978-1-4939-1444-9_4, © Springer Science+Business Media New York 2015 35 36 (spindle cells) express schwannian markers [5, 6] Uncommon exceptions to this rule include blue nevi, related lesions (e.g., deep penetrating nevi), and some Spitz nevi, in which the entire lesion is labeled with HMB-45 Therefore, we may consider that decreased expression of this marker with increasing depth in the dermis or diffuse expression throughout the lesion is suggestive of a benign diagnosis, i.e., nevus In contrast to nevi, primary cutaneous melanomas usually express gp100 in a patchy pattern, with isolated or clustered cells throughout the dermis; such pattern is also seen in nevoid melanoma [7] Furthermore, in addition to analyzing the dermal component, HMB-45 also labels the intraepidermal portion and, in melanoma, will help to highlight the characteristic single-cell pattern of growth or pagetoid upward migration MART1 (Melanoma Antigen Recognized by T cells): MART1 is one of the most important melanocytic markers [8] It is detected by two different antibodies (Melan-A and A-103) and is expressed by most melanocytic lesions, benign and malignant Therefore, it is very helpful in detecting melanocytic differentiation [9] Furthermore, the only melanocytic lesion that consistently lacks MART1 expression is spindle cell/desmoplastic melanoma Conversely, if anti-MART1 strongly and diffusely labels a spindle cell melanocytic lesion, desmoplastic melanoma is unlikely In addition to melanocytes, other cells may also express this marker In particular, steroidproducing tumors may react with A103 Also, and similar to gp100, angiomyolipoma, sugar cell tumor of lung, lymphangioleiomyomatosis, and “pecoma” consistently react with anti-MART1 [10] As a possible pitfall, since the antibody is so sensitive, the labeling of the cell processes of melanocytes in sun-exposed skin may give the appearance of more numerous-than-normal melanocytes, thus raising the consideration of melanoma in situ [11] To avoid this problem, when using anti-MART1 to evaluate the numbers of melanocytes in sun-damaged skin, we recommend counting nuclei of the cells labeled with the antibody rather than simply observing the “amount” of epidermis labeled As another pitfall, on occa- V.G Prieto et al sion, macrophages (particularly pigmented ones) are labeled with anti-MART1 [12] MIB1 (anti-Ki67): This is a proliferation marker expressed in the nuclei of non-G0, cycling cells Its pattern of expression, similar to that of gp100, helps highlight the presence or absence of “maturation” In general, benign melanocytic lesions display rare proliferating cells, which are located close to the epithelia (either epidermal or adnexal) In contrast, melanomas have a random pattern of immunoreactivity, with proliferating cells present even at the deep edge of the lesion In a study of 384 melanocytic lesions, there were significant differences in the amount and pattern of cell proliferation among various types of nevus and melanoma [13] Specifically, common nevi and dysplastic nevi exhibited reactivity in