New and evolving concepts of melanocytic nevi and melanocytomas


In daily clinical practice melanocytic nevi are commonly encountered. Traditionally, both benign and malignant melanocytic tumors have been sub-classified by their histopathologic characteristics with differing criteria for malignancy applied to each group. Recently, many of the mutations that initiate nevus formation have been identified and specific sets of mutations are found in different subtypes of nevi. Whereas a single mutation appears sufficient to initiate a nevus, but is not enough to result in melanoma, specific combinations of mutations have been identified in some melanocytic tumors that are regarded to be of low biologic potential. The term “melanocytoma” has recently been proposed by the World Health Organization to describe those tumors that demonstrate genetic progression beyond the single mutations that are found in nevi but are not frankly malignant. Melanocytomas occupy intermediate genetic stages between nevus and melanoma and likely have an increased risk of malignant transformation as compared to nevi. This review provides an update on the broad spectrum of melanocytic nevi and melanocytomas and outlines their key histopathologic and genetic features.

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  1. 1.

    Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19–20.

  2. 2.

    Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599–602.

  3. 3.

    Yeh I, von Deimling A, Bastian BC. Clonal BRAF mutations in melanocytic nevi and initiating role of BRAF in melanocytic neoplasia. J Natl Cancer Inst. 2013;105:917–9.

  4. 4.

    Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191–9.

  5. 5.

    Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014;5:3116.

  6. 6.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

  7. 7.

    Bataille V, Kato BS, Falchi M, et al. Nevus size and number are associated with telomere length and represent potential markers of a decreased senescence in vivo. Cancer Epidemiol Biomark Prev. 2007;16:1499–502.

  8. 8.

    Duffy DL, Zhu G, Li X, et al. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. Nat Commun. 2018;9:4774.

  9. 9.

    Wachsmuth RC, Turner F, Barrett JH, et al. The effect of sun exposure in determining nevus density in UK adolescent twins. J Invest Dermatol. 2005;124:56–62.

  10. 10.

    Newton-Bishop JA, Chang Y-M, Iles MM, et al. Melanocytic nevi, nevus genes, and melanoma risk in a large case-control study in the United Kingdom. Cancer Epidemiol Biomark Prev. 2010;19:2043–54.

  11. 11.

    Li W-Q, Cho E, Weinstock MA, et al. Cutaneous nevi and risk of melanoma death in women and men: a prospective study. J Am Acad Dermatol. 2019;80:1284–91.

  12. 12.

    Massi G, LeBoit PE. Histological diagnosis of nevi and melanoma. Berlin, Heidelberg: Springer; 2014.

  13. 13.

    Rongioletti F, Urso C, Batolo D, et al. Melanocytic nevi of the breast: a histologic case-control study. J Cutan Pathol. 2004;31:137–40.

  14. 14.

    Rongioletti F, Ball RA, Marcus R, et al. Histopathological features of flexural melanocytic nevi: a study of 40 cases. J Cutan Pathol. 2000;27:215–7.

  15. 15.

    Fabrizi G, Pagliarello C, Parente P, et al. Atypical nevi of the scalp in adolescents. J Cutan Pathol. 2007;34:365–9.

  16. 16.

    Clark WH Jr., Hood AF, Tucker MA, et al. Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal-stromal interactions in the biology of neoplasia. Hum Pathol. 1998;29:S1–24.

  17. 17.

    Kerl H, Trau H, Ackerman AB. Differentiation of melanocytic nevi from malignant melanomas in palms, soles, and nail beds solely by signs in the cornified layer of the epidermis. Am J Dermatopathol. 1984;6(Suppl:):159–60.

  18. 18.

    Boyd AS, Rapini RP. Acral melanocytic neoplasms: a histologic analysis of 158 lesions. J Am Acad Dermatol. 1994;31:740–5.

  19. 19.

    Requena C, Requena L, Kutzner H, et al. Spitz nevus: a clinicopathological study of 349 cases. Am J Dermatopathol 2009;31:107–16.

  20. 20.

    Herreid PA, Shapiro PE. Age distribution of spitz nevus vs. malignant melanoma. Arch Dermatol. 1996;132:352–3.

  21. 21.

    Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz’s nevus). Arch Dermatol. 1978;114:1811–23.

  22. 22.

    Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults. A review of 211 cases of the spitz nevus. Cancer. 1977;40:217–25.

  23. 23.

    Spitz S. Melanomas of childhood. Am J Pathol. 1948;24:591–609.

  24. 24.

    Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol. 2000;157:967–72.

  25. 25.

    Botton T, Yeh I, Nelson T, et al. Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell Melanoma Res. 2013;26:845–51.

  26. 26.

    Yeh I, Botton T, Talevich E, et al. Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun. 2015;6:7174.

  27. 27.

    Yeh I, Tee MK, Botton T, et al. NTRK3 kinase fusions in Spitz tumours. J Pathol. 2016;240:282–90.

  28. 28.

    VandenBoom T, Quan VL, Zhang B, et al. Genomic fusions in pigmented spindle cell nevus of reed. Am J Surg Pathol 2018;42:1042–51.

  29. 29.

    Quan VL, Zhang B, Mohan LS, et al. Activating structural alterations in MAPK genes are distinct genetic drivers in a unique subgroup of spitzoid neoplasms. Am J Surg Pathol 2019.

  30. 30.

    Newman S, Fan L, Pribnow A, et al. Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas. Nat Med 2019;25:597–602.

  31. 31.

    Busam KJ, Kutzner H, Cerroni L, et al. Clinical and pathologic findings of Spitz nevi and atypical Spitz tumors with ALK fusions. Am J Surg Pathol. 2014;38:925–33.

  32. 32.

    Yeh I, de la Fouchardiere A, Pissaloux D, et al. Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions. Am J Surg Pathol. 2015;39:581–91.

  33. 33.

    Amin SM, Haugh AM, Lee CY, et al. A comparison of morphologic and molecular features of BRAF, ALK, and NTRK1 fusion spitzoid neoplasms. Am J Surg Pathol. 2017;41:491–8.

  34. 34.

    Yeh I, Busam KJ, McCalmont TH, et al. Filigree-like rete ridges, lobulated nests, rosette-like structures, and exaggerated maturation characterize spitz tumors with NTRK1 fusion. Am J Surg Pathol. 2019;43:737–46.

  35. 35.

    Möller I, Murali R, Müller H, et al. Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi. Mod Pathol 2016.

  36. 36.

    Griewank KG, Müller H, Jackett LA, et al. SF3B1 and BAP1 mutations in blue nevus-like melanoma. Mod Pathol. 2017;30:928.

  37. 37.

    Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239–71.

  38. 38.

    Baykal C, Yılmaz Z, Sun GP, et al. The spectrum of benign dermal dendritic melanocytic proliferations. J Eur Acad Dermatol Venereol. 2019;33:1029–41.

  39. 39.

    Karvonen SL, Vaajalahti P, Marenk M, et al. Birthmarks in 4346 Finnish newborns. Acta Derm Venereol. 1992;72:55–7.

  40. 40.

    Castilla EE, da Graça Dutra M, Orioli-Parreiras IM. Epidemiology of congenital pigmented naevi: II. Risk factors. Br J Dermatol. 1981;104:421–7.

  41. 41.

    Krengel S, Scope A, Dusza SW, et al. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol. 2013;68:441–51.

  42. 42.

    Bauer J, Curtin JA, Pinkel D, et al. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127:179–82.

  43. 43.

    Salgado CM, Basu D, Nikiforova M, et al. BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi. Pediatr Dev Pathol. 2015;18:1–9.

  44. 44.

    Sarin KY, Sun BK, Bangs CD, et al. Activating hras mutation in agminated spitz nevi arising in a nevus spilus. JAMA Dermatol. 2013;149:1077–81.

  45. 45.

    Dessars B, De Raeve LE, El Housni H, et al. Chromosomal translocations as a mechanism of BRAF activation in two cases of large congenital melanocytic nevi. J Invest Dermatol. 2007;127:1468–70.

  46. 46.

    Martins da Silva V, Martinez-Barrios E, Tell-Martí G, et al. Genetic abnormalities in large to giant congenital nevi: beyond NRAS mutations. J Investig Dermatol 2018.

  47. 47.

    Baltres A, Salhi A, Houlier A, et al. Malignant melanoma with areas of rhabdomyosarcomatous differentiation arising in a giant congenital nevus with RAF1 gene fusion. Pigment Cell Melanoma Res 2019.

  48. 48.

    Radentz WH, Vogel P. Congenital common blue nevus. Arch Dermatol. 1990;126:124–5.

  49. 49.

    Kawasaki T, Tsuboi R, Ueki R, et al. Congenital giant common blue nevus. J Am Acad Dermatol. 1993;28:653–4.

  50. 50.

    Busam KJ, Lohmann CM. Congenital pauci-melanotic cellular blue nevus. J Cutan Pathol. 2004;31:312–7.

  51. 51.

    Lee MY, Jin S, Lee K-H, et al. A cellular blue nevus with pigmented epithelioid melanocytoma-like pattern on the ipsilateral upper arm associated with a congenital plaque-type blue nevus on the hand. J Cutan Pathol. 2019;46:383–8.

  52. 52.

    Findler G, Hoffman HJ, Thomson HG, et al. Giant nevus of the scalp associated with intracranial pigmentation. Case report. J Neurosurg. 1981;54:108–12.

  53. 53.

    Marano SR, Brooks RA, Spetzler RF, et al. Giant congenital cellular blue nevus of the scalp of a newborn with an underlying skull defect and invasion of the dura mater. Neurosurgery. 1986;18:85–9.

  54. 54.

    Madaree A, Ramdial PK, Du Trevou M. Giant congenital naevus of the scalp and cranium: case report and review of the literature. Br J Plast Surg. 1997;50:20–5.

  55. 55.

    Micali G, Innocenzi D, Nasca MR. Cellular blue nevus of the scalp infiltrating the underlying bone: case report and review. Pediatr Dermatol. 1997;14:199–203.

  56. 56.

    Kurokawa R, Kim P, Kawamoto T, et al. Intramedullary and retroperitoneal melanocytic tumor associated with congenital blue nevus and nevus flammeus: an uncommon combination of neurocutaneous melanosis and phacomatosis pigmentovascularis-case report. Neurol Med Chir. 2013;53:730–4.

  57. 57.

    Küsters-Vandevelde HVN, van Engen-van Grunsven IACH, Coupland SE, et al. Mutations in g protein encoding genes and chromosomal alterations in primary leptomeningeal melanocytic neoplasms. Pathol Oncol Res. 2015;21:439–47.

  58. 58.

    Thomas AC, Zeng Z, Rivière J-B, et al. Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis. J Investig Dermatol. 2016;136:770–8.

  59. 59.

    Kumar A, Zastrow DB, Kravets EJ, et al. Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: case series and literature review. Am J Med Genet Part A. 2019;179:966–77.

  60. 60.

    Shirley MD, Tang H, Gallione CJ, et al. Sturge–Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368:1971–9.

  61. 61.

    Groesser L, Peterhof E, Evert M, et al. BRAF and RAS mutations in sporadic and secondary pyogenic granuloma. J Invest Dermatol. 2016;136:481–6.

  62. 62.

    Liau J-Y, Lee J-C, Tsai J-H, et al. High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms. Mod Pathol 2019.

  63. 63.

    Elder DE, Massi D, Scolyer R, et al. WHO classification of skin tumours. 4th ed. Lyon, France: IARC Press; 2018.

  64. 64.

    Zembowicz A, Carney JA, Mihm MC. Pigmented epithelioid melanocytoma: a low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol. 2004;28:31–40.

  65. 65.

    Zembowicz A, Knoepp SM, Bei T, et al. Loss of expression of protein kinase a regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol. 2007;31:1764–75.

  66. 66.

    Mandal RV, Murali R, Lundquist KF, et al. Pigmented epithelioid melanocytoma: favorable outcome after 5-year follow-up. Am J Surg Pathol. 2009;33:1778–82.

  67. 67.

    Cohen JN, Joseph NM, North JP, et al. Genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in PRKAR1A, and PRKCA genes. Am J Surg Pathol. 2017;41:1333–46.

  68. 68.

    Isales MC, Mohan LS, Quan VL, et al. Distinct genomic patterns in pigmented epithelioid melanocytoma: a molecular and histologic analysis of 16 cases. Am J Surg Pathol. 2019;43:480–8.

  69. 69.

    Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26:89–92.

  70. 70.

    Seab JA, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol. 1989;13:39–44.

  71. 71.

    Yeh I, Lang UE, Durieux E, et al. Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi. Nat Commun. 2017;8:644.

  72. 72.

    High WA, Alanen KW, Golitz LE. Is melanocytic nevus with focal atypical epithelioid components (clonal nevus) a superficial variant of deep penetrating nevus? J Am Acad Dermatol. 2006;55:460–6.

  73. 73.

    Dadras SS, Lu J, Zembowicz A, et al. Histological features and outcome of inverted type-A melanocytic nevi. J Cutan Pathol 2018.

  74. 74.

    Cerroni L, Barnhill R, Elder D, et al. Melanocytic tumors of uncertain malignant potential. Am J Surg Pathol. 2010;34:314–26.

  75. 75.

    Wiesner T, Obenauf AC, Murali R, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–21.

  76. 76.

    Busam KJ, Sung J, Wiesner T, et al. Combined BRAF(V600E)-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. Am J Surg Pathol. 2013;37:193–9.

  77. 77.

    Yeh I, Mully TW, Wiesner T, et al. Ambiguous melanocytic tumors with loss of 3p21. Am J Surg Pathol. 2014;38:1088–95.

  78. 78.

    Wiesner T, Murali R, Fried I, et al. A distinct subset of atypical spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012;36:818–30.

  79. 79.

    Abdel-Rahman MH, Pilarski R, Cebulla CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 2011.

  80. 80.

    Carbone M, Yang H, Pass HI, et al. BAP1 and cancer. Nat Rev Cancer. 2013;13:153–9.

  81. 81.

    Popova T, Hebert L, Jacquemin V, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 2013.

  82. 82.

    Harvell JD, Meehan SA, LeBoit PE. Spitz’s nevi with halo reaction: a histopathologic study of 17 cases. J Cutan Pathol. 1997;24:611–9.

  83. 83.

    Requena C, Sanz V, Nagore E, et al. BAP1-deficient and VE1-negative atypical Spitz tumor. J Cutan Pathol. 2015;42:564–7.

  84. 84.

    Busam KJ, Murali R, Pulitzer M, et al. Atypical spitzoid melanocytic tumors with positive sentinel lymph nodes in children and teenagers, and comparison with histologically unambiguous and lethal melanomas. Am J Surg Pathol. 2009;33:1386–95.

  85. 85.

    Duncan LM. Atypical Spitz tumours and sentinel lymph nodes. Lancet Oncol. 2014;15:377–8.

  86. 86.

    Fullen DR, Poynter JN, Lowe L, et al. BRAF and NRAS mutations in spitzoid melanocytic lesions. Mod Pathol. 2006;19:1324–32.

  87. 87.

    Da Forno PD, Pringle JH, Fletcher A, et al. BRAF, NRAS and HRAS mutations in spitzoid tumours and their possible pathogenetic significance. Br J Dermatol. 2009;161:364–72.

  88. 88.

    Lazova R, Pornputtapong N, Halaban R, et al. Spitz nevi and Spitzoid melanomas: exome sequencing and comparison with conventional melanocytic nevi and melanomas. Mod Pathol 2017.

  89. 89.

    Gerami P, Scolyer RA, Xu X, et al. Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations. Am J Surg Pathol. 2013;37:676–84.

  90. 90.

    Lee S, Barnhill RL, Dummer R, et al. TERT promoter mutations are predictive of aggressive clinical behavior in patients with spitzoid melanocytic neoplasms. Sci Rep. 2015;5:11200.

  91. 91.

    Gerami P, Cooper C, Bajaj S, et al. Outcomes of atypical spitz tumors with chromosomal copy number aberrations and conventional melanomas in children. Am J Surg Pathol. 2013;37:1387–94.

  92. 92.

    Shain AH, Yeh I, Kovalyshyn I, et al. The genetic evolution of melanoma from precursor lesions. New Engl J Med. 2015;373:1926–36.

  93. 93.

    Kinsler VA, O’Hare P, Bulstrode N, et al. Melanoma in congenital melanocytic naevi. Br J Dermatol. 2017;176:1131–43.

  94. 94.

    Bastian BC, Xiong J, Frieden IJ, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol. 2002;161:1163–9.

  95. 95.

    Murphy MJ, Jen M, Chang MW, et al. Molecular diagnosis of a benign proliferative nodule developing in a congenital melanocytic nevus in a 3-month-old infant. J Am Acad Dermatol. 2008;59:518–23.

  96. 96.

    Rocas D, Castillo C, Lamarca S, et al. Unpigmented nodule with loss of BAP1 expression in a medium-sized congenital nevus. Eur J Dermatol. 2015;25:201–2.

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I am very grateful to my many generous colleagues and mentors over the years. My work with Dr. Boris Bastian has greatly informed my view of the genetics of melanocytic tumors. Dr. Philip LeBoit provided micrographs. Thank you to Dr. Richard Jordan for careful reading of the manuscript and helpful suggestions. This work was supported by the National Cancer Institute at the National Institutes of Health (grant number 1R35CA220481).

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Correspondence to Iwei Yeh.

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Yeh, I. New and evolving concepts of melanocytic nevi and melanocytomas. Mod Pathol 33, 1–14 (2020).

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