Abstract

BAP-1 (BRCA1-associated protein 1) inactivated melanocytic tumors are a group of familial or sporadic lesions with distinctive histology and molecular features. Inherited germline inactivating mutations in BAP1 has been associated with the development of multiple epithelioid melanocytic neoplasms resembling Spitz nevi and increased susceptibility for developing several malignancies, including uveal melanoma, cutaneous melanoma, renal cell carcinoma, mesothelioma, and other tumors. Cutaneous melanoma with loss of BAP1 expression is rare. We present a case of BAP1-inactivated melanoma with ALK fusion arising in a pre-existing BAP1-inactivated nevus in a 47-year-old female patient who presented with a dome shaped red papule on superior crus of right antihelix. Histology revealed intradermal melanocytic proliferation with bi-phenotypic morphology. There was proliferation of atypical melanocytes showing epithelioid and Spitzoid features in the background of nevus. Mitotic figures were identified in the cytologically atypical component of the lesion. Mart-1/Ki67 dual stain demonstrated higher proliferative index in the larger epithelioid atypical cells. Nuclear BAP-1 expression was lost in the larger atypical cells, as well as associated nevoid cells. PRAME stain demonstrated focal positive staining in 20-30% of the melanocytes. Interphase FISH study for melanoma was positive with extra copies of 6p25 (RREB1). The comprehensive next-generation sequencing revealed BRAF V600E mutation, TP53 mutation, ALK fusion, BAP1 loss (CNV=0.0, potentially germline) and loss of MAP2K7, VHL, FGFR3, CDKN2A, 19q and TERT. The tumor was microsatellite stable with low tumor mutational burden (5.76 mutations/Mb). The tumor was completely excised with negative margins. The patient is well on follow up with no recurrence.

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