Abstract 3671: A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression

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Abstract We recently reported that germline mutations in BAP1 cause a familial tumor syndrome characterized by high penetrance for melanocytic tumors with distinctive clinical and histologic features. Melanocytic neoplasms in affected individuals harbored BRAF mutations, showed loss of BAP1 expression, and histologically resembled so-called “atypical Spitz tumors” (ASTs). ASTs are an ill-defined and probably heterogenous group of melanocytic tumors that display histologic features seen in both Spitz nevi and melanomas. Their biologic behavior cannot be reliably predicted. Based on the histologic similarities of the familial tumors and ASTs, we hypothesized that a subset of ASTs might harbor genetic alterations seen in the familial tumors. To address this hypothesis, we analyzed 32 sporadic ASTs for BRAF mutations, and for BAP1 expression. To determine the utility of immunohistochemistry to assess BAP1 status, we analyzed samples from 42 patients with the above syndrome as well as 46 melanocytic nevi and found that loss of BAP1 expression was restricted to patients with the syndrome. Nine (28%) sporadic ASTs showed loss of BAP1 expression, of which of 8 (89%) had concomitant BRAF mutations. Only one of the BAP1-positive ASTs (4%) had a BRAF mutation (p<0.0001). BRAF mutated, BAP1-negative tumors were primarily located in the dermis, and were composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and well-defined cytoplasmic borders. Nuclei were commonly vesicular, and exhibited substantial pleomorphism and conspicuous nucleoli. The combination of BRAF mutation and loss of nuclear BAP1 expression thus characterizes a subset of ASTs with distinctive histologic features. The typical morphology of these tumors and BAP1 immunohistochemistry provide pathologic clues that will enable accurate identification of this subset. Future studies are necessary to determine whether this subset has a predictable clinical behavior. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3671. doi:1538-7445.AM2012-3671