Morphologic and Molecular Differences of BAP1 Melanocytomas and BAP1 Inactivated Melanomas

BAP1 inactivated melanocytomas are considered intermediate grade melanocytic tumors. They may have overlapping morphologic features with melanoma. Nuclear atypia, expansile growth, and mitotic activity often raise concern for the possibility of melanoma. However, there is limited information in the literature on outcomes-based diagnostic criteria that may be useful for the distinction of BAP1 inactivated melanocytomas from BAP1 inactivated melanomas. Herein, we present a series of 20 BAP1 inactivated melanomas with clinical follow-up (n = 17) and compare the genomic and morphologic features with 23 BAP1 inactivated melanocytomas. In this series, only BAP1 inactivated melanomas had ulceration, tumor necrosis, invasion of the subcutis, and mitotic activity ≥4/mm2. BAP1 inactivated melanomas had more pathogenic variants on average than BAP1 inactivated melanocytomas (6.6 vs. 2.4, P = 0.0001) and a higher TMB (31.2 m/Mb vs. 7.8 m/Mb, P = 0.0071). Pathogenic variants in TERT-promoter, CDKN2A, CDK4, MYC, the SWI/SNF complex, and the PI3K-AKT pathway were only seen in BAP1 inactivated melanomas. Because BAP1 inactivated melanomas are uncommon compared with BAP1 inactivated melanocytomas, useful diagnostic criteria must have very high specificity and be rare to absent in BAP1 inactivated melanocytomas. In this study, we identified morphologic and molecular features that were strongly associated with BAP1 inactivated melanomas but not seen in BAP1 inactivated melanocytomas. Our findings may be helpful for the diagnostic assessment of challenging melanocytic tumors with BAP1 inactivation.