Malignant MITF-Rearranged PEComa With Novel EEF1A1::MITF Fusion

MITF-rearranged PEComas are rare, and their relationship to MITF-altered melanocytic tumors remains incompletely characterized. We report a malignant superficial soft tissue neoplasm of the thigh in a 45-year-old woman harboring a novel EEF1A1::MITF fusion. The tumor was composed of epithelioid to plump spindle cells arranged in sheets, nests, and short fascicles with prominent capillary vasculature. Significant cytologic atypia, brisk mitotic activity, and necrosis were present. The tumor cells showed diffuse strong nuclear MITF and diffuse GPNMB expression, with patchy SMA, scattered desmin, and multifocal cathepsin K positivity, while S100, SOX10, HMB45, Melan A, PRAME, tyrosinase, pancytokeratin, CD34, and TFE3 were negative. Although atypical for classic PEComa, this immunophenotype resembles that described in MITF-overexpressing PEComas. Molecular studies identified an ATRX frameshift mutation, homozygous CDKN2A/CDKN2B deletion, complex copy number alterations, and an in-frame EEF1A1::MITF fusion. No canonical TSC1, TSC2, or FLCN alteration was identified. These findings expand the molecular spectrum of PEComa and support the emerging concept that a subset of cutaneous PEComas may be driven by MITF rearrangements.