TFE3 -rearranged PEComa-like neoplasm harboring a novel ZBED6::TFE3 fusion with an unusual immunophenotype

OBJECTIVES: TFE3-rearranged perivascular epithelioid cell tumor (PEComa)-like neoplasm is a recently described entity. Here, we report a rare TFE3-rearranged PEComa-like neoplasm in a 37-year-old female patient exhibiting unusual morphologic and immunohistochemical features and a novel ZBED6::TFE3 fusion. METHODS: Histopathologic, immunohistochemical, and molecular studies, including fluorescence in situ hybridization, next-generation sequencing, reverse transcriptase-polymerase chain reaction and Sanger sequencing were performed to characterize the current case. RESULTS: Morphologically, the lesion showed a mixture of spindled to ovoid cells arranged in interlacing fascicles. Tumor cells displayed eosinophilic to clear cytoplasm; spindled to ovoid nuclei with moderate atypia and mitotic figures were rare. The stroma was highly vascularized, with focal myxoid changes. The tumor displayed TFE3 positivity, focal SMA expression, and melanotic marker negativity. Fluorescence in situ hybridization detected TFE3 gene rearrangement, and next-generation sequencing identified a novel ZBED6::TFE3 fusion, further confirmed by reverse transcriptase-polymerase chain reaction and Sanger sequencing. CONCLUSIONS: Based on a literature search of PubMed using the terms "PEComa", "PEComa-like", and "TFE3", this is the first case of a TFE3-rearranged PEComa-like neoplasm with ZBED6::TFE3 fusion, along with unusual morphologic and immunohistochemical phenotypes. The identification of the current case further expands the pathologic and genetic spectrum of this rare entity, highlighting the importance of integrating morphologic, immunohistochemical, and molecular findings in such cases.