Primary Epithelioid Angiosarcoma of the Penis With Aberrant Expression of Synaptophysin: A Case Report and Review of Diagnostic Pitfalls

Primary penile sarcomas are rare malignancies, accounting for less than 5% of penile cancers, with epithelioid angiosarcoma representing an exceptionally uncommon and aggressive subtype, documented in only about 30 cases worldwide. We report the case of a 59-year-old man who presented with an ulcerative lesion of the balanopreputial sulcus, initially presumed to be infectious or traumatic. Histopathological assessment following surgical excision revealed a poorly differentiated neoplasm initially suggestive of carcinoma. However, further expert pathological review and an extensive immunohistochemical panel identified a vascular neoplasm, with tumor cells expressing ERG, Fli-1, c-MYC, and focal CD31, alongside aberrant synaptophysin expression. The neoplasm lacked cytokeratins, additional neuroendocrine markers, and markers of melanocytic or myogenic differentiation. Molecular studies excluded hallmark translocations of other vascular or perivascular tumors but confirmed MYC gene amplification, supporting a definitive diagnosis of high-grade epithelioid angiosarcoma. This case highlights the diagnostic complexity of rare penile tumors and emphasizes the critical role of integrated histopathological, immunophenotypic, and molecular analyses in distinguishing aggressive vascular malignancies from their mimics.