Androgen Receptor Positive EWSR1 :: FEV -Rearranged Prostatic Ewing Sarcoma Mimicking High-Grade Neuroendocrine Carcinoma

Ewing sarcoma (ES) is a rare aggressive neoplasm that is the second most common primary bone tumor of childhood and adolescence, with less frequent extraskeletal presentations. ES with EWSR1 :: FEV translocation is extremely rare and is characterized by extraskeletal location, varying morphology and immunophenotype, and an aggressive clinical course. We present a prostatic ES confirmed by EWSR1 :: FEV fusion, detailing its clinical presentation, histopathologic and immunophenotypic features, molecular profile, and management. A man in his mid-50s presented with urinary frequency and difficulty voiding. Imaging revealed a 4.4 cm prostatic mass with bladder invasion and right iliac lymphadenopathy. Serum PSA was within normal limits. Biopsy demonstrated a poorly differentiated epithelioid neoplasm with neuroendocrine features. Immunohistochemistry showed strong expression of keratins AE1/3 and CAM5.2, chromogranin, synaptophysin, NKX2.2, and CD99 (weak), while PSA was negative. NKX3.1 was focally positive in rare tumor cells and Ki67 was approximately 35%. Perineural invasion and intraductal spread were noted. The tumor was initially interpreted as poorly differentiated carcinoma with neuroendocrine features. The patient underwent radical prostatectomy, revealing a 5.5 cm tumor with perineural and lymphovascular invasion, and nodal metastasis. Next-generation sequencing confirmed an EWSR1 :: FEV fusion, establishing the diagnosis of ES. Immunostain for androgen receptor was strongly and diffusely positive in the primary tumor and in the nodal metastasis, which together with focal staining for NKX3.1 were suggestive of primary prostatic origin and invited consideration of androgen deprivation therapy. This report highlights a rare prostatic Ewing-family sarcoma harboring an EWSR1 :: FEV fusion and immunophenotypic features that mimic a neuroendocrine carcinoma.