Introduction: Prostatic acinar adenocarcinoma is defined by loss of the basal cell marker p63, a feature routinely used to distinguish malignant glands from benign mimickers. Rarely, prostate carcinomas demonstrate aberrant nuclear p63 expression, representing a diagnostically challenging subtype reported in less than 1% of cases. Most described tumors exhibit lower Gleason grades and relatively indolent clinical behavior. We report a rare case of high-grade prostatic adenocarcinoma with aberrant p63 expression and aggressive clinical course. Case Description: A 77-year-old Filipino male presented with worsening hematuria and fever. PET-CT demonstrated multifocal Prostate-Specific Membrane Antigen (PSMA)-avid lesions in the left prostate with enlargement, irregular contour, intravesical extension, and PSMA-avid retroperitoneal and iliac lymph nodes suggestive of metastatic disease. The patient had a prior diagnosis of prostatic adenocarcinoma (Gleason 4+5=9) in 2022 and had been treated with androgen-targeted therapy. Due to persistent symptoms, transurethral resection was performed. Histology revealed complete effacement of prostatic architecture by malignant cells arranged in sheets with enlarged vesicular nuclei, prominent nucleoli, and frequent mitoses. Immunostaining showed diffuse CK, CAM5.2, and PSA positivity with aberrant patchy nuclear p63 expression and a Ki-67 index of 60%. Lymphoid, urothelial, and neuroendocrine markers were negative. The tumor was diagnosed as prostatic adenocarcinoma, Gleason score 5+5=10, with aberrant nuclear p63 expression. Discussion: Aberrant p63-positive prostatic adenocarcinoma is a rare molecular subtype characterized by a mixed basal–luminal immunophenotype. Most reported cases demonstrate lower Gleason scores and organ-confined disease with relatively favorable outcomes. In contrast, our case exhibited an exceptionally high Gleason score with radiologic evidence of metastasis and rapid clinical deterioration, suggesting a broader and potentially more aggressive spectrum of behavior. Conclusion Recognition of aberrant p63 expression is essential to avoid diagnostic misinterpretation. Despite ongoing therapy, the patient developed acute intracranial hemorrhage and ultimately succumbed to the disease. This case highlights an aggressive presentation of a rare immunophenotypic variant and underscores the importance of clinicopathologic correlation to better define its prognostic significance.
Adenocarcinoma