Histology and immunohistochemistry of clear cell adenocarcinoma of the urethra: histogenesis and diagnostic problems

Clear cell adenocarcinoma (CCAC) of the urethra is a rare neoplasm, morphologically identical to its homologue arising in the female genital tract. The histogenesis of this neoplasm is uncertain. We present clinical, histopathologic, and immunohistochemical findings of four CCAC of the urethra and discuss the histogenesis and difficulties in diagnosis and differential diagnosis. CCAC of the urethra occurred in females (4/4). Two neoplasms were identified in urethral diverticulum; one of the two cases, in close proximity to a nephrogenic adenoma. CCAC exhibited tubulocystic, papillary, and diffuse/solid growth patterns. The neoplastic cells were cuboidal or columnar with eosinophilic or clear cytoplasm, and nuclear pleomorphism of at least moderate degree. Hobnail features and tumor necrosis were also observed. CCAC expressed p53 (4/4), AMACR (3/4), vimentin (3/4), PAX8 (2/4), CK7 (2/4), cytokeratin 34betaE12 (2/4), RCC (1/4), and CK20 (1/4) and were negative for PSA, WT1, ER, CA 125, uroplakin III, p16, and p63. The immunohistochemical profile supports a possible renal tubular cell differentiation/mesonephric origin for some urethral CCAC. Nephrogenic adenoma and metastatic clear cell carcinoma are the most important differential diagnostic considerations. Multicenter studies on more cases may improve our understanding of this malignancy.