Answer: Nephrogenic adenoma

Histology: The lesion is located in the prostatic urethra. It has a variable histology (image 1). There is a proliferation of small solid to hollow tubules, lined by low columnar to cuboidal epithelial cells with eosinophilic cytoplasm (image 2). In addition, there are vascular-like structures with attenuated epithelium, with or without hobnail nuclei (image 3). Atypical nuclei were seen in cells with an endothelial or hobnail appearance lining vascular-like dilated tubules (image 4), yet unaccompanied by mitotic figures. The lesion also had papillary structures lined by cuboidal epithelium. Tubules focally extended into the underlying prostatic smooth muscle.

Discussion: Nephrogenic adenomas usually arise in the setting of prior urothelial injury, such as past surgery (60%), calculi (14%), or trauma (9%). Eight percent have a history of renal transplantation. There are several lines of support that nephrogenic adenomas arising from shed renal tubular cells, including positivity for PAX2, a transcription factor expressed during renal development. Nephrogenic adenomas have a broad histologic spectrum. Proliferations of small solid to hollow tubules, lined by low columnar to cuboidal epithelial cells with eosinophilic cytoplasm, are identified in the majority of cases. Vascular-like structures with attenuated epithelium, with or without hobnail nuclei, are the second most common pattern. Verification that these vascular-like structures are epithelial can be accomplished with immunohistochemistry for cytokeratin, which can help establish the correct diagnosis. Papillary configurations and signet-ring cell-like structures (small tubules cut tangentially) are identified in a decreasing percent of cases. A distinguishing feature of nephrogenic adenoma not prominent in the current case is the presence of a thickened hyaline sheath around some of the tubules.

Nuclear atypia, when present, appears degenerative and mitoses are either absent or rare. Nuclei are enlarged and hyperchromatic, yet have a smudged indistinct chromatin pattern. These atypical nuclei often reside in cells with an endothelial or hobnail appearance lining vascular-like dilated tubules. The presence of prominent nucleoli in many cases examined is also a source of possible confusion with prostate cancer. However, prominent nucleoli are usually only focally present within a lesion, and often seen in association with degenerative nuclear atypia or with other features not commonly seen in prostate cancer, such as hobnail-like cells or peritubular hyaline sheaths. Cystic tubules may contain thyroid-like eosinophilic secretions.

We have found that a majority of cases of nephrogenic adenoma arising from the prostatic urethra have some degree of muscle involvement, and in conjunction with a tubule or cord-like architectural pattern, is the most likely source of confusion with prostate cancer. Features helpful to distinguish these cases of nephrogenic adenoma from prostate cancer include the presence of more typical nephrogenic adenoma architectural patterns in other areas of the lesion and that the lesion is located immediately below the urothelial lining, a site unusual for prostate cancer. Clear cell adenocarcinomas almost exclusively occur in females. Tubules and papillae are generally lined by flat, cuboidal, or rarely columnar cells. Sheet-like growth and cystic architecture may also be present. Clear cells, absent in nephrogenic adenoma, are abundant in most tumors although virtually all tumors also have cells with abundant eosinophilic cytoplasm as well. Hobnail cells are present in most tumors but are conspicuous in the minority. Nuclear atypia is moderate-to-severe although rare cases with bland cytology have been described. Mitotic activity, virtually absent in nephrogenic adenoma, is present but may be quite variable. Necrosis also lacking in nephrogenic adenoma may be evident in clear cell adenocarcinoma. Clear cell adenocarcinomas are usually high-grade, infiltrating carcinomas with frequent mitoses, nuclear pleomorphism, and areas of solid growth, all of which is absent in nephrogenic adenoma. However, in a limited biopsy it may be very difficult to distinguish the two lesions.

Reference(s):
– Allen CH, Epstein JI. Nephrogenic adenoma of the prostatic urethra: a mimicker of prostate adenocarcinoma. Am J Surg Pathol 25: 802-808, 2001.
– Herawi M, Drew PA, Pan CC, Epstein JI. Clear cell adenocarcinoma of the bladder and urethra: Cases diffusely mimicking nephrogenic adenoma. Hum Pathol (April) 41:594-01, 2010.