Nephrogenic adenoma, thought to be a benign metaplastic response of the urothelium to injury, can rarely affect the prostatic urethra. Extension of small tubules of nephrogenic adenoma into the underlying prostatic fibromuscular stroma can lead to the misdiagnosis of prostatic adenocarcinoma in transurethral resection specimens and prostate biopsies. We reviewed 26 cases of nephrogenic adenoma involving the prostatic urethra, seen at The Johns Hopkins Hospital from 1990 to 1998, to evaluate the histologic features, which may better define this lesion. Immunohistochemical results were evaluated for cases where the lesion was present on deeper sections. Histologic patterns included the following: tubules in 96% (25 of 26), structures resembling vessels in 73% (19 of 26), cords and individual cells in 46% (12 of 26), papillary configurations in 19% (5 of 26), and signet ring cell-like tubules in 12% (3 of 26). Other features of nephrogenic adenoma, such as thyroidization, were identified in 38% (10 of 26), and peritubular sheaths were seen in 65% (17 of 26) of cases. Nucleoli were prominent in 54% (14 of 26), and no case had mitoses. In the region of nephrogenic adenoma, urothelium was noted in 69% (18 of 26); in 61% (11 of 18) it showed cuboidal metaplasia and 28% (5 of 18) showed squamous metaplasia. Extension of nephrogenic adenoma into muscle was observed in 77% (20 of 26) of cases, 75% (15 of 20) of which had identifiable urothelium overlying the lesion. Blue-tinged mucinous secretions were observed in 32% (8 of 25) of cases. Inflammation was found in all but one case. Nephrogenic adenomas were diffusely positive for 34betaE12 in 11% (1 of 9) of cases, focally positive in 44% (4 of 9), and negative in 44% (4 of 9). In 100% (9 of 9), cytokeratin 7 stains were positive. Focal prostate specific antigen and PSAP positivity were seen in 36% (4 of 11) and 50% (5 of 10) of nephrogenic adenoma cases, respectively. In conclusion, nephrogenic adenoma of the prostatic urethra can mimic prostate cancer because of: 1) the presence of tubules, cords, and signet ring-like tubules; 2) prominent nucleoli; 3) muscle involvement; 4) blue-tinged mucinous secretions; 5) focal prostate specific antigen and PSAP positivity; and 6) negative staining in some cases for 34betaE12. Features useful in the diagnosis of nephrogenic adenoma include the following: 1) distinctive nephrogenic patterns, such as papillary and "vascular," 2) adjacent urothelium, 3) thyroidization, 4) peritubular sheaths, 5) associated inflammation, and 6) positivity for cytokeratin 7 and, in some cases, 34betaE12.