Nephrogenic adenoma (NA) is an uncommon benign lesion of the urothelial mucosa of the urinary tract (1,2). In 1949, Davis reported the first identified case of NA as a ‘hamartoma of the urinary bladder’ (3). In 1950, Fiedman and Kuhlenbeck named this lesion ‘nephrogenic adenoma’ based on its histological similarity to renal tubules (4). It has been reported that NA mainly arises in the urinary bladder (68.6%) and urethra (13.3%), but also in the ureter (8.2%), renal pelvis (8.2%) and, rarely, in the prostate (2%) (5). NAs exhibit a male predominance, with a male:female ratio of ~3.6:1. When NA occurs in the female urethra, approximately one-fourth of the cases are associated with a urethral diverticulum (6,7).

From a study including 134 cases of NA, Lopez reported that the mean age of NA patients was 66 years, with a range of 14–96 years (5). Furthermore, Husainet al reported 18 cases of NA in pediatric patients, ranging in age from 2 to 19 years (8), whereas Kaoet al reported 21 cases of pediatric NAs, with an age range of 2–16 years (9). The usual clinical presentation is hematuria, dysuria and frequency of micturition (10). Several predisposing factors have been reported to be associated with NA, in adults as well as in children, including genitourinary trauma, chronic inflammation, prior surgery, renal calculi, repeated instrumentation, irritated anatomical anomalies and pelvic irradiation, bacillus Calmette-Guérin (BCG) immunotherapy and diverticuli (1,8,9,11,12).

We herein present 3 cases of NA arising in the urinary bladder of elderly male patients.

Lopezet al analyzed 134 cases of NA with a mean patient age of 66 years, suggesting that elderly individuals appear to be more prone to development of NA (5). However, the studies of Husain et al and Kao et al involved pediatric cases of NA (8,9). Several predisposing factors have been reported to be associated with NA, in adults as well as in children (1,8,9,11,12). Our patients had also undergone various treatments prior to the development of the NAs; 1 patient was subjected to TUL due to a ureteral stone and TUR-P due to BPH; 1 patient had received TUR due to urothelial carcinoma in the urinary bladder; and the third patient had received TUR due to urothelial carcinoma in the urinary bladder, followed by treatment with BCG. Regarding the mechanisms underlying the origin of NA, it has been reported that the NAs arising in female recipients of renal transplantations from male donors display a male chromosomal status onin situ hybridization, while NAs arising in the male recipients of renal transplantations from female donors display a female chromosomal status (13). However, the stromal components of NA exhibit the sex chromosome status of the recipients. These results suggest that epithelial cells in NA are derived from the renal tubules, such that the detached epithelial cells in the renal tubules are able to become engrafted in the injured urinary tract, from which the urothelial epithelium has disappeared.

It has been reported that the epithelial cells of NA are similar to those of renal tubules and that the epithelial cells of NA express PAX2, PAX8 and CK7, but not p63 or PSA (2). The expression pattern of antigens is similar to that of renal tubules. These results also support the theory of NAs originating from the renal tubules. All our patients also exhibited the same patterns of expression of these antigens.

It has also been reported that NA occasionally mimics prostatic adenocarcinoma, due to the pseudoinvasive pattern of small tubules lacking a basal cell layer (14,15). Kunju presented an image of an NA in the superficial muscle layer of the urinary bladder (15). In our case 3, the NA was found in the interstitial tissue in the urinary bladder. Based on the theory that NA originates in the renal tubules, it is suggested that epithelial cells from the renal tubules become embedded in the urothelial tract wall followed by restoration of the structure of the wall. During the restoration process, the epithelial cells of the renal tubules may become implanted into the urothelial tract wall, even as deep as the muscle layer.

In the present study, we presented 3 cases of NA in elderly male patients with predisposing factors. Since NAs are benign lesions, it is important to make a definitive differential diagnosis of NAs based on their morphology, immunohistochemistry and the patient's history, particularly in cases with any predisposing factors.

The patients or their families provided informed consent for the publication of the case details, and the ethics committee of Toyooka Hospital approved the publication of this study.