Cystoscopy examination of this patient showed erythematous areas as well as an irregular papillary mass on the lateral wall of the bladder. Multiple urine cytology specimens collected over a one-year period showed atypical urothelial cells and corresponding biopsies showed polypoid cystitis and nephrogenic adenoma.

The current urine was collected as a routine follow-up and was diagnosed as positive for high-grade urothelial carcinoma (HGUC). There were clusters of urothelial cells which met the Paris system criteria for HGUC including: cellularity (at least 5-10 abnormal cells), N/C ratio >0.7, moderate to severe hyperchromasia, coarse chromatin, and irregular nuclear membrane (Pre-test image 1); other features such as cellular pleomorphism and prominent nucleoli were also noted in a subset of cells (Pre-test image 5). Interestingly, there were also clusters of cells with uniform, evenly spaced nuclei and finely granular chromatin which were consistent with benign urothelial tissue fragments (likely representing nephrogenic adenoma) as well as clusters of atypical urothelial cells with N/C ratio >0.5, mild nuclear contour irregularity, and prominent chromocenters which did not quite make the criteria for suspicious or positive for malignancy categories (Pre-test images 2-4). Follow-up examination and multiple biopsies of the prostatic urethra and bladder showed carcinoma in situ (Post-test image 1) and nephrogenic adenoma (Post-test image 2).

Nephrogenic adenoma is a benign lesion which may appear as papillary, polypoid, flat, or velvety lesions. It is frequently seen in renal transplant patients, and many are secondary to urothelial injury. It may be seen in association with carcinoma, intravesical therapy, instrumentation, repeated urinary tract infections, and calculi. An association with smoking history has also been reported. Although few studies have reported malignant transformation, a significant malignant potential is not established.

This case highlights the morphologic overlap and diagnostic challenges seen in mass-forming lesions of post-treatment patients. Nephrogenic adenoma can mimic urothelial carcinoma both on cystoscopy and on cytologic examination. It can also be seen concurrently with urothelial carcinoma in similar clinical context. Furthermore, this case highlights the clinical significance of a positive cytology diagnosis. Accurate diagnosis of malignant urothelial cells on cytology will prompt an active investigation to identify the source of the positive cells. In this case, careful examination of the bladder, upper urinary tract, and prostatic urethra led to the detection of carcinoma in situ. In a multivariate analysis (including tumor grade, tumor location, presence of lymphatic invasion, positive urine cytology, and postoperative systemic chemotherapy) in patients with upper urinary tract urothelial carcinoma, positive urine cytology was reported as an independent risk factor for tumor recurrence.

The management of atypical urothelial cells in comparison presents a diagnostic dilemma for the urologists. In the context of multiple previous biopsies consistent with nephrogenic adenoma, an atypical diagnosis in this case may have been attributed to known benign inflammatory lesions and not have prompted a thorough investigation.