Urethral carcinoma of the prostate (UCP) represents a rare entity, arising from the prostatic urothelium or from direct invasion into the prostate via the bladder, with a crude incidence of 0.06/100,000 per year. ¹ However, in isolation UCP may be underreported given that the incidence of UCP is observed in up to nearly 50% in cystectomy series where detailed pathologic evaluation of the prostate was undertaken, with stromal invasion in 8% to 17%. ^2–4 In patients with a history of nonmuscle invasive urothelial carcinoma, tumor recurrences may be identified in the prostatic urethra in 24% to 39% of cases. ⁵ Common presenting symptoms and signs include microscopic or gross hematuria and obstructive voiding symptoms. ⁶ Risk factors for UCP include carcinoma in situ (CIS) of the bladder neck or trigone and prior intravesical therapy, and involvement of the prostate by CIS is almost always associated with CIS within the bladder. ^2,7

The histologic subtype of UCP is urothelial carcinoma in 90% and squamous cell origin in 10%. The TNM Staging system for the prostatic urethra is presented in the Appendix. Of note, both primary papillary tumors of and CIS limited to the prostatic urethra are relatively rare, occurring in 2.7% and less than 4% of patients with primary bladder cancer, respectively. Urothelial carcinomas are risk stratified into low vs high grade disease according to the current WHO/ISUP grading system. For squamous cell and adenocarcinoma of the prostatic urethra, tumor grade is recommended to be described as well differentiated (G1), moderately differentiated (G2), poorly differentiated (G3) or indeterminate (Gx).

Figure. Histologic specimen demonstrating CIS extending into the prostatic ducts, focally suspicious for stromal invasion (credit, Dr. F. Vakar-Lopez).

Diagnostic Evaluation

In patients with a clinical suspicion for prostatic urethral carcinoma or undergoing evaluation for obstructive voiding, initial evaluation includes a digital rectal exam and serum prostatic specific antigen (PSA). Flexible cystoscopy in the clinic may demonstrate a mass within the prostatic urethra, which may be papillary or sessile in nature. The bladder should be carefully evaluated to rule out multifocality. Urine cytology may be obtained. However, the sensitivity of urine cytology in urethral carcinoma is somewhat limited (80% in urothelial carcinoma vs 50% in squamous cell carcinoma).

The patient is then taken to the operative room for exam under anesthesia and transurethral resection of the prostatic urothelial tumor including the prostatic stroma to establish the diagnosis. Enhanced cystoscopy, with either blue light cystoscopy or narrow-band imaging, is recommended if available for the evaluation of bladder cancer; however, there are no specific data available to date regarding its utility in the setting of UCP. Needle biopsy of the prostate (eg transurethral or transperineal ultrasound-guided biopsy of the prostate) may be undertaken if the digital rectal exam is abnormal. In addition to debulking any visualized tumor, transurethral resection of the prostate is generally obtained in the 5 and 7 o’clock positions in the prostatic urethra to ensure sampling of the prostatic ducts. These resections should extend from the bladder neck to just proximal to the verumontanum. A separate resection of the prostatic urethral floor may also be obtained. ⁷ Of note, in the setting of a positive cytology with a visually normal cystoscopy, the prostatic urothelium should be sampled in the manner described above.

If not already undertaken, in patients with urothelial carcinoma of the prostatic urethra, upper tract imaging should be performed with a computerized tomography (CT) urogram, retrograde pyelogram or magnetic resonance (MR)-urogram to complete evaluation of the remainder of the urothelium. Patients with urothelial carcinoma invading the prostatic ducts and acini or the prostatic stroma (pT1 or greater) should also undergo imaging of the chest (chest x-ray [CXR] vs CT chest) and cross-sectional imaging of the abdomen/pelvis if not already undertaken to rule out metastatic disease. Contrast-enhanced pelvic magnetic resonance imaging (MRI) provides the best resolution to delineate the local extent of the tumor and also evaluated regional lymph node involvement. Positron emission tomography (PET)/CT is utilized to identify systemic and nodal metastases in urothelial tumors, although data regarding its use in UCP are sparse.

Treatment

The management of UCP is determined based on tumor histology, stage and grade. ^6,8 For patients with CIS (see figure) or noninvasive urothelial UCP, transurethral resection is performed followed by induction Bacillus Calmette-Guerin (BCG), and patients are followed according to guideline-based surveillance recommendations. ⁵ This conservative and organ-sparing approach is appropriate only if the tumor can be completely resected. The resection should include resection of the bladder neck to permit reflux of the intravesical BCG into the prostatic urethra. These patients are followed carefully with surveillance cystoscopy and imaging because recurrence in the prostate is associated with poor prognosis. ⁷ Frequent random biopsies of the prostatic urethra are recommended during subsequent cystoscopies to detect local recurrence accurately. ⁷ Patients with recurrence of high-grade pTa or pTis are generally recommended to undergo radical cystoprostatectomy with or without urethrectomy, bilateral pelvic lymphadenopathy and urinary diversion. Patients who are unwilling to consider radical surgery or who are poor candidates for radical cystoprostatectomy may be offered reresection and reinduction with BCG and subsequent management according to principles of management of BCG unresponsive urothelial carcinoma but should be counseled that there are limited data regarding outcomes in this space.

Patients with urothelial carcinoma of the prostate involving the prostatic ducts and acini but without stromal invasion (pT1) may be managed with radical cystoprostatectomy with or without urethrectomy, bilateral pelvic lymphadenopathy and urinary diversion vs transurethral resection of the prostate (TURP) and induction BCG, with local recurrence prompting radical cystoprostatectomy with or without urethrectomy and bilateral pelvic lymphadenopathy. In the event of stromal invasion (pT2) or locally advanced nonmetastatic urothelial carcinoma of the prostate (pT3/4N0/xM0), neoadjuvant cisplatin-based chemotherapy followed by radical cystoprostatectomy with or without urethrectomy and pelvic lymphadenectomy is the treatment of choice. Patients who underwent frontline radical surgery should be considered for adjuvant systemic therapy. Patients with localized invasive nonurothelial tumors of the prostatic urethra (eg squamous cell carcinoma or adenocarcinoma) proceed to upfront radical cystoprostatectomy with or without urethrectomy.

In the event of metastatic UCP, patients proceed to systemic therapy appropriate for the histologic subtype. In patients with metastatic urothelial carcinoma who are cisplatin eligible, patients generally receive either gemcitabine or dose-dense MVAC with growth factor support. For patients who are cisplatin ineligible, preferred regimens currently include gemcitabine and carboplatin followed by avelumab, atezolizumab or pembrolizumab in patients with tumors expressing PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression.

Prognosis

Treatment of CIS of prostatic urethra associated with nonmuscle invasive bladder cancer (NMIBC) with TURP and BCG is associated with complete response rates of 70% to 100% in the prostatic urethra, as reviewed by Palou et al. ⁷ Stromal invasion of the prostate by urothelial carcinoma is associated with an increased risk of nodal metastases and poor prognosis overall. The 5-year cancer specific survival for patients with UCP with stromal invasion is estimated at 74% compared with 26% in those without stromal invasion. ³

Summary

UCP is a rare and often underrecognized entity, frequently associated with synchronous bladder cancer, that requires a high index of suspicion to accurately diagnose and identify its presence and extent both endoscopically and in patients who have undergone radical cystoprostatectomy. Management is risk stratified by histology, grade and stage. Correct staging and close followup in the setting of coexistent NMIBC is imperative to avoid progression secondary to undiagnosed stromal invasion ⁷ and accurately identify recurrences that should prompt consideration of radical extirpation.