Epidemiology and Risk Factors

Primary urethral carcinoma (PUC) is a rare malignancy with potentially devastating consequences for patients for both treatment and mortality. The incidence is approximately 4.3 per million and 1.5 per million for men and women, respectively.¹ Risk factors, histopathology, and treatment have gender based differences due to the anatomical and embryological distinctions between the male and female urethra. However, in both genders, advanced age (>60 years) is a significant risk factor.

Male PUC is more common in African Americans than Caucasians. The most common risk factor is chronic urethral irritation with urethral stricture, which can be found in up to 50% of men with PUC. The male urethra can be divided into the anterior urethra, which consists of the fossa navicularis, pendulous urethra, and bulbar urethra, and the posterior urethra, which consists of the membranous urethra and prostatic urethra. The anterior urethra is lined by stratified squamous epithelium, which transitions to stratified and pseudostratified columnar epithelium. The posterior urethra is lined by urothelium. As such, tumor histology varies by location of primary carcinoma, with urothelial carcinoma accounting for the majority of cases, followed by squamous cell and adenocarcinoma (fig. 1, a).

Figure 1. Male (a) and female (b) urethral anatomy. Reprinted from Campbell-Walsh-Wein Urology, 12th ed, 2021; chapter 80, pages 1777 and 1783, with permission from Elsevier.

Female PUC is exceedingly rare and, as such, relatively little is known about underlying causes. However, a urethral diverticulum may predispose women to PUC. The female urethra is approximately 4 cm long, with the distal 2/3 lined by nonkeratizing stratified squamous epithelium and the proximal third lined by urothelium (fig. 1, b). There is approximately equal prevalence of urothelial, squamous cell, and adenocarcinoma, with adenocarcinoma more likely to be found in women than men and serving as the predominant histology found within urethral diverticulum.

Clinical Presentation, Diagnostic Evaluation and Staging

The majority of patients present symptomatically with obstructive voiding uropathy, hematuria, or a penile/vaginal or perineal mass.² All patients with suspected urethral cancer should undergo an examination under anesthesia with bimanual examination, a thorough examination of the external genitalia, including urethra, rectum, perineum, and inguinal nodes to assess for lymphadenopathy. Cystoscopy should be performed in all patients and a tissue diagnosis is necessary. Transurethral, transvaginal, or percutaneous needle biopsies are all acceptable methods of tissue sampling.

Patients should undergo cross-sectional imaging of the abdomen and pelvis with a computerized tomography scan or magnetic resonance imaging (MRI). Though either imaging modality is acceptable, MRI provides superior soft tissue resolution and can allow for more accurate local staging (fig. 2). The American Joint Committee on Cancer (AJCC) urethral tumor, node, metastases (TNM) staging is based on the depth of invasion, presence or absence and number of nodes, and distant metastasis (see Appendix).

Figure 2. MRI of posterior urethral tumors of male (a) and female (b).

Appendix. The American Joint Committee on Cancer (AJCC) Urethral Cancer Tumor, Node, Metastases (TNM) Staging System Data from Hansel D, Reuter VE, Bochner B et al: Urethra. In: AJCC Cancer Staging Manual, 8th ed. Edited by MB Amin. New York: Springer 2017.

Disease Management
Male Anterior Urethra

Distal PUC (ie within the fossa navicularis or penile urethra) is often curable with aggressive local control, and because of this, penile preservation therapy has been explored. Tumor excision with a distal urethrectomy with or without a partial glansectomy is acceptable for localized cancers ≤T2N0M0.³ While historically a 1-cm negative margin has been required, a 5-mm negative margin is sufficient for cancer control.⁴ Care must be taken to ensure the proximal margin is negative if performing a partial urethrectomy. Patients with positive surgical margins may have a repeat resection, or undergo chemotherapy or radiation (XRT). Further, patients who refuse surgery may be treated with primary XRT. These patients should undergo prophylactic XRT to the inguinal lymph nodes as well. In contrast, patients with clinically node negative disease undergoing surgical excision are not required to have prophylactic inguinal lymph node dissection.³

Patients with advanced disease of the distal urethra (≥T3) should be considered for chemoradiation with or without surgical resection. Patients treated with 45–55 Gy of external beam radiation and systemic 5-FU and mitomycin C can have a 5-year disease specific survival of up to 68%.² Patients with node positive disease should also undergo either inguinal lymph node dissection on the side of clinically positive disease, have systemic chemoradiation, or be treated with both modalities.

Tumors arising from the proximal (bulbar) anterior urethra are not only more common than distal urethral tumors, but also have a much higher mortality, with survival rates as low as 20%–30%.⁵ Because these tumors typically present at a later stage, they often require aggressive surgical management with a urethrectomy with or without a cystoprostatectomy, pelvic lymphadenectomy, and total penectomy. In patients with advanced disease, surgical monotherapy has a poor overall 5-year survival of 26%. As the surgery itself is extremely debilitating, patients with advanced disease may consider chemoradiation as a primary modality of treatment (fig. 3).

Figure 3. Management algorithm adapted from European Association of Urology (EAU) guidelines on primary urethral carcinoma, 2020, with permission. TUR, transurethral resection. CT, computerized tomography. BCG, bacillus Calmette-Guérin.

Male Posterior Urethra

Men with posterior (prostatic) PUC should be evaluated for synchronous urothelial cancer of the bladder and upper tracts. Patients with Ta-Tis-T1 disease can be managed with complete transurethral resection of the prostate followed by induction BCG. Patients with stromal invasion (pT2) or more advanced disease should undergo neo-adjuvant cisplatin based chemotherapy followed by radical cystoprostatectomy with urethrectomy and pelvic lymphadenectomy (fig. 3).³

Female Urethra

Given the rarity of female PUC, the ideal treatment does not have robust supporting data. Tumors of the anterior urethra are typically low stage and can be cured with endoscopic resection or laser fulguration +/– bacillus Calmette-Guérin. Small, exophytic anterior tumors may be excised transvaginally with a portion of anterior vaginal wall. Because of the short female urethra, partial urethrectomy does carry a significant risk of incontinence. For more aggressive tumors of the anterior urethra, a radical urethrectomy with bladder neck closure and creation of a stoma may be employed.⁶ Radiation monotherapy is also an option for low stage anterior tumors.⁷ A prophylactic lymph node dissection is not generally performed. In the case of lymph node metastasis, aggressive multi-modal therapy with radiation, chemotherapy, and surgical excision should be employed.³

Posterior female PUC is typically advanced stage and aggressive. Surgical therapy involves an anterior pelvic exenteration. Surgery and radiation alone have similarly low rates of control and survival outcomes. As such, these patients should be treated with multimodal therapy including radiation, chemotherapy, and consolidative surgery (fig. 3).⁸

Followup

Given the rarity of PUC, ideal followup has not been critically studied. Generally, patients with urethra sparing surgery should undergo periodic urinary cytology, urethrocystoscopy, and cross-sectional imaging. Patients generally have a poor prognosis with less than 50% 5-year survival (see table).⁹