Carcinoma of the Urethra (Male AND Female)
EUGENE J. PIETZAK
THOMAS J. GUZZO
Primary urethral cancer is a rare tumor that accounts for less than 0.5% of all malignancies and only 1% of all genitourinary malignancies (1). Given the rarity of the disease, there exist no randomized controlled trials to guide management. Furthermore, the majority of literature on urethral cancer comes from retrospective analysis from single centers with cases spanning several decades. Many recommendations for treatment are based on general oncologic principles and extrapolation from other diseases.
Urethral cancer is also a heterogenous disease. There are various histologic subtypes including urothelial cell carcinoma (UCC) (54% to 65%), squamous cell carcinoma (SCC) (16% to 22%), adenocarcinoma carcinoma (10% to 16%), as well as a very small number of other tumor types (i.e., melanoma, clear cell carcinoma, sarcoma, etc.) (1). SCC was historically thought to be the most common subtype of urethral carcinoma, but data from both the European RARECARE project and Surveillance, Epidemiology, and End Results (SEER) have found UCC to be the most common (2,3). UCC of the urethra represents a “field defect” within the lower urinary tract, which mandates an evaluation of the upper urinary tract and consideration of excision of the bladder along with the entire urethra. Although histologic subtype has not been shown to affect outcomes, prognosis and treatment options do vary with the location and stage of the tumor (1). Distal tumors have a more favorable prognosis than proximal tumors in both men and women. Local control has been linked to improved cancer-specific survival; therefore, effective treatment of the primary tumor to reduce locoregional recurrence is of the utmost importance (4).
Historically, urethral cancer was once thought to be the only genitourinary cancer more common in females than males, but this was based on single center experiences (5). More recent data contradicts those findings and suggests the male-to-female ratio for urethral cancer is nearly 3:1 (2,3). Urethral carcinomas in men and women differ in several important aspects, including treatment, and therefore are discussed in separate sections of this chapter.
URETHRAL CARCINOMA IN MEN
Epidemiology, Risk Factors, and Presentation
The rate of urethral carcinoma is 4.3 cases per million for men, and only 1.5 cases per million in women according to an analysis of SEER data (3). The peak incidence of urethral carcinoma is between 75 and 84 years of age (3). Urethral cancer is exceedingly rare in those younger than 55 years old.
In men, urethral carcinoma is associated with several risk factors. Most common is a history of urethral stricture disease, which is present in over 50% of men with urethral cancer (1). Furthermore, over 25% have a history of sexually transmitted diseases (1). There is likely a causal relationship with human papillomavirus (HPV) 16 (1). Chronic urethritis and radiation exposure have also been implicated in urethral carcinoma development (1).
Nearly all patients with urethral carcinoma present with symptoms. The most common symptoms in men include hematuria/urethral bleeding, obstructive voiding symptoms, and a palpable mass. A high incidence of suspicion is required to reduce the delay to diagnosis.
Diagnosis and Staging
Physical examination of a patient with suspected urethral cancer should include inspection of urethral meatus with palpation of the entire urethra, looking for induration and fixation. Digital rectal examination and bimanual examination should be performed to determine the extent of tumor involvement. If needed, this can be done under anesthesia at time of cystoscopy with biopsies.
Tumor-node-metastasis system is the preferred staging system (Table 41.1), as prognosis is directly correlated with depth of tumor invasion, as well as nodal and distant metastatic involvement. In general, lymphatic drainage for distal tumors is to the superficial and deep inguinal lymph nodes, whereas proximal tumors drain to pelvic nodes. Because 20% to 30% of patients have nodal involvement at presentation, palpation of the bilateral inguinal lymph nodes must be done.
Cystourethroscopy should be performed to assess tumor extent and location. Cold-cup biopsies or transurethral resection should be performed to determine tumor histology. Biopsies distal and proximal to the tumor can provide useful information if organ-sparing surgery is considered. Complete cystoscopic examination should be done to rule out concomitant bladder tumors.
Radiographic imaging is obtained with the goal to accurately determine local tumor involvement and the presence of metastasis in lymph nodes and distant sites. Magnetic resonance imaging (MRI) is superior to computerized tomography (CT) scan regarding determining the extent of local tumor involvement including corpora cavernosa invasion (6). Either MRI or CT scan can be used for assessing regional metastasis in inguinal and pelvic lymph nodes. CT of the chest and abdomen is preferred for patients with invasive tumors to identify distant metastasis. In the absence of nodal involvement, a chest X-ray is likely adequate. Imaging of the upper urinary tract should be obtained for patients with urethral UCC to rule out any additional urothelial lesions.
TABLE 41.1 TUMOR-NODE-METASTASIS STAGING FOR PRIMARY URETHRAL CARCINOMA AND UROTHELIAL CELL CARCINOMA OF THE PROSTATE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Anatomy and Histopathology
The male urethra is approximately 22 cm long. The bulbar urethra should be considered part of the proximal segment with the prostatic and membranous urethra because treatment and prognosis is similar. Distal urethral tumors are those occurring in the penile urethra, fossa navicularis, and urethral meatus. Distal tumors have a superior survival rate to proximal tumors and distal tumors and may be more amenable to organsparing procedures (1). The difference in survival is thought to be from earlier detection of distal lesions that tend to present
with symptoms at smaller size due to the narrower caliber lumen and the ease of self-palpation for the distal urethra.
with symptoms at smaller size due to the narrower caliber lumen and the ease of self-palpation for the distal urethra.
The prostatic and bulbomembranous urethra are lined with urothelial cells, whereas the penile urethra is lined with pseudostratified columnar epithelium, and the meatus is lined with stratified squamous epithelium.
The proportions of histologic subtypes vary with location. Tumors within the prostatic urethra are almost exclusive UCC, with only 10% of prostatic urethral tumors being SCC, likely from squamous metaplasia in setting of chronic inflammation. Tumors of the bulbomembranous urethra are 80% SCC, 10% UCC, and 10% adenocarcinoma. For the penile urethra, 90% of tumors are SCC and 10% are UCC (7).
Urothelial Carcinoma of the Prostate
Urothelial carcinoma of the prostate represents a separate disease, which is reflected in the fact that there is a unique T staging for UCC of the prostate (Table 41.1). Cases of noninvasive UCC and urothelial carcinoma in situ (CIS) can be managed with a urethra-sparing approach with extensive transurethral resection (TUR) and subsequent bacille Calmette-Guérin (BCG) therapy (1). The addition of TUR with BCG improves freedom from urethral recurrence from 65.7% to 95.3% at median follow-up of 52 months; however, similar rates of overall recurrence are seen when bladder recurrence is considered (8). If prostatic urethra UCC is refractory to conservative treatment, or if stromal invasion is present, then radical cystoprostatectomy with pelvic lymphadenopathy should be performed. Neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) may be beneficial particularly if the tumor is locally advanced.
Concomitant urethrectomy at time of cystoprostatectomy for prostatic urethral carcinoma is controversial. Local recurrence within the urethra occurs in between 0.5% and 11.1% of patients with bladder cancer after cystoprostatectomy (7), and UCC of the prostatic urethra increases this risk. Some authors have argued, however, that provided the distal urethral margin is normal at the time of cystoprostatectomy, urethrectomy is not immediately indicated. If the urethra is left in situ, the surveillance after cystectomy is also highly contentious. A complete discussion of this topic is beyond the scope of this chapter.
Alternative Treatments
The primary treatment for urethral carcinoma in men is surgical excision; however, many men may potentially benefit from multimodal therapy. Given the rarity of urethral carcinoma, the optimal treatment paradigm has yet to be established, and patients with urethral carcinoma should be discussed in multidisciplinary team meetings, which involve the participation of urologic oncologists, medical oncologists, radiation oncologists, radiologists, and pathologists. In many situations, management of urethral carcinoma is extrapolated from experiences with other more common tumors (i.e., urethral UCC with bladder UCC and urethral SCC with anal SCC).
Radiation monotherapy can be used in men who refuse surgery with early-stage distal tumors. Although radiation can be penile-sparing in these select patients, common side effects include skin ulceration, necrosis, and urethral strictures (7). Little is known of the long-term outcomes of this approach, but the risk of new tumor occurrence is present. Radiation is often used as part of multimodal approach for advanced disease in the neoadjuvant and adjuvant setting.
Given the rarity of urethral cancer, little is known regarding the role for adjuvant and neoadjuvant chemotherapy. No consensus exists for the particular regimen, but often, cisplatin, bleomycin, and methotrexate or radiosensitizing 5-fluorouracil and mitomycin C is used for SCC urethral tumors, and MVAC is used for urethral UCC (7).
Case series using definitive chemoradiation have also been reported for advanced urethral carcinoma. The most impressive results come from a series using 5-fluorouracil and mitomycin C with 45 to 55 Gy to the pelvis with a 12 to 15 Gy boost for gross disease. For a group with considerably advanced disease, the outcomes of this series were excellent with a 5-year cancer-specific survival rate of 72% when surgery was used for salvage purposes (9).
Surgical Treatment of Distal Tumors of the Male Urethra
The aggressive nature of urethral carcinoma and the frequent delay in diagnosis results in many patients with advanced disease at the time of initial presentation. Radical surgery is often required for local control. Surgery alone will not be curative in many with advanced disease, which underscores the need for multidisciplinary care.
Compared to proximal lesions, distal tumors have a far more favorable prognosis (10). Organ preservation may be possible in highly selected cases of early-stage tumors in the distal urethra. The objective of penile-sparing surgery is functional preservation (ability to void standing, maintenance of erectile function with adequate length for penetration) and acceptable cosmesis without compromising cancer control. Penile preservation is certainly not appropriate for all cases of urethral carcinoma.
If penile-sparing surgery is considered, accurate staging is even more vital, and an MRI is recommended to ensure corpora cavernosal invasion is not present. If corpora invasion is present, then standard treatment is partial or total penectomy with at least a 2-cm margin. Some authors have suggested a margin of only 5 mm may be adequate for local control, but these results from small case series must be interpreted with caution (1,11). Both partial and total penectomy are described in other chapters in this book.
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