Primary urethral cancer (PUC) is a rare, but devastating genitourinary tumor that affects men and women. Although most PUC are localized, proximal PUC frequently presents with locally advanced disease, with 30% to 40% having lymph node metastasis. Single modality surgical or radiation therapy has dismal results. Multimodal therapy with cisplatin-based chemotherapy and consolidation surgery has greatly improved the local recurrence and overall survival rates for this aggressive disease. In locally advanced squamous cell carcinoma of the urethra, radiotherapy combined with radiosensitizing chemotherapy is an option for genital preservation. Prospective, multi-institutional studies are required to further define the optimal multidisciplinary treatment strategy for this destructive disease.
Key points
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Primary urethral cancer is rare, with proximal lesions accounting for 66% of diagnosed urethral tumors.
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Risk factors for survival include age, black race, tumor size, stage and grade, nodal involvement and metastasis, proximal location, histology, and the presence of concomitant bladder cancer.
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Patients with proximal urethral cancer who receive neoadjuvant multimodal therapy demonstrate improved survival compared with surgery with or without adjuvant chemotherapy.
Introduction
Primary urethral cancer (PUC) of the proximal urethra is an exceeding rare tumor, whose natural history is particularly aggressive. These tumors occur more commonly in men, and differ by location and histologic subtype. Patient symptoms often include urinary obstruction, irritative voiding symptoms, or hematuria. Risk factors include urethral strictures, chronic irritation, radiation treatment, human papilloma virus, and urethral diverticula (females). Most PUC are localized; however, 30% to 40% of patients present with regional lymph node metastasis. Although surgery and radiation treatment are options for early stage or distal urethral disease, advanced-stage and proximal PUC require multimodal treatment to optimize survival. However, controversy exists regarding the optimal multidisciplinary treatment strategy for male squamous cell carcinoma (SCC) of the urethra. Multi-institutional studies are critical to delineate the optimal treatment strategy in the future. This article examines this difficult disease, with a critical evaluation of the literature and an emphasis on the optimal treatment strategies for proximal PUC.
Epidemiology
PUC is exceeding rare, accounting for less than 1% of all malignancies. The incidence of PUC increases with age, peaking in the greater than 75 year age group, and is more common in African Americans. According to the Surveillance, Epidemiology, and End Results database, 4.3 per million and 1.5 per million men and women, respectively, in the United States develop PUC yearly. This is slightly higher than the reported rates of PUC in Europe, where 1.6 per million men and 0.6 per million women develop PUC yearly.
Etiology
The risk factors for developing PUC differ between men and women. Risk factors for men include urethral stricture, chronic irritation from intermittent catheterization, prior radiation therapy, and sexually transmitted disease (human papillomavirus serotype 16). This is in contrast to women, whose risk factors for developing PUC include the following : urethral diverticulum, chronic irritation and infection with human papillomavirus, and recurrent urinary tract infections.
Histology
The histologic subtypes of PUC reflect the gender and location of the primary tumor. In men, urothelial cancer is the most frequently seen histologic type, accounting for 47% to 73% of tumors, whereas SCC (12%–30%) and adenocarcinoma (5%–16%) account for the remaining cases. Females have a slightly different incidence of tumor type. Although urothelial cancers are the most common, occurring in 45% of cases, adenocarcinoma is more prevalent than SCC, occurring in 29% and 19% of cases, respectively.
Staging and Classification Systems
PUC is staged according to the TNM classification system, and is different depending on whether the tumor occurs in the prostatic urethra, or more distally ( Table 1 ). Although not directly measured by the TNM classification system, tumor location is an important factor that plays an integral role in PUC outcomes. PUC tumor locations are often referred to as occurring either proximally or distally. Although this is nonspecific nomenclature, its use has been propagated in the literature. Proximal PUC refer to tumors of the prostatic, membranous, and bulbar urethra, whereas distal tumors involve the penile and fossa navicularis urethra.
| T: Primary Tumor | |
| Tx | Primary tumor cannot be assessed |
| Tis | Carcinoma in situ |
| T0 | No evidence of primary tumor |
| T1 | Tumor invades subepithelial connective tissue |
| T2 | Tumor invades any of the following structures: corpus spongiosum, prostate, periurethral muscle |
| T3 | Tumor invades any of the following structures: corpus cavernosum, invasion beyond prostatic capsule, anterior vaginal wall, bladder neck |
| T4 | Tumor invades other adjacent organs |
| Primary Tumor in Prostatic Urethra | |
| Tx | Primary tumor cannot be assessed |
| Tis pu | Carcinoma in situ in the prostatic urethra |
| Tis pd | Carcinoma in situ in the prostatic ducts |
| T0 | No evidence of primary tumor |
| T1 | Tumor invades subepithelial connective tissue |
| T2 | Tumor invades any of the following structures: corpus spongiosum, prostatic stroma, periurethral muscle |
| T3 | Tumor invades any of the following structures: corpus cavernosum, beyond prostatic capsule, bladder neck |
| T4 | Tumor invades other adjacent organs |
| N: Regional Lymph Nodes | |
| Nx | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastases |
| N1 | Metastasis in a single lymph node ≤2 cm in greatest dimension |
| N2 | Metastasis in a single lymph node ≥3 cm in greatest dimension |
| M: Distant Metastasis | |
| Mx | Distant metastasis cannot be assessed |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
These anatomic considerations have treatment implications because of the varied lymphatic drainage of the urethra. The lymphatic drainage of the anterior urethra (bulbar, penile, and fossa navicularis urethra) is to the inguinal lymph nodes and subsequently pelvic lymph nodes, whereas the posterior urethra (prostatic and membranous urethra) drain into the pelvic lymph nodes. In women, the distal two-thirds drain into the superficial and deep inguinal lymph nodes, whereas the proximal third of the urethra drains into the pelvic lymph nodes.
Introduction
Primary urethral cancer (PUC) of the proximal urethra is an exceeding rare tumor, whose natural history is particularly aggressive. These tumors occur more commonly in men, and differ by location and histologic subtype. Patient symptoms often include urinary obstruction, irritative voiding symptoms, or hematuria. Risk factors include urethral strictures, chronic irritation, radiation treatment, human papilloma virus, and urethral diverticula (females). Most PUC are localized; however, 30% to 40% of patients present with regional lymph node metastasis. Although surgery and radiation treatment are options for early stage or distal urethral disease, advanced-stage and proximal PUC require multimodal treatment to optimize survival. However, controversy exists regarding the optimal multidisciplinary treatment strategy for male squamous cell carcinoma (SCC) of the urethra. Multi-institutional studies are critical to delineate the optimal treatment strategy in the future. This article examines this difficult disease, with a critical evaluation of the literature and an emphasis on the optimal treatment strategies for proximal PUC.
Epidemiology
PUC is exceeding rare, accounting for less than 1% of all malignancies. The incidence of PUC increases with age, peaking in the greater than 75 year age group, and is more common in African Americans. According to the Surveillance, Epidemiology, and End Results database, 4.3 per million and 1.5 per million men and women, respectively, in the United States develop PUC yearly. This is slightly higher than the reported rates of PUC in Europe, where 1.6 per million men and 0.6 per million women develop PUC yearly.
Etiology
The risk factors for developing PUC differ between men and women. Risk factors for men include urethral stricture, chronic irritation from intermittent catheterization, prior radiation therapy, and sexually transmitted disease (human papillomavirus serotype 16). This is in contrast to women, whose risk factors for developing PUC include the following : urethral diverticulum, chronic irritation and infection with human papillomavirus, and recurrent urinary tract infections.
Histology
The histologic subtypes of PUC reflect the gender and location of the primary tumor. In men, urothelial cancer is the most frequently seen histologic type, accounting for 47% to 73% of tumors, whereas SCC (12%–30%) and adenocarcinoma (5%–16%) account for the remaining cases. Females have a slightly different incidence of tumor type. Although urothelial cancers are the most common, occurring in 45% of cases, adenocarcinoma is more prevalent than SCC, occurring in 29% and 19% of cases, respectively.
Staging and Classification Systems
PUC is staged according to the TNM classification system, and is different depending on whether the tumor occurs in the prostatic urethra, or more distally ( Table 1 ). Although not directly measured by the TNM classification system, tumor location is an important factor that plays an integral role in PUC outcomes. PUC tumor locations are often referred to as occurring either proximally or distally. Although this is nonspecific nomenclature, its use has been propagated in the literature. Proximal PUC refer to tumors of the prostatic, membranous, and bulbar urethra, whereas distal tumors involve the penile and fossa navicularis urethra.
| T: Primary Tumor | |
| Tx | Primary tumor cannot be assessed |
| Tis | Carcinoma in situ |
| T0 | No evidence of primary tumor |
| T1 | Tumor invades subepithelial connective tissue |
| T2 | Tumor invades any of the following structures: corpus spongiosum, prostate, periurethral muscle |
| T3 | Tumor invades any of the following structures: corpus cavernosum, invasion beyond prostatic capsule, anterior vaginal wall, bladder neck |
| T4 | Tumor invades other adjacent organs |
| Primary Tumor in Prostatic Urethra | |
| Tx | Primary tumor cannot be assessed |
| Tis pu | Carcinoma in situ in the prostatic urethra |
| Tis pd | Carcinoma in situ in the prostatic ducts |
| T0 | No evidence of primary tumor |
| T1 | Tumor invades subepithelial connective tissue |
| T2 | Tumor invades any of the following structures: corpus spongiosum, prostatic stroma, periurethral muscle |
| T3 | Tumor invades any of the following structures: corpus cavernosum, beyond prostatic capsule, bladder neck |
| T4 | Tumor invades other adjacent organs |
| N: Regional Lymph Nodes | |
| Nx | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastases |
| N1 | Metastasis in a single lymph node ≤2 cm in greatest dimension |
| N2 | Metastasis in a single lymph node ≥3 cm in greatest dimension |
| M: Distant Metastasis | |
| Mx | Distant metastasis cannot be assessed |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
These anatomic considerations have treatment implications because of the varied lymphatic drainage of the urethra. The lymphatic drainage of the anterior urethra (bulbar, penile, and fossa navicularis urethra) is to the inguinal lymph nodes and subsequently pelvic lymph nodes, whereas the posterior urethra (prostatic and membranous urethra) drain into the pelvic lymph nodes. In women, the distal two-thirds drain into the superficial and deep inguinal lymph nodes, whereas the proximal third of the urethra drains into the pelvic lymph nodes.
Diagnosis
Presentation
Men may present with obstructive (41%–48%) or irritative urinary symptoms (20%), hematuria or urethral discharge (62%), pelvic pain (33%–45%), urethral stricture (76%), urethral/penile mass (48%–52%), urethrocutaneous fistula (10%), or abscess (5%). More than 70% of women often report recurrent urinary tract infections, irritative voiding symptoms, spotting, or dyspareunia, whereas obstructive voiding (23%) and hematuria (20%) present less frequently.
Physical Examination
A thorough physical examination that involves the external genitalia and rectal examination is mandatory in men, whereas women require a careful pelvic examination and palpation of the urethra. Both sexes should have bilateral inguinal evaluation to determine the presence of lymphadenopathy, and if present, whether the nodes are mobile. In cases of suspected PUC, an examination under anesthesia is important to properly stage the patient.
Tissue Diagnosis
Cystourethroscopy and biopsy are integral to confirm the diagnosis, establish the underlying histology and grade, determine the local extent of tumor, the precise location within the urethra, and whether a concomitant bladder tumor maybe present. The biopsy technique required may be varied depending on the location of the PUC within the urethra. Although distal lesions may be simply excised for a tissue diagnosis, proximal tumors are more difficult. Cold-cup biopsy forceps can often be used to obtain a representative tumor sampling. In situations where this is technically demanding, we have found a 14-gauge Temno biopsy needle to be helpful. This is performed by activating the biopsy needle transurethrally (percutaneously). Urothelial tumors of the prostatic urethra are different, and are biopsied with the resectoscope loop, beginning at the bladder neck and ending proximal to the verumontanum to avoid any injury to the external sphincter and impair urinary continence.
Imaging
Complete staging of patients with PUC requires imaging with either MRI or computed tomography of the chest, abdomen, and pelvis. MRI may be the preferred study because of its ability to accurately stage locoregional disease and distant metastases, and response to chemoradiation therapy. A recent multi-institutional study confirmed these findings, demonstrating that 93% of clinically positive nodes on MRI were pathologically positive. In cases of urothelial cancer, a computed tomography urogram should be performed to evaluate the entire urinary tract. The importance of accurate imaging cannot be underestimated, because 30% to 40% of all patients present with inguinal lymph node metastases, whereas up to 6% present with distant metastases.
Prognosis
According to a Surveillance, Epidemiology, and End Results database analysis, the median 5- and 10-year overall survival of PUC is 46% and 29%, respectively, whereas the cancer-specific survival is 68% and 60%, respectively. These rates are comparable with the findings of a European study that reported mean 1- and 5-year overall survival rates of 71% and 54%, respectively. Despite the rarity of PUC, and the paucity of well-powered studies, several risk factors for decreased survival have been elucidated including the following :
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Clinical stage, nodal involvement, grade, and metastases
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Proximal tumor location and size
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Tumor histology
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Treatment modality
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Age and black race
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Concomitant bladder tumor (patients with urothelial cancer)
However, the most important prognostic indicators as it relates to survival are clinical stage (presence of nodal metastasis) and location of the primary tumor (proximal vs distal). Although treatment of lower stage tumors results in survival rates of 67% to 100%, the outcomes for patients with advanced disease is reported between 33% to 45%. Similarly, survival rates for distal tumors is significantly better than for proximal PUC, with 60% to 72% of distal tumors and only 26% to 36% of proximal PUC demonstrating 5-year overall survival. This disparity elucidates the very different behavior of these tumors, and ultimately the treatment required to maximize successful outcomes.
Treatment of proximal primary urethral cancer
Urothelial Carcinoma of the Prostate
Several population-based studies have demonstrated that urothelial carcinoma of the prostatic urethra is the most common histologic type of cancer affecting the male urethra. Management of this disease entity is entirely different from the more aggressive SCC and adenocarcinoma of the proximal urethra, and is an extension of the management for urothelial cancer of the bladder. However, multimodal therapy remains the recommended treatment of clinical stage Ta or Tis prostatic urothelial carcinoma.
Transurethral Resection and Bacillus Calmette-Guérin
In patients with Ta or Tis urothelial cancer, aggressive transurethral resection of the tumor followed by once weekly instillations of bacillus Calmette-Guérin (BCG) for 6 weeks is performed with durable results. The complete response rate in the prostatic urethra and prostatic ducts has been shown in multiple small series to be 57% to 100% when transurethral resection is followed by intravesical BCG ( Table 2 ). This is significantly better than patients who only receive monotherapy BCG (65% complete response rate). However, up to 55% of patients who experienced a complete response later developed recurrence in either the urethra or bladder. In these limited studies, 28% to 30% of patients ultimately required cystoprostatectomy and urinary diversion for recurrent or progressive disease. In this highly select group, at a median follow-up of 7.5 years, disease-specific survival was 89% with this multimodal approach.
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