Urethral cancer

INTRODUCTION — 

Primary urethral carcinomas are rare but aggressive tumors that account for less than 1 percent of all genitourinary malignancies. Urethral cancer is not one malignancy but a spectrum of diseases with various histologies. The approach to management and prognosis depends upon sex, location of the tumor within the urethra, and extent of disease.

This topic will discuss the clinical presentation, evaluation, and treatment of urethral cancer.

EPIDEMIOLOGY — 

Urethral cancer is more common in male than female patients [1,2]. The incidence is also higher in older adults and African American populations. An analysis from the Surveillance, Epidemiology, and End Results (SEER) database included 1907 patients (1302 male patients and 605 female patients) diagnosed with urethral cancer from 2004 to 2016. The age-standardized incidence rates were 2.70 per million in male patients and 0.55 per million in female patients. The average annual percent change of the incidence regardless of sex was estimated to be 0.98 percent. The highest incidence rates were reported in those ≥75 years old (0.77 per million) and African American individuals (3.33 per million) [2].

A European study from the RARECARE project identified 1059 cases over a seven-year period and estimated that there are approximately 650 new cases per year in the European Union [3]. The age-standardized rates were 1.6 and 0.6 per million in males and females, respectively.

RISK FACTORS — 

Although the etiology of urethral cancer is not well understood, factors that have been associated with urethral cancer include:

●Chronic inflammation

•Male patients with urethral cancer often have a history of sexually transmitted infections, urethritis, or urethral stricture [4]. As an example, in one study, males with urethral cancer reported a history of gonococcal urethritis, urethral stricture, or significant trauma in 37, 35, and 7 percent of cases, respectively [5,6]. Urethral strictures, which may develop following urethral trauma, are most frequently found in the bulbomembranous urethra, which is also the most common urethral segment involved with cancer [7].

•In female patients, urethral diverticuli have been implicated in the development of cancer in up to 5 percent of cases, probably due to secondary chronic inflammation [8]. Urinary stasis and infection may also be contributing factors. As an example, in one series of 90 females undergoing diverticulectomy, five (6 percent) were found to have invasive adenocarcinoma, with some others having evidence of intestinal metaplasia and dysplasia [9].

●HPV – Human papillomavirus (HPV) 16 has been implicated in the development of both male and female urethral cancers [10-12]. As an example, in one series, HPV was identified in tumors from 11 of 18 female patients (61 percent) [10]. HPV 16 was present in 9 of the 11 cases. A similar causal relationship may exist in males. In one series, tumors from 4 of 14 patients (29 percent) harbored detectable HPV [12]. All four were the HPV 16 subtype. (See "Virology of human papillomavirus infections and the link to cancer".)

●Other urothelial malignancies – Urothelial carcinoma is often multifocal and may arise in the urethra simultaneously with, precede, or follow lesions of the bladder, ureters, or renal pelvis. (See "Epidemiology and risk factors of urothelial carcinoma of the bladder".)

ANATOMY AND HISTOLOGY

Males — Tumors of the male urethra are categorized by both location and histology.

The predominant histologic type is urothelial carcinoma (present in 54 to 65 percent of cases), followed by squamous cell carcinoma (16 to 22 percent) and adenocarcinoma (10 to 16 percent) [13].

The male urethra extends from the bladder neck to the urethral meatus, averages 21 cm in length, and is divided into the prostatic, bulbomembranous, and penile urethra [14]. The prostatic and bulbomembranous urethra segments are lined with transitional epithelium that is similar to the bladder and upper urinary tract. The penile urethra is lined with pseudostratified columnar epithelium, and the meatus is lined with stratified squamous epithelium. The most common site of involvement is the bulbomembranous urethra, followed by the penile and prostatic urethra (60, 30, and 10 percent of cases, respectively) [15].

Most of the carcinomas of the penile and bulbomembranous urethra are squamous cell in origin, with urothelial and adenocarcinomas accounting for the minority of the cases [16]. By contrast, the vast majority of prostatic urethral carcinomas are urothelial in origin, although squamous cell carcinomas account for 10 percent of these cancers [17].

Urethral cancer can directly extend into contiguous organs, such as the penis, or spread via the lymphatics drainage into the inguinal and pelvic nodes. The distal urethra drains into superficial and deep inguinal lymph nodes, while the proximal urethra drains into the external iliac, obturator, and internal iliac lymph node chains [18].

Females — The female urethra averages 3 to 4 cm in length space and is divided into an anterior segment, which comprises the distal third, and a posterior segment, which comprises the proximal two-thirds of the urethra. The proximal one-third is composed of transitional epithelium, while the distal two-thirds is stratified squamous epithelium. Along the entire urethra, however, there are submucosal glands, which are composed of columnar epithelium [18].

The lymphatic drainage of the female urethra is analogous to the male, with the distal one-third draining into the superficial or deep inguinal nodes, while the proximal two-thirds drains into the pelvic lymph nodes [14].

Squamous cell carcinomas represent the predominant histology in female patients, accounting for up to 60 percent of urethral cancers, while 15 to 20 percent are urothelial carcinomas, and 5 to 7 percent are adenocarcinomas [17,19]. Proximal squamous cell carcinomas most likely arise from squamous metaplasia in the nonsquamous epithelium as a result of chronic inflammation. Mixed histologies are not uncommon and may be the result of differentiation of urothelial carcinoma into glandular and/or squamous components. Adenocarcinomas arise from Skene glands as a prostatic homologue, with resultant prostate-specific antigen positivity in some cases [14], from glandular metaplasia leading to columnar/mucinous adenocarcinoma [18], and rarely, from other sources leading to clear cell adenocarcinoma [20-22].

CLINICAL PRESENTATION — 

The clinical presentation of urethral cancer varies depending upon sex.

●Male patients – In male patients with urethral cancer, symptoms may be nonspecific, and diagnosis is often delayed. Symptoms can overlap with and be attributed to benign urethral strictures, which are far more common than cancer. Thus, any patient presenting with recurrent strictures should undergo biopsy of the diseased urethral segment since urethral strictures are associated with urethral cancer.

Other symptoms include hematuria (often initial rather than terminal hematuria), difficulty voiding, dysuria, urethral discharge, and urinary retention in advanced disease. Unexplained perineal pain, genital swelling, priapism, periurethral abscess, or fistula in an older adult patient should also prompt work-up to rule out urethral carcinoma [17].

●Female patients – Most female patients with urethral cancer present with irritative voiding symptoms or hematuria, which is often mistaken for a urinary tract infection, which is far more common. In older female patients, recurrent or persistent pelvic symptoms, such as dyspareunia, should raise suspicion for the presence of urethral carcinoma.

●Lymph node and distant metastases – Up to 30 percent of male patients with urethral cancers have regional lymph node metastases at presentation, with less than one-half of these being clinically palpable [23]. Approximately 10 percent of patients have distant metastases at time of presentation, with the most frequent sites of involvement being the lungs, liver, and bone [23,24]. These patients generally have extensive locally advanced primary tumors, along with regional nodal involvement.

DIAGNOSIS AND EVALUATION — 

A detailed evaluation is essential to make the diagnosis and assess the extent of disease. Definitive diagnosis requires biopsy confirmation.

●Work-up should begin with a physical examination and evaluation of the palpable portion of the urethra as well as the inguinal lymph nodes. In female patients, this includes a bimanual examination.

●Cystourethroscopy should be performed to evaluate the extent of disease. Retrograde urethrography in male patients can help establish the exact location and extent of disease. In patients with recurrent or extensive urethral strictures or abnormal urethral mucosa, urine cytology should be sent. If clinical suspicion remains high, however, definitive diagnosis should be made with transurethral biopsies since the sensitivity of cytology is low [17].

●Cross-sectional imaging using computed tomography (CT) or magnetic resonance imaging (MRI) should be obtained to evaluate for locoregional spread of cancer. Chest imaging must be performed to rule out metastatic disease. Newer MRI techniques allow for local staging with superior soft tissue resolution and better delineation of tissue planes that may be helpful in surgical staging and planning and thus should include the entire urethra/phallus and inguinal nodal regions [25].

●CT imaging may be useful to exclude distant metastases [26]. Bone scan should only be ordered if there are symptoms, an elevated alkaline phosphatase, or suggestion of disease on cross-sectional imaging. There are no convincing data on use of positron emission tomography (PET) scan for imaging or staging.

STAGING SYSTEM — 

Accurate clinical staging is paramount given the array of various treatment options. Proper clinical staging consists of appropriate imaging, as mentioned above, examination under anesthesia with cystoscopy, and palpation of the genitalia, urethra, rectum, and perineum, in addition to bimanual examination to assess local tumor involvement.

Transurethral biopsy of the lesion is critical for accurate histologic evaluation. Cytologic studies of voided urine alone are not a reliable source for diagnosis of primary urethral carcinoma. Sensitivity of cytology is greatest with urothelial cell carcinomas (80 percent) and tumors in the pendulous urethra (73 percent) [27].

The tumor, node, metastasis staging system is used for staging carcinoma of the urethra (table 1). The eighth edition of this system (2017) is supported by both the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control. Staging is based on depth of invasion of the primary tumor and the presence or absence of regional lymph node involvement and distant metastasis.

The AJCC staging system has some limitations, particularly in staging urethral cancer in female patients. For instance, in female patients, pT3 tumors are solely defined as tumors invading the posteriorly-located vagina. However, there is no clear classification for tumors involving the anterior urethral wall, resulting in an understaging of tumors in this location. Moreover, despite the vagina being a separate organ, its involvement is not categorized as pT4, leading to stage compression [28].

TREATMENT

General approach — There are no prospective trials to guide treatment recommendations for patients with urethral cancer. The treatment approaches in both male and female patients are based on case series and extrapolation from the management of other malignancies of the urinary tract. Treatment varies widely based upon location, extent, histology, and sex. Contemporary reports have combined experience from higher volume centers to provide additional insight into the disease and its treatment [29].

●For patients with clinically localized disease (ie, pTa to T2), surgery is generally the preferred initial treatment. Surgical approaches range from transurethral resection/ablation to excision using partial or total urethrectomy techniques with or without radical cystectomy and heterotopic urinary diversion depending upon the site and extent of disease, as well as sex.

●Locally advanced cases are best treated with multimodal therapy consisting of neoadjuvant chemotherapy and/or radiation therapy (RT) followed by surgical extirpation, although experience is limited [30,31].

●Patients with metastatic disease have a poor prognosis. Management generally includes systemic therapy; in rare cases, palliative surgery may have a role.

Surgery

Surgical approaches for males — For male patients with urethral carcinoma, surgery depends upon the location and extent of disease:

●Patients with low-grade tumors or small, high-grade, noninvasive tumors may be treated with endoscopic resection [32]. While this approach allows maximal functional preservation, it is also associated with a high risk of recurrence, and vigilant endoscopic follow-up is required. Patients with high-grade disease invading the subepithelial layer (cT1) ideally should be treated with segmental resection, although endoscopic management is feasible in male patients if the tumor can be completely resected with a pathology showing no evidence of invasive disease into the corpora.

●Patients with larger tumors or more invasive disease should undergo segmental resection with primary anastomosis, if possible. Very distal tumors near the meatus can be treated with distal urethrectomy with creation of a hypospadias. Sexual function is generally not compromised with these approaches, and patients should maintain full function, as in urethral stricture management [33].

●More extensive tumors involving the corpus spongiosum (T2 lesions) but not the corpus cavernosum can be treated with subtotal urethrectomy and perineal urethrostomy [34].

●Patients with noninvasive urothelial carcinomas of the prostate may be treated endoscopically (ie, transurethral resection) along with adjuvant Bacillus Calmette-Guérin therapy. Complete response rates of up to 75 percent and five-year recurrence-free survival rates of 90 percent have been reported [35-37].

●Patients with urothelial carcinoma invading the stroma of the prostate can be treated with neoadjuvant chemotherapy, followed by radical cystoprostatectomy and urinary diversion, as in their bladder cancer counterpart, although there is a paucity of evidence for a survival benefit. It should be noted that prostatic stromal invasion from a primary prostatic urethral tumor is staged as T2, as compared with a bladder urothelial carcinoma that directly invades the prostatic stroma (T4). (See 'Neoadjuvant and adjuvant systemic therapy' below and "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder".)

●Patients with locally advanced disease (cT3 to T4) should be treated with multimodal therapy including histology-directed neoadjuvant chemotherapy. Subsequent management may require extensive surgical resection to include penectomy and cystoprostatectomy with perineal reconstruction and anterior pelvic exenteration. Patients who have tumors abutting the inferior pubic ramus should undergo en bloc inferior pubectomy, and those with inguinal lymphadenopathy should undergo inguinal lymphadenectomy [38,39]. (See 'Neoadjuvant and adjuvant systemic therapy' below.)

Surgical approaches for females — In female patients with urethral carcinoma, surgery depends upon the location and extent of disease [40]:

●Patients with low-grade tumors or small, high-grade, noninvasive tumors may be treated with endoscopic resection, although this is very difficult to perform given the anatomic limitations. Female patients can maintain continence as long as the urethral sphincter is preserved.

●Total urethrectomy with bladder neck closure and either suprapubic cystotomy, incontinent diversion (ileovesicostomy), or a continent catheterizable stoma using the Mitrofanoff principle may be utilized in female patients with more extensive disease.

●Female patients with advanced locoregional disease may require neoadjuvant chemotherapy followed by extensive surgical resection to include anterior pelvic exenteration, including anterior vaginectomy. Patients who have tumors abutting the inferior pubic ramus should undergo en bloc inferior pubectomy. Treatment may be followed by adjuvant radiation. (See 'Neoadjuvant and adjuvant systemic therapy' below.)

What is the role of lymphadenectomy? — The role of inguinal lymph node dissection remains controversial. Routine lymph node dissection is generally not indicated, except when enlarged nodes are identified on imaging or in those with palpable inguinal lymphadenopathy. There is some limited evidence that lymphadenectomy in male patients with palpable disease may improve the long-term outcomes [19,38,39,41,42]. The template of lymphadenectomy should be based on the anatomic location of the cancer within the urethra. If radical cystoprostatectomy is being performed, then a lymphadenectomy template similar to bladder cancer can be performed. In patients with prostatic urothelial carcinomas, a combined inguinal and pelvic lymphadenectomy is an option, particularly if the disease extends into the pendulous urethra. If the carcinoma is in the distal pendulous urethra only, then a superficial and deep inguinal lymphadenectomy can be performed.

Some investigators have suggested sentinel inguinal lymph node biopsy as an alternative to inguinal lymphadenectomy; however, unlike penile cancer, this approach has not been formally evaluated in patients with urethral cancer with high false-negative rates [41].

Radiation therapy — RT for urethral cancer is an alternative treatment that has the potential advantage of preserving function. Outcomes appear to be similar to those in surgical series, although the data are limited, and there is selection bias in the reported series [43]. Either external beam RT or brachytherapy may be used for anterior urethral tumors in male patients and more proximal tumors in female patients.

RT alone may be sufficient in patients with localized tumors (stage T1 or T2) with or without radiosensitizing chemotherapy. Locally advanced tumors are best treated with neoadjuvant chemotherapy, followed by assessment of the extent of disease prior to RT. RT may also be used for management of locally advanced disease not amenable to surgical resection, or for palliation in metastatic disease.

In male patients, complication rates can be as high as 20 percent following RT and include fibrosis, radiation cystitis, urethritis, chronic penile edema, and rarely, fistula formation [43]. Urethral strictures may result from treatment with RT, and strictures require biopsy to rule out recurrent disease.

In female patients, definitive RT is associated with good oncologic outcomes in early-stage urethral cancers. Local disease control rates between 60 and 100 percent have been reported using either brachytherapy, external beam RT, or a combination of both techniques [44-49]. In one observational series, 86 patients were treated with external beam RT, brachytherapy, or combination therapy after excision or biopsy [50]. The five-year local control rate was 64 percent. However, 27 of 55 patients (49 percent) who achieved local control had complications, most of which were moderate or severe in nature, including stenosis, fistulas, hemorrhage of the bladder, and/or necrosis.

Definitive chemoradiation — Definitive chemoradiation (CRT) can be utilized for patients who are not candidates for primary surgery or who refuse surgery [30,51-53]. Definitive CRT has been patterned after that used for anal cancer.

The results with this approach are illustrated by two series:

●In one, 18 male patients (17 with squamous cell carcinoma) were treated with RT to the primary lesion and the regional lymph nodes, followed by two cycles of mitomycin and fluorouracil [30]. Salvage surgery was performed for patients with a recurrence. Most patients (83 percent) had advanced disease (T3 or T4), and one-third had regional lymph node involvement. This approach led to complete response in 15 of 18 patients, with a five-year overall survival rate of 60 percent.

●In another series, 29 male patients (all with squamous cell carcinoma, 88 percent of whom had T3 and/or nodal disease) were treated with CRT consisting of two cycles of fluorouracil and mitomycin, and concurrent external beam RT to include the inguinal and external iliac lymph nodes. With a median follow-up of three years, 79 percent achieved complete response to the treatment. However, 8 of 19 (42 percent) patients with complete response had disease recurrence at a median of 12.5 months. Five-year overall and disease-specific survival rates were 52 and 68 percent [53].

Neoadjuvant and adjuvant systemic therapy — Perioperative treatment with systemic therapy or CRT may decrease tumor bulk and the extent of surgery required to treat a primary urethral carcinoma [54-57].

The choice of systemic therapy regimen is based on histology.

●For patients with urothelial carcinoma, options include cisplatin, gemcitabine, and ifosfamide (CGI); ifosfamide, paclitaxel, and cisplatin (ITP); or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).

●Patients with squamous cell carcinoma can be treated with either CGI or ITP.

●Patients with adenocarcinoma can be treated with gemcitabine, fluorouracil, leucovorin, and cisplatin.

Studies have evaluated the use of neoadjuvant chemotherapy or neoadjuvant CRT in urethral cancer [54-56,58]. As examples:

●In a systematic review of 92 studies that included 25,480 patients with urethral cancer, multimodality therapy with neoadjuvant chemotherapy prior to surgery demonstrated the most consistent overall survival benefits [56].

●The potential role of perioperative treatment was illustrated by a multicenter study of 124 patients with primary urethral cancer in which 39 received perioperative chemotherapy or CRT (12 with neoadjuvant chemotherapy, 6 with neoadjuvant chemotherapy plus RT, and 21 with adjuvant chemotherapy) [54]. At a median follow-up of 21 months, the objective response rates to neoadjuvant chemotherapy and CRT were 25 and 33 percent, respectively. In the overall series, 26 patients had cT3 and/or node-positive disease; in these patients, five had neoadjuvant chemotherapy, and three had neoadjuvant CRT. Surgery was followed by adjuvant chemotherapy in eight, and surgery was used alone in 10. The three-year overall survival rate for the eight patients who received neoadjuvant therapy was 100 percent, while 50 percent of those treated with surgery alone and 20 percent of those given surgery plus adjuvant chemotherapy were alive at three years.

●In an observational study from the National Cancer Database from 2004 to 2016 of 191 male patients with nonmetastatic T2-4 N0-2 M0 urethral cancer treated with radical extirpative surgery, 113 patients (59 percent) did not receive chemotherapy, while 39 patients (20 percent) and 39 patients (20 percent) received neoadjuvant and adjuvant chemotherapy, respectively [55]. At a median follow-up of 28 months, compared with no chemotherapy, neoadjuvant chemotherapy was associated with a decreased risk of all-cause mortality (hazard ratio [HR] 0.50, 95% CI 0.28-0.91), whereas adjuvant chemotherapy was not significantly associated with an overall survival benefit (HR 0.76, 95% CI 0.41-1.41).

For patients receiving neoadjuvant systemic therapy or neoadjuvant CRT, the systemic therapy regimen should be based upon the histology of the tumor. For squamous cell carcinomas that are treated with neoadjuvant CRT, options for concurrent radiosensitizing regimens include mitomycin plus fluorouracil [30] or cisplatin plus fluorouracil. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Concurrent chemotherapy regimen'.)

Urothelial carcinomas that are treated with neoadjuvant systemic therapy should receive a cisplatin-containing regimen, as is used in urothelial bladder cancer. These regimens are discussed separately. (See "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder".)

Adjuvant radiation therapy — Following surgical resection, adjuvant RT may be indicated in patients with locally advanced disease or positive resection margins, although there are limited data to guide management [54,59]. General oncologic principles should be followed when managing locally advanced disease.

One observational study from the National Cancer Database suggested that patients with locoregionally advanced disease treated with surgery may benefit from adjuvant RT, and those with adenocarcinoma histology may benefit from the use of definitive or adjuvant RT rather than surgery alone. This study evaluated the use of surgery, RT, or surgery plus adjuvant RT in approximately 2600 patients with either early stage (T0 to T2, N0) or locoregionally advanced (T3 or greater, node positive) urethral cancer [60]. A majority of the patients (58 percent) had urothelial carcinomas.

Among the entire study population, at median follow-up of 28 months, the three-year overall survival was 54 percent. Among the 1705 patients with early-stage disease, the addition of RT to surgery was not associated with an improvement in overall survival. By contrast, among the 501 patients with locoregionally advanced disease, surgery plus adjuvant RT was associated with an improvement in overall survival compared with surgery alone (52 versus 39 percent, HR 0.58, 95% CI 0.42-0.80). Among patients with squamous cell carcinoma, data suggested similar survival outcomes between all treatment approaches. However, among patients with adenocarcinoma, treatments that utilized RT were associated with improved overall survival compared with surgery alone (HR 0.20, 95% CI 0.07-0.60 for definitive RT alone; HR 0.27, 95% CI 0.10-0.75 for surgery plus adjuvant RT) [60].

Multimodal treatment — A retrospective observational study from Memorial Sloan Kettering Cancer Center suggested that patients with primary urethral cancer can benefit from multimodal therapy. This study evaluated various treatment approaches in 165 patients with primary carcinoma of the urethra [29]. Treatments were categorized as monotherapy: surgery or radiation (57 percent); dual therapy: surgery plus radiation, surgery plus chemotherapy, chemotherapy plus radiation (21 percent); or triple therapy: surgery plus radiation plus chemotherapy (10 percent). Treatment categories accounted for primary, neoadjuvant, and adjuvant treatments but excluded any salvage treatments given after disease recurrence or progression. Most patients in both the monotherapy and dual therapy groups received surgery.

The study cohort included 74 male and 91 female patients, with a median age of 61 years. Common histologies were squamous cell (36 percent), urothelial (27 percent), and adenocarcinoma (25 percent). Seventy-two percent of patients had invasive disease, 24 percent had nodal involvement, and 5 percent had metastases. The median follow-up was 4.7 years.

The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. Treatment patterns were different among male and female patients, with a higher percentage of female patients receiving RT as part of their primary treatment (65 percent) compared with male patients (18 percent). Five-year local recurrence-free, distant recurrence-free, disease-specific, and overall survival were 51, 53, 48, and 41 percent, respectively. Patients receiving monotherapy had lower recurrence-free survival than patients receiving dual or triple therapy. Treatment choice was not associated with distant recurrence, cancer-specific, or overall survival. Pathologic tumor (T) stage and metastatic (M) stage were associated with an increased risk of recurrence and/or death. Urothelial histology was associated with improved overall survival and cancer-specific survival.

PROGNOSIS — 

Factors that may affect prognosis include histology, stage, and location of tumor (eg, posterior tumors have a worse prognosis than anterior tumors [61]), as well as type of treatment facility. Patients treated at academic centers with experience in the management of urethral cancer typically demonstrate superior overall survival, most likely due to the more frequent use of neoadjuvant and adjuvant chemotherapy, radiation, and radical surgery [62]. The impact of various factors and the overall results are illustrated by several observational series:

●A multi-institutional series analyzed outcomes in 154 patients treated over a 10-year period; the series was predominantly comprised of urothelial carcinoma (47 percent), with squamous cell carcinoma (30 percent) and adenocarcinoma (11 percent) representing the majority of the rest. Clinical nodal stage was the only independent predictor for overall survival. Recurrence-free survival was significantly associated with tumor location and age, in addition to clinical nodal stage. No significant association was found between recurrence and histologic subtype [63].

●In an observational series from the Surveillance, Epidemiology, and End Results (SEER) database of 2065 male patients diagnosed with urethral cancer between 1988 and 2006, overall survival at 5 and 10 years was 46 and 29 percent, respectively, while cancer specific survival at 5 and 10 years was 68 and 60 percent, respectively [16]. Most patients were treated with simple surgical excision, with only 10 percent undergoing radical resection and 10 percent receiving radiation therapy (RT). On multivariate analysis, factors associated with an improved prognosis included younger age, the absence of nodal or distant metastases, and lower histologic grade. Prognosis seemed to be slightly better for patients with adenocarcinoma, with 5- and 10-year cancer-specific survivals of 68 and 60 percent, respectively. In the subset of patients with T2 to T4 nonmetastatic disease, surgery appeared to be associated with a survival benefit compared with RT, although there are numerous limitations to such comparisons.

●A SEER database study evaluated prognosis in 722 female patients with primary urethral cancers diagnosed between 1983 and 2008 [64]. There was an even distribution among urothelial, squamous, and adenocarcinomas; 25 percent of female patients identified as African American. Surgery was again the predominant form of treatment, with 69 percent undergoing some form of resection and with 42 percent receiving RT as part of their treatment. Five- and 10-year overall survivals were 43 and 32 percent, respectively, with 5- and 10-year cancer-specific survivals of 53 and 46 percent. In the multivariate analysis, negative prognostic factors included African American race, advanced tumor (T) stage, and node-positive disease. RT, whether used primarily or in the adjuvant setting, did not appear to improve cancer-specific survival, although again, there could have been some selection bias.

●A SEER database analysis of 419 patients with primary urethral cancer cases included 250 male and 169 female patients between 2004 and 2010 [65].The most common histology in male patients was urothelial (54 percent), followed by squamous (35 percent) and adenocarcinoma (29, 11.6 patients). The most common histology in female patients was adenocarcinoma (79, 46.7 percent), followed by squamous (25 percent) and urothelial (25 percent). Increased tumor stage and age were significantly associated with worse overall survival (risk ratio 1.033, 95% CI 1.020-1.046 per year of increased age; risk ratio of 3.71, 95% CI 2.72-5.05 for regional or distant spread).

●The impact of size and location of a urethral cancer in female patients was illustrated by a series of 72 patients treated at Memorial Sloan Kettering over a period of 36 years [66]. Those with tumors ≤2 cm in size in the distal urethra had a 60 percent five-year survival rate, while those with proximal lesions >4 cm only had a 13 percent five-year survival rate.

●In another series from the Republic of Korea, 32 female patients with urethral cancer were evaluated over a 20-year period [67]. At a median follow-up of 56 months, median overall and progression free survival were 70 and 16 months, respectively. On univariate analysis, tumors greater than T2, node-positive disease, and tumor size ≥3 cm were associated with inferior overall survival. There were 15 cases of distant metastasis and five local recurrences. Outcomes were best for squamous cell carcinoma and poor for proximal urethral adenocarcinomas despite extensive treatment.

SURVEILLANCE FOLLOWING TREATMENT — 

All patients require vigilant follow-up after potentially curative treatment given the significant rates of recurrence. Surveillance should include physical examination with close attention to the inguinal lymph nodes, and endoscopic evaluation to look for recurrent tumors in any retained urethra. Cross-sectional imaging may also be required. Recurrences tend to occur more often in the proximal rather than distal location [68].

While there is no evidence to suggest an optimal surveillance schedule, we follow general oncologic principles for follow-up, with visits every three to four months in the first two years, and semiannually for five years, after which patients can be seen annually.

TREATMENT OF RECURRENT OR METASTATIC DISEASE — 

Systemic therapy and/or radiation therapy (RT) is generally the treatment of choice for palliation of recurrent or metastatic disease, although neither is very effective at providing long-term local or distant control [16].

The European Association of Urology guidelines suggest either RT or surgery for local recurrences [69], while the National Comprehensive Cancer Network (NCCN) clinical guidelines suggest systemic therapy, RT, or surgery [70]. Some response has been observed with the combinations of cisplatin and fluorouracil, paclitaxel and ifosfamide, and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) [71]. In general, treatment approaches should be directed at the histology of the tumors. For example, patients with recurrent or metastatic urothelial malignancies may be evaluated for systemic agents used to treat metastatic urothelial carcinoma of the bladder. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

An observational series of 139 patients with recurrent urethral cancer evaluated salvage surgery and/or RT. For patients free of any recurrence, with solitary or concomitant urethral recurrence, and nonurethral recurrence, the three-year overall survival rates were 86, 75, and 48 percent, respectively [72]. In the 80 patients with recurrent disease, the treatment for recurrence was surgery in 30 patients (38 percent), RT in 8 patients (10 percent), and surgery plus RT in 5 patients (6 percent); 37 patients did not receive therapy for recurrence (46 percent). Patients who underwent therapy for recurrent disease demonstrated improved overall survival compared with those who did not receive therapy and demonstrated similar overall survival compared with those who never developed recurrence after primary treatment.

SUMMARY AND RECOMMENDATIONS

●Anatomy and histology – Urothelial carcinoma is more common in male than in female patients. In male patients, urothelial carcinoma is the most common histology, while in female patients, squamous cell carcinoma is more common. (See 'Anatomy and histology' above.)

●Clinical presentation – The clinical presentation of urethral carcinoma varies depending upon sex. Recurrent or persistent urethral stricture, dyspareunia, or unexplained lower urinary tract symptoms should warrant further work-up including thorough physical examination, imaging of the lower urinary tract, and cystoscopy. (See 'Clinical presentation' above.)

●Diagnostic evaluation – Early diagnosis is essential to maximizing the chance for cure. Diagnosis and staging include physical examination of the genitalia, perineum, and urethra, as well as bimanual examination. Cross-sectional imaging should be used for staging and to rule out distant disease. MRI generally provides the best anatomic detail to define the local extent of urethral cancer. (See 'Diagnosis and evaluation' above.)

●Treatment of localized disease – Prospective multi-institutional registries and trials are needed to further characterize this diverse disease to find optimal management strategies. Consultation with and referral to centers with experience is highly recommended and may improve outcomes.

•For male patients with stage Ta, Tis, and T1, solitary, low-grade, papillary lesions, we suggest local treatment with transurethral (endoscopic) resection or fulguration (Grade 2C). This approach allows maximal functional preservation; however, it is associated with a high risk of recurrence, and vigilant endoscopic follow-up is required. Distal lesions that cannot be controlled with endoscopic resection are typically managed with distal partial penectomy. (See 'Surgical approaches for males' above.)

•For female patients with Ta, T1, and T2 lesions of the distal urethra, we suggest local surgical excision (Grade 2C). Radiation therapy (RT) is a reasonable alternative. (See 'Surgical approaches for females' above and 'Radiation therapy' above.)

•For patients with locally advanced (stage T3 or T4) urethral cancer, management consists of a combined modality approach, including neoadjuvant chemotherapy followed by radiation or surgery, or chemoradiation (CRT) followed by consolidation surgery. Surgical treatment consists of an en bloc resection of the urethra, prostate, and bladder, along with penectomy in male patients, and anterior vagina and bladder in female patients with or without a partial pubectomy and may be followed by adjuvant radiation. (See 'Treatment' above.)

●Treatment of recurrent or metastatic disease – Chemotherapy and/or RT are generally the treatment of choice for palliation of recurrent or metastatic disease.

•Chemotherapy options include combinations of cisplatin and fluorouracil; paclitaxel and ifosfamide; and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).

•Patients with recurrent or metastatic urothelial malignancies may be evaluated for systemic agents used to treat metastatic urothelial carcinoma of the bladder. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)