Urethral Cancer

Updated: Jul 21, 2020
  • Author: Joseph Guidos; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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Practice Essentials

Primary urethral cancer (PUC) is an extremely rare lesion that accounts for less than 1% of the total incidence of all malignancies. It has a predilection for men and African Americans. [1, 2]

Nearly all information about the treatment of urethral cancer and the outcomes of therapy is derived from retrospective, single-center case series. The rarity of the disease prevents prospective studies in order to determine the best treatment outcomes. In addition, the differences in urethral anatomy between men and women alter the treatment options available. Location of tumor origin, as well as histology, can also affect treatment options and prognosis. As a result, diagnosed cases of urethral cancer usually lead to an individualized treatment approach.

Anatomic and histologic considerations are pertinent among cases of urethral cancer because of the differences of the urethra between males and females. The longer male urethra is divided into anterior and posterior components, while the female urethra is approximately 4 cm in length and does not require subdivisions.

In both the male and female urethra, the histologic pattern of the urethral mucous membrane progresses from transitional epithelium to squamous epithelium as it continues distally. These mucosal cells are what histologically classify urethral cancer as squamous cell cancer (SCC), urothelial carcinoma (also known as transitional cell carcinoma, TCC), or adenocarcinoma the most common histolog (AC). In men, urothelial carcinoma is the most common histology, followed by SCC and AC; in women, AC is most common, followed by SCC and urothelial carcinoma. [3]

In females, the most common sites of tumor invasion are the labia, vagina, and bladder neck. In males, the most common sites of extension are the vascular spaces of the corpora and periurethral tissues, deep tissues of the perineum, urogenital diaphragm, prostate, and the penile and scrotal skin, where it can cause abscesses and fistulae. [4]

As with most tumors, early detection affords the best chance of cure. Most tumors are localized, with regional metastases to nodal sites seen in up to 30% of cases in both genders. Distant metastases at presentation are rare (0–6%), but occur in up to 40% of cases with recurrent disease. [1]  

The need for multimodal therapy including chemotherapy, radiotherapy, and surgery in the management of PUC, especially for advanced disease, has been well described in the literature. Nevertheless, the ideal combination is unknown. [1, 5]


Relevant Anatomy

The urethra is a mucous membrane supported by a submucosal stroma of connective tissue, elastic fibers, and smooth muscle. The average length of the male urethra is 21 cm, and the female urethra averages 4 cm. In the male urethra, the type of epithelium of this mucosa varies with location. The urethral meatus and fossa navicularis are composed of stratified squamous epithelium.

The penile, bulbar, and membranous portions of the urethra contain pseudostratified and stratified columnar epithelium, whereas the prostatic urethra contains transitional-cell epithelium. In addition, the submucosal glands of Littré communicate with the urethra. The anterior urethra, which is drained by the inguinal nodes, includes the glanular (meatus, fossa navicularis) and penile portions. In contrast, the posterior urethra (bulbous, membranous, prostatic) empties into the pelvic nodes. The male urethra is surrounded by the corpus spongiosum, which lies between the corpora cavernosum. Urethral tumors can extend directly into adjacent structures and vascular spaces because each corpus is encased by a common fascial sheath (Buck).

Male urethral anatomy from most proximal to distal Male urethral anatomy from most proximal to distal. Shown is the prostatic urethra (from bladder neck to the urogenital diaphragm [UGD]), membranous urethra (traversing the UGD), bulbous urethra (from the UGD to the penoscrotal junction), and the penile or pendulous urethra (from the penoscrotal junction traversing distally) with its boat-shaped most distal aspect, the fossa navicularis. Note the adjacent structures of the corpus cavernosum, bladder, prostate, pubic symphysis, perineum, and scrotum, which are sites of local extension and often are excised en bloc.

The female urethra is much shorter, and its histology is somewhat less complex. The distal two thirds are composed of stratified squamous epithelium, while the proximal one third is composed of transitional cells. Skene glands are located in the submucosa of the urethral meatus and are continuous with the urethra. These structures contain pseudostratified and stratified columnar epithelium. The distal one third of the female urethra drains into the superficial or deep inguinal nodes; the proximal two thirds drain into the pelvic nodes (external iliac, internal iliac, obturator).



Given the low incidence of urethral cancer, specific pathophysiologic considerations are unknown. However, it is thought that chronic inflammation, infection, or irritation of the urethra usually precedes the development of urethral cancer. Rapid turnover of the urethral mucosal cells predisposes to the development of dysplasia and neoplasia. Inflammation, infection, and irritation may also impede the natural DNA repair mechanisms of the urethral mucosal cells. The tumor usually invades deeply and metastasizes to adjacent structures. Urethral cancer is often not diagnosed until late, which may limit the benefit of definitive therapies such as surgery and radiation.



The etiology of urethral cancer is obscure. Although cigarette smoking, exposure to aromatic amines, and analgesic abuse are associated with transitional-cell carcinoma of the bladder, no such correlation has been established with urethral carcinoma. However, patients with a history of bladder cancer are at an increased risk of urethral cancer.

Human papillomavirus (HPV) has been associated with nearly one-third of cases of urethral cancer in some studies. In men, the risk factors for PUC include urethral stricture (25–76%), sexually transmitted diseases (24–50%), and trauma (7%). In females, chronic irritation (including HPV infection), diverticula, sexual activity, and childbirth are associated with the development of PUC. [1]  

Chronic inflammation as an etiology of urethral cancer is highly controversial. One study found that 88% of male patients with urethral cancer had a history of stricture; another study found the correlation in only 16% of patients. This is further supported by the high prevalence of primary urethral cancer in the bulbomembranous urethra, which is also the most common location of urethral strictures.

In rare instances, arsenic ingestion has been associated with an increased risk of primary urethral cancer. [6]



A Surveillance, Epidemiology, and End Results (SEER) study representing roughly 10% of the US population reported an incidence of primary urethral carcinoma of 4.3 per million in males and 1.5 per million in females.The incidence increases with age; in the population aged 75-84 years, the incidence is 32 per million in males and 9.5 per million in females. Primary urethral cancer was found to be twice as likely in African Americans as in whites and nearly 3 times more common in males. [7]  

The RARECARE project was completed in 2011 and collected data from 1995-2002 and comprised 32% of the population of the 27 member states of the European Union. [8] The study found an age-adjusted incidence of 1.6 cases per million population in males and 0.6 case per million population in females. It confirmed the previous SEER study findings that incidence increased with age, with highest rates in patients aged 75 years or older.

Urethral cancer has been reported within an age range of 13-90 years, thus occurring at almost any age; however, it is diagnosed most commonly during the seventh decade of life.



In a review of 165 patients treated for primary urethral cancer, estimated 5-year survival rates were as follows [9] :

  • Local recurrence-free survival: 51%
  • Disease-specific survival: 48%
  • Overall survival: 41%

Distal cancers of the male urethra exhibit significantly improved survival rates compared with proximal tumors; the cure rate can reach 90%, thanks to a generally earlier detection referable to more evident symptoms. [8] Proximal neoplasms are usually invasive and more aggressive at presentation and require extended surgery, including resection of the penis, urethra, scrotum, and pubic bone with radical cystoprostatectomy. Disease-free survival for these patients is reported to be between 33% and 45%. [10]

A study using the SEER database concluded that, set against TCC, advanced age, higher grade, higher stage, systemic metastases, other histology (non-SCC, nonadenocarcinoma), and no surgery versus radical resection were predictive of increased likelihood of death as well as death from disease. As compared with TCC, adenocarcinoma was associated with a lower likelihood of death and death from disease. This study illuminates prognostic indicators that previous, smaller studies were unable to reveal, yet it is limited by its lack of data regarding tumor location. [11]

Another study using the SEER database found patient gender had a significant influence on the histologic variant of PUC found at the time of presentation and diagnosis. The most common histology in men was TCC (134, 53.6%), followed by SCC (87, 34.8%) and AC (29, 11.6%). The most common histology in women was AC (79, 46.7%), followed by SCC (43, 25.4%) and TCC (42, 24.9%).  AC cases of PUC have the highest proportion of locally advanced (T3 and T4) disease for males and females, at 41% and 65%, respectively. In male PUC, nodal and metastatic spread is most common in SCC, at 37% and 15%, respectively. However, in female PUC, nodal and metastatic spread is most common in UC cases, at 26% and 19%, respectively. [3]

The perioperative mortality rate is 1-2%. The local tumor recurrence rate is approximately 50%.