Urethral Cancer 

Urethral cancer is an extremely rare lesion, with fewer than 2000 reported cases. Urethral cancer comprises less than 1% of the total incidence of malignancies. Because many medical centers see only a few cases over many years, not enough data are available from large series to dictate the best-accepted treatment.

As with most tumors, early detection affords the best chance of cure. Once invasive cancer is detected, radical surgery is indicated, although the prognosis is usually poor.

Urethral carcinoma presents certain anatomic and histologic considerations, particularly concerning the differences between the male and female urethra and the respective adjacent structures. In general, however, in both males and females, urethral cancer tends to invade locally and to metastasize to adjacent soft tissues. Therefore, most of these tumors are locally advanced at the time of diagnosis, reflecting the generally poor prognosis despite aggressive treatment. Urethral cancer rarely metastasizes to distant loci. Only 14% of female patients with urethral cancer have evidence of metastatic spread.

Anatomic and histologic considerations exist among cases of urethral cancer because of the uniqueness 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, transitional-cell carcinoma, or even adenocarcinoma secondary to transitional cell metaplasia.

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 causes abscesses and fistulae.

Frequency

The incidence of primary urethral cancer is higher than was once speculated. A Surveillance, Epidemiology, and End Results (SEER) study representing roughly 10% of the US population reported an incidence of 4.3 per million in males and 1.5 per million in females. The incidence increases with age; an incidence of 32 per million and 9.5 per million was found in males and females aged 75-84 years, respectively. Primary urethral cancer was found to be twice as likely in African Americans as in whites.^[1]

Larger studies including a report using the SEER database suggest that primary urethral cancer may manifest as transitional cell carcinoma (55-77.6%), squamous cell carcinoma (11.9-21.5%), and/or adenocarcinoma (5-16.4%) and other histology (5.5%).^{[1, 2]} This is in contrast to findings in previous studies, which suggested squamous cell carcinoma was the most prevalent histiologic subtype.

Accurate epidemiology is difficult for many reasons. For one reason, many patients diagnosed with urethral cancer have advanced disease; thus, it may be difficult to distinguish between primary urethral transitional cell carcinoma and locally advanced transitional cell carcinoma of the bladder. Furthermore, the low incidence of primary urethral cancer complicates meta-analysis.

Cancers of the meatus and permeatus are rare because papillomas and condylomata rarely transform into malignant clones. Likewise, melanoma of the urethra is reported in the literature but is clinically rare.

Race:  African Americans are at twice the risk of developing primary urethral cancer as are whites.^[1]

Sex:  Literature suggests that primary urethral cancer is nearly 3 times more common in males.^[1]

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

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 exists with urethral carcinoma. Patients with a history of bladder cancer are at an increased risk of urethral cancer.

Various studies cite infection and chronic irritation as etiologic in the tumorigenesis of this malignancy.

Kaplan et al (1967) found that 37% of males with urethral cancer had some history of venereal disease.^[3]

Ray et al found a 44% concordance of urethral cancer and a history of sexually transmitted diseases. In addition, human papillomavirus (HPV) has been associated with some cases of urethral cancer. Wiener et al (1992) demonstrated HPV DNA in 4 of 14 (29%) cases of primary urethral cancer.^[4]

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.^[5]

No such associations have been established in females, although chronic irritations from parturition, coitus, and infection have been proposed as etiologic.

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 impede the natural DNA repair mechanisms of the urethral mucosal cells. The tumor develops and invades deeply in order to metastasize to adjacent structures. The tumor thus becomes elusive to definitive therapies such as surgery and radiation.

The signs and symptoms of urethral cancer vary and are neither diagnostic nor pathognomonic. Generally, the onset is insidious, and symptoms are usually more attributable to benign stricture disease (ie, bladder outlet obstruction, overflow incontinence) rather than malignancy (ie, perineal pain, hematuria). In fact, in both sexes, the cancer may be completely asymptomatic.

The interval between the onset of symptoms and diagnosis may be as long as 3 years because of misdiagnoses and failure by the patient to seek medical consultation. Remember that these tumors have a propensity to be highly advanced locally at the time of diagnosis. A raised index of suspicion is advisable if an elderly man presents with stricture disease, particularly if symptoms are more consistent with malignancy or local extension (ie, urethral fistulae, necrosis and abscess formation).

Early evaluation should include cytologic analysis, imaging, and endoscopic management with biopsy of the strictured area, particularly if it appears abnormal (ie, irregular borders, erythema, macular or papular appearance, surface ulceration and tissue sloughing). This is in contrast to benign urethral stricture disease, which generally appears as smooth gray-white areas of spongiofibrosis.

Symptoms

• Diminished stream, straining to void, and other obstructive voiding symptoms (Although these are often the symptoms of benign stricture disease, a neoplasm may be concealed by the presentation of a routine stricture. Keep a high index of suspicion in patients with a history of urethral stricture disease and keep a vigilant eye over the proceeding cytological analysis, radiographic imaging, and cystoscopy.)
• Frequency, nocturia, itching, dysuria, and other irritative voiding symptoms (These are reported notoriously in association with carcinoma in situ.)
• Incontinence (Generally, this is overflow incontinence caused by bladder outlet obstruction due to urethral stricture disease. However, severe urgency may progress to urge incontinence and distortion of the urethral anatomy in females and may lead to stress urinary incontinence.)
• Urinary retention from progressive urethral stricture disease
• Hematuria, urethral or vaginal spotting
• May produce no symptoms except a hard nodular area in the perineum, labia, or along the course of the penis
• Purulent, foul-smelling, or watery discharge
• Hematospermia
• Perineal, suprapubic, or urethral pain
• Dyspareunia
• Swelling
• Tenesmus
• Priapism

Signs and physical examination findings

• Urethrocutaneous fistula
• Urethrovaginal fistula
• Urethral diverticula
• Periurethral abscess or areas of tissue necrosis
• Recurrent urinary tract infection
• Penile or vaginal lesions
• Lymphadenopathy
• Palpable mass along the course of the urethra

Physical examination

• Care should be taken to palpate along the entire urethra and regional lymph nodes, as local invasion occurs early in the disease.
• The meatus should be examined closely with attention to mucosal irregularities or bloody discharge.
• Venereal diseases increase the risk of urethral cancer and should be identified during the examination.
• The perineum should be examined for abscesses and fistulae, as these may signs of locally advanced disease.
• Contrast extravasation during imaging is evidence of urethral fistula and should increase suspicion of urethral carcinoma.
• Bimanual examination is indicated, as it allows the clinician to estimate the extent of local invasion and involvement of the bladder.

Surgery is indicated to confirm a diagnosis of clinically suspected urethral cancer. More extensive surgery is indicated for local control of a primary urethral neoplasm and depends on the size, location, and extent of the tumor and the overall condition of the patient.

Tumors at the meatus can simply be excised, although the entire urethra requires inspection. Cytologic washings, cold-cup biopsies, and endoscopic transurethral resections (TURs) are useful for diagnostic information. Noninvasive lesions may be managed expectantly, with repeat TUR for recurrences. More invasive lesions require more extensive surgery with wide margins in an attempt to remove the burden of aggressive or locally invasive disease. Surgery can also be used for palliative measures. However, tissues may not heal well after surgery for locally advanced disease, resulting in fistulas and dehiscences.

Lymphadenopathy in the presence of urethral cancer again depends on the anatomic location of the primary tumor. Therapeutic lymphadenectomy has been reported as successful in anterior urethral lesions, but no advantage to prophylactic surgery has been documented as has been in primary penile cancer. Lymphadenopathy secondary to a primary posterior urethral cancer generally portends an ominous prognosis. Only occasionally has survival been reported after lymphadenectomy with positive nodes in posterior urethral carcinoma.

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).

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).

No absolute contraindications exist for the treatment of urethral cancer. Treatment is decided based on the clinical stage of the disease at the time of diagnosis. Considering the notoriously aggressive nature of the disease, radical surgery is generally recommended to improve 5-year disease-specific survival rates. Minimally invasive bladder-sparing techniques have been gaining acceptance in highly select patients in whom superficial disease is detected. This less aggressive approach preserves body image and cosmesis, as well as sexual and reproductive function; however, aggressive, careful, and frequent follow-up is mandatory.

Patients' medical conditions should be optimized prior to any operative intervention in order to decrease the likelihood of intraoperative complications. This should include standard preoperative testing and clearance by specialized services (eg, cardiologist, pulmonologist) in patients with complex medical histories. This medical treatment should likewise continue postoperatively to minimize postoperative morbidity.

Certain relative contraindications should be considered, particularly when the risks of surgery and the long anesthetic time required for radical surgery outweigh the benefits of the resection. Patients with multiple serious comorbidities and aggressive locally advanced or metastatic disease that will probably not be cured despite radical surgery may be considered as nonoperative candidates.

Additionally, local postoperative complications may occur (eg, poor wound healing and subsequent fistula and abscess formation) in patients with poor nutritional status. In such patients, radiation and chemotherapy may provide palliative care, although these treatments have their own complications. Radiation can lead to local ischemia, and, ultimately, the same local complications listed above may ensue. Each chemotherapeutic agent has its own specific adverse effects.

The basic principle is that the patient must understand the potential risks and benefits of the different treatments for the disease, and they must consider the biological nature of the disease. Once they understand these, they may decide whether they want to proceed with radical surgery. The health professionals may decide that radical intervention is relatively contraindicated based on a risk-benefit analysis.