Urethral Cancer

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]

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) , transitional-cell carcinoma (TCC), or adenocarcinoma (AC). Squamous cell carcinoma is most common among both genders but adenocarcinomas are noted in 15–35% of cases in women.^[1]

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.^[2]

As with most tumors, early detection affords the best chance of cure. Most tumours 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, 3]}

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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).

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Male urethral anatomy from most proximal to distal. Shown is the prostatic urethra (from bladder neck to the urogenital diaphragm [UGD]), membranous u....

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).

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Pathophysiology

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.

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Etiology

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.^[4]

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Epidemiology

According to the 2016 cancer statistics, malignancy of the urinary system other than bladder, kidney, and renal pelvis was projected to contribute 3,620 new cases and 920 deaths.^[5]  

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 and nearly 3 times more common in males.^[6]  

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.^[7] 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.

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Prognosis

Distal cancers of the male urethra exhibit significantly improved survival rates compared with proximal tumors, and present a cure rate which can reach 90% thanks to a generally earlier detection referable to more evident symptoms.^[7] 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%.^[8]

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.^[9]

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.^[10]

In patients treated with radiation therapy, complications include urethral stricture, radiation cystitis/urethritis, bowel irritation, fibrosis, infection, bleeding, and, rarely, fistula formation or secondary cancers; the overall risk of complication is roughly 20%.^[11]

Patients treated with urethrectomy or partial penectomy have a lower risk of complications from urethral stricture formation or development of urethral fistulae, but these risks should be addressed with the patient prior to surgery. Urinary incontinence may result from bladder overactivity and severe urgency or from damage to the external sphincter, which may lead to stress incontinence or progress to total urinary incontinence.

Tumor recurrence leads to erosion or abscess of the penile, scrotal, and perineal skin. Necrotic tissue at these sites may lead to poor wound healing and the development of fistulae and abscesses, culminating in sepsis.

In patients treated with radical cystoprostatectomy, complications include bowel obstruction, infection, and leakage, primarily due to the use of intestinal or colonic conduits for urinary diversion.

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

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History

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 except for a hard nodular area in the perineum, labia, or along the course of the penis.

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. Male patients may initially be diagnosed for more common causes of symptomatology such as benign prostatic hyperplasia (BPH) or urinary tract infection. Further investigation should be performed if a suspected urinary tract infection recurs quickly or if there is no resolution of symptoms.

Remember also 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, abscess formation, and necrosis).

Although stricture disease is less common in women, chronic inflammation or irritation in the form of infection, urethral polyps, caruncles, or urethral diverticula can give clues to the presence of urethral carcinoma.^[11]

Diminished stream, straining to void, and other obstructive voiding symptoms are common although these are often the symptoms of benign stricture disease or BPH, 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 are reported in association with carcinoma in situ. Incontinence is generally 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.

Other signs and symptoms include:

• Urinary retention from progressive urethral stricture disease 
• Hematuria, urethral or vaginal spotting
• Purulent, foul-smelling, or watery discharge
• Hematospermia
• Perineal, suprapubic, or urethral pain
• Dyspareunia
• Swelling
• Tenesmus
• Priapism

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Physical Examination

Early evaluation should include a thorough physical examination, including a complete genital and rectal examination, with palpation of the entire urethra and perineum. Care should be taken to palpate along the entire urethra and regional lymph nodes, as local invasion occurs early in the disease. Presence of lymphadenopathy should be noted for later surgical consideration. 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 routinely during the examination. The perineum should be examined for abscesses and fistulae, as these may signs of locally advanced disease.

Bimanual examination should be performed as well since it allows the clinician to estimate the extent of local invasion and involvement of the bladder.

Physical examination findings include:

• 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

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Laboratory Studies

Useful serologic studies include basic chemistry and liver function tests, particularly alkaline phosphatase, that may reveal bone metastases. Other useful laboratory studies include complete blood count, urinalysis, and urine cytology. Unfortunately, none of these are a good diagnostic study, and all yield poor sensitivity. Dalbagni et al showed that urine cytology in particular yields poor sensitivity in diagnosing urethral carcinoma.^[12] For proper and timely diagnosis, one must have a keen index of suspicion and access to cystoscopy.

Perform urine culture to rule out infection. Any and all local wound infections or drainages should be assessed via culture and cytology examination because local invasion of urethral cancer can create sinus tracts, fistulae, and abscesses.

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Imaging Studies

Contrast extravasation during imaging is evidence of urethral fistula and should increase suspicion of urethral carcinoma.

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(A) Normal anatomy. Sagittal T2-weighted image labelling the prostatic, membranous, and bulbous segments of the normal male urethra. (B) Normal anatom....

MRI has evolved into a superior imaging modality for the evaluation of urologic malignancies. MRI is being used increasingly in determining the extent of local invasiveness of urethral neoplasms for accurate staging and preoperative planning. Iodinated contrast is not needed. Blood flow into vascular spaces can often be visualized without enhancement.

When contrast is required to detect enhancing lesions, gadolinium-diethylenetriamine pentaacetic acid has been used as an intravascular agent. Reactions to this agent are rare, and renal function is not as significant a factor as it is for iodinated contrast, which is used for intravenous urography (IVU) and computed tomography (CT) scanning.

MRI offers multiplanar imaging using 3 orthogonal planes, thus providing more anatomic detail and excellent soft-tissue contrast with the use of spin-echo T1- and T2-weighted images. In both men and women, MRI can assess local disease extension and increase accuracy of staging with wide-field imaging and the use of special suprapubic and transrectal phased array coils. Lymph nodes can be evaluated simultaneously, and differentiation between nodes and vessels is easier with MRI than with CT scanning.

MRI also may be useful in monitoring the effect of neoadjuvant chemoradiotherapy changes prior to surgery. A retrospective study of a small number of female patients performed by Gourtsoyianni et al found that MRI was accurate in the evaluation of tumor extension in all patients after completion of chemoradiotherapy.^[13]

MRI is not without its drawbacks. In addition to its cost, it is a sophisticated imaging technique and requires specialized personnel to provide adequate imaging and interpretation. Benign urethral lesions may mimic characteristics of solid urethral masses. As with other imaging modalities, MRI is unable to detect micrometastases and cannot definitively determine prognosis. Despite these drawbacks, MRI is being used increasingly for the staging of urethral cancer and is typically the imaging modality of choice in the evaluation of patients with urethral cancer.

Staging of urethral cancer is typically performed via chest radiography and/or CT scanning of the chest, abdomen, pelvis, and perineum. Radionuclide bone scans are useful in detecting metastases with advanced local disease or elevated alkaline phosphatase levels.

Other studies that have historically been used and can be considered in the workup of urethral cancer. IVU primarily is useful in evaluating hematuria if this is the presenting symptom and the diagnosis has not yet been confirmed. However, if urethral cancer is strongly suspected, CT scanning would be preferable because it would help evaluate both the upper tracts regarding the hematuria and the adjacent pelvic structures for the extent of possible tumor invasion.

Retrograde urethrography and voiding cystourethrography may be helpful for diagnosis in conjunction with cystoscopy. An irregularly shaped urethra raises the index of suspicion. Remember that the association between urethral strictures and urethral cancer is highly significant.

Positron emission tomography (PET) is generally not indicated in patients with primary urethral cancer, but it may be useful if there is concern for metastases. PET scanning is most valuable in the evaluation for suspected metastases to distant sites after local treatment and in evaluating treatment for systemic disease with chemotherapy.

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Other Tests

Flexible cystoscopy is a minimally invasive office procedure that has proven to be the most sensitive test for detecting lower urinary tract cancer. One can evaluate the extent of urethral involvement of strictures or tumors in preparation for tissue diagnosis. Biopsies are probably best reserved for the operating room, where anesthesia is available.

Be wary of any papillary mass, macular or papular areas, or mucosal ulceration at the time of cystoscopy. Also be aware of any particularly erythematous areas. Benign urethral stricture disease is generally represented by spongiofibrosis, which appears smooth, flat, regular, and nonerythematous. Any of the aforementioned sites should raise one's index of suspicion, and biopsy would be indicated.

Because many urethral cancers create and/or arise in the setting of urethral stricture(s), it is often not possible to directly visualize the entire urethra. In the setting of known urethral cancer, it is not advisable to dilate the urethra, because this may result in further pain, bleeding, and disruption of the tumor.^[11]

Direct visual cystoscopy is appropriate, as urethral cancer (particularly transitional-cell carcinoma) is generally not the primary site if the bladder is also involved. For instance, primary urothelial carcinoma of the prostatic urethra without bladder involvement is staged as urethral cancer, but, if a synchronous bladder tumor is present, the cancer is staged as a bladder tumor based on the depth of invasion of the bladder lesion. Some experts contend that this is a stage 4 bladder cancer regardless because of the extension into the prostate.

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Diagnostic Procedures

Transurethral biopsy is essential to confirm a cystoscopic finding of urethral cancer. Under direct vision, biopsy forceps or an electric loop with a cutting current is extended from the cystoscope to resect and obtain a satisfactory biopsy specimen. In very superficial tumors, this resection technique can be both diagnostic and therapeutic. Caution is indicated, however, if the tumor is located close to the external sphincter muscle as urinary incontinence can result in both men and women from overly aggressive resection.

Percutaneous aspiration of a local fluctuant mass can be studied for culture and cytology.

Needle-core biopsy may prove diagnostic on a palpable lesion deep to the skin.

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Histologic Findings

Male urethra

Tumors of the male urethra can be categorized according to the location and histology of the cells. Anatomic distinctions are helpful not only in predicting the histologic association of the neoplastic cells but also in planning treatment. The male urethra is subclassified anatomically as follows:

• Prostatic urethra: This is the urethra as it traverses from the bladder neck to the urogenital diaphragm (UGD).
• Membranous urethra: This is the urethra traversing the UGD, including the external sphincter muscle.
• Bulbar urethra: This is the portion of the urethra measuring from the UGD to the penoscrotal junction.
• Penile or pendulous urethra: This is the remainder of the urethra as it extends from the penoscrotal junction to the urethral meatus. The terminal aspect of the penile urethra is referred to as the fossa navicularis.

The prostatic urethra is lined predominantly by transitional cells, while the bulbar, membranous, and penile urethras are lined by a stratified or pseudostratified columnar epithelium. Patches of stratified squamous epithelium are common in the bulbar and penile urethra and become predominant in the distal urethra. At the terminal fossa navicularis, stratified squamous epithelium occurs as a rule. Within the mucosa, occasional mucous goblet cells may be found throughout the length of the urethra.

Female urethra

The female urethra is 3-4 cm in length and is lined primarily by stratified squamous cells, although pseudostratified columnar epithelium can be found. The epithelium forms numerous invaginations, the outpocketings of which are lined by clear mucous cells.

Generally, the proximal two thirds of the female urethra demonstrates high-grade locally advanced tumors, while the distal third usually contains low-grade less extensive carcinomas.

Studies suggest that primary urethral cancer may manifest as transitional cell carcinoma (55%), squamous cell carcinoma (21.5%), and/or adenocarcinoma (16.4%).^[6] This is in contrast to findings in previous studies, which suggested squamous cell carcinoma was the most prevalent histiologic subtype. Studies prior to the SEER study concluded that these tumors occur predominantly in the bulbomembranous urethra (60%), followed by the penile urethra (30%), and then by the prostatic urethra (10%). The larger SEER study did not include information on tumor location.

See the image below.

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Illustration of the male urethra in the sagittal plane highlighting the percentage of urethral carcinoma by location (1st percentage) and the most com....

In general, proximal tumors (prostatic urethra in men, proximal third in women) are conventional urothelial carcinomas the majority of the time. Distal carcinomas (membranous, bulbar, or penile urethra in men, distal two thirds in women) may be transitional or squamous cell carcinomas. Adenocarcinoma may arise at any site along the urethra and is commonly associated with diverticula and prostatic adenocarcinoma. Other rare types of primary urethral cancer have been reported in the literature and include lymphoma, melanoma, paraganglioma, sarcoma, small cell, and undifferentiated tumors.^[11]

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Staging

Once the diagnosis is confirmed by biopsy, clinical staging is important in establishing a therapeutic plan and in determining prognosis. Staging is the primary factor influencing the type and extent of treatment. Modalities used to clinically stage urethral cancers include physical examination, chest radiography, and CT scans of the abdomen and pelvis.

Urethral cancer is staged according to the Tumor Node Metastasis (TMN) criteria outlined by the American Joint Committee on Cancer staging system, as shown below.^[14]

Primary tumor (T):

Male Penile Urethra and Female Urethra:

Tx - Primary tumor cannot be assessed

T0 - No evidence of primary tumor

Ta - Noninvasive papillary carcinoma

Tis - Carcinoma in situ

T1 - Tumor invading subepithelial connective tissue

T2 - Tumor invading corpus spongiosum or periurethral muscle

T3 - Tumor invading corpus cavernosum or anterior vagina

T4 - Tumor invades other adjacent organs (ie, bladder)

Prostatic Urethra

Tx - Primary tumor cannot be assessed

T0 - No evidence of primary tumor

Ta - Noninvasive papillary carcinoma

Tis - Carcinoma in situ involving the prostatic urethra or periurethral or prostatic ducts without stromal invasion

T1 - Tumor invading subepithelial connective tissue immediately underlying the urothelium

T2 - Tumor invading prostatic stroma surrounding ducts either by direct extension from the ureothelial surface or by invastion of the prostatic ducts

T3 - Tumor invading the preiprostatic fat

T4 - Tumor invades other adjacent organs (ie, bladder wall, rectal wall)

Regional lymph nodes (N):

Nx - Regional lymph nodes cannot be assessed

N0 - No regional lymph node metastasis

N1 -Metastases in a single regional lymph node in the inguinal region or true pelvis or presacral lymph node

N2 - Metastases in a multiple lymph nodes in the inguinal region or true pelvis or presacral lymph node

Distant metastases (M):

Mx - Distant metastases cannot be assessed

M0 - No distant metastases

M1 - Distant metastases

AJCC Prognostic Groups

Stage 0is: TIS, N0, M0

Stage 0a:  Ta, N0, M0

Stage I: T1, N0, M0

Stage II: T2, N0, M0

Stage III: T1, N1, M0; T2, N1, M0; T3, N0, M0; or, T3, N1, M0

Stage IV:  T4, N0, M0; T4, N1, M0; Any T, N2, M0; or Any T, Any N, M1

Histologic Grading

Gx Grade cannot be assessed

G1 Well differentiated

G2 Moderately differentiated

G3 Poorly differentiated

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Approach Considerations

Treatment is 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 patient's medical team may advise that radical intervention is relatively contraindicated based on a risk-benefit analysis.

Accurate staging of the tumor is essential prior to definitive surgery, particularly if significant reconstruction is required. The patient should have already been to the operating room at least once for a transurethral biopsy and examination under anesthesia. Based on these findings, an imaging modality such as MRI or CT scanning should be performed to predict the extent of local invasion.

After accurate staging, the urologist should have a lengthy discussion with the patient regarding the extent and severity of disease. The issues of reconstruction, urinary diversion, social and family support, and physical therapy are of paramount importance. Educational materials should be provided. A good source for both patient and physician is CancerNet.

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Medical Care

Therapeutic management varies with the stage and location of the lesion. Because of the rarity of this pathology and the lack of statistical analysis on the data, no consensus has been reached on treatment modalities. Distal urethral tumors are usually discovered earlier, at a lower stage, whereas proximal urethral malignancies present at a more clinically advanced stage.^[15]

If the disease is invasive, extending for more than half of the penile urethra, the radiotherapy can be a treatment option for unresectable lesions.  Radiotherapy and chemotherapy can be applied to tumors located in bulbocavernosus urethra even for those occurring in the prostatic urethra. In cases of advanced injuries, the treatment applied is extensive surgery with chemotherapy and adjuvant radiotherapy. Chemotherapy alone is the only option for cases of extensive metastasis.

Radiation therapy

Radiation therapy has several roles in the management of urethral cancer, including use as primary therapy, in combination with chemotherapy and/or surgery, or as adjuvant treatment for local recurrence after surgery. Radiation therapy includes external beam, brachytherapy, or a combination. Definitive radiation is sometimes used for advanced-stage tumors, but because monotherapy of large tumors has shown poor tumor control, it is more frequently incorporated into combined modality therapy after surgery or with chemotherapy. The most commonly used tumor doses are in the range of 60 Gy to 70 Gy.^[16]  

Severe complication rates for definitive radiation are about 16% to 20% and include fistula development, especially for large tumors invading the vagina, bladder, or rectum. Urethral strictures also occur in the setting of urethral-sparing treatment. Toxicity rates increase at doses greater than 65 Gy to 70 Gy. Intensity-modulated radiation therapy has come into more common use in an attempt to decrease local morbidity of the radiation.^[16]

Chemotherapy

The literature on chemotherapy for urethral carcinoma is restricted to retrospective, single-center case series or case reports. A wide variety of agents used alone or in combination have been reported over the years, and their use has largely been extrapolated from experience with other urinary tract tumors.^[16]

Combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or cisplatin, methotrexate, and vinblastine (CMV) regimens have shown survival benefit in the treatment of transitional-cell bladder cancer and have become the regimens of choice for metastatic urothelial cancer.^[17]  Although no prospective studies have been performed for urethral cancer, either regimen may provide benefit in locally advanced disease.

National Comprehensive Cancer Network (NCCN) guidelines recommend choosing the chemotherapy regimen on the basis of histology. Cisplatin, gemcitabine and ifosfamide are recommended for squamous cell carcinoma; 5-fluorouracil (5-FU), gemcitabine, and cisplatin-based regimens for adenocarcinoma; and MVAC for urothelial tumors. In addition, there is a reported efficacy of combined chemoradiation with 5-FU and mitomycin C in a series of male patients with squamous cell carcinoma.^[18]  

Dayyani et al retrospectively studied 44 patients (64% women) with primary urethral cancer, of whom 43% had lymph node–positive disease and 16% had distant metastases.^[19]  The overall response rate to platinum-containing neoadjuvant chemotherapy was 72%, with median overall survival for the entire cohort of 31.7 months. Twenty-one patients with locally advanced or lymph node positive disease underwent chemotherapy plus surgery, and their median overall survival from chemotherapy initiation was 25.6 months. Of patients with lymph node–positive disease at diagnosis, 44% were alive at a minimum follow-up of more than 3 years.

Multimodality therapy appears to be the mainstay treatment to achieve the longest survival without evidence of disease. Although patients with low-stage disease show good survival with single-modality therapy, Eng et al (2003), as well as others who have performed retrospective studies, have reported that patients with higher-stage cancer fared much better when they received multimodality therapy in the form of either chemotherapy with radiation therapy or neoadjuvant chemotherapy with radiation therapy prior to surgery.^[20]

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Surgical Care

Surgery is indicated to confirm a diagnosis of clinically suspected urethral cancer. More extensive surgery is required 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. Surgical excision remains the criterion standard as a primary mode of treatment for urethral cancer for both male and female patients. The extent of surgery depends on the location of the tumor within the urethra and the clinical stage. The extent of local invasion must be accurately predicted to ensure en bloc resection of all involved structures.

The literature describes the following four modalities of surgical management in male urethral cancer:

• Conservative therapy or local excision
• Partial penectomy
• Radical penectomy
• Pelvic lymphadenectomy and en bloc resection including penectomy and cystoprostatectomy with removal of the anterior pubis

Conservative therapy or local excision

More conservative procedures can be acceptable in selected cases with superficial involvement, papillary tumors, or low-degree tumors. Endoscopic treatment is performed with either transurethral electroresection or fulguration or transurethral laser therapy. This technique tends to work for patients with localized low-grade disease (clinical stage lower than T2), in whom the location allows adequate visualization and reduces the risk of iatrogenic incontinence. However, this approach carries the highest risk of recurrence and the potential for the development of urethral stricture disease.^[21]

Commonly used lasers for this purpose include the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, the carbon dioxide laser, and the holmium:YAG laser. The Nd:YAG and carbon dioxide lasers are used for vaporization and fulguration; therefore, these do not provide the surgeon with a tissue diagnosis. The holmium:YAG laser has been used to resect urothelial tumors in such a way that it provides a noncauterized tissue sample. Although it has not been exclusively studied in the management of urethral cancer, it has been reported as useful for urethral strictures and superficial bladder cancer and may provide benefit.

Segmental resection with reconstruction is another alternative for localized disease. The urethra can be surgically removed with clean margins for very distal urethral tumors in men, and the healthy urethra can be mobilized and advanced to create a new urethral meatus. In general, segmental resection is not reasonable in women except for very distal tumors. If the length of resected segment prevents advancing of the urethra, several options exist for reconstruction.

One such option is to leave the male patient with a hypospadic urethral meatus, which allows for voiding while sitting as long as the opening is along the penile shaft. If the urethral resection is too extensive, a perineal urethrostomy can be performed instead.

An alternative is to perform reconstruction at a later date by replacing the urethral mucosa with buccal mucosa. This should be considered after a period of 3-6 months to ensure that no recurrence is present at the proximal urethra.

Partial penectomy

Partial penectomy involves excision of the malignant lesion with 2-cm margins. This treatment modality can be used only for infiltrative, distally occurring lesions of the penile urethra. If the proximal half of the penile urethra is involved with infiltrating tumor, then a total penectomy is indicated. Ilioinguinal node dissection is performed only if the nodes are palpable. In contrast to penile cancer, no apparent benefit is associated with prophylactic groin dissection.

Total or radical penectomy

Total penectomy involves removal of the penis, urethra, and penile root. This surgery is used primarily for lesions that are not amenable to partial penectomy (ie, infiltrative proximal penile urethral carcinomas). This treatment for invasive disease is reported in literature in 10.1% of patients.^[8]

The calculated local recurrence rate in patients with posterior disease who underwent exenteration, with or without lymph node dissection, decreased from 68% to 24% with the addition of en bloc pubectomy.^[1]  

En bloc resection

En bloc resection is reserved for patients with T2/Nx/M0 or higher tumors in the bulbomembranous or prostatic urethra. Although poor survival figures are associated with these lesions, radical en bloc excision offers the best chance for long-term disease control and prevention of disease recurrence.

This surgery includes a pelvic lymphadenectomy with an en bloc total penectomy, cystoprostatectomy, urinary diversion, and in-continuity resection of the pubic rami and urogenital diaphragm. Portions of the scrotal and perineal skin and soft tissues may require excision with bulky tumor involvement of these structures. Similarly, the pubic symphysis is resected if bulky disease involves the presymphyseal tissues.

The testicles may be preserved in thigh pouches if extensive scrotal skin is excised. In females, removal of most if not all of the vagina is necessary. In males and females alike, inguinal lymphadenectomy is performed only if palpable disease is present. The most common form of urinary diversion in the event of cystectomy is an ileal conduit that is incontinent to the skin.

Kaplan et al (1967) used this procedure in a group of 28 patients with bulbomembranous urethra tumors. Of these patients, 16 died of this disease, 6 survived longer than 5 years, 3 developed local recurrences but did not die, and 3 were lost to follow-up.^[22]

Dinney et al (1994) described their study of 5 patients with bulbomembranous urethral cancer who were treated with radical cystoprostatectomy, penectomy, urethrectomy, scrotectomy, and resection of the inferior pubic rami. They cured 1 patient, but lost the other 4 patients—3 to local recurrence and 1 to heart disease. Because these patients had high-stage disease, consider selection bias when evaluating the efficacy of this therapy.^[23]

In 1998, Dalbangi et al retrospectively identified 46 patients who were treated by surgery (all 4 modalities). They found that 38% of 18 patients with anterior urethral tumors survived, whereas only 14% of 28 patients with posterior urethral malignancies survived. These studies indicate that surgery alone can be used as a definitive therapy in selected cases, namely low-grade or low-stage malignancies; however, it is an ineffective treatment in advanced urethral carcinomas.^[12]

Primary melanoma of the urethra presents a unique challenge compared with other histologic types. Oliva et al (2000) found that, despite distal locations and urethral confinement at the time of surgery, 9 of 15 patients survived less than 5 years.^[24]  Perhaps combination therapy, consisting of radical surgery and adjuvant chemotherapy and radiation therapy, may improve these rates by destroying cancer cells that evaded surgical treatment. Chemotherapy may have a particularly good effect on primary melanoma of the urethra, considering the brisk mitotic activity of this histologic subtype.

Postoperative Care

General postoperative precautions that are paramount to reducing complications include the following:

• Hemodynamic support with intravenous fluids, both crystalloid and colloid
• Intravenous antibiotics
• Incentive spirometry and aggressive pulmonary toilet
• Deep venous thrombosis prophylaxis

Strict measurement of 24-hour input and output from all drains should be carefully and clearly recorded in order to manage fluid status appropriately and determine whether spontaneous diuresis is progressing. Use of diuretic agents may be required based on these recordings.

Stoma nurse care and teaching is necessary, particularly for when the patient is discharged home, because they will likely need to record their output initially. Initial teaching of stomal appliance care and/or intermittent catheterization provides the patient with much- needed autonomy and leads to the development of a positive and proactive self-image. Visiting nurse assistance may be necessary if the patient cannot initially meet the high demands these procedures require.

Physical therapy is often required, particularly if portions of the pubic rami have been resected.

• References

Consultations

Consultations with a plastic surgeon and orthopedic surgeon should be requested prior to surgery, and their presence should be readily available in the operating room. Social interaction should be monitored because patients with this disease may require a psychiatric consultation liaison. Social support services may provide the patient with much-needed empathy.

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Long-Term Monitoring

On follow-up visits, carefully obtain a history, with particular attention to new symptoms such as the following:

• Hematuria
• Decreased urine output
• Voiding symptoms (if the urethra has been preserved)
• Gastrointestinal symptoms
• Changes in bowel habits
• Weight loss and other constitutional symptoms
• Bone, back, or flank pain
• Neurologic symptoms

Periodically examine the remaining urethra, pelvis, and inguinal regions. Perform urinalysis, urine cytology, and cystoscopy periodically. Significant hematuria, urinary tract infections, and malignant cells noted in the urine all should be addressed promptly and appropriately. If lesions are noted upon cystoscopy, they should be subsequently biopsied. Fistulae should be identified and treated quickly to minimize morbidity. Further investigation into tumor recurrence should be initiated if fistulae are identified.^[25]

Imaging studies of the pelvis (ie, CT scanning with intravenous contrast) should be performed every 6 months to a year to check for local recurrence or hydronephrosis.

Perform periodic chest radiography and comprehensive metabolic panel blood tests every 3 months initially for the first 2 years, then every 6 months for up to 5 years, and annually thereafter. Rising serum urea nitrogen and creatinine levels may suggest an obstructive process or some element of renal toxicity. A new lesion noted on a chest radiograph would require CT scanning to further characterize it and possibly obtain a CT-guided biopsy specimen. If metastatic disease is confirmed, systemic chemotherapy should be strongly considered.

• References

Guidelines Summary

The following organizaitons have released guidelines for the management of urethral carcinomas:

• National Comprehensive Cancer Network (NCCN) 
• European Society for Medical Oncology (ESMO) 

Diagnosis

NCCN guidelines recommend referral to a specialized center and require the following for a diagnosis^[18] :

• Cystourethroscopy including exam under anesthesia and transurethral resection or transvaginal biopsy
• Chest x-ray
• MRI of pelvis with our without contrast

If palpable inguinal lymph nodes are present, a CT scan and lymph node biopsy should be performed.^[18]  

There are no significant differences in the EAU guideline recommendations.^[7]

Treatment

Tis, Ta, T1

NCCN guidelines recommends repeat of transurethral resection followed by intraurethral chemotherapy of Bacillus Calmette-Guerin (BCG) therapy in select cases.^[18]

T2-Women

NCCN guidelines recommends either chemoradiotheapy or urethrectomy and cystectomy.^[18]

EAU guidelines recommend offering local radiotherapy as an alternative to urethral surgery, but cautions that local toxicity needs to be considered. In women with anterior urethral tumours, urethra-sparing surgery is an alternative to primary urethrectomy if negative surgical margins can be achieved intraoperatively.^[7]

T2-Men

NCCN guidelines treatment recommendations are summarized below.^[18]

For pendulous urethra, either:

• Distal urethrectomy
• Partial penectomy

If positive margins are present, either:

• Additional surgery
• Chemoradiotherapy (preferred)
• RT 

For bulbar urethra:

• Urethrectomy with or without cystoprostatectomy

If pT3/pT4, pN1, pN2 consider either:

• Chemotherapy
• Chemoradiotherapy

T3/T4

NCCN guidelines recommendations are summarized below.^[18]

For patients with regional lymph nodes staged cN0, either:

• Neoadjuvant chemotherapy and consolidation with surgery or RT
• Chemoradiotherapy (preferred)
• RT

For patients with regional lymph nodes staged cN1/cN2, either:

• RT with chemotherapy (preferred for squamous cell carcinoma)
• Chemotherapy
• Chemoradiotherapy followed by consideration of consolidation with surgery

Distant Metastasis

NCCN guidelines recommend either systemic therapy or chemoradiotherapy.^[18]

• References