eMedicine Specialties > Urology > Cancer, Bladder, Penis, and Urethra

Urethral Cancer

Christopher Powell, Senior Medical Student, Medical College of Georgia
Jack H Mydlo, MD, Chief, Department of Urology, Woodhull Hospital; Chair and Professor, Department of Urology, Temple University School of Medicine; Jeffrey M Donohoe, MD, Assistant Professor of Pediatric Urology, Department of Surgery, Division of Urology, Medical College of Georgia Children's Medical Center; Fellow of the American Academy of Pediatrics

Updated: Oct 29, 2009

Introduction

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.

History of the Procedure

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.

Problem

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

Recent larger studies suggest that primary urethral cancer may manifest as transitional cell carcinoma (55%), squamous cell carcinoma (21.5%), and/or adenocarcinoma (16.4%).¹ 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 the 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: Recent 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.

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 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.²

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.³

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

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

Pathophysiology

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.

Presentation

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.

Indications

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.

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 (adapted from Jordan, 1998): 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).

Contraindications

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.

Workup

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 is a good diagnostic study, and all yield a poor sensitivity. Dalbagni et al (1999) have proven that urine cytology in particular yields poor sensitivity in diagnosing urethral carcinoma.⁵ For proper and timely diagnosis, one must have a keen index of suspicion and access to a cystoscope.
• 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.

Imaging Studies

• Chest radiography and CT scanning of the abdomen, pelvis, and perineum are modalities used in staging urethral cancer.
• Intravenous urography (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.
• MRI has evolved into a superior imaging modality for the evaluation of urologic malignancies. Despite its expensive cost, MRI has several advantages over other techniques, as follows:
  • Iodinated contrast is not needed. Blood flow into vascular spaces can often be visualized without enhancement, and, 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 IVU and CT scanning.
  • MRI offers multiplanar imaging using 3 orthogonal planes, thus providing more anatomic detail, which is particularly helpful when imaging the pelvis.
  • Wide-field imaging and the use of special suprapubic and transrectal phased array coils make local staging more accurate.
  • Tissue contrast is superb with spin-echo T1-weighted and T2-weighted images.
  • Lymph nodes can be evaluated simultaneously, and differentiation between nodes and vessels is easier with MRI than with CT scanning.
• Hricak et al (1991) used MRI for diagnostic evaluation of the female urethra in a series of patients and found that primary or metastatic urethral neoplasms were detected in every patient who was clinically found to have disease. Furthermore, this study noted that local staging of primary or metastatic disease with MRI was correct in 8 of 11 patients (72%).⁶
• MRI is being used increasingly in determining the extent of local invasiveness of urethral neoplasms for accurate staging and preoperative planning.
• MRI is not without its drawbacks, as follows:
  • In addition to its cost, it is a sophisticated imaging technique and requires specialized personnel to provide adequate imaging and interpretation.
  • As with other imaging modalities, it 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 has shown to be promising.
• 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.
• Bone scintigraphy (bone scans) may be useful in confirming suspected bone metastases with advanced local disease or elevated alkaline phosphatase levels.
• Positron emission tomography (PET) has an increasing role in the management of urologic malignancies, most specifically, prostate, kidney, and testicular cancer. As with these other malignancies, PET scanning is most valuable in the evaluation for suspected metastases to distant sites after local treatment. It is also useful in evaluating treatment for systemic disease with chemotherapy. In fact, with its ability to quantify metabolic reactions in tissue noninvasively, thus enabling physicians to observe the direct moment-to-moment biochemical effect of a drug at the tissue level, PET may prove useful in the design and testing of new drugs for clinical trials. In theory, the ultimate response to chemotherapy could be predicted soon after initiation by measuring the percent decrease in tumor metabolism with PET.

Other Tests

• Flexible cystoscopy is a minimally invasive office procedure that has proven to be an excellent diagnostic tool for urethral lesions. 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.
  • Direct visual cystoscopy is appropriate, as urethral cancer, particularly transitional-cell carcinoma of the urethra, is generally not the primary site if the bladder is also involved. For instance, primary transitional-cell 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.

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 therapeutic and diagnostic.
• 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.

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.

Recent studies suggest that primary urethral cancer may manifest as transitional cell carcinoma (55%), squamous cell carcinoma (21.5%), and/or adenocarcinoma (16.4%).¹ 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.

Staging

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

Of all penile urethral tumors, 73% are staged at 0 or A. In contrast, only 32% of bulbourethral malignancies are staged at 0 or A. One hypothesis is that many of the proximal lesions, upon initial discovery, are dismissed as strictures. The literature cites that as many as 35% of patients have a history of treatment for stricture disease.

Urethral cancer is staged according to the Tumor Node Metastasis (TMN) criteria outlined by the American Joint Committee on Cancer staging system, as follows:

• Primary tumor (T) (men and women)
  • Tx - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • Ta - Noninvasive papillary, polypoid, or verrucous carcinoma
  • Tis - Carcinoma in situ
  • T1 - Tumor invading subepithelial connective tissue
  • T2 - Tumor invading any of the following: corpus spongiosum, prostate, periurethral muscle
  • T3 - Tumor invading any of the following: corpus cavernosum, beyond prostate capsule, anterior vagina, bladder neck
  • T4 - Tumor invades other adjacent organs
• Regional lymph nodes (N)
  • Nx - Regional nodes cannot be assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis in a single lymph node, 2 cm or less in greatest dimension
  • N2 - Metastasis in a single lymph node, larger than 2 cm in greatest dimension, or in multiple lymph nodes
• Distant metastases (M)
  • Mx - Distant metastasis cannot be assessed
  • M0 - No distant metastasis
  • M1 - Distant metastasis

Treatment

Medical Therapy

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.

Radiation therapy

Superficial tumors (stage 0 and A) can be managed with radiation alone or in combination with surgical excision.

Raghavaiah et al (1978) treated 4 patients with urethral carcinoma with external beam radiation. Two patients with metastatic disease died within 9 months. Two patients with distal penile carcinoma survived beyond 4 years.⁷

Bracken et al studied 6 patients with urethral malignancies. Three patients with anterior urethral lesions developed only local recurrence; the patients with posterior (proximal) lesions died of metastatic disease.

Dalbagni et al (1999) offered radiation treatment to 6 patients, but none responded.⁵ This outcome may be the result of selection bias because all 6 patients had T3 or higher lesions. Radiation therapy alone may be acceptable for lower-stage distal tumors; however, it is not acceptable for higher-staged proximal malignancies.

Kaplan et al (1967) monitored 46 patients who received either no therapy or palliation. In most of these patients, the cause of death was inadequate local disease control, with no evidence of pathology beyond local invasion or regional lymphatics.²

Gokce et al (2008) reported complete remission of a single urethral plasmacytoma with focused radiation alone.⁸

Although tumor control by irradiation has been reported, radiation has generally been reserved for patients with early-stage lesions of the anterior urethra who refuse surgery or as an adjunct to definitive surgery in more advanced disease. Surgical excision remains the primary mode of therapy, the extent depending on the location and stage of the primary tumor. Both irradiation and chemotherapy have been used as adjuvant modalities.

Chemotherapy

Combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin is used frequently in the treatment of transitional-cell bladder cancer. Scher et al (1988) studied the effects of this therapeutic regimen on extravesical urinary tract tumors. In the 4 patients with mixed or nontransitional cell type carcinoma, 1 patient had a partial remission and 3 had progression.⁹

Similar to the treatment for squamous-cell cancer of the esophagus and anal canal, a combination of radiation therapy and chemotherapy is used as a therapeutic measure. In a study by Licht et al (1995), 4 patients (2 male, 2 female) with locally advanced squamous-cell carcinoma of the urethra were treated with 5-fluorouracil (100 mg/m²) and mitomycin-C (15 mg/m²) followed by external beam radiation (30-50 Gy). The 2 female patients were alive 43 and 94 months later. One male subject survived 98 months posttreatment. The other male subject died of unrelated causes with residual disease 7 months after treatment.¹⁰

Tran et al (1995) successfully cured a 68-year-old patient with advanced-stage IVB squamous-cell cancer of the urethra with combined radiation therapy (5580 cGy) and chemotherapy (5-fluorouracil, mitomycin-C).¹¹

Baskin and Turzan (1992) reported on their study of a 66-year-old man with squamous-cell carcinoma of the pendulous urethra. They were able to completely eradicate the malignancy using simultaneous radiation therapy (4000 cGy in 20 fractions over 4 wk) and chemotherapy (mitomycin-C at 15 mg/m² and 5-fluorouracil at 1 mg/m²) followed by distal urethrectomy with en bloc resection of the adjacent corpora cavernosa.¹²

Gheiler et al (1998) successfully treated 3 patients with distal tumors using similar multimodal therapy: chemotherapy (cisplatin, 5-fluorouracil), radiation therapy (45 cGy external beam radiation), and surgical resection (distal urethrectomy). In their study of 10 patients with high-stage disease (>T3-4/N0-2/M0) in the proximal urethra, 5 were disease free, 2 were alive with local recurrence, and 2 died of metastatic disease.¹³

Klein et al (1983) treated 12 patients with preoperative irradiation (external beam: 2000-6000 rads) followed by surgical excision of the inferior pubic rami, total or partial symphysiectomy, anterior perineum, urogenital diaphragm, and genitalia en bloc with pelvic organs and lymph nodes. This treatment cured 5 of 12 patients and achieved improved local control in 83% of patients.¹⁴

Cohen et al (2008) demonstrated the efficacy of a multimodality approach in a recent study of chemoradiation with and without salvage surgery. Chemotherapy included 5-fluorouracil and mitomycin-C and was delivered concurrently with external beam radiation. The prevalent histology was moderately (7 of 18 patients [39%]) or poorly (10 of 18 [56%]) differentiated squamous cell carcinoma (17 of 18 [95%]), yet 5-year disease-free survival rates after chemoradiation therapy and after chemoradiation therapy with salvage surgery were 54% and 72%, respectively.¹⁵

Multimodality therapy appears to be the mainstay treatment to achieve the longest survival without evidence of disease. Eng et al (2003), as well as others who have performed retrospective studies, have reported that the patients who survived the longest without disease received combination therapy that consisted of either chemotherapy with radiation therapy or neoadjuvant chemotherapy with radiation therapy prior to surgery.¹⁶

Surgical Therapy

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 4 modalities of surgical management in male urethral cancer: (1) conservative therapy or local excision, (2) partial penectomy, (3) radical penectomy, and (4) pelvic lymphadenectomy and en bloc resection including penectomy and cystoprostatectomy with removal of the anterior pubis.

Conservative therapy or local excision

Konnak (1980) reported that lesions with a low grade and stage were the types best managed by transurethral resection, fulguration, or excision. In this study of 5 patients with anterior lesions and 3 patients with posterior lesions, all survived an average of 6 years. They found that this treatment modality was best reserved for localized, low-grade, distal urethral neoplasms in men.¹⁷

Dalbangi et al (1998) successfully cured 5 of 6 patients with distal urethral tumors using local surgical excision.¹⁸ However, Marshall (1957) reported that in his treatment of 3 patients' urethral malignancies with urethrotomy, conservative therapy was ineffective.¹⁹

Endoscopic treatment is performed with either transurethral electroresection or fulguration or transurethral laser therapy. 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. The holmium:YAG laser has not been exclusively studied in the management of urethral cancer; however, it has been reported as useful for urethral strictures and superficial bladder cancer. Since it has a low depth of penetration, the holmium:YAG laser may be ideal for management of superficial urethral cancer with minimal morbidity to the urethra and surrounding tissues while providing quality tissue samples for diagnosis.

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 by 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.

Zeidman et al (1992) described a series of 44 patients, in which 98% of patients with anterior urethral lesions had no local recurrences; 1 died of metastatic disease.²⁰

Dinney et al (1994) described 4 patients with urethral cancer in the fossa navicularis who were treated with partial penectomy or urethrectomy. All 4 patients survived without any local recurrences. In 6 patients with urethral cancer of the penile segment, 5 achieved remission and 1 died of recurrent disease 44 months later.²¹ Partial penectomy, similar to local excision and external beam radiation, is a viable option for low-stage malignancies of the distal urethra.

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).

Zeidman et al (1992) reported on 52 patients who underwent radical penectomy; 12 of these patients eventually died from their disease.²⁰

Mandle and Pool achieved a 50% success rate in their 4 patients with bulbomembranous urethral cancer. This result is expected because proximal urethral lesions are often discovered at a much later stage.

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, 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.

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.²

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.²¹

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.⁵

Primary melanoma of the urethra presents a unique challenge compared to other histologic types. Oliva et al (2000) found that, despite distal locations and urethral confinement at the time of surgery, 9 of 15 patients exhibited a survival rate of less than 5 years.²² 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.

Preoperative Details

Attempts to accurately stage the tumor should be exhausted prior to performing 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.

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.

Mechanical and biochemical bowel preparation should be performed one day prior to major pelvic surgery, particularly if urinary diversion is to be used.

Intraoperative Details

General anesthesia is generally required for en bloc excision. For diagnostic cystoscopy and transurethral biopsy, spinal anesthesia or even intravenous sedation may be sufficient.

The patient should be placed in the low lithotomy position to allow perineal access. Excision of scrotal or perineal skin is necessary with bulky tumors. Viable testes may be preserved in thigh pouches.

Postoperative Details

General postoperative precautions that are paramount to reducing complications include hemodynamic support with intravenous fluids, both crystalloid and colloid; intravenous antibiotics; incentive spirometry and aggressive pulmonary toilet; and deep venous thrombosis prophylaxis. These precautions should be used.

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 when and if 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.

Social interaction should be monitored because patients with this grave disease may require a psychiatric consultation liaison. Social support services may provide the patient with much needed empathy.

Follow-up

Carefully obtain a history, with particular attention to new symptoms such as 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; and 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.

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 a 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.

Complications

In patients treated with radiation therapy, urethrectomy, or partial penectomy, complications include urethral stricture formation and development of urethral fistulae. 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%.

Outcome and Prognosis

The current literature describes 2 distinct subsets of malignancy.

Distal urethral cancer can be managed by monotherapy with external beam radiation, local resection, partial penectomy, or radical penectomy. The 5-year survival rates range from 83% for low-stage tumors to 45% for advanced tumors. Overall 5-year survival rates associated with distal urethral cancers approach 60%.⁵

Proximal urethral cancer often is staged higher than distal urethral malignancy; as a result, it requires treatment that is more aggressive. Proximal urethral cancer is treated best with a multimodal treatment that consists of chemotherapy, radiation therapy, and surgical resection. However, despite aggressive therapy, the recurrence rate is higher than 50%.

Future and Controversies

Urethral cancer is a rare and difficult entity. Because of its low incidence and subtle clinical findings, little progress has been made regarding definitive treatment options. Combination chemotherapy has achieved encouraging results in patients with metastatic urethral cancer and in locally advanced disease when it is used as an adjunct to irradiation and definitive surgery.

Multimedia

Media file 1: Male urethral anatomy from most proximal to distal (adapted from Jordan, 1998): 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.

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Keywords

urethral neoplasms, urethral cancer, urethral carcinoma, squamous cell carcinoma of the urethra, transitional cell carcinoma of the urethra, urethral carcinoma, urethral stricture

Contributor Information and Disclosures

Author

Christopher Powell, Senior Medical Student, Medical College of Georgia
Christopher Powell is a member of the following medical societies: American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Jack H Mydlo, MD, Chief, Department of Urology, Woodhull Hospital; Chair and Professor, Department of Urology, Temple University School of Medicine
Jack H Mydlo, MD is a member of the following medical societies: American College of Surgeons, American Urological Association, International College of Surgeons US Section, and Society of University Urologists
Disclosure: Nothing to disclose.

Jeffrey M Donohoe, MD, Assistant Professor of Pediatric Urology, Department of Surgery, Division of Urology, Medical College of Georgia Children's Medical Center; Fellow of the American Academy of Pediatrics
Jeffrey M Donohoe, MD is a member of the following medical societies: American Academy of Pediatrics and American Urological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center
Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Gyrus-ACMI Honoraria Speaking and teaching

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

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