Urethral cancer is an extremely rare lesion, with only approximately 600 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 usually is poor.
History of the Procedure
Urethral carcinoma has 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 possesses a tendency to invade locally and to metastasize to adjacent soft tissues. Therefore, most of these tumors are locally advanced at the time of diagnosis, reflecting the generally poor prognosis despite aggressive treatment. Urethral cancer rarely metastasizes to distant loci. Only 14% of female patients with urethral cancer have evidence of metastatic spread.
Anatomic and histologic considerations exist among cases of urethral cancer because of the uniqueness of the urethra between males and females. The long male urethra is divided into anterior and posterior components, while the female urethra is approximately 3 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 because transitional cells can undergo adenomatous 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, the deep tissues of the perineum, the urogenital diaphragm, the prostate, and the penile and scrotal skin, where it causes abscesses and fistulae.
Again, this is a rare tumor, with only approximately 600 reported cases. In both males and females, the most common type of urethral malignancy is squamous-cell cancer. In men, these lesions comprise 78% of the total cases and occur primarily in the bulbomembranous and penile regions. Transitional-cell carcinoma is the second most common urethral malignancy in both sexes. In males, this lesion accounts for 15% of total cases and occurs in the prostatic urethra.
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: Urethral cancer is more common in whites than in blacks; however, blacks have a worse prognosis after diagnosis.
Sex: Urethral cancer is the only genitourinary malignancy that is more common in females than in males. This finding is surprising considering the complexity and length of the male urethra.
Age: Urethral cancer has been reported within an age range of 13-90 years, thus occurring at any age; however, it is observed most commonly during the seventh decade.
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 have an increased risk of urethral cancer. Various studies cite infection and chronic irritation as etiologic agents in the tumorigenesis of this malignancy. Kaplan and Grayhack found that 37% of males with urethral cancer had some history of venereal disease. Ray et al found a 44% concordance of patients with urethral cancer and a history of sexually transmitted diseases. In addition, human papilloma virus (HPV) recently was associated with urethral cancer.
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. No such associations have been established in females, although chronic irritations from parturition, coitus, and infection have been proposed as etiologic agents.
Chronic inflammation, infection, or irritation of the urethra usually precedes the development of urethral cancer. Rapid turnover of the urethral mucosal cells predisposes to the development of dysplasia and neoplasia. Inflammation, infection, and irritation may impede the natural DNA repair mechanisms of the urethral mucosal cells. The tumor develops and invades deeply in order to metastasize to adjacent structures. The tumor thus becomes elusive to definitive therapies such as surgery and radiation.
The signs and symptoms of urethral cancer vary and are neither diagnostic nor pathognomonic. Generally, the onset is insidious, and symptoms usually are 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 present that 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 (USD), which generally appears as smooth gray-white areas of spongiofibrosis.
- Diminished stream, straining to void, and other obstructive voiding symptoms (Although these often are 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 USD, 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 from bladder outlet obstruction due to USD. 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 USD
- 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
- Perineal, suprapubic, or urethral pain
Signs and physical examination findings
- Urethral-cutaneous fistula
- Urethral-vaginal fistula
- Urethral diverticula
- Periurethral abscess or areas of tissue necrosis
- Recurrent urinary tract infection
- Penile or vaginal lesions
- Palpable mass along the course of the urethra
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 is dependent 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 also can be used for palliative measures. However, tissues may not heal well after surgery for locally advanced disease, resulting in fistulas and dehiscences.
Lymphadenopathy in the presence of urethral cancer again depends on the anatomic location of the primary tumor. Therapeutic lymphadenectomy has been reported as successful in anterior urethral lesions, but no advantage to prophylactic surgery has been documented as has been in primary penile cancer. Lymphadenopathy secondary to a primary posterior urethral cancer generally portends an ominous prognosis. Only occasionally has survival been reported after lymphadenectomy with positive nodes in posterior urethral carcinoma.
The urethra is a mucous membrane supported by a submucosal stroma of connective tissue, elastic fibers, and smooth muscle. The average length of the male urethra is 21 cm, and the female urethra averages 4 cm. In the male urethra, the type of epithelium of this mucosa varies with location. The urethral meatus and fossa navicularis are composed of stratified squamous epithelium. The penile, bulbar, and membranous portions of the urethra contain pseudostratified and stratified columnar epithelium, whereas the prostatic urethra contains transitional-cell epithelium. In addition, the submucosal glands of Littré communicate with the urethra. The anterior urethra, which is drained by the inguinal nodes, includes the glanular (meatus, fossa navicularis) and penile portions. In contrast, the posterior urethra (bulbous, membranous, prostatic) empties into the pelvic nodes. The male urethra is surrounded by the corpus spongiosum, which lies between the corpora cavernosum. Urethral tumors can extend directly into adjacent structures and vascular spaces because each corpus is encased by a common fascial sheath (Buck).
The female urethra is much shorter, and its histology is somewhat less complex. The distal two thirds are composed of stratified squamous epithelium, while the proximal one third is composed of transitional cells. Skene glands are located in the submucosa of the urethral meatus and are continuous with the urethra. These structures contain pseudostratified and stratified columnar epithelium. The distal one third of the female urethra drains into the superficial or deep inguinal nodes; the proximal two thirds drain into the pelvic nodes (external iliac, internal iliac, obturator).
No absolute contraindications exist for the treatment of urethral cancer. Treatment is decided based on the clinical stage of the disease at the time of diagnosis. Considering the notoriously aggressive nature of the disease, radical surgery generally is 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 probably will not be cured despite radical surgery may be considered as nonoperative candidates.
Surgery probably will not provide a cure in such patients, and cardiopulmonary events within the operative and perioperative period may ensue. Additionally, local postoperative complications may occur (eg, poor wound healing and subsequent fistula and abscess formation) in these 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 make a decision whether or not they want to proceed with radical surgery. In worst-case scenarios, the health professionals may decide that radical intervention is relatively contraindicated based on a risk-benefit analysis.
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 usually are discovered earlier, at a lower stage, whereas proximal urethral malignancies present at a more clinically advanced stage.
Superficial tumors (stage 0 and A) can be managed with radiation alone or in combination with surgical excision. Raghaviah et al 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.
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 offered radiation treatment to 6 patients and none responded. 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 followed 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.
Although tumor control by irradiation has been reported, radiation generally has 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.
Combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin is used frequently in the treatment of transitional-cell bladder cancer. Scher et al 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.
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, 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.
Tran et al 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).
Baskin and Turzan 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.
Gheiler et al 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 are disease free, 2 are alive with local recurrence, and 2 died of metastatic disease. Klein et al 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.
These last 3 studies indicate that a combined therapeutic approach offers the best option for treatment of high-stage tumors of the proximal urethra. Multimodality therapy appears to be the mainstay treatment to achieve the longest survival without evidence of disease. Eng et al, 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.
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 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.
Dalbangi et al successfully cured 5 of 6 patients with distal urethral tumors using local surgical excision. However, Marshall reported that in his treatment of 3 patients' urethral malignancies with urethrotomy, conservative therapy was ineffective. 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 involves excision of the malignant lesion with 2-cm margins. This treatment modality can only be used 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 described a series of 44 patients, in which 98% of patients with anterior urethral lesions had no local recurrences; 1 died of metastatic disease. Dinney et al 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. 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 reported on 52 patients who underwent radical penectomy; 12 of these patients eventually died from their disease. Mandle and Pool achieved a 50% success rate in their 4 patients with bulbomembranous urethral cancer. This result is expected because proximal urethral lesions often are 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 a necessity. In males and females alike, inguinal lymphadenectomy is performed only if palpable disease is present.
Kaplan et al 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. Dinney et al 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.
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.
Primary melanoma of the urethra presents a unique challenge compared to other histologic types. Oliva et al 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. 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.
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 scan should be performed to predict the extent of local invasion. After accurate staging, a lengthy discussion with the patient regarding the extent and severity of disease should be used. 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. Plastic surgery and orthopedic surgery consults 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.
General anesthesia generally is 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.
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 often is 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.
Carefully obtain a history, with particular attention paid 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. Imaging studies of the pelvis (ie, CT scan with intravenous contrast) should be performed from every 6 months to a year to check for local recurrence or hydronephrosis.
Perform periodic chest radiographs 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 scan to further characterize it and possibly obtain a CT-guided biopsy specimen. If metastatic disease is confirmed, systemic chemotherapy should be strongly considered.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center, Kidneys and Urinary System Center, and Procedures Center. Also, see eMedicine's patient education articles Bladder Cancer, Blood in the Urine, Cystoscopy, and Prolapsed Bladder.
In patients treated with radiation therapy, urethrectomy, or partial penectomy, complications include urethral stricture formation and development of urethral fistulae. Urinary incontinence may occur because of 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 into sepsis. In those 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%.