Zachary L. Smith, MD
S. Bruce Malkowicz, MD, FACS
BASICS
DESCRIPTION
Squamous-cell carcinoma (SCC) of the urethra is a malignancy arising from the native squamous lining of the male and female urethra.
EPIDEMIOLOGY
Incidence
• Incidence is higher in African American patients as compared to their white counterparts.
– White males: 0.58 per 1,000,000
– African American males: 2.3 per 1,000,000
– White females: 0.43 per 1,000,000
– African American females: 0.69 per 1,000,000
• Incidence increases steadily with age, more steeply in men as compared to women (1).
Prevalence
N/A
RISK FACTORS
• Male urethral SCC:
– Chronic irritation after clean intermittent catheterization (CIC)
– History of sexually transmitted infection (STI): Nearly 25% of patients with urethral carcinoma will give history of STIs.
– Urethritis
– Urethral stricture disease (≥50% of patients).
– HPV
– History of external beam radiation therapy
• Female urethral SCC:
– Leukoplakia
– Chronic irritation
– Parturition
– Human papilloma virus
– Viral infections
– Recurrent urinary tract infections
– Possibly urethral diverticula: 4% of female urethral carcinoma is found within the diverticulum.
Genetics
• Possibility raised for aberrations in chromosomes Y, 2, 3, 4, 6, 7, 8, 11, and 20 (2).
• Notably, there have been no abnormalities described in chromosomes 9 and 17, those largely responsible for the development of urothelial carcinoma.
PATHOPHYSIOLOGY
• Male urethral SCC:
– Occurs in the male membranous urethra (80% SCC), bulbar urethra (80% SCC), and penile urethra (90% SCC).
• Female urethral SCC:
– Occurs in the distal 2/3 of the female urethra.
• Both male and female urethral carcinoma spread via direct local extension and via lymphatics:
– Anterior urethra drains to superficial and deep inguinal nodes.
– Posterior urethra drains to pelvic lymph nodes.
ASSOCIATED CONDITIONS
• Condyloma acuminatum
• History of STIs
• Presence of indwelling catheter
• Urethral diverticula
• Urethral stricture disease
GENERAL PREVENTION
Prevention of STIs with the use of barrier protection such as condoms
DIAGNOSIS
HISTORY
• Particular attention must be made to risk factors and associated GU conditions.
• Male urethral SCC:
– Urethral bleeding
– Perineal discomfort
– Decreased force of stream
– Urinary urgency or frequency
– Dysuria
– Urinary fistulae
– Chronic irritation (CIC, history of urethroplasty)
• Female urethral SCC:
– Urethral bleeding
– Palpable urethral mass
– Urinary urgency or frequency
– Induration of urethra or anterior vaginal wall
PHYSICAL EXAM
• Examiner should evaluate for potential mass arising from urethra:
– Formal pelvic exam for female patients
– Perineal exam (to evaluate proximal urethra) in male patients
• Particular attention should be given to the inguinal exam, as 20–30% of patients present initially with nodal metastases to the inguinal chain.
• Exam under anesthesia at time of cystoscopy including bimanual palpation of genitalia, urethra, rectum, and perineum helpful to determine extent of disease
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urinalysis
• Urine culture
• Urine polymerase chain reaction for Neisseria gonorrhoeae and Chlamydia trachomatis
• Cytology of 1st voided urine
Imaging
• Retrograde urethrogram/voiding cystourethrogram (RUG/VCUG):
– Evaluates entire urethra
– Aids in assessment for stricture disease, urinary fistulae, or urethral diverticula
• Cross-sectional imaging (CT or MRI):
– Aids in the determination of local involvement, spread to regional lymphatics, or invasion of contiguous structures
– MRI particularly helpful for assessment of corporal involvement
– CT urography provides evaluation of upper urinary tract drainage and presence or absence of upper urinary tract neoplasia (more critical in patients with urethral urothelial carcinoma)
Diagnostic Procedures/Surgery
• Cystoscopy with biopsy or transurethral resection:
– Gold standard in histologic diagnosis of urethral carcinoma
– Cystoscopic appearance of fungating growth extending into urethral lumen
• Sigmoidoscopy/colonoscopy if concern for involvement of GI tract based upon physical exam or imaging
– Particularly important in cases of urethral adenocarcinoma to rule out a GI primary source
Pathologic Findings
Fungating tumor with varied cytologic differentiation ranging from well-differentiated lesions producing keratohyaline pearls to anaplastic giant-cell tumors
ALERT
The clinician must have a very high index of suspicion when considering urethral carcinoma, considering the often insidious and nonspecific nature of the patient’s complaints.
DIFFERENTIAL DIAGNOSIS
• Condyloma acuminatum
• Benign neoplasms:
– Hemangioma
– Adenomatous polyps
– Squamous papilloma
– Urothelial cell papilloma
– Leiomyomas
Increased incidence in females aged 30–50 yr
– Polypoid urethritis
– Nephrogenic adenoma
– Amyloidosis
– Urethral caruncle: More common in postmenopausal women
• Leukoplakia
• Periurethral abscess
• Skene’s (periurethral) gland, inflammation/adenitis
• Urethral diverticulum
• Urethral fistula
• Urethral stricture
• Malignant neoplasms:
– Primary urethral carcinoma:
Squamous cell
Urothelial cell
Adenocarcinoma
Melanoma
Clear-cell adenocarcinoma has been associated with urethral diverticulum.
Skene (periurethral) gland adenocarcinoma
Metastases
TREATMENT
GENERAL MEASURES
• Treatment decisions based on sex, stage, and location of tumor
• TNM staging (See Reference tables: TNM: Urethra Cancer)
MEDICATION
First Line
• Localized disease:
– The precise role for chemotherapy in the treatment of localized urethral SCC is poorly defined; however, chemotherapy not considered 1st-line treatment
• Advanced disease:
– Preoperative chemotherapy (or chemoradiotherapy) has been shown to be of benefit over surgical resection alone.
Cisplatin-based poly-chemotherapeutic regimens should be used.
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Male bulbomembranous urethral SCC (3):
– Early lesions have been treated successfully with transurethral resection or local excision with end-to-end urethral anastomosis.
– Radical excision offers best chance at cure, with radical cystoprostatectomy, total penectomy, bilateral pelvic lymphadenectomy recommended.
– With locally advanced disease, consider en-bloc excision to include the pubic rami and urogenital diaphragm.
• Male penile urethral SCC (3):
– Transurethral resection, fulguration, or local excision may be employed for superficial low-grade tumors.
– For tumors invading the corpus spongiosum, partial penectomy with a 2-cm margin is treatment of choice if localized to the distal half of the penis
– With involvement of the proximal penile urethra, total penectomy is required to obtain an adequate margin of excision.
– Ilioinguinal lymphadenectomy is indicated only in presence of palpable disease, as there has been no documented benefit of prophylactic lymphadenectomy.
• Distal female urethral carcinoma (3):
– Tumors of the distal urethra tend to be low-stage with cure rates of 70–90% with local excision alone.
– External beam radiation therapy is also therapeutic option for distal female urethral carcinoma.
• Proximal female urethral SCC (3):
– Far more likely to extend into the anterior vaginal wall and bladder
– Requires anterior exenteration with wide resection of the vagina; pelvic lymph node dissection is often required to achieve negative surgical margins.
ADDITIONAL TREATMENT
Radiation Therapy
• Localized disease:
– Male urethral SCC:
Few series of radiation therapy for patients with early-stage lesions of the anterior urethra who refuse surgery
Possible role in palliation, with occasional adjuvant use with extensive resection
– Female urethral SCC:
Low-stage distal lesions can be treated with external beam radiation, brachytherapy, or combined therapy with 5-yr survival rates approaching 75%.
Although there appears to be some role to adjuvant external beam or brachytherapy in the treatment of locally advanced female proximal urethral carcinoma, the precise role of radiation therapy remains unclear.
• Advanced disease:
– While surgical resection remains standard of care, preoperative radiation therapy combined with cisplatin-based chemotherapy regimens have been shown to give remarkable results in comparison to surgical resection alone.
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Male urethral carcinoma (4):
– 5-yr overall survival (OS): 42.3%
– 5-yr OS (superficial disease): 83.3%
– 5-yr OS (invasive disease): 35.7%
– 5-yr OS (anterior urethra): 69.1%
– 5-yr OS (bulbar urethra): 44.7%
• Female urethral carcinoma (5):
– 5-yr OS: 32%
– 5-yr OS (low-stage): 78%
– 5-yr OS (high-stage): 33%
– 5-yr OS (anterior urethra): 54%
– 5-yr OS (posterior urethra): 25%
COMPLICATIONS
• Abscess
• Cystitis
• Incontinence
• Urethral stricture
• Urinary fistula
FOLLOW-UP
Patient Monitoring
• Vast majority of recurrences occur within 1–2 yr following definitive therapy.
• Surveillance is not well established, but routine cystoscopy and urinary cytology for 1–2 yr, with increasing interval between surveillance cystoscopy in the absence of recurrence seems reasonable
Patient Resources
Urology Care Foundation: Urethral cancer. http://www.urologyhealth.org/urology/index.cfm?article=65
REFERENCES
1. Swartz MA, Porter MP, Lin DW, et al. Incidence of primary urethral carcinoma in the US. Urology. 2006;68:1164–1168.
2. Fadl-Elmula I, Gorunova L, Mandahl N, et al. Chromosome abnormalities in squamous cell carcinoma of the urethra. Genes, Chromosomes, Cancer. 1998;23:72–73.
3. Sharp DS, Angermeier KW. Surgery of penile and urethral carcinoma. In: Wein AJ, et al., eds. Campbell-Walsh Urology, 10th ed. Philadelphia, PA: Elsevier; 2012.
4. Dalbagni G, Zhang ZF, Lacombe L, et al. Male urethral carcinoma: Analysis of treatment outcome. Urology. 1999;53:1126–1132.
5. Dalbagni G, Zhang ZF, Lacombe L, et al. Female urethral carcinoma: An analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol. 1998;82:835–841.
ADDITIONAL READING
• G. Gakis, Witjes JA, Compérat E, et al. ; members of the EAU Guidelines Panel on Muscle-invasive and Metastatic Bladder Cancer. Guidelines on Primary Urethral Carcinoma. The European Association of Urology (EAU) Guidelines Group on Muscle-invasive and Metastatic Bladder Cancer; 2013.
• Trabulsi E, Gomella LG. Penile and Urethral Cancer. In: DeVita V, et al., eds. Principles and Practice of Oncology. 9th ed. Philadelphia, PA: Saunders; 2011.
See Also (Topic, Algorithm, Media)
• Prostate Cancer, Urothelial
• Reference Tables: TNM: Urethra Cancer
• Skene (Paraurethral) Gland, Adenocarcinoma
• Urethra Diverticula
• Urethra Mass
• Urethra, General Considerations
• Urethral Stenosis/Stricture, Female
CODES
ICD9
• 189.3 Malignant neoplasm of urethra
• 598.9 Urethral stricture, unspecified
• V12.09 Personal history of other infectious and parasitic diseases
ICD10
• C68.0 Malignant neoplasm of urethra
• N35.9 Urethral stricture, unspecified
• Z86.19 Personal history of other infectious and parasitic diseases
CLINICAL/SURGICAL PEARLS
• Primary urethral SCC is a rare entity.
• Surgical excision is the mainstay of treatment.
• Distal tumors tend to be less advanced and more amenable to localized treatment.
• Proximal tumors tend to have a worse prognosis and require more aggressive treatment.
• Preoperative chemoradiotherapy may be used in advanced disease.