Michael A. Poch, MD
Philippe E. Spiess, MD
BASICS
DESCRIPTION
• Urethral carcinoma is a tumor arising from the lining of the male or female urethra
• Considered a rare cancer (<1% of all malignancies)
• Urothelial carcinoma is most common histologic type followed by squamous cell carcinoma and adenocarcinoma.
EPIDEMIOLOGY (1)
Incidence
• Incidence (male): 1.6 per 1,000,000
• Incidence (female): 0.6 per 1,000,000
• Incidence is higher in African American patients
• Incidence increases steadily with age, more steeply in men as compared to women peaks at age 75: 7.6/1,000,000
Prevalence
N/A
RISK FACTORS (1)
• Male
– Chronic inflammation
Intermittent catheterization, urethroplasty
– History of sexually transmitted infection (STI/STD)
HPV (condyloma with HVP 16)
– Urethritis
– Urethral stricture disease
– Prior radiation
External beam or seed implant
– Arsenic exposure (adenocarcinoma of bulbar urethra)
– Urethral stent
• Female
– Leukoplakia
– Chronic inflammation/recurrent UTI
– STI/STD
HPV, condyloma
– Parturition
– Urethral diverticula
Genetics
Unknown
PATHOPHYSIOLOGY
• Male
– Anatomic considerations: The male urethra (averages about 20 cm in length), is divided into distal and proximal portions. The distal urethra, which extends distally to proximally from the tip of the penis to just before the prostate, includes the meatus, the fossa navicularis, the penile or pendulous urethra, and the bulbar urethra. The proximal urethra, which extends from the bulbar urethra to the bladder neck, includes distally to proximally the membranous urethra and the prostatic urethraurethra
– Squamous-cell carcinoma: Occurs in the membranous urethra, bulbar urethra, and penile urethra
– Urothelial carcinoma: Typically occurs in the prostatic urethra
• Female
– Anatomicconsiderations: The female urethra is In adults, it is about 4 cm in length and is mostly contained within the anterior vaginal wall.
– Squamous-cell carcinoma: Occurs at distal 2/3 of female urethra
– Urothelial carcinoma: Occurs at the proximal 1/3 of the urethra
– Adenocarcinoma: Occurs in urethra diverticula
ASSOCIATED CONDITIONS
• STI/STD
• Indwelling catheter
• Urethral stricture disease
• Urethral diverticula
• Bladder cancer
GENERAL PREVENTION
• Prevention of STI
• Prevention of traumatic injury leading to stricture disease
• Smoking cessation
DIAGNOSIS
HISTORY
• Urethral bleeding
• Perineal discomfort
• Decrease force of stream
• Urinary frequency
• Urinary urgency
• Dysuria
• Urinary fistulae
• Urinary tract infection
• STI/STD, condyloma history
PHYSICAL EXAM
• Perineal exam
– Identifies palpable mass in proximal urethra
• Pelvic exam
– Identifies visual or palpable mass associated with female urethra
• Examination under anesthesia with bimanual exam
• Inguinal exam to evaluate palpable inguinal adenopathy
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urinalysis often demonstrates hematuria
• Urine culture
• Urine cytology
– Sensitivity 55–59%
Imaging
• Urethrography—Aids in the diagnosis of diverticula and/or stricture disease
– Voiding cystourethrogram (VCUG)
– Retrograde urethrogram
• Cross sectional imaging identifies local extension
– MRI of pelvis
Preferred imaging modality for urethral carcinoma
– CT scan of pelvis
– CT thorax and abdomen in patients with invasive disease (rule out metastasis)
Diagnostic Procedures/Surgery
Cystoscopy with biopsy/transurethral resection
Pathologic Findings (2)
• Urothelial carcinoma 50–60%
• Squamous-cell carcinoma 16–25%
– More common in women, traditionally considered-more prevalent
• Adenocarcinoma 10–16%
• Primary tumor staging based on TNM classification (See also Reference tables: TNM: Urethra Cancer)
– T—Primary tumor (men and women)
Tx Primary tumor cannot be assessed
Tis Carcinoma in situ
T0 No evidence of primary tumor
Ta Non-invasive papillary carcinoma
T1 Tumor invades subepithelial connective tissue
T2 Tumor invades any of the following structures: Corpus spongiosum, prostate, periurethral muscle
T3 Tumor invades any of the following structures: Corpus cavernosum, invasion beyond prostatic capsule, anterior vaginal wall, bladder neck
T4 Tumor invades other adjacent organs
– N—Regional lymph nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastasis in a single lymph node <2 cm in greatest dimension
N2 Metastasis in a single lymph node >2 cm in greatest dimension or in multiple nodes
– M—Distant metastasis
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
– Primary tumor in prostatic urethra:
Tx Primary tumor cannot be assessed
Tis pu Carcinoma in situ in the prostatic urethra
Tis pd Carcinoma in situ in the prostatic ducts
T0 No evidence of primary tumor
T1 Tumor invades subepithelial connective tissue (only in case of concomitant prostatic urethral involvement)
T2 Tumor invades any of the following structures: Corpus spongiosum, prostatic stroma, periurethral muscle
T3 Tumor invades any of the following structures: Corpus cavernosum, beyond prostatic capsule, bladder neck
T4 Tumor invades other adjacent organs
– N (Nodes) and M (metastasis) as above
DIFFERENTIAL DIAGNOSIS
• Adenomatous polyp
• Squamous papilloma
• Transitional cell papilloma
• Leiomyoma
• Nephrogenic adenoma
• Amyloidosis
• Urethral caruncle
• Leukoplakia
• Periurethral abscess
• Skene gland, inflammation/adenitis
• Urethral diverticulum
• Urethral fistula
• Urethral stricture
• Malignant neoplasms
– Adenocarcinoma
– Melanoma
– Metastatic disease
– Skene (paraurethral) gland, adenocarcinoma
– Squamous-cell carcinoma
– Urothelial carcinoma
TREATMENT
GENERAL MEASURES (1,3)
Based on pathology, stage, location of tumor
MEDICATION
First Line
• No medical therapy as first-line treatment
• Preoperative cisplatin-based systemic chemotherapy followed by surgery for locally advanced urothelial cancer has demonstrated a survival advantage
• Preoperative chemoradiation followed by surgery for locally advanced squamous-cell carcinoma has demonstrated a survival advantage
Second Line
Adjuvant systemic chemotherapy based on underlying tumor histopathology
SURGERY/OTHER PROCEDURES
• Male
– Penile urethra
Transurethral resection (TUR)
Corpus spongiosum—partial penectomy
Proximal penile urethra—total penectomy
– Prostatic urethra
TUR + BCG for Ta or Tis
Higher stage-radical cystoprostatectomy
– Bulbomembranous
TUR
Primary excision with primary anastomosis
Cystoprostatectomy with urethrectomy and total penectomy, with possible bilateral pelvic lymph node dissection
Locally advanced disease: Excision of pubic rami
• Female
– Distal
Partial urethrectomy or TUR
– Proximal—often presents at higher stage
Anterior pelvic exenteration
Pelvic lymph node dissection
ADDITIONAL TREATMENT
Radiation Therapy
• Used as primary therapy for low-stage distal urethral carcinoma in females
– Primary brachytherapy or external beam
• Used as adjuvant therapy for advanced cancer
Additional Therapies
Ilioinguinal lymphadenectomy only recommended for palpable disease or for high risk disease in the distal urethra
Complementary & Alternative Therapies
None
ONGOING CARE
PROGNOSIS (4)
• Male
– 5-yr survival: Depends on location, stage, and pathology
• Female
– 5-yr survival: Depends on location, stage, and pathology
• Complications
– Associated surgical complications
– Abscess
– Cystitis
– Incontinence
– Stricture
– Fistula
FOLLOW-UP
Patient Monitoring
• Q3–6 mo cystoscopy and urine cytology
• Cross sectional imaging to evaluate for local recurrence
• Recurrences often occur early (1–2 yr)
Patient Resources
Urology Care Foundation: Urethral cancer. http://www.urologyhealth.org/urology/index.cfm?article=65
REFERENCES
1. Gakis G, Witjes JA, Compérat E, et al. EAU guidelines on primary urethral carcinoma. Eur Urol. 2013;64(5):823–830.
2. Eng TY, Naguib M, Galang T, et al. Retrospective study of the treatment of urethral Cancer. Am J Clin Oncol. 2003;26(6):558.
3. Gheiler EL, Tefilli MV, Tiguert R, et al. Management of primary urethral cancer. Urology. 1998;52(3):487.
4. Dalbagni G, Zhang ZF, Lacombe L, et al. Male urethral carcinoma: Analysis of treatment outcome. Urology. 1999;53(6):1126.
ADDITIONAL READING
• Casey RG. The Management of urethral cancer. In: Spiess P, ed. Essentials and Updates in Urologic Oncology. NovaScience Publishers; 2013;441–467.
• 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, Diverticular Carcinoma
• Urethral Stenosis/Stricture, Female
• Urethra, Squamous Cell Carcinoma
• Urethra Mass
CODES
ICD9
• 189.3 Malignant neoplasm of urethra
• 597.80 Urethritis, unspecified
• 598.9 Urethral stricture, unspecified
ICD10
• C68.0 Malignant neoplasm of urethra
• N34.2 Other urethritis
• N35.9 Urethral stricture, unspecified
CLINICAL/SURGICAL PEARLS
• Urethral cancers appear to be associated with infection with human papillomavirus (HPV), particularly HPV16, a strain of HPV known to be causative for cervical cancer.
• Most urethral cancers are managed surgically.
• Low-grade female distal urethral cancer can be managed with radiotherapy.
• Most locally advanced urethral tumors are best approached by neoadjuvant systemic chemotherapy (±radiotherapy) followed by consolidative surgical resection.
• Outcome strongly correlates with stage