Owen C. Thomas and Neha Vapiwala
What is the estimated annual incidence of urethral cancer in the U.S.?
~500 cases/yr of urethral cancer in the U.S.
Is there a racial or gender predilection for urethral cancer?
Yes. The incidence of urethral cancer is greater in women at a 4:1 ratio. It is higher in white women and black men.
At what age does urethral cancer incidence peak?
The peak incidence of urethral cancer occurs in women age 40–50 yrs and in men age 75–84 yrs. It is very rare in men <55 yrs.
What are the conditions or exposures associated with urethral cancer?
Exposures associated with urethral cancer include possibly HPV in women. Many men have long-standing urethral infections, Hx of STDs, stricture, trauma, or urethritis.
Is there an association between urethral cancer and other malignancies?
Yes. There is an association between bladder cancer and urethral cancer. The risk of urethral cancer in men with bladder cancer has been reported as 4%–18%. A recent series of women with bladder cancer reports a 2% incidence of concurrent urethral cancer (Stenzyl A et al., J Urol 1995).
What are the avg length and anatomic divisions of the female urethra?
The avg length of the female urethra is 4 cm. It is anatomically divided into the distal one third (ant urethra) and proximal two thirds (post urethra).
In a female, what type of epithelium does the proximal and distal urethra have?
The distal two thirds of the female urethra has squamous epithelium. The proximal one third has transitional epithelium.
What are the avg length and anatomic divisions of the male urethra?
The avg length of the male urethra is 21 cm. It is divided into ant (distal) and post (proximal) portions, which are further subdivided from most distal to proximal as follows:
1. Anterior urethra: glandular, penile, bulbar
2. Posterior urethra: membranous, prostatic
In a male, what type of epithelium does the proximal and distal urethra have?
In the male urethra:
1. Squamous epithelium is present in the glandular and penile regions.
2. Pseudostratified or stratified columnar epithelium is present in the post proximal portion of the penile and bulbomembranous portions.
3. Transitional cell epithelium is present in the prostatic portion.
What is the histologic prevalence of urethral cancers?
Squamous cell carcinomas are the most common urethral cancers in both men and women → transitional cell carcinomas (TCCs) and adenocarcinoma.
What is the most common site of origin of urethral cancer in men?
In men, urethral cancer occurs most frequently in the bulbomembranous urethra (~60%). It occurs mainly as squamous metaplasia. The next most common sites are the penile urethra and prostatic urethra.
What is the main pattern of spread in urethral cancer?
The main pattern of spread is direct extension.
What is the lymphatic drainage for the urethra?
Traditionally, the distal urethra in women and glandular and penile urethra in men are drained by inguinal nodes, and the more proximal regions (bulbar and prostatic in men) are drained by pelvic nodes. However, crossover can occur, particularly with direct extension of Dz.
What portion of urethral cancer pts will be LN+ at Dx?
14%–30% of pts will be LN+ at Dx.
Are most clinically apparent nodes pathologically positive in urethral cancer?
Yes. ~75% of clinically apparent LNs are pathologically positive for cancer. This is in contrast to penile cancer, where ~50% of enlarged LNs are involved.
What % of urethral cancer pts have DM at Dx? What are the most common sites of mets?
10% of pts have metastatic Dz at Dx. The most common sites of mets are the lung, liver, and bone.
What are the most common presenting Sx of urethral cancer?
In women, hematuria and obstructive Sx are the most common. In men, a palpable mass and obstructive Sx are more common.
What is the workup of urethral cancer?
Urethral cancer workup: H&P, including palpation of length of urethra in men, inguinal nodal examination, and bimanual examination. The pt should have a cystourethroscopy with Bx, retrograde urethrography, CT/MRI pelvis, and basic labs. Consider PET or bone scan if mets are suspected.
What is the AJCC 7th edition (2009) T and N staging for primary tumors of the urethra?
1. Tis: CIS
2. Ta: noninvasive verrucous/papillary/polypoid carcinoma
3. T1: invasion of subepithelial connective tissue
4. T2: invasion of corpus spongiosum, prostate, or periurethral muscle
5. T3: invasion of corpus cavernosum, prostatic capsule, ant vagina, or bladder neck
6. T4: invasion of other adjacent organs
7. N1: mets to single LN <2 cm
8. N2: mets to single LN >2 cm or multiple +nodes
What is the AJCC 7th edition (2009) T staging for urothelial carcinoma (TCC) of the prostate?
1. Tis pu: CIS with involvement of prostatic urethra
2. Tis pd: CIS with involvement of prostatic ducts
3. T1: invasion of urethral subepithelial connective tissue
4. T2: invasion of prostatic stroma, corpus spongiosum, or periurethral muscle
5. T3: invasion of corpus cavernosum, beyond prostatic capsule, bladder neck
6. T4: invasion of adjacent organs
What factors affect the Tx strategy of urethral cancer?
Location (ant vs. post), size, DOI, and presence of nodal mets or DMs are the major factors affecting prognosis and Tx strategy.
Does location correlate to the stage/prognosis of urethral cancer?
Yes. Proximal lesions more often present at a higher stage and thus carry a worse prognosis.
What types of surgical resections have been used for male urethral cancer pts?
Multiple forms of conservative resections have been used for very early Dz (Tis-T1), including transurethral resection, laser ablation, and microsurgical resection. Radical resections, which have been the historical standard, include partial and total penectomy and penectomy with cystoprostatectomy.
What are the desired margins for a partial penectomy in urethral cancer?
A 2-cm margin is desired for a partial penectomy.
What is expected outcome for early-stage (Tis-T1) male pts treated with surgery alone?
Based on the MSKCC experience, among 10 male pts (Tis-T1) treated with various surgical strategies, DFS at 5 yrs was 83%. (Dalbagni G et al., Urology 1999)
What is the expected outcome for advanced-stage (≥T2) male pts treated with surgery alone?
Based on the MSKCC experience, among 36 male pts (T2-T4) treated with various surgical strategies, DFS at 5 yrs was 45% (Dalbagni G et al., Urology 1999). Of note, 6 pts were treated with surgical salvage after initial Tx with RT.
What are the outcomes for early-stage (Tis-T1) male pts treated with RT alone?
There is very little data for RT alone in treating male pts with urethral cancer. Only very small series are available. A series of 5 men with early-stage urethral cancer described LC in 4 of those men (Heysek R et al., J Urol 1985).
What types of surgical resections have been used for female urethral cancer pts?
Early-stage Dz (Tis-T1) has been treated with local excision, laser excision, transurethral resection, and partial urethrectomy. Radical resection for locally advanced Dz (≥T2) includes ant exenteration, which involves removal of pelvic nodes, the uterus, and appendages, and en bloc resection of pubic symphysis and inf rami.
In locally advanced female urethral cancer (≥pT2), what is the 5-yr OS and LF after ant exenteration alone?
The 5-yr OS is <20%, with a >66% LF rate in female pts with locally advanced urethral cancer treated with exenteration alone. (Narayan P, Urol Clin North Am 1992)
What are outcomes for early-stage (variable definition of early stage includes ant, node− pts without T stage) urethral cancer in female pts treated with RT alone?
A meta-analysis of RT alone in female pts with urethral cancer showed a 5-yr OS of 75% with early-stage Dz and 34% with advanced-stage Dz. (Kreig R, Oncology 1999)
What is the OS for female pts with advanced Dz (variable in definition but in general refers to >T1 Dz, post Dz, or node+ Dz) treated with combined surgery and RT?
Meta-analysis of 34 pts treated in this manner revealed 5-yr OS of 29% (Kreig R et al., Oncology 1999). The single-largest series revealed a 25% OS at 5 yrs among the 20 pts treated (Grabstald H et al., JAMA 1966).
What is typical single-modality RT Rx for female urethral cancer?
RT is often given as brachytherapy alone or brachytherapy + EB. Typical Rx include brachytherapy alone to 50–60 Gy and EBRT to 40–45 Gy → brachytherapy to 20–25 Gy. Inguinal nodes should be included.
What are the outcomes for advanced-stage pts treated with CRT?
A number of case reports have shown good results with combined RT and 5-FU/mitomycin-C in both men and women with advanced Dz. A retrospective study of 18 pts from the University of Texas–San Antonio, including male and female pts, demonstrated that among the 8 advanced-stage pts (T3-4N1M1), DFS was 45.2 mos for those treated with CRT compared to 23.3 mos for those treated with surgery alone. Chemo from this study was based on histology and included 5-FU/cisplatin for SCC and carboplatin/Taxol for TCC. There were 8 total high-stage pts in this study. (Eng T et al., Am J Clin Onc 2003)
What are the expected acute and late RT toxicities associated with Tx of urethral cancer?
1. Acute toxicities: dermatitis, urinary Sx, diarrhea
2. Late toxicities: urethral stricture/stenosis, urethrovaginal fistulas, incontinence