Urethral Carcinoma

Urethral carcinoma is a rare malignancy (less than 1 percent of all cancers; about 1 in 1,000,000 in men and 0.4 in 1,000,000 in women), usually in patients over 60 years.

In men, it affects the bulbomembranous urethra in about 60 percent, the penile urethra in 30 percent and the prostatic urethra in 10 percent. Squamous cell carcinoma accounts for 50 to 80 percent, followed by urothelial carcinoma (15 to 30 percent) and adenocarcinoma (5 percent).

In women, the most common type is squamous cell carcinoma in the distal third and urothelial carcinoma in the proximal urethra. Adenocarcinoma (clear cell, 'Müllerian type', often arising in urethral diverticula) is more frequent than in men (about 15 to 20 percent).

Risk factors:

• chronic irritation and inflammation (stricture disease, in about 50 percent of men with squamous carcinoma, chronic urethritis, sexually transmitted infections)
• human papillomavirus infection (types 16 and 18, especially in squamous cell cancers)
• urethral diverticula
• prior radiation
• a history of bladder cancer (for urothelial carcinoma)

Staging is by the tumour depth:

• Ta, Tis
• T1: subepithelial connective tissue
• T2: corpus spongiosum, prostate or periurethral muscle
• T3: corpus cavernosum, anterior vagina, bladder neck
• T4: adjacent organs

Prognosis depends on stage and location. The 5-year survival is about 40 to 50 percent overall, with posterior location and nodal metastasis as adverse factors.

• Obstructive voiding symptoms: weak stream, hesitancy, dysuria, urinary retention, and a stricture that does not respond to dilation.
• Haematuria or blood stained discharge, urethral bleeding, and pain.
• A palpable mass in the perineum or along the urethra (or urethral meatus in women, a caruncle like growth), and a periurethral abscess or fistula.
• Dyspareunia and vaginal bleeding in women.
• Palpable inguinal lymph nodes (in 20 to 40 percent at presentation; or necrotic).
• Systemic signs and symptoms in advanced disease (weight loss, bone pain).
• Delay in diagnosis is common because it is mistaken for stricture, urethritis or a urethral caruncle.

• Examination: palpation of the penile urethra, perineum and groin nodes; in women, pelvic examination.
• Urethroscopy and cystoscopy with biopsy (histology and grade), and examination of the bladder to exclude associated urothelial carcinoma (as well as upper tract imaging in urothelial type).
• MRI of the pelvis (the best imaging for local staging, assessing depth of invasion, and involvement of adjacent structures); CT of the chest, abdomen and pelvis for nodal and distant metastases; PET-CT optional.
• Urethrography for stricture and filling defects.
• Urine cytology, in urothelial types.
• Fine needle aspiration or sentinel node biopsy of inguinal nodes (palpable), with pelvic imaging for deeper nodes.
• Squamous cell carcinoma antigen is not routinely used; HPV testing may be informative.

Management is determined by sex, location, stage, histology and function preservation.

• Men:
  • Distal (penile) urethral tumour, superficial and low stage (Ta, Tis, T1): transurethral resection or urethral segmental excision with end-to-end anastomosis, or distal urethrectomy with meatoplasty, or laser ablation.
  • Distal (penile) urethral tumour, invasive: partial penectomy with at least 2 cm of tumour free margin. Consider total penectomy with perineal urethrostomy for proximal penile tumours.
  • Bulbomembranous urethra: radical surgery with en bloc cystoprostatectomy and total penectomy with perineal urethrostomy. This is mutilating and often combined with neoadjuvant chemotherapy or chemoradiotherapy to limit the extent.
  • Use urethral resection and end-to-end anastomosis for short segment small tumours.
  • Prostatic urethral urothelial carcinoma (Tis or superficial): transurethral resection and intravesical BCG 81 mg weekly for 6 weeks, with maintenance; stromal invasion needs radical cystoprostatectomy.
• Women:
  • Distal one third: partial urethrectomy with a 1 cm margin (or tumour excision with urethral reconstruction), or radiotherapy (external beam 60 to 70 Gy plus brachytherapy), which preserves continence.
  • Proximal or entire urethra: anterior pelvic exenteration (cystourethrectomy and vaginal wall removal) with urinary diversion, often combined with chemoradiation.
• Lymph node management: inguinal lymph node dissection for palpable or biopsy positive nodes; prophylactic dissection is controversial, with sentinel biopsy used; pelvic lymphadenectomy for tumours of the proximal urethra or bladder neck.
• Chemoradiation: concurrent cisplatin (40 mg/m2 weekly, or 75 mg/m2 every 3 weeks) or mitomycin C (10 mg/m2 on day 1) with 5-fluorouracil (1,000 mg/m2 on days 1 to 4), with radiotherapy (45 to 66 Gy), for locally advanced squamous cell carcinoma.
• Use either as organ preserving treatment or neoadjuvant or adjuvant therapy (the extrapolation from anal and cervical cancers).
• Systemic chemotherapy for metastatic disease:
  • urothelial histology: gemcitabine 1,000 mg/m2 on days 1 and 8 with cisplatin 70 mg/m2 on day 1 every 21 days
  • squamous cell histology: cisplatin and 5-fluorouracil or a taxane based regimen
  • adenocarcinoma: regimens used in colorectal cancer
  Immunotherapy (pembrolizumab 200 mg every 3 weeks) is used in selected cases.
• Surveillance: clinical examination, urethroscopy and imaging every 3 to 6 months for 2 years, then every 6 to 12 months; recurrences usually occur within 2 years, mostly local.
• Prognosis: favourable for distal anterior tumours (5-year survival 60 to 70 percent) and poor for posterior or proximal tumours with nodal disease (10 to 30 percent).