Urethral cancer is a rare disease. The pathophysiology of urethral cancer depends on the histological subtypes. It could be primary from epithelial origin or secondary like from bladder cancer which is more common than primary type ^{[1] [2]}.

Mucous cells in the urethra have the ability to turnover rapidly. In primary type of the urethral cancer It has been suggested that defect in “DNA repair mechanism” may cause urethral cancer.

Other etiologies for primary types are ^[3]:

• Chronic inflammation and strictures: May happen after any surgery on urethra like urethroplasty ^[4][5].
• Infection: sexually transmitted diseases like HPV type 16 ^[6].
• External radiation therapy ^[7]

• Urethral diverticula in female ^[8]

• Other: Arsenic ingestion

• Although cigarette smoking can cause bladder cancer but the role of it in causing primary urethral cancer is still unknown.

• Male: Prostatic and membranous portions of the urethra cancer are more from bladder cancer. Bulbous and membranous portions urethral cancers are most commonly squamous cell carcinoma.

• Female: Proximal 2/3 of the urethral cancer are more primary types and distal 1/3 is usually squamous cell carcinoma.

The exact gene and mutations that cause urethral cancer are unknown. But below genetic correlation are known to be involved in the pathogenesis:

• Mutation in TERT promoter, PAX8, GATA3, P63, P40, p53 may play role in sarcomatoid urothelial carcinoma ^[9].
• Fragile histidine triad (FHIT) gene may play a role in causing bladder urothelial carcinoma ^[10]. 

• Overexpression of the semaphorin 3A in patients with urethral cancer has been reported ^[11].

• Urethral cancers in proximal urethra have worse prognosis than those arising in the distal portion in men.

In end stage type, they may appear as an exophytic mass.

The microscopic view of urethral cancer is depended on the location of the cancer. The type of the cancer in the distal part of the urethra is usually squamous cell. ^[12]

• Female^[13]
  • The female urethra is lined by transitional cell mucosa proximally and stratified squamous cells distally.
  • Therefore, transitional cell carcinoma is most common in the proximal urethra
  • Adenocarcinoma may occur in both locations and arises from metaplasia of the numerous periurethral glands.

• Male
  • The male urethra is lined by transitional cells in its prostatic and membranous portion and stratified columnar epithelium to stratified squamous epithelium in the bulbous and penile portions.
  • The submucosa of the urethra contains numerous glands.
  • Therefore, urethral cancer in the male can manifest the histological characteristics of transitional cell carcinoma, squamous cell carcinoma, or adenocarcinoma.
  • Adenocarcinoma in the urethra is commonly associated with diverticula and prostatic adenocarcinoma.
  • Except for the prostatic urethra, where transitional cell carcinoma is most common, squamous cell carcinoma is the predominant histology of urethral neoplasms.
  • Transitional cell carcinoma of the prostatic urethra may be associated with transitional cell carcinoma of the bladder and/or transitional cell carcinoma arising in prostatic ducts.

• SCC: high mitotic activity, nuclear atypia. Positive with cytoplasmic beta-catenin stain. pleomorphic tumor cells with focal or abundant keratinization, intercellular bridges. Stains: High molecular weight cytokeratin (CK903, CK5/6), p63, p16.

• Adenocarcinoma ^[14]:  simple or pseudostratified columnar epithelium with hyperchromatic nuclei. vacuolated cytoplasm with mucin pools. Stains: P53, CK20.

• Clear Cell: clear or eosinophilic cytoplasm, vacuoles in the cytoplasm, hyperchromatic nuclei. Positive with  p53 and vimentin stain. Hobnail changes and extracellular mucoid material.