3. EPIDEMIOLOGY AETIOLOGY AND PATHOLOGY
3.1. Epidemiology
Primary urethral carcinoma is considered a rare cancer, accounting for < 1% of all genitourinary malignancies [6] (ICD-O3 topography code: C68.0) [7]. In 2013, the prevalence of urethral carcinoma in the 28 European Union countries was 3,986 cases with an estimated annual incidence of 1,504 new cases, with a male/female prevalence of 2.9:1 [8]. Likewise, in an updated analysis of the Surveillance, Epidemiology and End Results (SEER) database (2004–2016), the incidence of primary urethral carcinoma peaked in the > 75 years age group (7.6/million). The age-standardised rate was 4.3/million in men and 1.5/million in women and was almost negligible in those aged < 55 years (0.2/million) [9]. After matching for tumour and patient characteristics, women present with higher disease stage and exhibited higher cancer-specific mortality (CSM) [10].
3.2. Aetiology
For male primary urethral carcinoma, various predisposing factors have been reported, including urethral strictures [11,12], chronic irritation after intermittent catheterisation/urethroplasty [13-15], external beam irradiation therapy (EBRT) [16], radioactive seed implantation [17], chronic urethral inflammation/urethritis following sexually transmitted infections (i.e., condylomata associated with human papilloma virus 16) [18,19] and lichen sclerosis [12]. In female urethral carcinoma, urethral diverticula [20-22] and recurrent urinary tract infections [23] have been associated with primary urethral carcinoma. Mid-urethral sling meshes have not been associated with an increased risk of primary urethral carcinoma [24]. Clear-cell adenocarcinoma (AC) may also have a congenital origin [25,26].
3.3. Histopathology and genomic profiling
Both the Surveillance of Rare Cancers in Europe (RARECARE) project and SEER database have reported that urothelial carcinoma (UC) of the urethra is the predominant histological type of primary urethral cancer (54–65%), followed by squamous cell carcinoma (SCC) (16–22%) and AC (10–16%) [8,27].
A SEER analysis of 2,065 men with primary urethral carcinoma (mean age 73 years) found that UC was most common (78%), and SCC (12%) and AC (5%) were significantly less frequent [28]. In women, AC is the more frequent histology (38–46.7%) followed by SCC (25.4–28%), UC (24.9–28%) and other histological entities (6%) [29,30]. Primary UC with unconventional histological subtypes is very rare and has a poor prognosis [31]. An analysis of the SEER database from 2004 to 2016 identified 165 cases of Primary UC with unconventional histological subtypes, 70.3% of which were in women, and reported that Mullerian-type tumour is the most frequent unconventional histology of urethral cancer, followed by melanocytic-type histology [32].