Primary Female Urethral Carcinoma: Proposed Staging Modifications Based on Assessment of Female Urethral Histology and Analysis of a Large Series of Female Urethral Carcinomas

Abstract

Primary female urethral carcinoma is rare. Limited clinicopathologic information has hindered development of staging criteria in this disease. We analyzed 29 primary female urethral carcinoma resections from 3 academic medical centers to characterize histopathologic features, clinical outcomes, and applicability of current and a novel modified staging criteria. We complemented this analysis with review of fully embedded female autopsy urethras to detail anterior and posterior urethral wall histology. Primary female urethral carcinoma subtypes included urothelial carcinoma in situ (3/29, 10%), adenocarcinoma in situ (1/29; 3%), invasive urothelial carcinoma (13/29, 45%), clear cell carcinoma (5/29, 17%), adenocarcinoma not otherwise specified (4/29, 14%) and squamous cell carcinoma (3/29, 10%). Only 6/29 cases (21%) were originally assigned a stage at diagnosis. Using histologic landmarks specific to the female urethra, we modified existing eighth edition American Joint Committee on Cancer urethral staging to a histology-based female urethral carcinoma staging (UCS) system. UCS stages were defined as pTa/pTisUCS (noninvasive carcinoma), pT1UCS (subepithelial tissue invasion), pT2UCS (periurethral muscle invasion), pT3UCS (vaginal adventitia or surrounding fibrovascular tissue), and pT4UCS (anterior wall fibroadipose tissue or posterior vaginal wall). UCS staging was applicable to all cases and showed stepwise changes in disease recurrence with increasing stage and was statistically significant for disease-specific and overall survival in contrast to the American Joint Committee on Cancer staging system. This study of one of the largest cohort of primary female urethral carcinomas provides a modified histology-based staging system specific to female urethral anatomy that provides outcomes-related information, which may be further validated by larger multi-institutional studies.

FIGURE 1.

Histologic layers of the anterior and posterior urethral wall. These layers were used to derive the female UCS system and correlate to pTa/pTis_UCS (noninvasive carcinoma involving the urothelium), pT1_UCS (subepithelial tissue invasion), pT2_UCS (periurethral muscle invasion), pT3_UCS (vaginal adventitia, surrounding fibrovascular tissue, striated muscle), and pT4_UCS (anterior wall fibroadipose tissue or posterior wall vaginal wall).

FIGURE 2.

Noninvasive lesions of the female urethral included urothelial carcinoma in situ (A), adenocarcinoma in situ (B), and high-grade papillary urothelial carcinoma with an inverted growth pattern (C).

FIGURE 3.

Histologic subtypes of female urethral carcinoma included in staging analysis included urothelial carcinoma (A), clear cell carcinoma (B), adenocarcinoma NOS (C), adenocarcinoma with mucinous features (D), and squamous cell carcinoma (E). F, Angiolymphatic invasion was identified in 38% of cases. All images.

FIGURE 4.

Examples of pT_UCS staging. A, pTis_UCS stage consists of urothelial carcinoma with colonization of underlying von Brunn nests and periurethral glands in some instances. This is identical to pTis_AJCC. B, pT1_UCS is identical to pT1_AJCC and involves invasion of the subepithelial tissue. C, pT2_UCS is identical to pT2_AJCC and involves invasion of the periurethral muscle layers. D, pT3_UCS includes invasion into the adjacent fibrovascular and striated muscle layers that surround the periurethral muscle in the anterior and posterior urethra. By contrast, pT3_AJCC includes only invasion of the vaginal wall. E, pT4_UCS of the anterior female urethra includes invasion of the anterior fat and/or bladder wall, while pT4_UCS of the posterior female urethra includes invasion of the vaginal wall or bladder wall (F). By contrast, pT4_AJCC includes only invasion of the bladder wall.

FIGURE 5.

Kaplan-Meier curves for disease-specific survival and overall survival using UCS and AJCC staging systems. CI indicates confidence interval; HR, hazard ratio.