FOXA1 and CK14 as markers of luminal and basal subtypes in histologic variants of bladder cancer and their associated conventional urothelial carcinoma

Invasive bladder cancer is diverse, and includes several named histomorphologies that differ from conventional urothelial carcinoma, termed histologic variants. By transcriptional analysis, bladder cancers can be divided into luminal and basal subtypes. In this paper, we study associations between markers of transcriptional subtypes and variant histology in a retrospective cohort of 309 cystectomy specimens. Histology slides were methodically reviewed for all cases, and variant histology was documented. Immunohistochemistry for FOXA1 (luminal marker) and CK14 (basal maker) was performed on histologic variants and their associated conventional urothelial carcinomas. Invasive carcinoma was present in 270 of the cystectomy specimens, 35% of which contained a histologic variant. Squamous carcinomas expressed higher CK14 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the basal character of squamous carcinoma. Likewise, squamous carcinomas expressed lower FOXA1 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the luminal character of micropapillary carcinoma, and suggesting that nested and plasmacytoid cancers have luminal character. FOXA1 was expressed at lower levels in conventional urothelial carcinoma associated with squamous carcinoma than conventional urothelial carcinoma associated with micropapillary carcinoma (p = 0.0072, Wilcoxon rank sum). CK14 expression did not differ between conventional urothelial carcinomas associated with squamous versus micropapillary carcinoma (p = 0.89, Wilcoxon rank sum). Instead, CK14 expression was higher in squamous carcinoma than conventional urothelial carcinoma present in the same bladder (p = 0.014, Wilcoxon rank sum, paired). Overall, the findings show that squamous and micropapillary cancers have different expression patterns of CK14 and FOXA1 and suggest that they arise from distinct precursors.