Analysis of papillary urothelial carcinomas of the bladder with grade heterogeneity: supportive evidence for an early role of CDKN2A deletions in the FGFR3 pathway

Aims The dual pathway model of urothelial carcinogenesis does not fully explain grade and stage progression in patients with initial low‐grade, non‐muscle invasive urothelial carcinomas. Fibroblast growth factor receptor 3 (FGFR3) mutations are a hallmark of the low‐grade pathway, with subsequent progression to muscle invasion occurring when FGFR3 mutant tumours exhibit a homozygous CDKN2A deletion. We hypothesized that grade heterogeneity represents the morphological manifestation of molecular changes associated with disease progression. Methods and results We identified retrospectively 29 non‐muscle invasive papillary urothelial carcinomas with grade heterogeneity (