FGFR3 Mutations and a Normal CK20 Staining Pattern Define Low-Grade Noninvasive Urothelial Bladder Tumours

Objectives: Molecular markers superior to conventional clinicopathologic parameters are needed to predict disease courses in bladder cancer patients. In this study, we investigated four markers (Ki-67, TP53, CK20, FGFR3) in primary urothelial bladder tumours and compared them with traditional pathologic features. Methods: Tissue microarrays were used to analyse CK20, TP53, and Ki-67 expression immunohistochemically in 255 unselected patients. FGFR3 mutations were detected by SNaPshot analysis. Results: Abnormal CK20 expression was strongly associated with higher tumour grades and stages (p < 0.001); however, 65% of pTa tumours revealed an abnormal CK20 pattern. In the group of pTaG1 tumours, 59% presented with an abnormal CK20 pattern, whereas 82% carried the FGFR3 mutation. In the group of bladder tumours with normal CK20 pattern, the FGFR3 gene was mutated in 89%, whereas a mutated FGFR3 gene was found in only 37% of cases with abnormal CK20 expression (p < 0.001). All markers proved to be strong predictors of disease-specific survival in univariate studies. However, in multivariate analyses they were not independent from classical pathologic parameters. None of the molecular markers was significantly associated with tumour recurrence. Conclusions: Dysregulation of CK20 expression is an early event in the carcinogenesis of papillary noninvasive bladder cancer, but occurs later than FGFR3 mutations. The group of low-grade noninvasive papillary tumours is defined by the presence of an FGFR3 mutation and a normal CK20 expression pattern.

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