FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumors: van Oers JM, Wild PJ, Burger M, Denzinger S, Stoehr R, Rosskopf E, Hofstaedter F, Steyerberg EW, Klinkhammer-Schalke M, Zwarthoff EC, van der Kwast

Objectives lar 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 tumors and compared them with traditional pathologic features. s microarrays were used to analyze CK20, TP53, and Ki-67 expression immunohistochemically in 255 unselected patients. FGFR3 mutations were detected by SNaPshot analysis. s al CK20 expression was strongly associated with higher tumor grades and stages (P < 0.001); however, 65% of pTa tumors revealed an abnormal CK20 pattern. In the group of pTaG1 tumors, 59% presented with an abnormal CK20 pattern, whereas 82% carried the FGFR3 mutation. In the group of bladder tumors 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 tumor recurrence. sions ulation 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 tumors is defined by the presence of an FGFR3 mutation and a normal CK20 expression pattern.