FGFR3 immunohistochemistry as a surrogate biomarker for FGFR3 alterations in urothelial carcinoma

Abstract

FGFR3 alterations are common in urothelial carcinoma (UC) and have implications both in prognosis and treatment. FGFR3 analysis is the current gold standard, but limitations as cost, turnaround time or accessibility may exist. FGFR3 immunohistochemistry (IHC) could provide a faster and more cost-effective identification of FGFR3 alterations. The aim of this study was to establish the accuracy of FGFR3 IHC as a surrogate biomarker for FGFR3 variants in UC. We retrospectively reviewed 41 UC patients from an institutional database selected by stratified random sampling based on presence of muscle invasion and FGFR3 variants. FGFR3 genetic analysis had been stablished through quantitative polymerase chain reaction. FGFR3 IHC was performed using a FGFR3 mouse monoclonal antibody and blindly evaluated by three independent pathologists. Results were dichotomised into positive (membrane and cytoplasm positivity even in small foci of cells) or negative categories. The cohort included 37 patients with bladder cancer and four with upper tract urinary carcinoma (UTUC). Twenty-two patients had muscle-invasive tumours (11 without and 11 with FGFR3 variants), while the other 19 had non-muscle-invasive disease (10 without and 9 with FGFR3 variants). FGFR3 IHC exhibited 80 % sensitivity, 95 % specificity, 94 % PPV and 83 % NPV to detect FGFR3 variants. There was concordance among the three pathologists in 78 % of samples, which traduces a substantial agreement with a Fleiss' kappa statistic of 0.7. Our study suggests that FGFR3 IHC is feasible and could potentially eliminate the need for genetic testing in patients with positive immunohistochemical results. Our findings support a dichotomic evaluation for FGFR3 IHC, which has the potential to enhance reproducibility compared to more complex scoring systems. Still, further research is needed to validate this proposed diagnostic algorithm.

Keywords: Bladder cancer; Diagnosis; FGFR3, Immunochemistry; Upper tract urothelial cancer; Urothelial cancer.