Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

Abstract

In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (P<0.001), low tumour stage (P<0.001), low histological grade (P<0.001) and a papillary growth pattern (P<0.001). Positive FGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis.

Keywords: fibroblast growth factor receptor 3 protein; grading; molecular markers; prognosis; urothelial cancer.

Figure 1.

Immunohistochemical staining with FGFR3 antibody. (A) Representative image of negative FGFR3 staining in a high-grade invasive urothelial tumour. (B) Representative imageof positive FGFR3 immunoreactivity in a low-grade non-invasive urothelial bladder cancer specimen. FGFR3, fibroblast growth factor receptor 3.

Figure 2.

Comparison of FGFR3 staining intensity with (A) grade, (B) stage and (C) FGFR3 mutation of tumours. Frequency represents the percentage of tumours in a particular stage or grade. Dark blue bars represent FGFR3 negative staining and light blue bars represent FGFR3 positive staining. FGFR3, fibroblast growth factor receptor 3; IHC, immunohistochemistry; PUNLMP, papilllary urothelial neoplasia of low malignant potential.

Figure 3.

Kaplan-Meier survival plots with point-wise confidence bands (confidence level, 0.95) for disease-specific survival based on FGFR3 staining in (A) all (n=207) immunohistochemically analysable patients and in (B) a subgroup analysis (n=89) considering only high-grade tumours. Log-Rank tests were performed to test for equality in the survival expectation of each group. N-values represent the number of patients in each group. (C) A forest plot for the univariate Cox regression analysis of factors potentially affecting disease-specific survival of patients with urothelial bladder cancer. The dashed vertical line indicates the no effect point (a hazard ratio of 1.0). Horizontal lines represent 95% confidence intervals. The midpoint and the area of the box illustrate the mean effect estimate and the weight of each subgroup. FGFR3, fibroblast growth factor 3; IHC, immunohistochemistry; PUNLMP, papilllary urothelial neoplasia of low malignant potential; WHO, world health organisation; uni/multi, solitary/multifocal; neg/pos, negative/positive.