Abstract
BackgroundReduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guérin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). In the present study, we examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts.MethodsImmunohistochemical expression of ezrin was evaluated in tissue microarrays with tumours from one retrospective cohort of bladder cancer (n = 110; cohort I) and one population-based cohort (n = 342; cohort II). Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test and Cox regression proportional hazards’ modeling were used to evaluate the impact of ezrin on 5-year overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS).ResultsEzrin expression could be evaluated in tumours from 100 and 342 cases, respectively. In both cohorts, reduced membranous ezrin expression was significantly associated with more advanced T-stage (p < 0.001), high grade tumours (p < 0.001), female sex (p = 0.040 and p = 0.013), and membranous expression of podocalyxin-like protein (p < 0.001 and p = 0.009). Moreover, reduced ezrin expression was associated with a significantly reduced 5-year OS in both cohorts (HR = 3.09 95% CI 1.71-5.58 and HR = 2.15(1.51-3.06), and with DSS in cohort II (HR = 2.77, 95% CI 1.78-4.31). This association also remained significant in adjusted analysis in Cohort I (HR1.99, 95% CI 1.05-3.77) but not in Cohort II. In pTa and pT1 tumours in cohort II, there was no significant association between ezrin expression and time to progression.ConclusionsThe results from this study validate previous findings of reduced membranous ezrin expression in urothelial bladder cancer being associated with unfavourable clinicopathological characteristics and an impaired survival. The utility of ezrin as a prognostic biomarker in transurethral resection specimens merits further investigation.
Highlights
Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guérin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104)
Given previous findings of an in vitro interaction of ezrin with podocalyxin-like protein (PODXL), an established mediator of metastasis [21], and our recent results demonstrating that membranous PODXL expression is an independent predictor of tumour progression and poor prognosis in urothelial bladder cancer [22], we examined the correlations between tumour-specific expression of ezrin and PODXL
Distribution of ezrin expression and its association with clinicopathological characteristics Following antibody optimisation and staining, ezrin expression could be evaluated in tumours from 100/110 (90.9%) cases in Cohort I and 342/344 (99.4%) cases in Cohort II
Summary
Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guérin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). We examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts. Standard treatment for non-muscle-invasive carcinoma is transurethral resection of the bladder (TURB), with or without intravesical instillation of bacillus Calmette-Guérin (BCG), to prevent recurrence and progression. Non-muscle-invasive urothelial carcinoma has a high risk of recurrence and a substantial risk of progression [5], and muscle-invasive carcinoma is associated with a high mortality, despite aggressive treatment [3,6]. There is a great need for additional biomarkers to predict the risk of recurrence and progression into muscle invasive carcinoma for patients with early stage tumours
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