Incident urothelial cancer in the Malmö Diet and Cancer Study: cohort characteristics and further validation of ezrin as a prognostic biomarker.

Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with poor prognosis in urothelial bladder cancer in several independent studies. The present study provides a first description of clinicopathological characteristics of incident urothelial cancers, not only located to the bladder, in the prospective, population-based cohort study Malmö Diet and Cancer. In addition, the prognostic value of ezrin expression is validated in primary tumours, and the longitudinal expression of ezrin examined in a subset of primary and recurrent tumours (n=28). Among a total number of 355 incident tumours registered up until Dec 31 2010, 335 were located to the bladder. Immunohistochemical expression of cytoplasmic and membranous ezrin was evaluated in tissue microarrays with primary tumours from 272 cases and recurrent tumours from 28 cases. A combined score of the minimum, mean and maximum fraction and percentage of staining was calculated. Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test, univariable and multivariable Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin expression on 5-year overall survival (OS). Ezrin expression could be evaluated in 263/272 primary and all 28 recurrent tumours. Membranous but not cytoplasmic ezrin was significantly reduced in recurrent compared to primary tumours (p < 0.001). Low cytoplasmic and membranous ezrin expression were associated with more advanced T-stage (p = 0.004, p < 0.001) and high-grade tumours (p = 0.025, p < 0.001), but not with age, sex, tumour location or smoking status. Both low cytoplasmic and membranous ezrin staining were associated with a significantly reduced 5-year OS (HR = 1.65; 95% CI 1.06-2.57 and HR = 2.51, 95% CI 1.52-4.17), but only low membranous ezrin remained prognostic after adjustment for age, sex, stage, grade and smoking status (HR = 1.69, 95% CI 1.00-2.85). This study provides a first description of the clinicopathological characteristics of 355 incident urothelial cancers in the Malmö Diet and Cancer Study up until 2010. In addition, the value of ezrin expression as a prognostic biomarker is further consolidated in this type of cancer. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_189.