Background: Human epididymis protein 4 (HE4) has been indicated as a novel tumor marker for ovarian cancer diagnosis/monitoring and as a mediator of renal fibrosis. In this study, we investigated the potential role of HE4 in the pathogenesis of patients with renal cell carcinoma (RCC).Methods: We retrospectively enrolled 249 patients with RCC who underwent nephrectomies at a single center between 1997 and 2010. HE4 expression was evaluated by immunohistochemistry and RNA in situ hybridization

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... aining in both tumor and renal cortex tissue microarrays. The expression of HE4 was evaluated in line with the clinicopathologic features of each patient.Results: HE4-positive staining was confirmed in 37 (15.0%) tumor tissue microarrays and in 88 (38.3%) cortex tissue microarrays. High expression of HE4 in the tumor was not associated with overall survival (OS), cancer-specific survival (CSS), or recurrence free survival (RFS). However, high expression of HE4 in the renal cortex was strongly associated with an increased risk of OS, CSS, and RFS (HR 3.608 (95% confidence interval (CI) 2.127-6.118); p<0.001, HR 5.759 (95% CI 2.801-11.841); p<0.001 and HR 3.309 (95% CI 1.751-6.252); p<0.001, respectively). Multivariate analysis revealed that the Eastern Cooperative Oncology Scale of Performance Status (ECOG-PS), stage, pathological subtype, and high expression of HE4 in the renal cortex were independent risk factors for poor OS and that ECOG-PS, tumor size, stage, and high expression of HE4 in the renal cortex were independent risk factors for poor CSS.Conclusions: High expression of HE4 in the renal cortex is an independent risk factor of OS and CSS in RCC. Further investigations are needed to elucidate the underlying mechanisms of HE4 in the renal cortex in the progression of renal cell carcinoma.