Introduction

Enhancer of zeste homolog 2 is a methyltransferase encoded by the EZH2 gene. The role of EZH2 upregulation has been studied in several malignancies, including bladder cancer, though its role in upper tract urothelial carcinoma (UTUC) is poorly understood. We sought to evaluate the prognostic value of EZH2 expression in UTUC.

Methods

We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry for EZH2 was performed on tissue microarrays from RNU specimens. The percentage of staining was evaluated, with EZH2 positivity defined as >20% staining present. Clinicopathologic characteristics and oncologic outcomes including recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were compared between patients stratified by EZH2 positivity. Prognostic role of EZH2 was assessed using Kaplan-Meier (KM) analysis. Predictors of oncologic outcomes were identified using univariate (UVA) and multivariate (MVA) Cox regression analysis. Significance was defined for p<0.05.

Results

402 patients were included for analysis, with median follow-up 35.5 months. 313 (77.9%) patients were EZH2-negative and 89 (22.1%) were EZH2-positive. While gender, pT stage, pN stage, and prior bladder cancer were similar between groups, EZH2 expression was more often associated with ureteral location, sessile architecture, necrosis, and CIS (Table). On UVA, EZH2 was a significant predictor for worse RFS (HR 1.63, p=0.019), CSS (HR 1.87, p=0.004), and OS (HR 1.97, p<0.001). On MVA adjusted for age, pT, pN, and LVI, EZH2 remained a significant predictor for worse OS (HR 1.65, p=0.005), while significance was lost for RFS and CSS. KM curves are shown (Figure).

Conclusions

EZH2 expression appears to be associated with adverse pathologic features and may predict worse oncologic outcomes in patients with high-grade UTUC. The role of EZH2 pathways in UTUC pathogenesis remains to be further elucidated.

Funding

none