Prognostic Significance of Murine Double Minute 2 Expression in Tumor Cells in Upper Tract Urothelial Carcinoma: An Analysis of 341 Cases in a Large Chinese Center.

Abstract

Aims: The prognostic significance of murine double minute 2 (MDM2) expression remains unknown in patients with upper tract urothelial carcinoma (UTUC). This study was designed to evaluate MDM2 expression and its association with clinicopathological characteristics and tumor outcomes in UTUC patients. Materials and Methods: Expression levels of MDM2 and p53 were determined by immunohistochemistry in a cohort of 341 UTUC patients. Associations of MDM2 and p53 expression levels with clinicopathological characteristics, disease-free survival (DFS), cancer-specific survival (CSS), and intravesical recurrence-free survival (IVRFS) were analyzed. Results: Nuclear expression of MDM2 and p53 were detected in the tumor cells of 129 (37.8%) and 203 (59.5%) patients, respectively. Decreased p53 expression was associated with positive MDM2 staining in tumor cells (p = 0.002). MDM2 expression was correlated with the exposure to aristolochic acids (p = 0.020), better preoperative renal function (p = 0.016), ureter location (p = 0.002), higher pathological T stage (p = 0.006), high tumor grade (p < 0.001), presence of glandular differentiation (p = 0.036), and sarcoma differentiation (p = 0.020). Kaplan-Meier analysis showed that positive MDM2 staining was associated with shorter CSS (p < 0.001), DFS (p < 0.001), and IVRFS (p = 0.020); MDM2+/p53- was associated with shorter CSS (p < 0.001) and DFS (p < 0.001), but not IVRFS (p = 0.145); while CSS, DFS, and IVRFS did not differ significantly between the p53+ and p53- patients (p = 0.307, 0.089, and 0.198, respectively). Multivariate analyses revealed that MDM2 expression in tumor cells independently predicted shorter CSS (p < 0.001; hazard ratio [HR] = 2.600; 95% confidence interval [CI]: 1.625-4.161) and DFS (p < 0.001; HR = 1.863; 95% CI: 1.314-2.641), excepting IVRFS (p = 0.092; HR = 1.590; 95% CI: 0.928-2.726). Conclusions: UTUC patients with elevated MDM2 expression may exhibit more aggressive biological features of the tumor and tend to have shorter CSS and DFS.