Comparison and validation of different risk models for papillary renal cell carcinoma

Background: Several prognostic algorithms were specifically or nonspecifically used for papillary renal cell carcinoma (PRCC). No consensus was reached upon their efficacy of discrimination. We aim to compare the stratifying ability of current models or systems in predicting the risk of recurrence of PRCC. Methods: A PRCC cohort consisting of 308 patients from our institution and 279 patients from The Cancer Genome Atlas (TCGA) was generated. With ISUP grade, TNM classification, UCLA Integrated Staging System (UISS), STAGE, SIZE, GRADE AND NECROSIS (SSIGN), Leibovich model and VENUSS system, recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were studied using Kaplan-Meier method and concordance index (c-index) was compared. Differences between risk groups in gene mutation and infiltration of inhibitory immune cells were studied with TCGA database. Results: All the algorithms were able to stratify patients in RFS as well as DSS and OS (all P < 0.001). VENUSS score and risk group generally had the highest and balanced c-index (0.815 and 0.797 for RFS). ISUP grade, TNM stage and Leibovich model had the lowest c-indexes in all analysis. Among the 25 most frequently mutated genes in PRCC, eight had different mutation frequency between VENUSS low- and intermediate-/high-risk patients and mutated KMT2D and PBRM1 resulted in worsened RFS (P = 0.053 and P = 0.007). Increased Treg cells in tumors of intermediate-/high- risk patients were also identified. Conclusions: VENUSS system showed better predictive accuracy in RFS, DSS and OS compared with SSIGN, UISS and Leibovich risk models. VENUSS intermediate-/high-risk patients had increased frequency of mutation in KMT2D and PBRM1 and increased infiltration of Treg cells.