Pathological and genetic markers improve recurrence prognostication with the University of California Los Angeles Integrated Staging System for patients with clear cell renal cell carcinoma

Purpose: To elucidate which patients with clear cell renal cell carcinoma have the highest risk for disease relapse after curative nephrectomy is challenging but is acutely relevant in the era of approved adjuvant therapies. Pathological and genetic markers were used to improve the University of California Los Angeles Integrated Staging System (UISS) for the risk stratification and prognostication of recurrence free survival (RFS). Patients and methods: Necrosis, sarcomatoid features, Rhabdoid features, chromosomal loss 9p, combined chromosomal loss 3p14q and microvascular invasion (MVI) were tested in univariable and multivariable analyses for their ability to improve the discriminatory ability of the UISS. Results: In the development cohort, during the median follow-up time of 43.4 months (±SD 54.1 months), 50/240 (21%) patients developed disease recurrence. MVI (HR: 2.22; p = 0.013) and the combined loss of chromosome 3p/14q (HR: 2.89; p = 0.004) demonstrated independent association with RFS and were used to improve the assignment to the UISS risk category. In the current UISS high-risk group, only 7/50 (14%) recurrence cases were correctly identified; while in the improved system, 23/50 (45%) were correctly prognosticated. The concordance index meaningfully improved from 0.55 to 0.68 to distinguish patients at intermediate risk versus high risk. Internal validation demonstrated a robust prognostication of RFS. In the external validation cohort, there was no case with disease recurrence in the low-risk group, and the mean RFS times were 13.2 (±1.8) and 8.2 (±0.8) years in the intermediate and high-risk groups, respectively. Conclusions: Adding MVI and combined chromosomal loss3p/14q to the UISS improves the ability to define the patient group with clear cell renal cell carcinomawho are at the highest risk for disease relapse after surgical treatment.