Assessing the value of grade heterogenity among primary tumor and venous tumor thrombus in clear cell renal-cell carcinoma

Background: Recent evidence demonstrated the presence of nuclear grade heterogenity between primary tumor (PT) and venous tumor thrombus (VTT) in clear-cell renal cell carcinoma (ccRCC). Objective: To assess the rate of tumor grade discrepancy (GD) between PT and VTT in a cohort of ccRCC and the association with disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). Design, setting, and participants: This was a retrospective analysis of two prospectively collected databases in high-referral centers. Pathology slides were centrally reviewed. Outcomes measurements and statistical analysis: GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS. The Kaplan-Meier method and the log-rank test were applied to assess differences in survival. Results and limitations: In this study, data of 88 patients with locally advanced ccRCC and VTT were analyzed. GD was identified in 47 (53.5%) cases. VTT upgrading occurred in 27 (30.6%) patients, while downgrading was observed in 20 (22.9%) patients. The presence of GD was independently associated with significantly worse oncologic outcomes across all endpoints, regardless of the direction of the discrepancy. Multivariable Cox regression analysis revealed that GD correlated with a lower probability of DFS (HR 1.74), CSS (HR 1.68), and OS (HR 1.91). Specifically, VTT upgrading (GD +1 or +2) emerged as the most adverse prognostic indicator, with GD +2 patients facing the highest risk of recurrence (HR 1.88). These findings suggest that integrating thrombus-specific grading into postoperative frameworks could enhance risk stratification and help personalize adjuvant therapy strategies. Conclusions: Routine reporting of PT and VTT grade in locally-advanced ccRCC can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression.