Nuclear Grading of Tumor Thrombus: An Unheeded Prognostic Predictor in Non-metastatic Clear Cell Renal Cell Carcinoma

Abstract Background: The prognostic risk of non-metastatic clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is variable among individual patients following radical nephrectomy and thrombectomy. However, the prognostic potential of multiple pathological features of VTT are unexploited, and risk stratification models specific for these patients are lacking.Patients and methods: This retrospective, nationwide cohort comprised 1263 non-metastatic ccRCC patients with VTT from multicentre, including Training (n=664), China-validation (n=517) and Poland-Validation cohorts (n=82). In addition to the collection of traditional clinicopathologic features, the pathologic characteristics of VTT were centrally reviewed. Independent predictors from multivariable Cox regression analysis were developed into a prognostic model. Harrell's concordance index (c-index), area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate the association of the variables and prognostic models with overall survival (OS) and disease-free survival (DFS).Results: Using a multi-cohort of 1263 patients, we identified that VTT grading represents an unheeded and powerful independent prognostic factor of adverse outcomes across all cohorts in multivariate analysis for OS and DFS (P < .001; P < .001; P = 0.014 in Training, China-Validation, and Poland-Validation cohorts, respectively). Moreover, VTT grading showed superiority in predicting survival risk compared with the PT grading and other indicators. A risk positioning model, named the TT-GPS score, was constructed based on four independent predictors: VTT height, VTT Grading, Perinephric fat invasion, and Sarcomatoid differentiation in primary tumor. The TT-GPS score displayed better discriminatory ability than available models in risk assessment (OS, c-index: 0.736 and 0.746, AUC: 0.828 and 0.815; DFS, c-index: 0.705 and 0.710, AUC: 0.797 and 0.787 in Training and China-Validation cohorts, respectively). Poland-Validation cohort validated the superiority of the TT-GPS score (OS, c-index: 0.840, AUC: 0.874). Conclusions: VTT grading displayed superior accuracy in prediction of survival risk. By incorporating VTT grading, the TT-GPS score is a powerful predictor of adverse outcomes in non-metastatic ccRCC patients with VTT.