Objective To investigate the characteristics of spatiotemporal heterogeneity in pathological grading during the latent and invasive growth phases of non-metastatic renal cell carcinoma (RCC) and its correlation with clinical outcomes.

Methods A retrospective analysis was conducted on the case data of 316 RCC patients with local recurrence (LR) and 429 RCC patients with venous tumor thrombus (VTT) who underwent surgical treatment at 13 medical centers in China from January 2003 to December 2023. Pathological grade differences between primary tumor (PT) and LR, and between PT and VTT were selected as scenarios for the application of spatiotemporal heterogeneity in the dynamic progression of RCC. Pathological grading changes were defined according to a new four-tier scheme (upgrading, downgrading, stable low-grade, and stable high-grade). Stable low- or high-grade was defined as low-grade (WHO/ISUP grade Ⅰ or Ⅱ) or high-grade (WHO/ISUP grade Ⅲ or Ⅳ) in both PT and LR/VTT. Upgrading was defined as low-grade in the PT and high-grade in the LR/VTT; conversely, downgrading was defined as high-grade in the PT and low-grade in the LR/VTT. The potential influencing factors of pathological grading changes and their impact on patient prognosis were analyzed.

Results The median cancer-specific survival (CSS) for RCC patients with VTT and RCC patients with LR was 83 months and 76 months, respectively. The 5-year CSS rates were 65.6% and 60.6%, respectively. Pathological grading changes were observed in 38.0% of patients with PT and VTT and in 43.6% of patients with PT and LR. Lasso-Logistic regression analysis revealed a close correlation between primary tumor necrosis and pathological grading changes. Kaplan-Meier survival curves indicated a significant correlation between pathological grading changes and prognosis. Replacing the pathological grading in Leibovich, UISS, and GRANT scores with pathological grading changes significantly improved the predictive performance of the models (P <0.05).

Conclusions Spatiotemporal heterogeneity in pathological grading exists during the dynamic progression of non-metastatic RCC. Compared to the pathological grading of isolated events, the spatiotemporal variation in pathological grading serves as a more accurate independent prognostic factor for RCC patients with VTT and RCC patients with LR. Incorporating pathological grading changes can significantly improve the predictive performance of existing prognostic models.