Peritumoral Fat Radiomics for Dual Prediction of TNM Stage and Histological Grade in Clear Cell Renal Cell Carcinoma:...

Background/Objectives: Perirenal fat (PRF) constitutes a critical yet understudied component of the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). While radiomics enables non-invasive tissue characterization, whether PRF-derived features can simultaneously predict both TNM stage and histological grade, and whether optimal peritumoral distances differ between these distinct biological targets, remains unexplored in the literature. Methods: This multi-cohort retrospective study included 474 histopathologically confirmed ccRCC patients from three independent datasets (2007-2023). Automated nnU-Net segmentation delineated tumors and kidneys. Concentric PRF regions were systematically generated at 1-10 mm radial distances, yielding 18 distinct regions of interest. From each ROI, 1409 radiomic features were extracted using PyRadiomics. Sequential feature selection employed correlation filtering, SHAP-guided elimination, and LASSO regularization. Multiple machine learning classifiers underwent hyperparameter optimization with rigorous cross-cohort validation. Results: Systematic ROI screening revealed target-specific optimal distances: 4 mm PRF for TNM staging versus 10 mm PRF for histological grading. For staging, the integrated model (tumor + PRF radiomics + clinical variables) achieved AUC 0.829 (95% CI 0.781-0.877), sensitivity 80.2%, and specificity 67.8%. For grading, the combined model achieved AUC 0.780 (95% CI 0.598-0.962), sensitivity 79.7%, and specificity 63.3%, significantly outperforming all single-compartment models (DeLong p < 0.001). Conclusions: This study establishes that PRF radiomics enables accurate simultaneous non-invasive prediction of both TNM stage and histological grade in ccRCC. The novel discovery that optimal peritumoral distances differ substantially by prediction target (4 mm versus 10 mm) suggests distinct biological underpinnings for stage- and grade-related microenvironmental alterations, with important methodological implications for radiomic model development in oncology.