Distinct Prognostic and Molecular Profiles of Fat versus Vein Invasion in T3a Renal Cell Carcinoma

pT3a renal cell carcinoma (RCC) encompasses three different types of progression features –perinephric fat invasion, sinus fat invasion and renal vein (branch) invasion, leading to persistent debate on prognostic heterogeneity and the need for reclassification. RNA sequencing was performed on representative tumor samples from radical nephrectomy specimens of 11 sinus fat invasion (SFI) and 12 renal vein invasion (RVI) patients with clear cell RCC to identify differentially expressed genes and pathway enrichments. Transcriptomic profiling revealed that SFI tumors were enriched for epithelial-mesenchymal transition, KRAS signaling, and extracellular matrix reprogramming, whereas RVI tumors exhibited hypoxia, oxidative phosphorylation, and DNA repair pathway activation suggesting an intrinsically disparate competencies directing the tumors to adopt different invasion mechanisms.