Distinct prognostic and molecular profiles of fat versus vein invasion in T3a renal cell carcinoma.

BACKGROUND: pT3a renal cell carcinoma (RCC) encompasses three different types of progression features leading to persistent debate on prognostic heterogeneity and the need for reclassification. METHODS: Data of 1606 patients with pT3aN0/xM0 RCC was analyzed according to the site of invasion (perinephric fat (PFI), sinus fat (SFI), renal vein (RVI), PFI and SFI without RVI (PFI + SFI), and both fat and vein (RVI + FI)) using Kaplan-Meier and Cox proportional hazards methods. RNA sequencing was performed on tumor samples from 19 SFI and 14 RVI patients to identify differentially expressed genes and pathway enrichments. RESULTS: Five-year DFS were 76%, 68.5%, 62.4%, 63.9%, and 50.1% for SFI, PFI, PFI + SFI, RVI and RVI + FI groups, respectively (p < 0.001). Vein invasion tumors demonstrating consistently poorer survival on size-stratified analysis. Site of invasion was an independent prognostic factor. 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. CONCLUSION: In T3a RCC, site of invasion was an independent prognosticator of survival regardless of tumor size. SFI and RVI tumors exhibited distinct genomic and pathway profiles suggesting an intrinsically disparate competencies directing the tumors to adopt different invasion mechanisms.