Stratification of renal cell carcinoma patients by abundance of sarcomatoid features reveals differences in survival and underlying pathobiology

Sarcomatoid renal cell carcinoma (sRCC) is histologically heterogenous, with variable sarcomatoid amounts intermixed within epithelial carcinoma, however current classification of this aggressive disease is homogenous and agnostic to sarcomatoid proportion. We investigated whether sRCC sub-classification could improve prognostic value and reveal biology underlying dedifferentiation and its clinical aggressiveness. Based on intratumoral abundance of sarcomatoid features, cases were classified as sarcomatoid-high (≥10% sarcomatoid features) or sarcomatoid-low (<10% sarcomatoid features) within a consecutive sRCC nephrectomy patient cohort at a single center (n=104). Compared to sarcomatoid-low patients (n=52), sarcomatoid-high patients (n=52) had significantly shorter overall survival (median 14.5 vs. 62.9 months, p<0.001) including in multivariable analysis, and significantly shorter metastasis-free survival among clinically localized patients (median 10.7 vs. 39.0 months, p=0.043). Transcriptomic analyses of n=45 sRCC tumors revealed significant upregulation of 10 Hallmark pathways relating to cell cycle/proliferation, epithelial-to-mesenchymal transition, reactive oxidative species, and interferon-alpha signaling in sarcomatoid-high (n=24) versus sarcomatoid-low (n=21) tumors. Categorization into transcriptomic clusters revealed predominance of proliferative, inflammatory, and immune effector phenotypes within sarcomatoid-high tumors versus hypoxia/angiogenesis in sarcomatoid-low tumors. Altogether, these findings indicate prognostic value for sRCC sub-classification into high versus low sarcomatoid groups and highlight key biology underlying differences in clinical outcome.