Hyperpolarized 13C-pyruvate metabolism as a surrogate for tumor grade and poor outcome in renal cell carcinoma – a proof of principle study

Abstract

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is chal-lenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocy-toma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registra-tion between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ=0.92, P=0.009) and MCT1 expression (r=0.89, P=0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parame-ters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (P<0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of sur-vival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.