Hyperpolarized C-13-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study

Simple Summary We evaluated renal cancer with varying aggressive appearances on histology, using an emerging form of non-invasive metabolic MRI. This imaging technique assesses the uptake and metabolism of a breakdown product of glucose (pyruvate) labelled with hyperpolarized carbon-13. We show that pyruvate metabolism is dependent on the aggressiveness of an individual tumor and we provide a mechanism for this finding from tissue analysis of molecules influencing pyruvate metabolism, suggesting a role for its membrane transporter. Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-C-13]pyruvate (HP-C-13-MRI) and validated these findings with histopathology. Nine patients with treatment-naive renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-C-13-MRI and conventional proton (H-1) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (k(PL)) between C-13-pyruvate and C-13-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 k(PL) in ccRCC was correlated with increasing overall tumor grade (rho = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional H-1-MRI parameters 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-C-13-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-C-13-MRI may non-invasively characterize metabolic phenotypes within renal cancer.