K-Means Clustering of Hyperpolarised 13C-MRI Identifies Intratumoral Perfusion/Metabolism Mismatch in Renal Cell Carcinoma as the Best Predictor of the Highest Grade

<i>Background</i>: Early and accurate grading of renal cell carcinoma (RCC) improves patient risk stratification and has implications for clinical management and mortality. However, current diagnostic approaches using imaging and renal mass biopsy have limited specificity and may lead to undergrading. <i>Methods</i>: This study explored the use of hyperpolarised [1-¹³C]pyruvate MRI (HP ¹³C-MRI) to identify the most aggressive areas within the tumour of patients with clear cell renal cell carcinoma (ccRCC) as a method to guide biopsy targeting and to reduce undergrading. Six patients with ccRCC underwent presurgical HP ¹³C-MRI and conventional contrast-enhanced MRI. From the imaging data, three k-means clusters were computed by combining the <i>k</i>_PL as a marker of metabolic activity, and the ¹³C-pyruvate signal-to-noise ratio (SNR_Pyr) as a perfusion surrogate. The combined clusters were compared to those derived from individual parameters and to those derived from the percentage of enhancement on the nephrographic phase (%NG). The diagnostic performance of each cluster was assessed based on its ability to predict the highest histological tumour grade in postsurgical tissue samples. The postsurgical tissue samples underwent immunohistochemical staining for the pyruvate transporter (monocarboxylate transporter 1, MCT1), as well as RNA and whole-exome sequencing. <i>Results:</i> The clustering approach combining SNR_Pyr and <i>k</i>_PL demonstrated the best performance for predicting the highest tumour grade: specificity 85%; sensitivity 64%; positive predictive value 82%; and negative predictive value 68%. Epithelial MCT1 was identified as the major determinant of the HP ¹³C-MRI signal. The perfusion/metabolism mismatch cluster showed an increased expression of metabolic genes and markers of aggressiveness. <i>Conclusions:</i> This study demonstrates the potential of using HP ¹³C-MRI-derived metabolic clusters to identify intratumoral variations in tumour grade with high specificity. This work supports the use of metabolic imaging to guide biopsies to the most aggressive tumour regions and could potentially reduce sampling error.