Probing intratumoral metabolic compartmentalisation in a patient with fumarate hydratase-deficient renal cancer using clinical hyperpolarised 13C-MRI and mass spectrometry imaging

Fumarate hydratase-deficient renal cell carcinoma (FHd-RCC) is a rare and aggressive renal cancer subtype characterised by increased fumarate accumulation and upregulated lactate production. Renal tumours demonstrate significant intratumoral metabolic heterogeneity, which may contribute to treatment failure. Emerging non-invasive metabolic imaging techniques have clinical potential to more accurately phenotype tumour metabolism and its heterogeneity. In this case study we have used hyperpolarised 13C-pyruvate MRI (HP 13C-MRI) to assess 13C-lactate generation in a patient with an organ-confined FHd-RCC. Post-operative tissue samples were co-registered with imaging and underwent sequencing, IHC staining, and mass spectrometry imaging (MSI). HP 13C-MRI reveals two metabolically distinct tumour regions. The 13C-lactate-rich region shows a high lactate/pyruvate ratio and slightly lower fumarate on MSI compared to the other tumour region, as well as increased CD8 + T cell infiltration, and genetic dedifferentiation. Compared to the normal kidney, the vascularity in the tumour is decreased, while immune cell fraction is markedly higher. This study shows the potential of metabolic HP 13C-MRI to characterise FHd-RCC and how targeting of biopsies to regions of metabolic dysregulation could be used to obtain the tumour samples of greatest clinical significance, which in turn can inform on early and successful response to treatment. Horvat-Menih et al. use hyperpolarised 13C-pyruvate MRI (HP 13C-MRI) to assess 13C-lactate generation in a patient with a fumarate hydratase-deficient renal cell carcinoma (FHd-RCC), and correlate imaging findings with genetic and metabolic analysis on post-operative tissue samples. HP 13C-MRI reveals two metabolically distinct tumour regions. Kidney cancer resulting from a genetic mutation of a protein responsible for sugar metabolism, called “fumarate hydratase” is a rare and aggressive cancer. To understand this complex cancer better, our study aimed to assess the sugar metabolism directly in a patient bearing this tumour, using a specialised imaging technique. In addition, we performed biological analyses of the tumour. The results revealed two regions with different biology and aggressiveness within the same tumour. This shows the potential of the imaging technique to detect regions of varying aggressiveness within the same tumour, which could guide biopsies to obtain tumour samples and inform upon early treatment decisions.