Probing intratumoral metabolic compartmentalisation in fumarate hydratase-deficient renal cancer using clinical hyperpolarised13C-MRI and mass spectrometry imaging

Abstract Background 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. Methods Here we have used hyperpolarised 13 C-pyruvate MRI (HP 13 C-MRI) to assess 13 C-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). Results HP 13 C-MRI revealed two metabolically distinct tumour regions. The 13 C-lactate-rich region showed 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, vascularity in tumour was decreased, while immune cell fraction was markedly higher. Conclusions This study shows the potential of metabolic HP 13 C-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.