Diagnostic accuracy of proton magnetic resonance spectroscopy for non-invasive detection of 2-hydroxyglutarate and IDH mutation status in gliomas : a meta-analysis

Abstract

Isocitrate dehydrogenase (IDH) mutation status is a central determinant of modern glioma classification, prognosis, and therapeutic decision-making. Mutant IDH enzymes acquire a neomorphic catalytic function that leads to the pathological accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG), a metabolite that is largely absent in IDHwildtype gliomas and normal brain tissue. This mutation-specific metabolic alteration provides a unique opportunity for non-invasive molecular characterisation, as intracellular 2- HG accumulates to concentrations detectable in vivo using proton magnetic resonance spectroscopy (MRS). The recent approval of IDH-targeted therapy following the phase III INDIGO trial has further increased the clinical importance of early and accurate identification of IDH mutation status. This dissertation aimed to evaluate the diagnostic accuracy of in vivo proton MRS for 2-HG detection as a non-invasive biomarker of IDH1/IDH2 mutation in gliomas, and to assess whether diagnostic performance has changed over time in parallel with methodological advances in MRS acquisition and analysis. A systematic review and meta-analysis were conducted in accordance with PRISMADTA guidelines. PubMed, MEDLINE, and Scopus were searched for studies published between 2012 and 2023 that evaluated in vivo proton MRS for 2-HG detection in human glioma cohorts with histopathologically confirmed IDH status. Studies providing sufficient data to construct 2×2 contingency tables were included. Methodological quality was assessed using the QUADAS-2 tool. Pooled sensitivity and specificity were estimated using a bivariate random-effects model, and overall diagnostic performance was summarised using a summary receiver operating characteristic curve. A predefined temporal subgroup analysis compared studies published up to and including 2018 with those published after 2018. Twenty-one studies met the inclusion criteria. Proton MRS demonstrated high diagnostic accuracy for identifying IDH mutation status, with pooled sensitivity of 86.8% and pooled specificity of 84.3%, and an area under the summary receiver operating characteristic curve of 0.91. Diagnostic performance remained stable over time, with a trend toward improved specificity in more recent studies, consistent with increasing methodological standardisation and clinical translation. Risk of bias was low to moderate across studies, predominantly related to patient selection and diagnostic thresholds. In conclusion, proton MRS enables reliable, non-invasive detection of 2- hydroxyglutarate and accurate prediction of IDH mutation status in gliomas. In the context of newly approved IDH-targeted therapies, these findings support the role of 2-HG MRS as a clinically meaningful adjunct to tissue-based molecular diagnostics, particularly in patients for whom surgical sampling is limited or high-risk.