Spatial tumour characteristics as an indirect marker of metabolic dysregulation: evaluation for non-invasive IDH-genotyping of glioma using hybrid [18 F]FET-PET/MRI

Abstract

Purpose: The isocitrate dehydrogenase (IDH) genotype is crucial for diagnosing and managing adult-type diffuse glioma. We investigated spatial tumour characteristics in treatment-naïve glioma using an U-Net-based CNN and evaluated associations with metabolic dysfunction and IDH genotype.

Methods: Between 2015 and 2024 patients with confirmed contrast-enhancing glioma were pre-operatively investigated using MRI or [18 F]FET PET/MRI. Automated morphometry using a U-Net-based CNN on standard MRI sequences (T1c, T1, T2, FLAIR) was performed. Contrast-enhancing tumour fraction (CTF), metabolic tumour volume (MTV), total tumour volume (TTV) were determined. Dice coefficient assessed volume intersections. Comparative and statistical analyses included non-parametric tests, ROC curves, regression, and correlation.

Results: A total of 180 patients (male, 114; female, 66; age, M ± SD = 54 ± 15y; IDH-mutant, 63; IDH wild-type, 117) with treatment-naïve glioma were evaluated. [18 F]FET-PET metabolic activity correlated significantly with CTF (p < .05). IDH-mutant gliomas had lower CTF (p < .001) due to higher non-enhancing tumour mass (p < .001) relative to the enhancing mass, unlike IDH wild-type glioblastoma. The CTF predicted IDH genotype with high accuracy (AUC = 0.85, sensitivity 78%, specificity 90%) across datasets. Combining CTF with patient age or SUVmax further improved the classification (ΔAUC = 0.12, p = .02; ΔAUC = 0.09, p > .05). Subgroup analyses showed consistent performance across IDH-mutant subtypes. MTV from [18 F]FET-PET exceeded structurally apparent TTV (p = .033).

Conclusion: Spatial mapping of treatment-naïve glioma identified a non-invasive biomarker, which is linked to metabolic dysfunction and enabled robust IDH-genotype classification from standard MRI, suggesting a central role for radiogenomic assessment in adult-type diffuse gliomas prior to surgery.

Keywords: Neuro-oncology; PET/MRI; Predictive IDH-genotyping; Radiogenomic biomarker; Spatial phenotyping; Spatial tumour characteristics.

Fig. 1

Clinical role of IDH-genotyping in adult glioma. A In adult gliomas, IDH-genotype differentiates the group of IDH-mutated astrocytoma and oligodendroglioma from IDH wild-type glioblastoma. Molecular stratification prior to surgical resection opens a window-of-opportunity for neo-adjuvant treatment using molecular targeting strategies and may guide the extent of resection. B Metabolic dysfunction in glioma drives macrostructural changes visible on imaging. Severe hypoxia results from rapid tumour growth and insufficient vascular supply, promoting aberrant angiogenesis and leaky vessels, which may become apparent as contrast enhancement on MRI. Slow-growing, IDH-mutant gliomas typically show larger non-enhancing regions, while aggressive, IDH wild-type glioblastomas exhibit extensive hypoxia, necrosis, and predominantly contrast-enhancing tumour mass. IDH-MT/-WT = Isocitrate dehydrogenase mutated/wild-type. EOR = Extent of resection. EGFR = Epidermal Growth Factor Receptor. TERT = telomerase reverse transcriptase promoter mutation

Fig. 2

Patient selection flowchart. Selection of participants for the model building A and validation cohort B. Patients with open biopsy, partial resection or reactive gliosis after biopsy were excluded. IDH-MT/-WT = Isocitrate dehydrogenase mutated/wild-type, MGMT = O6-methylguanine-DNA-methyltransferase, LOH1p/19q = Loss of heterozygosity of 1p/19q. p/n/na = positive/negative/not applicable

Fig. 3

Volumetric analysis of spatial tumour characteristics and amino acid metabolism. A Contrast-enhancing tumour fraction (CTF) from structural MRI shows a significant association (p <.05) with amino acid uptake ([18 F]FET-PET) in glioma. B Metabolic tumour volume (MTV) surpassed total tumour volume (TTV) (p =.033, n = 33). (a) and (b) show representative examples of glioblastoma, IDH wild-type (CNS WHO grade 4), showing metabolically-active tumour that extends beyond the structurally apparent tumour margins. p-value < .05 was considered statistically significant

Fig. 4

Evaluation of contrast-enhancing tumour fraction (CTF) for predictive IDH-genotyping. A Compared to IDH wild-type glioblastoma, IDH-mutated gliomas exhibited significantly lower CTF values (adjusted p <.001). B Classification of the IDH mutational status using the CTF presents excellent diagnostic performance (AUC ± SE = 0.85 ± 0.04, p <.001) based on Receiver Operating Characteristic analysis with similar results in the validation dataset. C Illustration of automated morphometry using an U-Net-based CNN based on a clinical standard MRI protocol. Illustration of exemplary cases of high-grade astrocytoma IDH-mutant (CNS WHO grade 4) (a-b), which exhibit a low CTF, as the non-CE mass is characteristically greater than the CE tumour (p <.001) in IDH-mutant glioma. Glioblastoma, IDH-wild-type (CNS WHO grade 4) (c-d) demonstrate an inverse relationship, consecutively yielding a higher CTF. IDH-MT/-WT = Isocitrate dehydrogenase mutated/wild-type, CE = Contrast-enhancing, NE = Non-enhancing. p-value < .05 was considered statistically significant