Simple SummaryThe preoperative risk estimation of non-enhancing suspected “low-grade” glioma (NEG) is key in determining the optimal timing of diagnosis and treatment to delay malignant progression and avoid undertreatment. The updated 2021 WHO classification brought new facets to glioma grading. Therefore, we sought to identify preoperative risk factors of malignancy in NEG by considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A total of 72 NEG patients were analyzed, and a high prevalence of malignant gliomas was detected considering both the traditional WHO grading (WHO grade 3 + 4) and the integrated molecular classification (IDHwtglioblastoma WHO grade 4 and IDHmutastrocytoma WHO grade 4). Easily determinable preoperative factors (age, T2/FLAIR mismatch sign, and SVZ involvement) were identified by uni- and multivariate analyses and incorporated into a score. The score estimates the probability of an NEG harboring a malignant glioma. Finally, the score was validated in a cohort of 40 NEG patients and proved to be a better prediction model than the Pignatti score or the T2/FLAIR mismatch sign.AbstractThe preoperative grading of non-enhancing glioma (NEG) remains challenging. Herein, we analyzed clinical and magnetic resonance imaging (MRI) features to predict malignancy in NEG according to the 2021 WHO classification and developed a clinical score, facilitating risk estimation. A discovery cohort (2012–2017, n = 72) was analyzed for MRI and clinical features (T2/FLAIR mismatch sign, subventricular zone (SVZ) involvement, tumor volume, growth rate, age, Pignatti score, and symptoms). Despite a “low-grade” appearance on MRI, 81% of patients were classified as WHO grade 3 or 4. Malignancy was then stratified by: (1) WHO grade (WHO grade 2 vs. WHO grade 3 + 4) and (2) molecular criteria (IDHmutWHO grade 2 + 3 vs. IDHwtglioblastoma + IDHmutastrocytoma WHO grade 4). Age, Pignatti score, SVZ involvement, and T2/FLAIR mismatch sign predicted malignancy only when considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A multivariate regression confirmed age and T2/FLAIR mismatch sign as independent predictors (p= 0.0009;p= 0.011). A “risk estimation in non-enhancing glioma” (RENEG) score was derived and tested in a validation cohort (2018–2019, n = 40), yielding a higher predictive value than the Pignatti score or the T2/FLAIR mismatch sign (AUC of receiver operating characteristics = 0.89). The prevalence of malignant glioma was high in this series of NEGs, supporting an upfront diagnosis and treatment approach. A clinical score with robust test performance was developed that identifies patients at risk for malignancy.