MYCN amplification defines an aggressive phenotype in IDH-mutant gliomas

Abstract

In alignment with the latest WHO classification system, which underscores the integration of molecular alterations in glioma diagnosis and grading, this study investigates the prognostic significance of MYCN amplification in IDH-mutant gliomas, a relationship that remains poorly characterized despite its established association with adverse outcomes in various malignancies. A cohort of 190 patients with IDH-mutant gliomas was analyzed for clinical and pathological characteristics. MYCN amplification status was determined using fluorescence in situ hybridization (FISH) with an MYCN-specific probe. Survival outcomes were assessed via Kaplan–Meier analysis, while independent prognostic factors were identified through multivariable Cox proportional hazards regression models. Tumor morphology was systematically evaluated in cases with MYCN amplification. MYCN amplification was identified in 28 of 190 cases (14.7%), demonstrating a significant correlation with advanced tumor grade and elevated Ki-67 proliferation indices (p < 0.05). Patients harboring MYCN amplification exhibited markedly reduced overall survival compared to non-amplified cases (112.13 ± 6.58 versus 91.14 ± 14.96 months, p = 0.001), with this association being particularly pronounced in lower-grade (WHO grades 2 and 3) IDH-mutant gliomas (122.12 ± 6.81 versus 47.76 ± 6.58 months, p < 0.001). To address limitations in current grading systems, we propose a refined classification approach that upgrades lower-grade IDH-mutant astrocytomas with MYCN amplification to high-grade status. This MYCN-based grading system demonstrated significant prognostic stratification (112.84 ± 10.40 versus 77.65 ± 11.15 months, p < 0.001). Morphological analysis revealed that 50% of MYCN-amplified cases (14/28) exhibited distinct epithelioid features, characterized by abundant eosinophilic cytoplasm and nuclear displacement. In conclusion, MYCN amplification emerges as a critical prognostic indicator in IDH-mutant gliomas, particularly in lower-grade tumors, and is frequently associated with unique epithelioid histological features. These findings highlight the necessity of incorporating MYCN amplification status into grading paradigms for IDH-mutant gliomas to enhance prognostic accuracy and inform clinical decision-making.