Abstract
BACKGROUND: Among diffuse midline gliomas with H3K27-altered with MAPK pathway mutations, those with BRAF V600E mutations show the most histologic variability and potential for targeted therapy, yet remain incompletely characterized. We present a series of such tumors, focusing on imaging, histologic, molecular, and therapeutic features. METHODS: Pathology archives from 2016 to 2025 at our institution were searched for gliomas with H3K27M/BRAF V600E mutations. Clinical history, imaging, histology, molecular findings, therapy, and outcomes were reviewed. RESULTS: Eight patients were identified (6 males, 2 females; age 3-18 years, average 11). Six tumors were thalamic, one cervical, and one suprasellar. Histology fell into three categories: low-grade glioma-like (n = 3), ganglioglioma-like (n = 3), and high-grade glioma-like (n = 2). Tumors with low-grade morphology had no additional clinically significant mutations, while high-grade tumors had co-occurring variants including TERT, 1q/5q gains, and polysomy 7. Two tumors had no methylation class match; two clustered with diffuse midline glioma, and one clustered with high-grade glioma with piloid features. Six patients had maximal safe resections, and two had biopsies (1 low-grade, 1 high-grade). All received BRAF/MEK inhibitors; six also had radiation, and two had chemotherapy. The two patients with high-grade tumors had outcomes similar to classic H3K27M diffuse midline gliomas (both deceased at 17 and 12 months). Patients with low-grade glioma or ganglioglioma-like tumors had better outcomes (all alive, average 38-month follow-up, range 6-80 months). CONCLUSION: H3K27M/BRAF V600E-mutant gliomas may represent a distinct subgroup, with outcomes linked to histologic and co-occurring molecular features. Targeted therapy and a surgical approach may support long-term survival in low-grade cases.