Abstract
Pediatric highgrade gliomas (pHGGs) represent 8–12% of all pediatric central nervous system tumors and comprise a spectrum of histologies that includes anaplastic astrocytoma (WHO grade 3), glioblastoma (WHO grade 4), and diffuse midline glioma,
H3K27M
mutant (WHO grade 4). Diffuse intrinsic pontine gliomas (DIPG) are pHGG of the brainstem that are generally diagnosed based on clinical and imaging findings alone, but, if biopsied, pathology most commonly reveals diffuse midline glioma,
H3K27M
mutant. Evidence from genetic and epigenetic molecular profiling studies has revealed significant molecular diversity among pHGGs. These studies led to a major reclassification of pHGGs into molecularbased tumor subgroups, as compared to earlier primarily histologybased tumor subgroups. Findings show that these molecular subgroups of pHGG correlate with clinically meaningful factors, including tumor location and prognosis. The most important molecular groups are the histone mutations related pHGG (H3.K27mutated midline and H3.G34mutated hemispheric pHGG); the rare isocitrate dehydrogenase (IDH1/2)mutated pHGG occurring mainly in young adults; the BRAFV600E mutant cortical tumors arising from transformation of lower grade tumors, the heterogenous H3/IDH/BRAF wildtype pHGGs and infant HGGs. Another important group occurs in patients with constitutional mismatch repair deficiency, a cancer predisposition syndrome wherein patients develop hypermutant glioblastoma. Standard treatment for pHGG includes maximally safe surgical resection followed by radiation and chemotherapy. This chapter provides a comprehensive review of the clinical, genetic, and therapeutic aspects relevant to oncologists caring for children, adolescents, and young adults with pHGGs.