# Paediatric high-grade glioma (excluding diffuse midline glioma)

Source: https://onco.cc/cancers/paediatric-high-grade-glioma/  
OnCo record `paediatric-high-grade-glioma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

High-grade gliomas in children look like adult glioblastoma under the microscope but are driven by different genes, so they are now classified separately. Surgery and radiotherapy remain the mainstay and chemotherapy adds little; the real gains are in small subsets with a targetable gene change, such as BRAF V600E tumours and the fusion-driven tumours of infants.

## Summary

WHO 2021 separates paediatric-type diffuse high-grade gliomas from adult glioblastoma into four types: diffuse midline glioma, H3 K27-altered (covered on its own page); diffuse hemispheric glioma, H3 G34-mutant, of adolescents and young adults with TP53 and ATRX mutations; diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, with PDGFRA amplification, MYCN amplification or EGFR alteration defining methylation subgroups; and infant-type hemispheric glioma, defined by NTRK, ALK, ROS1 or MET fusions in children under about three. Hypermutant tumours arising in constitutional mismatch repair deficiency and radiation-induced gliomas after treatment of another childhood cancer are distinct further groups. Methylation profiling is essential because morphology cannot separate these entities and some low-grade-appearing tumours prove high grade molecularly.

Treatment is maximal safe resection followed by focal radiotherapy, with temozolomide during and after radiotherapy adopted from adult practice although the ACNS0126 study did not show it clearly improved on historical outcomes; the HERBY trial (2018) showed adding bevacizumab did not help. Radiotherapy is deferred or avoided in infants, whose tumours are chemosensitive and in whom fusion-directed drugs work: larotrectinib and entrectinib for NTRK fusions, alectinib or lorlatinib for ALK and ROS1 fusions, with responses that can allow less surgery. In BRAF V600E-mutant high-grade glioma dabrafenib plus trametinib produced durable responses in the paediatric cohort reported in 2023, and the combination has a tumour-agnostic approval for BRAF V600E solid tumours from the age of six. Constitutional mismatch repair deficiency tumours respond to PD-1 blockade.

The outlook for H3 G34-mutant and H3- and IDH-wildtype tumours has changed little; the pipeline includes CDK4/6 inhibition with temozolomide after radiotherapy, IDH inhibitors for the rare IDH-mutant adolescent tumours, CAR-T cells directed at GD2 and B7-H3 delivered into the ventricles, oncolytic viruses and focused-ultrasound opening of the blood-brain barrier. Late effects of radiotherapy on the developing brain weigh on every decision.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: pHGG; Childhood high-grade glioma; Paediatric glioblastoma; Diffuse hemispheric glioma, H3 G34-mutant; Infant-type hemispheric glioma
- Tags: subtype-page; cns; paediatric
- Group: paediatric
- Burden: A minority of childhood brain tumours but a leading cause of death among them; most children with hemispheric high-grade glioma die within a few years of diagnosis, while infants with fusion-driven tumours can do far better.
- Subtypes: Diffuse hemispheric glioma, H3 G34-mutant (adolescents; TP53 and ATRX); Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (grade 4; PDGFRA, MYCN or EGFR subgroups); Infant-type hemispheric glioma (NTRK, ALK, ROS1 or MET fusion); BRAF V600E-mutant high-grade glioma (including transformed pleomorphic xanthoastrocytoma); Hypermutant glioma in constitutional mismatch repair deficiency; Radiation-induced glioma after treatment of an earlier childhood cancer
- Biomarkers: H3 G34 mutation (H3F3A) and, to exclude diffuse midline glioma, H3 K27 status; IDH1/IDH2 (wildtype in most; mutant in some adolescents); NTRK, ALK, ROS1 and MET fusions in infants; BRAF V600E with CDKN2A deletion; PDGFRA, MYCN and EGFR amplification; Mismatch repair protein loss and tumour mutation burden (constitutional mismatch repair deficiency); DNA methylation class

## Standard of care

- Newly diagnosed, child over about three years: Maximal safe resection, focal radiotherapy and temozolomide during and after radiotherapy by extrapolation from adult practice; molecular profiling of every tumour. ([IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/))
- Infant-type hemispheric glioma with a fusion: Surgery and fusion-directed therapy: larotrectinib or entrectinib for NTRK fusions, alectinib or lorlatinib for ALK or ROS1 fusions; chemotherapy to defer radiotherapy. ([Larotrectinib](https://onco.cc/drugs/larotrectinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Alectinib](https://onco.cc/drugs/alectinib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/))
- BRAF V600E-mutant: Dabrafenib plus trametinib (paediatric high-grade glioma cohort 2023; tumour-agnostic approval for BRAF V600E solid tumours from age six). ([Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Dabrafenib](https://onco.cc/drugs/dabrafenib/), [Trametinib](https://onco.cc/drugs/trametinib/))
- Constitutional mismatch repair deficiency: PD-1 blockade (nivolumab or pembrolizumab) for hypermutant tumours; germline counselling for the family. ([Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/))
- Recurrence: No standard; re-resection, re-irradiation, clinical trials including CAR-T and oncolytic virus studies. ([Re-irradiation](https://onco.cc/terms/re-irradiation/), [CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)](https://onco.cc/technologies/glioma-car-t/))

## State of the art

- Molecular classification has split paediatric high-grade glioma into biologically distinct types, each with a different outlook and, for two of them, a targeted drug.
- Fusion-driven infant gliomas are now among the most treatable high-grade brain tumours.
- For the common H3- and IDH-wildtype and H3 G34-mutant tumours, surgery and radiotherapy remain the only treatments with proven benefit.

## Open problems

- No systemic therapy has improved survival in H3 G34-mutant or H3- and IDH-wildtype tumours.
- How long to continue fusion or BRAF inhibitors in children who respond, and what happens on stopping.
- Radiotherapy to the developing brain costs cognition and growth; avoiding it in infants depends on drugs that reach the brain.
- Small numbers make randomised trials slow; international platform trials are the answer being tried.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Glioma
- Wikipedia: https://en.wikipedia.org/wiki/Glioma
- NCI PDQ: childhood astrocytomas, other gliomas and glioneuronal tumours: https://www.cancer.gov/types/brain/hp/child-astrocytoma-treament-pdq

## Connected records

- cancers: [Brain and spinal cord tumours (all types)](https://onco.cc/cancers/brain-tumours/), [Childhood cancers (all types)](https://onco.cc/cancers/childhood-cancers/), [Diffuse midline glioma, H3 K27-altered (including DIPG)](https://onco.cc/cancers/dipg-dmg/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [Paediatric low-grade glioma](https://onco.cc/cancers/paediatric-low-grade-glioma/)
- technologies: [CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)](https://onco.cc/technologies/glioma-car-t/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Focused-ultrasound blood-brain barrier opening](https://onco.cc/technologies/bbb-focused-ultrasound/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/)
- targets: [ALK](https://onco.cc/targets/alk/), [BRAF](https://onco.cc/targets/braf/), [MEK1/2](https://onco.cc/targets/mek/), [NTRK](https://onco.cc/targets/ntrk/), [ROS1](https://onco.cc/targets/ros1/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Alectinib](https://onco.cc/drugs/alectinib/), [Bevacizumab (glioblastoma use)](https://onco.cc/drugs/bevacizumab-glioma/), [Dabrafenib](https://onco.cc/drugs/dabrafenib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Larotrectinib](https://onco.cc/drugs/larotrectinib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Trametinib](https://onco.cc/drugs/trametinib/)
- institutions: [Children's Oncology Group (COG)](https://onco.cc/institutions/childrens-oncology-group/), [SIOP Europe (European Society for Paediatric Oncology)](https://onco.cc/institutions/siop-europe/)
- pathways: [Glioma (KEGG map)](https://onco.cc/pathways/glioma-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [H3 K27M (diffuse midline glioma)](https://onco.cc/terms/h3k27m/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Re-irradiation](https://onco.cc/terms/re-irradiation/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/)

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