Pediatric Diffuse Gliomas

Pediatric diffuse gliomas are biologically distinct from adult diffuse gliomas — most strikingly in their molecular drivers (often histone H3 mutations) and their classification (separated entirely from adult gliomas in the 2021 WHO classification). The most clinically important pediatric diffuse high-grade glioma is diffuse midline glioma, H3 K27-altered (formerly diffuse intrinsic pontine glioma, DIPG), which has remained one of the most lethal childhood cancers. This page covers the pediatric diffuse glioma categories.

2021 WHO Pediatric Diffuse Gliomas

Four major categories:

  1. Diffuse astrocytoma, MYB- or MYBL1-altered (low-grade).
  2. Angiocentric glioma (low-grade).
  3. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY).
  4. Diffuse low-grade glioma, MAPK pathway-altered.
  5. Diffuse midline glioma, H3 K27-altered (high-grade).
  6. Diffuse hemispheric glioma, H3 G34-mutant (high-grade).
  7. Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype.
  8. Infant-type hemispheric glioma.

Diffuse Midline Glioma, H3 K27-Altered

Diagnostic Criteria

  • Diffusely infiltrating glioma in a midline location: brainstem (especially pons), thalamus, spinal cord, cerebellum vermis.
  • H3 K27M mutation (most common) or other H3 K27 alterations (e.g., EGFR mutations in some non-K27M cases).
  • Includes the entity historically known as DIPG.

Histology

  • Diffusely infiltrating glial neoplasm.
  • Variable cellularity, atypia.
  • Often with microvascular proliferation and necrosis (high-grade features).
  • H3 K27M IHC: highly sensitive and specific for the mutation.
  • H3K27me3 IHC: loss of nuclear staining (the mutation causes global loss of H3K27 trimethylation).

Clinical Features

  • Children and young adults; median age 5-10 years.
  • Brainstem location (pons most common): cranial nerve palsies (especially CN VI, VII), long tract signs, cerebellar dysfunction, hydrocephalus.
  • Thalamic location: hemiparesis, sensory, behavioral.
  • Spinal cord location: progressive myelopathy.

Prognosis and Treatment

  • Devastating; median survival ~9-12 months from diagnosis.
  • Surgery typically not feasible (pontine location); biopsy increasingly performed for molecular characterization.
  • Radiation: temporary benefit; not curative.
  • Clinical trials of targeted therapies (e.g., ONC201, dordaviprone — recently showed promising activity).
  • Among the most aggressive cancers in pediatrics.

Diffuse Hemispheric Glioma, H3 G34-Mutant

  • Cerebral hemisphere location (parietal or temporal often).
  • H3 G34R or H3 G34V mutation (G34R more common).
  • Adolescent and young adult patients.
  • High-grade glioma.
  • Poor prognosis, but somewhat longer survival than diffuse midline glioma.

Diffuse Pediatric High-Grade Glioma, H3-WT and IDH-WT

  • Hemispheric high-grade glioma in children that lacks H3 mutations and IDH mutations.
  • May have other genetic alterations (PDGFRA, MYCN, BCOR).
  • Heterogeneous molecular subtypes.
  • Often poor prognosis.

Infant-Type Hemispheric Glioma

  • Children under 1 year of age.
  • Large hemispheric tumors.
  • NTRK gene fusions (NTRK1, NTRK2, NTRK3), ALK, ROS1 fusions — targetable.
  • Better prognosis than other high-grade pediatric gliomas due to targeted therapy options.

Pediatric Low-Grade Gliomas

Diffuse Astrocytoma, MYB- or MYBL1-Altered

  • Children; cerebral hemisphere.
  • MYB or MYBL1 gene alterations.
  • Low-grade; slowly growing; often present with seizures.

Angiocentric Glioma

  • Children and young adults.
  • Often present with epilepsy.
  • MYB-QKI fusion.
  • Angiocentric growth pattern (around vessels) on histology.
  • Low-grade; often cured by resection.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY)

  • Young patients; cortical location.
  • BRAF V600E or FGFR fusion.
  • Calcifications common.
  • Often associated with epilepsy.
  • Indolent; surgical resection curative.

Diffuse Low-Grade Glioma, MAPK Pathway-Altered

  • Children; cerebral hemispheres or other.
  • Various MAPK pathway alterations: BRAF V600E, BRAF fusion (KIAA1549-BRAF), NF1 mutation, FGFR alterations.
  • Often responsive to MAPK pathway inhibitors.

Genetic Predisposition Syndromes

  • NF1: optic pathway glioma; brainstem glioma; cerebral hemispheric glioma. BRAF fusion common in pilocytic astrocytomas in NF1.
  • Li-Fraumeni (TP53): high-grade gliomas (often choroid plexus carcinomas, gliomas, medulloblastomas).
  • Constitutional mismatch repair deficiency (CMMRD): high-grade gliomas in children with hypermutated tumors; respond to immunotherapy.
  • Lynch syndrome: increased risk of various brain tumors.

🔍 Did You Know?

The discovery in 2012 that histone H3 mutations are recurrent drivers in pediatric diffuse gliomas transformed our understanding of these tumors. H3 K27M, found in 80% of diffuse intrinsic pontine glioma (now diffuse midline glioma, H3 K27-altered), produces a single amino acid change in histone H3 — a fundamental component of nucleosomes. The mutation has a dominant-negative effect on the PRC2 complex (which normally trimethylates H3K27), producing global loss of H3K27me3 across the genome. This epigenetic dysregulation drives the aggressive biology of these tumors. The discovery exemplified a recurring theme in modern pediatric oncology: tumors in children are often driven by mutations in epigenetic regulators, distinct from the mutations in oncogenes and tumor suppressors that drive adult cancers. The 2021 WHO classification separated pediatric gliomas from adult gliomas based largely on these molecular distinctions. The therapeutic implications are emerging: ONC201 (dordaviprone) targets dopamine receptor D2 (DRD2) and ClpP, with apparent activity against H3 K27M tumors and recent FDA accelerated approval. Other targeted therapies are in trials. The discovery of H3 mutations and their consequences also illustrates how identifying the molecular driver can transform a disease from “DIPG, untreatable, fatal in months” to “diffuse midline glioma, H3 K27-altered, targetable mutation, clinical trials available” — even when curative therapy remains elusive.

Pitfalls and Pearls

  • Pediatric gliomas are biologically distinct from adult gliomas; classified separately in 2021 WHO.
  • Diffuse midline glioma, H3 K27-altered: H3 K27M mutation; midline (pons most common); devastating prognosis.
  • H3 K27M IHC + loss of H3K27me3: diagnostic.
  • DIPG is now diffuse midline glioma, H3 K27-altered.
  • Diffuse hemispheric glioma, H3 G34-mutant: hemispheric; adolescent/young adult; poor prognosis.
  • Infant-type hemispheric glioma: NTRK/ALK/ROS1 fusions; targeted therapy.
  • BRAF V600E and BRAF fusions: common in pediatric low-grade gliomas; MAPK pathway inhibitors active.
  • NF1 + optic pathway glioma: classical pediatric presentation.
  • CMMRD: pediatric high-grade gliomas; hypermutated; immunotherapy responsive.
  • ONC201 (dordaviprone): targeted therapy for H3 K27-altered glioma.
  • Most pediatric low-grade gliomas are MAPK-pathway driven (BRAF KIAA1549 fusion, BRAF V600E, FGFR1, NF1); tumor mutational burden is lower than adult cancers. (“Epigenetic regulators” is the dominant theme of pediatric high-grade gliomas / DMG H3 K27-altered, not pLGG.)
  • MEK inhibitors (selumetinib): FDA-approved for symptomatic, inoperable plexiform neurofibromas in NF1 (not for optic pathway glioma as a labeled indication). Has clinical activity in NF1-associated and other pLGG and is used in trial/off-label settings.
  • BRAF-targeted therapy in pLGG: tovorafenib (Ojemda) received FDA accelerated approval in 2024 for relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion/rearrangement or BRAF V600 mutation; combination dabrafenib + trametinib is also used in BRAF V600-mutant pLGG.
  • Biopsy of brainstem tumors: increasingly performed for molecular characterization.
  • Resection extent: prognostic in low-grade pediatric gliomas.

References

  1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251.
  2. Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251-253.
  3. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226-231.
  4. Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520-537.e5.
  5. Arrillaga-Romany I, Gardner SL, Odia Y, et al. ONC201 (dordaviprone) in recurrent H3 K27M-mutant diffuse midline glioma. J Clin Oncol. 2024;42(13):1500-1508.
  6. Fangusaro J, Onar-Thomas A, Young Poussaint T, et al. Selumetinib in paediatric patients with BRAF-aberrant or NF1-associated recurrent, refractory, or progressive low-grade glioma. Lancet Oncol. 2019;20(7):1011-1022.
  7. Kilburn LB, Khuong-Quang DA, Hansford JR, et al. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med. 2024;30(1):207-217.
  8. US Food and Drug Administration. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. April 2024.