Neurosurgery notes/Tumours/Gliomas, Glioneuronal Tumors, and Neuronal Tumors/Paediatrics type diffuse astrocytoma/Paediatric-type high-grade diffuse gliomas/Diffuse hemispheric glioma, H3 G34-mutant

Diffuse hemispheric glioma, H3 G34-mutant

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Paediatric-type high-grade diffuse gliomas

Definition

  • Essential:
    • Cellular, infiltrative glioma with mitotic activity AND
    • H3.3 p.G35R (G34R) or p.G35V (G34V) mutation (H3-3A [H3F3A] c.103G>A, c.103G>C, or c.104G>T) AND
    • Hemispheric location AND (for unresolved lesions)
      • Methylation profile of diffuse hemispheric glioma, H3 G34-mutant
  • Desirable:
    • OLIG2 immunonegativity
    • Loss of ATRX expression
    • Diffuse p53 immunopositivity

Related terminology

  • Not recommended: paediatric glioblastoma, H3 3 G34-mutant.

Numbers

  • <1% of all gliomas
  • 15% of high-grade gliomas in adolescents and young adults
  • Median age of 18 years at diagnosis:
    • It should be noted that, like other ‘paediatric-type’ gliomas, diffuse hemispheric glioma also occurs in the adult population

CNS WHO grading

  • Grade 4

Localisation

  • Arises in the cerebral hemispheres.
    • Occasional spread to midline structures and leptomeningeal dissemination have been observed

Pathology

Macroscopic

  • Diffuse infiltration of the parenchyma generates enlargement and distortion of brain structures,
  • Softening and discolouration
  • Haemorrhagic and/or necrotic zones

Microscopic

  • Glioblastoma-like pattern
    • Characterized by a highly cellular
    • Infiltrative astrocytic tumour with brisk mitotic activity
  • CNS embryonal tumours like pattern
    • Tumour cells
      • Small
      • Monomorphic
      • Hyperchromatic nuclei
      • Scant cytoplasm.
    • Homer Wright rosettes are occasionally present,
    • Microvascular proliferation and necrosis are less prominent
Fig. 2 Diffuse hemispheric glioma, H3 G34-mutant, is a malignant, infiltrative glioma, typically of the cerebral hemispheres and with a missense mutation in the H3F3A gene that results in a G34R/V substitution of histone H3. (A) High-grade anaplastic features, sometimes with an embryonal appearance (H&E, x200) and (B) positive nuclear staining with H3 G34R/V immunohistochemistry (x100).
Diffuse hemispheric glioma, H3 G34-mutant, is a malignant, infiltrative glioma, typically of the cerebral hemispheres and with a missense mutation in the H3F3A gene that results in a G34R/V substitution of histone H3. (A) High-grade anaplastic features, sometimes with an embryonal appearance (H&E, ×200) and (B) positive nuclear staining with H3 G34R/V immunohistochemistry (×100).
 

Immunophenotyping

  • +
    • MAP2
    • FOXG1
    • p53 (nuclear accumulation)
  • -
    • OLIG2
    • ATRX expression
  • Variable
    • GFAP

Genetics

  • Key oncogenic pathogenesis
    • An acquired missense mutation in the H3-3A (H3F3A) gene, resulting in substitution at position p.G35 (G34) on the tail of the histone variant H3.3 → replacement of the amino acid glycine (G) with arginine (R) or valine (V) leads to steric hindrance and blocks the capacity of НЗ p.K37 (K36) methylation-modulating enzymes (SETD2 and KDM2A) to bind to the mutant histone H3.3 tail. → diminished levels of H3 p.K37me2 (K36me2) and H3 p.K37me3 (р.КЗ6meЗ) on the mutant histone H3.3 tail → transcriptional reprogramming → recapitulating that of the developing forebrain, and causes prominent upregulation of the protooncogene MYCN
      • flowchart LR
    A["Acquired missense mutation<br>in H3-3A (H3F3A) gene"] --> B["Substitution at position<br>p.G35 (G34) on H3.3 tail"]
    B --> C["Replacement of glycine (G)<br>with arginine(R) or valine(V)"]
    C --> D["Steric hindrance<br>affecting H3.3 tail structure"]
    D --> E["SETD2 and KDM2A unable<br>to bind mutant H3.3 tail"]
    E --> F["Reduced methylation:<br>↓ H3 p.K37me2 (K36me2)<br>and ↓ H3 p.K37me3 (K36me3)"]
    F --> G["Transcriptional reprogramming<br>of chromatin marks"]
    G --> H["Pattern resembles developing<br>forebrain expression program"]
    H --> I["Prominent upregulation<br>of proto-oncogene MYCN"]

Clinical features

  • Dependent on location
  • Seizures and motor or sensory deficits.

Radiology

  • Cases of leptomeningeal spread have been reported
  • In the adult cohort described by Picart et al. (range: 19–33 years)
    • All tumours were monocentric.
    • Midline involvement was evident in 4 cases but always as an extension of the primarily hemispheric tumour.
      • Most patients demonstrated either no or faint enhancement,
      • Cortical or subcortical in location,
      • Poorly delineated,
      • Infiltrative lesions mostly in a frontoparietal location
      • All but one H3 G34R-mutant glioma showed areas of restricted diffusion
      • Half of the tumours studied showed increased perfusion.
  • MRI
      • Tumours may present as multi-focal lesion
      • Typically showing an enhancing tumour with mass effect.
      • Internal areas of necrosis, haemorrhage, and calcification have been reported although no pathognomonic features are known
      • FLAIR (A–C), DWI (D), and T1w-CE (E, F)
        • Show multifocal areas of cortical and subcortical FLAIR signal abnormality involving the left peri-rolandic and temporal regions as well as the right cingulate, cuneus, and insular regions (arrows).
        • Several of these areas show patchy enhancement and mild restricted diffusion
      A close-up of a brain scan AI-generated content may be incorrect.
      A 14-year-old boy with a 4-week history of left-sided weakness, slurred speech, and loss of balance. Immunohistochemistry: H3.3 G34R nuclear staining. Molecular: IDH-wildtype.

Prognosis

  • Poor
    • Median progression-free survival of 9 months
    • Median overall survival of 18-22 months
  • Good prognosticator
    • MGMT methylation
    • Absence of oncogene amplifications (such as of PDG-FRA, EGFR, CDK4, MDM2, CDK6, CCND2, MYC, MYCN)