CNS tumor

Diffuse astrocytic and oligodendroglial tumors

Diffuse hemispheric glioma, H3 G34 mutant



Topic Completed: 2 December 2021

Minor changes: 2 December 2021

Copyright: 2021, PathologyOutlines.com, Inc.

PubMed Search: Diffuse hemispheric glioma pathology OR H3 G34 mutant "last 5 years"[DP]

Mariana Voudouri, M.D.
George Zanazzi, M.D., Ph.D.
Page views in 2021 to date: 203
Cite this page: Voudouri M, Zanazzi G. Diffuse hemispheric glioma, H3 G34 mutant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumordiffuseH3G34mutant.html. Accessed December 8th, 2021.
Definition / general
  • Malignant, infiltrative, hemispheric, IDH wild type glioma with a G34R/V mutation in H3F3A
Essential features
  • Predominates in children and young adults
  • Arises in the cerebral hemispheres
  • Histopathologically heterogeneous, often resembling CNS embryonal tumor
  • Histone H3 G34R/V mutations with concomitant TP53, ATRX and often PDGFRA mutations
  • Poor prognosis: overall survival 12 - 24 months
Terminology
  • Other names used today or historically that pathologists may be more familiar with:
    • Pediatric glioblastoma
    • Pediatric high grade glioma
    • CNS embryonal tumor
    • Primitive neuroectodermal tumor (PNET)
ICD coding
  • ICD-10:
    • C71.1 - malignant neoplasm of frontal lobe
    • C71.2 - malignant neoplasm of temporal lobe
    • C71.3 - malignant neoplasm of parietal lobe
    • C71.4 - malignant neoplasm of occipital lobe
    • C71.8 - malignant neoplasm of overlapping sites of brain
    • C71.9 - malignant neoplasm of brain, unspecified
Epidemiology
Sites
  • Cerebral hemispheres
Pathophysiology
  • Histone H3 G34R/V mutations impair SETD2 activity, reducing H3K36me3 to promote a unique gene expression profile that supports tumorigenesis (Proc Natl Acad Sci U S A 2020;117:27354)
  • Histone H3 G34R/V mutations inhibit the neuronal differentiation of GSX2 / DLX expressing interneuron progenitors (Cell 2020;183:1617)
  • PDGFRA signaling may promote gliomagenesis (Cell 2020;183:1617)
Etiology
  • Precise etiology is unclear, although recurrent histone H3 G34 R/V mutation is present
  • Child with Li-Fraumeni syndrome and a diffuse hemispheric glioma, H3 G34 mutant has been reported (Acta Neuropathol 2021;142:591)
Clinical features
  • Symptoms related to increased intracranial pressure, such as headache, nausea and vomiting
  • May have site dependent neurological deficits
  • Reference: Brain Tumor Pathol 2017;34:103
Diagnosis
  • Identification of a histone H3 G34R mutation (more commonly) or histone H3 G34V mutation that is confirmed by sequencing in a diffuse hemispheric glioma
Radiology description
  • Large, hemispheric, bulky tumors that are T2 hyperintense on MRI (J Neuroradiol 2018;45:316)
  • In one study, MRI showed multifocal lesions in 2 of 8 patients, contrast enhancement in 6 of 8, necrosis in 3 of 8, cysts in 3 of 8, hemorrhage in 1 of 8 and calcifications in 1 of 8 (Clin Nucl Med 2018;43:895)
Radiology images

Contributed by Mariana Voudouri, M.D. and George Zanazzi, M.D., Ph.D.

MRI of posterior left frontal tumor

Sagittal T1

Axial T2 / FLAIR

Axial postcontrast

Prognostic factors
Case reports
Treatment
  • Complete resection that is safely possible, followed by radiation and temozolomide
Gross description
  • Soft, tan-gray mass within the cortex and subcortical white matter
  • Hemorrhage or necrosis may occur
Microscopic (histologic) description
  • Tumor cells usually with either astrocytic morphology or CNS embryonal tumor morphology (Acta Neuropathol 2016;131:137)
  • Diffusely infiltrating growth pattern, often with high grade features such as mitotic activity, microvascular proliferation or necrosis
  • Even if high grade features are absent, the presence of an H3 G34R/V mutation confers a CNS WHO grade 4 (J Neuroradiol 2018;45:316)
Microscopic (histologic) images

Contributed by Mariana Voudouri, M.D. and George Zanazzi, M.D., Ph.D.

Hypercellular with clustering

Area of necrosis

Marked pleomorphism

ATRX


GFAP

Synaptophysin

p53

Positive stains
Molecular / cytogenetics description
Sample pathology report
  • Brain tumor, left frontal lobe, resection:
    • Diffuse hemispheric glioma, H3 G34 mutant, WHO grade 4
    • Histological diagnosis: CNS embryonal tumor, NEC, WHO grade 4
    • Molecular information:
      • H3 G34R: positive (immunohistochemistry; consistent with mutant)
      • ATRX: nuclear expression loss (immunohistochemistry; consistent with mutation)
      • p53: positive (immunohistochemistry; consistent with mutation)
      • IDH: negative (R132H immunohistochemistry; consistent with wild type)
Differential diagnosis
Board review style question #1

A 17 year old girl presents with word finding difficulties, right facial droop and right arm weakness. MRI shows a large, left frontal lobe mass in the brain with areas of contrast enhancement. A representative hematoxylin and eosin stained section of the resected tumor is shown. Some tumor cells are GFAP positive and there is abundant p53. There is loss of ATRX without an IDH mutation. The diagnosis is consistent with

  1. Diffuse hemispheric glioma, H3 G34 mutant, WHO grade 4
  2. Diffuse midline glioma, H3 K27 altered, WHO grade 4
  3. Glioblastoma, IDH wild type, WHO grade 4
  4. Pleomorphic xanthoastrocytoma, WHO grade 3
Board review style answer #1
A. Diffuse hemispheric glioma, H3 G34 mutant, WHO grade 4

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Reference: Diffuse hemispheric glioma, H3 G34 mutant
Board review style question #2
A 22 year old man undergoes resection of a temporal lobe brain tumor. Targeted next generation sequencing of the tumor reveals a missense mutation exchanging glycine for arginine in the histone H3.3 protein. This patient may be at increased risk for which syndrome?

  1. Li-Fraumeni syndrome
  2. Neurofibromatosis type 1
  3. Neurofibromatosis type 2
  4. Tuberous sclerosis
Board review style answer #2
A. Li-Fraumeni syndrome

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Reference: Diffuse hemispheric glioma, H3 G34 mutant
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