CNS & pituitary tumors
Gliomas, glioneuronal tumors and neuronal tumors
Pediatric type diffuse high grade gliomas
Diffuse hemispheric glioma, H3 G34 mutant
Editorial Board Member: Maria Martinez-Lage, M.D.
Deputy Editor-in-Chief: Chunyu Cai, M.D., Ph.D.
Last author update: 2 December 2021
Last staff update: 13 October 2023
Copyright: 2021, PathologyOutlines.com, Inc.
PubMed Search: Diffuse hemispheric glioma pathology OR H3 G34 mutant "last 5 years"[DP]
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Voudouri M, Zanazzi G. Diffuse hemispheric glioma, H3 G34 mutant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnstumordiffuseH3G34mutant.html. Accessed November 28th, 2024.
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
Epidemiology
- Incidence data not yet available
- M:F = 1.4:1 (Acta Neuropathol 2016;131:137)
- Median patient age: 19 years old (arises later than diffuse midline glioma, H3 K27 altered) (Acta Neuropathol 2016;131:137)
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
- Generally poor prognosis
- Median survival is 12 - 24 months (Neurooncol Adv 2021;3:vdab061, Brain Tumor Pathol 2021;38:4)
- No significant difference in prognosis between high grade glioma and CNS embryonal tumor morphologies
Case reports
- 13 year old boy with Li-Fraumeni syndrome and a left sided parietotemporal mass (Acta Neuropathol 2021;142:591)
- 16 year old boy with fronto-temporo-insular mass containing mixed glial and dysplastic neuronal components (Acta Neuropathol Commun 2019;7:78)
- 17 year old girl with a motor cortex mass and extraneural osseous metastases (Front Oncol 2019;9:373)
- 28 year old woman with a frontal lobe mass with embryonal histologic features and H3.3 G34V mutation (Indian J Pathol Microbiol 2020;63:262)
- 38 year old man with thalamus mass with histologically low grade gemistocytic astrocytoma and co-occurring K27M and G34R mutations in HIST1H3B (J Neuropathol Exp Neurol 2020;79:1038)
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
- H3F3A (G34R/V) (Am J Surg Pathol 2021;45:200)
- GFAP (variably positive) (J Neurooncol 2013;112:67)
- Synaptophysin (variably positive) (J Neurooncol 2013;112:67)
- p53 (strongly positive in most cases) (Nature 2012;482:226)
Negative stains
Molecular / cytogenetics description
- Defined by recurrent G34R/V mutations in H3F3A
- Additional mutations:
- TP53
- ATRX
- PDGFRA
- Amplifications:
- NMYC
- PDGFRA (more common with astrocytic morphology) (Acta Neuropathol 2016;131:137)
- CCND2 (more common with CNS embryonal tumor morphology) (Acta Neuropathol 2016;131:137)
- Chromosomal alterations:
- Chromosome 3q and 4q loss (Acta Neuropathol 2016;131:137)
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
- CNS embryonal tumor, NOS, WHO grade 4:
- No H3 G34R/V mutation
- ATRX preserved
- Glioblastoma, IDH wild type, WHO grade 4:
- No H3 G34R/V mutation
- Olig2 positive
- Astrocytoma, IDH mutant, WHO grade 4:
- Astrocytoma, IDH mutant, WHO grade 3:
- Astrocytoma, IDH mutant, WHO grade 2:
Additional references
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
- Diffuse hemispheric glioma, H3 G34 mutant, WHO grade 4
- Diffuse midline glioma, H3 K27 altered, WHO grade 4
- Glioblastoma, IDH wild type, WHO grade 4
- Pleomorphic xanthoastrocytoma, WHO grade 3
Board review style answer #1
A. Diffuse hemispheric glioma, H3 G34 mutant, WHO grade 4
Comment Here
Reference: Diffuse hemispheric glioma, H3 G34 mutant
Comment Here
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?
- Li-Fraumeni syndrome
- Neurofibromatosis type 1
- Neurofibromatosis type 2
- Tuberous sclerosis
Board review style answer #2
