CNS & pituitary tumors

Gliomas, glioneuronal tumors, and neuronal tumors

Glioblastoma, IDH wild type

Last author update: 27 July 2022
Last staff update: 2 March 2023

Copyright: 2022-2023,, Inc.

PubMed Search: Glioblastoma, IDH wild type

Bharat Ramlal, M.D.
Meaghan Morris, M.D., Ph.D.
Page views in 2022: 20,366
Page views in 2023 to date: 50,873
Cite this page: Ramlal B, Morris M. Glioblastoma, IDH wild type. website. Accessed September 25th, 2023.
Definition / general
  • An aggressive, infiltrating, astrocytic glioma that lacks mutations in IDH1, IDH2 and histone H3 genes and is:
    • Histologically defined by brisk mitotic activity and microvascular proliferation or necrosis
    • Or molecularly defined by the presence of TERT promoter mutation, EGFR gene amplification or copy number changes in the form of combined gain of chromosome 7 and loss of chromosome 10 (Acta Neuropathol 2018;136:793, Acta Neuropathol 2018;136:805)
Essential features
  • Characterized by diffusely infiltrative growth pattern with nuclear atypia and either:
    • Mitotic activity, necrosis or microvascular proliferation or
    • Molecularly defined by the present of TERT promoter mutation, EGFR amplification or combined gain of chromosome 7 and loss of chromosome 10
  • Lacks mutations in IDH1 / IDH2 and histone H3 genes
  • Various morphologic subtypes have been recognized (giant cell, small cell, epithelioid, sarcomatous / gliosarcoma) with similar prognosis
  • Primitive neuronal component has increased rate of cerebrospinal fluid dissemination (Brain Pathol 2009;19:81)
  • Glioblastoma, IDH wild type
  • Glioblastoma multiforme (not recommended)
  • Diffuse astrocytoma with molecular features of glioblastoma (no longer recommended)
ICD coding
  • ICD-O: 9440/3 - glioblastoma, NOS
  • ICD-11: 2A00.00 & XH5571 - glioblastoma of brain & glioblastoma, IDH wild type
  • Most commonly in supratentorial regions (frontal, temporal, parietal and occipital lobes), with highest incidence in the frontal lobes
  • Most often centered in subcortical white matter
    • Many cases show infiltration into cortex and across the corpus callosum with spread to contralateral hemisphere
  • Rare cases reported in the cerebellum and spinal cord (World Neurosurg 2013;80:e237, J Neurosurg Spine 2010;13:67, Neurooncol Adv 2021;3:vdab154)
  • Cell of origin undetermined
    • Some studies suggest a variety of CNS cell types can undergo malignant transformation with features of glioblastoma (GBM) (oligodendrocyte precursor cells, neural precursor cells, astrocytes and neurons)
  • Sequencing of human glioblastomas suggests that a neural precursor cell in the subventricular zone may be the cell of origin (Nature 2018;560:243)
Clinical features
  • Symptoms are dependent on tumor location
  • May present with signs of increased intracranial pressure (i.e., headaches, nausea, emesis), seizures or focal neurologic deficits (visual field defects, hemiparesis, aphasias, etc.) (BMJ 2021;374:n1560)
Radiology description
  • MRI: T2 / fluid attenuated inversion recovery (FLAIR) bright infiltrative lesion(s) with postcontrast T1 showing irregular peripheral rim enhancement with central necrosis
  • May cross the corpus callosum
  • May be multifocal
  • Lack of contrast enhancement may be observed in molecularly defined glioblastoma
  • Certain subtypes (i.e., gliosarcoma, epithelioid, giant cell) may appear well circumscribed (Neurosurg Rev 2021;44:3335, Eur Radiol 2019;29:429, Surg Pathol Clin 2020;13:249)
Radiology images

Contributed by Bharat Ramlal, M.D.


T1 postcontrast MRI

Prognostic factors
Case reports
  • Surgical resection where possible in younger patients (≤ 70 years old) and patients with good performance status, followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ)
  • Tumor treating fields (TTFields / Optune) under investigation - alternating electric field therapy using low intensity energy to stop glioma proliferation; relatively recent treatment option with rare reports showing favorable outcomes (Front Oncol 2020;10:477)
Gross description
  • Ill defined whitish gray mass with areas of hemorrhage and necrosis
  • Can expand gyri and cross the corpus callosum
Frozen section description
  • Hypercellular infiltrative lesion with variable morphology
    • Infiltration often difficult to assess on frozen sections but entrapped neurons may be useful
  • Nuclear hyperchromasia and nuclear elongation, possible giant cells
  • Mitotic activity
  • Necrosis; geographic or pseudopalisading
  • Microvascular proliferation
Frozen section images

Contributed by Bharat Ramlal, M.D.

Markedly hypercellular neoplasm

Nuclear atypia and palisading tumor cells

Pleomorphic, astrocytic tumor cells

Microscopic (histologic) description
  • Infiltrating, hypercellular astrocytic neoplasm often with hyperchromatic, elongated nuclei and irregular nuclear membranes
  • Typically mitotically active, though not required if molecular criteria are met
  • Microvascular proliferation or necrosis is required for a histologic diagnosis of GBM
    • Microvascular proliferation: multilayered, small caliber vessels with glomeruloid appearance (J Neuropathol Exp Neurol 1992;51:488)
    • Necrosis: can be geographic or pseudopalisading with neoplastic cells surrounding central necrosis
  • Variable cell morphology: undifferentiated / primitive neuronal cells, astrocytic, gemistocytic, oligodendroglial-like, small cell, lipidized, granular, epithelioid, giant cells, mesenchymal metaplasia and epithelial metaplasia
    • Primitive neuronal cells (embryonal): markedly increased cellularity composed of cells with high N/C ratio, brisk mitotic activity with apoptotic bodies, nuclear molding, sometimes with neuroblastic rosettes
      • Typically has conventional infiltrating astrocytic component, which is morphologically distinct
      • Loss of glial markers, expression of neuronal markers (synaptophysin)
      • Higher risk of CSF dissemination but similar survivals as classic GBM
      • Associated with MYC amplifications
    • Astrocytic: fibrillary, elongated processes
    • Gemistocytic: abundant eosinophilic cytoplasm with eccentric nuclei
    • Oligodendroglial-like: cells with small, round nuclei with perinuclear clearing in a vascular background
    • Small cell change: monomorphic cells with small, round or angulated, hyperchromatic nuclei and brisk mitotic activity
    • Lipidized / xanthomatous cells: cells with abundant foamy cytoplasm
      • Be sure to exclude pleomorphic xanthoastrocytoma
    • Granular cells: large cells with small nuclei and abundant granular cytoplasm
      • PAS positive
      • May be CD68 positive but negative for CD163
    • Epithelioid: large eosinophilic cells with prominent nucleoli
      • May resemble rhabdoid cells with more eccentric nuclei
      • May be immunoreactive to cytokeratins but negative for CAM5.2
      • May be more sharply demarcated with less infiltration
      • Often associated with BRAF V600E mutations, usually in younger individuals (Discov Med 2018;26:51, Int J Clin Exp Pathol 2020;13:1529)
    • Giant cell: well circumscribed tumors composed of markedly pleomorphic and bizarre cells, including multinucleated tumor cells
    • Mesenchymal / sarcomatous: may be well circumscribed; corresponds to cellular differentiation along various lineage; sarcomatous (spindled and fibroblastic), osseous, chondroid or myogenic differentiation (see Gliosarcoma)
    • Epithelial metaplasia: rare but may include squamous or adenomatous differentiation
      • Keratin pearls, epithelial whorls: CK5/6 positive
      • Glandular structures
Microscopic (histologic) images

Contributed by Bharat Ramlal, M.D. and Meaghan Morris, M.D., Ph.D.

Hypercellular neoplasm

Nuclear atypia and brisk mitotic activity

Atypical astrocytic tumor cells

Glomeruloid microvascular proliferation

Pseudopalisading necrosis

Marked nuclear pleomorphism

Primitive neuronal component

Adenoid morphology

Epithelioid glioblastoma

Granular cell morphology

Small cell glioblastoma

IDH1 R132H





Cytology description
  • Intraoperative smears may show marked cellularity, with moderate to markedly pleomorphic astrocytic / gemistocytic cells with fine fibrillar glial processes (Diagn Cytopathol 1986;2:312)
  • May show necrosis
  • Mitotic figures can be observed
Cytology images

Contributed by Bharat Ramlal, M.D.

Intraoperative smear preparation

Positive stains
Negative stains
Electron microscopy description
  • Bundles of cytoplasmic filaments 80 - 90 angstroms in diameter (Am J Pathol 1973;73:589)
  • Pleomorphic nuclei and prominent nucleoli with nuclear infoldings and cytoplasmic invaginations (intranuclear pseudoinclusions)
Molecular / cytogenetics description
Sample pathology report
  • Brain, right frontal lobe, biopsy:
    • Glioblastoma, IDH wild type, CNS WHO grade 4
    • Histologic diagnosis: glioblastoma
    • Grade: 4
    • Molecular information: EGFR amplified, negative for IDH1 / IDH2 and histone H3 alterations
Differential diagnosis
  • Astrocytoma, IDH mutant:
    • Younger individuals, presence of IDH1 / IDH2 gene mutations by immunohistochemistry or sequencing
    • Often have ATRX mutation (loss of expression) and p53 mutations (nuclear overexpression)
  • Diffuse hemispheric glioma, H3 G34 mutant:
    • Older adolescents and young adults (age 11 - 30) with hemispheric mass
    • May have classic GBM morphology or primitive neuronal / embryonal morphology
    • Characterized by histone H3 G34 mutation on sequencing
    • Classically lack Olig2 expression, show ATRX loss of expression (mutant) and have p53 mutations (nuclear overexpression)
  • Diffuse midline glioma, H3 K27 altered:
    • Midline tumor (brainstem, thalamus, spinal cord, less often basal ganglia or cerebellum)
    • Most positive for histone H3K27M mutant protein (nuclear)
    • All show loss of histone H3K27 trimethylation (H3K27me3)
  • Diffuse pediatric type high grade glioma, H3 wild type and IDH wild type:
    • Typically in a child or young adult
    • Frequent PDGFRA or EGFR alterations or MYCN amplification
    • Methylation profiling may be helpful in difficult cases
  • Pleomorphic xanthoastrocytoma:
    • Prominent xanthomatous cells
    • Often well circumscribed
    • Lower grade lesions have no necrosis and low mitotic activity
    • Eosinophilic granular bodies (EGBs), Rosenthal fibers and perivascular lymphocytic cuffing
    • Often BRAF V600E positive IHC / sequencing and CD34 positive
    • Pericellular reticulin deposition
  • Lymphoma:
    • More monotonous and discohesive with perivascular cuffing of tumor cells
    • Typically large B cell morphology
    • Positive for lymphoid markers (CD45, CD20, etc.)
    • Negative GFAP and Olig2
  • Tumefactive multiple sclerosis / demyelinating diseases:
    • Macrophage rich lesions (CD163 positive) with perivascular lymphoplasmacytic inflammation
    • Loss of myelin (LFB) with axonal preservation (neurofilament)
    • Creutzfeldt cells: astrocytic cells with nuclear fragmentation may mimic mitotic figures
    • Astrocytes have a reactive (fibrillary) appearance, which can be highlighted by GFAP IHC
  • Abscess:
    • Abundant necrosis with mixed acute and chronic inflammation
    • Peripheral granulation tissue and fibrosis
    • Neutrophilic inflammation predominates
    • Microorganisms may be identified
Board review style question #1

Which histologic subtype of glioblastoma, IDH wild type (pictured above) is important to diagnose due to increased risk of cerebrospinal fluid (CSF) dissemination?

  1. Epithelioid
  2. Gemistocytic
  3. Primitive neuronal component
  4. Sarcomatoid
Board review style answer #1
C. Primitive neuronal component. Glioblastomas with a primitive neuronal component have an increased risk of CSF spread and potential for distant metastasis in rare case reports. As such, this particular morphologic finding may be important to bring to the attention of the clinical team. A primitive neuronal component in glioblastoma can be diagnosed by identifying a morphologically distinct area with high cellularity, high mitotic activity, loss of expression of glial markers and expression of neuronal markers such as synaptophysin.

Comment Here

Reference: Glioblastoma, IDH wild type
Board review style question #2
BRAF V600E mutations are usually identified in low grade gliomas but are also present in a subset of glioblastomas with which histological features?

  1. Epithelioid
  2. Gemistocytic
  3. Giant cell
  4. Oligodendrolial-like features
Board review style answer #2
A. Epithelioid. BRAF V600E mutations are more frequently encountered in epithelioid glioblastomas and may allow for treatment with targeted therapies (Int J Mol Sci 2018;19:1090).

Comment Here

Reference: Glioblastoma, IDH wild type
Back to top
Image 01 Image 02