CNS tumor
Diffuse astrocytic and oligodendroglial tumors
Glioblastoma, IDH wildtype


Topic Completed: 30 October 2019

Revised: 5 December 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Glioblastoma IDH wildtype

Momal Tara Chand, M.D.
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Cite this page: Chand M, Kupsky W. Glioblastoma, IDH wildtype. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cnstumortumorglioIDHwild.html. Accessed February 21st, 2020.
Definition / general
  • An aggressive, WHO grade IV, diffuse glioma of astrocytic lineage featuring cellular pleomorphism, nuclear atypia, mitotic activity, diffuse growth pattern, microvascular proliferation or necrosis
  • Lacking mutations in IDH genes
Essential features
  • Most common and most malignant astrocytic glioma
  • Accounts for 90% of all glioblastomas
  • Characterized by high cellularity, high mitotic activity, necrosis or microvascular proliferation
  • Majority have astrocytic differentiation, however, other morphologies (such as small cell, multinucleated giant cell, sarcomatous, gemistocytic and oligodendroglial-like cells) may also be present in varying proportions (Neuro Oncol 2013;15:1635)
Terminology
  • Primary glioblastoma, IDH wild type
ICD coding
  • ICD-0: 9440/3 - glioblastoma multiforme
Epidemiology
Sites
  • Most commonly located in the supratentorial region (frontal, temporal parietal and occipital lobes), with the highest incidence in the frontal lobe, multiple lobes (overlapping tumors), followed by the temporal and parietal lobes (De Vleeschouwer: Glioblastoma, Chapter 8, 2017)
  • Rarely located in the cerebellum and spinal cord
Pathophysiology
Etiology
  • Mostly sporadic; no known environmental cause
  • A small portion of these tumors occur in Mendelian disorders, including neurofibromatosis, tuberous sclerosis and Li-Fraumeni syndrome (Neuro Oncol 2014;16:896)
Clinical features
  • Symptoms depend on the tumor location, manifesting as focal neurologic deficits and mass effect due to tumor and tumor associated edema causing rise in intracranial pressure
  • Most common presentations are headache, vomiting, diplopia and altered sensorium, indicating raised intracranial pressure
  • Children may present with acute neurological deterioration, usually from intratumoral hemorrhage or an episode of seizure (De Vleeschouwer: Glioblastoma, Chapter 15, 2017)
  • Infants and young children often present with nonspecific complaints, such as failure to thrive, lethargy, nausea / emesis and macrocephaly, making it difficult to diagnose (De Vleeschouwer: Glioblastoma, Chapter 15, 2017)
Diagnosis
  • Computed tomography (CT) and magnetic resonance imaging (MRI) for radiological assessment
  • Diagnosis is by biopsy or surgical resection
Radiology description
  • Irregularly shaped with ring enhancement around central, dark area of necrosis
  • Prominent T2 / fluid attenuated inversion recovery (FLAIR) hyperintensity (white) around enhancing area
  • Mass effect
Radiology images

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Edema and necrosis

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T1 C+ and FLAIR images

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Multifocal glioblastoma

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DH1-wild type and IDH1-mutant gliomas

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FLAIR imaging showing edema


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H3 K27M mutant tumors

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Midline gliomas

Prognostic factors
  • Most common and deadly primary brain tumor with a median overall survival of less than 15 months despite aggressive treatment (Nat Commun 2018;9:2087)
  • Increased survival in patients
    • Diagnosed under age 20 (Neuro Oncol 2014;16:63)
    • With complete macroscopic tumor resection
    • With MGMT promotor methylation or IDH mutation
    • More necrosis = shorter survival
    • Aggressive variant
    • Somewhat better prognosis than ordinary glioblastomas
Case reports
Treatment
Gross description
  • Diffusely infiltrative, friable and vascularized tumor
  • Peripheral greyish rim of tissue with central areas of yellowish necrosis from myelin breakdown
  • Thrombosed vessels (De Vleeschouwer: Glioblastoma, Chapter 15, 2017)
  • Foci of hemorrhage
Frozen section description
  • Variable cellular morphology with gemistocytes to small cells multinucleated cells etc.
    • Hyperchromatic nuclei
    • Fibrillary background
    • Variable number of mitoses
    • Necrosis, may be punctate with pseudopalisade
    • Microvascular proliferation
    • Nuclear pleomorphism
    • Presence of larger cells and pleomorphism
Frozen section images

Contributed by William Kupsky, M.D.
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Pleomorphic cells

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Microvascular proliferation

Microscopic (histologic) description
  • Highly anaplastic glial cells with nuclear atypia and pleomorphism
  • Microvascular proliferation:
    • Hallmark of glioblastoma
    • Glomerular tufts of mitotically active multilayered endothelial cells (may be associated with areas of necrosis)
    • Hypertrophic proliferation of endothelial cells (less common form)
  • Vascular thrombosis
  • Necrosis:
    • Essential feature
    • Palisading form "pseudopalisading"
    • Presence is strongest indicator of aggressive behavior (Cancer 1996;77:1161)
  • Apoptosis: mostly near the areas of necrosis
  • Inflammatory cells: variable
  • Mitoses: variable
  • Other cellular morphologies:
    • Small cell glioblastoma
      • Small cells with monomorphic oval nuclei, mild nuclear hyperchromasia, bland chromatin, occasional small nucleoli, minimal discernable cytoplasm and frequent mitotic figures (Cancer 2004;101:2318)
      • Resembles oligodendroglioma due to presence of chicken wire‚Äźlike capillary networks, clear perinuclear haloes, perineuronal satellitosis and microcalcifications (Cancer 2004;101:2318)
      • EGFR amplification (present in 70%)
      • Chromosome 10q loss (> 95% cases)
    • Primitive neuronal cells
      • Glioma containing primitive nodules with neuronal differentiation
      • Primitive foci have increased cellularity and high nuclear to cytoplasmic ratio
      • Homer Wright rosettes, cell wrapping and anaplastic cytology
      • These foci show immunoreactivity for synaptophysin, loss of GFAP expression and a high Ki67 proliferation index (Diagn Pathol 2019;14:16)
      • High rate of cerebrovascular fluid dissemination
      • Increased frequency of MYCN or MYC gene amplification (around 43%)
      • Some cases have 10q loss in primitive neuronal foci
    • Oligodendroglioma component
    • Lipidized cells:
      • Containing cells with foamy cytoplasm
    • Metaplasia
      • Foci of adenoid and squamous metaplasia
      • More common in gliosarcoma
    • Gemistocytes
      • Gemistocytes have copious, glassy, non fibrillary cytoplasm displacing dark, angulated nucleus to the periphery of the cell
      • Peripheral GFAP staining, central hyaline organelle rich zone largely unstained
      • Perivascular lymphocytes present in gemistocytic regions
      • More characteristic of IDH mutant glioblastoma
    • Multinucleated giant cells
      • Located subcortically in temporal and parietal lobes (Diagn Cytopathol 2012;40:440)
      • Less than 1% of intracranial tumors and 5% of glioblastoma
      • Composed of pleomorphic, giant and multinucleated cells
    • Granular cells
      • Large cells with a granular, periodic acid Schiff-positive cytoplasm scattered within glioblastoma
      • Larger granular tumor cells resemble macrophages and may be misinterpreted as demyelinating disease
      • Peripheral GFAP positivity but mostly negative
      • Macrophage marker CD68 positive but negative for specific markers such as CD163
Microscopic (histologic) images

Contributed by William Kupsky, M.D.
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Dense cellularity

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Microvascular proliferation

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Oligo-dendromaglioma-like component

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Necrosis, microvascular proliferation and vascular thrombi

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Glioblastoma, IDH wildtype


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GFAP

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CD34

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Ki67

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p53

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EGFR

Cytology description
  • Smear preparations are now preferred to frozen sections for the rapid diagnosis of CNS mass lesions, particularly in stereotactic needle biopsy specimens (Pathology 1992;24:27)
  • Cytopathology of glioblastoma, to our knowledge, has not been previously described, however the presence of following features helps in the diagnosis:
    • Pleomorphic or gemistocytic cells (J Cytol 2011;28:147)
    • Multipolar coarse fibrillary processes forming a meshwork (J Cytol 2011;28:147)
    • Necrosis
    • Microvascular proliferation
    • Hyperplastic vessels with multilayered cells
    • Apoptosis
    • Mitosis
Cytology images

Contributed by William Kupsky, M.D.
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Smear

Positive stains
Negative stains
Electron microscopy description
Electron microscopy images

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Tumor with cytoplasmic filaments

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Glioblastoma with convoluted membranes

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Tumor cells with giant mitochondria

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Tumor with fibrillogenesis

Molecular / cytogenetics description
  • No IDH1 / IDH2 mutation
  • Frequent TERT promotor mutations
  • EGFR amplification occurs in 40% of primary glioblastomas
    • Rare in secondary glioblastomas
  • TP53 mutations are less common in IDH wild glioblastomas (28%) versus IDH mutant glioblastomas (65%) (Am J Pathol 2007;170:1445)
  • PTEN mutations more frequent in IDH wildtype than in IDH mutant glioblastomas (Am J Pathol 2007;170:1445)
  • RB1 mutations more common in secondary (IDH mutant) glioblastomas than in primary glioblastomas (IDH wildtype)
  • Gain of 7p and loss of 10q - most common chromosomal abnormality
Sample pathology report
  • Brain, frontal lobe, biopsy:
    • Glioblastoma, IDH wildtype (WHO grade IV)
  • Brain, frontal lobe, biopsy:
    • Integrated diagnosis: glioblastoma, IDH wildtype
    • Histological diagnosis: glioblastoma
    • Focal oligodendroglial morphology
    • WHO histological grade: IV
    • Molecular information
      • IDH1 and IDH2: no mutation detected (molecular)
      • ATRX: nuclear expression retained
      • p53: diffuse nuclear immunoreactivity
      • EGFR: diffuse immunoreactivity
      • No 1p or 19q deletions detected IDH1 mutant (R132H immunohistochemistry)
Differential diagnosis
  • Glioblastoma, IDH mutant:
  • Pleomorphic xanthoastrocytoma:
    • WHO grade II tumor, characterized by a compact cellularity with a tendency to form a fascicular pattern, punctuated by large, multinucleated cells with a thin, foamy, xanthomatous cytoplasm, however, mitotic figures are difficult to find and no necrosis or vascular proliferation present (Adv Anat Pathol 2017;24:379)
    • Well circumscribed from the surrounding neuroglial parenchyma
    • Eosinophilic granular bodies and calcifications commonly seen as evidence of a low grade neoplasm in spite of the concerning pleomorphism (Adv Anat Pathol 2017;24:379)
  • Anaplastic oligodendroglioma:
    • High grade infiltrating glioma composed of round cells resembling oligodendrocytes, hyperchromatic rounded nuclei, perinuclear halos, increased mitotic activity, fine branching vasculature, scattered calcifications, variable microvascular proliferation and variable necrosis
    • 1p/19q codeletion and IDH1 mutations are required for the diagnosis
    • ATRX alterations and TP53 mutations are typically absent (Acta Neuropathol 2012;124:615, N Engl J Med 2009;360:765)
  • Lymphoma:
    • Lymphomas in the central nervous system are typically diffuse large B cell lymphomas, which lack the fine fibrillar cell processes typical of glial cells
    • Show angiocentric growth pattern and widening of the perivascular space
    • Neovascularization is not prominent (AJNR Am J Neuroradiol 2010;31:1699)
    • Diffuse large B cell lymphomas is positive for CD45 and CD20 but negative for GFAP and Olig2 by immunohistochemistry (AJNR Am J Neuroradiol 2010;31:1699)
    • Metastatic disease:
      • Both metastatic carcinoma and glioblastoma typically present radiologically as ring-enhancing mass lesions, however, microscopic examination usually clarifies the issue relatively easily (Adv Anat Pathol 2017;24:379)
    • Abscess
      • No cytologically malignant cells
      • Acute inflammation
      • Prominent lymphoplasmacytic infiltrate
Board review style question #1

    Which mutation is most commonly associated with IDH1 wild type glioblastoma in adults?

  1. H3 K27M
  2. IDH1
  3. IDH2
  4. PTEN
  5. TERT
Board review answer #1
E. TERT is the most common mutation in IDH wild type glioblastomas present in 72 - 90% of the tumors. H3 K27M mutations are exclusively found in diffuse midline gliomas in adults, PTEN in 25 - 30% and there is no IDH1 and IDH2 mutation.

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Reference: CNS tumor - Glioblastoma, IDH wildtype
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