Neurosurgery notes/Tumours/Gliomas, Glioneuronal Tumors, and Neuronal Tumors/Adult type diffuse astrocytoma/High grade Gliomas/Glioblastoma IDH mutant

Glioblastoma IDH mutant

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High grade Gliomas

Definition (old WHO 2016)

  • High grade infiltrating glioma with a point mutation in isocitrate dehydrogenase 1 or 2 (IDH1 / 2), AND
    • Microvascular proliferation OR
    • Necrosis OR
    • Presence of CDKN2A/B homozygous deletion OR

Aka secondary GBM

  • Arises from a diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III)

Numbers

  • 5th decade of life
  • Male:female 0.96:1
  • 10% of all GBM

WHO Grading

  • Grade 4

Localization

  • Frontal lobe (> 60%) > temporal lobe > parietal or occipital lobe > nonlobar CNS sites

Pathology

Macroscopic

  • Soft gray-tan tissue with variable yellow-tan necrotic material
  • Often fragmented Interface of tumor with brain parenchyma is indistinct
  • Usually absent large areas of central necrosis and haemorrhage vs IDH wildtype glioblastoma

Microscopic

  • Cellular morphology can be highly variable
  • Often predominantly tumor cells with oval hyperchromatic nuclei in a fibrillary background
  • Variably present larger cells and pleomorphism
  • Variable quantity of cells with eccentric nuclei and glassy eosinophilic cytoplasm (gemistocytes)
  • Some show predominantly small cells with little pleomorphism and scant cytoplasm
 
This tumor section demonstrates two common architectural patterns of glioblastoma with areas of high cellularity containing small cells with scant cytoplasm and less cellular areas containing cells with elongated nuclei and abundant fibrillar background; pseudopallisading necrosis is present
This tumor section demonstrates two common architectural patterns of glioblastoma with areas of high cellularity containing small cells with scant cytoplasm and less cellular areas containing cells with elongated nuclei and abundant fibrillar background; pseudopallisading necrosis is present
  • Pseudopallisading
      • Endothelial injury and the expression of procoagulant factors result in intravascular thrombosis and perivascular hypoxia (light blue). Tumour cells begin to migrate away, creating a peripherally wave of palisading cells.
      • The zone of hypoxia arm central necrosis expands. Hypoxic tumour cells palisades secrete proangiogenic factors (VEGF, IL8).
      • Microvascular proliferation in regions adjacent central hypoxia causes an accelerated outward migration of tumour cells towards a new vasculature.
      notion image

Genetic/Molecular

  • IDH1 R132 mutation or IDH2 R172 mutation present
  • Most common mutation is IDH1 R132H (> 80%)
  • Frequent TP53 mutations (> 70%)
  • TP53 mutations are more common in IDH mutant glioblastomas versus IDH wildtype glioblastomas
  • Majority show ATRX mutations and alternative lengthening of telomeres
  • Usually lack TERT promoter mutations
  • TERT promoter mutations are much less common in IDH mutant glioblastomas compared to IDH wildtype glioblastoma and oligodendrogliomas

Imaging

  • MRI
      • T2 / FLAIR (fluid attenuation inversion recovery) hyperintense
      • T1 hypointense to isointense mass with necrosis
      • Contrast enhancing with irregular nodular or ring pattern of enhancement
       
      Tl weighted MRI with gadolinium based contrast shows mixed nodular and ring enhancement within the mass
      Tl weighted MRI with gadolinium based contrast shows mixed nodular and ring enhancement within the mass
      These MRIs show the typical progression of a frontotemporal IDH1-mutant diffuse astrocytoma (left) to an IDH1-mutant secondary glioblastoma (right) over a period of 5 years {1533}. Note the absence of central necrosis.
      These MRIs show the typical progression of a frontotemporal IDH1-mutant diffuse astrocytoma (left) to an IDH1-mutant secondary glioblastoma (right) over a period of 5 years {1533}. Note the absence of central necrosis.
      • 32-year-old woman
      • WHO 2016
        • Previously diagnosed with grade IV glioblastoma, IDHmut.
      • WHO 2021 integrated diagnosis
        • (Molecular: IDHmut, 1p/19q retained, CKN2A status unknown): Astrocytoma, IDH-mutant, CNS WHO grade 4.
      • The left frontal, well-marginated lesion exhibits heterogenous high T2w signal (G) with partial suppression on FLAIR (H). The figure demonstrates a region of irregular peripheral enhancement with central necrosis on T1w-CE (I)
      notion image

Outcome

  • Average survival twice as long as patients with IDH wildtype glioblastomas (N Engl J Med 2009;360:765)
  • Although MGMT promoter methylation is a favorable prognostic factor in glioblastoma, particularly in patients receiving temozolomide chemotherapy, it is uncertain whether it stands as a favorable prognostic factor in IDH mutant glioblastomas