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Glioma

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glioma classification treatment

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Glioma

Gliomas are the most common malignant primary brain tumors, arising from glial cells. The 2021 WHO Classification fundamentally restructured their categorization by separating them into adult-type and pediatric-type diffuse gliomas, based on molecular genetic differences rather than histology alone.

1. Classification (2021 WHO CNS Tumor Classification)

Adult-Type Diffuse Gliomas

Tumor TypeKey Molecular Alterations
Astrocytoma, IDH-mutantIDH1, IDH2 (1p/19q intact)
Oligodendroglioma, IDH-mutant, 1p/19q-codeletedIDH1/IDH2 + 1p/19q co-deletion
Glioblastoma, IDH wild-typeChr 7 gain, Chr 10 loss; TERT, EGFR

Pediatric-Type Diffuse Gliomas (can occur in adults)

Tumor TypeKey Molecular Alterations
Diffuse midline glioma, H3 K27-alteredH3 K27M, EGFR, EZHIP
Diffuse hemispheric glioma, H3 G34-mutantH3.3 G34R/V
Diffuse pediatric high-grade glioma, H3/IDH wild-typeEGFR, PDGFRA, MYCN
Diffuse low-grade glioma, MAPK pathway-alteredBRAF V600E/fusion, FGFR mutations
The three key adult groups are defined by: IDH mutation status first, then 1p/19q co-deletion. Both carry significant prognostic impact.

2. Epidemiology & Clinical Presentation

  • Low-grade glioma (WHO Grade II): Peak incidence in the 4th decade; commonly presents with seizures initially
  • High-grade gliomas (WHO Grade III-IV): Present de novo in the 5th-6th decades, or by malignant transformation of low-grade tumors
  • Glioblastoma (GBM, IDH wild-type): Most common glial tumor; peak in 5th-6th decade; presents with headache, focal neurological deficits, cognitive change, or seizures
  • Rare presentation: Gliomatosis cerebri pattern - diffuse brain infiltration without focal mass, with cognitive symptoms; now categorized by biopsy pathology rather than as a separate entity
Hereditary syndromes predisposing to glioma include: NF1, NF2, Li-Fraumeni, Turcot, VHL, Lynch syndrome, TSC, and others.

3. Imaging

MRI with and without gadolinium is the preferred modality.
  • Low-grade: T2/FLAIR hyperintense, typically non-enhancing
  • High-grade/GBM: Ring-enhancing lesion with central necrosis and surrounding edema, mass effect
  • CT with contrast also used (see below - heterogeneous frontoparietal lesion with midline shift)
CT scan showing heterogeneous right frontoparietal glioblastoma with mass effect and midline shift
CT with contrast: heterogeneous right frontoparietal GBM with mass effect and midline shift - Bailey & Love's Surgery, Fig 48.22
Diffusion-weighted MRI is valuable to exclude brain abscess (which shows prominent restricted diffusion). CT chest/abdomen/pelvis is done to exclude extracranial primary (since metastasis is the main differential).
Pathological specimen showing the characteristic hemorrhagic, necrotic appearance of GBM:
Pathological brain specimen of glioblastoma multiforme showing large hemorrhagic and necrotic area
Pathological specimen of glioblastoma multiforme - Bailey & Love's Surgery, Fig 48.23

4. Management

Initial Measures

  • High-dose corticosteroids (dexamethasone) to alleviate mass effect
  • Anti-epileptics for seizures or when anticipated (temporal location)

Surgery

  • Surgical resection is the primary treatment: reduces disease burden and provides tissue for histological and molecular diagnosis
  • Awake craniotomy when tumor is near eloquent cortex (speech areas), allowing intraoperative speech mapping
  • Complete excision is impossible for most gliomas (except Grade I pilocytic astrocytoma in children) due to diffuse infiltration into surrounding brain
  • Stereotactic biopsy when resection is not feasible

Adjuvant Therapy

Glioblastoma (IDH wild-type):
  • Standard of care: Stupp protocol - concurrent temozolomide + radiotherapy (60 Gy in 30 fractions) followed by adjuvant temozolomide for 6 cycles
  • MGMT promoter methylation is the key predictive biomarker for temozolomide benefit
  • Bevacizumab (anti-VEGF) approved for recurrent GBM; improves progression-free survival
  • Tumour Treating Fields (TTFields) - low-intensity alternating electric fields - added to maintenance temozolomide for newly diagnosed GBM (FDA approved 2015)
IDH-mutant low/intermediate-grade gliomas:
  • Treatment depends on molecular subtype and risk stratification
  • Radiotherapy + PCV chemotherapy (procarbazine, lomustine, vincristine) or temozolomide following resection
  • Vorasidenib (IDH1/2 inhibitor) - a landmark 2023 New England Journal of Medicine trial showed benefit in IDH-mutant low-grade glioma and it received FDA approval in 2024 for this indication

Recurrence

  • Re-irradiation, repeat surgery, and systemic therapy options at recurrence
  • Clinical trials are strongly encouraged

5. Prognosis

TumorMedian Survival
GBM (IDH wild-type)~15 months (with Stupp protocol)
Anaplastic astrocytoma (IDH-mutant)3-5 years
Oligodendroglioma (IDH-mutant, 1p/19q-codeleted)10-15+ years
Low-grade astrocytoma (IDH-mutant)5-10 years
Favorable prognostic factors: IDH mutation, 1p/19q co-deletion, MGMT methylation, younger age, good performance status, maximal surgical resection.

6. Pediatric Gliomas

  • Pilocytic astrocytoma (WHO Grade I): Most common pediatric brain tumor; cerebellar location; often curable with complete resection; not infiltrative
  • Optic pathway gliomas: Common in NF1; often managed conservatively or with chemotherapy
  • Diffuse intrinsic pontine glioma (DIPG) / Diffuse midline glioma H3 K27-altered: Highly malignant; brainstem location precludes surgery; median survival ~12 months; H3 K27M mutation is diagnostic
  • Pediatric low-grade gliomas often harbor BRAF alterations (BRAF V600E or BRAF-KIAA1549 fusion)
Sources:
  • Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Ch. 95 - Diffuse Glioma
  • Bailey and Love's Short Practice of Surgery, 28th Ed., Ch. 48 - Glioma
  • Recent evidence: A 2025 umbrella review (Yang et al., Ann Med PMID 40598793) comparing glioma treatment strategies, and vorasidenib approval (Mellinghoff IK et al., NEJM 2023 - referenced in Harrison's 22E)
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