Glioblastoma

1. Introduction and Definition

Glioblastoma (GBM), historically termed Glioblastoma Multiforme (GBM), is the most aggressive, infiltrative, and common primary malignant brain tumour in adults. Classified by the World Health Organization (WHO) as a WHO Grade 4 diffuse astrocytic glioma, it carries a grave prognosis despite advances in multimodal therapy.

The 2021 WHO Classification of Tumours of the Central Nervous System (CNS5) represents a paradigm shift, moving from purely histological classification to an integrated genotypic-phenotypic diagnosis. Consequently, the term “Glioblastoma” is now strictly defined by molecular markers:

• Glioblastoma, IDH-wildtype: The most common form (~90% of cases), typically occurring in older adults (median age ~62 years), arising de novo (primary GBM) without evidence of a precursor lesion. It is defined by the absence of IDH mutation and the presence of one or more of the following: TERT promoter mutation, EGFR amplification, or whole chromosome 7 gain/whole chromosome 10 loss (+7/-10).
• Glioblastoma, IDH-mutant: A rarer subset (~10%), typically affecting younger patients (median age ~40 years), almost always evolving from a lower-grade diffuse astrocytoma (secondary GBM). These have a significantly better prognosis than their IDH-wildtype counterparts.

“Primary GBM” (de novo) vs. “Secondary GBM” (progressed from lower grade) are clinical concepts largely superseded by the molecular definitions above, though still used in clinical discourse to describe natural history.

2. Epidemiology and Risk Factors

Incidence and Demographics

• Incidence: ~3.2 per 100,000 person-years in the US/Europe.
• Prevalence: Accounts for 45–50% of all primary malignant brain tumours and ~15% of all intracranial tumours.
• Age: Bimodal distribution is a myth; incidence rises steadily with age, peaking at 75–84 years. Rare in children (< 3% of paediatric CNS tumours).
• Sex: Male predominance (Male:Female ratio ~1.6:1).
• Race/Ethnicity: Highest incidence in non-Hispanic Whites; lower in Black, Asian, and Hispanic populations.

Established and Suspected Risk Factors

Clinical Pearl: There are no screening recommendations** for GBM in the general population or high-risk groups (e.g., radiation survivors), as early detection has not been proven to alter mortality due to the tumour’s infiltrative nature at diagnosis.

3. Molecular Pathogenesis and Pathophysiology

Understanding the molecular landscape is critical for diagnosis, prognosis, and emerging targeted therapies. GBM is characterized by extreme inter- and intra-tumoural heterogeneity.

Core Pathways (The “Core Three” in IDH-wildtype GBM)

Defining Molecular Markers (Diagnostic & Prognostic)

• IDH1/IDH2 Mutation: R132H (IDH1) most common. Absence = IDH-wildtype. Presence = IDH-mutant (better prognosis). Detected by IHC (IDH1 R132H antibody) or sequencing.
• TERT Promoter Mutation (C228T/C250T): Present in ~80% of IDH-wt GBM. Drives telomerase reactivation/immortality. Diagnostic criterion for IDH-wt GBM if IDH wildtype.
• EGFR Amplification / EGFRvIII: EGFR amp in ~40-50% IDH-wt; EGFRvIII (exon 2-7 deletion) in ~50% of amplified cases. Constitutively active receptor. Target for CAR-T/vaccines.
• PTEN Loss: Mutation/deletion ~30-40%. Negative regulator of PI3K pathway. Associated with resistance to EGFR inhibitors.
• MGMT Promoter Methylation: Epigenetic silencing of O6-methylguanine-DNA methyltransferase (DNA repair enzyme). Predictive biomarker for benefit from temozolomide chemotherapy. Present in ~35-45% of cases.
• 1p/19q Co-deletion: Hallmark of Oligodendroglioma. Absent in GBM. If present, diagnosis shifts to Oligodendroglioma WHO Grade 3/4 (molecularly defined).
• H3 K27M / H3 G34R/V: Histone mutations defining Diffuse Midline Glioma (H3 K27-altered) or CNS High-grade Neuroepithelial Tumour with BCOR alteration. Excludes diagnosis of “Glioblastoma” if in midline/pediatric contexts.

Transcriptional Subtypes (Legacy but Biologically Relevant)

While not used for primary diagnosis in CNS5, the TCGA subtypes reflect biology:

1. Classical: EGFR amp, CDKN2A del, no TP53 mut. Best response to aggressive chemoradiation.
2. Mesenchymal: NF1 loss, PTEN loss, high immune infiltrate, necrosis. Worst prognosis, resistant to therapy.
3. Proneural: PDGFRA amp, IDH1 mut (often secondary), TP53 mut. Better baseline prognosis but prone to recurrence.
4. Neural: Gene expression resembling normal neurons (now often considered contamination/non-tumour component).

4. How Does It Look? (Radiological and Histopathological Appearance)

This section details the visual phenotype of GBM across imaging modalities and microscopy, essential for diagnosis and surgical planning.

Neuroimaging: Magnetic Resonance Imaging (MRI)

MRI with and without gadolinium-based contrast is the gold standard. Advanced sequences (Perfusion, Diffusion, Spectroscopy) add metabolic/physiological data.

Conventional MRI Features (The “Classic” GBM)

Advanced MRI (Physiological Imaging)

• Perfusion Weighted Imaging (PWI – DSC/DCE): Measures Relative Cerebral Blood Volume (rCBV). GBM shows markedly elevated rCBV within enhancing rim (angiogenesis). Low rCBV suggests treatment effect (pseudoprogression) or lower grade.
• Diffusion Weighted Imaging (DWI) / ADC Map: GBM typically shows intermediate to low ADC (restricted diffusion) due to high cellularity. High ADC in centre = necrosis/liquefaction.
• MR Spectroscopy (MRS): Elevated Choline (Cho) peak (membrane turnover), Decreased N-Acetylaspartate (NAA) (neuronal loss), Elevated Lipid/Lactate peaks (necrosis/anaerobic glycolysis). Cho/NAA ratio > 2 highly suggestive of high-grade glioma.
• Amino Acid PET (FET-PET / FDOPA-PET): Superior for defining biological tumour volume (BTV) for radiotherapy planning, detecting infiltration beyond FLAIR.

Differential Diagnosis on Imaging (The “Ring-Enhancing Lesion” List)

Histopathology (Microscopic Appearance)

Diagnosis requires tissue (biopsy or resection). The WHO Grade 4 diagnosis rests on two histological hallmarks (in IDH-wildtype context) or specific molecular markers.

Defining Histological Features

1. Microvascular Proliferation (MVP):

• Appearance: Endothelial cell hyperplasia, multilayering, glomeruloid bodies (tufts resembling renal glomeruli).
• Significance: Hallmark of Grade 4 (vs Grade 3). Driven by VEGF/HIF-1α.

1. Necrosis (Pseudopalisading Necrosis):

• Appearance: Geographical (coagulative) necrosis bordered by pseudopalisades—dense rows of hyperchromatic tumour cells “palisading” away from the hypoxic necrotic core.
• Significance: Hallmark of Grade 4. Represents hypoxia-driven invasion and VEGF upregulation.

Cellular Morphology

• Cell Type: Pleomorphic astrocytes (highly variable size/shape).
• Nuclei: Hyperchromatic, irregular membranes, prominent nucleoli.
• Mitoses: Frequent, often atypical.
• Giant Cells: Multinucleated, bizarre forms (common in “Giant Cell GBM” variant).
• Infiltration: Tumour cells infiltrate brain parenchyma (cortex, white matter), entrapping neurons (Satellitosis) and surrounding vessels (Perivascular satellitosis).

Histological Variants (WHO Recognized Patterns)

Immunohistochemistry (IHC) Panel (Standard Diagnostic Workup)

5. Clinical Presentation: Symptoms

Symptoms arise from mass effect (tumour bulk + edema), focal neurological deficit (infiltration/destruction of specific eloquent areas), and global intracranial hypertension. Onset is typically subacute (days to weeks), though seizures can be the sentinel event months prior.

Generalized Symptoms (Raised Intracranial Pressure – ICP)

• Headache: The most common initial symptom (~50%).
• Character: Progressive, worse in morning/awakening (supine position increases venous pressure/ICP), exacerbated by Valsalva (coughing, straining), often bifrontal or holocranial.
• Red Flag: New-onset headache >50 years old; change in pattern; nocturnal waking.
• Nausea and Vomiting: Often projectile, worse in morning, non-bilious. Caused by direct compression of vomiting centre (area postrema) or raised ICP.
• Papilledema: Optic disc swelling on fundoscopy (late sign, indicates sustained raised ICP). Absence does not rule out raised ICP.
• Altered Consciousness: Drowsiness, confusion, obtundation (late, sign of herniation/tran tentorial pressure).

Focal Neurological Deficits (Localization-Dependent)

The “eloquence” of the involved lobe dictates the deficit. Infiltration causes deficits earlier than displacement.

Seizures: A Distinct Clinical Entity

• Incidence: 60–80% of patients experience at least one seizure during disease course; ~25-40% present with seizure as first symptom.
• Types: Focal onset (aware or impaired awareness) most common; secondary generalization frequent.
• Status Epilepticus: Medical emergency; higher risk in GBM due to peritumoral excitability (glutamate, chloride dysregulation).
• Management: Prophylactic antiseizure medication (ASM) in seizure-naive patients is NOT recommended (AAN/NCCN guidelines) due to side effects (rash, hepatotoxicity, enzyme induction affecting chemo) and lack of efficacy for prevention. Treat only after first seizure.

Clinical Syndromes & Emergency Presentations

• Uncal (Transtentorial) Herniation: Unilateral dilated pupil (CN III compression), contralateral hemiparesis (Kernohan’s notch), decreased consciousness. Neurosurgical Emergency.
• Central (Tonsillar) Herniation: Cushing’s Triad (Hypertension, Bradycardia, Irregular respirations), pinpoint pupils, flaccid paralysis. Imminent death.
• Subfalcine Herniation: Contralateral leg weakness (ACA compression), confusion.
• Venous Infarction: Tumour invades/compresses dural sinuses (Sagittal/Transverse) -> venous congestion -> haemorrhagic infarction -> acute deficit.

6. Diagnostic Workup Algorithm

1. New neurological deficit, seizure, or headache → urgent MRI with and without contrast, plus DWI, SWI, and FLAIR.
2. Ring-enhancing lesion with oedema and mass effect → tumour board. Atypical imaging → consider biopsy, PET, or lumbar puncture first.
3. Prefer maximal safe resection. Stereotactic biopsy if the tumour is deep, eloquent, multifocal, or performance status is poor.
4. Histology and molecular panel: IDH1 R132H, then sequencing if negative; TERT, EGFR, 1p/19q, MGMT, H3 K27M.
5. Integrated WHO CNS5 diagnosis, then treatment planning (Stupp protocol, a modified plan, or palliative care).

Essential Baseline Labs: CBC, CMP (Lytes, LFTs, Renal), Coagulation, Magnesium (chemo toxicity), Hepatitis B/C/HIV (reactivation risk with steroids/chemo), Varicella Zoster IgG (Pneumocystis prophylaxis indication).

7. Standard of Care Treatment (The “Stupp Protocol” and Evolution)

Treatment is multimodal and palliative (curative intent not achievable with current standard therapy). Goals: Maximize survival, preserve neurological function, maintain quality of life (QoL).

Surgery: Maximal Safe Resection

• Goal: Gross Total Resection (GTR) of contrast-enhancing tumour (volumetric residual < 0.175 cm³ or < 2 cm max diameter).
• Evidence: Extent of Resection (EOR) correlates strongly with OS (GTR > Subtotal > Biopsy).
• Adjuncts: 5-ALA (Gliolan) fluorescence (visualizes tumour intraoperatively), Intraoperative MRI (iMRI), Awake Craniotomy with cortical/subcortical mapping (for eloquent areas), Neuro-navigation, Neurophysiology Monitoring (MEP/SSEP).
• Biopsy: Stereotactic (frame-based or frameless) if unresectable, deep, multifocal, or poor performance status (KPS < 70).

Radiotherapy (RT) + Concurrent Chemotherapy

• Standard Fractionation: 60 Gy in 30 fractions (2 Gy/fx, Mon-Fri) over 6 weeks to involved field (GTV + margin).
• Concurrent Temozolomide (TMZ): 75 mg/m² daily (7 days/week) during RT.
• Mechanism: Alkylating agent (methylates O6-guanine). Crosses BBB.
• Toxicity: Myelosuppression (lymphopenia common), nausea, hepatotoxicity, pneumonitis (rare).
• Supportive Care: Pneumocystis jirovecii pneumonia (PJP) prophylaxis (TMP-SMX) mandatory during concurrent RT/TMZ + until CD4 > 200/µL (lymphopenia risk). Antiemetics (5-HT3 antagonists).

Adjuvant Chemotherapy (Maintenance TMZ)

• Start: 4 weeks post-RT completion (allow hematologic recovery).
• Dose: 150–200 mg/m² Days 1–5 every 28-day cycle.
• Cycles: Standard 6 cycles (may continue up to 12–24 if tolerated and stable disease).
• Dose Modification: Based on Nadir ANC/Platelets (CTCAE v5.0).

Treatment Modifications by Population

Tumor Treating Fields (TTFields / Optune)

• Mechanism: Low-intensity (1-3 V/cm), intermediate-frequency (200 kHz) alternating electric fields disrupt mitotic spindle formation (tubulin dipole alignment) and cause dielectrophoretic dislocation of macromolecules.
• Indication: FDA approved for newly diagnosed GBM (with adjuvant TMZ after chemoradiation) and recurrent GBM.
• Usage: Transducer arrays on shaved scalp, ≥ 18 hours/day compliance critical.
• Evidence (EF-14 Trial): Median OS 20.9 vs 16.0 months (HR 0.63); PFS 6.7 vs 4.0 months. Skin irritation (contact dermatitis) main side effect.

8. Management of Recurrent/Progressive Disease

Recurrence is universal (median time ~7 months). “Pseudoprogression” (treatment effect mimicking progression) must be excluded (RANO criteria, usually < 3-6 months post-RT).

Surgical Re-resection

• Indicated for: Accessible lesion, significant mass effect, KPS ≥ 70, time from initial RT > 6-9 months, molecular eligibility for trials.
• Benefit: Debulking, symptom control, tissue for molecular profiling (evolution).

Systemic Therapy Options (Recurrent)

Re-irradiation

• Options: Stereotactic Radiosurgery (SRS – single fraction), Hypofractionated SRT (3-5 fx), Brachytherapy (Cs-131/I-125 seeds), Proton Therapy.
• Criteria: Small volume (< 3-4 cm), good KPS, > 6-12 months from prior RT. Risk: Radiation Necrosis (5-15%).

9. Supportive Care and Symptom Management

Critical for QoL. Requires proactive, multidisciplinary approach (Neuro-oncology, Palliative Care, Neuro-rehab, Social Work).

Corticosteroids (Dexamethasone)

• Indication: Symptomatic vasogenic edema / mass effect.
• Dosing: Start low: 4 mg PO/IV q6h (16 mg/day). Titrate to lowest effective dose.
• Tapering: Mandatory once stable on chemo/RT or after surgery. Rapid taper causes withdrawal/adrenal insufficiency; slow taper over weeks-months.
• Side Effect Management:
• GI Protection: PPI (Pantoprazole) while on steroids + TMZ.
• Hyperglycaemia: Monitor glucose; insulin sliding scale often needed.
• Insomnia/Psychosis: Morning dosing; avoid evening doses.
• Infection Risk: PJP prophylaxis (see 7.2); monitor for fungal/opportunistic.
• Myopathy/Weakness: Limit duration; physical therapy.
• Bone Health: Calcium/Vit D; Bisphosphonates/Denosumab if long-term (>3 mo).

Antiseizure Medications (ASMs)

• Preferred (Non-enzyme inducing): Levetiracetam (Keppra), Lacosamide (Vimpat), Brivaracetam, Zonisamide, Valproic Acid (VPA – potential histone deacetylase inhibition benefit/survival signal retrospective, but teratogenicity/weight gain/thrombocytopenia risks).
• Avoid (Enzyme Inducing – CYP3A4): Phenytoin, Carbamazepine, Phenobarbital, Oxcarbazepine. Decrease TMZ/Corticosteroid/Targeted Therapy levels. Drug interactions significant.
• Monitoring: Levels rarely needed for Levetiracetam; renal dose adjust. CBC/LFTs baseline and periodic for others.

Venous Thromboembolism (VTE) Prophylaxis

• Risk: Extremely high (20-30% VTE incidence). Tumour procoagulant activity + immobility + surgery + steroids + bevacizumab.
• Prophylaxis:
• Inpatient: Therapeutic/Intermediate dose LMWH (Enoxaparin 40 mg daily) or UFH. DOACs (Apixaban/Rivaroxaban) increasingly used (SELECT-D, CARAVAGGIO data supportive in cancer).
• Outpatient: Extended prophylaxis (LMWH or DOAC) for 4-6 weeks post-craniotomy; consider continued if high risk (KPS<70, steroids, bevacizumab).
• Therapeutic Anticoagulation for established VTE: LMWH preferred historically; DOACs non-inferior/safer bleeding in recent trials (intracranial haemorrhage risk ~2-4% with DOACs vs LMWH). Avoid in active intracranial haemorrhage / recent neurosurgery (< 2-4 wks).

Neuro-rehabilitation

• Early referral (Pre-hab / Early Post-op).
• Focus: Motor strength, gait/balance, ADLs, cognition (executive function), speech/swallow.
• Fatigue Management: Energy conservation, stimulants (Methylphenidate/Modafinil) cautious use.

Palliative Care & End-of-Life

• Early Integration: At diagnosis (ASCO/NCCN guideline).
• Advance Care Planning: Goals of care, Code status, Healthcare Proxy, POLST/MOLST forms.
• Symptom Control (Terminal Phase): Opioids (pain/dyspnea), Benzodiazepines (agitation/seizures), Anticholinergics (secretions), Steroids (cerebral edema/pressure), Palliative sedation (refractory symptoms).
• Hospice: Median survival after recurrence ~3-6 months; hospice enrollment often late.

10. Prognosis and Prognostic Factors

Survival Statistics (Modern Era: Stupp + TTFields + Molecular Stratification)

Key Prognostic Factors (Multivariate)

Recursive Partitioning Analysis (RPA) / Diagnostic Graded Prognostic Assessment (GPA)

• RPA Classes (Historical but referenced): Class III (KPS≥70, Age<50, GTR) best; Class VI (KPS<70) worst.
• Diagnosis-Specific GPA (Sperduto et al.): Incorporates Age, KPS, Molecular (IDH/MGMT). Score 0.0-4.0. Higher score = better survival.

11. Special Populations and Unique Clinical Scenarios

GBM in Pregnancy

• Rarity: ~1:10,000 pregnancies.
• Surgery: Safe in 2nd Trimester (14-24 wks); 1st Trimester (teratogenicity risk anaesthetics); 3rd Trimester (uterine size/hemodynamics).
• RT: Contraindicated 1st Trimester. Possible 2nd/3rd with abdominal shielding (fetal dose < 50-100 mGy).
• TMZ: Teratogenic (Category D). Contraindicated. Avoid conception 6 months post-TMZ (male/female).
• Steroids: Safe (Betamethasone/Dexamethasone cross placenta less; used for fetal lung maturity).
• Delivery: Vaginal preferred; C-section for obstetric indications. Coordinate neuro-oncology, maternal-fetal medicine, neurosurgery, radiation oncology, neonatology.

Paediatric / Adolescent & Young Adult (AYA) “GBM”

• WHO CNS5: True IDH-wildtype GBM is rare in children. Most “paediatric GBM” are molecularly distinct: Diffuse Midline Glioma H3 K27-altered, Diffuse Hemispheric Glioma H3 G34-mutant, Infant-type Hemispheric Glioma, Paediatric-type High-grade Glioma.
• Treatment: Maximize resection -> RT (often proton therapy to spare development) -> TMZ. Clinical trials paramount (e.g., ONC201 for H3 K27M).
• Late Effects: Neurocognitive decline, endocrinopathy, secondary malignancies, vascular injury.

Gliosarcoma

• Biphasic tumour (Glial + Mesenchymal).
• Metastatic Potential: ~5-10% risk of extracranial metastasis (lung, liver, lymph nodes, bone) via hematogenous spread (mesenchymal component).
• Staging: CT Chest/Abdomen/Pelvis or PET-CT at diagnosis and recurrence.
• Treatment: Same as GBM (Stupp). Consider doxorubicin/ifosfamide if sarcomatous component dominant (soft tissue sarcoma protocols).

12. Emerging Therapies and Clinical Trials Landscape

Participation in clinical trials is strongly recommended at all stages (NCCN Category 1).

13. Follow-Up and Survivorship Care Plan

Surveillance Imaging (MRI Brain)

• Frequency:
• Months 0-24: Every 2–3 months.
• Months 24-60: Every 3–4 months.
• Year 5+: Every 6 months (or annually if stable long-term survivor).
• Protocol: T1 pre/post, T2, FLAIR, DWI, SWI. Perfusion (PWI) and/or MRS highly recommended at baseline and for equivocal findings (pseudoprogression vs true progression).
• RANO Criteria: Standardized response assessment (Measurable enhancing / Non-measurable enhancing / Non-enhancing / Clinical).

Routine Laboratory Monitoring

• CBC with Diff: Monthly during adjuvant TMZ; q3mo thereafter (monitor lymphopenia).
• CMP (LFTs, Renal, Electrolytes): Monthly during active therapy; q3-6mo surveillance.
• Thyroid Function (TSH): Baseline, then annually (RT field includes pituitary/hypothalamus -> Central Hypothyroidism risk).
• Endocrine Panel (if pituitary/hypothalamus in field): LH, FSH, Testosterone/Estradiol, Cortisol (AM), IGF-1, Prolactin. Annually.
• Vitamin D / B12 / Folate: Annually (malabsorption, steroids, TMZ).
• CD4 Count: If prolonged lymphopenia (< 500) on steroids/TMZ.

Late Effects Surveillance

Quality of Life (QoL) & Psychosocial

• Tools: EORTC QLQ-C30 + BN20 (Brain module), FACT-Br.
• Caregiver Burden: High. Screen for burnout/depression. Respite care resources.
• Financial Toxicity: High cost of TMZ, TTFields, Bevacizumab, Novel agents. Social work/Financial navigator essential.
• Driving/Legal: Seizure freedom requirements vary by jurisdiction (usually 6-12 months). Cognitive fitness to drive assessment (On-road test). Employment disability planning.

14. Summary for Patients and Caregivers (Key Takeaways)

1. Diagnosis is Molecular: “Glioblastoma” is defined by IDH status. Ask your doctor: “Is it IDH-wildtype or IDH-mutant?” and “Is the MGMT promoter methylated?” These dictate prognosis and treatment nuance.
2. Surgery Matters: Maximal safe removal by an experienced neurosurgeon (using 5-ALA, mapping, iMRI) is the single most impactful modifiable factor for survival.
3. Standard is Stupp (+/- TTFields): Radiation + Daily Temozolomide -> 6-12 cycles Temozolomide. TTFields (Optune) adds survival benefit if you can wear it 18+ hrs/day.
4. Steroids are a Double-Edged Sword: Essential for swelling, but toxic long-term. Taper aggressively once stable. Prevent infections (Bactrim) and bone loss.
5. Seizures: Common. Levetiracetam is usually first choice (few interactions). Do not take enzyme-inducing seizure meds (Dilantin, Tegretol) if avoidable.
6. Blood Clots: High risk. Blood thinners (Lovenox/Eliquis/Xarelto) are standard after surgery and often during treatment. Report leg swelling/shortness of breath immediately.
7. Recurrence is Expected: Plan for it. Clinical trials offer the best hope at recurrence. Re-surgery, Re-radiation, Bevacizumab, Lomustine, Regorafenib, TTFields are standard options.
8. Palliative Care = Supportive Care: Involve them early (at diagnosis) for symptom management, goals of care, and family support. It does not mean “giving up.”
9. Rehabilitation is Treatment: Physical, Occupational, Speech, and Cognitive therapy preserve independence.
10. You Are Not Alone: Connect with advocacy groups (NBTS, ABTA, Musella Foundation, International Brain Tumour Alliance) for peer support, trial navigation, and financial aid.

15. Glossary of Key Terms

• Anaplasia: Loss of cellular differentiation, hallmark of malignancy.
• BBB (Blood-Brain Barrier): Endothelial tight junctions restricting drug entry; disrupted in GBM core, intact in infiltrative edge.
• CDK4/6 Inhibitors: Drugs (Palbociclib, Abemaciclib) targeting RB pathway; investigated in GBM.
• CNS5: WHO Classification of Tumours of the Central Nervous System, 5th Edition (2021).
• EOR (Extent of Resection): Volume/percentage of tumour removed.
• FLAIR (Fluid-Attenuated Inversion Recovery): MRI sequence suppressing CSF signal, best for edema/tumour infiltration.
• Gliosis: Reactive proliferation of astrocytes (scarring), mimics tumour on imaging.
• Heterogeneity: Genetic/phenotypic diversity within tumour (spatial/temporal); driver of resistance.
• IDH (Isocitrate Dehydrogenase): Metabolic enzyme; mutation produces oncometabolite 2-HG, altering epigenetics.
• KPS (Karnofsky Performance Status): 0-100 scale of functional ability. >70 = able to care for self.
• MGMT (O6-methylguanine-DNA methyltransferase): DNA repair protein removing TMZ-induced adducts. Silencing = TMZ sensitivity.
• Pseudoprogression: Transient contrast enhancement/edema 1-6 mo post-RT/TMZ mimicking progression; inflammation/demyelination.
• Pseudopalisading: Histological pattern of tumour cells aligning around necrosis.
• RANO (Response Assessment in Neuro-Oncology): Standardized criteria for glioma response.
• rCBV (Relative Cerebral Blood Volume): Perfusion MRI metric; high = angiogenesis (tumour); low = necrosis/treatment effect.
• TERT (Telomerase Reverse Transcriptase): Promoter mutations activate telomerase, immortalizing cells.
• TTFields (Tumor Treating Fields): Alternating electric fields disrupting mitosis.
• VEGF (Vascular Endothelial Growth Factor): Key driver of angiogenesis; target of Bevacizumab.

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