Glioblastoma is a highly aggressive, WHO grade IV primary brain tumor arising from astrocytes, characterized by rapid growth, necrosis, microvascular proliferation, and a poor prognosis.

Glioblastoma (GBM)

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumour in adults. The name breaks down as follows:

Glio- = glial cells (the supportive cells of the CNS, as opposed to neurons)
-blast- = immature/precursor cell (indicating high-grade, poorly differentiated)
-oma = tumour

So "glioblastoma" literally means "a tumour of immature glial cells" — and indeed, this is a highly cellular, rapidly proliferating, poorly differentiated astrocytic tumour.

Under the WHO Classification of CNS Tumours (5th Edition, 2021), glioblastoma is defined as:

A diffuse astrocytic glioma that is IDH-wildtype
WHO Grade 4
Characterised by microvascular proliferation and/or necrosis histologically, OR harbouring specific molecular alterations (TERT promoter mutation, EGFR amplification, +7/−10 chromosome copy number changes) even in the absence of classic histological features ^[1]^[2]

Key conceptual shift (WHO CNS5, 2021): Previously, the diagnosis of GBM was purely histological (Grade IV astrocytoma). Now, molecular markers are integrated into the diagnosis. An IDH-mutant astrocytoma, even if it looks like a GBM under the microscope, is classified as "Astrocytoma, IDH-mutant, Grade 4" — NOT glioblastoma. Glioblastoma is by definition IDH-wildtype. ^[1]

High Yield – WHO CNS5 Definition

Glioblastoma, IDH-wildtype, WHO Grade 4 is the only entity that carries the name "glioblastoma" in the current WHO classification. If it is IDH-mutant, it is called "Astrocytoma, IDH-mutant, Grade 4" regardless of histological appearance. This distinction is clinically critical because IDH-mutant tumours have a significantly better prognosis. ^[1]

Epidemiology

Most common primary malignant brain tumour in adults, accounting for approximately 45–50% of all malignant primary brain tumours and ~15% of all intracranial neoplasms ^[1]^[2]
Annual incidence: approximately 3–4 per 100,000 population in Western countries
In Hong Kong, brain tumours collectively account for ~2–3% of all cancers; GBM is the most common malignant subtype among adults

Peak incidence: 55–85 years old (median age at diagnosis ~64 years) ^[1]^[2]
Very rare in children (paediatric high-grade gliomas are usually molecularly distinct entities, e.g., diffuse midline glioma, H3K27-altered)

Male predominance — M:F ratio approximately 1.6:1 ^[1]^[2]

Higher incidence in Caucasians compared to Asian and African populations
However, GBM remains the most common malignant primary brain tumour across all ethnicities

Median overall survival: ~14–16 months with standard treatment (Stupp protocol) ^[1]^[2]
5-year survival rate: < 5–10%
This is one of the most lethal cancers in all of oncology — understanding why requires understanding its biology (see Pathophysiology below)

Risk Factors

Risk Factor	Explanation
Ionising radiation	The only well-established environmental risk factor. Prior cranial irradiation (e.g., for childhood leukaemia, tinea capitis) increases risk of gliomas including GBM with a latency of 10–30 years. Radiation causes DNA double-strand breaks → genomic instability → tumourigenesis ^[1]^[2]
Age	Risk increases with age; peak 55–85 years. Accumulation of somatic mutations over time (the "multi-hit" model of carcinogenesis applies)
Male sex	Hormonal/genetic factors may contribute; not fully understood

These account for < 5% of GBMs but are high-yield for exams because they connect to cancer genetics principles ^[3]:

Syndrome	Gene	Mechanism	Associated Tumours
Li-Fraumeni syndrome	TP53 (germline mutation)	Loss of the "guardian of the genome" → inability to arrest cell cycle or induce apoptosis in response to DNA damage → accumulation of mutations	Gliomas (including GBM), breast CA, sarcomas, adrenocortical CA, leukaemia
Neurofibromatosis type 1 (NF1)	NF1 (neurofibromin)	Loss of a RAS-GAP → constitutive RAS/MAPK pathway activation → uncontrolled proliferation	Optic pathway gliomas (pilocytic astrocytoma more common), but also higher-grade gliomas
Turcot syndrome (Type 1)	MLH1, PMS2 (mismatch repair genes)	Defective DNA mismatch repair → hypermutation phenotype	GBM, colorectal cancer
Lynch syndrome	Mismatch repair genes	As above	Increased glioma risk

Cancer Genetics Connection

Li-Fraumeni syndrome is the classic autosomal-dominant cancer predisposition syndrome tested in exams. Remember: germline TP53 mutation → "SBLA" cancers (Sarcoma, Breast, Leukaemia/lymphoma, Adrenal) PLUS brain tumours (especially GBM and choroid plexus carcinoma). The lecture on cancer genetics emphasises that hereditary cancer syndromes present earlier than their sporadic counterparts — so a young patient with GBM should raise suspicion for a germline predisposition. ^[3]

Mobile phone use: Despite public concern, large prospective studies (INTERPHONE, Danish cohort study, Million Women Study) have NOT demonstrated a consistent causal link
Head trauma: No convincing evidence
Dietary factors, occupational exposures: Inconsistent data

Anatomy and Function (Relevant Neuroanatomy)

Understanding GBM requires understanding WHERE it grows and WHY location matters for clinical presentation.

GBM arises within the cerebral hemispheres (supratentorial) in the vast majority of adult cases
Most common locations: frontal lobe > temporal lobe > parietal lobe > occipital lobe ^[1]^[2]
Has a predilection for white matter — it infiltrates along white matter tracts (corpus callosum is classic)
"Butterfly glioma": GBM crossing the corpus callosum to involve both hemispheres — a classic radiological appearance on MRI ^[1]
Can also arise in the brainstem, cerebellum, or spinal cord (rare in adults)

Location	Function	Deficit When Tumour Invades
Frontal lobe	Executive function, personality, Broca's area (dominant hemisphere), primary motor cortex (precentral gyrus)	Personality changes, abulia (apathy), contralateral hemiparesis, expressive aphasia (if dominant hemisphere), urinary incontinence (bilateral medial frontal)
Temporal lobe	Memory (hippocampus), Wernicke's area (dominant hemisphere), auditory processing, emotion (amygdala)	Memory impairment, receptive aphasia, contralateral upper quadrantanopia (Meyer's loop), complex partial seizures
Parietal lobe	Somatosensory cortex (postcentral gyrus), spatial awareness, calculation, language	Contralateral sensory loss, neglect syndrome (non-dominant), agraphia/acalculia/finger agnosia/R-L disorientation (Gerstmann syndrome — dominant parietal)
Occipital lobe	Primary visual cortex	Contralateral homonymous hemianopia
Corpus callosum	Interhemispheric connections	Disconnection syndromes, cognitive decline
Deep structures (internal capsule, thalamus, basal ganglia)	Motor/sensory relay, motor planning	Contralateral hemiparesis/hemisensory loss

The BBB is formed by tight junctions between brain capillary endothelial cells, astrocyte foot processes, and pericytes
In GBM, the tumour's rapid growth outstrips its blood supply → neovascularisation with abnormal, leaky vessels → BBB breakdown
This is why GBM shows ring enhancement on contrast MRI (gadolinium leaks through the disrupted BBB into the tumour periphery)
The central dark area on ring-enhancing lesions = necrosis (tumour centre has outgrown its blood supply)
BBB breakdown also causes vasogenic oedema → mass effect → clinical deterioration

Etiology and Pathophysiology

GBM's lethality comes from a convergence of biological features:

Rapid proliferation (high mitotic rate)
Diffuse infiltration into surrounding brain parenchyma (making complete surgical resection impossible)
Robust angiogenesis (but with abnormal, leaky vessels)
Intratumoral heterogeneity (different clones within the same tumour → treatment resistance)
Immune evasion (immunosuppressive tumour microenvironment)
Resistance to apoptosis

Molecular Pathogenesis

Understanding the molecular pathways is critical for understanding why GBM behaves the way it does and why targeted therapies have been largely unsuccessful.

Historically (before WHO CNS5), GBMs were classified as:

Feature	Primary (De Novo) GBM	Secondary GBM
Frequency	~90% of GBMs	~10% of GBMs
Clinical history	Arises rapidly without a precursor lesion	Arises from progression of a lower-grade glioma (WHO Grade 2 or 3 astrocytoma)
Patient age	Older (mean ~62 years)	Younger (mean ~45 years)
IDH status	IDH-wildtype	IDH-mutant
Key molecular features	EGFR amplification, PTEN loss, TERT promoter mutation, +7/−10	TP53 mutation, ATRX loss, IDH1/2 mutation
Prognosis	Worse	Better (but still poor)

Under WHO CNS5 (2021): "Secondary GBM" (IDH-mutant) is now reclassified as "Astrocytoma, IDH-mutant, Grade 4" and is no longer called glioblastoma. So when we say "glioblastoma" today, we ONLY mean the IDH-wildtype entity. ^[1]

1. EGFR (Epidermal Growth Factor Receptor) Amplification/Mutation (~60%)

EGFR is a receptor tyrosine kinase (RTK) on the cell surface
When EGF binds → receptor dimerisation → autophosphorylation → activation of RAS/MAPK and PI3K/AKT/mTOR pathways → cell proliferation, survival, migration
In GBM: EGFR gene amplification (extra copies of the gene → overexpression of the receptor) and/or EGFRvIII mutation (a constitutively active truncated form that signals without ligand binding)
Result: Continuous "grow" signals independent of external growth factors
Why this matters clinically: EGFRvIII has been a target for vaccines and antibody-drug conjugates (e.g., rindopepimut — though initial trials showed mixed results)

2. PTEN (Phosphatase and Tensin Homolog) Loss (~40%)

PTEN is a tumour suppressor that acts as a phosphatase, dephosphorylating PIP3 → inhibiting the PI3K/AKT/mTOR pathway
Loss of PTEN → unopposed PI3K/AKT/mTOR signalling → increased cell survival, proliferation, and resistance to apoptosis
Think of PTEN as the "brake" on the PI3K/AKT pathway; losing it means the car accelerates without brakes

3. TERT Promoter Mutation (~80%)

TERT = telomerase reverse transcriptase
Telomeres normally shorten with each cell division (the "biological clock") → eventually triggering senescence or apoptosis
TERT promoter mutations → upregulation of telomerase → telomere maintenance → cellular immortality
This is one of the defining molecular features for diagnosing GBM even in the absence of histological necrosis/microvascular proliferation

4. Chromosome +7/−10 (Gain of Chromosome 7, Loss of Chromosome 10)

Chromosome 7 harbours EGFR → gain = more EGFR expression
Chromosome 10 harbours PTEN → loss = less PTEN expression
This combined copy number change is highly characteristic of GBM and is one of the molecular diagnostic criteria under WHO CNS5

5. CDKN2A/B Homozygous Deletion

CDKN2A encodes p16^INK4a and p14^ARF — both critical tumour suppressors
p16^INK4a inhibits CDK4/6 → prevents RB phosphorylation → cell cycle arrest at G1/S checkpoint
p14^ARF stabilises p53 by inhibiting MDM2
Loss of CDKN2A → loss of BOTH p53 and RB tumour suppressor pathways simultaneously

6. TP53 Pathway Alterations (~30% in primary GBM)

TP53 is the "guardian of the genome" — induces cell cycle arrest, DNA repair, or apoptosis in response to DNA damage
Mutation/loss → cells with DNA damage continue to divide → genomic instability → tumour progression

Virtually all GBMs have alterations in three key pathways ^[1]^[2]:

Pathway	Normal Function	Alteration in GBM	Consequence
RTK/RAS/PI3K pathway	Growth factor signalling → proliferation	EGFR amplification, PTEN loss, PIK3CA mutation, NF1 loss	Uncontrolled proliferation and survival
TP53 pathway	DNA damage response, apoptosis	TP53 mutation, MDM2 amplification, CDKN2A deletion	Escape from apoptosis
RB pathway	Cell cycle control (G1/S checkpoint)	RB1 mutation, CDK4 amplification, CDKN2A deletion	Uncontrolled cell cycle progression

Why GBM is So Hard to Treat — The Molecular Explanation

GBM disrupts all three major tumour suppressor/oncogene pathways simultaneously. Even if you block one pathway (e.g., with an EGFR inhibitor), the tumour has multiple redundant growth signals through other pathways. This pathway redundancy and intratumoral heterogeneity (different cells within the same tumour may rely on different pathways) is why single-target therapies have failed in GBM, unlike in other cancers (e.g., imatinib in CML targeting BCR-ABL).

Pathological Features

Heterogeneous appearance: areas of grey tumour tissue mixed with yellow necrosis, red haemorrhage, and cystic changes
Poorly defined borders — tumour infiltrates beyond the visible margin
May cross midline via corpus callosum → "butterfly glioma"

The hallmark features that define WHO Grade 4 astrocytic tumour:

Microvascular proliferation ("glomeruloid" vessels)
- Multilayered endothelial cells forming tufted vessels that resemble renal glomeruli
- Driven by VEGF secretion from hypoxic tumour cells (see angiogenesis below)
Pseudopalisading necrosis
- Central areas of necrosis surrounded by a rim ("palisade") of viable tumour cells
- Why pseudopalisading? As the tumour outgrows its blood supply, central cells die (coagulative necrosis). The surviving cells at the periphery of the necrotic zone migrate outward, creating the characteristic palisading pattern
- This is virtually pathognomonic for GBM
High cellularity — densely packed, pleomorphic (variable size and shape) tumour cells
High mitotic activity — many mitotic figures
Nuclear atypia — enlarged, hyperchromatic, irregular nuclei

GFAP positive (Glial Fibrillary Acidic Protein) — confirms astrocytic lineage
IDH1 R132H immunohistochemistry NEGATIVE (by definition, since GBM is IDH-wildtype)
ATRX retained (ATRX loss is characteristic of IDH-mutant astrocytomas, not GBM)
Ki-67 (MIB-1) proliferation index: typically very high (often > 20%)

This is a critical concept linking pathophysiology to radiology:

GBM grows rapidly → central tumour outgrows its blood supply → hypoxia
Hypoxia stabilises HIF-1α (Hypoxia-Inducible Factor 1α)
HIF-1α translocates to the nucleus → upregulates VEGF (Vascular Endothelial Growth Factor)
VEGF drives neoangiogenesis — but the new vessels are structurally abnormal (lack normal BBB tight junctions, fenestrated, tortuous)
These leaky vessels allow contrast agent (gadolinium on MRI) to extravasate into the extravascular space → ring enhancement
The leaky vessels also allow plasma proteins and fluid to leak → vasogenic oedema → mass effect

This is why bevacizumab (anti-VEGF monoclonal antibody; "beva-" = a made-up prefix, "-ciz-" = chimeric, "-umab" = monoclonal antibody) was trialled in GBM: it blocks VEGF → reduces vessel permeability → reduces oedema and enhancement on MRI. However, it improves imaging appearance and symptoms (steroid-sparing effect) WITHOUT improving overall survival — the tumour adapts by infiltrating along existing vessels instead of making new ones.

GBM cells infiltrate the brain parenchyma in several ways:

Along white matter tracts (the corpus callosum, internal capsule, corona radiata)
Along the basement membrane of blood vessels (perivascular invasion)
Along the subpial surface (underneath the pia mater)
Through the extracellular matrix

The infiltrating edge of a GBM extends centimetres beyond the enhancing margin seen on MRI. This is why:

Even a "gross total resection" (removing all enhancing tumour) leaves behind infiltrating cells
Recurrence is virtually inevitable, typically at the resection margin

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme:

It removes alkyl groups from the O6 position of guanine in DNA
Temozolomide (the standard chemotherapy for GBM) works by alkylating DNA at O6-guanine → miscoding during replication → cell death
If MGMT is active (unmethylated promoter) → the enzyme repairs the damage caused by temozolomide → drug resistance
If MGMT promoter is methylated → the gene is silenced → the tumour cannot repair temozolomide-induced damage → better response to temozolomide and better prognosis

MGMT Promoter Status	Temozolomide Response	Median Survival with Stupp Protocol
Methylated (~40% of GBMs)	Good response	~21–23 months
Unmethylated (~60% of GBMs)	Poor response	~12–15 months

MGMT Methylation – Predictive AND Prognostic

MGMT promoter methylation is both predictive (predicts response to temozolomide) and prognostic (methylated patients do better regardless of treatment, suggesting MGMT methylation reflects a broader favourable tumour biology). It is the single most important molecular biomarker in GBM management. ^[1]^[2]

Classification

The modern classification of adult-type diffuse gliomas is based on layered diagnosis integrating histology + molecular markers:

Glioblastoma is ALWAYS:

IDH-wildtype
WHO Grade 4
1p/19q intact (codeletion defines oligodendroglioma)

Molecular Criteria for Diagnosing GBM (Even Without Classic Histology)

Under WHO CNS5, a diffuse astrocytic glioma that is IDH-wildtype can be diagnosed as GBM if it has ANY ONE of ^[1]:

Microvascular proliferation or necrosis on histology
TERT promoter mutation
EGFR gene amplification
Combined whole-chromosome gain of 7 and loss of 10 (+7/−10)

This means a tumour that looks like a lower-grade glioma histologically but has one of these molecular markers is upgraded to GBM — reflecting the aggressive biology.

The older WHO 2016 classification used the term "Glioblastoma, IDH-mutant" — this entity no longer exists under WHO CNS5. It is now "Astrocytoma, IDH-mutant, Grade 4."

Based on gene expression profiling (Verhaak et al., 2010), GBMs were classified into molecular subtypes. While not used in clinical practice for treatment decisions, they illustrate the heterogeneity of GBM:

Subtype	Key Features	Prognosis
Classical	EGFR amplification, no TP53 mutation	Intermediate; best response to aggressive chemoradiation
Mesenchymal	NF1 deletion/mutation, high immune cell infiltration	Worst prognosis; most aggressive
Proneural	IDH mutation, TP53 mutation, PDGFRA amplification	Better prognosis (note: IDH-mutant tumours would now be reclassified as astrocytoma, not GBM)

Clinical Features

The clinical features of GBM depend on: ^[1]^[2]

Tumour location — determines focal neurological deficits
Tumour size and growth rate — determines severity and acuity of symptoms
Raised intracranial pressure (ICP) — from mass effect (tumour + surrounding oedema)
Seizure activity — from cortical irritation

Most patients present with a relatively short history (weeks to months) because of the rapid growth rate. This contrasts with lower-grade gliomas, which may present insidiously over months to years.

GC Lecture Point – Clinical Presentation of Brain Tumours

Brain tumours can present with: (1) progressive focal neurological deficit, (2) raised ICP symptoms, (3) seizures, or (4) found incidentally. ^[1] The presentation depends on the location and rate of growth. GBM, being fast-growing, tends to present with a relatively acute/subacute history.

Symptoms

The Monro-Kellie doctrine states that the cranium is a rigid box containing brain parenchyma, CSF, and blood in a fixed volume. Any space-occupying lesion (tumour + oedema) increases volume → increased ICP.

Symptom	Pathophysiological Basis
Headache	Most common presenting symptom (~50%). Caused by traction on pain-sensitive structures: dura, blood vessels, cranial nerves (the brain parenchyma itself is insensitive to pain). Characteristically worse in the morning (because lying supine at night increases venous return to the brain → increased cerebral blood volume → worsened ICP), worsened by coughing, straining, bending forward (all increase intrathoracic/intra-abdominal pressure → impede venous drainage from the brain → raised ICP). May be described as a new-onset headache different from prior headaches
Nausea and vomiting	Raised ICP stimulates the vomiting centre in the medulla (area postrema and nucleus tractus solitarius). May be projectile (sudden, without preceding nausea) — this is classically associated with raised ICP but is non-specific. Vomiting often worst in the morning
Papilloedema	Raised ICP is transmitted along the optic nerve sheath → compresses the central retinal vein → impedes venous drainage from the retina → disc swelling. Patients may initially be asymptomatic but can develop transient visual obscurations (momentary blurring/blackouts of vision lasting seconds, often triggered by posture changes)
Visual changes	Blurred vision (from papilloedema), diplopia (from CN VI palsy — a false localising sign, because CN VI has the longest intracranial course and is stretched over the petrous ridge with raised ICP)
Cognitive/personality changes	Diffuse cerebral dysfunction from raised ICP; often mistaken for psychiatric illness or dementia, especially in frontal lobe GBM
Drowsiness/decreased consciousness	Progressive raised ICP → brainstem compression → reticular activating system dysfunction → depressed consciousness. Late sign indicating impending herniation

Why Headache is Worse in the Morning

During sleep, the patient is supine → impaired cerebral venous drainage (no gravity assist) → increased cerebral blood volume → worsened ICP. CO₂ also rises slightly during sleep (mild hypoventilation) → cerebral vasodilation → further ICP increase. On waking and becoming upright, venous drainage improves and symptoms partially abate.

Symptom	Pathophysiological Basis
New-onset seizures (~20–30% of GBM patients at presentation, higher in lower-grade gliomas)	Tumour cells infiltrating the cerebral cortex disrupt the normal balance of excitation and inhibition in cortical neuronal circuits. Peri-tumoural oedema also alters the ionic microenvironment (altered K⁺, glutamate levels) → neuronal hyperexcitability → abnormal synchronised electrical discharges. Any new-onset seizure in an adult, especially > 40 years old, must be investigated with brain imaging to exclude a mass lesion ^[1]^[2]
Focal (partial) seizures	Reflect the tumour location (e.g., temporal lobe GBM → complex partial seizures with aura; frontal lobe → motor seizures with contralateral tonic-clonic movements). May secondarily generalise
Todd's paralysis	Post-ictal focal weakness lasting minutes to hours after a focal seizure — transient neuronal exhaustion in the affected cortical area. Can mimic stroke

Red Flag – New-Onset Seizure in Adults

A first seizure in an adult over 40 years should be considered due to an intracranial mass lesion until proven otherwise. Brain imaging (preferably MRI with contrast) is mandatory. ^[1]^[2]

The specific deficit depends on which brain region the tumour involves. Symptoms are progressive (over weeks to months) because the tumour grows and infiltrates.

Location	Symptoms	Pathophysiological Basis
Frontal lobe	Personality/behavioural changes (apathy, disinhibition, poor judgment), loss of initiative, contralateral hemiparesis (if involving precentral gyrus/motor cortex), expressive (Broca's) aphasia (if dominant hemisphere, usually left), urinary incontinence (bilateral medial frontal involvement)	Disruption of prefrontal cortical circuits (executive function, personality); destruction of motor cortex or corticospinal tract; damage to Broca's area (posterior inferior frontal gyrus, dominant hemisphere)
Temporal lobe	Memory impairment, receptive (Wernicke's) aphasia (dominant hemisphere), contralateral superior quadrantanopia (Meyer's loop in temporal lobe), emotional/behavioural changes, olfactory/gustatory hallucinations (uncinate fits from medial temporal/uncal involvement)	Hippocampal/mesial temporal involvement; damage to Wernicke's area (posterior superior temporal gyrus); disruption of geniculocalcarine fibres in the temporal lobe (Meyer's loop carries inferior retinal fibres = superior visual field)
Parietal lobe	Contralateral hemisensory loss, contralateral inferior quadrantanopia, neglect syndrome (non-dominant hemisphere — patient unaware of contralateral space), Gerstmann syndrome (dominant parietal — acalculia, agraphia, finger agnosia, right-left disorientation), astereognosis, agraphaesthesia	Disruption of primary somatosensory cortex; damage to optic radiation fibres in parietal lobe; disruption of spatial awareness networks (right parietal) or dominant parietal functions
Occipital lobe	Contralateral homonymous hemianopia (with macular sparing if tip of occipital pole preserved due to dual blood supply from PCA and MCA)	Destruction of primary visual cortex (V1) in the calcarine sulcus
Corpus callosum ("butterfly glioma")	Cognitive decline, disconnection syndromes (e.g., alien hand syndrome), rapid deterioration	Disruption of interhemispheric white matter connections
Deep structures (internal capsule, basal ganglia, thalamus)	Contralateral hemiparesis (internal capsule), hemisensory loss (thalamus), movement disorders (basal ganglia)	Involvement of corticospinal tract fibres concentrated in the internal capsule; disruption of thalamic relay nuclei

Symptom	Basis
Fatigue, malaise	Metabolic demands of tumour, disruption of normal brain function, systemic effects of tumour cytokine release
Weight loss	Less common than in systemic cancers but can occur, especially with hypothalamic involvement or decreased oral intake from nausea
Mood changes, depression	Direct cerebral involvement (especially frontal/temporal) or reactive to diagnosis

Presentation	Mechanism
Tumour haemorrhage	GBM has fragile, abnormal neovascular vessels prone to rupture → intralesional haemorrhage → acute neurological deterioration mimicking a primary intracerebral haemorrhage (stroke). GBM is one of the brain tumours most likely to haemorrhage
Brain herniation	Rapid tumour growth + oedema → critical mass effect → uncal herniation (ipsilateral CN III palsy → fixed, dilated pupil; contralateral hemiparesis → progressing to bilateral), tonsillar herniation (respiratory arrest) — a neurosurgical emergency
Status epilepticus	Uncontrolled seizure activity > 5 minutes — a medical emergency requiring urgent treatment

Signs (Physical Examination Findings)

May appear well or unwell depending on disease stage
Cushing's triad (late sign of critically raised ICP): hypertension, bradycardia, irregular respiration — indicates brainstem compression and impending herniation. The mechanism: raised ICP compresses the medulla → ischaemia of vasomotor centre → sympathetic surge → hypertension → baroreceptor-mediated reflex bradycardia

Sign	Pathophysiological Basis
Papilloedema on fundoscopy	Raised ICP → impaired central retinal venous drainage → disc swelling (blurred disc margins, loss of venous pulsations, disc hyperaemia, flame haemorrhages in severe cases)
Focal motor deficit (upper motor neuron pattern: weakness with spasticity, hyperreflexia, extensor plantar/Babinski sign)	Tumour infiltrating/compressing the motor cortex or corticospinal tract → UMN lesion. Contralateral to the tumour (because corticospinal tract crosses at the medullary pyramids)
Sensory deficit (contralateral to tumour)	Involvement of somatosensory cortex or thalamocortical pathways
Visual field defects	Depends on location: homonymous hemianopia (occipital), quadrantanopia (temporal or parietal optic radiation involvement)
Aphasia	Broca's (expressive, non-fluent) if frontal; Wernicke's (receptive, fluent but nonsensical) if temporal; global if large lesion involving both
Cranial nerve palsies	CN VI (false localising sign of raised ICP); CN III if uncal herniation; other CN palsies if tumour directly involves brainstem or skull base
Gait abnormality	Motor cortex involvement → hemiparetic gait; frontal lobe → apraxic gait; raised ICP with hydrocephalus → broad-based, magnetic gait
Cognitive impairment on bedside testing (MMSE/MoCA)	Diffuse cortical involvement, raised ICP, or specific regional dysfunction
Neglect (e.g., fails to detect stimuli on one side during double simultaneous stimulation)	Non-dominant (usually right) parietal lobe involvement

Herniation Type	Key Signs	Mechanism
Uncal herniation	Ipsilateral fixed dilated pupil (CN III compression), contralateral hemiparesis, decreasing consciousness	Medial temporal lobe (uncus) herniates through the tentorial notch → compresses CN III (parasympathetic fibres run superficially → lost first → pupil dilation) and ipsilateral cerebral peduncle
Subfalcine herniation	Contralateral leg weakness (ACA territory compression)	Cingulate gyrus herniates under the falx cerebri → compresses ACA
Tonsillar herniation	Respiratory arrest, death	Cerebellar tonsils herniate through foramen magnum → compress medulla (respiratory centre)

Clinical Pearl – False Localising Signs in Raised ICP

CN VI palsy (lateral rectus palsy → cannot abduct the eye → convergent squint and diplopia) is a classic "false localising sign" of raised ICP. It does NOT mean the tumour is at the pons or CN VI nucleus. The long intracranial course of CN VI makes it susceptible to traction/compression from diffusely raised ICP. Similarly, Kernohan's notch phenomenon — contralateral cerebral peduncle is pressed against the opposite tentorial edge during uncal herniation → ipsilateral (not contralateral) hemiparesis — another false localising sign.

High Yield Summary

Definition: GBM = IDH-wildtype, WHO Grade 4 diffuse astrocytic glioma. The most common and most lethal primary malignant brain tumour in adults.

Epidemiology: Peak age 55–85, M > F (1.6:1), median survival ~14–16 months.

Risk Factors: Only established environmental RF = ionising radiation. Genetic syndromes: Li-Fraumeni (TP53), NF1, Turcot syndrome (MMR genes).

Key Molecular Features: EGFR amplification, PTEN loss, TERT promoter mutation, +7/−10, CDKN2A deletion. Three core pathways disrupted: RTK/RAS/PI3K, TP53, RB pathways.

MGMT promoter methylation: Most important biomarker — methylated (~40%) → better response to temozolomide, better prognosis.

Histology: Microvascular proliferation + pseudopalisading necrosis are the hallmarks. GFAP+, IDH-wildtype.

Clinical Features:

Raised ICP: Headache (worse in morning, with coughing/straining), nausea/vomiting, papilloedema, CN VI palsy
Seizures: New-onset seizure in adult > 40 = brain imaging mandatory
Progressive focal deficits: Depends on tumour location (frontal → personality change/hemiparesis/Broca's aphasia; temporal → memory/Wernicke's aphasia; parietal → sensory/neglect; occipital → hemianopia)
Acute presentations: Tumour haemorrhage, herniation, status epilepticus
Signs: UMN pattern weakness, visual field defects, papilloedema, Cushing's triad (late)

Classic Radiology: Ring-enhancing lesion with central necrosis, surrounding vasogenic oedema, crossing corpus callosum ("butterfly glioma").

Active Recall - Glioblastoma: Definition, Epidemiology, Pathophysiology, and Clinical Features

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf ^[2] Senior notes: Maksim Medicine Notes.pdf; Ryan Ho Neurology.pdf ^[3] Lecture slides: GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (File 1).pdf; GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (File 2).pdf; GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (Notes).pdf

Differential Diagnosis of Glioblastoma

When a patient presents with the classic GBM picture — a middle-aged or elderly adult with progressive focal neurological deficit, new-onset seizures, and/or raised ICP symptoms over weeks to months, and brain imaging reveals a ring-enhancing intra-axial mass with central necrosis and surrounding vasogenic oedema — the differential diagnosis revolves around one core question:

What else can produce a ring-enhancing (or heterogeneously enhancing) intra-axial brain lesion?

The mnemonic "MAGIC DR" is useful:

M – Metastasis
A – Abscess (brain abscess)
G – Glioma (high-grade, including GBM itself)
I – Infarct (subacute, with luxury perfusion)
C – Contusion / haemorrhage (resolving)
D – Demyelination (tumefactive)
R – Radiation necrosis / lymphoma (CNS)

However, the differential also depends on context — the patient's age, immune status, cancer history, travel/infection history, and the exact imaging characteristics all help narrow the list. Let's work through this systematically.

1. Neoplastic Differentials

High Yield – GC Lecture Point

Brain metastases are the commonest intracranial tumour in adults overall ^[1]^[4]. When you see a ring-enhancing brain lesion, metastasis must ALWAYS be considered, especially if there is a known or suspected primary malignancy. 10–15% of solitary cerebral mass lesions in a patient with pre-existing cancer are NOT metastases — so even in cancer patients, you cannot assume it is a met without further workup ^[4].

Feature	GBM	Brain Metastasis
Number of lesions	Usually solitary (single large lesion); multifocal GBM exists but is rare	Often multiple (though can be solitary in ~50%); if multiple lesions in different vascular territories → strongly favours mets
Location	Deep white matter, crosses midline via corpus callosum ("butterfly glioma")	Grey-white matter junction (watershed areas) — because tumour cell clumps lodge where vessel calibre narrows ^[4]; 80% cerebral hemispheres, ~15% cerebellum, ~5% brainstem ^[4]
Imaging appearance	Irregular ring enhancement, central necrosis, infiltrative irregular borders, extensive surrounding oedema	Well-circumscribed, round, ring- or homogeneously enhancing, large volume of oedema disproportionate to lesion size ^[4]
Corpus callosum crossing	Classic for GBM (butterfly glioma)	Very rare for metastasis
History	No known primary cancer; rapid progressive neurological decline	Known or suspected extracranial malignancy; may present with systemic symptoms (weight loss, cough, haemoptysis, breast lump)
Common primaries	N/A	Lung (16–20%), breast (5%), RCC (7–10%), colorectal (1–2%), melanoma (7%) ^[4]; in Hong Kong, lung and breast are the commonest
Route of spread	N/A	Haematogenous (NOT lymphatic — the brain lacks conventional lymphatic drainage) ^[4]
Age	Typically 55–85	Any age; depends on the primary cancer

How to distinguish clinically and radiologically:

Multiple lesions in different vascular territories = metastasis until proven otherwise
Solitary lesion crossing the corpus callosum = GBM until proven otherwise
A thorough systemic cancer screen (CT chest/abdomen/pelvis, tumour markers) is essential when metastasis is suspected
If doubt remains, biopsy is indicated — histological examination remains the most important component of diagnostic evaluation of brain tumours ^[5]^[6]

Primary CNS lymphoma is a non-Hodgkin lymphoma (almost always diffuse large B-cell lymphoma) confined to the CNS. It is critical to distinguish from GBM because the management is completely different (no surgery for PCNSL; treatment is high-dose methotrexate-based chemotherapy ± whole-brain radiotherapy).

Feature	GBM	Primary CNS Lymphoma
Patient population	Immunocompetent elderly (55–85)	Immunocompromised (HIV/AIDS, post-transplant) OR immunocompetent elderly (60–70s); incidence rising in immunocompetent patients
Number of lesions	Usually solitary	Often solitary in immunocompetent; multiple in immunocompromised
Location	Hemispheric white matter	Periventricular (deep subcortical white matter, corpus callosum, basal ganglia) — has a predilection for deep midline structures
Enhancement	Ring enhancement with central necrosis	Homogeneous dense enhancement in immunocompetent (because the tumour is densely cellular with intact BBB breakdown); ring enhancement in immunocompromised (due to necrosis from rapid growth with poor immune response)
DWI (Diffusion-Weighted Imaging)	Variable	Prominent diffusion restriction (high cellularity → restricted water diffusion) — classically a/w prominent diffusion restriction on DWI ^[4]^[7]
T2-weighted MRI	Heterogeneous high signal	T2W iso- to hypointense (unlike most brain tumours which are T2-bright; the dense cellularity of PCNSL makes it relatively dark on T2) ^[7]
Steroid response	Oedema improves, tumour unchanged	"Ghost tumour" — may dramatically shrink or even disappear with corticosteroids (steroids are lympholytic), then recur. This is why you should never give steroids before biopsy if PCNSL is in the differential
CSF	Usually non-diagnostic	May show malignant lymphocytes, elevated protein, elevated β2-microglobulin

Clinical Pearl – Steroids and PCNSL

If PCNSL is in your differential, avoid giving dexamethasone before biopsy (unless the patient is herniating and you have no choice). Steroids cause rapid tumour lysis → the biopsy may show only necrosis and reactive changes → non-diagnostic. This is a classic exam pitfall.

As discussed in the classification section, this was previously called "secondary GBM." While the clinical presentation may be similar to GBM, the key distinguishing features are:

Feature	GBM (IDH-wildtype)	Astrocytoma, IDH-mutant, Grade 4
Age	Older (median ~64)	Younger (median ~45)
History	De novo, no prior known glioma	Often a history of a previously diagnosed lower-grade glioma that has progressed/transformed
IDH status	IDH-wildtype	IDH-mutant (IDH1 R132H detectable on IHC or sequencing)
ATRX	Retained	Lost
Prognosis	Worse (median ~14–16 months)	Better (median ~3–4 years with standard treatment)

The distinction is made on molecular testing (IDH mutation status), not histology alone. This is why tissue diagnosis with molecular profiling is essential.

Entity	Key Distinguishing Features
Anaplastic astrocytoma (IDH-mutant, Grade 3)	IDH-mutant; enhances less intensely; no necrosis; younger patients
Anaplastic oligodendroglioma (IDH-mutant, 1p/19q-codeleted, Grade 3)	1p/19q codeletion is defining; calcification common; frontal lobe predilection; better prognosis; classically presents with seizures in younger adults
Diffuse midline glioma, H3K27-altered	Occurs in midline structures (thalamus, brainstem/pons, spinal cord); children and young adults; aggressive (WHO Grade 4); do NOT confuse with GBM — completely different molecular entity
Ependymoma	Typically arise from ependymal lining of ventricles; infratentorial (4th ventricle) in children, supratentorial in adults; can show calcification and cystic changes
Pleomorphic xanthoastrocytoma (PXA)	Young patients (children/young adults); superficial/cortical location; temporal lobe predilection; cystic with mural nodule; much better prognosis
Gliosarcoma	A variant of GBM (IDH-wildtype, Grade 4) with a biphasic pattern (glial + sarcomatous components); similar prognosis and management to GBM; may have more dural involvement and be more circumscribed than typical GBM

2. Infectious Differentials

Brain abscess is the most important non-neoplastic mimic of GBM on imaging.

Feature	GBM	Brain Abscess
Clinical context	No fever or infection source; subacute progressive deficit	Fever, systemic infection, recent neurosurgery, sinusitis/otitis media, dental abscess, endocarditis, congenital heart disease (R→L shunt), immunosuppression
Imaging — Ring enhancement	Irregularly thick enhancing wall, often with nodular areas	Smooth, thin, uniform enhancing ring (the abscess capsule is a smooth fibrous wall)
DWI	Variable diffusion restriction (often not prominently restricted, or only in areas of dense cellularity)	Bright on DWI / low ADC (restricted diffusion) — pus contains densely packed inflammatory cells and debris restricting water diffusion. This is one of the most reliable distinguishing features ^[8]
MR spectroscopy	Elevated choline (cellular membrane turnover), reduced NAA (neuronal loss), choline/NAA ratio elevated	Amino acid peaks (valine, leucine, isoleucine at 0.9 ppm), succinate and acetate peaks — products of bacterial metabolism. Reduced choline and NAA
Surrounding oedema	Present	Present (can be extensive)
Perilesional satellite lesions	May be present (infiltrating tumour)	May have daughter abscesses
Time course	Weeks to months	Days to weeks (more acute); patient may be systemically unwell

High Yield – DWI is the Key to Abscess vs GBM

Restricted diffusion (bright on DWI, dark on ADC map) within the cavity strongly favours abscess over GBM. The central necrotic cavity of GBM typically does NOT show true restricted diffusion (it contains acellular necrotic debris with relatively free water movement), whereas pus is densely cellular → restricted diffusion. This is perhaps the single most useful imaging feature to differentiate the two.

Feature	Details
Context	HIV/AIDS with CD4 < 100 — the most common CNS mass lesion in AIDS patients
Imaging	Multiple ring-enhancing lesions, often in basal ganglia; "eccentric target sign" (eccentric nodule along the enhancing ring)
Distinction from GBM	Multiple lesions in an immunocompromised patient; respond to empirical anti-toxoplasma therapy (pyrimethamine + sulfadiazine) within 2–3 weeks — trial of treatment is a diagnostic strategy
Distinction from PCNSL	PCNSL in AIDS → ring-enhancing, periventricular. Thallium-201 SPECT or FDG-PET can help: PCNSL is metabolically active (avid uptake), toxoplasmosis is not

Feature	Details
Context	Endemic areas (including parts of Asia); immunosuppression; extracranial TB
Imaging	Ring-enhancing lesion(s), often with surrounding oedema; may show central calcification; can be multiple
Distinction from GBM	History of TB exposure/contact, positive QuantiFERON/Mantoux, evidence of pulmonary or miliary TB; multiple lesions; responds to anti-TB therapy

3. Inflammatory / Demyelinating Differentials

This is a critical differential because it can look almost identical to GBM on imaging but has a completely different management (immunomodulation, not surgery/chemoradiation).

Feature	GBM	Tumefactive Demyelination
Patient age	55–85 typically	Younger (20–40, typical MS age)
History	Progressive, no prior neurological episodes	May have a history of relapsing-remitting neurological episodes (suggesting MS); may be the first presentation
Imaging — Enhancement	Ring enhancement, thick and irregular	Incomplete ring enhancement ("open ring sign" — the enhancing arc opens towards the cortex/grey matter, while the non-enhancing portion faces the white matter). This is fairly specific for demyelination ^[8]
Imaging — Mass effect	Significant oedema and mass effect	Less mass effect than expected for the size of the lesion (disproportionately little oedema)
DWI	Variable	May show peripheral restricted diffusion (at the leading edge of demyelination)
MR spectroscopy	Elevated choline/NAA ratio	May show elevated choline but also elevated glutamate/glutamine (reflecting excitotoxicity)
CSF	Usually non-specific	Oligoclonal bands, elevated IgG index (suggesting intrathecal immunoglobulin synthesis — classic for MS)
Other brain lesions	No	May have other white matter lesions typical of MS (Dawson fingers, periventricular/juxtacortical/infratentorial lesions)

Clinical Pearl – The Open Ring Sign

The "open ring sign" on post-contrast MRI (incomplete ring of enhancement with the gap facing the grey matter) is relatively specific for tumefactive demyelination and helps distinguish it from GBM (which has a closed, irregular ring). However, it is not always present, and biopsy may still be needed.

May present with enhancing intracranial lesions, cranial neuropathies, and leptomeningeal enhancement
Look for systemic features of sarcoidosis (bilateral hilar lymphadenopathy, skin lesions, uveitis, elevated ACE)
Biopsy shows non-caseating granulomas (vs caseating in TB)

4. Vascular Differentials

A cerebral infarct in the subacute phase (1–8 weeks) can show ring or gyral enhancement due to BBB breakdown ("luxury perfusion")
Distinguished from GBM by: conforming to a vascular territory, acute onset (stroke-like), known vascular risk factors, DWI positive acutely, clinical improvement over time

A resolving haematoma can show peripheral ring enhancement at 1–6 weeks (due to neovascularisation at the periphery of the haematoma)
Distinguished from GBM by: acute onset, blood products on MRI following a characteristic signal evolution (T1/T2 changes through stages of haemoglobin breakdown), known hypertension/coagulopathy
Caution: GBM itself can present with intratumoral haemorrhage mimicking a primary ICH — if there is any atypical feature (disproportionate oedema, irregular margins, enhancement remote from the bleed), consider underlying tumour and follow up with imaging ^[4]

5. Other Important Differentials

These are important differentials when the mass is in or near the sella turcica:

Feature	GBM	Pituitary Macroadenoma	Craniopharyngioma
Location	Hemispheric parenchyma	Sella turcica (intrasellar + suprasellar extension)	Suprasellar (can be intra- or suprasellar)
Enhancement	Ring, heterogeneous	Homogeneous (most)	Heterogeneous, cystic
Calcification	Rare	Rare	50% calcified (a key distinguishing feature) ^[9]
Presentation	Focal deficit, seizures, raised ICP	Bitemporal hemianopia, headache, hormonal dysfunction (hyper- or hyposecretion) ^[9]	Growth retardation (children), diabetes insipidus, bitemporal hemianopia, hydrocephalus ^[9]
Age	55–85	Adults	Bimodal: children (50% symptomatic in childhood) and adults 20–40 ^[9]

Feature	GBM	Meningioma
Location	Intra-axial (within brain parenchyma)	Extra-axial (arises from meninges, compresses brain from outside)
Enhancement	Ring, heterogeneous	Strong homogeneous enhancement with a dural tail
MRI signal	Heterogeneous T1/T2	T1-hypo/isointense, T2-iso/hyperintense ^[7]
CSF cleft	Absent	Present (CSF/vessel interposed between mass and brain → confirms extra-axial location)
Oedema	Extensive	Variable (can be significant with large meningiomas)
Growth rate	Rapid	Slow-growing (often incidental finding)
Calcification	Rare	Common

Intra-axial vs Extra-axial – Fundamental Distinction

The single most important first step when evaluating a brain mass on imaging is to determine whether it is intra-axial (within the brain parenchyma → gliomas, metastases, abscesses) or extra-axial (outside the brain, compressing it from the surface → meningiomas, schwannomas). The presence of a CSF cleft, dural tail, and brain displacement points to an extra-axial lesion. GBM is always intra-axial.

Diagnosis	Key Distinguishing Features from GBM
Brain metastasis	Multiple lesions; grey-white junction; history of systemic cancer; disproportionate oedema; haematogenous spread
Primary CNS lymphoma	Homogeneously enhancing (immunocompetent); periventricular; T2 iso/hypointense; prominent DWI restriction; responds to steroids; biopsy before steroids
Brain abscess	Fever/infection source; smooth thin ring enhancement; restricted diffusion on DWI; amino acid peaks on MRS
Tumefactive demyelination	Younger age; open ring sign; less mass effect; oligoclonal bands in CSF; other MS lesions
Toxoplasmosis	AIDS with CD4 < 100; multiple basal ganglia lesions; responds to empirical anti-toxoplasma Rx
Astrocytoma, IDH-mutant, Grade 4	Younger; prior lower-grade glioma history; IDH-mutant on molecular testing; better prognosis
Meningioma	Extra-axial; dural tail; homogeneous enhancement; CSF cleft
Subacute infarct	Vascular territory distribution; acute onset; DWI positive acutely
Resolving haematoma	Acute onset; characteristic MRI signal evolution of blood products

MRI with contrast is the imaging modality of choice — characterises location, enhancement pattern, signal characteristics
Advanced MRI techniques help narrow the differential:
- DWI/ADC: restricted diffusion → abscess or lymphoma
- MR spectroscopy: choline elevation → tumour; amino acid peaks → abscess; NAA loss → neuronal destruction
- MR perfusion: elevated rCBV → high-grade glioma or metastasis; reduced rCBV → abscess, demyelination
CT chest/abdomen/pelvis if metastasis is suspected (search for primary)
HIV testing if immunocompromised differentials are considered (PCNSL, toxoplasmosis)
Ultimately, histological examination via biopsy or surgical resection remains the gold standard for definitive diagnosis ^[5]^[6] — histological examination of biopsy specimen remains the most important component of diagnostic evaluation of brain tumours ^[5]

High Yield Summary – Differential Diagnosis of GBM

Always consider brain metastasis — the commonest intracranial tumour overall. Multiple lesions at grey-white junction with known cancer history strongly favours mets. But 10–15% of solitary masses in cancer patients are NOT mets.
Primary CNS lymphoma — homogeneous enhancement, periventricular, restricted diffusion on DWI, T2 iso/hypointense. Do NOT give steroids before biopsy (ghost tumour phenomenon).
Brain abscess — the key differentiator is restricted diffusion on DWI (bright DWI, dark ADC). Clinical context of fever/infection source is critical.
Tumefactive demyelination — younger patient, incomplete "open ring" enhancement, less mass effect, look for other MS lesions and oligoclonal bands.
Astrocytoma, IDH-mutant, Grade 4 — younger, may have prior glioma history; distinguished by IDH mutation testing (not histology alone).
Intra-axial vs extra-axial is the first step: meningioma (extra-axial, dural tail, homogeneous enhancement) should not be confused with GBM (intra-axial).
Tissue diagnosis with molecular profiling is essential for definitive diagnosis and guides treatment. Histological examination remains the gold standard.

Active Recall – Differential Diagnosis of Glioblastoma

References

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf ^[4] Senior notes: Ryan Ho Neurology.pdf (pp. 164–165, brain tumours/metastasis sections) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1258–1264, brain tumours) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 530–534, brain tumours) ^[7] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 431, MRI appearance of common tumours) ^[8] Senior notes: Ryan Ho Radiology.pdf (p. 17, neuroimaging approach) ^[9] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (pp. 1, 6)

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Glioblastoma

Diagnostic Criteria — WHO CNS5 (2021)

Unlike many medical conditions that have neat clinical diagnostic criteria (e.g., Jones criteria for rheumatic fever, Duke criteria for endocarditis), the diagnosis of GBM is fundamentally an integrated histomolecular diagnosis. You cannot diagnose GBM on clinical features or imaging alone — you need tissue.

High Yield – GC Lecture Point

Histological examination of biopsy specimen remains the most important component of diagnostic evaluation of brain tumours. ^[5]^[6] No matter how classic the MRI looks, tissue confirmation with molecular profiling is mandatory before starting definitive treatment.

A brain tumour is classified as Glioblastoma, IDH-wildtype, WHO Grade 4 when ALL of the following are met ^[1]^[5]^[6]:

1. Histological Criteria — Diffuse Astrocytic Glioma

The tumour must demonstrate features of a diffuse astrocytic glioma (infiltrative growth pattern, GFAP-positive astrocytic morphology)
It must NOT show oligodendroglial features (no 1p/19q codeletion)

2. Molecular Criteria — IDH-wildtype

IDH1 and IDH2 must be wildtype (no mutation detected)
Tested by:
- Immunohistochemistry (IHC) for IDH1 R132H (the most common IDH1 mutation, ~90% of IDH-mutant gliomas) — if negative:
- IDH1/2 sequencing (to exclude rarer IDH mutations) — particularly important in patients < 55 years (where IDH-mutant tumours are more common)
- In patients ≥ 55 years with a classic GBM on histology and negative IDH1 R132H IHC, sequencing may be omitted (the pre-test probability of an IDH mutation is very low)

3. Grading Criteria — WHO Grade 4

The tumour is assigned Grade 4 if it has at least ONE of the following ^[1]:

Criterion	Type	Explanation
Microvascular proliferation	Histological	Multilayered endothelial proliferation forming "glomeruloid" tufts — driven by VEGF from hypoxic tumour cells
Necrosis (especially pseudopalisading)	Histological	Central coagulative necrosis rimmed by viable tumour cells — the tumour outgrew its blood supply
TERT promoter mutation	Molecular	Upregulates telomerase → cellular immortality. Present in ~80% of GBMs
EGFR gene amplification	Molecular	Extra copies of EGFR → constitutive growth signalling
Combined +7/−10 (whole-chromosome gain of 7, loss of 10)	Molecular	Gain of chr7 (EGFR locus) + loss of chr10 (PTEN locus) — highly characteristic

The key paradigm shift: Under WHO CNS5, a diffuse astrocytic glioma that is IDH-wildtype and has ANY ONE of the three molecular markers (TERT promoter mutation, EGFR amplification, or +7/−10) is diagnosed as GBM Grade 4 even if it looks histologically like a lower-grade glioma (i.e., no necrosis or microvascular proliferation on biopsy). This prevents under-grading of molecularly aggressive tumours. ^[1]

Exam Pitfall – The 'Histologically Low-Grade but Molecularly High-Grade' Glioma

A diffuse astrocytic glioma that is IDH-wildtype with TERT promoter mutation but NO necrosis or microvascular proliferation on biopsy is still classified as GBM, IDH-wildtype, Grade 4 — NOT as a lower-grade astrocytoma. The molecular biology trumps the histological appearance. This is a frequently tested concept.

The practical diagnostic pathway for a patient with a suspected brain tumour proceeds in a logical sequence. The overarching principle is: clinical suspicion → imaging → tissue diagnosis → integrated molecular classification.

Step-by-Step Walkthrough

Step 1: Clinical Suspicion

A patient presenting with progressive focal neurological deficit, new-onset seizures (especially in adults > 40 years), or symptoms/signs of raised ICP should trigger urgent brain imaging ^[1]^[4]
Red flags: rapidly progressive symptoms (weeks), personality change, new seizure in an adult, headache with papilloedema

Step 2: Emergency CT Brain (Non-Contrast)

CT brain is the first-line imaging modality — rapid, widely available, good at detecting acute haemorrhage, mass effect, hydrocephalus, and calcification ^[4]^[10]
CT brain findings in GBM:
- Hypodense or mixed-density intra-axial mass (reflecting necrosis, cellular tumour, and oedema)
- Mass effect — midline shift, effacement of sulci, compression of ipsilateral ventricle
- Surrounding hypodense oedema (vasogenic oedema appears hypodense on CT)
- Calcification is rare in GBM (if calcification is prominent, think oligodendroglioma or meningioma)
- May show haemorrhage (hyperdense areas) — GBM is one of the tumours most prone to bleeding

Step 3: MRI Brain with Gadolinium Contrast — The Definitive Imaging Modality

MRI with contrast is generally preferred over CT for brain tumour characterisation because it provides better soft tissue delineation and is especially useful at the skull base, craniocervical junction, and brainstem ^[7].

Step 4: Advanced MRI Techniques (Pre-operative planning and differential diagnosis)

Step 5: Multidisciplinary Team (MDT) Discussion

Neuro-oncology MDT (neurosurgeon, neuro-oncologist, radiation oncologist, neuropathologist, neuroradiologist) reviews imaging and decides the tissue acquisition strategy

Step 6: Tissue Acquisition

Maximal safe surgical resection is preferred whenever feasible — serves both diagnostic AND therapeutic purposes (see Management section) ^[5]^[6]
Stereotactic needle biopsy is used when the tumour is in a surgically inaccessible or eloquent location (e.g., brainstem, deep thalamic, dominant hemisphere speech areas) ^[5]

Step 7: Integrated Histomolecular Diagnosis (WHO CNS5)

Step 8: MGMT Promoter Methylation Testing — guides temozolomide use and prognosis (see below)

Investigation Modalities — Detailed Findings and Interpretation

1. Neuroimaging

Finding	Interpretation	Pathophysiological Basis
Hypodense/mixed-density intra-axial mass	Tumour with areas of necrosis and viable tissue	Rapidly growing tumour with heterogeneous cellularity; necrosis is hypodense, cellular tumour is isodense/slightly hyperdense
Ring enhancement after contrast	Breakdown of BBB in the tumour periphery	Neovascular vessels lack tight junctions → contrast leaks through → enhances the viable tumour rim. Central necrotic core does not enhance (no viable vessels) ^[4]^[7]
Surrounding hypodensity	Vasogenic oedema	Leaky tumour vessels allow plasma proteins to extravasate → osmotic gradient pulls water into the extracellular space of white matter
Mass effect (midline shift, ventricular compression)	Space-occupying effect of tumour + oedema	Monroe-Kellie doctrine: expanding mass displaces other intracranial contents
Hyperdense areas within the mass	Haemorrhage	Fragile neovascular tumour vessels prone to spontaneous rupture
Normal brain tissue does not enhance (because intact BBB excludes contrast)	Enhancement indicates: (1) structures outside the BBB (e.g., meningioma, choroid plexus, pituitary), or (2) disruption of the BBB (high-grade tumours, inflammation, stroke) ^[4]	Only when the BBB is broken can gadolinium/iodinated contrast leak into the brain parenchyma

GC Lecture Point – Enhancement on Brain Imaging

Normal brain tissue does not enhance due to the intact blood-brain barrier. Enhancement on brain imaging indicates structures outside the BBB (e.g., meningioma) or disruption of the BBB (e.g., high-grade tumours, inflammation). ^[4] This is the fundamental principle underlying all contrast-enhanced brain imaging.

Sequence	GBM Findings	Why This Sequence Matters
T1-weighted (T1W)	Hypointense (dark) mass	T1W: water-containing tissues appear dark. Tumour cells and oedema have high water content → low T1 signal. Blood products may be hyperintense on T1 (methaemoglobin)
T1W + Gadolinium (T1W+Gd)	Irregular, thick ring enhancement with central non-enhancing necrosis — the classic "ring-enhancing lesion" ^[7]	Gadolinium shortens T1 → enhancing tissues appear bright on T1W. The enhancing rim = viable tumour with BBB disruption. Central dark area = necrosis. GBM enhancement is characteristically thick and irregular (vs thin, smooth ring of abscess)
T2-weighted (T2W) / FLAIR	Hyperintense (bright) signal in tumour and surrounding vasogenic oedema ^[7]	T2W/FLAIR: water appears bright. Both tumour and oedema contain excess water → high T2 signal. FLAIR suppresses CSF signal → better visualisation of periventricular oedema. The T2/FLAIR signal extends well beyond the enhancing rim — this represents a combination of vasogenic oedema AND infiltrating tumour cells (important for surgical and radiation planning)
Diffusion-Weighted Imaging (DWI) / ADC map	Variable: areas of mildly restricted diffusion within the cellular tumour; central necrosis typically does NOT show true restriction	DWI detects restricted Brownian motion of water molecules. High cellularity restricts diffusion (water molecules cannot move freely). However, GBM is less restrictive than abscess (pus) or lymphoma. If there is marked restriction in the cavity → think abscess, not GBM
MR Perfusion (dynamic susceptibility contrast, DSC)	Elevated relative cerebral blood volume (rCBV) in the enhancing tumour	High-grade tumours have increased angiogenesis → increased blood volume. rCBV is useful for: (1) grading gliomas (high-grade > low-grade), (2) distinguishing tumour recurrence from radiation necrosis (tumour: high rCBV; radiation necrosis: low rCBV)
MR Spectroscopy (MRS)	Elevated choline (Cho), decreased N-acetylaspartate (NAA), elevated Cho/NAA ratio. May show lipid/lactate peaks (necrosis)	Choline = marker of membrane turnover (high in proliferating tumour cells). NAA = marker of neuronal integrity (reduced when neurons are destroyed/displaced by tumour). Lipid/lactate = anaerobic metabolism and necrosis. MRS helps differentiate tumour from abscess (amino acid peaks) and from demyelination

MRI appearance of GBM in one sentence: Low T1W signal, heterogeneous ring enhancement with central necrosis on T1+Gd, high T2W/FLAIR signal extending beyond the enhancing rim, with elevated rCBV on perfusion and elevated choline on spectroscopy ^[4]^[7].

These are used for pre-operative planning, not for diagnosis per se ^[7].

Modality	Purpose	How It Works
Functional MRI (fMRI)	Identify important cortical areas (motor, language, visual) to guide surgical resection and avoid eloquent cortex ^[7]	Measures blood oxygen level-dependent (BOLD) signal changes during specific tasks (e.g., finger tapping for motor cortex, word generation for Broca's area). Active cortical areas have increased blood flow → increased oxyhaemoglobin → signal change on MRI
MRI Diffusion Tensor Imaging (DTI, tractography)	Identify important white matter tracts (corticospinal tract, arcuate fasciculus, optic radiation) to guide surgical resection ^[7]	DTI measures the directionality of water diffusion along white matter fibre bundles (anisotropic diffusion). Reconstructs 3D tract maps superimposed on structural MRI → surgeon can see which tracts are displaced/invaded by the tumour

GC Lecture Point – Pre-Operative Functional Imaging

fMRI identifies important cortical areas and DTI/tractography identifies important tracts to guide surgical resection. ^[7] These are essential for planning maximal safe resection — the goal is to remove as much tumour as possible while preserving neurological function.

Modality	Role	Key Points
SPECT scan (e.g., Thallium-201)	Distinguish benign from malignant brain lesions, predict histological grade, select areas for biopsy ^[5]^[6]	Utilises various isotopes to detect BBB abnormalities. Malignant tumours show increased uptake. Useful when MRI is equivocal
FDG PET-CT	Limited role for primary brain tumours (high background brain metabolic activity makes interpretation difficult); more useful for systemic staging if metastasis is suspected	PET-CT is not good for brain as the background activity is too hypermetabolic ^[4] — unlike lung or liver, the normal brain avidly takes up FDG, making it hard to distinguish tumour from normal tissue. Amino acid PET (e.g., methionine-PET, FET-PET) is better for brain tumour evaluation
Amino acid PET (11C-methionine PET, 18F-FET PET)	Better than FDG-PET for brain tumours; helps delineate tumour extent, distinguish recurrence from treatment effect	Amino acid tracers have low background uptake in normal brain → better tumour-to-background contrast. Increasingly used in neuro-oncology centres
CT chest/abdomen/pelvis	Exclude brain metastasis as the cause of the brain lesion — search for an extracranial primary	Mandatory when metastasis is in the differential (multiple lesions, grey-white junction location, known cancer history) ^[4]^[10]

There is no blood test that diagnoses GBM. However, baseline blood tests are essential for:

Pre-operative assessment
Identifying contraindications to treatment
Detecting paraneoplastic/systemic complications

Investigation	Rationale
CBC	Baseline before surgery/chemotherapy; detect anaemia, thrombocytopaenia (increased bleeding risk intraoperatively); detect leukocytosis (infection, steroid use)
Coagulation profile (PT, APTT, INR)	Pre-operative assessment; some brain tumours (especially GBM) can be associated with coagulopathy; patients on anticoagulants need reversal
LRFT (Liver and Renal Function Tests)	Baseline before chemotherapy (temozolomide is hepatically metabolised and can cause hepatotoxicity); renal function affects drug dosing
Electrolytes (Na, K, Ca)	Detect SIADH (hyponatraemia — can occur with any CNS pathology); detect hypercalcaemia (if metastasis suspected)
Blood glucose	Steroids (dexamethasone, universally given for peri-tumoural oedema) cause hyperglycaemia; baseline assessment
Serum LDH	Non-specific tumour marker; may be elevated in high-grade tumours; used in some prognostic models
Tumour markers (CEA, AFP, CA 19-9, PSA etc.)	Only if metastasis is suspected — to search for an occult primary cancer
HIV test	If immunocompromised differentials are considered (PCNSL, toxoplasmosis)

3. Histopathology — The Gold Standard

Tissue diagnosis is the definitive investigation ^[5]^[6]. The specimen is obtained via:

Method	When Used	Advantage	Disadvantage
Maximal safe surgical resection (craniotomy)	Operable tumour in non-eloquent location; serves both diagnostic AND therapeutic purpose	Large tissue sample for comprehensive analysis; simultaneous cytoreduction; intraoperative diagnosis (frozen section)	Major neurosurgical procedure; risk of neurological deficit, haemorrhage, infection
Stereotactic needle biopsy	Deep-seated, eloquent location, or poor surgical candidate	Minimally invasive; can sample specific areas under image guidance	Small tissue sample (may miss heterogeneous areas); non-therapeutic; ~2–5% complication rate (haemorrhage, infection)

Feature	Finding in GBM	Significance
Cellularity	High cellularity	Dense tumour cell population → aggressive biology
Mitotic activity	Numerous mitotic figures	High proliferation rate
Nuclear atypia	Marked pleomorphism (variable size, shape, hyperchromatic nuclei)	Poorly differentiated
Microvascular proliferation	Glomeruloid endothelial proliferation	VEGF-driven neoangiogenesis; WHO Grade 4 criterion
Pseudopalisading necrosis	Central necrosis rimmed by viable tumour cells	Tumour outgrows blood supply; virtually pathognomonic for GBM; WHO Grade 4 criterion
GFAP immunostain	Positive	Confirms astrocytic lineage (Glial Fibrillary Acidic Protein)
Ki-67 (MIB-1) proliferation index	Typically > 20%	High proliferative fraction; correlates with aggressive behaviour

Test	Method	Finding in GBM	Clinical Significance
IDH1/2 mutation status	IHC (IDH1 R132H) ± sequencing	Wildtype (negative)	Defines GBM; distinguishes from IDH-mutant astrocytoma (better prognosis). Sequencing especially important if age < 55
ATRX	IHC	Retained (nuclear expression present)	ATRX loss = IDH-mutant astrocytoma; retained ATRX supports IDH-wildtype GBM
1p/19q codeletion	FISH or array-based testing	Absent	Codeletion defines oligodendroglioma (IDH-mutant, 1p/19q-codeleted); must be excluded
TERT promoter mutation	PCR-based sequencing	Present (~80%)	Diagnostic criterion for Grade 4 (even without histological necrosis/microvascular proliferation); indicates telomerase activation → immortality
EGFR amplification	FISH, array CGH, or NGS	Present (~60%)	Diagnostic criterion for Grade 4; potential therapeutic target
+7/−10 chromosomal changes	Array CGH, SNP array, or NGS	Present	Diagnostic criterion for Grade 4
CDKN2A/B homozygous deletion	FISH or array	Often present	Indicates loss of both p16 and p14ARF → cell cycle dysregulation; prognostic significance
MGMT promoter methylation	Methylation-specific PCR (MSP) or pyrosequencing	Methylated (~40%) or Unmethylated (~60%)	The single most important predictive and prognostic biomarker — methylated = better response to temozolomide, better OS (~21–23 months vs ~12–15 months) ^[1]

High Yield – Molecular Testing Checklist for GBM

Every suspected GBM must have, at minimum:

IDH1 R132H IHC (± IDH1/2 sequencing if < 55 years or IHC negative)
ATRX IHC
1p/19q codeletion status (to exclude oligodendroglioma)
TERT promoter mutation (diagnostic criterion + prognostic)
EGFR amplification (diagnostic criterion + potential target)
MGMT promoter methylation (predictive for temozolomide response)

These are not optional — they are required for a complete integrated diagnosis under WHO CNS5. ^[1]

NOT routinely performed for GBM diagnosis — lumbar puncture is often contraindicated in the setting of a large mass lesion with raised ICP (risk of tonsillar herniation)
CSF cytology may show malignant cells if there is leptomeningeal dissemination (rare in GBM, more common in medulloblastoma)
CSF analysis may be useful in specific differentials:
- Oligoclonal bands → tumefactive MS
- Positive CSF cytology → leptomeningeal carcinomatosis (metastatic)
- Positive India ink, cryptococcal antigen → cryptococcal meningitis (immunocompromised)

Not diagnostic for GBM, but useful in patients with seizures — helps characterise seizure type and guide antiepileptic drug (AED) management
May show focal slowing or epileptiform discharges over the region of the tumour

Formal visual field assessment (Humphrey or Goldmann perimetry) is important when the tumour is near the visual pathways (temporal lobe, parietal lobe, occipital lobe, optic radiation)
Documents baseline deficits and monitors for post-operative change
Particularly important if the tumour causes homonymous hemianopia or quadrantanopia

Phase	Modality	Purpose
1. Clinical	History + neurological examination	Localise the lesion, identify red flags
2. Emergency imaging	CT brain (non-contrast)	Detect mass, haemorrhage, mass effect, hydrocephalus
3. Definitive imaging	MRI brain + gadolinium	Characterise tumour, plan surgery
4. Advanced imaging	MR perfusion, MRS, fMRI, DTI	Narrow differential, pre-operative planning
5. Systemic staging	CT CAP, tumour markers, HIV test	Exclude metastasis, assess fitness
6. Tissue diagnosis	Maximal safe resection or stereotactic biopsy	Histological confirmation
7. Molecular profiling	IDH, TERT, EGFR, +7/−10, MGMT, ATRX, 1p/19q	Integrated WHO CNS5 diagnosis + prognostication

High Yield Summary – Diagnosis of GBM

Histological examination is the gold standard — never treat based on imaging alone.
WHO CNS5 diagnostic criteria: Diffuse astrocytic glioma + IDH-wildtype + Grade 4 features (necrosis/microvascular proliferation histologically, OR TERT promoter mutation, EGFR amplification, or +7/−10 molecularly).
MRI with gadolinium is the imaging modality of choice: low T1, ring enhancement with central necrosis, high T2/FLAIR extending beyond enhancing rim.
Enhancement on brain imaging = BBB disruption (or structures outside the BBB). Normal brain does NOT enhance.
fMRI and DTI are for pre-operative planning — identifying eloquent cortex and critical white matter tracts.
MGMT promoter methylation is the most important prognostic/predictive biomarker — determines temozolomide benefit.
IDH mutation status is the most important diagnostic molecular marker — GBM is by definition IDH-wildtype.
Lumbar puncture is usually contraindicated in the setting of a large mass with raised ICP.

Active Recall – Diagnostic Criteria, Algorithm, and Investigations for GBM

References

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf ^[4] Senior notes: Ryan Ho Neurology.pdf (pp. 162–165, brain tumours and investigations) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1258–1264, brain tumours: diagnostic evaluation) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 530–534, brain tumours: diagnostic evaluation) ^[7] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 431, MRI appearance and functional imaging) ^[10] Senior notes: Ryan Ho Diagnostic Radiology.pdf (pp. 39–40, 50, CT interpretation and neuroimaging)

Management of Glioblastoma

Before diving into specifics, understand the strategic framework:

GBM is incurable with current therapies. The goal of treatment is to maximise survival and maintain quality of life — not to cure.
Maximal safe surgical resection is first-line for all operable gliomas ^[4] — it provides tissue diagnosis, relieves mass effect, and improves survival.
The Stupp protocol (2005, updated) — surgery followed by concurrent temozolomide + radiotherapy, then adjuvant temozolomide — remains the standard of care for newly diagnosed GBM in fit patients ^[1]^[4].
Treatment decisions are guided by: patient age, performance status (KPS/ECOG), tumour location/resectability, and MGMT promoter methylation status ^[1].
Management is multidisciplinary: neurosurgeon, neuro-oncologist/medical oncologist, radiation oncologist, neuropathologist, neuroradiologist, palliative care, physiotherapy, and neuropsychology.

A. Immediate / Supportive Management

Before definitive oncological treatment, the patient needs acute symptom management. Think of this as "stabilise first, then treat."

Aspect	Detail
Drug	Dexamethasone — the corticosteroid of choice for brain tumour-associated oedema ^[4]
Mechanism	Reduces vasogenic oedema by: (1) stabilising the BBB (restoring tight junctions in endothelial cells), (2) reducing capillary permeability, (3) decreasing VEGF expression. This reduces the volume of perilesional oedema → reduces mass effect → improves neurological function
Why dexamethasone specifically?	It has minimal mineralocorticoid activity (unlike prednisolone or hydrocortisone), so it causes less sodium/water retention. It also has a long half-life (~36–54 hours) allowing twice-daily dosing. It has excellent CNS penetration
Typical dose	Loading dose 8–16 mg IV, then 4–8 mg BD (tapered to lowest effective dose as soon as possible)
Clinical effect	Dramatic improvement often within hours — headache lessens, focal deficits may partially reverse, consciousness improves. This is because much of the neurological deficit is due to oedema rather than direct tumour destruction
Side effects	Hyperglycaemia (steroid-induced diabetes), immunosuppression, proximal myopathy, osteoporosis, weight gain/Cushingoid habitus, GI ulceration (co-prescribe PPI), insomnia, psychosis, adrenal suppression (must taper, not stop abruptly). Steroid myopathy is particularly important — can compound tumour-related weakness
Duration	Aim for shortest duration at lowest effective dose. Taper after surgery/RT reduces oedema. Prolonged use worsens the side-effect profile significantly

GC Lecture Point – Dexamethasone for Brain Tumours

Dexamethasone + antiepileptic drugs (AEDs) are the foundation of symptomatic management for brain tumours ^[4]. Dexamethasone rapidly reduces vasogenic oedema, while AEDs control seizures. These should be initiated before definitive oncological treatment.

Aspect	Detail
Indication	Patients who have had a seizure — NOT for primary prophylaxis in all brain tumour patients (evidence does not support routine prophylactic AEDs in patients who have not yet seized)
Perioperative prophylaxis	AEDs are often given perioperatively (around the time of craniotomy) and can be tapered/stopped within 1–2 weeks post-op if no seizures occur
Drug of choice	Levetiracetam (Keppra) — preferred because it has no hepatic enzyme induction (unlike phenytoin, carbamazepine, phenobarbital, which are CYP enzyme inducers → can reduce efficacy of chemotherapy, dexamethasone, and other medications via increased metabolism). Levetiracetam is renally excreted, has a wide therapeutic index, and requires no drug level monitoring
Why avoid enzyme-inducing AEDs?	Phenytoin and carbamazepine induce CYP3A4 and CYP2C9 → accelerate metabolism of temozolomide (the backbone chemotherapy), dexamethasone, and targeted therapies → reduced drug efficacy. This is a classic pharmacology interaction point
Side effects of levetiracetam	Irritability, mood changes, fatigue, drowsiness. These can overlap with tumour-related symptoms, so careful assessment is needed

Brain tumour patients are at high risk of venous thromboembolism (VTE) — both DVT and PE
Reasons: immobility, tumour procoagulant factors, post-operative state, steroids
Mechanical prophylaxis (compression stockings, intermittent pneumatic compression) is standard perioperatively
Pharmacological prophylaxis (LMWH) is used post-operatively once the risk of surgical bleeding is considered acceptable (typically 24–48 hours after craniotomy)
If a patient with GBM develops a proven DVT/PE, therapeutic anticoagulation (LMWH preferred over warfarin) is given — intracranial haemorrhage risk is a concern but the benefit of treating VTE generally outweighs the risk in most cases

Measure	Rationale
Proton pump inhibitor (PPI)	GI prophylaxis while on dexamethasone (steroids increase risk of peptic ulceration)
Physiotherapy / Rehabilitation	Address motor deficits, prevent deconditioning, maintain independence
Neuropsychology	Cognitive assessment, coping strategies
Palliative care early referral	Parallel planning — not just "end-of-life" but symptom management throughout the disease course
Driving cessation	Patients with seizures or significant visual field defects cannot drive (medicolegal issue)

B. Definitive Treatment — The Standard of Care

High Yield – GC Lecture Point: Surgery for Brain Tumours

Maximal safe resection without causing serious neurological sequelae is the key component of treatment for brain tumours ^[5]^[6]. Resection confirms diagnosis, relieves increased ICP, and establishes local control ^[6]. Surgical: maximal safe removal is 1st line in all operable gliomas ^[4].

Aspect	Detail
Goal	Remove as much tumour as possible while preserving neurological function — hence "maximal SAFE resection." Complete excision is virtually impossible due to GBM's infiltrative nature, but the greater the extent of resection (EOR), the better the survival
Evidence for extent of resection	Multiple studies show that gross total resection (GTR, removal of all enhancing tumour on post-op MRI) is associated with improved overall survival compared to subtotal resection or biopsy alone. Every additional percentage of tumour removed translates to incremental survival benefit. The target is ≥ 78% resection (threshold for survival benefit), ideally 100% of enhancing tumour
Technique	Craniotomy under general anaesthesia (or awake craniotomy for tumours near eloquent cortex — the patient performs tasks during surgery to ensure language/motor areas are preserved)
Intraoperative adjuncts	5-ALA (5-aminolevulinic acid) fluorescence-guided surgery: the patient drinks 5-ALA pre-operatively → it is metabolised to protoporphyrin IX, which accumulates preferentially in GBM cells → under blue-violet light in the operating theatre, tumour tissue fluoresces pink while normal brain does not → helps the surgeon identify and resect tumour tissue more completely. Randomised trials show 5-ALA increases the rate of GTR. Neuronavigation (frameless stereotaxy using pre-operative MRI), intraoperative MRI, intraoperative ultrasound, and cortical/subcortical stimulation mapping are additional tools
Indications for surgery	Accessible tumour, patient fit for anaesthesia (KPS ≥ 60), significant mass effect requiring decompression
Contraindications / situations favouring biopsy instead	Deep-seated tumour (thalamus, brainstem, basal ganglia), tumour in eloquent cortex where resection would cause unacceptable deficit, bilateral hemisphere involvement (diffuse butterfly glioma), poor performance status, significant comorbidities precluding craniotomy
Stereotactic needle biopsy	For inoperable tumours — provides tissue for histomolecular diagnosis with minimal morbidity (~2–5% complication rate: haemorrhage, infection). Does NOT provide cytoreduction

Post-operative assessment:

Post-operative MRI with gadolinium within 24–72 hours — assess extent of resection, detect residual enhancing tumour, establish a new baseline for future surveillance
This early post-op MRI must be done before post-operative inflammatory changes obscure the surgical cavity

Complications of surgery:

Complication	Mechanism/Notes
New or worsened neurological deficit	Damage to eloquent cortex or white matter tracts during resection
Haemorrhage (intracerebral, epidural, subdural)	Intra-operative vascular injury; coagulopathy
Infection (wound infection, meningitis, abscess)	Breach of sterile barrier
CSF leak	Inadequate dural closure
Seizures	Cortical irritation from surgical manipulation
Cerebral oedema	Surgical manipulation, reperfusion injury
DVT/PE	Post-operative immobility; brain tumour prothrombotic state

2. The Stupp Protocol — Concurrent Temozolomide + Radiotherapy, then Adjuvant Temozolomide

This is the landmark regimen established by the Stupp et al. EORTC/NCIC trial (NEJM 2005) and remains the gold standard for newly diagnosed GBM in patients < 70 with good performance status ^[1]^[4].

Component	Detail
Radiotherapy (RT)	External beam radiotherapy (EBRT) to the tumour bed + margin, total dose 60 Gy in 30 fractions (2 Gy per fraction, 5 days/week for 6 weeks) ^[4]
RT target	The clinical target volume (CTV) includes the enhancing tumour (on post-op MRI) + the surrounding T2/FLAIR abnormality + a 1.5–2 cm margin. This is because GBM cells infiltrate well beyond the enhancing rim
Why 60 Gy?	Dose-response studies showed that doses below 60 Gy had inferior outcomes, while doses above 60 Gy increased toxicity (especially radiation necrosis) without meaningful benefit. 60 Gy is the optimised balance
Temozolomide (TMZ)	75 mg/m² daily, given orally, every day throughout the 6-week RT course (including weekends) ^[4]
Mechanism of TMZ	Temozolomide ("temo-" = a naming convention; "-zolomide" = related to its imidazotetrazine chemical class) is an oral alkylating agent. It is a prodrug that spontaneously converts to MTIC (the active metabolite) at physiological pH → MTIC methylates DNA at the O6 position of guanine → mismatch during replication → futile repair cycles → double-strand breaks → apoptosis
Why concurrent?	TMZ acts as a radiosensitiser — the DNA damage from TMZ is synergistic with radiation-induced DNA damage. Cells that have TMZ-induced DNA alkylation are more susceptible to radiation-induced double-strand breaks, and vice versa. The combination is more effective than either modality alone
PCP prophylaxis	Concurrent TMZ + RT causes lymphopaenia (TMZ is myelosuppressive; radiation to the brain further depletes circulating lymphocytes) → increased risk of Pneumocystis jirovecii pneumonia (PCP). Therefore, co-trimoxazole (TMP-SMX) prophylaxis is given throughout the concurrent phase and continued until lymphocyte recovery

Component	Detail
Temozolomide	150–200 mg/m² daily for 5 days of each 28-day cycle, for 6 cycles ^[4]
Dose escalation	Start at 150 mg/m² in cycle 1; if well-tolerated (adequate blood counts), escalate to 200 mg/m² for cycles 2–6
Monitoring	CBC with differential before each cycle — TMZ causes myelosuppression (thrombocytopaenia is the dose-limiting toxicity). If platelets < 100 × 10⁹/L or ANC < 1.5 × 10⁹/L, delay the cycle until recovery

The Stupp Protocol in One Sentence

Surgery → 6 weeks of concurrent daily TMZ (75 mg/m²) + RT (60 Gy/30 fractions) → 4-week break → 6 cycles of adjuvant TMZ (150–200 mg/m², 5/28 days). This is the standard of care for GBM in fit patients. Know this cold. ^[1]^[4]

Property	Detail
Class	Oral alkylating agent (imidazotetrazine)
Prodrug	Yes — spontaneously converts to MTIC at physiological pH (no hepatic activation required)
Route	Oral (excellent bioavailability ~100%; crosses BBB well)
Key mechanism	O6-guanine methylation → DNA miscoding → futile mismatch repair → double-strand breaks → apoptosis
Resistance mechanism	MGMT enzyme — removes the methyl group from O6-guanine, repairing the damage before it becomes lethal. This is why MGMT promoter methylation (silencing MGMT) predicts better TMZ response ^[1]
Dose-limiting toxicity	Myelosuppression — especially thrombocytopaenia (nadir at days 21–28); also neutropaenia, lymphopaenia
Other side effects	Nausea/vomiting (antiemetics given: ondansetron), fatigue, constipation, hepatotoxicity (rare; monitor LFT), opportunistic infections (PCP — prophylaxis with co-trimoxazole), teratogenic
Drug interactions	Minimal CYP interaction (advantage over older alkylating agents). However, enzyme-inducing AEDs can reduce TMZ efficacy — another reason to prefer levetiracetam

Aspect	Detail
Modality	Intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) — modern techniques that conform the radiation dose to the tumour shape while minimising dose to surrounding normal brain
Target delineation	Based on post-operative MRI: gross tumour volume (GTV = enhancing residual tumour) + clinical target volume (CTV = GTV + margin for microscopic infiltration, typically 1.5–2 cm) + planning target volume (PTV = CTV + setup error margin)
Why not higher doses?	Brain tissue tolerance limits the dose. Higher doses → radiation necrosis (irreversible focal brain damage that mimics tumour on imaging — a major diagnostic challenge)
Side effects of brain RT	Acute (during RT): fatigue, headache, nausea, transient worsening of neurological symptoms, alopecia (localised to the radiation field), skin erythema over the entry beam. Subacute (1–6 months): somnolence syndrome (fatigue, cognitive slowing — transient demyelination). Delayed (months to years): radiation necrosis (focal brain damage mimicking tumour recurrence on MRI — distinguished by MR perfusion showing low rCBV), cognitive decline, endocrine dysfunction (if pituitary/hypothalamus in field), secondary malignancy (very rare)

MGMT status is not just prognostic — it directly influences treatment decisions, especially in elderly patients:

Scenario	MGMT Methylated	MGMT Unmethylated
Age < 70, good KPS	Standard Stupp protocol (TMZ + RT → adjuvant TMZ) — maximum benefit from TMZ	Standard Stupp protocol still offered — survival benefit from RT is clear; TMZ benefit is smaller but the combined protocol is still standard of care
Age ≥ 70, good KPS	Hypofractionated RT (40 Gy/15 fractions) + concurrent and adjuvant TMZ (Perry et al., NEJM 2017) — OR — TMZ monotherapy (if patient cannot tolerate RT). Strong TMZ benefit	Hypofractionated RT alone (40 Gy/15 fractions). TMZ adds minimal benefit if MGMT is unmethylated — spares the patient from unnecessary toxicity
Poor KPS (any age)	TMZ alone may be considered; or BSC	Best supportive care (BSC) — aggressive chemoRT unlikely to benefit and may worsen quality of life

MGMT Guides Elderly Management

In patients ≥ 70 years, MGMT promoter methylation status is the key decision-maker:

Methylated: TMZ monotherapy or hypofractionated RT + TMZ → strong benefit
Unmethylated: hypofractionated RT alone → TMZ adds nothing meaningful

This is one of the best examples of precision medicine in neuro-oncology — matching the treatment to the tumour's molecular biology. ^[1]

GBM recurs in virtually all patients, typically within 6–9 months of completing the Stupp protocol, most often at or near the original resection margin.

There is no established standard of care for recurrent GBM. Treatment is individualised via MDT discussion.

Modality	Detail
Re-resection	Considered if: symptomatic mass effect, good performance status, surgically accessible recurrence, long interval since first surgery. Provides tissue (to reassess molecular profile — tumour may have evolved), cytoreduction, and symptom relief. Survival benefit debated
Bevacizumab	Anti-angiogenesis agent (anti-VEGF monoclonal antibody) ^[4]. Mechanism: blocks VEGF → reduces neovascularisation → reduces oedema → clinical improvement and MRI improvement ("pseudoresponse" — the tumour looks better on imaging because the vessels are less leaky, but the tumour cells may still be infiltrating). Bevacizumab improves progression-free survival and quality of life but does NOT improve overall survival. It has a steroid-sparing effect (reduces the need for dexamethasone). Used as 2nd-line therapy ^[4]
Re-irradiation	Can be considered for small-volume, focal recurrence — stereotactic radiosurgery (SRS) or hypofractionated stereotactic RT. Risk of radiation necrosis increases with re-irradiation
Lomustine (CCNU)	An older alkylating agent sometimes used in recurrence, either alone or combined with bevacizumab
Tumour Treating Fields (TTFields)	A novel modality — the Optune device delivers low-intensity, intermediate-frequency (200 kHz) alternating electric fields to the brain via transducer arrays worn on the shaved scalp. Mechanism: disrupts mitotic spindle formation during cell division → mitotic catastrophe → cell death. The EF-14 trial showed that adding TTFields to adjuvant TMZ improved median OS from 16 to 20.9 months in newly diagnosed GBM (though it is also used at recurrence). Not widely available; requires wearing the device > 18 hours/day
Clinical trials	GBM patients should always be considered for clinical trials — immunotherapy (checkpoint inhibitors, CAR-T cells, vaccines), targeted therapies (EGFR inhibitors, CDK4/6 inhibitors), and novel combinations are under active investigation
Best supportive care (BSC)	When further active treatment is unlikely to benefit — focus on symptom control (dexamethasone, AEDs, analgesia), psychological support, palliative care, end-of-life planning

GBM patients inevitably enter the terminal phase. Key principles:

Aspect	Approach
Symptom control	Dexamethasone (for oedema-related symptoms), AEDs (seizure control — consider buccal midazolam or rectal diazepam for terminal seizures), opioids (headache/pain), antiemetics, anxiolytics
Steroid taper	As disease progresses, may need to increase steroids; but in truly terminal patients, steroids can sometimes be weaned if they are no longer providing benefit and are causing side effects
Communication	Advance care planning, DNACPR discussions, goals of care
Caregiver support	GBM causes progressive cognitive and personality changes → enormous caregiver burden
Hospice referral	When prognosis is weeks to months and no further active treatment is planned

E. Special Situations

The Stupp protocol was validated primarily in patients < 70
Hypofractionated RT (40 Gy in 15 fractions over 3 weeks) is equivalent to standard 60 Gy/30 fractions in the elderly and is better tolerated (shorter treatment time, less toxicity)
MGMT status guides TMZ use (as above)
The NOA-08 and Nordic trials showed that TMZ monotherapy is non-inferior to RT alone in MGMT-methylated elderly patients — but RT alone is preferred if MGMT is unmethylated

These patients do poorly regardless of treatment
Aggressive chemoRT may worsen quality of life without meaningful survival extension
BSC ± short-course RT ± TMZ monotherapy (if MGMT methylated) is the pragmatic approach

Stereotactic biopsy for tissue diagnosis → molecular profiling
Proceed with Stupp protocol (RT + TMZ) if fit, based on molecular findings
Outcome is generally worse than for resectable tumours (less cytoreduction)

Modality	Indication	Mechanism	Key Side Effects / Limitations
Dexamethasone	Perilesional oedema, raised ICP	Stabilises BBB, reduces VEGF expression	Hyperglycaemia, myopathy, immunosuppression, osteoporosis, Cushingoid
Maximal safe resection	All operable GBMs; 1st-line ^[4]^[5]^[6]	Cytoreduction, decompression, tissue diagnosis	New neurological deficit, haemorrhage, infection
External beam RT (60 Gy/30#)	Standard-of-care adjuvant for < 70, good KPS ^[4]	DNA double-strand breaks → cell death; synergistic with TMZ	Radiation necrosis, cognitive decline, fatigue, alopecia
Hypofractionated RT (40 Gy/15#)	Elderly ≥ 70 or frail patients	Same as above; shorter course → better tolerated	As above but generally fewer late effects due to lower total dose
Temozolomide	Concurrent with RT + adjuvant; elderly MGMT-methylated ^[1]^[4]	Oral alkylating agent; O6-guanine methylation → apoptosis	Myelosuppression (thrombocytopaenia), nausea, PCP risk, hepatotoxicity
Bevacizumab	2nd-line / recurrent GBM ^[4]	Anti-VEGF mAb → anti-angiogenesis, reduces oedema	Hypertension, proteinuria, wound healing impairment, haemorrhage, thromboembolic events; no OS benefit
TTFields (Optune)	Adjuvant (newly diagnosed) or recurrent GBM	Alternating electric fields disrupt mitosis	Skin irritation (scalp), compliance (must wear > 18 h/day), cost, availability
Levetiracetam	Seizure control (treatment, not prophylaxis in all)	Synaptic vesicle protein 2A (SV2A) modulation → reduces neurotransmitter release	Irritability, mood changes, fatigue
BSC / Palliative care	All patients (parallel approach); sole treatment if unfit	Symptom control, quality of life, end-of-life planning	N/A

High Yield Summary – Management of GBM

Dexamethasone for oedema + levetiracetam for seizures = immediate supportive management.
Maximal safe surgical resection is 1st-line — confirms diagnosis, relieves mass effect, improves survival. 5-ALA fluorescence and neuronavigation optimise extent of resection.
Stupp protocol = Surgery → Concurrent TMZ (75 mg/m²/day) + RT (60 Gy/30#) × 6 weeks → Adjuvant TMZ (150–200 mg/m², 5/28 days) × 6 cycles. Standard of care for age < 70, KPS ≥ 60.
MGMT promoter methylation guides treatment in elderly (≥ 70): methylated → TMZ beneficial; unmethylated → RT alone, TMZ adds little.
Bevacizumab = 2nd-line for recurrent GBM; improves PFS and QoL but NOT overall survival.
TMZ resistance = MGMT enzyme repairs TMZ-induced DNA damage. MGMT silencing (promoter methylation) = better TMZ response.
PCP prophylaxis with co-trimoxazole is mandatory during concurrent TMZ + RT (lymphopaenia risk).
Avoid enzyme-inducing AEDs (phenytoin, carbamazepine) — they reduce TMZ and dexamethasone efficacy via CYP induction.
GBM is incurable. Early palliative care integration improves quality of life. Median OS ~14–16 months with standard treatment.

Active Recall – Management of Glioblastoma

References

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf ^[4] Senior notes: Ryan Ho Neurology.pdf (pp. 162–165, glioma management) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1258–1264, brain tumour treatment principles) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 530–534, brain tumour surgical treatment and complications)

Complications of Glioblastoma

Complications of GBM can be conceptualised in three overlapping categories:

Complications of the tumour itself (from growth, infiltration, and mass effect)
Complications of treatment (surgery, radiotherapy, chemotherapy)
Systemic and end-of-life complications

These categories overlap significantly — for example, seizures can be caused by the tumour, by surgical cortical manipulation, OR by radiation-induced gliosis. The clinical challenge is always working out which cause is driving the complication and managing accordingly.

1. Complications of the Tumour Itself

Complication	Pathophysiological Basis	Clinical Features	Management
Raised ICP	GBM is a rapidly expanding mass + surrounding vasogenic oedema (from VEGF-driven leaky neovascularisation) → increases intracranial volume → overwhelms compensatory mechanisms (CSF displacement, venous compression) → ICP rises exponentially (Monro-Kellie doctrine)	Headache (worse morning, coughing, straining), nausea/vomiting, papilloedema, CN VI palsy (false localising sign), drowsiness, cognitive decline	Dexamethasone (reduces vasogenic oedema by stabilising BBB) ^[4]; elevate head of bed 30°; avoid hypercapnia; osmotic therapy (mannitol or hypertonic saline) for acute crises; surgical decompression (debulking or decompressive craniectomy) if indicated
Obstructive hydrocephalus	Large GBMs (especially those near the foramen of Monro, third ventricle, or posterior fossa — less common for supratentorial GBM) can obstruct CSF flow → dilated ventricles proximal to the obstruction → acutely raised ICP	Rapid deterioration: headache, vomiting, decreased consciousness, Parinaud syndrome (upward gaze palsy from compression of tectal plate in aqueductal obstruction)	Emergency external ventricular drain (EVD) or ventriculoperitoneal (VP) shunt; definitive management = tumour resection to relieve the obstruction
Brain herniation	Critical mass effect from tumour + oedema → brain tissue shifts across rigid intracranial compartments (falx cerebri, tentorium cerebelli, foramen magnum)	Uncal herniation: ipsilateral fixed dilated pupil (CN III compression — parasympathetics run superficially), contralateral hemiparesis, decreasing GCS. Subfalcine herniation: contralateral leg weakness (ACA compression). Tonsillar herniation: respiratory arrest (medullary compression) → Cushing's triad: hypertension, bradycardia, irregular respiration (the terminal autonomic response)	Neurosurgical emergency: IV mannitol (1 g/kg bolus) or hypertonic saline; hyperventilation (target pCO₂ 30–35 mmHg — cerebral vasoconstriction reduces cerebral blood volume → buys time); emergency surgical decompression (craniotomy/craniectomy). Dexamethasone also given but takes hours to work

Why Hyperventilation Works in Acute Herniation

CO₂ is a potent cerebral vasodilator. By hyperventilating the patient, you lower pCO₂ → cerebral vasoconstriction → reduced cerebral blood volume → reduced ICP. This is a temporising measure only (effect wanes after 24–48 hours as CSF bicarbonate adjusts) and must NOT be maintained long-term (chronic vasoconstriction → cerebral ischaemia).

Complication	Pathophysiological Basis	Clinical Features	Management
Tumour-related epilepsy (affects 50–80% of primary brain tumour patients, ~20–30% of GBM at presentation) ^[4]	Cortical infiltration by tumour cells disrupts the excitation-inhibition balance in neuronal circuits; peri-tumoural oedema alters ionic microenvironment (K⁺ shifts, glutamate excess); gliosis creates epileptogenic foci. Always supratentorial (infratentorial cerebellar cortex is inhibitory by nature) ^[4]	Focal seizures (motor, sensory, complex partial) ± secondary generalisation; typically repetitive and stereotyped in a given patient ^[4]; post-ictal deficits (Todd's paralysis)	Levetiracetam is first-line AED (non-enzyme-inducing); add/switch to lacosamide, valproate, or brivaracetam if refractory. Avoid phenytoin/carbamazepine (CYP enzyme inducers → reduce TMZ and dexamethasone efficacy). Address reversible triggers: infection, electrolyte imbalance, medication non-compliance
Status epilepticus (seizure > 5 min or recurrent seizures without recovery between episodes)	As above but sustained; can become self-perpetuating due to excitotoxic glutamate release, neuronal injury, and progressive failure of inhibitory mechanisms (GABA receptor internalisation)	Continuous convulsive or non-convulsive seizure activity; decreased consciousness; risk of aspiration, hypoxia, rhabdomyolysis, metabolic acidosis, brain injury	Emergency protocol: ABC, IV benzodiazepine (lorazepam 4 mg IV or diazepam 10 mg IV); if persisting → IV phenytoin or levetiracetam loading; if refractory → ICU for general anaesthesia (propofol/midazolam/thiopental infusion). Must identify and treat underlying trigger (tumour progression, infection, metabolic derangement)

Aspect	Detail
Pathophysiology	GBM has fragile, abnormal neovascular vessels (thin-walled, lacking basement membrane and pericyte support) that are prone to spontaneous rupture. The tumour microenvironment is also procoagulant and pro-haemorrhagic simultaneously. GBM is one of the brain tumours most likely to present with haemorrhage
Clinical presentation	Acute deterioration: sudden headache, new focal deficit, decreased consciousness — mimics a primary intracerebral haemorrhage (stroke). May be the presenting event in a patient not yet known to have a brain tumour
Diagnostic clue	On CT/MRI, the haemorrhage may appear atypical for a hypertensive bleed — e.g., disproportionate surrounding oedema, irregular margins, enhancement in areas remote from the haematoma, unusual location (not the typical deep basal ganglia/thalamic location of hypertensive bleeds). Always consider underlying tumour in any atypical-looking ICH
Management	Neurosurgical evacuation if large and causing herniation; supportive care; once stabilised, MRI with contrast to look for an underlying mass; if discovered, proceed with standard GBM workup

As GBM grows and infiltrates, neurological deficits progressively worsen — this is the natural history of the disease
The specific deficit depends on which eloquent brain region is being destroyed (see Clinical Features section)
Progressive hemiparesis, aphasia, visual field loss, and cognitive decline are the most common trajectories
Some deficit is due to oedema (reversible with dexamethasone) and some is due to neuronal destruction (irreversible). It is the clinician's task to distinguish the reversible component and treat it

Complication	Pathophysiological Basis
Progressive cognitive decline	Direct tumour infiltration of cortical and subcortical cognitive networks; raised ICP; white matter disconnection. Frontal GBM → executive dysfunction, apathy, disinhibition. Temporal → memory loss
Personality and behavioural changes	Frontal lobe infiltration → loss of social judgment, inappropriate behaviour, emotional blunting, abulia (severe apathy/lack of will). Can be mistaken for psychiatric illness or depression
Depression and anxiety	Reactive (to diagnosis and prognosis) AND organic (direct brain involvement). Prevalence ~15–40%. May be undertreated because attributed to "expected" sadness. SSRIs are safe and effective
Delirium	Multifactorial: raised ICP, medications (dexamethasone, opioids, AEDs), infection, metabolic derangement (hyponatraemia from SIADH, steroid-induced hyperglycaemia), sleep deprivation. Must exclude all reversible causes before attributing to disease progression

Aspect	Detail
Incidence	20–30% of GBM patients develop VTE (DVT and/or PE) during their disease course — one of the highest rates among all cancers
Why so common?	GBM produces tissue factor (TF) and other procoagulant molecules → activates the extrinsic coagulation pathway → hypercoagulable state (Trousseau's syndrome). Additional factors: immobility (hemiparesis, post-operative), steroid use (prothrombotic), surgery, chemotherapy
Clinical significance	PE is a significant cause of death in GBM patients. Must maintain a high index of suspicion for sudden dyspnoea, tachycardia, hypoxia, or leg swelling
Management	Therapeutic anticoagulation with LMWH (preferred over warfarin — more predictable, no CYP interactions with TMZ). Concern about intracranial haemorrhage exists but is generally manageable. IVC filter only if anticoagulation absolutely contraindicated

Aspect	Detail
Pathophysiology	Any CNS pathology (tumour, surgery, radiation, infection) can cause inappropriate ADH secretion from the posterior pituitary or hypothalamus → excessive water reabsorption in renal collecting ducts → dilutional hyponatraemia (low serum Na⁺, low serum osmolality, concentrated urine)
Clinical features	Often asymptomatic if mild. Severe hyponatraemia (Na⁺ < 120 mmol/L) → confusion, nausea, seizures, coma
Importance	Hyponatraemia lowers the seizure threshold and can worsen cerebral oedema — a double hit in a patient already at risk from the tumour
Management	Fluid restriction (first-line); if severe/symptomatic → IV hypertonic saline (3% NaCl); correct slowly (avoid osmotic demyelination syndrome if chronic); treat underlying cause

2. Complications of Treatment

Post-operative complications ^[4]^[5]^[6]:

Complication	Mechanism / Explanation
New or worsened neurological deficit	Intraoperative damage to eloquent cortex or critical white matter tracts despite precautions (5-ALA, neuronavigation, stimulation mapping). Risk is higher for tumours in or near primary motor cortex, speech areas, optic radiations. May be transient (oedema, retraction injury) or permanent (direct parenchymal damage)
Postoperative haemorrhage	Intraoperative vascular injury, incomplete haemostasis, or coagulopathy → epidural, subdural, or intracerebral haematoma. May require emergency re-operation if causing mass effect
Infection (wound infection, osteomyelitis of bone flap, meningitis, brain abscess)	Breach of sterile barrier; immunosuppression from steroids and chemotherapy increases risk. Post-craniotomy meningitis is a serious complication requiring prolonged IV antibiotics
CSF leak	Inadequate dural closure → CSF leaks through the wound → risk of ascending infection (meningitis). Managed with lumbar drainage, wound repair, or dural patching
Cerebral oedema	Surgical manipulation causes local inflammation and BBB disruption → worsened peri-operative oedema → transient neurological worsening. Managed with dexamethasone
Seizures	Cortical irritation from surgical manipulation and cortical gliosis at the resection margin → epileptogenic focus. Perioperative AED prophylaxis mitigates this
DVT/PE	Post-operative immobility + brain tumour hypercoagulability. Mechanical and pharmacological prophylaxis (see above)

Complications are classified by timing — this is a high-yield framework:

Timing	Complication	Pathophysiological Basis	Clinical Features	Management
Acute (during RT, weeks 1–6)	Worsened cerebral oedema	RT causes local inflammation and further BBB disruption → increased vasogenic oedema → increased mass effect → transient worsening of neurological symptoms	Headache, nausea, worsened focal deficits	Increase dexamethasone dose
Acute	Fatigue	Widespread effect of cranial irradiation on normal brain function; also systemic inflammatory response	Profound fatigue, somnolence	Supportive; usually improves after RT completion
Acute	Alopecia (localised to radiation field)	Direct radiation damage to hair follicle stem cells → hair loss in the beam path	Patchy hair loss in the irradiated field	Usually temporary; may be permanent with high doses
Acute	Scalp erythema/desquamation	Radiation dermatitis in the skin overlying the treatment field	Red, sore, peeling scalp skin	Gentle skin care, topical emollients
Subacute (1–6 months post-RT)	Somnolence syndrome	Transient demyelination of white matter in the radiation field → impaired axonal conduction	Fatigue, cognitive slowing, excessive sleepiness; typically self-limiting over weeks	Reassurance; short course of steroids if severe
Delayed (months to years)	Radiation necrosis	Vascular endothelial damage → ischaemia → coagulative necrosis of brain tissue in the irradiation field. Occurs in ~5–25% of patients. The most important delayed complication because it mimics tumour recurrence on imaging	Ring-enhancing lesion on MRI (identical to GBM recurrence!); new or worsened focal deficits, seizures	Distinguish from tumour recurrence: MR perfusion (radiation necrosis = low rCBV; tumour = high rCBV), MR spectroscopy, amino acid PET. Managed with steroids, bevacizumab (reduces necrosis-associated oedema), or surgical excision if severe
Delayed	Cognitive decline	Progressive white matter damage, small vessel vasculopathy, hippocampal neuronal loss	Memory impairment, executive dysfunction, processing speed reduction. Can be profound and progressive	Cognitive rehabilitation; memantine (NMDA antagonist) may have a neuroprotective role if started during RT
Delayed	Endocrine dysfunction	If hypothalamic-pituitary axis is within the radiation field → radiation-induced hypopituitarism	GH deficiency (most common and earliest to appear), hypothyroidism, adrenal insufficiency, hypogonadism	Regular endocrine monitoring; hormone replacement as needed
Delayed	Cerebrovascular disease	Radiation-induced accelerated atherosclerosis and vasculopathy of intracranial and cervical arteries → increased stroke risk years later	Ischaemic stroke, Moyamoya-like vasculopathy, intracranial haemorrhage	Vascular risk factor management; antiplatelet therapy; neurovascular surveillance
Delayed	Secondary malignancy (radiation-induced tumour)	Radiation causes DNA damage in normal cells → rarely, a second primary tumour arises within the radiation field years to decades later (e.g., meningioma, sarcoma, GBM in a previously irradiated low-grade glioma patient)	New mass in the radiation field, typically ≥ 5 years after RT	Standard oncological management of the new tumour

Radiation Necrosis vs Tumour Recurrence – The Critical Distinction

Radiation necrosis and tumour recurrence look identical on standard contrast MRI (both are ring-enhancing lesions with surrounding oedema). This is one of the most challenging diagnostic dilemmas in neuro-oncology. Key differentiators:

MR perfusion: Tumour recurrence → elevated rCBV (neovascular tumour). Radiation necrosis → low rCBV (avascular necrotic tissue)
MR spectroscopy: Tumour → elevated choline. Necrosis → elevated lipid/lactate
Amino acid PET (FET-PET): Tumour → avid uptake. Necrosis → no uptake
Ultimately, biopsy may be needed if non-invasive methods are inconclusive

Complication	Pathophysiological Basis	Clinical Significance	Management
Myelosuppression (dose-limiting toxicity)	TMZ alkylates DNA in haematopoietic stem/progenitor cells → impaired blood cell production. Thrombocytopaenia is the most common dose-limiting toxicity (nadir at days 21–28 of the cycle); also neutropaenia and lymphopaenia	Increased risk of bleeding (thrombocytopaenia), infection (neutropaenia, lymphopaenia). Monitor CBC before each TMZ cycle — delay if platelets < 100 × 10⁹/L or ANC < 1.5 × 10⁹/L	Dose reduction or delay; G-CSF for severe neutropaenia; platelet transfusion if severe thrombocytopaenia with bleeding
Lymphopaenia and opportunistic infections	Concurrent TMZ + RT is profoundly lymphodepletive (both modalities target rapidly dividing lymphocytes). CD4 count can drop to levels seen in HIV/AIDS	Risk of Pneumocystis jirovecii pneumonia (PCP), herpes zoster reactivation, other opportunistic infections	Co-trimoxazole (TMP-SMX) prophylaxis throughout the concurrent phase and until lymphocyte recovery. Pentamidine inhalation or dapsone if co-trimoxazole intolerant
Nausea and vomiting	Central (chemoreceptor trigger zone stimulation) and peripheral emetogenic effects of alkylating agents	Common during adjuvant TMZ cycles; usually manageable	Prophylactic ondansetron (5-HT₃ antagonist) before each TMZ dose
Hepatotoxicity	TMZ metabolites cause direct hepatocellular damage (rare but can be severe)	Transaminitis; rarely fulminant hepatic failure	Monitor LFT during treatment; discontinue TMZ if significant hepatotoxicity
Fatigue	Multifactorial: myelosuppression, direct CNS effect, cumulative treatment burden	Very common; significantly impacts quality of life	Supportive care; dose adjustment if severe; exclude other reversible causes (anaemia, hypothyroidism, depression)
Secondary myelodysplasia / leukaemia	TMZ is an alkylating agent → can cause DNA damage in normal haematopoietic stem cells → rarely, treatment-related myelodysplastic syndrome (t-MDS) or acute myeloid leukaemia (t-AML) years later	Very rare given GBM's short median survival; more relevant in long-term survivors	Haematology referral; standard MDS/AML management
Pseudoprogression	TMZ + RT-induced tumour cell death and inflammation → transient increase in enhancement and oedema on MRI at 1–3 months post-RT, mimicking disease progression. More common in MGMT-methylated tumours (paradoxically, because these tumours are more responsive to treatment → more cell death → more inflammation)	Can lead to premature cessation of effective treatment if misinterpreted as true progression. Occurs in 20–30% of GBM patients	Continue treatment; repeat MRI in 4–8 weeks. If the enhancement stabilises or decreases → pseudoprogression. If it continues to grow → true progression. MR perfusion and spectroscopy can help differentiate

Pseudoprogression – Don't Stop Treatment Prematurely

Pseudoprogression occurs in ~20–30% of GBM patients within 1–3 months of completing chemoradiation. The MRI shows increased enhancement mimicking tumour growth, but this actually represents treatment-induced inflammation and necrosis — a sign that treatment is working. It is more common in MGMT-methylated tumours. If you mistake pseudoprogression for true recurrence and stop temozolomide, you rob the patient of effective therapy. Continue treatment and repeat imaging in 4–8 weeks before making decisions.

Given that virtually all GBM patients receive prolonged dexamethasone, steroid side effects are ubiquitous:

Complication	Mechanism	Clinical Significance
Steroid-induced diabetes / hyperglycaemia	Dexamethasone increases hepatic gluconeogenesis, promotes insulin resistance, and reduces peripheral glucose uptake	Very common; requires regular glucose monitoring; may need insulin or oral hypoglycaemics. Poorly controlled glucose worsens outcomes (immune suppression, infection risk, impaired wound healing)
Proximal myopathy	Steroids cause type II muscle fibre atrophy (fast-twitch fibres)	Difficulty rising from a chair, climbing stairs. Compounds tumour-related weakness. Often confused with disease progression. Managed by minimising steroid dose and physiotherapy
Immunosuppression	Steroids suppress multiple arms of immunity (T-cell function, neutrophil migration, cytokine production)	Increased infection risk (bacterial, fungal, viral). Combined with TMZ-induced lymphopaenia → profound immunosuppression
Osteoporosis	Steroids reduce osteoblast activity and increase osteoclast resorption; reduce calcium absorption	Vertebral compression fractures, hip fractures — particularly relevant in longer-surviving patients. Calcium/vitamin D supplementation ± bisphosphonates if prolonged steroid use expected
Cushingoid habitus	Redistribution of fat → moon face, truncal obesity, buffalo hump; skin thinning, striae, easy bruising	Cosmetically distressing; generally reversible with steroid taper
Psychiatric effects	Steroid-induced mood changes → insomnia, irritability, euphoria, depression, psychosis (rare)	Dose-related; worsens quality of life. May require dose reduction or psychiatric intervention
GI ulceration	Steroids reduce prostaglandin synthesis → reduced gastric mucosal protection	Co-prescribe PPI (omeprazole/pantoprazole) for prophylaxis
Adrenal suppression	Prolonged exogenous steroid → suppresses endogenous ACTH and cortisol production via HPA axis negative feedback	Must taper steroids gradually — abrupt cessation can cause adrenal crisis (hypotension, shock, hypoglycaemia, hyperkalaemia). Stress-dose steroids needed if acute illness during taper

3. Systemic and End-of-Life Complications

Complication	Detail
Progressive neurological decline	Inevitable as tumour recurs and infiltrates; progressive hemiplegia, aphasia, dysphagia, incontinence, loss of consciousness
Dysphagia and aspiration	Bulbar dysfunction or decreased consciousness → inability to protect the airway → aspiration pneumonia. A common terminal event
Seizures in the terminal phase	May become more frequent and harder to control. Buccal midazolam or subcutaneous midazolam/levetiracetam for patients who can no longer take oral medications
Loss of consciousness → coma	Progressive raised ICP, diffuse tumour infiltration, or brainstem herniation → progressive obtundation → coma → death
Venous thromboembolism	Immobility + tumour hypercoagulability. PE is a significant cause of death
Infections (pneumonia, UTI, wound)	Immobility, immunosuppression (steroids + chemotherapy), Foley catheter, dysphagia with aspiration

Scenario	Median Overall Survival
Untreated GBM	~3–4 months
Surgery alone	~6 months
Surgery + RT alone	~12 months
Surgery + RT + TMZ (Stupp protocol)	~14–16 months ^[4]^[7]
Stupp protocol, MGMT methylated	~21–23 months
5-year overall survival	< 5–10% ^[4]^[7]

GBM, Grade IV: very malignant → mean lifespan 14 months ^[4]^[7]. This makes it one of the most lethal cancers in all of medicine.

High Yield Summary – Complications of GBM

Tumour-related:

Raised ICP and brain herniation — manage with dexamethasone, osmotherapy, surgical decompression. Cushing's triad (HTN, bradycardia, irregular respiration) = imminent herniation.
Seizures (50–80% of primary brain tumour patients; always supratentorial). Use levetiracetam; avoid enzyme-inducing AEDs.
Intratumoral haemorrhage — GBM has fragile neovessels. Can mimic primary ICH.
VTE — 20–30% of patients. Tissue factor production → hypercoagulability. Treat with LMWH.
SIADH → hyponatraemia → lowers seizure threshold and worsens oedema.

Treatment-related:

Surgery: new deficits, haemorrhage, infection, CSF leak, seizures.
Radiotherapy: Acute (oedema, fatigue), subacute (somnolence syndrome), delayed (radiation necrosis — mimics recurrence on MRI; distinguish by MR perfusion/spectroscopy/PET; cognitive decline; endocrine dysfunction; secondary malignancy).
Temozolomide: Myelosuppression (thrombocytopaenia is dose-limiting; monitor CBC each cycle), lymphopaenia → PCP risk (co-trimoxazole prophylaxis mandatory), nausea, hepatotoxicity.
Pseudoprogression: 20–30% of patients at 1–3 months post-chemoRT; MRI mimics recurrence but is actually treatment-induced inflammation. More common if MGMT methylated. Do NOT stop treatment prematurely.
Radiation necrosis vs tumour recurrence: Key differentiator = MR perfusion (necrosis = low rCBV, tumour = high rCBV).
Dexamethasone: Hyperglycaemia, myopathy, immunosuppression, osteoporosis, Cushingoid features, GI ulceration, adrenal suppression (must taper).

Active Recall – Complications of Glioblastoma

References

^[1] Lecture slides: GC 108. A mass in the brain brain tumours.pdf ^[4] Senior notes: Ryan Ho Neurology.pdf (pp. 162–165, brain tumour management and complications) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 1258–1264, surgical complications and RT complications) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp. 530–534, surgical and RT complications) ^[7] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 431, glioma prognosis and management)

High Yield Summary

Definition: GBM = IDH-wildtype, WHO Grade 4 diffuse astrocytic glioma. The most common and most lethal primary malignant brain tumour in adults.

Epidemiology: Peak age 55–85, M > F (1.6:1), median survival ~14–16 months.

Risk Factors: Only established environmental RF = ionising radiation. Genetic syndromes: Li-Fraumeni (TP53), NF1, Turcot syndrome (MMR genes).

Key Molecular Features: EGFR amplification, PTEN loss, TERT promoter mutation, +7/−10, CDKN2A deletion. Three core pathways disrupted: RTK/RAS/PI3K, TP53, RB pathways.

MGMT promoter methylation: Most important biomarker — methylated (~40%) → better response to temozolomide, better prognosis.

Histology: Microvascular proliferation + pseudopalisading necrosis are the hallmarks. GFAP+, IDH-wildtype.

Clinical Features:

Raised ICP: Headache (worse in morning, with coughing/straining), nausea/vomiting, papilloedema, CN VI palsy
Seizures: New-onset seizure in adult > 40 = brain imaging mandatory
Progressive focal deficits: Depends on tumour location (frontal → personality change/hemiparesis/Broca's aphasia; temporal → memory/Wernicke's aphasia; parietal → sensory/neglect; occipital → hemianopia)
Acute presentations: Tumour haemorrhage, herniation, status epilepticus
Signs: UMN pattern weakness, visual field defects, papilloedema, Cushing's triad (late)

Classic Radiology: Ring-enhancing lesion with central necrosis, surrounding vasogenic oedema, crossing corpus callosum ("butterfly glioma").

High Yield Summary – Differential Diagnosis of GBM

Always consider brain metastasis — the commonest intracranial tumour overall. Multiple lesions at grey-white junction with known cancer history strongly favours mets. But 10–15% of solitary masses in cancer patients are NOT mets.
Primary CNS lymphoma — homogeneous enhancement, periventricular, restricted diffusion on DWI, T2 iso/hypointense. Do NOT give steroids before biopsy (ghost tumour phenomenon).
Brain abscess — the key differentiator is restricted diffusion on DWI (bright DWI, dark ADC). Clinical context of fever/infection source is critical.
Tumefactive demyelination — younger patient, incomplete "open ring" enhancement, less mass effect, look for other MS lesions and oligoclonal bands.
Astrocytoma, IDH-mutant, Grade 4 — younger, may have prior glioma history; distinguished by IDH mutation testing (not histology alone).
Intra-axial vs extra-axial is the first step: meningioma (extra-axial, dural tail, homogeneous enhancement) should not be confused with GBM (intra-axial).
Tissue diagnosis with molecular profiling is essential for definitive diagnosis and guides treatment. Histological examination remains the gold standard.

High Yield Summary – Diagnosis of GBM

Histological examination is the gold standard — never treat based on imaging alone.
WHO CNS5 diagnostic criteria: Diffuse astrocytic glioma + IDH-wildtype + Grade 4 features (necrosis/microvascular proliferation histologically, OR TERT promoter mutation, EGFR amplification, or +7/−10 molecularly).
MRI with gadolinium is the imaging modality of choice: low T1, ring enhancement with central necrosis, high T2/FLAIR extending beyond enhancing rim.
Enhancement on brain imaging = BBB disruption (or structures outside the BBB). Normal brain does NOT enhance.
fMRI and DTI are for pre-operative planning — identifying eloquent cortex and critical white matter tracts.
MGMT promoter methylation is the most important prognostic/predictive biomarker — determines temozolomide benefit.
IDH mutation status is the most important diagnostic molecular marker — GBM is by definition IDH-wildtype.
Lumbar puncture is usually contraindicated in the setting of a large mass with raised ICP.

High Yield Summary – Management of GBM

Dexamethasone for oedema + levetiracetam for seizures = immediate supportive management.
Maximal safe surgical resection is 1st-line — confirms diagnosis, relieves mass effect, improves survival. 5-ALA fluorescence and neuronavigation optimise extent of resection.
Stupp protocol = Surgery → Concurrent TMZ (75 mg/m²/day) + RT (60 Gy/30#) × 6 weeks → Adjuvant TMZ (150–200 mg/m², 5/28 days) × 6 cycles. Standard of care for age < 70, KPS ≥ 60.
MGMT promoter methylation guides treatment in elderly (≥ 70): methylated → TMZ beneficial; unmethylated → RT alone, TMZ adds little.
Bevacizumab = 2nd-line for recurrent GBM; improves PFS and QoL but NOT overall survival.
TMZ resistance = MGMT enzyme repairs TMZ-induced DNA damage. MGMT silencing (promoter methylation) = better TMZ response.
PCP prophylaxis with co-trimoxazole is mandatory during concurrent TMZ + RT (lymphopaenia risk).
Avoid enzyme-inducing AEDs (phenytoin, carbamazepine) — they reduce TMZ and dexamethasone efficacy via CYP induction.
GBM is incurable. Early palliative care integration improves quality of life. Median OS ~14–16 months with standard treatment.

High Yield Summary – Complications of GBM

Tumour-related:

Raised ICP and brain herniation — manage with dexamethasone, osmotherapy, surgical decompression. Cushing's triad (HTN, bradycardia, irregular respiration) = imminent herniation.
Seizures (50–80% of primary brain tumour patients; always supratentorial). Use levetiracetam; avoid enzyme-inducing AEDs.
Intratumoral haemorrhage — GBM has fragile neovessels. Can mimic primary ICH.
VTE — 20–30% of patients. Tissue factor production → hypercoagulability. Treat with LMWH.
SIADH → hyponatraemia → lowers seizure threshold and worsens oedema.

Treatment-related:

Surgery: new deficits, haemorrhage, infection, CSF leak, seizures.
Radiotherapy: Acute (oedema, fatigue), subacute (somnolence syndrome), delayed (radiation necrosis — mimics recurrence on MRI; distinguish by MR perfusion/spectroscopy/PET; cognitive decline; endocrine dysfunction; secondary malignancy).
Temozolomide: Myelosuppression (thrombocytopaenia is dose-limiting; monitor CBC each cycle), lymphopaenia → PCP risk (co-trimoxazole prophylaxis mandatory), nausea, hepatotoxicity.
Pseudoprogression: 20–30% of patients at 1–3 months post-chemoRT; MRI mimics recurrence but is actually treatment-induced inflammation. More common if MGMT methylated. Do NOT stop treatment prematurely.
Radiation necrosis vs tumour recurrence: Key differentiator = MR perfusion (necrosis = low rCBV, tumour = high rCBV).
Dexamethasone: Hyperglycaemia, myopathy, immunosuppression, osteoporosis, Cushingoid features, GI ulceration, adrenal suppression (must taper).

Glioblastoma

Definition

Epidemiology

Incidence

Age

Sex

Race/Geography

Prognosis (to set the stage)

Risk Factors

Established Risk Factors

Genetic Predisposition Syndromes (Rare but Important)

Factors NOT Proven to Increase Risk

Anatomy and Function (Relevant Neuroanatomy)

Typical Location

Key Anatomical Relationships and Their Clinical Correlates

Blood-Brain Barrier (BBB) Relevance

Etiology and Pathophysiology

Overview: Why GBM is So Aggressive

Molecular Pathogenesis

Primary (De Novo) vs Secondary GBM — The Historical Framework

Key Molecular Alterations in GBM (IDH-wildtype)

The Three Core Signalling Pathways Disrupted in GBM

Pathological Features

Gross Pathology

Histopathology (What You See Under the Microscope)

Immunohistochemistry

Angiogenesis in GBM — Why It Enhances on MRI

Invasion and Infiltration — Why Surgery Can Never Be Curative

MGMT Promoter Methylation — The Most Important Prognostic/Predictive Biomarker

Classification

WHO Classification of CNS Tumours (5th Edition, 2021) — The Integrated Diagnosis

Previous Classification (for Historical Context — Still Appears in Older Notes)

GBM Subtypes (Transcriptomic Classification — Research/Conceptual)

Clinical Features

General Principles of Presentation

Symptoms

A. Symptoms of Raised Intracranial Pressure (ICP)

B. Seizures

C. Progressive Focal Neurological Deficit

D. Non-Specific/Constitutional Symptoms

E. Acute Presentations (Emergencies)

Signs (Physical Examination Findings)

A. General Examination

B. Neurological Examination

C. Signs of Herniation (Late/Emergency)

Summary of Clinical Presentation by Pathophysiology

Active Recall - Glioblastoma: Definition, Epidemiology, Pathophysiology, and Clinical Features

References

Approach to the Differential Diagnosis

Differential Diagnosis Framework

1. Neoplastic Differentials

A. Brain Metastasis — The Most Important Differential

B. Primary CNS Lymphoma (PCNSL)

C. Astrocytoma, IDH-Mutant, Grade 4

D. Other High-Grade Gliomas and CNS Tumours to Consider

2. Infectious Differentials

A. Brain Abscess

B. Toxoplasmosis (in Immunocompromised Patients)

C. Tuberculoma

3. Inflammatory / Demyelinating Differentials

A. Tumefactive Demyelination (Tumefactive MS)

B. Neurosarcoidosis

4. Vascular Differentials

A. Subacute Cerebral Infarct with Luxury Perfusion

B. Resolving Intracerebral Haematoma

5. Other Important Differentials

A. Pituitary Macroadenoma / Craniopharyngioma (Sellar/Suprasellar Region)

B. Meningioma

Summary Table: Key Differentiating Features

Clinical Decision-Making: When the Differential is Uncertain

Active Recall – Differential Diagnosis of Glioblastoma

Diagnostic Criteria — WHO CNS5 (2021)

The WHO CNS5 Integrated Diagnostic Criteria for GBM

Summary of Diagnostic Requirements

Diagnostic Algorithm — Clinical Approach

Investigation Modalities — Detailed Findings and Interpretation

1. Neuroimaging

A. CT Brain (Non-Contrast and Contrast)

B. MRI Brain with Gadolinium Contrast — Gold Standard for Characterisation

C. Functional MRI (fMRI) and Diffusion Tensor Imaging (DTI/Tractography)