Medulloblastoma
Medulloblastoma is a highly malignant embryonal tumor of the cerebellum that predominantly occurs in children and tends to disseminate via cerebrospinal fluid pathways.
Medulloblastoma
Medulloblastoma is a highly malignant (WHO Grade IV), embryonal tumour of the central nervous system that arises from primitive neuroectodermal cells in the posterior fossa (cerebellum). It is the most common malignant brain tumour in children and the most common embryonal tumour of the CNS [1][2][3].
Breaking down the name:
- "Medullo-" refers to the medulla / brainstem region (posterior fossa origin)
- "-blast-" from Greek blastos = immature/embryonic cell
- "-oma" = tumour
So the name literally tells you: an embryonal tumour arising near the medulla/cerebellum. It belongs to the broader category of embryonal tumours in the WHO Classification of CNS Tumours (WHO CNS5, 2021), replacing the older umbrella term "primitive neuroectodermal tumour (PNET)" which is no longer used for CNS tumours.
Key Concept — Malignancy in Brain Tumours
The concept of malignancy is different in primary intracranial tumours [4]. A histologically "benign-looking" brain tumour can behave aggressively (e.g., occupying functionally important areas preventing removal), while a histologically "malignant-looking" brain tumour rarely shows extracranial metastasis (∵ no lymphatic drainage) [4]. However, medulloblastoma is a notable exception — it is one of the few primary brain tumours that can metastasise outside the CNS (e.g., bone, bone marrow, lymph nodes, lungs) and routinely seeds along the craniospinal axis via CSF (drop metastases). TNM staging is therefore not typically used; instead, a specific Chang staging system and molecular subgrouping guide risk stratification.
2. Epidemiology
- Accounts for approximately 15–20% of all paediatric CNS tumours and ~40% of posterior fossa tumours in children [1][2][3].
- Overall incidence: ~5 per million children per year.
- Most common malignant brain tumour in children [1][2].
- In adults, medulloblastoma is rare (~0.5–1 per million per year), accounting for <2% of adult CNS tumours.
- Bimodal peak: highest incidence at 3–7 years (peak ~5 years), with a smaller second peak in young adulthood (20–40 years).
- Children 2–12 years old: 70% infra-tentorial — medulloblastoma, cerebellar astrocytoma, ependymoma, germ cell tumours [5].
- Very rare in infants <1 year (but when it occurs, often desmoplastic/nodular subtype with better prognosis).
- Male predominance: M:F ≈ 1.5–2:1 (overall).
- The sex ratio varies by molecular subgroup (see Classification below) — e.g., SHH subgroup is roughly equal, while Group 3 and Group 4 are strongly male-predominant.
- Follows global trends. No known ethnic predisposition specific to Hong Kong Chinese, though overall paediatric CNS tumour incidence in East Asia is broadly similar to Western populations.
- In Hong Kong, paediatric brain tumours are the second most common childhood malignancy (after leukaemia), and medulloblastoma is the leading malignant subtype in the posterior fossa [3].
3. Risk Factors
The vast majority of medulloblastomas are sporadic with no identifiable risk factor. However, recognised risk factors include:
Familial syndromes are an important category of risk factors for brain tumours [5][6]:
| Syndrome | Gene Mutated | Inheritance | Associated Medulloblastoma Subtype | Other Features |
|---|---|---|---|---|
| Gorlin syndrome (Naevoid basal cell carcinoma syndrome) | PTCH1 (Patched 1) on 9q22 | AD | SHH subgroup (desmoplastic/nodular) | Multiple basal cell carcinomas, odontogenic keratocysts, skeletal anomalies, calcified falx cerebri |
| Turcot syndrome (Type 2) | APC (5q21-22) | AD | WNT subgroup | Familial colon cancer + brain tumours [7]. Also associated with FAP (colonic polyposis + medulloblastoma, ependymomas, high-grade astrocytomas) |
| Li-Fraumeni syndrome | TP53 | AD | SHH subgroup (often with TP53 mutation = very poor prognosis) | Multiple early-onset cancers (sarcomas, breast, leukaemia, adrenal cortical carcinomas) |
| Rubinstein-Taybi syndrome | CREBBP | AD | — | Broad thumbs/toes, intellectual disability |
| Fanconi anaemia | Multiple FA genes | AR | — | Bone marrow failure, congenital anomalies |
High Yield — Turcot Syndrome
Turcot syndrome = familial colon cancer + brain tumours [7]. There are two types:
- Type 1: Mismatch repair gene mutations (MLH1, MSH2 etc.) → glioblastoma + HNPCC (Lynch syndrome)
- Type 2: APC gene mutation → medulloblastoma + FAP (familial adenomatous polyposis) [7]
This is a favourite exam association. If you see a child with medulloblastoma AND a family history of colonic polyps/cancer, think Turcot syndrome Type 2 / APC / FAP.
- High-dose ionizing radiation is the only proven environmental factor for brain tumours (primarily linked to meningiomas and gliomas) [5]. The evidence for radiation causing medulloblastoma specifically is less robust, but prior cranial irradiation is a recognised risk.
- No strong evidence for mobile phones, power lines, dietary factors, or other environmental exposures causing medulloblastoma.
- No association with EBV (unlike primary CNS lymphoma) [5].
- Advanced paternal age has been inconsistently associated with childhood cancers including medulloblastoma, but is not a strong independent risk factor.
4. Anatomy and Function
Understanding the anatomy is essential because the location determines the clinical features.
The posterior fossa (infratentorial compartment) is the space behind/below the tentorium cerebelli. It contains:
- Cerebellum (two hemispheres + midline vermis)
- Brainstem (midbrain, pons, medulla oblongata)
- Fourth ventricle (between cerebellum posteriorly and brainstem anteriorly)
- Cranial nerves IV–XII exit from the brainstem here
The cerebellum ("little brain") coordinates:
- Voluntary movement (timing, coordination, precision)
- Balance and posture (via vestibular connections)
- Motor learning
Key anatomical subdivisions:
- Vermis (midline): primarily controls truncal/axial coordination and gait (truncal ataxia)
- Cerebellar hemispheres (lateral): primarily control ipsilateral limb coordination (appendicular ataxia)
- Cerebellar peduncles: connect cerebellum to brainstem (superior → midbrain, middle → pons, inferior → medulla)
The 4th ventricle sits in the posterior fossa between the cerebellum (roof) and the brainstem (floor). CSF flows:
Lateral ventricles → Foramina of Monro → 3rd ventricle → Cerebral aqueduct (of Sylvius) → 4th ventricle → Foramina of Luschka (lateral) & Magendie (median) → Subarachnoid spaceWhy this matters: Medulloblastoma classically arises from the cerebellar vermis and grows into/compresses the 4th ventricle, obstructing CSF flow → obstructive (non-communicating) hydrocephalus → raised intracranial pressure (↑ICP).
The floor of the 4th ventricle contains cranial nerve nuclei (especially CN V, VI, VII, VIII, IX, X, XII). Tumour invasion or compression of the floor can produce cranial nerve palsies — particularly CN VI (abducens — longest intracranial course, most vulnerable to ↑ICP) and CN VII.
Medulloblastoma has a notorious tendency to seed through the CSF to distant sites along the craniospinal axis ("drop metastases"). This is because:
- The tumour sits directly adjacent to CSF spaces (4th ventricle, cisterna magna)
- Embryonal tumour cells are poorly cohesive and easily shed into CSF
- CSF circulates continuously, carrying tumour cells to the spinal leptomeninges, cerebral surfaces, and cauda equina
5. Aetiology and Pathophysiology
Medulloblastoma arises from cerebellar progenitor cells — specifically:
- Granule neuron precursors (GNPs) in the external granular layer (EGL) of the developing cerebellum → particularly relevant for SHH subgroup
- Progenitor cells in the ventricular zone / rhombic lip → relevant for Group 3 and Group 4
- Lower rhombic lip progenitors → relevant for WNT subgroup
These are embryonal/primitive cells that normally proliferate during cerebellar development and then differentiate and migrate. When mutations disrupt this process, the cells continue proliferating → medulloblastoma.
5.2 Key Molecular Pathways
The WHO CNS5 classification (2021) defines four molecular subgroups, each with distinct driver pathways:
- Pathway: Wingless/WNT signalling pathway activation
- Key mutations: CTNNB1 (β-catenin, somatic activating mutation in ~90%), monosomy 6 (loss of one copy of chromosome 6, highly characteristic), APC germline mutations (Turcot syndrome)
- Pathophysiology: Constitutive WNT pathway activation → nuclear accumulation of β-catenin → transcription of pro-proliferative target genes
- Cell of origin: lower rhombic lip / dorsal brainstem progenitors
- Prognosis: Excellent (>95% 5-year OS) — the "good" subgroup
- Pathway: Sonic Hedgehog signalling pathway activation
- Key mutations: PTCH1 (loss of function → loss of Hedgehog pathway inhibition), SMO (gain of function), SUFU, GLI2, MYCN amplification
- Further subdivided by TP53 status: TP53-mutant (very poor prognosis) vs. TP53-wildtype (intermediate/good)
- Pathophysiology: SHH pathway normally drives granule neuron precursor (GNP) proliferation during cerebellar development. Loss of pathway inhibitors (PTCH1, SUFU) or gain-of-function in activators (SMO) → uncontrolled GNP proliferation
- Cell of origin: external granular layer GNPs
- Associations: Gorlin syndrome (PTCH1), Li-Fraumeni (TP53)
- Age distribution: bimodal — infants and adults (less common in mid-childhood)
Cancer Genetics — Tumour Suppressors and Proto-Oncogenes
Tumour suppressors act as "brakes" on cell growth. They follow the two-hit hypothesis (Knudson) — both alleles must be inactivated for loss of function [8]:
- PTCH1 is a tumour suppressor that normally inhibits the Hedgehog pathway by suppressing SMO
- APC is a tumour suppressor that normally promotes β-catenin degradation
- TP53 is the "guardian of the genome" — a tumour suppressor involved in DNA damage response and apoptosis
Proto-oncogenes become oncogenes through gain-of-function mutations (only ONE allele needs to be mutated) [8]:
- SMO (Smoothened) — gain-of-function activates Hedgehog pathway
- CTNNB1 (β-catenin) — gain-of-function activating mutations
- MYC / MYCN amplification — drives proliferation in Group 3 and SHH subgroups
- Pathway: MYC amplification, photoreceptor/GABAergic differentiation programmes
- Key alterations: MYC amplification (most important), isochromosome 17q [i(17q)], GFI1/GFI1B activation
- Pathophysiology: MYC is a powerful oncogene — its amplification drives uncontrolled proliferation and is associated with aggressive behaviour, large cell/anaplastic histology, and high rates of CSF dissemination
- Cell of origin: cerebellar stem cells
- Prognosis: Worst of all subgroups (~50% 5-year OS or less, especially with MYC amplification)
- Demographics: almost exclusively children (peak 3–5 years), strong male predominance
- Pathway: least understood; involves epigenetic deregulation (histone modifications), PRDM6, KDM6A, ZMYM3, isochromosome 17q
- Key alterations: i(17q) (most common cytogenetic abnormality), MYCN amplification (some), CDK6 amplification, tandem duplications of SNCAIP
- Pathophysiology: epigenomic dysregulation of gene expression → neuronal differentiation block
- Prognosis: Intermediate (~75% 5-year OS)
- Demographics: most common subgroup overall, male predominance, peak in mid-childhood
| Feature | WNT | SHH | Group 3 | Group 4 |
|---|---|---|---|---|
| Frequency | ~10% | ~30% | ~25% | ~35% |
| Age | Children >4y, some adults | Bimodal (infants + adults) | Infants/young children | All ages, peak mid-childhood |
| Sex | M ≈ F | M ≈ F | M >> F | M >> F |
| Key Pathway | WNT/β-catenin | Sonic Hedgehog | MYC | Epigenetic |
| Key Mutations | CTNNB1, monosomy 6 | PTCH1, SMO, SUFU, TP53 | MYC amplification, i(17q) | i(17q), KDM6A |
| Histology | Classic | Desmoplastic/nodular (infants), classic/LC-A | LC-A common, classic | Classic |
| Metastasis at dx | Rare (~5%) | Intermediate | Common (~40–50%) | Intermediate (~35%) |
| Syndrome | Turcot (APC) | Gorlin (PTCH1), Li-Fraumeni (TP53) | — | — |
| Prognosis (5y OS) | >95% | Variable (TP53-wt: good; TP53-mut: poor) | ~50% (worst) | ~75% |
High Yield: The four molecular subgroups (WNT, SHH, Group 3, Group 4) now define biologically and clinically distinct diseases and guide risk stratification and treatment intensity in current protocols.
The clinical manifestations of medulloblastoma are directly explained by the tumour's location and behaviour:
6. Classification
Medulloblastoma is classified under Embryonal Tumours. All medulloblastomas are WHO Grade IV (the highest grade).
Histological subtypes:
| Histological Subtype | Description | Molecular Association | Prognosis Implication |
|---|---|---|---|
| Classic | Sheets of small, round, blue cells with high nuclear:cytoplasmic ratio, Homer-Wright rosettes | Any subgroup | Standard |
| Desmoplastic/nodular (DN) | Reticulin-free "pale islands" (nodules) surrounded by densely packed desmoplastic internodular areas | SHH (especially infants) | Favourable (in infants) |
| Extensive nodularity (MBEN) | Extreme version of DN with very large nodules | SHH (infants) | Very favourable |
| Large cell / anaplastic (LC/A) | Large cells with prominent nucleoli (large cell) + marked nuclear pleomorphism and high mitotic rate (anaplastic) | Group 3 (MYC-amplified), SHH (TP53-mutant) | Worst |
As detailed above: WNT-activated, SHH-activated (TP53-wildtype / TP53-mutant), Group 3, Group 4.
The modern diagnosis of medulloblastoma is an integrated diagnosis combining histology + molecular subgroup + additional molecular features (e.g., MYC amplification, TP53 status).
This older staging system assesses tumour extent (T) and metastasis (M):
| Stage | Description |
|---|---|
| T1 | Tumour <3 cm, limited to vermis/roof of 4th ventricle |
| T2 | Tumour ≥3 cm, filling 4th ventricle |
| T3a | Extension into aqueduct of Sylvius or foramen of Luschka → marked hydrocephalus |
| T3b | Extension into brainstem or floor of 4th ventricle |
| T4 | Extension through aqueduct to 3rd ventricle/midbrain, OR extension below foramen magnum |
| M0 | No metastasis |
| M1 | Tumour cells in CSF (cytology positive) |
| M2 | Intracranial subarachnoid metastasis (nodular seeding beyond primary site) |
| M3 | Spinal subarachnoid metastasis (drop metastases) |
| M4 | Extraneural metastasis (bone, lung, etc.) — rare |
For treatment planning, patients are broadly stratified into:
| Risk Category | Criteria | 5-Year OS |
|---|---|---|
| Standard risk | Age >3 years, ≤1.5 cm² residual tumour, M0 | ~75–85% |
| High risk | Age <3 years, >1.5 cm² residual, M1-M4, MYC/MYCN amplification, LC/A histology, Group 3 | ~50–60% |
Molecular subgrouping is increasingly integrated into risk stratification (e.g., WNT → very low risk regardless of other factors; SHH TP53-mutant → very high risk).
7. Clinical Features
Medulloblastoma: arises in midline of posterior fossa → cerebellar signs ± hydrocephalus [1][4].
The clinical presentation is dominated by two main pathophysiological processes:
- Obstructive hydrocephalus / ↑ICP (from 4th ventricle obstruction) — often the presenting feature
- Cerebellar dysfunction (from destruction/compression of cerebellar tissue)
Additional features arise from brainstem compression, cranial nerve involvement, and CSF dissemination.
Important clinical pearl: The average time from symptom onset to diagnosis is approximately 2–3 months. Symptoms are often initially misattributed to gastroenteritis (vomiting), migraine, or behavioural changes. A high index of suspicion is needed in children with progressive headache and vomiting, especially morning vomiting, with new-onset ataxia.
7.1 Symptoms
| Symptom | Pathophysiological Basis |
|---|---|
| Headache (generalised, dull, constant, worse in morning) | Tumour obstructs 4th ventricle → obstructive hydrocephalus → ↑ICP. Headache is worse in the morning because lying supine at night impairs venous drainage (↑venous pressure → ↑ICP), and CO₂ retention during sleep causes cerebral vasodilation → further ↑ICP. The headache improves during the day with upright posture. |
| Vomiting (especially early morning, often projectile, may occur without preceding nausea) | ↑ICP stimulates the vomiting centre in the medulla (area postrema on the floor of the 4th ventricle). Additionally, direct compression of the area postrema by the tumour itself contributes. "Vomiting without nausea" is characteristic of raised ICP (central mechanism bypasses the nausea pathway). |
| Lethargy / drowsiness / ↓consciousness | ↑ICP → decreased cerebral perfusion pressure (CPP = MAP – ICP) → global cerebral hypoperfusion → depressed consciousness. Also, pressure on the reticular activating system (brainstem) impairs arousal. |
| Irritability / personality change (especially in young children) | Non-specific effect of ↑ICP on frontal lobe function and general cerebral dysfunction. In infants, irritability may be the only behavioural cue. |
| Diplopia (double vision) | CN VI (abducens) palsy — a false localising sign of ↑ICP. CN VI has the longest intracranial course and is stretched/compressed against the petrous apex when ICP rises, causing lateral rectus weakness → esotropia (convergent squint) → horizontal diplopia. This is NOT specific to posterior fossa tumours — it occurs with any cause of ↑ICP. |
| Visual disturbance / blurred vision | Papilloedema (see Signs) → visual obscurations (transient visual blurring lasting seconds, often with posture change). Chronic papilloedema → optic atrophy → permanent visual loss. |
In infants (<1 year) [1]:
- Bulging fontanelle and progressive ↑head circumference (HC) — because cranial sutures are not yet fused, ↑ICP is partially compensated by skull expansion rather than classical headache.
- Irritability, poor feeding, developmental regression, "sun-setting" eyes (tonic downward gaze deviation from compression of tectal plate → upgaze palsy / Parinaud syndrome).
| Symptom | Pathophysiological Basis |
|---|---|
| Unsteady gait / frequent falls (truncal ataxia) | Tumour arises in/near the cerebellar vermis → vermis coordinates midline/truncal balance and gait. Destruction of vermis → loss of truncal coordination → wide-based, staggering gait. The child may fall backwards or to either side. |
| Clumsiness / difficulty with fine motor tasks (appendicular ataxia) | If the tumour extends into a cerebellar hemisphere, it disrupts ipsilateral limb coordination → intention tremor, past-pointing, dysdiadochokinesis. |
| Slurred speech (dysarthria) | Cerebellar dysarthria ("scanning speech" — irregular, staccato, with variable volume) due to incoordination of muscles of articulation. The cerebellum coordinates the timing of speech production. |
| Symptom | Pathophysiological Basis |
|---|---|
| Facial weakness | CN VII compression/invasion at brainstem. |
| Dysphagia / dysphonia | CN IX, X involvement → difficulty swallowing, hoarse voice. |
| Neck pain / head tilt (torticollis) | Tonsillar herniation through foramen magnum (if tumour extends inferiorly), or direct irritation of upper cervical nerve roots. Also, head tilt may be compensatory for diplopia (CN IV palsy). |
| Symptom | Pathophysiological Basis |
|---|---|
| Back pain / radiculopathy | Drop metastases to spinal leptomeninges → nerve root compression. |
| Lower limb weakness / sensory changes | Spinal cord compression from leptomeningeal disease or intramedullary metastasis. |
| Bladder/bowel dysfunction | Cauda equina involvement from drop metastases. |
| Symptom | Pathophysiological Basis |
|---|---|
| Weight loss / failure to thrive | Diencephalic syndrome [1] is more associated with hypothalamic tumours (e.g., craniopharyngioma), but severe illness, persistent vomiting, and catabolic state in medulloblastoma can also lead to weight loss. Additionally, chronic ↑ICP suppresses appetite. |
| Fatigue / malaise | Non-specific effect of chronic illness and raised ICP. |
7.2 Signs
| Sign | Pathophysiological Basis |
|---|---|
| Papilloedema (bilateral disc swelling on fundoscopy) | ↑ICP is transmitted along the optic nerve sheath (which is continuous with subarachnoid space) → compresses the central retinal vein at the optic disc → venous congestion → disc swelling and haemorrhages. This is a late feature [1][4]. |
| Cushing's triad (hypertension, bradycardia, irregular respiration) | A late feature [1][4] indicating impending brainstem herniation. ↑ICP → brainstem ischaemia → Cushing reflex: sympathetic activation → hypertension; baroreceptor-mediated reflex bradycardia; respiratory centre dysfunction → irregular breathing. This is a neurosurgical emergency. |
| ↓Glasgow Coma Scale (GCS) | Progressive impairment of consciousness from ↑ICP → decreased cerebral perfusion and brainstem compression. |
| Bulging fontanelle, progressive ↑HC (infants) | Open sutures allow skull expansion as a compensatory mechanism for ↑ICP. |
| "Sun-setting" eyes (Parinaud syndrome / upgaze palsy) | Compression of the tectal plate (dorsal midbrain / superior colliculi) by dilated 3rd ventricle or upward herniation → paralysis of upward gaze. The eyes deviate downward, with the sclerae visible above the iris — resembling a "setting sun." |
| CN VI palsy (lateral rectus weakness → esotropia) | False localising sign of ↑ICP, as described above. |
| Sign | Pathophysiological Basis |
|---|---|
| Truncal ataxia (wide-based, staggering gait; unable to tandem walk; Romberg +/−) | Vermis involvement → midline/truncal cerebellar dysfunction. The child cannot sit or stand without swaying. Gait is wide-based because the patient widens the base of support to compensate for poor truncal balance. |
| Appendicular ataxia (intention tremor, past-pointing, dysmetria on finger-nose test) | Hemisphere involvement → ipsilateral limb incoordination. The tremor worsens as the finger approaches the target (intention tremor) because the cerebellum fails to make corrective adjustments. |
| Dysdiadochokinesis | Inability to perform rapid alternating movements (e.g., pronation/supination) due to cerebellar timing dysfunction. |
| Nystagmus (often gaze-evoked, multidirectional) | Disruption of vestibulocerebellar connections (flocculonodular lobe/fastigial nucleus) → failure to maintain stable gaze → rhythmic oscillation of eyes. May be horizontal, vertical, or rotatory. |
| Hypotonia (ipsilateral to hemisphere lesion) | The cerebellum normally facilitates muscle tone via connections with the reticular formation. Loss of cerebellar input → decreased tone. |
| Pendular reflexes | Due to hypotonia — the limb swings back and forth after reflex testing (like a pendulum) instead of briskly returning to position. |
| Sign | Pathophysiological Basis |
|---|---|
| CN defects, pyramidal tract signs, cerebellar signs [1] | Tumour invasion of or compression on the brainstem → cranial nerve palsies (especially lower CN), long tract signs (UMN weakness — hyperreflexia, upgoing plantars, spasticity), and combined cerebellar signs. |
| CN VI palsy (abducens) | Most vulnerable CN to ↑ICP (long intracranial course). Also directly compressed if tumour invades brainstem. |
| CN VII palsy (facial nerve — LMN type if brainstem nuclei involved) | Tumour invasion of brainstem CN VII nucleus → ipsilateral LMN facial weakness (forehead AND lower face affected). |
| Lower CN palsies (IX, X, XI, XII) | Inferiorly extending tumour or tonsillar herniation compresses lower medullary nuclei → dysphagia, dysphonia, tongue deviation. |
| Pyramidal tract signs (UMN signs) | Compression of corticospinal tracts in brainstem → contralateral (or bilateral) spastic weakness, hyperreflexia, Babinski sign positive (upgoing plantars). |
| Sign | Pathophysiological Basis |
|---|---|
| Spinal tenderness | Leptomeningeal metastases irritating spinal meninges. |
| Lower limb UMN signs | Spinal cord compression from drop metastases. |
| Cauda equina signs (reduced perineal sensation, loss of anal tone, absent ankle jerks) | Drop metastases to cauda equina → LMN damage. |
| Sign | Type of Herniation |
|---|---|
| Ipsilateral pupil dilation (CN III palsy) | Uncal (transtentorial) herniation: the uncus of the temporal lobe herniates through the tentorial notch, compressing CN III → fixed dilated pupil. Less common in pure posterior fossa tumours but can occur with upward transtentorial herniation. |
| Neck stiffness / head tilt | Tonsillar herniation: cerebellar tonsils herniate through foramen magnum → compression of cervicomedullary junction → neck stiffness (meningism), torticollis, and eventually respiratory arrest. This is the most dangerous herniation pattern in posterior fossa tumours. |
| Decerebrate / decorticate posturing | Severe brainstem compression from herniation. |
Clinical Pearl — Classic Presentation of Medulloblastoma
The classic presenting child is a 3–7-year-old boy with:
- Progressive morning headaches and projectile vomiting (↑ICP from obstructive hydrocephalus)
- Unsteady gait / truncal ataxia (midline cerebellar vermis involvement)
- Papilloedema on fundoscopy
This triad should trigger urgent neuroimaging (MRI brain with contrast). Do NOT perform a lumbar puncture first — the posterior fossa mass may cause tonsillar herniation (coning) if CSF is drained from below.
Important — Why NOT Lumbar Puncture First?
A common and dangerous mistake: performing LP in a patient with signs of ↑ICP from a posterior fossa mass. Removing CSF from the lumbar space creates a pressure gradient → cerebellar tonsils herniate through foramen magnum → brainstem compression → respiratory arrest → death. Always image first (CT or MRI) before considering LP in a child with headache, vomiting, and neurological signs.
| Mechanism | Clinical Features |
|---|---|
| Obstructive hydrocephalus / ↑ICP | Headache (worse in morning), projectile vomiting, papilloedema, ↓GCS, CN VI palsy, bulging fontanelle/↑HC (infants), Cushing's triad, sun-setting eyes |
| Cerebellar vermis destruction | Truncal ataxia, wide-based gait, nystagmus |
| Cerebellar hemisphere involvement | Ipsilateral appendicular ataxia, intention tremor, dysmetria, dysdiadochokinesis, hypotonia |
| Brainstem compression/invasion | CN palsies (VI, VII, IX-XII), pyramidal signs, dysarthria, dysphagia |
| CSF dissemination | Back pain, radiculopathy, lower limb weakness, cauda equina syndrome |
| Tonsillar herniation | Neck stiffness, head tilt, respiratory arrest |
A child with cancer — paediatric cancers [3]:
- Paediatric brain tumours are the most common solid tumour in children and the second most common childhood malignancy (after leukaemia) [3].
- In children 2–12 years, 70% of brain tumours are infra-tentorial [5].
- Medulloblastoma is the most common malignant paediatric brain tumour but not the most common paediatric brain tumour overall (pilocytic astrocytoma is the most common paediatric brain tumour if including all grades).
- Young age (<3 years) is a poor prognostic factor because:
- Craniospinal irradiation (CSI) causes devastating neurocognitive sequelae in very young children → treatment is modified (chemotherapy-only protocols attempted)
- Some molecular subtypes presenting in infants (e.g., Group 3 with MYC amplification) are inherently aggressive
High Yield Summary
Medulloblastoma — Key Facts for Exams
- Definition: WHO Grade IV embryonal tumour of the cerebellum (posterior fossa). Most common malignant brain tumour in children.
- Epidemiology: Peak age 3–7 years, M > F. 15–20% of paediatric CNS tumours. Children 2–12yo: 70% infratentorial.
- Location: Arises in midline of posterior fossa (cerebellar vermis) → cerebellar signs ± hydrocephalus.
- Risk factors: Mostly sporadic. Genetic syndromes: Turcot syndrome (APC → FAP + medulloblastoma), Gorlin syndrome (PTCH1), Li-Fraumeni (TP53). High-dose ionizing radiation is the only proven environmental factor for brain tumours.
- Molecular subgroups (4): WNT (best prognosis, monosomy 6), SHH (PTCH1, TP53 matters), Group 3 (MYC amplification, worst prognosis), Group 4 (most common, intermediate prognosis).
- Pathophysiology: 4th ventricle obstruction → obstructive hydrocephalus → ↑ICP. Cerebellar destruction → ataxia. CSF seeding → drop metastases (spinal, leptomeningeal).
- Classic presentation: Young child with progressive morning headache, projectile vomiting, truncal ataxia, and papilloedema.
- Key signs: Truncal ataxia, wide-based gait, nystagmus, papilloedema, CN VI palsy (false localising sign), Cushing's triad (late).
- Danger: Never LP before imaging in suspected posterior fossa mass — risk of tonsillar herniation.
- Malignancy concept: Primary brain tumours rarely metastasise extracranially (∵ no lymphatic drainage) — but medulloblastoma is a notable exception that CAN (M4 stage, rare).
- Histological subtypes: Classic, desmoplastic/nodular, extensive nodularity (MBEN), large cell/anaplastic (worst).
- Risk stratification: Standard risk (>3y, gross total resection, M0) vs. High risk (<3y, residual tumour, M+, MYC amp, LC/A).
Active Recall - Medulloblastoma (Definition, Epidemiology, Pathophysiology, Classification, Clinical Features)
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 430 — Clinical Approach to Paediatric Brain Tumours) [2] Senior notes: Ryan Ho Neurology.pdf (p. 161 — Intracranial Tumours) [3] Lecture slides: Block C - A child with cancer_ paediatric cancers.pdf; GC 140. A child with cancer_paediatric cancers.pdf [4] Senior notes: Ryan Ho Neurology.pdf (p. 161 — General Principles of Intracranial Tumours); Adrian Lui Pediatrics Notes.pdf (p. 430) [5] Senior notes: Maksim Surgery Notes.pdf (p. 360 — Brain Tumours: Epidemiology, Classifications, Tumour locations by age) [6] Lecture slides: GC 156. Many of my family members have cancers Cancer genetics and cytogenetics (File 2).pdf [7] Senior notes: Ryan Ho GI.pdf (p. 181 — Familial Adenomatous Polyposis, Turcot Syndrome) [8] Lecture slides: Cancer Block - CMB22 Part2 - Cancer genetics - Tumor Suppressors Proto-Oncogenes.pdf; Cancer Block - CMB22 Part1 - Cancer genetics - Passenger vs. Driver and Germline vs. Somatic.pdf
Differential Diagnosis of Medulloblastoma
When a child presents with the classic triad of progressive headache, vomiting, and ataxia — or more broadly, features of a posterior fossa mass — medulloblastoma sits at the top of the differential, but several other conditions can present in a very similar manner. The differential can be structured by thinking about what else can occupy the posterior fossa in a child, and what else can mimic raised ICP with cerebellar signs.
The key clinical question is: In children 2–12 years old, 70% of brain tumours are infra-tentorial [5] — so the DDx is dominated by posterior fossa tumours. In adults (where 80–85% of brain tumours are supratentorial [4]), the DDx shifts dramatically.
Think of the differential in two tiers:
- Other posterior fossa tumours (the main DDx — same location, overlapping features)
- Non-neoplastic posterior fossa lesions (infections, vascular, congenital malformations that can mimic)
Tier 1: Other Posterior Fossa Tumours in Children
These are the most important differentials because they share the same anatomical compartment and therefore produce similar symptoms (↑ICP from hydrocephalus, cerebellar signs, brainstem compression). The distinction is made on age, precise location within the posterior fossa, imaging characteristics, and ultimately histopathology.
PA is the most common astrocytoma in children and is classified as Grade I (WHO) [9][10].
| Feature | Pilocytic Astrocytoma | Medulloblastoma |
|---|---|---|
| WHO Grade | Grade I (low grade, benign behaviour) | Grade IV (highly malignant) |
| Incidence | Most common paediatric posterior fossa tumour overall (most common paediatric brain tumour when including all sites) | Most common malignant paediatric brain tumour |
| Age | Peak 5–15 years (slightly older than medulloblastoma) | Peak 3–7 years |
| Location | Cerebellar hemisphere (lateral) > vermis. Classical site is cerebellum but can occur anywhere in CNS including hypothalamus, optic nerve and chiasmal region [9][10] | Midline cerebellar vermis → 4th ventricle |
| Predominant signs | Appendicular ataxia (ipsilateral limb incoordination) because hemisphere location | Truncal ataxia (midline gait disturbance) because vermis location |
| Growth rate | Slow, indolent | Rapid, aggressive |
| Imaging (MRI) | Well-demarcated, cystic with enhancing mural nodule ("cyst + nodule" pattern), minimal oedema | Solid, homogeneously enhancing midline mass filling 4th ventricle, restricted diffusion on DWI (high cellularity) |
| CSF dissemination | Low metastatic potential [9][10] | High propensity to disseminate through subarachnoid space (leptomeningeal dissemination) [9][10] |
| Prognosis | Excellent (>95% cure with surgery alone) | Depends on subgroup (50–95%) |
| Associations | NF1 (optic pathway glioma variant) | Turcot syndrome (APC), Gorlin (PTCH1), Li-Fraumeni (TP53) |
Why does location help you differentiate? Pilocytic astrocytoma favours the cerebellar hemisphere → predominantly appendicular ataxia (clumsy hand, past-pointing on finger-nose). Medulloblastoma favours the vermis → predominantly truncal ataxia (wide-based staggering gait, can't sit unsupported). This is a classic exam discriminator.
High Yield — Pilocytic Astrocytoma vs Medulloblastoma
Both are common posterior fossa tumours in children. The key clinical distinction:
- JPA: lateral hemisphere, cystic + mural nodule on MRI, slow-growing, appendicular ataxia, Grade I, excellent prognosis, rarely invasive and rarely undergo malignant transformation [9][10]
- Medulloblastoma: midline vermis, solid enhancing mass, restricted diffusion, rapid onset, truncal ataxia, Grade IV, CSF seeding common
Ependymoma: arises in 4th ventricle or other CSF spaces → hydrocephalus or spinal cord S/S [1].
| Feature | Ependymoma | Medulloblastoma |
|---|---|---|
| Cell of origin | Ependymal cells lining the ventricles | Cerebellar progenitor cells (embryonal) |
| WHO Grade | Grade II (classic) or Grade III (anaplastic); some Grade I (subependymoma, myxopapillary) | Grade IV |
| Age | Peak <5 years (posterior fossa type); also occurs in adults (spinal ependymoma) | Peak 3–7 years |
| Location | Arises from floor of 4th ventricle, tends to extend through foramina of Luschka (laterally) into the cerebellopontine angle (CPA), or through foramen of Magendie (inferiorly) — described as "plastic" or "toothpaste-like" growth | Arises from roof of 4th ventricle / cerebellar vermis, fills 4th ventricle |
| Key imaging feature | Heterogeneous, calcification common (~50%), may extend through 4th ventricle foramina ("squeeze" pattern) | Homogeneous, solid, restricted diffusion (high cellularity) |
| CSF dissemination | Less common than medulloblastoma (~10–15%) but can occur | Very common (~30–40% at diagnosis) |
| Brainstem involvement | Frequently adherent to brainstem floor → making surgical resection difficult and incomplete → high recurrence | Less likely to invade brainstem directly (more compressive) |
| Treatment | Surgery (extent of resection is the most important prognostic factor) ± focal radiotherapy. Chemotherapy has limited efficacy | Surgery + craniospinal irradiation + chemotherapy |
Why the distinction matters clinically: Ependymoma tends to present with more cranial nerve deficits early (because it arises from the floor of the 4th ventricle where CN nuclei reside), and often presents with neck stiffness/torticollis (extension through foramen of Magendie). Its extension through the foramina gives a characteristic "cast-like" appearance on imaging.
| Feature | AT/RT | Medulloblastoma |
|---|---|---|
| Age | Typically <3 years (median ~1 year) — this is the key distinguisher | Peak 3–7 years |
| WHO Grade | Grade IV | Grade IV |
| Molecular hallmark | Loss of INI1/SMARCB1 (or rarely SMARCA4) — pathognomonic. INI1 is a tumour suppressor on chromosome 22q11.2, part of the SWI/SNF chromatin remodelling complex | Molecular subgroups (WNT, SHH, Grp3, Grp4) |
| Histology | Heterogeneous — rhabdoid cells, epithelial, mesenchymal, and primitive neuroectodermal components (hence "teratoid") | Small round blue cells, Homer-Wright rosettes |
| Imaging | Can be very similar to medulloblastoma; may have heterogeneous enhancement, haemorrhage, cystic change | More homogeneously solid and enhancing |
| Prognosis | Very poor (<30% 2-year survival historically) — worse than medulloblastoma overall | Varies by subgroup (50–95%) |
Exam pearl: If an infant (<2–3 years) presents with a posterior fossa mass that looks like a medulloblastoma on imaging, you must rule out AT/RT. The two can look identical on MRI. The key is INI1 immunohistochemistry — loss of INI1 nuclear staining is diagnostic of AT/RT.
Brainstem glioma: arises in brainstem → CN defects, pyramidal tract signs, cerebellar signs [1].
| Feature | Diffuse Midline Glioma | Medulloblastoma |
|---|---|---|
| Location | Pons (brainstem — ventral, expanding the pons diffusely) | Cerebellum (vermis) / 4th ventricle |
| Molecular hallmark | H3 K27M mutation (histone mutation) — now classified as "Diffuse midline glioma, H3 K27-altered" in WHO CNS5 | WNT, SHH, Grp3, Grp4 |
| WHO Grade | Grade IV | Grade IV |
| Age | 5–10 years (peak ~6–7) | 3–7 years |
| Presentation | CN defects (especially VI, VII), pyramidal tract signs, cerebellar signs [1]. Classic triad: cranial neuropathies + long tract signs + ataxia. ↑ICP is a late feature (unlike medulloblastoma where it's often presenting) | ↑ICP and truncal ataxia are typically early/presenting features |
| Imaging | T2/FLAIR hyperintense, diffusely expanding pons (>50% of pons), often non-enhancing, no restricted diffusion | Midline cerebellar mass, enhancing, restricted diffusion |
| Biopsy | Historically diagnosed on imaging alone (biopsy risky); now stereotactic biopsy increasingly performed to confirm H3 mutation | Surgical resection → histological diagnosis |
| Prognosis | Dismal (median survival ~9–11 months, <10% 2-year survival) | Variable (50–95% depending on subgroup) |
Why differentiation matters: DIPG/diffuse midline glioma is not surgically resectable (diffusely infiltrating the pons makes resection impossible without devastating neurological injury). This is in stark contrast to medulloblastoma where maximal safe resection is the cornerstone of treatment. The clinical triad of DIPG (CN palsies + long tract signs + ataxia with a diffusely expanded pons on MRI) is quite distinct from medulloblastoma's presentation (↑ICP + truncal ataxia with a discrete 4th ventricle mass).
| Tumour | Key Distinguishing Features |
|---|---|
| Choroid plexus papilloma / carcinoma | Arises from choroid plexus within 4th ventricle. Papillomas are benign (Grade I). Can cause hydrocephalus by CSF overproduction or obstruction. Peak in infants. Imaging: lobulated, intensely enhancing intraventricular mass. |
| Haemangioblastoma | Benign (Grade I), vascular tumour. Typically in adults (rare in children unless von Hippel-Lindau syndrome). Cystic + enhancing mural nodule (can mimic JPA). Highly vascular → bright on angiography. |
| Dermoid / epidermoid cyst | Congenital inclusion cysts. Dermoid: midline, may contain fat/calcification. Epidermoid: off-midline (CPA), restricted diffusion. Both slow-growing, may present with chemical meningitis if rupture. |
| Germ cell tumours [5] | More commonly supratentorial (pineal region, suprasellar) but can rarely occur in posterior fossa. Peak in adolescents. Elevated tumour markers (AFP, β-hCG) in serum/CSF. |
These mimic the presentation of medulloblastoma because they also cause posterior fossa signs ± hydrocephalus, but they are not tumours.
| Condition | How It Mimics Medulloblastoma | How to Differentiate |
|---|---|---|
| Cerebellar abscess | Headache, vomiting, ataxia, ↑ICP, posterior fossa mass on imaging | History of chronic otitis media / mastoiditis (direct spread) or congenital heart disease with right-to-left shunt (haematogenous). Fever and raised inflammatory markers. MRI: ring-enhancing lesion with restricted diffusion centrally (pus restricts diffusion — similar to medulloblastoma, but the ring enhancement pattern and central cavity differ from a solid mass). |
| Acute post-infectious cerebellitis | Acute ataxia in a child — can mimic cerebellar tumour | Typically post-viral (varicella, EBV, influenza). Acute onset over days, often self-limiting. MRI: diffuse cerebellar swelling without a discrete mass. History of preceding viral illness 1–3 weeks prior. |
| Arachnoid cyst (posterior fossa) | Can cause obstructive hydrocephalus and cerebellar compression | Usually an incidental finding, slow-growing. MRI: CSF-signal cyst without enhancement or solid component. No restricted diffusion. |
| Dandy-Walker malformation | Posterior fossa cyst + hydrocephalus in infancy | Congenital: cystic dilatation of 4th ventricle + hypoplasia/agenesis of cerebellar vermis + enlarged posterior fossa. Usually diagnosed antenatally or in infancy. No solid enhancing mass. |
| Cerebellar haemorrhage / infarct | Acute posterior fossa symptoms (headache, vomiting, ataxia, ↓GCS) | Hyperacute onset (minutes to hours) rather than subacute (weeks). CT: hyperdense blood (haemorrhage) or hypodense area (infarct). Context: trauma, coagulopathy, vascular malformation (haemorrhage) or cardiac disease (infarct). |
| Tuberculoma | Posterior fossa mass with ↑ICP | Endemic area exposure, chronic symptoms, constitutional features. Ring-enhancing lesion with central caseation. CSF: lymphocytic pleocytosis, low glucose, elevated protein. |
These are conditions that share some clinical features with medulloblastoma but arise from different locations or pathologies:
| Condition | Shared Features | How to Differentiate |
|---|---|---|
| Craniopharyngioma | ↑ICP, headache, vomiting | Arises in suprasellar region → VF defect, hypopituitarism, diencephalic syndrome [1]. Presence of calcifications (50%) [11]. Symptoms: growth retardation, DI, bitemporal hemianopia, hydrocephalus (from 3rd ventricle obstruction) [11]. Not a posterior fossa tumour. |
| Pituitary adenoma | Headache, visual disturbance | Pituitary adenomas → adults [11]. Suprasellar, bitemporal hemianopia, endocrine dysfunction. Very rare in children. |
| Pineal region tumours (germinoma, pineoblastoma) | ↑ICP (aqueductal obstruction), Parinaud syndrome | Aqueductal stenosis from pineal mass → obstructive hydrocephalus. Parinaud syndrome (upgaze palsy, convergence-retraction nystagmus, light-near dissociation). Elevated tumour markers (AFP, β-hCG for germ cell tumours). Imaging: mass in pineal region, NOT in posterior fossa. |
| Retinoblastoma (trilateral retinoblastoma) | Midline brain tumour in a child | Trilateral retinoblastoma = bilateral retinoblastoma + midline intracranial tumour (usually pineoblastoma, but can be suprasellar PNET). Presents with leukocoria + intracranial mass. Associated with germline RB1 mutations [12]. |
| Feature | Medulloblastoma | Pilocytic Astrocytoma | Ependymoma | DIPG / Diffuse Midline Glioma |
|---|---|---|---|---|
| Grade | IV | I | II–III | IV |
| Cell origin | Embryonal (progenitor) | Astrocyte | Ependymal | Glial (astrocytic lineage) |
| Location | Vermis / 4th ventricle roof | Cerebellar hemisphere | 4th ventricle floor | Pons (brainstem) |
| Peak age | 3–7y | 5–15y | <5y | 5–10y |
| Presenting feature | ↑ICP + truncal ataxia | Appendicular ataxia → ↑ICP later | ↑ICP + CN palsies + torticollis | CN palsies + long tract signs + ataxia |
| MRI | Solid, midline, enhancing, restricted diffusion | Cyst + mural nodule, lateral | Heterogeneous, calcification, extends through foramina | Diffuse pontine expansion, T2-bright, non-enhancing |
| CSF seeding | Very common | Very rare | Uncommon | Rare |
| Surgery | Maximal safe resection | Curative resection | Resection (often incomplete) | Not resectable |
| Prognosis | 50–95% (by subgroup) | >95% | 50–75% | <10% (2y) |
Clinical Pearl — The 6-Year-Old with Posterior Fossa Signs
A 6-year-old presenting with acute onset, unwell, effortless vomiting, unsteady gait, double vision [13]:
- Esotropic squint → L CN VI palsy [13]
- Adult: think mononeuritis multiplex, vasculitis, HT, DM [13]
- Child: think false localising sign of raised ICP [13]
- CN VI at risk of compression in raised ICP [13]
- Plus morning vomiting, cerebellar signs → raised ICP from posterior fossa lesion
- Neuroimaging: usually inferior fossa lesion → MRI brain with contrast to look for intracranial tumour [13]
This is a classic ophthalmology/neurology crossover exam question. The CN VI palsy in a child is NOT a microvascular palsy (that's for adults with diabetes/hypertension) — it is a red flag for raised ICP until proven otherwise.
In practice, the differentiation is made by:
- Age: AT/RT (<3y), ependymoma (<5y), medulloblastoma (3–7y), JPA (5–15y), DIPG (5–10y)
- Precise location: vermis (medulloblastoma), hemisphere (JPA), 4th ventricle floor (ependymoma), pons (DIPG)
- Imaging characteristics:
- Restricted diffusion (DWI bright, ADC dark) → high cellularity → medulloblastoma or AT/RT (both embryonal with densely packed small cells)
- Cyst + mural nodule → pilocytic astrocytoma or haemangioblastoma
- Calcification + extension through foramina → ependymoma
- Diffuse pontine expansion → DIPG
- CSF cytology (post-operatively or at staging): positive in medulloblastoma (CSF seeding)
- Histopathology and molecular markers: definitive diagnosis
- INI1 loss → AT/RT
- H3 K27M → Diffuse midline glioma
- β-catenin nuclear staining + monosomy 6 → WNT medulloblastoma
- GFAP+, EMA+ → Ependymoma
- Piloid architecture, BRAF-KIAA1549 fusion → Pilocytic astrocytoma
High Yield Summary — DDx of Medulloblastoma
Top differentials for a posterior fossa mass in a child:
- Pilocytic astrocytoma (JPA) — most common overall posterior fossa tumour; cerebellar hemisphere, cyst + nodule, Grade I, excellent prognosis
- Ependymoma — 4th ventricle floor, extends through foramina, calcification, adherent to brainstem
- Atypical teratoid / rhabdoid tumour (AT/RT) — infants <3y, looks like medulloblastoma on MRI, INI1 loss, very poor prognosis
- Diffuse midline glioma / DIPG — pons, H3 K27M, CN palsies + long tracts, not resectable, dismal prognosis
- Craniopharyngioma — suprasellar not posterior fossa, but enters DDx of paediatric brain tumour with ↑ICP; calcification, visual field defects, endocrine dysfunction
Key discriminators: Age, location within posterior fossa, MRI features (especially DWI), molecular markers, CSF seeding tendency.
Non-neoplastic mimics: Cerebellar abscess (ring-enhancing, fever, otitis media), acute cerebellitis (post-viral, no mass), arachnoid cyst, Dandy-Walker, cerebellar haemorrhage/infarct.
Active Recall - DDx of Medulloblastoma
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 430 — Clinical Approach to Paediatric Brain Tumours) [4] Senior notes: Ryan Ho Neurology.pdf (p. 161 — General Principles of Intracranial Tumours) [5] Senior notes: Maksim Surgery Notes.pdf (p. 360 — Brain Tumours: Tumour locations by age) [9] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1258 — Features of different brain tumours: Astrocytomas, PNETs) [10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 530 — Features of different brain tumours: Astrocytomas, PNETs) [11] Senior notes: Block A - I keep on bumping into people on my side_ pituitary tumours; hypopituitarism.pdf (p. 6 — Craniopharyngiomas) [12] Senior notes: Ryan Ho Opthalmology.pdf (p. 120 — Retinoblastoma) [13] AOS material: AOS - Ophthalmology (Ans:Notes).pdf (p. 3 — CN VI palsy in child, false localising sign of raised ICP)
Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Medulloblastoma
Unlike many systemic cancers, medulloblastoma does not have a simple set of "diagnostic criteria" akin to, say, the Jones criteria for rheumatic fever or the ACR criteria for SLE. Instead, the diagnosis is an integrated, stepwise process combining:
- Clinical suspicion (symptoms/signs of posterior fossa mass + ↑ICP)
- Neuroimaging (MRI brain with contrast — the pivotal investigation)
- Surgical resection and histopathological examination — the definitive diagnostic step
- Molecular classification (determines subgroup, risk stratification, and treatment)
- Staging investigations (craniospinal MRI + CSF cytology to assess dissemination)
Histological examination of biopsy specimen remains most important component of diagnostic evaluation of brain tumours [9][10]. Histological confirmation is obtained at the time of surgical exploration for resection [9][10]. This means that in medulloblastoma, diagnosis and initial treatment (resection) happen simultaneously — you don't typically biopsy first and operate later. The tumour is resected, and the specimen is sent for comprehensive analysis.
The WHO CNS5 classification requires an integrated diagnosis that layers together:
| Layer | What It Tells You | How It's Obtained |
|---|---|---|
| 1. Histological type | Confirms it is medulloblastoma (not ependymoma, AT/RT, etc.) + determines histological subtype (classic, DN, MBEN, LC/A) | Light microscopy of resected tumour, immunohistochemistry |
| 2. WHO Grade | All medulloblastomas are Grade IV | Defined by the entity itself |
| 3. Molecular subgroup | WNT, SHH (TP53-wt or TP53-mut), Group 3, or Group 4 | Molecular testing (methylation profiling, IHC for β-catenin/GAB1/YAP1/filamin A, FISH/sequencing for TP53, MYC, MYCN) |
| 4. Additional molecular features | MYC/MYCN amplification, TP53 status, i(17q), monosomy 6, etc. | Cytogenetics (FISH, karyotyping), next-generation sequencing (NGS), methylation arrays |
Example of an integrated diagnosis: Medulloblastoma, SHH-activated, TP53-wildtype, WHO Grade IV, desmoplastic/nodular histology
Why an Integrated Diagnosis?
The same histological appearance can belong to different molecular subgroups with vastly different prognoses and treatment responses. For instance, a "classic" medulloblastoma could be WNT (>95% cure) or Group 3 (~50% survival) — you cannot distinguish these by microscopy alone. Modern protocols require molecular subgrouping before finalising treatment intensity. This is analogous to how ALL requires cytogenetics/molecular genetics for risk stratification before treatment [14].
The following algorithm represents the clinical pathway from initial presentation to completed diagnosis and staging:
Key points about the algorithm:
-
CT brain is the first imaging in the acute setting — it is fast (1 minute), widely available, and excellent at detecting hydrocephalus, calcification, and gross mass effect. However, CT is inferior to MRI for characterising the tumour and detecting leptomeningeal disease [4][15].
-
MRI brain with gadolinium contrast is the gold-standard neuroimaging — it provides superior soft tissue detail, multiplanar imaging, and the ability to detect CSF seeding [15]. Neuroimaging: usually inferior fossa lesion → MRI brain with contrast to look for intracranial tumour [13].
-
Pre-operative spinal MRI is ideal — performed before surgery if possible, because post-operative blood products in the CSF can create artefacts mimicking drop metastases. If pre-op spinal MRI is not possible, it should be done ≥2 weeks post-operatively to allow blood products to clear.
-
CSF cytology is obtained post-operatively (usually ≥2 weeks post-surgery), NOT pre-operatively — because LP is contraindicated before surgery in the presence of a posterior fossa mass (risk of tonsillar herniation). The CSF is obtained either via LP or intra-operatively.
-
Surgical resection provides tissue for the definitive histological and molecular diagnosis.
Investigation Modalities — Detailed
A. Neuroimaging
| Feature | Details |
|---|---|
| Role | First-line emergency imaging. Rapid exclusion of hydrocephalus, haemorrhage, and large mass lesions. CT brain: site and multiplicity, mass effect [4]. |
| Why CT first? | Fast (1 minute), widely available 24/7, excellent for detecting acute blood (hyperdense) and calcification, and for assessing ventricular size (hydrocephalus) [15]. |
| Typical findings in medulloblastoma | Hyperdense (iso- to hyperdense compared to brain parenchyma, because of high cellularity → high nuclear:cytoplasmic ratio → dense tissue) midline posterior fossa mass centred on the vermis/4th ventricle. Hydrocephalus (dilated lateral and 3rd ventricles) in >90%. Calcification in ~10–20% (less common than in ependymoma or craniopharyngioma). May see perilesional oedema. |
| Contrast enhancement | Normal brain tissue does not enhance (due to BBB). Enhancement indicates: (1) outside BBB, e.g. meningioma (homogeneously enhancing), or (2) disruption of BBB, e.g. high-grade tumours, stroke, inflammation [4]. Medulloblastoma shows moderate-to-intense, relatively homogeneous enhancement because the tumour disrupts the BBB. |
| Limitations | Poor soft tissue contrast compared to MRI. Cannot reliably characterise tumour type. Cannot detect leptomeningeal disease. Posterior fossa artefact (beam-hardening from dense petrous bones) can obscure small lesions [15]. |
This is the definitive pre-operative neuroimaging investigation.
| MRI Sequence | Findings in Medulloblastoma | Why / Pathophysiological Basis |
|---|---|---|
| T1-weighted | Iso- to hypointense (dark relative to brain) | High cellularity with scant cytoplasm → low water content → low T1 signal |
| T1 + Gadolinium | Heterogeneous enhancement (often intense) | BBB disruption by high-grade tumour → gadolinium leaks into tumour tissue → T1 shortening → bright signal. The heterogeneity reflects areas of necrosis/cyst that don't enhance |
| T2-weighted | Iso- to hyperintense (brighter than brain) | Increased water content in tumour tissue relative to normal brain, though less bright than pure fluid because of dense cellularity |
| FLAIR | Hyperintense | Suppresses CSF signal → highlights tumour and perilesional oedema against dark CSF |
| DWI (Diffusion-Weighted Imaging) | Restricted diffusion — bright on DWI, dark on ADC map | This is the key MRI feature that distinguishes medulloblastoma from most other posterior fossa tumours. High cellularity = densely packed small round cells → water molecules cannot diffuse freely between cells → restricted diffusion. This is why medulloblastoma (and AT/RT) show restricted diffusion, while pilocytic astrocytoma (fewer, larger cells with more extracellular space) does not. |
| MR spectroscopy | Elevated choline (cell membrane turnover), elevated taurine (relatively specific for medulloblastoma), reduced N-acetyl aspartate (NAA) (neuronal loss), elevated choline/NAA ratio | Choline reflects rapid cell proliferation (membrane synthesis). NAA is a marker of mature neurons — its reduction indicates replacement of normal neurons by tumour. Taurine peak is somewhat characteristic of medulloblastoma among posterior fossa tumours. |
| Spinal MRI (whole spine with Gd) | Leptomeningeal enhancement, nodular deposits ("drop metastases") along spinal cord or cauda equina | CSF dissemination of tumour cells → implantation on leptomeninges → enhancing nodules |
High Yield — Restricted Diffusion on DWI
Restricted diffusion (DWI bright, ADC dark) is the imaging hallmark that strongly suggests a highly cellular embryonal tumour (medulloblastoma or AT/RT) rather than a pilocytic astrocytoma or ependymoma. This is tested frequently in radiology and neuroscience exams. The mechanism is simple: pack cells tightly together → less extracellular space → water molecules can't move freely → restricted diffusion.
Why pre-operative spinal MRI? Post-surgical blood products in the CSF can enhance on T1+Gd, mimicking leptomeningeal metastases (false positive). Pre-operative spinal MRI avoids this. If not done pre-operatively, wait ≥14 days post-operatively.
| Modality | Role | Key Points |
|---|---|---|
| MR perfusion | Assesses tumour vascularity | Medulloblastoma shows elevated relative cerebral blood volume (rCBV) reflecting angiogenesis in a high-grade tumour. Helps differentiate from low-grade tumours. |
| MR tractography (DTI) | Pre-operative planning | Maps white matter tracts (e.g., corticospinal tract, cerebellar peduncles) relative to the tumour → guides surgical approach to minimize neurological damage. |
| SPECT scan | Distinguishes benign from malignant brain lesions, predicts histological grade of brain tumours, selects areas for biopsy [9][10] | Single photon emission CT (SPECT) utilizes various isotopes such as thallium-201 to detect abnormalities in BBB [9][10]. Less commonly used now with advances in MRI. |
| PET-CT (FDG or amino acid tracers) | Assesses metabolic activity, detects recurrence | FDG-PET is limited in the brain because normal brain has very high background glucose metabolism → difficult to distinguish tumour from normal cortex [16]. Amino acid tracers (e.g., ¹¹C-methionine, ¹⁸F-FET) are preferred for brain tumours as they have lower background uptake. |
Used when MRI is unavailable, the patient is too unstable for MRI, or there are MRI-incompatible implants. Shows a hyperdense, homogeneously enhancing midline posterior fossa mass with hydrocephalus. Inferior to MRI for tumour characterisation, posterior fossa detail, and detection of leptomeningeal disease.
| Investigation | Timing | Purpose | Key Findings |
|---|---|---|---|
| CSF cytology | Post-operative (≥14 days after surgery) via LP, OR intra-operatively from ventricular CSF (if EVD placed) | Detect CSF dissemination (M1 in Chang staging) | Malignant cells: small round blue cells with high N:C ratio, scant cytoplasm. Positive CSF cytology upstages to M1 even without visible leptomeningeal nodules on MRI. |
| CSF tumour markers | Post-operative | Rule out germ cell tumour (which can mimic medulloblastoma in the posterior fossa, though rare) | AFP and β-hCG — should be negative in medulloblastoma. Tumour markers, e.g. AFP, β-hCG (more sensitive in CSF than blood) [1] — if elevated, consider germ cell tumour instead. |
| CSF protein/glucose | If obtained | Non-specific | May show elevated protein (tumour-related BBB disruption, leptomeningeal disease) and mildly low glucose (tumour consumption). Not diagnostic. |
Important — CSF Cytology Timing
Never perform LP before surgery in a child with a posterior fossa mass and raised ICP — risk of tonsillar herniation. CSF is obtained either:
- Intra-operatively from the ventricle or cisterna magna during resection
- Post-operatively ≥14 days after surgery via LP (to avoid confounding blood products from surgery)
Positive CSF cytology = M1 disease = high risk stratification, regardless of MRI findings.
These are not diagnostic for medulloblastoma itself but are essential for pre-operative assessment, baseline organ function before chemotherapy/radiotherapy, and ruling out alternative diagnoses.
| Investigation | Purpose | Relevance |
|---|---|---|
| CBC with differential | Baseline haematological function; rule out leukaemia (ALL can present with bone marrow failure ± CNS involvement) | Medulloblastoma: usually normal CBC. If pancytopaenia + blasts → think ALL instead [14]. |
| Coagulation profile (PT, aPTT, fibrinogen) | Pre-operative assessment, rule out DIC or coagulopathy | Essential before any craniotomy. |
| LRFT (Liver and Renal Function Tests) | Baseline organ function before chemotherapy (cisplatin is nephrotoxic; vincristine is hepatically metabolised) | Documenting baseline GFR is critical before cisplatin. |
| Electrolytes (Na, K, Ca, PO₄) | Detect electrolyte abnormalities (e.g., SIADH from CNS disease causing hyponatraemia; hypercalcaemia from paraneoplastic syndrome — rare) | Post-operative diabetes insipidus (DI) can also cause hypernatraemia — important to monitor. |
| LDH | Non-specific tumour marker | Elevated in highly proliferative tumours; may be elevated in medulloblastoma. |
| Serum AFP, β-hCG | Rule out intracranial germ cell tumour | GCTs: more common in Asians (6× Caucasians) [1]. If elevated → NOT medulloblastoma, consider germ cell tumour. Must be negative for medulloblastoma diagnosis. |
| TFT (Thyroid Function Tests) | Baseline before craniospinal irradiation (CSI causes hypothyroidism in >10%) | Not diagnostic, but essential for long-term follow-up. |
| Audiogram | Baseline hearing before cisplatin (ototoxic) and CSI | Ototoxicity (Cisplatin-induced) [9][10] — need pre-treatment baseline. |
| GH, cortisol, gonadotropins (endocrine panel) | Baseline pituitary function | CSI causes endocrine abnormalities: ↓GH (94%), ↓ACTH (43%), ↓TSH (10%) [9][10]. Baseline essential. |
| G6PD status | Hong Kong specific (high prevalence of G6PD deficiency in Southern Chinese) | Relevant if certain drugs are used; also a routine paediatric baseline in HK. |
| Viral serology (HBV, HCV, HIV) | Baseline before immunosuppressive chemotherapy | HBV reactivation risk with chemotherapy; need to know carrier status. |
D. Histopathology (Definitive Diagnosis)
Histological examination of biopsy specimen remains most important component of diagnostic evaluation of brain tumours [9][10].
The tissue is obtained at the time of maximal safe surgical resection (not a separate biopsy procedure).
| Subtype | Histological Features |
|---|---|
| Classic | Sheets of small, round, blue cells (embryonal morphology) with high nuclear:cytoplasmic ratio, dark hyperchromatic nuclei, scant cytoplasm. Homer-Wright rosettes (tumour cells arranged around a central core of neuropil — i.e. neurofibrillary material, NOT a blood vessel). Brisk mitotic activity. |
| Desmoplastic/nodular (DN) | "Pale islands" (reticulin-free nodules) of more differentiated cells surrounded by reticulin-rich (desmoplastic) internodular tissue with densely packed undifferentiated cells. Best seen on reticulin stain. |
| Extensive nodularity (MBEN) | Extreme form of DN with very large, expanded nodules and minimal internodular tissue. Occurs in infants. |
| Large cell / anaplastic (LC/A) | Large cell: cells with large vesicular nuclei, prominent nucleoli, abundant cytoplasm. Anaplastic: marked nuclear pleomorphism, cell wrapping, very high mitotic rate, apoptosis. Often co-occur. |
IHC stains confirm the diagnosis and help with molecular subgrouping:
| Marker | Result in Medulloblastoma | Significance |
|---|---|---|
| Synaptophysin | Positive | Confirms neuronal differentiation (embryonal tumours of neuronal lineage express this synaptic vesicle protein) |
| NeuN | Often positive (especially in nodules of DN type) | Neuronal marker |
| GFAP | Variable (may be positive in reactive astrocytes within tumour, but tumour cells themselves are usually negative or focally positive) | Helps distinguish from ependymoma (GFAP strongly positive) and astrocytoma |
| INI1 (SMARCB1) | Retained (positive nuclear staining) | Distinguishes from AT/RT — loss of INI1 is pathognomonic for AT/RT. Must always check this, especially in infants. |
| Ki-67 (MIB-1) | High (often >30–50%) | Proliferation index — confirms high-grade nature |
| β-catenin | Nuclear positive in WNT subgroup (normally cytoplasmic/membranous; nuclear accumulation = constitutive WNT activation) | Screening IHC for WNT subgroup |
| GAB1 | Positive in SHH subgroup | Screening IHC for SHH subgroup |
| YAP1 | Positive in WNT and SHH, negative in Group 3 and 4 | Helps distinguish subgroups |
| Filamin A | Positive in WNT, negative in others | Screening IHC for WNT subgroup |
| p53 | Strongly positive (aberrant accumulation) in TP53-mutant SHH | TP53 mutation → loss of normal p53 degradation → protein accumulates → strong IHC staining. Important because TP53-mutant SHH has very poor prognosis |
These are essential for the integrated diagnosis and risk stratification:
| Investigation | Method | Key Findings | Clinical Significance |
|---|---|---|---|
| DNA methylation profiling | Methylation array (e.g., Illumina 850k) | Classifies into WNT, SHH, Grp3, Grp4 with highest accuracy; can also detect copy number alterations | Gold standard for molecular subgrouping. Also identifies novel subtypes within each group. |
| FISH | Fluorescence in situ hybridisation | Monosomy 6 (WNT), i(17q) (Grp3/4), MYC amplification (Grp3), MYCN amplification (SHH/Grp4) | MYC amplification → high risk. Monosomy 6 → WNT → excellent prognosis. |
| Karyotyping | Conventional cytogenetics | Gross chromosomal abnormalities | Complementary to FISH; lower resolution. |
| Sequencing (targeted panel or WES) | Next-generation sequencing (NGS) | CTNNB1, PTCH1, SMO, SUFU, TP53, KDM6A mutations | Identifies driver mutations and actionable targets (e.g., SMO inhibitors for SHH). |
| IHC panel (as above) | Quick turnaround | β-catenin (WNT), GAB1 (SHH), YAP1, filamin A, p53 | Rapid preliminary subgrouping while awaiting methylation results. |
High Yield — Molecular Subgrouping Methods
There are three tiers of molecular subgrouping:
- Screening IHC (fastest, ~2 days): β-catenin nuclear+ → WNT; GAB1+ → SHH; both negative → Grp3/4
- NanoString / gene expression (moderate speed): classifies all 4 subgroups reliably
- DNA methylation array (gold standard, ~1–2 weeks): most accurate, also gives copy number profile
In resource-limited settings, IHC + FISH (for MYC, monosomy 6, i17q) is the minimum requirement. In tertiary centres (including Hong Kong), methylation profiling is increasingly standard.
Staging determines the extent of disease and is critical for risk stratification:
| Investigation | What It Assesses | Timing | Key Findings |
|---|---|---|---|
| Pre-operative MRI brain with Gd | Primary tumour extent (T stage), intracranial leptomeningeal disease (M2) | Before surgery (ideally) | Tumour size, invasion of brainstem/4th ventricle, enhancement pattern, intracranial nodular seeding |
| Pre-operative MRI whole spine with Gd | Spinal leptomeningeal disease (M3) | Before surgery (ideally) or ≥14 days post-op | Enhancing nodules on spinal cord surface, nerve roots, or cauda equina = drop metastases |
| Post-operative MRI brain with Gd | Residual tumour assessment | Within 24–72 hours of surgery (before post-operative enhancement/granulation tissue develops) | Residual enhancing tumour. >1.5 cm² residual = high risk. |
| CSF cytology | M1 staging (microscopic CSF dissemination) | ≥14 days post-operatively via LP, or intra-operatively | Malignant cells in CSF = M1 |
| Bone marrow biopsy, bone scan (if clinically indicated) | M4 staging (extraneural metastasis) | Only if clinical suspicion (bone pain, cytopaenia) | Rarely positive; medulloblastoma can rarely metastasise to bone/bone marrow |
Post-Operative MRI Timing: Why 24–72 Hours?
After ~72 hours, surgical granulation tissue and reactive enhancement at the resection margin begin to develop. This post-surgical enhancement can be mistaken for residual tumour (false positive). Performing the MRI within 24–72 hours avoids this confounding factor and gives a clean assessment of whether there is true residual enhancing tumour.
| Investigation | Purpose |
|---|---|
| Ophthalmological examination (fundoscopy) | Detect papilloedema (raised ICP), assess visual acuity and fields (important baseline before treatment). Swollen optic disc: any neurological signs → look for the other eye [13]. |
| Formal audiometry | Baseline before cisplatin and CSI — both cause ototoxicity [9][10]. |
| Neuropsychological testing | Baseline cognitive function before craniospinal irradiation (CSI causes neurocognitive impairment [9][10], especially in young children). |
| Echocardiogram | If anthracyclines or other cardiotoxic agents are planned (not standard in medulloblastoma but may be relevant in some protocols). |
| GFR measurement (e.g., ⁵¹Cr-EDTA or cystatin C) | Accurate baseline renal function before cisplatin (serum creatinine alone is unreliable in children due to low muscle mass). |
| Genetic counselling / germline testing | If clinical suspicion of predisposition syndrome (young age, family history, syndromic features). Test for APC (Turcot), PTCH1 (Gorlin), TP53 (Li-Fraumeni), SUFU. |
| Modality | Key Finding | Interpretation |
|---|---|---|
| CT brain | Hyperdense midline posterior fossa mass + hydrocephalus | High cellularity tumour obstructing 4th ventricle |
| MRI brain (T1+Gd) | Heterogeneously enhancing vermian mass | BBB disruption by high-grade tumour |
| MRI (DWI) | Restricted diffusion (DWI bright, ADC dark) | Dense packing of small embryonal cells |
| MRI spine | Enhancing leptomeningeal nodules | CSF drop metastases (M2/M3) |
| Post-op MRI brain | Residual enhancing tissue | > 1.5 cm² = high risk |
| CSF cytology | Malignant small round blue cells | M1 stage (CSF dissemination) |
| CSF AFP/β-hCG | Negative | Rules out germ cell tumour |
| Histology | Small round blue cells, Homer-Wright rosettes, INI1 retained, synaptophysin+ | Confirms medulloblastoma, excludes AT/RT |
| IHC: β-catenin | Nuclear positive | WNT subgroup |
| FISH: monosomy 6 | Present | Confirms WNT subgroup (excellent prognosis) |
| FISH: MYC amplification | Present | Group 3, worst prognosis |
| Methylation array | Definitive molecular subgroup | Gold standard classification |
High Yield Summary — Investigations for Medulloblastoma
- First-line imaging: CT brain (emergency — detects hydrocephalus and mass). CT brain: site, multiplicity, mass effect, contrast enhancement indicates BBB disruption [4].
- Gold standard imaging: MRI brain with gadolinium contrast [13]. Key finding = restricted diffusion on DWI (high cellularity).
- Pre-operative spinal MRI: Essential for staging (drop metastases). Do before surgery or ≥14 days post-op.
- Post-operative MRI brain: Within 24–72 hours to assess residual tumour (> 1.5 cm² = high risk).
- CSF cytology: Post-operative ≥14 days. Positive = M1 = high risk. Never LP before imaging/surgery in posterior fossa mass.
- Definitive diagnosis: Histological examination at time of surgical resection [9][10]. Must confirm with IHC (synaptophysin+, INI1 retained) and molecular subgrouping.
- Molecular subgrouping: IHC screening (β-catenin, GAB1) → FISH (monosomy 6, MYC) → methylation array (gold standard).
- Staging = Chang system: T stage (tumour extent) + M stage (M0-M4). M0 + GTR + age >3y = standard risk; M+ or residual or LC/A or MYC amp = high risk.
- Baseline assessments: Audiometry, endocrine panel, renal function, neuropsychological testing — all essential before treatment with cisplatin and CSI.
- Rule out mimics: Serum/CSF AFP and β-hCG negative (excludes GCT); INI1 retained (excludes AT/RT).
Active Recall - Diagnosis and Investigations of Medulloblastoma
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 432 — PNETs and Medulloblastoma; p. 432 — Germ Cell Tumours, CSF tumour markers) [4] Senior notes: Ryan Ho Neurology.pdf (p. 162 — Investigations for Intracranial Tumours: CT brain, contrast enhancement, MRI) [5] Senior notes: Maksim Surgery Notes.pdf (p. 360 — Brain Tumours: Tumour locations by age) [9] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1262 — SPECT scan, Surgical exploration and biopsy, histological examination) [10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 534 — SPECT scan, Surgical exploration and biopsy, histological examination) [13] AOS material: AOS - Ophthalmology (Ans:Notes).pdf (p. 3 — MRI brain with contrast for intracranial tumour, swollen optic disc) [14] Senior notes: Ryan Ho Haemtology.pdf (p. 61 — ALL diagnosis: MCICM approach, molecular genetics for risk stratification) [15] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p. 39 — CT interpretation; p. 50 — MRI vs CT comparison) [16] Senior notes: Ryan Ho Respiratory.pdf (p. 144 — PET-CT: brain background activity too hypermetabolic)
Management of Medulloblastoma
The management of medulloblastoma is multimodal and follows a strictly sequenced approach. Think of it as a three-legged stool — all three legs are needed for optimal outcomes:
- Surgery (maximal safe resection) — the foundation
- Radiotherapy (craniospinal irradiation ± posterior fossa boost) — the backbone of adjuvant treatment
- Chemotherapy (multi-agent regimens) — augments radiotherapy and addresses micrometastatic disease
The intensity of each modality is calibrated by risk stratification, which itself is determined by the staging and molecular subgrouping completed in the diagnostic workup.
Maximal safe resection without causing serious neurological sequelae is the key component of treatment [9][10]. Resection confirms diagnosis, relieves increased ICP and establishes local control [9][10].
Step 1: Emergency Management of Raised Intracranial Pressure
Before any definitive tumour treatment, the immediate priority is managing life-threatening raised ICP from obstructive hydrocephalus. Over 90% of children with medulloblastoma present with hydrocephalus.
| Intervention | Mechanism | Details |
|---|---|---|
| Dexamethasone (high-dose IV) | Reduces vasogenic oedema around the tumour. Corticosteroids stabilise the BBB → reduce leakage of plasma proteins into brain parenchyma → decrease water content of peritumoral tissue → lower ICP. | Typical dose: 0.5–1 mg/kg loading then 0.25–0.5 mg/kg/day divided Q6h. Focal neurological deficits due to oedema are typically responsive to steroids [4]. Onset of effect: hours to days. Not a definitive treatment — buys time for surgery. |
| Head elevation (30°) | Promotes venous drainage from the head via gravity → reduces intracranial venous pressure → reduces ICP. | Simple but important nursing measure. |
| Avoid hypercapnia | CO₂ is a potent cerebral vasodilator. Hyperventilation → ↓pCO₂ → cerebral vasoconstriction → ↓cerebral blood volume → ↓ICP. | Short-term measure only (hours). Prolonged hyperventilation causes cerebral ischaemia. Target pCO₂ ~30–35 mmHg. |
| Osmotic therapy (mannitol or hypertonic saline) | Creates an osmotic gradient → draws water from brain parenchyma into intravascular space → reduces brain volume → reduces ICP. | Used in acute deterioration / impending herniation as a bridge to surgery. Mannitol 0.5–1 g/kg IV bolus. Hypertonic saline (3% NaCl) as alternative. |
Why Dexamethasone and Not Hydrocortisone?
Dexamethasone is chosen specifically because it has potent anti-oedema (glucocorticoid) effects with minimal mineralocorticoid activity (so less salt/water retention). It also has a long half-life (~36h), allowing less frequent dosing. Hydrocortisone is only for steroid-sensitive cancers e.g. lymphoma, myeloma [17] — medulloblastoma is NOT steroid-sensitive in the oncological sense, but the peritumoral oedema responds to dexamethasone's anti-inflammatory properties.
If the child is acutely deteriorating from raised ICP (↓GCS, impending herniation), emergency CSF diversion may be needed before definitive tumour resection:
| Procedure | Description | When Used |
|---|---|---|
| External Ventricular Drain (EVD) | A catheter is inserted through a burr hole into the lateral ventricle to drain CSF externally into a collection bag. Allows ICP monitoring and controlled CSF drainage. | Acute, life-threatening hydrocephalus. Temporary measure — removed after definitive surgery. Risk: infection (~5–10%), overdrainage. |
| Endoscopic Third Ventriculostomy (ETV) | An endoscope is passed into the 3rd ventricle, and a hole is made in the floor of the 3rd ventricle → CSF bypasses the obstructed 4th ventricle/aqueduct and flows directly into the prepontine cistern (subarachnoid space). | Preferred over VP shunt in obstructive hydrocephalus (avoids permanent shunt). May be done at the same sitting as tumour resection in some centres. |
| Ventriculoperitoneal (VP) Shunt | Permanent CSF diversion from ventricle to peritoneal cavity. | Generally avoided in medulloblastoma because: (1) risk of peritoneal seeding of tumour via shunt, (2) most patients' hydrocephalus resolves after tumour resection (~60–70% do not need permanent CSF diversion). Reserved for persistent post-operative hydrocephalus. |
Important: ~30–40% of children will have persistent hydrocephalus after tumour resection (because the 4th ventricle outflow may remain impaired from scarring or residual disease) and will require a permanent CSF diversion procedure (ETV or VP shunt).
Step 2: Surgical Resection (Definitive — First-Line Treatment)
Maximal safe resection without causing serious neurological sequelae is the key component of treatment [9][10].
| Goal | Explanation |
|---|---|
| Tissue diagnosis | Histological confirmation is obtained at the time of surgical exploration for resection [9][10]. The tissue is sent for histology, IHC, and molecular studies. |
| Relieve raised ICP | Debulking the tumour opens the 4th ventricle → restores CSF flow → resolves obstructive hydrocephalus. |
| Establish local control | The extent of resection is one of the most important prognostic factors. Gross total resection (GTR) — defined as no visible residual tumour on post-operative MRI — is the goal. Residual tumour >1.5 cm² → classified as high risk. |
| Enable accurate staging | Intra-operative CSF can be sent for cytology. Post-operative MRI (within 24–72h) assesses residual disease. |
- Suboccipital craniotomy (posterior fossa craniotomy) — the standard approach to access the cerebellar vermis and 4th ventricle.
- The patient is positioned either prone or in the concorde (sitting) position (sitting position allows gravity-assisted CSF drainage but carries risk of venous air embolism).
- The surgeon opens the dura, identifies the tumour in the vermis/4th ventricle, and performs a systematic resection using microsurgical techniques, often aided by intra-operative neuronavigation and neurophysiological monitoring (monitoring CN function, particularly facial nerve, and brainstem auditory evoked potentials).
| Extent of Resection | Definition | Prognostic Impact |
|---|---|---|
| Gross total resection (GTR) | No visible residual on post-op MRI (within 24–72h) | Best outcomes — standard risk if other criteria met |
| Near-total resection (NTR) | Residual ≤1.5 cm² | Still considered standard risk in many protocols |
| Subtotal resection (STR) | Residual >1.5 cm² | High risk — associated with increased recurrence |
Why not just remove everything? The tumour may be adherent to the brainstem floor (particularly in ependymoma, but sometimes in medulloblastoma). Aggressive resection of tumour infiltrating the brainstem risks devastating neurological injury (quadriplegia, CN palsies, respiratory failure, death). The surgeon must balance oncological completeness against neurological safety — hence "maximal safe resection."
| Complication | Mechanism | Details |
|---|---|---|
| Posterior fossa syndrome (Cerebellar mutism) | Postoperative complication caused by injury to cerebellar vermis or dentate nuclei during resection of tumours in midline cerebellum [9][10] | Appears 1–2 days after surgery and resolves within weeks to months. Characterized by impaired language production with emotional lability [9][10]. Occurs in ~25% of midline posterior fossa resections. May also include worsened ataxia, hypotonia, and behavioural changes. Recovery is variable — some children have permanent speech/cognitive deficits. |
| Worsened cerebellar signs | Direct surgical injury to cerebellar tissue or peduncles | Ataxia, dysarthria, nystagmus — usually improve over weeks but may persist. |
| Cranial nerve palsies | Manipulation/injury of CN nuclei on brainstem floor or CN roots | CN VII (facial weakness), CN VI (diplopia), lower CN palsies (dysphagia) — may require NG tube for feeding temporarily. |
| CSF leak | Failure of watertight dural closure | Risk of meningitis. May require re-operation or lumbar drainage. |
| Infection (meningitis, wound infection) | Post-operative surgical site contamination | Treated with IV antibiotics. |
| Hydrocephalus (persistent) | Failure of CSF pathway to re-establish after tumour removal | ~30–40% require permanent CSF diversion (ETV or VP shunt). |
| Haemorrhage (post-operative) | Bleeding from tumour bed or vascular injury | May require emergency re-exploration. |
High Yield — Posterior Fossa Syndrome / Cerebellar Mutism
This is a favourite exam topic. Key points:
- Injury to cerebellar vermis or dentate nuclei [9][10]
- Appears 1–2 days post-operatively (there is a "lucid interval" — the child is initially fine immediately post-op, then deteriorates)
- Impaired language production (mutism or severe dysarthria) with emotional lability [9][10]
- Recovery: weeks to months, but some have permanent deficits
- NOT the same as aphasia (language comprehension is preserved — it is a problem of speech production due to disruption of cerebello-cerebral circuitry)
After surgery, the patient is classified into a risk group based on clinical, pathological, and molecular features:
| Feature | Standard Risk | High Risk |
|---|---|---|
| Age | >3 years | <3 years |
| Metastasis | M0 (no metastasis) | M1–M4 (CSF+, leptomeningeal, extraneural) |
| Residual tumour | ≤1.5 cm² (GTR or NTR) | >1.5 cm² (STR) |
| Histology | Classic or desmoplastic/nodular | Large cell / anaplastic (LC/A) |
| Molecular | WNT subgroup (very favourable) | Group 3 with MYC amplification; SHH with TP53 mutation |
Current clinical trials (e.g., SJMB12, SIOP-PNET5) are increasingly using molecular subgroups to refine risk stratification beyond the traditional clinical criteria.
Step 4: Radiotherapy
Radiotherapy is the backbone of adjuvant treatment in medulloblastoma. Because medulloblastoma has a high propensity to seed through the CSF, the entire craniospinal axis must be irradiated — not just the posterior fossa.
Radiotherapy controls residual posterior fossa disease and treats any disease that has spread along the craniospinal axis [9][10].
| Protocol | CSI Dose | Posterior Fossa Boost | Indication |
|---|---|---|---|
| Standard risk | Reduced-dose: 23.4 Gy | Boost to 54–55.8 Gy to posterior fossa (or tumour bed) | Age >3y, M0, GTR/NTR, favourable histology/molecular |
| High risk | Full-dose: 36 Gy | Boost to 54–55.8 Gy + boost to any metastatic sites | M+, STR, LC/A, MYC amp, unfavourable molecular |
| WNT subgroup (ongoing trials) | Under investigation: possible reduced to 18 Gy or even omission of CSI | Reduced boost | Excellent prognosis allows de-escalation to reduce toxicity — active research area |
Why craniospinal and not just posterior fossa?
- Medulloblastoma seeds through CSF → the entire neuraxis is at risk
- Historical data showed unacceptably high rates of spinal/intracranial relapse with focal RT alone
- CSI addresses both macro- and micro-metastatic disease throughout the neuraxis
Fractionation: CSI is delivered in daily fractions (typically 1.5–1.8 Gy/fraction, 5 days/week) over ~4–6 weeks. The fractionation allows normal tissue repair between doses while preferentially killing rapidly dividing tumour cells (tumour cells repair DNA damage less efficiently than normal cells).
Technique: Modern CSI uses proton beam therapy where available (superior to conventional photon RT because protons deposit most of their energy at a specific depth [Bragg peak] → less exit dose → spares organs anterior to the spine [heart, lungs, GI tract, gonads]). In Hong Kong, proton therapy is not yet widely available, so conventional photon-based techniques (intensity-modulated RT, IMRT, or 3D conformal RT) are used, with some patients referred overseas for proton therapy.
Craniospinal radiation is avoided or delayed in children due to severe toxicity to the rapidly developing CNS such as neurocognitive impairment [9][10].
| Complication | Mechanism | Details |
|---|---|---|
| Neurocognitive impairment | Radiation damages developing white matter, oligodendrocytes, and neural progenitor cells → progressive demyelination and loss of neuroplasticity | The most devastating long-term toxicity in paediatric medulloblastoma survivors. IQ declines by ~2–4 points per year post-CSI. Younger children are more severely affected (the developing brain is more vulnerable). This is the main reason CSI is avoided/delayed in children <3 years. |
| Ototoxicity [9][10] | Radiation to the cochlea (within the posterior fossa boost field) damages hair cells → sensorineural hearing loss | Compounded by cisplatin-induced ototoxicity (see below). High-frequency hearing loss first, then progresses to conversational frequencies. Requires serial audiometry. |
| Short stature (↓GH) [9][10] | CSI damages the hypothalamic-pituitary axis (GH-producing somatotroph cells are the most radiation-sensitive) and also directly irradiates spinal vertebral growth plates → impaired bone growth | GH deficiency is the most common endocrine sequela — occurs in 94% [9][10]. Replacement GH therapy is given after tumour control is confirmed. |
| Endocrine abnormalities | Hypothalamic-pituitary axis damage → multiple hormone deficiencies | ↓GH (94%), ↓ACTH (43%), ↓TSH (10%) [9][10]. Also hypogonadism → delayed/absent puberty. Requires lifelong endocrine surveillance and hormone replacement. |
| Cerebrovascular abnormalities | Radiation vasculopathy → intimal fibrosis and accelerated atherosclerosis of cerebral vessels | Stroke, intracranial haemorrhage [9][10]. Risk increases with time post-RT. Moyamoya syndrome (progressive stenosis of ICA bifurcation) is a recognised late complication. |
| Secondary malignancies | Radiation-induced DNA damage in normal tissues → mutagenesis → new primary tumours years later | Risk of meningiomas, gliomas, thyroid cancer, bone/soft tissue sarcomas within the radiation field. Cumulative incidence ~3–5% at 20 years. |
| Hypothyroidism | Direct thyroid irradiation (within spinal field at cervical level) → thyroid follicular cell damage | Primary hypothyroidism requiring thyroxine replacement. |
| Gonadal dysfunction | Scatter dose to gonads (especially in spinal field) → impaired fertility | Oligospermia/azoospermia in males, premature ovarian failure in females. Fertility preservation (sperm banking, oocyte cryopreservation) should be discussed pre-treatment where age-appropriate. |
| Spinal growth impairment | Direct irradiation of vertebral growth plates → asymmetric or stunted spinal growth | Short sitting height, scoliosis. Combined with GH deficiency → significantly reduced adult height. |
Why Avoid CSI in Infants (<3 years)?
The developing brain in infants is exquisitely sensitive to radiation. CSI at this age causes devastating neurocognitive impairment — profound learning disability, reduced IQ, behavioural problems. Therefore, chemotherapy-only strategies are used in infants to delay or avoid CSI entirely. If the tumour is SHH desmoplastic/nodular (favourable biology in infants), outcomes can be excellent even without RT.
Step 5: Chemotherapy
The goals of chemotherapy are [9][10]:
- Decrease incidence of recurrence
- Minimize craniospinal radiation exposure (allows reduced-dose CSI in standard risk)
- Delay or avoid irradiation to the developing brain and spinal cord (especially critical in infants <3y)
- Treat high-risk disease that is not amenable to surgical resection
Example: Vincristine / Cisplatin / Cyclophosphamide [9][10] — the "Packer regimen" is the most widely used:
| Drug | Mechanism of Action | Key Toxicities | Clinical Notes |
|---|---|---|---|
| Vincristine (VCR) | Vinca alkaloid → binds tubulin → inhibits microtubule polymerisation → mitotic arrest at metaphase (M-phase specific) | Peripheral neuropathy (dose-limiting) — numbness, tingling, foot drop, constipation (autonomic neuropathy). Vincristine = "vincere" (Latin: to conquer) | Given weekly during RT (radiosensitiser — enhances RT effectiveness), then in maintenance cycles |
| Cisplatin (CDDP) | Platinum compound → forms DNA cross-links → prevents DNA replication and transcription → apoptosis | Ototoxicity (Cisplatin-induced) [9][10] — irreversible sensorineural hearing loss (high frequency first). Nephrotoxicity (direct tubular damage) — requires aggressive hydration. Nausea/vomiting (highly emetogenic). | Cumulative ototoxicity is a major concern, especially combined with RT to cochlea. Carboplatin may be substituted in some protocols (less ototoxic but more myelosuppressive). |
| Cyclophosphamide (CPM) | Alkylating agent → forms DNA cross-links → prevents DNA replication | Haemorrhagic cystitis (acrolein metabolite → urothelial damage; prevented by co-administration of mesna). Myelosuppression. Gonadotoxicity (infertility risk). | "Cyclo-" = ring structure; "phosph-" = phosphorus-containing; "-amide" = amide bond |
| Lomustine (CCNU) | Alkylating nitrosourea → crosses BBB well → DNA cross-links | Myelosuppression (delayed — nadir at 4–6 weeks; cumulative). Pulmonary fibrosis (rare, cumulative). | Used in some protocols instead of or in addition to cyclophosphamide. Good BBB penetration is advantageous for CNS tumours. |
| Risk Group | Chemotherapy Approach |
|---|---|
| Standard risk (age >3y) | Vincristine weekly during CSI → post-RT maintenance with vincristine + cisplatin + cyclophosphamide (or lomustine) for 6–8 cycles |
| High risk (age >3y) | More intensive chemotherapy: higher doses, additional agents, or high-dose chemotherapy with autologous stem cell transplant (ASCT) in some protocols |
| Infants (<3y) | Chemotherapy-only protocols to avoid/delay CSI. Regimens include intensive induction with cisplatin/vincristine/cyclophosphamide + methotrexate (systemic and intrathecal) ± etoposide. If good response and favourable biology (SHH-DN), may avoid RT entirely. If high-risk biology, focal RT to tumour bed may be added after age 3. |
- Used in high-risk or recurrent medulloblastoma
- Principle: administer myeloablative doses of chemotherapy (e.g., carboplatin + thiotepa + etoposide) to kill residual tumour cells → rescue the patient's bone marrow with previously harvested autologous stem cells
- This approach exploits the steep dose-response curve of chemotherapy — higher doses kill more tumour cells, but the dose is normally limited by bone marrow toxicity. Stem cell rescue "removes" this ceiling.
| Contraindication | Rationale |
|---|---|
| Severe renal impairment (for cisplatin) | Cisplatin is directly nephrotoxic and renally excreted — will worsen renal failure. Use carboplatin (renally dosed) as alternative. |
| Pre-existing significant sensorineural hearing loss (for cisplatin) | Cisplatin ototoxicity is cumulative and irreversible — unacceptable in a child already hearing-impaired. Switch to carboplatin or non-platinum agent. |
| Active uncontrolled infection | Chemotherapy causes immunosuppression (neutropenia) → overwhelming sepsis risk. Must control infection before starting chemo. |
| Poor performance status / severe organ dysfunction | High risk of treatment-related mortality if the child cannot tolerate cytotoxic therapy. |
| G6PD deficiency (relative — relevant in HK) | Some agents may provoke haemolysis. Must be screened pre-treatment. |
These are not yet standard of care for most patients but represent the frontier of medulloblastoma treatment:
| Therapy | Target | Application | Status |
|---|---|---|---|
| Vismodegib / Sonidegib | SMO (Smoothened) inhibitors — block Hedgehog pathway | SHH subgroup (especially adults with SMO or PTCH1 mutations) | FDA-approved for BCC; clinical trials for SHH medulloblastoma. Response rates in SHH-mutant adults are promising. Limited efficacy in downstream mutations (e.g., SUFU, GLI2). Contraindicated in growing children — SMO inhibitors cause premature growth plate fusion (the Hedgehog pathway is essential for normal bone growth). |
| Immunotherapy (anti-PD-1, anti-GD2) | Checkpoint inhibitors, anti-tumour antibodies | Under investigation in recurrent medulloblastoma | Limited data so far. Medulloblastoma is generally an immunologically "cold" tumour (low mutational burden). GD2-targeting antibodies show some promise. |
| CDK4/6 inhibitors (e.g., palbociclib) | Cyclin-dependent kinase inhibitors → G1 arrest | Group 4 with CDK6 amplification | Preclinical and early clinical trials. |
| BET bromodomain inhibitors | Epigenetic regulators → suppress MYC transcription | Group 3 with MYC amplification | Preclinical. MYC is "undruggable" directly, so targeting its transcriptional regulators is the strategy. |
After completion of treatment (surgery + RT + chemo, typically spanning ~12 months), long-term surveillance is essential for:
- Tumour recurrence detection (highest risk in first 2 years)
- Late effects monitoring (endocrine, neurocognitive, auditory, secondary malignancies)
| Surveillance Domain | Protocol |
|---|---|
| MRI brain + spine with Gd | Every 3 months for first 2 years → every 6 months for next 2 years → annually thereafter (for at least 10 years, ideally lifelong) |
| Endocrine assessment | Annual GH, TSH, cortisol, gonadotropins, IGF-1. ↓GH (94%), ↓ACTH (43%), ↓TSH (10%) [9][10]. Initiate hormone replacement as needed. |
| Audiometry | Serial audiograms every 6–12 months (cisplatin + RT ototoxicity is progressive and cumulative) |
| Neuropsychological testing | Annual cognitive assessments (IQ, processing speed, memory, attention). Neuropsychological rehabilitation and educational support as needed. |
| Ophthalmology | Annual visual acuity and fundoscopy |
| Growth and puberty | Growth velocity monitoring, bone age, pubertal staging. GH replacement if deficient. |
| Secondary malignancy screening | Annual physical examination, age-appropriate cancer screening. Low threshold for imaging if new symptoms. |
| Psychosocial support | Ongoing psychological support for the child and family. Survivorship care plans. |
Special Scenarios
Recurrence carries a very poor prognosis (5-year survival <30% for most). Options include:
- Re-resection if focal and resectable
- Re-irradiation (limited by prior RT dose to critical structures — risk of radiation necrosis)
- Salvage chemotherapy (e.g., temozolomide, irinotecan, topotecan)
- High-dose chemotherapy with ASCT
- Clinical trials (targeted therapy, immunotherapy)
- Palliative care — must be discussed early and offered throughout
Given the >95% survival with current standard treatment, ongoing trials are testing reduced-intensity therapy for WNT medulloblastoma:
- Reduced CSI dose (18 Gy instead of 23.4 Gy)
- Fewer cycles of chemotherapy
- Potential omission of CSI entirely (with close surveillance)
The rationale: these children are almost all cured, but the treatment causes devastating long-term toxicity. If the tumour biology is so favourable, can we safely give less treatment? This is an active area of clinical research.
For patients with treatment-refractory or multiply recurrent disease:
- Symptom management: analgesics (WHO pain ladder), anti-emetics, dexamethasone (for cerebral oedema), anti-epileptics
- Hospice care and advanced care planning
- Family support and bereavement counselling
High Yield Summary — Management of Medulloblastoma
- Emergency: Dexamethasone for peritumoral oedema + EVD/ETV for acute hydrocephalus.
- Surgery: Maximal safe resection — confirms diagnosis, relieves ICP, establishes local control [9][10]. Post-op MRI within 24–72h. Residual > 1.5 cm² = high risk.
- Complication of surgery: Posterior fossa syndrome (cerebellar mutism) — appears 1–2 days post-op, injury to vermis/dentate nuclei, impaired language production + emotional lability, resolves weeks to months [9][10].
- Risk stratification: Standard risk (>3y, M0, GTR, non-LC/A, no MYC amp) vs. High risk (M+, STR, LC/A, MYC amp, Group 3).
- Radiotherapy: CSI controls residual posterior fossa disease and craniospinal axis metastasis [9][10]. Standard risk = 23.4 Gy CSI + 54 Gy PF boost. High risk = 36 Gy CSI + boost. Avoided/delayed in <3y due to neurocognitive toxicity [9][10].
- Chemotherapy: Vincristine / Cisplatin / Cyclophosphamide [9][10]. Adjunct to surgery and RT — decreases recurrence, minimizes CSI exposure, delays irradiation in young children [9][10]. Key toxicities: cisplatin ototoxicity [9][10], nephrotoxicity, neuropathy.
- RT late effects: ↓GH (94%), ↓ACTH (43%), ↓TSH (10%), ototoxicity, cerebrovascular abnormalities (stroke/ICH), neurocognitive impairment [9][10].
- Infants (<3y): Chemotherapy-only protocols to avoid CSI. Focal RT added later if needed.
- WNT subgroup: Trials exploring treatment de-escalation (excellent prognosis, reduce late toxicity).
- Targeted therapy: SMO inhibitors (vismodegib) for SHH subgroup in adults (contraindicated in growing children — growth plate fusion).
- Surveillance: Serial MRI Q3mo → Q6mo → annual. Lifelong endocrine, auditory, neurocognitive, and secondary malignancy monitoring.
Active Recall - Management of Medulloblastoma
References
[4] Senior notes: Ryan Ho Neurology.pdf (p. 162 — Focal neurological deficits and oedema responsive to steroids) [9] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1262–1264 — Treatment of Medulloblastoma: surgery, chemotherapy, radiotherapy, complications) [10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 534 — Treatment of Medulloblastoma: surgery, chemotherapy, radiotherapy, complications) [17] Senior notes: Maksim Medicine Notes.pdf (p. 45 — Hydrocortisone only for steroid-sensitive cancers)
Complications of Medulloblastoma
Complications of medulloblastoma can be divided into three broad categories:
- Complications of the disease itself (from the primary tumour and its spread)
- Complications of treatment (surgery, radiotherapy, chemotherapy)
- Long-term sequelae in survivors (the "price of cure")
This division is clinically important because medulloblastoma is a curable disease in a substantial proportion of children — meaning that many survivors live for decades with the cumulative burden of treatment-related toxicity. Managing late effects is as much a part of the oncological care as treating the tumour itself.
Category 1: Complications of the Disease Itself
These arise from the tumour's anatomical location, its growth characteristics, and its propensity for CSF dissemination.
| Complication | Mechanism | Clinical Consequence |
|---|---|---|
| Obstructive (non-communicating) hydrocephalus | Tumour in cerebellar vermis / 4th ventricle obstructs CSF outflow through the aqueduct of Sylvius or foramina of Luschka/Magendie → CSF accumulates proximal to the obstruction → lateral and 3rd ventricle dilatation | Raised ICP → headache, vomiting, papilloedema, ↓consciousness. Present in >90% at diagnosis. |
| Acute raised ICP / brain herniation | Progressive tumour growth → critical ICP threshold exceeded → brain tissue shifts | Tonsillar herniation (cerebellar tonsils through foramen magnum → brainstem compression → cardiorespiratory arrest) is the most dangerous pattern in posterior fossa tumours. Upward transtentorial herniation (cerebellum herniates upward through tentorial notch → midbrain compression → CN III palsy, ↓consciousness). |
| Chronic hydrocephalus (post-treatment) | Even after tumour resection, ~30–40% of patients develop persistent hydrocephalus due to scarring / fibrosis of CSF pathways, leptomeningeal disease, or incomplete restoration of 4th ventricle outflow | Requires permanent CSF diversion (ETV or VP shunt). Shunt malfunction is a lifelong risk requiring surveillance. |
Why does hydrocephalus persist after "successful" surgery? The tumour may have caused chronic inflammatory changes in the ependymal lining or arachnoid villi. Post-operative blood in the CSF can also organise and obstruct the foramina. Additionally, prior leptomeningeal disease may impair CSF absorption even after the primary obstruction is relieved. This is analogous to how post-meningitis communicating hydrocephalus develops — the inflammatory process damages the absorptive capacity of the arachnoid granulations.
| Complication | Mechanism |
|---|---|
| Cerebellar dysfunction (truncal ataxia, appendicular ataxia, dysarthria, nystagmus) | Destruction of cerebellar vermis and/or hemispheres by the growing tumour |
| Brainstem compression/invasion (CN palsies, long tract signs, respiratory depression) | Tumour extension into or compression of the brainstem |
| Cognitive and behavioural changes | Chronic raised ICP affecting global cortical function; posterior fossa lesions can also impair cognition via disruption of cerebello-cerebral circuits (the cerebellum contributes to cognition, particularly executive function, through connections to the prefrontal cortex) |
Medulloblastoma has a high propensity to disseminate through the subarachnoid space (leptomeningeal dissemination) [1][9][10].
| Complication | Mechanism | Clinical Consequence |
|---|---|---|
| Spinal leptomeningeal metastases ("drop metastases") | Tumour cells shed into CSF → carried by CSF flow → implant on spinal leptomeninges, particularly cauda equina (gravity-dependent) | Spinal cord compression: progressive paraparesis, sensory level, sphincter dysfunction. Cauda equina syndrome: bilateral leg weakness, saddle anaesthesia, urinary retention/incontinence, absent ankle jerks [18]. |
| Intracranial subarachnoid metastases | Tumour cells seed along cerebral convexities, suprasellar cistern, or other intracranial CSF spaces | Hydrocephalus (communicating type now — tumour deposits impair CSF absorption at arachnoid granulations), cranial neuropathies, seizures (if cortical involvement). |
| Extraneural metastases (M4 — rare) | Haematogenous spread or direct extension through dural sinuses/venous channels | Bone, bone marrow, lymph nodes, lungs, liver. Rare (<5%), but medulloblastoma is one of the few primary brain tumours that can metastasise extracranially. |
| Complication | Mechanism |
|---|---|
| SIADH → hyponatraemia | CNS disease (including brain tumours, post-operative state, and meningeal disease) is a recognised cause of SIADH → excess ADH secretion → dilutional hyponatraemia [19]. |
| Tumour lysis syndrome (TLS) | Rare in medulloblastoma at presentation (more common after initiating chemotherapy in highly proliferative haematological malignancies), but can theoretically occur after surgery or chemotherapy if there is rapid tumour cell death → release of intracellular contents (potassium, phosphate, uric acid, LDH) → hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia → renal failure, arrhythmia. |
| Malnutrition / failure to thrive | Chronic vomiting (↑ICP), anorexia, increased catabolic state from malignancy. |
Category 2: Complications of Treatment
Resection confirms diagnosis, relieves increased ICP and establishes local control [9][10] — but surgery itself carries risks:
| Complication | Mechanism | Incidence / Details |
|---|---|---|
| Posterior fossa syndrome (Cerebellar mutism) | Postoperative complication caused by injury to cerebellar vermis or dentate nuclei during resection of tumours in midline cerebellum [9][10] | Appears 1–2 days after surgery and resolves within weeks to months. Characterized by impaired language production with emotional lability [9][10]. Incidence ~25% of midline posterior fossa resections. Often also includes worsened ataxia, hypotonia, and behavioural disturbance. Some children have permanent residual speech and cognitive deficits despite partial recovery. The pathophysiology involves disruption of dentato-thalamo-cortical pathways — the cerebellum sends output via the superior cerebellar peduncle → dentate nucleus → thalamus → cerebral cortex (especially speech and motor cortex). Bilateral damage to this pathway produces mutism. |
| Worsened cerebellar ataxia | Direct surgical injury to cerebellar tissue, peduncles, or deep cerebellar nuclei | Expected after vermis-splitting approach. Usually improves with rehabilitation, but some degree of ataxia may persist permanently. |
| Cranial nerve palsies | Manipulation of CN nuclei on the floor of the 4th ventricle or CN roots during resection | CN VII (facial weakness), CN VI (diplopia), lower CNs (dysphagia → may require temporary NG tube feeding). Usually transient if due to neuropraxia; permanent if nerve transected. |
| CSF leak / pseudomeningocele | Incomplete dural closure → CSF leaks through wound or into subcutaneous tissues | Risk of ascending bacterial meningitis. May require surgical revision or lumbar drainage. |
| Post-operative haemorrhage | Bleeding from tumour bed or vascular injury | May require emergency re-exploration. Can be immediately life-threatening if posterior fossa haematoma → acute brainstem compression. |
| Infection (wound, meningitis, ventriculitis) | Post-surgical contamination; especially if EVD placed or CSF leak present | IV antibiotics; EVD removal/replacement if ventriculitis. |
| Persistent hydrocephalus | CSF pathway does not recover after tumour removal (scarring, inflammation) | ~30–40% require permanent CSF diversion (ETV or VP shunt). |
| Venous air embolism | If sitting position used for surgery — opened dural sinuses are above heart level → air entrained into venous system → travels to right heart/lungs | Detected by precordial Doppler or end-tidal CO₂ drop. Managed by flooding the field with saline, aspirating air from central venous catheter, placing patient in left lateral decubitus position. |
2.2 Radiotherapy Complications
Craniospinal radiation is avoided or delayed in children due to severe toxicity to the rapidly developing CNS such as neurocognitive impairment [9][10].
Radiotherapy complications are divided by temporal onset:
| Complication | Mechanism |
|---|---|
| Somnolence syndrome | Transient demyelination of cerebral white matter during CSI → excessive sleepiness, anorexia, irritability occurring 4–8 weeks post-RT. Self-limiting (resolves in 1–3 weeks). |
| Nausea and vomiting | Irradiation of the posterior fossa / brainstem area postrema (chemoreceptor trigger zone). Managed with anti-emetics. |
| Skin erythema / alopecia | Direct radiation damage to skin and hair follicles in the radiation field. Hair loss within the posterior fossa boost field is expected; with CSI, diffuse alopecia may occur. Usually temporary but may be permanent at the boost site. |
| Myelosuppression | CSI irradiates the spine → bone marrow suppression → pancytopaenia. Nadir at 2–4 weeks. Recovery is slower if concurrent chemotherapy. Requires CBC monitoring and transfusion support. |
| Mucositis / oesophagitis | Irradiation of cervical spine field → mucosal damage to oropharynx and oesophagus. |
| Complication | Mechanism |
|---|---|
| Radiation necrosis | Direct vascular endothelial damage and parenchymal injury → focal necrosis within the high-dose boost field (posterior fossa). Can mimic tumour recurrence on MRI (both enhance). Distinguished by MR spectroscopy (↑lipid-lactate peak in necrosis vs. ↑choline in recurrence) or PET. Treated with dexamethasone ± bevacizumab (anti-VEGF). |
| Lhermitte sign | Transient demyelination of posterior columns of cervical spinal cord within the radiation field → electric shock-like sensation down the spine on neck flexion. Self-limiting, resolves in months. |
These are the most clinically significant complications in long-term survivors:
| Complication | Mechanism | Details |
|---|---|---|
| Neurocognitive impairment | Radiation damages oligodendrocytes, myelin, and neural progenitor cells in the developing brain → progressive white matter injury, loss of neuroplasticity, reduced processing speed | The single most devastating long-term complication. IQ declines ~2–4 points per year post-CSI. Younger children (<7 years) are most vulnerable (the brain is still rapidly developing). Manifests as reduced processing speed, attention deficits, memory impairment, executive dysfunction. Eventually impacts academic performance, employment, and quality of life. CSI is avoided or delayed in children < 3 years due to severe toxicity to the rapidly developing CNS [9][10]. |
| Growth hormone deficiency → short stature | GH-secreting somatotrophs in the anterior pituitary are the most radiosensitive cells in the hypothalamic-pituitary axis → GH deficiency after CSI. Additionally, direct irradiation of spinal vertebral growth plates by the spinal RT field → impaired vertebral body growth → disproportionately short sitting height. | ↓GH (94%) [9][10]. GH replacement is standard once tumour recurrence is excluded (typically ≥1 year post-treatment). Even with GH replacement, adult height is usually below genetic potential because of direct spinal growth plate damage. |
| Hypothyroidism | Primary: direct irradiation of the thyroid gland (within the cervical spinal field) damages thyroid follicular cells → primary hypothyroidism (elevated TSH, low fT4). Central: radiation to hypothalamus/pituitary → TSH deficiency (low TSH, low fT4). | ↓TSH (10%) [9][10] — this refers to central hypothyroidism. Primary hypothyroidism is much more common (~30–60%). Requires lifelong thyroxine replacement. Annual TFT monitoring. |
| Adrenal insufficiency | Radiation damage to corticotrophs in the hypothalamic-pituitary axis → ACTH deficiency → secondary adrenal insufficiency | ↓ACTH (43%) [9][10]. Risk of adrenal crisis (acute haemodynamic collapse) during physiological stress (illness, surgery) if unrecognised. Requires hydrocortisone replacement and stress-dose counselling. |
| Hypogonadism | Radiation to hypothalamus/pituitary → gonadotropin (LH/FSH) deficiency → delayed or absent puberty. Additionally, scatter dose from spinal RT to gonads → direct gonadal damage. | Precocious puberty (early activation of HPG axis by low-dose radiation) paradoxically can occur before eventual hypogonadism develops. Requires sex steroid replacement at appropriate pubertal age. |
| Infertility | Direct gonadal damage (scatter from spinal field) + gonadotropin deficiency | Males: oligospermia/azoospermia (Sertoli cell damage). Females: premature ovarian failure. Fertility preservation (sperm banking, oocyte/ovarian tissue cryopreservation) should be discussed pre-treatment where age-appropriate. |
| Ototoxicity [9][10] | Combined effect of (a) cranial RT to the posterior fossa (cochlea is within the boost field) damaging cochlear hair cells, and (b) cisplatin chemotherapy, which is also directly cochleotoxic. The two are synergistic. | Sensorineural hearing loss, initially high-frequency (>4 kHz), progressing to conversational frequencies. Hearing aids may be required. Grading: Common Terminology Criteria for Adverse Events (CTCAE) or Brock criteria. Serial audiometry is mandatory. |
| Cerebrovascular abnormalities | Radiation vasculopathy → accelerated atherosclerosis, intimal fibrosis, vessel wall thickening → stenosis and occlusion of cerebral vessels. Specifically, radiation can induce moyamoya syndrome (progressive stenosis of ICA bifurcation → compensatory fragile collaterals → risk of haemorrhage and ischaemia). | Stroke, intracranial haemorrhage [9][10]. Risk increases with time post-RT. Cumulative incidence of stroke is ~3–5% at 20 years. Moyamoya may present with TIAs, ischaemic stroke, or ICH years after CSI. |
| Secondary malignancies | Radiation-induced DNA damage in normal cells within the radiation field → mutagenesis → second primary tumour arising years to decades later | Risk: ~3–5% cumulative incidence at 20 years. Types: meningiomas (most common radiation-induced intracranial tumour), high-grade gliomas, thyroid cancer (from cervical field irradiation), bone/soft tissue sarcomas. Latency: typically 10–20 years for solid tumours. The risk is lifelong and never returns to baseline. |
| Leukoencephalopathy | Chronic progressive white matter damage from radiation | May manifest as progressive cognitive decline, spasticity, ataxia years after treatment. MRI shows diffuse white matter T2/FLAIR hyperintensity. |
| Spinal deformities | Asymmetric irradiation of vertebral growth plates → scoliosis, kyphosis. Also contributes to overall short trunk height. | Requires orthopaedic monitoring in childhood. |
High Yield — Endocrine Late Effects of CSI
Endocrine abnormalities after craniospinal irradiation: ↓GH (94%), ↓ACTH (43%), ↓TSH (10%) [9][10].
Why is GH the most affected? Because GH-secreting somatotrophs have the lowest radiation threshold of all pituitary cell types (~18 Gy). ACTH-secreting corticotrophs require ~40 Gy, and TSH-secreting thyrotrophs require >40 Gy. Since the pituitary receives dose from the cranial component of CSI (typically 23–36 Gy), GH deficiency is nearly universal, ACTH deficiency is common, and TSH deficiency is least common.
Mnemonic for order of radiosensitivity: G > Gn > A > T ("GH, Gonadotropins, ACTH, TSH" — from most to least radiosensitive).
| Drug | Key Toxicities | Mechanism | Monitoring / Prevention |
|---|---|---|---|
| Cisplatin | Ototoxicity [9][10] | Cisplatin accumulates in the cochlea → generates reactive oxygen species → destroys outer hair cells of the organ of Corti, preferentially at the cochlear base (high-frequency region → high-frequency hearing loss first) | Serial audiometry (before each cycle and during follow-up). Dose reduction or switch to carboplatin if significant hearing loss. Sodium thiosulfate (protective agent) under investigation. |
| Nephrotoxicity | Direct tubular epithelial cell toxicity → acute tubular necrosis, chronic tubulointerstitial nephritis, electrolyte wasting (Mg²⁺, K⁺) | Aggressive IV hydration before and after each dose. Monitor RFT, serum Mg²⁺. Baseline and serial GFR measurement. | |
| Severe nausea/vomiting | Stimulation of chemoreceptor trigger zone (area postrema) + peripheral serotonin (5-HT₃) release from GI mucosa | Highly emetogenic — requires triple anti-emetic prophylaxis (5-HT₃ antagonist + NK1 antagonist + dexamethasone). | |
| Peripheral neuropathy | Dorsal root ganglion toxicity → sensory neuropathy | Less dose-limiting than in adults; monitor clinically. | |
| Vincristine | Peripheral neuropathy (dose-limiting) | Vinca alkaloid → disrupts axonal microtubules → impaired axoplasmic transport → axonal degeneration | Numbness, tingling (sensory), foot drop (motor), constipation (autonomic). Dose reduction if significant neuropathy. |
| Constipation / ileus | Autonomic neuropathy → reduced GI motility | Prophylactic laxatives. | |
| Jaw pain | Trigeminal nerve neuropathy | Transient, typically with first doses. | |
| Cyclophosphamide | Haemorrhagic cystitis | Acrolein (toxic metabolite) is excreted in urine → direct urothelial damage → haemorrhagic inflammation of bladder | Prevented by co-administration of mesna (2-mercaptoethanesulfonate sodium) — mesna binds and inactivates acrolein in the urinary tract. Adequate hydration. |
| Myelosuppression | Direct bone marrow toxicity → neutropenia, anaemia, thrombocytopaenia | Nadir ~7–14 days. Neutropenic fever is a medical emergency → broad-spectrum IV antibiotics. G-CSF may be used for support. | |
| Gonadotoxicity | Alkylating agents are particularly damaging to gonadal germ cells | Infertility risk. Fertility preservation pre-treatment. | |
| Secondary leukaemia | Alkylating agents cause DNA damage in haematopoietic stem cells → therapy-related MDS/AML years later | Risk ~1–3% at 10 years. Typically occurs 5–7 years post-treatment. | |
| Lomustine (CCNU) | Delayed myelosuppression | Nitrosourea → cumulative bone marrow toxicity with prolonged nadir (4–6 weeks) | Monitor CBC closely. Cumulative dose limits to reduce risk of permanent marrow damage. |
| Pulmonary fibrosis (rare, cumulative) | Direct pneumocyte toxicity | Avoid exceeding cumulative dose limits. |
If high-dose chemotherapy with autologous stem cell transplant (ASCT) is used [20]:
| Complication | Mechanism |
|---|---|
| Infection (early) | Prolonged neutropenia post-conditioning → bacterial, fungal (Aspergillus, Candida), viral (CMV, HSV) infections |
| Haemorrhage (early) | Severe thrombocytopaenia from conditioning |
| Veno-occlusive disease of liver (VOD) | Conditioning chemotherapy damages hepatic venous endothelium → sinusoidal obstruction → painful hepatomegaly, ascites, jaundice ± fulminant hepatic failure [20] |
| Endocrine dysfunction and infertility (late) | Total body irradiation (if used) and high-dose alkylating agents → hypothalamic-pituitary damage + direct gonadal damage |
| Secondary malignancy (late) | DNA damage from conditioning → therapy-related MDS/AML, solid tumours [20] |
| Cataract (late) | Mainly due to total body irradiation (TBI) [20] |
Category 3: Long-Term Sequelae in Survivors ("The Price of Cure")
Medulloblastoma survivors carry a substantial long-term morbidity burden. Over two-thirds of long-term survivors have at least one chronic health condition, and over one-third have a severe or life-threatening condition. This is sometimes called the "price of cure" — the treatment that saves the child's life leaves a legacy of health problems.
| Sequela | Details |
|---|---|
| Intellectual disability | IQ decline of ~2–4 points/year post-CSI. Particularly affects processing speed, working memory, and attention. Many survivors require special educational support. |
| Executive dysfunction | Cerebellar injury (surgical + RT) disrupts cerebello-frontal circuits → impaired planning, cognitive flexibility, and impulse control. |
| Academic underachievement | Combined effect of IQ decline, school absences during treatment, fatigue, and hearing loss. |
| Psychological / psychiatric | Increased rates of depression, anxiety, social isolation, and PTSD. Reduced quality of life. Lower rates of employment, independent living, and marriage compared to peers. |
| Posterior fossa syndrome (residual) | Some children never fully recover speech fluency or emotional regulation after posterior fossa syndrome. |
- GH deficiency (94%) → short stature even with replacement (vertebral growth plate damage)
- Hypothyroidism (primary + central) → lifelong thyroxine
- Adrenal insufficiency (43%) → hydrocortisone replacement + sick-day rules
- Hypogonadism → sex steroid replacement for puberty induction and bone health
- Precocious puberty → paradoxical early puberty before eventual hypogonadism (low-dose radiation can "disinhibit" the HPG axis)
- Obesity / metabolic syndrome → GH deficiency + hypothalamic damage + reduced physical activity
- Short stature (multifactorial: GH deficiency + vertebral growth plate damage + early puberty)
- Osteoporosis (hypogonadism + GH deficiency + corticosteroid use + reduced physical activity)
- Avascular necrosis (AVN) (particularly if high-dose corticosteroids used)
- Scoliosis / kyphosis (asymmetric vertebral irradiation)
- Radiation-induced tumours: meningiomas, gliomas, sarcomas, thyroid cancer
- Chemotherapy-induced: therapy-related MDS/AML (from alkylating agents)
- Cumulative risk increases indefinitely — lifelong cancer surveillance is required
| Timing | Disease-Related | Surgery-Related | RT-Related | Chemo-Related |
|---|---|---|---|---|
| Acute | Hydrocephalus, herniation, CN palsies | Haemorrhage, CSF leak, infection, posterior fossa syndrome | Somnolence, nausea, myelosuppression, mucositis | Nausea/vomiting, myelosuppression, haemorrhagic cystitis |
| Subacute | CSF dissemination symptoms, SIADH | Persistent hydrocephalus, meningitis | Radiation necrosis, Lhermitte sign | Ototoxicity (cisplatin), neuropathy (vincristine) |
| Late/Chronic | Recurrence, extraneural metastasis | Permanent cerebellar deficits, CN palsies | Neurocognitive decline, endocrinopathies, secondary malignancies, cerebrovascular disease, ototoxicity, growth failure | Infertility, secondary AML, cardiomyopathy (if anthracyclines used) |
High Yield Summary — Complications of Medulloblastoma
Disease-related:
- Obstructive hydrocephalus (>90%) → raised ICP → herniation (life-threatening)
- CSF dissemination → drop metastases → spinal cord/cauda equina compression
- Persistent hydrocephalus (~30-40% post-resection)
Surgery-related:
- Posterior fossa syndrome (cerebellar mutism): injury to vermis/dentate nuclei, appears 1-2 days post-op, impaired language production + emotional lability, resolves weeks to months [9][10]
- CN palsies, CSF leak, haemorrhage, infection
Radiotherapy-related (the most devastating long-term burden):
- Neurocognitive impairment: IQ decline ~2-4 points/year — most devastating late effect
- Endocrine: ↓GH (94%), ↓ACTH (43%), ↓TSH (10%) [9][10]
- Ototoxicity (synergistic with cisplatin) [9][10]
- Cerebrovascular abnormalities (stroke, ICH, moyamoya) [9][10]
- Secondary malignancies (~3-5% at 20 years): meningiomas, gliomas, thyroid cancer, sarcomas
- Growth failure (GH deficiency + vertebral growth plate damage)
Chemotherapy-related:
- Cisplatin: ototoxicity, nephrotoxicity, nausea
- Vincristine: peripheral neuropathy (dose-limiting), constipation
- Cyclophosphamide: haemorrhagic cystitis (prevent with mesna), gonadotoxicity, secondary leukaemia
- Lomustine: delayed myelosuppression, pulmonary fibrosis
Mnemonic for order of pituitary radiosensitivity: G > Gn > A > T (GH most sensitive, TSH least)
Active Recall - Complications of Medulloblastoma
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 432 — Medulloblastoma: high propensity to disseminate via subarachnoid space) [9] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1262–1264 — Treatment and Complications of Medulloblastoma: chemotherapy ototoxicity, RT complications, posterior fossa syndrome) [10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 534 — Treatment and Complications of Medulloblastoma: chemotherapy ototoxicity, RT complications, posterior fossa syndrome) [18] Senior notes: Maksim Medicine Notes.pdf (p. 47 — Cord compression: clinical features and differential) [19] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (p. 21 — CNS causes of SIADH) [20] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p. 34 — Complications of HSCT); Ryan Ho Haemtology.pdf (p. 156 — Complications and Prognosis of HSCT)
High Yield Summary
Medulloblastoma — Key Facts for Exams
- Definition: WHO Grade IV embryonal tumour of the cerebellum (posterior fossa). Most common malignant brain tumour in children.
- Epidemiology: Peak age 3–7 years, M > F. 15–20% of paediatric CNS tumours. Children 2–12yo: 70% infratentorial.
- Location: Arises in midline of posterior fossa (cerebellar vermis) → cerebellar signs ± hydrocephalus.
- Risk factors: Mostly sporadic. Genetic syndromes: Turcot syndrome (APC → FAP + medulloblastoma), Gorlin syndrome (PTCH1), Li-Fraumeni (TP53). High-dose ionizing radiation is the only proven environmental factor for brain tumours.
- Molecular subgroups (4): WNT (best prognosis, monosomy 6), SHH (PTCH1, TP53 matters), Group 3 (MYC amplification, worst prognosis), Group 4 (most common, intermediate prognosis).
- Pathophysiology: 4th ventricle obstruction → obstructive hydrocephalus → ↑ICP. Cerebellar destruction → ataxia. CSF seeding → drop metastases (spinal, leptomeningeal).
- Classic presentation: Young child with progressive morning headache, projectile vomiting, truncal ataxia, and papilloedema.
- Key signs: Truncal ataxia, wide-based gait, nystagmus, papilloedema, CN VI palsy (false localising sign), Cushing's triad (late).
- Danger: Never LP before imaging in suspected posterior fossa mass — risk of tonsillar herniation.
- Malignancy concept: Primary brain tumours rarely metastasise extracranially (∵ no lymphatic drainage) — but medulloblastoma is a notable exception that CAN (M4 stage, rare).
- Histological subtypes: Classic, desmoplastic/nodular, extensive nodularity (MBEN), large cell/anaplastic (worst).
- Risk stratification: Standard risk (>3y, gross total resection, M0) vs. High risk (<3y, residual tumour, M+, MYC amp, LC/A).
High Yield Summary — DDx of Medulloblastoma
Top differentials for a posterior fossa mass in a child:
- Pilocytic astrocytoma (JPA) — most common overall posterior fossa tumour; cerebellar hemisphere, cyst + nodule, Grade I, excellent prognosis
- Ependymoma — 4th ventricle floor, extends through foramina, calcification, adherent to brainstem
- Atypical teratoid / rhabdoid tumour (AT/RT) — infants <3y, looks like medulloblastoma on MRI, INI1 loss, very poor prognosis
- Diffuse midline glioma / DIPG — pons, H3 K27M, CN palsies + long tracts, not resectable, dismal prognosis
- Craniopharyngioma — suprasellar not posterior fossa, but enters DDx of paediatric brain tumour with ↑ICP; calcification, visual field defects, endocrine dysfunction
Key discriminators: Age, location within posterior fossa, MRI features (especially DWI), molecular markers, CSF seeding tendency.
Non-neoplastic mimics: Cerebellar abscess (ring-enhancing, fever, otitis media), acute cerebellitis (post-viral, no mass), arachnoid cyst, Dandy-Walker, cerebellar haemorrhage/infarct.
High Yield Summary — Investigations for Medulloblastoma
- First-line imaging: CT brain (emergency — detects hydrocephalus and mass). CT brain: site, multiplicity, mass effect, contrast enhancement indicates BBB disruption [4].
- Gold standard imaging: MRI brain with gadolinium contrast [13]. Key finding = restricted diffusion on DWI (high cellularity).
- Pre-operative spinal MRI: Essential for staging (drop metastases). Do before surgery or ≥14 days post-op.
- Post-operative MRI brain: Within 24–72 hours to assess residual tumour (> 1.5 cm² = high risk).
- CSF cytology: Post-operative ≥14 days. Positive = M1 = high risk. Never LP before imaging/surgery in posterior fossa mass.
- Definitive diagnosis: Histological examination at time of surgical resection [9][10]. Must confirm with IHC (synaptophysin+, INI1 retained) and molecular subgrouping.
- Molecular subgrouping: IHC screening (β-catenin, GAB1) → FISH (monosomy 6, MYC) → methylation array (gold standard).
- Staging = Chang system: T stage (tumour extent) + M stage (M0-M4). M0 + GTR + age >3y = standard risk; M+ or residual or LC/A or MYC amp = high risk.
- Baseline assessments: Audiometry, endocrine panel, renal function, neuropsychological testing — all essential before treatment with cisplatin and CSI.
- Rule out mimics: Serum/CSF AFP and β-hCG negative (excludes GCT); INI1 retained (excludes AT/RT).
High Yield Summary — Management of Medulloblastoma
- Emergency: Dexamethasone for peritumoral oedema + EVD/ETV for acute hydrocephalus.
- Surgery: Maximal safe resection — confirms diagnosis, relieves ICP, establishes local control [9][10]. Post-op MRI within 24–72h. Residual > 1.5 cm² = high risk.
- Complication of surgery: Posterior fossa syndrome (cerebellar mutism) — appears 1–2 days post-op, injury to vermis/dentate nuclei, impaired language production + emotional lability, resolves weeks to months [9][10].
- Risk stratification: Standard risk (>3y, M0, GTR, non-LC/A, no MYC amp) vs. High risk (M+, STR, LC/A, MYC amp, Group 3).
- Radiotherapy: CSI controls residual posterior fossa disease and craniospinal axis metastasis [9][10]. Standard risk = 23.4 Gy CSI + 54 Gy PF boost. High risk = 36 Gy CSI + boost. Avoided/delayed in <3y due to neurocognitive toxicity [9][10].
- Chemotherapy: Vincristine / Cisplatin / Cyclophosphamide [9][10]. Adjunct to surgery and RT — decreases recurrence, minimizes CSI exposure, delays irradiation in young children [9][10]. Key toxicities: cisplatin ototoxicity [9][10], nephrotoxicity, neuropathy.
- RT late effects: ↓GH (94%), ↓ACTH (43%), ↓TSH (10%), ototoxicity, cerebrovascular abnormalities (stroke/ICH), neurocognitive impairment [9][10].
- Infants (<3y): Chemotherapy-only protocols to avoid CSI. Focal RT added later if needed.
- WNT subgroup: Trials exploring treatment de-escalation (excellent prognosis, reduce late toxicity).
- Targeted therapy: SMO inhibitors (vismodegib) for SHH subgroup in adults (contraindicated in growing children — growth plate fusion).
- Surveillance: Serial MRI Q3mo → Q6mo → annual. Lifelong endocrine, auditory, neurocognitive, and secondary malignancy monitoring.
High Yield Summary — Complications of Medulloblastoma
Disease-related:
- Obstructive hydrocephalus (>90%) → raised ICP → herniation (life-threatening)
- CSF dissemination → drop metastases → spinal cord/cauda equina compression
- Persistent hydrocephalus (~30-40% post-resection)
Surgery-related:
- Posterior fossa syndrome (cerebellar mutism): injury to vermis/dentate nuclei, appears 1-2 days post-op, impaired language production + emotional lability, resolves weeks to months [9][10]
- CN palsies, CSF leak, haemorrhage, infection
Radiotherapy-related (the most devastating long-term burden):
- Neurocognitive impairment: IQ decline ~2-4 points/year — most devastating late effect
- Endocrine: ↓GH (94%), ↓ACTH (43%), ↓TSH (10%) [9][10]
- Ototoxicity (synergistic with cisplatin) [9][10]
- Cerebrovascular abnormalities (stroke, ICH, moyamoya) [9][10]
- Secondary malignancies (~3-5% at 20 years): meningiomas, gliomas, thyroid cancer, sarcomas
- Growth failure (GH deficiency + vertebral growth plate damage)
Chemotherapy-related:
- Cisplatin: ototoxicity, nephrotoxicity, nausea
- Vincristine: peripheral neuropathy (dose-limiting), constipation
- Cyclophosphamide: haemorrhagic cystitis (prevent with mesna), gonadotoxicity, secondary leukaemia
- Lomustine: delayed myelosuppression, pulmonary fibrosis
Mnemonic for order of pituitary radiosensitivity: G > Gn > A > T (GH most sensitive, TSH least)
Gangliocytoma
A gangliocytoma is a rare, benign (WHO grade I) central nervous system tumor composed of mature, neoplastic ganglion cells (neurons).
Intracranial Germinoma
Intracranial germinoma is a malignant germ cell tumor most commonly arising in the pineal or suprasellar region, predominantly in children and young adults, that is highly radiosensitive and carries a favorable prognosis.