Medulloblastoma

Description

Medulloblastoma is a highly malignant primary brain tumour that originates in the cerebellum or posterior fossa, frequently in the region of the fourth ventricle. It is the most common malignant central nervous system tumour in children and typically presents with symptoms of raised intracranial pressure due to obstructive hydrocephalus.

Pathogenesis

Medulloblastomas are embryonal tumours that derive from progenitor cells of the granule cell lineage in the cerebellum. The pathogenesis often involves mutations in the WNT, SHH, Group 3, and Group 4 pathways, which are essential for cerebellar development.

They are thought to originate from a group of neuroepithelial cells located in the roof of the fourth ventricle that migrate outward and laterally to form the cerebellar external granular layer, hence occurrence in the cerebellar hemispheres in older patients.

Subtype

• WNT-activated medulloblastoma: These tumours are most commonly found in the cerebellar vermis in children and adults and are associated with a more favourable prognosis.
• Sonic hedgehog (SHH) activated medulloblastoma: These are typically desmoplastic/nodular medulloblastomas and are most commonly found in infants and adults (rare in children).
• Group 3 medulloblastoma: These are often large and invasive, typically spreading to the brainstem and spinal cord. They have the worst prognosis among medulloblastoma subtypes. Not usually seen in adults.
• Group 4 medulloblastoma: This is the most common type, seen across all age groups but typically in children and usually presents in the cerebellar hemispheres. More likely to haemorrhage.

Epidemiology, Risk Factors & Associations

• Peak incidence in the first decade of life (approximately 20% of all childhood brain tumours)
• Slightly more common in males (M:F ratio ~1.5:1)

Medulloblastomas have been associated with:

• Gorlin syndrome (nevoid basal cell carcinoma syndrome): basal cell nevi, odontogenic karatocyst, falx calcification and increased risk of various cancers, including medulloblastoma (SHH-activated subtype)
• Turcot syndrome: Associated with risks of both colorectal polyps and brain tumours, including medulloblastoma.
• Li-Fraumeni syndrome: Greatly increases the risk of developing several types of cancer, particularly in children and young adults.
• Cowden syndrome: Rare genetic disorder characterised by multiple hamartomas and an increased risk of certain forms of cancer, including breast, thyroid, endometrial (uterine), and possibly brain.
• Gardner syndrome: A variant of familial adenomatous polyposis (FAP) that is also characterised by the growth of noncancerous tumours in the skin and soft connective tissue. The association with medulloblastoma is rare.
• Coffin-Siris syndrome: A rare genetic condition that can cause developmental delay, intellectual disability, coarse facial features, and abnormalities of fingers and toes. The association with medulloblastoma is extremely rare.
• Rubinstein-Taybi syndrome: Characterised by intellectual disability, distinctive facial features, and broad thumbs and first toes. An association with medulloblastoma has been described, but this is very rare.
• L-2-hydroxyglutaric aciduria: Very rare metabolic disorder. Its association with medulloblastoma is extremely rare and only a few cases have been reported.

Clinical Features

• Raised intracranial pressure symptoms: headache, nausea, vomiting, and papilledema
• Ataxia, dysmetria, and nystagmus due to cerebellar involvement
• Cranial nerve palsies due to brainstem invasion or compression

Complications

• Obstructive hydrocephalus
• Leptomeningeal spread and CSF seeding leading to drop metastases is common
• Systemic metastasis (bone, lymph nodes and lung) is rarer.
• Bone metastases are usually sclerotic
• Metastasis to the abdominal cavity may occur via ventriculoperitoneal shunt catheter
• Neurological deficits due to local invasion or compression

Pathological Features

Histopathology

• Macroscopic: Homogeneous greyish-white mass, often with necrosis and haemorrhage
• Microscopic: Small blue round cells with high nucleus-to-cytoplasm ratio, frequent mitoses, and a tendency to form Homer Wright rosettes

Genetics

• WNT subgroup tumours harbor mutations in the WNT signaling pathway, often involving the CTNNB1 gene. They may originate from progenitor cells in the lower rhombic lip or dorsal brain stem.
• SHH subgroup tumours are characterised by mutations in the Sonic Hedgehog signaling pathway, such as PTCH1, SMO, or SUFU. They are thought to originate from granule neuron precursors in the cerebellum.
• Group 3 tumours often show amplification of the MYC oncogene and are currently thought to possibly originate from progenitor cells in the dorsal brain stem. This subgroup is associated with the poorest prognosis.
• Group 4 tumours have the least defined genetic landscape and cell of origin. They often exhibit isochromosome 17q and CDK6 amplification.

Radiological Features

• Usually midline posterior fossa mass, majority arising from cerebellar vermis or posterior medullary velum (roof of the 4th ventricle). Typically well-defined, round or oval.
  • WNT-activated: More likely to involve cerebellar peduncle, cerebellopontine angle, foramen of Luschka
  • SHH: More likely to involve the cerebellar hemisphere (adolescents and adults)
  • Group 3: Ill-defined margins but prominent enhancement (worse prognosis).
  • Group 4: Most common. Midline. More likely to demonstrate haemorrhage.
• Often causes effacement or obstruction of the fourth ventricle and hydrocephalus. Do not usually extend into the basal cisterns.
• Cyst formation and necrosis is common (40-50%)
• Calcifications are rarely in the primary tumour unless there has been previous radiation therapy
• Leptomeningeal enhancement may be seen with leptomeningeal spread
• Drop metastases to the spinal subarachnoid space and cauda equina occur is common (approx. 40% of cases) hence post-contrast imaging of total neuraxis is essential.

CT

• Non-contrast: Hyperdense mass in posterior fossa reflecting high cellularity. Surrounding oedema and obstructive hydrocephalus may be seen.
• Contrast-enhanced: Marked heterogeneous enhancement, salt-and-pepper appearance due to high vascularity. Metastases may be seen as enhancing nodules in the subarachnoid space, particularly in the spinal canal (drop metastases).

MRI

• T1WI: Hypointense mass to grey matter in posterior fossa
• T2WI: Intermediate to hyperintense mass.
• FLAIR: Peritumoural oedema often seen
• T1 C+: Heterogeneous enhancement. WNT-activated tumours tend to enhance vividly and group 4 tumours tend to enhance less. Metastases appear as high signal foci in the subarachnoid space.
• DWI/ADC: Restricted diffusion suggestive of high cellularity
• Spectroscopy: Elevated choline, decreased NAA

NM

• PET FDG: High uptake due to increased metabolic activity of the tumour

Grading and Staging

Chang Staging System for Medulloblastoma with Risk Stratification

Tumour

• T1: Tumour less than 3 cm in diameter, confined to the midline or lateral cerebellum, or roof of the fourth ventricle.
• T2: Tumour more than 3 cm in diameter, extending into adjacent structures, such as the brainstem, without causing significant deformity.
• T3a: Tumour more than 3 cm in diameter, with significant involvement of the brainstem, causing moderate deformity or encasement of cranial nerves or major vessels.
• T3b: Tumour more than 3 cm in diameter, with significant deformity of the brainstem and/or fourth ventricle, often extending into the foramen of Luschka or foramen of Magendie.
• T4: Tumour more than 3 cm in diameter, with extension through the aqueduct of Sylvius into the third ventricle, through the foramina of Luschka into the cerebellopontine angle, or with bilateral extension into the cerebellopontine angles, causing hydrocephalus.

Metastasis

• M0: No evidence of gross subarachnoid or hematogenous metastasis.
• M1: Microscopic tumour cells found in cerebrospinal fluid (CSF).
• M2: Gross nodular seeding in the cerebellar, cerebral subarachnoid space, or in the third or lateral ventricles.
• M3: Gross nodular seeding in the spinal subarachnoid space.
  • M3a: Metastasis confined to the cervical spine.
  • M3b: Metastasis confined to the thoracic spine.
  • M3c: Metastasis confined to the lumbar spine.
• M4: Extraneural metastasis (outside the central nervous system).

Risk Stratification

• Standard Risk
  • Patients aged 3-18 years.
  • Gross total resection or minimal residual disease (≤1.5 cm² post-operative residual tumour).
  • M0 status (no metastasis).
• High Risk:
  • Patients younger than 3 years or older than 18 years.
  • Subtotal resection or significant residual disease (>1.5 cm² post-operative residual tumour).
  • M1-M4 status (presence of metastatic disease).
  • Large cell/anaplastic histology.

Diagnosis

The diagnosis is made based on imaging findings and confirmed by histopathological examination of the surgical specimen. Due to CSF seeding, imaging of the whole neuraxis is required to identify drop metastases and leptomeningeal spread.

Differential Diagnosis

• Ependymoma: Usually older children. Arises from the floor of the fourth ventricle, capping the ventricle rather than filling it, typically extends through foramen of Luschka. Does not usually diffusion restrict. May contain characteristic perivascular pseudorosettes on histology
• Atypical teratoid/rhabdoid tumour (AT/RT): Highly aggressive (irregular and heterogenous, may be indistinguishable). More commonly seen in children under 3 years of age, often with a characteristic rhabdoid histology
• Cerebellar pilocytic astrocytoma: Typically cystic with a vividly enhancing mural nodule, and occurs more commonly in the cerebellar hemispheres than the vermis
• Haemangioblastoma: Typically cystic with a vividly enhancing mural nodule. Demonstrates T2 dark flow voids. Associated with von Hippel Lindau.
• Choroid plexus papilloma: Typically lateral ventricle, lobulated and more intensely enhancing

Management

Treatment usually involves surgical resection followed by craniospinal irradiation and chemotherapy. Prognosis varies significantly with the subtype, with WNT-activated medulloblastomas having the best prognosis.