Medulloblastoma

Medulloblastoma is the most common individual malignancy of the CNS in children.

Epidemiology

Medulloblastoma makes up 4% of all paediatric malignancies and 20% of CNS malignancies by itself. It is slightly more common in boys. Most cases occur before the age of 10, and 80% before 20. It can occur in young adults but is very rare thereafter.

Aetiology

Most cases are sporadic. There is association with several germline mutations:

  • Naevoid Basal Cell Carcinoma Syndrome (Gorlin syndrome): Deactivating mutation in the tumour suppressor PTCH means that children are more susceptible to development of medulloblastoma, which may be the first manifestation of the syndrome
  • Familial Adenomatous Polyposis (Turcot syndrome): Deactivating mutation of APC allows overexpression of the WNT signally pathway through dysregulation of ╬▓-catenin.

Natural History

The tumour is prone to spread within the CSF spaces of the CNS. This necessitates treatment of the craniospinal axis to prevent tumour recurrence.

Clinical Features

Patients typically present with headache, somnolence, and balance issues. Cranial nerve symptoms may occur.
Imaging demonstrates a homogenously enhancing mass in the posterior fossa, usually arising from the vermis and extending into the 4th ventricle.
Workup should include craniospinal MRI and CSF cytology to determine Chang stage.

Pathological Features

The tumour is pink or grey, and invades surrounding brain tissue without a capsule.
Microscopically, the tumour cells are small round blue cells that may arrange into Homer-Wright rosettes. The cells are usually arranged in sheets. Other patterns may be apparent:

  • Desmoplastic/nodular medulloblastoma contains nodules of larger, differentiated cells surrounded by a 'stroma' of small round blue cells. This variant is most commonly seen with PTCH mutations.
  • Medulloblastoma with extensive nodularity occurs when there are large nodules of differentiated cells; this is associated with a good prognosis
  • Anaplastic change is sometimes seen in medulloblastoma; cells may be variable sizes, have high mitotic counts, but still maintain a high NC ratio. This is associated with a poor prognosis.
  • Large cell medulloblastoma is formed exclusively by large, malignant cells and overlaps with anaplastic changes; the nuclei are often vesicular and there is often eosinophilic cytoplasm. This is associated with a very poor prognosis.
  • Minor variants with melanocytic or rhabdoid differentiation may be seen.

Immunohistochemical stains are positive for neurone specific enolase and synpatophysin.
Genetic changes are complex, and include:

  • Loss of 17p (~25%), poor prognostic factor
  • Amplification of MYCC and MYCN (5-10%) poor prognostic factor
  • Amplification of ERBB2 (poor prognostic factor)
  • PTCH mutations (~10-20%)
  • APC mutations (3-4%), associated with desmoplastic/nodular medulloblastoma and good prognosis

Risk stratification

High risk includes patients with:

  • Metastatic disease, including positive CSF cytology (Chang M1)
  • Incomplete debulking (1.5 cm3 or more remaining)
  • Young age (< 3)
  • Anaplastic or large cell phenotype
  • MYC amplification
  • Loss of 17p

Other patients are standard risk and are treated with lower doses of craniospinal irradiation.


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