Medulloblastoma

Aetiological factors are unknown; however, there are reported associations with the following inherited familial syndromes:[13][14][15]

Ataxia-telangiectasia
Rubinstein-Taybi syndrome
Gorlin syndrome (nevoid basal cell carcinoma syndrome [NBCCS])
Turcot syndrome
Lynch syndrome/constitutional mismatch repair deficiency (CMMRD)
Li-Fraumeni syndrome (TP53 germline mutation)
Other germline mutations: BRCA2, PALB2, GPR161, ELP1, CREBBP, and EP300.

Medulloblastoma refers to a tumour of primitive neuroepithelial cells of the cerebellum. These tumours correspond to World Health Organization grade IV. Medulloblastoma may be categorised as desmoplastic, classic, large-cell, anaplastic, and variants with extensive nodularity, with myogenic and with melanotic differentiation. There is some evidence that children with large-cell and diffuse anaplastic variants have a worse prognosis.

Gene expression profiling has demonstrated that medulloblastoma is a heterogenous group of diseases with distinct demographic, clinical, and molecular characteristics, and it has been categorised into four molecular groups: wingless (WNT), sonic hedgehog (SHH), and two additional groups called group 3 and 4.[1][2][3][16][17] Patients whose tumours show WNT pathway activation usually have an excellent prognosis, while patients with SHH pathway-activated tumours generally have an intermediate prognosis. Outcome for the remaining patients is less favourable than that for patients with WNT pathway activation.

Mutations in medulloblastoma cases are observed in a subtype-specific manner, with CTNNB1 mutations observed in the WNT subtype, and with PTCH1, SMO, and SUFU mutations observed in the SHH subtype. The prognostic significance of recurring mutations is closely aligned with that of the molecular subtype with which they are associated. There is strong evidence that amplification of the MYC oncogene (n-myc or c-myc), and deletions of chromosome 17p, are associated with poor outcome.[18][19][20]

Molecularly classified subtypes[1][2][3][16][17]

Subtype 1: WNT medulloblastoma have Wnt/Wg pathway activation and are associated with a distinctively favourable clinical behaviour. Beta-catenin status (a marker of Wnt/Wg pathway activation) is an independent marker of good outcome as observed in several clinical trial-based studies.[21] Expression of the neurotrophin-3 receptor TrkC appears to correlate with a favourable prognosis.[22] These tumours are infrequently metastasised at diagnosis. Molecularly, they have 6q loss and CTNNB1 mutations and there may be occasional MYC overexpression. The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance.
Subtype 2: SHH medulloblastoma are characterised by chromosome 9q deletions; desmoplastic/nodular histology; and mutations in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2. Subtype 2 tumours are observed mostly in children younger than 3 years. Prognosis for patients with SHH medulloblastoma appears to be negatively affected by other molecular genetic changes, such as chromosome 17p loss, chromosome 3q gain, chromothripsis, p53 amplification, TP53 mutation, and the finding of large-cell/anaplastic histology. The outcome for patients with SHH medulloblastoma is relatively favourable, primarily in children younger than 3 years and adults.
Subtype 3 (group 3): histology of subtype 3 tumours is either classic or large-cell/anaplastic and these are frequently metastasised at the time of diagnosis. A variety of different mutations have been noted in these tumours including the presence of i17q and, most characteristically, MYC amplification. Subtype 3 tumours occur throughout childhood and may occur in infants. Males predominate females in a 2:1 ratio. Patients with MYC amplification or MYC overexpression have a poor prognosis. This prognosis is especially bad in children younger than 4 years at the time of diagnosis.
Subtype 4 (group 4): subtype 4 tumours are either classic or large-cell/anaplastic tumours. Metastasis at diagnosis is common, but not as frequent as in subtype 3 tumours. These tumours have a CDK6 amplification and MYCN amplification and may also have an i17q abnormality. Subtype 4 tumours occur throughout infancy and childhood and into adulthood. They predominate in males. The prognosis is better than in subtype 3 tumours, but not as good as in subtype 1. Prognosis for subtype 4 patients is affected by additional factors such as the presence of metastatic disease and chromosome 17p loss.[23]

Further subdivision within subgroups based on molecular characteristics is likely in the future, although there is no consensus regarding an alternative classification at present. In addition, translation of this molecular data into pathologist-friendly techniques that could be universally applied is a major challenge.

Medulloblastoma predominantly arises from the vermis of the cerebellum and fills the fourth ventricle, blocking the outflow of cerebrospinal fluid. The result is raised intracranial pressure due to obstructive hydrocephalus that causes headaches, nausea, lethargy, impaired upward gaze, vomiting that often relieves the headache, and sixth cranial nerve palsies (e.g., impaired horizontal gaze and diplopia). In infants, the hydrocephalus can cause a rapid growth in head circumference and a bulging anterior fontanelle.[24] Other symptoms result from the mass effect exerted on the cerebellum, and include truncal and appendicular ataxia, nystagmus, a wide-based gait, and head tilt.

Molecular classification of medulloblastoma[1][2][3]

Medulloblastoma has been classified into 4 molecular subgroups using a variety of different genomic approaches and platforms including gene expression profiling, microRNA profiling, and methylation arrays:

Subtype 1 - wingless (WNT) medulloblastoma

Subtype 2 - sonic hedgehog (SHH) medulloblastoma

Subtype 3 - group 3 medulloblastoma

Subtype 4 - group 4 medulloblastoma.

World Health Organization (WHO) classification of tumours of the central nervous system (2021)[4]

The updated WHO classification includes both molecularly and histologically defined subgroups, as follows:

Medulloblastoma, molecularly defined

Medulloblastoma, WNT-activated
Medulloblastoma, SHH-activated and TP53-mutant
Medulloblastoma, SHH-activated and TP-53-wildtype
Medulloblastoma, non-WNT/non-SHH
- Medulloblastoma, group 3
- Medulloblastoma, group 4.

Medulloblastoma, histologically defined

Medulloblastoma, classic

Medulloblastoma, desmoplastic/nodular

Medulloblastoma with extensive nodularity

Medulloblastoma, large cell/anaplastic.

Pathophysiology

Classification

Molecular classification of medulloblastoma[1][2][3]

World Health Organization (WHO) classification of tumours of the central nervous system (2021)[4]