Medulloblastoma
Updates to Article Attributes
Medulloblastomas are the most common malignant brain tumour of childhood. They most commonly present as midline masses in the roof of the 4th ventricle with associated mass effect and hydrocephalus. Treatment typically consists of surgical resection, radiation therapy, and chemotherapy, with the prognosis strongly influenced by surgical resection, presence of CSF metastases at the time of diagnosis, and expression of the c-erbB-2 (HER2/neu) oncogene.
Although medulloblastoma has been classically thought of as a single entity it is becoming increasingly evident that there are a number of distinct molecular subgroups with, albeit overlapping, clinical, histological and imaging features 8.
These molecular subgroups have been named WNT, SHH, Group 3 and Group 4 8. Perhaps counterintuitively what most of us think of as the typical medulloblastoma (midline tumour in early childhood) is group 4.
The article below provides a general overview of medulloblastoma, but is not surprisingly confusing. As such we are in the process of creating individual articles for each subgroup.
Epidemiology
Overall medulloblastomas account for 12-25 % of all paediatric CNS tumours, and 30-40% of paediatric posterior fossa tumours 1,7. They are also seen in adults, but only account for 0.4-1.0% of adult brain tumours 1. Since there are many more adults than children, 14-30% of all medulloblastomas are found in adults.
Taken as a group, there is a moderate male predilection with a M:F ratio of 2:1, although this is only true of group 3 and 4 tumours 8.
They usually present in childhood with 77% of cases before the age of 19. The median age of diagnosis is 9 years. When diagnosed in adulthood, they typically present in the 3rd and 4th decades and are more likely to arise in atypical locations (see below). When they present in adulthood, there is often a better prognosis.
Importantly age of presentation and gender ratio is influenced by tumour genomics 7-9:
- WNT
- children and adults (not seen in infancy)
- M:F 1:1
- SHH
- infants and adults (rare in children)
- M:F 1:1
- Group 3
- infants and children (rare in adults)
- M > F
- Group 4
- typically children (rare in infants)
- M:F 2:1
Clinical presentation
Growth of these very cellular tumours is often rapid and accounts for their relatively rapid clinical. Typically, presentation occurs over a few weeks with features that are dominated by symptoms of raised intracranial pressure as a result of obstructive hydrocephalus 7.
In approximately 40% of patients there is evidence of CSF seeding at the time of diagnosis 7.
Pathology
The tumours in general tend to be extremely cellular and is an example of a small round blue cell tumour which results in predictable imaging features. They are categorised as CNS primitive neuroectodermal tumours (WHO grade IV).
Traditionally four 'common' sub types with two additional rare types have been described based on histology and morphology. Recent genomic work however is replacing this classical division with one based on tumour transcriptome 7.
World Health Organization 2007 (WHO) classification
-
classic
:- dense sheet like growth of cells
- hyperchromatic round-to-oval nuclei
- increased mitotic activity
- conspicuous apoptosis
- neuroblastic or Homer-Wright rosettes (neoplastic cell nuclei disposed in a radial arrangement around fibrillary processes) are common features
- necrosis is less common
-
desmoplastic
:- more common in adults
- once termed "circumscribed arachnoidal cerebellar sarcoma"
-
extensively nodular with neuronal differentiation
:- usually in children less than 3 years of age
- also known as cerebellar neuroblastoma
- "grapelike" macroscopic nodularity
- intranodular
:- cellular uniformity
- fine fibrillary matrix
- occasional mature ganglion cells
-
large cell / anaplastic
:- rarest histologic subtype
- high mitotic activity and pleomorphism
- large round nuclei with variable eosinophilic cytoplasm
- not distinguishable on imaging from other types
- haemorrhage and necrosis is common
Genomic classification
A classification derived from the tumours' transcriptome divides medulloblastomas into four groups, each with different demographics, biological behaviour and prognosis 7:
- WNT
- least common subgroup (11% of all medulloblastomas) 8
. - histology: usually classic, rarely large cell
- genetics:
somaticsomatic mutations of CTNNB1 encoding b-catenin - gene expression: WNT signaling
- least common subgroup (11% of all medulloblastomas) 8
- SHH (Sonic hedgehog)
:- histology: desmoplastic/nodular, classic, large cell
- genetics:
- Shh receptor PTCH mutation leading to Gorlin syndrome
- Shh inhibitor SUFU mutations
- amplifications of GLI1 and GLI2
- gene expression: Sonic Hedgehog signaling
- group 3
:- 27% of all medulloblastomas 8
- histology: classic, large cell
- genetics: MYC amplification
- gene expression: photoreceptor/GABAergic
- group 4
:- most common subgroup (34% of all medulloblastomas) 8
- histology: classic, large cell
- genetics: CDK6 and MYCN amplification
- gene expression:
Neuronal/Glutamatergicneuronal/glutamatergic
Associations
MedullobastomasMedulloblastomas are associated with a number of syndromes, including:
- Coffin-Siris syndrome
- Cowden syndrome
- Gardner syndrome
- Gorlin syndrome
- Li-Fraumeni syndrome
- Rubinstein-Taybi syndrome
- Turcot syndrome
Radiographic features
The radiographic features are strongly influenced by histological type and molecular subtype of the tumour. Many of the imaging characteristics can, however, be remembered by thinking of medulloblastoma as a small round blue cell tumour.
Overall the vast majority (94%) of medulloblastomas arise in the cerebellum and the majority of these, from the vermis (75%). They tend to protrude into the fourth ventricle from its roof, and may even grow directly into the brainstem 1,7. This pattern is particularly common in group 3 and group 4, and in some SHH subgroup tumours 10.
Other areas are less common, and are seen more frequent in older children and adults. In such cases the tumour is also more likely to be poorly marginated and demonstrate larger cyst formation 7. Adult medulloblastomas are usually located laterally, in the cerebellar hemispheres, with only 28% centred in the vermis; these are most commonly of the SHH subgroup 10.
Cerebellar peduncle is almost exclusively seen in the relatively indolent WNT subgroup 8-10.
CT
On CT, medulloblastomas appear as a mass arising from the vermis, resulting in effacement of the fourth ventricle / basal cisterns and obstructive hydrocephalus.
They are usually hyperdense (90%) and cysts formation/necrosis is common (40-50%), especially in older patients. Calcification is seen in 10-20% of cases 7.
Enhancement is present in over 90% of cases and is usually prominent 7.
MRI
-
T1
- hypointense to grey matter
-
T1 C+ (Gd)
- overall 90% enhance, often heterogeneously
- group 4 tumours tend to enhance less 10
-
T2/FLAIR
- overall are iso to hyperintense to grey matter
- heterogeneous due to calcification, necrosis and cyst formation
- surrounding oedema is common 10
-
DWI/ADC
- restricted diffusion (low ADC values)
-
MR spectroscopy
- elevated choline
- decreased NAA
- may show a taurine peak 5
MRI is able to delineate the fourth ventricle and subarachnoid space to a much greater degree than CT. Although medulloblastomas project into the fourth ventricle, unlike ependymomas they do not usually extend into the basal cisterns 7.
As CSF seeding is common at presentation, imaging with contrast of the whole neuraxis is recommended to identify drop metastases and leptomeningeal spread. Although rare, extraneural spread is reported.
Predicting molecular subgroup from imaging
So if all this sounds confusing, that's because it is. Molecular subgroups, histology, location, appearance and demographics all interact, but this notwithstanding, you can make some fairly robust predictions based on imaging when taking all of these together. Location is the key to this approach.
- cerebellar peduncle
- very likely WNT subgroup and therefore best prognosis
- cerebellar hemisphere
- very likely SHH subgroup and therefore intermediate prognosis
- likely desmoplastic/nodular/medulloblastoma with extensive nodularity (MBEN)
- midline
- may be group 3, group 4 or SHH
- typically infants with poorly defined tumour, with prominent enhancement, likely group 3 (or SHH) and therefore worst prognosis
- typically children with well defined tumours, with mild or no enhancement, likely group 4 and therefore slightly better prognosis
- adults with variably defined and variably enhancing tumours, are likely SHH (or group 4)
Treatment and prognosis
Treatment typically consists of surgical resection, radiation therapy, and chemotherapy. In general the tumours are quite radiosensitive.
Prognosis depends on complete surgical resection, and presence of CSF metastases at the time of diagnosis, which are generally common in infants and children (~25%) and uncommon in adults (~2%) 1.
Expression of the c-erbB-2 (HER2/neu) oncogene is useful in staging of medulloblastomas. Increased c-erbB-2 expression reflects an increase in the proliferative activity of a tumour (widely used in breast cancer staging).
- no CSF metastases, complete surgical resection and negative c-erbB-2 expression: 5-year-survival 100%
- no CSF metastases, complete surgical resection and positive c-erbB-2 expression: 5-year-survival 54%
- CSF metastases and/or incomplete surgical resection: 5-year-survival 20%
New genomic classification is also useful in predicting prognosis 7-9:
- WNT: very good
- SHH: infants good, others intermediate
- group 3: poor
- group 4: intermediate
Differential diagnosis
In the paediatric population consider:
-
ependymoma:
- usually arises from the floor of the 4th ventricle
- typically squeezes out the foramen of Luschka
- choroid plexus papilloma (CPP): more common in lateral ventricles in children
- pilocytic astrocytoma
- atypical teratoid/rhabdoid tumour
- brainstem glioma (exophytic)
In the adult population consider:
-<strong>classic:</strong><ul>- +<strong>classic</strong><ul>
-<strong>desmoplastic:</strong><ul>- +<strong>desmoplastic</strong><ul>
-<strong>extensively nodular with neuronal differentiation</strong>:<ul>- +<strong>extensively nodular with neuronal differentiation</strong><ul>
-<li>intranodular:<ul>- +<li>intranodular<ul>
-<strong>large cell / anaplastic</strong><strong>:</strong><ul>- +<strong>large cell / anaplastic</strong><strong></strong><ul>
-<li>least common subgroup (11% of all medulloblastomas) <sup>8</sup>. </li>- +<li>least common subgroup (11% of all medulloblastomas) <sup>8</sup>
- +</li>
-<li>genetics: somatic mutations of CTNNB1 encoding b-catenin</li>- +<li>genetics: somatic mutations of CTNNB1 encoding b-catenin</li>
-<li>SHH (Sonic hedgehog):<ul>- +<li>SHH (Sonic hedgehog)<ul>
-<li>group 3:<ul>- +<li>group 3<ul>
-<li>group 4:<ul>- +<li>group 4<ul>
-<li>gene expression: Neuronal/Glutamatergic</li>- +<li>gene expression: neuronal/glutamatergic</li>
-</ul><h5>Associations</h5><p>Medullobastomas are associated with a number of syndromes, including:</p><ul>- +</ul><h5>Associations</h5><p>Medulloblastomas are associated with a number of syndromes, including:</p><ul>
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