General
- An embryonal neuroepithelial tumour
- Arising in the cerebellum or dorsal brain stem
- Presenting mainly in childhood and
- Consisting of densely packed small round undifferentiated cells with mild to moderate nuclear pleomorphism and a high mitotic count.
- Small round blue cells with Homer-Wright rosettes.
Genetic profile | WNT-activated | SHH-activated, TP53-mutant | SHH-activated, TP53-wildtype | Non-WNT/non-SHH, group 3 | Non-WNT/non-SHH, group 4 |
Predominant age(s) at presentation | Childhood | Childhood | Infancy , adulthood | Infancy, childhood | All age groups |
M : F ratio | 1 : 2 | 1 : 1 | 1 : 1 | 2 : 1 | 3 : 1 |
Proposed cell of origin | Lower rhombic lip progenitor cells | Cerebellar granule neuron cell precursors of the external granule cell layer and cochlear nucleus (Neural stem cells of the subventricular zone) | Same with TP53-mutant | CD133+/lineage-neural stem cells (Cerebellar granule neuron cell precursors of the external granule cell layer) | Unknown |
Frequent copy number alterations | Monosomy 6 | MYCN amplification, GLI2 amplification, 17p loss | PTCH1 deletion, 10q loss | MYC amplification, isodicentric 17q | MYCN amplification, isodicentric 17q |
Frequent genetic alterations | CTNNB1 mutation, DDX3X mutation, TP53 mutation | TP53 mutation | PTCH1 mutation, SMO mutation (adults), SUFU mutation (infants), TERT promoter mutation | PVT1-MYC, GFI1/GFI1B structural variants | KDM6A, GFI1/GFI1B structural variants |
Genes with germline mutation | APC | TP53 | PTCH1, SUFU | ㅤ | ㅤ |
Histology & prognosis | 1. Classic: Low-risk tumour; classic morphology found in almost all WNT-activated tumours 2. Large cell / anaplastic (very rare): Tumour of uncertain clinicopathological significance | 1. Classic: Uncommon high-risk tumour 2. Large cell / anaplastic: High-risk tumour; prevalent in children aged 7–17 years 3. Desmoplastic / nodular (very rare): Tumour of uncertain clinicopathological significance | 1. Classic: Standard-risk tumour 2. Large cell / anaplastic: Tumour of uncertain clinicopathological significance 3. Desmoplastic / nodular: Low-risk tumour in infants; prevalent in infants and adults 4. Extensive nodularity: Low-risk tumour of infancy | 1. Classic: Standard-risk tumour 2. Large cell / anaplastic: High-risk tumour | 1. Classic: Standard-risk tumour; classic morphology found in almost all group 4 tumours 2. Large cell / anaplastic (rare): Tumour of uncertain clinicopathological significance |
Definition
- Essential:
- A medulloblastoma AND
- Absence of histological features qualifying for the diagnosis of desmoplastic/nodular medulloblastoma or medulloblastoma with extensive nodularity AND
- Absence of predominant areas with severe cytological anaplasia and/or large cell cytology AND
- Retained expression of SMARCB1 (INI1)
Numbers
- Most common CNS embryonal tumour
- Most common malignant tumour of childhood
- Second in frequency only to pilocytic astrocytoma
- 25% of intracranial neoplasm
- Median age 9 yrs
- 30-50% posterior fossa
- Annual overall incidence 1.8/1million population
- For children only is 6/1million population
- 1/4 of all medulloblastomas occur in adults,
- But < 1% of adult intracranial tumours are medulloblastomas
- Over all Male:Female → 1.7:1
- Children 2:1
Localisation
- Cerebellum growing into 4th ventricle
- Children: 94% cerebellum and 75% from the vermis
- Adult: mainly located laterally (cerebellar hemispheres) only 28% centred in the vermis;
- These are most commonly of the SHH subgroup
- Cerebellar peduncle epicentre is almost exclusively seen in the relatively indolent WNT subgroup
- 30% have a Chang stage M1-M4
Origin
General
- Stem cells in medulloblastomas
- Medulloblastoma provides an excellent example of how co-option of neural stem cell pathways may drive brain tumour stem cell proliferation.
- Distinct medulloblastoma subgroups demonstrate gene mutations in either the sonic hedgehog pathway, or the Wnt/ B- catenin pathway.
- These pathways demonstrate a degree of functional redundancy, converging to drive tumour stem cell self- renewal proliferation and medulloblastoma histology.
- MB subgroup cellular hierarchies deduced from single-cell RNA sequencing.
- Illustration of malignant cell types inferred in medulloblastoma (MB) subgroups.
- WNT MB comprises undifferentiated progenitor-like populations and more differentiated neuron-like cells. The undifferentiated, cycling cells in Sonic hedgehog (SHH) MB resemble granule neuron progenitor (GNP) cells, whereas differentiated cells resemble granule neurons.
- The frequency of these cell populations varies with age-associated subtypes, with more differentiated cells in infant patients and more GNP-like cells in adults.
- Group 3 and Group 4 MBs comprise undifferentiated progenitor-like cells and more differentiated types of neurons that share expression of marker genes with glutamatergic cerebellar nuclei (GluCN) and unipolar brush cells (UBCs).
- A continuum of frequencies of these cell types is observed, with Group 3 tumours being fully or mostly undifferentiated, Group 4 tumours being predominantly differentiated and some intermediate tumours being located in between.
- These transcriptional states are superimposed on genetic alterations that are associated with molecular subtypes.
Wnt-activated
- Lower rhombic lip progenitor cells (LRL)
- WNT-MB tended to localise to the cerebellar peduncle/cerebellopontine angle
SHH-activated
- From upper rhomboid lip
- More commonly seen in the cerebellar hemispheres.
- Cerebellar granule neuron cell precursors of the external granule cell layer and cochlear nucleus (aka neural stem cells of the subventricular zone)
- Granule neuron progenitor (GNP) populations
- NeuroD1 enhancer and promoter are repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Importantly, pharmacological inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced tumour cell differentiation, which consequently reduces tumour growth
Non-WNT/SHH Group 3
- Localisation
- From upper rhomboid lip
- Within the midline 4th ventricle
- Origin
- CD133+/ stem cells (Cerebellar granule neuron cell precursors of the external granule cell layer)
- Mostly undifferentiated
Non-WNT/SHH Group 4
- Localisation
- From upper rhomboid lip
- Within the midline 4th ventricle
- Origin
- Glutamatergic cerebellar nuclei (GluCN; also known as deep cerebellar nuclei)
- Unipolar brush cells (UBCs)
- Mostly differentiated and some intermediate tumours
CNS WHO grading
- All types are Grade 4
Classification of medulloblastoma
Medulloblastoma
- Each characterised by distinct -omic (that is, genomic, epigenomic, transcriptomic and proteomic)
- Base on transcriptome profiling medulloblastomas can be separated into several distinct molecular clusters
- Genetic profile
- Molecular subtypes (See above)
- References:
- Values for age and gender distribution, frequency of metastasis, and 5-year overall survival (OS) for the WNT and Sonic hedgehog (SHH) subgroups are derived from the Cavalli et al. study.
- Driver events were additionally derived from the Kool et al. and Robinson et al. studies.
- Values for the Group 3 and Group 4 subgroups of medulloblastoma were derived from the Sharma et al. study.
- BCOR, BCL-6 co-repressor; CTDNEP1, CTD nuclear envelope phosphatase 1; CTNNB1, β-catenin; DDX3X, DEAD-box helicase 3X-linked; GFI1, growth factor independent 1 transcriptional repressor; i17q, isochromosome 17q; KBTBD4, Kelch repeat and BTB domain containing 4; KDM6A, lysine demethylase 6A; KMT2C, lysine methyltransferase 2C; LCA, large-cell/anaplastic; MBEN, MB with extensive nodularity; OTX2, orthodenticle homeobox 2; PRDM6, PR/SET domain 6; PTCH1, patched homologue 1; SMARCA4, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4; SMO, smoothened homologue; SUFU, suppressor of fused homologue; TERT, telomerase reverse transcriptase; ZMYM3, zinc finger MYM-type containing 3.
Abbreviations:
Pathology
Macroscopic
Microscopic
- Dominant population of undifferentiated cells with a high nuclear-to-cytoplasmic ratio and mitotic figures is a common feature, justifying the designation “embryonal”,
- Other cancers with "embryonal" like pattern
- High-grade small cell gliomas
- Some ependymomas
- Two distinctive morphological variants of medulloblastoma that can occur in the setting of a classic or large cell/anaplastic tumour (rare but can form)
- Medulloblastoma with myogenic differentiation (previously called medullomyoblastoma)
- Spindle-shaped rhabdomyoblastic cells and sometimes large cells with abundant eosinophilic cytoplasm
- Medulloblastoma with melanotic differentiation (previously called melanocytic medulloblastoma).
- Small number of melanin-producing cells, which sometimes form clumps
Immunophenotype
- Positive
- Synaptophysin, NeuN
- Nuclear SMARCB1 / INI1 and SMARCA4
- SOX11, PAX5, TTF1 and ISL1
- Medulloblastoma with melanocytic differentiation: HMB45, melanA
- Medulloblatoma with myogenic differentiation: desmin and myogenin
- Negative
- GFAP
- NFP
Associated syndromes
- Coffin-Siris syndrome
- Cowden syndrome
- Gardner syndrome
- Gorlin syndrome
- Li-Fraumeni syndrome
- Rubinstein-Taybi syndrome
- Turcot syndrome
Clinical feature
- Obstruction HCP
- Cerebellar compression
- Ataxia
Investigation
- Imaging of the whole craniospinal axis (see Radiology)
- CSF sampling
Radiology
CT
- 90% hyperdense
- 50% Cysts formation/necrosis (especially in older patients)
- 20% Calcification is seen
- Enhancement is present in over 90% of cases and is usually prominent
MRI
- T1
- Hypointense to grey matter
- T1 C+ (Gd)
- Overall 90% enhance, often heterogeneously
- Seen as solid, avidly enhancing masses with perilesional oedema
- Group 4 tumours tend to enhance less
- T2/FLAIR
- Overall are iso-hyperintense to grey matter
- Heterogeneous due to calcification, necrosis and cyst formation
- Surrounding oedema is common
- MBs with extensive nodularity (which align with the SHH group) have demonstrated multiple small T2w cystic areas within the tumour in a ‘grapelike’ morphology on MRI
- DWI/ADC (hypercellular)
- High DWI signal ("restricted diffusion")
- Low ADC values (lower than normal cerebellum e.g. ~550 x 10-6 mm2/s)
- MR spectroscopy
- Elevated choline
- Decreased NAA
- 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.
Imaging
Predicting molecular subgroup from imaging
- 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
- Maybe group 3, group 4 or SHH
- Typically infants with a tumour with ill-defined margins but prominent enhancement: likely group 3 (or SHH) and therefore worst prognosis
- Typically children with a tumour with well-defined margins but mild or no enhancement: likely group 4 and therefore slightly better prognosis
- Adults with variably defined and variably enhancing tumours: most likely SHH; haemorrhage raises the probability of group
- MR spectroscopy may also be distinctive:
- Group 3 or 4
- Taurine peak
- High creatine
- SHH
- Little or no taurine
- Low creatine
Prognosis
Poor prognostic factors
- Spread at the time of presentation
- CSF pathways
- 40% of patients, there is evidence of CSF seeding at the time of diagnosis
- Can spread to peritoneum thru VP shunts
- 10%
- Need to screen whole neuroaxis for mets
- Subtotal excision of the primary tumour
- Younger age
Proposed risk stratification for non-infant medulloblastoma
Risk Category | Low Risk | Standard Risk | High Risk | Very High Risk |
Survival (%) | >90 | 75–90 | 50–75 | <50 |
Subgroup, clinical and molecular characteristics | Non-metastatic; Non-metastatic and Chromosome 11 loss | Non-metastatic, TP53 WT and no MYCN amplification; Non-metastatic and no MYC amplification; Non-metastatic and no chromosome 11 loss | One or both: - Metastatic - MYCN amplification; Metastatic | TP53 Mutation; Metastatic |
- WNT: blue; SHH: red; Group 3: yellow; Group 4: green. WT=wild type.
- Conclusion:
- Treatment de-escalation for WNT
- Targeted therapy for SHH
- Treatment escalation for high risk group.
Differential diagnosis
In the paediatric population consider
- Ependymoma
- Usually arises from the floor of the 4th ventricle
- Typically squeezes out the foramen of Luschka
- Does not usually cause as much diffusion restriction
- Atypical teratoid/rhabdoid tumour
- Very young children
- Aggressive
- Pilocytic astrocytoma
- Usually cystic
- Brainstem glioma (exophytic)
- Choroid plexus papilloma (CPP) : more common in lateral ventricles in children
In the adult population consider
- Cerebellar metastasis
- Haemangioblastoma
- Choroid plexus papilloma
- Ependymoma
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