Author: PathologyMCQ Editorial Team
Category: Neuropathology – CNS Tumours
Last Updated: October 2026
Read Time: 18–22 minutes
Difficulty: Moderate to difficult (postgraduate neuropathology level)

At a glance

• What it is: a malignant embryonal tumour of the cerebellum (CNS WHO grade 4), the commonest malignant brain tumour of childhood.
• How it is classified (WHO CNS5, 2021): 4 molecular types (WNT-activated; SHH-activated TP53-wildtype; SHH-activated TP53-mutant; non-WNT/non-SHH), each combined with a histological pattern.
• Key morphology clues: MBEN and desmoplastic/nodular point to SHH (favourable in infants); large cell/anaplastic points to high-risk disease (MYC, TP53).
• Key IHC: nuclear β-catenin (WNT), YAP1 + GAB1 (SHH), both negative (non-WNT/non-SHH), p53 for TP53 status, INI1 and LIN28A to exclude mimics.

What is medulloblastoma as per WHO CNS5 (2021)?

Medulloblastoma is a malignant, embryonal, primary CNS tumour arising in the cerebellum or dorsal brainstem, defined in the WHO 2021 classification (CNS5) by integrated histological and molecular features. It is always CNS WHO grade 4.

It accounts for most malignant paediatric posterior fossa tumours, is composed of densely cellular sheets of undifferentiated neuroepithelial cells, and tends to spread through the cerebrospinal fluid, so staging requires neuraxis MRI and CSF cytology. WHO CNS5 lists four molecularly defined types: WNT-activated; SHH-activated and TP53-wildtype; SHH-activated and TP53-mutant; and non-WNT/non-SHH. When molecular testing is not possible, the tumour is reported as medulloblastoma, histologically defined, with its morphological pattern: classic, desmoplastic/nodular, extensive nodularity (MBEN) or large cell/anaplastic.

How is classic medulloblastoma histology described?

• Diffuse sheets of small blue round cells with hyperchromatic round to oval or carrot-shaped nuclei, scant cytoplasm and a high N:C ratio.
• Frequent mitoses and apoptotic bodies; Ki-67 is high, often 30–40% or more.
• Homer Wright rosettes: tumour cells arranged around central fibrillary neuropil (no true lumen), showing neuroblastic differentiation.
• Delicate stroma with thin-walled vessels; infiltration of cerebellar cortex and leptomeninges explains subarachnoid spread.

What are the histological patterns?

Pattern	Defining features	Reticulin / Ki-67	Usual molecular type and age
Classic	Diffuse sheets of small round cells, Homer Wright rosettes	Little reticulin; high Ki-67	WNT, group 3, group 4; children
Desmoplastic/nodular (D/N)	Pale reticulin-free nodules of neurocytic cells within reticulin-rich, proliferative internodular zones	Reticulin around, not within, nodules; Ki-67 high in internodular zones	Almost always SHH; infants and adults
Extensive nodularity (MBEN)	Large, confluent, elongated reticulin-free nodules (grape-like), streaming neurocytic cells, little internodular tissue	Very low Ki-67 within nodules	SHH, infants under 3 years; favourable
Large cell/anaplastic (LC/A)	Marked pleomorphism, large vesicular nuclei with prominent nucleoli, nuclear moulding, cell wrapping, abundant apoptosis and mitoses	Very high Ki-67	Group 3 (MYC), SHH TP53-mutant; high risk

Tip: desmoplasia alone is not enough for D/N. You need reticulin-free nodules surrounded by reticulin-rich internodular zones, so always do a reticulin stain. Anaplasia must be widespread (diffuse) to call LC/A; focal anaplasia in a classic tumour is reported but does not change the pattern.

How does immunohistochemistry support diagnosis and subtyping?

IHC confirms neuronal differentiation, excludes mimics, measures proliferation and, through a short surrogate panel, assigns the molecular type when genomic testing is not available.

Marker	WNT-activated	SHH-activated	Non-WNT/non-SHH
β-catenin	Nuclear (may be patchy)	Cytoplasmic/membranous	Cytoplasmic/membranous
YAP1	Positive	Positive	Negative
GAB1 (or SFRP1)	Negative	Positive	Negative
OTX2	Positive	Usually negative	Often positive
p53	May be positive (TP53 mutation is common but not adverse in WNT)	Diffuse strong (or null) = TP53-mutant; scattered weak = wildtype	Wildtype pattern

• Differentiation: synaptophysin diffusely positive (and in rosette neuropil); NeuN variable; GFAP usually only in reactive astrocytes.
• Proliferation: Ki-67 high in classic and LC/A, very low inside MBEN and D/N nodules.
• Exclusion stains: INI1 (SMARCB1) and BRG1 retained (lost in AT/RT); LIN28A negative (positive in ETMR).
• Even a few nuclei with strong nuclear β-catenin count. Confirm WNT status with CTNNB1 sequencing and/or monosomy 6 where possible.

The 4 molecular types of WHO CNS5

Type	Frequency and age	Usual histology	Key genetics	Outcome
WNT-activated	~10%; children 7–14 years, adults	Classic (rarely LC/A)	CTNNB1 mutation (~90%), monosomy 6; germline APC in CTNNB1-wildtype cases	Excellent (>90% survival in children)
SHH-activated, TP53-wildtype	~25%; infants and adults	D/N, MBEN, classic	PTCH1, SUFU, SMO mutations; germline SUFU/PTCH1 in infants, ELP1 in children	Good in infants with D/N or MBEN; intermediate otherwise
SHH-activated, TP53-mutant	~5%; children 5–18 years	Often LC/A	TP53 (germline Li–Fraumeni in about half), MYCN and GLI2 amplification, chromothripsis	Poor
Non-WNT/non-SHH (groups 3 and 4)	~60%; children (group 3 also infants)	Classic, LC/A	Group 3: MYC amplification, isochromosome 17q. Group 4: isochromosome 17q, MYCN, CDK6, KDM6A	Group 4 intermediate; group 3 with MYC amplification worst

Integrated diagnosis format: layered reporting combines histology, molecular type and grade, for example “Medulloblastoma, SHH-activated and TP53-wildtype; desmoplastic/nodular histology; CNS WHO grade 4”.

Updates: molecular subtypes, risk groups and germline testing

• Subtypes: WHO CNS5 recognises methylation-based subtypes: SHH has 4 (SHH-1 and SHH-2 in infants, SHH-3 in children often with TP53 or ELP1, SHH-4 in adults) and non-WNT/non-SHH has 8 (subgroups 1–8). These are listed as “provisional” and are not yet required for routine diagnosis.
• Consensus risk groups (children 3–17 years): low risk = non-metastatic WNT; standard risk = non-metastatic SHH TP53-wildtype or group 4 without adverse features; high risk = metastatic SHH or group 4, or MYCN-amplified SHH; very high risk = SHH TP53-mutant or metastatic group 3 with MYC amplification.
• Germline predisposition: up to about 6% of medulloblastomas arise in children with an inherited syndrome. Consider genetic counselling and testing for SHH tumours (SUFU, PTCH1/Gorlin syndrome, TP53/Li–Fraumeni, ELP1, GPR161), WNT tumours without CTNNB1 mutation (APC/FAP), and group 3/4 tumours with BRCA2 or PALB2 variants.
• Therapy implications: SHH infants with D/N or MBEN can often avoid craniospinal irradiation; WNT tumours are the focus of de-escalation trials; very high-risk groups receive intensified treatment.

Morphology–risk correlations

• Favourable: SHH-activated MBEN. Large reticulin-free nodules with very low Ki-67 in an infant, often in a cerebellar hemisphere rather than the vermis. Recognising it allows de-escalated therapy.
• High risk: large cell/anaplastic. Marked atypia, prominent nucleoli, nuclear moulding and very high Ki-67, usually group 3 with MYC amplification or SHH TP53-mutant; associated with metastasis and poorer survival.
• Midline vermis tumour in a 7–14-year-old with classic histology: think WNT (often extending into the cerebellopontine angle or fourth ventricle) or group 4.

Differential diagnosis

Mimic	Clues	Deciding test
Atypical teratoid/rhabdoid tumour (AT/RT)	Infants; rhabdoid cells with eccentric nuclei and eosinophilic cytoplasm; polyphenotypic (EMA, SMA, GFAP)	Loss of INI1 (SMARCB1) or BRG1 (SMARCA4)
Embryonal tumour with multilayered rosettes (ETMR)	Young children; multilayered true rosettes, neuropil-rich areas	LIN28A positive; C19MC amplification or DICER1 alteration
CNS neuroblastoma, FOXR2-activated / other CNS embryonal tumours	Usually supratentorial; neuroblastic and neurocytic differentiation	Methylation profiling, FOXR2 or BCOR testing
Ependymoma (posterior fossa)	Perivascular pseudorosettes, true ependymal rosettes, GFAP+	GFAP and dot-like EMA positive; H3 K27me3 loss in PFA
High-grade glioma, small cell type	Infiltrative glioma, GFAP/OLIG2 positive	OLIG2, H3 K27M, IDH and molecular testing
Lymphoma, metastatic small cell carcinoma	Adults; angiocentric or cohesive nests	CD45/CD20; cytokeratin, TTF-1

Integrated diagnosis workflow

1. H&E: confirm an embryonal small round blue cell tumour in the posterior fossa and identify the pattern (classic, D/N, MBEN, LC/A). Add reticulin.
2. Exclusion IHC: synaptophysin, INI1, BRG1, LIN28A, GFAP, OLIG2 as needed.
3. Surrogate IHC: β-catenin, YAP1, GAB1, OTX2 and p53, plus Ki-67.
4. Molecular: CTNNB1 and TP53 sequencing, MYC/MYCN FISH, chromosome 6 status; DNA methylation profiling where available.
5. Report: layered integrated diagnosis with type, histology, grade and risk-relevant alterations; flag possible germline predisposition.

In low-resource settings a surrogate IHC panel assigns the molecular type with reasonable accuracy, but WNT status and TP53 status in SHH tumours should be confirmed molecularly whenever possible.

High-yield MCQs

Exam pearl and key takeaway

Exam pearl: nuclear β-catenin in a cerebellar small blue cell tumour = WNT-activated medulloblastoma, with an excellent prognosis in non-metastatic children. YAP1+ GAB1+ = SHH; check p53 because TP53-mutant SHH is very high risk and often germline.

Key takeaway: medulloblastoma is diagnosed by integrating morphology, a targeted IHC panel and molecular testing into a layered WHO CNS5 diagnosis, which drives risk-adapted therapy and germline counselling.