Molecular Classification of Medulloblastoma
Medulloblastoma is classified into four well-established molecular subgroups: WNT-activated, SHH-activated (subdivided by TP53 status), Group 3, and Group 4, with molecular characterization now serving as the gold standard for diagnosis and risk stratification. 1
The Four Primary Molecular Subgroups
WNT-Activated Medulloblastoma
- Represents approximately 10% of all medulloblastomas and carries an excellent prognosis with long-term survival rates exceeding 90% 1
- Distinguished by CTNNB1 mutation in 90% of cases, resulting in positive nuclear β-catenin immunohistochemistry and chromosome 6 loss 1
- Most common in children aged 7-14 years 1
- Germline mutations like CMMRD and APC are rare in this subtype 1
SHH-Activated Medulloblastoma
- Represents 10-20% of medulloblastomas and is subdivided into two distinct entities based on TP53 status 1
- SHH-activated/TP53-wild-type: Frequent mutations in PTCH1 (associated with Gorlin syndrome), SUFU, SMO, MLL1, MYCN, LDB1, and GLI1 1
- SHH-activated/TP53-mutant: DNA methylation changes are more prominent, and TP53 mutations with MYCN amplification confer a very poor prognosis, worse than TP53 mutation alone 1
Group 3 and Group 4 (Non-WNT/Non-SHH)
Understanding Group 3 Medulloblastoma
Group 3 medulloblastomas represent approximately 25-35% of all medulloblastomas and carry the worst prognosis among all molecular subgroups, with 5-year survival rates between 20-30%. 1
Key Molecular Features of Group 3:
- Generally not associated with germline mutations 1
- MYC amplification is frequently present and serves as a critical prognostic marker 1, 2, 3
- Isodicentric chromosome 17q alterations can be found 1
- Frequently harbor large cell/anaplastic histology 1
- MYC amplification occurs in approximately 20% of non-WNT/non-SHH cases and is associated with the worst prognosis 2, 3
Clinical Characteristics of Group 3:
- More common in males 1
- Often presents with metastatic disease at diagnosis 1
- Requires high-risk treatment protocols including high-dose craniospinal irradiation (36 Gy) 4
- Patients with MYC amplification should receive carboplatin as a radiosensitizer prior to each radiation fraction 4
Understanding Group 4 Medulloblastoma
Group 4 medulloblastomas represent approximately 25-35% of all medulloblastomas and have a significantly better prognosis than Group 3, with overall survival rates between 75-90%. 1
Key Molecular Features of Group 4:
- Generally not associated with germline mutations 1
- Frequently harbor copy number alterations on chromosome 17 or MYCN amplification 1
- Isodicentric chromosome 17q alterations are common 1
- MYC amplification can occur but is less frequent than in Group 3 1
Clinical Characteristics of Group 4:
- Most common molecular subgroup overall (approximately 32-35% of cases) 1, 5
- Better prognosis compared to Group 3, with excellent survival rates in some cohorts (up to 87% progression-free survival) 5
- Treatment stratification depends on presence of metastatic disease, extent of resection, and MYC status 1, 4
Critical Diagnostic Approach
Integration of morphologic, immunohistochemical, and molecular data is necessary for accurate diagnosis and treatment planning. 1
Practical Diagnostic Algorithm:
- Immunohistochemistry provides rapid screening: β-catenin (for WNT), GAB1 and YAP1 (for SHH), and p53 (for TP53 status) 1, 2, 3
- FISH for MYC amplification is essential for risk stratification in non-WNT/non-SHH tumors 2, 3
- DNA methylation profiling is robust for subtyping but data are not yet fully mature for routine clinical use 1
- When DNA methylation analysis is performed, findings should be integrated with genetic profiling that includes germline testing 1
Important Caveat:
Immunohistochemistry alone cannot reliably distinguish between Group 3 and Group 4 tumors, which is why they are often combined as "non-WNT/non-SHH" in clinical practice when advanced molecular testing is unavailable 2, 3. However, distinguishing between these groups is clinically important given their vastly different prognoses (20-30% vs 75-90% 5-year survival) 1.
Risk Stratification Based on Molecular Groups
Metastatic disease, subtotal resection, or MYC amplification automatically classify a patient into the high-risk group irrespective of molecular subgroup. 1
Group 3 and 4 Specific Risk Factors:
- The 2025 NCCN guidelines removed the intermediate risk category for Groups 3 and 4 tumors due to insufficient evidence 1
- MYC amplification versus MYC gain remains an area requiring further clarification, as distinguishing features are not clearly defined 1
- Large cell/anaplastic histology alone is not considered a risk factor for recurrence, as it is subjective and varies across institutions 1
Germline Testing Requirement
The NCCN panel recommends germline testing and genetic counseling in all diagnosed cases of medulloblastoma, as certain molecular subgroups (particularly SHH-activated) can be associated with hereditary cancer syndromes like Gorlin syndrome (PTCH1 mutations) 1