Medulloblastoma, non–WNT/non–SHH-activated

The WHO classification combines group 3 and group 4 medulloblastoma cases into a single entity, partly based on the absence of immediate clinical impact for this distinction. Group 3 represents approximately 25% of medulloblastoma cases, while group 4 represents approximately 40% of medulloblastoma cases.[112,116] Both group 3 and group 4 medulloblastoma patients are predominantly male.[101,114] Group 3 and group 4 medulloblastomas can be further subdivided based on characteristics such as gene expression and DNA methylation profiles, but the optimal approach to their subdivision is not established.[112,113]

Various genomic alterations are observed in group 3 and group 4 medulloblastomas. However, no single alteration occurs in more than 10% to 20% of cases. Genomic alterations include the following:

Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis.[114] Fewer than 50% of these patients survive 5 years after diagnosis.[112] This poor prognosis is especially true in children younger than 4 years at diagnosis.[108] However, patients with group 3 medulloblastoma without MYC amplification who are older than 3 years have a prognosis similar to that of most patients with non-WNT medulloblastoma, with a 5-year PFS rate higher than 70%.[137,140]

Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastomas. Prognosis may be affected by additional factors such as the presence of metastatic disease, chromosome 11q loss, and chromosome 17p loss.[105,106,112,136] One study found that group 4 patients with either chromosome 11 loss or gain of chromosome 17 were low risk, regardless of metastases. In cases lacking both of these cytogenetic features, metastasis at presentation differentiated between high and intermediate risk.[136]

For group 3 and group 4 standard-risk patients (i.e., without MYC amplification or metastatic disease), the gain or loss of whole chromosomes appears to connote a favorable prognosis. This finding was derived from the data of 91 patients with non-WNT/non-SHH medulloblastoma enrolled in the SIOP-PNET-4 (NCT01351870) clinical trial and was confirmed in an independent group of 70 children with non-WNT/non-SHH medulloblastoma treated between 1990 and 2014.[140] Chromosomal abnormalities include the following:

The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[112,113,139,141,142] Further subdivision within subgroups based on molecular characteristics is likely because each of the subgroups is further molecularly dissected, although the studies are nearing consensus as data from multiple independent studies are merged. As an example, using complementary bioinformatics approaches, concordance was analyzed among multiple large, published cohorts, and a more unified subgrouping was described. For children with group 3 and group 4 medulloblastomas, eight distinct subgroups were determined by DNA methylation clustering. Specific subgroups had different prognoses.[105,116,127,143]

It is unknown whether the classification for adults with medulloblastoma has a predictive ability similar to that for children.[106,108] In one study of adult patients with medulloblastoma, MYC oncogene amplifications were rarely observed, and tumors with 6q deletion and WNT activation (as identified by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas. However, another study did confirm an excellent prognosis for WNT-activated tumors in adults.[106,108]

For information about the treatment of childhood medulloblastoma, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.