**6. Staging**

Survival for Shh subgroup medulloblastomas is similar to Group 4 medulloblastomas and intermediate between that of Wnt and Group 3 medulloblastomas and varies significantly

The non-Wnt/Shh tumor subgroup encompasses Group 3 and Group 4, in which the underlying genetic predisposition of mutations have yet not been recognized [49]. These types are associated with a higher incidence of tumor dissemination and approximately 30% of patients have metastasis at the time of diagnosis [6]. Despite these similarities, features of Group 3 and Group 4 subgroup medulloblastomas vary regarding the demographic, clinical, transcriptional, and genetic differences between them and these advocate that they are actually distinct

Nearly 30% of medulloblastomas are of the Group 3 subgroup and histologically mostly are of the "classic" variety of medulloblastomas [6, 55–57]. These tumors genetically are more likely to have high-level expression and amplification of MYC, MYCN and OTX2 with imbalance of chromosome 17 [42, 49, 51, 58]. Group 3 tumors show gain of chromosome 1q, and/ or loss of chromosome 5q and chromosome 10q more than Group 4 tumors [42]. They occur more frequently in infants and children, and has the worst outcome among all molecular subgroups, with 10-year overall survival of 39% in infants and 50% in children [6, 42, 49, 51, 59].

About 35% of medulloblastomas overall are of Group 4 subgroup and the peak incidence for this subgroup is in late childhood and early adolescents [6, 42]. The prognosis of Group 4 tumors is similar to Shh subgroups tumors and is intermediate between those of Wnt and Group3 subgroup tumors. Patients with metastatic disease or MYC amplifications in this Group have significantly poorer outcomes [49, 50]. Though isochromosome 17q is also seen in Group 3 tumors, it is more common in Group 4 tumors. Another prominent cytogenetic alteration among Group 4 tumors is loss of the X chromosome, which is found in 80% of females with Group 4 medulloblastoma [42]. Recently, the discovery of seven novel molecular subgroups has permitted to categorize patients further to envisage better disease subclassification and outcome predictions. These subgroup dependent grouping stratified patients into four clinical risk groups for 5-year progression-free survival: favorable risk (91% survival); standard risk (81% survival); highrisk (42% survival); and very high-risk (28% survival) [41]. Another study recommended total of 12 subgroups based on the integration of transcriptomic and methylation data. In that analysis medulloblastoma encompasses 12 subtypes; 2 Wnt, 4 Shh, 3 Group 3, and 3 Group 4 groups. These subtypes of each subgroup are clinically and biologically pertinent [54].

In 2016, for the first time, the molecular characteristics was incorporated into the WHO classification for the diagnosis of CNS tumors. This integration of histological features with genetic

based on age and histologic subtype [10, 42, 48].

entities with molecular diversity [42, 54].

*5.2.3. Non-Wnt/Shh tumors*

142 Brain Tumors - An Update

*5.2.3.1. Group 3 MB*

*5.2.3.2. Group 4 MB*

**5.3. Integrated classification**

There is no well-established staging system for medulloblastoma for prediction from which treatment plan and outcome prediction can be made. In 1969, Chang et al. suggested an operative staging system for medulloblastomas adapting the TNM classification for other tumors [62]. According to the size and extent of primary tumor, T category was divided into four main groups with subdivisions of T3 (T1, T2, T3a, T3b or T4) and the M category had five groups (M0, M1, M2, M3 and M4) based on the degree of tumor spread in the CSF pathway or extra-CNS metastases [9]. Overall, M staging has remained more useful in prognostic evaluation, while the T staging is less valuable as a prognostic indicator [63]. Several studies have stratified the patients into "high-risk" and "average" or "standard-risk" groups depending on age of the patient, residual disease after surgery, pathologic variant, and M staging [8, 64]. This risk stratification is a good predictor of outcome. Standard-risk and high-risk categories have long term survival rates of approximately 85% and 70%, respectively [6].
