470 patients have an intermediate prognosis, similar to indi- viduals with Shh tumors. Although Group 4 tumors make up [30% of all medulloblastomas, we probably understand the least about the molecular pathogenesis of this subgroup, and no mouse models of Group 4 have been reported. Histology: special considerations While most investigators in the ﬁeld feel strongly that molecular markers will assume increasing importance in the diagnosis and classiﬁcation of medulloblastoma in the near future, still there will clearly be a role for histopa- thology. True nodular/desmoplastic tumors, and likely all of the MBENs belong to the Shh subgroup of tumors [11, 26]. Classic histology, however, is spread over all four of the principal subgroups, and can even be difﬁcult to dis- tinguish from atypical teratoid/rhaboid tumors on the basis of morphology alone. Large cell/anaplastic tumors also appear to be found in all four principal subgroups, although the majority are Group 3. However, LCA histology main- tains its prognostic signiﬁcance after accounting for subgroup, and the diagnosis of LCA histology may there- fore retain signiﬁcance in a ‘post-subgroup’ world [28]. We would suggest, however, that the prognostic signiﬁcance of LCA histology needs to be assessed separately in large cohorts of each subgroup as the ﬁeld moves forward. Adult medulloblastoma The degree of molecular and clinical similarity between adult and pediatric medulloblastoma is not entirely clear, yet. Some authors have certainly reported distinct molec- ular proﬁles [24] and clinical behavior [44, 45] when comparing adults and children/infants. However, the dis- tribution of cases across the subgroups is very different in adults as compared to children [2, 28, 37, 38]. The most comprehensive study on adult MB published to date sug- gests that group 3 tumors are exceptionally rare in adults, whereas SHH tumors comprise about two-thirds of cases in this age group [38], which makes adult MB patients a particularly attractive cohort for molecular-targeted thera- pies. However, the exact proportions of subgroups and genetic as well as transcriptomic differences between adult and pediatric patients attributed to the same subgroups have yet to be studied in more detail in larger cohorts. Conclusions 123 While histology and the WHO classiﬁcation have not been supplanted, it has become clear that histology alone is Acta Neuropathol (2012) 123:465–472 inadequate for the diagnosis and classiﬁcation of ‘medullo- blastoma’. The current generation of studies supports a model in which transcriptionally similar tumors share clinical and molecular features that will be useful in the clinic. The iden- tiﬁcation of molecular subgroup will likely assume great importance in the design and implementation of targeted therapies. While transcriptionally driven classiﬁcations of medulloblastoma will increase in importance over time, we predict that classiﬁcation based on whole genome or exome sequencing of tumor DNA will likely assume additional importance as sequencing technologies become less expen- sive, more widely available, and more reliable. While it is clear that distinct molecular subgroups of medulloblastoma exist and are clinically important, we should not lose sight of the fact that there are also commonalities seen across the subgroups, such as mutations in TP53 and MLL2 which are seen in several subgroups [32, 34]. The challenges facing the medulloblastoma community in moving forward are (1) to achieve sufﬁcient inter-center co-operation to assemble large cohorts of tumors for both discovery and validation, (2) determine the true extent and nature of inter-tumoral hetero- geneity as deﬁned by transcriptional proﬁling, and (3) development of clinically practical tests for medulloblastoma subgroup assignment that will be feasible for both clinical trials, and inclusion in the day to day clinical care of medul- loblastoma patients across the globe. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References 1. 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