Acta Neuropathol (2012) 123:465–472 Shh medulloblastomas resemble infant Shh medulloblas- toma remains to be determined by the analyses of larger cohorts of tumors. Some recent series [28], but not others [7] have found a preponderance of females among Shh medul- loblastoma. Taken into account all published studies, the gender ratio is approximately 1:1. Most, if not all nodular/ desmoplastic medulloblastomas belong to the Shh subgroup. However, this is not an effective marker for the subgroup as up to 50% of Shh subgroup medulloblastomas are not nod- ular/desmoplastic. The prognosis of Shh medulloblastoma appears to be similar to Group 4 medulloblastomas, and intermediate between that Wnt medulloblastomas (good) and Group 3 medulloblastomas (poor). The recent demon- stration that small molecules targeting smoothened (SMO) are highly effective, albeit temporarily, against Shh medul- loblastoma underlines the urgent need to develop effective and practical markers for Shh medulloblastoma [6, 40, 49]. Group 3 Group 3 tumors are mostly ‘classic’ medulloblastomas, although they do encompass the majority of the LCA tumors. The current gold standard for diagnosis of a Group 3 tumor is a transcriptional proﬁle that clusters with other Group 3 tumors [7, 22, 28]. Immunohistochemical posi- tivity for NPR3 has been suggested as a Group 3 marker [28]. While Shh subgroup tumors have high levels of expression of MYCN, and Wnt subgroup and Group 3 tumors have high levels of expression of MYC, whereas Group 4 tumors have relatively low expression of both MYC and MYCN, apart from the few cases that have MYCN ampliﬁcation [20, 22, 28]. As such, it has been suggested by one group that Group 3 tumors could be called the MYC group [20]. Similarly, MYC ampliﬁcation (but not MYCN ampliﬁcation) appears to be almost always limited to Group 3 [7, 22, 28]. Ampliﬁcation and over-expression of the medulloblastoma oncogene OTX2 appears to be restricted to Group 3 and Group 4 tumors [1, 9, 10, 28]. Group 3 tumors over-express a number of genes that were initially identiﬁed through their role in retinal develop- ment, although the role of these genes in the pathogenesis in Group 3 tumors is currently opaque [7, 22, 28]. Group 3 tumors are much more likely than Group 4 tumors to show gain of chromosome 1q, and/or loss of chromosome 5q and chromosome 10q. Group 3 tumors occur more commonly in males than females, and are found in infants and children, but are almost never observed in adults. Group 3 tumors have a high incidence of LCA histology, and are very frequently met- astatic [28]. Indeed, it has been suggested that prior identiﬁcation of metastatic status as risk factor for poor prognosis in medulloblastoma was in fact identifying a 469 group of patients enriched for Group 3 patients [28]. The best evidence for a clear ‘subset of a subgroup’ in medul- loblastoma to date is found in Group 3, in which one subset (Group 3a) includes all of the patients with MYC ampliﬁ- cations, and which assumes that most of the high risk of recurrence and death associated with a Group 3 diagnosis. Conversely, Group 3b patients were not found to harbor MYC ampliﬁcations, and had a clinical outcome similar to Group 4 patients [7]. This exciting ﬁnding awaits validation in additional cohorts, and the development of clinically expedient markers for the identiﬁcation of Group 3a and Group 3b patients. Although Group 3 tumors are likely more similar to Group 4 tumors than to Shh or Wnt tumors, the demographic, clinical, transcriptional, and genetic dif- ferences between the Group 3 and Group 4 suggest that they are indeed distinct entities [22, 28]. Clearly, the terrible prognosis of Group 3 patients indicates that the medullo- blastoma community needs to focus further on this subgroup to develop practical biomarkers, understand its underlying pathogenesis, and develop accurate mouse models. Group 4 Group 4 medulloblastomas are the prototypical medullo- blastoma: a 7-year-old boy with a classic histology medulloblastoma that has an isochromosome 17q. As the molecular pathogenesis of Group 4 tumors is not currently clear, the generic name ‘Group 4’ has been chosen for the current consensus nomenclature pending further insights. Currently, Group 4 medulloblastomas are identiﬁed through a transcriptional proﬁle that clusters with other Group 4 medulloblastomas. KCNA1 has been suggested as an immunohistochemical marker for Group 4 tumors but requires validation in additional cohorts [7, 28]. Although isochromosome 17q is also seen in Group 3 tumors (26%), it is much more common in Group 4 tumors where it is the most common cytogenetic change observed (66%) as also seen in the meta-analysis paper by Kool et al. on all pub- lished data sets in this issue of the journal [21, 28]. Similarly, isolated 17p deletion is seen in both Group 3 and Group 4, but almost never in Wnt or Shh subgroup medulloblastomas. The only other notable cytogenetic change among Group 4 tumors is loss of the X chromo- some, which is seen in 80% of females with Group 4 medulloblastoma. The high incidence of X chromosome loss in females with Group 4 medulloblastomas is partic- ularly poignant in light of the high male:female ratio in Group 4 patients (2:1). Multiple publications have identi- ﬁed over-representation of genes involved in neuronal differentiation and neuronal development in Group 4 tumors, although neither the genetic basis, nor the clinical relevance of this is yet apparent [7, 22, 28]. Group 4 123