MORPHOLOGYInchildren,medulloblastomasarelocatedinthemidlineofthecerebellum;lateraltumorsoccurmoreofteninadults.Thetumorofteniswellcircumscribed,gray,andfriableandmaybeseenextendingtothesurfaceofthecerebellarfoliaandinvolvingtheleptomeninges(
Fig.23.32A ).Medulloblastomasaredenselycellular,withsheetsofanaplastic(“smallblue”)cells(see
Fig.
23.32B ).Individualtumorcellsaresmall,withlittlecytoplasmandhyperchromaticnuclei;mitosesareabundant.Often,focalneuronaldifferentiationisseenintheformofrosettes,whichcloselyresembletherosettesencounteredinneuroblastomas;theyarecharacterizedbyprimitivetumorcellssurroundingcentralneuropil(delicatepinkmaterialformedbyneuronalprocesses).
Genetic analysis of medulloblastoma has revealed several subtypes associated with different clinical outcomes. Current approaches separate medulloblastoma into distinct groups with different core pathogenic pathways or driver mutations. Examples of oncogenic pathways in these tumors are the following:
Wnt pathway activation, most commonly associated with gain of function mutations in the gene for β-catenin; these have the most favorable prognosis of all of the genetic subtypes and are commonly classic-type tumors.
Hedgehog pathway activation, most commonly associated with loss of function mutations in PTCH1, a negative regulator of the Hedgehog; these tumors have an intermediate prognosis, but the concomitant presence of TP53 mutation confers a very poor prognosis.
MYC overexpression, due to MYC amplification as well as other changes that result in increased expression; these tumors have the poorest prognosis.
Clinical trials are ongoing that seek to tailor therapy targeted to molecular alterations, with the goal of avoiding radiation therapy when possible.
Primary CNS lymphoma, occurring mostly as diffuse large B-cell lymphomas, accounts for 2% of extranodal lymphomas and 1% of intracranial tumors. It is the most common CNS neoplasm in immunosuppressed individuals, in whom the tumors are nearly always positive for Epstein-Barr virus (EBV). In nonimmunosuppressed populations, the age spectrum is relatively wide, with the incidence increasing after 60 years of age. Regardless of the clinical context, primary brain lymphoma is an aggressive disease with a relatively poor response to chemotherapy as compared with peripheral lymphomas.
Fig. 23.32 Medulloblastoma.(A)Sagittalsectionofabrainshowingmedulloblastomainvolvingthesuperiorvermisofthecerebellum.(B)Microscopicappearanceofmedulloblastoma,showingmostlysmall,blue,primitive-appearingtumorcells.
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Patients with primary brain lymphoma often are found to have multiple tumor nodules within the brain parenchyma, yet involvement of sites outside of the CNS is uncommon. Conversely, lymphoma originating outside the CNS rarely spreads to the brain parenchyma; when this occurs, the tumor usually also involves the CSF or the meninges.