● 4 genetic “clusters” (categories): 1) WNT-activated; 2) SHH-activated (TP53-mutant & -wildtype); 3) non-WNT/non-SHH, group 3; 4) non-WNT/non-SHH, group 4
● the 4 genetic clusters are further characterized by 4 histologic types: classic; desmoplastic/nodular; extensive nodularity; large cell/anaplastic
● brainstem invasion usually limits complete surgical excision
● all patients must be evaluated for “drop metastases”
Several lines of evidence implicate granule neuron precursors (GNP) in the external granule layer (EGL) of the developing cerebellum as likely cells of origin for certain classes of medulloblastomas.
1). For example, cells that compose a preneoplastic stage of medulloblastoma colocalize with GNPs in the EGL and they express molecular markers of immature granule neurons ( 2). Another possible medulloblastoma cell of origin has been identified: a neural progenitor located in the cerebellar white matter and expressing both nestin and prominin ( 3). Signal transduction pathways that stimulate proliferation and inhibit differentiation of GNPs and other neural progenitor cells during development have been implicated in medulloblastoma. Thus, understanding the mitogenic functions of these pathways will yield insights into medulloblastoma formation.
The overexpression of proteins that normally stimulate proliferation of neural progenitor cells may initiate medulloblastoma formation. Two known mitogens for neural progenitors are the c-Myc oncoprotein and Sonic hedgehog (Shh), a crucial determinant of embryonic pattern formation in the central nervous system.
Several genes have been implicated in the development of medulloblastoma in children, including Patched-1 and Smoothened. The protein products of these genes function within the sonic hedgehog molecular signaling pathways, which are important in neural development and disease.
Combined activation of the Shh/Ptc and IGF signaling pathways is an important mechanism in MB pathogenesis 2).
Both pathways are essential regulators of granule neuron precursors (GNP) proliferation during cerebellar development. In cultured GNPs, IGF signaling stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen synthase kinase 3beta-dependent phosphorylation and consequent degradation of N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain unknown
Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shh-mediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma 3).
Cerebrospinal fluid (CSF) dissemination to the cranio-spinal axis occurs in 30% to 40% of cases 4).
Usually arises from the floor of the 4th ventricle
Typically squeezes out the foramen of Luschka.
Chen et al. encountered a patient with medulloblastoma in which the neuroimaging findings mimicked those of dysplastic cerebellar gangliocytoma. In patients with a posterior fossa tumor suggestive of a dysplastic gangliocytoma on neuroimaging studies, a pathologic confirmation is necessary 10).
Obstructive hydrocephalus by blocking CSF pathways around the aqueduct. Extraneural metastases is probably a relatively low risk of cerebrospinal fluid shunt 11). A tumor filter may eventually become occluded by tumor cells and need replacement; may be able to radiate tumor filter to “sterilize” it 12).
Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), Cerebrospinal fluid cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined.
Warren et al. recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other RANO recommendations, these need to now be prospectively validated in clinical trials 13).