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Histopathology, genetics, and molecular groups of medulloblastoma

Histopathology, genetics, and molecular groups of medulloblastoma
Literature review current through: Jan 2024.
This topic last updated: Jan 08, 2024.

INTRODUCTION — Medulloblastomas are the most common malignant brain tumor of childhood and occur exclusively in the cerebellum. Histologically, they are highly cellular tumors with dark staining, round or oval nuclei. On a molecular level, medulloblastomas are heterogeneous and can be divided into four distinct groups with divergent tumor cell histology, genetics, clinical behavior, and patient outcomes.

The histopathology and molecular pathogenesis of medulloblastoma will be reviewed here. The clinical presentation, diagnosis, and treatment of medulloblastoma in children and adults, prognosis, and the delayed complications in survivors are discussed separately. (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma".)

HISTOPATHOLOGY — At surgery, medulloblastomas are soft, friable tumors, often with necrosis. They are highly cellular tumors with abundant dark staining, round or oval nuclei, and little cytoplasmic differentiation. The spectrum of histopathologic appearance ranges from tumors with extensive nodularity to those with large cell/anaplastic (LCA) features. The clinical outcome appears to be worse with increasing grade and extent of anaplasia [1]. Mitoses are often abundant, and neuroblastic Homer Wright rosettes can be found in up to 40 percent of cases [2,3].

Immunohistochemical studies most often demonstrate the expression of the neuronal markers synaptophysin and neuron-specific enolase. Nestin, a marker of primitive neuroepithelial cells, consistent with their presumed origin from neuronal progenitors in the cerebellum, is also expressed [4]. Some medulloblastoma subtypes express markers specific for cerebellar granule cells [5,6], supporting the conclusion that they arise most often by oncogenic transformation of cerebellar granule cell progenitors; others express markers suggesting that they arise from multipotential progenitor cells from earlier stages of neural development. Nuclear beta-catenin staining is present in most Wingless-related integration site (Wnt) pathway tumors, and p53 immunostaining can be performed to identify tumors with tumor protein p53 (TP53) mutations. (See 'Molecular groups' below.)

Several histologic variants of medulloblastoma have been described, including classic, desmoplastic/nodular, large cell, and anaplastic (figure 1 and table 1) [7]. The desmoplastic variant has abundant collagen and reticulin in the interstitial spaces as well as reticulin-free "pale islands" [3]. This variant is associated with mutations in the patched-1 (PTCH1) gene on chromosome 9 and may have a better prognosis [8]. A second variant, the LCA medulloblastoma, is characterized by cerebrospinal fluid dissemination and a more aggressive clinical course [9]. The LCA variant is most commonly associated with the group 3 molecular subtype in children and with group 4 tumors in adults. (See 'Group 3' below and 'Group 4' below.)

The prognostic implications of these histopathologic variants are discussed separately. (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma", section on 'Histopathology'.)

GENETIC PREDISPOSITION — Approximately 5 to 6 percent of children with medulloblastoma have germline mutations in specific genes that predispose to the development of medulloblastoma and other cancers (table 2) [10-12]. The likelihood of a cancer predisposition syndrome varies by molecular group and is highest in patients with sonic hedgehog (SHH) pathway tumors [12]. An understanding of the molecular pathways involved in these genetic syndromes has provided insights into the pathogenesis of sporadic medulloblastomas as well.

Nevoid basal cell carcinoma syndrome (PTCH1, SUFU) — Nevoid basal cell carcinoma syndrome (NBCCS; also called Gorlin syndrome) is the most common genetic syndrome associated with medulloblastoma. It is an autosomal dominant disease due to germline mutations in the PTCH1 gene on chromosome 9, a key component in the SHH pathway. Less commonly, NBCCS is due to germline mutations in the suppressor of fused (SUFU) gene [13,14]. The mechanism through which PTCH1 mutations lead to overactivation of the SHH pathway in NBCCS is discussed separately. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)", section on 'Pathogenesis'.)

During normal cerebellar development, SHH is produced by Purkinje neurons and stimulates growth and migration of granule neuron precursor cells. Overactive SHH signaling plays a key role in the pathogenesis of a subset of sporadic medulloblastomas as well as those associated with NBCCS. The first sporadic mouse model of medulloblastoma was created by germline deletion of one PTCH1 allele [15]. (See 'SHH pathway' below.)

Medulloblastoma develops in 3 to 5 percent of patients with NBCCS, typically by the age of three, and may be the earliest overt manifestation of the syndrome [16]. Importantly, SUFU mutation-associated NBCCS appears to be associated with a much higher risk of medulloblastoma than that of PTCH1-associated NBCCS [13,14]. Tumors often show desmoplastic histologic features. Other tumors associated with NBCCS include multiple basal cell cancers and ovarian fibromas. The clinical manifestations of NBCCS are discussed separately. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

Familial adenomatous polyposis (APC) — Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by inactivating mutations in the adenomatous polyposis coli (APC) gene on chromosome 5. A germline mutation in one APC allele plus a "second hit" deletion of the other allele results in loss of all functional APC protein and a high propensity for colonic polyp formation. The genetics of FAP are discussed separately. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Genetics'.)

APC is part of a protein complex in the Wingless-related integration site (Wnt) signaling pathway, which is a network of proteins that controls cell proliferation and differentiation during development and healing. Loss of APC, as occurs in FAP, ultimately leads to excessive intranuclear accumulation of beta-catenin, an intracellular protein involved in the pathogenesis of medulloblastoma. Deregulation of the Wnt pathway by somatic mutations in the beta-catenin gene, CTNNB1, is also recognized in a subset of sporadic medulloblastomas. CTNNB1 mutations appear to be mutually exclusive with germline APC mutations. (See 'Wnt pathway' below.)

Medulloblastoma develops in less than 1 percent of patients with FAP, but the risk may not be uniform across all families [17,18]. It appears to be highest in those with mutations in segment 2 of the APC gene [19]. If this observation is confirmed, patients with mutations in this portion of the APC gene might be candidates for earlier genetic counseling and surveillance.

Li-Fraumeni syndrome (TP53) — Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome associated with abnormalities in the TP53 gene on chromosome 17p. The spectrum of malignancies associated with LFS includes osteosarcoma, soft tissue sarcoma, breast cancer, adrenocortical carcinoma, and a range of brain tumors, including high-grade gliomas, medulloblastoma, and choroid plexus carcinoma. (See "Li-Fraumeni syndrome".)

Germline TP53 mutations are rarely identified in unselected patients with medulloblastoma but make up approximately 8 percent of SHH pathway tumors [12]. When present, they are usually associated with somatic inactivation of the wildtype TP53 allele, complex genomic rearrangements, and a poor prognosis compared with other SHH pathway tumors [20-22]. (See 'SHH pathway' below.)

In a multinational retrospective study of 47 children with LFS-associated medulloblastoma (all SHH pathway tumors), the median age at diagnosis was 9.1 years, 66 percent of patients were male, and the majority (77 percent) presented with stage M0 disease [21]. Two- and five-year progression-free survival were 36 and 20 percent, respectively, and two- and five-year overall survival were 53 and 23 percent. Nearly all patients received both radiation therapy (91 percent) and chemotherapy (89 percent). Approximately three-quarters of deaths were due to recurrent/progressive medulloblastoma, and the remaining deaths were due to a different subsequent malignancy.

Other germline mutations (BRCA2, PALB2, GPR161) — Germline mutations in several genes have been identified in patients with medulloblastoma.

BRCA2 – Biallelic (homozygous or compound heterozygous) mutations in the breast cancer type 2 susceptibility (BRCA2, also known as FANCD1) gene are a cause of Fanconi anemia, and heterozygous BRCA2 mutations are a well-established cause of familial breast and ovarian cancer. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

Both types of pathogenic germline BRCA2 abnormalities (ie, heterozygous mutations and biallelic mutations) have been identified in patients with medulloblastoma [12,23]. In a cohort of over 1000 patients with medulloblastoma, BRCA2 mutations were identified in 11 patients (1 percent) [12]. The median age at diagnosis was 5.7 years. Four of 11 patients had compound heterozygosity; all of these had SHH pathway tumors and clinical features of Fanconi anemia. Tumors associated with heterozygous BRCA2 mutations were distributed across multiple molecular groups (SHH, group 3, and group 4).

PALB2 – Rare pathogenic germline mutations in the partner and localizer of BRCA2 (PALB2) gene have been described in patients with medulloblastoma across multiple molecular groups (SHH, group 3, and group 4) [12]. All reported cases associated with medulloblastoma have been heterozygous mutations, which separately have been associated with hereditary predisposition to adult-onset breast and ovarian cancer. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'PALB2'.)

GPR161 – A novel brain tumor predisposition syndrome caused by mutations in the SHH regulator G protein-coupled receptor 161 (GPR161) gene has been described [24]. Such mutations may be present in approximately 5 percent of patients with infantile SHH medulloblastoma. Mutations are associated with loss of heterozygosity at chromosome 1q, leading to biallelic inactivation of GPR161. SHH medulloblastoma in infancy (median age, 1.5 years) is the defining tumor based on the small number of cases identified to date. Further studies are needed to define the full phenotypic spectrum, which may include increased risk of colorectal cancer and ovarian cancer in adulthood.

Medulloblastomas associated with BRCA2 or PALB2 mutations have an increased prevalence of homologous recombination repair deficiency (HRD). An HRD-like mutation spectrum has also been observed in medulloblastomas associated with heterozygous germline mutations in ataxia telangiectasia mutated (ATM), Fanconi anemia complementation group A (FANCA), and FANCQ [12].

Genetic counseling and testing — The identification of a cancer predisposition gene has important implications for the patient and family members with regard to future risk, screening, and reproductive decision-making. Although a large majority of medulloblastomas are sporadic, the likelihood of a cancer predisposition mutation varies by molecular group and may be as high as 20 percent for SHH pathway tumors. Importantly, only 40 to 45 percent of patients with medulloblastoma related to a germline cancer predisposition gene have a family history of cancer or clinical signs of a predisposing syndrome, suggesting that genetic predisposition syndrome testing must be considered even without a family history [12].

Proposed guidelines (table 2) recommend that genetic testing and counseling be offered to all patients with SHH pathway tumors, all patients with Wnt pathway tumors that are not known to have a somatic CTNNB1 mutation, and selected patients with group 3 and 4 tumors (eg, tumors with an HRD molecular signature and patients with a family history of BRCA-associated tumors) [12].

MOLECULAR GROUPS — Gene expression profiling using tumor tissue microarrays is an approach to molecular classification of medulloblastoma. Several large studies using medulloblastoma samples pooled from multiple centers have attempted to subclassify medulloblastoma based on genome-wide DNA copy number, mRNA expression profiles, and somatic copy number aberrations [25-30]. Several different classifications have been generated; the most widely accepted separates medulloblastoma into four distinct molecular groups: sonic hedgehog (SHH), Wingless-related integration site (Wnt), group 3, and group 4 [31]. Somatic mutations identified through whole genome or whole exome sequencing also appear to segregate into these groups [32-34].

These groups have divergent tumor cell histology, genetics, clinical behavior, and patient outcomes (figure 2) and are recognized genetically defined diagnoses in the World Health Organization (WHO) classification system (table 1) [25-27,32,35]. Molecular groups are playing an increasingly important role in the design of clinical trials and development of new treatment paradigms, including targeted therapies [36].

SHH pathway — The granule cell progenitors can be stimulated to proliferate by the cerebellar Purkinje cells in a process that is mediated by SHH protein. Overactive signaling by SHH appears to have a proliferative effect on these cells and thus contributes to the pathogenesis of medulloblastoma in several ways:

SHH binds to its receptor, PTCH1. In the absence of binding to SHH, PTCH1 normally interacts with Smoothened (SMO), blocking the activation of a number of downstream transcription pathways. Overactive signaling by SHH prevents the inhibition of these pathways by PTCH1 (figure 3).

SHH appears to upregulate the MYCN gene. N-myc, the protein product of MYCN, has multiple effects in the cell cycle, and degradation of N-myc appears necessary for the granule cell progenitors to exit the cell cycle.

In some cases, SHH signaling is enhanced by loss of function of a tumor suppressor gene. One example is GNAS, which encodes the G protein alpha subunit [37]. The alpha subunit is enriched in granule neuron precursors in the cerebellum and suppresses SHH signaling through cyclic adenosine monophosphate (cAMP)-dependent pathway regulation, among other functions. The importance of this pathway is further supported by the finding of medulloblastoma in an infant with a homozygous nonsense mutation within the GNAS coding region [38]. Another example is the tumor suppressor gene GPR161, which acts as a negative regulator of SHH signaling [24].

Activation of the SHH pathway can occur in the absence of germline or somatic mutations to PTCH1 in patients with medulloblastoma. These include truncating mutations of PTCH2, a homologue of PTCH1 that is localized to the short arm of chromosome 1 [39]; both somatic and germline mutations in the SUFU, another gene involved in the SHH pathway that is localized to chromosome 10q [40]; and mutations in GLI3, a downstream component of the SHH pathway, located on chromosome 7p [41]. A subset of these tumors have mutations in isocitrate dehydrogenase type 1 (IDH1) and exhibit a hypermethylation phenotype [42]. Approximately 20 percent harbor mutations that target histone acetyltransferase (HAT) complexes.

Alterations in the SHH pathway are present in approximately 30 percent of medulloblastomas. As in nevoid basal cell carcinoma syndrome (NBCCS) associated tumors, these medulloblastomas are often desmoplastic [40]. (See 'Nevoid basal cell carcinoma syndrome (PTCH1, SUFU)' above.)

Somatic TP53 mutations have been identified in 10 to 20 percent of SHH tumors and are important biologically and prognostically [12,20]. TP53-mutant SHH tumors often harbor high-level MYC amplification and chromosomal instability [20,43]. Unlike TP53 wildtype SHH tumors, which are overrepresented in infants and adults with medulloblastoma [26], TP53-mutant SHH tumors have a peak incidence in adolescence [20]. Patients with TP53-mutant SHH tumors have a much worse survival outcome compared with those with TP53 wildtype SHH tumors, with a five-year overall survival of approximately 40 percent. A significant number harbor germline mutations in TP53, indicative of the Li-Fraumeni cancer predisposition syndrome. (See "Li-Fraumeni syndrome".)

SHH tumors with wildtype TP53 are most common in infants and adults with medulloblastoma [26]. Patients with these tumors have an intermediate prognosis, with overall survival rates of approximately 80 percent.

Antagonists of the SHH pathway are an active area of investigation, although early enthusiasm has been dampened by acquired resistance and early relapse with monotherapy [44,45]. In addition, SHH antagonist therapy causes bony abnormalities in developing children and must be given with caution to patients who have incomplete skeletal growth or who are skeletally immature.

Wnt pathway — The Wnt protein binds to its receptor, Frizzled, and this interaction destabilizes a multiprotein complex that includes the APC protein. This in turn initiates a sequence of events that can activate various transcription factors, which are important in the pathogenesis of medulloblastoma. Loss of chromosome 6 and somatic mutations of CTNNB1 that promote stabilization and nuclear localization of beta-catenin are present in approximately 85 to 90 percent of Wnt pathway tumors [42]. TP53 mutations are present in approximately 15 percent of Wnt pathway tumors [12,20]. Most tumors that lack a somatic CTNNB1 mutation are associated with germline APC mutations [12].

Wnt pathway tumors make up approximately 10 percent of all medulloblastomas, making it the least common group [31]. Approximately 6 to 8 percent of patients with Wnt pathway tumors harbor a germline APC mutation as seen in familial adenomatous polyposis (FAP) [12]. (See 'Familial adenomatous polyposis (APC)' above.)

Wnt tumors are seen in children and adults but rarely infants. They metastasize infrequently and, in children, are associated with the most favorable prognosis out of the four groups, with a five-year survival of over 95 percent [26,46]. However, prognosis appears to be worse in adults [46]. (See 'Familial adenomatous polyposis (APC)' above.)

Group 3 — High-level amplification of the MYC proto-oncogene is characteristic of group 3 medulloblastomas, and almost all cases exhibit aberrant MYC expression [25,28]. Group 3 tumors are also characterized by high levels of genomic instability. In approximately one-third of group 3 tumors, somatic genomic rearrangements have been described that lead to activation of growth factor independence 1 (GFI1) or GFI1B proto-oncogenes, a process termed "enhancer hijacking" [42,47]. Group 3 is also enriched in alterations in the Notch and transforming growth factor-beta (TGF-beta) signaling pathways as well as hotspot insertions targeting KBTBD4 [42].

Group 3 tumors comprise approximately 25 percent of sporadic medulloblastomas and are seen primarily in children [31,46]. They are enriched for the large cell/anaplastic (LCA) histologic variant and are frequently metastatic at the time of diagnosis. Up to 2 percent of group 3 tumors are associated with germline mutations in a cancer predisposition gene such as the BRCA2 gene [12]. (See 'Other germline mutations (BRCA2, PALB2, GPR161)' above.)

Group 3 tumors have the worst prognosis of the four groups, with an increased likelihood of metastatic recurrence [48] and a five-year survival of approximately 50 percent [26].

Group 4 — Many group 4 tumors exhibit amplification of the proto-oncogenes MYCN and cyclin-dependent kinase 6 (CDK6). Characteristic cytogenetic abnormalities include isochromosome 17q and loss of one copy of the X chromosome (in females). A small proportion of group 4 tumors have GFI1 or GFI1B activation due to somatic structural variants, as described more commonly in group 3 tumors [42,47]. More commonly, group 4 tumors exhibit structural variants in SNCAIP associated with enhancer hijacking of the PRDM6 gene [42]. Hotspot insertions targeting KBTBD4 are also common [42].

Approximately 35 percent of sporadic medulloblastomas fall into this group [31]. Tumors usually exhibit classic histology. There is a strong male predominance (3:1) and a peak incidence in adolescence. Rare patients harbor a germline mutation in BRCA2 or the PALB2 gene [12]. (See 'Other germline mutations (BRCA2, PALB2, GPR161)' above.)

The prognosis in children is similar to the SHH group, with a 35 to 40 percent rate of metastasis at diagnosis and five-year survival of approximately 75 percent [31]. By contrast, the prognosis of group 4 tumors in adults appears to be significantly worse than that of SHH tumors, with a high incidence of high-risk disease and LCA histology [46].

CELL OF ORIGIN — There is evidence that the cell of origin differs according to molecular group, and putative cells of origin have been identified for each group [49].

Available data suggest that sonic hedgehog (SHH) medulloblastomas arise from cerebellar granule cell progenitor cells in the upper rhombic lip [49-51]. Wingless-related integration site (Wnt) tumors appear to arise in lower rhombic lip multipotential progenitors of the dorsal brainstem [49,52]. Group 3 and 4 tumors likely arise from cells in the rhombic lip germinal zone, which give rise to glutamatergic neurons including photoreceptor cells and unipolar brush cells of the cerebellum [49,53,54].

Progression to medulloblastoma is thought to occur when these progenitor cells are subject to continued stimulation or there is a failure of these cells to exit the cell cycle.

GENETIC REGULATION OF METASTASIS — Medulloblastomas have a tendency to disseminate throughout the central nervous system early in the course of the disease, and metastatic disease is associated with a poor outcome. Studies of matched primary and recurrent tissue samples show that the four-group molecular signature is retained at the time of recurrence [48]. Group 3 and 4 tumors in particular have a higher likelihood of metastatic recurrence compared with sonic hedgehog (SHH) pathway tumors, which are more likely to recur locally. (See "Clinical presentation, diagnosis, and risk stratification of medulloblastoma".)

In one report of 23 primary medulloblastomas, of which 10 were metastatic and 13 nonmetastatic, the platelet-derived growth factor receptor (PDGFR)-alpha was upregulated and overexpressed in the metastatic tumors and associated with migratory behavior [55]. Cell culture experiments with medulloblastoma cell lines demonstrated that overexpression of PDGFR-alpha increased the phosphorylation and upregulation of downstream Ras/mitogen-activated protein (MAP) kinase signal transduction pathways, while inhibition of these MAP kinases prevented PDGFR-alpha-stimulated migration in a cell culture assay. Further analysis revealed upregulated expression of PDGFR-beta in metastatic medulloblastomas, indicating a role of several PDGFR isoforms in medulloblastoma biology [56].

SUMMARY

Histopathology – Medulloblastomas are highly cellular tumors presumed to arise from neuronal precursors in the cerebellum. (See 'Histopathology' above.)

Genetic predisposition – In approximately 5 to 6 percent of cases, medulloblastomas are associated with an underlying genetic predisposition due to a germline mutation in one of several cancer susceptibility genes (table 2). (See 'Genetic predisposition' above.)

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is due to mutations in the patched-1 (PTCH1) or suppressor of fused (SUFU) genes, which are key components in the sonic hedgehog (SHH) pathway. (See 'Nevoid basal cell carcinoma syndrome (PTCH1, SUFU)' above.)

In familial adenomatosis polyposis (FAP) syndrome, medulloblastomas are seen in conjunction with colonic polyposis. This syndrome is caused by mutations in the adenomatous polyposis coli (APC) gene, which affect the Wingless-related integration site (Wnt) pathway. (See 'Familial adenomatous polyposis (APC)' above.)

Genetic counseling and testing – The identification of a cancer predisposition gene has important implications for the patient and family members with regard to future risk, screening, and reproductive decision-making. Although a large majority of medulloblastomas are sporadic, the likelihood of a cancer predisposition mutation varies by molecular group and may be as high as 20 percent for SHH pathway tumors (table 2). (See 'Genetic counseling and testing' above.)

Molecular groups – Four molecular groups of medulloblastoma have been identified that have divergent tumor cell histology, genetics, clinical behavior, and patient outcomes: SHH, Wnt, group 3, and group 4 (table 1 and figure 2). (See 'Molecular groups' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Scott L Pomeroy, MD, PhD, who contributed to earlier versions of this topic review.

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Topic 5218 Version 31.0

References

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