Abstract
Medulloblastoma is an invasive, high-grade (WHO grade IV) embryonal tumor defined both by histologic grade and location in the cerebellum.
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Keywords
- Medulloblastoma
- Large cell medulloblastoma
- Anaplastic medulloblastoma
- Nodular medulloblastoma
- Desmoplastic medulloblastoma
- Extensively nodular
- Medullomyoblastoma
1 Overview
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Medullobl astoma is an invasive, high-grade (WHO grade IV) embryonal tumor defined both by histologic grade and location in the cerebellum.
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Even though this tumor shares histologic features with other central nervous system (CNS) embryonal tumors (primitive neuroectodermal tumors), it has been historically regarded as a distinct entity.
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Recent molecular studies, including genomic and gene expression profiling as well as signaling pathway dysregulation and biologic studies, have now justified its historical clinical definition as a distinct clinicopathologic entity with predominant occurrence in children.
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Most are sporadic.
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They occur less frequently in the setting of hereditary syndromes. These include Turcot’s syndrome, with germline mutation of the adenomatous polyposis coli (APC) gene, and Gorlin’s syndrome, the nevoid basal cell carcinoma syndrome with germline mutation of the PTCH gene, seen in less than 2 % of medulloblastomas.
2 Clinical Features
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Medulloblastomas account for 20 % of malignant CNS tumors in childhood, the second most common mali gnancy in childhood.
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Most tumors occur in children below the age of 20, with a peak between 5 and 8 years of age. A second but smaller peak is seen at ages 35–40 years. Rarely, it may be congenital.
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Patients present with symptoms and signs of cerebellar dysfunction, including truncal and appendicular ataxia, and raised intracranial pressure due to obstruction of the fourth ventricle and CSF flow, with headache, vomiting, and progressive lethargy.
3 Neuroimaging
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Early onset of calcification of the falx cerebri, tentorium cerebelli, and dura, with bridging of the se lla turcica due to calcification of the diaphragma sellae is seen with CT scans in 60–80 % of patients with Gorlin’s syndrome (Fig. 8.1).
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Midline vermian mass lesions in children or lateral cerebellar hemispheric tumors in adults are typical.
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Characteristically, MRI shows a predominantly solid mass, hypointense or isointense with gray matter, with moderate diffuse, nonhomogenous enhancement (Figs. 8.2, 8.3, 8.4, 8.5, 8.6, and 8.7).
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There is often associated restricted diffusion consistent with a small-cell and densely cellular tumor (Figs. 8.2 and 8.6).
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MR spectroscopy shows marked elevation of choline with little, if any, NAA peak (Fig. 8.8A).◦
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Elevation of the taurine peak may also be seen in medulloblastoma.
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The extensively nodular variant often seen in patients less than 1 year old may present with multiple, grapelike, enhancing nodular features (Fig. 8.8B and C).
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Diffuse leptomeningeal enhancement and thecal sac drop metastases, when present, are consistent with CSF dissemination and poorer prognosis (Figs. 8.9, 8.10, 8.11, 8.12, and 8.13).
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There is often evidence of mass effect, including severe dilatation of the third and lateral ventricles, transepend ymal CSF flow, and brainstem compression (Figs. 8.10 and 8.12).
4 Pathology
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Grossly, medul loblastoma presents commonly as a midline vermian mass (Fig. 8.14).
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Resection specimens or intraoperative biopsies are often soft, gray-pink, and appear necrotic. Extensively nodular or desmoplastic tumors may sometimes have a soft to slightly firm consistency with a lobulated appearance.
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Intraoperative cytologic imprints or smears
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◦ Moderate cellular ity is characteristic. There is a good correlation between cytologic features and histologic classification as classic or nodular, anaplastic, or large cell medulloblastomas.
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◦ Classic and nodular medulloblastomas demonstrate monolayered sheets of relatively uniform, round to oval (occasionally elongated or carrot-shaped) molded nuclei with hyperchromasia and some chromatin clumping (Fig. 8.15A). Molded, markedly atypical cells with high nucleocytoplasmic ratio in CSF cytospin are consistent with dissemination (Fig. 8.15B). Rosette-like arrangements representing Homer Wright rosettes may be seen (Fig. 8.16).
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◦ Anaplastic medulloblastomas demonstrate a significant component of large, pleomorphic cells with prominent chromatin clumping and visible nucleoli. “Cell wrapping” or “cannibalism” (the nucleus of one cell wrapped around the nucleus of another) and apoptotic nuclei are frequent (Fig. 8.17). Occasional multinucleated cells may sometimes be seen.
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◦ Large cell medulloblastoma, when present or predominant, often shows a discohesive, monotonous population of large cells with open chromatin and visible nucleoli, sometimes mimicking the cytologic monotony of large cell lymphomas (Fig. 8.18).
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◦ Endothelial proliferation and mitosis may be present in all cytologic types.
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◦ Rare evidence of cytologic differentiation with astrocytic, ganglionic, or melanocytic differentiation (with melanin pigments), or rhabdomyoblastic differentiation (strap cells) may be seen.
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Histology: Varied histol ogic features may be seen between and within tumors.
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◦ Classic medulloblastomas are com posed of monotonous sheets of small cells (Fig. 8.19).
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Slight nuclear irregularity is often present.
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Mitoses are present but often variable.
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Necrosis may be present, with or without pseudopalisading.
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Apoptosis is often present.
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Endothelial proliferation is present and sometimes can be florid.
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Neuroblastic differentiation is seen as the Homer Wright rosette (Fig. 8.20).
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Mature neuronal differentiation as ganglion or “ganglioid” cells may be seen but must be distinguished from entrapped neurons.
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A spindle or fascicular pattern, when present, is usually focal (Fig. 8.21)
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Prominent nuclear irregularity with nucleoli and pleomorphism suggests the presence of anaplastic features, which may be focal; a transition from classic to anaplastic may be appreciable (Fig. 8.22). Extensive anaplasia may justify designation as an anaplastic subtype.
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Anaplasia may vary from slight to moderate to severe (Figs. 8.23 and 8.24).
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◦ Regions with monomorphic, discohesive, large round cells with prominent nucleoli are suggestive of the presence of a large cell component (Fig. 8.25).
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Predomin ance of large cells or severe anaplasia represents the large cell or anaplastic subtype and accounts for about 4 % of medulloblastoma.
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Severe anaplasia is often associated with increased apoptosis, increased frequency of mitotic activity, and cell wrapping or cannibalism.
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◦ Nodular (desmoplastic) medulloblastoma is characterized by the presence of multiple reticulin-fre e, pale nodules of neurocytic cells within a neuropil-like background, which are rarely mitotic with increased apoptosis (Figs. 8.26, 8.27, and 8.28).
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Leptomeningeal invasion with florid, reactive desmoplasia (collagenous fibrosis), often demonstrating medium- to large-sized leptomeningeal vessels, may occur but does not constitute a desmoplastic medulloblastoma (Fig. 8.29).
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Internodular areas are reticulin-rich and are composed of cells similar to those of classic medulloblastoma.
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◦ These areas tend to exhibit more brisk mitotic activity than is seen within the pale nodules.
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Internodular areas may sometimes show varying degrees of anaplasia (see Fig. 8.23).
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◦ The extensively nodular medulloblastoma (previously termed cerebellar neuroblastoma) is a variant showing florid nodularity and neurocytic differentiation with an absent or minimal undifferentiated internodular component.
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◦ Biphasic medulloblastoma rep resents a tumor with mixed classic and nodular components, in which the nodular component is not surrounded by desmoplasia; that is, the internodular areas are reticulin-free. This distinction from the nodular/desmoplastic medulloblastoma is important.
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◦ Infrequent patterns of differentiation include:
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Astrocytic differentiation, which must be distinguished from entrapped reactive astrocytes (Figs. 8.33 and 8.34).
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Skeletal muscle or rhabdomyoblastic differentiation may rarely be seen as strap cells with or without striations; this pattern constitutes the medulloblastoma with myogenic differentiation (synonym: medullomyoblastoma) (Fig. 8.35).
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Melanocytic di fferentiation with melanin pigment production constitutes the rare medulloblastoma with melanotic differentiation (synonym: melanotic medulloblastoma) (Fig. 8.36).
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Premelanosomes and melanosomes are demonstrable by electron microscopy.
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5 Immunohistochemistry
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Medulloblastomas show diffuse immunopositivity for synaptophysin (Fig. 8.37) and varia ble immunopositivity for chromogranin, neurofilament protein, and the neuronal marker NeuN.
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Glial fibrillary acidic protein (GFAP) often highlights trapped reactive astrocytes. Rare positivity of tumor cells is seen (see Figs. 8.33 and 8.34).
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Immunopositivity for retinal S-antigen and rhodopsin may be rarely seen in tumors with photoreceptor differentiation.
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Epithelial membrane antigen (EMA) is usually negative.
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p53 immunopositivity is seen in a subset of medulloblastomas. An increased proportion of positive cells often correlates with increasing anaplasia and poorer survival (Fig. 8.38).
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The MIB-1 (proliferation) index is variable, often very high (30–80 %) (Fig. 8.39).
6 Electron Microscopy
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Electron microscopy shows tumor cells (often paucicellular) in organelles but with demonstrable neurose cretory granules.
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Cellular processes are frequent and contain microtubules.
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Synaptic-type junctions may be seen.
7 Molecular Pathology
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Medulloblastomas are presumed to arise from precursor stem cells in the external granular layer for lateral hemispheric nodular or desmoplastic medulloblastomas, and from dysplastic precursor cells arrested during migration for other vermian variants.
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Using gene expression profiling, medulloblastomas are molecularly classified into four groups:
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◦ Group A with wnt pathway activation
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◦ Group B with SHH pathway activation
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◦ Groups C and D, collectively referred to as non A/non B. Non A/non B classification is often associated with aggressive histology, MYC amplification, and poor prognosis.
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Activation of the wnt signaling pathway through mutation of the APC gene has been associated with Turcot syndrome and only 3–4 % of sporadic medulloblastoma.
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Wnt pathway–activated tumors account for about 10 % of medulloblastomas and show demonstrable nuclear localization for beta catenin and/or monosomy 6. DDX3X gene mutation is also seen in 50 % of wnt pathway tumors.
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PTCH gene loss of function mutation, as well as mutations of SMO, SUFU, and Gli2 result in the activation of the sonic hedgehog (SHH) signaling pathway in 30 % of medulloblastomas.
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SHH pathway activation is seen classically in nodular or desmoplastic medulloblastoma. Gli1 and Gli2, representing downstream effectors of SHH pathway activation, are also often demonstrable in up to 85 % of medulloblastomas. The proportion of tumors classified as SHH molecular subgroup drops significantly when classified based on the expression of GAB1, filamin A, and/or YAP1. SHH-activated tumors with p53 mutation carry a significantly poor prognosis.
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Amplification of MYCC and less commonly MYCN is a common finding in large cell/anaplastic medulloblastoma (Figs. 8.40 and 8.41); MYCC amplification is frequently associated with Group C, and MYCN amplification, with group D.
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Gains of CDK6 (7q21), hTERT (5p15), OTX2 (14q22) (more frequently seen in group C), and FoxG1 (14q12) have been reported.
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17p deletion with isochromosome 17q is the commonest cytogenetic abnormality in medulloblastoma, present in 30–40 % of tumors (Fig. 8.42); it is seen particularly in group D tumors. Potential target genes in the 17p deletion include HIC1 (17p13.3), frequently hypermethylated in medulloblastoma, and REN (17p13.2), a negative regulator of the SHH signaling pathway.
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Losses of 16q, 10q, and 11q are present in a subset of the tumors.
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Increased activation of the Notch signal ing pathway; overexpression of PAX5, PAX6 and SOX4; and overexpression of repressors of neural differentiation REST and FoxG1 have all been reported in medulloblastoma.
8 Differential Diagnosis
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Medulloblastomas may have areas with prominent perivascular pseudorosettes, thus raising anaplastic ependymoma as a major differential diagnosis.
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◦ Ependymomas tend to show variation in cellularity, however, including regions of well-differentiated ependymoma.
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◦ EMA is often positive in ependymomas and negative in medulloblastoma.
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◦ Synaptophysin is positive in perivascular pseudorosettes of medulloblastoma, whereas GFAP staining is more characteristic of ependymoma.
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◦ Nuclear positivity for NeuN is not helpful, as it may be positive in both tumor types.
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Atypical teratoid /rhabdoid tumor (AT/RT) may have a prominent PNET-like small round cell component, whereas large cell or anaplastic medulloblastoma may mimic AT/RT.
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◦ FISH with INI-1 locus-specific probe shows no demonstrable allelic deletion in medulloblastoma.
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◦ Similarly, immunostain with BAF-47 (anti-INI1) antibody shows positive nuclear staining in the neoplastic cells in medulloblastoma but negative staining in AT/RT.
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Medulloblastoma needs to also be differentiated from small cell glioblastoma.
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◦ Small cell glioblastoma will characteristically show widespread GFAP positivity and lack evidence of neural differentiation (presence of Homer Wright rosettes or neuronal immunohistochemical markers typical of medulloblastoma).
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Other small round blue cell tumors of children metastatic to the CNS (rhabdomyosarcoma, Ewing sarcoma, leukemia/lymphoma, etc.) can all be effectively differentiated from medulloblastoma by immunohistochemistry.
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◦ Metastatic neuroblastoma may closely mimic medulloblastoma, but it would be unlikely for neuroblastoma to present solely as a CNS metastasis without the primary peripheral lesion having been identified by imaging studies or a previous biopsy.
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9 Prognosis
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The following clinic al characteristics define high-risk patients:
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◦ Age less than 3 years.
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◦ Postresection residual tumor larger than 1.5 cm.
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◦ Metastatic disease at presentation with Chang stages M1–4.
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Large cell and anaplastic histology are associated with poor survival.
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Poor prognostic molecular markers include amplification of MYCC or MYCN and overexpression of c-erbB2 or p53.
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The nodular/desmoplastic and the extensively nodular phenotypes are associated with favorable outcome and better survival than the classic medulloblastoma.
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Wnt pathway activation with nuclear expression of β-catenin and/or monosomy 6 has been reported as a good prognostic marker.
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Adesina, A.M., Hunter, J.V. (2016). Medulloblastoma. In: Adesina, A., Tihan, T., Fuller, C., Poussaint, T. (eds) Atlas of Pediatric Brain Tumors. Springer, Cham. https://doi.org/10.1007/978-3-319-33432-5_8
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