Histopathology and molecular pathogenesis of medulloblastoma
- Scott L Pomeroy, MD, PhD
Scott L Pomeroy, MD, PhD
- Bronson Crothers Professor of Neurology
- Harvard Medical School
- Section Editors
- Jay S Loeffler, MD
Jay S Loeffler, MD
- Section Editor — Neurooncology
- Professor of Radiation Oncology
- Harvard Medical School
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
- Amar Gajjar, MD
Amar Gajjar, MD
- Section Editor — Pediatric Neurooncology
- Scott and Tracie Hamilton Endowed Chair
- Director, Division of Neuro Oncology
- Co Leader Neurobiology and Brain Tumor Program
- Co Chair and Member, Department of Oncology
- St Jude Children’s Research Hospital
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 subgroups 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".)
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 features. The clinical outcome appears to be worse with increasing grade and extent of anaplasia . 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, and nestin, a marker of primitive neuroepithelial cells, consistent with their presumed origin from neuronal progenitors in the cerebellum . 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 β-catenin staining is present in most wingless (WNT) pathway tumors, and p53 immunostaining can be performed to identify tumors with TP53 mutations. (See 'Molecular subgroups' below.)
Several histologic variants of medulloblastoma have been described (figure 1 and table 1) . The desmoplastic variant has abundant collagen and reticulin in the interstitial spaces as well as reticulin free "pale islands" . This variant is associated with mutations in the patched-1 (PTCH1) gene on chromosome 9 and may have a better prognosis . A second variant, the large cell/anaplastic (LCA) medulloblastoma, is characterized by cerebrospinal fluid dissemination and a more aggressive clinical course . 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.)
- Eberhart CG, Kepner JL, Goldthwaite PT, et al. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 2002; 94:552.
- Kleihues P, Burger PC, Scheithauer BW. Histological Typing of Tumors of the Central Nervous System, Springer-Verlag, Berlin 1993.
- Katsetos CD, Liu HM, Zacks SI. Immunohistochemical and ultrastructural observations on Homer Wright (neuroblastic) rosettes and the "pale islands" of human cerebellar medulloblastomas. Hum Pathol 1988; 19:1219.
- McLendon RE, Friedman HS, Fuchs HE, et al. Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study. Histopathology 1999; 34:154.
- Kozmik Z, Sure U, Rüedi D, et al. Deregulated expression of PAX5 in medulloblastoma. Proc Natl Acad Sci U S A 1995; 92:5709.
- Yokota N, Aruga J, Takai S, et al. Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res 1996; 56:377.
- Giangaspero, F, Eberhart, CG, Haapasalo, H, et, al.. Medulloblastoma. In: WHO Classification of Tumours of the Central Nervous System, 4th, Louis, DN, Ohgaki, H, Wiestler, OD, Cavenee, WK. (Eds), IARC, Lyon 2007. p.132.
- Sure U, Berghorn WJ, Bertalanffy H, et al. Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir (Wien) 1995; 132:59.
- Leonard JR, Cai DX, Rivet DJ, et al. Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features. J Neurosurg 2001; 95:82.
- Bigner DD, McLendon RE, Bruner JM. Russell and Rubenstein's Pathology of Tumors of the Nervous System, Arnold, London 1998.
- Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002; 415:436.
- Evans G, Burnell L, Campbell R, et al. Congenital anomalies and genetic syndromes in 173 cases of medulloblastoma. Med Pediatr Oncol 1993; 21:433.
- Evans DG, Farndon PA, Burnell LD, et al. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 1991; 64:959.
- Smith MJ, Beetz C, Williams SG, et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 2014; 32:4155.
- Goodrich LV, Milenković L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997; 277:1109.
- Amlashi SF, Riffaud L, Brassier G, Morandi X. Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer 2003; 98:618.
- Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995; 332:839.
- Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57:704.
- Attard TM, Giglio P, Koppula S, et al. Brain tumors in individuals with familial adenomatous polyposis: a cancer registry experience and pooled case report analysis. Cancer 2007; 109:761.
- Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011; 29:1408.
- Kool M, Korshunov A, Remke M, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012; 123:473.
- Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 2012; 488:49.
- Cho YJ, Tsherniak A, Tamayo P, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 2011; 29:1424.
- Kool M, Koster J, Bunt J, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 2008; 3:e3088.
- Thompson MC, Fuller C, Hogg TL, et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006; 24:1924.
- Northcott PA, Jones DT, Kool M, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer 2012; 12:818.
- Pugh TJ, Weeraratne SD, Archer TC, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012; 488:106.
- Robinson G, Parker M, Kranenburg TA, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 2012; 488:43.
- Jones DT, Jäger N, Kool M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 2012; 488:100.
- WHO Classification of Tumours of the Central Nervous System, Revised 4th Edition, Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds), IARC, Lyon 2016.
- Shih DJ, Northcott PA, Remke M, et al. Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 2014; 32:886.
- He X, Zhang L, Chen Y, et al. The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma. Nat Med 2014; 20:1035.
- Huh JY, Kwon MJ, Seo KY, et al. Novel nonsense GNAS mutation in a 14-month-old boy with plate-like osteoma cutis and medulloblastoma. J Dermatol 2014; 41:319.
- Smyth I, Narang MA, Evans T, et al. Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol Genet 1999; 8:291.
- Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet 2002; 31:306.
- Erez A, Ilan T, Amariglio N, et al. GLI3 is not mutated commonly in sporadic medulloblastomas. Cancer 2002; 95:28.
- Zhukova N, Ramaswamy V, Remke M, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013; 31:2927.
- Rausch T, Jones DT, Zapatka M, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012; 148:59.
- Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009; 361:1173.
- Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res 2011; 71:5057.
- Zhao F, Ohgaki H, Xu L, et al. Molecular subgroups of adult medulloblastoma: a long-term single-institution study. Neuro Oncol 2016; 18:982.
- Northcott PA, Lee C, Zichner T, et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014; 511:428.
- Ramaswamy V, Remke M, Bouffet E, et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol 2013; 14:1200.
- Schüller U, Heine VM, Mao J, et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 2008; 14:123.
- Grammel D, Warmuth-Metz M, von Bueren AO, et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol 2012; 123:601.
- Polkinghorn WR, Tarbell NJ. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 2007; 4:295.
- Oliver TG, Wechsler-Reya RJ. Getting at the root and stem of brain tumors. Neuron 2004; 42:885.
- Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 2008; 14:135.
- Pei Y, Moore CE, Wang J, et al. An animal model of MYC-driven medulloblastoma. Cancer Cell 2012; 21:155.
- Kawauchi D, Robinson G, Uziel T, et al. A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell 2012; 21:168.
- Gibson P, Tong Y, Robinson G, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 2010; 468:1095.
- MacDonald TJ, Brown KM, LaFleur B, et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 2001; 29:143.
- Gilbertson RJ, Clifford SC. PDGFRB is overexpressed in metastatic medulloblastoma. Nat Genet 2003; 35:197.