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Childhood Central Nervous System Embryonal Tumors Treatment (PDQ®)

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Last Modified: 05/02/2014

Cellular and Molecular Classification of CNS Embryonal Tumors

        Biologically/molecularly defined subtypes of medulloblastoma
CNS Primitive Neuroectodermal Tumors (PNETs) and Pineoblastoma
        Biological subtypes of CNS PNETs


By definition, medulloblastomas must arise in the posterior fossa.[1,2] The following five histologic types of medulloblastoma are recognized by the World Health Organization (WHO) classification:[1]

  • Medulloblastoma (commonly referred to as classic medulloblastoma).
  • Anaplastic medulloblastoma.
  • Large cell medulloblastoma.
  • Desmoplastic/nodular medulloblastoma.
  • Medulloblastoma with extensive nodularity (MBEN).

Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[3,4] Using the criteria of anaplasia is subjective because most medulloblastomas have some degree of anaplasia. Foci of anaplasia may appear in tumors with histologic features of both classic and large cell medulloblastomas, and there is significant overlap between the anaplastic and large cell variant.[3,4] One convention is to consider medulloblastomas as anaplastic when anaplasia is diffuse (variably defined as anaplasia occurring in 50% to 80% of the tumor).

The incidence of medulloblastoma with the desmoplastic variant is higher in infants, is less common in children, and increases again in adolescents and adults. The desmoplastic variant subtype is different from MBEN; the nodular variant has an expanded lobular architecture. The nodular subtype occurs almost exclusively in infants and carries an excellent prognosis.[5,6]

Biologically/molecularly defined subtypes of medulloblastoma

Multiple medulloblastoma subtypes have been identified based on gene expression profiles.[7-21] As of 2012, there was a general consensus that medulloblastoma can be molecularly separated into at least four subtypes; however, it is likely that further subclassification will occur.[20-22]

The following four core subtypes of medulloblastoma have been identified:[20,21,23]

  • Subtype 1: WNT tumors (medulloblastoma with aberrations in the WNT signaling pathway). Subtype 1 shows a WNT signaling gene expression signature and beta-catenin nuclear staining. They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. They are infrequently metastasized at diagnosis. Genetically, these tumors have 6q loss and CTNNB1 mutations and have activated WNT signaling; there may be occasional MYC overexpression.

    The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region. Subtype 1 tumors are associated with a very good outcome.[24]

  • Subtype 2: Sonic hedgehog (SHH) tumors (medulloblastoma with aberrations in the SHH pathway). Subtype 2 tumors are characterized by chromosome 9q deletions, desmoplastic/nodular histology, and mutations in SHH pathway genes including PTCH1, as well as PTCH2, SMO, and SUFU.

    The SHH subset shows a bimodal age distribution and is observed primarily in children younger than 3 years, as well as in older adolescents and adults. The tumors are believed to emanate from the external granular layer of the cerebellum. Prognosis for patients with SHH medulloblastoma appears to be negatively affected by additional factors such as chromosome 17p loss, chromosome 3q gain, chromothripsis, p53 amplification, and the finding of large cell/anaplastic histology.[21] Outcome in this group is relatively favorable, especially for children younger than 3 years. For adolescents and young adults, outcome is not different from non-WNT pathway activated tumors.

  • Subtype 3 (Group 3): Histology of Subtype 3 tumors is either classic or large cell/anaplastic and these tumors are frequently metastasized at the time of diagnosis. A variety of different mutations have been noted in these tumors including the presence of i17q and, most characteristically, MYC amplification.

    Subtype 3 tumors occur throughout childhood and may occur in infants. Males outnumber females in a 2:1 ratio in this medulloblastoma subtype. Subtype 3 patients have the least favorable outcome among the molecularly defined medulloblastoma subtypes.[23]

  • Subtype 4 (Group 4): Subtype 4 tumors are either classic or large cell/anaplastic tumors. Metastasis at diagnosis is common, but not as frequent as is seen in Subtype 3 tumors. Molecularly, they have a CDK6 amplification and MYCN amplification and may also have an i17q abnormality.

    Subtype 4 tumors occur throughout infancy and childhood and into adulthood. They also predominate in males. The prognosis is better than Subtype 3 tumors but not as good as Subtype 1 tumors. Prognosis for Subtype 4 patients is affected by additional factors such as the presence of metastatic disease and chromosome 17p loss.[20,21]

Optimal ways of identifying the four core medulloblastoma subtypes for clinical use is under active study, and both immunohistochemical methods and methods based on gene expression analysis are under development.[24,25] It is likely that the classification of medulloblastoma into four major subtypes will be altered in the near future. Further subdivision within subgroups based on molecular characteristics is likely, although there is no consensus regarding an alternative classification.[20,22]

Whether the classification for adults with medulloblastoma has similar predictive ability in children is unknown.[21,23] In one study of adult medulloblastoma, MYC oncogene amplifications were rarely observed and tumors with 6q deletion and WNT activation (as measured by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas, although another study did confirm an excellent prognosis for WNT-activated tumors in adults.[21,23]

CNS Primitive Neuroectodermal Tumors (PNETs) and Pineoblastoma

Genome-wide molecular characterization of PNETs and pineoblastomas has demonstrated substantial heterogeneity among these tumors.[26]

Pineoblastoma is histologically similar to medulloblastoma; however, according to the WHO, its histogenesis is linked to the pineocyte (a type of pineal cell).[1]

CNS PNETs generally arise in the cerebrum or suprasellar region, but may arise in the brain stem and spinal cord.[27] According to the 2007 WHO classification, tumors demonstrating areas of distinct neuronal differentiation are termed cerebral neuroblastomas and, if ganglion cells are also present, ganglioneuroblastomas.

Biological subtypes of CNS PNETs

Integrative genomic analysis has been used to molecularly subdivide CNS PNETs, with subtypes defined primarily based on their gene expression profiles. In a study of 142 hemispheric tumors, the following three molecular subsets were identified:[28]

  • Group 1 (Neural): Group 1 tumors showed gene expression profiles enriched for genes associated with embryonic or neural stem cells and occurred more commonly in young children (median age of 2.9 years) with a female predominance (1.7:1.0).

  • Group 2 (Oligoneural): Group 2 tumors showed upregulation of expression of genes associated with oligoneural differentiation, had no clear-cut sex predominance, and had a median age at presentation of 7.9 years.

  • Group 3 (Mesenchymal): Group 3 tumors showed reduced expression of neural differentiation genes and upregulation of epithelial and mesenchymal differentiation genes. They occurred more frequently in males (1.6:1.0), with a median age at presentation of 5.9 years.

Survival was shortest for Group 1 tumors, although treatment varied among all three groups. Group 3 tumors showed the highest rate of metastatic disease at diagnosis.[28]


Medulloepithelioma is identified as a histologically discrete tumor within the WHO classification system.[29,30] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly but may arise infratentorially, in the cauda, and even extraneural, along nerve roots.[29,30]


Ependymoblastoma is identified as a histologically discrete tumor within the WHO classification system; however, the existence of ependymoblastoma as a discrete entity has been questioned by others.[29] Ependymoblastoma tumors are rare and tend to arise most commonly in infants and young children. Ependymoblastoma is characterized by the presence of true multilayered (or ependymoblastic) rosettes.[31,32] The tumor has a supratentorial predilection, but like medulloepithelioma, it may occur in the spine, especially in the sacrococcygeal region.

Histologically, the tumor shares features with other embryonal tumors and with a rare tumor type, the embryonal tumor with abundant neuropil and true rosettes (ETANTR).[31-34] The latter entity is characterized by young age at diagnosis (median age of approximately 2 years), primarily supratentorial presentation, poor prognosis, and tumors showing true multilayered/ependymoblastic rosettes within a background of abundant neuropil-like areas.[32,34,35]

In addition to sharing clinical characteristics (i.e., age, primary site, and prognosis), ependymoblastoma and ETANTR show common genomic alterations, including chromosome 2 gain and focal amplification at chromosome band 19q13.42. The latter chromosome region contains a cluster of microRNA coding genes,[36] and its amplification appears to be present in virtually all pediatric embryonal tumors with true multilayered rosettes (i.e., ependymoblastoma and ETANTR).[35-37] By contrast, 19q13.42 amplification has not been detected in more than 300 other pediatric brain tumors, suggesting that it may be a useful diagnostic marker for ependymoblastoma and ETANTR.[35]

  1. Louis DN, Ohgaki H, Wiestler OD, et al., eds.: WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007. 

  2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42 (1): 1-15, 1983.  [PUBMED Abstract]

  3. McManamy CS, Lamont JM, Taylor RE, et al.: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62 (6): 627-32, 2003.  [PUBMED Abstract]

  4. Eberhart CG, Kratz J, Wang Y, et al.: Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol 63 (5): 441-9, 2004.  [PUBMED Abstract]

  5. Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999.  [PUBMED Abstract]

  6. Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome--a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009.  [PUBMED Abstract]

  7. Onvani S, Etame AB, Smith CA, et al.: Genetics of medulloblastoma: clues for novel therapies. Expert Rev Neurother 10 (5): 811-23, 2010.  [PUBMED Abstract]

  8. Dubuc AM, Northcott PA, Mack S, et al.: The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10 (3): 215-23, 2010.  [PUBMED Abstract]

  9. Thompson MC, Fuller C, Hogg TL, et al.: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24 (12): 1924-31, 2006.  [PUBMED Abstract]

  10. 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 3 (8): e3088, 2008.  [PUBMED Abstract]

  11. Tabori U, Baskin B, Shago M, et al.: Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol 28 (8): 1345-50, 2010.  [PUBMED Abstract]

  12. Pfister S, Remke M, Benner A, et al.: Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol 27 (10): 1627-36, 2009.  [PUBMED Abstract]

  13. Ellison DW, Onilude OE, Lindsey JC, et al.: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23 (31): 7951-7, 2005.  [PUBMED Abstract]

  14. Polkinghorn WR, Tarbell NJ: Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4 (5): 295-304, 2007.  [PUBMED Abstract]

  15. Giangaspero F, Wellek S, Masuoka J, et al.: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112 (1): 5-12, 2006.  [PUBMED Abstract]

  16. Northcott PA, Korshunov A, Witt H, et al.: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29 (11): 1408-14, 2011.  [PUBMED Abstract]

  17. Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002.  [PUBMED Abstract]

  18. Jones DT, Jäger N, Kool M, et al.: Dissecting the genomic complexity underlying medulloblastoma. Nature 488 (7409): 100-5, 2012.  [PUBMED Abstract]

  19. Peyrl A, Chocholous M, Kieran MW, et al.: Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59 (3): 511-7, 2012.  [PUBMED Abstract]

  20. Taylor MD, Northcott PA, Korshunov A, et al.: Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123 (4): 465-72, 2012.  [PUBMED Abstract]

  21. 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 123 (4): 473-84, 2012.  [PUBMED Abstract]

  22. Northcott PA, Jones DT, Kool M, et al.: Medulloblastomics: the end of the beginning. Nat Rev Cancer 12 (12): 818-34, 2012.  [PUBMED Abstract]

  23. 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 29 (11): 1424-30, 2011.  [PUBMED Abstract]

  24. Ellison DW, Dalton J, Kocak M, et al.: Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121 (3): 381-96, 2011.  [PUBMED Abstract]

  25. Northcott PA, Shih DJ, Remke M, et al.: Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol 123 (4): 615-26, 2012.  [PUBMED Abstract]

  26. Miller S, Rogers HA, Lyon P, et al.: Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma. Neuro Oncol 13 (8): 866-79, 2011.  [PUBMED Abstract]

  27. Benesch M, Sperl D, von Bueren AO, et al.: Primary central nervous system primitive neuroectodermal tumors (CNS-PNETs) of the spinal cord in children: four cases from the German HIT database with a critical review of the literature. J Neurooncol 104 (1): 279-86, 2011.  [PUBMED Abstract]

  28. Picard D, Miller S, Hawkins CE, et al.: Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 13 (8): 838-48, 2012.  [PUBMED Abstract]

  29. Louis DN, Ohgaki H, Wiestler OD, et al.: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114 (2): 97-109, 2007.  [PUBMED Abstract]

  30. Sharma MC, Mahapatra AK, Gaikwad S, et al.: Pigmented medulloepithelioma: report of a case and review of the literature. Childs Nerv Syst 14 (1-2): 74-8, 1998 Jan-Feb.  [PUBMED Abstract]

  31. Judkins AR, Ellison DW: Ependymoblastoma: dear, damned, distracting diagnosis, farewell!*. Brain Pathol 20 (1): 133-9, 2010.  [PUBMED Abstract]

  32. Eberhart CG, Brat DJ, Cohen KJ, et al.: Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol 3 (4): 346-52, 2000 Jul-Aug.  [PUBMED Abstract]

  33. Norris LS, Snodgrass S, Miller DC, et al.: Recurrent central nervous system medulloepithelioma: response and outcome following marrow-ablative chemotherapy with stem cell rescue. J Pediatr Hematol Oncol 27 (5): 264-6, 2005.  [PUBMED Abstract]

  34. Gessi M, Giangaspero F, Lauriola L, et al.: Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol 33 (2): 211-7, 2009.  [PUBMED Abstract]

  35. Korshunov A, Remke M, Gessi M, et al.: Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol 120 (2): 253-60, 2010.  [PUBMED Abstract]

  36. Li M, Lee KF, Lu Y, et al.: Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 16 (6): 533-46, 2009.  [PUBMED Abstract]

  37. Pfister S, Remke M, Castoldi M, et al.: Novel genomic amplification targeting the microRNA cluster at 19q13.42 in a pediatric embryonal tumor with abundant neuropil and true rosettes. Acta Neuropathol 117 (4): 457-64, 2009.  [PUBMED Abstract]