Embryonal Tumors

  • David RaleighEmail author
  • Corey Raffel
  • Daphne A. Haas-Kogan
Part of the Pediatric Oncology book series (PEDIATRICO)


Embryonal tumors comprise a large fraction of pediatric brain tumors (Ostrom et al. 2014), but their cell(s) of origin, histopathologic classification, and treatment remain controversial. For others, such as medulloblastoma, recent molecular studies have identified both oncogenic “driver” mutations and promising therapeutic targets. The prognosis of these tumors was at one time exceedingly poor, but therapeutic advances have led to substantial improvement in survival. Despite these gains, current treatment protocols, which rely on surgery, adjuvant radiation and cytotoxic chemotherapy, often lead to debilitating and severe late effects.


Posterior Fossa Pediatric Brain Tumor Embryonal Tumor Gorlin Syndrome Pineal Parenchymal Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Albright AL, Wisoff JH, Zeltzer P, Boyett J, Rorke LB, Stanley P, Geyer JR, Milstein JM (1995) Prognostic factors in children with supratentorial (nonpineal) primitive neuroectodermal tumors. A neurosurgical perspective from the Children’s Cancer Group. Pediatr Neurosurg 22:1–7PubMedCrossRefGoogle Scholar
  2. Al-Halabi H, Nantel A, Klekner A, Guiot M-C, Albrecht S, Hauser P, Garami M, Bognar L, Kavan P, Gerges N et al (2011) Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma. Acta Neuropathol 121:229–239PubMedCrossRefGoogle Scholar
  3. Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13:11–26PubMedCrossRefGoogle Scholar
  4. Archer TC, Weeraratne SD, Pomeroy SL (2012) Hedgehog-GLI pathway in medulloblastoma. J Clin Oncol 30:2154–2156PubMedCrossRefGoogle Scholar
  5. Ashley DM, Meier L, Kerby T, Zalduondo FM, Friedman HS, Gajjar A, Kun L, Duffner PK, Smith S, Longee D (1996) Response of recurrent medulloblastoma to low-dose oral etoposide. J Clin Oncol 14:1922–1927PubMedGoogle Scholar
  6. Ashley D, Merchant T, Zhou T, Coleman L, Pollack I, Duffner P, Burger P, Miller D, Buxton A, Douglas S (2008) P9934: systemic chemotherapy, second-look surgery and conformal radiation therapy limited to the posterior fossa and primary site for children >8 months and. Neuro Oncol 10:436–437Google Scholar
  7. Bailey CC, Gnekow A, Wellek S, Jones M, Round C, Brown J, Phillips A, Neidhardt MK (1995) Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25:166–178PubMedCrossRefGoogle Scholar
  8. Batora NV, Sturm D, Jones DTW, Kool M, Pfister SM, Northcott PA (2014) Transitioning from genotypes to epigenotypes: why the time has come for medulloblastoma epigenomics. Neuroscience 264:171–185PubMedCrossRefGoogle Scholar
  9. Belza MG, Donaldson SS, Steinberg GK, Cox RS, Cogen PH (1991) Medulloblastoma: freedom from relapse longer than 8 years – a therapeutic cure? J Neurosurg 75:575–582PubMedCrossRefGoogle Scholar
  10. Berger MS, Baumeister B, Geyer JR, Milstein J, Kanev PM, LeRoux PD (1991) The risks of metastases from shunting in children with primary central nervous system tumors. J Neurosurg 74:872–877PubMedCrossRefGoogle Scholar
  11. Biegel JA (2006) Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 20, E11PubMedCrossRefGoogle Scholar
  12. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74–79PubMedGoogle Scholar
  13. Bigner SH, Mark J, Friedman HS, Biegel JA, Bigner DD (1988) Structural chromosomal abnormalities in human medulloblastoma. Cancer Genet Cytogenet 30:91–101PubMedCrossRefGoogle Scholar
  14. Bouffet E, Bernard JL, Frappaz D, Gentet JC, Roche H, Tron P, Carrie C, Raybaud C, Joannard A, Lapras C et al (1992) M4 protocol for cerebellar medulloblastoma: supratentorial radiotherapy may not be avoided. Radiat Oncol Biol 24:79–85CrossRefGoogle Scholar
  15. Bourgouin PM, Tampieri D, Grahovac SZ, Léger C, Del Carpio R, Melançon D (1992) CT and MR imaging findings in adults with cerebellar medulloblastoma: comparison with findings in children. AJR Am J Roentgenol 159:609–612PubMedCrossRefGoogle Scholar
  16. Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, Kun LE, Goldthwaite PT, Burger PC (2000) “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol 59:857–865PubMedCrossRefGoogle Scholar
  17. Burger PC, Yu IT, Tihan T, Friedman HS, Strother DR, Kepner JL, Duffner PK, Kun LE, Perlman EJ (1998) Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol 22:1083–1092PubMedCrossRefGoogle Scholar
  18. Chang CH, Housepian EM, Herbert C (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359PubMedCrossRefGoogle Scholar
  19. Chi SN, Zimmerman MA, Yao X, Cohen KJ, Burger P, Biegel JA, Rorke-Adams LB, Fisher MJ, Janss A, Mazewski C et al (2009) Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 27:385–389PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cho Y-J, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG et al (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424–1430PubMedCrossRefGoogle Scholar
  21. Cohen BH, Zeltzer PM, Boyett JM, Geyer JR, Allen JC, Finlay JL, McGuire-Cullen P, Milstein JM, Rorke LB, Stanley P et al (1995) Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial. J Clin Oncol 13:1687–1696PubMedGoogle Scholar
  22. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DYR, Reiter JF (2005) Vertebrate smoothened functions at the primary cilium. Nature 437:1018–1021PubMedCrossRefGoogle Scholar
  23. Curran EK, Sainani KL, Le GM, Propp JM, Fisher PG (2009) Gender affects survival for medulloblastoma only in older children and adults: a study from the Surveillance Epidemiology and End Results Registry. Pediatr Blood Cancer 52:60–64PubMedCrossRefGoogle Scholar
  24. De Potter P, Shields CL, Shields JA (1994) Clinical variations of trilateral retinoblastoma: a report of 13 cases. J Pediatr Ophthalmol Strabismus 31:26–31PubMedGoogle Scholar
  25. Deutsch M, Reigel DH (1980) The value of myelography in the management of childhood medulloblastoma. Cancer 45:2194–2197PubMedCrossRefGoogle Scholar
  26. Deutsch M, Thomas PR, Krischer J, Boyett JM, Albright L, Aronin P, Langston J, Allen JC, Packer RJ, Linggood R et al (1996) Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma. A Combined Children’s Cancer Group-Pediatric Oncology Group Study. Pediatr Neurosurg 24:167–176; discussion 176–7PubMedCrossRefGoogle Scholar
  27. Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, Sanford RA, Mulhern RK, James HE, Freeman CR et al (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:1725–1731PubMedCrossRefGoogle Scholar
  28. Duffner PK, Cohen ME, Sanford RA, Horowitz ME, Krischer JP, Burger PC, Friedman HS, Kun LE (1995) Lack of efficacy of postoperative chemotherapy and delayed radiation in very young children with pineoblastoma. Pediatric Oncology Group. Med Pediatr Oncol 25:38–44PubMedCrossRefGoogle Scholar
  29. Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 94:552–560PubMedCrossRefGoogle Scholar
  30. Eberhart CG, Kratz J, Wang Y, Summers K, Stearns D, Cohen K, Dang CV, Burger PC (2004) Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol 63:441–449Google Scholar
  31. Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC (2005) Beta-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 23:7951–7957PubMedCrossRefGoogle Scholar
  32. Evans AE, Jenkin RD, Sposto R, Ortega JA, Wilson CB, Wara W, Ertel IJ, Kramer S, Chang CH, Leikin SL et al (1990) The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:572–582PubMedCrossRefGoogle Scholar
  33. Fauchon F, Jouvet A, Paquis P, Saint-Pierre G, Mottolese C, Ben Hassel M, Chauveinc L, Sichez JP, Philippon J, Schlienger M et al (2000) Parenchymal pineal tumors: a clinicopathological study of 76 cases. Radiat Oncol Biol 46:959–968CrossRefGoogle Scholar
  34. Fine HA (2002) Polyomavirus and medulloblastoma: a smoking gun or guilt by association? J Natl Cancer Inst 94:240–241PubMedCrossRefGoogle Scholar
  35. Fowler M, Simpson DA (1962) A malignant melanin-forming tumour of the cerebellum. J Pathol Bacteriol 84:307–311PubMedCrossRefGoogle Scholar
  36. Freeman CR, Taylor RE, Kortmann RD, Carrie C (2002) Radiotherapy for medulloblastoma in children: a perspective on current international clinical research efforts. Med Pediatr Oncol 39:99–108PubMedCrossRefGoogle Scholar
  37. Gajjar AJ, Heideman RL, Douglass EC, Kun LE, Kovnar EH, Sanford RA, Fairclough DL, Ayers D, Look AT (1993) Relation of tumor-cell ploidy to survival in children with medulloblastoma. J Clin Oncol 11:2211–2217PubMedGoogle Scholar
  38. Gajjar A, Fouladi M, Walter AW, Thompson SJ, Reardon DA, Merchant TE, Jenkins JJ, Liu A, Boyett JM, Kun LE et al (1999) Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors. J Clin Oncol 17:1825–1828PubMedGoogle Scholar
  39. Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, Wallace D, Lau C, Chintagumpala M, Ashley DM et al (2004) Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22:984–993PubMedCrossRefGoogle Scholar
  40. Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ et al (2006) Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7:813–820PubMedCrossRefGoogle Scholar
  41. Gentet JC, Bouffet E, Doz F, Tron P, Roche H, Thyss A, Plantaz D, Stephan JL, Mottolese C, Ponvert D et al (1995) Preirradiation chemotherapy including “eight drugs in 1 day” regimen and high-dose methotrexate in childhood medulloblastoma: results of the M7 French Cooperative Study. J Neurosurg 82:608–614PubMedCrossRefGoogle Scholar
  42. Geyer JR, Sposto R, Jennings M, Boyett JM, Axtell RA, Breiger D, Broxson E, Donahue B, Finlay JL, Goldwein JW et al (2005) Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol 23:7621–7631PubMedCrossRefGoogle Scholar
  43. Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, Zorzi F, Montaldi A (1992) Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 16:687–693PubMedCrossRefGoogle Scholar
  44. Giangaspero F, Wellek S, Masuoka J, Gessi M, Kleihues P, Ohgaki H (2006) Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112:5–12PubMedCrossRefGoogle Scholar
  45. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J et al (2010) Subtypes of medulloblastoma have distinct developmental origins. Nature 468:1095–1099PubMedPubMedCentralCrossRefGoogle Scholar
  46. Gilbertson R (2002) Paediatric embryonic brain tumours. Biological and clinical relevance of molecular genetic abnormalities. Eur J Cancer 38:675–685PubMedCrossRefGoogle Scholar
  47. Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones-Wallace D, Crolla J, Perry R, Lunec J, Pearson A et al (2001) Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 85:705–712PubMedPubMedCentralCrossRefGoogle Scholar
  48. Gilheeney SW, Saad A, Chi S, Turner C, Ullrich NJ, Goumnerova L, Scott RM, Marcus K, Lehman L, De Girolami U et al (2008) Outcome of pediatric pineoblastoma after surgery, radiation and chemotherapy. J Neurooncol 89:89–95PubMedCrossRefGoogle Scholar
  49. Gorlin RJ, Goltz RW (1960) Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med 262:908–912PubMedCrossRefGoogle Scholar
  50. Gorlin RJ, Vickers RA, Kellen E, Williamson JJ (1965) Multiple basal-cell nevi syndrome. An analysis of a syndrome consisting of multiple nevoid basal-cell carcinoma, Jaw cysts, skeletal anomalies, medulloblastoma, and hyporesponsiveness to parathormone. Cancer 18:89–104PubMedCrossRefGoogle Scholar
  51. Grill J, Sainte-Rose C, Jouvet A, Gentet JC, Lejars O, Frappaz D, Doz F, Rialland X, Pichon F, Bertozzi AI et al (2005) Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6:573–580PubMedCrossRefGoogle Scholar
  52. Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, Zhao H, Cnaan A, Phillips PC, Lee VM et al (2000) TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18:1027–1035PubMedGoogle Scholar
  53. Grotzer MA, Geoerger B, Janss AJ, Zhao H, Rorke LB, Phillips PC (2001) Prognostic significance of Ki-67 (MIB-1) proliferation index in childhood primitive neuroectodermal tumors of the central nervous system. Med Pediatr Oncol 36:268–273PubMedCrossRefGoogle Scholar
  54. Gurney JG, Smith MA, Bunin GR (1999) CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds) Cancer incidence and survival among children and adolescents: United States SEER program 1975–1995. National Cancer Institute, SEER Program, BethesdaGoogle Scholar
  55. Gururangan S, McLaughlin C, Quinn J, Rich J, Reardon D, Halperin EC, Herndon J, Fuchs H, George T, Provenzale J et al (2003) High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 21:2187–2191PubMedCrossRefGoogle Scholar
  56. Halberg FE, Wara WM, Fippin LF, Edwards MS, Levin VA, Davis RL, Prados MB, Wilson CB (1991) Low-dose craniospinal radiation therapy for medulloblastoma. Radiat Oncol Biol 20:651–654CrossRefGoogle Scholar
  57. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B et al (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847PubMedCrossRefGoogle Scholar
  58. Hartsell WF, Gajjar A, Heideman RL, Langston JA, Sanford RA, Walter A, Jones D, Chen G, Kun LE (1997) Patterns of failure in children with medulloblastoma: effects of preirradiation chemotherapy. Radiat Oncol Biol 39:15–24CrossRefGoogle Scholar
  59. Haslam RH, Lamborn KR, Becker LE, Israel MA (1998) Tumor cell apoptosis present at diagnosis may predict treatment outcome for patients with medulloblastoma. J Pediatr Hematol Oncol 20:520–527PubMedCrossRefGoogle Scholar
  60. He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, Wang H, Deng Y, Yu Y, Xia Y, et al (2014) The G protein L., Chen, Y., Remke, M., Shih, D., Lu, F., Wang, H., Deng, Y., Yu, Y., Xia, Y., et al.
  61. Hilden JM, Watterson J, Longee DC, Moertel CL, Dunn ME, Kurtzberg J, Scheithauer BW (1998) Central nervous system atypical teratoid tumor/rhabdoid tumor: response to intensive therapy and review of the literature. J Neurooncol 40:265–275PubMedCrossRefGoogle Scholar
  62. Hilden JM, Meerbaum S, Burger P, Finlay J, Janss A, Scheithauer BW, Walter AW, Rorke LB, Biegel JA (2004) Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22:2877–2884PubMedCrossRefGoogle Scholar
  63. Hirato J, Nakazato Y (2001) Pathology of pineal region tumors. J Neurooncol 54:239–249PubMedCrossRefGoogle Scholar
  64. Honig PJ, Charney EB (1982) Children with brain tumor headaches. Distinguishing features. Am J Dis Child 136:121–124PubMedCrossRefGoogle Scholar
  65. Hovestadt V, Jones DTW, Picelli S, Wang W, Kool M, Northcott PA, Sultan M, Stachurski K, Ryzhova M, Warnatz H-J et al (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510:537–541PubMedCrossRefGoogle Scholar
  66. Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, Klekota J, Tamayo P, Nguyen PTL, Tolstorukov M et al (2010) Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 16:1429–1433PubMedCrossRefGoogle Scholar
  67. Jakacki RI (1999) Pineal and nonpineal supratentorial primitive neuroectodermal tumors. Childs Nerv Syst 15:586–591PubMedCrossRefGoogle Scholar
  68. Jakacki RI, Zeltzer PM, Boyett JM, Albright AL, Allen JC, Geyer JR, Rorke LB, Stanley P, Stevens KR, Wisoff J et al (1995) Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol 13:1377–1383PubMedGoogle Scholar
  69. Kim JY, Sutton ME, Lu DJ, Cho TA, Goumnerova LC, Goritchenko L, Kaufman JR, Lam KK, Billet al, Tarbell NJ et al (1999) Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 59:711–719Google Scholar
  70. Kleinman GM, Hochberg FH, Richardson EPJ (1981) Systemic metastases from medulloblastoma: report of two cases and review of the literature. Cancer 48:2296–2309PubMedCrossRefGoogle Scholar
  71. Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, Troost D, Meeteren NS-V, Caron HN, Cloos J et al (2008) Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 3:e3088PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kool M, Korshunov A, Remke M, Jones DTW, Schlanstein M, Northcott PA, Cho Y-J, Koster J, Schouten-van Meeteren A, van Vuurden D et al (2012) 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 123:473–484PubMedPubMedCentralCrossRefGoogle Scholar
  73. Kool M, Jones DTW, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M et al (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related responseto smoothened inhibition. Cancer Cell 25:393–405PubMedPubMedCentralCrossRefGoogle Scholar
  74. Kortmann RD, Kuhl J, Timmermann B, Mittler U, Urban C, Budach V, Richter E, Willich N, Flentje M, Berthold F et al (2000) Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT ’91. Radiat Oncol Biol 46:269–279CrossRefGoogle Scholar
  75. Krischer JP, Ragab AH, Kun L, Kim TH, Laurent JP, Boyett JM, Cornell CJ, Link M, Luthy AR, Camitta B (1991) Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. A Pediatric Oncology Group study. J Neurosurg 74:905–909PubMedCrossRefGoogle Scholar
  76. Kuhl J, Muller HL, Berthold F, Kortmann RD, Deinlein F, Maass E, Graf N, Gnekow A, Scheurlen W, Gobel U et al (1998) Preradiation chemotherapy of children and young adults with malignant brain tumors: results of the German pilot trial HIT“88/”89. Klin Padiatr 210:227–233PubMedCrossRefGoogle Scholar
  77. Leonard JR, Cai DX, Rivet DJ, Kaufman BA, Park TS, Levy BK, Perry A (2001) Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features. J Neurosurg 95:82–88PubMedCrossRefGoogle Scholar
  78. Levy RA, Blaivas M, Muraszko K, Robertson PL (1997) Desmoplastic medulloblastoma: MR findings. AJNR Am J Neuroradiol 18:1364–1366PubMedGoogle Scholar
  79. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109PubMedPubMedCentralCrossRefGoogle Scholar
  80. Mabbott DJ, Spiegler BJ, Greenberg ML, Rutka JT, Hyder DJ, Bouffet E (2005) Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol 23:2256–2263PubMedCrossRefGoogle Scholar
  81. Marinesco G, Goldstein M (1933) Sur une forme anatomique, non encore decrite, de medulloblastoma: medullomyoblastoma. Ann Anat Pathol 10:513–525Google Scholar
  82. McManamy CS, Lamont JM, Taylor RE, Cole M, Pearson AD, Clifford SC, Ellison DW (2003) Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62:627–632PubMedCrossRefGoogle Scholar
  83. McManamy CS, Pears J, Weston CL, Hanzely Z, Ironside JW, Taylor RE, Grundy RG, Clifford SC, Ellison DW (2007) Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior. Brain Pathol 17:151–164PubMedCrossRefGoogle Scholar
  84. McNeil DE, Coté TR, Clegg L, Rorke LB (2002) Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance epidemiology and end results. Med Pediatr Oncol 39:190–194PubMedCrossRefGoogle Scholar
  85. Merchant TE, Kun LE, Krasin MJ, Wallace D, Chintagumpala MM, Woo SY, Ashley DM, Sexton M, Kellie SJ, Ahern V et al (2008) Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Radiat Oncol Biol 70:782–787CrossRefGoogle Scholar
  86. Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X (2009) Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27:3691–3697PubMedPubMedCentralCrossRefGoogle Scholar
  87. Minn AY, Pollock BH, Garzarella L, Dahl GV, Kun LE, Ducore JM, Shibata A, Kepner J, Fisher PG (2001) Surveillance neuroimaging to detect relapse in childhood brain tumors: a Pediatric Oncology Group study. J Clin Oncol 19:4135–4140PubMedGoogle Scholar
  88. Morland BJ, Parkes SE (1995) Decline in incidence of medulloblastoma in children. Cancer 76:155–156PubMedCrossRefGoogle Scholar
  89. Mosijczuk AD, Nigro MA, Thomas PR, Burger PC, Krischer JP, Morantz RA, Kurdunowicz B, Mulne AF, Towbin RB, Freeman AI et al (1993) Preradiation chemotherapy in advanced medulloblastoma. A Pediatric Oncology Group pilot study. Cancer 72:2755–2762PubMedCrossRefGoogle Scholar
  90. Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, Al-Halabi H, Albrecht S, Jabado N, Eberhart CG et al (2011a) Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol 122:231–240PubMedPubMedCentralCrossRefGoogle Scholar
  91. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P et al (2011b) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:1408–1414PubMedCrossRefGoogle Scholar
  92. Northcott PA, Jones DTW, Kool M, Robinson GW, Gilbertson RJ, Cho Y-J, Pomeroy SL, Korshunov A, Lichter P, Taylor MD et al (2012a) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12:818–834PubMedPubMedCentralCrossRefGoogle Scholar
  93. Northcott PA, Shih DJH, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE et al (2012b) Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488:49–56PubMedPubMedCentralCrossRefGoogle Scholar
  94. Northcott PA, Lee C, Zichner T, Stütz AM, Erkek S, Kawauchi D, Shih DJH, Hovestadt V, Zapatka M, Sturm D et al (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428–434PubMedPubMedCentralCrossRefGoogle Scholar
  95. Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. Embo J 31:2670–2684PubMedPubMedCentralCrossRefGoogle Scholar
  96. Olson TA, Bayar E, Kosnik E, Hamoudi AB, Klopfenstein KJ, Pieters RS, Ruymann FB (1995) Successful treatment of disseminated central nervous system malignant rhabdoid tumor. J Pediatr Hematol Oncol 17:71–75PubMedCrossRefGoogle Scholar
  97. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro-Oncology 16(Suppl 4):iv1–iv63PubMedPubMedCentralCrossRefGoogle Scholar
  98. Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson HS, Mulne L, Boyett J, D’Angio G, Wechsler-Jentzsch K et al (1994) Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:690–698PubMedCrossRefGoogle Scholar
  99. Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH et al (1999) Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol 17:2127–2136PubMedGoogle Scholar
  100. Packer RJ, Biegel JA, Blaney S, Finlay J, Geyer JR, Heideman R, Hilden J, Janss AJ, Kun L, Vezina G et al (2002) Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 24:337–342PubMedCrossRefGoogle Scholar
  101. Packer RJ, Gajjar A, Vezina G, Rorke-Adams L, Burger PC, Robertson PL, Bayer L, LaFond D, Donahue BR, Marymont MH et al (2006) Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24:4202–4208PubMedCrossRefGoogle Scholar
  102. Packer R, Zhou T, Vezina G, Holmes E, Gajjar A (2008) Long-term event-free, overall survival, and second malignant neoplasms in children with medulloblastoma treated with radiotherapy and adjuvant chemotherapy: results of COG-A9961. Neuro Oncol 10:482Google Scholar
  103. Palmer SL, Armstrong C, Onar-Thomas A, Wu S, Wallace D, Bonner MJ, Schreiber J, Swain M, Chapieski L, Mabbott D et al (2013) Processing speed, attention, and working memory after treatment for medulloblastoma: an international, prospective, and longitudinal study. J Clin Oncol 31:3494–3500PubMedPubMedCentralCrossRefGoogle Scholar
  104. Patel S, Bhatnagar A, Wear C, Osiro S, Gabriel A, Kimball D, John A, Fields PJ, Tubbs RS, Loukas M (2014) Are pediatric brain tumors on the rise in the USA? Significant incidence and survival findings from the SEER database analysis. Childs Nerv Syst 30:147–154PubMedCrossRefGoogle Scholar
  105. Pearson AD, Craft AW, Ratcliffe JM, Birch JM, Morris-Jones P, Roberts DF (1982) Two families with the Li-Fraumeni cancer family syndrome. J Med Genet 19:362–365PubMedPubMedCentralCrossRefGoogle Scholar
  106. Pelc K, Vincent S, Ruchoux MM, Kiss R, Pochet R, Sariban E, Decaestecker C, Heizmann CW (2002) Calbindin-d(28k): a marker of recurrence for medulloblastomas. Cancer 95:410–419Google Scholar
  107. Perkins SM, Fei W, Mitra N, Shinohara ET (2013) Late causes of death in children treated for CNS malignancies. J Neurooncol 115:79–85PubMedCrossRefGoogle Scholar
  108. Peterson K, Walker RW (1995) Medulloblastoma/primitive neuroectodermal tumor in 45 adults. Neurology 45:440–442PubMedCrossRefGoogle Scholar
  109. Pietsch T, Waha A, Koch A, Kraus J, Albrecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N et al (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of drosophila patched. Cancer Res 57:2085–2088PubMedGoogle Scholar
  110. Pizer BL, Weston CL, Robinson KJ, Ellison DW, Ironside J, Saran F, Lashford LS, Tait D, Lucraft H, Walker DA et al (2006) Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur J Cancer 42:1120–1128PubMedCrossRefGoogle Scholar
  111. Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C et al (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415:436–442PubMedCrossRefGoogle Scholar
  112. Poretti A, Meoded A, Huisman TAGM (2012) Neuroimaging of pediatric posterior fossa tumors including review of the literature. J Magn Reson Imaging 35:32–47PubMedCrossRefGoogle Scholar
  113. Prados MD, Warnick RE, Wara WM, Larson DA, Lamborn K, Wilson CB (1995) Medulloblastoma in adults. Radiat Oncol Biol 32:1145–1152CrossRefGoogle Scholar
  114. Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL et al (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488:106–110PubMedPubMedCentralCrossRefGoogle Scholar
  115. Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845PubMedGoogle Scholar
  116. Rausch T, Jones DTW, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J, Jäger N, Remke M, Shih D, Northcott PA et al (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148:59–71PubMedPubMedCentralCrossRefGoogle Scholar
  117. Reddy AT, Janss AJ, Phillips PC, Weiss HL, Packer RJ (2000) Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88:2189–2193PubMedCrossRefGoogle Scholar
  118. Roberts RO, Lynch CF, Jones MP, Hart MN (1991) Medulloblastoma: a population-based study of 532 cases. J Neuropathol Exp Neurol 50:134–144PubMedCrossRefGoogle Scholar
  119. Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X et al (2012) Novel mutations target distinct subgroups of medulloblastoma. Nature 488:43–48PubMedPubMedCentralCrossRefGoogle Scholar
  120. Rogers L, Pattisapu J, Smith RR, Parker P (1988) Medulloblastoma in association with the Coffin-Siris syndrome. Childs Nerv Syst 4:41–44PubMedGoogle Scholar
  121. Rorke LB (1983) The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1–15PubMedCrossRefGoogle Scholar
  122. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B et al (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178PubMedCrossRefGoogle Scholar
  123. Russo C, Pellarin M, Tingby O, Bollen AW, Lamborn KR, Mohapatra G, Collins VP, Feuerstein BG (1999) Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 86:331–339PubMedCrossRefGoogle Scholar
  124. Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986PubMedCrossRefGoogle Scholar
  125. Scheurlen WG, Schwabe GC, Joos S, Mollenhauer J, Sorensen N, Kuhl J (1998) Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. J Clin Oncol 16:2478–2485PubMedGoogle Scholar
  126. Schild SE, Scheithauer BW, Schomberg PJ, Hook CC, Kelly PJ, Frick L, Robinow JS, Buskirk SJ (1993) Pineal parenchymal tumors. Clinical, pathologic, and therapeutic aspects. Cancer 72:870–880PubMedCrossRefGoogle Scholar
  127. Schild SE, Scheithauer BW, Haddock MG, Wong WW, Lyons MK, Marks LB, Norman MG, Burger PC (1996) Histologically confirmed pineal tumors and other germ cell tumors of the brain. Cancer 78:2564–2571PubMedCrossRefGoogle Scholar
  128. Shuster J, Hart Z, Stimson CW, Brough AJ, Poulik MD (1966) Ataxia telangiectasia with cerebellar tumor. Pediatrics 37:776–786PubMedGoogle Scholar
  129. Smoll NR, Drummond KJ (2012) The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci 19:1541–1544PubMedCrossRefGoogle Scholar
  130. St Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, Kooy HM, Loeffler JS, Tarbell NJ (2004) Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 58:727–734PubMedCrossRefGoogle Scholar
  131. Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, de Sauvage FJ et al (1999) Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. J Cell Sci 112(Pt 23):4437–4448PubMedGoogle Scholar
  132. Tait DM, Thornton-Jones H, Bloom HJ, Lemerle J, Morris-Jones P (1990) Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:464–469PubMedGoogle Scholar
  133. Tarbell NJ, Friedman H, Kepner J, Barnes P, Burger P, Kun LE (2000) Outcome for children with high stage medulloblastoma: results of the pediatric oncology group 9031. Int J Radiat Oncol Biol Phys 48(Suppl 1):179CrossRefGoogle Scholar
  134. Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG, Drake JM, Rutka JT (2000) Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. Am J Hum Genet 66:1403–1406PubMedPubMedCentralCrossRefGoogle Scholar
  135. Taylor RE, Bailey CC, Lucraft H, Robinson K, Weston C, Gilbertson R, Lashford LS (2001) Results of a randomised study of pre-radiation chemotherapy (carboplatin, vincristine, cyclophosphamide, etoposide) with radiotherapy alone in Chang stage M0/M1 medulloblastoma (SIOP/UKCCSG PNET-3) [abstract]. Med Pediatr Oncol 37:191Google Scholar
  136. Taylor MD, Liu L, Raffel C, Hui C-C, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A et al (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310PubMedCrossRefGoogle Scholar
  137. Taylor RE, Bailey CC, Robinson KJ, Weston CL, Walker DA, Ellison D, Ironside J, Pizer BL, Lashford LS (2005) Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy. Eur J Cancer 41:727–734Google Scholar
  138. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho Y-J, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A et al (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472PubMedCrossRefGoogle Scholar
  139. Tekautz TM, Fuller CE, Blaney S, Fouladi M, Broniscer A, Merchant TE, Krasin M, Dalton J, Hale G, Kun LE et al (2005) Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 23:1491–1499PubMedCrossRefGoogle Scholar
  140. Thomas PR, Deutsch M, Kepner JL, Boyett JM, Krischer J, Aronin P, Albright L, Allen JC, Packer RJ, Linggood R et al (2000) Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 18:3004–3011PubMedGoogle Scholar
  141. Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ et al (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931PubMedCrossRefGoogle Scholar
  142. Thorne RN, Pearson AD, Nicoll JA, Coakham HB, Oakhill A, Mott MG, Foreman NK (1994) Decline in incidence of medulloblastoma in children. Cancer 74:3240–3244PubMedCrossRefGoogle Scholar
  143. Timmermann B, Kortmann RD, Kuhl J, Meisner C, Dieckmann K, Pietsch T, Bamberg M (2002) Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20:842–849PubMedCrossRefGoogle Scholar
  144. Vasen HFA, Möslein G, Alonso A, Aretz S, Bernstein I, Bertario L, Blanco I, Bülow S, Burn J, Capella G et al (2008) Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 57:704–713PubMedCrossRefGoogle Scholar
  145. Weil MD, Lamborn K, Edwards MS, Wara WM (1998) Influence of a child’s sex on medulloblastoma outcome. JAMA 279:1474–1476PubMedCrossRefGoogle Scholar
  146. Wetmore C, Eberhart DE, Curran T (2000) The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res 60:2239–2246PubMedGoogle Scholar
  147. Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61:513–516PubMedGoogle Scholar
  148. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G (1997) Mutations in the human homologue of the drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 57:2581–2585PubMedGoogle Scholar
  149. Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP et al (1997) Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res 57:2369–2372PubMedGoogle Scholar
  150. Yauch RL, Dijkgraaf GJP, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T et al (2009) Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574PubMedCrossRefGoogle Scholar
  151. Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H et al (1999) Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17:832–845PubMedGoogle Scholar
  152. Zurawel RH, Chiappa SA, Allen C, Raffel C (1998) Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 58:896–899PubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  • David Raleigh
    • 1
    Email author
  • Corey Raffel
    • 2
  • Daphne A. Haas-Kogan
    • 3
  1. 1.Department of Radiation OncologyUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Department of Neurological SurgeryUniversity of California San Francisco & UCSF Benioff Children’s HospitalSan FranciscoUSA
  3. 3.Department of Radiation OncologyBrigham and Women’s Hospital, Dana-Farber Cancer Institute, & Boston Children’s HospitalBostonUSA

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