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Childhood Central Nervous System Embryonal Tumors Treatment (PDQ®)

Health Professional Version
Last Modified: 12/14/2011

General Information

Diagnostic Evaluation
Predictors of Outcome

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. The PDQ childhood brain tumor treatment summaries are organized primarily according to the 2000 World Health Organization classification of nervous system tumors.[1]

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[2] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer 1 for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors 2 for information about the general classification of childhood brain and spinal cord tumors.

Diagnostic Evaluation

Every patient with newly diagnosed medulloblastoma should be evaluated with diagnostic imaging of the entire neuraxis and, when possible and safe, lumbar cerebrospinal fluid analysis.

Predictors of Outcome

Patients with disseminated disease at diagnosis are clearly at highest risk for disease relapse.[3-5] Other factors that portend an unfavorable outcome include younger age at diagnosis (in the absence of extensive nodularity) and possibly, a subtotal resection; however, the amount of residual disease after surgery has not been found to be a robust predictor of outcome, especially when chemotherapy was added to radiation therapy as part of postoperative treatment.[6,7] Similarly, the presence of brain stem involvement at diagnosis has not been shown to be predictive of outcome.[7,8]

In addition, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[9,10] These molecular genetic immunohistochemical and histopathologic findings have not been shown to be predictive of outcome in prospective studies and with the exception of anaplasia/large cell variant, are not yet incorporated into stratification schema. However, it is likely that one or more of these biologic findings may yet be utilized, possibly in combination with factors such as extent of dissemination at the time of diagnosis, age of the patient, and amount of residual disease after surgery to better categorize patients with medulloblastoma into risk subgroups.[11-16]

A host of biologic parameters that may be predictive of outcome have been identified. These parameters include the following:

  • DNA ploidy.[17-20]
  • TrkC (neurotrophin-3 receptor) expression.[21,22]
  • MYC expression.[23-26]
  • ERBB 2 expression.[22,27]
  • Chromosomal 17p loss.[24,28]
  • Overexpression of platelet-derived growth factor receptor.[29]
  • p53 expression.[22,30,31]
  • Chromosome 6q gains and losses.[32]
  • Survivin expression.[33]
  • Beta-catenin immunostaining.[34]
  • mRNA expression profiling.[35]
  • Multigene expression profiling.[36]

Among these genetic alterations, the most robust predictors of outcome appear to be the following:

  1. Amplification of MYC family oncogenes (approximately 5%–10% of cases) and TP53 mutations, which confers the worst prognosis.
  2. Loss of chromosome 6q associated with activated Wnt pathway in conjunction with mutations of beta-catenin in tumors typically found in older children, which confers the best prognosis.

Integrated genomics identifies multiple medulloblastoma subtypes with distinct genetic profiles, pathway signatures, and clinicopathological features. Interestingly, in a recent study of adult medulloblastomas, MYC oncogene amplifications were rarely observed and tumors with 6q deletion and nuclear beta-catenin activation did not share the excellent prognosis seen with pediatric medulloblastomas.[11-14,30,32,34,37-39]

Furthermore, DNA sequencing studies have demonstrated fewer mutations in medulloblastoma than in adult carcinomas and a positive correlation between patient age and the number of mutations found. The relatively low numbers of mutations suggest that fewer driver mutations are required for medulloblastoma tumorigenesis. In addition, genome-wide association studies have identified mutated genes previously not implicated in medulloblastoma pathogenesis, such as the tumor suppressors MLL2 and MLL3, from the family of genes affecting histone methylation.[40] These findings add an additional layer of complexity to the biologic understanding of medulloblastoma.

References

  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. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.  [PUBMED Abstract]

  3. Fouladi M, Gajjar A, Boyett JM, et al.: Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 17 (10): 3234-7, 1999.  [PUBMED Abstract]

  4. Zeltzer PM, Boyett JM, Finlay JL, et al.: 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 (3): 832-45, 1999.  [PUBMED Abstract]

  5. Yao MS, Mehta MP, Boyett JM, et al.: The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III study in a high-risk patient population. Int J Radiat Oncol Biol Phys 38 (3): 469-76, 1997.  [PUBMED Abstract]

  6. Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 38 (2): 265-71, 1996.  [PUBMED Abstract]

  7. Packer RJ, Siegel KR, Sutton LN, et al.: Efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma: a preliminary report. Ann Neurol 24 (4): 503-8, 1988.  [PUBMED Abstract]

  8. Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003.  [PUBMED Abstract]

  9. 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]

  10. Rutkowski S, von Hoff K, Emser A, et al.: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28 (33): 4961-8, 2010.  [PUBMED Abstract]

  11. 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]

  12. 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]

  13. 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]

  14. 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]

  15. Korshunov A, Remke M, Werft W, et al.: Adult and pediatric medulloblastomas are genetically distinct and require different algorithms for molecular risk stratification. J Clin Oncol 28 (18): 3054-60, 2010.  [PUBMED Abstract]

  16. von Hoff K, Hartmann W, von Bueren AO, et al.: Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer 54 (3): 369-76, 2010.  [PUBMED Abstract]

  17. Zerbini C, Gelber RD, Weinberg D, et al.: Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol 11 (4): 616-22, 1993.  [PUBMED Abstract]

  18. Schofield DE, Yunis EJ, Geyer JR, et al.: DNA content and other prognostic features in childhood medulloblastoma. Proposal of a scoring system. Cancer 69 (5): 1307-14, 1992.  [PUBMED Abstract]

  19. Tomita T, Yasue M, Engelhard HH, et al.: Flow cytometric DNA analysis of medulloblastoma. Prognostic implication of aneuploidy. Cancer 61 (4): 744-9, 1988.  [PUBMED Abstract]

  20. Gajjar AJ, Heideman RL, Douglass EC, et al.: Relation of tumor-cell ploidy to survival in children with medulloblastoma. J Clin Oncol 11 (11): 2211-7, 1993.  [PUBMED Abstract]

  21. Grotzer MA, Janss AJ, Fung K, et al.: TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18 (5): 1027-35, 2000.  [PUBMED Abstract]

  22. Ray A, Ho M, Ma J, et al.: A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10 (22): 7613-20, 2004.  [PUBMED Abstract]

  23. Grotzer MA, Hogarty MD, Janss AJ, et al.: MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7 (8): 2425-33, 2001.  [PUBMED Abstract]

  24. Lamont JM, McManamy CS, Pearson AD, et al.: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10 (16): 5482-93, 2004.  [PUBMED Abstract]

  25. Aldosari N, Bigner SH, Burger PC, et al.: MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group. Arch Pathol Lab Med 126 (5): 540-4, 2002.  [PUBMED Abstract]

  26. Herms J, Neidt I, Lüscher B, et al.: C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer 89 (5): 395-402, 2000.  [PUBMED Abstract]

  27. Gilbertson RJ, Perry RH, Kelly PJ, et al.: Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 57 (15): 3272-80, 1997.  [PUBMED Abstract]

  28. Pan E, Pellarin M, Holmes E, et al.: Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 11 (13): 4733-40, 2005.  [PUBMED Abstract]

  29. 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 29 (2): 143-52, 2001.  [PUBMED Abstract]

  30. 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]

  31. Pfaff E, Remke M, Sturm D, et al.: TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma. J Clin Oncol 28 (35): 5188-96, 2010.  [PUBMED Abstract]

  32. 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]

  33. Pizem J, Cört A, Zadravec-Zaletel L, et al.: Survivin is a negative prognostic marker in medulloblastoma. Neuropathol Appl Neurobiol 31 (4): 422-8, 2005.  [PUBMED Abstract]

  34. 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]

  35. Grotzer MA, von Hoff K, von Bueren AO, et al.: Which clinical and biological tumor markers proved predictive in the prospective multicenter trial HIT'91--implications for investigating childhood medulloblastoma. Klin Padiatr 219 (6): 312-7, 2007 Nov-Dec.  [PUBMED Abstract]

  36. Fernandez-Teijeiro A, Betensky RA, Sturla LM, et al.: Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas. J Clin Oncol 22 (6): 994-8, 2004.  [PUBMED Abstract]

  37. 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]

  38. 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]

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

  40. Parsons DW, Li M, Zhang X, et al.: The genetic landscape of the childhood cancer medulloblastoma. Science 331 (6016): 435-9, 2011.  [PUBMED Abstract]



Table of Links

1http://www.cancer.gov/cancertopics/pdq/treatment/lateeffects/HealthProfessional
2http://www.cancer.gov/cancertopics/pdq/treatment/childbrain/healthprofessional