General Information

Diagnostic Evaluation
Predictors of Outcome

The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization classification of nervous system tumors.[1,2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.

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%.[3] 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 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.

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.

Patients with disseminated disease at diagnosis are clearly at highest risk for disease relapse.[4-6] 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.[7,8] Similarly, the presence of brain stem involvement at diagnosis has not been shown to be predictive of outcome.[8,9]

In addition, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[10,11] 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. A host of biological tumor cell characteristics have also been associated with prognosis, including DNA ploidy,[12,13] MYC expression and amplification,[14-16] chromosomal 17p loss,[17-19] p53 mutation status,[20,21] and chromosome 6q status.[22]

As a result of integrated molecular characterization of medulloblastoma, multiple medulloblastoma subtypes with distinct genetic profiles, pathway signatures, and clinicopathological features have been identified.[20,22-30] These subtypes themselves have prognostic associations, and it is clear that predictors of outcome can best be understood within the context of individual biological subtypes. The following four core subtypes have been identified:[31-33]

• One subset shows a WNT signaling gene expression signature and occurs in cases with monosomy 6 and beta-catenin nuclear staining. The WNT subset is primarily observed in older children and adolescents and does not show a male predominance. It is associated with a very good outcome.

• A second subset is characterized by sonic hedgehog (SHH) pathway signaling and arises most commonly, but not exclusively, in patients with desmoplastic tumors. The SHH subset shows a bimodal age distribution and is observed primarily in young children as well as in older adolescents and adults. Among young children, outcome is generally favorable, while for older patients there is an intermediate prognosis. Prognosis for patients with SHH medulloblastoma appears to be negatively affected by additional factors such as chromosome 17p loss, chromosome 3q gain, and the finding of large cell/anaplastic histology.[31]

• Two other subsets (termed Groups 3 and 4) can be defined by gene expression profiling and are enriched for the presence of isochromosome 17q (i17q). These subsets show a strong male predominance, include cases with classic as well as large cell/anaplastic histology, and include most medulloblastoma cases that present with metastatic disease. Group 3 patients have the least favorable outcome among the molecularly defined medulloblastoma subtypes and include most medulloblastoma cases with MYC amplification. Prognosis for Group 4 patients is intermediate and is affected by additional factors such as the presence of metastatic disease and chromosome 17p loss.

Optimal ways of identifying the four core medulloblastoma subtypes for clinical use is not clear, and both immunohistochemical methods and methods based on gene expression analysis are under development and evaluation.[34,35]

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 sequencing 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.[36] These findings add an additional layer of complexity to the biologic understanding of medulloblastoma.

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. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. McCabe MG, Bäcklund LM, Leong HS, et al.: Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma. Neuro Oncol 13 (4): 376-83, 2011.  [PUBMED Abstract]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    
28. 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]
    
    
29. 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]
    
    
30. Northcott PA, Korshunov A, Witt H, et al.: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29 (11): 1408-14, 2011.  [PUBMED Abstract]
    
    
31. 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]
    
    
32. 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]
    
    
33. Taylor MD, Northcott PA, Korshunov A, et al.: Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123 (4): 465-72, 2012.  [PUBMED Abstract]
    
    
34. 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]
    
    
35. 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]
    
    
36. Parsons DW, Li M, Zhang X, et al.: The genetic landscape of the childhood cancer medulloblastoma. Science 331 (6016): 435-9, 2011.  [PUBMED Abstract]