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%. 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.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.[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.
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.
- 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. These findings add an additional layer of complexity to the biologic understanding of medulloblastoma.References
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- 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]
- 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]
- 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]
- 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]
- 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]
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