Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Evidence suggests that medulloblastomas originate in the granular cells of the cerebellum near the roof of the fourth ventricle. The tumors may spread contiguously to the cerebellar peduncle, along the floor of the fourth ventricle, into the cervical spine, or above the tentorium. At the time of diagnosis there is spread via the cerebrospinal fluid (CSF) to other intracranial sites, the spinal cord, or both in 10% to 30% of patients.[1-3] Every patient with newly diagnosed medulloblastoma should be evaluated with diagnostic imaging of the entire neuroaxis and, when possible and safe, lumbar CSF analysis for free-floating tumor cells. Magnetic resonance imaging (MRI) is the method of choice to evaluate for intracranial or spinal cord subarachnoid metastases. To avoid postoperative artifacts, such imaging is best performed preoperatively, but postoperative evaluation is also useful. The entire spine must be imaged in at least two planes, with contiguous magnetic resonance slices performed before and after gadolinium enhancement. The significance of positive CSF cytology in samples obtained within the first 7 to 10 days of diagnosis is unclear, as is the significance of tumor cells in cisternal fluid obtained at the time of surgery. However, CSF tumor cells found 2 to 3 weeks after diagnosis portends a poorer prognosis.[1-3] Extracranial spread of medulloblastoma at the time of diagnosis is infrequent. Although bone scans and bone marrows have been routinely obtained in some older prospective studies, their yield was low and they are primarily now recommended for infants or those with widespread intracranial disease, intraspinal disease or both.[2] CSF shunts placed at the time of surgery have not been shown to increase the risk of leptomeningeal relapse.[2]

Historically, staging has been primarily based on an intraoperative evaluation of both the size and extent of the tumor, coupled with postoperative neuroimaging of the brain and spine and cytological evaluation of CSF. MRI of the brain and spine (often done preoperatively), postoperative MRI of the brain to determine the amount of residual disease, and lumbar CSF analysis are now used to determine staging.[1-3] Surgical impressions—including direct observation of dissemination at the time of diagnosis, extent of residual disease following surgery, and involvement of the brain stem—are incorporated into staging systems.

Patients with disseminated disease at diagnosis are clearly at highest risk for disease relapse.[1-3] Other factors that portend an unfavorable outcome include younger age at diagnosis 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.[2,4,5] Similarly, the presence of brainstem involvement at diagnosis has not been shown to be predictive of outcome.[5,6]

On the basis of neuroradiographic evaluation for disseminated disease, CSF cytological examination, postoperative neuroimaging evaluation for the amount of residual disease, age of the patient, and impression of the surgeon at the time of surgery, patients with medulloblastoma have been historically stratified into the following two risk groups:

• Average risk: children older than 3 years with tumors that are totally resected or near-totally resected (less than 1.5 cm of residual disease) and no metastatic disease.[2]
• High risk: children aged 3 years and younger, or those with metastatic disease [2] and/or subtotal resection (>1.5 cm of residual disease).

The 1.5 cm standard was arbitrarily chosen for evaluation in prospective studies. Metastatic disease includes neuroradiographic evidence of disseminated disease, positive cerebral spinal cytology in lumbar or ventricular fluid obtained more than 7 days postsurgery, or extraneural disease.[2]

A host of biologic parameters that may be predictive of outcome have been identified. These parameters include DNA ploidy, expression of neurotrophin-3 receptor (TrkC), MYCC expression, ERBB 2 expression, chromosomal 17p loss, overexpression of platelet-derived growth factor receptor, p53 expression, survivin expression, B-catenin immunostaining, and multigene expression profiling.[7-22][Level of evidence: 3iiiDi] In addition, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analysis to correlate with outcome. These molecular genetic immunohistochemical and histopathological findings have not been shown to be predictive of outcome in prospective studies and 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.[23-26][Level of evidence: 3iiiDi][27][Level of evidence: 3iiiDi]

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. Gajjar A, Hernan R, Kocak M, et al.: Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22 (6): 984-93, 2004.  [PUBMED Abstract]
    
    
24. 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]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    

Back to Top

< Previous Section  |  Next Section >