References for this Review were identified through searches of PubMed from 1966 until August, 2007, with the terms “medulloblastoma”, “pediatric”, and “brain tumour”. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.
ReviewMedulloblastoma in childhood: new biological advances
Introduction
Medulloblastoma is the most common brain tumour in children. The tumour is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum, although there is debate about the exact cellular origin. Patients are currently divided into stratification groups on the basis of age, the degree of resection, and disease dissemination. Standard treatment includes surgery, chemotherapy, and depending on the age of the patient, radiation therapy; however, greater understanding of the molecular signals in the development and proliferation of medulloblastoma will probably change the stratification and management of the disease. This Review will focus on the current means of diagnosis and treatment, which have led to improved survival rates but a disappointingly high incidence of sequelae. We also provide an overview of the molecular biology of medulloblastoma and its potential to dramatically alter risk stratification and future therapy. Advances in understanding the signalling pathways in neuro-oncogenesis will, hopefully, lead to more effective and less toxic targeted therapy.
Section snippets
Epidemiology
The Central Brain Tumor Registry of the United States reports that the incidence of medulloblastoma in patients up to 19 years old ranges from 0·48 (girls) to 0·75 (boys) per 100 000 patient-years and accounts for 16% of all paediatric brain tumours; 40% of all cerebellar tumours in childhood are medulloblastoma. Medulloblastoma occurs bimodally with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10–15% of medulloblastomas are diagnosed in infancy.1 Although
Clinical presentation
Patients with medulloblastoma frequently present with signs of intracranial pressure related to obstructive hydrocephalus due to tumour growth and compression of the fourth ventricle. Preceding signs of intracranial pressure include an increase in head circumference in children whose fontanelles are still open, and early morning headache with vomiting, irritability, and lethargy. Because many paediatric medulloblastomas arise in the cerebellar midline, axial instability can be seen, which
Neuroimaging
CT is usually the first-line neuroimaging modality for patients with posterior fossa tumours because of its availability in an emergency setting. A typical feature of medulloblastoma seen with CT is a midline, homogeneous, contrast-enhancing cerebellar vermian mass.9 However, this radiographic feature is seen in only 30–55% of patients. Atypical CT features include cystic changes, hypodense non-enhancing lesions, and calcifications.10, 11
MRI has helped with the diagnosis of childhood
Staging and risk stratification
Staging and subsequent risk stratification are crucial in the management of medulloblastoma. Current staging classification requires analysis of the CSF and MRI of the brain and entire spine with gadolinium. CSF from the lumbar region is preferred because it is more sensitive than ventricular fluid for detecting disseminated disease.30 CSF should be obtained from the lumbar region 2 weeks postoperatively to avoid the false-positive cytology from the initial resection. Assessment of the CSF for
Surgery
Surgical resection of medulloblastoma is a fundamental part of treatment that has led to improved survival in randomised trials, particularly in children with localised disease.39, 40 Depending on the location and extent of the tumour, a ventricular shunt or third ventriculostomy might be needed emergently before resection to relieve increased intracranial pressure secondary to obstruction at the level of the foramen of Luschka, foramen of Magendie, or aqueduct of Sylvius. A sample of CSF to
Diagnosis and management of disease relapse
Relapses of medulloblastoma occur, and in patients who are treated with both radiotherapy and chemotherapy more than half of relapses have a component of disseminated disease.49, 60 Relapses occur earlier in children; nearly 75% of relapses in children are seen within 2 years. The median time to recurrence for adults is 26 months, and nearly a third of relapses occur more than 5 years after initial therapy.2
Relapse is most commonly diagnosed by neuroimaging; occasionally, clinical progression
Long-term treatment sequellae
Because multimodal therapies improve survival, a host of long-term neurological effects are being reported. In many cases, the location and extent of the metastases can contribute to the deleterious effects, but, inevitably, treatment with radiation and chemotherapy also have long-term consequences. Neurocognitive difficulties are one of the most pervasive of all long-term effects and occur across all age groups.72 Despite receiving reduced doses of intracranial radiation, children younger than
Controversies in the management of medulloblastoma
Although many of the developments in the management of children with medulloblastoma are the result of well performed, prospective multi-institutional randomised trials, areas of controversy remain. One of the most pressing is how best to incorporate the new biological understanding of the disease into everyday management. Compelling evidence exists that certain biological parameters are correlated with disease control; however, there is no consensus on which parameters or combination of
Molecular biology of medulloblastoma
During the past decade, our understanding of the molecular basis of medulloblastoma formation and progression has greatly improved. Research into medulloblastoma has focused on two areas. The first is understanding the pathogenesis. Medulloblastoma, although not conclusively established, has been postulated to arise from the two germinomal zones of the cerebellum: the ventricular zone, which contains multipotentional stem progenitors, for classic and midline tumours, and the external granular
Future directions
Although much progress has been made in the diagnosis and treatment of childhood medulloblastoma, much work still needs to be done. Probably the most useful and exciting progress has been in understanding and classifying the molecular biology of medulloblastoma. As the mechanisms of signal transduction in neuro-oncogenesis are elucidated, more specifically targeted therapies can be developed. Furthermore, a greater understanding of the genetics of medulloblastoma will enable more sophisticated
Search strategy and selection criteria
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