Elsevier

The Lancet Neurology

Volume 6, Issue 12, December 2007, Pages 1073-1085
The Lancet Neurology

Review
Medulloblastoma in childhood: new biological advances

https://doi.org/10.1016/S1474-4422(07)70289-2Get rights and content

Summary

Medulloblastoma is the most common embryonal tumour in children. Patients with medulloblastoma are currently staged as average-risk or poor-risk on the basis of clinical findings. With current multimodality therapy, nearly 90% of children with average-risk, non-disseminated medulloblastoma have 5-year event-free survival, and those with high-risk disease have a 60–65% survival rate; however, the outcome for younger children, particularly infants, is worse. Children who survive medulloblastoma are at risk of long-term sequelae related to the neurological effects of the tumour, surgery, or radiotherapy, and the additive effects of chemotherapy. Molecular biology has changed our understanding of medulloblastoma and has implications for diagnostic stratification and treatment. As newer biological agents are translated from the lab to the bedside, clinicians need to understand the fundamental signalling pathways that are targeted during therapy. Greater understanding of the molecular biology of medulloblastoma is needed so that more children can be cured or have an improved quality of life.

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

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.

References (108)

  • MD Prados et al.

    Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumors: results of a Phase II study

    Int J Radiat Oncol Biol Phys

    (1999)
  • RE Taylor et al.

    Outcome for patients with metastatic (M2–3) medulloblastoma treated with SIOP/UKCCSG PNET-3 chemotherapy

    Eur J Cancer

    (2005)
  • RD Kortmann et al.

    Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91

    Int J Radiat Oncol Biol Phys

    (2000)
  • C Carrie et al.

    Impact of targeting deviations on outcome in medulloblastoma: study of the French Society of Pediatric Oncology (SFOP)

    Int J Radiat Oncol Biol Phys

    (1999)
  • S Baruchel et al.

    Safety and pharmacokinetics of temozolomide using a dose-escalation, metronomic schedule in recurrent paediatric brain tumours

    Eur J Cancer

    (2006)
  • CG Eberhart

    In search of the medulloblast: neural stem cells and embryonal brain tumors

    Neurosurg Clin N Am

    (2007)
  • DW Ellison et al.

    What's new in neuro-oncology? Recent advances in medulloblastoma

    Eur J Paediatr Neurol

    (2003)
  • JT Romer et al.

    Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−) p53(−/−) mice

    Cancer Cell

    (2004)
  • CBTRUS, Central Brain Tumor Registry of the United States (2004–2005) Primary Brain Tumors in the United States,...
  • AW Chan et al.

    Adult medulloblastoma: prognostic factors and patterns of relapse

    Neurosurgery

    (2000)
  • SR Hamilton et al.

    The molecular basis of Turcot's syndrome

    N Engl J Med

    (1995)
  • JC Allen et al.

    Medulloblastoma and other primary malignant neuroectodermal tumors of the CNS. The effect of patients' age and extent of disease on prognosis

    J Neurosurg

    (1982)
  • M Deutsch et al.

    The value of myelography in the management of childhood medulloblastoma

    Cancer

    (1980)
  • EC Halperin et al.

    Is there a correlation between duration of presenting symptoms and stage of medulloblastoma at the time of diagnosis?

    Cancer

    (1996)
  • EC Halperin et al.

    Duration of symptoms prior to diagnosis is related inversely to presenting disease stage in children with medulloblastoma

    Cancer

    (2001)
  • T Tsuchida et al.

    CT findings of medulloblastoma

    Childs Brain

    (1984)
  • M Nelson et al.

    Paediatric medulloblastoma: atypical CT features at presentation in the SIOP II trial

    Neuroradiology

    (1991)
  • R Kumar et al.

    Uncommon presentation of medulloblastoma

    Childs Nerv Syst

    (2001)
  • SM Malheiros et al.

    MRI of medulloblastoma in adults

    Neuroradiology

    (2003)
  • U Buhring et al.

    MRI features of primary, secondary and metastatic medulloblastoma

    Eur Radiol

    (2002)
  • A Moreno-Torres et al.

    Taurine detection by proton magnetic resonance spectroscopy in medulloblastoma: contribution to non-invasive differential diagnosis with cerebellar astrocytoma

    Neurosurgery

    (2004)
  • S Gururangan et al.

    [18F]fluorodeoxyglucose-positron emission tomography in patients with medulloblastoma

    Neurosurgery

    (2004)
  • S Barai et al.

    Evaluation of single photon emission computerised tomography (SPECT) using Tc99m-tetrofosmin as a diagnostic modality for recurrent posterior fossa tumours

    J Postgrad Med

    (2003)
  • M Smits et al.

    Incorporating functional mr imaging into diffusion tensor tractography in the preoperative assessment of the corticospinal tract in patients with brain tumors

    Am J Neuroradiol

    (2007)
  • DJ Mabbott et al.

    Diffusion tensor imaging of white matter after cranial radiation in children for medulloblastoma: correlation with IQ

    Neuro Oncol

    (2006)
  • D Qiu et al.

    Diffusion tensor magnetic resonance imaging finding of discrepant fractional anisotropy between the frontal and parietal lobes after whole-brain irradiation in childhood medulloblastoma survivors: reflection of regional white matter radiosensitivity?

    Int J Radiat Oncol Biol Phys

    (2007)
  • F Giangaspero et al.

    Medulloblastoma

  • CM Coffin et al.

    A clinicopathologic and immunohistochemical analysis of 53 cases of medulloblastoma with emphasis on synaptophysin expression

    Mod Pathol

    (1990)
  • PC Burger et al.

    Differentiation in the medulloblastoma. A histological and immunohistochemical study

    Acta Neuropathol (Berl)

    (1987)
  • PC Burger et al.

    Tumors of the Central Nervous System. Atlas of Tumor Pathology

    (1994)
  • CD Katsetos et al.

    Cerebellar desmoplastic medulloblastomas. A further immunohistochemical characterization of the reticulin-free pale islands

    Arch Pathol Lab Med

    (1989)
  • F Giangaspero et al.

    “Desmoplastic” versus “classic” medulloblastoma: comparison of DNA content, histopathology and differentiation

    Virchows Arch A Pathol Anat Histopathol

    (1991)
  • F Giangaspero et al.

    Large-cell medulloblastomas. A distinct variant with highly aggressive behavior

    Am J Surg Pathol

    (1992)
  • HG Brown et al.

    “Large cell/anaplastic” medulloblastomas: a pediatric oncology group study

    J Neuropathol Exp Neurol

    (2000)
  • A Gajjar et al.

    Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors

    J Clin Oncol

    (1999)
  • RJ Packer et al.

    Medulloblastoma: present concepts of stratification into risk groups

    Pediatr Neurosurg

    (2003)
  • A Korshunov et al.

    Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c-myc expression

    J Neurooncol

    (2002)
  • N Aldosari 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

    (2002)
  • MA Grotzer et al.

    MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma

    Clin Cancer Res

    (2001)
  • HS Min et al.

    Medulloblastoma: histopathologic and molecular markers of anaplasia and biologic behavior

    Acta Neuropathol

    (2006)
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