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Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification

Nature Clinical Practice Oncology volume 4, pages 295–304 (2007)Cite this article

Abstract

Medulloblastoma is the most common brain malignancy in children and tremendous advances have recently been made in understanding the pathogenesis of this tumor. The Hedgehog and Wingless signaling pathways are implicated in medulloblastoma development, and both pathways were discovered as a result of analyses of genetic syndromes associated with the tumor. Over the past 80 years, considerable progress has been made in the treatment of what was once a fatal disease. The first survival reports followed the introduction of craniospinal irradiation, and yet the success of this modality, which continues to be a central component of treatment regimens for patients older than 3 years, comes at a significant cost. The present challenge in medulloblastoma treatment is to improve upon existing survival rates and to minimize the side effects of treatment. The current tools of clinical risk assessment fail to adequately identify patients older than 3 years who require less radiation and those who require more radiation. Significant effort has been made to improve clinical risk stratification and titration of treatment by analyzing properties of the tumor cells themselves for prognostic significance. These efforts include identifying histopathologic, cytogenetic, and molecular features that may correlate with prognosis.

Key Points

  • Studies of murine models suggest that aberrant granule-cell development might result in a subset of medulloblastoma tumors; recently identified cerebellar neural stem cells might be another potential cell of origin for the tumor

  • Overactive SHH signaling is the best characterized of the molecular aberrations resulting in medulloblastoma, although roles for WNT signaling and other pathways have been described

  • Patients diagnosed with medulloblastoma are stratified for treatment by clinical criteria resulting in a significant number of patients being under treated or over treated with significant consequences

  • Accurate risk assessment is complicated by the variability of tumor behavior, and consequently considerable effort has been made over the past 20 years to assign risk on the basis of a better understanding of the biology of the tumor

  • Biologic parameters investigated for prognostic value include histopathologic, cytogenetic, and molecular features; although promising associations have been demonstrated, none has been used for patient stratification in a clinical trial

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Figure 1: Post-gadolinium MRI of a 4-year-old with medulloblastoma presenting with morning vomiting and ataxia
Figure 2: Granule-cell development and tumorigenesis of medulloblastoma
Figure 3: Sonic hedgehog and Wingless signaling pathways implicated in the formation of medulloblastoma
Figure 4: Postoperative risk stratification and treatment of medulloblastoma
Figure 5: Histopathologic subtypes of medulloblastoma
Figure 6: Chromosomal instability and medulloblastoma prognosis

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Article 14 October 2021

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Acknowledgements

We would like to thank WH Polkinghorn for her support and assistance in preparing the manuscript.

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  1. WR Polkinghorn is a preliminary-year resident in the Department of Pediatrics at Massachusetts General Hospital, and NJ Tarbell is the CC Wang Professor of Radiation Oncology at the Harvard Medical School, and Chief of the Pediatric Radiation Oncology Unit at Massachusetts General Hospital, Boston, MA, USA.,

    William R Polkinghorn & Nancy J Tarbell

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Correspondence to Nancy J Tarbell.

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Polkinghorn, W., Tarbell, N. Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Rev Clin Oncol 4, 295–304 (2007). https://doi.org/10.1038/ncponc0794

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