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

The current tools of clinical risk assessment for medulloblastoma cannot sufficiently identify patients older than 3 years who require aggressive or less-intensive radiation treatment, but considerable effort has been made to improve clinical risk stratification. The current paradigm for stratifying patients for treatment is discussed and the authors highlight that an understanding of the biology of medulloblastoma will help improve clinical risk stratification that currently under treats and over treats a significant percentage of patients. 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