Medulloblastoma: Tumorigenesis, Current Clinical Paradigm, & Risk
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.

Medulloblastoma is the most common brain malignancy in children, with approximately 540 cases in the US diagnosed each year. The peak incidence is at 7 years of age, with a higher incidence in boys than girls. Classic presenting symptoms include headaches, morning vomiting, and ataxia, and subsequent imaging reveals a mass occupying the posterior fossa (Figure 1). This cerebellar neoplasm typically arises in the midline vermis and often invades and obliterates the fourth ventricle; further invasion through the floor of the ventricle to involve the brainstem can also occur. In a smaller proportion of patients, usually adolescents, the tumor arises within one of the cerebellar hemispheres.


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Post-gadolinium MRI of a 4-year-old with medulloblastoma presenting with morning vomiting and ataxia. Note the well-defined enhancing mass obliterating the fourth ventricle.

The WHO classifies medulloblastoma as one of five embryonal tumors, each of which share a primitive 'embryonal' cellular morphology, and are classified as grade IV owing to their aggressive behavior. Classification of such tumors has been a source of great controversy, with many in the past considering medulloblastoma and supratentorial peripheral neuroectodermal tumors to be indistinguishable other than their anatomic location, and, as such, they were collectively called peripheral neuroectodermal tumors or 'PNETs'. Gene-array data from Pomeroy et al., however, confirm that medulloblastoma constitutes a distinct tumor type with a distinguishable molecular phenotype, and this is consistent with the abundant literature describing a unique developmental origin for the tumor, which is discussed below.

An insidious feature of medulloblastoma is its propensity to metastasize and disseminate through the subarachnoid space, with approximately 30% of children demonstrating cerebrospinal fluid (CSF) metastasis at diagnosis. Indeed, it was this metastatic feature that foiled treatment attempts for several decades following the original description of medulloblastoma in 1925 by Bailey and Cushing. Of Cushing's original series of 61 patients, only one patient survived for 3 years following surgery. It was only following the introduction of intensive craniospinal irradiation (CSI) that significant improvement in survival was reported, with Bloom et al. reporting a 32% survival rate at 5 years in 1969. Today, current treatment protocols that include surgery, CSI, and chemotherapy have achieved 5-year overall survival rates of around 60%, and these survival rates are much higher for standard-risk disease. Of those who do survive, however, nearly all experience debilitating side effects from radiation, including cognitive impairment, psychiatric disorders, endocrine dysfunction, and skeletal growth retardation. Despite recent advances in the delivery of radiation therapy using protons as opposed to photons, the late effects of radiation treatment remain a serious concern.

In the current era of treating medulloblastoma, the challenge is to improve upon existing survival rates, particularly for those with high-risk disease, but also to minimize the life-altering side effects of treatment for those cured of the disease. An individual tumor's aggressiveness and sensitivity to treatment varies considerably, thereby complicating accurate risk assessment and the tailoring of treatment plans that achieve survivability while minimizing side effects. In order to better address the heterogeneity of tumor behavior, considerable effort has been made to assign risk based upon the biology of each tumor. In this article, we review the pathogenesis of medulloblastoma in order to provide context for the discussion of how the tumor biology might influence treatment decisions. We then discuss the current paradigm of stratifying patients for treatment by clinical parameters, and the shortcomings therein. The remainder of the Review concerns efforts to improve upon clinical risk stratification by using biologic variables, including histopathologic, cytogenetic, and molecular prognostic factors.