The origin of this tumor remained in doubt for a long time and is still not entirely settled, but some recent insights are notable. Bailey and Cushing introduced the name medulloblastoma, although medulloblasts have never been identified in the fetal or adult human brain; nevertheless the term has been retained for no reason other than its familiarity. The current view of the tumor is that it originates from pluripotential stem cells that can differentiate into neuronal or glial elements and have been prevented from maturing to their normal growth-arrested state. For this reason, newer (WHO) classifications include it with the primitive neuroectodermal tumors (PNETs).
The tumor may differentiate unior pluripotentially, varying from case to case, and accounting for the recognized histologic variants, ranging from an undifferentiated medulloblastoma and extending to medulloblastoma with glial, neuronal, or even myoblastic components. Rosette formation, highly characteristic of the below-described neuroblastoma is seen in half of medulloblastomas. Certain molecular, genetic similarities relate the medulloblastoma to retinoblastomas and pineal cell tumors, and, rarely, to autosomal dominant diseases such as nevoid basal cell carcinoma. Chromosomal studies of medulloblastomas reveal a deletion on chromosome 17 distal to the p53 region. Schmidek proposed that this accounts for the neoplastic transformation of cerebellar stem cells at various stages of their differentiation into tumor cells. It is also notable that medulloblastomas are encountered in Gorlin syndrome, caused by mutations in the gene encoding “patched,” the receptor for sonic hedgehog ligand, and in Turcot syndrome, as a consequence of mutations in DNA repair genes (Louis et al). Gene expression profiling has given evidence that amplification or overexpression of the transcription factor MYCN (N-MYC) is associated with a poorer prognosis (as it is in neuroblastoma). Aberrations in the copy number of chromosomes 6q and 17q also appear to have predictive value for the behavior of the tumor. Maris has reviewed the complex genetic aspects of the tumor and has introduced the possibility that a combination of common variants may be a risk factor for its development. Another line of research has tentatively implicated the JC virus, the same agent that causes progressive multifocal leukoencephalopathy (see Chap. 32). Genomic sequences from this virus have been found in up to 72 percent of tumors in some series (Khalili et al), and an experimental transgenic model in which the JC protein is expressed is characterized by a cerebellar tumor that resembles the medulloblastoma.
The majority of affected patients are children 4 to 8 years of age, and males outnumber females 3:2 or 3:1 in most reported series. As a rule, symptoms have been present for 1 to 5 months before the diagnosis is made. The clinical picture is fairly distinctive and derives from secondary hydrocephalus and raised intracranial pressure as a result of blockage of the fourth ventricle. Typically, the child becomes listless, vomits repeatedly, and has a morning headache. The first diagnosis that suggests itself may be gastrointestinal disease or abdominal migraine. Soon, however, a stumbling gait, frequent falls, and diplopia as well as strabismus lead to a neurologic examination and the discovery of papilledema or sixth nerve palsies. However, when the tumor is located in the lateral cerebellum or in the cerebrum, as it usually is in adults, signs of raised intracranial pressure may be delayed. Dizziness (positional) and nystagmus are then frequent. A small proportion of children have a slight sensory loss on one side of the face and a mild facial weakness. Head tilt, the occiput being tilted back and away from the side of the tumor, indicates a developing cerebellar-foraminal herniation. Rarely, signs of spinal root and subarachnoid metastases precede cerebellar signs.