The cerebellar tumors traditionally designated as medulloblastomas are the most common of the primitive neuroepithelial neoplasms. Noted for a peak incidence in the latter half of life's first decade, these embryonal lesions account for 20% to 25% of all intracranial tumors arising in childhood and for some 40% of those situated in the posterior fossa. Roughly one fourth of afflicted patients are beyond their teenage years and approximately 65% are male. Although most medulloblastomas present in sporadic fashion, they may complicate a variety of heritable multisystem disorders. Chief among the latter is the nevoid basal cell carcinoma—or "Gorlin"—syndrome, an autosomal dominant disorder characterized principally by skeletal anomalies (including craniomegaly), lamellar calcium deposition in the falx cerebri and diaphragma sellae, cutaneous epidermoid cysts and pits on the palms and soles, odontogenic keratocysts, calcifying ovarian fibromas, and multifocal basal cell carcinomas noted for their early age at presentation, involvement of hidden, as well as sun-exposed, skin, melanotic pigmentation, associated calcifications and clinical indolence. Medulloblastomas may also constitute a defining feature of Turcot's syndrome, previously mentioned in relation to diffuse fibrillary astrocytomas and characterized by the occurrence of central neuroepithelial neoplasms in complex with polyposis coli.

The cellular origins of the medulloblastoma are unclear. Certainly, the human cerebellum has not been shown to harbor a cell type having the properties ascribed to the putative "medulloblast" (i.e., the capacity to spawn successive generations of uncommitted offspring able, in turn, to differentiate along both neuronal and glial lines). Enthusiastically championed in this regard are remnants of the fetal external granular cell layer, known to persist after birth, as well as elements of the posterior medullary velum and hypothesized stem cells in the subependymal matrix. Given the morphologic and immunophenotypic heterogeneity of neoplasms to which the designation of medulloblastoma is currently extended, a nonuniform cytogenesis would not be surprising.

At least 75% of childhood medulloblastomas arise in the midline, occupying the cerebellar vermis and expanding to fill the fourth ventricle. Consequently, their presenting manifestations usually reflect intracranial hypertension secondary to CSF blockade and consist most commonly of lethargy, headache, and morning emesis. These are frequently accompanied by truncal ataxia and disturbed gait. The relative proportion of laterally positioned, hemispheric lesions increases with age. In either location, medulloblastomas appear as solid, intensely and homogeneously contrast-enhancing masses on CT or MR imaging. Unlike ependymomas, the major differential diagnostic consideration in the region of the fourth ventricle, they are not prone to conspicuous calcification and hang from the ventricle's roof rather than bulge upward from its floor. Not infrequently, brainstem invasion is apparent on neuroradiologic assessment at diagnosis, and CSF-borne metastases, also common, may be visualized as foci of nodular or diffuse contrast enhancement in the subarachnoid space.
Medulloblastomas have long been separated into "classical" and "desmoplastic" variants, although there would now appear to be no compelling clinical reason to do so. Classical medulloblastomas, at their most primitive, are solid masses of friable, grayish-white tissue composed of diminutive, undifferentiated-appearing cells closely arrayed in packed sheets. Nuclei are often densely hyperchromatic, round or angulated, and invested with little or no definable cytoplasm and are thus prone to deformation or "molding" by their neighbors. A tendency to swirling or a fascicular architecture and fusiform cellular profiles may be encountered, as may nuclei disposed in perivascular pseudorosettes or regimented in compact, rhythmic palisades. Stromal elements are typically scanty, consisting of scattered small blood vessels that only exceptionally exhibit hyperplastic changes and these rarely comparable to the glomeruloid microvascular alterations characteristic of high-grade gliomas. Mitotic figures and the karyorrhectic remains of singly degenerate cells usually abound, but most medulloblastomas exhibit little evidence of zonal coagulative necrosis—a phenomenon seemingly at odds with their high cellular density and proliferative activity. When present, however, such foci may be bordered by tumor cells in a palisading array. Patterns of local spread commonly encountered in neurosurgical material include diffuse permeation of adjoining neural parenchyma along the lesion's perimeter, arresting subpial accumulations of neoplastic cells that invite comparison to a persistent fetal external granular layer, and extension into the subarachnoid compartment with reinvasion of the underlying cerebellar cortex along a broad front or via penetrating perivascular spaces.

The desmoplastic medulloblastoma may occupy a midline, vermal position and present in childhood but is clearly over-represented among laterally situated tumors of adult onset, characteristically lying in the superior aspect of the affected cerebellar hemisphere. Here it may appear at operation as a leptomeningeal-based, lobulated, and sharply delimited mass. A firm consistency reflects the collagenization for which the lesion is named, a process that forces tumor cells into regimented Indian-file and trabecular arrangements, vague whorls, or even storiform arrays. Because a fibroplastic reaction selectively characterizes foci of subarachnoid space invasion by otherwise classic medulloblastomas, the desmoplastic variant's histology has been interpreted as resulting simply from the reaction of mesenchymal leptomeningeal elements to tumoral permeation. Noteworthy, however, is this lesion's tendency to harbor micronodular, reticulin-free zones ("pale islands") that lend to some examples an appearance likened to that of lymph nodes exhibiting follicular hyperplasia. Characterized by reduced cellularity, a rarefied fibrillary matrix, and the frequent emergence of an oligodendroglial-like populace, the pseudofollicle is not merely free of connective tissues but appears, as presently discussed, to represent a locus of progressive neuronal and, possibly, astrocytic differentiation
These bring to mind the primary CNS rhabdoid tumors of the cerebellar region discussed later, but their cytoplasm lacks globular hyaline inclusions and is reactive for neuron-specific enolase and synaptophysin, rather than EMA, on immunocytochemical assay. One of four reported cases contained admixed small cell elements typical of conventional medulloblastoma, whereas another was found on cytogenetic analysis to harbor the latter's most common karyotypic abnormality, isochromosome 17q. The melanotic medulloblastoma is defined by its content of pigmented cells disposed in clusters, tubules, and papillae. These are appropriately stained by conventional histochemical methods for the demonstration of melanin and can be shown to contain melanosomes in varying stages of maturation. Although this lesion bears a certain histologic resemblance to the indolent melanotic neuroectodermal tumors of infancy that arise in the maxillary and epididymal regions, it is a virulent neoplasm prone to early and widespread neuraxis dissemination along CSF pathways.

The medullomyoblastoma is a small cell neuroepithelial neoplasm containing heterologous rhabdomyoblastic elements. This curious neoplasm has been variously interpreted as a medulloblastoma evidencing the extreme plasticity of its multipotential neuroepithelial progenitors; as a tumor of neural crest (ectomesenchymal) derivation; as a composite lesion whose myoblastic constituents arise via the secondary neoplastic induction of vessel-associated, or leptomeningeal, stromal elements; and finally, as a bidermal teratoma. Although otherwise typical medulloblastomas have been reported to contain scattered desmin-immunoreactive tumor cells, supporting their capacity for divergent differentiation along mesenchymal lines, noteworthy is an account of a cystic, tridermal cerebellar teratoma harboring solid regions evidencing medullomyoblastomatous features.Tumors containing both muscular and melanotic elements have been described, as have medulloblastomas exhibiting chondroid differentiation and lipoblastic and adipocytic features.
Although controversy still surrounds the conventional medulloblastoma's cellular origins, most observers grant its capacity to differentiate along both neuronal and glial lines. It is the former option that is exercised most frequently, although maturation to recognizable neurons (ganglion cells) is exceptional. Reliable indices of neuronal differentiation that can be apprehended at the light microscopic level include the radial arrangement of tumor cell nuclei about small tangles of fibrillar material to form Homer Wright rosettes and the emergence of "pale islands," previously described as a particularly arresting feature of some desmoplastic medulloblastomas but occasionally encountered in classical variants. Ultrastructural studies have confirmed that the cells participating in these distinctive formations elaborate neurite-like cytoplasmic processes joined by specialized adhesion plaques and laden with microtubules in parallel, longitudinal array—features restricted in combination to embryonal neurons. Furthermore, both the Homer Wright rosette and pale island constitute loci of concentrated immunoreactivity for neuron-specific enolase and various cytoplasmic antigens of a more restricted neuronal distribution (e.g., the class III beta-tubulin isotype, microtubule-associated protein 2, and synaptophysin). The latter's oligodendroglia-like constituents are actually neuroblastic in nature.

Ultrastructural evidences of more advanced neuronal maturation that include the presence of clear and dense-core secretory vesicles and, in some cases, synapse formation characterize select neuroblastic medulloblastomas that have also been termed cerebellar neuroblastomas. These tumors often contain elements of conventional desmoplastic medulloblastoma but exhibit a more strikingly lobular microarchitecture, their reticulin-free zones having unusually elongated profiles, being particularly rich in fibrillary matrix material and populated by cells arrayed in linear streams. Neoplasms of this sort have been shown to occasionally undergo sequential maturation to highly differentiated ganglion cell tumors. It has been suggested that they constitute a subset of medulloblastomas carrying an especially favorable prognosis.

Only rarely is glial differentiation sufficiently advanced as to be obvious on routine histologic assessment of a medulloblastoma. Immunocytochemical screening for GFAP expression, however, may disclose included astrocytic elements of an unquestionably neoplastic nature, these varying greatly in number and distribution. Noteworthy is the observation that the desmoplastic medulloblastoma often harbors within its pale islands a conspicuous network of GFAP-reactive cells, suggesting that these micronodular zones are organized loci of divergent astroglial, as well as neuronal, outgrowth. The possibility, however, that such cells are reactive astrocytes recruited to these foci is not easily dismissed. It should be pointed out that many medulloblastomas contain scattered GFAP-positive elements that tend to lie near stromal blood vessels and that display the stellate cytoplasmic configurations typical of non-neoplastic astroglia. Their presence should not be construed as evidence of a tumor's ability to differentiate along astrocytic lines. We mention in passing immunocytochemical studies suggesting that medulloblastomas share with retinoblastomas and pineoblastomas the capacity to express photoreceptor-associated proteins such as opsin and the S-antigen. Although interpreted as supporting the unified cytogenesis of these embryonal neuroepithelial neoplasms, the biologic significance of this phenomenon is far from clear.

The reader should note that we have elected to cite only a small sample of the more recent studies detailing the medulloblastoma's immunohistochemical profile and make no attempt to analyze the conflicting data that have emerged from repeated efforts to correlate the expression of neuronal, glial, or photoreceptor-associated antigens with this tumor's clinical behavior. Simply put, neither immunophenotype nor conventional light microscopic evidences of differentiation along specific cell lines have been shown to influence outcome in a consistently predictable fashion, although the neuroblastic medulloblastoma ("cerebellar neuroblastoma") may well emerge as a relatively indolent variant.  Features associated with decreased survival rates include conspicuous mitotic activity, necrosis, a diploid DNA histogram, a high proliferative index, and amplification of the c-myc gene, but none of these are widely applied to management planning, and all medulloblastomas are currently approached as potentially aggressive neoplasms. Among clinical variables, only disseminated disease at diagnosis (i.e., cytologic or neuroradiologic evidence of CSF seeding) has clearly emerged as being of independent (and understandably ominous) prognostic import. The excess mortality noted in infants and very young children may simply reflect the particularly high incidence of neuraxis metastasis at diagnosis in this cohort and the reluctance of treating physicians to expose the immature nervous system to the tumoricidal, but ultimately toxic, doses of radiation required to control this disease. Whether less than total resection prejudices matters against afflicted patients remains uncertain, but most neuro-oncologists and neurosurgeons believe that operative extirpation of all visible tumor should be the immediate goal of therapy if technically feasible.

The prognosis for patients with medulloblastomas has improved dramatically over the last several decades, largely because of recognition that disease control requires, in addition to high-dose irradiation of the posterior fossa contents, inclusion of the entire craniospinal subarachnoid space in the treatment field to address the tendency of these aggressive neoplasms to disseminate via CSF pathways. Five-year survival rates of 70% or better have been achieved by irradiation alone in patients with tumors confined at diagnosis to the posterior fossa and free of the brainstem. The addition of chemotherapy has succeeded in increasing the 5-year actuarial survival of patients with locally advanced disease (including bulbar infiltration) to better than 80%. Unfortunately, however, many children evidence leptomeningeal metastasis on initial evaluation, and the outlook for such patients is not nearly so favorable. Although late relapses are well documented, the great majority of pediatric medulloblastomas conform to Collins' law, which defines the risk period for recurrence of an embryonal childhood neoplasm as equal to the patient's age at diagnosis plus 9 months. Most deaths occur within 2 to 3 years of presentation.

Local (i.e., posterior fossa) recurrence has been the major pattern of treatment failure in the era of whole neuraxis irradiation, but the incidence of systemic metastases may well be on the rise with increasingly effective control of CNS disease. In fact, no neuroepithelial tumor rivals the medulloblastoma in its proclivity for extraneural spread, a complication that may ultimately supervene in more than 10% to 15% of conventionally treated patients. Inasmuch as skeletal deposits, often widespread, account for more than 90% of systemic metastases and occasionally develop early in the medulloblastoma's clinical evolution, neuro-oncologists now routinely include bone marrow examination in the staging evaluation of afflicted patients. Lymph nodes and lungs may also be involved and ventriculoperitoneal shunts inserted to relieve persistent hydrocephalus can grant tumors access to the abdominal cavity. The addition of chemotherapy to the initial treatment regimen may exert some protective effect against distant metastasis and is also being explored as a means of lowering the radiation doses required to effect cure. Disheartening is the price exacted of many survivors by childhood irradiation for this tumor, its complications including growth failure, serious intellectual impairment, behavioral disturbances, and the induction of secondary neoplasms. References to radiation-associated meningiomas, sarcomas, and glioblastomas arising in this setting are provided in the sections dealing with these specific tumor types.

Regarding matters of differential diagnosis, it is the neuronal immunophenotype of many medulloblastomas that merits emphasis. Although relatively few can be shown to elaborate neurofilament protein on assay with commercially available reagents, the large majority at least focally express synaptophysin. In problematic cases, this property may be exploited to exclude from further consideration such potentially confounding lesions as the poorly differentiated fourth ventricular ependymoma, other anaplastic gliomas, and primary cerebellar lymphomas (typified by a B-cell immunoprofile). We have not encountered a solitary cerebellar metastasis as the presenting manifestation of an otherwise occult small cell carcinoma, but this diagnosis may be entertained by the pathologist confronted with an adult-onset medulloblastoma. Although synaptophysin reactivity may be shared by both neoplasms, it has been our experience that the expression of EMA, a conspicuous feature of anaplastic small cell carcinomas, is generally foreign to the medulloblastoma. The latter, it should be noted, may contain cytokeratin-positive elements, although these are usually few and far between.