CHAPTER SEVEN
TUMORS OF THE CENTRAL NERVOUS SYSTEM

MEDULLOBLASTOMA AND OTHER EMBRYONAL TUMORS

Medulloblastoma is the second most frequent BT in children after pilocytic astrocytoma. Most medulloblastomas occur in the first decade of life. There is a second peak in the early 20s. Several genetic tumor syndromes are associated with medulloblastoma. Medulloblastoma is an embryonal tumor of the brain, analogous to Wilms tumor of the kidney and adrenal neuroblastoma. Its embryonal nature is underlined by its high incidence in infants and children and by its undifferentiated, immature appearance, which resembles developing neural tissue.

The external granular layer

The term primitive neuroectodermal tumor (PNET), which has been applied to medulloblastoma and other "small blue cell tumors" of the brain, reflects the embryonal nature and undifferentiated appearance of these tumors and their potential for neuronal and glial diffferentiation. Peripheral PNET (pPNET) refers also to some extracranial embryonal tumors with neural phenotype, related to Ewing’s sarcoma. Medulloblastomas are thought to arise from stem cells located in the subependymal matrix and the external granular layer (EGL) of the cerebellum. This layer is formed from precursor cells that migrate from the rhombic lip (the most lateral and dorsal part of the hindbrain) to the surface of the developing cerebellum where they divide and differentiate. Neurons then move inwards forming the permanent granular layer of the cerebellar cortex. The EGL persists until the beginning of the second year of life. Different stem cells from the subependymal matrix around the IV ventricle give rise to the cerebellar nuclei and Purkinje cells.

Medulloblastoma	Medulloblastoma

Medulloblastomas are tumors of the cerebellum, arising more ffrequently in the midline, especially in the posterior vermis, adjacent to the roof of the fourth ventricle. A few of them arise in the cerebellar hemispheres (see table below). On MRI imaging, they are mostly compact, isointense, and show contrast enhancing. On gross examination, medulloblastomas are soft, pink-red, and well demarcated. They can block the fourth ventricle and the aqueduct, causing hydrocephalus.

Medulloblastoma: "Small blue cell" tumor	Medulloblastoma: Homer-Wright rosettes

Microscopically, classical medulloblastoma (the majority) is a highly cellular tumor composed of diffuse masses of small, undifferentiated oval or round cells. Some medulloblastomas show neuronal, glial and other differentiation. Neuronal differentiation is manifested by neuropil and rosette formation. Rosettes are groups of tumor cells arranged in a circle around a fibrillary center. Infrequent mature neurons may also be found in medulloblastomas. Glial differentiation in some tumors is reflected by GFAP-positive cells. There may also be differentiation along oligodendroglial or ependymal lines. More unusual lines of differentiation result in formation of striated muscle cells (medullomyoblastoma) and melanin-producing cells.

Desmoplastic/nodular medulloblastoma	Anaplastic medulloblastoma

Desmoplasmic/nodular medulloblastoma is a variant of medulloblastoma with a firm consistency and a collagenous stroma. Some desmoplastic medulloblastomas are located superficially and are circumscribed, such that they can be shelled out. In these tumors, the fibroblastic reaction which gives this variant its peculiar texture occurs when the tumor extends into the subarachnoid space. Another variant, large-cell/anaplastic medulloblastoma, shows large anaplastic nuclei with a high rate of mitosis and apoptosis. This variant is has worse prognosis (see table below).

The genesis of MB is driven by genetic pathways that are also involved in the development of the cerebellum. Abnormalities in these pathways convert precursor cells to tumor cells. Two such pathways, the WNT pathway and the SHH pathway, have been defined and others are being studied.

MOLECULAR PATHWAY	WNT	SHH
Genes involved	Beta-Catenin mutation, monosomy 6	PTCH1 deletion, SUFU deletion, n-myc overexpression
Clinical profile	Older patients, good prognosis	Very young patients, poor prognosis
Tumor location	IV ventricle, infiltration of dorsal brainstem	Cerebellar hemispheres
Histology	Classical	Desmoplastic, anaplastic
Cell of origin	Precursors around IV ventricle	EGL
Tumor syndrome	Turcot	Gorlin

Medulloblastoma in CSF	Medulloblastoma growing around the spinal cord

Medulloblastoma is a highly malignant tumor. It infiltrates and destroys brain tissue and tends to seed the subarachnoid space and spread along the walls of the ventricles. The CSF shows high protein and low glucose, and contains tumor cells. CSF cytology is used to monitor the spread of the tumor. Extracranial metastases occur rarely, usually after operation or shunting. Treatment combines resection, to reduce the tumor mass and decompress the fourth ventricle, shunting of the lateral ventricles, radiation of the tumor bed and the entire neuraxis, and intrathecal chemotherapy.

Hydrocephalus in medulloblastoma

Medulloblastoma, cerebellar pilocytic astrocytoma, and other posterior fossa tumors compress the aqueduct and 4th ventricle (or grow in these spaces) causing hydrocephalus. They usually present with symptoms of increased intracranial pressure such as as morning headache, vomiting, and blurred vision. Fundoscopic examination reveals papilledema. Other symptoms include ataxia, strabismus, nystagmus, and stiff neck. The latter is a sign that the tumor is extending through the foramen magnum. Absence of focal deficits compounded by the difficulty of getting a history from a young child may lead to the wrong diagnosis, such as gastroenteritis or aseptic meningitis. A lumbar puncture, in this setting, can induce cerebellar tonsillar herniation ending up in disaster.

Other embryonal tumors are less frequent. Tumors identical to medulloblastoma that arise in the cerebral hemispheres are called supratentorial PNETs. Some cerebellar and extracerebellar embryonal tumors resemble closely adrenal neuroblastoma. These tumors are called cerebral neuroblastomas. One important embryonal trumor is Atypical Teratoid Rhabdoid Tumor, (ATRT), a highly aggressive neoplasm affecting very young children. ATRT arises in the cerebellum and extracerebellar locations and is composed of rhabdoid cells and diverse other neuroectodermel and mesenchymal elements, hence the term teratoid. It has a distinct molecular signature shared by extraneural rhabdoid tumors, i.e., loss of both copies of the INI1 gene, located on 22q11.3. The product of this gene is involved in chromatin remodeling.

Further reading

Gilbertson RJ, Ellison DW. The Origins of Medulloblastoma Subtypes. Annu Rev Pathol Mech Dis 2008;3:341-65. PubMed

Dhall G. Medulloblastoma. J Child Neurol 2009;24:1418-30. PubMed

Updated: April, 2011