Chapter 7

TUMORS OF THE CENTRAL NERVOUS SYSTEM

MEDULLOBLASTOMA AND OTHER EMBRYONAL TUMORS


The external granular layer

Cerebellum at 30 weeks gestation. The external graular layer.

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 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. Midline cerebellar tumor. Reproduced with the permission of the Department of Radiology of Akron Children's Hospital.


Medulloblastoma

Medulloblastoma. Midline cerebellar tumor and hydrocephalus. Reproduced with the permission of the Department of Radiology of Akron Children's Hospital.

Medulloblastomas are tumors of the cerebellum, arising more frequently 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. Diffuse masses of small blue cells, similar to other embryonal tumors.


Medulloblastoma: Homer-Wright rosettes

Medulloblastoma. Homer-Wright rosettes (groups of tumor cells arranged in a circle around a fibrillary center). Similar rosettes are seen in adrenal neuroblastoma.

Four histological varians of medulloblatoma are recognized: classic, nodular-desmoplastic, large cell-anaplastic, and medulloblastoma with extensive nodularity. Classic 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

Desmoplastic-nodular medulloblastoma. Sparsely cellular nodules with neuropil-like stroma surrounded by desmoplastic tumor.


Desmoplastic/nodular medulloblastoma

Desmoplastic/nodular medulloblatoma, reticulin stain. Reticulin fibers permeate the tumor but are absent in the center of the nodule.


Anaplastic medulloblastoma.

Desmoplasmic/nodular medulloblastoma is called nodular because of its architecture and desmoplastic because it is permeated by fine collagen (reticulin) fibers that give it a firm consistency. The centers of the nodules (pale islands) are reticulin-free. They are less cellular than the surrounding densely packed small cells and are composed of larger cells with neuronal differentiation. The fibroblastic (desmoplastic) reaction occurs when the tumor extends into the subarachnoid space. Some of these tumors are located superficially and are circumscribed and easier to resect. Desmoplasmic/nodular medullablastoma is more common in infants and may have a better prognosis than the classic form. Medulloblastoma with extensive nodularity may be difficult to distinguish from nodular/desmoplastic. It occurs also in infants and has a good prognosis. Another variant, large-cell/anaplastic medulloblastoma (LCA), shows large anaplastic nuclei with a high rate of mitosis and apoptosis. This variant has poor prognosis. Distinct molecular signatures correspond to some of these clinicopathological phenotypes (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 stem cells to tumor cells. Four molecular subtypes of medulloblastoma have been described. Two of these subtypes, involving the WNT and the SHH pathway, have been defined in greater detail, and the other two are less well understood. The main features of these are partially listed in the table below. These groups are not homogeneous in their clinical and pathological phenotypes. In the future, molecular characterization may lead to personalized therapy for these tumors.

MOLECULAR PATHWAY WNT SHH Group 3 Group 4
Genes involved Beta-Catenin mutation,
monosomy 6
PTCH1 deletion, SUFU deletion, MYCN overexpression MYC amplification Isochromosome 17q
Clinical profile Older children and adults, good prognosis Infants, children and adults, good to intermediate prognosis Infants and children, poor prognosis Older children and adults, the most common form, intermediate prognosis
Tumor location IV ventricle, infiltration of dorsal brainstem Cerebellar hemispheres Cerebellum NOS Cerebellum NOS
Histology Classic Desmoplastic, anaplastic Classic, LCA Classic, LCA
Cell of origin Precursors around the IV ventricle EGL NA NA
Tumor syndrome Turcot Gorlin None None

Medulloblastoma in CSF

Medulloblastoma. Cluster of tumor cells in the CSF.


Medulloblastoma growing around the spinal cord

Medulloblastoma. A thick layer of tumor around the spinal cord, matting together the roots of the cauda equina (right).

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. Leptomeningeal dissemination occurs more frequently in medullablastoma than any other BT and is particularly common in Group 3 and Group 4 medullablatoma. 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

Hydrocephalus and transependymal edema in a child with a posterior fossa tumor. T2 MRI. Reproduced with the permission of the Department of Radiology of Akron Children's Hospital.

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.


ATRT MRI

ATRT MRI. A large posterior fossa mass. Reproduced with the permission of the Department of Radiology of Akron Children's Hospital.


ATRT

ATRT. A poorly differentiated embryonal tumor.


ATRT-INI1

ATRT-INI1 immunnostain. No nuclear staining of tumor cells and normal staining of vascular cells in the tumor.


ATRT-FISH

ATRT. Chromosome 22 FISH. A normal cell (left) has two 9 chromosome signals (red) and two 22 signal (green). The ATRT cell (right) has only one chromosome 22.

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. On immunohistochemical staining, INI1 is absent in tumor nuclei and present in non-neoplastic nuclei. Loss of one copy of INI1 in the germline results in the Rhabdoid Tumor Predisposition Syndrome, in which patients develop renal and extrarenal rhabdoid tumors, including ATRTs, and choroid plexus tumors.

Further Reading


Updated: July, 2013

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