Tumors of the Nervous System

General principles of neoplasia are applicable to CNS tumors

The neoplastic cell must have a growth advantage within the microenvironment. Therefore, they tend to phenotypically resemble cells normally present within the CNS.

The chance of transformational events depends on the number of replicating cells "at risk".

Once transformation is established, mutational events leading to growth advantage correlate with decreased cellular differentiation and more aggressive behavior.

Cellular Origin of CNS Tumors

(1) Neurons - Differentiated neurons don’t normally divide so tumors (ganglion cell tumors) are rare and benign.

Exception: because the external granular cell neurons of the cerebellum are actively replicating and migrating well into post-natal life, tumors derived from these primitive neurons (medulloblastomas) are among the most common childhood tumors. Their primitive phenotype gives rise to rapidly dividing poorly differentiated discohesive cells with a high propensity for leptomeningeal (pia and arachnoid) dissemination. These growth characteristics also, however, render the neoplastic cells highly susceptible to therapy.

(2) Glia

Astrocytes are main replicating cell type within brain so astrocytomas are most common CNS tumors, and the only ones that have grading system of malignancy:

Grade I - Least aggressive; cells closely resemble normal astrocytes

Grade II - Similar to grade I but with some pleomorphism and vascular changes

Grade III - Anaplastic Astrocytoma. Exhibits more marked pleomorphism, prominent mitoses, hyperplastic vasculature with endothelial hyperplasia and some tissue necrosis.

Grade IV - Glioblastoma Multiforme is the most common primary brain cancer of adults. Characterized by rapid growth resulting in necrosis and vascular endothelial proliferation (maybe related to production of PDGF-A by the neoplastic astrocytes).

Adult’s astrocytic tumors Þ majority supratentorial

Kid’s astrocytic tumors Þ majority infratentorial because cerebellum continues differentiating in childhood.

However, even though these are metastatic, the unique ‘Bergmann glia’ of the region providing the scaffolding of granular neuron migration are biologically different from other astrocytes and give rise to well circumscribed, benign, usually easily resected tumors with excellent long-term survivals.

Oligodendrocytes do not replicate very much and consequently comprise a relatively small proportion of CNS tumors. May look a lot like astrocytic tumors, but tend to behave in a slightly more benign fashion.

Ependymal cells also don’t replicate much once brain development is completed, and therefore are predominantly tumors of the childhood posterior fossa.

(3) Leptomeninges - Meningiomas are the most common extraparenchymal neoplasms affecting the CNS (15-20% of intracranial tumors). Predominantly occur in middle to late adult life, and tend to involve the cerebral convexity, parasagittal region, sphenoid ridge or spinal cord. Linked to a variety of environmental and genetic factors including trauma, radiation, DNA tumor viruses, and bilateral acoustic neurofibromatosis, and are associated with a loss of information on chromosome 22. About 10% of meningiomas are "aggressive" or "malignant", which in this setting primarily indicates more rapid recurrence; extraneural dissemination is rare.

(4) Schwann cells - "glia" of PNS, including CN III-XI, as well as spinal nerve roots. As such, they affect CNS by compression resulting from growth within extraparenchymal, intradural compartment. They show a remarkable tendency to arise from sensory nerves, especially the vestibular nerve in the cerebellopontine angle. These tumors used to be called "acoustic neuromas" but are now correctly referred to as Vestibular Schwannomas. Grow eccentrically from surface of nerve root. Current surgical treatment attempts to preserve nerve function as much as possible, as recurrence and malignant degeneration are rare.

(5) Epithelial cells - do not occur normally within CNS, so must metastasize from other sites, usually lung or breast. As non-welcome residents, they tend to be well circumscribed. Solitary metastases occur in approximately ½ of cases. In addition, about ½ patients presenting with brain metastasis have no prior diagnosis of systemic cancer.

Pathological Diagnostic Aids

*Intermediate Filament*	Neural Tumors	Glial Tumors	Meningiomas	Schwannomas	Metastases
Neurofilament	+	-	-	-	-
Glial fibrillary acidic protein	-	+	-	-	-
Vimentin	±	+	+	+	-
Cytokeratin	-	-	-	-	+

The Cell Cycle - Applied and Basic

Applied - Proliferation index (PI) = % of total # of cells in proliferation phases of cell cycle; it is a measure of biological processes that are potentially important in predicting the behavior of a tumor. Immunostaining with Ki-67 antibodies (react with nuclear Ag detectable only during proliferative stages) most efficacious.

Basic - CNS tumors are associated with p53 and Epidermal growth factor receptor (EGFR) mutations. EGFR gene is most commonly activated oncogene in human glial tumors.

High-Yield Summary

Type	Incidence	Most Frequent Site	Characteristics
Glioblastoma Multiforme (Astrocytoma)	Older persons	Cerebral hemispheres	Highly malignant, rapidly growing tumor; Most common 1⁰ brain cancer
Meningioma	Middle and later life; more frequent in women	Convexities of cerebral hemispheres, para-sagittal region, falx cerebri, sphenoid ridge	Benign tumor external to brain and usually resectable; second most common 1⁰ brain cancer
Medulloblastoma	Young children	Cerebellum	Highly malignant tumor; most common brain cancer of kids (there were 15 in UH last year)
Schwannoma	Middle and later life	Eighth cranial nerve	Acoustic schwannoma is common, 3^rd most common adult brain cancer; most often benign and usually resectable
Metastatic Tumors	Variable	From primary sites in lung, breast, skin, kidney, GI, and thyroid	Almost equal in incidence to glioblastoma multiforme

High Yield Facts

CNS tumors are the 2^nd most common form of malignancy in kids (Leukemia is #1)

Primary malignant CNS tumors rarely metastasize

Benign intracranial tumors can result in devastating clincial consequences due to compression phenomenon.

In order of freq most common brain cancers are:

(1) Glioblastoma Multiforme

(2) Metastatic tumors

(3) Meningioma

(4) Acoustic Neuroma