CHAPTER SEVEN
TUMORS OF THE CENTRAL NERVOUS SYSTEM

The term "glioma" refers to all glial tumors in general (primarily glioblastoma, astrocytoma, oligodendroglioma, and ependymoma) but is also used sometimes instead of astrocytoma. The following introduction refers to astrocytic tumors in general, which are the most frequent gliomas.

Cytoplasmic filaments	GFAP immunostain

Neoplastic astrocytes share with normal ones the presence of intermediate cytoplasmic filaments. The protein of these filaments, glial fibrillary acidic protein (GFAP), can be detected by immunohistochemistry.

Astrocytomas have a wide spectrum of clinical behavior that can be expressed as a grade. The most commonly used WHO grading system, uses four grades with grade I being the least malignant and grade IV the most malignant.

WHO GRADING SYSTEM

Grade I-Pilocytic astrocytoma	Benign cytological features-see below
Grade II-Low-grade astrocytoma	Moderate cellularity-no anaplasia or mitotic activity
Grade III- Anaplastic astrocytoma	Cellularity, anaplasia, mitoses
Grade IV-Glioblastoma	Same as Grade III plus microvascular proliferation and necrosis

Other systems use three grades: low grade astrocytoma, anaplastic astrocytoma, and glioblastoma. High-grade astrocytoma includes WHO grades III and IV. Low grade astrocytomas are more frequent in young patients and high grade astrocytomas in older ones. Grading is used by oncologists to design treatment. It has practical usefulness and prognostic value but it may be subjective and some tumors do not fit neatly into a given grade. Progress in the molecular biology of gliomas has revealed some correlation between molecular changes and grade (see below). In the three grade system, anaplastic astrocytoma is not in the middle of the biological spectrum, but closer to the malignant end. Thus, it can be argued that there are basically low-grade and high-grade astrocytomas, the latter including GBM. Grading is subject to sampling error, particularly with small (stereotactic needle) biopsies. Some astrocytic tumors are malignant from the outset. Others start as low-grade and evolve into high grade. The WHO system applies best to astrocytic tumors but, modified, it is used also for other gliomas.

PILOCYTIC ASTROCYTOMA-WHO GRADE I

Pilocytic astrocytoma (PA) is a biologically and histologically distinct form of astrocytoma of children and young adults. Most PAs arise in the cerebellum and hypothalamus. Some arise in the cerebral hemispheres and other locations.

PA of the cerebellum	PA of the pons	Hypothalamic PA

Grossly, pilocytic astrocytomas are circumscribed and often cystic. Histologically, they are sparsely cellular tumors without anaplasia or mitoses. They show a biphasic pattern, consisting of cellular and fibrillary perivascular areas, alternating with loose microcystic zones.

Pilocytic astrocytoma	Eosinophilic granular bodies

The tumor cells often contain Rosenthal fibers and eosinophilic granular bodies. The word pilocytic (hair cell) refers to the fiber-like appearance of the tumor cells and their fibrillary stroma, but large parts of these tumors, especially in the loose areas, do not fit this description. PAs are highly vascular and enhance with contrast injection. Most PAs are biologically low grade, probably benign, and do not evolve into more malignant tumors. Surgical excision of cerebellar PA alone (even partial resection in some instances) sometimes results in permanent cure. Cerebellar PA and medulloblastoma are the most frequent BT in children.

LOW-GRADE ASTROCYTOMA (LGA)-WHO GRADE II

LGAs are most frequent in children and young adults. They arise anywhere in the CNS, but are most frequent in the cerebral hemispheres. Most LGAs are poorly demarcated and it is difficult to determine, by imaging, direct observation during surgery, or by gross pathological examination where the tumor ends and normal tissue begins.

Astrocytoma	Pontine astrocytoma	Gemistocytic astrocytoma

All that is seen may be an enlargement of the involved portion of the brain and blurring of anatomical landmarks. Some astrocytomas involve a large part of the brain or the entire CNS in a diffuse fashion (gliomatosis cerebri). Most pontine and medullary astrocytomas are diffuse. Histologically, the tumor cells can be stellate, spindle-shaped with fiber like processes, or plump with a large eosinophilic cytoplasmic mass (gemistocytic astrocytomas). They spread in a diffuse fashion but may also form microcysts and other tissue patterns.

The genesis of astrocytoma and glioblastoma entails a cascade of molecular events that involves several oncogenes and tumor suppressor genes and evolves over a period of years. The pivotal event in the transformation of normal to neoplastic astrocytes is mutation of the tumor supressor gene p53 on 17p. Specialized diagnostic laboratories are set up to detect the chromosomal and molecular changes that underlie the development of astrocytoma and GBM. The results can be used for grading and patient management. The labeling index, determined by Ki 67(MIB-1) immunohistochemistry, can help distinguish grade II from grade III astrocytoma. Even low-grade astrocytomas may be clinically malignant because their location and diffuse spread make surgical excision impossible, and they are not very susceptible to chemotherapy or radiation.

GLIOBLASTOMA MULTIFORME-WHO GRADE IV

Glioblastoma multiforme (GBM-Grade IV) is the most malignant glioma. It occurs most frequently in middle aged adults. Its most common sites are the frontal and temporal lobes, but it may occur at any age and involve any part of the CNS. GBM arises most commonly de novo (primary GBM). Some GBMs arise by malignant transformation of low-grade astrocytomas (secondary GBM). Primary GBMs are more common in older patients and are more aggressive. Survival from glioblastoma rarely exceeds one year. Postoperative irradiation and chemotherapy prolong survival minimally.

Imaging shows a large irregular mass of variable density with cavitation, surrounded by a large area of edema. Vascularity accounts for the contrast-enhancing properties of GBM. Contrast enhancing should not be equated with malignancy. Pilocytic astrocytoma also enhances.

Glioblastoma	GBM of the pons

On naked eye examination , GBM is a poorly defined mass with variegated (multiform) appearance due to necrosis and hemorrhage. If the tumor is near the center of the cerebrum, it may spread from one hemisphere to the other through the corpus callosum. Other malignant BT can have the same pattern. Also, large MS lesions, especially Schilder's disease, may involve both hemispheres and be confused with GBM.

Microscopically, GBM shows high cellularity, cellular and nuclear anaplasia which is the basis of the designation "multiforme", mitoses, microvascular proliferation, and necrosis.

Anaplasia	Necrosis and pseudopalisading	Microvascular proliferation

Densely cellular arrays of tumor cells are often arranged in a perpendicular (pseudopalisading) fashion around serpiginous necrotic areas. It has been proposed that these tumor cells are migrating away from a central hypoxic area. Thrombosed vessels are often seen in the central necrotic area while microvascular proliferation in adjacent areas sustains tumor growth. GBM is one of the most highly vascular solid tumors. Angiogenesis in GBM is a complex molecular process. Hypoxia, which develops as GBM outgrows its vascular supply, induces upregulation of hypoxia inducible factor 1 (HIF-1), which, in turn, stimulates the expression of vascular endothelial growth factor (VEGF). Overexpression of these genes in GBM induces formation of new vessels, which allow continuing tumor growth. The new vessels are often arranged in glomeruloid formations, and lack a blood-brain barrier. The latter property contributes to cerebral edema, a clinically important feature of GBM. Primary GBMs are often composed of small undifferentiated cells (small cell glioblastoma) and show extensive ischemic necrosis and a higher proliferative index. Secondary GBMs are composed of larger cells with astrocytic differentiation.

Losses of chromosome 10 involving the tumor suppressor PTEN (Phosphatase and Tensin Homologue Deleted in Chromosome Ten) and other chromosomal loci convert low-grade astrocytoma to anaplastic astrocytoma and GBM. Overexpression of the Epidermal Growth Factor Receptor (EGFR) gene on 7p characterizes GBMs that arise de novo (primary GBMs) and provides a potential target for EGFR inhibitors. An important epigenetic alteration in GBM and other gliomas is silencing of the O6-Methylguanine-DNA Methyltransferase gene (MGMT) through hypermethylation of its promoter. The MGMT gene encodes a DNA repair enzyme which removes alkyl groups created by alkylating agents, such as temozolomide (TMZ), thus countering the effects of chemotherapy. Its inactivation makes these tumors more sensitive to TMZ. GBM patients with hypermethylated MGMT, treated with TMZ and radiotherapy survive longer than similarly treated patients without MGMT hypermethylation.

GLIOMATOSIS CREREBRI

Gliomatosis	Gliomatosis

Gliomatosis cerebri (GC) is a diffusely infiltrating neoplasm that may involve 2-3 lobes of the brain, an entire hemisphere, or the entire brain. Most cases of GC do not have a tumor mass, but in some a mass may be present from the start or appear later. Clinically, GC begins insidiously with changes of mental status, seizures, and focal deficits. This vague clinical presentation, coupled with a diffuse MRI signal abnormality, often suggests encephalitis, ADEM, or other entities. Histologically, most GC cases are composed of poorly differentiated glial cells, probably astrocytes, that infiltrate the brain diffusely and crowd around neurons and blood vessels and under the pia. These cases are comparable to WHO grade III astrocytoma. Such cases advance rapidly and have a poor prognosis. Some GC cases are due proliferation of more mature astrocytes or oligodendrocytes and have a more protracted course.

OLIGODENDROGLIOMA

Oligodendroglioma	Oligodendroglioma MRI

Oligodendrogliomas arise usually in the cerebral hemispheres of middle-aged adults. They are insidious, slow-growing tumors and have a mean survival of five years. Oligodendrogliomas are more circumscribed than astrocytomas. Microscopically, the tumor cells are uniform and have round central nuclei surrounded by a clear space or halo (unstained cytoplasm) which is an artifact of processing. They infiltrate the cortex diffusely. Oligodendrogliomas are traversed by delicate capillaries and have a tendency to calcify, which is helpful in radiological and histological diagnosis. On EM examination, the tumor cells produce abundant plasma membrane that tends to form concentric layers mimicking myelin. Some oligodendrogliomas have an astrocytic component. Such mixed tumors are called oligoastrocytomas. Oligodendrogliomas can be classified as low-grade or high-grade based on cellularity, mitotic activity, vascular endothelial proliferation, and necrosis. These histological parameters correlate with the length of survival. Oligodendrogliomas are among the most chemosensitive solid tumors. They show losses of chromosomes 1p and 19q which correlate with increased sensitivity to PVC and temozolomide chemotherapy and longer survival.

EPENDYMOMA

Ependymomas are predominantly tumors of children and adolescents.

Ependymoma of the 4th ventricle	Ependymoma of the 4th ventricle and hydrocephalus.	Ependymoma of the 4th ventricle

They arise most frequently in the fourth ventricle and cause hydrocephalus by blocking CSF flow. However, they may occur anywhere in relation to the ventricular system or central canal and are the most common primary intra-axial tumors in the spinal cord and filum terminale. Ependymomas are well demarcated from the surrounding brain and spinal cord and grow in an exophytic fashion, protruding into and out of the fourth ventricle. Spinal ependymomas are circumscribed intra-axial masses.

Ependymoma:perivascular pseudorosettes	Ependymoma: true rosettes

Microscopically, the tumor cells resemble normal ependymal cells and are arranged in perivascular formations, tubular structures like the central canal of the spinal cord, and papillary formations. An anaplastic version of ependymoma, called ependymoblastoma, is seen infrequently in young children. Most ependymomas are histologically and biologically low-grade, but surgical resection of fourth-ventricle ependymomas is difficult.

Further reading:
Mellinghoff IK et al. Molecular Determinants of the Response of Glioblastomas th EGFR Kinase Inhibitors. N Engl J Med2005;353:2012-24. PubMed

Hegi ME et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 2004 15;10:1871-4. PubMed

Rong Y, Durden DL, Van Meir EG, Brat DJ. "Pseudopalisading" necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 2006;65:529-39. PubMed

Schiff D, Brown P D, Giannini C. Outcome of adult low-grade glioma. The impact of prognostic factors and treatment. Neurology 2007;69:1366-73. PubMed

Yip S, Iafrate J, Louis D N. Molecular diagnostic testing in malignant gliomas: a practical update on predictive markers. J Neuropath Exp Neurol 2008; 67:1-15. PubMed

Updated: November, 2011