Chapter 7

TUMORS OF THE CENTRAL NERVOUS SYSTEM

TUMORS OF GLIAL CELLS

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

Intermediate filaments in a neoplastic astrocyte.


GFAP immunostain

Astrocytoma. 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

"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). 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. Adaptations of the WHO system are used to grade other brain tumors.

PILOCYTIC ASTROCYTOMA-WHO GRADE I

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


PA of the cerebellum

Pilocytic astrocytoma. Cerebellar cyst with solid component.


PA of the pons

Pilocytic astrocytoma of the pons.


Hypothalamic PA

Pilocytic astroctoma of the hypothalamus.

Grossly, pilocytic astrocytomas are circumscribed and often cystic with a solid mural nodule. 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. Some PAs are mostly compact, consisting usually of fiber-like spindle cells.


Pilocytic astrocytoma

Biphasic (cystic and solid) pilocytic astrocytoma with numerous Rosenthal fibers.


Eosinophilic granular bodies

Pilocytic astrocytoma. Granular eosinophilic 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. Some PAs contain clear (oligodendroglioma-like) cells, multinucleated cells, and calcifications. PAs are highly vascular and enhance with contrast injection. Most PAs are biologically low grade 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.

The vast majority of cerebellar PAs and a smaller proportion of extracerebellar ones show duplication of BRAF or its fusion with KIAA1549, a contiguous gene on 7q34. This is the most common molecular change in PA. KIAA1549:BRAF duplication/fusion activates the MAPK oncogenic signaling cascade, which is involved in the pathogenesis of PA. The same pathway is activated by the V600E BRAF mutation, which is is common in pleomorphic xanthoastrocytoma, ganglioglioma, and, less frequently, in other low-grade pediatric gliomas. This mutation is also seen in colorectal cancer, melanoma, and thyroid carcinoma. These BRAF changes can be detected by molecular analysis. In addition to their diagnostic and prognostic value, these findings open the road for specific pharmacological interventions aiming to inhibit the activated pathways.

PLEOMORPHIC XANTHOASTROCYTOMA-WHO GRADE II


PXA

PXA. Superficial cystic mass with a solid nodule.


PXA

PXA. Cellular atypia and granular eosinophilic bodies.


PXA

PXA. Lipidized tumor cells.

Pleomorphic xanthoastrocytoma (PXA) is a rare glioma of children and young adults. Typically, it is a superficially located supratentorial cystic tumor that has a solid mural nodule. The "xantho" part of the term refers to the presence of vacuolated tumor cells containing lipid droplets. The "pleomorphic" designation indicates that the tumor displays significant cellular and nuclear pleomorphism. In spite of this, PXA does not have a high proliferative index. Most PXAs are WHO grade II. Occasional ones are malignant. Eosinophilic granular bodies are a frequent histological marker of PXA.

LOW-GRADE ASTROCYTOMA (LGA)-WHO GRADE II


Astrocytoma

Low-grade astrocytoma extending from the left thalamus to the brain stem.


Pontine astrocytoma

Diffuse astrocytoma of the pons. The pons is enlarged and wraps around the basilar artery.


Gemistocytic astrocytoma

Gemistocytic astrocytoma. The tumor cells are similar to certain reactive astrocytes.

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. 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. The Isocitrate Dehydrogenase 1 (IDH1) and 2 (IDH2) genes are mutated in 50-80% of grade II and III astrocytomas, oligodendrogliomas, oligoastrocytomas, and in secondary but not primary GBMs (see below). Tumors with IDH1/2 mutations also have TP53 mutations or 1p/19q loss. BT patients with such mutations have longer survival than patients with wild type IDH. IDH mutations also occur in some cases of acute myelogenous leukemia and other cancers. IDH mutations may make tumor cells less viable by increasing their susceptibility to oxidative damage. IDH mutations can be detected by immunohistochemistry.

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-WHO GRADE IV

Glioblastoma multiforme (GBM-Grade IV) is the most malignant glioma. About 18,000 patients are diagnosed with GBM in the United States annually. 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

Glioblastoma. A variegated appearance with necrosis and old hemorrhage.


GBM of the pons

Malignant astrocytoma-glioblastoma of the pons. Necrosis and hemorrhage.

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

Cellular anaplasia in large cell GBM.


Necrosis and pseudopalisading

GBM. Palisading of viable cells around a necrotic area. Necrosis in the upper part of the image and microvascular proliferation along the left and right borders


Microvascular proliferation

GBM. Vascular endothelial 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.

Glioblastoma is a heterogeneous entity. In addition to the distinction between primary and secondary GBM, molecular analysis has identified 4 subtypes of GBM, termed proneural, classical, mesenchymal, and neural, each with distinct prevalent genomic changes. This terminology is not based on morphology but rather on expression of gene sets associated with oligodendrocytes (proneural), astrocytes (classical), cultured astroglial cells (mesenchymal) and neurons -but also oligodendrocytes and astrocytes (neural). Thus, proneural GBM shows PDGFRA amplification and IDH1 mutations; classical shows chromosome 7 amplification, chromosome 10 loss, and EGFR amplification; mesenchymal shows NF1 and p53 loss, and neural shows expression of diverse neural markers. Molecular classification of GBM and correlation of these subtypes with histology and clinical behavior are evolving.

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 CEREBRI


Gliomatosis

Gliomatoosis cerebri. Diffuse signal abnormality without a tumor mass.


Gliomatosis

Gliomatosis cerebri. Poorly differentiated glial cells infiltrate the brain and crowd around blood vessels and neurons.

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 AND OLIGOASTROCYTOMA


Oligodendroglioma

Oligodendroglioma. Uniform cells with clear cytoplasm.A fine capillary network.


Oligodendroglioma

Oligodendroglioma. Calcifications.


Oligodendroglioma MRI

Most oligodendrogliomas arise in the cerebral cortex. In this example, the tumor follows the contour of cortical gyri.

Oligodendrogliomas are 5%-6% of gliomas. They are insidious, slowly growing tumors and arise usually in the cerebral hemispheres of middle-aged adults. Oligodendrogliomas are more circumscribed than astrocytomas. Microscopically, the tumor cells are uniform and have round central nuclei with fine chromatin surrounded by a clear halo (unstained cytoplasm), which is an artefact of processing. Some tumors contain mini-gemistocytes. They infiltrate the cortex diffusely and accumulate under the pia, around neurons (satellitosis), and around blood vessels. Oligodendrogliomas are traversed by a delicate capillary network and have a tendency to calcify, which is helpful in radiological and histological diagnosis. They may form microcysts. On EM examination, the tumor cells produce abundant plasma membrane that tends to form concentric layers mimicking myelin. Some oligodendrogliomas contain neoplastic astrocytes which may be mixed with the oligodendroglial cells or grow in adjacent but separate areas. Such mixed tumors are called oligoastrocytomas. Oligodendrogliomas and oligoastrocytomas can be classified as low-grade (WHO grade II) or high-grade/anaplastic (WHO grade III) based on cellularity, anaplasia, mitotic activity, microvascular proliferation, and necrosis. Median survival for grade II and grade III oligodendroglioma is about 11 and 4-5 years respectively, shorter for oligoastrocytomas

The signature molecular change of oligodendrogliomas is co-deletion of the entire arms of 1p and 19q, caused by an unbalanced translocation t(1;19)(q10;p10). I addition to being a diagnostic marker for oligodendroglioma, the 1p19q deletion predicts increased chemosensitivity and better prognosis, and is associated with classic oligodendroglioma morphology and frontal location. Most pediatric oligodendrogliomas lack the 1p19q deletion.

EPENDYMOMA


Ependymoma of the 4th ventricle

Ependymoma of the 4th ventricle. Lateral view. Reproduced with the permission of the Department of Radiology of Akron Children's Hospital.


Ependymoma of the 4th ventricle and hydrocephalus.

Ependymoma of the 4th ventricle and hydrocephalus. T2 MRI, coronal view. Reproduced with the permission of the Department of Radiology of Akron Children's Hospital.


Ependymoma of the 4th ventricle

Ependymoma arising from the floor of the 4th ventricle.

Ependymomas are predominantly tumors of children and adolescents. 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 pseudoresette.

Ependymoma: true rosettes

Ependymoma. Tubular formations (true rosettes). Perivascular pseudorosettes are also present.


Ependymoma-EM

Ependymoma-EM.Cilia, microvilli, desmosomes.


Myxopapillary ependymoma

Myxopapillary ependymoma. Papillary formations with a mucinous (clear) core.


Myxopapillary ependymoma

Myxopapillary ependymoma. Papillary formations with a mucinous core. Alcian blue stain

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. Ependymoma has distinctive ultrastructural features, including cilia, microvilli, and desmosomes. Myxopapillary ependymoma, characterized by papillary formations with a mucinous core, is a special variant, arising most commonly in the lumbosacral spinal cord and sometimes in the soft tissues of the lumbosacral region. 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.

CHOROID PLEXUS TUMORS


Choroid plexus papilloma

Choroid plexus papilloma. Benign appearance, similar to normmal choroid plexus.


Choroid plexus carcinoma

Choroid plexus carcinoma. Papillary architecture but high cellularity and atypia.

Choroid plexus tumors affect mostly children and young adults. Choroid plexus carcinoma-CPC (WHO grade III) is most common in very young children, and choroid plexus papilloma-CPP (WHO grade I) is seen in older patients. In children, CPP and CPC arise in both, lateral and fourth ventricles. In adults, CPP is more frequent in the fourth ventricle and sometimes arises in the cerebellopontine angle. CPP is seen in the Aicardi syndrome, an X-linked syndrome in females, characterized by agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms. CPC occurs in the rhabdoid tumor predisposition syndrome, caused by germline mutations of the INI1 gene. Choroid plexus tumors cause hydrocephalus and increased intracranial pressure by blocking CSF pathways and by oversecreting CSF. CPC can also seed the subarachnoid space. Both, CPP and CPC have a papillary basic structure. In CPP the papillae are covered by a single layer of benign epithelial cells, similar to normal choroid plexus. In CPC the tumor cells are multilayered, atypical, and mitotic, and the papillary structure may be effaced such that the tumor appears solid.

Further Reading


Updated: June, 2013

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