Glioma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2], Sujit Routray, M.D. [3]

Overview

Pathogenesis of glioma involves astrocytes, members of the glial family. The hallmark of the pathology of cerebral gliomas is invasion of the astrocytes into the adjacent normal brain. Although in certain areas the margin of the tumor may seem to be macroscopically well defined from the brain, there are always microscopic nests of tumor cells extending well out into the brain.^[1] Genes involved in the pathogenesis of glioma include ERCC1, ERCC2, XRCC1, MGMT, IDH1, IDH2, p53, EGFR, TSC1, TSC2, RB1, APC, hMLH1, hMSH2, PMS2, PTEN, NF1, and NF2.^[2]^[3] The gross and microscopic histopathological appearance of glioma varies with the tumor grade.

Pathophysiology

Pathogenesis

Pathogenesis of glioma involves astrocytes, members of the glial family.
The hallmark of the pathology of cerebral gliomas is invasion of the astrocytes into the adjacent normal brain. Although in certain areas the margin of the tumor may seem to be macroscopically well defined from the brain, there are always microscopic nests of tumor cells extending well out into the brain.^[1]
Astrocytic projections interact with vessels and act as additional elements of the blood brain barrier (BBB). The tumors take advantage of the blood brain barrier to ensure survival and continuous growth.
Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue.
Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema.^[4]

Genetics

Genes involved in the pathogenesis of glioma include:^[2]^[3]

ERCC1
ERCC2
XRCC1
MGMT
IDH1
IDH2
p53
EGFR
TSC1
TSC2
RB1
APC
hMLH1
hMSH2
PMS2
PTEN
NF1
NF2

Associated Conditions

Gliomas may be associated with:^[3]^[1]

Gross Pathology

The gross pathological appearance of glioma varies with the tumor grade.^[5] Common findings are listed below:


Type of glioma	Gross pathological features

Pilocytic astrocytoma	1. Well-circumscribed cystic tumor 2. Solid mural nodule 3. Commonly located in the cerebellum
Low-grade astrocytoma	1. Poorly demarcated tumor 2. Tumor mass causing enlargement of the involved portion of the brain and blurring of anatomical landmarks 3. Commonly located in the cerebral hemisphere
Anaplastic astrocytoma	1. Spongy or gelationous mass 2. Ill defined borders 3. Microcysts 4. Calcification 5. Commonly located in frontal lobe, temporal lobe, brain stem, or spinal cord
Glioblastoma multiforme	1. Poorly-marginated, diffusely infiltrating tumor 2. Firm or gelatinous in consistency 3. Central necrotic core 4. Commonly located in the frontal and temporal lobe
Oligodendroglioma	1. Well circumscribed tumor 2. Pinkish-white in color 3. Mucinous changes 4. Commonly located in the frontal lobe, followed by parietal and temporal lobes
Ependymoma	1. Well-differentiated tumor 2. Exophytic pattern of growth 3. Commonly located at the fourth ventricle and filum terminale

Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

The histopathological appearance of glioma varies with the tumor grade, with increasing cellular atypia, mitoses, endothelial and adventitial cell proliferation and necrosis with increasing grade of the tumor.^[5] Common findings are listed below:


Type of glioma	Microscopic histopathological features

Pilocytic astrocytoma	1. Low cellularity without mitoses or anaplasia 2. Classically biphasic Fibrillar Microcystic 3. Hair-like fibres best observed on smear or with GFAP 4. Rosenthal fibres 5. Eosinophilic granular bodies 6. Microvascular proliferation 7. Focal pseudopalisading necrosis
Low-grade astrocytoma	1. Stellate, spindle-shaped tumor cells with fiber like processes 2. Large eosinophilic cytoplasmic mass 3. Forms microcysts
Anaplastic astrocytoma	1. Astrocytic tumor cells with: Moderate cellularity Moderate nuclear atypia and mitoses No necrosis No microvascular proliferation
Glioblastoma multiforme	1. Astrocytic tumor cells with: High cellularity Marked nuclear atypia and mitoses Pseudopalisading necrosis Microvascular proliferation
Oligodendroglioma	1. Diffusely growing tumor 2. Highly cellular lesion resembling fried eggs with: Round nucleus Distinct cell borders Moderate-to-marked nuclear atypia Clear cytoplasm Few have eosinophilic cytoplasm with focal perinuclear clearing Acutely branched capillary sized vessels: chicken-wire like appearance Calcifications Perifocal edema is rare Few may exhibit eosinophilic granular bodies Some may have a spongioblastoma-like growth pattern
Ependymoma	1. Tadpole-shaped cells resembling an ice cream cone 2. Nuclear features monotonous, i.e. "boring" Little variation in size, shape, and staining 3. Rosettes: circular nuclear free zones/cells arranged in a pseudoglandular fashion (2 types) Perivascular pseudorosettes: tumor cells arranged around a blood vessel; nuclei of cells distant from the blood vessel, i.e. rim of cytoplasm (from tumor cells) surrounding blood vessel (nucleus-free zone). More common than ependymal rosette but less specific Ependymal rosette (true ependymal rosette): rosette has an empty space at the centre

Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

CNS: Pilocytic astrocytoma: variations in histologic appearance. As illustrated, many lesions are composed largely of spongy tissue rich in microcysts. Characteristic of pilocytic astrocytomas in general, the lesion is largely a solid mass of neoplastic cells without an obvious background of infiltrated brain.
CNS: Pilocytic astrocytoma: variations in histologic appearance. The perivascular radiating processes in some lesions can create a likeness to an ependymoma. Note the spongy background unusual for ependymomas.

CNS: Pilocytic astrocytoma: variations in histologic appearance. Other pilocytic astrocytomas are solid, rather than microcystic, and may be lobular.
CNS: Pilocytic astrocytoma: variations in histologic appearance. Rosenthal fibers, usually confined to the solid rather than spongy regions are found in many pilocytic astrocytomas, but are not requisite for the diagnosis.

CNS: Pilocytic astrocytoma: variations in histologic appearance. Rosenthal fibers are extremely abundant in some lesions. Particularly in the cerebellum, it can be difficult to distinguish such solid, paucicellular, highly fibrillar pilocytic astrocytomas from reactive gliosis with abundant Rosenthal fiber formation.
CNS: Pilocytic astrocytoma: variations in histologic appearance. A loose array of polar cells creates an additional variant of pilocytic astrocytoma.

CNS: Pilocytic astrocytoma: variations in histologic appearance. Some pilocytic astrocytomas are traversed by prominent collagenous septa.
CNS: Pilocytic astrocytoma: variations in histologic appearance. Unusual pilocytic astrocytomas have an extensive mucinous background without microcysts.

CNS: Comparison of normal optic nerve and pilocytic astrocytoma of the optic nerve. These two figures compare, at the same magnification, the normal optic nerve (left) with one containing a pilocytic astrocytoma (right). The neoplasm enlarges the compartments of the nerve and extends in collar-like fashion into the subarachnoid space.
CNS: Pilocytic astrocytoma; The "hair cells" for which this lesion is named are readily seen.

CNS: Pilocytic astrocytoma; Nuclear hyperchromasia and pleomorphism are common. Note the typical cellular elongation, and, at the center of the illustration, the eosinophilic granular body that populates pilocytic astrocytomas and certain other slowly growing gliomas.
CNS: Pilocytic astrocytoma; Intracytoplasmic Rosenthal fibers are prominent in some pilocytic neoplasms.

Brain: Malignant ependymoma: Micro med mag H&E tumor cells.
$CNS: Oligodendroglioma; Occasional oligodendrogliomas contain cells with minute, refractile eosinophilic bodies representing miniature Rosenthal fibers.$

CNS: Oligodendroglioma; Occasional oligodendrogliomas contain cells with minute, refractile eosinophilic bodies representing miniature Rosenthal fibers.

CNS: Oligodendroglioma; The cells of some oligodendrogliomas acquire sufficient cytoplasm and process formation to become decidedly astrocytic, but their nuclei retain the roundness, uniformity, and chromatin distribution typical of oligodendroglioma.
Anaplastic oligodendroglioma: Anaplastic oligodendrogliomas are highly cellular and associated with vascular proliferation.

CNS: Oligodendroglioma (frozen section); Oligodendrogliomas in frozen sections lack the distinctive halos so often seen in permanent sections. Cellular monomorphism and infiltration of cerebral cortex with perineuronal satellitosis suggest the correct diagnosis.
CNS: Clear cell ependymoma; Perinuclear clearing similar to that seen in oligodendrogliomas is a prominent feature of the clear cell variant. Note the vague perivascular pseudorosettes. The lesion was a discrete occipital intraventricular mass.

CNS: Glioblastoma multiforme; Brain: Glioblastoma multiforme. Grade I-Ii: Micro med mag with H&E, tumor well shown
CNS: Glioblastoma multiforme arising in an astrocytoma. At higher magnification, gemistocytic astrocytoma with microcystic change is apparent at the bottom of the illustration and cellular nodules of glioblastoma multiforme are seen at the top. The 6-year history of symptoms attested to the initially low-grade nature of this astrocytic tumor.

CNS: Glioblastoma multiforme; Characteristic of most glioblastomas are small cells with elongated nuclei and bipolar processes. As here, the chromatin is generally not markedly dense nor are nucleoli usually prominent.
CNS: Glioblastoma multiforme; Vascular proliferation, a common feature of glioblastoma, produces tufts which often grow directionally. Here, as is often the case, they are oriented toward a focus of necrosis (top right).

CNS: Glioblastoma multiforme; At high magnification, the neovascular tuft is a mass which, as can be confirmed by immunohistochemistry, is formed of both endothelial cells and smooth muscle cells (pericytes).
CNS: Glioblastoma multiforme; In many instances, necrosis is surrounded by a distinctive collar of cells, which are often smaller than those in surrounding neoplastic tissue. The phenomenon is referred to as pseudopalisading.

CNS: Cerebrospinal dissemination of glioblastoma multiforme; As seen at low (left) and high (right) magnification, the small undifferentiated-appearing cells of this glioblastoma are drop metastases colonizing the nerve roots of the cauda equina.
CNS: Cerebrospinal dissemination of glioblastoma multiforme; As seen at low (left) and high (right) magnification, the small undifferentiated-appearing cells of this glioblastoma are drop metastases colonizing the nerve roots of the cauda equina.

CNS: Glioblastoma multiforme; Higher magnification reveals the small cell nature of such tumors.
CNS: Glioblastoma multiforme; Some glioblastomas are especially infiltrative of the cerebral cortex where subpial, perivascular, and perineuronal accumulations are prominent.

CNS: Glioblastoma multiforme; Although this densely cellular and largely undifferentiated lesion technically merits a diagnosis of anaplastic astrocytoma, it is, for practical purposes, a glioblastoma.
Brain: Glioblastoma multiforme malignant astrocytoma