Chapter 7



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.

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 (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 have 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.

Pilocytic astrocytomas

Pilocytic astrocytoma. Spindle cells in a compact fibrillary background with numerous Rosenthal fibers.

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 (even partial resection in some instances) sometimes results in permanent cure.

The vast majority of sporadic cerebellar and midline PAs and a smaller proportion of extracerebellar ones show activation of BRAF. This is most commonly caused by fusion of BRAF with KIAA1549, a contiguous gene on 7q34, producing a fusion gene that lacks the BRAF regulatory domain. KIAA1549:BRAF duplication/fusion activates the MAPK oncogenic signaling cascade, which is involved in the pathogenesis of PA. This BRAF alteration is not seen in PA associated with NF1. The same pathway can be activated by the V600E BRAF mutation, which is common in pleomorphic xanthoastrocytoma, ganglioglioma, and, less frequently, in other low-grade pediatric gliomas. The V600E 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.



PXA. Superficial cystic mass with a solid nodule.


PXA. Cellular atypia and granular eosinophilic bodies.


PXA. The tumor cells are arranged in fascicles.


PXA. Lipidized tumor cells.


PXA. Lipidized tumor cells. Oil red O stain.

Pleomorphic xanthoastrocytoma (PXA) is a rare glioma of children and young adults. Typically, it is a superficially located, supratentorial, intra-axial cystic tumor that has a solid mural nodule. It has the tendency to invade the subarachnoid space, and, rarely, it arises in the meninges, thus mimicking the neuroimaging appearance of meningioma. 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 but may undergo malignant transformation, especially when they recur after resection. Eosinophilic granular bodies are a frequent histological marker of PXA. Most PXAs carry the V600E BRAF mutation.



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.


Glioblastoma multiforme (GBM-Grade IV) is the most malignant glioma. About 18,000 patients are diagnosed with glioblastom 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. Glioblastoma arises most commonly de novo (primary glioblastoma). Some glioblastomas arise by malignant transformation of low-grade astrocytomas (secondary glioblastoma). Primary glioblastomas 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 glioblastoma. Contrast enhancing should not be equated with malignancy. Pilocytic astrocytoma also enhances.


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, glioblastoma is a poorly defined intra-axial mass with variegated (multiform) appearance due to necrosis and hemorrhage. If the tumor is near the center of the cerebrum, it may spread across the corpus callosum from one hemisphere to the other. 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, glioblastoma shows high cellularity, cellular and nuclear anaplasia which is the basis of the designation "multiforme", mitoses, microvascular proliferation, and necrosis. Glioblastoma has a wide range of histological appearance. Some tumors (small cell glioblastoma) are composed of poorly differentiated, uniform, small cells. At the other end of the spectrum, giant cell glioblastoma, is characterized by extreme anaplasia. This rare variant tends to be superficial and more circumscribed.


Cellular anaplasia in large cell glioblastoma.

Giant cell glioblastoma

Extreme anaplasia in giant cell glioblastoma.

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

glioblastoma. 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. Glioblastoma is one of the most highly vascular solid tumors. Angiogenesis in glioblastoma is a complex molecular process. Hypoxia, which develops as glioblastoma 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 glioblastoma 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 glioblastoma. Primary glioblastomas are often composed of small undifferentiated cells (small cell glioblastoma) and show extensive ischemic necrosis and a higher proliferative index. Secondary glioblastomas are composed of larger cells with astrocytic differentiation.


Isocitrate dehydrogenase (IDH)
Isocitrate dehydrogenase (IDH) is a citric acid cycle enzyme that catalyzes the conversion of isocitrate to a-ketoglutarate. The isoenzymes IDH1 and IDH2 are frequently mutated in gliomas. IDH1, in particular, is mutated in 70-80% of grade II and III astrocytomas, oligodendrogliomas, oligoastrocytomas, and in secondary but not primary glioblastomas. IDH2 mutations are more common in oligodendrogliomas. One subset of IDH1 mutant gliomas have also TP53 mutations and ATRX loss (see below) and another subset have 1p19q loss (see oligodendroglioma below). BT patients with mutant IDH1 have longer survival than patients with wild type IDH1. 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. Detection of IDH1 mutations by immunohistochemistry is an important tool in the diagnosis of gliomas. IDH1 mutations are not seen in diffuse astrocytomas from children and are not a feature of PA or PXA. IDH mutations can be detected by immunohistochemistry which shows cytoplasmic and weaker nuclear staining for IDH.

Tumor Protein 53 (TP53) is a tumor suppressor encoded by the TP53 gene on17p. It repairs DNA damage and induces apoptosis when damage cannot be repaired. Its mutation promotes tumor formation by enabling damaged cells to survive and grow. TP53 mutations are common in diffuse astrocytoma, anaplastic astrocytoma, and secondary glioblastoma, and help distinguish glioma from gliosis. Mutations can be detected by immunohistochemistry which shows strong nuclear staining for p53.

ATRX (α-thalassemia/mental retardation syndrome X-linked)
The ATRX gene, on Xq21.1, is important for chromatin remodeling, and, through this process, regulates the activity of other genes. ATRX mutations have been reported in a large proportion of adult grade II and grade III astrocytomas, oligoastrocytomas, and secondary glioblastomas. Mutations are less frequent in oligodendrogliomas and pediatric glioblastomas, and rare in primary glioblastomas. These mutations result in loss of nuclear ATRX staining which can be detected by immunohistochemistry.

The TERT (telomerase reverse transcriptase) gene, located on 5p15, encodes a component of the enzyme polymerase, which maintains telomeres. Mutations not of the protein-coding sequence but of the TERT promoter were first reported in melanomas and subsequently in several other tumors. TERT promoter mutations are also very common in brain tumors, especially primary glioblastomas, oligodendrogliomas, some medulloblastomas, and other brain tumors.

PTEN and LOH chromosome 10
Loss of the tumor suppressor gene PTEN (Phosphatase and Tensin Homologue Deleted in Chromosome Ten) on 10q as a result of deletion of 10q or the entire chromosome 10 is the most common genetic abnormality in glioblastoma, occurring in the majority of these tumors and less frequently in grade II and III astrocytomas.

Epidermal Growth Factor Receptor (EGFR)
Overexpression of EGFR, on 7p, occurs in 40 % of glioblastomas (more commonly primary ones) and less frequently in lower grade astrocytomas and provides a potential target for EGFR inhibitors.

BRAF mutations
The BRAF gene, on 7q34, encodes a protein that activates the MAPK oncogenic signaling cascade. In cerebellar PA, this cascade is activated by BRAF fusions and insertions. The same pathway can be activated by the V600E BRAF mutation, which is common in pleomorphic xanthoastrocytoma, ganglioglioma, and, less frequently, in other low-grade pediatric gliomas. The V600E mutation is also seen in colorectal cancer, melanoma, and thyroid carcinoma. The BRAF V600E mutation can be detected by by molecular analysis and immunohistochemistry.

An important epigenetic alteration in glioblastoma 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 repairs DNA crosslinks created by alkylating agents, such as temozolomide (TMZ), thus countering the effects of chemotherapy. Its inactivation makes these tumors more sensitive to TMZ. MGMT promoter methylation is detected by promoter methylation assay and is found in a large proportion of diffuse gliomas, including glioblastomas. Glioblastoma patients with hypermethylated MGMT, treated with TMZ and radiotherapy survive longer than similarly treated patients without MGMT hypermethylation.

Detection of many of the molecular changes that underlie the development of gliomas and other BT can now be done by immunohistochemistry and is getting into the mainstream of the diagnostic workup of BT. The results can be used for grading and customizing management by inhibiting activated pathways. 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.



Gliomatosis cerebri. Diffuse signal abnormality without a tumor mass.


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


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 are 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). In 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. The 1p19q codeletion is specific for oligodendroglioma. The vast majority of oligodendrogliomas with the 1p19q codeletion carry also IDH1 mutations. Most pediatric oligodendrogliomas lack the 1p19q deletion.


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.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 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: March, 2016

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