Glioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Swathi Venkatesan, M.B.B.S.[2]

A glioma is a type of primary central nervous system (CNS) tumor that arises from glial cells. The most common site of involvement of gliomas is the brain, but gliomas can also affect the spinal cord or any other part of the CNS, such as the optic nerve.^[1] Gliomas were reported as early as the 1850s. Retinal gliomas were most commonly reported because they were easier to detect and sample in the absence of advanced imaging and surgical techniques. Glioma may be classified into several subtypes based on the type of cell, grade, and location.^[2] The pathogenesis of cerebral glioma involves invasion of the tumor cells into the adjacent normal brain tissue. The gross and histopathological appearance of glioma varies with the tumor grade and type.^{[3][4][5][6][7]} Glioma must be differentiated from primary CNS lymphoma, cerebral metastases, meningioma, brain abscess, cavernous malformation, stroke, acute disseminated encephalomyelitis, cavernous sinus syndrome, intracranial hemorrhage, gerstmann syndrome, spinal tuberculosis, hamartoma, germinoma, teratoma, piloid gliosis, and progressive multifocal leukoencephalopathy.^[3][2] The incidence of glioma is estimated to be 4.9 cases per 100,000 individuals in the US.^[8] Patients of all age groups may develop glioma. Males are more commonly affected with glioma than females. It usually affects individuals of the caucasian race. African american, latin american, and asian individuals are less likely to develop glioma. Common risk factors in the development of glioma are occupational factors, environmental factors, genetic factors, and viruses.^{[2][3][8][5][9]} Common complications of glioma include brain herniation, coma, metastasis, and recurrence. The prognosis of glioma varies with the grade of tumor. The 1-year and 2-year survival rate of patients with malignant glioma is approximately 50% and 25%, respectively.^[10] Common symptoms of glioma include morning headaches, nausea and vomiting, seizures, drowsiness, changes in speech, difficulty in swallowing, vision changes, abnormal eye movements, changes in personality, memory loss, loss of balance, difficulty in walking, weakness in extremities, numbness in extremities, pain in extremities, and loss of appetite.^[2] The CT scan and MRI findings of glioma vary with the tumor grade and type.^{[2][4][3][5][10][6]} The predominant therapy for glioma is surgical resection. Adjunctive chemotherapy and radiation may be required.^[2]

• Gliomas were reported as early as the 1850s.
• The first recorded reports of gliomas were given in British scientific reports, by Berns in 1800 and in 1804 by Abernety
• With the first comprehensive histomorphological description being given in 1865 by Rudolf Virchow.
• In 1926 Percival Bailey and Harvey Cushing gave the base for the modern classification of gliomas.
• Between 1934 and 1941 the most prolific researcher in glioma research was Hans-Joachim Scherer, who postulated some of the clinico-morphological aspects of Glioblastoma multiforme.
• Retinal gliomas were most commonly reported because they were easier to detect and sample in the absence of advanced imaging and surgical techniques.

• The classification and grading of gliomas have evolved over time, beginning in 1926 with a system devised by Bailey and Cushing and later revised by Kernohan, Ringertz, and others.
• As of the 2016 edition of the WHO classification, gliomas are classified based not only on histopathologic appearance but also on well-established molecular parameters
• Glioma may be classified into several subtypes based on the type of cell (ependymoma, astrocytoma, oligodendroglioma, and mixed gliomas), grade (low-grade and high-grade gliomas), and location (infratentorial and supratentorial).^[2]

• Astrocytomas are glial cell tumors
  • Develop from connective tissue cells called astrocytes.
  • The most common primary intra-axial brain tumor, accounting for nearly half of all primary brain tumors.
  • They are most often found in the cerebrum (the large, outer part of the brain), but also in the cerebellum (located at the base of the brain).
  • Astrocytomas can develop in adults or in children.
  • Pilocytic astrocytomas are low-grade cerebellum gliomas commonly found in children. In adults, astrocytomas are more common in the cerebrum.
  • High-grade astrocytomas, called glioblastoma multiforme, are the most malignant of all brain tumors.

• Brain stem gliomas
  • Also called diffuse infiltrating brainstem gliomas, or DIPGs, are rare tumors found in the brain stem.
  • Cannot be surgically removed because of their remote location, where they intertwine with normal brain tissue and affect the delicate and complex functions this area controls.
  • These tumors occur most often in school-age children
  • Responsible for the greatest number of childhood deaths from primary brain tumors.

The pathogenesis of cerebral glioma involves invasion of the tumor cells into the adjacent normal brain tissue. 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.^[3] 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][8] The gross and histopathological appearance of glioma varies with the tumor grade and type.^{[11][4][5][6][7]}

There are no established causes for glioma.

Glioma must be differentiated from primary CNS lymphoma, cerebral metastases, meningioma, brain abscess, cavernous malformation, stroke, acute disseminated encephalomyelitis, cavernous sinus syndrome, intracranial hemorrhage, gerstmann syndrome, spinal tuberculosis, hamartoma, germinoma, teratoma, piloid gliosis, and progressive multifocal leukoencephalopathy.^[2][3]

Glioma is the most common primary intracranial tumor. The incidence of glioma is estimated to be 4.9 cases per 100,000 individuals in the US.^[8] Patients of all age groups may develop glioma. Males are more commonly affected with glioma than females. It usually affects individuals of the caucasian race. African american, latin american, and asian individuals are less likely to develop glioma.

Common risk factors in the development of glioma are occupational factors, environmental factors, genetic factors, and viruses.^{[2][3][8][5][9]}

There is insufficient evidence to recommend routine screening for glioma.^[12]

Common complications of glioma include brain herniation, coma, metastasis, and recurrence. The prognosis of glioma varies with the grade of tumor. The 1-year and 2-year survival rate of patients with malignant glioma is approximately 50% and 25%, respectively.^[10]

There is no established system for the staging of glioma.^[10]

Common symptoms of glioma include morning headaches, nausea and vomiting, seizures, drowsiness, changes in speech, difficulty in swallowing, vision changes, abnormal eye movements, changes in personality, memory loss, loss of balance, difficulty in walking, weakness in extremities, numbness in extremities, pain in extremities, and loss of appetite.^[2]

Common physical examination findings of glioma include aphasia, vision loss, strabismus, memory loss, sensory loss, paresis, abnormal gait, ataxia, papilledema, and focal neurological deficits.^[2]

There are no diagnostic lab findings associated with glioma.

There are no x-ray findings associated with glioma.

Head CT scan may be diagnostic of glioma. The CT scan findings of glioma vary with the tumor grade and type.^{[2][4][3][5][10][6]}

Brain MRI may be diagnostic of glioma. The MRI findings of glioma vary with the tumor grade and type.^{[2][4][3][5][10][6]}

There are no ultrasound findings associated with glioma.

Other imaging studies for high-grade gliomas include PET scan, which demonstrates accumulation of [18F]-fluorodeoxyglucose (increased glucose metabolism).^[2]

Other diagnostic studies for glioma include biopsy, which demonstrates astrocytes with or without atypia and mitoses, depending on the type of glioma.^[2]

Treatment for glioma depends on the location and grade. The predominant therapy for glioma is surgical resection. Adjunctive chemotherapy and radiation may be required.^[2]

Surgery is the mainstay of treatment for glioma.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.

Gliomas were reported as early as the 1850s. Retinal gliomas were most commonly reported because they were easier to detect and sample in the absence of advanced imaging and surgical techniques.

• The earliest mention of gliomas in the literature dates back to the late 19th century (1850-1860).
• Most reported cases involved retinal gliomas, which were more easily detected and sampled. ^[1]
• Publications from Virchow in Germany were the earliest to distinguish retinal neuroglia from other connective tissue. This allowed the classification of these tumors as gliomata rather than sarcomas. ^[2][3]

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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]

Glioma may be classified into several subtypes based on the type of cell (ependymoma, astrocytoma, oligodendroglioma, and mixed gliomas), grade (low-grade and high-grade gliomas), and location (infratentorial and supratentorial).^[1]

Glioma may be classified into several subtypes based on the type of cell, grade, and location.^[1]

Glioma may be classified according to the type of cell into four subtypes:^[1]

• Ependymomas — ependymal cells
• Astrocytomas — astrocytes
• Oligodendrogliomas — oligodendrocytes
• Mixed gliomas (oligoastrocytomas) — cells from different types of glia

Glioma may be classified according to the grade into two subtypes:^[1]

• Low-grade gliomas are well-differentiated tumors. These are benign tumors.
• High-grade gliomas are undifferentiated or anaplastic tumors. These are malignant tumors.

WHO grading system for astrocytomas

Glioma may be classified according to the location into two subtypes:^[1]

• Infratentorial: mostly in children (70%)
• Supratentorial: mostly in adults (70%)

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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]

The pathogenesis of cerebral glioma involves invasion of the tumor cells into the adjacent normal brain tissue. 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 histopathological appearance of glioma varies with the tumor grade and type.^{[4][5][6][7][8]}

• The pathogenesis of cerebral glioma involves invasion of the tumor cells into the adjacent normal brain tissue. 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.^[9]

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

Gliomas may be associated with:^[3][10]

• Neurofibromatosis type 1
• Neurofibromatosis type 2
• Tuberous sclerosis
• Li-Fraumeni syndrome
• Turcot syndrome
• Maffucci syndrome
• Von Hippel-Lindau disease
• Retinoblastoma

The gross pathological appearance of glioma varies with the tumor grade and type. Common findings are listed below:^{[4][5][6][7][8]}

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

The histopathological appearance of glioma varies with the tumor grade and type, with increasing cellular atypia, mitoses, endothelial cell proliferation, and necrosis. Common findings are listed below:^{[4][5][6][7][8]}

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

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Common causes of glioma include genetic mutations (ERCC1, ERCC2, XRCC1, MGMT, IDH1, IDH2, p53, EGFR, TSC1, TSC2, RB1, APC, hMLH1, hMSH2, PMS2, PTEN, NF1, and NF2).^[1][2]

• Common causes of glioma include genetic mutations.
• The various genes include:^[1][2]
  • ERCC1
  • ERCC2
  • XRCC1
  • MGMT
  • IDH1
  • IDH2
  • p53
  • EGFR
  • TSC1
  • TSC2
  • RB1
  • APC
  • hMLH1
  • hMSH2
  • PMS2
  • PTEN
  • NF1
  • NF2

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Glioma must be differentiated from primary CNS lymphoma, cerebral metastases, meningioma, brain abscess, cavernous malformation, stroke, acute disseminated encephalomyelitis, cavernous sinus syndrome, intracranial hemorrhage, gerstmann syndrome, spinal tuberculosis, hamartoma, germinoma, teratoma, piloid gliosis, and progressive multifocal leukoencephalopathy.^[1][2]

Glioma must be differentiated from:^[1][2]

• Primary CNS lymphoma
• Cerebral metastases
• Meningioma
• Brain abscess
• Cavernous malformation
• Stroke
• Acute disseminated encephalomyelitis
• Cavernous sinus syndrome
• Intracranial hemorrhage
• Gerstmann syndrome

• Spinal tuberculosis
• Hamartoma
• Germinoma
• Teratoma
• Piloid gliosis
• Progressive multifocal leukoencephalopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Glioma is the most common primary intracranial tumor. The incidence of glioma is estimated to be 4.9 cases per 100,000 individuals in the US.^[1] Patients of all age groups may develop glioma. Males are more commonly affected with glioma than females. It usually affects individuals of the caucasian race. African american, latin american, and asian individuals are less likely to develop glioma.

• Glioma is the most common primary intracranial tumor.
• The incidence of glioma is estimated to be 4.9 cases per 100,000 individuals in the US.^[1]

• Patients of all age groups may develop glioma.
• Pilocytic astrocytoma is a common disease that tends to affect children and adolescents. The median age at diagnosis is 17 years.
• Glioblastoma multiforme is a common disease that tends to affect the elderly population. The median age at diagnosis is 62 years.

• Males are more commonly affected with glioma than females.^[1]

• Glioma usually affects individuals of the caucasian race. African american, latin american, and asian individuals are less likely to develop glioma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Common risk factors in the development of glioma may be occupational, environmental, genetic, and viral.^{[1][2][3][4][5]}

Common risk factors in the development of glioma may be occupational, environmental, genetic, and viral.^{[1][2][3][4][5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

There is insufficient evidence to recommend routine screening for glioma.^[1]

There is insufficient evidence to recommend routine screening for glioma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Common complications of glioma include brain herniation, hydrocephalus, coma, metastasis, recurrence, side effects of chemotherapy, and side effects of radiation therapy. The prognosis of glioma varies with the grade of tumor. The 1-year and 2-year survival rate of patients with malignant glioma is approximately 50% and 25%, respectively.^[1]

Common complications of glioma include:

• Brain herniation
• Hydrocephalus
• Coma
• Metastasis
• Recurrence
• Side effects of chemotherapy
• Side effects of radiation therapy

• The prognosis of glioma varies with the grade of tumor: WHO grade 1 and WHO grade 4 have the most favorable and worst prognosis, respectively.
• The 1-year and 2-year survival rate of patients with malignant glioma is approximately 50% and 25%, respectively.
• Post-operative radiation therapy is often used as an adjunct to surgery in the treatment of high-grade gliomas as it has shown to double the median survival for high-grade gliomas to 37 weeks (versus 17 weeks with surgery alone).
• The prognosis of glioma may depend on other factors which include:^[1]

• Location of the tumor (brain or spinal cord)
• Resectability
• Primary diagnosis vs. recurrence
• Specific mutations:

• DNA methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter
• Mutation of isocitrate dehydrogenase: IDH1 or IDH2 genes
• Codeletion of chromosomes 1p and 19q