Oligodendroglioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

Oligodendrogliomas are a type of glioma that are believed to originate from the tripotential glial precursor cells. The term “oligodendroglioma” was first coined by Bailey and Cushing in 1926 following the observation that the tumor cells are morphologically similar to oligodendrocytes. According to the new 2016 edition of WHO classification of gliomas based on histopathologic appearance and well-established molecular parameters, oligodendrogliomas are subclassified into grade II tumors including oligodendroglioma IDH–mutant and 1p/19q-codeleted, oligodendroglioma NOS, oligoastrocytoma NOS, and grade III tumors including anaplastic oligodendroglioma IDH–mutant and 1p/19q-codeleted, anaplastic oligodendroglioma NOS, and anaplastic oligoastrocytoma NOS. Genes associated with the pathogenesis of oligodendroglioma include t[1;19][q10;p10], ATRX, NJDS, IDH1, IDH2, TERT promoter, H3 K27M (H3F3A, HIST1H3B/C), CIC, FUBP1, p53, Leu-7, TCF-12, TP53, MGMT, TP73, BRAF, EGFR, and PTEN. Common intracranial sites involved by oligodendroglioma include cerebral hemispheres, posterior fossa, and intramedullary spinal cord. On gross pathology, oligodendroglioma is characterized by a well-circumscribed, gelatinous, calcified, cystic, gray mass with focal hemorrhage which may expand a gyrus and remodel the skull. On microscopy, it shows a diffuse growth pattern of highly cellular lesion of monomorphic cells having rounded nucleus with atypia, speckled “salt-and-pepper” chromatin pattern and perinuclear halo resembling fried eggs, distinct cell borders, clear cytoplasm, abundant calcification and “chicken-wire” like vascularity pattern. Common causes of oligodendroglioma include genetic mutations, some viral cause or irradiation of pituitary adenoma. On the basis of seizure, visual disturbance, and constitutional symptoms, oligodendroglioma must be differentiated from astrocytoma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis. It constitutes about 9.4% of all CNS tumors and 5%–18% of all glial neoplasms with incidence of oligodendroglioma and anaplastic oligodendroglioma to be 0.32 and 0.17 cases per 100,000 individuals in the United States, respectively. Oligodendroglioma is a disease that tends to affect the middle-aged adult population mainly occurring in the 4th and 5th decade of life with median age at the time of diagnosis to be 35-47 years. Males are more commonly affected than females with the male to female ratio of approximately 1.3:1. Oligodendroglioma usually affects individuals of the Caucasian race and African American, Latin American, and Asian individuals are less likely to develop oligodendroglioma. The most potent risk factor for the development of oligodendroglioma is family history of brain tumors. If left untreated, patients with oligodendroglioma may progress to develop seizures, focal neurological deficits, hydrocephalus, brain herniation, intracranial hemorrhage, and ultimately death. Common complications associated with oligodendroglioma include hydrocephalus, intracranial hemorrhage, coma, bone marrow metastasis, recurrence, venous thromboembolism, parkinsonism, and side effects of chemotherapy and radiotherapy. The overall prognosis is good but the prognosis may vary depending upon various prognostic factors such as population based estimates, clinical factors, tumor grade (II versus III), mechanism of chemosensitivity, and molecular markers such as 1p/19q-codeletion, IDH1/2 mutation, and TERT promoter mutations. Symptoms associated with oligodendroglioma include seizure, headache, nausea, vomiting, vertigo, visual loss, diplopia, strabismus, muscle weakness, numbness, speech difficulties, mood disturbances, personality changes, memory problems, low energy, fatigue, urge to sleep, loss of interest in daily activities, abulia, lack of spontaneity, loss of consciousness with syncope (few tonic-clonic jerks), and classic triad of headache, nausea, and papilledema due to raised intracranial pressure. Findings on CT scan suggestive of oligodendroglioma are round or oval, marginated, hypo- to isodense mass with hemorrhage, ribbon-like calcification, ill-defined enhancement following intravenous contrast administration, pressure erosion/remodelling of overlying skull, and marked ventricular enlargement suggestive of hydrocephalus. On brain MRI, oligodendroglioma is characterized by a mass which is typically hypointense on T1–weighted images and hyperintense on T2-weighted images. Calcification is observed as areas of “blooming” on T2 decay component of MRI. Other imaging studies for oligodendroglioma include MR spectroscopy (dominant N-acetyl aspartate peak, increased choline levels and decreased NAA levels with a myo-inositol peak), MR perfusion (increased “chicken wire” network of vascularity, which results in elevated relative cerebral blood volume), PET scan (to differentiate between oligodendroglioma from anaplastic oligodendroglioma and tumor recurrence from tumor necrosis), and bone scan (bone metastasis). Other diagnostic studies for oligodendroglioma include biopsy (homogeneous, compact, rounded cells with distinct borders and clear cytoplasm surrounding a dense central nucleus and perinuclear halo) and fluorescent in-situ hybridization (FISH) technique (deletions of chromosome 1p and 19q). The predominant therapy for oligodendroglioma is surgical resection. Adjunctive chemotherapy and radiation are required. Supportive therapy for oligodendroglioma includes anticonvulsants and corticosteroids.

In 1926, the term “oligodendroglioma” was first coined by Bailey and Cushing, and was first described and published by W. E. Carnegie Dickson. Oligodendrogliomas were first classified and graded in a system devised by Bailey and Cushing, and later revised by Kernohan, Ringertz, and others, and since then, classification and grading of gliomas have evolved over the time. Modern WHO classification of oligodendrogliomas was first published in 1979 and revised four times since then, with the most recent published in 2016. In 1997, a Westergaard’s study showed that patients younger than 20 years had a median survival of 17.5 years. In 2001, a study at Mayo Clinic was conducted to assess the prognostic value of histological grading of oligodendroglial tumors in tumor grading and significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis on univariate analysis, but only age and presence of endothelial proliferation were found to be independently associated with survival on a multivariable analysis. In 2009, NJDS mutation was first identified in the pathogenesis of oligodendroglioma by Kevin Smith. It was suggested in 2009 ASCO Annual Meeting that PCV therapy may be superior in efficacy to the newer temozolomide therapy. Irradiation of pituitary adenoma was also discovered to be associated with oligodendroglioma by Kevin Smith et al.

According to the old 2007 WHO classification of the central nervous system tumors, oligodendrogliomas were divided into five subtypes: oligodendroglioma (OII), anaplastic oligodendroglioma (OIII), oligoastrocytoma (OAII), anaplastic oligoastrocytoma (OAIII), and glioblastoma with oligodendroglioma component (GBMo). But the new 2016 edition of WHO classification of gliomas is based not only on histopathologic appearance but also on well-established molecular parameters, and oligodendroglial tumors are now more narrowly defined by molecular diagnostics to include only those diffuse gliomas having both a mutation in isocitrate dehydrogenase type 1 (IDH1) or type 2 (IDH2) and codeletion of chromosomes 1p and 19q. This new pattern of classification divides oligodendrogliomas into grade II tumors including oligodendroglioma IDH–mutant and 1p/19q-codeleted, oligodendroglioma NOS, oligoastrocytoma NOS, and grade III tumors including anaplastic oligodendroglioma IDH–mutant and 1p/19q-codeleted, anaplastic oligodendroglioma NOS, and anaplastic oligoastrocytoma NOS.

Oligodendroglioma arises from the tripotential glial precursor cells and not from the bipotential oligodendrocytes. Genes associated with the pathogenesis of oligodendroglioma include t[1;19][q10;p10], ATRX, NJDS, IDH1, IDH2, TERT promoter, H3 K27M (H3F3A, HIST1H3B/C), CIC, FUBP1, p53, Leu-7, TCF-12, TP53,MGMT, TP73, BRAF, EGFR, and PTEN. Common intracranial sites involved by oligodendroglioma include cerebral hemispheres, posterior fossa, and intramedullary spinal cord. On gross pathology, oligodendroglioma is characterized by a well-circumscribed, gelatinous, calcified, cystic, gray mass with focal hemorrhage which may expand a gyrus and remodel the skull. On microscopic histopathological analysis, oligodendroglioma is characterized by diffuse growth pattern of highly cellular lesion of monomorphic cells having rounded nucleus with atypia, speckled “salt-and-pepper” chromatin pattern and perinuclear halo resembling fried eggs, distinct cell borders, clear cytoplasm, abundant calcification and “chicken-wire” like vascularity pattern. Oligodendroglioma is demonstrated by positivity to tumor markers such as IDH1-R132H, MAP2, GFAP, S-100, SOX10, EMA, ATRX, Ki-67, NSE, synaptophysin, OLIG1, and OLIG2.

The most common etiology of oligodendroglioma includes genetic mutations such as t(1;19)(q10;p10), NJDS, IDH1, IDH2, CIC, FUBP1, p53, Leu-7, TCF-12,MGMT, TP73, EGFR and PTEN. It may be associated with some viral cause or irradiation of pituitary adenoma.

On the basis of seizure, visual disturbance, and constitutional symptoms, oligodendroglioma must be differentiated from astrocytoma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

Oligodendroglioma, although rare, is the third most common glioma. In adults, it constitutes about 9.4% of all primary brain and central nervous system tumors and 5%–18% of all glial neoplasms. The incidence of oligodendroglioma and anaplastic oligodendroglioma is estimated to be 0.32 and 0.17 cases per 100,000 individuals in the United States, respectively. Oligodendroglioma tends to affect the middle-aged adult population, most commonly occurring in the 4th and 5th decade of life. Median age at the time of diagnosis of oligodendroglioma is 35-47 years. Males are more commonly affected with oligodendroglioma than females with male to female ratio being approximately 1.3:1. Oligodendroglioma usually affects individuals of the Caucasian race. African American, Latin American, and Asian individuals are less likely to develop oligodendroglioma.

The most potent risk factor for the development of oligodendroglioma is a positive family history of brain tumors.

There is insufficient evidence for recommending routine screening for oligodendroglioma.

If left untreated, patients with oligodendroglioma may progress to develop seizures, focal neurological deficits, hydrocephalus, brain herniation, intracranial hemorrhage, and ultimately death.Common complications associated with oligodendroglioma include hydrocephalus, intracranial hemorrhage, coma, bone marrow metastasis, recurrence, venous thromboembolism, parkinsonism, and side effects of chemotherapy and radiotherapy. Oligodendroglioma is a slow growing tumor having a good prognosis overall with prolonged survival. But the prognosis of oligodendroglioma may vary depending upon various prognostic factors such as population based estimates, clinical factors, tumor grade (II versus III), mechanism of chemosensitivity, and molecular markers such as 1p/19q-codeletion, IDH1/2 mutation, and TERT promoter mutations. The median survival time for oligodendroglioma is 11.6 years for grade II and 3.5 years for grade III.

• CT or MRI scan is necessary to characterize the anatomy of oligodendroglial tumors such as:
  • Tumor size
  • Tumor location
  • Hetero/homogeneity
• However, the confirmation of final diagnosis is dependent on histopathologic examination of the biopsy specimen.

There is no established system for the staging of oligodendroglioma.

When evaluating a patient for oligodendroglioma, a detailed history of the presenting symptom (onset, duration, and progression), other associated symptoms, a thorough past medical history review, and review of common risk factors such as family history of brain tumors. Oligodendroglioma is a slow–growing, infiltrative tumor that may be clinically silent for many years. With tumor progression, symptoms may vary depending upon the location, size, and rate of tumor growth. Oligodendroglioma mainly involves the frontal lobe. Symptoms associated with oligodendroglioma include seizure, headache, nausea, vomiting, vertigo, visual loss, diplopia, strabismus, muscle weakness, numbness, speech difficulties, mood disturbances, personality changes, memory problems, low energy, fatigue, urge to sleep, loss of interest in daily activities, abulia, lack of spontaneity, loss of consciousness with syncope (few tonic-clonic jerks), and classic triad of headache, nausea, and papilledema due to raised intracranial pressure.

Common physical examination findings of oligodendroglioma include nystagmus, papilledema, esotropia, visual field loss, altered mental status, aphasia, ataxia,hemiparesis, tremor, and focal neurological deficits including cranioneuropathies, corticospinal and spinocerebellar defects.

Some patients with oligodendroglioma may have elevated protein and cell count with normal glucose and lactate on CSF analysis, which is usually suggestive of hydrocephalus. Immunohistochemistry of oligodendrogliomas shows positive staining for IDH1-R132H, ATRX, GFAP, SOX10, MAP2, S-100, EMA, Ki-67, NSE, synaptophysin, OLIG1, and OLIG2, and negative staining for p53, and keratins.

Chest x-ray may be performed to detect the metastases of anaplastic oligodendroglioma to lungs.

Head CT scan may be helpful in the diagnosis of oligodendroglioma. Findings on CT scan suggestive of oligodendroglioma are round or oval, marginated, hypo- to isodense mass with hemorrhage, ribbon-like calcification, ill-defined enhancement following intravenous contrast administration, pressure erosion/remodelling of overlying skull, and marked ventricular enlargement suggestive of hydrocephalus.

Brain MRI is helpful in the diagnosis of oligodendroglioma. On brain MRI, oligodendroglioma is characterized by a mass which is typically hypointense on T1–weighted images and hyperintense on T2-weighted images. Calcification is observed as areas of “blooming” on T2 decay component of MRI. T1 C + gadolinium shows heterogeneous contrast enhancement and diffusion weighted images help differentiate lower grade oligodendrogliomas from higher grade astrocytomas which have higher ADC values because of lower cellularity and greater hyaluronan proportion. MR perfusion (PWI) is 95% sensitive for diagnosis of oligodendrogliomas and 87% sensitive for distinguishing grade II from grade III oligodendrogliomas. On PWI, “chicken wire” network of vascularity results in elevated relative cerebral blood volume (rCBV) of grade II vs grade III and rCBV above the threshold of 1.75 demonstrates more rapid tumor progression.

There are no ultrasound findings associated with oligodendroglioma.

Other imaging studies for oligodendroglioma include MR spectroscopy (dominant N-acetyl aspartate peak, increased choline levels and decreased NAA levels with a myo-inositol peak), MR perfusion (increased “chicken wire” network of vascularity, which results in elevated relative cerebral blood volume), PET scan (to differentiate between oligodendroglioma from anaplastic oligodendroglioma and tumor recurrence from tumor necrosis), and bone scan (bone metastasis).

Other diagnostic studies for oligodendroglioma include biopsy (homogeneous, compact, rounded cells with distinct borders and clear cytoplasm surrounding a dense central nucleus and perinuclear halo) and fluorescent in-situ hybridization (FISH) technique (deletions of chromosome 1p and 19q).

Innovative treatment options:

• Brain tumors can be complex and require a combination of treatments for the best outcome.
• There is quite a wide range of treatments to meet the individual needs of each patient which includes standard therapies, precision medicine and clinical trials.
• Some of them are listed below:
  • Brachytherapy:
    • Destroys tumors by implanting radioactive medicine directly to or near the treatment site.
  • Chemotherapy:
    • Reaches cancer that may have spread, even microscopically, throughout the body.
  • Craniotomy:
    • Surgical procedure that removes a bone flap, a section of the skull, to access the brain.
  • Intensity-modulated radiation therapy:
    • Uses computer technology to deliver radiation treatment that precisely fits the size and shape of the tumor.
  • Minimally invasive cranial base surgery:
    • Uses smaller incisions and specially designed instruments to eliminate a tumor while saving the surrounding tissue from damage.
  • Stereotactic radiosurgery & radiotherapy:
    • A noninvasive procedure that applies large doses of radiation directly to a tumor.

The predominant therapy for oligodendroglioma is surgical resection. Adjunctive chemotherapy and radiation are required. Supportive therapy for oligodendroglioma includes anticonvulsants and corticosteroids.

Surgery is the first-line treatment option for patients with oligodendroglioma. However, oligodendrogliomas cannot be completely resected because of their diffusely infiltrating nature. The aim of surgery is to make a definitive diagnosis, debulk the tumor to relieve elevated intracranial pressure and reduce the tumor mass as a precursor to adjuvant treatment. CSF shunting is usually reserved for patients with hydrocephalus and includes two types of shunts: external ventricular drain-temporary shunt and internal drain-permanent shunt.

There is no established method for primary prevention of oligodendroglioma.

There are no secondary preventive measures available for oligodendroglioma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

In 1926, the term “oligodendroglioma” was first coined by Bailey and Cushing, and was first described and published by W. E. Carnegie Dickson. Oligodendrogliomas were first classified and graded in a system devised by Bailey and Cushing, and later revised by Kernohan, Ringertz, and others, and since then, classification and grading of gliomas have evolved over the time. Modern WHO classification of oligodendrogliomas was first published in 1979 and revised four times since then, with the most recent published in 2016. In 1997, a Westergaard’s study showed that patients younger than 20 years had a median survival of 17.5 years. In 2001, a study at Mayo Clinic was conducted to assess the prognostic value of histological grading of oligodendroglial tumors in tumor grading and significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis on univariateanalysis, but only age and presence of endothelial proliferation were found to be independently associated with survival on a multivariable analysis. In 2009, NJDSmutation was first identified in the pathogenesis of oligodendroglioma by Kevin Smith. It was suggested in 2009 ASCO Annual Meeting that PCV therapy may be superior in efficacy to the newer temozolomide therapy. Irradiation of pituitary adenoma was also discovered to be associated with oligodendroglioma by Kevin Smith et al.

• The term oligodendroglioma was derived from the Greek words “oligo” meaning few and “dendro” meaning trees.
• In 1926, the term “oligodendroglioma” was first coined by Bailey and Cushing following the observation that the tumor cells are morphologically similar to oligodendrocytes.^[1]
• In 1926, oligodendroglioma was first described and published by W. E. Carnegie Dickson.^[2]
• In 1926, oligodendrogliomas were first classified and graded in a system devised by Bailey and Cushing, and later revised by Kernohan, Ringertz, and others, and since then, classification and grading of gliomas have evolved over the time.
• In 1979, modern classification of gliomas based on the World Health Organization (WHO) Classification of Central Nervous System Tumors was first published and revised four times since then.
• In 1997, a Westergaard’s study showed that patients younger than 20 years had a median survival of 17.5 years.^[3]
• In March 2001, 7 neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic during the period of 1960 to 1990. In this study, the prognostic value of histological grading of oligodendroglial tumors in tumor grading was assessed, and significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis on univariate analysis. However, only age and presence of endothelial proliferation were found to be independently associated with survival on a multivariable analysis.^[4]
• In 2009 Oxford Neurosymposium study by Kevin Smith, it was first discovered that there is a 69% correlation between NJDS gene mutation and oligodendroglial tumor initiation.^[5]
• In 2009 ASCO Annual Meeting, it was suggested that PCV therapy may be superior in efficacy to the newer temozolomide therapy. This study showed that median time to progression for patients with 1p19q co-deletion is longer following PCV alone (7.6 years) than with temozolomide alone (3.3 years); median overall survival is also longer with PCV treatment versus temozolomide treatment (not reached, vs. 7.1 years).^[6]
• Kevin Smith et al also discovered that irradiation of pituitary adenoma is associated with precipitation of oligodendroglioma.
• In 2016 edition of the most recent WHO classification, gliomas are classified based not only on histopathologic appearance but also on well-established molecular parameters.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

According to the old 2007 WHO classification of the central nervous system tumors, oligodendrogliomas were divided into five subtypes: oligodendroglioma (OII), anaplastic oligodendroglioma (OIII), oligoastrocytoma (OAII), anaplastic oligoastrocytoma (OAIII), and glioblastoma with oligodendroglioma component (GBMo). But the new 2016 edition of WHO classification of gliomas is based not only on histopathologic appearance but also on well-established molecular parameters, and oligodendroglial tumors are now more narrowly defined by molecular diagnostics to include only those diffuse gliomas having both a mutation in isocitrate dehydrogenase type 1 (IDH1) or type 2 (IDH2) and codeletion of chromosomes 1p and 19q. This new pattern of classification divides oligodendrogliomas into grade II tumors including oligodendroglioma IDH–mutant and 1p/19q-codeleted, oligodendroglioma NOS, oligoastrocytoma NOS, and grade III tumors including anaplasticoligodendroglioma IDH–mutant and 1p/19q-codeleted, anaplastic oligodendroglioma NOS, and anaplastic oligoastrocytoma NOS.

• The new 2016 edition of WHO classification of gliomas is based not only on histopathologic appearance but also on well-established molecular parameters
• In 2016 updated World Health Organization (WHO) classification of central nervous system tumors, oligodendroglial tumors are now more narrowly defined by molecular diagnostics to include only those diffuse gliomas having both a mutation in isocitrate dehydrogenase type 1 (IDH1) or type 2 (IDH2) and codeletion of chromosomes 1p and 19q^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]}

2016 World Health Organization (WHO) classification of diffuse astrocytic and oligodendroglial tumors

Tumor classification	Tumor grade	Defining* or characteristic molecular genetic features
Astrocytic tumors
Diffuse astrocytoma, IDH–mutant	II	IDH1/2 mutation*, TP53 mutation, ATRX mutation
Diffuse astrocytoma, IDH–wildtype	II	No IDH1/2 mutation
Anaplastic astrocytoma, IDH–mutant	III	IDH1/2 mutation*, TP53 mutation, ATRX mutation
Anaplastic astrocytoma, IDH–wildtype	III	No IDH1/2 mutation
Glioblastoma, IDH–mutant	IV	IDH1/2 mutation*, TP53 mutation, ATRX mutation
Glioblastoma, IDH–wildtype	IV	No IDH1/2 mutation, TERT promoter mutations
Glioblastoma, NOS	IV	Genetic testing not done or inconclusive
Midline diffuse glioma, H3 K27M-mutant	IV	H3 K27M mutation*
Oligodendroglial tumors
Oligodendroglioma, IDH–mutant and 1p/19q-codeleted	II	IDH1/2 mutation*, 1p/19q-codeletion*, no ATRX mutation, TERT promoter mutations
Oligodendroglioma, NOS	II	Genetic testing not done or inconclusive
Oligoastrocytoma, NOS	II	Genetic testing not done or inconclusive
Anaplastic oligodendroglioma, IDH–mutant and 1p/19q-codeleted	III	IDH1/2 mutation*, 1p/19q-codeletion*, no ATRX mutation, TERT promoter mutations
Anaplastic oligodendroglioma, NOS	III	Genetic testing not done or inconclusive
Anaplastic oligoastrocytoma, NOS	III	Genetic testing not done or inconclusive

IDH: isocitrate dehydrogenase; NOS: not otherwise specified

• Alterations that define the WHO classification entity are marked by an asterisk.

Data from: WHO classification of tumors of the central nervous system, revised 4th ed, Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds), IARC, Lyon 2016

• According to the old 2007 WHO classification of the central nervous system tumors, oligodendrogliomas were divided into five subtypes:^[42]

WHO classification of tumors of CNS

WHO grade II

WHO grade III

WHO grade IV

Oligodendroglioma (OII)

Oligoastrocytoma (OAII)

Anaplastic oligodendroglioma (OIII)

Anaplastic oligoastrocytoma (OAIII)

Glioblastoma with oligodendroglioma component (GBMo)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [16]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[17]Sujit Routray, M.D. [18]

Oligodendroglioma arises from the tripotential glial precursor cells and not from the bipotential oligodendrocytes. Genes associated with the pathogenesis of oligodendroglioma include t[1;19][q10;p10], ATRX, NJDS, IDH1, IDH2, TERT promoter, H3 K27M (H3F3A, HIST1H3B/C), CIC, FUBP1, p53, Leu-7, TCF-12, TP53,MGMT, TP73, BRAF, EGFR, and PTEN. Common intracranial sites involved by oligodendroglioma include cerebral hemispheres, posterior fossa, and intramedullary spinal cord. On gross pathology, oligodendroglioma is characterized by a well-circumscribed, gelatinous, calcified, cystic, gray mass with focal hemorrhage which may expand a gyrus and remodel the skull. On microscopic histopathological analysis, oligodendroglioma is characterized by diffuse growthpattern of highly cellular lesion of monomorphic cells having rounded nucleus with atypia, speckled “salt-and-pepper” chromatin pattern and perinuclear haloresembling fried eggs, distinct cell borders, clear cytoplasm, abundant calcification and “chicken-wire” like vascularity pattern. Oligodendroglioma is demonstrated by positivity to tumor markers such as IDH1-R132H, MAP2, GFAP, S-100, SOX10, EMA, ATRX, Ki-67, NSE, synaptophysin, OLIG1, and OLIG2.

• Oligodendroglioma does not arise from the bipotential oligodendrocytes, although the tumor cells look very similiar.^[1]
• Oligodendroglioma arises from the tripotential glial precursor cells.

• Development of oligodendroglioma is the result of multiple genetic mutations.^{[2][3][4][5][6][7][8][9][10][11][12]}
• Genes associated with the pathogenesis of oligodendroglioma include:^{[13][14][15][16][17][18][19][20][21][22][23][24][25]}

• t(1;19)(q10;p10) (co-deletion of chromosomal arms 1p36 and 19q13; most common)^[26][10][27]
• ATRX^[28]
• IDH1^{[29][30][31][32][33][34][35][36][37]}
• IDH2^{[38][39][40][41][42][43]}
• TERT promoter^{[22][44][45][46][47][48]}
• H3 K27M mutations in either H3F3A (one of two genes encoding the histone H3.3 variant) or HIST1H3B/C (encoding the histone H3.1 variant).^{[49][50][51][52][53][54]}
• NJDS (A 2009 Oxford Neurosymposium study illustrated that there’s a 69% correlation between NJDS gene mutation and tumor initiation).
• CIC^[55][16]
• FUBP1
• TP53
• p53^[56]
• BRAF alterations:^[57]
  • KIAA1549–BRAF fusion
  • BRAF V600E mutation
• Leu-7
• TCF-12
• MGMT
• TP73
• EGFR
• PTEN

• There is a strong association of oligodendroglioma with expression of receptor tyrosine kinases that activate PI3K/AKT, RAS/MAP, and PLC/PKC pathways.^[20]

• On gross pathology, oligodendroglioma is characterized by a well-circumscribed, gelatinous, gray mass which may expand a gyrus and remodel the skul.l^[58]
• Other characteristic gross pathological features associated with oligodendroglioma include:^[58][20]
  • Calcification (70-90%; one of the most frequently calcifying tumors)
  • Focal hemorrhage
  • Cystic (20%)
• Common intracranial sites associated with oligodendroglioma include:^[59]
  • Cerebral hemispheres (cortex and white matter) – distribution between frontal (most common, > 50% of cases), parietal, temporal, and occipital lobe approximates 3:2:2:1.
  • Posterior fossa (rare)
  • Intramedullary spinal cord (very rare, only 1.5% of oligodendrogliomas).

On microscopic histopathological analysis, oligodendroglioma is characterized by:^{[20][60][61][62][63]}

• Diffusely growing, infiltrative tumor
• Moderate cellularity
• Highly cellular lesion composed of typically monomorphic cells resembling fried eggs with:
  • Round nucleus – key feature
  • Distinct cell borders
  • Moderate-to-marked nuclear atypia with speckled “salt-and-pepper” chromatin pattern
  • Inconspicuous nucleoli
  • Clear cytoplasm (artifactual retraction of the cytoplasm on routinely processed formalin fixed, paraffin embedded material, leading to the characteristic “fried egg” appearance).
    • Some oligodendrogliomas have eosinophilic cytoplasm with focal perinuclear clearing.
  • Dense network of acutely fine branched capillary sized vessels -classically referred to as a “chicken-wire” like appearance/pattern.^[64]
    • Abundant and delicate appearing; may vaguely resemble a paraganglioma at low power.
• Small punctate calcifications, particularly along the blood vessels is a striking feature (but not a specific finding).
• Perifocal edema – rare
• Few tumors may exhibit eosinophilic granular bodies
• Some tumors may show a spongioblastoma-like growth pattern
• Tumor cells may form following secondary structures in the surrounding infiltrated brain parenchyma:
  • Perineuronal satellitosis
  • Subpial accumulation
  • Perivascular distribution (less common)
• Microgemistocytic appearance of tumor cells with a rounded belly of eccentric GFAP+ eosinophilic cytoplasm (maybe present).^[65]
• A predominant fibrillar astrocytic phenotype is compatible with the diagnosis when following appropriate molecular findings are present:^[21]
  • IDH mutation
  • 1p/19q codeletion

On microscopic histopathological analysis, anaplastic oligodendroglioma, IDH mutant and 1p/19q codeleted, is characterized by:^[60]

• Focal or diffusely increased cell density
• Atypical to frankly pleomorphic cells or multinucleated giant cells
• Tumor cells may be plasmacytoid (i.e. have a plasma cell-like appearance)
  • Also called as minigemistocytes
• Significant/brisk infrequent mitotic activity (≥ 6 mitoses per 10 HPF)^[66][67]
• Rare foci of:
  • Necrosis
  • Apoptotic cells
  • Microvacular proliferation either in the form of:
    • Glomeruloid‘ vessels or
    • Endothelial hyperplasia

Oligodendroglioma is demonstrated by positivity to tumor markers such as:^{[68][69][20][7]}

• IDH1-R132H (majority of cases)^[70]
• MAP2
• GFAP (positive in intermingled reactive astrocytes and minigemistocytes)
• SOX10
• S-100
• EMA
• ATRX
• Ki-67
• NSE
• Synaptophysin
• OLIG1
• OLIG2

Oligodendroglioma stains negative for:

• p53 (rare weakly positive cells can be seen)
• Keratins (although cocktails may show cross reactivity)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

The most common etiology of oligodendroglioma includes genetic mutations such as t(1;19)(q10;p10), NJDS, IDH1, IDH2, CIC, FUBP1, p53, Leu-7, TCF-12,MGMT, TP73, EGFR and PTEN. It may be associated with some viral cause or irradiation of pituitary adenoma.

• The most common etiology of oligodendroglioma includes mutations in the following genes:^{[1][2][3][4][5][6][7][8]}
  • t(1;19)(q10;p10)
  • NJDS (A 2009 Oxford Neurosymposium study illustrated that there’s a 69% correlation between NJDS gene mutation and tumor initiation)^[9]
  • IDH1
  • IDH2
  • CIC
  • FUBP1
  • p53
  • Leu-7
  • TCF-12
  • MGMT
  • TP73
  • EGFR
  • PTEN
• It may be associated with some viral cause
• A single case report linked oligodendroglioma to the irradiation of pituitary adenoma

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

On the basis of seizure, visual disturbance, and constitutional symptoms, oligodendroglioma must be differentiated from astrocytoma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

On the basis of seizure, visual disturbance, and constitutional symptoms, oligodendroglioma must be differentiated from astrocytoma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, craniopharyngioma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

Diseases	Clinical manifestations					Para-clinical findings			Gold standard	Additional findings
	Symptoms				Physical examination
						Lab Findings	MRI	Immunohistopathology
	Head- ache	Seizure	Visual disturbance	Constitutional	Focal neurological deficit
Adult primary brain tumors
Oligodendroglioma [1][2][3]	+	+	+/−	−	+	−	Almost always in cerebral hemisphers (frontal lobes) Hypointense on T1 Hyperintense on T2 Calcification Chicken wire capillary pattern	Oligodendrocyte origin Calcification + Fried egg cell appearance	Biopsy	Highest incidence is between 40 and 50 years of age. Most of the time, epileptic seizure is the presenting sign.
Glioblastoma multiforme [4][5][6]	+	+/−	+/−	−	+	−	Supratentorial Irregular ring-nodular enhancing lesions Central necrosis Surrounding vasogenic edema Cross corpus callosum (butterfly glioma)	Astrocyte origin Pleomorphic cell Pseudopalisading appearance GFAP + Necrosis + Hemorrhage + Vascular prolifration +	Biopsy	Highest incidence in fifth and sixth decades of life Most of the time, focal neurological deficit is the presenting sign.
Meningioma [7][8][9]	+	+/−	+/−	−	+	−	Well circumscribed Extra-axial mass Dural attachment CSF vascular cleft sign Sunburst appearance of the vessels	Arachnoid origin Psammoma bodies Whorled spindle cell pattern	Biopsy	Highest incidence is between 40 and 50 years of age. Most of the time, focal neurological deficit and epileptic seizure are the presenting signs. May be associated with NF-2
Hemangioblastoma [10][11][12][13]	+	+/−	+/−	−	+	−	Infratentorial Cystic lesion with a solid enhancing mural nodule	Blood vessel origin Capillaries with thin walls	Biopsy	Might secret erythropoietin and cause polycythemia May be associated with von hippel-lindau syndrome
Pituitary adenoma [14][15][6]	−	−	+ Bitemporal hemianopia	−	−	Endocrine abnormalities as a result of functional adenomas or pressure effect of non-functional adenomas	Isointense to normal pituitary gland in T1	Endocrine cell hyperplasia	Biopsy	It is associated with MEN1 disease. Initialy presents with upper bitemporal quadrantanopsia followed by bitemporal hemianopsia (pressure on optic chiasma from below)
Schwannoma [16][17][18][19]	−	−	−	−	+	−	Split-fat sign Fascicular sign Often have areas of hemosiderin	Schwann cell origin S100+	Biopsy	It causes hearing loss and tinnitus May be associated with NF-2 (bilateral schwannomas)
Primary CNS lymphoma [20][21]	+	+/−	+/−	−	+	−	Usually deep in the white matter Single mass with ring enhancement	B cell origin Similar to non hodgkin lymphoma (diffuse large B cell)	Biopsy	Usually in young immunocompromised patients (HIV) or old immunocompetent person.
Childhood primary brain tumors
Pilocytic astrocytoma [22][23][24]	+	+/−	+/−	−	+	−	Infratentorial Solid and cystic component Mostly in posterior fossa Usually in cerebellar hemisphers and vermis	Glial cell origin Solid and cystic component GFAP +	Biopsy	Most of the time, cerebellar dysfunction is the presenting signs.
Medulloblastoma [25][26][27]	+	+/−	+/−	−	+	−	Infratentorial Mostly in cerebellum Non communicating hydrocephalus	Neuroectoderm origin Homer wright rosettes	Biopsy	Drop metastasis (metastasis through CSF)
Ependymoma [28][6]	+	+/−	+/−	−	+	−	Infratentorial Usually found in 4th ventricle Mixed cystic/solid lesion Hydrocephalus	Ependymal cell origin Perivascular pseudorosette	Biopsy	Causes an unusually persistent, continuous headache in children.
Craniopharyngioma [29][30][31][6]	+	+/−	+ Bitemporal hemianopia	−	+	Hypopituitarism as a result of pressure effect on pituitary gland	Calcification Lobulated contour Motor-oil like fluid within tumor	Ectodermal origin (Rathkes pouch) Calcification +	Biopsy	Initialy presents with lower bitemporal quadrantanopsia followed by bitemporal hemianopsia (pressure on optic chiasma from above)
Pinealoma [32][33][34]	+	+/−	+/−	−	+ vertical gaze palsy	B-hCG rise leads to precocious puberty in males	Hydrocephalus (compression of cerebral aqueduct)	Similar to testicular seminoma	Biopsy	May cause prinaud syndrome (vertical gaze palsy, pupillary light-near dissociation, lid retraction and convergence-retraction nystagmus
Vascular
AV malformation [35][36][6]	+	+	+/−	−	+/−	−	Supratentorial: ~85% Flow voids on T2 weighted images	We do not perform biopsy for AVM	Angiography	We may see bag of worms appearance in CT angiography
Brain aneurysm [37][38][39][40][41]	+	+/−	+/−	−	+/−	−	In magnetic resonance angiography, we may see aneurysm mostly in anterior circulation (~85%)	We do not perform biopsy for brain aneurysm	MRA and CTA	It is associated with autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome, pseudoxanthoma elasticum and Bicuspid aortic valve (Angiography is reserved for patients who have negative MRA and CTA)
Infectious
Bacterial brain abscess [42][43]	+	+/−	+/−	+	+	Leukocytosis Elevated ESR Blood culture may be positive for underlying organism	Central hypodense signal and surrounding ring-enhancement in T1 Central hyperintense area surrounded by a well-defined hypointense capsule with surrounding edema in T2	We do not perform biopsy for brain abscess	History/ imaging	The most common causes of brain abscess are Streptococcus and Staphylococcus.
Tuberculosis [44][6][45]	+	+/−	+/−	+	+	Positive acid-fast bacilli (AFB) smear in CSF specimen Positive CSF nucleic acid amplification testing Hyponatremia (inappropriate secretion of antidiuretic hormone) Mild anemia Leukocytosis	Hydrocephalus combined with marked basilar meningeal enhancement	We do not perform biopsy for brain tuberculosis	Lab data/ Imaging	It is associated with HIV infection
Toxoplasmosis [46][47]	+	+/−	+/−	−	+	Normal CSF	Multifocal masses with ring enhancement Mostly in basal ganglia, thalami, and corticomedullary junction.	We do not perform biopsy for brain toxoplasmosis	History/ imaging	It is associated with HIV infection
Hydatid cyst [48][6]	+	+/−	+/−	+/−	+	Positive serology (Antibody detection for E. granulosus)	Honeycomb appearance Necrotic area	We do not perform biopsy for hydatid cysts	Imaging	Brain, eye, and splenic cysts may not produce detectable amount of antibodies
CNS cryptococcosis [49]	+	+/−	+/−	+	+	Positive CSF antigen testing (coccidioidomycosis) CSF lymphocytic pleocytosis Elevated CSF proteins and lactate Low CSF glucose	Dilated perivascular spaces Basal ganglia pseudocysts Soap bubble brain lesions (cryptococcus neoformans)	We may see numerous acutely branching septate hyphae	Lab data/ Imaging	It is the most common brain fungal infection It is associated with HIV, immunosuppressive therapies, and organ transplants In may happen in immunocompetent patients undergoing invasive procedures ( neurosurgery) or exposed to contaminated devices or drugs Since brain biopsies are highly invasive and may may cause neurological deficits, we diagnose CNS fungal infections based on laboratory and imaging findings
CNS aspergillosis [50]	+	+/−	+/−	+	+	Positive galactomannan antigen testing (aspergillosis) CSF lymphocytic pleocytosis Elevated CSF proteins and lactate Low CSF glucose	Multiple abscesses Ring enhancement Peripheral low signal intensity on T2	We may see numerous acutely branching septate hyphae	Lab data/ Imaging	It is associated with HIV, immunosuppressive therapies, and organ transplants In may happen in immunocompetent patients undergoing invasive procedures ( neurosurgery) or exposed to contaminated devices or drugs Since brain biopsies are highly invasive and may may cause neurological deficits, we diagnose CNS fungal infections based on laboratory and imaging findings
Other
Brain metastasis [51][6]	+	+/−	+/−	+	+	−	Multiple lesions Vasogenic edema	Based on the primary cancer type we may have different immunohistopathology findings.	History/ imaging	Most common primary tumors that metastasis to brain: Lung cancer Renal cell carcinoma Breast cancer Melanoma Gastrointestinal tract If there is any uncertainty about etiology, biopsy should be performed

ABBREVIATIONS

CNS=Central nervous system, AV=Arteriovenous, CSF=Cerebrospinal fluid, NF-2=Neurofibromatosis type 2, MEN-1=Multiple endocrine neoplasia, GFAP=Glial fibrillary acidic protein, HIV=Human immunodeficiency virus, BhCG=Human chorionic gonadotropin, ESR=Erythrocyte sedimentation rate, AFB=Acid fast bacilli, MRA=Magnetic resonance angiography, CTA=CT angiography

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

Oligodendroglioma, although rare, is the third most common glioma. In adults, it constitutes about 9.4% of all primary brain and central nervous system tumors and 5%–18% of all glial neoplasms. The incidence of oligodendroglioma and anaplastic oligodendroglioma is estimated to be 0.32 and 0.17 cases per 100,000 individuals in the United States, respectively. Oligodendroglioma tends to affect the middle-aged adult population, most commonly occurring in the 4th and 5th decade of life. Median age at the time of diagnosis of oligodendroglioma is 35-47 years. Males are more commonly affected with oligodendroglioma than femaleswith male to female ratio being approximately 1.3:1. Oligodendroglioma usually affects individuals of the Caucasian race. African American, Latin American, and Asian individuals are less likely to develop oligodendroglioma.

• Oligodendroglioma, although rare, is the third most common glioma.^[1]
• It occurs primarily in adults constituting about 9.4% of all primary brain and central nervous system tumors and 5%–18% of all glial neoplasms.^[2]
• It can also be found in children comprising about 4% of all primary brain tumors.
• Oligodendroglioma and anaplastic oligodendroglioma, together are one-tenth as common as glioblastoma (most commonly occurring malignant primary brain tumor in adults).

• Incidence of oligodendroglioma and anaplastic oligodendroglioma is estimated to be 0.32 and 0.17 cases per 100,000 individuals in the United States, respectively.^[3][4]
• Approximately, 1000 oligodendroglial tumors are diagnosed each year in United States.

• Oligodendroglioma is a disease that tends to affect the middle-aged adult population (adults between 25 and 45 years of age).^[1]
• Oligodendroglioma most commonly occurs in the 4th and 5th decade of life.
• Median age at diagnosis of oligodendroglioma is 35-47 years.^[5]
• Median age at diagnosis is approximately 5 to 10 years older for World Health Organization (WHO) grade III (anaplastic) tumors compared with WHO grade II (low-grade) tumors.
• Oligodendroglioma is occasionally diagnosed in teenagers and in adults over the age of 65 years.^[6]

• Males are more commonly affected with oligodendroglioma than females.
• The male to female ratio is approximately 1.3:1.^[7]

• Oligodendroglioma usually affects individuals of the Caucasian race.
• African American, Latin American, and Asian individuals are less likely to develop oligodendroglioma.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

The most potent risk factor for the development of oligodendroglioma is a positive family history of brain tumors.

The most potent risk factor for the development of oligodendroglioma is a positive family history of brain tumors.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

There is insufficient evidence for recommending routine screening for oligodendroglioma.

There is insufficient evidence for recommending routine screening for oligodendroglioma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]Sujit Routray, M.D. [3]

If left untreated, patients with oligodendroglioma may progress to develop seizures, focal neurological deficits, hydrocephalus, brain herniation, intracranial hemorrhage, and ultimately death.Common complications associated with oligodendroglioma include hydrocephalus, intracranial hemorrhage, coma, bone marrow metastasis, recurrence, venous thromboembolism, parkinsonism, and side effects of chemotherapy and radiotherapy. Oligodendroglioma is a slow growing tumor having a good prognosis overall with prolonged survival. But the prognosis of oligodendroglioma may vary depending upon various prognostic factors such as population based estimates, clinical factors, tumor grade (II versus III), mechanism of chemosensitivity, and molecular markers such as 1p/19q-codeletion, IDH1/2 mutation, and TERT promoter mutations. The median survival time for oligodendroglioma is 11.6 yearsfor grade II and 3.5 years for grade III.

• Oligodendrogliomas tend to be low grade and less aggressive than other types of gliomas.
• These tumors are slow growing.
• The tumors may be present for many years before they are diagnosed.^[1]
• Anaplastic oligodendroglioma usually grows quickly.
• These tumors may develop in one place or in many places throughout the brain.
• If left untreated, patients with oligodendroglioma may progress to develop seizures, focal neurological deficits, hydrocephalus, brain herniation, intracranial hemorrhage, and ultimately death.^[2]
• Recurrence is a very common feature of oligodendrogliomas.
• Recurrence can be either of the same grade or higher grade at the primary site.^[3]
• Transformation into glioblastoma (grade 4) may occur a few years later, which may be associated with gain of chromosome 7 and loss of chromosome 10.^[3]

Common complications associated with oligodendroglioma include:^{[4][5][6][7][8][9][10]}

• Hydrocephalus
• Intracranial hemorrhage
• Coma
• Bone marrow metastasis
• Recurrence
• Venous thromboembolism
• Parkinsonism
• Side effects of chemotherapy
• Side effects of radiotherapy

• Depending on the extent and grade of the tumor at the time of diagnosis, the prognosis of oligodendroglioma may vary.
• However, the prognosis is generally regarded as good overall.^[11][12]
• Oligodendrogliomas are slowly growing tumors with prolonged survival.
• In March 2001, 7 neuropathologists and 6 surgical pathologists experienced in brain tumor–diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic during the period of 1960 to 1990. In this study, the prognostic value of histological grading of oligodendroglial tumors in tumor grading was assessed, and following parameters of significant association with survival was found:^[13]

Type of analysis	Factors significantly associated with survival
Univariate analysis	Age High cellularity Presence of mitoses Endothelial hypertrophy Proliferation and necrosis
Multivariable analysis	Age Presence of endothelial proliferation

Estimated mean survival of patients with different oligodendroglial tumors (both low-grade and anaplastic oligodendrogliomas)^[14]

Oligodendroglial tumor characteristics	Mean survival
1p/19q deletion with radiation	121 months
1p/19q deletion with chemotherapy	over 160 months (mean not yet reached)
No 1p/19q deletion with radiation	58 months
No 1p/19q deletion with chemotherapy	75 months

Estimated median survival of patients with anaplastic oligodendrogliomas^[15]

Anaplastic oligodendroglioma characteristics	Median survival
Combined 1p/19q loss	>123 months
1p loss only	71 months
1p intact with TP53 mutation	71 months
1p intact with no TP53 mutation	16 months

Following are the few prognostic factors associated with oligodendroglial tumors:

• According to the population based estimates, despite of the prolonged clinical course of oligodendroglial tumors, outcome is almost always fatal.
• Overall median survival for patients with low-grade oligodendroglioma is approximately 10 to 15 years.^[16][17]
• Median survival for patients with anaplastic oligodendroglioma is approximately 5 to 9 years.^[11]
• Median survival of patients with 1p/19q-codeleted oligodendrogliomas who are treated with radiation plus procarbazine, lomustine, and vincristine (PCV) may be closer to 20 years for grade II tumors and 15 years for grade III tumors.^[18][19][20]
• The presence of 1p/19q codeletion is associated with a better prognosis and greater chemosensitivity.^{[4][21][22][23]}
• Several other molecular markers have a potential clinical significance as IDH1 mutations, confirming the strong prognostic role for overall survival.^{[24][25][26][27][28][29]}
• The presence of EGFR gene mutation is associated with a worse prognosis.^[30]

Following is a list of more commonly identified clinical features that predict worse overall survival:

• Older age
• Poor functional status
• Baseline neurologic deficits
• Nonepilepsy presentation
• Tumor location other than frontal and parietal lobes
• Large tumor size (>4 to 5 cm)

Clinical features that are independently associated with improved overall survival in patients with anaplastic oligodendroglial tumors include:^[31][32]

• Younger age
• Confirmed absence of residual tumor by imaging after surgery
• Frontal tumor location
• Good performance status

• WHO grade III anaplastic oligodendrogliomas have worse prognosis comparative to low-grade tumors, with an average difference of approximately five years in overall survival(11.6 years for grade II and 3.5 years for grade III).^[29][33]
• The 5-year survival rates for oligodendroglioma and anaplastic oligodendroglioma varying with ages are tabulated below:^[34][13]

WHO grade of tumor	Age	5-year survival rate
Oligodendroglioma (Grade II)	20-44	82%
	45-54	67%
	55-64	48%
Anaplastic oligodendroglioma (Grade III)	20-44	64%
	45-54	50%
	55-64	23%

• 1p/19q-codeletion:
  • Presence of 1p/19q-codeletion is associated with improved survival in patients with IDH–mutant diffuse gliomas (with regard to both natural history of disease and better response to therapy).^{[35][36][37][38][39][40][24]}
  • Presence of polysomy of chromosomes 1 and 19 may be useful in identifying patients with poorer prognosis who have a subset of both anaplastic oligodendroglioma and a characteristic 1p/19q-codeletion.^[41][42]
  • Patients with 1p/19q loss and polysomy have a significantly shorter median progression-free survival compared with those without polysomy.^[41]
  • Capicua transcriptional repressor (CIC) inactivating mutations are associated with worse outcome in 1p/19q-codeleted oligodendrogliomas.^[43]
• IDH1/2 mutation:
  • IDH1 and IDH2 mutations are associated with improved survival in patients of glial tumors, irrespective of the treatment received.^[44][24]
  • Prognostic significance of IDH1/2 mutations is equally as strong as that of the 1p/19q-codeletion.^[24]
  • IDH mutations are found in diffuse gliomas with and without the 1p/19q-codeletion.
  • North American Radiation Therapy Oncology Group (RTOG) 9402 and 9802 studies suggested that IDH mutations are predictive for outcome to adjuvant chemotherapy, independent of other molecular factors.^{[18] [45]}
• TERT promoter mutations:
  • Prognostic significance is dependent on the genetic background of the tumor (as Telomerase reverse transcriptase (TERT) promoter mutations occur in virtually all 1p/19q-codeleted, IDH–mutant tumors and also in glioblastoma).
  • Negatively associated with alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutations (occur in most IDH–mutant astrocytomas).

• Studies have shown a high response rate with single-agent temozolomide.
• IDH mutations result in metabolic alterations, including:^[46]
  • Decreased alpha-ketoglutarate
  • Increased levels of 2-hydroxyglutarate (2HG)
  • Changes in nicotinamide adenine dinucleotide phosphate (NADP) levels
  • Decrease in alpha-ketoglutarate
  • Increase in 2HG
• This leads to epigenetic alterations and development of a CpG island hypermethylated phenotype (CIMP), which includes MGMT promoter methylation.^[47]
• MGMT is a nuclear enzyme responsible for deoxyribonucleic acid (DNA) repair following alkylating-agent chemotherapy and may mediate part of the cellular resistance to alkylating agents.
• MGMT expression can be silenced by methylation of its promoter.^[48]

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