Glioblastoma multiforme

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

Glioblastoma multiforme, also known as glioblastoma, is the most common adult primary intracranial neoplasm worldwide. Glioblastoma multiforme may be classified into several subtypes based on the origin and molecular alterations. On gross pathology, the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central necrotic core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include pleomorphic astrocytes with marked atypia, mitosis, necrosis, and microvascular proliferation. The incidence of glioblastoma multiforme is estimated to be 3.2 cases per 100,000 individuals worldwide. Glioblastoma multiforme is a common disease that tends to affect older adults and the elderly population. The median age at diagnosis is 64 years. Males are more commonly affected with glioblastoma multiforme than females. Common risk factors in the development of glioblastoma multiforme are radiation exposure, viruses, polyvinyl chloride, alcohol, and genetic disorders. Common complications of glioblastoma multiforme include herniation, systemic illness, brainstem invasion by tumor, neutron-induced cerebral injury, weakness, fatigue, numbness, surgical complications, and coma. Prognosis is generally poor, and the 5-year survival rate of patients with glioblastoma multiforme is less than 10%. Symptoms of glioblastoma multiforme include headache, seizure, memory loss, irritability, changes in speech, difficulty reading or concentrating, drowsiness, nausea, vomiting, muscle weakness, sensory loss, diplopia, blurred vision, vertigo, hearing loss, and hiccups. Common physical examination findings of glioblastoma multiforme include personality changes, memory loss, aphasia, hemiparesis, sensory loss, and ataxia. Head CT scan and brain MRI are helpful in the diagnosis of glioblastoma multiforme. On head CT scan, glioblastoma multiforme is characterized by a butterfly shaped mass with marked midline shift, irregular and heterogenous enhancement of margins, necrotic center, surrounding vasogenic edema, and hemorrhage. On brain MRI, glioblastoma multiforme is characterized by hypointense mass on T1-weighted MRI and hyperintense mass on T2-weighted MRI. The predominant therapy for glioblastoma multiforme is surgical resection. Adjunctive chemotherapy and radiation may be required. Supportive therapy for glioblastoma multiforme includes anticonvulsants and corticosteroids.

The term glioblastoma multiforme was first coined by Percival Bailey and Harvey Cushing in 1926.

Glioblastoma multiforme may be classified into several subtypes based on the origin (primary and secondary) and molecular alterations (classic, proneural, mesenchymal, and neural).

Genes involved in the pathogenesis of glioblastoma multiforme include Mdm2, PTEN, IDH1, p53, EGFR, PDGFRA, and chromosomes 10p, 10q, 17p, and 19q. On gross pathology, the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central necrotic core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include pleomorphic astrocytes with marked atypia, mitosis, necrosis, and microvascular proliferation.

There are no established causes for glioblastoma multiforme.

Glioblastoma multiforme must be differentiated from cerebral metastasis, primary CNS lymphoma, cerebral abscess, anaplastic astrocytoma, tumefactive demyelination, stroke, cerebral toxoplasmosis, radiation necrosis, encephalitis, oligodendroglioma, and seizure disorder.

Glioblastoma multiforme is the the most common adult primary intracranial neoplasm worldwide. The incidence of glioblastoma multiforme is estimated to be 3.2 cases per 100,000 individuals worldwide. Glioblastoma multiforme is a common disease that tends to affect older adult and elderly population. The median age at diagnosis is 64 years. Males are more commonly affected with glioblastoma multiforme than females. The male to female ratio is approximately 1.5 to 1. Glioblastoma multiforme usually affects individuals of the Caucasian race.

Common risk factors in the development of glioblastoma multiforme are radiation exposure, viruses, polyvinyl chloride, alcohol, and genetic disorders.

Screening for glioblastoma multiforme is not recommended.

If left untreated, glioblastoma multiforme may extend into the meninges, ventricular wall, or spinal cord. Common complications of glioblastoma multiforme include herniation, hydrocephalus, systemic illness, brainstem invasion by tumor, neutron-induced cerebral injury, weakness, fatigue, numbness, surgical complications, and coma. Prognosis is generally poor, and the 5-year survival rate of patients with glioblastoma multiforme is less than 10%.

There is no established system for the staging of glioblastoma multiforme.

Symptoms of glioblastoma multiforme include headache, seizure, memory loss, irritability, changes in speech, difficulty reading or concentrating, drowsiness, nausea, vomiting, muscle weakness, sensory loss, diplopia, blurred vision, vertigo, hearing loss, and hiccups.

Common physical examination findings of glioblastoma multiforme include personality changes, memory loss, aphasia, hemiparesis, sensory loss, and ataxia.

There are no diagnostic lab findings associated with glioblastoma multiforme.

There are no x-ray findings associated with glioblastoma multiforme.

Head CT scan is helpful in the diagnosis of glioblastoma multiforme. On head CT scan, glioblastoma multiforme is characterized by a butterfly shaped mass with marked midline shift, irregular and heterogenous enhancement of margins, necrotic center, surrounding vasogenic edema, and hemorrhage.

Brain MRI is helpful in the diagnosis of glioblastoma multiforme. On brain MRI, glioblastoma multiforme is characterized by a butterfly shaped mass, which is hypointense on T1-weighted MRI and hyperintense on T2-weighted MRI.

There are no ultrasound findings associated with glioblastoma multiforme.

Other imaging tests for glioblastoma multiforme include PET scan, which demonstrates accumulation of [18F]-fluorodeoxyglucose (increased glucose metabolism).

Other diagnostic studies for glioblastoma multiforme include biopsy, which demonstrates pleomorphic astroctyes with marked atypia and mitoses.

The predominant therapy for glioblastoma multiforme is surgical resection. Adjunctive chemotherapy and radiation may be required. Supportive therapy for glioblastoma multiforme includes anticonvulsants and corticosteroids.

Surgery is the mainstay of treatment for glioblastoma multiforme.

There are no established measures for primary prevention of glioblastoma multiforme.

There are no established measures for secondary prevention of glioblastoma multiforme.

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

The term “glioma” was first introduced by Rudolf Virchow in 1864. The suffix multiforme was meant to describe the various appearances of hemorrhage, necrosis, and cysts. the first successful removal of a brain tumor is credited to the Scottish neurosurgeon Sir William Macewen in 1879. The first successful removal of a brain tumor is credited to the Scottish neurosurgeon Sir William Macewen in 1879. In 1926 Percival Bailey and Harvey Cushing published “A Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis” and the term “glioblastoma multiforme” (GBM) was coined. The WHO classification dropped the term multiforme and thus it is best referred as glioblastoma or grade IV astrocytoma.

• The term “glioma” was first introduced by Rudolf Virchow in 1864.
• The suffix multiforme was meant to describe the various appearances of hemorrhage, necrosis, and cysts.
• the first successful removal of a brain tumor is credited to the Scottish neurosurgeon Sir William Macewen in 1879.
• In 1922 Bailey and Cushing created a histological laboratory to examine Cushing’s collection of brain tumours found within his registry.
• In 1926 Percival Bailey and Harvey Cushing published “A Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis” and the term “glioblastoma multiforme” (GBM) was coined.
• In 1940 neuropathologist Hans-Joachim Scherer made distinction between primary and secondary GBMs.
• Initially known as “spongioblastoma multiforme”, Bailey and Cushing adopted the term glioblastoma to limit confusion.
• In 1976 the International Classification of Diseases for Oncology (ICD-O) was created by the WHO for recording the incidence of malignancy and survival.
• In 1993, GBM was removed from its original category and placed in the spectrum of “Astrocytic Tumours” and is classed as WHO grade IV astrocytoma.
• The WHO classification dropped the term multiforme and thus it is best referred as glioblastoma or grade IV astrocytoma.

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

Glioblastoma multiforme may be classified into several subtypes based on the origin (primary and secondary) and molecular alterations (classic, proneural, mesenchymal, and neural).The heterogeneity of GBM profiles leads to different treatment efficacy among patients. The therapy must be personalized to target each patient’s alterations in the molecular level. ^[1]

Glioblastoma multiforme may be classified according to the origin into two subtypes: Primary and secondary.

Subtype of Glioblastoma multiforme	Characteristic features
Primary glioblastoma multiforme	De novo origin More aggressive Occurs in older patients
Secondary glioblastoma multiforme	Arises from pre-existing lower grade gliomas Less aggressive Occurs in younger patients

• Primary GBM is the most common form (about 95%) and arises typically de novo, within 3–6 months, in older patients.
• Secondary GBM arises from prior low-grade astrocytomas (over 10–15 years) in younger patients.
• Primary and secondary forms show some molecular differences.
• The end result of both sub type is same since the same pathways are affected and respond similarly to current standard treatment.
• Primary GBM often has amplified and mutated epidermal-growth factor receptor (EGFR) which encodes altered EGF receptor.
• Secondary GBM has increased signaling through PDGF-A receptor.
• Both types of mutations lead to increased tyrosine kinase receptor (TKR) activity and consequently to activation of RAS and PI3K pathways.
• Primary and secondary GBM may be indistinguishable histologically but apparently differ in genetic and epigenetic profiles.

• the Cancer Genome Atlas (TCGA) divided GBM according to the molecular alterations into four subtypes:^[1]

1. Classic
2. Proneural
3. Mesenchymal
4. Neural

• Classical GBM is defined by aberrant EGFR amplification with astrocytic cell expression pattern and loss of chromosome 10.
• The mesenchymal subtype is defined by NF1 and PTEN mutations, a mesenchymal expression profile and less EGFR amplification than in other GBM types.
• The proneural subtype is characterized by PDGFRA focal amplification, TP53 and IDH1 mutations with an oligodenrocytic cell expression profile and younger presentation age.
• The neural subtype is characterized by normal brain tissue gene expression wuth astrocytic and oligodendrocytic cell markers.
• Most GBM tumors with IDH1 mutations have the proneural gene expression pattern but only 30% of preneural GBM has the IDH1 mutation.
• IDH1 mutation is a reliable and definitive molecular diagnostic criterion of secondary GBM compared to clinical criteria.
• The heterogeneity of GBM profiles leads to different treatment efficacy among patients.
• The therapy must be personalized to target each patient’s alterations in the molecular level.

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

Genes involved in the pathogenesis of glioblastoma multiforme include Mdm2, PTEN, IDH1, p53, EGFR, PDGFRA, and chromosomes 10p, 10q, 17p, and 19q. On gross pathology, the characteristic findings of glioblastoma multiforme include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with a central necrotic core. On microscopic histopathological analysis, the characteristic findings of glioblastoma multiforme include pleomorphic astrocytes with marked atypia, mitosis, necrosis, and microvascular proliferation. Another important alteration is methylation of MGMT, a suicide DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide. Glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. Upregulating these ion channels, the tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids the tumor cells in changing cellular volume very rapidly.

• There are four subtypes of glioblastoma multiforme.^[1]
• Tumors in the “classical” subtype is characterized by mutations in EGFR.
• The “proneural” subtype often has high rates of alterations in TP53, PDGFRA, and IDH1.
• The “mesenchymal” subtype is characterized by mutations in NF1, and EGFR.
• The “neural” subtype has several mutations in many of the same genes as the other groups.
• Majority of the genetic alterations in glioblastoma multiforme are clustered in three pathways: p53, Rb, and PI3K/AKT.
• Another important alteration is methylation of MGMT, a suicide DNA repair enzyme. Methylation is described to impair DNA transcription and therefore, expression of the MGMT enzyme. Since MGMT can only repair one DNA alkylation due its suicide repair mechanism, reverse capacity is low and methylation of the MGMT gene promoter greatly affects DNA repair capacity. Hence, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.

• Cancer cells with stem cell-like properties have been found to be a cause of resistance to conventional treatment and high recurrence rate of glioblastoma multiforme.
• A biomarker that exhibits cancer stem cell properties, Hes3, has been shown to regulate cells of glioblastoma multiforme when placed in culture.

• The IDH1 gene is frequently mutated in glioblastoma multiforme (primary: 5%, secondary: 80%). By producing very high concentrations of the oncometabolite D-2-hydroxyglutarate and dysregulating the function of the wild-type IDH1-enzyme, it induces profound changes to the metabolism of IDH1-mutated glioblastoma multiforme compared with IDH1 wild-type glioblastoma multiforme or healthy astrocytes.
• The IDH1 mutation increases the dependence of glioblastoma multiforme on glutamine or glutamate as an energy source. Since healthy astrocytes excrete glutamate, IDH1-mutated glioblastoma multiforme cells do not favor dense tumor structures but instead migrate, invade and disperse into healthy parts of the brain where glutamate concentrations are higher. This may explain the invasive behavior of these IDH1-mutated glioblastoma multiforme.

• Glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels.
• Upregulating these ion channels, the tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H₂O movement through osmosis, which aids the tumor cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior, because quick adaptations in cellular volume can facilitate movement through the extracellular matrix of the brain.

• Development of glioblastoma multiforme is the result from multiple genetic mutations.
• Genes involved in the pathogenesis of glioblastoma multiforme include the following:^[2]

Types of glioblastoma multiforme	Genes
Primary​	Mdm2 PTEN Gene on chromosome 10p
Secondary	IDH1 p53 Gene on chromosome 10q Gene on chromosome 17p Gene on chromosome 19q
Classic	EGFR
Proneural	TP53 PDGFRA IDH1
Mesenchymal	NF-1

Glioblastoma multiforme may be associated with:^[2]

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

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On gross pathology, the characteristic findings of glioblastoma multiforme include:^[2][3]

• Supratentorial white matter is the most common location
• Poorly-marginated, diffusely infiltrating mass with a central necrotic core
• Ill-defined borders
• Firm or gelatinous in consistency
• Variable appearance (firm and white, to soft and yellow, to cystic with hemorrhage)
• Midline shift due to tumor mass
• Bihemispheric “butterfly glioma” in the corpus callosum

On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:^[2][3]

• Pleomorphic astrocytes with marked atypia and mitosis
• Necrosis and microvascular proliferation
• (+/-) Pseudopalisading necrosis
  • Tumor cells lined-up like a picket fence around necrotic areas

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According to WHO classification of brain tumors, glioblastoma multiforme is termed as grade IV tumor.^[2]

Glioblastoma multiforme is demonstrated by positivity to tumor markers such as GFAP.^[2]

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

Common causes of glioblastoma multiforme include genetic mutations.^[1]

Type of glioblastoma multiforme	Genes
Primary​	Mdm2 PTEN Gene on chromosome 10p
Secondary	IDH1 p53 Gene on chromosome 10q Gene on chromosome 17p Gene on chromosome 19q
Classic	EGFR
Proneural	TP53 PDGFRA IDH1
Mesenchymal	NF-1

Common causes of glioblastoma multiforme include genetic mutations.^[1]

Type of glioblastoma multiforme	Genes
Primary​	Mdm2 PTEN Gene on chromosome 10p
Secondary	IDH1 p53 Gene on chromosome 10q Gene on chromosome 17p Gene on chromosome 19q
Classic	EGFR
Proneural	TP53 PDGFRA IDH1
Mesenchymal	NF-1

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

Glioblastoma multiforme must be differentiated from cerebral metastasis, primary CNS lymphoma, cerebral abscess, anaplastic astrocytoma, tumefactive demyelination, stroke, cerebral toxoplasmosis, radiation necrosis, encephalitis, oligodendroglioma, and seizure disorder.^[1]

Glioblastoma multiforme must be differentiated from the following:^[1]

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
Glioblastoma multiforme [2][3][4]	+	+/−	+/−	−	+	−	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.
Oligodendroglioma [5][6][7]	+	+	+/−	−	+	−	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.
Meningioma [8][9][10]	+	+/−	+/−	−	+	−	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 [11][12][13][14]	+	+/−	+/−	−	+	−	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 [15][16][4]	−	−	+ 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 [17][18][19][20]	−	−	−	−	+	−	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 [21][22]	+	+/−	+/−	−	+	−	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 [23][24][25]	+	+/−	+/−	−	+	−	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 [26][27][28]	+	+/−	+/−	−	+	−	Infratentorial Mostly in cerebellum Non communicating hydrocephalus	Neuroectoderm origin Homer wright rosettes	Biopsy	Drop metastasis (metastasis through CSF)
Ependymoma [29][4]	+	+/−	+/−	−	+	−	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 [30][31][32][4]	+	+/−	+ 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 [33][34][35]	+	+/−	+/−	−	+ 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 [36][37][4]	+	+	+/−	−	+/−	−	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 [38][39][40][41][42]	+	+/−	+/−	−	+/−	−	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 [43][44]	+	+/−	+/−	+	+	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 [45][4][46]	+	+/−	+/−	+	+	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 [47][48]	+	+/−	+/−	−	+	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 [49][4]	+	+/−	+/−	+/−	+	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 [50]	+	+/−	+/−	+	+	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 [51]	+	+/−	+/−	+	+	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 [52][4]	+	+/−	+/−	+	+	−	Multiple lesions Vasogenic edema	Based on the primary cancer type we may have different immunohistopathology findings.	History/ imaging	References ↑ 1.0 1.1 DDx of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/glioblastoma ↑ Sathornsumetee S, Rich JN, Reardon DA (November 2007). “Diagnosis and treatment of high-grade astrocytoma”. Neurol Clin. 25 (4): 1111–39, x. doi:10.1016/j.ncl.2007.07.004. PMID 17964028. ↑ Pedersen CL, Romner B (January 2013). “Current treatment of low grade astrocytoma: a review”. Clin Neurol Neurosurg. 115 (1): 1–8. doi:10.1016/j.clineuro.2012.07.002. PMID 22819718. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Mattle, Heinrich (2017). Fundamentals of neurology : an illustrated guide. Stuttgart New York: Thieme. ISBN 9783131364524. ↑ Smits M (2016). “Imaging of oligodendroglioma”. Br J Radiol. 89 (1060): 20150857. doi:10.1259/bjr.20150857. PMC 4846213. PMID 26849038. ↑ Wesseling P, van den Bent M, Perry A (June 2015). “Oligodendroglioma: pathology, molecular mechanisms and markers”. Acta Neuropathol. 129 (6): 809–27. doi:10.1007/s00401-015-1424-1. PMC 4436696. PMID 25943885. ↑ Kerkhof M, Benit C, Duran-Pena A, Vecht CJ (2015). “Seizures in oligodendroglial tumors”. CNS Oncol. 4 (5): 347–56. doi:10.2217/cns.15.29. PMC 6082346. PMID 26478444. ↑ Zee CS, Chin T, Segall HD, Destian S, Ahmadi J (June 1992). “Magnetic resonance imaging of meningiomas”. Semin. Ultrasound CT MR. 13 (3): 154–69. PMID 1642904. ↑ Shibuya M (2015). “Pathology and molecular genetics of meningioma: recent advances”. Neurol. Med. Chir. (Tokyo). 55 (1): 14–27. doi:10.2176/nmc.ra.2014-0233. PMID 25744347. ↑ Begnami MD, Palau M, Rushing EJ, Santi M, Quezado M (September 2007). “Evaluation of NF2 gene deletion in sporadic schwannomas, meningiomas, and ependymomas by chromogenic in situ hybridization”. Hum. Pathol. 38 (9): 1345–50. doi:10.1016/j.humpath.2007.01.027. PMC 2094208. PMID 17509660. ↑ Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, Chew EY, Zhuang Z, Linehan WM, Oldfield EH (May 2014). “Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease”. J. Neurosurg. 120 (5): 1055–62. doi:10.3171/2014.1.JNS131431. PMC 4762041. PMID 24579662. ↑ Hussein MR (October 2007). “Central nervous system capillary haemangioblastoma: the pathologist’s viewpoint”. Int J Exp Pathol. 88 (5): 311–24. doi:10.1111/j.1365-2613.2007.00535.x. PMC 2517334. PMID 17877533. ↑ Lee SR, Sanches J, Mark AS, Dillon WP, Norman D, Newton TH (May 1989). “Posterior fossa hemangioblastomas: MR imaging”. Radiology. 171 (2): 463–8. doi:10.1148/radiology.171.2.2704812. PMID 2704812. ↑ Perks WH, Cross JN, Sivapragasam S, Johnson P (March 1976). “Supratentorial haemangioblastoma with polycythaemia”. J. Neurol. Neurosurg. Psychiatry. 39 (3): 218–20. PMID 945331. ↑ Kucharczyk W, Davis DO, Kelly WM, Sze G, Norman D, Newton TH (December 1986). “Pituitary adenomas: high-resolution MR imaging at 1.5 T”. Radiology. 161 (3): 761–5. doi:10.1148/radiology.161.3.3786729. PMID 3786729. ↑ Syro LV, Scheithauer BW, Kovacs K, Toledo RA, Londoño FJ, Ortiz LD, Rotondo F, Horvath E, Uribe H (2012). “Pituitary tumors in patients with MEN1 syndrome”. Clinics (Sao Paulo). 67 Suppl 1: 43–8. PMC 3328811. PMID 22584705. ↑ Donnelly, Martin J.; Daly, Carmel A.; Briggs, Robert J. S. (2007). “MR imaging features of an intracochlear acoustic schwannoma”. The Journal of Laryngology & Otology. 108 (12). doi:10.1017/S0022215100129056. ISSN 0022-2151. ↑ Feany MB, Anthony DC, Fletcher CD (May 1998). “Nerve sheath tumours with hybrid features of neurofibroma and schwannoma: a conceptual challenge”. Histopathology. 32 (5): 405–10. PMID 9639114. ↑ Chen H, Xue L, Wang H, Wang Z, Wu H (July 2017). “Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns”. Sci Rep. 7 (1): 5470. doi:10.1038/s41598-017-05769-0. PMID 28710469. ↑ Hardell, Lennart; Hansson Mild, Kjell; Sandström, Monica; Carlberg, Michael; Hallquist, Arne; Påhlson, Anneli (2003). “Vestibular Schwannoma, Tinnitus and Cellular Telephones”. Neuroepidemiology. 22 (2): 124–129. doi:10.1159/000068745. ISSN 0251-5350. ↑ Chinn RJ, Wilkinson ID, Hall-Craggs MA, Paley MN, Miller RF, Kendall BE, Newman SP, Harrison MJ (December 1995). “Toxoplasmosis and primary central nervous system lymphoma in HIV infection: diagnosis with MR spectroscopy”. Radiology. 197 (3): 649–54. doi:10.1148/radiology.197.3.7480733. PMID 7480733. ↑ Paulus, Werner (1999). “Classification, Pathogenesis and Molecular Pathology of Primary CNS Lymphomas”. Journal of Neuro-Oncology. 43 (3): 203–208. doi:10.1023/A:1006242116122. ISSN 0167-594X. ↑ Sathornsumetee S, Rich JN, Reardon DA (November 2007). “Diagnosis and treatment of high-grade astrocytoma”. Neurol Clin. 25 (4): 1111–39, x. doi:10.1016/j.ncl.2007.07.004. PMID 17964028. ↑ Pedersen CL, Romner B (January 2013). “Current treatment of low grade astrocytoma: a review”. Clin Neurol Neurosurg. 115 (1): 1–8. doi:10.1016/j.clineuro.2012.07.002. PMID 22819718. ↑ Mattle, Heinrich (2017). Fundamentals of neurology : an illustrated guide. Stuttgart New York: Thieme. ISBN 9783131364524. ↑ Dorwart, R H; Wara, W M; Norman, D; Levin, V A (1981). “Complete myelographic evaluation of spinal metastases from medulloblastoma”. Radiology. 139 (2): 403–408. doi:10.1148/radiology.139.2.7220886. ISSN 0033-8419. ↑ Fruehwald-Pallamar, Julia; Puchner, Stefan B.; Rossi, Andrea; Garre, Maria L.; Cama, Armando; Koelblinger, Claus; Osborn, Anne G.; Thurnher, Majda M. (2011). “Magnetic resonance imaging spectrum of medulloblastoma”. Neuroradiology. 53 (6): 387–396. doi:10.1007/s00234-010-0829-8. ISSN 0028-3940. ↑ Burger, P. C.; Grahmann, F. C.; Bliestle, A.; Kleihues, P. (1987). “Differentiation in the medulloblastoma”. Acta Neuropathologica. 73 (2): 115–123. doi:10.1007/BF00693776. ISSN 0001-6322. ↑ Yuh, E. L.; Barkovich, A. J.; Gupta, N. (2009). “Imaging of ependymomas: MRI and CT”. Child’s Nervous System. 25 (10): 1203–1213. doi:10.1007/s00381-009-0878-7. ISSN 0256-7040. ↑ Brunel H, Raybaud C, Peretti-Viton P, Lena G, Girard N, Paz-Paredes A, Levrier O, Farnarier P, Manera L, Choux M (September 2002). “[Craniopharyngioma in children: MRI study of 43 cases]”. Neurochirurgie (in French). 48 (4): 309–18. PMID 12407316.CS1 maint: Unrecognized language (link) ↑ Prabhu, Vikram C.; Brown, Henry G. (2005). “The pathogenesis of craniopharyngiomas”. Child’s Nervous System. 21 (8–9): 622–627. doi:10.1007/s00381-005-1190-9. ISSN 0256-7040. ↑ Kennedy HB, Smith RJ (December 1975). “Eye signs in craniopharyngioma”. Br J Ophthalmol. 59 (12): 689–95. PMC 1017436. PMID 766825. ↑ Ahmed SR, Shalet SM, Price DA, Pearson D (September 1983). “Human chorionic gonadotrophin secreting pineal germinoma and precocious puberty”. Arch. Dis. Child. 58 (9): 743–5. PMID 6625640. ↑ Sano, Keiji (1976). “Pinealoma in Children”. Pediatric Neurosurgery. 2 (1): 67–72. doi:10.1159/000119602. ISSN 1016-2291. ↑ Baggenstoss, Archie H. (1939). “PINEALOMAS”. Archives of Neurology And Psychiatry. 41 (6): 1187. doi:10.1001/archneurpsyc.1939.02270180115011. ISSN 0096-6754. ↑ Kucharczyk, W; Lemme-Pleghos, L; Uske, A; Brant-Zawadzki, M; Dooms, G; Norman, D (1985). “Intracranial vascular malformations: MR and CT imaging”. Radiology. 156 (2): 383–389. doi:10.1148/radiology.156.2.4011900. ISSN 0033-8419. ↑ Fleetwood, Ian G; Steinberg, Gary K (2002). “Arteriovenous malformations”. The Lancet. 359 (9309): 863–873. doi:10.1016/S0140-6736(02)07946-1. ISSN 0140-6736. ↑ Chapman, Arlene B.; Rubinstein, David; Hughes, Richard; Stears, John C.; Earnest, Michael P.; Johnson, Ann M.; Gabow, Patricia A.; Kaehny, William D. (1992). “Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease”. New England Journal of Medicine. 327 (13): 916–920. doi:10.1056/NEJM199209243271303. ISSN 0028-4793. ↑ Castori M, Voermans NC (October 2014). “Neurological manifestations of Ehlers-Danlos syndrome(s): A review”. Iran J Neurol. 13 (4): 190–208. PMC 4300794. PMID 25632331. ↑ Schievink, W. I.; Raissi, S. S.; Maya, M. M.; Velebir, A. (2010). “Screening for intracranial aneurysms in patients with bicuspid aortic valve”. Neurology. 74 (18): 1430–1433. doi:10.1212/WNL.0b013e3181dc1acf. ISSN 0028-3878. ↑ Germain DP (May 2017). “Pseudoxanthoma elasticum”. Orphanet J Rare Dis. 12 (1): 85. doi:10.1186/s13023-017-0639-8. PMC 5424392. PMID 28486967. ↑ Farahmand M, Farahangiz S, Yadollahi M (October 2013). “Diagnostic Accuracy of Magnetic Resonance Angiography for Detection of Intracranial Aneurysms in Patients with Acute Subarachnoid Hemorrhage; A Comparison to Digital Subtraction Angiography”. Bull Emerg Trauma. 1 (4): 147–51. PMC 4789449. PMID 27162847. ↑ Haimes, AB; Zimmerman, RD; Morgello, S; Weingarten, K; Becker, RD; Jennis, R; Deck, MD (1989). “MR imaging of brain abscesses”. American Journal of Roentgenology. 152 (5): 1073–1085. doi:10.2214/ajr.152.5.1073. ISSN 0361-803X. ↑ Brouwer, Matthijs C.; Tunkel, Allan R.; McKhann, Guy M.; van de Beek, Diederik (2014). “Brain Abscess”. New England Journal of Medicine. 371 (5): 447–456. doi:10.1056/NEJMra1301635. ISSN 0028-4793. ↑ Morgado, Carlos; Ruivo, Nuno (2005). “Imaging meningo-encephalic tuberculosis”. European Journal of Radiology. 55 (2): 188–192. doi:10.1016/j.ejrad.2005.04.017. ISSN 0720-048X. ↑ Be NA, Kim KS, Bishai WR, Jain SK (March 2009). “Pathogenesis of central nervous system tuberculosis”. Curr. Mol. Med. 9 (2): 94–9. PMC 4486069. PMID 19275620. ↑ Chinn RJ, Wilkinson ID, Hall-Craggs MA, Paley MN, Miller RF, Kendall BE, Newman SP, Harrison MJ (December 1995). “Toxoplasmosis and primary central nervous system lymphoma in HIV infection: diagnosis with MR spectroscopy”. Radiology. 197 (3): 649–54. doi:10.1148/radiology.197.3.7480733. PMID 7480733. ↑ Helton KJ, Maron G, Mamcarz E, Leventaki V, Patay Z, Sadighi Z (November 2016). “Unusual magnetic resonance imaging presentation of post-BMT cerebral toxoplasmosis masquerading as meningoencephalitis and ventriculitis”. Bone Marrow Transplant. 51 (11): 1533–1536. doi:10.1038/bmt.2016.168. PMID 27348541. ↑ Taslakian B, Darwish H (September 2016). “Intracranial hydatid cyst: imaging findings of a rare disease”. BMJ Case Rep. 2016. doi:10.1136/bcr-2016-216570. PMC 5030532. PMID 27620198. ↑ McCarthy M, Rosengart A, Schuetz AN, Kontoyiannis DP, Walsh TJ (July 2014). “Mold infections of the central nervous system”. N. Engl. J. Med. 371 (2): 150–60. doi:10.1056/NEJMra1216008. PMC 4840461. PMID 25006721. ↑ McCarthy M, Rosengart A, Schuetz AN, Kontoyiannis DP, Walsh TJ (July 2014). “Mold infections of the central nervous system”. N. Engl. J. Med. 371 (2): 150–60. doi:10.1056/NEJMra1216008. PMC 4840461. PMID 25006721. ↑ Pope WB (2018). “Brain metastases: neuroimaging”. Handb Clin Neurol. 149: 89–112. doi:10.1016/B978-0-12-811161-1.00007-4. PMC 6118134. PMID 29307364. Template:WikiDoc Sources

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

Glioblastoma multiforme is the the most common adult primary intracranial neoplasm worldwide. The incidence of glioblastoma multiforme is estimated to be 3.2 cases per 100,000 individuals worldwide. Glioblastoma multiforme is a common disease that tends to affect older adults and the elderly population. The median age at diagnosis is 64 years. Males are more commonly affected with glioblastoma multiforme than females. The male to female ratio is approximately 1.5 to 1. Glioblastoma multiforme usually affects individuals of the Caucasian race.

• Glioblastoma multiforme is the the most common adult primary intracranial neoplasm worldwide.^[1]
• The incidence of glioblastoma multiforme is estimated to be 3.2 cases per 100,000 individuals worldwide.^[2]
• This is highest IR among brain and CNS tumors with malignant behavior. ^[3]
• Incidence is highest in the northeast and lowest in the south-central region of US.^[4]

• Glioblastoma multiforme is the most malignant astrocytoma.^[5]
• The median overall survival (OS) is approximately 12 months and a 5‐year OS of 4.8%‐5.4%.

• Glioblastoma multiforme is a common disease that tends to affect older adults and the elderly population.
• The median age at diagnosis is 64 years.^[2]
• The incidence increases with age peaking at 75–84 years and drops after 85 years.^[4]
• Glioblastoma multiforme is uncommon in children.

• Males are more commonly affected with glioblastoma multiforme than females.
• The male to female ratio is approximately 1.6 to 1.^[1]
• Marital status is an independent prognostic factor for GBM.^[6]
• One observational study shows protective effect of marriage on GBM survival especially in male older than 60 years of age.^[6]

• Incidence of GBM is 2.0 times higher in Caucasians compared to Africans and Afro-Americans. ^[7]
• There is lower incidence in Asians and American Indians.^[8]

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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 glioblastoma multiforme are radiation exposure, viruses, polyvinyl chloride, alcohol, and genetic disorders.^[1]

Common risk factors in the development of glioblastoma multiforme are:^[1]

• Radiation exposure
• Viruses (SV40, HHV-6, and cytomegalovirus)
• Polyvinyl chloride
• Alcohol
• Genetic disorders
  • Neurofibromatosis type 1
  • Tuberous sclerosis
  • Von Hippel-Lindau disease
  • Li-Fraumeni syndrome
  • Turcot syndrome

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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]

Screening for glioblastoma multiforme is not recommended.

Screening for glioblastoma multiforme is not recommended.

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

If left untreated, glioblastoma multiforme may extend into the meninges, ventricular wall, or spinal cord. Common complications of glioblastoma multiforme include herniation, hydrocephalus, systemic illness, brainstem invasion by tumor, neutron-induced cerebral injury, weakness, fatigue, numbness, surgical complications, and coma. Prognosis is generally poor, and the 5-year survival rate of patients with glioblastoma multiforme is less than 10%.

• Glioblastoma multiforme usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% grow slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma.
• It may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid.
• The tumor cells carried in the CSF may rarely spread to the spinal cord. However, metastasis of glioblastoma multiforme beyond the central nervous system is rare. About 50% of glioblastoma multiforme are bilateral.
• It arises from the cerebrum and may rarely exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.

Common complications of glioblastoma multiforme include:^[1]

• Herniation (axial, transtentorial, subfalcine, tonsillar)
• Hydrocephalus
• Systemic illness
• Brainstem invasion by tumor
• Neutron-induced cerebral injury
• Weakness
• Fatigue
• Numbness
• Surgical complications (cerebral hemorrhage, edema)
• Coma

• Prognosis is generally poor, and the 5-year survival rate of patients with glioblastoma multiforme is less than 10%.
• Negative prognostic factors include:^[2]
  • Degree of necrosis
  • Degree of enhancement
  • Deep location (e.g. thalamus)
• With standard treatment (surgery, radiotherapy, and chemotherapy), the median survival is approximately 14 months.^[3]
• Removal of 98% or more of the tumor by surgery has been associated with a better prognosis.

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