Glioblastoma multiforme pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Glioblastoma is characterized by the presence of small areas of [[Necrosis|necrotizing]] tissue that are surrounded by [[anaplastic]] cells. Genes involved in the pathogenesis of glioblastoma include ''[[Mdm2]]'', ''[[PTEN]]'', ''IDH1'', ''[[p53]]'', and chromosomes 10p, 10q, 17p, and 19q. On gross pathology, the characteristic findings of glioblastoma include a poorly-marginated, diffusely infiltrating, firm or gelatinous mass with central [[necrosis|necrotic]] core. On microscopic histopathological analysis, the characteristic findings of | Glioblastoma multiforme is characterized by the presence of small areas of [[Necrosis|necrotizing]] tissue that are surrounded by [[anaplastic]] cells. Genes involved in the pathogenesis of glioblastoma multiforme include ''[[Mdm2]]'', ''[[PTEN]]'', ''IDH1'', ''[[p53]]'', 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 central [[necrosis|necrotic]] core. On microscopic histopathological analysis, the characteristic findings of Glioblastoma multiforme include [[pleomorphic]] [[astrocytes]] with marked [[atypia]], [[mitosis]], [[necrosis]], and microvascular proliferation.<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref> | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
Glioblastoma is characterized by the presence of small areas of [[Necrosis|necrotizing]] tissue that are surrounded by [[anaplastic]] cells. Presence of [[hyperplastic]] blood vessels differentiates | Glioblastoma multiforme is characterized by the presence of small areas of [[Necrosis|necrotizing]] tissue that are surrounded by [[anaplastic]] cells. Presence of [[hyperplastic]] blood vessels differentiates Glioblastoma multiforme from grade 3 [[astrocytomas]]. | ||
====Molecular alterations==== | ====Molecular alterations==== | ||
*There are four subtypes of glioblastoma.<ref name="pmid20129251">{{cite journal| author=Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al.| title=Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. | journal=Cancer Cell | year= 2010 | volume= 17 | issue= 1 | pages= 98-110 | pmid=20129251 | doi=10.1016/j.ccr.2009.12.020 | pmc=PMC2818769 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20129251 }} </ref> | *There are four subtypes of glioblastoma multiforme.<ref name="pmid20129251">{{cite journal| author=Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al.| title=Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. | journal=Cancer Cell | year= 2010 | volume= 17 | issue= 1 | pages= 98-110 | pmid=20129251 | doi=10.1016/j.ccr.2009.12.020 | pmc=PMC2818769 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20129251 }} </ref> | ||
*Tumors in the "''classical''" subtype carry extra copies of the [[epidermal growth factor receptor]] (''[[EGFR]]'') gene, and most have higher than normal expression of [[epidermal growth factor receptor]] (EGFR), whereas the gene ''[[TP53]]'', which is often mutated in glioblastoma, is rarely mutated in this subtype. | *Tumors in the "''classical''" subtype carry extra copies of the [[epidermal growth factor receptor]] (''[[EGFR]]'') gene, and most have higher than normal expression of [[epidermal growth factor receptor]] (EGFR), whereas the gene ''[[TP53]]'', which is often mutated in glioblastoma multiforme, is rarely mutated in this subtype. | ||
*The "''proneural''" subtype often has high rates of alterations in ''TP53'', and in ''PDGFRA'', the gene encoding a-type [[platelet-derived growth factor receptor]], and in ''IDH1'', the gene encoding [[isocitrate dehydrogenase]]-1. | *The "''proneural''" subtype often has high rates of alterations in ''TP53'', and in ''PDGFRA'', the gene encoding a-type [[platelet-derived growth factor receptor]], and in ''IDH1'', the gene encoding [[isocitrate dehydrogenase]]-1. | ||
*The "''mesenchymal''" subtype is characterized by high rates of mutations or other alterations in ''[[NF1]]'', the gene encoding [[Neurofibromin 1]] and fewer alterations in the ''EGFR'' gene and less expression of EGFR than other types. Many other genetic alterations have been described in glioblastoma, and the majority of them are clustered in three pathways, the ''[[p53]]'', ''[[Rb]]'', and PI3K/AKT. | *The "''mesenchymal''" subtype is characterized by high rates of mutations or other alterations in ''[[NF1]]'', the gene encoding [[Neurofibromin 1]] and fewer alterations in the ''EGFR'' gene and less expression of EGFR than other types. Many other genetic alterations have been described in glioblastoma multiforme, and the majority of them are clustered in three pathways, the ''[[p53]]'', ''[[Rb]]'', and PI3K/AKT. Glioblastoma multiforme have alterations in 64-87 %, 68-78 % and 88% of these pathways respectively. 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 enzyme 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. Indeed, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as [[temozolomide]]. | ||
*The "''neural''" subtype has several mutations in many of the same genes as the other groups. The prognosis is worse with aggressive treatment with respect to classical and mesenchymal subtypes. | *The "''neural''" subtype has several mutations in many of the same genes as the other groups. The prognosis is worse with aggressive treatment with respect to classical and mesenchymal subtypes. | ||
* | *Glioblastoma multiforme usually form in the cerebral [[white matter]], grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade [[astrocytoma]] or anaplastic astrocytoma. These are called secondary glioblastoma multiformes and are more common in younger patients (mean age 45 versus 62 years). | ||
*The tumor may extend into the [[meninges]] or [[ventricular system|ventricular]] wall, leading to high protein content in the [[cerebrospinal fluid]] (CSF) (> 100 mg/dL), as well as an occasional [[pleocytosis]] of 10 - 100 cells, mostly [[lymphocyte]]s. [[Malignant]] cells carried in the CSF may rarely spread to the [[spinal cord]] or cause meningeal gliomatosis. However, [[metastasis]] of glioblastoma beyond the [[central nervous system]] is extremely unusual. About 50% of | *The tumor may extend into the [[meninges]] or [[ventricular system|ventricular]] wall, leading to high protein content in the [[cerebrospinal fluid]] (CSF) (> 100 mg/dL), as well as an occasional [[pleocytosis]] of 10 - 100 cells, mostly [[lymphocyte]]s. [[Malignant]] cells carried in the CSF may rarely spread to the [[spinal cord]] or cause meningeal gliomatosis. However, [[metastasis]] of glioblastoma multiforme beyond the [[central nervous system]] is extremely unusual. About 50% of glioblastoma multiforme occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the [[cerebrum]] and may rarely exhibit the classic infiltration across the [[corpus callosum]], producing a butterfly (bilateral) [[glioma]]. | ||
*The tumor may take on a variety of appearances, depending on the amount of [[hemorrhage]], [[necrosis]], or its age. | *The tumor may take on a variety of appearances, depending on the amount of [[hemorrhage]], [[necrosis]], or its age. | ||
====Glioblastoma stem-like cells==== | ====Glioblastoma multiforme stem-like cells==== | ||
*Cancer cells with stem cell-like properties have been found in | *Cancer cells with stem cell-like properties have been found in glioblastoma multiforme, which may be a cause of their resistance to conventional treatment and high recurrence rate. | ||
*A [[biomarker]] that exhibits [[cancer stem cell]] properties, Hes3, has been shown to regulate cells of glioblastoma when placed in culture. | *A [[biomarker]] that exhibits [[cancer stem cell]] properties, Hes3, has been shown to regulate cells of glioblastoma multiforme when placed in culture. | ||
====Metabolism==== | ====Metabolism==== | ||
*The ''IDH1'' gene encodes for the enzyme [[isocitrate dehydrogenase]] 1 and is frequently [[mutated]] in glioblastoma (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 compared with ''IDH1'' wild-type glioblastoma or healthy astrocytes. | *The ''IDH1'' gene encodes for the enzyme [[isocitrate dehydrogenase]] 1 and 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. | ||
*Among others, it increases the dependence of glioblastoma on [[glutamine]] or [[glutamate]] as an energy source. It has been hypothesized that ''IDH1''-mutated glioblastoma use [[glutamate]] as a chemotactic signal. Since healthy [[astrocyte]]s excrete glutamate, ''IDH1''-mutated glioblastoma 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 behaviour of these ''IDH1''-mutated glioblastoma. | *Among others, it increases the dependence of glioblastoma multiforme on [[glutamine]] or [[glutamate]] as an energy source. It has been hypothesized that ''IDH1''-mutated glioblastoma multiforme use [[glutamate]] as a chemotactic signal. Since healthy [[astrocyte]]s 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 behaviour of these ''IDH1''-mutated glioblastoma multiforme. | ||
====Ion channels==== | ====Ion channels==== | ||
*Glioblastoma exhibits numerous alterations in [[genes]] that encode for [[ion channels]], including upregulation of gBK potassium channels and ClC-3 chloride channels. | *Glioblastoma multiforme exhibits numerous alterations in [[genes]] that encode for [[ion channels]], including upregulation of gBK potassium channels and ClC-3 chloride channels. | ||
*It has been hypothesized that by upregulating these ion channels, glioblastoma tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H<sub>2</sub>O movement through [[osmosis]], which aids glioblastoma 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. | *It has been hypothesized that by upregulating these ion channels, glioblastoma multiforme tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H<sub>2</sub>O movement through [[osmosis]], which aids glioblastoma multiforme 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. | ||
===Genetics=== | ===Genetics=== | ||
*Development of glioblastoma is the result from multiple genetic [[mutations]]. | *Development of glioblastoma multiforme is the result from multiple genetic [[mutations]]. | ||
*Genes involved in the pathogenesis of glioblastoma include the following:<ref name=ddd>Pathology of | *Genes involved in the pathogenesis of glioblastoma multiforme include the following:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref> | ||
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|valign=top| | |valign=top| | ||
|+ | |+ | ||
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of | ! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of Glioblastoma multiforme}} | ||
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Genes}} | ! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Genes}} | ||
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===Associated Conditions=== | ===Associated Conditions=== | ||
Glioblastoma may be associated with:<ref name=ddd>Pathology of | Glioblastoma multiforme may be associated with:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref> | ||
*[[Neurofibromatosis type 1]] | *[[Neurofibromatosis type 1]] | ||
*[[Li-Fraumeni syndrome]] | *[[Li-Fraumeni syndrome]] | ||
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===Gross Pathology=== | ===Gross Pathology=== | ||
On gross pathology, the characteristic findings of | On gross pathology, the characteristic findings of glioblastoma multiformes include:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref><ref name=ccc>Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma multiforme</ref> | ||
*[[Supratentorial]] [[white matter]] is the most common location | *[[Supratentorial]] [[white matter]] is the most common location | ||
*Poorly-marginated, diffusely infiltrating mass with central [[necrosis|necrotic]] core | *Poorly-marginated, diffusely infiltrating mass with central [[necrosis|necrotic]] core | ||
Line 83: | Line 83: | ||
===Microscopic Pathology=== | ===Microscopic Pathology=== | ||
On microscopic histopathological analysis, the characteristic findings of | On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref><ref name=ccc>Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma multiforme</ref> | ||
*[[Pleomorphic]] [[astrocytes]] with marked [[atypia]] and [[mitosis]] | *[[Pleomorphic]] [[astrocytes]] with marked [[atypia]] and [[mitosis]] | ||
*[[Necrosis]] and microvascular proliferation | *[[Necrosis]] and microvascular proliferation | ||
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**[[Tumor]] cells lined-up like a picket fence around necrotic areas | **[[Tumor]] cells lined-up like a picket fence around necrotic areas | ||
According to WHO classification of [[brain tumors]], glioblastoma is termed as grade IV tumor.<ref name=ddd>Pathology of | According to WHO classification of [[brain tumors]], glioblastoma multiforme is termed as grade IV tumor.<ref name=ddd>Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref> | ||
<div align="left"> | <div align="left"> | ||
<gallery heights="175" widths="175"> | <gallery heights="175" widths="175"> | ||
Image:Glioblastoma (1).jpg|Glioblastoma (histology slide) | Image:Glioblastoma multiforme (1).jpg|Glioblastoma multiforme (histology slide) | ||
</gallery> | </gallery> | ||
</div> | </div> | ||
===Markers=== | ===Markers=== | ||
Glioblastoma is demonstrated by positivity to [[tumor markers]] such as [[GFAP]].<ref name=ddd>Pathology of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/ | Glioblastoma multiforme is demonstrated by positivity to [[tumor markers]] such as [[GFAP]].<ref name=ddd>Pathology of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme</ref> | ||
==References== | ==References== |
Revision as of 17:05, 18 September 2015
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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]
Overview
Glioblastoma multiforme is characterized by the presence of small areas of necrotizing tissue that are surrounded by anaplastic cells. Genes involved in the pathogenesis of glioblastoma multiforme include Mdm2, PTEN, IDH1, p53, 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 central necrotic core. On microscopic histopathological analysis, the characteristic findings of Glioblastoma multiforme include pleomorphic astrocytes with marked atypia, mitosis, necrosis, and microvascular proliferation.[1]
Pathophysiology
Pathogenesis
Glioblastoma multiforme is characterized by the presence of small areas of necrotizing tissue that are surrounded by anaplastic cells. Presence of hyperplastic blood vessels differentiates Glioblastoma multiforme from grade 3 astrocytomas.
Molecular alterations
- There are four subtypes of glioblastoma multiforme.[2]
- Tumors in the "classical" subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of epidermal growth factor receptor (EGFR), whereas the gene TP53, which is often mutated in glioblastoma multiforme, is rarely mutated in this subtype.
- The "proneural" subtype often has high rates of alterations in TP53, and in PDGFRA, the gene encoding a-type platelet-derived growth factor receptor, and in IDH1, the gene encoding isocitrate dehydrogenase-1.
- The "mesenchymal" subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding Neurofibromin 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types. Many other genetic alterations have been described in glioblastoma multiforme, and the majority of them are clustered in three pathways, the p53, Rb, and PI3K/AKT. Glioblastoma multiforme have alterations in 64-87 %, 68-78 % and 88% of these pathways respectively. 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 enzyme 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. Indeed, MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.
- The "neural" subtype has several mutations in many of the same genes as the other groups. The prognosis is worse with aggressive treatment with respect to classical and mesenchymal subtypes.
- Glioblastoma multiforme usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Less than 10% form more slowly following degeneration of low-grade astrocytoma or anaplastic astrocytoma. These are called secondary glioblastoma multiformes and are more common in younger patients (mean age 45 versus 62 years).
- The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 - 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may rarely spread to the spinal cord or cause meningeal gliomatosis. However, metastasis of glioblastoma multiforme beyond the central nervous system is extremely unusual. About 50% of glioblastoma multiforme occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may rarely exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.
- The tumor may take on a variety of appearances, depending on the amount of hemorrhage, necrosis, or its age.
Glioblastoma multiforme stem-like cells
- Cancer cells with stem cell-like properties have been found in glioblastoma multiforme, which may be a cause of their resistance to conventional treatment and high recurrence rate.
- A biomarker that exhibits cancer stem cell properties, Hes3, has been shown to regulate cells of glioblastoma multiforme when placed in culture.
Metabolism
- The IDH1 gene encodes for the enzyme isocitrate dehydrogenase 1 and 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.
- Among others, it increases the dependence of glioblastoma multiforme on glutamine or glutamate as an energy source. It has been hypothesized that IDH1-mutated glioblastoma multiforme use glutamate as a chemotactic signal. 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 behaviour of these IDH1-mutated glioblastoma multiforme.
Ion channels
- Glioblastoma multiforme exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels.
- It has been hypothesized that by upregulating these ion channels, glioblastoma multiforme tumor cells can facilitate increased ion movement over the cell membrane, thereby increasing H2O movement through osmosis, which aids glioblastoma multiforme 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.
Genetics
- Development of glioblastoma multiforme is the result from multiple genetic mutations.
- Genes involved in the pathogenesis of glioblastoma multiforme include the following:[1]
Types of Glioblastoma multiforme | Genes |
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|
|
|
|
Associated Conditions
Glioblastoma multiforme may be associated with:[1]
- Neurofibromatosis type 1
- Li-Fraumeni syndrome
- Turcot syndrome
- Ollier disease
- Maffucci syndrome
- Tuberous sclerosis
- Von Hippel-Lindau disease
Gross Pathology
On gross pathology, the characteristic findings of glioblastoma multiformes include:[1][3]
- Supratentorial white matter is the most common location
- Poorly-marginated, diffusely infiltrating mass with 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
Microscopic Pathology
On microscopic histopathological analysis, the characteristic findings of glioblastoma multiformes include:[1][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
According to WHO classification of brain tumors, glioblastoma multiforme is termed as grade IV tumor.[1]
-
Glioblastoma multiforme (histology slide)
Markers
Glioblastoma multiforme is demonstrated by positivity to tumor markers such as GFAP.[1]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Pathology of Glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/Glioblastoma multiforme
- ↑ Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD; et al. (2010). "Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma multiforme characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1". Cancer Cell. 17 (1): 98–110. doi:10.1016/j.ccr.2009.12.020. PMC 2818769. PMID 20129251.
- ↑ 3.0 3.1 Pathology of Glioblastoma multiforme. Libre Pathology. http://librepathology.org/wiki/index.php/Glioblastoma multiforme