View source for Glioma

{{Short description|Tumor of the glial cells of the brain or spine}}
{{Copy edit|date=January 2025}}
{{Use dmy dates|date=September 2019}}
{{Infobox medical condition (new)
| name            = Glioma
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| image           = Glioma.gif
| caption         = Glioma in the left parietal lobe (brain CT scan), WHO grade 2
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| field           = [[Oncology]], [[Neurology]]
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| risks           = Advanced age, ionizing radiation<ref name="ref1">{{Cite journal |date=2024-05-09 |title=Glioma |journal=Nature Reviews Disease Primers |language=en |volume=10 |issue=1 |page=34 |doi=10.1038/s41572-024-00524-y |issn=2056-676X |doi-access=free |pmid=38724549 }}</ref> 
| diagnosis       = [[Neuroimaging|Brain imaging]]<ref name = "ref1"/>
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A '''glioma''' is a type of [[primary tumor|primary]] [[Neoplasm|tumor]] that starts in the [[glial cells]] of the [[Human brain|brain]] or [[spinal cord]]. They are [[Malignancy|malignant]] but some are extremely slow to develop.<ref name="CRUK23">{{cite web |title=Glioma |url=https://www.cancerresearchuk.org/about-cancer/brain-tumours/types/glioma-adults?_gl=1*iiq8vr*_gcl_au*MTg2NjcyMDYyNy4xNzIxODM0MjY4*_ga*NDI2Mjg3MDg3LjE3MjE4MzM3MTM.*_ga_58736Z2GNN*MTcyMTgzMzcxMy4xLjEuMTcyMTgzNDI2Ny42LjAuMA.. |website=www.cancerresearchuk.org |access-date=24 July 2024 |language=en}}</ref><ref name="CRUK">{{cite web |title=Primary and secondary brain tumours |url=https://www.cancerresearchuk.org/about-cancer/brain-tumours/types/primary-secondary-tumours#:~:text=Primary%20brain%20tumours%20can%20be,that%20protect%20the%20brain%20(meninges) |website=www.cancerresearchuk.org |access-date=24 July 2024 |language=en}}</ref> Gliomas comprise about 30% of all [[brain tumor|brain]] and [[central nervous system|central]] [[Nervous system tumor|nervous system tumors]] and 80% of all malignant brain tumors.<ref name=Goodenberger2012>{{cite journal |vauthors = Goodenberger ML, Jenkins RB |title = Genetics of adult glioma |journal = Cancer Genetics |volume = 205 |issue = 12 |pages = 613–21 |date = December 2012 |pmid = 23238284 |doi = 10.1016/j.cancergen.2012.10.009}}</ref> They are a few common types that include [[astrocytoma]] (cancer of [[Astrocyte|astrocytes]]), [[glioblastoma]] (an aggressive form of astrocytoma), [[oligodendroglioma]] (cancer of [[Oligodendrocyte|oligodendrocytes]]), and [[ependymoma]] (cancer of [[Ependyma|ependymal]] cells).

==Signs and symptoms==
Symptoms of gliomas depend on the part of the [[central nervous system]] (CNS) that is affected.  A brain glioma can cause [[headaches]], [[nausea|vomiting]], [[memory loss]], [[seizures]], [[Visual impairment|vision problems]], [[speech disorder|speech difficulties]], and [[cranial nerve]] disorders as a result of increased [[intracranial pressure]].<ref>{{Cite web |title=Glioma - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/glioma/symptoms-causes/syc-20350251 |access-date=2025-03-28 |website=Mayo Clinic |language=en}}</ref> [[Cognitive impairment|Cognitive impairments]] such as [[vision loss]] arise in glioma patients when a tumor arises in or around their [[optic nerve]].<ref>{{Cite journal |last1=Loon |first1=Ellen M. P. van |last2=Heijenbrok-Kal |first2=Majanka H. |last3=Loon |first3=Wouter S. van |last4=Bent |first4=Martin J. van den |last5=Vincent |first5=Arnaud J. P. E. |last6=Koning |first6=Inge de |last7=Ribbers |first7=Gerard M. |date=2015-05-08 |title=Assessment methods and prevalence of cognitive dysfunction in patients with low-grade glioma: A systematic review. |url=https://medicaljournalssweden.se/jrm/article/view/15568 |journal=Journal of Rehabilitation Medicine |language=en |volume=47 |issue=6 |pages=481–488 |doi=10.2340/16501977-1975 |pmid=25994416 |issn=1651-2081}}</ref> Spinal cord gliomas can cause pain, weakness, or [[numbness]] in the extremities. Gliomas do not usually [[metastasis|metastasize]] by the bloodstream, but they can spread via the [[cerebrospinal fluid]] and cause "[[CNS metastasis|drop metastases]]" to the spinal cord. Complex [[visual hallucination]]s have been described as a symptom of [[grading (tumors)|low-grade]] glioma.<ref>{{cite journal|vauthors=Lim A, Weir P, O'Brien TJ, Kaye AH |title=Complex visual hallucinations as a presentation of temporal low-grade glioma |journal=Journal of Clinical Neuroscience |volume=18 |issue=1 |pages=157–9 |date=January 2011 |pmid=20965734 |doi=10.1016/j.jocn.2010.07.112 |s2cid=34392868 }}</ref>

Children with sub-acute [[Central nervous system disease|CNS disorders]] that produces cranial nerve abnormalities (especially of [[cranial nerve VII]] and the lower bulbar nerves), long-tract signs, unsteady gait secondary to spasticity, and some behavioral changes are likely to have a [[Pons|pontine]] glioma, a tumor of the brainstem.<ref>PRETEST pediatrics p. 224</ref>

==Causes==
===Hereditary disorders===
The exact causes of gliomas are not known. [[genetic disorders|Hereditary disorders]] such as [[neurofibromatoses]] (type 1 and type 2) and [[tuberous sclerosis complex]] are known to predispose to their development.<ref>{{cite book |vauthors=Reuss D, von Deimling A |title=Gliomas |chapter=Hereditary Tumor Syndromes and Gliomas |volume=171 |pages=83–102 |year=2009 |pmid=19322539 |doi=10.1007/978-3-540-31206-2_5 |isbn=978-3-540-31205-5 |series=Recent Results in Cancer Research}}</ref> Different [[oncogene]]s can cooperate in the development of gliomas.<ref>{{cite journal |vauthors = Radner H, el-Shabrawi Y, Eibl RH, Brüstle O, Kenner L, Kleihues P, Wiestler OD |title = Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose |journal = Acta Neuropathologica |volume = 86 |issue = 5 |pages = 456–65 |year = 1993 |pmid = 8310796 |doi = 10.1007/bf00228580 |s2cid = 2972931}}</ref>

===Radiation===
The best-known risk factor is exposure to [[ionizing radiation]], and [[CT scan]] radiation is an important cause.<ref name="nrsCT1">Smoll NR, Brady Z, Scurrah KJ, Lee C, Berrington de González A, Mathews JD. Computed tomography scan radiation and brain cancer incidence. Neuro-Oncology. 2023 Jan 14;https://doi.org/10.1093/neuonc/noad012</ref><ref name="nrsIR1">Smoll NR, Brady Z, Scurrah K, Mathews JD. Exposure to ionizing radiation and brain cancer incidence: The Life Span Study cohort. Cancer Epidemiology. 2016 Jun;42:60–5.</ref> The dose-response for the relationship between low-dose ionizing radiation and glioma risk is a risk increase of 55% per 100 milligray of radiation.<ref name="nrsCT1" /> A link between gliomas and [[electromagnetic radiation]] from [[cell phones]] has not been conclusively proven.<ref>{{cite journal | vauthors = Söderqvist F, Carlberg M, Hansson Mild K, Hardell L | title = Childhood brain tumour risk and its association with wireless phones: a commentary | journal = Environmental Health | volume = 10 | issue = 106 | pages = 106 | date = December 2011 | pmid = 22182218 | pmc = 3278351 | doi = 10.1186/1476-069X-10-106 | doi-access = free | bibcode = 2011EnvHe..10..106S }}</ref> It was considered possible,<ref>{{cite journal | vauthors = Morgan LL, Kesari S, Davis DL |title=Why children absorb more microwave radiation than adults: The consequences |journal=Journal of Microscopy and Ultrastructure |year=2014 |volume=4 |issue=2 |pages=197–204 |doi=10.1016/j.jmau.2014.06.005 |doi-access=free }}</ref><ref>{{cite press release |title=IARC classifies radiofrequency electromagnetic fields as possibly carcinogenic to humans |url=http://www.iarc.fr/en/media-centre/pr/2011/pdfs/pr208_E.pdf |publisher=IARC |date=31 May 2011 |access-date=1 June 2011 |archive-date=1 June 2011 |archive-url=https://web.archive.org/web/20110601063650/http://www.iarc.fr/en/media-centre/pr/2011/pdfs/pr208_E.pdf |url-status=live }}</ref> though several large studies have found no conclusive evidence, as summarized by the [[National Institute of Health]]'s [[National Cancer Institute]] review of the topic<ref>{{Cite web|url=http://www.cancer.gov/about-cancer/causes-prevention/risk/radiation/cell-phones-fact-sheet|title=Cell Phones and Cancer Risk|website=National Cancer Institute|access-date=2016-05-29|archive-date=2 June 2016|archive-url=https://web.archive.org/web/20160602054156/http://www.cancer.gov/about-cancer/causes-prevention/risk/radiation/cell-phones-fact-sheet|url-status=live}}</ref> and its numerous citations,<ref>{{Cite web|url=http://www.cancer.gov/about-cancer/causes-prevention/risk/radiation/cell-phones-fact-sheet#r1|title=Cell Phones and Cancer Risk (References)|website=National Cancer Institute|access-date=2016-05-29|archive-date=2 June 2016|archive-url=https://web.archive.org/web/20160602054156/http://www.cancer.gov/about-cancer/causes-prevention/risk/radiation/cell-phones-fact-sheet#r1|url-status=live}}</ref> and the [[FCC]].<ref>{{Cite web|url=https://www.fcc.gov/consumers/guides/wireless-devices-and-health-concerns|title=Wireless Devices and Health Concerns|date=2011-05-26|website=[[Federal Communications Commission]] (FCC)|access-date=2016-05-29}}</ref> However, further research is still being pursued to obtain more robust evidence and verify that there is no relationship (the NIH's National Institute of Environmental Health Sciences most recent press release discussed an ongoing study<ref>{{Cite press release|url=http://www.niehs.nih.gov/news/newsroom/releases/2016/may27/|title=Media Telebriefing: NTP Cell Phone Radiofrequency Radiation Study: Partial Release of Findings|website=niehs.nih.gov|access-date=2016-05-29|archive-date=6 June 2016|archive-url=https://web.archive.org/web/20160606001251/http://www.niehs.nih.gov/news/newsroom/releases/2016/may27/|url-status=live}}</ref> showing mildly positive results,<ref>{{cite bioRxiv | vauthors=Wyde M, Cesta M, Blystone C, Elmore S, Foster P, Hooth M, Kissling G, Malarkey D, Sills R, Stout M, Walker N, Witt K, Wolfe M, Bucher J | author7-link=Grace E. Kissling | display-authors=3 | date=2018-01-01 | title=Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley SD rats (Whole Body Exposure) | biorxiv=10.1101/055699 }}</ref> although it appears there may have been issues with the control group dying prematurely<ref>{{Cite news|url=http://www.cnn.com/2016/05/27/health/cell-phone-radiation-cancer-study/index.html|title=Cell phone radiation increases cancers in rats, but should we worry?|last=Storrs|first=Carina|publisher=CNN|date=27 May 2016|access-date=2016-05-29|name-list-style=vanc|archive-date=29 May 2016|archive-url=https://web.archive.org/web/20160529041504/http://www.cnn.com/2016/05/27/health/cell-phone-radiation-cancer-study/index.html|url-status=live}}</ref>).

===Infection with cytomegalovirus===
Some studies have reported that glioblastomas are infected with [[cytomegalovirus]], with suggestions that this may speed the development of tumors.<ref>{{cite journal | vauthors = Michaelis M, Baumgarten P, Mittelbronn M, Driever PH, Doerr HW, Cinatl J | title = Oncomodulation by human cytomegalovirus: novel clinical findings open new roads | journal = Medical Microbiology and Immunology | volume = 200 | issue = 1 | pages = 1–5 | date = February 2011 | pmid = 20967552 | doi = 10.1007/s00430-010-0177-7 | s2cid = 22444291 }}</ref><ref>{{cite journal | vauthors = Barami K | title = Oncomodulatory mechanisms of human cytomegalovirus in gliomas | journal = Journal of Clinical Neuroscience | volume = 17 | issue = 7 | pages = 819–23 | date = July 2010 | pmid = 20427188 | doi = 10.1016/j.jocn.2009.10.040 | s2cid = 6952978 }}</ref><ref>{{cite journal | vauthors = Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L, Cobbs CS | display-authors = 6 | title = Consensus on the role of human cytomegalovirus in glioblastoma | journal = Neuro-Oncology | volume = 14 | issue = 3 | pages = 246–55 | date = March 2012 | pmid = 22319219 | pmc = 3280809 | doi = 10.1093/neuonc/nor227 | others = HCMV and Gliomas Symposium }}</ref> However, this is a controversial opinion, with recent in-depth studies failing to find an association between [[oncovirus|viral infection]] and glioma growth.<ref>{{cite journal |last1=Strong |first1=MJ |last2=Blanchard E |first2=4th |last3=Lin |first3=Z |last4=Morris |first4=CA |last5=Baddoo |first5=M |last6=Taylor |first6=CM |last7=Ware |first7=ML |last8=Flemington |first8=EK |title=A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus&nbsp;— tumor association. |journal=Acta Neuropathologica Communications |date=11 July 2016 |volume=4 |issue=1 |pages=71 |doi=10.1186/s40478-016-0338-z |pmid=27402152|pmc=4940872 |doi-access=free }}</ref> There is also evidence that previous studies may have been impacted by [[false-positive]] [[immunostaining|antibody staining]] artifacts.<ref>{{cite journal |last1=Holdhoff |first1=M |last2=Guner |first2=G |last3=Rodriguez |first3=FJ |last4=Hicks |first4=JL |last5=Zheng |first5=Q |last6=Forman |first6=MS |last7=Ye |first7=X |last8=Grossman |first8=SA |last9=Meeker |first9=AK |last10=Heaphy |first10=CM |last11=Eberhart |first11=CG |last12=De Marzo |first12=AM |last13=Arav-Boger |first13=R |title=Absence of Cytomegalovirus in Glioblastoma and Other High-grade Gliomas by Real-time PCR, Immunohistochemistry, and ''In Situ'' Hybridization. |journal=Clinical Cancer Research |date=15 June 2017 |volume=23 |issue=12 |pages=3150–3157 |doi=10.1158/1078-0432.CCR-16-1490 |pmid=28034905|pmc=5474132 |doi-access=free }}</ref>

===Farming===

Studies have shown that farmers have higher rates of gliomas compared to the general population. In a 2021 meta-analysis, 40 of 52 studies since 1998 reported positive associations between farming and brain cancer with effect estimates ranging from 1.03 to 6.53, of which 80% are gliomas. [[Livestock farming]] was associated with a greater risk compared with [[crop farming]]. Farmers with documented exposure to [[pesticide]]s had greater than a 20% elevated risk of brain cancer.<ref>{{Cite journal |last1=Gatto |first1=Nicole M. |last2=Ogata |first2=Pamela |last3=Lytle |first3=Brittany |date=2021-09-05 |title=Farming, Pesticides, and Brain Cancer: A 20-Year Updated Systematic Literature Review and Meta-Analysis |journal=Cancers |volume=13 |issue=17 |pages=4477 |doi=10.3390/cancers13174477 |doi-access=free |issn=2072-6694 |pmc=8431399 |pmid=34503287}}</ref>{{unreliable source?|date=January 2024}} The TRACTOR project study, including 1,017 brain tumors among 1,036,069 farm managers, published in 2022, showed an increased risk of glioma in [[pig farming]] (HR = 2.28), crop farming (HR = 1.28) and [[fruit]] [[arboriculture]] (HR = 1.72)<ref>{{Cite journal |last1=Petit |first1=Pascal |last2=Gandon |first2=Gérald |last3=Chabardès |first3=Stéphan |last4=Bonneterre |first4=Vincent |date=2022-11-15 |title=Agricultural activities and risk of central nervous system tumors among French farm managers: Results from the TRACTOR project |journal=International Journal of Cancer |volume=151 |issue=10 |pages=1737–1749 |doi=10.1002/ijc.34197 |issn=1097-0215 |pmc=9796624 |pmid=35781883 }}</ref>{{medical citation needed|date=January 2024}}

===Other causes===
Data show that [[architect]]s, [[surveying|surveyors]], [[retail worker]]s, [[butcher]]s, and [[engineer]]s have higher rates of gliomas.<ref name=":0">{{cite journal | vauthors = Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS | display-authors = 6 | title = The epidemiology of glioma in adults: a "state of the science" review | journal = Neuro-Oncology | volume = 16 | issue = 7 | pages = 896–913 | date = July 2014 | pmid = 24842956 | pmc = 4057143 | doi = 10.1093/neuonc/nou087 }}</ref>

===Inherited polymorphisms of the DNA repair genes===
Germ-line (inherited) [[gene polymorphism|polymorphism]]s of the DNA repair genes ''[[ERCC1]]'', ''[[ERCC2]]'' (''XPD'') and ''[[XRCC1]]'' increase the risk of glioma.<ref name="pmid24500421">{{cite journal |vauthors = Adel Fahmideh M, Schwartzbaum J, Frumento P, Feychting M |title = Association between DNA repair gene polymorphisms and risk of glioma: a systematic review and meta-analysis |journal = Neuro-Oncology |volume=16 |issue=6 |pages=807–14 |date=June 2014 |pmid=24500421 |pmc=4022225 |doi = 10.1093/neuonc/nou003}}</ref> This indicates that altered or deficient repair of DNA damage contributes to the formation of gliomas.  DNA damages are a likely major primary cause of progression to cancer in general.<ref name="Bernstein">{{Citation |last1=Bernstein |first1=Carol |title=DNA Damage, DNA Repair and Cancer |date=2013-05-22 |url=http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer |work=New Research Directions in DNA Repair |editor-last=Chen |editor-first=Clark |publisher=InTech |language=en |doi=10.5772/53919 |isbn=978-953-51-1114-6 |access-date=2022-07-03 |last2=R. |first2=Anil |last3=Nfonsam |first3=Valentine |last4=Bernstei |first4=Harris |doi-access=free |archive-date=29 January 2021 |archive-url=https://web.archive.org/web/20210129094755/https://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer |url-status=live }}</ref> Excess DNA damages can give rise to mutations through [[Mutation#Error prone replication by-pass|translesion synthesis]]. Furthermore, incomplete DNA repair can give rise to [[Epigenetics|epigenetic]] alterations or epimutations.<ref>{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | display-authors = 6 | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}</ref><ref>{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | date = August 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | author-link3 = Stephen B. Baylin | doi-access = free }}</ref> Such mutations and epimutations may provide a cell with a proliferative advantage which can then, by a process of natural selection, lead to progression to cancer.<ref name="Bernstein"/>

[[Cancer epigenetics|Epigenetic]] repression of DNA repair genes is often found in progression to [[Cancer#Heredity|sporadic]] [[glioblastoma]].  For instance, [[methylation]] of the DNA repair gene [[O-6-methylguanine-DNA methyltransferase|''MGMT'']] [[Promoter (genetics)|promoter]] was observed in 51% to 66% of glioblastoma specimens.<ref name="pmid22672670">{{cite journal | vauthors = Skiriute D, Vaitkiene P, Saferis V, Asmoniene V, Skauminas K, Deltuva VP, Tamasauskas A | title = MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma | journal = BMC Cancer | volume = 12 | pages = 218 | date = June 2012 | pmid = 22672670 | pmc = 3404983 | doi = 10.1186/1471-2407-12-218 | doi-access = free }}</ref><ref name=Spiegel>{{cite journal | vauthors = Spiegl-Kreinecker S, Pirker C, Filipits M, Lötsch D, Buchroithner J, Pichler J, Silye R, Weis S, Micksche M, Fischer J, Berger W | display-authors = 6 | title = O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients | journal = Neuro-Oncology | volume = 12 | issue = 1 | pages = 28–36 | date = January 2010 | pmid = 20150365 | pmc = 2940563 | doi = 10.1093/neuonc/nop003 }}</ref> In addition, in some glioblastomas, the MGMT protein is deficient due to another type of epigenetic alteration.  MGMT protein expression may also be reduced due to increased levels of a [[microRNA]] that inhibits the ability of the ''MGMT'' [[messenger RNA]] to produce the MGMT protein.<ref name=Spiegel /> Zhang et al.<ref name="pmid22570426">{{cite journal | vauthors = Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, Jiang T, Chen CC | display-authors = 6 | title = miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression | journal = Neuro-Oncology | volume = 14 | issue = 6 | pages = 712–9 | date = June 2012 | pmid = 22570426 | pmc = 3367855 | doi = 10.1093/neuonc/nos089 }}</ref> found, in the glioblastomas without methylated ''MGMT'' [[Promoter (genetics)|promoters]], that the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and that the direct target of miR-181d is the ''MGMT'' mRNA 3'UTR (the three prime untranslated region of ''MGMT'' messenger RNA).<ref>{{Cite journal |last1=Zhang |first1=Wei |last2=Zhang |first2=Jing |last3=Hoadley |first3=Katherine |last4=Kushwaha |first4=Deepa |last5=Ramakrishnan |first5=Valya |last6=Li |first6=Shouwei |last7=Kang |first7=Chunsheng |last8=You |first8=Yongping |last9=Jiang |first9=Chuanlu |last10=Song |first10=Sonya Wei |last11=Jiang |first11=Tao |date=2012-06-01 |title=miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression |journal=Neuro-Oncology |volume=14 |issue=6 |pages=712–719 |doi=10.1093/neuonc/nos089 |issn=1522-8517 |pmc=3367855 |pmid=22570426}}</ref>

Epigenetic reductions in expression of another DNA repair protein, ''[[ERCC1]]'', were found in an assortment of 32 gliomas.<ref name="pmid19626585">{{cite journal | vauthors = Chen HY, Shao CJ, Chen FR, Kwan AL, Chen ZP | title = Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas | journal = International Journal of Cancer | volume = 126 | issue = 8 | pages = 1944–1954 | date = April 2010 | pmid = 19626585 | doi = 10.1002/ijc.24772 | doi-access = free }}</ref> For 17 of the 32 (53%) of the gliomas tested, ERCC1 protein expression was reduced or absent.  In the case of 12 gliomas (37.5%) this reduction was due to methylation of the ''ERCC1'' promoter.  For the other 5 gliomas with reduced ERCC1 protein expression, the reduction could have been due to epigenetic alterations in [[microRNA]]s that affect ''ERCC1'' expression.<ref>{{Cite journal |last1=Gao |first1=Dan |last2=Herman |first2=James G. |last3=Guo |first3=Mingzhou |date=2016-03-07 |title=The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer |url=https://www.oncotarget.com/article/7949/text/ |journal=Oncotarget |language=en |volume=7 |issue=24 |pages=37331–37346 |doi=10.18632/oncotarget.7949 |issn=1949-2553 |pmc=5095080 |pmid=26967246 |access-date=3 July 2022 |archive-date=15 June 2022 |archive-url=https://web.archive.org/web/20220615143503/https://www.oncotarget.com/article/7949/text/ |url-status=live }}</ref>

When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and such excess damages cause increased frequencies of mutation.<ref name=Narayanan>{{cite journal | vauthors = Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM | title = Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 7 | pages = 3122–7 | date = April 1997 | pmid = 9096356 | pmc = 20332 | doi = 10.1073/pnas.94.7.3122 | bibcode = 1997PNAS...94.3122N | doi-access = free }}</ref><ref name=Hegan>{{cite journal | vauthors = Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM | title = Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6 | journal = Carcinogenesis | volume = 27 | issue = 12 | pages = 2402–8 | date = December 2006 | pmid = 16728433 | pmc = 2612936 | doi = 10.1093/carcin/bgl079 }}</ref><ref name=Tutt>{{cite journal | vauthors = Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A | title = Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation | journal = EMBO Reports | volume = 3 | issue = 3 | pages = 255–60 | date = March 2002 | pmid = 11850397 | pmc = 1084010 | doi = 10.1093/embo-reports/kvf037 }}</ref> Mutations in gliomas frequently occur in either ''[[isocitrate dehydrogenase]]'' (''IDH'') ''1'' or ''2'' genes.<ref name=":1">{{cite journal | vauthors = Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE | title = The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1846 | issue = 2 | pages = 326–41 | date = December 2014 | pmid = 24880135 | doi = 10.1016/j.bbcan.2014.05.004 }}</ref> One of these mutations (mostly in ''IDH1'') occurs in about 80% of low grade gliomas and secondary high-grade gliomas.<ref name=Cohen>{{cite journal | vauthors = Cohen AL, Holmen SL, Colman H | title = IDH1 and IDH2 mutations in gliomas | journal = Current Neurology and Neuroscience Reports | volume = 13 | issue = 5 | pages = 345 | date = May 2013 | pmid = 23532369 | pmc = 4109985 | doi = 10.1007/s11910-013-0345-4 }}</ref> Wang et al.<ref name="pmid22824796">{{cite journal | vauthors = Wang P, Dong Q, Zhang C, Kuan PF, Liu Y, Jeck WR, Andersen JB, Jiang W, Savich GL, Tan TX, Auman JT, Hoskins JM, Misher AD, Moser CD, Yourstone SM, Kim JW, Cibulskis K, Getz G, Hunt HV, Thorgeirsson SS, Roberts LR, Ye D, Guan KL, Xiong Y, Qin LX, Chiang DY | display-authors = 6 | title = Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas | journal = Oncogene | volume = 32 | issue = 25 | pages = 3091–100 | date = June 2013 | pmid = 22824796 | pmc = 3500578 | doi = 10.1038/onc.2012.315 }}</ref> pointed out that ''IDH1'' and ''IDH2'' mutant cells produce an excess metabolic intermediate, 2-hydroxyglutarate, which binds to catalytic sites in key enzymes that are important in altering [[histone]] and DNA [[Promoter (genetics)|promoter]] methylation. Thus, mutations in ''IDH1'' and ''IDH2'' generate a "DNA CpG island methylator phenotype or CIMP"<ref name="pmid10411935">{{cite journal | vauthors = Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP | title = CpG island methylator phenotype in colorectal cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 15 | pages = 8681–6 | date = July 1999 | pmid = 10411935 | pmc = 17576 | doi = 10.1073/pnas.96.15.8681 | bibcode = 1999PNAS...96.8681T | author-link2 = Nita Ahuja | author-link4 = James G. Herman | doi-access = free }}</ref><ref name="pmid24834258">{{cite journal | vauthors = Nazemalhosseini Mojarad E, Kuppen PJ, Aghdaei HA, Zali MR | title = The CpG island methylator phenotype (CIMP) in colorectal cancer | journal = Gastroenterology and Hepatology from Bed to Bench | volume = 6 | issue = 3 | pages = 120–8 | year = 2013 | pmid = 24834258 | pmc = 4017514 }}</ref> that causes promoter hypermethylation and concomitant silencing of tumor suppressor genes such as DNA repair genes ''MGMT'' and ''ERCC1''.  On the other hand, Cohen et al.<ref name=Cohen /> and Molenaar et al.<ref name=":1" /> pointed out that mutations in ''IDH1'' or ''IDH2'' can cause increased oxidative stress.  Increased oxidative damage to DNA could be mutagenic. This is supported by an increased number of DNA double-strand breaks in ''IDH1''-mutated glioma cells.<ref>{{cite journal | vauthors = Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, Henneman P, Khurshed M, Lenting K, Mul AN, Dimitrakopoulou D, van Drunen CM, Hoebe RA, Radivoyevitch T, Wilmink JW, Maciejewski JP, Vandertop WP, Leenders WP, Bleeker FE, van Noorden CJ | display-authors = 6 | title = Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198 | journal = Cancer Research | volume = 75 | issue = 22 | pages = 4790–802 | date = November 2015 | pmid = 26363012 | doi = 10.1158/0008-5472.CAN-14-3603 | doi-access = free | url = https://aacr.figshare.com/articles/journal_contribution/Supplementary_Table_S1_from_Radioprotection_of_i_IDH1_i_-Mutated_Cancer_Cells_by_the_IDH1-Mutant_Inhibitor_AGI-5198/22412268/1/files/39858192.pdf }}</ref> Thus, ''IDH1'' or ''IDH2'' mutations act as driver mutations in glioma carcinogenesis, though it is not clear by which role they are primarily acting.  A study, involving 51 patients with brain gliomas who had two or more biopsies over time, showed that mutation in the ''IDH1'' gene occurred prior to the occurrence of a ''p53'' mutation or a 1p/19q loss of heterozygosity, indicating that an ''IDH1'' mutation is an early driver mutation.<ref name="pmid19246647">{{cite journal | vauthors = Watanabe T, Nobusawa S, Kleihues P, Ohgaki H | title = IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas | journal = The American Journal of Pathology | volume = 174 | issue = 4 | pages = 1149–53 | date = April 2009 | pmid = 19246647 | pmc = 2671348 | doi = 10.2353/ajpath.2009.080958 }}</ref>

==Pathophysiology==
High-grade gliomas are highly [[vascular tumor]]s and have a tendency to infiltrate diffusely.<ref name="Malignant glioma: genetics and biol"/>  They have extensive areas of [[necrosis]] and [[hypoxia (medical)|hypoxia]].  Often, tumor growth causes a breakdown of the [[blood–brain barrier]] in the vicinity of the tumor.  As a rule, high-grade gliomas almost always grow back even after complete surgical excision, so are commonly called recurrent cancer of the brain.{{medical citation needed|date=September 2019}}<ref>{{Cite journal |last1=Pasqualini |first1=Claudia |last2=Kozaki |first2=Tatsuya |last3=Bruschi |first3=Marco |last4=Nguyen |first4=Thi Hai Hoa |last5=Minard-Colin |first5=Véronique |last6=Castel |first6=David |last7=Grill |first7=Jacques |last8=Ginhoux |first8=Florent |date=December 2020 |title=Modeling the Interaction between the Microenvironment and Tumor Cells in Brain Tumors |journal=Neuron |volume=108 |issue=6 |pages=1025–1044 |doi=10.1016/j.neuron.2020.09.018 |pmid=33065047 |s2cid=222413763 |issn=0896-6273|doi-access=free }}</ref>

Conversely, low-grade gliomas grow slowly, often over many years, and can be followed without treatment unless they grow and cause symptoms.{{medical citation needed|date=September 2019}}  

Several acquired (not inherited) genetic mutations have been found in gliomas. [[P53|Tumor suppressor protein 53]] (p53) is mutated early in the disease.<ref>{{cite journal | vauthors = von Deimling A, Eibl RH, Ohgaki H, Louis DN, von Ammon K, Petersen I, Kleihues P, Chung RY, Wiestler OD, Seizinger BR | display-authors = 6 | title = p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma | journal = Cancer Research | volume = 52 | issue = 10 | pages = 2987–90 | date = May 1992 | pmid = 1349850 }}</ref> p53 is the "guardian of the genome", which, during DNA and cell duplication, makes sure the DNA is copied correctly and destroys the cell ([[apoptosis]]) if the DNA is mutated and cannot be fixed. When p53 itself is mutated, other mutations can survive. [[Phosphatase and tensin homolog]] (PTEN), another tumor suppressor gene, is itself lost or mutated. [[Epidermal growth factor receptor]], a growth factor that normally stimulates cells to divide, is amplified and stimulates cells to divide too much. Together, these mutations lead to cells dividing uncontrollably, a hallmark of cancer. In 2009, mutations in ''[[IDH1]]'' and'' [[IDH2]]'' were found to be part of the mechanism and associated with a less favorable prognosis.<ref>{{cite journal | vauthors = Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD | display-authors = 6 | title = IDH1 and IDH2 mutations in gliomas | journal = The New England Journal of Medicine | volume = 360 | issue = 8 | pages = 765–73 | date = February 2009 | pmid = 19228619 | pmc = 2820383 | doi = 10.1056/NEJMoa0808710 }}</ref>

==Diagnosis==
===Classification===

====By type of cell====
Gliomas are named according to the specific type of cell with which they share [[Histology|histological]] features, but not necessarily from which they originate. The main types of glioma are:<ref>{{cite web|title=Gliomas|url=http://www.hopkinsmedicine.org/healthlibrary/conditions/nervous_system_disorders/gliomas_134,22/|website=Johns Hopkins Medicine Health Library|access-date=19 April 2017|archive-date=10 May 2017|archive-url=https://web.archive.org/web/20170510033017/http://www.hopkinsmedicine.org/healthlibrary/conditions/nervous_system_disorders/gliomas_134,22/|url-status=live}}</ref>
* [[Ependymoma]]s: [[ependymal cell]]s
* [[Astrocytoma]]s: [[astrocyte]]s ([[glioblastoma multiforme]] is a malignant astrocytoma and the most common primary brain tumor among adults).
* [[Oligodendroglioma]]s: [[oligodendrocyte]]s
* [[Brainstem glioma]]: develop in the [[brain stem]]
* [[Optic nerve glioma]]: develop in or around the [[optic nerve]]
* Chordoid glioma, a rare low-grade tumor of the [[third ventricle]]<ref name="Zarghouni">{{cite journal |last1=Zarghouni |first1=M |last2=Vandergriff |first2=C |last3=Layton |first3=KF |last4=McGowan |first4=JB |last5=Coimbra |first5=C |last6=Bhakti |first6=A |last7=Opatowsky |first7=MJ |title=Chordoid glioma of the third ventricle. |journal=Proceedings (Baylor University. Medical Center) |date=July 2012 |volume=25 |issue=3 |pages=285–6 |doi=10.1080/08998280.2012.11928853 |pmid=22754136|pmc=3377302 }}</ref>
* Mixed gliomas, such as [[oligoastrocytomas]], contain cells from different types of glia

====By grade====
Gliomas are further categorised according to their [[Grading (tumors)|grade]], which is determined by [[pathology|pathologic]] evaluation of the tumor. The neuropathological evaluation and diagnostics of brain tumor specimens is performed according to WHO Classification of Tumours of the Central Nervous System.<ref>{{cite journal | vauthors = Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW | display-authors = 6 | title = The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary | journal = Acta Neuropathologica | volume = 131 | issue = 6 | pages = 803–20 | date = June 2016 | pmid = 27157931 | doi = 10.1007/s00401-016-1545-1 | doi-access = free }}</ref><ref>{{Cite book|title=WHO classification of tumours of the central nervous system| veditors = Louis DN, Ohgaki H, Wiestler OD, Cavenee WK |others=World Health Organization |publisher=International Agency for Research on Cancer |isbn=9789283244929 |edition= Revised 4th |location=Lyon |oclc=951745876 |year=2016}}{{page needed|date=October 2019}}</ref>

[[Image:MRI glioma 28 yr old male.JPG|thumb|right|Low-grade brain glioma in a 28-year-old male. (Taken on 10 July 2007)]]
* Biologically benign gliomas [WHO grade I] are comparatively low risk and can be removed surgically depending on their location<ref name="Malignant glioma: genetics and biol">{{cite journal | vauthors = Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA | title = Malignant glioma: genetics and biology of a grave matter | journal = Genes & Development | volume = 15 | issue = 11 | pages = 1311–33 | date = June 2001 | pmid = 11390353 | doi = 10.1101/gad.891601 | doi-access = free }}</ref>
* Low-grade gliomas [WHO grade II] are well-differentiated (not [[Anaplasia|anaplastic]]); these tend to exhibit [[cancer|benign]] tendencies and portend a better prognosis for the patient. However, they have a uniform rate of recurrence and increase in grade over time so should be classified as malignant.
* High-grade [WHO grades III–IV] gliomas are undifferentiated or [[anaplastic]]; these are [[cancer|malignant]] and carry a worse prognosis. Despite being classified as a high-grade glioma, infant-type hemispheric gliomas  have relatively good clinical outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.<ref>Neuro-Oncology, Volume 25, Issue Supplement_1, June 2023, Pages i38–i39, https://doi.org/10.1093/neuonc/noad073.152</ref>

Of numerous grading systems in use, the most common is the [[World Health Organization]] (WHO) grading system for astrocytoma, under which tumors are graded from I (least advanced disease—best prognosis) to IV (most advanced disease—worst prognosis).

====By location====
Gliomas can be classified according to whether they are above or below a membrane in the brain called the [[tentorium cerebelli|tentorium]].<ref>{{Cite journal |last1=Fyllingen |first1=Even Hovig |last2=Bø |first2=Lars Eirik |last3=Reinertsen |first3=Ingerid |last4=Jakola |first4=Asgeir Store |last5=Sagberg |first5=Lisa Millgård |last6=Berntsen |first6=Erik Magnus |last7=Salvesen |first7=Øyvind |last8=Solheim |first8=Ole |date=2021-07-01 |title=Survival of glioblastoma in relation to tumor location: a statistical tumor atlas of a population-based cohort |url=https://doi.org/10.1007/s00701-021-04802-6 |journal=Acta Neurochirurgica |language=en |volume=163 |issue=7 |pages=1895–1905 |doi=10.1007/s00701-021-04802-6 |issn=0942-0940 |pmc=8195961 |pmid=33742279}}</ref> The tentorium separates the [[cerebrum]] (above) from the [[cerebellum]] (below).
* The [[supratentorial]] is above the tentorium, in the cerebrum, and mostly found in adults (70%).<ref name="Persaud-Sharma 16">{{Cite journal |last1=Persaud-Sharma |first1=Dharam |last2=Burns |first2=Joseph |last3=Trangle |first3=Jeran |last4=Moulik |first4=Sabyasachi |date=September 2017 |title=Disparities in Brain Cancer in the United States: A Literature Review of Gliomas |journal=Medical Sciences |language=en |volume=5 |issue=3 |pages=16 |doi=10.3390/medsci5030016 |issn=2076-3271 |pmc=5635804 |pmid=29099032|doi-access=free }}</ref>
* The [[infratentorial]] is below the tentorium, in the cerebellum, and mostly found in children (70%).<ref name="Persaud-Sharma 16"/>
* The pontine tumors are located in the [[pons]] of the brainstem. The brainstem has three parts (pons, midbrain, and medulla); the pons controls critical functions such as breathing, making surgery on these extremely dangerous.<ref>{{Cite journal |last1=Liu |first1=Huanbing |last2=Qin |first2=Xiaowei |last3=Zhao |first3=Liyan |last4=Zhao |first4=Gang |last5=Wang |first5=Yubo |year=2021 |title=Epidemiology and Survival of Patients With Brainstem Gliomas: A Population-Based Study Using the SEER Database |journal=Frontiers in Oncology |volume=11 |doi=10.3389/fonc.2021.692097 |issn=2234-943X |pmc=8237753 |pmid=34195093 |doi-access=free }}</ref>

===Integrated diagnosis===
[[File:Diagnosis of diffuse glioma.png|thumb|Diagnosis of diffuse glioma. MVP = microvascular proliferation. The presence and absence of the diagnostically most relevant molecular alterations for each tumor type are highlighted with red and green boxes.<ref name=Weller2020>{{cite journal| author=Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G | display-authors=etal| title=EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. | journal=Nat Rev Clin Oncol | year= 2021 | volume= 18 | issue= 3 | pages= 170–186 | pmid=33293629 | doi=10.1038/s41571-020-00447-z | pmc=7904519 }}<br>"This article is licensed under a Creative Commons Attribution 4.0 International License"</ref>]]
The modern approach to the diagnosis of diffuse gliomas takes mainly the histopathology and molecular profile into account.<ref name=Weller2020/> Tissue specimens obtained through biopsy sampling in patients with diffuse gliomas are routinely assessed by immunohistochemistry for the presence of R132H-mutant IDH1 and loss of nuclear ATRX.<ref name=Weller2020/> In patients aged >55 years with a histologically typical glioblastoma, without a pre-existing lower grade glioma, with a non-midline tumor location and with retained nuclear ATRX expression, immunohistochemical negativity for IDH1 R132H suffices for the classification as IDH-wild-type glioblastoma.<ref name=Weller2020/> In all other instances of diffuse gliomas, a lack of IDH1 R132H immunopositivity should be followed by IDH1 and IDH2 DNA sequencing to detect or exclude the presence of non-canonical mutations.<ref name=Weller2020/> IDH-wild-type diffuse astrocytic gliomas without microvascular proliferation or necrosis should be tested for EGFR amplification, TERT promoter mutation and a +7/–10 cytogenetic signature as molecular characteristics of IDH-wild-type glioblastomas.<ref name=Weller2020/> In addition, the presence of histone H3.3 G34R/V mutations should be assessed by immunohistochemistry or DNA sequencing to identify H3.3 G34-mutant [[diffuse hemispheric glioma]]s, in particular in young patients with IDH-wild-type gliomas (such as those <50 years of age with nuclear ATRX loss in tumour cells).<ref name=Weller2020/> Diffuse gliomas of the thalamus, brainstem or spinal cord should be evaluated for histone H3 K27M mutations and loss of nuclear K27-trimethylated histone H3 (H3K27me3) to identify H3 K27M-mutant diffuse midline gliomas.<ref name=Weller2020/>

==Treatment==
[[File:Management of IDH wild type glioblastoma.png|thumb|Management of IDH wild type glioblastoma, WHO grade 4. KPS, Karnofsky performance status.<ref name=Weller2020/>]]
[[File:Management of IDH-mutant glioma.png|thumb|Management of IDH-mutant glioma. KPS, Karnofsky performance status; PCV, procarbazine, lomustine and vincristine.<ref name=Weller2020/>]]
Treatment for brain gliomas depends on the location, the cell type, and the grade of malignancy. Current treatment options include surgical removal, radiation ([[radiation therapy]]), and [[chemotherapy]]. In some cases, tumour treating fields ([[alternating electric field therapy]]), a recently developed technology, may be used.<ref>{{cite journal |vauthors=Tan AC, etal |title=Management of glioblastoma: State of the art and future directions |journal=CA: A Cancer Journal for Clinicians |volume=70 |issue=4 |pages=299–312 |date=July 2020 |doi=10.3322/caac.21613 |pmid=32478924 |doi-access=free|hdl=10536/DRO/DU:30138185 |hdl-access=free }}</ref>
Often, treatment is a combined approach, using surgery, [[radiation therapy]], and [[chemotherapy]]. For many, treatment consists of just surgery, or even "watchful waiting" (waiting to see when an intervention is justified due to tumour progression). Doctors carefully balance the specifics of the patient's tumour and the downsides of intervention, since there can be significant side effects from medical intervention, despite recent attempts to predict outcomes  have been  proposed.<ref>{{cite journal
 | last1       = Falcó-Roget | first1      = Joan
 | last2       = Cacciola | first2      = Alberto
 | last3       = Sambataro | first3      = Fabio
 | last4       = Crimi | first4      = Alessandro
 | year        = 2024
 | title       = Functional and structural reorganization in brain tumors: a machine learning approach using desynchronized functional oscillations
 | journal     = Nature Communications Biology
 | volume      = 7
 | issue       = 1
 | pages       = 419
 | doi         =  10.1038/s42003-024-06119-3
 | doi-access  = free
 | pmid        = 38582867
 | pmc         = 10998892 }}</ref>

[[Awake craniotomy|Awake surgery]] can be performed to monitor for example language and other cognitive functions, as well as motor functions and vision.<ref>{{Cite journal |last1=Soffietti |first1=R. |last2=Baumert |first2=B.G. |last3=Bello |first3=L. |last4=Von Deimling |first4=A. |last5=Duffau |first5=H. |last6=Frénay |first6=M. |last7=Grisold |first7=W. |last8=Grant |first8=R. |last9=Graus |first9=F. |last10=Hoang-Xuan |first10=K. |last11=Klein |first11=M. |last12=Melin |first12=B. |last13=Rees |first13=J. |last14=Siegal |first14=T. |last15=Smits |first15=A. |date=September 2010 |title=Guidelines on management of low-grade gliomas: report of an EFNS–EANO* Task Force |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2010.03151.x |journal=European Journal of Neurology |language=en |volume=17 |issue=9 |pages=1124–1133 |doi=10.1111/j.1468-1331.2010.03151.x |pmid=20718851 |issn=1351-5101}}</ref> Awake surgery is known to improve extent of resection while preserving functions<ref>{{Cite journal |last1=Duffau |first1=Hugues |last2=Capelle |first2=Laurent |last3=Denvil |first3=Dominique |last4=Sichez |first4=Nicole |last5=Gatignol |first5=Peggy |last6=Taillandier |first6=Luc |last7=Lopes |first7=Manuel |last8=Mitchell |first8=Mary-Christine |last9=Roche |first9=Sabine |last10=Muller |first10=Jean-Charles |last11=Bitar |first11=Ahmad |last12=Sichez |first12=Jean-Pierre |last13=Effenterre |first13=Rémy van |date=2003-04-01 |title=Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located within eloquent brain regions: functional results in a consecutive series of 103 patients |url=https://thejns.org/view/journals/j-neurosurg/98/4/article-p764.xml |journal=Journal of Neurosurgery |language=en-US |volume=98 |issue=4 |pages=764–778 |doi=10.3171/jns.2003.98.4.0764|pmid=12691401 |url-access=subscription }}</ref> and exetent of resection is directly associated with survival in low-grade gliomas.<ref>{{Cite journal |last1=McGirt |first1=Matthew J. |last2=Chaichana |first2=Kaisorn L. |last3=Attenello |first3=Frank J. |last4=Weingart |first4=Jon D. |last5=Than |first5=Khoi |last6=Burger |first6=Peter C. |last7=Olivi |first7=Alessandro |last8=Brem |first8=Henry |last9=Quinoñes-Hinojosa |first9=Alfredo |date=October 2008 |title=Extent of Surgical Resection Is Independently Associated With Survival in Patients With Hemispheric Infiltrating Low-Grade Gliomas |url=https://journals.lww.com/neurosurgery/abstract/2008/10000/extent_of_surgical_resection_is_independently.19.aspx |journal=Neurosurgery |language=en-US |volume=63 |issue=4 |pages=700-7; author reply 707-8 |doi=10.1227/01.NEU.0000325729.41085.73 |pmid=18981880 |issn=0148-396X|url-access=subscription }}</ref>

Radiation and chemotherapy remain the mainstays of treatment beyond surgery. Radiation therapy is delivered in the form of external beam radiation or the [[stereotactic surgery|stereotactic]] approach using [[radiosurgery]]. [[Temozolomide]] is a common chemotherapy drug which can be administered easily in an outpatient setting and is able to cross the [[blood–brain barrier]] effectively.

There are a wide variety of novel treatments currently being tested in clinical trials, ranging from IDH inhibitors like [[Ivosidenib]], to the recently approved [[Dendritic cell-based cancer vaccine]] approach.<ref name="Hart2013" /> Treatment using [[immunotherapy]] is another promising research path that may help treat glioma in the near future.<ref>{{cite journal | vauthors = Platten M, Bunse L, Wick W, Bunse T | title = Concepts in glioma immunotherapy | journal = Cancer Immunology, Immunotherapy | volume = 65 | issue = 10 | pages = 1269–75 | date = October 2016 | pmid = 27460064 | doi = 10.1007/s00262-016-1874-x | s2cid = 22635893 | pmc = 11029493 }}</ref><ref>{{cite journal | vauthors = Patel MA, Pardoll DM | title = Concepts of immunotherapy for glioma | journal = Journal of Neuro-Oncology | volume = 123 | issue = 3 | pages = 323–30 | date = July 2015 | pmid = 26070552 | pmc = 4498978 | doi = 10.1007/s11060-015-1810-5 }}</ref> Experimental therapies like oncolytic viruses have shown potential therapeutic benefits in clinical trials (but have not been approved for use in non-experimental settings).<ref>{{cite journal | vauthors = Suryawanshi YR, Schulze AJ | title = Oncolytic Viruses for Malignant Glioma: On the Verge of Success? | journal = Viruses | volume = 13 | issue = 7 | pages = 1294 | date = July 2021 | pmid = 34372501 | doi = 10.3390/v13071294 | pmc = 8310195 | doi-access = free }}</ref>

===Refractory disease===
For recurrent high-grade glioblastoma, recent studies have taken advantage of [[angiogenic]] blockers such as [[bevacizumab]] in combination with conventional chemotherapy, with encouraging results.<ref name="pmid17947716">{{cite journal | vauthors = Wong ET, Brem S | s2cid = 6164155 | title = Taming glioblastoma: targeting angiogenesis | journal = Journal of Clinical Oncology | volume = 25 | issue = 30 | pages = 4705–6 | date = October 2007 | pmid = 17947716 | doi = 10.1200/JCO.2007.13.1037 | doi-access = free }}</ref>

===Relative effectiveness===
A 2017 meta-analysis compared surgical resection versus biopsy as the initial surgical management option for a person with a low-grade glioma.<ref name=Jiang2017>{{cite journal | vauthors = Jiang B, Chaichana K, Veeravagu A, Chang SD, Black KL, Patil CG | title = Biopsy versus resection for the management of low-grade gliomas | journal = The Cochrane Database of Systematic Reviews | volume = 4 | pages = CD009319 | date = April 2017 | issue = 6 | pmid = 28447767 | pmc = 6478300 | doi = 10.1002/14651858.CD009319.pub3 }}</ref> Results show the evidence is insufficient to make a reliable decision.<ref name=Jiang2017 /> The relative effectiveness of surgical resection compared to biopsy for people with malignant glioma (high-grade) is unknown.<ref>{{cite journal | vauthors = Hart MG, Grant GR, Solyom EF, Grant R | title = Biopsy versus resection for high-grade glioma | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | pages = CD002034 | date = June 2019 | issue = 6 | pmid = 31169915 | pmc = 6553559 | doi = 10.1002/14651858.CD002034.pub2 }}</ref>

For high-grade gliomas, a 2003 meta-analysis compared radiotherapy with radiotherapy and chemotherapy.  It showed a small but clear improvement from using chemotherapy with radiotherapy.<ref>{{cite journal | title = Chemotherapy for high-grade glioma | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD003913 | year = 2002 | pmid = 12519620 | doi = 10.1002/14651858.CD003913 | editor1-last = Stewart | collaboration = Glioma Meta-analysis Trialists Group | editor1-first = Lesley | author1 = Glioma Meta-Analysis Trialists (GMT) Group | volume = 2014 | pmc = 10625440 }}</ref> A 2019 meta-analysis suggested that for people with less aggressive gliomas, radiotherapy may increase the risk of long term neurocognitive side effects.<ref name=":2">{{cite journal | vauthors = Lawrie TA, Gillespie D, Dowswell T, Evans J, Erridge S, Vale L, Kernohan A, Grant R | display-authors = 6 | title = Long-term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma | journal = The Cochrane Database of Systematic Reviews | volume = 8 | pages = CD013047 | date = August 2019 | issue = 8 | pmid = 31425631 | pmc = 6699681 | doi = 10.1002/14651858.cd013047.pub2 }}</ref> Whilst, evidence is uncertain on whether there are long term neurocognitive side effects associated with chemoradiotherapy.<ref name=":2" />

Temozolomide is effective for treating Glioblastoma Multiforme (GBM) compared to radiotherapy alone.<ref name=Hart2013>{{cite journal | vauthors = Hart MG, Garside R, Rogers G, Stein K, Grant R | title = Temozolomide for high grade glioma | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD007415 | date = April 2013 | pmid = 23633341 | pmc = 6457743 | doi = 10.1002/14651858.CD007415.pub2 }}</ref> A 2013 meta-analysis showed that Temozolomide prolongs survival and delays progression, but is associated with an increase in side effects such as blood complications, fatigue, and infection.<ref name="Hart2013" /> For people with recurrent GBM, when comparing temozolomide with chemotherapy, there may be an improvement in the [[Time to progression|time-to-progression]] and the person's quality of life, but no improvement in overall survival, with temozolomide treatment.<ref name=Hart2013 /> Evidence suggests that for people with recurrent high-grade gliomas who have not had chemotherapy before, there are similar survival and time-to-progression outcomes between treatment with temozolomide or the chemotherapy multidrug known as PCV (procarvazine, lomustine and vincristine).<ref>{{cite journal | vauthors = Parasramka S, Talari G, Rosenfeld M, Guo J, Villano JL | title = Procarbazine, lomustine and vincristine for recurrent high-grade glioma | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD011773 | date = July 2017 | issue = 7 | pmid = 28744879 | pmc = 6483418 | doi = 10.1002/14651858.cd011773.pub2 }}</ref>

A mutational analysis of 23 initial low-grade gliomas and recurrent tumors from the same patients has challenged the benefits and usage of Temozolomide. The study showed that when lower-grade brain tumors of patients are removed and patients are further treated with Temozolomide, 6 out of 10 times the recurrent tumors were more aggressive and acquired alternative and more mutations.<ref>{{cite journal | vauthors = Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJ, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF | display-authors = 6 | title = Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma | journal = Science | volume = 343 | issue = 6167 | pages = 189–193 | date = January 2014 | pmid = 24336570 | pmc = 3998672 | doi = 10.1126/science.1239947 | bibcode = 2014Sci...343..189J }}</ref> As one of the last authors, Costello, stated "They had a 20- to 50-fold increase in the number of mutations. A patient who received surgery alone who might have had 50 mutations in the initial tumor and 60 in the recurrence. But patients who received TMZ might have 2,000 mutations in the recurrence."<ref>{{cite web|title=Recurrent Brain Cancers Follow Distinctive Genetic Paths|url=http://www.ucsf.edu/news/2013/12/110811/recurrent-brain-cancers-follow-distinctive-genetic-paths-ucsf-team-shows|website=University of California Santa Cruz|date=17 December 2013|publisher=University of California San Francisco|access-date=17 June 2015|archive-date=20 April 2015|archive-url=https://web.archive.org/web/20150420094122/http://www.ucsf.edu/news/2013/12/110811/recurrent-brain-cancers-follow-distinctive-genetic-paths-ucsf-team-shows|url-status=live}}</ref> Further, new mutations were verified to carry known signatures of Temozolomide induced mutations. The research suggests that Temozolomide for the treatment of certain brain tumors should be thoroughly thought. Unjudicious usage of Temozolomide might lower the prognosis of the patients further, or increase their burden. Further understanding of the mechanisms of Temozolomide induced mutations and novel combination approaches could be promising.{{medical citation needed|date=September 2019}}
===New Research Directions===
[[Newcastle disease]] has been noted to be helpful in some cases of glioma.<ref>{{cite journal |journal=Anticancer Research |url=https://pubmed.ncbi.nlm.nih.gov/10216468/ |title=Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine |last1=Csatary |first1=L K |last2=Moss |first2=R W |last3=Beuth |first3=J |last4=Töröcsik |first4=B |last5=Szeberenyi |first5=J |last6=Bakacs |first6=T|date=1999 |volume=19 |issue=1B |pages=635–638 |pmid=10216468 }}</ref> [[Phase III trials]] with Newcastle Disease Virus Vaccine (MTH-68/H) are expected soon. Strains of Newcastle disease virus have also been used to create viral vector vaccine candidates against [[Ebola]] and [[Covid-19]].<ref>{{cite journal |title=Newcastle Disease Virus as a Vaccine Vector for Development of Human and Veterinary Vaccines |last1=Kim |first1=Shin-Hee |last2=Samal |first2=Siba K |journal=Viruses |date=2016 |volume=8 |issue=7 |page=183 |doi=10.3390/v8070183 |doi-access=free |pmid=27384578 |pmc=4974518 }}</ref> [[Torticollis]] in fowl shows the level of avian severity.

==Prognosis==
{{update|section|(see {{PMID|24711712}} for a better source)|date=September 2020}}
Prognosis of gliomas is given in relation to what grade (as scored by the World Health Organization system) of tumour the patient presents with. Typically, any tumour presenting as above WHO grade I (i.e. a malignant tumour as opposed to a benign tumour) will have a prognosis resulting in eventual death, varying from years (WHO grade II/III) to months (WHO grade IV).<ref name="Malignant glioma: genetics and biol"/><ref>{{cite journal | vauthors = Sanai N, Chang S, Berger MS | title = Low-grade gliomas in adults | journal = Journal of Neurosurgery | volume = 115 | issue = 5 | pages = 948–65 | date = November 2011 | pmid = 22043865 | doi = 10.3171/2011.7.JNS101238 }}</ref> Prognosis can also be given based on cellular subtype, which may also impact prognosis.

===Low grade===
For low-grade tumors, the prognosis is somewhat more optimistic. Patients diagnosed with a low-grade glioma are 17 times as likely to die as matched patients in the general population.<ref name="lgg">{{cite journal | vauthors = Smoll NR, Gautschi OP, Schatlo B, Schaller K, Weber DC | title = Relative survival of patients with supratentorial low-grade gliomas | journal = Neuro-Oncology | volume = 14 | issue = 8 | pages = 1062–9 | date = August 2012 | pmid = 22773277 | pmc = 3408266 | doi = 10.1093/neuonc/nos144 }}</ref>
The age-standardized 10-year relative survival rate was 47% according to research in 2014.<ref name="lgg"/> One study reported that low-grade [[oligodendroglioma]] patients have a median survival of 11.6 years;<ref>{{cite journal | vauthors = Ohgaki H, Kleihues P | title = Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas | journal = Journal of Neuropathology and Experimental Neurology | volume = 64 | issue = 6 | pages = 479–89 | date = June 2005 | pmid = 15977639 | doi = 10.1093/jnen/64.6.479 | doi-access = free }}</ref> another reported a median survival of 16.7 years.<ref>{{cite journal | vauthors = Olson JD, Riedel E, DeAngelis LM | title = Long-term outcome of low-grade oligodendroglioma and mixed glioma | journal = Neurology | volume = 54 | issue = 7 | pages = 1442–8 | date = April 2000 | pmid = 10751254 | doi = 10.1212/WNL.54.7.1442 | s2cid = 26335770 }}</ref> Unfortunately, approximately 70% of low-grade (WHO grade-II) will progress to high-grade tumours within 5–10 years<ref name="Malignant glioma: genetics and biol"/> Grade II gliomas, despite often being labeled as benign, are considered a uniformly fatal illness.<ref>{{Cite journal |last1=Claus |first1=Elizabeth B. |last2=Walsh |first2=Kyle M. |last3=Wiencke |first3=John K. |last4=Molinaro |first4=Annette M. |last5=Wiemels |first5=Joseph L. |last6=Schildkraut |first6=Joellen M. |last7=Bondy |first7=Melissa L. |last8=Berger |first8=Mitchel |last9=Jenkins |first9=Robert |last10=Wrensch |first10=Margaret |date=Jan 2015 |title=Survival and low-grade glioma: the emergence of genetic information |journal=Neurosurgical Focus |volume=38 |issue=1 |pages=E6 |doi=10.3171/2014.10.FOCUS12367 |issn=1092-0684 |pmc=4361022 |pmid=25552286}}</ref>

===High grade===
This group comprises [[anaplastic astrocytoma]]s and [[glioblastoma multiforme]]. Whereas the median overall survival of anaplastic (WHO grade III) gliomas is approximately 3 years, [[glioblastoma multiforme]] has a poor median overall survival of c. 15 months.<ref>{{cite journal | vauthors = Bleeker FE, Molenaar RJ, Leenstra S | title = Recent advances in the molecular understanding of glioblastoma | journal = Journal of Neuro-Oncology | volume = 108 | issue = 1 | pages = 11–27 | date = May 2012 | pmid = 22270850 | pmc = 3337398 | doi = 10.1007/s11060-011-0793-0 }}</ref>

Postoperative conventional daily radiotherapy improves survival for adults with good functional well‐being and high grade glioma compared to no postoperative radiotherapy. Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma.<ref>{{cite journal |vauthors=Khan L, Soliman H, Sahgal A, Perry J, Xu W, Tsao MN |title=External beam radiation dose escalation for high grade glioma |journal=Cochrane Database of Systematic Reviews |volume=5 |pages=CD011475 |date=May 2020 |issue=8 |pmid=32437039 |doi=10.1002/14651858.CD011475.pub3 |pmc=7389526 }}</ref>

===Diffuse midline glioma===
[[Diffuse midline glioma]] (DMG), also known as diffuse intrinsic pontine glioma (DIPG), primarily affects children, usually between the ages of 5 and 7.<ref>{{cite web |url=http://www.dipgregistry.org/patients-families/basic-facts/ |title=Patients & Families: Basic Facts |website=DIPG Registry |access-date=2014-05-01 |archive-url=https://web.archive.org/web/20140502033258/http://www.dipgregistry.org/patients-families/basic-facts/ |archive-date=2014-05-02 |df=dmy-all}}</ref> The median survival time with DIPG is under 12 months.<ref>{{cite journal | vauthors = Kebudi R, Cakir FB | title = Management of diffuse pontine gliomas in children: recent developments | journal = Paediatric Drugs | volume = 15 | issue = 5 | pages = 351–62 | date = October 2013 | pmid = 23719782 | doi = 10.1007/s40272-013-0033-5 | s2cid = 207491201 }}</ref> Surgery to attempt tumour removal is usually not possible or advisable for pontine gliomas. By their very nature, these tumours invade diffusely throughout the brain stem, growing between normal nerve cells. Aggressive surgery would cause severe damage to neural structures vital for arm and leg movement, eye movement, swallowing, breathing, and even consciousness.<ref>{{cite journal | vauthors = Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, Foer DR, Goldthwaite PT, Tihan T, Burger PC | display-authors = 6 | title = A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities | journal = Cancer | volume = 89 | issue = 7 | pages = 1569–76 | date = October 2000 | pmid = 11013373 | doi = 10.1002/1097-0142(20001001)89:7<1569::aid-cncr22>3.0.co;2-0 | s2cid = 25562391 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Donaldson SS, Laningham F, Fisher PG | title = Advances toward an understanding of brainstem gliomas | journal = Journal of Clinical Oncology | volume = 24 | issue = 8 | pages = 1266–72 | date = March 2006 | pmid = 16525181 | doi = 10.1200/jco.2005.04.6599 }}</ref>{{MEDRS|date=May 2014}} Trials of drug candidates have been unsuccessful.<ref>{{cite journal | vauthors = Jansen MH, van Vuurden DG, Vandertop WP, Kaspers GJ | title = Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology | journal = Cancer Treatment Reviews | volume = 38 | issue = 1 | pages = 27–35 | date = February 2012 | pmid = 21764221 | doi = 10.1016/j.ctrv.2011.06.007 }}</ref> The disease is primarily treated with radiation therapy alone.{{medical citation needed|date=October 2019}}

===''IDH1'' and ''IDH2-''mutated glioma===
Patients with glioma carrying mutations in either ''IDH1'' or ''IDH2'' have a relatively favorable survival, compared with patients with glioma with wild-type ''IDH1/2'' genes. In WHO grade III glioma, ''IDH1/2''-mutated glioma have a median prognosis of ~3.5 years, whereas ''IDH1/2'' wild-type glioma perform poor with a median overall survival of c. 1.5 years.<ref name=":1" /><ref>{{cite journal | vauthors = Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, Wesseling P, Hulsebos TJ, Troost D, van Tilborg AA, Leenstra S, Vandertop WP, Bardelli A, van Noorden CJ, Bleeker FE | display-authors = 6 | title = The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone | journal = Neuro-Oncology | volume = 16 | issue = 9 | pages = 1263–73 | date = September 2014 | pmid = 24510240 | pmc = 4136888 | doi = 10.1093/neuonc/nou005 }}</ref>

==References==
{{Reflist}}

==External links==
* [https://www.proteinatlas.org/humanpathology/glioma Glioma] {{Webarchive|url=https://web.archive.org/web/20170925230247/https://www.proteinatlas.org/humanpathology/glioma |date=25 September 2017 }} at [https://www.proteinatlas.org the Human Protein Atlas] {{Webarchive|url=https://web.archive.org/web/20200304041657/http://www.proteinatlas.org/ |date=4 March 2020 }}
* [https://web.archive.org/web/20080824224047/http://www.abta.org/index.cfm?contentid=59 American Brain Tumor Association: Malignant Gliomas]
* [https://web.archive.org/web/20080513082649/http://www.ninds.nih.gov/disorders/brainandspinaltumors/detail_brainandspinaltumors.htm Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke)]
* [https://web.archive.org/web/20070703183739/http://rad.usuhs.mil/rad/who/who-index.html WHO Classification of Glioma]
* [https://web.archive.org/web/20090126005415/http://rad.usuhs.mil/medpix/medpix.html?mode=image_finder&action=search&srchstr=malignant%20glioma&srch_type=all#top Glioma Images] MedPix Database

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|   ICDO           = {{ICDO|9380|3}}-9460/3
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[[Category:Brain tumor]]