Uveal melanoma pathophysiology: Difference between revisions
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{{CMG}}{{AE}} {{Fs}},{{Simrat}} | {{CMG}}{{AE}} {{Fs}},{{Simrat}} | ||
==Overview== | ==Overview== | ||
It is understood that [[Uvea (anatomy)|uveal]] [[melanoma]] is the result of [[genetic mutations]]. Activating [[Mutation|mutations]] in [[GNAQ]] or [[GNA11]], [[genes]] encoding for [[G protein]] alpha subunits. These [[mutations]] lead to activation of downstream signaling pathways including the [[MAPK]] pathway in [[Uvea (anatomy)|uveal]] [[melanoma]]. Inactivating [[Somatic mutation|somatic mutations]] are present in the [[gene]] encoding [[BRCA1]]-associated protein 1 ([[BAP1]]) on [[chromosome]] 3p21.1. The [[mutations]] in the [[gene]] ''[[BAP1]]'' are strongly linked to [[Metastasis|metastatic]] spread and patient survival. Conditions associated with [[Uvea (anatomy)|uveal]] [[melanoma]] include [[ocular]] [[nevi]], [[Immune system disorder|impaired immune system]], [[pregnancy]], and [[trauma]]. On microscopic histopathological analysis, we have 5 subtypes according to [[cell]] type into | It is understood that [[Uvea (anatomy)|uveal]] [[melanoma]] is the result of [[genetic mutations]]. Activating [[Mutation|mutations]] in [[GNAQ]] or [[GNA11]], [[genes]] encoding for [[G protein]] alpha subunits. These [[mutations]] lead to activation of downstream signaling pathways including the [[MAPK]] pathway in [[Uvea (anatomy)|uveal]] [[melanoma]]. Inactivating [[Somatic mutation|somatic mutations]] are present in the [[gene]] encoding [[BRCA1]]-associated protein 1 ([[BAP1]]) on [[chromosome]] 3p21.1. The [[mutations]] in the [[gene]] ''[[BAP1]]'' are strongly linked to [[Metastasis|metastatic]] spread and patient [[Survival rate|survival]]. Conditions associated with [[Uvea (anatomy)|uveal]] [[melanoma]] include [[ocular]] [[nevi]], [[Immune system disorder|impaired immune system]], [[pregnancy]], and [[trauma]]. On microscopic histopathological analysis, we have 5 subtypes according to [[cell]] type into [[Spindle cells|spindle]] A, [[Spindle cells|spindle]] B, epitheliolid, mixed, and [[necrotic]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
=== Pathogenesis === | === Pathogenesis === | ||
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== Genetics == | == Genetics == | ||
[[Gene|Genes]] involved in the [[pathogenesis]] of uveal melanoma include: | [[Gene|Genes]] involved in the [[pathogenesis]] of uveal melanoma include: | ||
* Activating [[mutations]] in [[GNAQ]] or [[GNA11]], [[genes]] encoding for [[G protein]] alpha subunits. <ref name="pmid21083380">{{cite journal| author=Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T et al.| title=Mutations in GNA11 in uveal melanoma. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 23 | pages= 2191-9 | pmid=21083380 | doi=10.1056/NEJMoa1000584 | pmc=PMC3107972 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21083380 }} </ref><ref name="pmid19078957">{{cite journal| author=Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM et al.| title=Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. | journal=Nature | year= 2009 | volume= 457 | issue= 7229 | pages= 599-602 | pmid=19078957 | doi=10.1038/nature07586 | pmc=PMC2696133 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19078957 }} </ref><ref name="pmid25304237">{{cite journal| author=Shoushtari AN, Carvajal RD| title=GNAQ and GNA11 mutations in uveal melanoma. | journal=Melanoma Res | year= 2014 | volume= 24 | issue= 6 | pages= 525-34 | pmid=25304237 | doi=10.1097/CMR.0000000000000121 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25304237 }} </ref> | * Activating [[mutations]] in [[GNAQ]] or [[GNA11]], [[genes]] encoding for [[G protein]] alpha subunits.<ref name="pmid21083380">{{cite journal| author=Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T et al.| title=Mutations in GNA11 in uveal melanoma. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 23 | pages= 2191-9 | pmid=21083380 | doi=10.1056/NEJMoa1000584 | pmc=PMC3107972 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21083380 }} </ref><ref name="pmid19078957">{{cite journal| author=Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM et al.| title=Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. | journal=Nature | year= 2009 | volume= 457 | issue= 7229 | pages= 599-602 | pmid=19078957 | doi=10.1038/nature07586 | pmc=PMC2696133 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19078957 }} </ref><ref name="pmid25304237">{{cite journal| author=Shoushtari AN, Carvajal RD| title=GNAQ and GNA11 mutations in uveal melanoma. | journal=Melanoma Res | year= 2014 | volume= 24 | issue= 6 | pages= 525-34 | pmid=25304237 | doi=10.1097/CMR.0000000000000121 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25304237 }} </ref> | ||
* These [[mutations]] lead to activation of downstream signaling pathways including the [[MAPK]] pathway in uveal melanoma. | * These [[mutations]] lead to activation of downstream signaling pathways including the [[MAPK]] pathway in uveal melanoma. | ||
* Inactivating somatic [[Mutation|mutations]] are present in the [[gene]] encoding [[BRCA1]]-associated protein 1 ([[BAP1]]) on [[chromosome]] 3p21.1. | * Inactivating somatic [[Mutation|mutations]] are present in the [[gene]] encoding [[BRCA1]]-associated protein 1 ([[BAP1]]) on [[chromosome]] 3p21.1. | ||
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== Microscopic Pathology == | == Microscopic Pathology == | ||
On microscopic [[Histopathology|histopathological]] analysis, we have 5 subtypes according to cell type | On microscopic [[Histopathology|histopathological]] analysis, we have 5 subtypes according to cell type include [[Spindle]] A, [[spindle]] B, epitheliolid, mixed, and [[Necrosis|necrotic]].<ref name="McLeanFoster1983">{{cite journal|last1=McLean|first1=Ian W.|last2=Foster|first2=Walter D.|last3=Zimmerman|first3=Lorenz E.|last4=Gamel|first4=John W.|title=Modifications of Callender's Classification of Uveal Melanoma at the Armed Forces Institute of Pathology|journal=American Journal of Ophthalmology|volume=96|issue=4|year=1983|pages=502–509|issn=00029394|doi=10.1016/S0002-9394(14)77914-0}}</ref> | ||
{| | {| | ||
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Cell type | ! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Cell type | ||
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{{reflist|2}} | {{reflist|2}} | ||
[[Category:Medicine]] | |||
[[Category: | |||
[[Category:Oncology]] | [[Category:Oncology]] | ||
[[Category: | [[Category:Up-To-Date]] | ||
[[Category: | [[Category:Surgery]] | ||
Latest revision as of 00:37, 30 July 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.,Simrat Sarai, M.D. [2]
Overview
It is understood that uveal melanoma is the result of genetic mutations. Activating mutations in GNAQ or GNA11, genes encoding for G protein alpha subunits. These mutations lead to activation of downstream signaling pathways including the MAPK pathway in uveal melanoma. Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1. The mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival. Conditions associated with uveal melanoma include ocular nevi, impaired immune system, pregnancy, and trauma. On microscopic histopathological analysis, we have 5 subtypes according to cell type into spindle A, spindle B, epitheliolid, mixed, and necrotic.
Pathophysiology
Pathogenesis
- It is understood that uveal melanoma is the result of genetic mutations.
- Uveal melanoma arises from melanocytes, which are normally involved in melanin production.
Genetics
Genes involved in the pathogenesis of uveal melanoma include:
- Activating mutations in GNAQ or GNA11, genes encoding for G protein alpha subunits.[1][2][3]
- These mutations lead to activation of downstream signaling pathways including the MAPK pathway in uveal melanoma.
- Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1.
- The mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival.[4]
- In approximately five percent of patients with uveal melanomas germline mutations have been identified in BAP1, and these have been associated with involvement of the ciliary body and larger tumors.[5]
- In approximately 18.6 percent of primary uveal melanomas recurring mutations occurring exclusively at codon 625 of the SF3B1 gene, encoding splicing factor 3B subunit 1 were identified.[6]
Associated Conditions
Conditions associated with uveal melanoma include:[7][8][9]
- Ocular nevi
- Impaired immune system
- Pregnancy
- Trauma
Gross Pathology
Microscopic Pathology
On microscopic histopathological analysis, we have 5 subtypes according to cell type include Spindle A, spindle B, epitheliolid, mixed, and necrotic.[10]
| Cell type | Explanation |
|---|---|
| Spindle A | |
| Spindle B |
|
| Epithelioid | |
| Mixed |
|
| Necrotic |
|
References
- ↑ 1.0 1.1 Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T; et al. (2010). "Mutations in GNA11 in uveal melanoma". N Engl J Med. 363 (23): 2191–9. doi:10.1056/NEJMoa1000584. PMC 3107972. PMID 21083380.
- ↑ 2.0 2.1 Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM; et al. (2009). "Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi". Nature. 457 (7229): 599–602. doi:10.1038/nature07586. PMC 2696133. PMID 19078957.
- ↑ 3.0 3.1 Shoushtari AN, Carvajal RD (2014). "GNAQ and GNA11 mutations in uveal melanoma". Melanoma Res. 24 (6): 525–34. doi:10.1097/CMR.0000000000000121. PMID 25304237.
- ↑ McGrath JJ (1986). "Nicotine and carbon monoxide: effects on the isolated rat heart". Alcohol. 3 (2): 157–60. PMID 3087380.
- ↑ Gupta MP, Lane AM, DeAngelis MM, Mayne K, Crabtree M, Gragoudas ES; et al. (2015). "Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations". JAMA Ophthalmol. 133 (8): 881–7. doi:10.1001/jamaophthalmol.2015.1119. PMID 25974357.
- ↑ Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM (2013). "Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma". Nat Genet. 45 (2): 133–5. doi:10.1038/ng.2523. PMC 3789378. PMID 23313955.
- ↑ Fisher, M.; Kripke, M. (1982). "Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice". Science. 216 (4550): 1133–1134. doi:10.1126/science.6210958. ISSN 0036-8075.
- ↑ Siegel, Ralph (1963). "Malignant Ocular Melanoma During Pregnancy". JAMA: The Journal of the American Medical Association. 185 (6): 542. doi:10.1001/jama.1963.03060060140028. ISSN 0098-7484.
- ↑ Baba, F. E.; Blumenkranz, M. (1986). "Malignant Melanoma at the Site of Penetrating Ocular Trauma". Archives of Ophthalmology. 104 (3): 405–409. doi:10.1001/archopht.1986.01050150105038. ISSN 0003-9950.
- ↑ McLean, Ian W.; Foster, Walter D.; Zimmerman, Lorenz E.; Gamel, John W. (1983). "Modifications of Callender's Classification of Uveal Melanoma at the Armed Forces Institute of Pathology". American Journal of Ophthalmology. 96 (4): 502–509. doi:10.1016/S0002-9394(14)77914-0. ISSN 0002-9394.