Uveal melanoma pathophysiology: Difference between revisions

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Latest revision as of 00:37, 30 July 2020

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

Most of the uveal melanomas arise from a uveal nevi.^[1]^[2]^[3]

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]

Gross Pathology

https://en.wikipedia.org/wiki/File:Malignant_melanoma.jpg

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	Fine nuclear chromatin Cells with small spindle nuclei and central dark stripe No distinct nucleoli Rare mitotic features
Spindle B	Commen Coarse nuclear chromatin Distinct nucleoli Rare mitotic features
Epithelioid	Rarest Large round nuclei Prominent nucleoli Mitotic features are common
Mixed	Most common Contains both spindle cells and epithelioil cells
Necrotic	uncommon Necrotic tumor with unidentifiable cell type

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.

[pmid21083380-1] 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.

[pmid19078957-2] 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.

[pmid25304237-3] 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.

[pmid3087380-4] McGrath JJ (1986). "Nicotine and carbon monoxide: effects on the isolated rat heart". Alcohol. 3 (2): 157–60. PMID 3087380.

[pmid25974357-5] 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.

[pmid23313955-6] 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.

[FisherKripke1982-7] 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.

[Siegel1963-8] 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.

[BabaBlumenkranz1986-9] 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.

[McLeanFoster1983-10] 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.

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@@ Line 1: / Line 1: @@
-_NOTOC__
+__NOTOC__
 {{Uveal melanoma}}
-{{CMG}}{{AE}}{{Simrat}}
+{{CMG}}{{AE}} {{Fs}},{{Simrat}}
 ==Overview==
-Genes involved in the pathogenesis of uveal melanoma include GNAQ, GNA11, and BAP1.
+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==
-*Uveal melanoma frequently harbors early 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.<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>
+=== Pathogenesis ===
-*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.<ref name="pmid3087380">{{cite journal| author=McGrath JJ| title=Nicotine and carbon monoxide: effects on the isolated rat heart. | journal=Alcohol | year= 1986 | volume= 3 | issue= 2 | pages= 157-60 | pmid=3087380 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3087380  }} </ref> 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.<ref name="pmid25974357">{{cite journal| author=Gupta MP, Lane AM, DeAngelis MM, Mayne K, Crabtree M, Gragoudas ES et al.| title=Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. | journal=JAMA Ophthalmol | year= 2015 | volume= 133 | issue= 8 | pages= 881-7 | pmid=25974357 | doi=10.1001/jamaophthalmol.2015.1119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974357  }} </ref>
-*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.<ref name="pmid23313955">{{cite journal| author=Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM| title=Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. | journal=Nat Genet | year= 2013 | volume= 45 | issue= 2 | pages= 133-5 | pmid=23313955 | doi=10.1038/ng.2523 | pmc=PMC3789378 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23313955  }} </ref
+* Most of the uveal melanomas arise from a [[Uvea (anatomy)|uveal]] [[nevi]].<ref name="pmid21083380" /><ref name="pmid19078957" /><ref name="pmid25304237" />
+* It is understood that uveal melanoma is the result of [[genetic]] [[Mutation|mutations]].
+* Uveal melanoma arises from [[Melanocyte|melanocytes]], which are normally involved in [[melanin]] production.
+== Genetics ==
+[[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>
+* 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.
+* The [[mutations]] in the gene [[BAP1]] are strongly linked to [[Metastasis|metastatic]] spread and patient [[Survival rate|survival]].<ref name="pmid3087380">{{cite journal| author=McGrath JJ| title=Nicotine and carbon monoxide: effects on the isolated rat heart. | journal=Alcohol | year= 1986 | volume= 3 | issue= 2 | pages= 157-60 | pmid=3087380 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3087380  }} </ref>
+* In approximately five percent of patients with uveal melanomas [[germline]] [[Mutation|mutations]] have been identified in [[BAP1]]'','' and these have been associated with involvement of the [[ciliary body]] and larger [[tumors]].<ref name="pmid25974357">{{cite journal| author=Gupta MP, Lane AM, DeAngelis MM, Mayne K, Crabtree M, Gragoudas ES et al.| title=Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. | journal=JAMA Ophthalmol | year= 2015 | volume= 133 | issue= 8 | pages= 881-7 | pmid=25974357 | doi=10.1001/jamaophthalmol.2015.1119 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974357  }} </ref>
+*In approximately 18.6 percent of primary uveal melanomas recurring [[Mutation|mutations]] occurring exclusively at [[codon]] 625 of the [[SF3B1]] [[gene]], encoding splicing factor 3B subunit 1 were identified.<ref name="pmid23313955">{{cite journal| author=Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM| title=Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. | journal=Nat Genet | year= 2013 | volume= 45 | issue= 2 | pages= 133-5 | pmid=23313955 | doi=10.1038/ng.2523 | pmc=PMC3789378 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23313955  }} </ref>
+== Associated Conditions ==
+Conditions associated with uveal melanoma include:<ref name="FisherKripke1982">{{cite journal|last1=Fisher|first1=M.|last2=Kripke|first2=M.|title=Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice|journal=Science|volume=216|issue=4550|year=1982|pages=1133–1134|issn=0036-8075|doi=10.1126/science.6210958}}</ref><ref name="Siegel1963">{{cite journal|last1=Siegel|first1=Ralph|title=Malignant Ocular Melanoma During Pregnancy|journal=JAMA: The Journal of the American Medical Association|volume=185|issue=6|year=1963|pages=542|issn=0098-7484|doi=10.1001/jama.1963.03060060140028}}</ref><ref name="BabaBlumenkranz1986">{{cite journal|last1=Baba|first1=F. E.|last2=Blumenkranz|first2=M.|title=Malignant Melanoma at the Site of Penetrating Ocular Trauma|journal=Archives of Ophthalmology|volume=104|issue=3|year=1986|pages=405–409|issn=0003-9950|doi=10.1001/archopht.1986.01050150105038}}</ref>
+*[[Ocular]] [[nevi]]
+*Impaired [[immune system]]
+*[[Pregnancy]]
+*[[Trauma]]
+== Gross Pathology ==
+<br />
+[[File:Malignant melanomaa.jpg|400px|none|thumb|https://en.wikipedia.org/wiki/File:Malignant_melanoma.jpg]]
+== Microscopic Pathology ==
+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;" |Explanation
+|-
+! style="background: #DCDCDC; text-align: center;" |Spindle A
+| style="background: #F5F5F5;" |
+* Fine [[nuclear]] [[chromatin]]
+*[[Cells]] with small [[Spindle cells|spindle]] [[nuclei]] and central dark stripe
+* No distinct [[nucleoli]]
+* Rare [[mitotic]] features
+|-
+! style="background: #DCDCDC; text-align: center;" |Spindle B
+| style="background: #F5F5F5;" |
+* Commen
+* Coarse [[nuclear]] [[chromatin]]
+* Distinct [[nucleoli]]
+* Rare [[mitotic]] features
+|-
+! style="background: #DCDCDC; text-align: center;" |Epithelioid
+| style="background: #F5F5F5;" |
+* Rarest
+* Large round [[nuclei]]
+* Prominent [[nucleoli]]
+*[[Mitotic]] features are common
+|-
+! style="background: #DCDCDC; text-align: center;" |Mixed
+| style="background: #F5F5F5;" |
+* Most common
+* Contains both [[spindle cells]] and epithelioil [[cells]]
+|-
+! style="background: #DCDCDC; text-align: center;" |Necrotic
+| style="background: #F5F5F5;" |
+* uncommon
+* Necrotic [[tumor]] with unidentifiable [[cell]] type
+|}
+<br />
 ==References==
 {{reflist|2}}
+[[Category:Medicine]]
+[[Category:Oncology]]
+[[Category:Up-To-Date]]
+[[Category:Surgery]]