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| {{Infobox disease | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
| | Name = Uveal melanoma
| | {{Uveal melanoma}} |
| | Image = Iris_melanoma.jpg
| | {{CMG}}{{AE}}{{Fs}}{{Simrat}} |
| | Caption = Iris melanoma
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| }} | |
| {{CMG}} | |
| {{SI}} | |
| ==Overview==
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| '''Uveal melanoma''' is a cancer ([[melanoma]]) of the [[human eye|eye]] involving the [[iris (anatomy)|iris]], [[ciliary body]], or [[choroid]] (collectively referred to as the [[uvea]]). Tumors arise from the pigment cells ([[melanocyte]]s) that reside within the [[uvea]] giving color to the eye. These melanocytes are distinct from the [[retinal pigment epithelium]] cells underlying the [[retina]] that do not form melanomas.
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| ==Epidemiology==
| | {{SK}} Malignant uveal melanoma; Choroidal melanoma; iris melanoma; UM |
| Uveal melanomas are the most common primary intraocular tumor in adults.<ref name=Kumar>{{cite book|last=Kumar|first=Vinay|title=Robbins and Cotran Pathologic Basis of Disease, Professional Edition.|year=2009|chapter=Uvea: Neoplasms|publisher=Elsevier.|location=Philadelphia, PA|isbn=978-1-4377-0792-2|edition=8th}}</ref> The incidence has remained stable for several years.
| | ==[[Uveal melanoma overview|Overview]]== |
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| ==Cause== | | ==[[Uveal melanoma historical perspective|Historical Perspective]]== |
| The cause of uveal melanoma is unclear, but UV light is a risk factor. Uveal nevi are common (10% of caucasians), but rarely progress to melanoma.
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| ==Types== | | ==[[Uveal melanoma classification|Classification]]== |
| Uveal melanomas, often referred to by the media and in the general population as ocular melanomas, may arise from any of the three parts of the uvea, and are sometimes referred to by their location, as choroidal melanoma, ciliary body melanoma, or iris melanoma. Large tumors often encompass multiple parts of the uvea and can be named accordingly. True iris melanomas, originating from within the iris as opposed to originating elsewhere and invading the iris, are distinct in their etiology and prognosis, such that the other tumors are often referred to collectively as Posterior uveal melanomas.
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| ===Iris melanoma=== | | ==[[Uveal melanoma pathophysiology|Pathophysiology]]== |
| Uveal tumors can originate from melanocytes residing within the iris. Benign melanocytic tumors, such as iris [[freckles]] and moles ([[Melanocytic nevus|nevi]]), are common and pose no health risks, unless they show signs of malignancy, in which case they are classified as iris melanomas. Though derived from uveal melanocytes, iris melanomas share more in common with cutaneous (skin) [[melanomas]], in that they frequently harbor [[BRAF (gene)|BRAF]] mutations associated with [[ultraviolet]] damage.<ref>{{cite journal | author = Henriquez F, Janssen C, Kemp EG, Roberts F | title = The T1799A BRAF mutation is present in iris melanoma | journal = Invest Ophthalmol Vis Sci | volume = 48 | issue = 11 | pages = 4897–4900 | year = 2007 | pmid = 17962436 | doi = 10.1167/iovs.07-0440}}</ref><ref>{{cite journal | author = Hocker T, Tsao H | title = Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants | journal = Hum Mutat | volume = 28 | issue = 6 | pages = 578–588 | year = 2007 | pmid = 17295241 | doi = 10.1002/humu.20481}}</ref> Iris melanomas are much less likely to [[metastasis|metastasize]] than other uveal melanomas, and less likely to impair vision if detected and treated early. Approximately 5% of uveal melanomas involve the iris.<ref>{{cite web|author = Damato B , Coupland S |publisher= Melanoma Molecular Map Project |accessdate = 2013-02-02| title = Ocular melanoma | year= 2008 | url = http://www.mmmp.org/MMMP/import.mmmp?page=ocular.mmmp}}</ref>
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| ===Posterior uveal melanoma=== | | ==[[Uveal melanoma causes|Causes]]== |
| [[Image:Malignant melanoma.jpg|thumb|Variably pigmented, mushroom-shaped choroidal tumor has ruptured the Bruch membrane and grown into the subretinal space.]]
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| Benign melanocytic tumors of the choroid, such as choroidal [[freckles]] and [[Melanocytic nevus|nevi]], are very common and pose no health risks, unless they show signs of malignancy, in which case they are considered melanomas.<ref>{{cite journal | author = Augsburger JJ | title = Is observation really appropriate for small choroidal melanomas | journal = Trans Am Ophthalmol Soc | year = 1993 | volume = 91 | pages = 147–175 | pmid = 8140689 | pmc = 1298464}}</ref><ref>{{cite journal | author = Shields CL, Demirci H, Materin MA, Marr BP, Mashayekhi A, Shields JA | title = Clinical factors in the identification of small choroidal melanoma | journal = Can J Ophthalmol | year = 2004 | volume = 39 | issue = 4 | pages = 351–357 | pmid = 15327099}}</ref> Uveal melanoma is distinct from most skin melanomas associated with [[ultraviolet]] exposure; however, it shares several similarities with non-sun-exposed melanomas, such as acral melanomas and mucosal melanomas. [[BRAF (gene)|BRAF]] mutations are extremely rare in posterior uveal melanomas;<ref>{{cite journal | doi = 10.4161/cbt.5.2.2429 | author = Malaponte G, Libra M, Gangemi P, Bevelacqua V, Mangano K, D'Amico F, Mazzarino MC, Stivala F, McCubrey JA, Travali S | title = Detection of BRAF gene mutation in primary choroidal melanoma tissue | journal = Cancer Biol Ther | volume = 5 | issue = 2 | pages = 225–227 | year = 2006 | pmid = 16410717}}</ref> instead, uveal melanomas frequently harbor [[Gq alpha subunit|GNAQ/GNA11]] mutations, a trait shared with blue nevi, [[Nevus of Ota]], and [[Ocular melanosis]].<ref>{{cite journal | author = Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, Simpson EM, Barsh GS, Bastian BC | title = Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi | journal = Nature | volume = 457 | issue = 7229 | pages = 599–602 | year = 2009 | pmid = 19078957 | doi = 10.1038/nature07586 | pmc = 2696133}}</ref><ref>{{cite journal | author = Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O'Brien J, Bastian BC | title = Mutations in GNA11 in uveal melanoma | journal = N Engl J Med | volume = 363 | issue = 23 | pages = 2191–2199 | year = 2010 | pmid = 21083380 | doi = 10.1056/NEJMoa1000584 | pmc=3107972}}</ref> As seen in [[BRAF (gene)|BRAF]], mutations in [[Gq alpha subunit|GNAQ/GNA11]] are early events in tumorigenesis and are not prognostic for tumor stage or later metastatic spread.<ref>{{cite journal | author = Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, Harbour JW | title = Oncogenic mutations in GNAQ occur early in uveal melanoma | journal = Invest Ophthalmol Vis Sci | volume = 49 | issue = 12 | pages = 5230–5234 | year = 2008 | pmid = 18719078 | doi = 10.1167/iovs.08-2145 | pmc = 2634606}}</ref> In contrast, mutations in the gene [[BAP1]] are strongly linked to metastatic spread and patient survival.<ref name="Harbour2010">{{cite journal | author = Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM | title = Frequent mutation of BAP1 in metastasizing uveal melanomas | journal = Science | volume = 330 | issue = 6009 | pages = 1410–1413 | year = 2010 | pmid = 21051595 | doi = 10.1126/science.1194472 | pmc=3087380}}</ref> Incidence of posterior uveal melanoma is highest among people with light skin and blue eyes. Other risk factors, such as blue light exposure and arc welding have been put forward, but are still debated in the field. [[Mobile phone]] use is not a risk factor for uveal melanoma.<ref>{{cite journal | author = Stang A, Schmidt-Pokrzywniak A, Lash TL, Lommatzsch PK, Taubert G, Bornfeld N, Jöckel KH | title = Mobile phone use and risk of uveal melanoma: results of the risk factors for uveal melanoma case-control study | journal = J Natl Cancer Inst | year = 2009 | volume = 101 | issue = 2 | pages = 120–123 | pmid = 19141780 | doi = 10.1093/jnci/djn441 | pmc = 2639317}}</ref>
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| ==Treatment== | | ==[[Uveal melanoma differential diagnosis|Differentiating Uveal melanoma from other Diseases]]== |
| The treatment protocol for uveal melanoma has been directed by many clinical studies, the most important being "The Collaborative Ocular Melanoma Study" (COMS). The treatment varies depending upon many factors, chief among them, the size of the tumor. Primary treatment can involve removal of the affected eye ([[enucleation of the eye|enucleation]]); however, this is now reserved for cases of extreme tumor burden or other secondary problems. Advances in radiation therapies have significantly decreased the number of patients treated by enucleation in developed countries. The most common radiation treatment is plaque [[brachytherapy]], in which a small disc-shaped shield (plaque) encasing radioactive seeds (most often [[Iodine-125]], though [[Ruthenium-106]] and [[Palladium-103]] are also used) is attached to the outside surface of the eye, overlying the tumor. The plaque is left in place for a few days and then removed. The risk of metastasis after plaque radiotherapy is the same as that of enucleation, suggesting that micrometastatic spread occurs prior to treatment of the primary tumor. Other modalities of treatment include transpupillary [[thermotherapy]], external beam [[proton therapy]], resection of the tumor, Gamma Knife stereotactic radiosurgery or a combination of different modalities. Different surgical resection techniques can include trans-scleral partial choroidectomy, and transretinal endoresection.
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| ==Prognostic factors== | | ==[[Uveal melanoma epidemiology and demographics|Epidemiology and Demographics]]== |
| Several clinical and pathological prognostic factors have been identified that are associated with higher risk of metastasis of uveal melanomas. These include large tumor size, [[ciliary body]] involvement, presence of [[Lipofuscin|orange pigment]] overlying the tumor, and older patient age.<ref>{{cite journal | doi = 10.1002/1097-0142(19901001)66:7<1596::AID-CNCR2820660726>3.0.CO;2-6 | author = Augsburger JJ, Gamel JW | title = Clinical prognostic factors in patients with posterior uveal malignant melanoma | journal = Cancer | volume = 66 | issue = 7 | pages = 1596–1600 | year = 1990 | pmid = 2208011}}</ref><ref>{{cite web|title=General Information About Intraocular (Uveal) Melanoma|url=http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/patient|publisher=National Institutes of Health|accessdate=26 November 2013}}</ref> Likewise several histological and cytological factors are associated with higher risk of metastasis including presence and extent of cells with [[wikt:epithelioid|epithelioid]] morphology, presence of looping extracellular matrix patterns, increased infiltration of [[White blood cell|immune cells]],<ref name=Kumar /> as well as staining with several [[Immunohistochemistry|immunohistochemical]] markers.<ref>{{cite journal | author = Pardo M, Dwek RA, Zitzmann N | title = Proteomics in uveal melanoma research: opportunities and challenges in biomarker discovery | journal = Expert Rev Proteomics | volume = 4 | issue = 2 | pages = 273–286 | year = 2007 | pmid = 17425462 | doi = 10.1586/14789450.4.2.273}}</ref>
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| The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of [[BAP1]], which most often occurs through mutation of one [[allele]] and subsequent loss of an entire copy of [[Chromosome 3 (human)|Chromosome 3]] ([[Monosomy]] 3) to unmask the mutant copy.<ref name="Harbour2010" /> Because of this function in inactivation of BAP1, monosomy 3 correlates strongly with metastatic spread<ref>{{cite journal | doi = 10.1016/S0140-6736(96)90736-9 | author = Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R | title = Prognostic implications of monosomy 3 in uveal melanoma | journal = Lancet | volume = 347 | issue = 9010 | pages = 1222–1225 | year = 1996 | pmid = 8622452}}</ref> Where BAP1 mutation status is not available, gains on chromosomes [[Chromosome 6 (human)|6]] and [[Chromosome 8 (human)|8]] can be used to refine the predictive value of the Monosomy 3 screen, with gain of 6p indicating a better prognosis and gain of 8q indicating a worse prognosis in [[Aneuploidy|disomy]] 3 tumors.<ref>{{cite journal | author = Damato BE, Dopierala J, Klaasen A, van Dijk M, Sibbring J, Coupland S | title = Multiplex Ligation-Dependent Probe Amplification of Uveal Melanoma: Correlation with Metastatic Death | journal = Invest Ophthalmol Vis Sci | year = 2009 | pmid = 19182252 | doi = 10.1167/iovs.08-3165 | volume = 50 | issue = 7 | pages = 3048–55}}</ref> In rare instances, monosomy 3 tumors may duplicate the BAP1-mutant copy of the chromosome to return to a disomic state referred to as [[isodisomy]].<ref>{{cite journal | doi = 10.1016/S0165-4608(97)00290-2 | author = White VA, McNeil BK, Horsman DE | title = Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma | journal = Cancer Genet Cytogenet | volume = 102| issue = 1 | pages = 40–45 | year = 1998 | pmid = 9530338}}</ref> Thus, isodisomy 3 is prognostically equivalent to monosomy 3, and both can be detected by tests for chromosome 3 [[loss of heterozygosity]].<ref>{{cite journal | author = Onken MD, Worley LA, Person E, Char DH, Bowcock AM, Harbour JW | title = Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma | journal = Clin Cancer Res | volume = 13 | issue = 10 | pages = 2923–2937 | year = 2007 | pmid = 17504992 | doi = 10.1158/1078-0432.CCR-06-2383}}</ref> Monosomy 3, along with other chromosomal gains, losses, amplifications, and LOH, can be detected in fresh or paraffin embedded samples by [[Virtual Karyotype|virtual karyotyping]].
| | ==[[Uveal melanoma risk factors|Risk Factors]]== |
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| The most accurate prognostic factor is molecular classification by [[Gene expression profiling in cancer|gene expression profiling]] of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas: class 1 tumors that have a very low risk of metastasis and class 2 tumors that have a very high risk of metastasis.<ref>{{cite journal | author = Tschentscher F, Hüsing J, Hölter T, Kruse E, Dresen IG, Jöckel KH, Anastassiou G, Schilling H, Bornfeld N, Horsthemke B, Lohmann DR, Zeschnigk M | title = Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities | journal = Cancer Res | volume = 63 | issue = 10 | pages = 2578–2584 | year = 2003 | pmid = 12750282}}</ref><ref>{{cite journal | author = Onken MD, Worley LA, Ehlers JP, Harbour JW | title = Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death | journal = Cancer Res | volume = 64 | issue = 20 | pages = 7205–7209 | year = 2004 | pmid = 15492234 | doi = 10.1158/0008-5472.CAN-04-1750}}</ref> [[Gene expression profiling in cancer|Gene expression profiling]] outperforms all of the above-mentioned factors at predicting metastatic spread of the primary tumor, including monosomy 3.<ref>{{cite journal | author = Petrausch U, Martus P, Tönnies H, Bechrakis NE, Lenze D, Wansel S, Hummel M, Bornfeld N, Thiel E, Foerster MH, Keilholz U | title = Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases | journal = Eye | volume = 22 | issue = 8 | pages = 997–1007 | year = 2008 | pmid = 17384575 | doi = 10.1038/sj.eye.6702779}}</ref><ref>{{cite journal | author = van Gils W, Lodder EM, Mensink HW, Kiliç E, Naus NC, Brüggenwirth HT, van Ijcken W, Paridaens D, Luyten GP, de Klein A | title = Gene expression profiling in uveal melanoma: two regions on 3p related to prognosis | journal = Invest Ophthalmol Vis Sci | volume = 49 | issue = 10 | pages = 4254–4262 | year = 2008 | pmid = 18552379 | doi = 10.1167/iovs.08-2033}}</ref><ref>{{cite journal | author = Worley LA, Onken MD, Person E, Robirds D, Branson J, Char DH, Perry A, Harbour JW | title = Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma | journal = Clin Cancer Res | year = 2007 | volume = 13 | issue = 5 | pages = 1466–1471 | pmid = 17332290 | doi = 10.1158/1078-0432.CCR-06-2401}}</ref>
| | ==[[Uveal melanoma screening|Screening]]== |
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| ==Metastasis== | | ==[[Uveal melanoma natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| Because there are no lymphatic channels to the uveal tract, metastasis occurs through local extension and/or blood borne dissemination.<ref>{{cite web| accessdate = 2013-07-04| title = Classification and Stage Information for Intraocular (Uveal) Melanoma | url = http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/HealthProfessional/ |publisher = [[National Cancer Institute]]}}</ref> The most common site of [[metastasis]] for uveal melanoma is the [[liver]];<ref name=Kumar /> the liver is the first site of metastasis for 80%-90% of ocular melanoma patients.<ref>{{cite web | accessdate = 2013-02-02 | title = Prognostic Indicators | url = http://www.ocularmelanoma.org/prognostic-indicators.htm | publisher = Ocular Melanoma Foundation | year = 2012}}</ref> Other common sites of metastasis include the lung, bones and just beneath the skin (subcutaneous). Approximately 50 percent of patients will develop metastases within 15 years after treatment of the primary tumor, and the liver will be involved 90% of the time.<ref>{{cite journal|last=Spagnolo|first=Francesco|author2=Graziano Caltabiano |author3=Paola Queirolo |title=Uveal melanoma|journal=Cancer Treatment Reviews|date=January 2012|volume=38|issue=5|doi=10.1016/j.ctrv.2012.01.002|url=http://www.cancertreatmentreviews.com/article/S0305-7372(12)00003-5/abstract|accessdate=24 November 2013}}</ref> Metastasis can occur more than 10 years after treatment of the primary tumor, and patients should not be considered cured even after a 10 year interval of monitoring.<ref>{{cite journal|last=Kolandjian|first=NA|author2=Wei C |author3=Patel SP |author4=Richard JL |author5=Dett T |author6=Papadopoulos NE |author7=Bedikian AY |title=Delayed systemic recurrence of uveal melanoma|journal=American Journal of Clinical Oncology|date=October 2013|doi=10.1097/COC.0b013e3182546a6b|pmid=22706174|url=http://www.ncbi.nlm.nih.gov/pubmed/22706174?dopt=Citation|accessdate=24 November 2013 |volume=36 |issue=5 |pages=443–9}}</ref> Molecular features of the tumor including [[Chromosome 3]] status, Chromosome 6p status, and Chromosome 8q status and gene expression profiling (such as the [[DecisionDx-UM]] test) can be used to adjust this likelihood of metastasis for an individual patient.
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| The average survival time after diagnosis of liver metastases depends on the extent of systemic spread. The disease-free interval, the performance status, the liver substitution by metastases and the serum level of lactic dehydrogenase are the most important prognostic factors for metastatic uveal melanoma.<ref>{{cite journal|last=Valpione Sara| title=Development and external validation of a prognostic nomogram for metastatic uveal melanoma.|journal=Plos One|date=Mar 2015|doi=10.1371/journal.pone.0120181|pmid=25780931 |url=http://www.ncbi.nlm.nih.gov/pubmed/25780931?dopt=Citation|accessdate=17 March 2015 |volume=10 |issue=3 |display-authors=etal}}</ref> There is currently no cure for metastatic uveal melanoma.
| | ==Diagnosis== |
| | [[Uveal melanoma staging|Staging]] | [[Uveal melanoma history and symptoms|History and Symptoms]] | [[Uveal melanoma physical examination|Physical Examination]] | [[Uveal melanoma laboratory tests|Laboratory Findings]] | [[Uveal melanoma chest x ray|Chest X Ray]] | [[Uveal melanoma CT|CT]] | [[Uveal melanoma MRI|MRI]] | [[Uveal melanoma ultrasound|Ultrasound]] | [[Uveal melanoma other imaging findings|Other Imaging Findings]] | [[Uveal melanoma other diagnostic studies|Other Diagnostic Studies]] |
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| ==Surveillance== | | ==Treatment== |
| Currently, there is no consensus regarding type or frequency of scans following diagnosis and treatment of the primary eye tumor. Of the 50% of patients who develop metastatic disease, more than 90% of patients will develop liver metastases. As such, the majority of surveillance techniques are focused on the liver. These include abdominal magnetic resonance imaging (MRI), abdominal ultrasound and liver function tests. The scientific community is currently working to develop guidelines, but until then, each patient must take into consideration their individual clinical situation and discuss appropriate surveillance with their doctors.<ref>{{cite web|title=MRF CURE OM|url=http://www.melanoma.org/learn-more/types-of-melanoma/cure-ocular-melanoma/om-prognosis|publisher=Melanoma Research Foundation|accessdate=30 March 2012}}</ref>
| | [[Uveal melanoma medical therapy|Medical Therapy]] | [[Uveal melanoma surgery|Surgery]] | [[Uveal melanoma primary prevention|Primary Prevention]] | [[Uveal melanoma secondary prevention|Secondary Prevention]] | [[Uveal melanoma cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Uveal melanoma future or investigational therapies|Future or Investigational Therapies]] |
| Some ophthalmologists have also found promise with the use of intravitreal avastin injections in patients suffering from radiation-induced retinopathy, a side effect of plaque brachytherapy treatment, as well as imaging surveillance with SD-OCT.
| | ==References== |
| | | {{reflist|2}} |
| == See also ==
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| * [[Melanoma]]
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| == References ==
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| {{Reflist|2}}
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| ==Foundations supporting uveal melanoma research, education, and advocacy==
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| * [http://www.cureom.org/ CURE Ocular Melanoma (an initiative of the Melanoma Research Foundation)]
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| * [http://www.eyecancerfoundation.net/ The Eye Cancer Foundation]
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| * [http://www.ocumeluk.org/ OcuMel UK - Charity supporting people affected by Ocular Melanoma in the UK]
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| * [http://www.tumori.org/ The Tumori Foundation]
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| * [http://www.ocularmelanoma.org Ocular Melanoma Foundation]
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| ==External links==
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| * [http://www.fighteyecancer.com/ Ocular Oncology Service (Dr. Shields), Wills Eye Hospital, Philadelphia, PA]
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| * [http://www.myuvealmelanoma.com MyUVEALMelanoma - Overview of DecisionDX-UM from Castle BioSciences]
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| * [http://eyetumor.wustl.edu/ The Ocular Oncology Service at Washington University St. Louis]
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| * [http://eyecancer.com The Eye Cancer Network]
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| * [http://www.eyecancermd.org/index.html Ocular Oncology - Bascom Palmer Eye Institute]
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| * [http://clinicaltrials.gov/ct2/results?term=melanoma+metastatic+liver&recr=Open All NCI-approved clinical trials for uveal melanoma that has spread to the liver]
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| * [http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=6511412&vers=2 [[National Cancer Institute]] Clinical Trials Search Results]
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| * [http://www.eyemelanoma.org EyeMelanoma.org]
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| * [http://rad.usuhs.edu/medpix/cow_image.html?mode=case_viewer&imid=41488&pt_id=11836 Uveal Melanoma] MR Scans of ocular melanoma
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| *[http://paultfingermd.com The New York Eye Cancer Center]
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