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Melanoma pp 273-312 | Cite as

Uveal Melanoma

  • Ronald W. MilamJr.
  • Anthony B. Daniels
Chapter

Abstract

Uveal melanoma, the most common primary intraocular malignancy, includes melanomas of the iris, ciliary body, and choroid. Uveal melanoma is distinctly different from cutaneous melanoma in its clinical and molecular features as well as its risk factors, genetics, pathogenesis, metastatic behavior, and treatment. The rate of distant metastasis approaches 50%, with the most common site of initial metastasis being the liver. Once metastatic disease develops, it is universally fatal, as there are currently no truly effective treatment options for metastatic disease. There are a number of host susceptibility factors and a limited number of well-conserved genetic derangements associated with uveal melanoma, including derangements of chromosomes 1, 3, 6, and 8 and mutations in the GNAQ, GNA11, SF3B1, EIF1AX, and BAP1 genes. Advanced genetic techniques, such as gene expression profiling (GEP) and multiplex ligand-dependent probe amplification (MLPA), have enhanced our ability to stratify patients into low and high risk for the development of metastatic disease. The diagnosis of uveal melanoma is clinical, with numerous adjuvant ophthalmic imaging techniques available to assist in distinguishing borderline benign lesions from melanoma. Currently, the vast majority of uveal melanomas are treated with globe-conserving radiotherapy (predominantly brachytherapy), with local control rates >95%. Enucleation is reserved for larger melanomas, although even these can be treated with various advanced forms of external radiotherapy. Despite successful and durable treatment of the primary tumor, long-term survival rates remain poor. This is likely due to micrometastatic disease that is not clinically or radiographically identified, and indeed present, at the time of initial diagnosis of the primary tumor. These micrometastases have the ability to remain dormant for many years, as patients may develop overt metastatic disease even decades after their initial treatment. Future studies that focus upon the earlier detection, prevention, and treatment of metastatic disease are greatly needed.

Keywords

Uveal melanoma Ocular melanoma Choroidal melanoma Iris melanoma Ciliary body melanoma Risk factors Prognosis Genetics GEP MLPA Radiotherapy Brachytherapy Radiation retinopathy 

References

  1. 1.
    Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Kosary C, et al. Cancer Statistics Review, 1975–2014—SEER Statistics, National Cancer Institute. SEER Cancer Statistics Review, 1975–2014. 2016. http://seer.cancer.gov/csr/1975_2014/
  2. 2.
    Shields JA, Shields CL. Management of posterior uveal melanoma. In: Intraocular tumors: a textbook and Atlas. Philadelphia: WB Saunders; 1992. p. 171–205.Google Scholar
  3. 3.
    Weis E, Salopek TG, McKinnon JG, Larocque MP, Temple-Oberle C, Cheng T, et al. Management of uveal melanoma: a consensus-based provincial clinical practice guideline. Curr Oncol. 2016;23(1):e57–64.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Milam RW, Batson SA, Breazzano MP, Ayala-Peacock DN, Daniels AB. Modern and novel radiotherapy approaches for the treatment of uveal melanoma. Int Ophthalmol Clin [Internet]. 2017;57(1):11–27.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011;118(9):1881–5.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Bichakjian CK, Halpern AC, Johnson TM, Foote Hood A, Grichnik JM, Swetter SM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2011;65(5):1032–47.CrossRefPubMedGoogle Scholar
  7. 7.
    Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med [Internet]. 2004;351(10):998–1012. http://www.nejm.org/doi/full/10.1056/NEJMra041245PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD, et al. Uveal melanoma: from diagnosis to treatment and the science in between. Cancer [Internet]. 2016;122(15):2299–12. http://onlinelibrary.wiley.com/doi/10.1002/cncr.29727/abstract;jsessionid=58601C38771BB3963A9DD2C1864E3DB2.f02t01PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology. 2003;110(5):956–61.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, et al. Incidence of uveal melanoma in Europe. Ophthalmology. 2007;114(12):2309–15.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Tuomaala S, Kivelä T. Correspondence regarding Conjunctival melanoma: is it increasing in the United States? Am J Ophthalmol [Internet]. 2003 [cited 2017 Aug 18];136(6):1189–90; author reply 1190.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Yu GP, Hu DN, McCormick S, Finger PT. Conjunctival melanoma: is it increasing in the United States? Am J Ophthalmol. 2003;135(6):800–6.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83(8):1664–78.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW. Incidence of noncutaneous melanomas in the U.S. Cancer. 2005;103(5):1000–7.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Damato B. Progress in the management of patients with uveal melanoma. The 2012 Ashton Lecture. Eye [Internet]. 2012;26(9):1157–72.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Cerbone L, Van Ginderdeuren R, Van den Oord J, Fieuws S, Spileers W, Van Eenoo L, et al. Clinical presentation, pathological features and natural course of metastatic uveal melanoma, an orphan and commonly fatal disease. Oncology. 2014;86(3):185–9.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Yu G-P, Hu D-N, McCormick SA. Latitude and incidence of ocular melanoma. Photochem Photobiol [Internet]. 2006 [cited 2017 Oct 3];82(6):1621. http://www.ncbi.nlm.nih.gov/pubmed/16922607
  18. 18.
    Nayman T, Bostan C, Logan P, Burnier MN. Uveal melanoma risk factors: a systematic review of meta-analyses. Curr Eye Res [Internet]. 2017 [cited 2017 Aug 19];42(8):1085–93. http://www.ncbi.nlm.nih.gov/pubmed/28494168PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Yu G-P, Hu D-N, McCormick SA. Latitude and incidence of ocular melanoma. Photochem Photobiol. 2006;82(6):1621.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Damato EM, Damato BE. Detection and time to treatment of uveal melanoma in the United Kingdom: an evaluation of 2384 patients. Ophthalmology. 2012;119(8):1582–9.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Andreoli MT, Mieler WF, Leiderman YI. Epidemiological trends in uveal melanoma. Br J Ophthalmol [Internet]. 2015;99(11):1550–3. http://www.ncbi.nlm.nih.gov/pubmed/25904122PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Kivela T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol [Internet]. 2009 Sep 1 [cited 2017 Oct 3];93(9):1129–31. http://www.ncbi.nlm.nih.gov/pubmed/19704035PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The association of cutaneous and iris nevi with uveal melanoma: a meta-analysis. Ophthalmology. 2009;116(3):536–43.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Shields CL, Kaliki S, Livesey M, Walker B, Garoon R, Bucci M, et al. Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872 consecutive eyes. JAMA Ophthalmol [Internet]. 2013;131(8):993–1003. http://www.ncbi.nlm.nih.gov/pubmed/23681424PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009):1410–3.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Gallagher RP, Elwood JM, Rootman J, Spinelli JJ, Hill GB, Threlfall WJ, et al. Risk factors for ocular melanoma: Western Canada Melanoma Study. J Natl Cancer Inst. 1985;74(4):775–8.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Shah CP, Weis E, Lajous M, Shields JA, Shields CL. Intermittent and chronic ultraviolet light exposure and uveal melanoma: a meta-analysis. Ophthalmology. 2005;112(9):1599–607.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Holman HDAJ, Armstrong BK. Pigmentary traits, ethnic origin, benign nevi, and family history as risk factors for cutaneous malignant melanoma. J Natl Cancer Inst. 1984;72(2):257–66.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Mark Elwood J, Jopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer. 1997;73(2):198–203.CrossRefGoogle Scholar
  30. 30.
    Whiteman DC, Stickley M, Watt P, Hughes MC, Davis MB, Green AC. Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol. 2006;24(19):3172–7.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Shields CL. The hunt for the secrets of uveal melanoma. Clin Exp Ophthalmol. 2008;36:277–80.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Tucker MA, Shields JA, Hartge P, Augsburger J, Hoover RN, Fraumeni Jr JF. Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med [Internet]. 1985;313(13):789–92. http://www.ncbi.nlm.nih.gov/pubmed/4033707PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Kaliki S, Shields C. Uveal melanoma: relatively rare but deadly cancer. Eye [Internet]. 2016 [cited 2017 Aug 28];31:241–57. http://www.nature.com.proxy.library.vanderbilt.edu/eye/journal/v31/n2/pdf/eye2016275a.pdfPubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Schmidt-Pokrzywniak A, Jöckel K-H, Bornfeld N, Sauerwein W, Stang A. Positive interaction between light iris color and ultraviolet radiation in relation to the risk of uveal melanoma: a case-control study. Ophthalmology [Internet]. 2009 Feb [cited 2017 Oct 3];116(2):340–8. http://linkinghub.elsevier.com/retrieve/pii/S0161642008010063PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci [Internet]. 1991;88(22):10124–8. http://www.pnas.org/cgi/doi/10.1073/pnas.88.22.10124CrossRefGoogle Scholar
  36. 36.
    Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(12):5230–4.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599–602.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191–9.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    De Lange MJ, Razzaq L, Versluis M, Verlinde S, Dogrusöz M, Böhringer S, et al. Distribution of GNAQ and GNA11 mutation signatures in uveal melanoma points to a light dependent mutation mechanism. PLoS One. 2015;10(9):e0138002.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cruz F, Rubin BP, Wilson D, Town A, Schroeder A, Haley A, et al. Absence of BRAF and NRAS mutations in uveal melanoma. Cancer Res. 2003;63(18):5761–6.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Rimoldi D, Salvi S, Liénard D, Lejeune FJ, Speiser D, Zografos L, et al. Lack of BRAF mutations in uveal melanoma. Cancer Res. 2003;63(18):5712–5.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Daniels AB, Lee JE, MacConaill LE, Palescandolo E, Van Hummelen P, Adams SM, et al. High throughput mass spectrometry-based mutation profiling of primary uveal melanoma. Invest Ophthalmol Vis Sci. 2012;53(11):6991–6.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Milam RW, Daniels AB. Genetics of uveal melanoma. In: eLS: encyclopedia of life sciences. Hoboken: John Wiley and Sons Ltd, 2018.Google Scholar
  45. 45.
    Coupland SE, Lake SL, Zeschnigk M, Damato BE. Molecular pathology of uveal melanoma. Eye (Lond). 2013;27(2):230–42.CrossRefGoogle Scholar
  46. 46.
    Maat W, Ly LV, Jordanova ES, de Wolff-Rouendaal D, Schalij-Delfos NE, Jager MJ. Monosomy of chromosome 3 and an inflammatory phenotype occur together in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(2):505–10.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Prescher G, Bornfeld N, Horsthemke B, Becher R. Chromosomal aberrations defining uveal melanoma of poor prognosis. Lancet (London, England). 1992;339(8794):691–2.CrossRefGoogle Scholar
  48. 48.
    Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet (London, England). 1996;347(9010):1222–5.CrossRefGoogle Scholar
  49. 49.
    Damato B, Duke C, Coupland SE, Hiscott P, Smith PA, Campbell I, et al. Cytogenetics of uveal melanoma: a 7-year clinical experience. Ophthalmology. 2007;114(10):1925–31.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Cassoux N, Rodrigues MJ, Plancher C, Asselain B, Levy-Gabriel C, Rouic LL-L, et al. Genome-wide profiling is a clinically relevant and affordable prognostic test in posterior uveal melanoma. Br J Ophthalmol. 2014;98(6):769–74.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Delaunay J, Martin L, Bressac-de Paillerets B, Duru G, Ingster O, Thomas L. Improvement of genetic testing for cutaneous melanoma in countries with low to moderate incidence. JAMA Dermatol [Internet]. 2017 [cited 2017 Oct 3]; http://www.ncbi.nlm.nih.gov/pubmed/28903138
  52. 52.
    Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell [Internet]. 2015;161(7):1681–96. http://linkinghub.elsevier.com/retrieve/pii/S0092867415006340
  53. 53.
    Daniels AB, Abramson DH. c-KIT in uveal melanoma: big fish or red herring? Arch Ophthalmol (Chicago, Ill 1960). 2009;127(5):695–7.Google Scholar
  54. 54.
    Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell. 2014;25(6):831–45.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z, et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell. 2014;25(6):822–30.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Bauer J, Kilic E, Vaarwater J, Bastian BC, Garbe C, de Klein A. Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma. Br J Cancer. 2009;101(5):813–5.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Matatall KA, Agapova OA, Onken MD, Worley LA, Bowcock AM, Harbour JW. BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma. BMC Cancer. 2013;13:371.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    White VA, McNeil BK, Horsman DE. Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma. Cancer Genet Cytogenet. 1998;102(1):40–5.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    van Essen TH, van Pelt SI, Versluis M, Bronkhorst IH, van Duinen SG, Marinkovic M, et al. Prognostic parameters in uveal melanoma and their association with BAP1 expression. Br J Ophthalmol. 2014;98(12):1738–43.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Yavuzyigitoglu S, Koopmans AE, Verdijk RM, Vaarwater J, Eussen B, van Bodegom A, et al. Uveal melanomas with SF3B1 mutations: a distinct subclass associated with late-onset metastases. Ophthalmology. 2016;123(5):1118–28.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Bonnal S, Vigevani L, Valcarcel J. The spliceosome as a target of novel antitumour drugs. Nat Rev Discov. 2012;11(11):847–59.CrossRefGoogle Scholar
  62. 62.
    Maciejewski JP, Padgett RA. Defects in spliceosomal machinery: a new pathway of leukaemogenesis. Br J Haematol. 2012;158(2):165–73.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Field MG, Harbour JW. Recent developments in prognostic and predictive testing in uveal melanoma. Curr Opin Ophthalmol. 2014;25(3):234–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Martin M, Masshofer L, Temming P, Rahmann S, Metz C, Bornfeld N, et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet. 2013;45(8):933–6.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Coupland SE, Anastassiou G, Stang A, Schilling H, Anagnostopoulos I, Bornfeld N, et al. The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma. J Pathol. 2000;191(2):120–6.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Brantley MA Jr, Harbour JW. Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region. Cancer Res. 2000;60(16):4320–3.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Brantley MA Jr, Harbour JW. Deregulation of the Rb and p53 pathways in uveal melanoma. Am J Pathol. 2000;157(6):1795–801.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Abdel-Rahman MH, Yang Y, Zhou XP, Craig EL, Davidorf FH, Eng C. High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. J Clin Oncol. 2006;24(2):288–95.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Ehlers JP, Worley L, Onken MD, Harbour JW. Integrative genomic analysis of aneuploidy in uveal melanoma. Clin Cancer Res. 2008;14(1):115–22.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95(1):29–39.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–7.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273(22):13375–8.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003;17(3):590–603.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte JF. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann N Y Acad Sci. 2003;983:84–100.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Herlihy N, Dogrusoz M, van Essen TH, Harbour JW, van der Velden PA, van Eggermond MC, et al. Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma. Invest Ophthalmol Vis Sci. 2015;56(3):1447–58.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, et al. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012;18(2):408–16.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Field MG, Harbour JW. GNAQ/11 mutations in uveal melanoma: is YAP the key to targeted therapy? Cancer Cell. 2014;25(6):714–5.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Onken MD, Ehlers JP, Worley LA, Makita J, Yokota Y, Harbour JW. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006;66(9):4602–9.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Sahel JA, Pesavento R, Frederick AR, Albert DM. Melanoma arising de novo over a 16-month period. Arch Ophthalmol (Chicago, Ill 1960) [Internet]. 1988;106(3):381–5. http://www.ncbi.nlm.nih.gov/pubmed/3278703PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Aleksidze N, Medina CA, Singh AD. De novo evolution of a small choroidal melanoma. Ocul Oncol Pathol [Internet]. 2015 [cited 2017 Dec 2];1(2):83–7. http://www.ncbi.nlm.nih.gov/pubmed/27231689PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Shields CL, Furuta M, Mashayekhi A, Berman EL, Zahler JD, Hoberman DM, et al. Clinical spectrum of choroidal nevi based on age at presentation in 3422 consecutive eyes. Ophthalmology. 2008;115(3):546–552.e2.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Shields CL, Kaliki S, Furuta M, Mashayekhi A, Shields JA. Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina. 2012;32:1363–72.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Bove R, Char DH. Nondiagnosed uveal melanomas. Ophthalmology. 2004;111(3):554–7.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Scotto J, Fraumeni JF Jr, Lee JA. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. J Natl Cancer Inst. 1976;56(3):489–91.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Augsburger JJ, Schneider S, Freire J, Brady LW. Survival following enucleation versus plaque radiotherapy in statistically matched subgroups of patients with choroidal melanomas: results in patients treated between 1980 and 1987. Graefes Arch Clin Exp Ophthalmol. 1999;237(7):558–67.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Kapoor A, Beniwal V, Beniwal S, Mathur H, Kumar HS. Management of uveal tract melanoma: a comprehensive review. J Egypt Natl Canc Inst. 2016;28(2):65–72.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Nichols EE, Richmond A, Daniels AB. Tumor characteristics, genetics, management, and the risk of metastasis in uveal melanoma. Semin Ophthalmol. 2016;31(4):304–9.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Shields JA, Shields CL. Intraocular tumors: an atlas and textbook. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2015. 608 p.Google Scholar
  89. 89.
    Shields JA, Sanborn GE, Augsburger JJ. The differential diagnosis of malignant melanoma of the iris. A clinical study of 200 patients. Ophthalmology [Internet]. 1983 [cited 2017 Dec 5];90(6):716–20. http://www.ncbi.nlm.nih.gov/pubmed/6888862
  90. 90.
    Ah-Fat FG, Damato BE. Delays in the diagnosis of uveal melanoma and effect on treatment. Eye (Lond). 1998;12(Pt 5):781–2.CrossRefGoogle Scholar
  91. 91.
    Eagle Jr RC, Grossniklaus HE, Syed N, Hogan RN, Lloyd WC, Folberg R, et al. Inadvertent evisceration of eyes containing uveal melanoma. Arch Ophthalmol [Internet]. 2009;127(2):141–5.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Shields CL. Choroidal nevus transformation into melanoma. Arch Ophthalmol. 2009;127(8):981–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol (Chicago, Ill 1960) [Internet]. 2009;127(8):989–98. http://www.ncbi.nlm.nih.gov/pubmed/19667335PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Fuller DG, Snyder WB, Hutton WL, Vaiser A. Ultrasonographic features of choroidal malignant melanomas. Arch Ophthalmol (Chicago, Ill 1960) [Internet]. 1979 [cited 2017 Oct 3];97(8):1465–72. http://www.ncbi.nlm.nih.gov/pubmed/464871
  95. 95.
    Bedi DG, Gombos DS, Ng CS, Singh S. Sonography of the eye. Am J Roentgenol. 2006;187(4):1061–72.CrossRefGoogle Scholar
  96. 96.
    Ossoinig KC. Standardized echography: basic principles, clinical applications, and results. Int Ophthalmol Clin [Internet]. 1979 [cited 2017 Oct 3];19(4):127–210. http://www.ncbi.nlm.nih.gov/pubmed/395120PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Pavlin CJ, McWhae JA, McGowan HD, Foster FS. Ultrasound biomicroscopy of anterior segment tumors. Ophthalmology [Internet]. 1992 [cited 2017 Oct 3];99(8):1220–8. http://www.ncbi.nlm.nih.gov/pubmed/1513574
  98. 98.
    Pavlin CJ, McWhae JA, McGowan HD, Foster FS. Ultrasound biomicroscopy of anterior segment tumors. Ophthalmology. 1992;99(8):1220–8.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Conway RM, Chew T, Golchet P, Desai K, Lin S, O’Brien J. Ultrasound biomicroscopy: role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours. Br J Ophthalmol [Internet]. 2005 [cited 2017 Oct 3];89(8):950–5. http://www.ncbi.nlm.nih.gov/pubmed/16024841PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Yung M, Klufas MA, Sarraf D. Clinical applications of fundus autofluorescence in retinal disease. Int J Retin Vitr [Internet]. 2016 [cited 2017 Oct 18];2(1):12. http://journalretinavitreous.biomedcentral.com/articles/10.1186/s40942-016-0035-x
  101. 101.
    Shields CL, Pirondini C, Bianciotto C, Materin MA, Harmon SA, Shields JA. Autofluorescence of choroidal nevus in 64 cases. Retina [Internet]. 2008;28(8):1035–43. http://www.ncbi.nlm.nih.gov/pubmed/18779708PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular tumours. Curr Opin Ophthalmol [Internet]. 2013;24(3):222–32. http://www.ncbi.nlm.nih.gov/pubmed/23429597PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Lavinsky D, Belfort RN, Navajas E, Torres V, Martins MC, Belfort R. Fundus autofluorescence of choroidal nevus and melanoma. Br J Ophthalmol [Internet]. 2007;91(10):1299–302. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2000998&tool=pmcentrez&rendertype=abstractPubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Albertus DL, Schachar IH, Zahid S, Elner VM, Demirci H, Jayasundera T. Autofluorescence quantification of benign and malignant choroidal nevomelanocytic tumors. JAMA Ophthalmol [Internet]. 2013;131(8):1004–8. http://www.ncbi.nlm.nih.gov/pubmed/23787920PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Espinoza G, Rosenblatt B, Harbour JW. Optical coherence tomography in the evaluation of retinal changes associated with suspicious choroidal melanocytic tumors. Am J Ophthalmol. 2004;137:90–5.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Shields CL, Mashayekhi A, Materin MA, Luo CK, Marr BP, Demirci H, et al. Optical coherence tomography of choroidal nevus in 120 patients. Retina. 2005;25:243–52.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Augsburger JJ, Golden MI, Shields JA. Fluorescein angiography of choroidal malignant melanomas with retinal invasion. Retina [Internet]. 1984 [cited 2017 Oct 18];4(4):232–41. http://www.ncbi.nlm.nih.gov/pubmed/6531518
  108. 108.
    Shields CL, Shields JA, De Potter P. Patterns of indocyanine green videoangiography of choroidal tumours. Br J Ophthalmol [Internet]. 1995 [cited 2017 Oct 19];79(3):237–45. http://www.ncbi.nlm.nih.gov/pubmed/7703202PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Folberg R, Rummelt V, Parys-Van Ginderdeuren R, Hwang T, Woolson RF, Pe’er J, et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology [Internet]. 1993;100(9):1389–98.  https://doi.org/10.1016/S0161-6420(93)31470-3PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Mueller AJ, Bartsch D-U, Folberg R, Mehaffey MG, Boldt HC, Meyer M, et al. Imaging the microvasculature of choroidal melanomas with confocal indocyanine green scanning laser ophthalmoscopy. Arch Ophthalmol [Internet]. 1998;116(1):31–9. http://www.ncbi.nlm.nih.gov/pubmed/9445206PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Tartaglione T, Pagliara MM, Sciandra M, Caputo CG, Calandrelli R, Fabrizi G, et al. Uveal melanoma: evaluation of extrascleral extension using thin-section MR of the eye with surface coils. Radiol Med [Internet]. 2014 [cited 2017 Oct 19];119(10):775–83. http://www.ncbi.nlm.nih.gov/pubmed/24469990PubMedCrossRefGoogle Scholar
  112. 112.
    Henderson E, Margo CE. Iris melanoma. Arch Pathol Lab Med [Internet]. 2008;132(2):268–72. http://www.ncbi.nlm.nih.gov/pubmed/18251588
  113. 113.
    Shields CL, Shields JA, Shields MB, Augsburger JJ. Prevalence and mechanisms of secondary intraocular pressure elevation in eyes with intraocular tumors. Ophthalmology [Internet]. 1987;94(7):839–46. http://www.ncbi.nlm.nih.gov/pubmed/3658352PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Shields CL, Kaliki S, Shah SU, Luo W, Furuta M, Shields JA. Iris melanoma: features and prognosis in 317 children and adults. J AAPOS. 2012;16(1):10–6.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Bianciotto C, Shields CL, Guzman JM, Romanelli-Gobbi M, Mazzuca D, Green WR, et al. Assessment of anterior segment tumors with ultrasound biomicroscopy versus anterior segment optical coherence tomography in 200 cases. Ophthalmology. 2011;118(7):1297–302.PubMedGoogle Scholar
  116. 116.
    Shields CL, Shields JA, Kiratli H, De Potter P, Cater JR. Risk factors for growth and metastasis of small choroidal melanocytic lesions. Trans Am Ophthalmol Soc. 1995;93:259.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Shields CL, Cater J, Shields JA Singh AD, Santos MC, Carvalho C Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol [Internet]. 2000;118(3):360–4. http://www.ncbi.nlm.nih.gov/pubmed/10721958PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol [Internet]. 1997;115(12):1537–44. http://www.ncbi.nlm.nih.gov/pubmed/9400787
  119. 119.
    Eskelin S, Pyrhönen S, Summanen P, Hahka-Kemppinen M, Kivelä T. Tumor doubling times in metastatic malignant melanoma of the uvea: Tumor progression before and after treatment. Ophthalmology. 2000;107(8):1443–9.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Eskelin S, Kivel T, References F. Uveal melanoma: implications of tumor doubling time. author’s reply. Ophthalmology [Internet]. 2001 [cited 2017 Aug 26];108(5):830–1. http://www.aaojournal.org/article/S0161-6420(00)00608-4/pdf
  121. 121.
    Chien JL, Sioufi K, Surakiatchanukul T, Shields JA, Shields CL. Choroidal nevus: a review of prevalence, features, genetics, risks, and outcomes. Curr Opin Ophthalmol. 2017;28(3):228–37.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Scholes AG, Damato BE, Nunn J, Hiscott P, Grierson I, Field JK. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci. 2003;44(3):1008–11.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Seddon JM, Albert DM, Lavin PT, Robinson N. A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol [Internet]. 1983;101(12):1894–9. http://www.ncbi.nlm.nih.gov/pubmed/6651594PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Singh AD, Shields CL, Shields JA. Prognostic factors in uveal melanoma. Melanoma Res. 2001;11(3):255–63.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Diener-West M, Earle JD, Fine SL, Hawkins BS, Moy CS, Reynolds SM, et al. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol (Chicago, Ill 1960). 2001;119(7):969–82.CrossRefGoogle Scholar
  126. 126.
    Mortality in patients with small choroidal melanoma. COMS report no. 4. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol (Chicago, Ill 1960) [Internet]. 1997;115(7):886–93. http://www.ncbi.nlm.nih.gov/pubmed/9230829
  127. 127.
    Group COMS. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol (Chicago, Ill 1960). 2006;124(12):1684–93.Google Scholar
  128. 128.
    Margo CE. The Collaborative Ocular Melanoma Study: an overview. Cancer Control. 2004;11(5):304–9.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Diener-West M, Hawkins BS, Markowitz JA, Schachat AP. A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol. 1992;110(2):245–50.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Hawkins BS, Group COMS. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report number 24. Am J Ophthalmol. 2004;138(6):936–51.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    McLean MJ, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol [Internet]. 1977;95(1):48–58.PubMedCrossRefGoogle Scholar
  132. 132.
    Shields CL, Sioufi K, Alset AE, Boal NS, Casey MG, Knapp AN, et al. Clinical features differentiating benign from malignant conjunctival tumors in children. JAMA Ophthalmol [Internet]. 2017;135(3):215–24. http://archopht.jamanetwork.com/article.aspx?doi=10.1001/jamaophthalmol.2016.5544PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Vine A, Sneed S, Elner V, Wolter R, Willis J, Itani K, et al. Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS report no. 1. Arch Ophthalmol. 1990;108(9):1268–73.CrossRefGoogle Scholar
  134. 134.
    Biscotti CV, Singh AD. Uveal metastases. In: Monographs in clinical cytology [Internet]. 2011 [cited 2017 Dec 5]. p. 17–30. http://www.ncbi.nlm.nih.gov/pubmed/22024581Google Scholar
  135. 135.
    Eide N, Walaas L. Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review. Acta Ophthalmol [Internet]. 2009 [cited 2017 Dec 5];87(6):588–601. http://www.ncbi.nlm.nih.gov/pubmed/19719804PubMedCrossRefGoogle Scholar
  136. 136.
    Singh AD, Biscotti CV. Fine needle aspiration biopsy of ophthalmic tumors. Saudi J Ophthalmol Off J Saudi Ophthalmol Soc [Internet]. 2012 [cited 2017 Dec 5];26(2):117–23. http://www.ncbi.nlm.nih.gov/pubmed/23960981
  137. 137.
    Augsburger JJ, Shields JA, Folberg R, Lang W, O’Hara BJ Claricci JD. Fine needle aspiration biopsy in the diagnosis of intraocular cancer. Cytologic-histologic correlations. Ophthalmology [Internet]. 1985 [cited 2017 Dec 5];92(1):39–49. http://www.ncbi.nlm.nih.gov/pubmed/3974994PubMedCrossRefGoogle Scholar
  138. 138.
    Shields CL, Manquez ME, Ehya H, Mashayekhi A, Danzig CJ, Shields JA. Fine-needle aspiration biopsy of iris tumors in 100 consecutive cases: technique complications. Ophthalmology. 2006;113(11):2080–6.PubMedCrossRefGoogle Scholar
  139. 139.
    Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64(20):7205–9.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Harbour JW, Chen R. The decisionDx-UM gene expression profile test provides risk stratification and individualized patient care in uveal melanoma. PLoS Curr. 2013;5. doi: https://doi.org/10.1371/currents.eogt.af8ba80fc776c8f1ce8f5dc485d4a618.
  141. 141.
    Walter SD, Chao DL, Feuer W, Schiffman J, Char DH, Harbour JW. Prognostic implications of tumor diameter in association with gene expression profile for uveal melanoma. JAMA Ophthalmol. 2016;134(7):734–40.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. In: AJCC cancer staging manual [Internet]. 7th ed. New York: Springer; 2010. p. 547–59. http://www.springer.com/it/book/9780387884400#aboutBook
  143. 143.
    Shields CL, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields JA. American Joint Committee on Cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients. Ophthalmology. 2013;120(10):2066–71.PubMedCrossRefGoogle Scholar
  144. 144.
    Kujala E, Damato B, Coupland SE, Desjardins L, Bechrakis NE, Grange JD, et al. Staging of ciliary body and choroidal melanomas based on anatomic extent. J Clin Oncol. 2013;31(22):2825–31.PubMedCrossRefGoogle Scholar
  145. 145.
    Malignant melanoma of the uvea staging form. In: AJCC cancer staging manual. 7th ed. New York City: Springer; 2010. p. 555.Google Scholar
  146. 146.
    Faulkner-Jones BE, Foster WJ, Harbour JW, Smith ME, Davila RM. Fine needle aspiration biopsy with adjunct immunohistochemistry in intraocular tumor management. Acta Cytol. 2005;49(3):297–308.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Earle JD. Results from the Collaborative Ocular Melanoma Study (COMS) of enucleation versus preoperative radiation therapy in the management of large ocular melanomas. Int J Radiat Oncol Biol Phys. 1999;43(5):1168–9.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Hicks C, Foss AJ, Hungerford JL. Predictive power of screening tests for metastasis in uveal melanoma. Eye. 1998;12:945–8.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Wang MX, Shields JA, Donoso LA. Subclinical metastasis of uveal melanoma. Int Ophthalmol Clin [Internet]. 1993 [cited 2017 Aug 27];33(3):119–27. http://www.ncbi.nlm.nih.gov/pubmed/8407176PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Zimmerman L, McLean I. Changing concepts concerning the malignancy of ocular tumors. Arch Ophthalmol. 1975;78:487–94.Google Scholar
  151. 151.
    Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells. Br J Ophthalmol. 1978;62(6):420–5.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Earle J, Kline RW, Robertson DM. Selection of iodine 125 for the Collaborative Ocular Melanoma Study. Arch Ophthalmol (Chicago, Ill 1960). 1987;105(6):763–4.Google Scholar
  153. 153.
    Marwaha G, Macklis R, Singh AD, Wilkinson A. Brachytherapy. Dev Ophthalmol. 2013;52:29–35.PubMedCrossRefGoogle Scholar
  154. 154.
    Cox J, Ang K. Radiation oncology: rational, technique, results. 9th ed. Philadelphia: Mosby Elsevier; 2010.Google Scholar
  155. 155.
    Chang MY, Kamrava M, Demanes DJ, Leu M, Agazaryan N, Lamb J, et al. Intraoperative ultrasonography-guided positioning of iodine 125 plaque brachytherapy in the treatment of choroidal melanoma. Ophthalmology. 2012;119(5):1073–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Classic KL, Furutani KM, Stafford SL, Pulido JS. Radiation dose to the surgeon during plaque brachytherapy. Retina. 2012;32(9):1900–5.PubMedCrossRefGoogle Scholar
  157. 157.
    Nag S, Quivey JM, Earle JD, Followill D, Fontanesi J, Finger PT, et al. The American Brachytherapy Society recommendations for brachytherapy of uveal melanomas. Int J Radiat Oncol Biol Phys. 2003;56(2):544–55.PubMedCrossRefGoogle Scholar
  158. 158.
    Finger PT. Radiation therapy for choroidal melanoma. Surv Ophthalmol. 1997;42(3):215–32.PubMedCrossRefGoogle Scholar
  159. 159.
    Dendale R, Rouic LL-L, Noel G, Feuvret L, Levy C, Delacroix S, et al. Proton beam radiotherapy for uveal melanoma: results of Curie Institut-Orsay proton therapy center (ICPO). Int J Radiat Oncol Biol Phys. 2006;65(3):780–7.PubMedCrossRefGoogle Scholar
  160. 160.
    Wilson MW, Hungerford JL. Comparison of episcleral plaque and proton beam radiation therapy for the treatment of choroidal melanoma. Ophthalmology. 1999;106(8):1579–87.PubMedCrossRefGoogle Scholar
  161. 161.
    Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol. 1998;125(1):81–9.PubMedCrossRefGoogle Scholar
  162. 162.
    Gragoudas ES, Lane AM. Uveal melanoma: proton beam irradiation. Ophthalmol Clin North Am. 2005;18(1):111–8. ixPubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Vavvas D, Kim I, Lane AM, Chaglassian A, Mukai S, Gragoudas E. Posterior uveal melanoma in young patients treated with proton beam therapy. Retina. 2010;30(8):1267–71.PubMedCrossRefGoogle Scholar
  164. 164.
    Young LH, Gragoudas ES. Macular uveal melanoma treated with proton beam irradiation. 10-year follow-up observation with histopathologic correlation. Retina. 1994;14(1):43–6.PubMedCrossRefGoogle Scholar
  165. 165.
    Gragoudas E, Li W, Goitein M, Lane AM, Munzenrider JE, Egan KM. Evidence-based estimates of outcome in patients irradiated for intraocular melanoma. Arch Ophthalmol (Chicago, Ill 1960). 2002;120(12):1665–71.PubMedCrossRefGoogle Scholar
  166. 166.
    Mourtada F, Koch N, Newhauser W. 106Ru/106Rh plaque and proton radiotherapy for ocular melanoma: a comparative dosimetric study. Radiat Prot Dosimetry. 2005;116(1–4 Pt 2):454–60.PubMedCrossRefGoogle Scholar
  167. 167.
    Gragoudas ES, Lane AM, Regan S, Li W, Judge HE, Munzenrider JE, et al. A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol (Chicago, Ill 1960). 2000;118(6):773–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Fakiris AJ, Lo SS, Henderson MA, Witt TC, Worth RM, Danis RP, et al. Gamma-knife-based stereotactic radiosurgery for uveal melanoma. Stereotact Funct Neurosurg. 2007;85(2–3):106–12.PubMedCrossRefGoogle Scholar
  169. 169.
    Cohen VM, Carter MJ, Kemeny A, Radatz M, Rennie IG. Metastasis-free survival following treatment for uveal melanoma with either stereotactic radiosurgery or enucleation. Acta Ophthalmol Scand. 2003;81(4):383–8.PubMedCrossRefGoogle Scholar
  170. 170.
    Abrams MJ, Gagne NL, Melhus CS, Mignano JE. Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses. Brachytherapy. 2016;15(2):216–23.PubMedCrossRefGoogle Scholar
  171. 171.
    Sikuade MJ, Salvi S, Rundle PA, Errington DG, Kacperek A, Rennie IG. Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for choroidal melanoma. Eye (Lond). 2015;29(9):1194–8.CrossRefGoogle Scholar
  172. 172.
    Damato B, Kacperek A, Chopra M, Campbell IR, Errington RD. Proton beam radiotherapy of choroidal melanoma: the Liverpool-Clatterbridge experience. Int J Radiat Oncol Biol Phys. 2005;62(5):1405–11.PubMedCrossRefGoogle Scholar
  173. 173.
    Weber DC, Bogner J, Verwey J, Georg D, Dieckmann K, Escude L, et al. Proton beam radiotherapy versus fractionated stereotactic radiotherapy for uveal melanomas: a comparative study. Int J Radiat Oncol Biol Phys. 2005;63(2):373–84.PubMedCrossRefGoogle Scholar
  174. 174.
    Shields CL, Shields JA, Perez N, Singh AD, Cater J. Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology. 2002 Feb;109(2):225–34.PubMedCrossRefGoogle Scholar
  175. 175.
    Rahmi A, Mammar H, Thariat J, Angellier G, Herault J, Chauvel P, et al. Proton beam therapy for presumed and confirmed iris melanomas: a review of 36 cases. Graefes Arch Clin Exp Ophthalmol. 2014;252(9):1515–21.PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Shields CL, Shah SU, Bianciotto CG, Emrich J, Komarnicky L, Shields JA. Iris melanoma management with iodine-125 plaque radiotherapy in 144 patients: impact of melanoma-related glaucoma on outcomes. Ophthalmology. 2013;120(1):55–61.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Demirci H, Shields CL, Shields JA, Eagle RC, Honavar SG. Diffuse iris melanoma: a report of 25 cases. Ophthalmology. 2002;109(8):1553–60.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Melia BM, Abramson DH, Albert DM, Boldt HC, Earle JD, Hanson WF, et al. Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16. Ophthalmology. 2001;108(2):348–66.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Finger PT, Berson A, Szechter A. Palladium-103 plaque radiotherapy for choroidal melanoma: results of a 7-year study. Ophthalmology. 1999;106(3):606–13.PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Jensen AW, Petersen IA, Kline RW, Stafford SL, Schomberg PJ, Robertson DM. Radiation complications and tumor control after 125I plaque brachytherapy for ocular melanoma. Int J Radiat Oncol Biol Phys. 2005;63(1):101–8.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Gragoudas ES, Egan KM, Seddon JM, Walsh SM, Munzenrider JE. Intraocular recurrence of uveal melanoma after proton beam irradiation. Ophthalmology. 1992;99(5):760–6.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Munzenrider JE. Uveal melanomas. Conservation treatment. Hematol Oncol Clin North Am. 2001;15(2):389–402.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Egger E, Schalenbourg A, Zografos L, Bercher L, Boehringer T, Chamot L, et al. Maximizing local tumor control and survival after proton beam radiotherapy of uveal melanoma. Int J Radiat Oncol Biol Phys. 2001;51(1):138–47.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Seddon JM, Gragoudas ES, Albert DM, Hsieh CC, Polivogianis L, Friedenberg GR. Comparison of survival rates for patients with uveal melanoma after treatment with proton beam irradiation or enucleation. Am J Ophthalmol. 1985;99(3):282–90.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Seddon JM, Gragoudas ES, Egan KM, Glynn RJ, Howard S, Fante RG, et al. Relative survival rates after alternative therapies for uveal melanoma. Ophthalmology. 1990;97(6):769–77.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Dinca EB, Yianni J, Rowe J, Radatz MW, Preotiuc-Pietro D, Rundle P, et al. Survival and complications following gamma knife radiosurgery or enucleation for ocular melanoma: a 20-year experience. Acta Neurochir. 2012;154(4):605–10.PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Wackernagel W, Holl E, Tarmann L, Avian A, Schneider MR, Kapp K, et al. Visual acuity after Gamma-Knife radiosurgery of choroidal melanomas. Br J Ophthalmol. 2013;97(2):153–8.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Wackernagel W, Holl E, Tarmann L, Mayer C, Avian A, Schneider M, et al. Local tumour control and eye preservation after gamma-knife radiosurgery of choroidal melanomas. Br J Ophthalmol. 2014;98(2):218–23.PubMedCrossRefPubMedCentralGoogle Scholar
  189. 189.
    Mueller AJ, Talies S, Schaller UC, Horstmann G, Wowra B, Kampik A. Stereotactic radiosurgery of large uveal melanomas with the gamma-knife. Ophthalmology. 2000;107(7):1381–8.PubMedCrossRefPubMedCentralGoogle Scholar
  190. 190.
    Rennie I, Forster D, Kemeny A, Walton L, Kunkler I. The use of single fraction Leksell stereotactic radiosurgery in the treatment of uveal melanoma. Acta Ophthalmol Scand. 1996;74(6):558–62.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Zehetmayer M, Kitz K, Menapace R, Ertl A, Heinzl H, Ruhswurm I, et al. Local tumor control and morbidity after one to three fractions of stereotactic external beam irradiation for uveal melanoma. Radiother Oncol. 2000;55(2):135–44.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Mashayekhi A, Shields CL, Rishi P, Atalay HT, Pellegrini M, McLaughlin JP, et al. Primary transpupillary thermotherapy for choroidal melanoma in 391 cases: Importance of risk factors in tumor control. Ophthalmology. 2015;122(3):600–9.PubMedCrossRefPubMedCentralGoogle Scholar
  193. 193.
    Harbour JW, Meredith TA, Thompson PA, Gordon ME. Transpupillary thermotherapy versus plaque radiotherapy for suspected choroidal melanomas. Ophthalmology. 2003;110(11):2207–14.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Finger PT, Berson A, Ng T, Szechter A. Palladium-103 plaque radiotherapy for choroidal melanoma: an 11-year study. Int J Radiat Oncol Biol Phys. 2002;54(5):1438–45.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Lommatzsch PK, Werschnik C, Schuster E. Long-term follow-up of Ru-106/Rh-106 brachytherapy for posterior uveal melanoma. Graefes Arch Clin Exp Ophthalmol. 2000;238(2):129–37.PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Mensink HW, Vaarwater J, Kilic E, Naus NC, Mooy N, Luyten G, et al. Chromosome 3 intratumor heterogeneity in uveal melanoma. Invest Ophthalmol Vis Sci. 2009;50(2):500–4.PubMedCrossRefPubMedCentralGoogle Scholar
  197. 197.
    Shields CL, Ganguly A, Bianciotto CG, Turaka K, Tavallali A, Shields JA. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology. 2011;118(2):396–401.PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Damato B, Dopierala JA, Coupland SE. Genotypic profiling of 452 choroidal melanomas with multiplex ligation-dependent probe amplification. Clin Cancer Res. 2010;16(24):6083–92.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119(8):1596–603.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Chang SH, Worley LA, Onken MD, Harbour JW. Prognostic biomarkers in uveal melanoma: evidence for a stem cell-like phenotype associated with metastasis. Melanoma Res. 2008;18(3):191–200.PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Augsburger JJ, Correa ZM, Augsburger BD. Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy. Am J Ophthalmol. 2015;159(2):248–56.PubMedCrossRefPubMedCentralGoogle Scholar
  202. 202.
    Field MG, Decatur CL, Kurtenbach S, Gezgin G, van der Velden PA, Jager MJ, et al. PRAME as an independent biomarker for metastasis in uveal melanoma. Clin Cancer Res. 2016;22(5):1234–42.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002;30(12):e57.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Damato B, Dopierala J, Klaasen A, van Dijk M, Sibbring J, Coupland SE. Multiplex ligation-dependent probe amplification of uveal melanoma: correlation with metastatic death. Invest Ophthalmol Vis Sci. 2009;50(7):3048–55.PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Schopper VJ, Correa ZM. Clinical application of genetic testing for posterior uveal melanoma. Int J Retin Vitr. 2016;2:4. eCollection 2016CrossRefGoogle Scholar
  206. 206.
    Singh AD, Topham A. Survival rates with uveal melanoma in the United States: 1973–1997. Ophthalmology. 2003;110(5):962–5.PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    Yonekawa Y, Kim IK. Epidemiology and management of uveal melanoma. Hematol Oncol Clin North Am. 2012;26(6):1169–84.PubMedCrossRefPubMedCentralGoogle Scholar
  208. 208.
    Kujala E, Makitie T, Kivela T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44(11):4651–9.PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Bishop KD, Olszewski AJ. Epidemiology and survival outcomes of ocular and mucosal melanomas: a population-based analysis. Int J Cancer. 2014;134(12):2961–71.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Burr JM, Mitry E, Rachet B, Coleman MP. Survival from uveal melanoma in England and Wales 1986 to 2001. Ophthalmic Epidemiol. 2007;14(1):3–8.PubMedCrossRefPubMedCentralGoogle Scholar
  211. 211.
    Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, et al. Survival in patients with uveal melanoma in Europe. Arch Ophthalmol (Chicago, Ill 1960). 2008;126(10):1413–8.Google Scholar
  212. 212.
    Grossniklaus HE. Progression of ocular melanoma metastasis to the liver: the 2012 Zimmerman lecture. JAMA Ophthalmol [Internet]. 2013;131(4):462–9. http://www.ncbi.nlm.nih.gov/pubmed/23392528PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Lane AM, Kim IK, Gragoudas ES. Long-term risk of melanoma-related mortality for patients with uveal melanoma treated with proton beam therapy. JAMA Ophthalmol. 2015;133(7):792–6.PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Singh AD, Rennie IG, Kivela T, Seregard S, Grossniklaus H. The Zimmerman-McLean-Foster hypothesis: 25 years later. Br J Ophthalmol [Internet]. 2004 [cited 2017 Dec 5];88(7):962–7. http://www.ncbi.nlm.nih.gov/pubmed/15205248PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Borthwick NJ, Thombs J, Polak M, Gabriel FG, Hungerford JL, Damato B, et al. The biology of micrometastases from uveal melanoma. J Clin Pathol [Internet]. 2011 [cited 2017 Dec 8];64(8):666–71. http://www.ncbi.nlm.nih.gov/pubmed/21593344PubMedCrossRefPubMedCentralGoogle Scholar
  216. 216.
    Mahipal A, Tijani L, Chan K, Laudadio M, Mastrangelo MJ, Sato T. A pilot study of sunitinib malate in patients with metastatic uveal melanoma. Melanoma Res. 2012;22(6):440–6.PubMedCrossRefPubMedCentralGoogle Scholar
  217. 217.
    Huppert PE, Fierlbeck G, Pereira P, Schanz S, Duda SH, Wietholtz H, et al. Transarterial chemoembolization of liver metastases in patients with uveal melanoma. Eur J Radiol. 2010;74(3):e38–44.PubMedCrossRefPubMedCentralGoogle Scholar
  218. 218.
    Schmittel A, Schuster R, Bechrakis NE, Siehl JM, Foerster MH, Thiel E, et al. A two-cohort phase II clinical trial of gemcitabine plus treosulfan in patients with metastatic uveal melanoma. Melanoma Res. 2005;15(5):447–51.PubMedCrossRefPubMedCentralGoogle Scholar
  219. 219.
    Agarwala SS, Panikkar R, Kirkwood JM. Phase I/II randomized trial of intrahepatic arterial infusion chemotherapy with cisplatin and chemoembolization with cisplatin and polyvinyl sponge in patients with ocular melanoma metastatic to the liver. Melanoma Res. 2004;14(3):217–22.PubMedCrossRefPubMedCentralGoogle Scholar
  220. 220.
    Kivela T, Suciu S, Hansson J, Kruit WH, Vuoristo MS, Kloke O, et al. Bleomycin, vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma. Eur J Cancer. 2003;39(8):1115–20.PubMedCrossRefPubMedCentralGoogle Scholar
  221. 221.
    Breazzano MP, Milam RW, Batson SA, Johnson DB, Daniels AB. Immunotherapy for Uveal Melanoma. Int Ophthalmol Clin. 2017;57(1):29–39.PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Bhatia S, Moon J, Margolin KA, Weber JS, Lao CD, Othus M, et al. Phase II trial of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic uveal melanoma: SWOG S0512. PLoS One. 2012;7(11):e48787.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Homsi J, Bedikian AY, Papadopoulos NE, Kim KB, Hwu WJ, Mahoney SL, et al. Phase 2 open-label study of weekly docosahexaenoic acid-paclitaxel in patients with metastatic uveal melanoma. Melanoma Res. 2010;20(6):507–10.PubMedCrossRefPubMedCentralGoogle Scholar
  224. 224.
    Fiorentini G, Aliberti C, Del Conte A, Tilli M, Rossi S, Ballardini P, et al. Intra-arterial hepatic chemoembolization (TACE) of liver metastases from ocular melanoma with slow-release irinotecan-eluting beads. Early results of a phase II clinical study. In Vivo. 2009;23(1):131–7.PubMedPubMedCentralGoogle Scholar
  225. 225.
    O’Neill PA, Butt M, Eswar CV, Gillis P, Marshall E. A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma. Melanoma Res. 2006;16(3):245–8.PubMedCrossRefPubMedCentralGoogle Scholar
  226. 226.
    Schmittel A, Schmidt-Hieber M, Martus P, Bechrakis NE, Schuster R, Siehl JM, et al. A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma. Ann Oncol. 2006;17(12):1826–9.PubMedCrossRefPubMedCentralGoogle Scholar
  227. 227.
    Patel K, Sullivan K, Berd D, Mastrangelo MJ, Shields CL, Shields JA, et al. Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study. Melanoma Res. 2005;15(4):297–304.PubMedCrossRefPubMedCentralGoogle Scholar
  228. 228.
    Schmidt-Hieber M, Schmittel A, Thiel E, Keilholz U. A phase II study of bendamustine chemotherapy as second-line treatment in metastatic uveal melanoma. Melanoma Res. 2004;14(6):439–42.PubMedCrossRefPubMedCentralGoogle Scholar
  229. 229.
    Alexander HR Jr, Libutti SK, Pingpank JF, Steinberg SM, Bartlett DL, Helsabeck C, et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res. 2003;9(17):6343–9.PubMedPubMedCentralGoogle Scholar
  230. 230.
    Alexander HR, Libutti SK, Bartlett DL, Puhlmann M, Fraker DL, Bachenheimer LC. A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res. 2000;6(8):3062–70.PubMedPubMedCentralGoogle Scholar
  231. 231.
    Pyrhonen S, Hahka-Kemppinen M, Muhonen T, Nikkanen V, Eskelin S, Summanen P, et al. Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma. Cancer. 2002;95(11):2366–72.PubMedCrossRefPubMedCentralGoogle Scholar
  232. 232.
    Eroglu Z, Smalley KSM, Sondak VK. Improving patient outcomes to targeted therapies in melanoma. Expert Rev Anticancer Ther [Internet]. 2016;16(6):633–41. http://www.ncbi.nlm.nih.gov/pubmed/27137746PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Maio M, Danielli R, Chiarion-Sileni V, Pigozzo J, Parmiani G, Ridolfi R, et al. Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma. Ann Oncol. 2013;24(11):2911–5.PubMedCrossRefPubMedCentralGoogle Scholar
  234. 234.
    Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013;119(20):3687–95.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Buder K, Gesierich A, Gelbrich G, Goebeler M. Systemic treatment of metastatic uveal melanoma: review of literature and future perspectives. Cancer Med. 2013;2(5):674–86.PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Moser JC, Pulido JS, Dronca RS, McWilliams RR, Markovic SN, Mansfield AS. The Mayo Clinic experience with the use of kinase inhibitors, ipilimumab, bevacizumab, and local therapies in the treatment of metastatic uveal melanoma. Melanoma Res. 2015;25(1):59–63.PubMedCrossRefGoogle Scholar
  237. 237.
    Page DB, Postow MA, Callahan MK, Wolchok JD. Checkpoint modulation in melanoma: an update on ipilimumab and future directions. Curr Oncol Rep. 2013;15(5):500–8.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer [Internet]. 2016 [cited 2017 Dec 8];122(21):3344–53. http://doi.wiley.com/10.1002/cncr.30258PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Finger PT, Kurli M, Reddy S, Tena LB, Pavlick a C. Whole body PET/CT for initial staging of choroidal melanoma. Br J Ophthalmol. 2005;89(10):1270–4.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Freton A, Chin KJ, Raut R, Tena LB, Kivelä T, Finger PT. Initial PET/CT staging for choroidal melanoma: AJCC correlation and second nonocular primaries in 333 patients. Eur J Ophthalmol [Internet]. 2012 [cited 2017 Dec 8];22(2):236–43. http://www.ncbi.nlm.nih.gov/pubmed/21959680PubMedCrossRefPubMedCentralGoogle Scholar
  243. 243.
    Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. Screening for metastasis from choroidal melanoma: The Collaborative Ocular Melanoma Study group report 23. J Clin Oncol. 2004;22(12):2438–44.PubMedCrossRefPubMedCentralGoogle Scholar
  244. 244.
    Eskelin S, Pyrhönen S, Summanen P, Prause JU, Kivelä T. Screening for metastatic malignant melanoma of the uvea revisited. Cancer. 1999;85(5):1151–9.PubMedCrossRefPubMedCentralGoogle Scholar
  245. 245.
    Kuan a K, Jackson FI, Hanson J. Multimodality detection of metastatic melanoma. J R Soc Med. 1988;81(10):579–82.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Marshall E, Romaniuk C, Ghaneh P, Wong H, McKay M, Chopra M, et al. MRI in the detection of hepatic metastases from high-risk uveal melanoma: a prospective study in 188 patients. Br J Ophthalmol [Internet]. 2013 [cited 2017 Dec 8];97(2):159–63. http://www.ncbi.nlm.nih.gov/pubmed/23159448PubMedCrossRefPubMedCentralGoogle Scholar
  247. 247.
    Semelka RC, Martin DR, Balci C, Lance T. Focal liver lesions: comparison of dual-phase CT and multisequence multiplanar MR imaging including dynamic gadolinium enhancement. J Magn Reson Imaging. 2001;13(3):397–401.PubMedCrossRefPubMedCentralGoogle Scholar
  248. 248.
    Choudhary MM, Gupta A, Bena J, Emch T, Singh AD. Hepatic ultrasonography for surveillance in patients with uveal melanoma. JAMA Ophthalmol [Internet]. 2016 [cited 2017 Dec 8];134(2):174. http://www.ncbi.nlm.nih.gov/pubmed/26633182PubMedCrossRefPubMedCentralGoogle Scholar
  249. 249.
    Gupta MP, Lane AM, DeAngelis MM, Mayne K, Crabtree M, Gragoudas ES, et al. Clinical characteristics of uveal melanoma in patients with germline BAP1 mutations. JAMA Ophthalmol. 2015;133(8):881–7.PubMedCrossRefPubMedCentralGoogle Scholar
  250. 250.
    Rai K, Pilarski R, Boru G, Rehman M, Saqr AH, Massengill JB, et al. Germline BAP1 alterations in familial uveal melanoma. Genes Chromosomes Cancer. 2017;56(2):168–74.PubMedCrossRefPubMedCentralGoogle Scholar
  251. 251.
    Njauw C-NJ, Kim I, Piris A, Gabree M, Taylor M, Lane AM, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. In: Dadras SS, editor. PLoS One [Internet]. 2012 [cited 2017 Dec 8];7(4):e35295. http://www.ncbi.nlm.nih.gov/pubmed/22545102PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Rai K, Pilarski R, Cebulla CM, Abdel-Rahman MH. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet. 2016;89(3):285–94.PubMedCrossRefPubMedCentralGoogle Scholar
  253. 253.
    Pilarski R, Rai K, Cebulla C, Abdel-Rahman M. BAP1 tumor predisposition syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. Seattle (WA): University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved; 1993. (GeneReviews(R)).Google Scholar
  254. 254.
    Hammer H, Oláh J, Tóth-Molnár E. Dysplastic nevi are a risk factor for uveal melanoma. Eur J Ophthalmol [Internet]. 1996 [cited 2017 Aug 19];6(4):472–4. http://www.ncbi.nlm.nih.gov/pubmed/8997595PubMedCrossRefGoogle Scholar
  255. 255.
    Abdel-Rahman MH, Rai K, Pilarski R, Davidorf FH, Cebulla CM. Germline BAP1 mutations misreported as somatic based on tumor-only testing. Fam Cancer. 2016;15(2):327–30.PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Laíns I, Bartosch C, Mondim V, Healy B, Kim IK, Husain D, et al. Second primary neoplasms in patients with uveal melanoma: a SEER database analysis. Am J Ophthalmol. 2016;165:54–64.PubMedCrossRefGoogle Scholar
  257. 257.
    Shields JA, Shields CL. Eyelid, conjunctival, and orbital tumors: an atlas and textbook. 3rd ed. Philadelphia: Lippincott Wolters Kluwers; 2016. 806 pGoogle Scholar
  258. 258.
    Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology. 2004;111:1747–54.PubMedCrossRefGoogle Scholar
  259. 259.
    Shields CL, Alset AE, Boal NS, Casey MG, Knapp AN, Sugarman JA, et al. Conjunctival Tumors in 5002 Cases. Comparative Analysis of Benign Versus Malignant Counterparts. The 2016 James D. Allen Lecture. Am J Ophthalmol. 2017;173:106–33.PubMedCrossRefGoogle Scholar
  260. 260.
    Ciralsky J, Colby K. Conjunctival melanomas: can the cancer stem cell hypothesis be applied? Semin Ophthalmol [Internet]. 2009 [cited 2017 Oct 26];24(3):161–5. http://www.tandfonline.com/doi/full/10.1080/08820530902802351
  261. 261.
    Norregaard JC, Gerner N, Jensen OA, Prause JU. Malignant melanoma of the conjunctiva: occurrence and survival following surgery and radiotherapy in a Danish population. Graefes Arch Clin Exp Ophthalmol [Internet]. 1996 [cited 2017 Oct 26];234(9):569–72. http://www.ncbi.nlm.nih.gov/pubmed/8880155
  262. 262.
    Shields CL, Chien JL, Surakiatchanukul T, Sioufi K, Lally SE, Shields JA. Conjunctival tumors:review of clinical features, risks, biomarkers, and outcomes—the 2017 J. Donald M. Gass lecture. Asia-Pacific J Ophthalmol [Internet]. 2017 [cited 2017 Aug 18];6(2):109–20. http://www.ncbi.nlm.nih.gov/pubmed/28399347PubMedCrossRefGoogle Scholar
  263. 263.
    Katsambas A, Nicolaidou E. Cutaneous malignant melanoma and sun exposure. Recent developments in epidemiology. Arch Dermatol [Internet]. 1996;132(4):444–50. http://www.ncbi.nlm.nih.gov/pubmed/8629849PubMedCrossRefGoogle Scholar
  264. 264.
    Foster CS, Azar DT, Dohlman CH. Smolin and Thoft’s the cornea: scientific foundations and clinical practice. Philadelphia: Lippincott Williams and Wilkins. 1339 pGoogle Scholar
  265. 265.
    Poothullil AM, Colby KA. Topical medical therapies for ocular surface tumors. Semin Ophthalmol. 2006;21:161–9.PubMedCrossRefGoogle Scholar
  266. 266.
    Sugiura M, Colby KA, Mihm MC, Zembowicz A. Low-risk and high-risk histologic features in conjunctival primary acquired melanosis with atypia: Clinicopathologic analysis of 29 cases. Am J Surg Pathol. 2007;31(2):185–92.PubMedCrossRefGoogle Scholar
  267. 267.
    Shields CL. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Trans Am Ophthalmol Soc. 2000;98:471–92.PubMedPubMedCentralGoogle Scholar
  268. 268.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.PubMedCrossRefPubMedCentralGoogle Scholar
  269. 269.
    Wang Y, Fischle W, Cheung W, Jacobs S, Khorasanizadeh S, Allis CD. Beyond the double helix: writing and reading the histone code. Novartis Found Symp. 2004;259:3–21-169.PubMedPubMedCentralGoogle Scholar
  270. 270.
    Barlesi F, Giaccone G, Gallegos-Ruiz MI, Loundou A, Span SW, Lefesvre P, et al. Global histone modifications predict prognosis of resected non small-cell lung cancer. J Clin Oncol. 2007;25(28):4358–64.PubMedCrossRefPubMedCentralGoogle Scholar
  271. 271.
    Park YS, Jin MY, Kim YJ, Yook JH, Kim BS, Jang SJ. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann Surg Oncol. 2008;15(7):1968–76.PubMedCrossRefPubMedCentralGoogle Scholar
  272. 272.
    Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005;435(7046):1262–6.PubMedCrossRefPubMedCentralGoogle Scholar
  273. 273.
    Song JS, Kim YS, Kim DK, Park SI, Jang SJ. Global histone modification pattern associated with recurrence and disease-free survival in non-small cell lung cancer patients. Pathol Int. 2012;62(3):182–90.PubMedCrossRefPubMedCentralGoogle Scholar
  274. 274.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Ophthalmology and Visual SciencesVanderbilt University Medical Center, Vanderbilt Eye InstituteNashvilleUSA
  2. 2.Department of Ophthalmology and Visual Sciences, Department of Radiation OncologyVanderbilt-Ingram Cancer Center, Vanderbilt University Medical CenterNashvilleUSA
  3. 3.Program in Cancer BiologyVanderbilt UniversityNashvilleUSA

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