Uveal melanoma (UM)1–4 is an uncommon cancer, accounting for only 3% of all melanomas (Fig. 1). Singh et al5 reviewed the SEER (Surveillance, Epidemiology, and End Results) program database in the United States from 1973 to 2008, which showed that the age-adjusted incidence of UM is 5.1 per million and that it has remained unchanged during this time period. By far the majority of patients (97.8%) are white, with a male to female ratio of 5.8:4.4. Although the etiology is unknown, risk factors include light skin color,6 red or blonde hair and blue or light irides,7 uveal nevi,8 dysplastic nevi,9,10 and oculodermal melanocytosis.11 Although sun exposure has been suggested as a risk factor, its role is unclear with conflicting data reported in UV exposure studies12 compounded by the fact that rates of UM have not increased over recent decades, unlike that of cutaneous melanoma, where sun exposures is known to have a role.3 The RARECARE project in Europe13 looked at 89 cancer registries covering approximately 32% of the European population to study the epidemiology of rare and poorly understood cancers, including UM. Those data showed geographical variation in rates, ranging from <2 cases per million in Southern Europe to >8 cases in Scandinavian countries. Thus there may be a sun-susceptibility factor in play. Familial UM is recognized but is rare (<1%).14
TREATMENT AND PROGNOSIS
Treatment has traditionally been enucleation following a funduscopic clinical diagnosis without histopathologic confirmation, a fairly unique scenario in cancer treatment. A decreasing trend has been observed in patients being treated with surgery at the time of diagnosis. From 1973 to 1975, the rate was 93.8% compared with 28.3% during the years 2006 to 2008. There was a corresponding increase in cases treated with radiation (currently plaque radiotherapy) during that time frame (1.8% for 1973 to 1975 vs. 62.5% for 2006 to 2008).3 Therefore, ocular pathologists see approximately one third the number of enucleated eyes as in the previous years. Some ocular oncologists do fine needle aspiration biopsy of the tumor at the time of plaque placement to confirm their diagnosis of melanoma and/or to acquire tumor cells for genetic prognostic testing.15,16 Prognostic applications exceed diagnostic, however, and the cells acquired are typically submitted for fluorescence in situ hybridization (FISH), single-nucleotide polymorphism arrays, or gene expression profiling (GEP).15 Despite a shift toward more conservative treatments at the time of diagnosis as well as advances in treating metastases, survival has not improved in the last 50 years. Death occurs due to metastasis, particularly to the liver (93%), but also to the lung (24%) and bone (16%).17 The mortality rate at 15 years postdiagnosis is about 50%,18 with many of the deaths occurring in the first 5 years. It is important to note that while UM shows histopathologic similarities to cutaneous and other melanomas, including expression of melanocytic lineage markers (HMB-45, melanA, S-100), as well as similarities with high metastatic potential and resistance to known therapies, it differs in many ways. There is no in situ melanoma or basement membrane invasion as in cutaneous melanoma, lymphatics in the eye are mostly absent (so it typically spreads hematogenously), and it demonstrates different changes in genetic pathways. For example, cutaneous melanoma has been found to frequently harbor BRAF or NRAS mutations in a mutually exclusive manner, but these are rare in UM.19 Thus the search for molecular targets for therapy as well as for prognosis has over the years focused on different pathways than that of cutaneous melanoma. This divergence creates a disadvantage for UM research as the case numbers are so much less.
PROGNOSTICATION FOR UVEAL MELANOMA
UM occurs most commonly in the choroid, followed by the ciliary body and finally the iris. Location is prognostically significant, with ciliary body melanomas having the worse prognosis20 and iris melanomas the best.21 Other clinical factors are advanced age at diagnosis and tumor size,22 which is measured as largest basal diameter and height by B-scan ultrasonography as well as pathologic measurements. Interestingly, tumor site and size have recently been reported to be related to sex,23 which will be discussed in further detail below. Macroscopically, these tumors can form a focal tumor, which in the choroid sometimes takes on a mushroom-like appearance, when Bruch’s membrane is breached; or they can grow in a diffuse pattern within the choroid, in which a mass effect does not occur. In a similar fashion, ciliary body melanomas can form a localized tumor that invades anterior chamber structures or grow in a circumferential pattern along the trabecular meshwork, known as a ring melanoma.24 Extraocular extension of melanoma, which occurs via the vortex veins, is associated with increased mortality.25
Histopathologic prognostic factors include cell type (spindle cell vs. epithelioid), mitotic count per 40 high-power fields (HPFs), pigmentation, presence of tumor-infiltrating lymphocytes, and vasculogenic mimicry patterns. Callendar26 is credited with the classification of UMs in 1931 as being of spindle cell (A or B) or epithelioid type. This was modified in 1983 at the Armed Forces Institute of Pathology27 which deleted the spindle A type, which are considered to represent nevi, and reclassified these tumors as being spindle, epithelioid, or mixed-cell type. Increasing proportions of epithelioid cells typically worsens prognosis. However, it is often difficult to assign an exact classification leading to both intraobserver and interobserver variability in assignment of cell type. Significant tumor-infiltrating lymphocytes are present when there are 100 or more intratumoral lymphocytes per 20 HPFs, and unlike in cutaneous melanoma, their presence is a poor prognostic indicator.28 Also the presence of intratumoral macrophages has been found to contribute to a poorer prognosis.29–31 Vasculogenic mimicry refers to the formation of a fluid-conducting system, which is actually produced by the tumor cells and thus not considered to represent angiogenesis. It is called mimicry because these channels are not lined by endothelial cells. It is demonstrated by staining with PAS and is enhanced if the hematoxylin counterstain is omitted and viewed with a green filter.32–36
CYTOGENETIC AND MOLECULAR PATHOLOGY
The cytogenetic and molecular aberrations of UM have been the focus of much research. Loss of 1 copy of chromosome 3 (monosomy 3) is the most frequent and prognostically significant cytogenetic marker,37–42 occurring in approximately 50% of cases and strongly associated with metastatic death. The evaluation of this chromosome has been considered by many the gold standard for both prognostication as well as for triaging patients for closer follow-up and possible entry into clinical trials. Other changes include loss on 1p,43,44 6q, and 8p, as well as gain on 1q, 6p, and 8q, which are variously identified by traditional karyotyping, FISH, comparative genomic hybridization, single-nucleotide polymorphism, or multiplex ligation-dependent probe amplification, as well as other means. GEP will be discussed below.
Because of the implication that a tumor suppressor gene resides on this chromosome, attention has been drawn to partial deletions or other partial 3 alterations, with published frequencies ranging from 0% to 48%.45 Abdel-Rahman et al45 studied partial deletions using cytogenetics and comparative genomic hybridization and found partial chromosome 3 alterations in 38% of cases, but many were gains and not just losses. These changes did not predict poor outcome. One issue in making conclusions from the literature on this aspect is the differences in specimen types (fresh, frozen, formalin-fixed paraffin-embedded) used and the molecular techniques employed. More recently, inactivating somatic mutations of the BAP1 (BRCA1-associated protein 1) gene, located on chromosome 3p21.1, were identified using exome capture coupled with massively parallel sequencing.46 This gene may represent a tumor suppressor gene involved in UM pathogenesis. This finding is exciting because the BAP1 protein is a deubiquitinating enzyme,47 and the BAP1 pathway has some potential for therapeutic targeting. Hereditary UM is rare, but a germline truncating BAP1 mutation has been reported in a family in which there is UM as well as meningioma, abdominal adenocarcinoma, and cutaneous melanoma.48 Several studies have found UMs to be heterogeneous in regard to monosomy 3 by FISH,49 as well as abnormalities with chromosomes 1p, 3, 6, and 8 by multiplex ligation-dependent probe amplification.50 This has implications both in regard to the type of sample obtained for analysis, as well as cutoff points. Typically for the diagnosis of monosomy 3 a cutoff point of 20% is used, but some think that even 5%51 or 8%52 may be best for sensitivity and specificity.
LOSS OF 1p
Loss of all or part of 1p occurs in approximately 25% of UMs, often with monosomy 3, and the literature suggests on the one hand that this aberration is an independent predictor of decreased disease-free survival44 and that it loses its predictive value after adjusting for certain demographic and tumor variables.53
GAIN OF 6p
Gain of 6p is usually associated with loss of 6q and thought to represent formation of isochromosome 6p.41 In general, 6p gain confers a better prognosis40,54; however, relative mutual exclusivity of 6p gain and monosomy 3 has been noted.55,56 These findings have led support to the idea that these 2 abnormalities represent alternative evolutionary pathways for tumor progression, the former leading to a good prognosis and the latter to a poor prognosis.
GAIN OF 8q
Gain of 8q has been found in approximately 40% of UMs and 8p loss in approximately 25%.57–59 8q gain has been shown to have a statistical association with metastasis,54,60 especially in association with monosomy 3.40 However, Onken et al61 found that 8p loss rather than 8q gain was more significant, and in a recent study using whole-genome copy number variation and comparing results with clinical data such as sex and tumor size, 8p loss was found to impart increased risk for metastasis even after monosomy 3 and 8q gain were acquired by the tumor.53
GENE EXPRESSION PROFILING
In 2004, Onken et al46 used GEP to classify UMs into 2 prognostically significant groups: class 1 (low metastatic risk) and class 2 (high metastatic risk). Several subsequent studies have demonstrated the prognostic power of this assay.62–65 A large collaborative study of 459 patients from 12 medical centers,66 found a strong association between GEP class 2 and other adverse prognostic factors, including increased age, ciliary body involvement, larger tumor diameter and thickness, epithelioid cell type, and monosomy 3. However, in multivariate analysis, no combination of other variables, including chromosome 3 status, was more closely associated with metastasis than GEP alone. This test has recently become available to patients with a patented assay (DecisionDx-UM) and has received much publicity in the lay media.
An alternative predictive model is that of artificial neural networks in which multivariate assessment of age, sex, clinical tumor stage, cytogenetic type, and histologic grade is incorporated.67 This type of algorithm has been used and found to be an effective tool in the United Kingdom for determining the frequency of clinical follow-up to rule out metastases.
METASTASES AND TREATMENT TRENDS
Most deaths due to UM are due to metastases, usually hepatic; and this occurs in approximately 50% of patients despite successful local treatment of the eye. Metastases usually occur within the first 5 years following diagnosis, but may occur as much as 25 years later.18 As previously mentioned, enucleation rates have decreased and brachytherapy (or external beam radiation) rates have increased. These alternate therapies have been proven effective only for tumors that do not involve the optic disc and are small to medium in size. The Collaborative Ocular Melanoma Study group reported that after 10 years of follow-up, brachytherapy with Iodine-125 (I-125) is as good as enucleation in terms of survival.68 Ruthenium-106 is now often preferred for better sight preservation and less damage to other parts of the eye.69 However, approximately half of tumors still prove to be lethal, and this is probably because clinically undetectable micrometastases are probably already present in the liver at the time of local therapy with the tumors having high metastasizing potential (class 2 or those with monosomy 3 with or without 8q gain). There is currently no adjuvant chemotherapy available to prevent or eliminate micrometastases. Thus, survival has improved little in the last 50 years. Still, there is some reason for optimism, as studies showing that with aggressive treatment of the liver metastases, especially if found early, survival can be prolonged. Frenkel et al70 looked at surgically treated patients (ranging from wedge resections of liver metastases to lobectomies) and found that these patients had a 3-fold increase in metastatic survival than those patients who did not have surgery. Other options for treatment include systemic therapy and isolated hepatic perfusion. Long-term survival with metastatic UM was seen in a series of 9 patients who underwent treatment (surgical, systemic therapy, or isolated hepatic perfusion) with survivals averaging 51 months (range, 27 to 123 mo),71 far better than the median of 5 to 7 months previously reported.72 A more pessimistic view was reported by Augsburger et al73 in which a literature search was performed to evaluate the effectiveness of surveillance and aggressive treatment when metastases were detected. While acknowledging the increased survival times reported in various reports, the concern of selection bias, surveillance bias, and publication bias was raised. The lack of randomized phase III clinical trials was noted. This is a known problem with a tumor with such a low prevalence. Obviously, the need for early intervention requires cost-effective and directed surveillance to triage patients for more intensive follow-up, which has generally consisted of abdominal ultrasound examinations directed towards the liver and serum liver function testing (ALK-P, AST, ALT, GGT, LDH, and total bilirubin). Tumor markers that have been studied include osteopontin, melanoma inhibitory activity, S-100β, and tissue polypeptide-specific antigen.74 More recently, it was reported that significantly lower serum levels of insulin-like growth factor-1 (IGF-1) at 10 years in disease-free UM patients were present compared with levels in healthy subjects, and they were even lower levels in patients with metastases.75 They also found a trend in decreasing values in the 6 months before diagnosis of metastasis. Since high expression levels of IGF-1R (IGF-1 receptor) are known to correlate with lower survival rates,76 and blockage of IGF-1R activity with picropodophyllin causes tumor regression in xenografted mice,77 this suggests a possible therapeutic target.
SEX AND UVEAL MELANOMA
This author has been intrigued by the role sex and hormonal influences may play in UM The RARECARE project in which 4097 cases of UM were evaluated13 found that 5-year survival rates were better for women than for men. In another study of 723 patients, men were noted to have earlier and more frequent metastases in the first decade after diagnosis.78 Tumors have been found to be larger and more posterior, including location within 3 mm of the optic disc, in men in a study of 3380 patients.23 Finally, this author has found a trend for the immunohistochemical presence of estrogen receptor to correlate with monosomy 3, metastasis, and death due to disease, especially in males (unpublished data of small patient set).79 Hopefully, further study will elucidate the role of sex and hormones, potentially leading to a therapeutic target.
Recently, various groups have begun to look at emotional issues in patients diagnosed with UM. In a current and ongoing prospective study, Schuermeyer and colleagues (current study) have been using the Hospital Anxiety and Depression Scale to look at not only anxiety and depression but also decision regret. The latter is relevant to all involved in the diagnosis and treatment of UM because, at the present time, the prognostic tests now available are helpful for research, surveillance protocols, and life planning; but they cannot guide adjuvant therapy. Preliminary findings indicate a decline in depression and anxiety over the first 3 months, but plans are to continue to monitor this for 12 months (I. Schuermeyer, current study).
In summary, UM is a lethal disease usually due to liver metastasis in approximately half of patients; and to date, the prognosis for these patients is dismal. One of the largest challenges is the relative rarity of the disease, making data difficult to interpret and funding for research difficult to obtain. However, with the increasing understanding of the molecular pathways and novel approaches to surveillance and treatment that are occurring, there is hope for better outcomes in the future.
1. Eagle RC Jr .The pathology of ocular cancer.Eye. 2013; 27:128–136.
2. Nelson CC, Hertzberg BS, Klintworkth GK .A histopathologic study of 716 unselected eyes in patients with cancer at the time of death.Am J Ophthalmol. 1983; 95:788–793.
3. Shields CL, Shields JA, Gross NE, et al .Survey of 520 eyes with uveal metastases.Ophthalmology. 1997; 104:1265–1276.
4. Bianciotto C, Demirci H, Shields CL, et al .Metastatic tumors to the eyelid: report of 20 cases and review of the literature.Arch Ophthalmol. 2009; 127:999–1005.
5. Singh AD, Turell ME, Topham AK .Uveal melanoma: trends in incidence, treatment, and survival.Ophthalmology. 2011; 118:1881–1885.
6. Seddon JM, Gragoudas ES, Glynn RJ, et al .Host factors, UV radiation, and risk of uveal melanoma. A case-control study.Arch Ophthalmol. 1990; 108:1274–1280.
7. Gallagher RP, Elwood JM, Rootman J, et al .Risk factors for ocular melanoma: Western Canada Melanoma Study.J Natl Cancer Inst. 1985; 74:775–778.
8. Ganley JP, Comstock GW .Benign nevi and malignant melanomas of the choroid.Am J Ophthalmol. 1973; 76:19–25.
9. Hammer H, Olah J, Toth-Molnar E .Dysplastic nevi are a risk factor for uveal melanoma.Eur J Ophthalmol. 1996; 6:742–747.
10. Albert DM, Chang MA, Lamping K, et al .The dysplastic nevus syndrome. A pedigree with primary malignant melanomas of the choroid and skin.Ophthalmology. 1985; 92:1728–1734.
11. Singh AD, De Potter P, Fijal BA, et al .Lifetime prevalence of uveal melanoma in white patients with oculo (dermal) melanocytosis.Ophthalmology. 1998; 105:195–198.
12. Singh AD, Bergman L, Seregard S .Uveal melanoma: epidemiologic aspects.Ophthalmol Clin North Am. 2005; 18:75–84
13. Mallone S, De Vries E, Guzzo M, et al. The RARECARE WG .Descriptive epidemiology of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe.Eur J Cancer. 2012; 48:1167–1175.
14. Singh AD, Shields CL, De Potter P, et al .Familial uveal melanoma-clinical observations on 56 patients.Arch Ophthalmol. 1996; 114:392–399.
15. Singh AD, Dolan B, Biscotti CV, Biscotti CV, Singh AD .FNA cytology of ophthalmic tumors.Monogr Clin Cytol. 2012; 21:90–96.
16. Augsburger JJ, Correa ZM, Trichopoulos N .Prognostic implications of cytopathologic classification of melanocytic uveal tumors evaluated by fine-needle aspiration biopsy.Arq Bras Oftalmol. 2013; 76:72–79.
17. Diener-West M, Reynolds SM, Agugliaro JJ, et al .Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26.Arch Ophthalmol. 2005; 123:1639–1643.
18. Kujala E, Makitie T, Kivele T .Very long-term prognosis of patients with malignant uveal melanoma.Invest Ophthalmol Vis Sci. 2003; 44:4651–4659.
19. Cruz F III, Rubin BP, Wilson D, et al .Absence of BRAF and NRAS mutations in uveal melanoma.Cancer Res. 2003; 63:5761–5766.
20. Schmittel A, Bechrakis NE, Martus P, et al .Independent prognostic factors for distant metastases and survival in patients with primary uveal melanoma.Eur J Cancer. 2004; 16:2389–2395.
21. Shields CL, Shields JA, Materin M, et al .Iris melanoma: risk factors in 169 consecutive cases.Ophthalmology. 2001; 108:172–178.
22. Augsburger JJ, Gamel JW .Clinical prognostic factors in patients with posterior uveal malignant melanoma.Cancer. 1990; 7:1596–1600.
23. Damato BE, Coupland SE .Differences in uveal melanomas between men and women from the British Isles.Eye. 2012; 26:292–299.
24. Mudhar HS, Parsons MA, Sisley K, et al .A critical appraisal of the prognostic and predictive factors for uveal malignant melanoma.Histopathology. 2004; 45:1–12.
25. Seddon JM, Albert DM, Lavin PT, et al .A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma.Arch Ophthalmol. 1983; 101:1894–1900.
26. Callender GR .Malignant melanotic tumors of the eye. A study of histologic types in 111 cases.Trans Am Acad Ophthalmo Otolaryngol. 1931; 36:131–140.
27. McLean IW, Foster WD, Zimmerman LE, et al .Modification of Callender’s classification of uveal melanoma at the Armed Forces Institute of Pathology.Am J Ophthalmol. 1983; 96:502–509.
28. Davidorf FH, Lang JR. Peyman GA, Apple DJ, Sanders DR .Immunology and immunotherapy of malignant uveal melanomas.Intraocular Tumours. 1977; .New York:Appleton/Century/Crofts; 119–133.
29. Makitie T, Summanen P, Tarkkanen A, et al .Tumor-infiltrating macrophages (CD68+ cells) and prognosis in malignant uveal melanoma.Invest Ophthalmol Vis Sci. 2001; 42:1414–1421.
30. Jager MJ, Ly LV, El Filali M, et al .Macrophages in uveal melanoma and in experimental ocular tumor models: Friends or foes? Prog Retin Eye Res. 2011; 30:129–146.
31. Herwig MC, Grossniklaus HE .Role of macrophages in uveal melanoma.Expert Rev Ophthalmol. 2011; 6:405–407.
32. Maniotis AJ, Folberg R, Hess A, et al .Vasuclar channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.Am J Pathol. 1999; 155:739–752.
33. Folberg R, Pe-er J, Gruman LM, et al .The morphologic characteristics of tumour blood vessels as a marker of tumour progression in primary human uveal melanoma: a matched case-control study.Hum Pathol. 1992; 23:1298–1305.
34. Folberg R, Rummelt V, Parys-Van Ginderdeuren R, et al .The prognostic value of tumor blood vessel morphology in primary uveal melanoma.Ophthalmology. 1993; 100:1389–1398.
35. Lin AY, Maniotis AJ, Valyi-Nagy K, et al .Distinguishing fibrovascular septa from vasculogenic mimicry patterns.Arch Pathol Lab Med. 2005; 129:884–892.
36. Kivela T, Makitie T, Al-Jamal RT, et al .Microvascular loops and networks in uveal melanoma.Can J Ophthalmol. 2004; 39:409–421.
37. Prescher G, Bornfeld N, Becher R .Nonrandom chromosomal abnormalities in primary uveal melanoma.J Natl Cancer Inst. 1990; 82:1765–1769.
38. Prescher G, Bornfeld N, Hirche H, et al .Prognostic implications of monosomy 3 in uveal melanoma.Lancet. 1996; 347:1222–1225.
39. Scholes AG, Damato BE, Nunn J, et al .Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival.Invest Ophthalmol Vis Sci. 2003; 44:1008–1011.
40. White VA, Chambers JD, Courtright PD, et al .Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma.Cancer. 1998; 83:354–359.
41. Aalto Y, Eriksson L, Seregard S, et al .Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma.Invest Ophthalmol Vis Sci. 2001; 42:313–317.
42. Patel KA, Edmondson ND, Talbot F, et al .Prediction of prognosis in patients with uveal melanoma using fluorescence in situ hybridization.Br J Ophthalmol. 2001; 85:1440–1444.
43. Hausler T, Stang A, Anastassiou G, et al .Loss of heterozygosity of 1p in uveal melanomas with monosomy 3.Int J Cancer. 2005; 116:909–913.
44. Kilic E, Naus NC, Van Gils W, et al .Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased disease-free survival in uveal melanoma patients.Invest Ophthalmol Vis Sci. 2005; 46:2253–2257.
45. Abdel-Rahman MH, Christopher BN, Faramawi MF, et al .Frequency, molecular pathology and potential clinical significance of partial chromosome 3 aberrations in uveal melanoma.Mod Pathol. 2011; 24:954–962.
46. Onken MD, Worley LA, Ehlers JP .Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death.Cancer Res. 2004; 64:7205–7209.
47. Harbour JW, Onken MD, Roberson EDO, et al .Frequent mutation of BAP1 in metastasizing uveal melanomas.Science. 2010; 330:1410–1413.
48. Abdel-Rahman MH, Pilarski R, Cebulla CM, et al .Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.J Med Genet. 2011; 48:856–859.
49. Schoenfield L, Pettay J, Tubbs RR, et al .Variation of monosomy 3 status within uveal melanoma.Arch Pathol Lab Med. 2009; 133:1219–1222.
50. Dopierala J, Damato BE, Lake SL, et al .Genetic heterogeneity in uveal melanoma assessed by multiplex ligation-dependent probe amplification.Invest Ophthalmol Vis Sci. 2010; 51:4898–4905.
51. Bronkhorst IHG, Maae W, Jordanova ES, et al .Effect of heterogeneous distribution of monosomy 3 on prognosis in uveal melanoma.Arch Pathol Lab Med. 2011; 135:1042–1047.
52. Singh AD, Aronow ME, Sun Y, et al .Chromosome 3 status in uveal melanoma: a comparison of fluorescence in situ hybridization and single-nucleotide polymorphism array.Invest Ophthalmol Vis Sci. 2012; 53:3331–3339.
53. Ewens KG, Kanetsky PA, Richards-Yutz J, et al .Genomic profile of 320 uveal melanoma cases: chromosome 8p-loss and metastatic outcome.Invest Ophthalmol Vis Sci. 2013; 54:5721–5725.
54. Damato BE, Dopierala J, Klaasen A, et al .Multiplex ligation-dependent probe amplification of uveal melanoma: correlation with metastatic death.Invest Ophthalmol Vis Sci. 2009; 50:3048–3055.
55. Parrella P, Sidransky D, Merbs SL .Allelotype of posterior uveal melanoma: implications for a bifurcated tumor progression pathway.Cancer Res. 1999; 59:3032–3037.
56. Landreville S, Agapova OA, Harbour JW .Emerging insights into the molecular pathogenesis of uveal melanoma.Future Oncol. 2008; 4:626–636.
57. Hoglund M, Gisselsson D, Hansen GB, et al .Dissecting karyotypic patterns in malignant melanomas: temporal clustering of losses and gains in melanoma karyotypic evolution.Int J Cancer. 2004; 108:57–65.
58. Damato B, Dopierala JA, Coupland SE .Genotypic profiling of 452 choroidal melanomas with multiplex ligation-dependent probe amplification.Clin Cancer Res. 2010; 16:6083–6092.
59. Coupland SE, Lake SL, Zeschnigk M, et al .Molecular pathology of uveal melanoma.Eye. 2013; 27:230–242.
60. Sisley K, Rennie IG, Parsons MA, et al .Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis.Genes Chromosom Cancer. 1997; 19:22–28.
61. Onken MD, Worley LA, Harbour JW .A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis.Clin Cancer Res. 2008; 14:3737–3745.
62. Harbour JW .The genetics of uveal melanoma: an emerging framework for targeted therapy.Pigment Cell Melanoma Res. 2012; 25:171–181.
63. Worley LA, Onken MD, Person E, et al .Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma.Clin Cancer Res. 2007; 13:1466–1471.
64. Singh AD, Sisley K, Xu Y, et al .Reduced expression of autotoxin predicts survival in uveal melanoma.Br J Ophthalmol. 2007; 91:1385–1392.
65. van Gils W, Lodder EM, Mensink HW, et al .Gene expression profiling in uveal melanoma: two regions on 3p related to prognosis.Invest Ophthalmol Vis Sci. 2008; 49:4254–4262.
66. Onken MD, Worley LA, Char DH, et al .Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.Ophthalmology. 2012; 119:1596–1603.
67. Damato B, Eleuteri A, Fisher AC, et al .Artificial neural networks estimating survival probability after treatment of choroidal melanoma.Ophthalmology. 2008; 115:1598–1607.
68. 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. 2006; 124:1684–1693.
69. Pe’er J .Ruthenium-106 brachytherapy.Dev Ophthalmol. 2012; 49:27–40.
70. Frenkel S, Nir I, Hendler K, et al .Long-term survival of uveal melanoma patients after surgery for liver metastases.Br J Ophthalmol. 2009; 93:1042–1046.
71. Buzzacco DM, Abdel-Rahman MH, Park S, et al .Long-term survivors with metastatic uveal melanoma.Open Ophthalmol J. 2012; 6:49–53.
72. Bedikian AY, Legha SS, Mavligit G, et al .Treatment of uveal melanoma metastatic to the liver: a review of the M.D. Anderson Cancer Center experience and prognostic factors.Cancer. 1995; 76:1665–1670.
73. Augsburger JJ, Correa ZM, Shaikh AH .Effectiveness of treatments for metastatic uveal melanoma.Am J Ophthalmol. 2009; 148:119–127.
74. Hendler K, Pe’er J, Kaiserman I, et al .Trends in liver function tests: a comparison with serum tumor markers in metastatic uveal melanoma (part 2).Anticancer Res. 2011; 31:351–358.
75. Frenkel S, Zloto O, Pe’er J, et al .Insulin-like growth factor-1 as a predictive biomarker for metastatic uveal melanoma in humans.Invest Ophthalmol Vis Sci. 2013; 54:490–493.
76. All-Ericsson C, Girnita L, Seregard S, et al .Insulin-like growth factor-1 receptor in uveal malanoma: a predictor for metastatic disease and a potential therapeutic target.Invest Ophthalmol Vis Sci. 2002; 43:1–8.
77. Girnita A, All-Ericsson C, Economou MA, et al .The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells.Acta Ophthalmol. 2008; 4:26–34.
78. Zloto O, Pe’er J, Frenkel S .Gender differences in clinical presentation and prognosis of uveal melanoma.Invest Ophthalmol Vis Sci. 2013; 54:652–656.
79. Schoenfield L, Downs-Kelly E, Plesec T, et al .
Gender differences and estrogen and progesterone receptor expression in uveal melanoma, ARVO poster, Seattle. 2013. Unpublished