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Review |

Ocular Melanoma:  A Review and the Relationship to Cutaneous Melanoma FREE

Eva A. Hurst, MD; J. William Harbour, MD; Lynn A. Cornelius, MD
[+] Author Affiliations

From the Division of Dermatology, Department of Medicine (Drs Hurst and Cornelius) and the Department of Ophthalmology and Visual Sciences (Dr Harbour), Washington University School of Medicine, St Louis, Mo. The authors have no relevant financial interest in this article.


Arch Dermatol. 2003;139(8):1067-1073. doi:10.1001/archderm.139.8.1067.
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Objectives  The main objective of this review is to critically evaluate the present evidence regarding a relationship between ocular melanoma (OM) and cutaneous melanoma (CM). Melanomas are malignant neoplasms that develop from dendritic melanocytes that are found in the skin, eye, mucosal epithelia, and leptomeninges. While the skin is the most common site of melanoma development, these neoplasms can occur in any tissue that contains melanocytes. We review the incidence and characteristics of OM, evaluate the existent data regarding its potential relationship to CM, and provide some guidance for the dermatologist regarding the evaluation and diagnosis of this ocular tumor.

Data Sources  A retrospective review of the literature.

Study Selection  Studies included those relevant to disease pathogenesis and incidence, cohort studies (ie, studies evaluating the incidence of CM in patients with OM), and pertinent investigations from the dermatologic literature (ie, cases of atypical nevus syndromes). The referenced study designs and methodologies varied.

Data Extraction and Synthesis  Data were extracted by 2 independent reviewers, and the main results are presented in a qualitative, descriptive manner.

Conclusion  Evidence for comorbid OM and CM exists in patients with strong phenotypic expression of atypical nevi and conjunctival melanoma, although CDKN2A mutations have not been documented in patients with OM.

Figures in this Article

THE INCIDENCE of cutaneous melanoma (CM) is rising at a faster rate than any other cancer, with an average annual incidence of 13.8 persons per 100 000 and over 50 000 new cases developing each year. In the year 2003, an estimated 54 200 new cases of melanoma will be diagnosed; 7600 deaths are expected to occur due to melanoma.1 Cutaneous melanoma currently accounts for approximately 1% of all cancer deaths, with over 7000 deaths per year. It is the leading cause of cancer deaths in women aged 25 to 32 years.2,3

Melanomas are malignant neoplasms that develop from dendritic melanocytes, which are found in the skin, eye, mucosal epithelia, and leptomeninges.4,5 While the skin is the most common site of melanoma development, these neoplasms can occur in any tissue that contains melanocytes. In this review, we focus on the incidence of ocular melanoma (OM) and its potential relationship to CM.

Ocular melanoma is the most common primary intraocular malignancy in adults and is the second most likely location for primary melanoma after the skin. In the white population, it has an average annual incidence of 6 cases per million, with approximately 1200 cases diagnosed each year.6,7 The average age at diagnosis is 55 years. An excellent review of OM and OM lesions has been recently published by Grin et al.8 In the eye (Figure 1), these tumors occur in the uvea more commonly than in the conjunctiva. The uveal tumors occur more often in the posterior tract (the ciliary body [Figure 2] and choroid [Figure 3]) than in the anterior tract (the iris [Figure 4]).7,9 In one large registry, the relative ratio of occurrence of uveal melanomas to conjunctival tumors was 35:1.10 A recent review reported the annual age-adjusted incidence rate for conjunctival melanoma to be 0.012 per 100 000.11 Pigmented lesions of the iris also make up a small portion of all ocular tumors. They are usually diagnosed rather early and may even be benign or borderline tumors at the time of discovery.12

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Figure 1.

Structure of the eye.

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Figure 2.

Ciliary body melanoma. An external photograph showing a ciliary body melanoma that has extended through the sclera and is also invading into the anterior segment, as indicated by the iris being pushed centrally toward the pupil. Note also the prominent episcleral sentinel vessels.

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Figure 3.

Choroidal melanoma. A digitally created collage of several fundus photographs showing a lightly pigmented choroidal melanoma just superonasal to the optic disc. The fovea is seen as the dark spot just to the right of the disc.

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Figure 4.

Iris melanoma. External photograph of an isolated iris melanoma that arises from the iris stroma and is growing vertically into the anterior chamber.

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Although OM is a relatively rare tumor, local tissue destruction, visual loss, and propensity to metastasize result in significant patient morbidity and mortality.4 Uveal tract tumors metastasize to the liver via hematogenous spread owing to the absence of lymphatics draining these intraocular compartments. Mortality rates have historically approached 40% for choroidal and ciliary body melanoma, which together account for approximately 90% of all OMs.13 Conjunctival melanomas, however, have a propensity for regional spread to the lymph nodes analogous to cutaneous disease.14 In conjunctival tumors, 10- year survival rates of over 80% have been reported,10 but overall mortality rates may approach 30%.15

As in cutaneous disease, early recognition and diagnosis of OM is essential, although oftentimes difficult, because therapeutic intervention can be curative in the early stages. Visual symptoms present late, and it is not clear that identifiable risk factors predisposing to the disease exist. Some studies suggest that patients with atypical nevus syndromes may be at higher risk for the development of both CMs and OMs. The presence of clinically atypical nevi and a family history of melanoma have previously been called the atypical mole syndrome (AMS),16,17 the dysplastic nevus syndrome (DNS),18 the B-K mole syndrome,19 and the familial atypical mole and malignant melanoma syndrome (FAMMMS).20 As described by Platz et al,21 the clinical characteristics of affected family members with these syndromes include an increased risk of CM and multiple primary melanomas, diagnosis at an early age, and the presence of clinically atypical nevi or "dysplastic nevi." For the purpose of this review, we include relevant findings from investigations that reference any of these kindreds. In present practice, the use of the term dysplastic nevus is discouraged, and clinically these nevi can be more accurately described as atypical. Clinical characteristics of these nevi include size greater than 5 mm; indistinct, irregular "fuzzy" borders; and pigment gradations of tan and pink.22 Histologically, these nevi may demonstrate architectural disorder and varying degrees of cytologic atypia.

While a relationship between primary OM and CM has been proposed, there are no absolute guidelines that address whether patients diagnosed with OM should have dermatologic examinations or, conversely, whether patients with CM should have ophthalmologic evaluation. In a recent American Academy of Dermatology survey, it was found that 60% of dermatologists recommend ophthalmologic examinations for their patients with dysplastic nevi, although only 3% do so consistently.23 Therefore, we review the existent data regarding the relationship between OM and CM, and propose recommendations to aid the physician in referring patients with melanoma for additional examinations.

UV Radiation Exposure

Cutaneous and ocular melanocytes are derived from melanoblasts that migrate out from the neural crest during embryogenesis.24 The differentiated melanocytes in each tissue bed are identical, and shared immunologic antigens have been described.25 It has therefore been proposed that similar environmental risk factors contributing to the development of disease may play a role in CM and OM, namely, exposure to UV radiation. It is well supported that UV radiation exposure contributes to the development of CM and melanocyte transformation in vitro.26,27 There is also evidence for high incidence rates in fair-skinned individuals with significant UV exposure27 and association with multiple sunburns, with initial evidence supporting a stronger association when the sunburns occur during childhood.28 However, the relationship of UV exposure to the development of OM is less well recognized. Unlike CM, the overall incidence of OM is not increasing (and may actually be decreasing) in the United States. In certain northern European countries such as England, the incidence of OM is actually stable.29

In more specific studies, one group of investigators evaluated UV radiation exposure and UV dose distribution to the eye and its correlation to choroidal melanoma location.30 Using a method of geographic tumor mapping on the eye, the authors determined that it was "very unlikely" that UV radiation exposure was responsible for the choroidal tumors seen. They also concluded that UV-B did not reach the choroid and UV-A was predominantly filtered by the cornea and lens. Similarly, a recent study of over 12 000 patients with CM and over 2000 patients with OM in Denmark31 found that although the risk of nonmelanoma skin cancer was significantly increased in persons with CM, it was not increased in patients with OM. Since UV exposure has been associated with nonmelanoma skin cancer development, and a significant sunburn history correlates with CM, the authors extrapolate that these data argue against solar radiation as an etiologic factor in OM.31 However, the investigators also recognize that different types of UV exposure may play a specific role in each disease.

Despite such reports, data regarding the relationship between UV exposure and the development of OM remain equivocal. Although several investigations have failed to demonstrate a significant relationship, certain studies have found a positive correlation between exposure and disease.30,3234 One study reported a relative risk (RR) greater than 3 of OM in patients with a significant UV exposure history.35 Researchers in Australia determined that sun exposure was an independent risk factor for choroid and ciliary body melanoma, using patient recall of time outdoors on weekdays as the measured variable.36 A similar association could not be made for iris or conjunctival melanomas, although these tumor numbers were low. Further suggestive evidence includes the extremely low incidence of OM in nonwhite races6 where increased choroidal pigment potentially serves a UV protective effect. In a somewhat related study, blue eyes were identified as a risk factor for the development of OM (type not specified), with an increased overall risk of 3.0 compared with persons with brown eye color.37 Another study supported an association between OM and decreasing latitude: persons born in the southern United States were reported to have an increased risk of disease compared with those born in the northern United States.38 Nonetheless, data on UV exposure as a risk factor for the development of OM are not conclusive.

Occupational Risk Factors

Causative associations have been examined between occupational and chemical exposure and the development of OM, but little significant evidence exists. Recent case-control studies have supported an increased risk of OM among welders, who have increased occupational exposure to artificial UV light.39

The co-occurrence of primary CM and OM has been examined. A study by van Hees et al40 explored the relationship in 109 consecutive patients with uveal melanoma (UM) in the Netherlands. Dermatologic examinations were performed on the patients and their first-degree relatives. Cutaneous and ocular melanomas coexisted in 2 patients, and 4 first-degree relatives of the patients with OM had CM. In 3 of these 4 cases of first-degree relatives with CM, an association with DNS or FAMMMS was found. These authors used the definition of FAMMMS as an autosomal dominant inherited susceptibility to multiple (dysplastic) nevi with associated increased risk of multiple CMs occurring at a younger age than sporadic melanoma. However, in the 2 index patients with both primary melanoma and OM, there was no personal or family history of atypical nevi.

An earlier study by Bataille et al41 examined 207 consecutive patients with OM in England to determine the co-occurrence of AMS. To determine AMS phenotype, these investigators used a scoring system based on the presence of a "large" number of nevi, clinically atypical nevi, and nevi on unusual sites (buttocks, dorsum of the feet, and anterior aspect of the scalp). The skin of the patients with OM was examined, and 5 patients with primary melanomas of both the skin and eye were found. One patient had primary acquired ocular melanosis, 3 had choroidal melanoma, and 1 had conjunctival melanoma. Three of these patients also had atypical nevi. A positive family history of AMS was found in 2 of the 3. The incidence of CM in this OM cohort was statistically significant (P<.001), and the authors concluded that a relationship existed between OM and CM in this patient population.

Data from the above 2 studies and an additional 10 cases of OM and CM co-occurring in the same individual have been reported4151 (Table 1). Of these 17 cases, 9 occurred in association with either clinically suggestive or histologically confirmed atypical nevi: DNS, FAMMMS, or the B-K mole syndrome. Interestingly, a several-year time lag between ocular and cutaneous diagnoses was noted in some of these patients. Three (18%) of the 17 OM cases were conjunctival melanomas. Considering the relatively low incidence of conjunctival melanoma (age-adjusted incidence rate of 0.012 per 100 000),11 these reports support an association of atypical nevus syndromes with conjunctival melanoma. Possibly relevant as well, the 3 most common histologic patterns of CM—lentigo maligna melanoma (melanoma in situ), superficial spreading melanoma, and nodular melanoma—have histologic counterparts in conjunctival melanoma and are similarly reported to be related to disease prognosis.52 In addition, similar to cutaneous disease, the regional lymph nodes are believed to be the most common first site of metastasis in this OM subtype.14

Table Graphic Jump LocationTable 1. Cases of Ocular and Cutaneous Melanoma in the Same Individual

In addition to the reported co-occurring cases of OM and CM, 13 cases of OMs occurring in association with atypical nevus syndromes in either the patient or family members have been reported44,48,50,5356 (Table 2). Six of the 13 individuals had a family history of CM. Three (23%) of the reported OM cases were conjunctival melanoma, again suggestive of an increased incidence of conjunctival melanoma occurring in association with atypical nevi.

Table Graphic Jump LocationTable 2. Cases of Ocular Melanoma in Association With Atypical Nevus Syndromes

It has been established that not only atypical nevi, but also a large number of nevi (>100) are markers for the development of CM.5759 Studies have attempted to determine if increased numbers of nevi, either cutaneous or ocular, are a risk factor for OM. Three studies used self-reporting of nevi number by patients and found a small increase in risk of OM with increasing number of cutaneous nevi.35,59,60 Seddon et al35 reported an RR of 2.7 for individuals with 10 or more cutaneous nevi compared with none. Holly et al59 quoted an RR of 1.4 for those with 4 or more large nevi.

In 1995, Bataille et al56 published the first case-controlled study where 211 patients with OM had nevi examined by dermatologists. As in their previous studies, AMS phenotype was determined in the context of a scoring system that included the presence of a large number of nevi that were clinically atypical as well as nevi in unusual sites (buttocks, dorsum of the feet, and anterior scalp). The researchers found a significant risk of OM associated with increasing numbers of clinically atypical cutaneous nevi (P<.001). Specifically, patients with 4 or more atypical nevi had a much higher risk of OM than those with no atypical nevi (odds ratio, 22.1). There was also an increased risk with greater number of nevi of the iris (P<.001), with 27% of cases having 1 or more pigmented iris lesions compared with 12% of controls (odds ratio, 3.2). Although Bataille et al56 found an increased risk of OM associated with an increased total number of cutaneous nevi, this was not independent of the number of atypical nevi. In this study, 6 of the 211 patients with OM had primary CMs, 4 of which were diagnosed during the study (1 of these 6 is not included in Table 1 because details of the case were not specified). A total of 9% of the OM subjects had AMS compared with 1% of controls. In patients with AMS, Bataille et al56 reported an odds ratio of 7.3 for OM compared with an odds ratio of 10.4 for CM. These authors estimated a seemingly high cumulative lifetime risk of 1 in 200 for patients with AMS to contract OM. There were a relatively large number of conjunctival melanomas in their OM patient cohort (n = 31/211). Interestingly, in these patients, the AMS phenotype was more common. A total of 16% of conjunctival melanoma cases scored 3 or more on the AMS phenotype scale compared with 8% of choroidal melanoma cases.56 Other cases of conjunctival melanoma in the context of dysplastic nevi have also been reported (Table 2).40,50,5355

The identification of AMS as a risk factor for the development of OM has similarly been disputed.48,61 Taylor et al48 looked at the prevalence of dysplastic nevi in 44 patients with UM and 46 with CM. They reported prevalence rates of dysplastic nevi to be 41% in patients with CM and 4.5% in those with UM, a prevalence approaching that of the general population.62 In another study, Greene et al61 reported the results of ophthalmic examinations in 2 kindreds where CM, OM, and DNS occurred. In 26 patients with hereditary CM, DNS, or both, they found no atypical ocular lesions, although their sample size was small.

It is important to recognize that inherent in all of these studies, and possibly explanatory of some of the conflicting data, are the differences in interpreting the definitions of dysplastic and atypical nevi by each group and the patient populations studied. In each described study, we have attempted not only to delineate the criteria used for the diagnosis of AMS and/or DNS, but also segregate the types of OMs reported. Nonetheless, we propose that the data support an association of AMS and DNS with OM when strict criteria are applied—possibly most strongly in patients with conjunctival melanoma.

With regard to genomic alterations, the suggestion of a link between AMS and OM has prompted investigations into a shared genetic predisposition. Several nonrandom chromosomal alterations have been reported in UM tumors, including loss of chromosome 3, gain of the q arm of chromosome 8, and chromosome 6 abnormalities.63 These may be associated with poor overall survival.64 However, as is true with environmental risk factors, genetic factors and factors inciting somatic alterations related to the development of OM have not been well defined.

Approximately 5% to 10% of CMs are estimated to be hereditary, and there are several isolated reports of familial cases of OM.6567 Approximately 40% of these hereditary CMs have been linked to the p16 gene (CDKN2) on chromosome 9p.6870 Despite the reported associations with atypical nevus syndromes, convincing evidence for CDKN2 mutations in patients with OM is currently lacking. Loss of heterozygosity studies of UMs have been performed, and loss of 9p-linked markers bordering the CDKN2 locus have been demonstrated, but sequence analysis has not revealed deletions in the CDKN2 gene.68,69 These findings suggest the possibility of another susceptibility gene in this region, deletions in intronic sequences, or gene methylation. In another study,70 p16 analysis was performed in 13 patients with UM and a family history of UM (n = 6) or CM (n = 7) and in 24 patients with OM and a negative family history. Using polymerase chain reaction–single-stranded conformational polymorphism and DNA sequencing, the authors did not find a significant relationship between p16 genetic alterations and UM. Altered p16 was demonstrated in only 1 (8%) of the 13 patients with a positive family history of OM and in 4 (17%) of the 24 patients with UM without a family history (P = .64). Other studies have similarly failed to identify significant mutations in p16/CDKN2A in patients with OM.71,72 Possibly, subgroup analysis of patients with conjunctival melanoma with coexistent atypical nevi and a personal or family history of melanoma are indicated.

Genetic mutations in another gene, the melanocortin-1 receptor (MC1R) gene, have been investigated in patients with UM.73 The MC1R gene encodes for the α-melanocyte-stimulating hormone keratinocyte receptor and regulates eumelanin production. Point mutations in this gene are associated with skin types I and II and have been implicated in phenotypic susceptibility to CM.74,75 Unlike some patients with CM, patients with UM were not found to have specific MC1R genetic variants, although a significant increase in blue eye color was found.72

A genetic susceptibility locus that may predispose to OM and CM as well as breast cancer is BRCA2 on chromosome 13. BRCA2 mutations are known to predispose women to breast and ovarian cancer, with lifetime risks of 84% and 27%, respectively.76 The Breast Cancer Linkage Consortium found a statistically significant increased risk of CM in BRCA2 patients, with an RR of 2.58.77 In addition, recent studies provide evidence that BRCA2 may be an OM predisposition gene,78,79 albeit in a small percentage of cases. In a group of 400 patients with OM involving the choroid and/or ciliary body, 23 patients reporting 1 or more cases of breast or ovarian cancer in a first-degree relative or a family history of OM or a personal history of breast cancer were selected for genetic analysis.80 Three germline mutations in BRCA2 were found that were thought to be associated with disease in patients with a personal history of breast cancer, but only 1 of the 3 patients had a family history of breast and/or ovarian cancer or OM. A recent Australian study81 investigated BRCA2 germline mutations in 71 OM patients with breast cancer who were 50 years or younger at diagnosis or had bilateral disease or a reported family history of disease. The Australian researchers estimated the prevalence of possible loss of function changes in BRCA2 in patients with OM at 3% (95% confidence interval, 0%-10%) as compared with a mutation rate of 2.1% in a representative sample of young women with breast cancer.81 While far from conclusive, these data suggest that there may be a genetic association in a small subgroup of patients with breast cancer and melanoma.

The most common somatic mutations in human CM are in ras genes,82 and in certain murine models, ras has been demonstrated to play an essential role in tumor maintenance.83 Pigmented intraocular tumors, some of which resemble melanoma histologically, have been reported in transgenic mice that express a mutated Ha-ras gene in melanin-producing cells.84 Studies investigating human tumors, however, have found no association between ras mutations and UMs.85 Finally, activating mutations in BRAF, that encodes a RAS-regulated kinase, have been found in 66% of CMs evaluated in one study.86 Currently there are no published studies looking at BRAF in patients with OM.

Data identifying common risk factors for OM and CM, specifically exposure to UV radiation, are equivocal. However, there is limited evidence to suggest that early intensive sun exposure in light-eyed individuals may be a risk for OM,36,38 compared with evidence that receiving multiple sunburns in light-skinned individuals places them at risk for CM. The genetics of OM are not well-defined, with early small cohort studies suggesting that p16 (CDKN2A) mutations do not play a role in OM as they do in certain cases of familial CM.6870

The strongest evidence for a relationship between OM, and more specifically conjunctival melanoma, and CM exists in the atypical nevus syndromes, familial syndromes in which affected members have atypical nevi and an increased risk for CM. Many investigations have supported an association between atypical nevi and OM, with one group citing a cumulative lifetime risk of 1 in 200.40,47,56 Coexistent cases of primary OM and CM without AMS have also been reported,40,47 with 2 patients developing OM more than 10 years after their CM.43,45 Nevi of the iris, a feature of the AMS phenotype, was identified as a risk factor for all types of OM in one study.56

It has been recommended that patients with OM have a dermatologic examination to evaluate for atypical nevi or CM.40,47,56 In some studies, CM was only discovered retrospectively, and patients had initial skin examinations by nondermatologists.40,56 In light of such findings, an initial screening skin examination by a dermatologist for patients diagnosed with OM (particularly conjunctival melanoma) may be warranted, especially if they have features suggestive of AMS. All patients should be educated on the clinical features characteristic of CM, and yearly dermatologic screening may be indicated in patients with more than 4 atypical nevi, a personal history of multiple early sunburns, or a family history of CM.

It is probably not cost-effective for all patients with atypical nevus syndromes to undergo routine ophthalmic screening, particularly since indirect ophthalmoscopy is recommended to visualize the greatest area of the uveal tract. In an attempt to address this issue, Bataille et al56 used a systematic point scoring system to evaluate the expression of the AMS phenotype and found that the RR of OM increased with the severity of expression of the AMS phenotype. Based on this finding, the performance of routine ophthalmic examinations is suggested for persons with strong expression of the AMS phenotype, AMS patients with nevi of the iris, and patients diagnosed with CM in the context of AMS. For patients diagnosed with CM in the setting of a negative family history for CMs or AMS, current evidence does not support ophthalmologic screening. Increased recognition and investigation of comorbid patients should help to determine shared environmental, phenotypic, and genetic risk factors. Importantly, cost analysis studies to support such recommendations are warranted.

Corresponding author and reprints: Lynn A. Cornelius, MD, Division of Dermatology, Washington University School of Medicine, 660 S Euclid, St Louis, MO 63110 (e-mail: cornelil@msnotes.wustl.edu).

Accepted for publication March 19, 2003.

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Augsburger  JJShields  JAMastrangelo  MJFrank  PE Diffuse primary malignant melanoma after prior primary cutaneous malignant melanoma. Arch Ophthalmol. 1980;981261- 1264
PubMed
Bellet  REShields  JASoll  DBBernardino  EA Primary choroidal and cutaneous melanomas occurring in a patient with the B-K mole syndrome phenotype. Am J Ophthalmol. 1980;89567- 570
PubMed
Gilbert  CMel Baba  FSchachat  APGrossniklaus  HGreen  WR Nonsimultaneous primary choroidal and cutaneous melanomas: report of a case. Ophthalmology. 1987;941169- 1172
PubMed
Lynch  HTFusaro  RMPester  J  et al.  Tumour spectrum in the FAMMM syndrome. Br J Cancer. 1981;44553- 560
PubMed
McCarthy  JMRootman  JHorsman  DWhite  VA Conjunctival and uveal melanoma in the dysplastic nevus syndrome. Surv Ophthalmol. 1993;37377- 386
PubMed
Taylor  MRGuerry  DBondi  EE  et al.  Lack of association between intraocular melanoma and cutaneous dysplastic nevi. Am J Ophthalmol. 1984;98478- 482
PubMed
Oosterhuis  JAWent  LNLynch  HT Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas. Br J Ophthalmol. 1982;66230- 233
PubMed
Vink  JCrijns  MBMooy  CMBergman  WOosterhuis  JAWent  LN Ocular melanoma in families with dysplastic nevus syndrome. J Am Acad Dermatol. 1990;23858- 862
PubMed
Korting  HCBlick  UHamperl  WD Coincidence of primary malignant melanoma of skin and eye: report of a case without B-K mole syndrome but with a further malignancy. Dermatologica. 1983;167317- 321
PubMed
Bernadino  VBNaidoff  MAClark  WA Malignant melanomas of the conjunctiva. Am J Ophthalmol. 1976;82383- 394
PubMed
Albert  DMChang  MALamping  KWeiter  JSober  A The dysplastic nevus syndrome: a pedigree with primary malignant melanomas of the choroid and skin. Ophthalmology. 1985;921728- 1734
PubMed
Friedman  RJRodriguez-Sains  RJakobiec  F Ophthalmologic oncology: conjunctival malignant melanoma in association with sporadic dysplastic nevus syndrome. J Dermatol Surg Oncol. 1987;1331- 34
PubMed
Jensen  OAMovin  MMuller  J Malignant melanoma of the choroid in an infant with the dysplastic naevus syndrome. Acta Ophthalmol (Copenh). 1987;6591- 100
PubMed
Bataille  VSasieni  PCuzick  JHungerford  JLSwerdlow  ABishop  JA Risk of ocular melanoma in relation to cutaneous and iris naevi. Int J Cancer. 1995;60622- 626
PubMed
Augustsson  AStierner  URosdahl  ISuurkula  M Common and dysplastic naevi as risk factors for cutaneous malignant melanoma in a Swedish population. Acta Derm Venereol. 1991;71518- 524
PubMed
Grob  JJGouvernet  JAymar  D  et al.  Count of benign melanocytic nevi as a major indicator of risk for nonfamilial nodular and superficial spreading melanoma. Cancer. 1990;66387- 395
PubMed
Holly  EAKelly  JWShpall  SNChiu  SH Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol. 1987;17459- 468
PubMed
Tucker  MAHartge  PShields  JA Epidemiology of intraocular melanoma. Recent Results Cancer Res. 1986;102159- 165
PubMed
Greene  MHSanders  RJChu  FCClark  WH  JrElder  DECogan  DG The familial occurrence of cutaneous melanoma, intraocular melanoma, and the dysplastic nevus syndrome. Am J Ophthalmol. 1983;96238- 245
PubMed
Crutcher  WASagebiel  RW Prevalence of dysplastic naevi in a community practice. Lancet. 1984;1729
PubMed
Naus  NCvan Drunen  Ede Klein  A  et al.  Characterization of complex chromosomal abnormalities in uveal melanoma by fluorescence in situ hybridization, spectral karyotyping, and comparative genomic hybridization. Genes Chromosomes Cancer. 2001;30267- 273
PubMed
Aalto  YEriksson  LSeregard  SLarsson  OKnuutila  S 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;42313- 317
PubMed
Canning  CRHungerford  J Familial uveal melanoma. Br J Ophthalmol. 1988;72241- 243
PubMed
Shields  JAShields  CLDe Potter  PSingh  AD Diagnosis and treatment of uveal melanoma. Semin Oncol. 1996;23763- 767
PubMed
Singh  ADDonoso  LA Genetic aspects of uveal melanoma. Int Ophthalmol Clin. 1993;3347- 52
PubMed
Ohta  MNagai  HShimizu  M  et al.  Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene, CDK4I, in melanoma. Cancer Res. 1994;545269- 5272
PubMed
Speicher  MRPrescher  Gdu  MS  et al.  Chromosomal gains and losses in uveal melanomas detected by comparative genomic hybridization. Cancer Res. 1994;543817- 3823
PubMed
Wang  XEgan  KMGragoudas  ESKelsey  KT Constitutional alterations in p16 in patients with uveal melanoma. Melanoma Res. 1996;6405- 410
PubMed
Tsao  HBenoit  ESober  AJThiele  CHaluska  FG Novel mutations in the p16/CDKN2A binding region of the cyclin-dependent kinase-4 gene. Cancer Res. 1998;58109- 113
PubMed
Singh  ADShields  CLShields  JAEagle  RCDe Potter  P Uveal melanoma and familial atypical mole and melanoma (FAM-M) syndrome. Ophthalmic Genet. 1995;1653- 61
PubMed
Metzelaar-Blok  JAter Huurne  JAHurks  HMKeunen  JEJager  MJGruis  NA Characterization of melanocortin-1 receptor gene variants in uveal melanoma patients. Invest Ophthalmol Vis Sci. 2001;421951- 1954
PubMed
Box  NFWyeth  JRO'Gorman  LEMartin  NGSturm  RA Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet. 1997;61891- 1897
PubMed
Frandberg  PADoufexis  MKapas  SChajlani  V Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochem Biophys Res Commun. 1998;245490- 492
PubMed
Ford  DEaston  DFStratton  M  et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998;62676- 689
PubMed
The Breast Cancer Linkage Consortium, Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;911310- 1316
PubMed
Wooster  RNeuhausen  SLMangion  J  et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;2652088- 2090
PubMed
Sinilnikova  OMEgan  KMQuinn  JL  et al.  Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer. 1999;82325- 328
PubMed
Iscovich  JAbdulrazik  MCour  CFischbein  APe'er  JGoldgar  DE Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients. Int J Cancer. 2002;9842- 44
PubMed
Scott  RVajdic  CArmstrong  B  et al.  BRCA2 mutations in a population-based series of patients with ocular melanoma. Int J Cancer. 2002;102188- 191
PubMed
Shukla  VKHughes  DCHughes  LEMcCormick  FPadua  RA Ras mutations in human melanotic lesions. Oncogene Res. 1989;5121- 127
PubMed
Chin  LTam  APomerantz  J  et al.  Essential role for oncogneic Ras in tumour maintenance. Nature. 1999;400468- 472
PubMed
Kramer  TBPowell  MBWilson  MMSalvatore  JGrossniklaus  HE Pigmented uveal tumors in a transgenic mouse model. Br J Ophthalmol. 1998;82953- 960
PubMed
Soparker  CNO'Brien  JMAlbert  DM Investigation of the role of the ras protooncongene point mutation in human uveal melanomas. Invest Ophthal Vis Sci. 1993;342203- 2209
PubMed
Davies  HBignell  GRCox  C  et al.  Mutations of the BRAF gene in human cancer. Nature. 2002;417949- 954
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Structure of the eye.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Ciliary body melanoma. An external photograph showing a ciliary body melanoma that has extended through the sclera and is also invading into the anterior segment, as indicated by the iris being pushed centrally toward the pupil. Note also the prominent episcleral sentinel vessels.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Choroidal melanoma. A digitally created collage of several fundus photographs showing a lightly pigmented choroidal melanoma just superonasal to the optic disc. The fovea is seen as the dark spot just to the right of the disc.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Iris melanoma. External photograph of an isolated iris melanoma that arises from the iris stroma and is growing vertically into the anterior chamber.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Cases of Ocular and Cutaneous Melanoma in the Same Individual
Table Graphic Jump LocationTable 2. Cases of Ocular Melanoma in Association With Atypical Nevus Syndromes

References

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English  DRArmstrong  BKKricker  AFleming  C Sunlight and cancer. Cancer Causes Control. 1997;8271- 283
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Gilchrest  BAEller  MSGeller  ACYaar  M Mechanisms of disease: the pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med. 1999;3401341- 1348
PubMed
Elwood  JMJopson  J Melanoma and sun exposure: an overview of published studies. Int J Cancer. 1997;73198- 203
PubMed
Foss  AJDolin  PJ Trends in eye cancer mortality among adults in the USA and England and Wales. Br J Cancer. 1996;741687- 1689
PubMed
Schwartz  LHFerrand  RBoelle  PYMaylin  CD'hermies  FVirmont  J Lack of correlation between the location of choroidal melanoma and ultraviolet-radiation dose distribution. Radiat Res. 1997;147451- 456
PubMed
Swerdlow  AJStorm  HHSasieni  PD Risks of second primary malignancy in patients with cutaneous and ocular melanoma in Denmark, 1943-1989. Int J Cancer. 1995;61773- 779
PubMed
Graham  SMarshall  JHaughey  B  et al.  An inquiry into the epidemiology of melanoma. Am J Epidemiol. 1985;122606- 619
PubMed
Dolin  PJJohnson  GJ Solar ultraviolet radiation and ocular disease. Ophthalmic Epidemiol. 1994;1155- 164
PubMed
Dolin  PJFoss  AJHungerford  JL Uveal melanoma: is solar ultraviolet radiation a risk factor? Ophthalmic Epidemiol. 1994;127- 30
PubMed
Seddon  JMGragoudas  ESGlynn  RJEgan  KMAlbert  DMBlitzer  PH Host factors, UV radiation, and risk of uveal melanoma: a case-control study. Arch Ophthalmol. 1990;1081274- 1280
PubMed
Vajdic  CMKricker  AGiblin  M  et al.  Eye color and cutaneous nevi predict risk of ocular melanoma in Australia. Int J Cancer. 2001;92906- 912
PubMed
Gallagher  RPElwood  JMRootman  J  et al.  Risk factors for ocular melanoma: Western Canada Melanoma Study. J Natl Cancer Inst. 1985;74775- 778
PubMed
Tucker  MAShields  JAHartge  PAugsburger  JHoover  RNFraumeni  JF  Jr Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med. 1985;313789- 792
PubMed
Guenel  PLaforest  LCyr  D  et al.  Occupational risk factors, ultraviolet radiation, and ocular melanoma: a case-control study. Cancer Causes Control. 2001;12451- 459
PubMed
van Hees  CLJager  MJBleeker  JCKemme  HBergman  W Occurrence of cutaneous and uveal melanoma in patients with uveal melanoma and their first degree relatives. Melanoma Res. 1998;8175- 180
PubMed
Bataille  VPinney  EHungerford  JLCuzick  JBishop  DTNewton  JA Five cases of coexistent primary ocular and cutaneous melanoma. Arch Dermatol. 1993;129198- 201
PubMed
Abramson  DHRodriguez-Sains  RSRubman  R B-K mole syndrome: cutaneous and ocular malignant melanoma. Arch Ophthalmol. 1980;981397- 1399
PubMed
Augsburger  JJShields  JAMastrangelo  MJFrank  PE Diffuse primary malignant melanoma after prior primary cutaneous malignant melanoma. Arch Ophthalmol. 1980;981261- 1264
PubMed
Bellet  REShields  JASoll  DBBernardino  EA Primary choroidal and cutaneous melanomas occurring in a patient with the B-K mole syndrome phenotype. Am J Ophthalmol. 1980;89567- 570
PubMed
Gilbert  CMel Baba  FSchachat  APGrossniklaus  HGreen  WR Nonsimultaneous primary choroidal and cutaneous melanomas: report of a case. Ophthalmology. 1987;941169- 1172
PubMed
Lynch  HTFusaro  RMPester  J  et al.  Tumour spectrum in the FAMMM syndrome. Br J Cancer. 1981;44553- 560
PubMed
McCarthy  JMRootman  JHorsman  DWhite  VA Conjunctival and uveal melanoma in the dysplastic nevus syndrome. Surv Ophthalmol. 1993;37377- 386
PubMed
Taylor  MRGuerry  DBondi  EE  et al.  Lack of association between intraocular melanoma and cutaneous dysplastic nevi. Am J Ophthalmol. 1984;98478- 482
PubMed
Oosterhuis  JAWent  LNLynch  HT Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas. Br J Ophthalmol. 1982;66230- 233
PubMed
Vink  JCrijns  MBMooy  CMBergman  WOosterhuis  JAWent  LN Ocular melanoma in families with dysplastic nevus syndrome. J Am Acad Dermatol. 1990;23858- 862
PubMed
Korting  HCBlick  UHamperl  WD Coincidence of primary malignant melanoma of skin and eye: report of a case without B-K mole syndrome but with a further malignancy. Dermatologica. 1983;167317- 321
PubMed
Bernadino  VBNaidoff  MAClark  WA Malignant melanomas of the conjunctiva. Am J Ophthalmol. 1976;82383- 394
PubMed
Albert  DMChang  MALamping  KWeiter  JSober  A The dysplastic nevus syndrome: a pedigree with primary malignant melanomas of the choroid and skin. Ophthalmology. 1985;921728- 1734
PubMed
Friedman  RJRodriguez-Sains  RJakobiec  F Ophthalmologic oncology: conjunctival malignant melanoma in association with sporadic dysplastic nevus syndrome. J Dermatol Surg Oncol. 1987;1331- 34
PubMed
Jensen  OAMovin  MMuller  J Malignant melanoma of the choroid in an infant with the dysplastic naevus syndrome. Acta Ophthalmol (Copenh). 1987;6591- 100
PubMed
Bataille  VSasieni  PCuzick  JHungerford  JLSwerdlow  ABishop  JA Risk of ocular melanoma in relation to cutaneous and iris naevi. Int J Cancer. 1995;60622- 626
PubMed
Augustsson  AStierner  URosdahl  ISuurkula  M Common and dysplastic naevi as risk factors for cutaneous malignant melanoma in a Swedish population. Acta Derm Venereol. 1991;71518- 524
PubMed
Grob  JJGouvernet  JAymar  D  et al.  Count of benign melanocytic nevi as a major indicator of risk for nonfamilial nodular and superficial spreading melanoma. Cancer. 1990;66387- 395
PubMed
Holly  EAKelly  JWShpall  SNChiu  SH Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol. 1987;17459- 468
PubMed
Tucker  MAHartge  PShields  JA Epidemiology of intraocular melanoma. Recent Results Cancer Res. 1986;102159- 165
PubMed
Greene  MHSanders  RJChu  FCClark  WH  JrElder  DECogan  DG The familial occurrence of cutaneous melanoma, intraocular melanoma, and the dysplastic nevus syndrome. Am J Ophthalmol. 1983;96238- 245
PubMed
Crutcher  WASagebiel  RW Prevalence of dysplastic naevi in a community practice. Lancet. 1984;1729
PubMed
Naus  NCvan Drunen  Ede Klein  A  et al.  Characterization of complex chromosomal abnormalities in uveal melanoma by fluorescence in situ hybridization, spectral karyotyping, and comparative genomic hybridization. Genes Chromosomes Cancer. 2001;30267- 273
PubMed
Aalto  YEriksson  LSeregard  SLarsson  OKnuutila  S 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;42313- 317
PubMed
Canning  CRHungerford  J Familial uveal melanoma. Br J Ophthalmol. 1988;72241- 243
PubMed
Shields  JAShields  CLDe Potter  PSingh  AD Diagnosis and treatment of uveal melanoma. Semin Oncol. 1996;23763- 767
PubMed
Singh  ADDonoso  LA Genetic aspects of uveal melanoma. Int Ophthalmol Clin. 1993;3347- 52
PubMed
Ohta  MNagai  HShimizu  M  et al.  Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene, CDK4I, in melanoma. Cancer Res. 1994;545269- 5272
PubMed
Speicher  MRPrescher  Gdu  MS  et al.  Chromosomal gains and losses in uveal melanomas detected by comparative genomic hybridization. Cancer Res. 1994;543817- 3823
PubMed
Wang  XEgan  KMGragoudas  ESKelsey  KT Constitutional alterations in p16 in patients with uveal melanoma. Melanoma Res. 1996;6405- 410
PubMed
Tsao  HBenoit  ESober  AJThiele  CHaluska  FG Novel mutations in the p16/CDKN2A binding region of the cyclin-dependent kinase-4 gene. Cancer Res. 1998;58109- 113
PubMed
Singh  ADShields  CLShields  JAEagle  RCDe Potter  P Uveal melanoma and familial atypical mole and melanoma (FAM-M) syndrome. Ophthalmic Genet. 1995;1653- 61
PubMed
Metzelaar-Blok  JAter Huurne  JAHurks  HMKeunen  JEJager  MJGruis  NA Characterization of melanocortin-1 receptor gene variants in uveal melanoma patients. Invest Ophthalmol Vis Sci. 2001;421951- 1954
PubMed
Box  NFWyeth  JRO'Gorman  LEMartin  NGSturm  RA Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet. 1997;61891- 1897
PubMed
Frandberg  PADoufexis  MKapas  SChajlani  V Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochem Biophys Res Commun. 1998;245490- 492
PubMed
Ford  DEaston  DFStratton  M  et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998;62676- 689
PubMed
The Breast Cancer Linkage Consortium, Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;911310- 1316
PubMed
Wooster  RNeuhausen  SLMangion  J  et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;2652088- 2090
PubMed
Sinilnikova  OMEgan  KMQuinn  JL  et al.  Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer. 1999;82325- 328
PubMed
Iscovich  JAbdulrazik  MCour  CFischbein  APe'er  JGoldgar  DE Prevalence of the BRCA2 6174 del T mutation in Israeli uveal melanoma patients. Int J Cancer. 2002;9842- 44
PubMed
Scott  RVajdic  CArmstrong  B  et al.  BRCA2 mutations in a population-based series of patients with ocular melanoma. Int J Cancer. 2002;102188- 191
PubMed
Shukla  VKHughes  DCHughes  LEMcCormick  FPadua  RA Ras mutations in human melanotic lesions. Oncogene Res. 1989;5121- 127
PubMed
Chin  LTam  APomerantz  J  et al.  Essential role for oncogneic Ras in tumour maintenance. Nature. 1999;400468- 472
PubMed
Kramer  TBPowell  MBWilson  MMSalvatore  JGrossniklaus  HE Pigmented uveal tumors in a transgenic mouse model. Br J Ophthalmol. 1998;82953- 960
PubMed
Soparker  CNO'Brien  JMAlbert  DM Investigation of the role of the ras protooncongene point mutation in human uveal melanomas. Invest Ophthal Vis Sci. 1993;342203- 2209
PubMed
Davies  HBignell  GRCox  C  et al.  Mutations of the BRAF gene in human cancer. Nature. 2002;417949- 954
PubMed

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
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