Uveal melanoma is the most common primary intraocular malignancy. Canning and Hungerford (1988) found reports of 12 families with adequate documentation of the occurrence of uveal melanomas in 2 or more members. They described 2 more families, each ... Uveal melanoma is the most common primary intraocular malignancy. Canning and Hungerford (1988) found reports of 12 families with adequate documentation of the occurrence of uveal melanomas in 2 or more members. They described 2 more families, each with 2 affected members: a brother and sister who presented at ages 69 and 63 years, respectively, and a mother and son who presented at ages 33 and 20, respectively. Young et al. (1994) reported 11 families in which 2 or more members had uveal melanoma. The median age at diagnosis was 56.5 years, similar to the median age at diagnosis of the other patients treated at their institution. Of the 24 affected persons, 13 were male and 11 were female. In a review of medical charts of 4,500 patients with uveal melanoma, Singh et al. (1996) found 56 patients in 27 families with a family history. The uveal melanoma was unilateral in all 56 familial cases. In 17 cases (63%), the second affected relative was a first-degree relative; second-degree relatives accounted for 22% and third-degree relatives for 15%. In 25 families (93%), only 2 members were affected, and in 2 families (7%), 3 members had uveal melanoma. Patients with familial uveal melanoma were 4 times as likely to have a second primary malignant neoplasm than persons in the general population; however, unaffected relatives of these patients were apparently not at higher risk of having another primary malignant neoplasm. The authors stated that the occurrence of familial uveal melanoma is rare, comprising only 0.6% of all uveal melanoma patients. Singh and Topham (2003) determined the incidence of primary uveal melanoma in the United States over a 25-year period (1973-1997). They found 2,493 cases of uveal melanoma, representing 2.9% of all recorded cases of melanoma. The mean age-adjusted incidence was 4.3 per million. Most cases (97.8%) occurred in the white population. There was a significant variation of incidence between genders (males, 4.9; females, 3.7). There was no significant variation of incidence by the geographic location of the registry. The mean age-adjusted incidence of uveal melanoma in the United States (4.3 per million) was similar to that reported from European countries. The age-adjusted incidence rate of uveal melanoma had remained stable for over the 25 years. Singh et al. (2000) reported a man who presented with choroidal melanoma at the age of 41 and his 68-year-old father who presented with the same condition 6 months after his son. Using principles of probability, they stated that the likelihood of familial occurrence of uveal melanoma was approximately 1 in 10 million. Li et al. (2000) reviewed 1,848 consecutive primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation. They concluded that patients with melanomas of presumed ciliary body origin are subject to a higher risk of death resulting from melanoma metastasis. Al-Jamal et al. (2003) reported that the mean of the 10 largest nucleoli (MLN) was an independent predictor of survival in patients with uveal melanoma, when adjusting in turn for the presence of epithelioid cells, loops and networks, and microvascular density (MVD). The authors concluded that MLN and microvascular loops and networks were unrelated, independent predictors of survival. MLN and MVD were found to be partially interrelated. Multivariate models that included MVD in addition to MLN fitted better with observed melanoma-specific survival than models that excluded MVD. Subretinal fluid is a strong risk factor for growth of choroidal melanocytic tumors. Espinoza et al. (2004) found that optical coherence tomography was useful in distinguishing active subretinal fluid from chronic retinal changes overlying a choroidal melanocytic tumor and might be of predictive value in identifying tumors that are likely to grow and require treatment. Toivonen et al. (2004) investigated the relationship between progression to hepatic metastasis and tumor-infiltrating macrophages and microcirculation attributes in uveal melanoma, a cancer that almost invariably disseminates hematogenously to the liver. The authors found that the hepatic metastases had a significantly lower grade of pigmentation, more frequent epithelioid cells, more intermediate and dendritic types of CD68 (153634)-immunopositive macrophages than round ones, and a higher MVD than the primary uveal melanomas that spawned the metastases. Patient survival after diagnosis of disseminated disease tended to be shorter if hepatic metastases had a high MVD. Shields et al. (2004) reported the clinical variation and natural course of optic disc melanocytoma in 115 patients. Although optic disc melanocytoma is generally considered to be a benign, stationary lesion, they found that it can produce several local complications, can cause visual loss, can grow slowly, and can, rarely, undergo malignant transformation into melanoma. Shields et al. (2004) concluded that patients with optic disc melanocytoma should undergo periodic ocular examination. Zografos et al. (2004) reviewed 37 cases of optic disc melanocytoma in European patients. Tumor growth was demonstrated in 6 of 9 patients followed for at least 6 years. In 2 cases, presumed malignant transformation required treatment. Zografos et al. (2004) concluded that the risk of melanocytoma progression, although sometimes occurring as much as several years after the initial diagnosis, justifies a cautious approach with long-term regular surveillance. Elner et al. (2004) reviewed the clinical and echographic characteristics of a chronic, inactive choroidal nevus and a malignant choroidal melanoma. They concluded that documented growth is not an unequivocal indicator of malignant transformation for small melanocytic tumors. Elner et al. (2004) stated that the Collaborative Ocular Melanoma Study Group (1990) reported histopathologic examination of 413 eyes with a clinical diagnosis of choroidal melanoma and a misdiagnosis rate of 0.48%. All of these melanomas had a height greater than 2.5 mm, and Elner et al. (2004) noted that with lesions less than 2 mm in height, it is more difficult to distinguish a nevus from a melanoma. Hadden and Damato (2003) reported the occurrence of 2 entirely separate choroidal melanomas in the same eye of 1 patient, a 30-year-old woman. The first developed in her left eye. It was successfully treated with proton beam radiotherapy. One year later, she developed a pigmented lesion on her right calf. Excision biopsy revealed melanoma-in-situ. Four years later, a small choroidal tumor was noted in her left eye and was presumed to be a nevus. It was observed for 1 year. Because of rapid growth, choroidal melanoma was diagnosed. This second choroidal melanoma was treated with a ruthenium plaque. Six years later, both tumors had continued to regress and the patient remained in good health. Only 19 cases of multifocal uveal melanoma had been reported previously. Hadden and Damato (2003) concluded that a second uveal melanoma in the same eye suggested a genetic predisposition. Smith et al. (2007) evaluated a kindred in which several members had both uveal and cutaneous (see 155600) melanomas. The proband and his mother had uveal melanoma, 3 cutaneous melanomas occurred between 2 sibs, and 2 other sibs had basal cell carcinomas. No germline mutations were detected in the melanoma-associated tumor suppressor genes p16(INK4A) (600160) and p14(ARF) (see 600160). Seven of 10 sibs had a history of cutaneous and/or ocular nevi. Of the 3 subjects without nevi, 2 had histories of eye or skin malignancies (1 uveal melanoma and 1 basal cell carcinoma). Three of the 10 sibs had relevant ocular findings (2 choroidal nevi and 1 uveal melanoma). Six were also found to be in the 'high-risk' classification for cutaneous malignancies. Smith et al. (2007) concluded that their results strengthened the association between uveal melanoma, atypical nevi, and cutaneous melanoma.
Hearle et al. (2003) screened 385 patients with uveal melanomas for germline mutations in the BRCA2 (600185), p16(INK4A)/p14(ARF) (600160), and p15 (600431) genes. Their findings suggested that fewer than 2% of uveal melanoma cases could be ascribed to ... Hearle et al. (2003) screened 385 patients with uveal melanomas for germline mutations in the BRCA2 (600185), p16(INK4A)/p14(ARF) (600160), and p15 (600431) genes. Their findings suggested that fewer than 2% of uveal melanoma cases could be ascribed to germline mutations in BRCA2, p16/p14, or p15. The authors concluded that it is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma. - Somatic Mutations Maat et al. (2008) noted that mutations in the genes that control call proliferation in cutaneous melanoma are generally uncommon in uveal melanoma. However, using the very sensitive pyrophosphorolysis-activated polymerization (PAP) assay to screen for mutations in exon 15 of the BRAF gene (164757) in 11 uveal melanoma cell lines and 45 primary uveal melanomas, Maat et al. (2008) identified mutations in 2 cell lines (V600E; 164757.0001) and 6 primary tumors. Direct sequencing of the exon 15 PCR product did not reveal the mutations found with the PAP assay, indicating a low frequency of the mutant allele in primary samples. Maat et al. (2008) concluded that the relative scarcity of the BRAF mutations excluded an elemental role for them in uveal melanoma. Van Raamsdonk et al. (2009) reported frequent somatic mutations in the heterotrimeric G protein alpha-subunit (GNAQ; 600998) in blue nevi (603670) (83%) and ocular melanoma of the uvea (46%). The mutations occurred exclusively in codon 209 in the Ras-like domain and resulted in constitutive activation, turning GNAQ into a dominant-acting oncogene. Van Raamsdonk et al. (2009) concluded that their results demonstrated an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention. Populo et al. (2011) identified the GNAQ Q209 mutation in 36% of 22 enucleated uveal melanomas. No associations were found between the presence of the GNAQ mutation and prognostic parameters, the expression of ERK1/2 (MAPK3, 601795/MAPK1, 176948), phosphorylated ERK1/2, and cell cycle markers. Populo et al. (2011) suggested that GNAQ-mutated uveal melanomas do not exhibit a higher deregulation of proliferation or higher activation of the MAP kinase signaling pathway than uveal melanomas without GNAQ activation. Van Raamsdonk et al. (2010) identified somatic mutations affecting residue Q209 of the GNA11 gene (139313) in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. Mutations in the same codon (Q209) of the paralogous GNAQ gene were found in 55% of blue nevi, 45% of primary uveal melanomas, and 22% of uveal melanoma metastases. The sample group included a total of 713 melanocytic neoplasms. Sequencing of exon 4 of both these genes, affecting residue R183, in 453 melanocytic neoplasms showed a lower prevalence of mutations, in 2.1% of blue nevi and 4.9% of primary uveal melanomas. The mutations were mutually exclusive, except for a single tumor that carried mutations at both Q209 and R183 in GNA11. In total, 83% of all uveal melanomas examined had oncogenic mutations in either GNAQ or GNA11. Mice injected with cells transduced with the GNA11 Q209L mutation developed rapidly growing tumors and metastases, whereas injection with GNA11 R183C-transduced cells showed lesser potency. Western blot analysis of melanocytes transduced with GNA11 Q209L showed constitutive activation of the MAPK pathway. Although GNA11 mutations appeared to have a more potent effect on melanocytes than did GNAQ mutations, there was no difference in patient survival among those with GNA11 mutations compared to those with GNAQ mutations. Harbour et al. (2010) used exome capture coupled with massively parallel sequencing to search for metastasis-related mutations in highly metastatic uveal melanomas of the eye. Inactivating somatic mutations were identified in the gene encoding BRCA1-associated protein-1 (BAP1; 603089) on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin carboxyl-terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele. Harbour et al. (2010) concluded that their findings implicated loss of BAP1 in uveal melanoma metastasis. Wiesner et al. (2011) found somatic mutations in the BAP1 gene in 13 (40%) of 33 uveal melanomas. All the uveal melanomas with BAP1 mutations also carried mutations at codon 209 in either GNAQ or GNA11. Harbour et al. (2013) described mutations occurring exclusively at codon 625 of the SF3B1 gene (605590) in low-grade uveal melanoma with good prognosis.