Lack of association between intraocular melanoma and cutaneous dysplastic nevi

The occurrence of uveal and cutaneous malignant melanoma and the dysplastic nevus syndrome in the same individual suggests an etiologic relationship among these diseases. Thus, the dysplastic nevus syndrome could be viewed as marking an increased risk of both cutaneous and ocular melanoma. We postulated that if such a relationship exists, patients with both forms of melanoma should have a high prevalence of dysplastic nevi. We examined 44 patients (31 women and 13 men ranging in age from 20 to 80 years) with uveal melanoma for evidence of cutaneous melanoma and dysplastic nevi. We also examined photographs of 46 patients (24 men and 22 women ranging in age from 19 to 67 years) with nonfamilial cutaneous melanoma to determine the prevalence of dysplastic nevi. We found a 4.5% prevalence of dysplastic nevi in patients with uveal melanoma, significantly lower than the 41% prevalence in patients with cutaneous melanoma (two of 44 patients vs 19 of 46 patients). This study indicates that uveal and cutaneous melanoma are not etiologically linked through dysplastic nevi and suggests that patients with uveal melanoma are no more likely to have cutaneous dysplastic nevi than the general population.     

Lack of BRAF mutation in primary uveal melanoma

PURPOSE: BRAF T1796A activating mutations have been found in a high proportion of cutaneous melanomas, cutaneous nevi, and papillary thyroid carcinoma and in a small fraction of other cancers. This study was designed to investigate the incidence of BRAF T1796A mutation in uveal melanoma. METHODS: Twenty-nine formalin-fixed, paraffin-embedded posterior uveal melanomas were included in the study. DNA was extracted from the paraffin sections followed by PCR amplification of exon 15 and detection of the common BRAF missense mutation (T-->A transversion at nucleotide 1796) using restriction enzyme analysis. RESULTS: Although positive cutaneous melanoma control cell lines harbored the T1796A BRAF mutation, none of the 29 uveal melanomas harbored the mutation. CONCLUSIONS: These data suggest that BRAF T1796A activating mutation is not common in primary uveal melanoma. These findings are in accord with known differences in tumorigenesis between uveal and cutaneous melanomas.     

The dysplastic nevus syndrome. A pedigree with primary malignant melanomas of the choroid and skin

Intraocular and cutaneous melanomas developed in a family with features of the dysplastic nevus syndrome. (The proband had a choroidal melanoma, his son had a cutaneous melanoma, and his grandchildren have mildly atypical melanocytic lesions clinically.) The syndrome is characterized by clinically and histologically atypical nevi, which may serve as cutaneous markers to identify persons at high risk for melanomas, both of the skin and the eye. Although it has been proposed recently that the association of intraocular melanoma with cutaneous melanoma and the dysplastic nevus syndrome may be coincidental, statistical analysis suggests that the occurrence of the two forms of melanoma in the same patient and in different members of the same family is not explained by chance alone. Therefore, until the relationship between intraocular and cutaneous melanomas is more fully elucidated, recognition of the dysplastic nevus syndrome is important, and the skin of patients suspected of having intraocular melanomas should be examined routinely for evidence of atypical melanocytic lesions.     

Uveal melanoma: epidemiologic aspects

Melanomas of the ocular and adnexal structures comprise approximately 5% of all melanomas. The majority (85%) of ocular melanomas are uveal in origin; primary conjunctival and orbital melanomas are rare. The diagnosis of uveal melanoma is made by clinical examination including indirect ophthalmoscopy and by ancillary studies such as fluorescein angiography and ultrasonography. Metastases to the liver develop within 15 years after the initial diagnosis and treatment in approximately 50% of patients with posterior uveal melanoma; however, clinically evident metastatic disease at the time of initial presentation is uncommon, indicating that there is early subclinical metastasis in most cases.     

Cutaneous malignant melanoma metastatic to the eye, lids, and orbit

The incidence of malignant cutaneous melanoma is increasing faster than any other cancer. Thus, it will become an increasingly common source of metastatic disease to the eye, lids, and orbit. Herein, we have performed a systematic review of previously published cases including patient characteristics, clinical presentation, diagnostic techniques, current treatments, and outcomes. At the time of ocular diagnosis, nearly all reported patients had a known history of cutaneous melanoma and synchronous non-ocular metastases. Several aspects help in differentiating the tumors from primary uveal melanomas such as the presence of symptoms, rapidly growing multifocal tumors, vitreous seeding, and histopathological findings. Intraocular metastases (uvea, vitreous, retina, and anterior-segment) are more common and occur in younger patients than extraocular metastases (eyelids, orbit, and extraocular muscles). Palliative radiation therapy is often used for intraocular disease. Orbital metastases from cutaneous melanoma commonly involve the extraocular muscles resulting in diplopia and exophthalmos. The mainstays of extraocular treatment are surgical resection and radiation therapy. Unfortunately, there are few good options for systemic treatment of diffusely metastatic melanoma. Therefore, patients with ocular metastasis should be managed to prevent loss of vision or loss of the eye, and to maximize their quality of life.     

Uveal melanoma: a study on incidence of additional cancers in the Swedish population

PURPOSE: To investigate the occurrence of other primary malignancies before and after diagnosis of uveal melanoma in a Swedish population. METHODS: In the Swedish Cancer Registry 2995 patients with uveal melanoma were notified during the period 1960 to 1998. In the same registry, a search for additional malignancies among these patients was performed. A matched case-control study with 2,916 patients and 14,577 population control subjects was set up for malignancies before diagnosis of uveal melanoma. Malignancies after diagnosis of uveal melanoma were evaluated in 2,995 patients through standardized incidence ratios (SIRs), based on the expected rates in the Swedish population. RESULTS: Before the diagnosis of uveal melanoma, the odds ratio (OR) for the risk of cancer was 1.25 (95% CI: 0.98-1.59). No significantly increased risk was found for any specific malignancy. The OR for cutaneous melanoma was 1.74 (95% CI: 0.78-3.89). The risk of subsequent cancers was increased, SIR 1.13 (95% CI: 1.02-1.26). After reevaluation of archival specimens, the SIR of a cutaneous melanoma's developing after a uveal melanoma was found to be 1.75 (95% CI: 0.87-3.12). CONCLUSIONS: An increased risk of second primary cancers was observed among Swedish patients with uveal melanoma. Metastases from uveal melanoma were found to be misclassified as cutaneous melanoma or as primary liver cancer.     

BRAF mutations in conjunctival melanoma

PURPOSE: An activating mutation in exon 15 of the BRAF gene has been found in a high proportion of cutaneous melanomas and cutaneous nevi but not in uveal melanoma. Conjunctival melanoma shows greater clinical similarity to cutaneous melanoma than does uveal melanoma. The purpose of this study was to determine whether the T1799A BRAF mutation found in cutaneous melanoma is also present in conjunctival melanoma. METHODS: DNA was extracted from paraffin sections obtained from glutaraldehyde or formalin-fixed, paraffin-embedded conjunctival melanomas. Forty-two specimens were identified from 25 patients. Seminested PCR was used to amplify exon 15 of the BRAF gene, and the resultant PCR product was purified and directly sequenced. Sequences from conjunctival melanomas were compared with the wild-type sequence of the BRAF gene. The presence or absence of the BRAF mutation was compared with the clinicopathological features. RESULTS: The T1799A (V600E) mutation was detected by sequencing in melanomas from 5 of 22 patients as well as in the positive control, a cutaneous melanoma cell line. In this small series, no statistically significant associations between the presence of the BRAF mutation and clinicopathological characteristics were detected, although tumors with this mutation tended to have a larger diameter and greater depth of invasion and to contain epithelioid cells. CONCLUSIONS: Others have demonstrated a BRAF T1799A-activating mutation in cutaneous but not uveal melanoma. In this study, this BRAF mutation was demonstrated in some conjunctival melanoma tissue samples, suggesting that some conjunctival melanomas may share biological features in common with cutaneous melanoma.     

Bilateral uveal melanomas. Five case reports

PURPOSE: Uveal malignant melanoma is the most common primary intraocular tumor in adults. The occurrence of bilateral uveal melanoma is an extremely rare event, but the observed frequency is nevertheless higher than what can be attributed to chance. Possible responsible factors may include a genetic predisposition. PATIENTS AND METHODS: This retrospective study investigated the charts of patients examined from July 1988 to July 2001. For each patient, the clinical characteristics of the tumor (diameter, thickness, location), treatments, and results were noted, as were the eye involved, the presence of ocular melanocytosis, cutaneous melanoma, and second primary cancers. The information was then subjected to statistical analysis. RESULTS: Of 2 461 patients with unilateral primary uveal melanoma, five were identified as having bilateral uveal melanoma (0.2%). The expected number of cases would be less than one, hypothesizing an incidence of second melanoma identical to the incidence of a primary melanoma in the general population. The interval between the diagnosis of first and second primary uveal melanomas ranged from 0 to 6 years (median, 2 years). There was no clinical evidence of ocular melanocytosis in any of the five patients. The uveal melanoma was choroidal in three patients and affected the ciliary body or iris and choroid in two patients. DISCUSSION: The discrepancy between the estimated incidence (thought by Shammas to be one case every 18 years) and the observed incidence of bilateral primary uveal melanoma could be the result of many possible factors. An increased incidence of unilateral uveal melanoma could be a cause but in fact the incidence of uveal melanoma seems stable. Uveal melanoma may have been misdiagnosed in earlier years. The presence of a genetic predisposition to uveal melanoma is a possible explanation (suspected because of bilateral cases, familial cases and association with other primary malignancies). Ocular melanocytosis, which is described as more common in patients with bilateral uveal melanoma, was not seen in our series. CONCLUSION: Bilateral primary uveal melanoma occurs more frequently than expected. Unidentified germline mutations may be involved in pathogenesis. These cases serve as a reminder of the of the importance of careful examination of the second eye.     

Progress in the studies of etiology, epidemiology and pathogenesis of ocular melanomas

Our population-based epidemiological studies demonstrated that the epidemiological aspects of ocular melanomas are different from those in cutaneous melanoma. The incidences of conjunctival melanoma increased in the past decades and was higher in the South (greater sun exposure), which is consistent with the occurrence of cutaneous melanoma. On the contrary, incidences of uveal melanoma are in the opposite direction of cutaneous melanomas.This indicates that solar radiation does not cause an increase of incidences of melanoma in ocular tissues (uveal melanoma) that are not exposed to solar radiation. Solar radiation increases the incidence of melanoma only in tissues exposed to said radiation, such as in conjunctival and eyelid melanomas.Uveal melanoma incidences in lightpigmented individuals are much greater than in dark-pigment- ed individuals. This result cannot be attributed to a melanin photo-screening effect, and is possibly related to melanin's biophysical and biochemical effects. The difference in incidences between light-and dark-pigmented individuals in conjunctival melanomas, as well as in vulvar and vaginal melanomas, are much lower than that in the uveal and cutaneous melanomas. This difference may be related to the different histological structures in these melanomas; conjunctival and vaginal melanomas occur in the mucous membrane, whereas cutaneous melanomas occur in the skin. Recent molecular biological studies indicate that each type of melanoma has its own molecular changes which are different from the others. Therefore, independent studies are required for each type of melanoma to discover their own etiology and pathogenesis, and to develop relevant novel prevention and treatment procedures.     

Survival from uveal melanoma in England and Wales 1986 to 2001

PURPOSE: To analyse survival from uveal melanoma diagnosed in England and Wales between 1986-1999 and followed up to 2001. METHODS: Data from the National Cancer Registry at the Office for National Statistics were analysed. The data were compiled from population-based cancer registries covering all of England and Wales for all adults (aged 15-99) diagnosed with primary ocular malignancy, excluding eyelid tumours. Level of poverty was based on the national classification of area of residence at time of diagnosis. Regression models explored the influence of sex, age, and level of poverty on relative survival for patients diagnosed with uveal melanoma during successive calendar periods. RESULTS: Of 5,519 adults identified with primary ocular malignancy, 4,717 had melanoma, of which 4,308 (91%) were eligible for analysis. Two-thirds (67%) of the ocular melanomas were uveal, 5% conjunctival, and 2% orbital; the subsite was unspecified in 26%. Relative survival from uveal melanoma was 95% at 1 year and 72% at 5 years. There was no statistically significant variation in 1-year or 5-year survival by sex or poverty level and no significant trend over time. Older patients had significantly worse survival (p < 0.001). CONCLUSIONS: This study provides national population-based survival estimates for England and Wales for uveal melanoma, the most common primary intraocular malignancy in adults. Five-year relative survival, an important indicator of the quality of cancer care, has not improved since the 1980s. Greater age, but not gender or level of poverty, is associated with a poorer prognosis. A standardised classification of uveal melanoma is required to improve reporting to cancer registries. Further research is required to explore reasons for lower relative survival in older persons.     

Ocular and oculodermal melanocytosis associated with uveal melanoma

Fifteen patients with ocular or oculodermal melanocytosis were found after reviewing 1210 cases of histologically proven uveal melanomas. The melanoma in each of these patients developed in the eye affected with ocular or oculodermal melanocytosis and not in the unaffected eye. In the one case of bilateral involvement with oculodermal melanocytosis, the patient developed the melanoma in the eye more affected with melanocytosis. In the only case of partial ocular melanocytosis, the melanoma developed in a sector of the eye affected with melanocytosis. A comparison of the prevalence of ocular or oculodermal melanocytosis in patients with uveal melanoma with the prevalence of ocular or oculodermal melanocytosis in the general population, implies that there is an increased incidence of uveal melanomas in patients with ocular or oculodermal melanocytosis.     

Osteopontin expression and serum levels in metastatic uveal melanoma: a pilot study

PURPOSE: This was a pilot study conducted to examine the expression of osteopontin in uveal melanoma and to determine whether serum osteopontin can be used in detecting metastatic uveal melanoma. METHODS: Osteopontin mRNA was measured in three uveal melanoma cell lines of various invasive potential by real-time PCR. Tissue sections of primary and metastatic uveal melanomas were stained for osteopontin. Serum osteopontin levels were measured by ELISA assays in 15 patients with metastatic uveal melanoma and in 37 patients who were disease-free for at least 10 years after treatment of the primary tumor. Paired serum samples drawn from eight patients before and after development of metastasis were analyzed. RESULTS: By real-time PCR, highly invasive primary and metastatic uveal melanoma cells expressed 6- and 250-fold excess osteopontin mRNA, respectively, compared with poorly invasive primary uveal melanoma cells. Tissue sections of primary uveal melanomas lacking looping vasculogenic mimicry patterns either did not stain for osteopontin or exhibited weak, diffuse staining. In primary melanomas containing looping vasculogenic mimicry patterns, strong osteopontin staining was detected in the tumor periphery where patterns were located. Diffuse strong expression of osteopontin was detected in eight samples of uveal melanomas metastatic to the liver. Serum osteopontin levels were significantly higher in patients with metastatic uveal melanoma than in patients who had been disease free for at least 10 years after treatment (P = 0.0001) or in age-matched control subjects. Serum osteopontin levels were significantly higher (P = 0.008) after metastasis than before the detection of metastasis in eight patients. When a cutoff of 10 ng/mL was used, the sensitivity and specificity of serum osteopontin in detecting metastatic melanoma was 87.5%, and the area under the receiver operator characteristic curve was 96%. CONCLUSIONS: Osteopontin is expressed diffusely in tissue sections of hepatic metastases from uveal melanoma, and increased serum osteopontin levels correlate with melanoma metastasis to the liver with high specificity and sensitivity.     

Iris melanoma arising in iris nevus in oculo(dermal) melanocytosis

A 50-year-old white man with oculo(dermal) melanocytosis and longstanding iris nevus was found to have growth of the iris mass. Excision and histopathologic examination revealed a mixed cell type malignant melanoma. Benign nevus cells were present at the periphery of the tumor surrounding the entire melanoma. White patients with oculo(dermal) melanocytosis have a predisposition to uveal melanoma, which is usually choroidal in origin. Literature review showed only three confirmed cases of iris melanoma in this setting. Two additional cases initially published as spindle A melanoma have been reclassified as iris nevi based on the modified Callender classification of uveal melanomas. It is recommended that patients with oculo(dermal) melanocytosis be followed for the occurrence of uveal melanoma.     

Ocular abnormalities associated with cutaneous melanoma and vitiligolike leukoderma

Several varieties of ocular pathology are associated with acquired cutaneous hypomelanosis (leukoderma; vitiligo). Our current study was undertaken to investigate the relationship between ophthalmologic disorders and a specific depigmentary phenomenon, the vitiligolike leukoderma of cutaneous melanoma. Over the past 14 years, eight patients with cutaneous melanoma and widespread areas of hypopigmentation were identified at the Pigmented Lesion Clinic of the Massachusetts General Hospital. The seven patients who underwent ophthalmologic examination had pigment-related ocular abnormalities. Among these were inflammations of the uveal tract in three patients, heterochromia in two, halo nevi of the choroid in one, and hypopigmentation and/or atrophy of the retinal pigment epithelium or choroid in four. Our findings demonstrate that ocular disease may be a component in a syndrome consisting also of cutaneous melanoma and vitiligolike leukoderma and suggest the need for complete ophthalmologic examinations in patients with melanoma and leukoderma.Work supported in part by NIH Grant EY01917     

Melanocortin 1 receptor is expressed by uveal malignant melanoma and can be considered a new target for diagnosis and immunotherapy

PURPOSE: Uveal melanoma is the most common primary malignant ocular cancer in adults. This tumor has a distinct expression pattern of markers compared with cutaneous melanoma. MC1R is under study as a potential target for antitumor immunity. Because of the potential immunogenicity of MC1R, it is important to evaluate its expression on uveal melanomas. METHODS: Two novel monoclonal antibodies (MP1.1C11 and MP1.1B7) were used to examine the expression of MC1R in uveal melanomas. Tissue samples obtained from 17 patients were analyzed for expression of MC1R by immunohistochemistry. Additionally, uveal melanoma cell lines were treated with proinflammatory cytokines, after which MC1R cell surface expression was analyzed by flow cytometry. RESULTS: Results demonstrated that MC1R is expressed by uveal melanoma to a significantly greater extent than other melanoma markers. With the use of MP1.1C11 or MP1.1B7, MC1R was detected in 95% of the tested melanoma tissues, including one liver metastasis. In contrast, MART-1, S100-specific protein, and gp-100 were only expressed by 66%, 33%, and 67% of the analyzed samples, respectively. Results also demonstrated that even though MC1R is mainly located intracellularly, its cell surface expression can be promoted by cytokines such as IFN-gamma, TNF-alpha, IL-4, and IL-10. CONCLUSIONS: These observations support the inclusion of MC1R in the panel of markers for the diagnosis of uveal melanoma. Therapeutic use of MC1R-specific antibodies targeting cytokine-induced MC1R potentially requires expression of the target molecule on the surfaces of tumor cells. Data presented here support MC1R as a new marker and a putative therapeutic target for uveal melanoma.     

Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma

PURPOSE: Reports suggest that a subset of uveal melanoma is familial. The association of uveal melanoma with breast and ovarian cancer and the increased risk in BRCA2-linked families implicates germline BRCA2 mutations as the cause of a subset of uveal melanomas. Similarly, the association between cutaneous and uveal melanomas in some families, coupled with the high frequency of somatic deletions of the INK4A-ARF locus in uveal melanomas, strongly suggests that mutations in P16(INK4A) and P15 account for a proportion of uveal melanomas. METHODS: To examine this proposition, a systematically ascertained series of 385 patients with uveal melanoma were screened for germline mutations in BRCA2, P16(INK4A), P14(ARF), and P15. RESULTS: One patient was found to harbor a Gly35Ala substitution in exon 1alpha of P16(INK4A), which has previously been reported to be pathogenic. No mutations were detected in P14(ARF) or P15. None of the patients harbored germline nucleotide changes that lead to truncation or that create or disrupt consensus splice sites of BRCA2 or missense variants with clear pathogenic potential. CONCLUSIONS: These findings suggest that less than 2% of cases of uveal melanoma can be ascribed to germline mutations in BRCA2, P16(INK4A), P14(ARF), or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma.     

Pyrophosphorolysis detects B-RAF mutations in primary uveal melanoma

PURPOSE: Mutations in the genes that control cell proliferation in cutaneous melanoma are generally uncommon in uveal melanoma. Despite the absence of known activating mutations, the RAF-MEK-ERK, or mitogen-activated protein kinase (MAPK), pathway is usually activated in uveal melanoma. An assay with increased potential to identify mutations is now available, and this study was therefore conducted to reanalyze uveal melanoma cell lines and primary tumors for this mutation. METHODS: Eleven uveal melanoma cell lines and 45 primary uveal melanomas were analyzed for mutations in exon 15 of the B-RAF gene by using pyrophosphorolysis-activated polymerization (PAP). Mutations were validated by sequencing of the PAP product. RESULTS: B-RAF mutations were detected in cell lines OCM-1 and -3 (V600E) and in six primary uveal melanomas. The V600K mutation was detected in one primary uveal melanoma, for which the V600E assay turned out to be sensitive as well. 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. CONCLUSIONS: Because of the very sensitive PAP technology, B-RAF mutations were found in cell lines and primary uveal melanomas, which suggests that they may occasionally play a role in the activation of the MAPK pathway in uveal melanoma and indicates a higher prevalence of B-RAF mutations in uveal melanoma than was reported earlier. However, the relative scarcity of the B-RAF mutation excludes an elemental role for this mutation in uveal melanoma.     

Prevention of metastasis of intraocular melanoma in mice treated with difluoromethylornithine

The antimetastatic potential of a novel chemotherapeutic agent, alpha-difluoromethylornithine (DFMO), was evaluated in a murine model of intraocular melanoma. In vivo studies demonstrated that DFMO retarded the growth and spontaneous metastasis of murine intraocular melanomas. Further studies indicated that oral DFMO also exercised antimetastatic effects against the blood-borne stage of melanoma metastases. In vitro studies revealed that DFMO exerted impressive antiproliferative effects on three murine melanoma cell lines, four human cutaneous melanoma cell lines, one human uveal melanoma cell line, and one conjunctival melanoma cell line. DFMO inhibited in vitro DNA synthesis in human cutaneous melanoma cell lines by 84%–98% and that in two human ocular melanoma cell cultures by 62% and 86%, respectively. DFMO possesses several characteristics that render it an attractive chemotherapeutic agent for potential use in the management of uveal melanoma. These include its antiproliferative effect against a wide range of murine and human melanomas, its extremely low toxicity, and its ease of administration. Offprint requests to: J. Niederkorn     

Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma

PURPOSE: Because lymphatic vessels are absent from the normal eye and because uveal melanomas are presumed to spread by a hematogenous route in the absence of tumor exposure to conjunctival lymphatics, this study was undertaken to investigate the presence of lymphatic vessels in primary uveal melanomas. METHODS: The presence of lymphatics in 2 control eyes and in 33 primary uveal, 10 primary cutaneous, and 3 metastatic cutaneous melanomas was evaluated by using a double-immunostaining protocol that differentially highlights blood and lymphatic vasculature. In addition, 14 uveal melanomas were immunostained for the lymphatic growth factor vascular endothelial growth factor (VEGF)-C (with anti-VEGF-C polyclonal antibodies [pAbs]), its receptors Flt-4 (with monoclonal antibody [mAb] 9D9) and KDR (with anti-KDR mAb [Clone KDR-2]), and the hemangiogenic factor VEGF-A (with anti-VEGF pAbs). RESULTS: Lymphatics were not detected in normal eyes or in uveal melanoma. As a consequence, signs of lymphangiogenesis were not present. There was coexpression of VEGF-C with Flt-4 and KDR in 6 (43%) of the 14 melanomas. Staining for VEGF-A was completely negative in 25 uveal melanomas analyzed. CONCLUSIONS: The strictly hematogenous metastasis of primary uveal melanomas is explained by the absence of lymphatics in and around the tumor. The current data suggest that, in the presence of endothelial Flt-4, VEGF-C expression is not sufficient to induce lymphangiogenesis from preexisting blood vessels in human cancer.