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Ocular melanoma.

Intraocular melanoma of the ciliary body and choroid, together called the posterior uvea, is the most common primary ocular malignant tumor in adults. (1,2,3) However, metastatic carcinoma is the most common overall intraocular malignancy. Iris melanomas are a subset of uveal melanomas that tend to have a more benign course when compared to posterior uveal melanomas, with a lower incidence of metastases when compared to ciliary body and choroidal melanomas (4); they account for about 5% of all uveal melanomas. The incidence of uveal melanoma increases with age and reaches a maximum between the 6th and 7th decade of life. The overall, mean, age-adjusted incidence in the United States is 6 per million. (3) It is slightly more common in males and is uncommon in children and dark-skinned individuals. (1) Uveal melanomas are rarely bilateral; however, the number of patients with bilateral involvement is greater than would be predicted by chance alone, thus implying a possible genetic predisposition. In a large clinical series, (5) 8 of 4500 patients presented with bilateral melanoma; no specific syndrome was identified other than ocular melanocytosis for 2 patients. Melanomas generally occur as sporadic tumors. Whether some environmental exposure triggers the development of uveal melanoma remains an open question. Sunlight has been proposed as an environmental risk factor for uveal melanoma because it is known to cause melanoma of the skin and both diseases are rare in nonwhite races. Unlike cutaneous melanoma, incidence rates for uveal melanoma have not increased over time and do not vary by latitude. (6) Xeroderma pigmentosum, an inherited disorder of DNA repair, predisposes patients to development of numerous skin cancers including melanoma; for these patients, the risk of developing uveal melanoma is 23 times higher than that for the general population. (7) Ocular melanocytosis is a developmental condition in which the ocular surfaces and the uveal tract are hyperpigmented; it is called oculodermal melanocytosis or nevus of Ota when it involves the skin of the eyelids and face. The disease is most prevalent in Asian persons, but when it occurs in white patients, the incidence of uveal melanoma increases by approximately 30-fold, presumably because of the increased number of melanocytes in the uveal tract. (8) The relationship between the dysplastic nevus syndrome and uveal melanoma is controversial; reported series fail to show a higher than chance association between the two. Similarly, pregnancy has been suggested to enhance the growth of and metastases in uveal melanoma. (9)

Although much progress has been made in the diagnosis and earlier local treatment of intraocular melanoma, survival rates have not improved and have remained constant for the past 50 years. The overall mortality resulting from intraocular choroidal melanoma has been reported as 35% in 5 years and 50% in 10 years. (10-13) Despite successful local control, the available data suggest that up to 50% of patients with intraocular melanoma will have metastatic disease. Although uveal and cutaneous melanomas arise from similar melanocytic cells, they differ in their biologic behavior in that choroidal and ciliary body melanomas metastasize first to the liver, while cutaneous melanomas spread to regional lymph nodes. (12-14) This observation is explained by the absence of demonstrable lymphatics within the uveal tract or the posterior orbit; thus, spread is likely hematogenous. When metastases occur, prognosis is poor, with an average life expectancy of 7 months after diagnosis of metastasis. (13)

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THE UVEAL TRACT: NORMAL MORPHOLOGY

The uveal tract is a vascular intraocular coat composed of the iris, the ciliary body, and the choroid. The iris and ciliary body are located anteriorly to the ora serrata, the site that marks the beginning of the retina. The ciliary body is contiguous with the iris anteriorly and the choroid posteriorly. It can be divided into an anterior ring or the pars plicata and a posterior ring, the pars plana. The vascular layer of the ciliary body is located between its muscle layer and the 2 layers of ciliary epithelium. The choroid, the largest and most posterior portion of the uvea, is located between the retinal pigment epithelium and the sclera and extends from the ora serrata to the optic nerve. (15) It consists mainly of blood vessels, nerve fibers, and pigmented melanocytic cells in a loose connective tissue matrix, as shown in Figure 1. The choroid's prime function is to nourish the outer half of the retina. It is supplied by branches of the posterior and anterior ciliary vessels derived from the ophthalmic artery and drained by tributaries of the 4 or more vortex veins into the orbital ophthalmic veins, and through the superior orbital fissure into the cavernous sinus.

CLINICAL FEATURES OF UVEAL MELANOMA

Patients with uveal melanoma may present with complaints of visual loss, but many are without symptoms and the condition is discovered on routine ocular examination. In eyes with clear media, the diagnosis of posterior uveal melanoma can be made by indirect ophthalmoscopy. Ancillary studies such as transillumination, fundus photography, fluorescein angiography, indocyanine green angiography, ultrasonography (A and B modes), ultrasound biomicroscopy, optical coherence tomography, computed tomography, magnetic resonance imaging, radioactive phosphorus uptake test (P32 test), and fine-needle aspiration biopsy can help confirm the diagnosis and determine the tumor site and size. (6,16-18) Ultrasonography is the most accurate method of substantiating the diagnosis and determining tumor size; serial fundus color photographs and fluorescein angiography aid in determining tumor diameter. The A-scan ultrasonography provides accurate information about internal reflectivity and the B-scan provides 2-dimensional topographic information. Computed tomography, magnetic resonance imaging, and the P32 test are rarely necessary to make a diagnosis. (17,18)

Iris melanomas arise in the iris stroma, have a predilection for white persons, and are usually located in the inferior portion of the iris. There are several clinical variations described, including circumscribed, diffuse, tapioca, and trabecular-meshwork types. The circumscribed type can have variable pigmentation and present as a well-defined mass in the iris stroma, whereas the tapioca melanoma appears as multiple hard nodules giving a surface appearance of tapioca pudding. The diffuse type is less common and can produce a clinical picture of acquired hyperchromic heterochromia and secondary glaucoma. In the trabecular-meshwork melanoma variant, the tumor grows diffusely around the anterior chamber angle without producing a distinct mass and patients present with ipsilateral glaucoma. Iris melanomas usually have typical clinical features and can be diagnosed with slit lamp biomicroscopy alone. (4,10) Most circumscribed melanocytic iris lesions do not require immediate surgical excision; only approximately 5% show tumor growth during the first 5 years after initial diagnosis. (19)

Posterior uveal melanomas differ in their clinical presentation and appearance, depending on their site of growth. A ciliary body melanoma can attain a large size before it is clinically recognized. (16-18,20) It is seen in association with 1 or more dilated episcleral blood vessels, an epibulbar pigmented lesion if there is transscleral extension of the tumor, a cataractous lens, and/or lens subluxation due to impingement on the lens by the tumor, or secondary glaucoma due to infiltration of the trabecular meshwork in the angle of the eye. The tumor can be visualized clinically through a widely dilated pupil as a dome-shaped mass in the affected area or it can have a diffuse circumferential growth pattern known as ring melanoma. It can grow into the anterior chamber angle and iris (iridociliary melanoma) or posteriorly into the choroid (ciliochoroidal melanoma). (6,16-18)

A choroidal melanoma usually presents as a sessile or dome-shaped mass located under the retina and is visualized by indirect ophthalmoscopy and fluorescein angiography, as illustrated in Figure 2. Surface orange pigment at the level of the retinal pigment epithelium can be visualized clinically, especially in smaller posterior melanomas. Retinal detachments can be seen secondary to the tumor growth as well as rupture of Bruch membrane (basement membrane under the retinal pigment epithelium). Choroidal melanoma can be pigmented or nonpigmented and can also assume a diffuse growth pattern with only minimal tumor thickness. (16-18,20) Like ciliary body melanoma, choroidal melanomas can cause cataracts, secondary glaucoma, and extraocular extension into the orbit, usually when large, and thus they carry a worse prognosis.

CLINICAL PROGNOSTIC FACTORS

Metastatic uveal melanomas are typically resistant to therapy. Accurate predictive testing may some day allow systemic prophylaxis in high-risk patients. However, it is difficult to predict clinical outcome in individual cases of uveal melanoma on the basis of intraocular tumor size because of the spectrum of clinical, morphologic, and cytologic changes and a lack of discrete stages. (6,14) Tumor size is one of the best parameters used to predict metastatic disease. A small tumor is defined as measuring 3 mm or less in thickness and less than 10 mm in diameter; a tumor is classified as medium-sized if it measures between 3 to 5 mm in thickness and between 10 to 15 mm in diameter, and as large if greater than 5 mm in thickness and more than 15 mm in diameter. A comparative analysis of uveal melanoma (21) has indicated that the 5-year mortality rates after enucleation were 16% for small, 32% for medium-sized, and 53% for large tumors. Known high-risk clinical factors predictive of tumor growth include greater tumor thickness, posterior tumor margin touching the optic disc, subretinal fluid, symptoms of flashes, floaters, blurred vision, and orange pigment. (20) Recently, Shields et al (19) evaluated 8033 uveal melanomas by ultrasonography for accurate tumor measurements. They concluded that increased tumor thickness, by millimeter, increases the risk of metastasis in all but one thickness range. Based on exact tumor thickness, the 10year risk of metastasis was reported at 6% (for 0-1.0 mm thickness), 12% (1.1-2.0 and 2.1-3.0 mm), 16% (3.1-4.0 mm), 27% (4.1-5.0 mm), 28% (5.1-6.0 mm), 29% (6.1-7.0 mm), 41% (7.1-8.0 mm), 50% (8.1-9.0 mm), 44% (9.1-10 mm), and 51% (>10 mm); each millimeter increase imparted a 1.06 hazard ratio. (19) Additional clinical prognostic parameters include a larger tumor diameter, presence of extrascleral growth, tumor margin location anterior to the equator of the eye, older age, male gender, and tumor-induced glaucoma. (6,16,18)

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PATHOLOGY OF POSTERIOR UVEAL MELANOMA AND PROGNOSTIC FACTORS

Gross examination of an enucleated eye can reveal signs of extrascleral or anterior chamber invasion, growth pattern (dome shaped, mushroom shaped or diffuse), extent of secondary retinal detachment, pigmentation, and other important features. (6,15,18) A large pigmented uveal melanoma with retinal detachment and cataractous lens is shown in Figure 3. Standard histologic evaluations of uveal melanoma include the analysis of the largest basal tumor diameter, tumor height, cell type, presence of scleral invasion, ciliary body involvement, mitotic figures, presence of closed vascular loops and extracellular matrix patterns. (6) Histopathologically, these tumors have a spectrum of cell types, ranging from thin and plump spindle cells to epithelioid cells. In 1931, Callender (22) developed a cytologic classification of uveal melanomas by dividing them into 6 cell types: spindle A, spindle B, fascicular, mixed, epithelioid, and necrotic. McLean et al (23,24) modified the classification and proposed 3 main tumor types: spindle-cell, mixed-cell, and epithelioid-cell types. Spindle-cell tumors, as illustrated in Figure 4, tend to grow in a compact cohesive fashion surrounded by a dense reticulin framework; epithelioid cells grow less cohesively and are not surrounded by a network of reticulin; and mixed-cell-type tumors are composed of a mixture of the 2 cell types, as shown in Figure 5, A and B. The cell type of uveal melanoma is related to prognosis. Patients with tumors composed of pure spindle cells have a more favorable prognosis, and those with a component of epithelioid cells (mixed- or epithelioid-cell types) have a worse prognosis. (18,23,25,26) Melanomas with a low mitotic activity show a better prognosis; tumor infiltration by lymphocytes has been associated with decreased survival. (6,27) There are other histopathologic parameters that can be evaluated, such as the size of nucleoli; specific extracellular matrix patterns (25,28); and expression of various cell surface markers, such as metalloproteinases, gangliosides, adhesion molecules, and immunologic markers. (29,30,31) The standard deviation of the nucleolar area (SDNA), coupled with the largest tumor dimension (LTD), correlates highly with survival: the nucleolar area is larger and more pleomorphic in the more malignant types of uveal melanomas (epithelioid or mixed-cell types). A simpler prognosticator is the measurement of the 10 largest nucleoli (MLN) found in a strip 5 mm long and 1 oil-immersion-field wide through the center of the tumor. (32-34) When compared, the prognostic variables LTD, cell type, SDNA, and MLN correlated equally with tumor-related death. (32-35) Extraocular tumor extension can occur through different routes, mainly the vortex veins, aqueous channels, the ciliary arteries, and ciliary nerves; all are associated with a poor prognosis. (26) A large uveal melanoma with extraocular invasion of scleral canals and orbital tissues is shown in Figure 6.

CYTOGENETIC STUDIES

The most common cytogenetic changes in uveal melanoma include loss of DNA on chromosome 3, gain on 6p, loss on 6q, and gain on 8q. Loss of an entire chromosome 3 (or monosomy 3), which is an early event in tumorigenesis, is detected in approximately 50% of tumors. (36-38) The presence of monosomy 3 may be determined by karyotyping, by using fluorescence in situ hybridization (FISH) on cultured cells, or by FISH analysis of tissue sections or cells obtained by fine-needle aspiration. Figure 7 illustrates malignant melanoma cells from a small choroidal melanoma; they were obtained by fine-needle aspiration and show monosomy 3 by cytogenetic analysis. Long-term studies have shown that almost 70% of patients with monosomy 3 in the primary tumor have died of metastases within 4 years after the initial diagnosis, while tumors with normal chromosome 3 status rarely give rise to metastatic disease. A histopathologic study of monosomy 3 status in 17 cases of uveal melanoma (39) suggested that a scleral approach would be the preferred route for obtaining tumor tissue because of disparities in results depending on the site of the fine-needle aspiration biopsy. Monosomy 3 was found in 10 of 17 cases (59%); in 7, monosomy 3 was found in both the apex and base of the tumor; while in 3 cases, there were disparate results between the apex and the base, with monosomy present only at the base. (39) Gain of chromosome arm 6p has been shown to have favorable prognosis. Chromosome 8 gains have also been reported to be associated with poor prognosis if coupled with other variables such as tumor diameter and cell type. (40,41) Chromosome 3 monosomy and chromosome 8 aneusomy have been reported not only in the primary tumor but also within hepatic metastatic lesions. (42)

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GENE EXPRESSION PROFILING AND MOLECULAR CLASSIFICATION OF UVEAL MELANOMA

It has been proposed that the loss of chromosome 3 is part of a multistep mechanism typical for the inactivation of tumor suppressor genes. Two regions of deletion overlap on chromosome 3 have been reported; they are UVM1 and UVM2. (43,44) These loci provide information on the location of the suppressor genes in uveal melanoma. The expression patterns of more than 12 500 genes in 20 primary uveal melanomas showed that 7 genes were absent in tumors with monosomy 3, three of which are located on chromosome 3. CHL1 and fls485 are 2 of these genes, which map within or close to the uveal melanoma susceptibility locus UVM2 at 3p25. Unsupervised hierarchical cluster analysis of gene expression profiling showed that 20 uveal melanomas separated into 2 groups, correlating with the status of chromosome 3. The dissimilarity between these 2 classes of uveal melanomas is based on the expression patterns of genes assigned to diverse biologic pathways. A tumor classification scheme has been developed from these data: class 1, which shows good prognosis (disomy 3), and class 2 (monosomy 3) with poor prognosis. The survival analysis of 50 patients showed the presence of only 1 metastasis among class 1 patients, with a 92-month survival probability of 95%, as compared to 8 deaths among class 2 patients and a 92-month survival probability of 31%. (41,43) Moreover, monosomy 3, large basal tumor diameter, and epithelioid-cell type are the most significant factors for tumor-related death.40 Multiple chromosomal abnormalities have also been shown in primary cutaneous malignant melanoma. In this case, it is the loss on chromosome 9 (9p21) that is present in 81% of tumors, implying a relevance in tumor development. (45)

Recently, an early oncogenic mutation has been identified in ocular melanomas. GNAQ, a G-protein [alpha]-subunit, is mutated in approximately half of the tumors, and this mutation leads to melanocyte proliferation in mice and also to cooperation with other oncogenes to transform melanocytes. This genetic mutation occurs in the RAF/MEK/ERK pathway, which has been identified as initiating mutations in other cancers, (46) and leads to activation of cell cycle genes, a fact that helps to explain the overexpression of cyclin D1 in uveal melanoma.

OTHER PROGNOSTIC PARAMETERS

Other parameters related to prognosis include immunologic determinants such as human leukocyte antigen expression (HLA), and leukocyte and macrophage infiltration. (30,47,48) Increased expression of HLA class I as well as HLA class II carries an unfavorable prognosis, occurs more frequently in epithelioid-cell-type tumors, and is associated with an increased number of CD3 and CD4 T lymphocytes, as well as with an increased density of CD11b macrophages. High numbers of tumor-infiltrating, CD68+ macrophages have also been described in association with poorer prognosis, along with other markers of inflammation such as COX-2. (49,50) These markers have been identified as part of an inflammatory phenotype of uveal malignant melanomas. Human leukocyte antigen expression was not found to be an independent prognostic indicator of metastatic disease. (50) Tumors showing monosomy 3 had a higher HLA class I and II expression than did tumors without this aberration. Since natural killer cells are unable to lyse circulating tumor cells with a high HLA-class I expression, it has been hypothesized that when highly malignant melanoma cells break away from the eye, they cannot be lysed before reaching the liver, thereby circumventing one of the immunologic defense mechanisms of the body. (47,48)

CURRENT TREATMENT OF UVEAL MALIGNANT MELANOMA

The 2 most commonly used treatments of uveal malignant melanoma are radiation therapy and enucleation. The most frequently used system for delivering radiation is plaque therapy; other methods include proton-beam-charged particles and [gamma] knife. Radiation-plaque therapy offers good tumor control, can often preserve useful vision, and has a systemic prognosis that is comparable to that of enucleation.51-53 Enucleation remains the standard method of management of most large melanomas of the choroid and ciliary body. Small lesions with questionable diagnosis are followed up with fundus photography and ultrasonography to document tumor growth before definitive treatment. Benign choroidal nevi are seen in approximately 6% of the population and they are managed by observation. Only 1 in 500 choroidal nevi will evolve into a choroidal melanoma and the risk factors predictive of small melanocytic lesions developing into melanoma have been described. (51) A recent study of 2514 choroidal nevi (54) described the most important factors predictive of growth into melanoma, namely, tumor thickness greater than 2 mm, subretinal fluid, symptoms, orange pigment, tumor margin within 3 mm of the disc, ultrasonographic hollowness, and halo absence. The Collaborative Ocular Melanoma Study (COMS), (10,18,55) a randomized clinical trial evaluating primary enucleation versus external beam radiation followed by enucleation in the management of patients with choroidal melanomas, showed that both treatments offer the same prognosis for medium-sized melanomas. In the review of patient outcome within the COMS large-tumor study, combined external beam radiotherapy followed by enucleation was shown to limit orbital recurrence of tumor. However, the Kaplan-Meier 5-year estimates of survival were not statistically different between the 2 treatment arms and were 57% and 62% for enucleation alone and for enucleation followed with external beam radiotherapy, respectively. (10,55) Shields and Shields (18) recently showed a correlation between the rate and extent of regression and chromosome 3 status. Tumors with monosomy 3 showed faster and greater regression of tumor thickness at 12 and 15 months after "sandwich" therapy. These same authors and colleagues (53) report combined treatment of most uveal melanomas in their clinic, including plaque radiotherapy combined with transpupillary thermotherapy with infrared light and a diode laser delivery system.

Clinical trials of new therapeutic agents have been initiated for patients with metastatic uveal melanoma, as well as in the adjuvant setting after primary therapy. New systemic therapy with molecularly targeted agents is being tested in preclinical studies, with agents including inhibitors of Bcl-2, ubiquitin-proteasome, histone deacetylase, mitogen-activated protein kinase, and phosphatidylinositol-3-kinase-AKT pathway, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. (56)

In summary, the eye is the second most common site of malignant melanoma, as reported in a summary of more than 84 000 cases of melanoma from the United States National Cancer Data Base. (57) Although an uncommon tumor, it is the most common primary intraocular malignant tumor in adults. It is important to recognize the clinical and histopathologic features of intraocular malignant melanoma, in order to offer patients the best possible treatments available. Pathologists should report on the overall tumor size and location, the tumor cell type, and presence of extraocular extension. Physicians should be aware of the new classification of ocular melanoma, namely, class 1 (low metastatic risk) and class 2 (high metastatic risk), that is based on chromosome 3 status. Even with the current treatment modalities, a significant percentage of patients die of metastatic disease. These findings indicate that new treatments are needed to gain better long-term control of the disease and improve the overall survival rates for patients with uveal malignant melanomas.

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Nora V. Laver, MD; Margaret E. McLaughlin, MD; Jay S. Duker, MD

Accepted for publication November 24, 2009.

From Ocular Pathology Laboratory (Drs Laver and McLaughlin) and the Department of Ophthalmology (Dr Duker), New England Eye Center, Tufts Medical Center, Boston, Massachusetts.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Nora V. Laver, MD, Ocular Pathology Laboratory, Box 802, Tufts Medical Center, 800 Washington St, Boston, MA 02111 (e-mail: nlaver@tuftsmedicalcenter.org).
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Author:Laver, Nora V.; McLaughlin, Margaret E.; Duker, Jay S.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Disease/Disorder overview
Date:Dec 1, 2010
Words:5262
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