Signs and Symptoms
Both choroidal nevi and choroidal melanomas represent space-occupying masses of the uveal tract. Choroidal nevi appear as round or oval, flat or slightly elevated (1mm or less) lesions within the posterior fundus; the margins are typically detectable but indistinct. Nevi may present in a variety of hues, but most commonly they appear slate-blue or greenish-gray in coloration; there may be overlying areas of drusen noted as well.1 Rarely, there may be associated subretinal neovascularization.2 The vast majority of choroidal nevi remain under 5mm in size.3 Larger nevi, particularly those in excess of 4DD or 6mm carry increased suspicion of malignancy.3,4 Generally, patients with choroidal nevi are asymptomatic with the lesion detected on routine ophthalmoscopy.
Choroidal melanomas appear as thickened, dome-shaped lesions of the ocular fundus with widely variable coloration, ranging from complete amelanosis (i.e., white) to black. Most commonly, lesions are a non-uniform greenish-gray. There may be significant elevation in some cases. As they grow, melanomas may break through Bruch’s membrane, taking on a “mushroom-shaped” appearance. Serous retinal detachments are commonly associated with this presentation.4,5 Overlying orange pigmentation known as lipofuscin may also be seen; this is considered by many to be a pathognomonic sign of malignancy.6
Patients with small choroidal melanomas may be asymptomatic or report vague visual complaints; in most cases, these lesions are detected via dilated indirect ophthalmoscopy on routine ophthalmic visits. Larger lesions or those in close proximity to the macula typically induce symptoms such as photopsia, visual field deficit, metamorphopsia or decreased acuity secondary to subretinal fluid and/or hyperopic refractive shift.4
The vast majority of patients with choroidal melanoma are over the age of 50, with a peak incidence between the ages of 70 and 79.7 The tumor may rarely occur in childhood.8-10 Race also plays a significant role in the distribution of choroidal melanoma. Caucasians are perhaps three times more likely than Asians to manifest choroidal melanoma, with an incidence that is eight times more likely than those of African descent.11-13 Not surprisingly, patients with light-colored irides (e.g., blue or gray) also seem to be at greater risk for developing uveal melanomas.14,15 The presence of numerous cutaneous nevi—particularly dysplastic nevi—is yet another risk factor.15
Recently, optical coherence tomography (OCT) has emerged as a valuable tool in the differentiation of choroidal nevi and melanomas. In one study, 3D spectral-domain OCT identified a higher prevalence of subretinal fluid (91% vs. 14%), retinal edema (61% vs. 14%), and subretinal deposits (61% vs. 11%) in choroidal melanoma as compared with nevi.16 In addition, Shields et al. suggested that the presence of subretinal fluid is a significant risk for metastasis after studying 8,033 cases of uveal melanoma.17
Choroidal nevi and melanomas are both derived from uveal melanocytes. In the mid-1960s, Naumann and associates18 identified the four atypical cell types inherent in choroidal nevi; in order of prevalence, these include: plump polyhedral cells, slender spindle cells, intermediate cells and balloon cells.15
In contrast, melanomas are comprised of malignant melanocytes. The Callendar classification system for choroidal melanomas suggests that there are also four types of cells in these lesions: spindle A, spindle B, fascicular and epithelioid.19,20 In general, the presence of epithelioid cells within a melanoma heralds a poorer prognosis.21
There is some controversy regarding the precise pathogenesis of melanomas. It is believed that nevi may convert to malignancy in a small percentage of individuals; a recent study suggests a rate of one in 8,845.22 Risk factors for malignant transformation of nevi include diameter (>5mm) thickness (>2mm), the presence of subretinal fluid, lipofuscin, ultrasonographic hollowness and lack of an amelanotic halo.23,24
Ultraviolet (UV) radiation has also been associated with the development of ocular and non-ocular melanoma.4 Some studies have suggested a causal relationship between UV exposure and the development of choroidal melanoma, while others are less conclusive.25-28 It seems that the specifics of this variable are presently uncertain, but the prevailing opinion is that UV is not a significant factor in the pathogenesis of choroidal melanoma.
More than likely, the greatest prognostic indicator for choroidal melanoma development and malignant progression is a genomic variation in chromosomes 3, 6 or 8.4,29
While some choroidal nevi possess the capacity for malignant growth, the majority are completely benign and require only periodic monitoring. Of course, differentiating between a large, atypical nevus and a small choroidal melanoma requires experience and expertise. In 2009, Shields and associates proposed the following mnemonic to recall the most significant risk factors for choroidal melanoma: “To find small ocular melanomas, use helpful hints daily,” or TFSOM-UHHD.23
The first letter of each word in the phrase represents the characteristics that distinguish melanoma: thickness (melanomas are thicker than nevi on ultrasonography and OCT), fluid (melanomas are more likely to show subretinal fluid), symptoms, orange pigment, margin (the margins of melanomas are less distinct than those of nevi), ultrasonographic hollowness, absence of halo and absence of drusen.23 The ancillary procedures that help to facilitate an accurate diagnosis include stereo photography, standardized ultrasonography, fluorescein angiography, fundus autofluorescence photography and OCT.30 More invasive procedures, including transvitreal fine-needle aspiration biopsy, are also sometimes used to differentiate suspicious lesions.31,32
Those patients diagnosed with or suspected of having choroidal melanoma should be referred for prompt medical evaluation by an ocular oncologist. Specific medical testing is warranted to ascertain whether there are any additional primary or metastatic malignancies present. The systemic work-up should include a thorough medical and family history as well as a physical examination and directed laboratory evaluation.
Choroidal melanomas have been known to spread to numerous organ systems, including the lungs, skin, gastrointestinal tract and especially the liver, which is frequently the primary site of metastasis for uveal melanoma.4 Depending upon the physical findings, specific ancillary tests may consist of a chest X-ray or computed tomography (CT), cellular hematology and liver enzyme studies. The most sensitive tests of hepatic function include serum alkaline phosphatase, glutamic-oxaloacetic transaminase, lactic dehydrogenase and gamma-glutamyl transpeptidase. Genetic profile testing can also serve as a good prognostic indicator. Higher rates of metastasis have been found in those with chromosome 3 loss (i.e., monosomy 3), chromosome 8 gain, chromosome 6p gain and chromosome 1p loss.33
Therapy for choroidal melanoma has changed radically in the last four decades. Until the late 1970s, enucleation was considered the only definitive treatment and the best option for survival among those with ocular melanoma. In 1978 a pivotal paper by Zimmerman and associates challenged conventional thinking, suggesting that enucleation might actually contribute to systemic metastasis.30,34 This article and another subsequent publication35 provided the impetus to develop alternative therapies for choroidal melanoma, most notably radiotherapy and tumor resection.
Today, therapy for choroidal melanoma is dictated primarily by the size of the lesion. The Collaborative Ocular Melanoma Study (COMS) defined tumors as small (5-16mm in basal diameter and 1.0-2.5mm in height), medium (<16mm diameter and 2.5-10.0mm in height) or large (>16mm diameter and/or >10mm in height).36 The treatment recommendation of the study for small tumors was simple observation, with pharmacologic therapy initiated if any sign of growth or visual compromise is encountered. Focal laser photocoagulation, cryotherapy and more recently, transpupillary thermotherapy (TTT), have been employed successfully for selected small melanomas,although TTT as a stand-alone therapy is probably inadequate.37-39
For some small melanomas, as well as the majority of medium-sized choroidal melanomas, radiation remains the treatment of first choice.37 Brachytherapy—in which a plaque with embedded radioactive material is temporarily sutured to the episclera overlying the tumor—is the most common method used today.40 Another approach, employing charged particle irradiation (a.k.a., external beam irradiation) may also be employed for certain tumors. Overall, the success rates and complications (including radiation retinopathy and cataract formation) for plaque therapy and external beam therapy are similar. However, since external beam irradiation does not require surgery, it may be preferred in some cases.
Another treatment option for small- and medium-sized tumors is block excision, which involves a local resection of the tumor using a partial lamellar sclerouvectomy technique.39 This procedure may offer advantages over radiation therapy with regard to collateral tissue damage, but it is also quite involved and carries significant risk for surgical complications, including retinal detachment. Local resection of choroidal melanoma is preferred for smaller, more anteriorly located tumors.39
Despite controversy, enucleation is still used for the treatment of some large uveal melanomas. It has been suggested that enucleation is indicated in the following settings: (1) in a patient who, after being informed of the diagnosis, requests this operation; (2) in a patient with a tumor involving over 40% of ocular volume; (3) after treatment with an alternative modality that has failed; and (4) in patients with significant ocular neovascularization before any therapy.4 As a matter of protocol, when enucleation is performed on an eye with melanoma, care is taken not to clamp the optic nerve or aggressively handle the eye, in an effort to reduce potential tumor seeding and metastasis.37 For those advanced tumors that demonstrate massive extrascleral extension into the orbit, and in which the eye is blind and painful, eyelid-sparing orbital exenteration is typically justified.41
• While the majority of choroidal melanomas occur in older, white individuals, younger patients and those of African or Asian descent are not immune. Our experience has shown that melanomas can affect a wide range of demographics. Delayed diagnosis can make the overall prognosis far worse.
• An emerging, valuable tool in the differential diagnosis and management of nevi and choroidal melanomas is enhanced depth imaging optical coherence tomography (EDI-OCT). EDI-OCT appears to have greater sensitivity than standardized ultrasonography with regard to tumor thickness, and can also provide information regarding subretinal fluid, subretinal lipofuscin deposition, and retinal irregularities (e.g., “shaggy photoreceptors” which are consistent with melanoma).42
• The Collaborative Ocular Melanoma Study, initiated in 1986, has yielded some interesting results. In one of the COMS trials, comparable survival rates were observed for individuals with medium-sized melanomas undergoing radiotherapy vs. enucleation.43 In another trial, pre-enucleation radiotherapy for large tumors did not appear to significantly alter the rate of survival as compared to those who underwent enucleation alone.44 These results have forced experts to again ponder the issues raised by Zimmerman in 1978—namely, whether enucleation, as a treatment option for choroidal melanoma, is a better or worse option in the long run.
• In recent years, intravitreal anti-VEGF agents such as bevacizumab have been widely administered for a variety of choroidal and retinal disorders, including “wet” macular degeneration, clinically significant macular edema and some proliferative vitreoretinopathies. In the case of choroidal melanoma, despite speculation and positive results from experimental animal models, these agents appear to be of little clinical value. In a recent report, three patients who were inadvertently treated with bevacizumab due to misdiagnosis experienced tumor progression with complications in the form of gliotic/fibrotic membrane formation.45
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