Choroidal Melanoma

Michael W. Stewart, M.D.
Michael W. Stewart, M.D. is a Retina Specialist with Mayo Clinic Jacksonville.

Introduction

The choroid is the layer of the eye wall between the retina and sclera. The choroid has the highest blood flow in the body and is considered part of the uveal tract composed of the iris and ciliary body anteriorly and the Choroid posteriorly. Metastatic tumors of the choroids are the most common intraocular malignancy and are only slightly more common than melanoma. Choroidal melanoma is the most common primary intraocular malignant tumor.1 As a potentially lethal ocular conditions, melanoma is feared by both patients and physicians. Our understanding of choroidal melanoma steadily improved during the 20th century and ongoing studies continue to identify the most effective local treatments. The treatment of metastatic melanoma remains ineffective, but fortunately most choroidal melanomas are confined to the globe. This paper will discuss the epidemiology, diagnosis, and current available treatments of choroidal melanoma.

Epidemiology

The yearly incidence of choroidal melanoma in the United States is 6 to 7 cases per million people. There is a wide age variation from 3 per million per year in the under 50 age group to 21 per million per year in the over 50 age group.2 Sixty-five percent of melanoma patients are over the age of 50.3 Choroidal melanoma is rarely seen in children though they tend to have a slightly better prognosis than adults.

Choroidal melanoma is more common in whites than in other races.4 Whites are eight times more likely to have melanoma than African-Americans and three times more likely than Asians. Not surprisingly, the majority of cases occur in North America and Europe as choroidal melanoma is rarely diagnosed in Asia, Africa and Latin America.

Clinical and histopathologic evidence suggests that most melanomas arise from pre-existing, benign choroidal nevi. The prevalence of nevi is 1-2%5 and the incidence of malignant degeneration into melanoma is less than 1%. Though most patients with choroidal nevi can be counseled that their condition is likely benign, nevi should be evaluated yearly with ophthalmoscopy, photography and, if the tumor has observable thickness, ultrasound. Any signs of growth must prompt the examiner to consider the possibility of malignant change into melanoma.

Congenital ocular melanocytosis is probably the most important predisposing factor for melanoma development. Still the incidence in patients with congenital ocular melanocytosis is probably less than 5%.6 Patients with neurofibromatosis have an increased incidence of many cancers, including uveal melanomas.7 Despite these observations there are no clearly recognized genetic factors responsible for the development of melanoma, but some studies raise this possibility. There is no association between choroidal melanomas and the p16 related mutations found in cutaneous melanomas and there does not appear to be a familial tendency to develop uveal melanoma. Therefore, the genetic mechanism leading to the development of choroidal melanomas remains unknown.

Exposure to sunlight has been implicated in the development of iris melanomas but there is no convincing evidence to show that sunlight causes choroidal melanomas. Pregnancy accelerates the growth of existing melanoma perhaps through endocrine factors such as excess melanocyte-stimulating hormone.8

Three cell types are found in melanomas: spindle A, spindle B and epithelioid. The recently modified melanoma classification system recognizes 3 groups of uveal melanocytic tumors: spindle cell nevi, spindle cell melanomas and mixed cell melanomas.9 A study of patients with small melanomas showed that outcome following enucleation correlated with cell type, pigmentation, size, scleral extension and mitotic activity.10 Seddon identified five predictors of survival: number of epithelioid cells per high-powered field, largest tumor dimension, location of the anterior tumor margin, invasion to the line of transection and degree of pigmentation.11

The Collaborative Ocular Melanoma Study (COMS) studied enucleated eyes and reported tumor extension into the retina in 49%, the vitreous in 25% and the sclera in 64%.12 Treatment of both the sclera and choroid are important for medium and large tumors because intra- and episcleral tumor invasion is seen in 55.7% and 8.2% of patients.13

Diagnosis

Many melanoma patients have asymptomatic tumors discovered on routine ophthalmic examination. This fact emphasizes the importance of routine, periodic, dilated ocular examinations. Other patients with melanoma will be symptomatic, complaining of visual loss, photopsias and visual field defects. Decreased visual acuity from melanoma is usually due to tumor encroachment on the macula or optic nerve, an exudative retinal detachment or secondary cataract. Severe ocular pain, an unusual complaint, is due to secondary inflammation, extraocular extension or neovascular glaucoma.

The patient's clinical history helps define the level of visual disability but is sometimes not helpful in differentiating melanoma from other suspicious choroidal lesions. The past medical record may reveal a non-ocular malignancy, particularly breast or lung carcinoma, which would be more suggestive of a metastatic lesion. However, this information must be interpreted carefully as 6-10% of melanoma patients have another primary neoplasm. Diagnosis is based largely upon the clinical experience of the examiner and modern diagnostic tests. Important elements of the examination consist of indirect ophthalmoscopy, fluorescein angiography, scleral transillumination, b-scan ultrasonography and sequential diagnostic examinations. Using all these methods, the COMS reported a diagnostic accuracy rate of 99.7%.14 The differential diagnosis includes choroidal nevus, extramacular disciform scar, retinal pigment epithelial hypertrophy or hyperplasia, choroidal hemangioma, metastatic carcinoma and lymphoma.15

Some melanomas involving the posterior pole of the eye can be visualized with the direct ophthalmoscope but most require examination with an indirect ophthalmoscope through a dilated pupil. In fact indirect ophthalmoscopy is the most important diagnostic examination, leading to a correct diagnosis in more than 95% of melanoma cases. The classic indirect ophthalmoscopic appearance of a melanoma is a pigmented, dome or collar-button shaped tumor with or without an associated exudative retinal detachment (Figure 1). A collar-button configuration, signifying extension through Bruch's membrane, exists in only a minority of cases. Tumors are generally pigmented but one fourth are relatively non-pigmented or amelanotic. Exudative retinal detachments are seen with tumors more that 4 mm thick. Lipofuscin, an orange pigment, is characteristically seen at the level of the retinal pigment epithelium (RPE). Some large melanomas, especially those involving the ciliary body, have prominent episcleral feeder vessels called sentinel vessels.

Figure 1. Inferotemporal melanoma
with adjacent subretinal fluid.

The identification of a large initial tumor size, orange pigment (lipofuscin) on the tumor surface, the absence of drusen (deposits of the RPE) and the absence of RPE changes are suggestive of malignant growth.16 Conversely, signs of chonicity which include extensive drusen, hypopigmentation around the periphery of the lesion and choroidal pigmentation are more suggestive of a benign choroidal nevus. However, because of the risk of malignant degeneration, these lesions need to be followed carefully with sequential dilated fundus examinations, b-scan ultrasound and photography for evidence of growth and the development of suspicious signs that include exudative retinal detachment and lipofuscin deposition.

Less common presentations such as diffuse melanoma must always be suspected. This relatively flat, infiltrative tumor is less than 5 mm thick, covers at least 25% of the uveal tract and is difficult to diagnose. Its extrascleral extension rate is 50%.17

Some clinical findings are more suggestive of alternative diagnoses. Hemorrhage, though seen occasionally with large melanomas or those that break through Bruch's membrane, is more suggestive of an eccentric disciform scar, a ruptured macroaneurysm or a localized choroidal detachment. Multiple choroidal masses are more consistent with metastatic lesions or lymphoma. A tumor with an orange-pink color is more commonly a hemangioma or choroidal osteoma. Dark black pigmentation is rare and is more commonly seen with RPE hypertrophy, hyperplasia or melanocytoma. The absence of pigmentation, though seen with amelanotic melanoma, is more suggestive of a metastasic tumor or choroidal hemangioma. Significant intraocular inflammation is occasionally seen with large melanomas but is more suggestive of a primary inflammatory etiology.

Scleral transillumination is frequently used to evaluate tumors. It helps differentiate a melanoma from a choroidal effusion.18 Visual fields are not very helpful differentiating melanomas from nevi.

Fluorescein angiography is only moderately helpful with a 50% diagnostic accuracy rate. Some larger melanomas have an intrinsic tumor circulation, called double circulation, consisting of late staining of the lesion and multiple pin-point leaks at the level of the pigment epithelium (Figure 2).19 Angiography is more helpful in diagnosing lesions which simulate melanomas, such as retinal arterial macroaneurysms, disciform lesions (choroidal neovascular scars often seen in advanced age-related macular degeneration) or choroidal detachments (especially hemorrhagic detachments which simulate choroidal pigmentation).

Figure 2. Fluorescein angiogram showing both retinal and choroidal circulations.

Combined A-mode and B-mode ultrasonography is the most important ancillary test. The classic signs of melanoma seen with B-mode ultrasonography include an acoustically silent zone within the melanoma, choroidal excavation and acoustic shadowing of the orbit. The A-mode shows medium to low internal reflectivity. For tumors greater than 3 mm thick, combined A and B mode ultrasound is more than 95% accurate in diagnosing melanoma.20

Radiographic imaging with computerized tomography and magnetic resonance imaging is generally not helpful in establishing a diagnosis.

Fine-needle biopsy of a suspected melanoma has been described but is rarely done. Cytologic interpretation of the aspirate is difficult and tumor seeding of the needle tract has been reported.21,22 Biopsy is more commonly performed when the suspected diagnosis is a metastasis or other melanoma simulating lesion.

Often the most difficult lesions to distinguish from melanomas are pigmented lesions 1.5-3.0 mm thick. The evaluation of these small tumors involves many of the same factors as with medium-sized melanomas. The typical diagnostic dilemma is differentiating a small melanoma from a nevus.

Once a diagnosis of melanoma is established, a medical evaluation of the patient is performed for 2 main reasons. First, the general medical health of the patient needs to be known to see if he is an acceptable risk for surgical treatment. Additionally, 15% of melanoma patients will be found to have a second primary tumor within 10 years. If there exists any doubt as to whether the choroidal lesion is primary or metastatic then a thorough tumor work-up is indicated. The second purpose of the exam is to rule out metastatic lesions from the eye though, fortunately, few patients have metastatic melanoma at the time of diagnosis. Systemic work-up consists of a thorough history, physical examination and directed laboratory evaluation by an internist. Chest x-ray, CBC, and liver function studies are indicated. If the liver function is abnormal, then further investigation with ultrasound, CT or MRI is indicated.

Uveal metastases usually become manifest within 5 years but may occur decades later. The long delay may be due to a long doubling time of tumor cells and immunologic and hormonal influences. The most common metastatic site is the liver followed by lungs, skin and bone. The median survival time of melanoma patients with hepatic metastases is 5-7 months compared to 18 months for metastases to other sites.23 Treatment of metastatic choroidal melanomas with chemotherapy or immunotherapy has not been successful.24,25 Resection of solitary liver metastases has been reported.26

Treatment

There are multiple therapeutic approaches to choroidal melanoma. These depend upon the size and location of the tumor and the goals and biases of the physician and patient. Therapeutic approaches include local radiation with charged particles or episcleral plaque brachytherapy, tumor resection, enucleation and hyperthermia.16 The three most important determinants of success in melanoma treatment are survival, vision and quality of life.27

Prospective studies have shown that twenty-five percent of small melanomas (1.5 - 3.0 mm thick) followed for 5 years grew from small to medium or large.28 Previously, these tumors would be observed for signs of growth. However, waiting for a potentially fatal tumor to exhibit signs of growth is a concept discouraged in oncology. The recent identification of high-risk factors and the development of transpupillary thermotherapy have allowed physicians to become more aggressive by treating these lesions earlier without causing significant visual loss. The hope, though it is too early to be conclusive, is that earlier treatment will decrease the risk of extraocular metastases.

Transpupillary thermotherapy (TTT) is a promising new method for treating small melanomas. An infrared diode laser (810 nm) and a modified slit-lamp delivery system deliver energy through the pupil to the choroid. The long wavelength passes through most ocular tissues and pigments, including lutein and hemoglobin. It reaches the RPE and choroid where it is preferentially absorbed by melanin, which is found in high concentration in most melanomas. This causes an elevation of local tissue temperatures to 45-60°C resulting in tissue necrosis. Using subcoagulation energy levels, it takes at least 40 seconds to reach ablative tissue temperatures. Multiple, overlapping laser spots are placed to achieve confluent treatment over the tumor. TTT is capable of causing necrosis of tumors up to 3.9 mm in thickness (Figure 3A, Figure 3B).

Figure 3A. Small melanoma in posterior pole before treatment.
Figure 3B. Melanoma following TTT.

The exact mechanism by which hyperthermia destroys neoplastic tissue is unknown. It is believed that there exists an impaired tumor cooling system due to absent or aberrant vascular channels. Neovascular tissue then acts as a heat sink. However, not all melanomas respond equally well to treatment. Peripapillary tumors may require more retreatments or even enucleation. The visual acuity decreases in 43% of treated eyes especially those with tumors near the macula or optic nerve.29 TTT is most effective for mid-peripheral tumors with good baseline visual acuity. Because TTT is limited to the slit-lamp delivery system, it is not indicated in patients with medial opacities (such as cataracts or vitreous hemorrhage), small pupils or peripheral tumors.

TTT offers several appealing advantages over enucleation and radiation. The visual outcome following TTT may be better than with radiation because light, unlike radiation, can be finely focused on the tumor with less resultant collateral damage. Therefore, TTT avoids the radiation-related complications of cataract, retinopathy and optic neuropathy. However, cystoid macular edema can occur after TTT.30 TTT is more cost effective than enucleation and radiation as it involves outpatient treatment without the need for incisional surgery. Since there are fewer side effects, there is a tendency toward administering earlier treatment when it may have the greatest likelihood of favorably affecting mortality and morbidity.

TTT, however, is not without treatment failures. Intrascleral invasion of melanoma cells may survive treatment and become a focus for tumor recurrence, which carries a 2-3 fold higher rate of metastasis. Juxtapapillary tumors, in particular, may have the highest risk of recurrence. To reduce the risk of recurrence, some investigators propose a "sandwich" treatment where TTT treats the tumor apex and brachytherapy treats the tumor base.31 This combination therapy enables TTT to be used in tumors greater that 4 mm in thickness and, coupled with lower radiation doses, may decrease the risk of radiation related complications.32 However, because TTT has only been recently been introduced, 5 and 10 year post-treatment data are not yet available.29

Large melanomas (> 10 mm in thickness or > 1125 cm2 in basal area) are usually managed with enucleation.33 In 1882 Fuchs wrote that all choroidal melanomas were treated with enucleation and the only untreated cases were in the "old literature."1 Enucleation remains the treatment of choice for large melanomas of the choroid and ciliary body. These tumors remain too large for effective treatment with alternative methods. Unfortunately, affected patients have the poorest prognosis because the large tumors indicate a longer duration and more aggressive cytology.34 Despite enucleation, the 25-year morbidity rate for tumors with bases >100 mm2 is 63%.35

When enucleation is planned, the approach to the patient is crucial. This loss of an eye due to a potentially lethal tumor can be very upsetting to an asymptomatic patient. Enucleation raises fears of disfiguring surgery despite the fitting of a prosthesis. Also, patients fear poor vision or blindness in the fellow eye. Radiation therapy, on the other hand, causes concerns about residual viable tumor, poor vision and ocular discomfort and irritation. Considerable counseling time is required to answer the patient's questions and allay fears, and family members are encouraged to participate in the discussion. Patients are encouraged to take time to contemplate the decision for surgery and second ophthalmologic opinions are encouraged.

At the time of surgery, great care is taken to avoid enucleation of the wrong eye. The surgical eye is dilated and examined with the patient under anesthesia to confirm the tumorous eye. Following enucleation, 87% of patients reported no change in their ability to work, drive, read or view television. Fifteen years following enucleation, 90% of patients were driving and 96% could read.36

The COMS large melanomas (>10 mm in height, or >16 mm in diameter) study arm evaluated the effect of pre-enucleation external beam irradiation on long-term survival. The study concluded that radiation immediately prior to enucleation has no beneficial effect on preventing the development of metastases.

Medium sized tumors (300 mm2 _ 1125 mm2 basal area or 3-10 mm in thickness) present more of a therapeutic problem. Many factors such as age, general health, and vision in the involved and opposite eye must be considered. A patient with a medium sized tumor is also more likely to be asymptomatic.

In evaluating survival after enucleation for melanoma, Zimmerman reported a pre-operative mortality of 1%, rising to 4% during the first postoperative year, 8-12% the second year and tapering to 1-2% over the next 3-5 years. Zimmerman suggested that enucleation may have an adverse, rather than a beneficial effect, with respect to the development of metastatic disease from malignant melanoma of the choroid and ciliary body for many of the patients on which it was performed.37 Zimmerman attributed two-thirds of melanoma deaths to enucleation itself. He postulated that enucleation caused dissemination of tumor cells or a weakening of the immune system.38 Many other investigators have questioned this conclusion.

Many studies have shown a 5-year survival of 50% - 70% and a 10-year survival of 35%-65% following enucleation. These numbers led to the disappointing conclusion that enucleation was a relatively ineffective method for treating medium sized melanomas. Ellsworth stated that this 50% overall survival rate led to the evaluation of other treatment methods to spare the affected eye.39 From this, radiation plaque therapy, or brachytherapy, developed as an alternative treatment.

The first radiation therapy of choroidal melanoma was performed by implanting radon seeds directly into the tumor.40 The technique was then modified by placing the seeds episclerally.41

Cobalt plaques were successfully used but because of their high energy, surrounding tissues could not be adequately shielded.42 Currently the most common isotope, 125I radiation therapy is considered excellent for intraocular tumors because since it lacks alpha or beta rays, its penetrance allows the treatment of large tumors and the seeds are commercially available and can be reused.43 Radiation therapy causes tumor destruction in 2 ways:

  1. direct damage to the cell's DNA, preventing further cell division and multiplication.44
  2. damage to capillary endothelium, altering the tumor's blood supply.45
stewart2.jpg (44089 bytes) Figure 4A. Radioactive seeds imbedded within plaque. Figure 4B. Plaque being sutured onto sclera during surgery.

In preparing an eye for brachytherapy, the most important tumor measurement is the largest basal diameter since a 2mm margin of plaque around the base of the tumor is recommended to ensure adequate 125I treatment to the entire tumor. Measurements are best made by ultrasonography, transillumination or clinical comparison to the optic nerve. Radioactive plaques remain on the eye for 3-7 days depending upon the size of the tumor and rate of radiation delivery (Figure 4A and 4B). The recommended radiation delivery for 125I is 100 Gy to the tumor apex at a dose rate of 50-125 cGy/hr.46 Confirmation of the location of the plaque can be done intraoperatively with ophthalmoscopy or ultrasound47 or with postoperative MRI.48

The ongoing COMS randomized trial is investigating the efficacy of enucleation vs. 125I plaque brachytherapy for the treatment of medium sized melanomas. This study has closed to recruitment but survival statistics have not been reported.

The postoperative response to brachytherapy is best evaluated by clinical evaluation, color photography and ultrasound. Previously, shrinkage of the tumor to a flat scar was considered tumor regression49 but investigators now look for decrease in tumor height or failure of further growth.50 Early complications of plaque brachytherapy include transient exudative retinal detachment,51 hemorrhage, and cataract. The local recurrence rate of melanomas treated with 125I plaques is 4%.52

Up to 31% of eyes will develop radiation retinopathy or optic neuropathy.53 Radiation retinopathy is characterized by occlusive vascular disease from radiation-related endothelial damage to retinal vessels.54 The risk increases with the plaque's proximity to the macula or optic nerve. The 5-year incidence of radiation maculopathy following plaque therapy is 42% and for proliferative retinopathy is 8%. Factors predictive of radiation retinopathy include diabetes mellitus, tumor thickness greater than 5mm, and high radiation doses to the tumor base and apex.55 Manifestations of radiation retinopathy include capillary closure, telangiectasia, microaneurysms, hemorrhages, exudates, macular edema, vascular sheathing, disc pallor, disc edema and nerve fiber layer infarcts. Focal laser treatment has been shown to improve macular edema at 6 months but the results were not sustainable at 2 years.56

External beam irradiation of melanomas with charged particles, protons or helium nuclei, has been performed since 1975. Proponents praise the treatment's accuracy and ability to treat larger tumors, up to 30% of the ocular volume.57 Patients treated with proton beam irradiation had a 64% incidence of maculopathy for tumors within four disc diameters of the macula.58 This treatment is only available in selected centers in the U.S. and Europe.

Radiation therapy is about twice as expensive as enucleation ($13,500 vs. $7,300). There appear to be no significant quality of life differences between patients treated with radiation or enucleation.

Resection of choroidal melanomas has been reported. External resection is reserved for anterior tumors without evidence of retinal invasion. Internal resection has been reported but is controversial because of the concern over the dissemination of tumor cells. Neither surgical method has gained widespread acceptance.

Conclusion

The treatment of choroidal melanomas continues to evolve. Prospective studies are attempting to define the roles of enucleation and radiation in long-term survival. The introduction of TTT allows physicians to treat smaller tumors, at an earlier stage, with less associated visual loss and, hopefully, better survival. Most research efforts focus on the primary tumor since treatment of metastatic lesions remains disappointing.

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September, 2000/ Jacksonville Medicine

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