Choroidal Melanoma: Updates for a Challenging Disease

Prognostic biopsy and radiation attenuation represent fundamental strides in ocular oncology.

TARA A. MCCANNEL, MD, PhD

Choroidal melanoma is a rare and potentially fatal cancer that continues to be challenging in all respects. From the initial diagnosis, the retina specialist plays a key role in counseling patients, not only at the outset of their journey but also after treating the tumor, in managing the complications of radiation retinopathy, and in monitoring the patient for metastasis.

Retina specialists must familiarize themselves with not only the basics but also with recent advances in the field of ocular oncology. Most ocular melanoma patients and their families now educate themselves on the Internet.

INCIDENCE AND RISK FACTORS

Choroidal melanoma has an annual incidence of six cases per million people per year.¹ Other than having blue or green eyes and a light complexion, studies have not identified any definite risk factors or exposures that predispose patients to developing this cancer.

A recently potentially identified mutation in BAP1 has been associated with a cluster of familial cancers, which may include mesothelioma, prostate cancer, renal cell carcinoma, and, now, choroidal melanoma.²

MAKING THE DIAGNOSIS

Frequently patients receive referrals to retina specialists with the finding of a retinal detachment or an incidental pigmented lesion on fundus examination by the optometrist or general ophthalmologist.

Patients themselves may present with photopsias or blurred vision from the tumor or from associated retinal detachment. The physician must always consider choroidal melanoma in the evaluation of retinal detachment, especially when no retinal breaks, vitreous hemorrhage, or indeterminate lesion can be found.

Diagnosing a choroidal melanoma may be challenging in many cases because no single test exists that aids in the diagnosis. As a result, one of the most important parts of the evaluation is clinical examination with indirect ophthalmoscopy.

The Role of Imaging in Diagnosis

If the physician suspects choroidal melanoma, he or she can then use the ancillary diagnostic tests — ultrasound, fluorescein angiography, and OCT — to help support the diagnosis.

Classically, we are taught that ultrasonography of choroidal melanoma reveals a domed-shaped lesion of low to medium reflectivity by A-scan. However, many small choroidal melanomas may be highly reflective, and melanomas may also have irregular or diffuse shapes other than a dome.

In addition, we are taught that fluorescein angiography of choroidal melanoma reveals a “double-circulation.” However, this is rarely seen with most choroidal melanomas in the real world. Angiography usually reveals some degree of hyperfluorescence of the lesion, but many benign choroidal lesions may have a similar angiographic appearance compared to a choroidal melanoma.

Finally, OCT can reveal subtle subretinal and intraretinal fluid associated with a choroidal melanoma. However, benign choroidal lesions may also demonstrate overlying cyst-like cavitations, which may not represent true fluid leakage. OCT can image most choroidal melanomas, which frequently demonstrate intra- and subretinal fluid.

Beginning With Observation

At our center, we recommend close observation of suspicious indeterminate lesions for documented growth (both in height and basal dimensions) or for the development of subretinal fluid adjacent or distant to the lesion.

Although we feel that biopsy plays an important role in informing patients with choroidal melanoma of their prognosis for metastasis, biopsy performed purely for diagnostic purposes is rarely necessary, given the clinical information that we can obtain noninvasively.

If we see growth or development of serous exudation, we consider the lesion a choroidal melanoma, and we recommend brachytherapy with iodine-125 for local tumor control. We do not recommend treating small “suspicious” lesions due to the potential for unnecessary visual morbidity caused by the side effects of radiation.

Furthermore, no data have emerged that indicate that observing small or suspicious choroidal lesions increases a patient’s metastatic risk.

TREATING THE EYE

Treatments for choroidal melanoma may broadly be divided into enucleation and globe-sparing. Enucleation is usually performed for large tumors with poor vision. The Collaborative Ocular Melanoma Study definition of a large tumor — tumor height greater than 10 mm and largest basal dimension greater than 16 mm — may be a guideline to follow.³

However, experienced centers may be comfortable treating larger tumors with globe-sparing strategies. Such strategies almost always involve treatment with radiation. The most common form of radiotherapy in North America is brachytherapy with iodine-125.

A few centers perform proton beam radiotherapy, which offers the advantage of technically being able to treat very large tumors or tumors that involve more than 180º of the optic nerve that plaque could not safely treat. However, brachytherapy offers the advantages of fewer ocular surface and adnexal complications and lower rates of neovascular glaucoma.

METASTASIS FROM CHOROIDAL MELANOMA

The most devastating outcome for patients diagnosed with choroidal melanoma is metastatic disease. Approximately 50% of patients will develop and succumb to metastatic disease, which involves the liver in more than 90% of these cases and less frequently may develop in the lungs.⁴

Unlike cutaneous melanoma metastasis, in which multiple organs may develop metastatic disease, diffuse metastatic disease in choroidal melanoma is usually observed in the end stages of metastasis.

Although many patients with liver metastasis may receive focal therapies to reduce tumor burden, and a number of clinical trials may be available for certain patients, no proven cures exist for choroidal melanoma metastasis. It is critical to discuss metastatic risk from choroidal melanoma with patients from the outset.

PROGNOSTIC BIOPSY

Among the latest revolutions in the management of choroidal melanoma are the knowledge and ability to provide molecular prognostication regarding risk of metastatic development.⁵ Although UCLA was the first US center to offer prognostic biopsy routinely, many ophthalmic oncology centers now may offer biopsy for prognosis.

The physician can perform fine needle biopsy at the time of brachytherapy or enucleation to provide material for molecular analysis. The strongest risk factor associated with a poor prognosis for metastasis is monosomy 3 within the tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) can identify abnormalities on chromosome 3 and other chromosomal locations associated with high metastatic risk.⁶

In addition to tumor cytogenetics, the physician can also send biopsy material for gene expression profiling, which divides melanomas into class 1 (good prognosis) or class 2 (poor prognosis).

Counseling the Patient

Despite the lack of proven successful treatments for metastasis, patients indeed want to know prognostic information about their cancer.⁷ Furthermore, clinical trials exist in which patients at high risk for metastasis, as defined by prognostic biopsy, may receive chemotherapy before metastasis develops.

Although some specialists may decide to alter systemic screening for metastasis based on molecular prognostication, unpublished reports have emerged of patients developing metastatic disease despite their tumors being identified as low-risk class 1 melanomas.

It is critical to inform patients diagnosed with choroidal melanoma that determining prognosis by biopsy is possible and available at most ophthalmic oncology centers. A thorough discussion of the potential biopsy test results before treatment of the primary tumor is an imperative part of both educating the patient and the informed consent process.

We have not only found that patients want information about their tumors, although the information may not affect their medical management, but also that a poor prognostic test result does not result in depression.⁷

MANAGING COMPLICATIONS OF RADIOTHERAPY

Tumor Recurrence

A review of local treatment failure or tumor recurrence for globe-sparing choroidal melanoma therapy demonstrated that radiation treatment offered higher success rates than various forms of laser or surgical removal of the tumor.⁸

Among centers that have reported their success rates for radiation, successful treatment may be between 85% and 100% depending on the center, treatment modality, use of intraoperative ultrasonography for optimal plaque localization, and length of follow-up.⁹

Despite high success rates with radiation for tumor control, the potential side effects of radiation remain difficult to treat, and they may cause significant visual loss. Side effects can potentially affect all parts of the eye or adnexal structures.¹⁰ Larger tumors and those treated with proton radiotherapy may have a higher rate of neovascular glaucoma and adnexal complications, such as chronic dry eye, eyelid abnormalities, including loss of eyelashes, or epiphora from cannalicular damage.

Other intraocular complications include cataract and radiation retinopathy with macular edema or proliferative radiation retinopathy, resulting in vitreous hemorrhage.

Treating Radiation Retinopathy

Intravitreal anti-VEGF agents remain the most hopeful treatments for radiation maculopathy. However, few reports have suggested the treatments result in any lasting visual improvement.

A recent study by Shields et al suggested that frequent anti-VEGF use may help to suppress the development of radiation maculopathy.¹¹ Many patients may stop benefiting from intravitreal bevacizumab (Avastin, Genentech, South San Francisco, CA) once the macula edema evolves into foveal atrophy.

A new method to reduce radiation retinopathy is to decrease the exposure of healthy nontumor tissue within the eye at the time the tumor receives the radiation treatment.

In contrast to the use of bevacizumab and other agents that are administered after the damage from the radiation has occurred, a strategy that reduces radiation exposure from the outset may be more effective.

Silicone to Attenuate Radiation

Our group reported the radiation-attenuating effect of 1,000-cSt silicone oil as a vitreous substitute during brachytherapy with iodine-125 plaque.¹² As a result, at the time of brachytherapy, vitrectomy with placement of silicone oil could provide a shield to limit radiation exposure beyond the tumor receiving treatment.

When compared to patients who did not receive vitrectomy with 1,000-cSt silicone oil for radiation attenuation, patients who underwent radiation attenuation had less radiation retinopathy with an average of two years of follow-up.¹³ Our center has adopted this new treatment approach and offers it to patients with good visual potential.

RESOURCES FOR PATIENTS

Because “eye cancer” is rare, most patients have not heard of it before. One of the most important things that a retina specialist can be is the patient’s advocate: make sure patients see someone who can help them and give expert information, remind them to stay current with systemic surveillance, and communicate with the oncologist or internist. Providing reliable and informative resources may help patients learn about their cancer and offer ways to navigate the Internet for more information.

Several excellent sources of online patient information are the CURE OM, the Ocular Melanoma Foundation, and the Eye Cancer Network. All of these sites help to increase awareness, provide forums for education, offer guides to treatments, both ocular and systemic, and provide a framework for research funding in ocular melanoma to improve the lives of people affected by this disease. RP

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