June 13, 2022
Years published: 2018
NORD gratefully acknowledges Prithvi Mruthyunjaya, MD, MHS, Associate Professor of Ophthalmology, Ocular Oncology and Vitreoretinal Surgery; Director, Ocular Oncology Service, Byers Eye Institute at Stanford, and the Ocular Melanoma Foundation, for assistance in the preparation of this report.
Ocular melanoma is an extremely rare form of cancer that affects the eye with an incidence of 5 per million adults. Although rare, it is the most common primary cancer of the eye in adults. Primary means that the cancer began at that site (in this case the eye) and did not spread there from another part of the body. In most people, this cancer arises in a part of the eye known as the uveal tract. The uveal tract is the colored (pigmented) layer of tissue that is found beneath the white of the eye (sclera) and is composed of normally pigmented cells and blood vessels. In the front of the eye, the uvea is made up of the colored part of the eye (iris) and a circle of muscle tissue (ciliary body) that releases a transparent fluid (aqueous humor) into the eye and helps to control the shape of the lens. The largest area of the uveal tract is in the back part of the eye (choroid) which is located beneath the retina, the vision sensing portion of the eye. In most instances, ocular melanomas arise within the choroid. Ocular melanoma arises from cells called melanocytes, which are the cells of the body that produce pigment. Ocular melanoma is a cancerous (malignant) tumor that can potentially spread (metastasize) to other parts of the body, most often to the liver. The exact cause of this disorder is unknown, but several risk factors have been identified.
Although these choroidal melanocytes are similar to those cells found in the skin that produce skin pigment, when choroidal melanocytes transform into cancerous cells it is called choroidal (or uveal) melanoma. However, cutaneous (skin) melanoma and uveal (ocular) melanoma are distinct conditions which share the same name but are biologically and genetically very different diseases. It is extremely rare for skin melanoma to spread into the eye and nearly unheard of for ocular melanoma to spread to the skin.
Ocular melanoma may or may not cause symptoms. This generally depends on the exact location, size of the tumor within the eye, and if the tumor is causing secondary effects to the retina. An ocular melanoma may not cause any symptoms (clinically silent) for many years before symptoms begin. When symptoms develop they can include blurred vision, double vision (diplopia), irritation, pain, a perception of flashes of light in the eye (photopsia), a reduction in the total field of vision, and loss of vision. Additional symptoms that have been reported include a sensation of a foreign body like a speck of dust in the field of vision (floaters), redness, bulging or displacement of the eye (proptosis), a change in the shape of the pupil, and pressure within the eye. Some individuals may develop metamorphopsia, a distortion of vision where, when a person looks at a grid of straight lines, the lines appear wavy and parts of the grid appears blank.
When an ocular melanoma occurs in the choroid, this can lead to detachment of the retina, the nerve-rich membrane lining the back of the eyes. When an ocular melanoma occurs in the ciliary body, it can displace the lens of the eye causing blurry vision from cataract or a rapid change in eyeglass prescription (astigmatism).
An ocular melanoma has the potential to spread (metastasize) to other areas of the body. The liver is the most common organ in the body affected by metastasis of an ocular melanoma (80% of cases) but less often may involve the lungs, skin or soft tissue, and bone. Some estimates suggest that in 40-50% of individuals, an ocular melanoma will metastasize. Based on the aggressiveness of the particular tumor, as defined by clinical and genetic features, metastasis may be detected as early as 2-3 years after diagnosis and rarely as late as decades after treatment. Symptoms will depend upon what part of the body is affected and how long the metastasis has been present. Metastasis is a severe complication of the disease that has a high mortality rare due to lack of definitive treatments to eradicate all metastasis, though recent advances have shown success in certain instances.
There are some differences in metastatic risk based on where in the uveal tract the ocular melanoma develops. For example, iris melanomas have a very low rate of metastasis compared to ciliary body and choroidal melanomas. Advances in genetic testing of individual ocular melanoma tumors has helped to better customize a patient’s risk of developing metastasis independent of the tumor location or tumor size.
As with many forms of cancer, the exact, underlying cause of ocular melanoma is unknown. Researchers speculate that multiple factors including genetic and environmental ones play a role in the disorder’s development. Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In ocular melanoma, cancer arises from changes or errors in the DNA of cells called melanocytes (or pigment cells). Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.
Several risk factors have been identified in individuals with ocular melanoma including light- colored eyes, fair skin, and an inability to tan or skin that sunburns easily. People who have another disorder called dysplastic nevus syndrome (also called atypical mole syndrome) are at a greater risk of developing melanoma including ocular melanoma than people who do not have the disorder. Other conditions that increase the risk of developing ocular melanoma include atypical cutaneous nevi, common cutaneous nevi, cutaneous freckles, and iris nevi. Nevus or nevi are growths or marks on tissue such as the skin that are usually discolored and sometimes raised. They are sometimes described as an “eye freckle.” The concern with ocular nevi is whether there is a risk of the abnormal tissue becoming cancerous. Patients with a strong family history of systemic and ocular cancers may have a rare genetic mutation called the BAP1 cancer predisposition syndrome which may increase the risk of developing ocular melanoma.
Melanoma of the skin has been linked to exposure to ultraviolet (UV) rays from the sun. However, research on whether exposure to UV rays contributes to ocular melanoma is inconclusive. If UV rays do influence the development of an ocular melanoma, their impact is significantly less than in the development of melanoma of the skin.
Changes in a few genes have been noted to occur in some affected individuals than in people without an ocular melanoma. Researchers have shown that abnormalities on chromosomes 3, 6, 8, and 1 are common in these tumors. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females.
In approximately 50% of people there is a loss (deletion or monosomy) of genetic material on one chromosome 3. About 70% of people who experience the spread of cancer outside of the uvea (metastasis), have this monosomy. There is a gene located on chromosome 3 called the BAP1 gene. Sometimes, people with uveal melanoma do not have a monosomy of chromosome 3, but they have an altered (mutated) version of this gene. The BAP1 gene is a tumor suppressor gene, which is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Patients with an altered BAP1 gene tend to have larger tumor diameters, and higher rates of metastasis than people without this alteration. Ciliary body tumors are also more highly associated with BAP1 changes.
Researchers have also determined that other genes, namely EIF1AX and a SRSF2/SF3B1 combination gene also occur with greater frequency in individuals with ocular melanomas. Other genes that have been shown to occur with greater frequency in ocular melanoma than otherwise would be expected include the GNAQ, GNA11, PLCB4, and CYSLTR2 genes.
The genetics involving uveal melanoma are not fully understood and investigators are conducting research to better understand the underlying factors that contribute to tumor formation and growth in this disorder. As researchers uncover the genetic components of uveal melanomas this should lead to better, more targeted therapies.
Ocular melanoma is the most common primary cancer affecting the eye. However, it is a rare disorder and is estimated to be diagnosed in about 2,500 people in the United States each year. The incidence is unknown, but one estimate places it at about 5-6 people per every 1,000,000 people in the general population. This cancer can affect men and women and individuals of all ethnic or racial groups. It occurs most commonly in older individuals with the highest incidence in the seventh and eighth decade of life. However, ocular melanoma has been reported in children as well. The disorder occurs more often in people who are fair skinned and have lighter colored eyes. The rate of occurrence is 8-10 times higher in Caucasian individuals compared to people of African descent. Ocular melanoma accounts for about 3-4% of all people with melanoma and is less common than melanoma of the skin.
A diagnosis of ocular melanoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. In many individuals, an ocular melanoma is discovered during a routine eye examination by an optometrist or general ophthalmologist without any symptoms being present, but is confirmed by an ocular oncologist who specializes in the diagnosis and treatment of eye cancer.
Clinical Testing and Workup
An eye doctor may suspect ocular melanoma following a routine eye exam. Individuals may visit an eye doctor because of problems with vision or soreness in one eye. An eye doctor can detect a melanoma with a routine piece of equipment called an ophthalmoscope, a handheld instrument that contains a perforated mirror and lens and allows a physician to view structures of the eye. In other situations, special pictures are taken of the eye to assess general eye health which may detect an asymptomatic lesion which then requires further examination.
A physician may order a specialized ocular ultrasound examination of the eye. An ultrasound is a test that uses high frequency sounds waves to create pieces of organs and tissues of the body. A small device is rubbed over the skin by the eye or the eyelid. This device produces sound waves which bounce back (or echo) and are recorded and then converted into images by a computer.
Sometimes, a test called a fluorescein angiography may be used to aid in a diagnosis. During this test, a colored dye called fluorescein is injected into a vein in an arm. This dye will travel via the bloodstream to blood vessels in the eye. A small camera with special filters is used to take a series of pictures of the eye. The filters can detect the dye, which enables doctors to form a picture of structures of the eye to detect any damage or presence of a tumor.
Optical coherence tomography (OCT) is a noninvasive imaging test performed routinely. The computer detects alterations in light waves that give a cross sectional image of the retina and parts of the choroid. This can help determine the location and associated features of a choroidal nevus or a small choroidal melanoma.
Fine needle aspiration biopsy is used in some cases to confirm the diagnosis of an ocular tumor as well as to try and determine the underlying genetic abnormalities associated with the tumor, which can help doctors predict the risk of the cancer spreading (metastasizing) and help identify high risk patients. This test involves passing a thin, hollow needle through into the eye tumor through a delicate surgical procedure. The specimen can then be analyzed for with a variety of tests to determine the exact type of cancer cells and specific genetic testing.
The therapeutic management of individuals with ocular melanoma may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of eye disorders (ocular oncologists who are specially trained ophthalmologists), eye surgeons, physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), and other healthcare specialists. Psychosocial support for the entire family is essential as well.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific location of the tumor within the eye; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of radiation therapy, experimental therapies, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Very small melanomas may not require treatment, and physicians may recommend watch and wait. Watch and wait refers to when physicians follow a patient with a slow-growing disorder without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing therapies for many years. However, there is an increasing trend to treat even small melanomas earlier in many centers around the world.
Historically, the main therapeutic options have been radiation therapy or surgery. Procedures that use local radiation to destroy tissue and cancer cells (radiotherapy) such as brachytherapy are often used, especially for small- or medium-sized ocular melanomas. Radiation therapy produces damage to the tumor cells causing them to die and the tumor to slowly shrink in size. The most common method of treating the eye with radiation therapy is a process called brachytherapy, which may also be known as “plaque therapy,” endocurietherapy, or sealed source radiotherapy. During brachytherapy, radioactive material (implant) is placed on a small disk called a plaque. This disk is inserted into the eye socket next to or near the base of a tumor and secured to the outside of the eye. The disk is left in place for several days and then removed. Sometimes, external beam radiotherapy may be used with a specialized technique called proton beam radiation. This procedure uses a machine outside of the body that delivers laser beams to the eye to destroy cancer cells. There are different types of external beam radiotherapy. Both plaque brachytherapy and proton therapy are effective treatments for ocular melanoma.
In 2022, the U.S. Food and Drug Administration (FDA) approved tebentafusp-tebn (Kimmtrak) for adult patients with uveal melanoma that has spread (metastasized) or cannot be surgically removed. In order receive this therapy, a patient must have a blood test to determine if they have a specific human leukocyte antigen (HLA) called HLA-A*02:01.
Other procedures that have been used to treat ocular melanoma include the use of an intense, focused light (e.g. laser therapy) to heat and destroy tissue and cancer cells (laser photocoagulation) or the use of a different type of laser to heat and destroy tissue and cancer cells (transpupillary thermotherapy).
There are a variety of surgical techniques that are also used to treat ocular melanoma. Sometimes, physicians will recommend surgical removal (resection) of the entire affected eye (enucleation). Other times, physicians may recommendation surgical removal of the tissue that is affected by the disease (local resection). For example, an iris melanoma is often treated by surgical removal (resection) of the affected tissue.
There is no approved therapy treatment for metastatic disease arising from a uveal melanoma. Various therapeutic options have been tried in individuals or small series of patients. These treatments include chemotherapy, drugs that target the immune system to treat cancer (immunotherapy), the use of cold to destroy cancerous tissue (cryotherapy), drugs that targets specific proteins thought play a role in tumor growth, and surgery. None of these therapies have yet to show significant or lasting improvement. More research is necessary to find better therapies for individuals with uveal melanomas.
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