Ocular Melanoma

Disease Overview

Summary

Ocular melanoma is an extremely rare type of cancer that occurs in about 5 out of every million adults. Despite its rarity, it is the most common primary cancer of the eye in adults. A primary cancer means that the cancer begins in the eye itself and has not spread there from another part of the body. The exact cause of ocular melanoma is unknown, but several risk factors have been identified, including genetic factors and possibly environmental influences. Despite this uncertainty, early detection and treatment are crucial for the best outcomes.

Introduction

Eye (ocular) cancer can refer to any cancer that starts in the eye.

The eye is a complex organ with three main parts:

Eyeball (globe): The main part of the eye, filled with a jelly-like substance called vitreous humor. It has three layers:
- Sclera: The tough, white outer layer
- Uvea: The middle layer, responsible for nourishment and containing the eye’s pigmented cells
- Retina: The innermost layer, which senses light and is crucial for vision
Orbit: The tissues surrounding the eyeball
Adnexal structures: These include accessory parts like the eyelids and tear glands

Different types of cancer can develop in these areas depending on the type of cells involved. Ocular melanoma typically arises from cells called melanocytes, which produce pigment. When these melanocytes in the choroid become cancerous, the condition is known as choroidal or uveal melanoma. Although these melanocytes are similar to those in the skin, skin melanoma and ocular melanoma are distinct conditions, each with different biological and genetic characteristics. It is rare for skin melanoma to spread to the eye or vice versa.

Uveal melanomas

Ocular melanoma can start at the uveal tract, the colored layer of tissue beneath the white of the eye (sclera). The uvea consists of three parts:

Iris: The colored part of the eye which surrounds the pupil
Ciliary body: A ring of muscle tissue that releases aqueous humor (a clear fluid) and helps control the lens’s shape for focusing
Choroid: The largest part of the uveal tract, located at the back of the eye beneath the retina. This area is rich in blood vessels and pigmented cells.

Most ocular melanomas develop in the choroid or ciliary body. About 9 out of 10 intraocular melanomas occur in these areas. Iris melanomas are less common and usually easier to detect because they often start as a dark spot on the iris that grows over time. Iris melanomas are generally slow-growing and rarely spread, leading to a relatively good prognosis.

Uveal melanomas can spread through the bloodstream, most often reaching the liver, where the cancer can become life-threatening.

Conjunctival melanomas

The conjunctiva is a thin, clear layer covering the sclera. Conjunctival melanomas are extremely rare but tend to be more aggressive. They can grow into nearby structures and spread through both the blood and lymphatic systems, reaching distant organs like the lungs, liver or brain.

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Synonyms

OM
eye melanoma

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Subdivisions

uveal melanoma
conjunctival melanoma

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Signs & Symptoms

Ocular melanoma may or may not cause symptoms, depending on where the tumor is in the eye, its size, and whether it affects the retina. Sometimes, ocular melanoma doesn’t cause any noticeable symptoms for many years, meaning it can be “clinically silent.” However, when symptoms do appear, they might include:

Blurred vision
Double vision
Irritation or pain in the eye
Seeing flashes of light
Reduced field of vision or loss of vision

Other possible symptoms include:

Sensation of something in the eye like a speck of dust (known as floaters)
Redness in the eye
Bulging or displacement of the eye
Change in the shape of the pupil
Increased pressure within the eye
Distorted vision, where straight lines appear wavy or parts of a grid seem to be missing

If the melanoma develops in the choroid (the layer beneath the retina), it can cause the retina to detach, which can lead to vision problems. If it occurs in the ciliary body (the part of the eye that controls the lens) it can displace the lens, leading to blurry vision or a sudden change in a patient’s eyeglass prescription.

Ocular melanoma has the potential to spread to other parts of the body, a process known as metastasis. Estimates suggest that in 40-50% of people with ocular melanoma the cancer will metastasize. The liver is the most common organ affected, with about 80% of cases spreading there, though it can also spread to the lungs, skin, soft tissues and bones. This spread can happen as early as 2-3 years after the initial diagnosis, but sometimes it can occur decades later. The symptoms of metastasis depend on where the cancer has spread and how long it has been there.

Metastasis is a serious complication and can be difficult to treat, often leading to a poor prognosis. However, recent advances in treatment have shown success in certain patients. The risk of metastasis can vary depending on where the melanoma starts in the eye. For example, melanomas in the iris are less likely to spread compared to those in the ciliary body or choroid. Advances in genetic testing now allow doctors to better assess an individual’s risk of metastasis, regardless of the tumor’s size or location.

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Causes

The exact cause of ocular melanoma is still not fully understood. Researchers think that a combination of genetic and environmental factors may contribute to the development of this rare eye cancer. It is thought that changes or errors in the DNA of melanocytes, the pigment-producing cells in the eye, lead to the formation of cancer. DNA is the material that carries our genetic information and abnormalities in DNA can cause cells to grow uncontrollably, leading to cancer.

Several risk factors have been identified that may increase a person’s likelihood of developing ocular melanoma:

Light-colored eyes and fair skin: People with these features, especially those who burn easily or cannot tan are at a higher risk.
Dysplastic nevus syndrome: Also known as atypical mole syndrome, this condition increases the risk of developing both skin and eye melanomas.
Atypical or common cutaneous nevi: These are unusual moles or “eye freckles” that can sometimes become cancerous.
Family history: Some families have BAP1 cancer predisposition syndrome, which increases the risk of ocular melanoma.

While exposure to ultraviolet (UV) rays from the sun is a well-known risk factor for skin melanoma, its role in ocular melanoma is less clear. Research has not definitively linked UV exposure to ocular melanoma and if UV rays do play a role, their impact is likely less significant than in skin cancer.

Scientists have found that certain genetic changes are more common in people with ocular melanoma. For example:

Chromosome abnormalities: Changes on chromosomes 3, 6, 8 and 1 have been observed in some tumors. Chromosomes carry our genetic information and abnormalities can lead to cancer.
BAP1 gene variants: This gene normally helps control cell growth and prevent cancer. However, in some people with ocular melanoma, either the BAP1 gene is missing (due to a loss of part of chromosome 3) or it is altered. Variants in this gene are associated with larger tumors and a higher risk of the cancer spreading.
Other gene variants: Changes in genes like EIF1AX, SRSF2/SF3B1, GNAQ, GNA11, PLCB4 and CYSLTR2 are also more common in individuals with ocular melanoma.

Research into the genetics of ocular melanoma is ongoing with the goal of finding more targeted treatments.

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Affected populations

Ocular melanoma is the most common primary eye cancer, but it is still quite rare, affecting about 2,500 people in the United States each year. The incidence is estimated at 5-6 cases per million people.

This cancer can occur in males and females and across all ethnic groups, but it is most common in older adults, particularly people in their 60s and 70s. Ocular melanoma is about 8-10 times more common in Caucasians than in people of African descent. Although rare in children, it can occur. Overall, ocular melanoma accounts for about 3%-4% of all melanoma cases, making it less common than melanoma of the skin.

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Disorders with Similar Symptoms

Several other eye conditions can have symptoms similar to those of ocular melanoma, which can make diagnosis challenging:

Orbital lymphoma: The most common primary cancer of the eye socket
Benign tumors: Such as choroidal hemangioma (a collection of blood vessels) or choroidal osteoma (abnormal bone formation in the eye)
Uveal tumors: Such as leiomyosarcomas and rhabdomyosarcomas which may resemble ocular melanomas
Retinoblastoma: The most common intraocular tumor in children
Choroidal nevus: A benign counterpart to ocular melanoma which may need to be monitored for signs of becoming cancerous
Secondary eye cancer: Cancer that starts in another part of the body like the lungs or breasts can spread to the eye. This is known as secondary eye cancer and can sometimes be mistaken for ocular melanoma. Lung and breast cancers are the most common types to spread to the eye.

Some eye conditions can mimic the appearance of ocular melanoma but are not cancerous:

Atypical bleeding in the choroid: This can create a “blood blister” that looks similar to melanoma.
Retinal detachment: When fluid collects under the retina it can cause an elevated area that resembles melanoma.

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Diagnosis

Diagnosing ocular melanoma involves identifying specific symptoms, taking a detailed medical history and performing a thorough eye examination. Many cases are discovered during routine eye exams when no symptoms are present. To confirm the diagnosis, an ocular oncologist, a specialist in eye cancers, will perform additional tests.

Several tests may be used to diagnose ocular melanoma:

Ophthalmoscopy: A routine eye examination using an ophthalmoscope which is a handheld instrument that contains a perforated mirror and lens and allows a doctor to see inside the eye and can also allow to take pictures which may detect an asymptomatic lesion
Ocular ultrasound: A test using sound waves to create images of the eye, helping to detect tumors
Fluorescein angiography: A test where a dye is injected into the bloodstream and special photos are taken to examine the eye’s blood vessels
Optical coherence tomography (OCT): A noninvasive imaging test that provides cross-sectional images of the retina and choroid, helping to locate and assess tumors
Fine needle aspiration biopsy: A procedure used in to confirm the diagnosis of an ocular tumor as well as to try and determine the genetic abnormalities of 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.

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Standard Therapies

Treatment depends on disease stage, tumor size, location of the tumor within the eye, specific symptoms, age and other factors. It may include radiotherapy, surgery and other procedures and therapies. Early detection and treatment can improve outcomes.

People who are affected with ocular melanoma may need to see several specialists. The medical team may include the 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.

Treatment options may include:

Observation (watchful waiting):

- For very small melanomas, particularly those under 12 mm in diameter and less than 2-3 mm in height, no treatment may be indicated.
- The observation involves regular monitoring every 2-4 months using imaging techniques like fundus photography, ultrasound and optical coherence tomography (OCT).

It is important to note that there is an increasing trend to treat even small melanomas earlier in many centers around the world to prevent progression.

Radiation therapy (RT): Produces damage to the tumor cells causing them to die and the tumor to slowly shrink in size

- Plaque brachytherapy: 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. It is the most common form of RT for ocular melanoma. The plaque is covered with gold, and it contains a radioactive source (like Iodine-125) that is delivered to the eyeball to target radiation to the tumor. This treatment is especially effective for small to medium-sized melanomas.
- Charged-particle RT (proton beam therapy): This external beam therapy is preferred for tumors encircling the optic nerve or those too large for brachytherapy.

- - Proton beam therapy: This procedure uses a machine outside of the body that delivers laser beams to the eye to destroy cancer cells delivering high-energy beams directly to the tumor, sparing the surrounding tissues. There are different types of external beam radiotherapy.
  - After the treatment, doctors recommend regular ophthalmologic examinations to monitor for complications and to assess if the treatment is working.

Laser therapies:

- Transpupillary thermotherapy (TTT): This technique uses a type of laser known as infrared diode laser to heat and destroy tumor cells. It is often used together with RT, but the tumor may come back (recur) in about 30% of patients after three years.
- Laser photocoagulation: Involves using high-temperature thermal energy to damage and shrink the tumor, however, due to the high rate of recurrence and complications, this method is used less frequently.

Surgical interventions:

- Local surgical resection: This procedure involves the removal of the tumor or affected tissue and, while it is effective in certain patients, particularly for iris melanoma, it has many risks of severe complications and local recurrence of the tumor.

- - This surgery is often combined with RT to reduce recurrence risk.

- Enucleation: This procedure involves the removal of the entire eye and it is generally reserved for large tumors.

- - It does not seem to be better than plaque brachytherapy but may be preferred for specific clinical reasons or patient preferences.

Advanced and metastatic treatment options:

- Tebentafusp-tebn (Kimmtrak): This medication was approved by the U.S. Food and Drug Administration (FDA) in 2022 for metastatic or uveal melanomas that could not be removed. This therapy targets patients who have the HLA-A*02:01 antigen, improving overall survival by mobilizing the immune system against cancer cells.
- Darovasertib: A “protein kinase C inhibitor” showing promise in increasing survival rates in patients with metastatic uveal melanoma.

Molecular genetic testing helps determine a patient’s risk of metastasis, guiding the frequency and type of surveillance required:

Low-risk patients: These patients, often with specific genetic markers such as disomy 3 or EIF1AX variants, are monitored annually with systemic imaging.
Medium-risk patients: Patients with markers like SF3B1 variants undergo more frequent imaging every 6 to 12 months for up to 10 years, followed by as-needed evaluations.

High-risk patients: This group, identified by factors such as monosomy 3, BAP1 variants, extensive tumor involvement, or ciliary body involvement, requires image tests every 3 to 6 months initially, then every 6 to 12 months in the following years.

The preferred image test to monitor the progression of the disease is MRI, though CT and ultrasound are alternatives for low-risk patients.

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 their case, a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preference and other appropriate factors.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Frenkel S, Rosenne H, Briscoe D, et al. Long-term uveal melanoma survivors: measuring their quality of life. Acta Ophthalmol. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29369538

Blasi MA, Pagliara MM, Lanza A, et al. Photodynamic therapy in ocular oncology. Biomedicines. 2018;6:E17. https://www.ncbi.nlm.nih.gov/pubmed/29414877

Mahendraraj K, Shrestha S, Lau CSM, Chamberlain RS. Ocular melanoma – when you have seen one, you have not seen them all: a clinical outcome study from the Surveillance, Epidemiology, and End Results (SEER) database (1973-2012). Clin Ophthalmol. 2017;11:153-160. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221652/

Farquhar N, Thorton S, Coupland SE, et al. Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. J Pathol Clin Res. 2017;4:26-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783957/

Yavuzyigitoglu S, Drabarek W, Smith KN, et al. Correlation of gene mutation status with copy number profile in uveal melanoma. Ophthalmology. 2017;124:573-575. https://www.ncbi.nlm.nih.gov/pubmed/27916271

Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017;11:279-289. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298817/

Robertson AG, Shih J, Yau C, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell. 2017;32:204-220. https://www.ncbi.nlm.nih.gov/pubmed/28810145

Rose AM, Luthert PJ, Jayasena CN, Verity DH, Rose GE. Primary orbital melanoma: presentation, treatment, and long-term outcomes for 13 patients. Front Oncol. 2017;7:316. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741819/

Schneider B, Riedel K, Zhivov A, et al. Frequent and yet unreported GNAQ and GNA11 mutations are found in uveal melanomas. Pathol Oncol Res. 2017;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/29209985

Vidoris AAC, Maia A, Lowen M, et al. Outcomes of primary endoresection for choroidal melanoma. Int J Retina Vitreous. 2017;3:42. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674241/

Gupta MP, Lane AM, DeAngelis MM, et al. Clinical characteristics of uveal melanoma in patients with germline BAP1 mutations. JAMA Ophthalmol. 2015;133:881887. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2290670

Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, et al. Ocular melanoma: an overview of the current status. Int J Clin Exp Pathol. 2013;6:1230-1244. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693189/

INTERNET
Patel DR, Blair K, Patel BC. Ocular Melanoma. [Updated 2024 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551647/ Accessed Aug 20, 2024.

Eye Cancer. American Cancer Society. March 2, 2023. https://www.cancer.org/cancer/types/eye-cancer/about/what-is-eye-cancer.html Accessed Aug 20, 2024.

Intraocular (Uveal) Melanoma Treatment (Health Professional Version). National Cancer Institute. May 12, 2023. https://www.cancer.gov/types/eye/hp/intraocular-melanoma-treatment-pdq Accessed Aug 20, 2024.

Carvajal RD. Management of metastatic uveal melanoma. UpToDate, Inc. April 3, 2024. Available at: https://www.uptodate.com/contents/management-of-metastatic-uveal-melanoma Accessed Aug 20, 2024.

Harbour JW, Shih HA. Initial management of uveal and conjunctival melanoma. UpToDate, Inc. June 4, 2024. Available at: https://www.uptodate.com/contents/initial-management-of-uveal-and-conjunctival-melanomas Accessed Aug 20, 2024

Mayo Clinic for Medical Education and Research. Eye Melanoma. Aug 9, 2022. Available at: https://www.mayoclinic.org/diseases-conditions/eye-melanoma/symptoms-causes/syc-20372371
Accessed Aug 20, 2024.

Porter D, Janigian RH Jr. What is Ocular Melanoma. American Academy of Ophthalmology. May 9, 2024. Available at: https://www.aao.org/eye-health/diseases/what-is-ocular-melanoma Accessed Aug 20, 2024.

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