Uveal Melanoma: Detailed Insights and Information

What is uveal melanoma?

Uveal melanoma is the most common primary intraocular malignancy in adults, and it develops from melanocytes in the uveal tract of the eye. The uveal tract, which includes the iris, ciliary body, and choroid, is the middle vascular layer of the eye and is responsible for supplying blood to the retina and other structures. Uveal melanoma is a serious and potentially fatal condition because of its ability to metastasize, particularly to the liver, even after successful treatment of the primary tumor in the eye.

Anatomy of the Uveal Tract

To understand uveal melanoma, one must first understand the basic anatomy of the uveal tract.

1. Iris: The iris is the colored part of the eye that regulates the diameter and size of the pupil, thereby controlling the amount of light that reaches the retina. It contains melanocytes, which are pigment-producing cells that can give rise to melanoma.
2. Ciliary Body: The ciliary body, located behind the iris, produces aqueous humor, the fluid that fills the anterior chamber of the eye. It also houses the ciliary muscle, which regulates the shape of the lens during focusing.
3. Choroid: The choroid is a layer of blood vessels and connective tissue located between the sclera (the white part of the eye) and the retina. It contains a high concentration of melanocytes and is the most common site for uveal melanoma development.

Pathophysiology Of Uveal Melanoma

Uveal melanoma develops from melanocytes, which produce melanin, the pigment that gives color to the skin, eyes, and hair. Melanocytes in the uveal tract can become malignant as a result of genetic mutations, environmental factors, or a combination of the two. This transformation causes uncontrolled proliferation of melanocytes, which forms a tumor.

1. Genetic Mutations: Uveal melanoma is associated with a number of genetic mutations. Mutations in the GNAQ and GNA11 genes are present in about 80-90% of uveal melanomas. These mutations activate the MAPK pathway, which promotes cell proliferation and survival. Other genetic abnormalities, such as mutations in the BAP1 gene, have been associated with an increased risk of metastasis.
2. Chromosomal Aberrations: Chromosomal alterations, particularly monosomy 3 (loss of one copy of chromosome 3) and chromosome 8q abnormalities, are strongly associated with a poor prognosis in uveal melanoma. Monosomy 3 is frequently associated with an increased risk of metastasis, especially to the liver.
3. Tumor Growth: Uveal melanoma usually develops as a dome-shaped mass in the uveal tract. As the tumor grows, it can cause a variety of ocular symptoms as it affects the surrounding structures. Tumor growth can cause retinal detachment, increased intraocular pressure, and, ultimately, vision loss. In some cases, the tumor may spread beyond the eye, infiltrating the sclera and surrounding tissues.
4. Metastasis: One of the most concerning aspects of uveal melanoma is its ability to metastasize. Despite successful local treatment of the primary tumor, uveal melanoma cells can spread to other organs, most commonly the liver, but also the lungs, bones, and skin. Metastasis affects approximately 50% of patients and is frequently associated with a poor prognosis.

Risk Factors and Epidemiology

Uveal melanoma is a rare cancer that affects approximately 5 to 6 million people each year. It primarily affects adults, with a median diagnosis age of approximately 60 years. There are several risk factors that increase the likelihood of developing uveal melanoma:

1. Race and Skin Type: People with lighter skin, light-colored eyes (blue or green), and Caucasians are more likely to develop uveal melanoma. It is uncommon in people of African or Asian ancestry.
2. Genetic Predisposition: A small percentage of uveal melanoma cases are in people who have a family history of the disease, indicating a genetic predisposition. Inherited mutations in genes such as BAP1, which is linked to other cancers such as mesothelioma and renal cell carcinoma, can increase the risk of developing uveal melanoma.
3. Environmental Factors: Although the role of ultraviolet (UV) radiation in the development of uveal melanoma is not as well established as it is for cutaneous melanoma, some studies suggest that UV exposure may increase the risk, especially in people with light-colored eyes who have less melanin to protect against UV damage.
4. Preexisting Ocular Conditions: Certain benign ocular conditions, such as choroidal nevi (pigmented lesions in the choroid) and ocular melanocytosis (increased pigmentation of the uveal tract), have been linked to an increased risk of uveal melanoma. Choroidal nevi affect up to 10% of the population, but only a small percentage of these lesions develop into melanoma.
5. Age and Gender: The incidence of uveal melanoma rises with age, and men are slightly more likely to develop it than women.

Clinical Features of Uveal Melanoma

The symptoms of uveal melanoma vary according to the tumor’s location and size. In many cases, the condition is asymptomatic in its early stages and is usually discovered by chance during a routine eye examination. However, as the tumor develops, it can cause a variety of ocular symptoms:

1. Visual Disturbances: The most common sign of uveal melanoma is a change in vision. Patients may experience blurred vision, visual field defects, or the appearance of floaters (small dots or lines that move across the field of vision). These symptoms are frequently caused by the tumor’s effect on the retina or the presence of subretinal fluid as a result of retinal detachment.
2. Photopsia: Photopsia, or seeing flashes of light, is another common symptom of uveal melanoma. This happens when the growing tumor mechanically stimulates the retina or when the retina detaches.
3. Visible Mass: In some cases, especially when melanoma develops in the iris or ciliary body, the tumor may appear as a dark spot or mass within the eye. The patient may notice this or an eye examination may reveal it.
4. Pain: Although uveal melanoma is typically painless, some patients may experience ocular discomfort or pain, especially if the tumor increases intraocular pressure (glaucoma) or invades the sclera.
5. Asymptomatic Cases: Many cases of uveal melanoma are asymptomatic, particularly in their early stages. These tumours are frequently discovered during routine eye examinations, emphasising the importance of regular ophthalmic check-ups, especially for those at higher risk.

Subtypes of Uveal Melanoma

Uveal melanoma can develop in any part of the uveal tract, and the clinical characteristics may differ depending on the tumor’s location:

1. Iris Melanoma: Iris melanomas are the least common subtype, accounting for only 5% of all uveal melanomas. They typically appear as a pigmented mass in the iris and are visible to the naked eye. Iris melanomas have a better prognosis than those that develop in other parts of the uveal tract because they are more likely to be detected early.
2. Ciliary Body Melanoma: Because they are located behind the iris and are not visible without special imaging techniques, iliary body melanomas are more difficult to detect. These tumors frequently grow to a large size before causing symptoms, resulting in a worse prognosis than iris melanomas.
3. Choroidal Melanoma: Choroidal melanoma is the most prevalent subtype, accounting for 85-90% of all uveal melanomas. These tumors frequently cause visual symptoms due to their impact on the retina and are discovered during a fundoscopic examination. Choroidal melanomas can grow large and are more likely to metastasize.

Complications from Uveal Melanoma

Uveal melanoma can cause a number of serious complications, both from the tumor and from treatment:

1. Vision Loss: As the tumor grows, it can cause retinal detachment, glaucoma, or direct invasion of the optic nerve, all of which can result in severe vision loss.
2. The most serious complication of uveal melanoma is metastasis. Metastatic spread is most common in the liver, then in the lungs and bones. Metastatic uveal melanoma has a poor prognosis, with few treatment options and a median survival time of less than a year from diagnosis.
3. Secondary Glaucoma: Tumors that invade the anterior chamber angle or cause inflammation can result in secondary glaucoma, which is characterized by increased intraocular pressure and potential optic nerve damage.
4. Ocular Disfigurement: In advanced cases, uveal melanoma can cause significant ocular disfigurement as a result of tumor growth, scleral invasion, or enucleation (eye removal) during treatment.

Diagnostic methods

To confirm and differentiate uveal melanoma from other ocular conditions, a combination of clinical evaluation, imaging studies, and, in some cases, biopsy is required.

Clinical Evaluation

1. Comprehensive Eye Examination: During a comprehensive eye examination, the ophthalmologist thoroughly examines the anterior and posterior segments of the eye. The slit-lamp biomicroscopy provides a detailed view of the iris, ciliary body, and lens. When examining the fundus, the ophthalmologist looks for pigmented lesions, irregularities, or masses in the retina and choroid that may indicate the presence of a melanoma. The size, shape, and color of any observed lesions are recorded, as these characteristics can aid in distinguishing benign from malignant growths. This examination may also reveal the presence of subretinal fluid, retinal detachment, or orange pigment clumping, all of which are commonly associated with uveal melanoma.
2. Indirect Ophthalmoscopy: Indirect ophthalmoscopy gives the ophthalmologist a broader view of the retina and allows him to examine the peripheral retina for signs of tumor spread or secondary effects like retinal detachment. This method is especially useful for visualizing tumors in the eye’s periphery that are difficult to see with direct ophthalmoscopy.

Imaging Studies

1. Ultrasound Biomicroscopy (UBM): UBM is an imaging technique that uses high-frequency ultrasound to create detailed images of the eye’s anterior segment, which includes the iris and ciliary body. It is especially useful for detecting tumors that are not visible under a slit lamp, such as those located in the ciliary body or the anterior choroid. UBM can provide information about the tumor’s size, shape, and internal characteristics, which can help distinguish between benign and malignant lesions.
2. B-scan Ultrasonography is an important diagnostic tool for uveal melanoma. This non-invasive technique employs sound waves to generate cross-sectional images of the eye, allowing the clinician to determine the tumor’s size, location, and internal structure. B-scan ultrasound is especially useful for detecting tumors that are difficult to see with standard ophthalmoscopy, such as those in the posterior choroid. The echogenicity (reflectivity) of the tumor can reveal information about its nature, as most uveal melanomas have low-to-medium internal reflectivity on ultrasound.
3. Fluorescein Angiography (FA): An intravenous injection of fluorescein dye highlights the blood vessels in the retina and choroid. This imaging technique is especially useful for determining the vascularity of the tumour and detecting any associated retinal abnormalities, such as leakage or choroidal neovascularization. In uveal melanoma, FA may have irregular filling patterns, areas of hyperfluorescence due to leakage, and fluorescence blockage caused by the tumor.
4. Indocyanine Green Angiography (ICGA): ICGA is similar to FA, but it uses indocyanine green dye, which is more readily absorbed by the choroidal vasculature. ICGA provides detailed imaging of the choroidal blood vessels, which is especially useful for detecting deeply pigmented tumors or those located in the posterior choroid. This technique assesses the tumor’s blood supply and detects any feeder vessels, which can help with treatment planning.
5. Optical Coherence Tomography (OCT): OCT is a non-invasive imaging technique for obtaining high-resolution cross-sectional images of the retina and choroid. It is especially effective at detecting retinal abnormalities associated with uveal melanoma, such as subretinal fluid, retinal edema, or detachment. Enhanced depth imaging OCT (EDI-OCT) can also be used to visualize the choroid and measure tumor thickness, providing more information about its size and potential impact on surrounding tissues.
6. Magnetic Resonance Imaging (MRI): When the diagnosis is unclear or there is concern about extraocular extension, MRI can be used to obtain detailed images of the eye and orbit. MRI is especially useful for visualizing the soft tissues of the eye and surrounding structures, and it can aid in distinguishing uveal melanoma from other ocular tumors or diseases. Gadolinium-enhanced MRI can reveal additional details about the tumor’s vascularity and extent of spread.

Biopsy & Histopathology

1. Fine Needle Aspiration Biopsy (FNAB): In some cases, a biopsy may be required to confirm the diagnosis of uveal melanoma, particularly if imaging findings are unclear. FNAB involves extracting a small sample of cells from the tumor with a fine needle for cytological analysis. While FNAB can provide a definitive diagnosis, there is a risk of complications such as intraocular hemorrhage or tumor seeding, so it is typically reserved for cases where the diagnosis is uncertain.
2. Histopathological Examination: If the tumor is surgically removed, a histopathological examination is carried out to confirm the diagnosis and evaluate the tumor’s characteristics. The examination includes determining the tumor’s cell type (spindle, epithelioid, or mixed), mitotic activity, and the presence of any chromosomal abnormalities, such as monosomy 3, which is associated with an increased risk of metastasis.

Genetic Testing and Molecular Profiling

Genetic testing and molecular profiling are becoming more important in the detection and treatment of uveal melanoma. These tests can detect specific genetic mutations linked to the development and progression of uveal melanoma, including GNAQ, GNA11, and BAP1 mutations. Chromosomal analysis, especially for monosomy 3 and chromosome 8q gains, can provide important prognostic information and help guide treatment decisions.

Uveal Melanoma Management

The treatment of uveal melanoma is multifaceted and depends on a variety of factors, including the tumor’s size and location, the presence of metastases, the patient’s overall health, and the potential impact on vision. The primary goals of treatment are to control the primary tumor, prevent metastasis, and maintain as much vision as possible. Treatment options include eye-sparing therapies and more invasive procedures like enucleation.

Eye-Sparing Treatments

1. Plaque Radiotherapy (Brachytherapy): One of the most common treatment options for small to medium-sized uveal melanomas is plaque radiotherapy, also known as brachytherapy. This method entails suturing a small, radioactive plaque to the sclera above the tumor. The plaque delivers a large dose of radiation directly to the tumor while sparing the surrounding healthy tissues. The plaque stays in place for a few days before being removed. In the majority of cases, brachytherapy effectively controls the local tumor while also preserving the eye and, in many cases, some degree of vision. However, possible side effects include radiation retinopathy, optic neuropathy, and cataract formation.
2. Proton Beam Therapy: Proton beam therapy is another type of radiation therapy used to treat uveal melanoma, especially for larger tumors or those close to critical structures such as the optic nerve. Proton therapy uses charged particles (protons) to deliver a highly focused dose of radiation to the tumor while minimizing exposure to healthy tissue. This precision lowers the risk of side effects when compared to conventional photon-based radiation therapy. Proton beam therapy has demonstrated high rates of local control and is especially useful for tumors that do not respond to brachytherapy.
3. Transpupillary Thermotherapy (TTT): TTT is a laser-based treatment that uses infrared radiation to heat and kill tumor cells. It works best on small, thin melanomas and is sometimes used in conjunction with other treatments, such as brachytherapy. TTT is an outpatient procedure that is relatively noninvasive. However, it is typically reserved for specific cases because it is less effective for larger or thicker tumors.
4. Laser Photocoagulation: Laser photocoagulation is the use of a laser to coagulate the blood vessels that supply the tumor, effectively cutting off its blood supply and causing tumor necrosis. This method is typically combined with other treatments, such as brachytherapy or TTT, to improve the therapeutic effect. Laser photocoagulation is most commonly used for small, well-defined tumors and may not be effective for larger or more diffuse melanomas.

Enucleation

Enucleation, or surgical removal of the eye, is considered when the tumor is large and causing significant pain, or when other treatments are unlikely to be effective. Enucleation may also be required if the tumor has spread beyond the eye or threatens to invade nearby structures such as the optic nerve. While enucleation effectively removes the primary tumor and eliminates the risk of local recurrence, it causes loss of vision in the affected eye. Following enucleation, an orbital implant is typically used to keep the shape of the eye socket, and a prosthetic eye can be fitted for cosmetic purposes.

Adjuvant and Systemic Therapies

1. Immunotherapy: Immunotherapy is an emerging treatment option for uveal melanoma, especially in cases where metastasis is likely or has already occurred. Immune checkpoint inhibitors, such as pembrolizumab or nivolumab, have demonstrated promise in the treatment of metastatic uveal melanoma by improving the immune system’s ability to recognize and destroy cancer cells. However, the efficacy of immunotherapy in uveal melanoma is still being investigated, and it is usually used in clinical trials or as part of a combination therapy.
2. Chemotherapy: Chemotherapy has limited efficacy in treating uveal melanoma, especially the primary tumor. However, it may be considered for metastatic disease, particularly if all other treatment options have been exhausted. Chemotherapeutic agents, such as dacarbazine, have been used, but response rates are typically low, and side effects are severe. Chemotherapy is frequently combined with other treatments, such as targeted therapy or immunotherapy, to enhance results.
3. Targeted Therapy: Targeted therapies seek to block specific molecular pathways that promote tumor growth. Therapies targeting the MAPK/ERK pathway, such as MEK inhibitors, are under investigation for uveal melanoma. These therapies are especially important for tumors with specific genetic mutations, such as GNAQ or GNA11 mutations. Targeted therapies are frequently used in conjunction with other treatments and are usually reserved for advanced or metastatic cancers.

Follow-Up and Monitoring

Following the initial treatment, regular follow-up is required to monitor for local recurrence, metastatic spread, and treatment-related complications. Follow-up usually includes:

• Ophthalmologic Examinations: Regular eye exams are essential for detecting tumor recurrence or the onset of complications like radiation retinopathy or glaucoma.
• Imaging Studies: Regular imaging studies, such as liver ultrasound, MRI, or PET scans, are recommended to detect early signs of metastasis, especially in the liver, which is the most common site of uveal melanoma metastasis.
• Genetic and Molecular Testing: For patients at high risk of metastasis, genetic and molecular testing can help guide surveillance strategies and determine eligibility for adjuvant therapies or clinical trials.

Prognosis

The prognosis for uveal melanoma depends on a number of factors, including tumor size, location, genetic mutations, and the presence of metastasis. While most patients achieve local control with treatment, the risk of metastasis, particularly to the liver, remains a major concern. Early detection, appropriate treatment, and close monitoring are critical for improving outcomes and extending survival in uveal melanoma patients.

Trusted Resources and Support

Books

• “Ocular Oncology: Clinical and Pathological Basis of Tumor Diagnosis and Management” by Jerry A. Shields and Carol L. Shields: This comprehensive book provides in-depth information on the diagnosis and management of ocular tumors, including uveal melanoma. It is an essential resource for ophthalmologists and oncologists specializing in eye cancer.
• “Clinical Ophthalmic Oncology: Uveal Tumors” by Arun D. Singh and Bertil Damato: This book offers a detailed exploration of uveal tumors, including melanoma, with a focus on clinical management, diagnostic techniques, and emerging therapies. It is an excellent resource for clinicians and researchers involved in the care of patients with ocular malignancies.

Organizations

• American Academy of Ophthalmology (AAO): The AAO provides a wealth of information on eye health, including resources for patients and clinicians dealing with uveal melanoma. Their website offers access to educational materials, clinical guidelines, and the latest research in ophthalmic oncology.
• Ocular Melanoma Foundation (OMF): The OMF is dedicated to supporting patients with ocular melanoma by providing educational resources, promoting research, and advocating for better treatments. They offer patient support services, including a network for connecting with others affected by the condition, and information on clinical trials and emerging therapies.