How to Manage Choroidal Melanoma: From Diagnosis to Treatment

Choroidal Melanoma: Diagnosis, Management, and Innovative Treatments

Choroidal melanoma is the most common primary intraocular malignancy in adults and poses significant risks both for visual function and survival. This rare but dangerous cancer arises from melanocytes within the choroid, the vascular layer of the eye. Although it accounts for approximately 85% of uveal melanomas, the rarity of the disease often means that diagnosis can be delayed, impacting treatment outcomes. Innovations in diagnosis and management have improved the prognosis for many patients, though the risk of metastasis, especially to the liver, remains high.

This article will delve into the diagnosis, management, and innovative treatment strategies for choroidal melanoma, with an emphasis on providing medical students and doctors a comprehensive understanding of the topic.

Understanding Choroidal Melanoma

Epidemiology

Choroidal melanoma is a rare disease, with an incidence of 5 to 7 cases per million people annually. It predominantly affects Caucasians, particularly those with lighter skin tones, blue or green eyes, and a family history of ocular or cutaneous melanoma. Unlike cutaneous melanoma, which is associated with UV exposure, choroidal melanoma has less definitive links to sunlight, though some research suggests that UV radiation may still play a role.

Pathophysiology and Genetic Factors

Choroidal melanoma arises from melanocytes in the uveal tract, particularly the choroid. Key genetic mutations are often implicated in its pathogenesis. The most common mutations involve the GNAQ and GNA11 genes, which regulate cellular signaling pathways involved in cell growth and differentiation. Another important genetic alteration is the BAP1 mutation, particularly in high-risk tumors that metastasize early.

The tumor’s biological behavior is dictated by these genetic mutations, which influence not only the rate of tumor growth but also the likelihood of metastasis, especially to the liver. Understanding these mutations has led to advancements in prognostication and the development of targeted therapies.

Clinical Presentation

Choroidal melanoma can present with a wide range of symptoms, depending on the size, location, and associated complications of the tumor. Early detection is crucial as the tumor’s initial stages are often asymptomatic, allowing for more conservative and vision-sparing treatments.

Common Symptoms:

• Blurred or distorted vision: Tumors growing near the macula may cause metamorphopsia (distorted vision) or progressive vision loss.
• Flashes of light and floaters: These symptoms arise from retinal involvement, either through physical traction or secondary detachment.
• Peripheral vision loss: Tumors located away from the macula may primarily affect the visual fields, leading to peripheral vision loss.
• Asymptomatic: Many patients are diagnosed incidentally during routine eye exams, particularly if the melanoma is located peripherally.

Late-stage Symptoms:

• Pain: Although uncommon, pain can occur in cases where the tumor invades surrounding structures, such as the sclera, or causes significant intraocular pressure.
• Vision loss: Larger tumors, particularly those near the optic nerve or macula, can cause severe and permanent vision loss.

Diagnosis of Choroidal Melanoma

Early and accurate diagnosis of choroidal melanoma is crucial for effective management and improved outcomes. Various diagnostic tools are used to evaluate the tumor, assess its growth, and differentiate it from other ocular conditions such as choroidal nevi, hemangiomas, or metastases.

1. Clinical Examination

Fundoscopic examination is the first step in diagnosing choroidal melanoma. Using an ophthalmoscope, an eye care professional can observe the tumor’s appearance. Choroidal melanoma typically appears as a dome-shaped or mushroom-shaped mass that may be pigmented or non-pigmented.

Key features:

• Orange pigment: Lipofuscin granules, often visible on the surface of the tumor, are a characteristic sign of choroidal melanoma.
• Subretinal fluid: Retinal detachment or the accumulation of subretinal fluid is common in larger tumors.
• Mushroom shape: This occurs when the tumor breaks through Bruch’s membrane, a sign that may indicate a more aggressive growth pattern.

2. Ultrasonography (B-Scan)

B-scan ultrasonography is one of the most valuable tools in the diagnosis of choroidal melanoma. This imaging technique provides information about the tumor’s size, shape, and internal characteristics. On B-scan, choroidal melanoma appears as an elevated, dome-shaped or mushroom-shaped mass with low-to-medium internal reflectivity.

3. Optical Coherence Tomography (OCT)

Optical coherence tomography (OCT) is a non-invasive imaging technique that provides high-resolution cross-sectional images of the retina and underlying structures. OCT is particularly useful for detecting subretinal fluid, macular edema, and retinal detachment, which are common in patients with choroidal melanoma.

4. Fluorescein Angiography (FA) and Indocyanine Green Angiography (ICG)

Fluorescein angiography (FA) and indocyanine green angiography (ICG) are used to assess the vascularity of the tumor. Fluorescein angiography shows how the tumor fluoresces over time, revealing leakage and neovascularization. Indocyanine green angiography, on the other hand, highlights the choroidal circulation, helping differentiate choroidal melanoma from other vascular tumors like hemangiomas.

5. Fine Needle Aspiration Biopsy (FNAB)

In some cases, particularly when the diagnosis is unclear or when genetic testing is needed for prognostication, a fine needle aspiration biopsy (FNAB) may be performed. This minimally invasive procedure involves collecting tumor cells for cytological analysis. Genetic profiling can identify mutations such as monosomy 3 or BAP1 loss, both of which are associated with a higher risk of metastasis.

6. Genetic Testing and Cytogenetics

Genetic testing has become an essential component in the management of choroidal melanoma, providing valuable prognostic information. Cytogenetic analysis can identify chromosomal abnormalities such as monosomy 3, which is linked to a higher likelihood of metastasis, particularly to the liver. Tumors with monosomy 3 or BAP1 mutations are classified as high-risk and may require more aggressive monitoring and treatment.

Management of Choroidal Melanoma

The management of choroidal melanoma involves balancing the goals of tumor control, preservation of vision, and prevention of metastasis. Treatment decisions are influenced by tumor size, location, metastatic risk, and the patient’s overall health.

1. Observation and Monitoring

In small, asymptomatic melanomas, particularly those less than 2 mm in thickness, observation with regular follow-up may be an appropriate option. These lesions may remain stable for long periods and may not require immediate intervention. However, serial monitoring using fundus photography, OCT, and ultrasonography is essential to detect any signs of tumor growth or activity.

2. Plaque Brachytherapy

Plaque brachytherapy is one of the most common treatments for medium-sized choroidal melanomas. It involves placing a radioactive plaque (typically made of iodine-125 or ruthenium-106) on the sclera, directly overlying the tumor. The plaque delivers localized radiation to the tumor while sparing surrounding healthy tissues.

• Success rate: Plaque brachytherapy achieves local tumor control in over 90% of cases.
• Side effects: While effective, this treatment can lead to complications such as radiation retinopathy, optic neuropathy, and cataract formation, particularly if the tumor is located near critical structures like the macula or optic nerve.

3. Enucleation

For large melanomas or those causing significant complications, enucleation, or surgical removal of the eye, may be necessary. Enucleation is also indicated when the tumor is unlikely to respond to radiation or when there is a high risk of metastasis. While enucleation effectively removes the tumor, it does not eliminate the risk of systemic spread, particularly to the liver.

• Prognosis after enucleation: Patients who undergo enucleation require lifelong surveillance for metastasis, as the risk remains even after removal of the primary tumor.

4. Transpupillary Thermotherapy (TTT)

Transpupillary thermotherapy (TTT) is a laser-based treatment that uses heat to destroy tumor cells. TTT is typically used for small melanomas, especially those located near the macula, where other treatments could result in significant vision loss. TTT may also be combined with plaque brachytherapy to enhance treatment efficacy.

5. Proton Beam Therapy

Proton beam therapy is a form of external radiation therapy that uses protons instead of X-rays to target the tumor. Proton therapy provides more precise radiation delivery, reducing damage to surrounding healthy tissues. It is particularly useful for tumors located near critical structures, such as the optic nerve or macula, where traditional radiation therapy may cause significant complications.

6. External Beam Radiation Therapy (EBRT)

External beam radiation therapy (EBRT) involves delivering high-dose radiation from an external source. It is typically reserved for large or inaccessible tumors that cannot be treated with plaque brachytherapy or TTT. While EBRT is effective in controlling tumor growth, it is associated with a higher risk of radiation-related complications, including radiation retinopathy and optic neuropathy.

7. Systemic Treatments for Metastatic Disease

Once choroidal melanoma metastasizes, particularly to the liver, the prognosis becomes poor. Historically, there have been limited options for treating metastatic uveal melanoma, but recent advances in systemic therapies are providing new hope.

• Immunotherapy: Drugs such as ipilimumab and nivolumab, which are checkpoint inhibitors used in treating cutaneous melanoma, are now being studied for metastatic uveal melanoma. Early results show some promise, although the response rates are lower than in cutaneous melanoma.
• Targeted therapies: Investigational drugs targeting mutations specific to uveal melanoma, such as BAP1 loss, are under development and offer potential for improving outcomes in high-risk patients.

Innovative Treatments for Choroidal Melanoma

Recent advancements in the understanding of choroidal melanoma biology have led to the development of innovative treatment strategies. These therapies aim to improve local tumor control, reduce metastasis risk, and minimize treatment-related complications.

1. Gene Therapy

Gene therapy is an emerging field in the treatment of choroidal melanoma. Researchers are exploring the use of gene-editing techniques to target specific genetic mutations (e.g., GNAQ and BAP1) that drive tumor growth and metastasis. By correcting these genetic defects, gene therapy holds the potential to halt tumor progression and reduce the likelihood of metastasis.

2. Immunotherapy and Combination Treatments

Immunotherapy, which harnesses the power of the immune system to target cancer cells, has shown promise in treating metastatic uveal melanoma. Combination therapies involving checkpoint inhibitors and targeted drugs are being explored to improve patient outcomes.

3. Advanced Imaging Techniques

New imaging modalities, such as optical coherence tomography angiography (OCT-A) and photoacoustic imaging, provide high-resolution views of tumor vascularity and blood flow. These innovations help in early diagnosis, monitoring treatment response, and assessing the risk of metastasis.

Prognosis and Long-Term Outcomes

The prognosis for patients with choroidal melanoma depends on several factors, including tumor size, location, genetic mutations, and the presence of metastasis.

• Small tumors: Early-stage tumors have an excellent prognosis, particularly when treated with brachytherapy or TTT. Local control rates exceed 90%, and many patients retain useful vision.
• Large tumors or metastasis: The prognosis worsens significantly if the tumor is large, involves the optic nerve, or has metastasized. Once metastasis occurs, particularly to the liver, the 5-year survival rate drops to approximately 15%.

Conclusion

Choroidal melanoma is a complex and potentially life-threatening ocular malignancy. Advances in diagnostic techniques, local treatment options such as brachytherapy and proton beam therapy, and emerging systemic treatments like immunotherapy are transforming the landscape of care for patients with this rare cancer. Early detection and personalized treatment strategies are essential for optimizing outcomes and preventing metastasis.