The uvea of the eye includes the choroid, ciliary body, and iris. Uveal melanoma is the most common malignant primary intraocular tumor in adults, making up approximately 95% of ocular melanomas, with conjunctival melanomas and orbit/eyelid melanomas comprising the remaining 5%.1
Despite presenting in roughly 2,500 new cases per year, uveal melanoma falls under the category of orphan diseases as its occurrence does not exceed 4,000 yearly cases.1 Therefore, it currently receives little funding from the National Institute of Health and the National Eye Institute.2
Much of the available data on uveal melanoma risk factors, treatments, and outcomes is thanks to the Collaborative Ocular Melanoma Study (COMS). COMS was a prospective multicenter trial that was funded and organized by the National Eye Institute in 1985 to evaluate the effectiveness of different interventions for patients with uveal melanoma.3
In the US general population, there are approximately five cases of choroidal melanoma per year per million.4 The choroid gives rise to 85 to 90% of all uveal melanomas, while the ciliary body accounts for 5 to 8%, and the remaining 2 to 5% of uveal melanomas involve the iris.5
Etiology of uveal melanoma
A proliferation of atypical melanocytes in the choroid, ciliary body, or iris forms a uveal melanoma.6 These malignant tumors typically arise from nevi and are the result of a series of gene mutations.
Genetic component
Specific oncogenes and tumor suppressor genes have been identified as risk factors for developing uveal melanoma. GNAQ and GNA11 are oncogenes that are present in 95% of patients with choroidal nevi and have the potential to mutate and turn on in association with uveal melanoma.
Epigenetics, such as environment and lifestyle, influence whether an individual carrying the GNAQ or GNA11 oncogene will develop a choroidal melanoma from a choroidal nevus. Somatic mutations in either GNAQ or GNA11 are found in 83% to 89% of uveal melanomas.2,7
Additionally, a choroidal nevus can develop into a choroidal melanoma if there are mutations to the BAP1, SF3B1, or E1F1AX tumor suppressor genes. In general, a tumor suppressor gene’s function in the body's immune cell response is to identify and destroy tumor cells.
A mutation in the BAP1 or other tumor suppressor gene demonstrates the highest risk for malignancy because it eliminates immune cells and causes the melanoma to enter a growth and metastatic phase.2
Risk factors for uveal melanoma
There are a range of risk factors for uveal melanoma, including:8,9,10,11
- Light iris color, light skin color, and tendency to burn rather than tan when exposed to sunlight
- Caucasians are about three times more likely than Asians to develop choroidal melanoma and at least eight times more likely than those of African descent
- Age over 50 years old
- Presence of multiple cutaneous nevi, especially dysplastic nevi
- Presence of a nevus of Ota on the conjunctiva
Risk factors for metastasis to the uveal tract include:12
- History of cancer
- Breast cancer carries the highest risk for metastasis to the eye in women
- Lung cancer carries the highest risk for metastasis to the eye in men
Presentation of uveal melanomas
In this section, we will cover the presentation and classification of the major types of uveal melanomas including:
- Choroidal
- Ciliary body
- Iris
Choroidal melanoma
Choroidal melanomas, also known as posterior uveal melanomas, typically present as a unilateral elevated gray-brown mass of the choroid with irregular margins. On rare occasions, a melanoma may have an amelanotic appearance.
Some choroidal nevi are difficult to distinguish from small choroidal melanomas. Shields et al. identified high-risk features predictive of growth in suspicious choroidal nevi that can be remembered using the mnemonic TFSOM-UHHD: “To Find Small Ocular Melanoma, Use Helpful Hints Daily.”13
TFSOM-UHHD:13
- Thickness > 2mm
- Fluid subretinal
- Symptoms of flashes or floaters
- Orange pigment (lipofuscin)
- Margin within 3mm (1 disc diameter) of the optic nerve head
- Ultrasound Hollow
- Halo absent: A halo of depigmentation surrounding a pigmented choroidal lesion is more commonly seen in nevi and congenital hypertrophy of the retinal pigment epithelium (CHRPE) and indicates stability
- Drusen absent: Drusen overlying choroidal lesions suggest a longstanding lesion
Choroidal melanoma size and thickness
The size and thickness of a choroidal melanoma are considered to be the most important clinical features in determining prognosis and treatment strategy.
Size is classified into three categories according to COMS:3
- Small: 5mm to 16mm in basal diameter and/or < 2.5mm in height
- Medium: < 16mm diameter and/or 2.5 to 10.0mm in height
- Large: > 16mm diameter and/or > 10mm in height
Metastatic risk increases with each milliliter of tumor thickness. Choroidal melanocytic tumors that display none of the risk factors from the TFSOM-UHHD mnemonic are most likely choroidal nevi and have a 3% chance for growth at 5 years. Tumors that possess one risk factor have a 38% chance of growth, and those with two or more factors have the potential to show growth in over 50% of cases at 5 years.14
Ciliary body melanoma
Melanomas of the ciliary body are the most difficult uveal melanoma to find and typically require a dilated exam with views extending to the pars plana. After dilation, the tumors typically present as a dome-shaped mass with variable pigmentation, which can extend to the iris or to the posterior pole of the eye. Dilation of the episcleral vessels feeding into the area of the tumor, also known as sentinel vessels, is another high-risk indicator.
Patients with ciliary body melanomas may report blurry vision due to induced astigmatism or lens dislocation from the growth of the melanoma, hazy vision from a hyphema, floaters from a vitreous hemorrhage, painless visual field loss, or pain as a result of an acute angle closure.15 Similar to choroidal melanoma, the size of the tumor is the most important factor.
The classification for ciliary body melanoma size is as follows:16
- Small: Diameter is ≤ 11mm
- Medium: Diameter is 11 to 15mm
- Large: Diameter is > 15mm
Ciliary body melanomas are often relatively large when diagnosed. They are rarely diagnosed alone and are more often associated with choroidal melanoma or iris melanoma due to a local extension. Generally, patients with ciliary body melanoma are asymptomatic for an extended period and are often diagnosed when metastasis is already present, more so than other uveal melanomas.
Metastasis appears earlier in patients with ciliary body melanoma than other types of uveal melanomas due to their long and silent evolution and the rich vascularization of the ciliary body.6
Iris melanoma
Iris melanomas develop from an iris nevi and present as an elevated pigmented mass on the iris.
There are several clinical variations of iris melanomas, including circumscribed, diffuse, and tapioca:17
- A circumscribed iris melanoma appears as a variably pigmented, well-defined mass in the iris stroma and is usually found in the inferior half of the iris.
- Diffuse iris melanomas present with progressive iris discoloration, accumulation of pigment in the anterior chamber, and disappearance of iris crypts.
- Caution must be taken to not misdiagnose these findings as pigmentary glaucoma or pigment dispersion syndrome rather than iris melanoma.
- Tapioca melanoma describes a variant of iris melanoma with multiple amelanotic nodules on the surface, giving the appearance of tapioca pudding.17
In an analysis of eyes with iris melanoma by Shields et al., clinical features included corectopia, ectropion uveae, glaucoma, angle seeding, inflammatory posterior synechiae, heterochromia, chronic uveitis, and spontaneous hyphema.18 Secondary glaucoma is rare, but in advanced cases of iris melanoma, tumors can extend into the angle and block the trabecular meshwork or cause neovascularization.19
Diagnostic procedures for uveal melanomas
The key diagnostic tools for uveal melanoma are:
- Fundus photography
- Fundus autofluorescence (FAF)
- Ultrasound
- Ultrasound biomicroscopy
- Ocular coherence tomography (OCT)
- Fluorescein angiography (FA)
Fundus photography
Serial fundus photos are an important tool for monitoring choroidal nevi and melanoma. Many widefield retinal imaging systems provide caliper features for measuring diameter, as well as red-free filters that can allow for easier assessment if the retinal color appears distorted in the photo. It is imperative that all choroidal nevi are documented and measured routinely.
Figure 1: Fundus photography revealing a large posterior pole choroidal melanoma. Elevation is visible by examining blood vessel arching, and lipofuscin can be found on the superior aspect of the lesion.
Figure 1: Courtesy of Elizabeth Davis, OD.
Fundus autofluorescence (FAF)
Fundus autofluorescence imaging is helpful for differentiating lipofuscin from drusen. Lipofuscin will appear brighter than drusen on a choroidal lesion and suggest a high-risk lesion.
Ultrasound
Ultrasound testing can be used to confirm a diagnosis of melanoma and provide information on the thickness and basal dimensions of the lesion. If the lesion is in fact a choroidal melanoma, the B-scan may show an acoustically hollow lesion, subretinal fluid, and choroidal excavation with orbital shadowing.
A dome shape on B-scan is most common, while a mushroom or button appearance from the tumor invading through Bruch’s membrane is less common.7
Ultrasound biomicroscopy
Studies utilizing ultrasound biomicroscopy (UBM) to evaluate anterior segment tumors have found clinical features that might aid in the characterization of lesions, including the presence of internal reflectivity, anterior bowing of the iris plane, and extension of the lesion into the angle.
It has also been found useful in identifying ciliary body lesions, such as melanomas and iridociliary cysts. UBM was superior at identifying ciliary body and peripheral iris involvement of melanomas compared to B-scan.20
Ocular coherence tomography (OCT)
Standard spectral domain OCT (SD-OCT) can be used to visualize changes in the neurosensory retina and retinal pigment epithelium (RPE) in the area of a choroidal lesion. Subretinal fluid adjacent to a choroidal melanoma or lipofusion at the level of the RPE can be assessed using SD-OCT. Newer technology, in the form of enhanced depth imaging OCT (EDI-OCT), allows for assessment of the deep choroid or internal sclera.
Several findings on OCT have high sensitivity for diagnosing choroidal melanomas, such as:21
- Optical shadowing
- Thinning of overlying choriocapillaris
- Subretinal fluid
- Subretinal lipofuscin deposits
- Shaggy photoreceptors
Anterior segment OCT that utilizes a 1,310nm wavelength beam can reliably image a variety of iris lesions. Older OCTs that use an 840 to 870nm wavelength beam are more limited in their resolution of anterior segment structures. OCT is also useful for determining whether an iris lesion has infiltrated the angle structures.
An iris cyst demonstrates low central reflectivity due to its fluid-filled center. Iris nevi are visualized as areas of high anterior reflectivity with shadowing of the iris pigment epithelium. An iris melanoma appears as a lesion with a highly corrugated surface and variable internal reflectivity. Thicker melanoma can demonstrate shadowing of the pigment epithelium, which is typically highly reflective.22
Fluorescein angiography (FA)
Fluorescein angiography can be performed on atypical iris lesions, but it does not often provide conclusive results. Color photos or green monochromatic photos should be taken before the procedure in order to locate the abnormality. There is no fluorescein pattern standard for FA of the iris because all irides are different.
Lesion pigmentation that masks underlying fluorescence is typically considered benign if there is no dye leakage or uptake observed at any phase of the FA. Melanomas may show disorganized vasculature with gross leaking, a ring of hyperfluorescence around the lesion, or continuous diffuse leakage.23
Differential diagnoses of melanomas
Choroidal melanomas should be differentiated from benign melanocytic lesions, such as choroidal nevi, CHRPE, or melanocytoma, as well as choroidal neovascular membranes (CNVM). Thoroughly evaluating a choroidal lesion using the TFSOM-UHHD risk factors and proper imaging can differentiate a nevus from a melanoma.
Furthermore, CHRPE are located in the retina, not the choroid, often present with lacunae, and are more heavily pigmented than choroidal lesions. Using a red-free filter can determine whether a lesion is in the choroid or the retina; a CHRPE will still be visible with a red-free filter.
Figure 2: Fundus image of CHRPE consisting of large lacunae.
Figure 2: Courtesy of Kevin Cornwell, OD.
Melanocytoma tends to be located on the border of the optic nerve and black in color with feathery margins. There is a 2% chance of developing into a melanoma and these can be monitored with the same frequency of a choroidal nevus.2 Lastly, CNVM can present as gray-colored masses in the choroid but are easily diagnosed with the use of OCT.
Figure 3: Fundus photo and macular OCT revealing CNVM due to exudative macular degeneration.
Figure 3: Courtesy of Kevin Cornwell, OD.
Differentiating characteristics of melanomas
Choroidal metastasis tends to appear less pigmented than primary melanomas and look more like an amelanotic nevi or sclerochoroidal calcification.2 It is less common for primary ocular melanomas to be amelanotic. History of cancer is a red flag in these patients.
Iris melanomas need to be differentiated from iris nevi, Lisch nodules, iris pigmented cysts, and iris melanocytomas, among other iris abnormalities. A lesion should raise suspicion if it is nodular, solitary, unilateral, > 3mm, demonstrates growth, has associated vascularization/sentinel vessels, or affects the pupil shape. In highly suspicious lesions, a fine needle aspiration biopsy can help make a diagnosis.24
Ciliary body melanomas mainly need to be differentiated from atypical ciliary body melanocytomas. Evaluation of the episcleral vessels, intraocular pressure (IOP), crystalline lens, and lesion on dilation are important details to have in the patient's chart. If there is a concern for melanoma, fine needle aspiration biopsy is, once again, the course of action.25
Management/treatment of uveal and choroidal melanoma
The goals of uveal melanoma treatment include preserving vision in the affected eye, eliminating the tumor, and preventing metastasis and recurrence. The treatment strategy is dictated by many risk factors, including the state of the other eye, location, extent of the tumor, size of the tumor, vision status, the age of the patient, and the patient’s overall health.
Chemotherapy is ineffective for uveal melanomas; therefore, one of the following treatment methods is indicated.
Enucleation
Historically, the first treatment for uveal melanoma was enucleation. This persisted until the late 1970s, at which time there was a concern that enucleation could actually contribute to systemic metastasis. Physicians began exploring the use of eye-sparing treatment options such as radiotherapy and tumor resection.26
Today, enucleation is still used in cases of advanced melanomas that occupy most of the intraocular space, have invaded the optic nerve, or cause irreversible damage to the eye through secondary glaucoma or total retinal detachment. In an effort to reduce potential tumor seeding and metastasis, care is taken to avoid clamping the optic nerve or aggressively handling the eye during the enucleation procedure.27
The COMS study found that there is no increase in life expectancy when radiotherapy is done before enucleation, so it is typically a monotherapy.
Radiotherapy
Radiation therapy uses high-energy waves to eliminate cancer cells. There are two types of radiotherapy available for treating uveal melanoma: proton beam radiation and brachytherapy. Proton beam radiation is also known as external radiation therapy and targets the tumor with radiation from outside the body.
Brachytherapy, or internal radiation therapy, involves implanting a radiation plaque on or near the tumor in the eye. Overall, the success rates and complications for internal and external radiation therapy are similar.28
Utilizing brachytherapy for uveal melanomas
The most commonly used form of radiotherapy for uveal melanomas is brachytherapy. Brachytherapy involves suturing a temporary radioactive plaque onto the episclera overlying the tumor. The COMS study evaluated more than 1,300 patients over 12 years to follow the outcomes of uveal melanoma and found no significant difference in mortality from brachytherapy treatment compared to enucleation.29
Accordingly, radiotherapy is now the standard of treatment in uncomplicated uveal melanoma cases. Brachytherapy is most successful in choroidal melanomas up to 12mm in thickness and ciliary body melanomas up to 15mm, but can still be used for larger tumors with custom plaques. In larger tumors, the risk of complications is higher and often leads to poor visual outcomes.7
Radiotherapy comes with potential risks and a high likelihood of side effects. Brachytherapy is inherently risky as it involves two invasive operations, each requiring anesthesia, and emitting radiotoxic activity to healthy ocular tissue. Side effects of brachytherapy include neovascular glaucoma, radiation retinopathy, macular edema, serous retinal detachment, and radiation optic neuropathy.30
Figure 4: Fundus image of a choroidal melanoma after undergoing plaque radiotherapy with chorioretinal atrophy surrounding the tumor.
Figure 4: Courtesy of Elizabeth Davis, OD, FAAO.
Anti-vascular endothelial growth factor (VEGF) treatments or laser therapies are often employed after radiotherapy to reduce the likelihood of vascular complications or to treat retinopathy. Anterior segment complications can also occur with the treatment of uveal melanomas. Cataracts, keratoconjunctivitis, anterior uveitis, and scleral necrosis are all potential side effects of radiotherapy, especially if an iris or ciliary body melanoma is undergoing brachytherapy.
The dosage of the radioisotope plaque is based on the size and location of the tumor. The plaque is made of gold and has radioactive beads glued to it. Iodine-125 is the most commonly used isotope for brachytherapy in the United States.
The plaque is left in place for 4 days, but due to the high levels of radiation required for treatment, radiation retinopathy can occur up to 5 years after the plaque is removed.2 It is necessary for ophthalmologists and radiation oncologists to co-manage these patients.
Laser therapies
Laser therapies, including focal laser photocoagulation, transpupillary thermotherapy (TTT), and photodynamic therapy (PDT), have been successful in treating small ocular melanomas. These are rarely used in isolation and are often combined with radiotherapy to combat radiation-induced side effects. When used as the primary management method, there are high rates of incomplete treatment and tumor recurrence.7
There are additional limitations of laser treatments. Focal laser photocoagulation cannot be used in ciliary body melanomas. TTT can only be used on small choroidal melanomas with less than 3mm of thickness that are located more than 3mm from the fovea.7
The “sandwich method” is commonly used and involves anti-VEGF injections every 4 months after a brachytherapy plaque and TTT have been completed. This schedule of injections continues for 2 years to ideally prevent radiation retinopathy.2
Some consider PDT to be the best option when treating amelanotic choroidal melanoma. This procedure involves intravenous administration of a photosensitizer that is activated by a specific wavelength of light to release factors within tumor vasculature to induce endothelial changes and thrombosis. Published studies have shown short-term tumor control while circumventing the risks of radiation retinopathy in small melanomas, but long-term tumor control rates are lower.7
Local resection
This technique can be used to remove small ciliary body melanomas or small and medium-sized choroidal melanomas near the equator. It should be noted that brachytherapy with a plaque is considered to be less invasive and can be used for the same type of tumors. The patient's survival is considered to be the same with local resection as with enucleation and radiotherapy.7
This procedure is considered to be challenging even for experienced surgeons and carries with it significant risks for vitreous hemorrhage, retinal detachment, and cataract formation.32 Depending on the ocular tissues affected in an iris or ciliary body melanoma, iridectomy, iridocyclectomy, or irido-trabeculectomy may also be considered.
Follow-up and referral
Approximately 6.5% of the Caucasian population has a choroidal nevus.33 About 1 in 8,800 of these choroidal nevi will evolve into a choroidal melanoma.34 Patients with suspicious nevi should be re-examined 3 months after the nevi is first documented. If no change in size is noted, retinal exams and fundus photos can be performed every 6 months.
If a patient has three or more high-risk characteristics from the TFSOM-UHHD mnemonic, a referral for evaluation by a retinal specialist is required without waiting for documentation of lesion growth. Small non-growing iris lesions may be just periodically observed and thoroughly documented with photos and measurements.
A referral and further testing are warranted if a mass is exhibiting documented growth, surface nodularity, height greater than 2mm, prominent vascularity, or associated hyphema.7
Complications of uveal melanoma
Several ocular complications can result from uveal melanoma, including:
Glaucoma
In ciliary body and iris melanoma, tumor-induced glaucoma is due to obstruction of the trabecular meshwork by pigment cells, macrophages, or tumor cells. Obstruction can also occur due to direct invasion of the angle structures by the tumor itself, leading to acute angle closure glaucoma. Neovascular glaucoma is also a concern for a uveal melanoma present in any of the three locations.18
Retinal detachment
Exudative retinal detachment can occur from a choroidal melanoma. Patients may present with metamorphopsia, decreased acuity secondary to subretinal fluid accumulation, and/or a hyperopic refractive shift if the detachment affects the macula.34
Systemic metastasis
Nearly half of all patients with uveal melanoma will develop metastatic disease. Uveal melanoma metastasis spreads through the bloodstream since the eye does not have lymphatic vessels.6 For this reason, the proximity of a lesion to the optic nerve is a concerning risk factor in choroidal melanoma.
In the COMS, the most frequent sites of metastases at the time of death were the liver (93%), lung (24%), and bone (16%). More than 80% of patients had multiple sites of metastasis.7 Prognosis is very poor after metastasis has occurred.
Prognosis of uveal and choroidal melanomas
As discussed, the size of a tumor can often predict the likelihood of the patient having metastasis to the liver or other organs. When uveal melanoma is diagnosed, the primary concern is evaluating for metastasis, while preserving vision and the globe is also important. Within 15 years after the diagnosis of uveal melanoma, 50% of patients have metastatic disease.
The median survival after diagnosis of metastasis is 6 months; the 10-year mortality for uveal melanoma depends on the size of the tumor and is 50% for large tumors, 25% for medium tumors, and 12% for small tumors.33 Iris melanomas exhibit a lower metastasis rate than ciliary body or choroidal melanomas. The rate of iris melanoma metastasis is approximately 3% at 5 years, 5% at 10 years, and 10% at 20 years.21
Fine needle aspiration biopsy of uveal melanoma is used for prognostication and is performed in eyes during brachytherapy plaque placement or after enucleation. Chromosomal and genetic analysis, along with gene expression profiling, can aid in predicting outcomes and directing treatment decisions.
An overview of gene expression profiling
Gene expression profiling (GEP) is the standard at ocular oncology clinics for classifying uveal melanomas and determining proper treatment. GEP allows oncologists to accurately predict which patients with uveal melanoma will develop metastatic disease.
The goal of GEP is to be able to offer therapy to high-risk classes of patients before metastasis is noted on imaging. GEP class also determines how often imaging is recommended for the liver and other organs where metastasis is a concern.2
GEP divides uveal melanoma into 2 molecular subgroups: Class 1A and 1B (low risk) and Class 2A and 2B (high risk). Classification requires a needle biopsy from the tumor, which can be done at enucleation or before the plaque is placed.
The prevalence and risk of metastasis for different classes of uveal melanoma are as follows:34
- Class 1A tumors account for 50% of all uveal melanomas, with a 2% risk of metastasis
- Class 1B accounts for 17% of uveal melanomas, with a 21% risk of metastasis
- Class 2A and 2B account for 33% of uveal melanomas, with a 72% risk of metastasis in the next 5 years
The goal of GEP is to be able to offer proactive therapy and screening to all Class 2 patients and select Class 1B patients in the near future.35
The future for uveal melanoma diagnosis
The Collaborative Ocular Oncology Group (COOG) is investigating blood biomarkers for diagnosing melanoma cells as an alternative to fine needle aspiration biopsy. While macrophages bind to circulating tumor cells, they are not ideal for screening because they do not differentiate between metastatic and non-metastatic cells.
In contrast, circulating hybrid cells (tumor cells engulfed by macrophages) are more likely to metastasize and pose a higher mortality risk.2 Patients with these cells can be identified for aggressive liver therapy and treatment with immunomodulators. This technology aims to enable earlier detection of melanoma and reduce mortality rates from uveal melanoma metastasis.
Conclusion
As primary eyecare providers, optometrists play a crucial role in diagnosing and monitoring ocular lesions. All choroidal and iris nevi should be routinely evaluated with photography and additional testing as indicated.
Patient education on the potential for nevi to develop into melanoma should be discussed and documented in the chart, as well as the schedule for follow-up exams. Optometrists should have high suspicion for any choroidal lesion fulfilling two or more of the TFSOM-UHHD risk factors and refer to a retinal specialist as warranted.
Therapy for choroidal melanoma is dictated primarily by the size of the lesion, with brachytherapy being the most common treatment. Once a diagnosis of melanoma is made, these patients will be co-managed with oncology for systemic evaluation and undergo gene expression profiling, as the most devastating consequence of uveal melanoma is metastasis to other organs.
Early diagnosis of uveal melanomas can not only preserve a patient’s vision but can literally save their life as well.
