Clinical Evaluation of Choroidal Melanoma

Article initiated by:

Fabiola V. Monsivais-Rodríguez, MD

All authors and contributors:

Adam R. Sweeney, MD, Andrew W. Stacey, Divakar Gupta, MD, Fabiola V. Monsivais-Rodríguez, MD, Constance Fry, MD

Assigned editor:

Constance Fry, MD

Review:

Assigned status Update Pending

 by Constance Fry, MD on January 19, 2022.

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Contributing Editors:	add

Choroidal melanoma

Choroidal melanoma. Courtesy of Paul Griggs, MD. © 2019 American Academy of Ophthalmology

DiseasesDB

2614

Disease Entity

Disease

Choroidal melanoma is the second most common intraocular tumor – metastasis being the most frequent – and the most common primary intraocular malignancy in the adult population. Uveal melanoma is rare and has an age-adjusted incidence of 5.1 per million. This incidence has been stable since the 1970s ). It arises from uveal melanocytes. The choroid posterior to the equator is the most common site involved, accounting for approximately 85% of cases. Posterior uveal melanoma has distinct clinical characteristics that facilitate its differentiation from other pigmented and non-pigmented lesions of the choroid.  Anterior uveal melanoma refers to tumors involving the choroid anterior to the equator, the ciliary body and/or iris and comprises 9-15% of uveal melanomas; of these, 2-4% of melanomas are iris melanomas and 4-7% are ciliary body melanomas. Iris melanomas carry a better prognosis than other uveal melanomas and will be discussed elsewhere.

Risk Factors

While development of uveal melanoma is largely considered to be a sporadic event, certain risk factors including light iris color, light skin color, a tendency to freckle, northern European ancestry, welding and rarely a family history of uveal melanoma have been reported to predispose individuals to uveal melanoma .  Other conditions with an increased incidence of uveal melanoma include dysplastic nevi and Nevus of Ota (estimated that 1:400 will develop uveal melanoma). While ocular nevi are a risk factor, the estimated rate of transformation into melanoma is approximately 1/5000-1/8845 .

Pathophysiology

The pathophysiology of uveal melanoma is currently not well understood. There have been several advances in the molecular mechanisms involved in this malignancy. Monosomy 3 has long been known to be associated with development of aggressive uveal melanoma. More recently, specific abnormalities in loci associated with high-risk melanoma have been identified including 3p and 1p losses and 8q gain. Currently, numerous genetic mutations have been demonstrated to be highly conserved in the clonal proliferation of uveal melanocytes.

At the cellular level, the molecular expression for metastasis is heavily biased towards one of the three cell types that make up uveal melanoma tumors.

The three cell types classically comprising almost all uveal melanoma tumors are

• type A
• type B oblong spindle-shaped cells
• Large, polygonal shaped epitheloid cells. These epitheloid cells appear to have an intrinsic affinity for metastasis and are considered to be the make up more high-risk lesion, however, 87% of primary tumors have a mixture of all three cell types.

Diagnosis

Symptoms

Melanomas are often asymptomatic. Symptoms are not a common initial presentation of small melanomas, but can be present in larger lesions and melanomas that affect the macula. The main symptoms are decreased visual acuity, visual field defects (scotomas), metamorphopsia, photopsia and floaters. Less common symptoms are pain and red eye.

Ciliary body melanoma Ciliary body melanomas present relatively later and are larger. A sentinel vessel (dialted, tortuous episcleral vessel overlying the tumor) is more common in ciliary body tumors. In advanced cases, there may be a secondary glaucoma due to displacement of the lens-iris diaphragm and secondary angle closure. The presence of symptoms is more commonly found in melanomas than in choroidal nevi.

Iris melanoma

Iris melanomas are often asymptomatic and detected on routine ocular evaluation. They may be brown or tanish (tapioca) in color. They may be associated with corectopia and/or ectropion iridis.

Clinical diagnosis

Posterior uveal melanomas typically present as an elevated domed-shaped gray-brown colored lesion of the choroid with irregular margins not sharply demarcated. Less commonly, a melanoma will be amelanotic. When the melanoma breaks through Brüch membrane it acquires a classic mushroom-shaped configuration; this occurs about 20% of the time.

Several clinical characteristics should be looked for during the evaluation of a suspicious lesion:

• Color: Grayish-to-brownish neoplasm located in the choroid with overlying retinal vessels. However, there are also amelanotic tumors with a yellowish appearance.
• Thickness: choroidal melanomas tend to be lesions more than 2 mm thick. In contrast, choroidal nevi – the main disorder in the differential diagnosis – are more likely to present as flat or slightly elevated masses.
• Subretinal fluid: The presence of an exudative detachment of the neurosensory retina or the retinal pigment epithelium (RPE) is common.
• Orange pigment: Lipofuscin accumulation in the RPE overlying choroidal melanomas is a frequent finding.
• Sentinel vessel: A tortuous and dilated episcleral vessel is visible overlying a melanoma.
• Secondary glaucoma: Secondary angle-closure glaucoma can develop due to anterior displacement of the iris-lens diaphragm by the mass.

Certain features are more common in benign choroidal nevi including:

• Drusen: are more commonly seen in chronic neoplasms and are more common in nevi than in melanoma.
• Halo of depigmentation around a pigmented choroidal lesion: is more commonly seen in nevi and correlated with stability of the nevus. The depigmentation represents a lymphohistiocytic infiltrate.

The size of choroidal melanomas is one of the most important clinical characteristics. Size is used to classify these tumors, according to a modification of the criteria of the Collaborative Ocular Melanoma Study (COMS). This study classified melanomas using largest basal dimension and apical height in three groups: small, medium and large melanomas. Treatment strategies vary depending on this classification.

	Apical height	Largest basal diameter
Small	1.0 - 2.5 mm	5.0 - 16.0 mm
Medium	2.5 - 10 mm	less than 16 mm
Large	more than 10 mm	more than 16 mm

Cilary Body/Ciliochoroidal melanoma

Melanomas of the ciliary body are often relatively large when they present. They have the same characteristics as choroidal melanoma but more frequently have a sentinel vessel (dilated tortuous episcleral vessel overlying the tumor). Additionally, these tumors are more likely to present with anterior displacement of the lens-iris diaphragm and a secondary angle closure glaucoma.

Iris melanoma

Most pigmented iris tumors are nevi according to a histopathologic study by Jakobiec in 1981. Iris melanomas are often asymptomatic and detected on routine ocular evaluation. They may be brown or tanish (tapioca) in color. They may be associated with corectopia, ectropion iridis, and cataract. The risk of an iris nevus transforming into an iris melanoma in a tertiary referral center was 11% in 20 years (Shields 2013). Risk factors for transformation create the ABCDEF mnemonic:

• Age </= 40 at presentation
• Blood - spontaneous hyphema*
• Clock hour - inferior 4:00-9:00*
• Diffuse involving the entire iris*
• Ectropion uveae
• Feathery edges

*The hazard ratio for each of these features predicting malignant transformation is substantially higher than the other three characteristics.

However, according to Jakobiec even iris nevi may have some of the above characteristics.

Diagnostic procedures

Additional ancillary tests can aid in the clinical evaluation of a melanoma:

Fundus Photography

Serial fundus photos are critical in the follow up of choroidal nevi and melanoma. The widefield retinal (WFR) imaging such as Optos creates an easily replicated map of the fundus. Certain WFR imaging systems distort the color of the tumor and fundus.

Fundus autoflorescence

Orange lipofuscin pigmentation possesses autofluorescent properties. Liposfuscin is present in suspicious nevi and many melanomas. Lipofuscin fluorescence is brighter than that of drusen (drusen are common in choroidal nevi).

Ultrasound

Bscan ultrasonography showing a dome shaped choroidal mass. Courtesy of Constance L. Fry, MD

This is the primary diagnostic test that confirms the diagnosis of melanoma. Ultrasound also is useful in determining the size, e.g. thickness (apical height) and basal dimension, extraocular extension (such as scleral nodules), and document growth during the follow up of a suspicious nevus/small melanoma.

• Standardized A-mode: Posterior uveal melanomas classically show medium to low internal reflectivity (88%), often in a decrescendo fashion, a.k.a, positive angle kappa, with regularity of structure. The internal blood flow (vascularity) of the tumor can be seen as a fast movement of the internal spikes. Uncommonly, a large melanoma may be more irregular, particularly if there is necrosis.
• B-mode: Shapes: Dome-shaped is most common, mushroom-shaped, i.e. collar button is the most classic shape, and an irregular shape is uncommon. Other features: acoustically hollow zone within the tumor, choroidal excavation, and subretinal fluid.
• Ultrasound biomicroscopy is utilized to better delineate ciliary body and iris melanomas.

Color Doppler ultrasound

Choroidal melanomas show pulsatile blood flow at the tumor base. This finding is not found in nevi.

Fluorescein and indocyanin green angiography (ICGA)

• Hypofluorescence: Due to blockage of the choroidal blood flow by the pigmentation inherent to the tumor.
• Hyperfluorescence: Small hyperfluorescent spots may be seen due to lipofuscin deposition at the RPE level. Pinpoint hyperfluorescence is a high risk characteristic seen in choroidal nevi and if present with other high risk characteristics, one should consider that the tumor may be undergoing malignant transformation.
• Circulation:“Double circulation” pattern consisting of an internal circulation within the lesion and the normal vascularity of the overlying retina. This characteristic is more evident in ICGA
• Neovascularization: is not typical of melanoma and its presence suggests another diagnosis should be sought.

Standard spectral domain OCT (SD-OCT)

Standard spectral domain OCT does not penetrate deeply enough for detecting the internal characteristics of choroidal neoplasms. However, it is useful in visualizing changes in the neurosensory retina and the retinal pigment epithelium (RPE). As it was mentioned earlier, posterior uveal melanomas may show serous retinal detachment in the areas adjacent to the tumor. i.e. subretinal fluid. Lipofuscin deposition is also seen at the level of the RPE.

Enhanced Depth Imaging Spectral Domain OCT (EDI-OCT)

Enhanced Depth Imaging Spectral Domain OCT is a relatively new technology that is now commercially available. It is a method that allows for the evaluation of deeper structures such as the choroid and the internal portion of the sclera. In a study of 37 eyes by Carol Shields, et al. it was found that the distinguishing characteristics of choroidal melanomas readily seen in EDI-OCT are:

• Optical shadowing (100%)
• Thinning of overlying choriocapillaris (100%)
• Subretinal fluid (92%)
• Subretinal lipofuscin deposits (95%)
• Shaggy photoreceptors (49%)
• Other retinal changes included: Loss of photoreceptors, loss of external limiting membrane, loss of inner segment-outer segment junction, irregularity of inner plexiform layer, irregularity of ganglion cell layer, intraretinal edema

Magnetic Resonance Imaging (MRI)

MRI may be used occasionally to aid in establishing a diagnosis and to look for extrascleral extension. MRI is most useful distinguishing melanoma from blood. Pigmented melanomas and subacute hemorrhage are similar in appearance on T1- and T2-weighted images, i.e. each is hyperintense on T1 and hypointense on T2. However, only melanoma demonstrates marked enhancement with administration of contrast. Of note, amelanotic choroidal melanomas will not resemble blood on exam or by MRI. An amelanotic lesion will not be hyperintense on T1-weighted images but it will still show marked enhancement with contrast.

Laboratory test

Posterior uveal melanomas spread via vortex veins to the vascular system. Most metastasis are to the liver (92%), but the tumor can also spread to the lungs and the skin. Uncommonly, melanoma can demonstrate extension into optic nerve and brain. There is a lack of consensus on the optimum screening methodology for uveal melanoma. Among the tests that may be ordered during the metastatic workup for a patient with choroidal melanoma are:

• CT Chest/Abdomen/Pelvis with contrast
• Laboratory: Liver function tests with liver ultrasound
• PET CT

Genetic Testing

Most uveal melanomas have no genetic predisposition. Only about 1% are thought to be inherited. An alteration in tumor suppressor genes found on chromosome 3 is associated with some hereditary melanomas. There are two germline mutations responsible for hereditable melanoma: loss of BAP 1 expression as in BRAC1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) and more recently, inactivation of Methyl-CpG Binding Domain 4 (MBD4).

Differential diagnosis

The differential for choroidal melanoma includes benign nevus, suspicious nevus, hemorrhagic macular and extramacular degeneration, metastasis, hemangioma, hamartoma of the retina and retinal pigment epithelium, congenital hypertrophy of the retinal pigment epithelium, diffuse melanocytic proliferation, and detachment of the pigment epithelium, retina, or choroid.

There is evidence that choroidal melanomas arise from choroidal nevi, since nevi cells have been found in histopathological samples of melanomas. Thus, Shields and colleagues analyzed 2,514 cases of choroidal nevi to determine predictive features of growth into melanoma. Using the data obtained in this study, they developed a mnemonic for these predictive features: “To Find Small Ocular Melanoma Using Helpful Hints Daily”.

• T: Thickness > 2 mm
• F: Fluid (subretinal)
• S: Symptoms (decreased vision, flashes or floaters)
• O: Orange pigment (presence of)
• M: Margin within 3 mm of the optic disc
• UH: Ultrasonographic hollowness
• H: Absence of surrounding halo. Nevi usually show a surrounding clear halo consisting of atrophied retina.
• D: Absence of drusen. Drusen are chronic changes seen more commonly in slow growing lesions such as choroidal nevi than in melanomas.

The above are listed in the order in which they impact growth. Melanocytic tumors of the choroid that display none of these features have a 3% chance of growth in 5 years and are typically nevi. Those that have one risk factor have a 38% chance of growth in 5 years and are indeterminant lesions. If three or more of these factors are present, the risk of growth is 50% at 5 years and thus may represent small melanomas.

A ciliary body tumor that may simulate a melanoma include: iridociliary epithelial cyst, intraocular foreign body granuloma, melanocytic nevus, melanocytoma, leiomyoma, Fuchs adenoma, sarcoid nodule, and metastatic tumor.

The differential diagnosis for iris lesions suspected of being melanoma should include the findings and frequency of iris pseudomelanomas reported by Shields et al: primary iris cyst (38%), iris nevus (31%), essential iris atrophy (5.7%), iris foreign body (4.5%), peripheral anterior synechia (2.5%), and iris metastasis (2.5%).

Additional Resources

• Carol L Shields MD. Choroidal Nevus: When to Suspect Melanoma. 1-minute videos. American Academy of Ophthalmology. https://www.aao.org/1-minute-video/choroidal-nevus-when-to-suspect-melanoma Accessed June 28, 2019.

References

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11. Cheung A, Scott IU, Murray TG, Shields CL. Distinguishing a Choroidal Nevus from a Choroidal Melanoma. Ophthalmic Pearls, EyeNet Magazine. Feb, 2012.
12. Chapter 8: Oncology. In: Yannuzzi LA. The Retinal Atlas. Elsevier, 2010.
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