Advances in multimodal imaging for diagnosis of pigmented ocular fundus lesions

Abstract

Pigmented ocular fundus lesions can range from benign to malignant. While observation is reasonable for asymptomatic benign lesions, early recognition of tumors that are vision- or life-threatening is critical for long-term prognosis. With recent advances and increased accessibility of multimodal imaging, it is important that providers understand how to best use these tools to detect tumors that require early referral to subspecialty centers. This review aims to provide an overview of pigmented ocular fundus lesions and their defining characteristics using multimodal imaging. We cover the spectrum of pigmented ocular fundus lesions, including freckle/focal aggregates of normal or near normal uveal melanocytes (FANNUM), retinal pigment epithelium (RPE) hyperplasia, congenital hypertrophy of the retinal pigment epithelium (CHRPE), RPE hamartoma associated with familial adenomatous polyposis (FAP), congenital simple hamartoma of the RPE (CSHRPE), combined hamartoma of the retina and RPE (CHRRPE), choroidal nevus, melanocytosis, melanocytoma, melanoma, adenoma, and RPE adenocarcinoma. We describe key diagnostic features using multimodal imaging modalities of ultra-widefield fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), enhanced-depth imaging OCT (EDI-OCT), ultrasonography (US), fluorescein angiography (FA), indocyanine green angiography (ICG), and OCT angiography (OCTA), with particular attention to diagnostic features that could be missed on fundus examination alone. Finally, we review what is on the horizon, including applications of artificial intelligence. Through skilled application of current and emerging imaging technologies, earlier detection of sight- and life-threatening melanocytic ocular fundus tumors can lead to improved patient prognosis.

Introduction

Multimodal imaging has earned a key role in diagnosis and monitoring of retinal and choroidal disease. Rapid expansion of technology has improved capture of the far retinal periphery with ultra-widefield (UW) imaging, and optical coherence tomography (OCT) has revealed subtle features that are invisible by clinical examination alone, such as subretinal fluid, layer-by-layer lesion localization, and micron-level thickness measurement of choroidal lesions using enhanced-depth imaging (EDI-OCT).¹ Novel technologies such as OCT angiography (OCTA) have been applied as non-invasive alternatives to traditional angiography, with attempts to uncover new imaging features to refine diagnosis and prognosis. Appropriate interpretation of multimodal imaging can provide a high degree of diagnostic confidence, making the eye one of the few places in the body where tumors are directly visualized and routinely diagnosed by imaging rather than histopathology. Understanding how to apply this technology is particularly important for the evaluation of pigmented ocular fundus lesions, as accurate and early diagnosis can potentially improve both visual prognosis and patient survival.

The spectrum of pigmented intraocular lesions ranges from benign to malignant, with uveal melanoma at the forefront given its propensity to metastasize. Early detection of uveal melanoma, when the tumor is small (American Joint Committee on Cancer [AJCC] Category T1), confers a lower risk of metastatic disease and improved patient survival.² When applied appropriately, multimodal imaging can non-invasively distinguish uveal melanoma from benign intraocular lesions and predict the risk for choroidal nevus transformation to melanoma, aiding in early diagnosis for high-risk lesions while avoiding potentially vision-threatening biopsy in low-risk melanocytic tumors. The purpose of this review is to describe diagnostic applications of multimodal imaging for pigmented ocular fundus lesions. For each lesion, we analyze standard of care and emerging imaging features that will push the field toward earlier diagnosis and improved prognosis for sight- and life-threatening intraocular melanocytic tumors.

Methods

PubMed was searched on September 16, 2022 for English language studies with key words choroidal freckle, focal aggregates of near normal uveal melanocytes (FANNUM), retinal pigment epithelium (RPE) hyperplasia, congenital hypertrophy of the RPE (CHRPE), familial adenomatous polyposis (FAP), Gardner syndrome, RPE hamartoma, congenital simple hamartoma of the RPE (CSHRPE), combined hamartoma of the retina and RPE (CHRRPE), choroidal nevus, melanocytosis, melanocytoma, choroidal melanoma, RPE adenoma, and RPE adenocarcinoma. For this narrative review, studies were specifically identified to provide detailed clinical and imaging features of pigmented ocular fundus lesions. Large series were reviewed when available, but small series and case reports were included when no large studies were available. Representative images were identified from the Mayo Clinic Ocular Oncology Service.

Results

Imaging modalities

Multimodal imaging refers to the integrated application of two or more imaging modalities, each of which provide distinct diagnostic information. Fundus photography allows serial monitoring for subtle tumor growth, and UW imaging documents peripheral lesions, which were historically difficult or impossible to capture.³ Fundus autofluorescence (FAF) uses a low-powered laser beam (excitation filter 488 nm, emission filter 500–530 nm) to detect endogenous fluorophores, mainly lipofuscin.^{4, 5} OCT uses near-infrared light to capture cross-sectional images at micron-level detail,⁶ allowing visualization of retinal layers, subtle subretinal fluid, and deep choroidal lesions using EDI-OCT.¹ B-scan ultrasonography (US) uses sound waves to produce real-time 2D images to assess lesion size and shape, while A-scan measures reflectivity.⁷ Fluorescein angiography (FA) uses an intravenous dye (excitation wavelength 465–490 nm, emission 520–530 nm) to visualize retinal blood flow and integrity of the blood-retinal barrier,⁸ while indocyanine green angiography (ICG) (peak absorption 790–805 nm, emission 835 nm) permits better visualization of deeper choroidal vasculature.⁹ On the cutting edge of technology, OCTA utilizes rapid imaging speed with motion contrast to detect blood flow noninvasively, without dye.¹⁰ Applications to pigmented fundus lesions are described below and summarized in Table 1.

Table 1.

Imaging features of pigmented fundus lesions

Lesion	Imaging Modalities
	Clinical Appearance	FAF	OCT	US	FA/ICG	OCTA
Benign
FANNUM	Pigmented Discrete Flat	IsoAF	Hyperreflective or nearly imperceptible Sometimes shadowing	Flat	Non-contributory	Normal overlying vasculature
RPE hyperplasia	Deeply pigmented Discrete Associated with trauma or inflammation	HypoAF	Optically dense Posterior shadowing	Acoustically solid High internal reflectivity	Hypofluorescent early, hyperfluorescent zones late	Can show vascular flow signals on outer retinal slab
CHRPE Solitary  Multifocal (bear tracks)	Deeply pigmented Well demarcated Round Flat or minimally elevated Depigmented lacunae Depigmented halo Unilateral Clustered Sector distribution Smaller than solitary No lacunae or halo	HypoAF Lacunae can be hyperAF	Overlying retinal thinning, photoreceptor loss RPE thick, irregular RPE loss in lacunae Moderate shadowing Subretinal cleft Choroidal atrophy	≤1 mm thick	Blocked choroidal fluorescence Window defect in lacunae No leakage	Normal retinal and choroidal vasculature
RPE hamartoma associated with FAP and Gardner (pigmented ocular fundus lesions)	Gray Irregular depigmented margins Fish-tail, comma, or comet configuration Flat, minimally elevated Multifocal, randomly distributed (not sector) Bilateral Associated with FAP and Gardner Syndrome	HypoAF	Outer retinal attenuation RPE thick	Too thin to resolve	Blocked choroidal fluorescence Window defect in depigmented areas Associated telangiectatic dilations hyperfluorescent	Reduced vascular density in superficial capillary plexus Increased vascular density in deep capillary plexus
Congenital simple hamartoma of the RPE	Deeply pigmented Discrete Solitary nodule, protrudes through sensory retina Central macula, usually adjacent to foveola Minimally dilated feeding artery and draining vein Mild retinal traction Sometimes exudation Sometimes pigmented vitreous cell	HypoAF	Hyperreflective Abruptly elevated Solid mass in inner retina Dome-shaped Elevation into vitreous Complete optical shadowing	Too thin to resolve	Hypofluorescent	Vascular networks at the superficial and deep plexus
Combined hamartoma of the retina and RPE	Gray Ill-defined Tortuous or straightened retinal vessels Retinal dragging Peripheral retinal ischemia, neovascularization Unilateral, if bilateral consider NF2	HypoAF	Vitreoretinal traction Retinal striae Sawtooth or folded pattern replacing full thickness retina Epiretinal membrane	Acoustically solid mass	Late staining on FA Patchy hypercyanescence on ICG	Disorganized intralesional retinal microcirculation
Suspect
Nevus	Pigmented or partially pigmented Less often amelanotic Well-demarcated Overlying drusen Overlying RPE changes Sometimes depigmented halo Less often CNV Risk factors for growth to melanoma: Visual acuity loss to 20/50 or worse Diameter >5mm	HypoAF Halo slightly hyper AF Orange hyperAF Orange pigment	Thick, elevated choroid Overlying SRF Overlying retinal edema PEDs, drusen Fibrous metaplasia SRF	Solid or hollow Usually <2mm thick Thickness >2mm Acoustic hollowness	Variable on FA Hypocyanescent	Hyporeflective Intense vascular rim called surface microvasculature Avascular areas Intact RPE-Bruch’s complex Possible CNV
Melanocytosis	Gray to brown Diffuse or sector Usually unilateral Concomitant iris, episcleral, cutaneous involvement Congenital 1/400 risk of uveal melanoma	IsoAF	Choroid thick	Used to help detect melanoma	Utilized if concern for melanoma	Normal overlying vasculature
Melanocytoma	Dark brown to black Feathery margin Usually unilateral Commonly involves optic disc Can have choroidal and retinal component Sometimes vitreous seeds	HypoAF	Optically dense Dome-shaped Abrupt shadowing	Dome Medium to high internal reflectivity	Hypofluorescent	Intact overlying retinal vasculature Irregular intratumoral vascular network
Malignant
Melanoma	Pigmented or partially pigmented Less often amelanotic Well-demarcated Less often diffuse Serous retinal detachment Shifting subretinal fluid Orange pigment Blocks transillumination	Orange hyperAF	Thick, elevated choroid Subretinal fluid Shaggy photoreceptors Thin or compressed choriocapillaris	Dome or mushroom Acoustically hollow Low internal reflectivity	Mottled hyperfluorescene in filling phases Diffuse late staining Pinpoint leaks (hot spots) Double circulation sign Hypocyanescent	Iso- to hyporeflective Avascular areas Vascular loops Vascular networks Loss of choriocapillaris flow Obscured RPE-Bruch’s complex Obscured outer retinal layer Dilated and tortuous feeding vessels
RPE adenoma / adenocarcinoma	Deeply pigmented Feeder arterioles Exudation Arising from CHRPE	Not well described	High reflectivity Dense posterior shadowing	Abruptly elevated, “derby hat” Acoustically solid High internal reflectivity	Hypofluorescent early, hyperfluorescent zones late	Minimal flow (single case report)

Abbreviations: FAF = fundus autofluorescence, OCT = optical coherence tomography, US = ultrasound, FA/ICG = fluorescein angiography/indocyanine green angiography, OCTA = optical coherence tomography angiography, FANNUM = focal aggregates of normal or near normal uveal melanocytes, IsoAF = isoautofluorescent, RPE = retinal pigment epithelium, HypoAF = hypoautofluorescent, CHRPE = congenital hypertrophy of the retinal pigment epithelium HyperAF = hyperautofluorescent, FAP = familial adenomatous polyposis, NF2 = neurofibromatosis type 2, SRF = subretinal fluid, PED = pigment epithelial detachment CNV = choroidal neovascularization

The Spectrum of Pigmented Fundus Lesions

Choroidal Freckle/Focal aggregates of normal or near normal uveal melanocytes (FANNUM)

FANNUM are small, flat, pigmented lesions with discrete margins (Figure 1A, C), often referred to as choroidal freckles owing to a clinical appearance similar to nevus with absent elevation. Freckles can be solitary, grouped, unilateral, or bilateral.¹¹ Association with linear nerve-like structures supports a possible embryologic origin.^{11, 12}

Figure 1.

Focal aggregates of normal or near normal uveal melanocytes (FANNUM). (A) Color fundus photograph of discrete, pigmented FANNUM. On (B) optical coherence tomography angiography (OCTA), the lesion slab has normal vascular flow. (C) Color fundus photograph of FANNUM. On (D) fundus autofluorescence (FAF), the lesion is isoautofluorescent. With (E) OCT, the lesion is flat and hyperreflective (arrow). OCTA shows a (F) relatively normal superficial retinal vascular flow and (G) reduced choriocapillaris flow in the area of the lesion (arrow).

FANNUM are isoautofluorescent (Figure 1D) and nearly imperceptible or hyperreflective by OCT, sometimes with posterior shadowing (Figure 1E). Unlike nevus, FANNUM are never elevated on US.¹¹ On OCTA, overlying retinal vasculature appears relatively normal. However, in our practice, we have noticed some cases with reduced choriocapillaris flow (Figure 1B, F, G).

Retinal pigment epithelium (RPE) hyperplasia

RPE hyperplasia is a benign proliferation of RPE cells, possibly associated with inflammation, trauma, or toxicity. This is a dark, irregularly shaped lesion with discrete margins, sometimes having concomitant fibrosis (Figure 2A).

Figure 2.

Choroidal nevus with overlying retinal pigment epithelium (RPE) hyperplasia. (A) Color fundus photograph of a pigmented choroidal nevus with overlying clumps of dark RPE hyperplasia (arrow). By (B) fundus autofluorescence imaging, the areas of RPE hyperplasia are hypoautofluorescent (arrow). On (C) optical coherence tomography (OCT), the areas of RPE hyperplasia are optically dense with posterior shadowing (arrows). With (D) OCT angiography (OCTA), there are corresponding vascular flow signals on the outer retinal slab (arrow).

RPE hyperplasia is hypoautofluorescent (Figure 2B) and optically dense with occasional posterior shadowing by OCT (Figure 2C). Minimally elevated lesions are imperceptible by US, but larger, nodular lesions are acoustically solid on B-scan with high internal reflectivity on A-scan, which must be distinguished from choroidal melanoma.¹³ On FA, lesions are hypofluorescent in the filling phase and can have zones of hyperfluorescence in late phases.¹³ Chen et al., in a study of non-vascularized pigment epithelial detachment (PED) in age-related macular degeneration, described areas of lump RPE hyperplasia outside the foveal avascular zone, which showed vascular flow signals on the outer retinal slab of OCTA imaging (Figure 2D), mimicking neovascularization.¹⁴

Congenital hypertrophy of the retinal pigment epithelium (CHRPE)

CHRPE is a benign hyperplasia, consisting of RPE cells with an increased amount of atypical, enlarged melanosomes. CHRPE is present in 1.2% of the population with little to no malignant potential¹⁵ and no relation to hereditary cancer syndromes like FAP or Gardner syndrome.¹⁶

Solitary CHRPE is unilateral, deeply pigmented, well demarcated, round, and flat or minimally elevated (Figure 3A). Occasionally, depigmented intralesional lacunae and a depigmented halo are visible.¹⁵ Rarely, solitary CHRPE can give rise to adenoma.¹⁷ Clustered CHRPE, multifocal CHRPE, or bear tracks follow a sector distribution and are smaller than solitary CHRPE with no lacunae or halo (Figure 3D).¹⁸ Amelanotic multifocal CHRPE has been termed polar bear tracks.¹⁵

Figure 3.

Congenital hypertrophy of the retinal pigment epithelium (CHRPE). (A) Color fundus photograph of a well-demarcated solitary CHRPE lesion with depigmented lacunae (arrow). On (B) fundus autofluorescence (FAF), CHRPE is hypoautofluorescent. (C) Optical coherence tomography (OCT) demonstrates thickened, irregular RPE, moderate shadowing, and photoreceptor loss (arrow, inset). (D) Fundus photograph of multifocal CHRPE. On (E) FAF, multifocal CHRPE is hypoautofluorescent.

CHRPE is dark on FAF, but lacunae can be hyperautofluorescent (Figure 3B, E).^{19, 20} OCT can reveal choroidal atrophy, overlying retinal thinning, and photoreceptor loss, (Figure 3C) which can give rise to a subretinal cleft.^21–23 RPE is hyperreflective, thickened, and irregular, with lacunar RPE loss.²⁴ Thickened RPE causes optical shadowing.²⁵ On B-scan, CHRPE is flat and acoustically solid.²¹ On FA/ICG, the lesions block choroidal fluorescence, with window defects in the lacunae. Associated retinal and choroidal vasculature appear normal on OCTA.²⁶

RPE hamartoma (pigmented ocular fundus lesions)

RPE hamartoma is a gray, irregularly depigmented, flat or minimally elevated lesion with defined margins associated with familial adenomatous polyposis (FAP) and Garner syndrome. FAP is a hereditary condition in which patients develop colonic polyps with frequent malignant transformation. Gardner syndrome is a subtype of FAP associated with extracolonic manifestations.²⁷ RPE hamartoma can be fish-tail-, comma-, or comet-shaped (Figure 4A) with bilateral, multifocal, random distribution, not in a sector pattern. Also named pigmented ocular fundus lesions (POFL), these have been mislabeled as CHRPE. However, CHRPE is associated with RPE hypertrophy, whereas POFL has hyperplasia and hamartomatous changes.²⁸

Figure 4.

Retinal pigment epithelium (RPE) hamartoma associated with familial adenomatous polyposis (FAP). (A) Color fundus photograph demonstrates a comet-shaped pigmented lesion. On (B) fundus autofluorescence imaging, RPE hamartoma is hypoautofluorescent.

RPE hamartoma is hypoautofluorescent (Figure 4B) with outer retinal attenuation and RPE thickening on OCT. RPE extension into the retina can distinguish CHRPE from POFL.²⁹ On FA/ICG, the deeply pigmented lesions block choroidal fluorescence, with window defect in depigmented areas.^{30, 31} Associated telangiectatic vessels are hyperfluorescent with slight dye leakage.³² On OCTA, there is reduction in vascular density in the superficial capillary plexus. An observed increase in vascular density in the deep vascular plexus could be artifact.²⁸

Congenital simple hamartoma of the RPE (CSHRPE)

CSHRPE is a deeply pigmented discrete, solitary nodule that protrudes through sensory retina. Location is in the central macula, usually adjacent to the foveola, with a minimally dilated feeding artery and draining vein. Mild retinal traction can be observed, occasionally with exudation or pigmented vitreous cells.³³

CSHRPE is hypoautofluorescent.³⁴ On OCT, there is a hyperreflective and abruptly elevated dome-shaped solid mass in the inner retina, protruding into vitreous, with distinct borders and abrupt shadowing of the deeper retinal layers.^35–37 Simple hamartoma is hypofluorescent on FA/ICG.³⁷ OCTA can visualize vascular networks at the superficial and deep plexus and reveals an extensive intratumoral vascular network.^{37, 38}

Combined hamartoma of the retina and RPE (CHRRPE)

CHRRPE is gray, with ill-defined margins.³⁹ Characteristic glial proliferation can cause retinal traction and vision loss. Retinal vessels are tortuous or straightened, and peripheral lesions create a ‘dragged disc’ appearance. CHRRPE can be associated with peripheral retinal ischemia, neovascularization, and telangiectatic vessels.⁴⁰ Usually unilateral, autosomal dominant neurofibromatosis type 2 should be considered in the case of bilateral lesions.⁴¹

CHRRPE is hypoautofluorescent. OCT highlights vitreoretinal traction with an epiretinal membrane and retinal striae, in a sawtooth or folded pattern, replacing full thickness retina.^{24, 42} CHRRPE is acoustically solid on US.⁴³ During FA, there is patchy, late staining and abnormal retinal vasculature,⁴⁴ with hypercyanescence on ICG.⁴⁵ Gupta et al. graded density of flow signals, referred to as the filigree pattern on OCTA, and found a high density of filigree vascular pattern in most peripapillary lesions, associated with full-thickness retinal involvement. In contrast, macular lesions showed a low density of filigree pattern and only partial thickness retinal involvement.⁴⁶ Arrigo et al. reviewed six lesions and found decreased vessel densities in the choriocapillaris and superficial and deep capillary plexus.⁴⁷ Scupola et al. found increased vascular tortuosity, vessel caliber, and vascular traction in two lesions.⁴⁸

Choroidal nevus

Choroidal nevus is pigmented (Figure 5A, E, I, Figure 6A), partially pigmented, or amelanotic, with well-defined margins.⁴⁹ United States adult incidence is 4.7%.⁴⁹ Nevus can be associated with overlying drusen, RPE changes, a depigmented, yellow halo, and rarely choroidal neovascularization (CNV).⁵⁰

Figure 5.

Choroidal nevus. (A) Color fundus photograph of a pigmented, well-demarcated choroidal nevus. On (B) optical coherence tomography (OCT), the nevus is hyperreflective with choroidal thickening, posterior shadowing, and overlying drusen (inset). The lesion is well-defined by OCT angiography (OCTA) with (C) relatively normal overlying retinal vasculature with mild flow void density and (D) hyperreflective choroidal vessels and avascular areas on the lesion slab. (E) Fundus photograph of a well-demarcated nevus. (F) Enhanced depth imaging-OCT (EDI-OCT) demonstrates overlying drusen and pigment epithelial detachments (PEDs). On (G) B-scan ultrasonography (US), the lesion is dome-shaped and acoustically dense with corresponding (H) high internal reflectivity on A-scan. (I) Fundus photograph of a pigmented choroidal nevus. (J) OCT demonstrates a central overlying PED. On (K) OCTA avascular areas can be seen in the lesion slab. (L) Fundus photograph of a choroidal nevus with secondary choroidal neovascularization (CNV). OCT (M) demonstrates subretinal hyperreflective material and retinal edema. On (N) OCTA, CNV is seen on the outer retinal slab.

Figure 6.

Choroidal nevus with risk factors for transformation to melanoma. (A) Fundus photograph of a choroidal nevus with subtle overlying orange pigment (inset, arrow). On (B) fundus autofluorescence, the nevus is hypoautofluorescent, with overlying hyperautofluorescent orange pigment (inset, arrow). By (C) optical coherence tomography (OCT), a small cleft of subretinal fluid can be seen. OCT angiography (OCTA) shows (D) relatively normal overlying retinal vasculature with mild flow void density inferonasally and possible artifact superotemporally; (E) the lesion slab reveals irregular vessels with a vascular rim and avascular areas within the lesion.

Nevus is hypoautofluorescent but can have associated hyperautofluorescent orange pigment due to accumulation of lipofuscin overlying the lesion (Figure 6B). On OCT, the choroid is thick and elevated (Figure 5B, J). Overlying drusen (Figure 5B), PED (Figure 5J), retinal edema, subretinal fluid (Figure 6C), and fibrous metaplasia can be visualized. EDI-OCT (Figure 5F) can be used to measure thickness, aiding in early detection of growth, especially for lesions that appear flat on US.^{51, 52} Nevus is usually <2mm thick and can be acoustically solid (Figure 5G) or hollow on US corresponding to high (Figure 5H) or low A-scan internal reflectivity. Nevus is hypofluorescent on FA. Associated halo is slightly hyperfluorescent, and CNV (Figure 5L, M) can be detected.⁴⁹ On OCTA, nevus has well defined borders and is hyporeflective, without significant deformity of the RPE-Bruch’s membrane complex (Figure 5C, K).^53–55 The overlying superficial retinal plexus, deep retinal plexus (Figure 5C, 6D), outer retinal layer, and choroidal capillary vasculature appear normal.^{55, 56 57} Avascular areas can be present in some elevated nevi (Figure 5D, K, 6E).^{56, 58} There can be an intense vascular rim within the surface microvasculature (Figure 6E).⁵³ Pellegrini showed, in 11 eyes with nevus-associated CNV, that OCTA detects CNV with greater sensitivity than FA/ICG (Figure 5N).⁵⁹

About 1 in 8845 choroidal nevi transform into melanoma.⁶⁰ Shields et al. evaluated risk factors for malignant transformation based on multimodal imaging.⁶¹ The mnemonic ‘To Find Small Ocular Melanoma Doing IMaging’ describes risk factors: Thickness >2mm on US, subretinal Fluid on OCT, Symptoms (visual acuity 20/50 or worse), Orange pigment on FAF, Melanoma acoustic hollowness on US, and tumor DIaMeter >5mm on fundus photography.⁶² Others have distilled these features to mushroom shape, orange pigment, large size, enlargement over time, and presence of subretinal fluid, creating the MOLES scoring system, which Flanagan et al. demonstrated could be accurately applied by optometrists presented with a multimodal imaging panel, suggesting that this scoring system could improve diagnostic accuracy compared to fundus examination alone.⁶³

Although invasive biopsy can be avoided for low-risk lesions, suspicious choroidal nevi can be evaluated by fine-needle biopsy for assessment of gene expression profile (GEP), a standard of care practice for uveal melanoma prognostication. Interestingly, Harbour et al. found the only risk factors associated with Class 2 GEP and, therefore high metastatic potential, were patient age >60 years and tumor thickness >2.25mm.⁶⁴ Other risk factors for malignant growth were not associated with Class 2 GEP. While the absence of Class 2 GEP does not necessarily indicate lack of malignancy, as Class 1 tumors can also metastasize, current multimodal imaging features might not correlate with prognosis for suspicious melanocytic lesions. Future studies, currently underway, are required to determine if imaging features can be used to predict metastatic risk.

Melanocytosis

Choroidal melanocytosis is a congenital, typically unilateral, gray to brown discoloration often associated with iris, episcleral, and cutaneous involvement, conferring a 1 in 400 risk for uveal melanoma.⁶⁵

Melanocytosis is isoautofluorescent.⁶⁶ OCT shows choroidal thickening. US can rule out elevated nodules indicative of melanoma. On OCTA, overlying retinal vasculature is normal.⁶⁶

Melanocytoma

Melanocytoma is usually unilateral, deeply pigmented with feathery margins, and commonly involves the optic disc, occasionally with choroidal and retinal components.⁶⁷ Sometimes vitreous seeds form.⁶⁸

Melanocytoma is hypoautofluorescent⁶⁷ and optically dense with distinct abrupt shadowing on OCT.⁶⁹ By US, the dome-shaped lesion has medium to high internal reflectivity.⁷⁰ Melanocytoma is hypofluorescent on FA/ICG, but associated edema is hyperfluorescent. On OCTA, pigment blocks the signal, leading to a hyporeflective plexus with intact overlying retinal vasculature.^{54, 71} The vascular network within the tumor is fine and irregularly distributed, while the tumor is hyporeflective, with a hyperreflective halo.⁷² Outer retinal and choroidal layers appear normal.⁵⁷

Melanoma

Uveal melanoma, the most common adult primary intraocular malignancy, is pigmented, partially pigmented, or occasionally amelanotic (Figure 7A, D, 8A). Most are well demarcated, but rarely lesions are diffuse.⁶⁵ Associated orange pigment (Figure 8A), subretinal fluid, or serous retinal detachment are characteristic,⁷³ with a dark shadow on transillumination.⁷⁴ Vitreous seeding has occasionally been reported.^{75, 76}

Figure 7.

Choroidal melanoma. (A) Color fundus photograph of choroidal melanoma. On (B) B-scan ultrasonography (US), the melanoma is dome-shaped and acoustically hollow with corresponding (C) low internal reflectivity by A-scan. (D) Fundus photograph of choroidal melanoma with Bruch’s membrane rupture. (E) Optical coherence tomography (OCT) demonstrates the break in Bruch’s membrane. On (F) B-scan ultrasonography (US), the lesion has an early mushroom shape. (G) OCT of choroidal melanoma demonstrates an elevated, dome-shaped choroidal lesion with a (H) gravity-dependent puddle of subretinal fluid. (I) OCTA angiography (OCTA) reveals vascular networks.

Figure 8.

Choroidal melanoma with overlying orange pigment. (A) Fundus photograph of choroidal melanoma with overlying orange pigment (arrow, inset). On (B) fundus autofluorescence, the orange pigment is hyperautofluorescent (arrow, inset). (C) Optical coherence tomography (OCT) demonstrates shaggy photoreceptors (arrow) and subretinal fluid. On (D) B-scan ultrasonography (US), the melanoma is dome-shaped and acoustically hollow. (E) Fluorescein angiography (FA) demonstrates hyperfluorescent hot spots, and by (F) indocyanine green angiography (ICG), the lesion is hypocyanescent.

Choroidal melanoma is slightly hyperautofluorescent, with more robustly hyperautofluorescent orange pigment on FAF (Figure 8B).⁷⁷ Involved choroid is thick and elevated on OCT (Figure 7G, 8C), often with subretinal fluid (Figure 7H, 8C), thin or compressed choriocapillaris,⁷⁸ and outer retinal alterations such as shaggy photoreceptors (Figure 8C).²⁴ Melanoma is acoustically hollow on B-scan (Figure 7B, 8D) with low internal reflectivity (Figure 7C).⁷⁹ Often dome shaped on US (Figure 7B, 8D), melanoma can become mushroom-shaped if the lesion penetrates Bruch’s membrane (Figure 7E, F).⁶⁵ On FA/ICG melanoma has mottled hyperfluorescence in filling phase and diffuse late staining.⁸⁰ Pinpoint leaks, or hot spots, (Figure 8E) and double circulation sign can be visible due to the tumor’s internal vascularization.⁷³ Melanoma is hypocyanescent (Figure 8F). On OCTA, melanoma is isoreflective to hyporeflective, possibly surrounded by a hyperreflective ring in the choriocapillaris layer.^{81, 82} Tumor borders are ill-defined.^{54, 55} RPE-Bruch’s membrane complex is obscured; feeding vessels are dilated and tortuous; and the rate of blood flow in the choriocapillaris layer is decreased.^{53, 83} The tumor has heterogenous, disorganized vasculature (Figure 7I) with ring-like blood vessels, vascular loops, and areas of decreased vascularity.^{58, 84} In addition to its role in diagnosis of uveal melanoma, OCTA can also help detect early radiation retinopathy after melanoma treatment.⁸⁵ After irradiation, OCTA can show an increased foveal avascular zone, reduced capillary density, and reduced vessel complexity.^{59, 86} Veverka et al. described 7 cases using their adaptation of the Horgan grading system for radiation retinopathy, including OCTA data.⁸⁷

RPE adenoma and adenocarcinoma

RPE adenoma and adenocarcinoma are deeply pigmented, unilateral, abruptly elevated or dome-shaped, with associated feeder arterioles, exudation, and ocular inflammation. Lesions can arise from CHRPE and are more common in females.^{88, 89}

OCT reveals dense posterior shadowing, high anterior tumor reflectivity, and retinal invasion, with occasional vitreous seeds.⁸⁹ On US, the tumor is abruptly elevated with a ‘derby hat’ configuration and acoustically solid with high internal reflectivity.⁸⁹ By FA/ICG, there is early hypofluorescence, followed by hyperfluorescent zones in later stages, with leakage or staining.⁸⁹ Feeder vessels are accentuated.^{88, 89} Mehta et al. reported minimal flow signal on OCTA in a single presumed adenoma after treatment with intravitreal bevacizumab for associated exudative maculopathy.⁹⁰

On the horizon

Artificial intelligence (AI) and machine learning are rapidly being applied to ophthalmic images. Abràmoff et al. trained the Iowa Detection Program to analyze retinal images from diabetic patients.⁹¹ A combination of automated diabetic retinopathy image assessment systems was both clinically and cost effective.⁹² Gao et al. proposed a deep-learning-based high-resolution angiogram to enhance quality of OCTA images, leading to improved contrast, vascular connectivity, and lower noise intensity.⁹³ Application of AI to intraocular tumors could lead to earlier detection and treatment of life- and sight-threatening diseases, like uveal melanoma, but studies are still in early phases.⁹⁴

Yu et al. used two-dimensional UW fundus photography to assess choroidal melanocytic lesion thickness in 141 patients, correlating US thickness with tumor brightness.⁹⁵ Zabor et al. designed a deep learning protocol to minimize diagnostic uncertainty in a training set of 123 patients with choroidal nevus or small melanoma, pointing to important predictors of orange pigment, subretinal fluid, thickness, and distance to optic disc.⁹⁶ Although we must proceed with caution and human oversight to avoid erroneous diagnosis and management, AI could have a future role in early detection of small choroidal melanoma. Such models could eventually be utilized for accessible remote screening and could even lead to the discovery of new, clinically relevant biomarkers that are not detectable by the human eye.

Conclusion

In this review, we illustrated the utility of multimodal imaging to diagnose pigmented ocular fundus lesions, with particular attention to the importance of early recognition of malignant tumors. Fundus photography, FAF, OCT, US, FA and ICG remain important, as each modality can disclose key features of diagnostic and prognostic importance. Subtle orange pigment by FAF or subretinal fluid by OCT can raise concern for small melanoma, while such features could be missed by fundus examination alone. EDI-OCT can precisely measure lesion thickness in tumors too small to accurately assess by US, which can disclose early micron-level tumor growth. OCTA, a novel non-invasive technique to image vascular flow, is being actively investigated for utility in diagnosis of intraocular tumors, including features that could distinguish choroidal nevus from small choroidal melanoma. Looking to the future, AI and machine learning have potential as diagnostic aids to detect choroidal melanoma at its earliest stage.