Choroidal Nevus

Key points of this disease

• Choroidal nevus is a benign proliferation of choroidal melanocytes, often found incidentally during fundus examination in adults.
• The prevalence is about 5% in Westerners, but low at about 0.3% in Japanese.
• Most are stationary and malignant transformation is rare, but risk factor assessment using TFSOM-UHHD (8-item risk evaluation criteria) is important.
• If there are 0 risk factors, the probability of growth within 5 years is only about 3%, but if 2 or more, it rises to over 50%.
• Low-risk lesions are followed with regular fundus examinations every 12–24 months, and high-risk lesions every 6 months.
• If growth is confirmed, the treatment strategy is changed to that for choroidal malignant melanoma.

1. What is a choroidal nevus?

A choroidal nevus is a pigmented lesion caused by benign proliferation of melanocytes in the choroid. It appears as a gray-black, roundish subretinal lesion on fundus examination and usually follows a stationary (non-growing) course.

The prevalence is about 5% in Westerners and about 0.3% in Japanese, with a relatively high distribution in the posterior pole. It may also be found near the equator or the far periphery near the ora serrata. In many cases, it is discovered incidentally during routine eye examinations in adults or during evaluation of other diseases.

The frequency of malignant transformation is reported as 0.5–3% per 10 years in Western reports. It is considered even rarer in Japanese, but if malignant transformation occurs, it is treated as choroidal malignant melanoma (choroidal melanoma). About 10% of choroidal melanomas are reported to arise from a preexisting nevus.

Q I was told there is a dark shadow on my retina. Could it be cancer?

A

A choroidal nevus is a benign pigmented lesion and is usually not a problem. However, if multiple risk factors such as thickness or fluid accumulation are present, regular follow-up is necessary. Follow your doctor’s instructions for regular check-ups, and if you experience changes in vision, floaters, or flashes of light, seek medical attention promptly.

2. Main symptoms and clinical findings

Fundus photograph of a pigmented choroidal nevus adjacent to the optic disc (left eye)

Villegas VM, et al. Optical Coherence Tomography Angiography of Two Choroidal Nevi Variants. Case Rep Ophthalmol Med. 2017. Figure 1. PMCID: PMC5654279. License: CC BY.

A fundus photograph of the left eye shows a pigmented choroidal nevus adjacent to the optic disc (juxtapapillary type). This corresponds to the typical fundus findings of choroidal nevus discussed in the section “Main symptoms and clinical findings.”

Subjective symptoms

The majority of choroidal nevi are asymptomatic and discovered without subjective symptoms. If the lesion extends to the macula or near the optic disc, or if subretinal fluid is present, the following symptoms may appear.

• Decreased vision and metamorphopsia: when the macula is involved
• Photopsia: due to mechanical stimulation of the retina
• Floaters: Rarely occur due to vitreous involvement

Clinical Findings

Typical findings of choroidal nevus are as follows:

• Gray-black, roundish subretinal elevation
• Diameter usually within 3 optic disc diameters (DD)
• Height (thickness) less than 2 mm, low profile, ≤1/5 of diameter
• Relatively well-defined borders
• Usually stationary (non-progressive) course

Orange pigment (lipofuscin deposition) is an important predictor of malignant transformation. It is deposition of aging pigment produced by the RPE (retinal pigment epithelium) and appears as hyperautofluorescence on fundus autofluorescence.

Presence of subretinal fluid is a concerning finding and suggests disruption of the RPE barrier. If subretinal fluid is present, further evaluation for malignant transformation is necessary.

Risk Assessment for Malignant Transformation Using TFSOM-UHHD

To differentiate choroidal nevus from choroidal melanoma, the TFSOM-UHHD criteria, which evaluate the following 8 risk factors, are used.

Factor	Criteria	Significance
Thickness	Greater than 2 mm	Increase in tumor volume
Fluid	Presence of subretinal fluid	RPE barrier breakdown
Symptoms	Photopsia and floaters	Indicator of tumor activity
Orange pigment	Lipofuscin deposition	Tumor metabolic activity
Margin	Within 3 mm of the optic disc	Risk of optic disc infiltration
Ultrasound Hollow (hypoechoic)	Internal hypoechogenicity	Tumor vascular density
Halo absent	No halo (light ring)	Absence of benign indicator
Drusen absent	No drusen	Absence of chronic changes

The relationship between the number of risk factors and the probability of growth within 5 years is shown below.

Number of risk factors	5-year growth probability
0	Approximately 3%
1	Approximately 38%
2 or more	>50%

3. Causes and Risk Factors

Pathogenesis

Choroidal nevus is a benign proliferation of melanocytes in the choroid, and the exact cause is unknown. It often occurs sporadically.

Risk Factors for Malignant Transformation

The following systemic and clinical factors are thought to increase the risk of malignant transformation.

• Light-colored iris and fair skin (Caucasian/Northern European descent)
• Congenital ocular melanocytosis (ocular disease associated with nevus of Ota)
• Family history of uveal melanoma
• BAP1 tumor predisposition syndrome (germline mutation of BRCA1-associated protein 1)

Each factor of TFSOM-UHHD reflects the local risk of malignant transformation.

• Orange pigment (lipofuscin): Accumulation of aging pigment from RPE indicates tumor activity
• Subretinal fluid: Suggests disruption of the RPE barrier by the tumor
• Thickness ≥2 mm: Reflects increase in tumor volume
• Tumor contact with the optic disc: Increased risk of optic nerve invasion
• Internal low reflectivity on ultrasound: Suggests presence of intratumoral vessels

Genetic Abnormalities and Malignant Transformation

Malignant transformation to choroidal melanoma involves accumulation of genetic abnormalities. Main associated abnormalities include monosomy 3 and BAP1 mutations. These mutations are frequently detected in choroidal melanoma but are usually not found in benign nevi.

4. Diagnosis and Examination Methods

Fundus Examination and Fundus Photography

Fundus examination (ophthalmoscopy, wide-field fundus photography) is the basis for screening and follow-up. Serial fundus photography is essential for determining tumor growth, and wide-field fundus photography (e.g., Optos) is also useful.

Optical Coherence Tomography (OCT)

OCT is excellent for visualizing subretinal fluid and RPE changes. EDI-OCT (enhanced depth imaging OCT) allows evaluation of choroidal structure, and the following findings are observed:

• Optical choroidal shadowing
• Presence of subretinal fluid
• RPE changes (atrophy, elevation)
• Subretinal hyperreflective material (SRHM)

Fundus Autofluorescence

Orange pigment (lipofuscin) appears as brighter hyperfluorescence than drusen. It is useful for evaluating lipofuscin deposition and helps assess the risk of malignant transformation.

Fluorescein Angiography (FA)

FA (fluorescein angiography) shows a hyperfluorescent pattern. Blocking fluorescence due to pigment and hyperfluorescence due to lipofuscin deposition are mixed.

Ultrasonography (B-mode, Color Doppler)

B-mode ultrasound is used to measure tumor height and evaluate internal echo patterns. Color Doppler ultrasound can confirm the presence or absence of pulsatile blood flow at the tumor base. Choroidal nevi are often color Doppler negative (no tumor blood flow), while melanomas are often color Doppler positive. This finding is an important distinguishing feature between nevi and melanomas.

Differential Diagnosis of Choroidal Tumors (Three Major Diseases)

The characteristics of the main differential diagnoses of choroidal tumors are shown below.

	Malignant Melanoma	Hemangioma	Metastatic Tumor
Color	Black, gray, brown	Orange-red	Yellow-white
Shape	Tall	Fusiform	Plate-like
Retinal detachment	None to moderate	None to mild	Marked
Growth	Relatively slow	None	Fast

Other differential diagnoses include congenital hypertrophy of the retinal pigment epithelium (CHRPE), choroidal hemorrhage, and melanocytoma.

Q What is the risk of malignant transformation of a choroidal nevus?

A

It varies greatly depending on the number of risk factors. Among the 8 items of TFSOM-UHHD, if there are 0 risk factors, the probability of growth within 5 years is about 3%. However, with 1 risk factor it rises to about 38%, and with 2 or more it exceeds 50%. Regular follow-up with ultrasound and fundus photography is important, and if enlargement is observed, promptly switch to treatment for choroidal malignant melanoma.

5. Standard Treatment

The basic treatment for choroidal nevus is observation. Currently, there is no drug therapy or surgical indication for the nevus itself, and regular fundus examinations are performed to monitor for enlargement of the lesion.

Low-risk lesions (no risk factors, small nevus)

Small nevi without risk factors according to TFSOM-UHHD are managed as low risk.

• Observation interval: Regular fundus examination every 12–24 months
• Record growth using fundus photography and B-mode ultrasound
• If no abnormal findings, continue follow-up at the same interval

Intermediate/High-Risk Lesions (with risk factors)

If one or more TFSOM-UHHD risk factors are present, careful regular observation is performed.

• Re-examine 3 months after initial examination (check for growth)
• Thereafter, continue every 6 months with fundus photography and ultrasound for life
• For small tumors with 3 or more risk factors, consider prompt treatment initiation without waiting for growth documentation

When Growth Is Confirmed

If tumor growth is confirmed during follow-up, the treatment strategy is changed to that for choroidal malignant melanoma. Specific treatment options are determined based on tumor size and visual function, and include radiation therapy (plaque brachytherapy, proton beam therapy) or enucleation (see the article on choroidal and ciliary body melanoma for details).

Importance of Regular Examinations

Even if diagnosed with choroidal nevus, most cases progress without problems. Continuing fundus examinations at the intervals specified by your doctor is the best way to detect early changes. If new symptoms such as photopsia, floaters, or vision changes appear, seek medical attention promptly without waiting for the next scheduled examination.

Long-Term Observation of Nevi with Risk Factors

Nevi with multiple risk factors such as thickness ≥2 mm, subretinal fluid, orange pigment, or proximity to the optic disc require lifelong regular observation. Interrupting observation carries the risk of missing malignant transformation. It is important to continue regular examinations even without symptoms.

Q How often is follow-up needed for choroidal nevus?

A

The observation interval varies depending on the risk. For low-risk lesions without risk factors, an interval of once every 12 to 24 months is standard. For intermediate- or high-risk lesions with risk factors, re-examination is performed after the first 3 months, followed by lifelong fundus examination and ultrasound every 6 months. Continuing regular observation is most important.

6. Pathophysiology and Detailed Mechanisms

Mechanism of Benign Proliferation

A choroidal nevus is a lesion caused by localized benign proliferation of choroidal melanocytes. Normal choroidal melanocytes originate from neural crest cells and have pigment-producing ability. In the benign proliferation stage, cell morphology is preserved, and invasive growth or metastasis does not occur.

Molecular Mechanisms of Malignant Transformation

Malignant transformation from choroidal nevus to melanoma requires the accumulation of multiple genetic abnormalities.

• GNAQ/GNA11 mutations: Initiating mutations detected in about 90% of choroidal melanomas. They cause constitutive GTP-binding activation, persistently activating multiple signaling pathways such as the MAPK pathway.
• Monosomy 3: A secondary mutation strongly associated with metastatic risk.
• BAP1 mutations: Associated with the highest metastatic risk. Also known as the causative gene for BAP1 tumor predisposition syndrome.
• SF3B1 mutations: Moderate metastatic risk, characterized by late metastasis.
• EIF1AX mutations: Lowest metastatic risk.

These malignant mutations are usually not found in the nevus stage. It is thought that the accumulation of genetic abnormalities leads to a continuous change from benign to malignant.

Biological Significance of Risk Factors

Each item of TFSOM-UHHD reflects the following pathology.

Orange pigment (lipofuscin): An aging pigment produced by the RPE. It reflects the metabolic activity of the tumor and the interaction between the tumor and RPE; accumulation increases with higher tumor activity.

Subretinal fluid: A finding suggesting disruption of the RPE barrier by the tumor. When the tumor grows and becomes active, the RPE pump function decreases, and fluid accumulates under the retina.

Internal low reflectivity on ultrasound: Suggests high density of intratumoral vessels. Choroidal melanoma often has abundant intratumoral vessels and shows internal low reflectivity. Benign nevi usually have a uniform, high-reflectivity internal echo pattern.

Color Doppler positive (pulsatile flow): Indicates that the tumor has its own blood supply. Nevi are often color Doppler negative, which is an important distinguishing feature from melanoma.

7. Latest Research and Future Perspectives

For patients: Please read this

The following content is currently at the research stage and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Validation of TFSOM-UHHD Criteria Accuracy

Validation studies of the sensitivity and specificity of the TFSOM-UHHD criteria are ongoing, and improvements in clinical accuracy are expected. In the future, more precise risk stratification incorporating a 5-year risk calculation model may be realized.

Application of OCT Angiography

Non-invasive visualization of intratumoral vessels using OCT angiography (OCTA) is being studied. Combined with color Doppler ultrasound, it is expected to further improve the accuracy of differentiating nevi from melanoma.

Quantitative Assessment of Orange Pigment

Development of a quantitative assessment method for lipofuscin (orange pigment) using fundus autofluorescence is progressing. The goal is to improve risk prediction accuracy by quantifying the amount of pigment.

Risk Stratification Using Molecular Biomarkers

Research on non-invasive genomic assessment using liquid biopsy (e.g., circulating tumor DNA in blood) is advancing. In the future, it may be combined with fundus findings for early detection of malignant transformation.

8. References

1. Finger PT. Laser treatment for choroidal melanoma. Surv Ophthalmol. 2023;68(2):211-224.
2. Qureshi MB, Lentz PC, Xu TT, White LJ, Olsen TW, Pulido JS, et al. Choroidal Nevus Features Associated with Subspecialty Referral. Ophthalmol Retina. 2023;7(12):1097-1108. PMID: 37517800.
3. Chien JL, Sioufi K, Surakiatchanukul T, Shields JA, Shields CL. Choroidal nevus: a review of prevalence, features, genetics, risks, and outcomes. Curr Opin Ophthalmol. 2017;28(3):228-237. PMID: 28141766.