Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that occurs in patients with malignant melanoma. Neural antigens ectopically expressed in malignant tumors are recognized by the immune system, leading to the production of specific antibodies that damage the retina through an autoimmune mechanism.
It is classified as a type of cancer-associated retinopathy (CAR) in a broad sense. While CAR primarily affects rod photoreceptors, MAR mainly targets retinal bipolar cells. The most common cause of CAR is small cell lung cancer, whereas MAR is exclusively caused by malignant melanoma.
Previously reported only in Western countries, MAR has become known in Japan in recent years. The largest case series is a collection of 62 cases by Keltner et al. (2001)2). It is more common in men and typically occurs with metastatic cutaneous melanoma, but cases associated with uveal melanoma or nasal melanoma have also been reported4).
The onset of MAR symptoms may indicate metastasis or recurrence of melanoma2)3). The average survival time after diagnosis is about 5.9 years, but some patients survive for decades. Reports suggest that the presence of antibodies in advanced melanoma correlates with a better prognosis, indicating that autoantibodies may play a protective role in eliminating melanoma cells.
Visual symptoms of MAR can be an early sign of melanoma metastasis or recurrence2)3). If a patient with a history of melanoma develops new visual symptoms, ophthalmic examination and systemic oncological evaluation are recommended.
The onset of MAR is usually acute, presenting with progressive and painless visual impairment.
Symptoms are usually bilateral, but there are rare reports of unilateral involvement1).
Fundus findings in MAR are often normal in the early stages. As the disease progresses, the following findings appear.
Early Stage
Fundus findings: Often normal. No obvious abnormalities in the optic nerve, retinal vessels, or retinal pigment epithelium.
OCT findings: Often within normal range in the early stage2)3). Abnormalities may be detected approximately 6 months later than on electroretinography.
Advanced stage
Optic disc pallor: Appears as retinal degeneration progresses.
Retinal vascular attenuation: Reflects ongoing retinal degeneration.
RPE changes: Loss and granular changes of the retinal pigment epithelium. May also cause chorioretinal atrophy5).
OCT findings: Thinning of the inner nuclear layer (INL) and inner plexiform layer (IPL)2), cystoid changes within the INL4), and loss of the interdigitation zone4).
The cause of MAR is malignant melanoma. Tumor cells ectopically express retinal antigens, which are recognized by the immune system, leading to the production of anti-retinal antibodies. These autoantibodies damage retinal bipolar cells, causing retinal dysfunction.
The main risk factors are as follows:
The clinical diagnosis of MAR is based on the following triad:
Electroretinography is an essential test for diagnosing MAR. It is characterized by a marked reduction in b-wave amplitude with preservation of the a-wave, resulting in a negative ERG. This finding resembles congenital stationary night blindness (CSNB), but differs in that it is acquired.
ERG can detect abnormalities earlier than OCT 2). In some cases, ERG showed marked abnormalities at onset, whereas OCT detection of abnormalities was delayed by about 6 months 2).
The ERG findings of MAR and other paraneoplastic retinopathies are compared below.
| Disease | a-wave | b-wave |
|---|---|---|
| MAR | Nearly normal | Markedly reduced |
| CAR | Decreased | Decreased |
Serum autoantibodies against retinal bipolar cells are detected by Western blotting or immunohistochemistry. This is useful for definitive diagnosis, but antibody titers fluctuate with disease activity, so at least three measurements are necessary. Even if antibodies are not detected, MAR cannot be ruled out3).
Major target antigens include the following:
No definitive treatment for MAR has been established. Treatment consists of two pillars: control of the primary tumor and immunomodulation for retinopathy.
Treatment of the primary lesion is the first priority. Reduction of tumor burden may decrease antigenic stimulation and suppress autoantibody production 3). Resection of metastases, chemotherapy, and radiation therapy are considered.
There is a report that administration of pembrolizumab (anti-PD-1 antibody) led to normalization of the electroretinogram and complete remission of visual symptoms3).
Khaddour et al. (2021) reported that pembrolizumab was administered to a patient with autoantibody-negative MAR without immunosuppressants, and after 2 cycles (6 weeks), visual symptoms improved and the b-wave of the electroretinogram normalized 3). Metastatic melanoma also achieved complete metabolic remission, with no recurrence observed 30 months after the end of treatment.
Tshuva-Bitton et al. (2025) reported a detailed 7-year follow-up showing that after starting pembrolizumab, the b-wave amplitude of the dark-adapted electroretinogram improved by more than 60%, and OCT also showed increased macular thickness and improved visual field 2).
Tumor Treatment
Control of primary tumor: Reducing tumor burden to decrease antigenic stimulation. Includes surgery, chemotherapy, and radiation therapy.
Immune checkpoint inhibitors: PD-1 inhibitors such as pembrolizumab. There are reports of efficacy in both tumor control and improvement of MAR 2)3).
Immunomodulatory Therapy
Intravenous immunoglobulin therapy (IVIG): Visual field improvement has been reported through immunomodulation. Evidence of efficacy is limited.
Immunosuppressive drugs: azathioprine, cyclosporine, etc. When used in combination with other treatments, they may improve visual field and electroretinogram findings in some cases2).
Plasma exchange therapy: aims to remove antibodies, but benefit has been shown in only a few cases.
Systemic steroid administration for MAR is generally contraindicated. Steroids may suppress cancer immunity and reduce the antitumor effect of ICI 3). For details, see the “Standard Treatment” section.
The pathology of MAR is based on an autoimmune reaction against retinal antigens ectopically expressed in malignant melanoma. Tumor cells and retinal cells share common antigens, and antitumor antibodies cross-react with the retina, impairing retinal function.
The main target in MAR is TRPM1 (transient receptor potential cation channel subfamily M member 1) 1)4). TRPM1 is an mGluR6-coupled ion channel that plays a key role in the signal transduction pathway of retinal ON bipolar cells 4). Identified as a melanocyte-specific protein, TRPM1 is thought to generate neoantigens through abnormal mRNA splicing in malignant melanoma cells, triggering an immune response 1).
TRPM1 and TRPM3 have similar sequences, and sera from MAR patients may show cross-reactivity to both 4). This cross-reactivity is suggested to cause widespread effects on the retina, potentially involving not only bipolar cells but also photoreceptor damage 4).
Anti-TRPM1 antibodies inhibit synaptic transmission in ON-type bipolar cells, blocking rod system signals at the bipolar cell level. This selective dysfunction results in a preserved a-wave (photoreceptor-derived) but a markedly reduced b-wave (bipolar cell-derived) on electroretinography.
Cohen et al. (2024) performed detailed SD-OCT analysis in a case of unilateral MAR and found that the normal five-layered structure of the inner plexiform layer (IPL) was lost, with disappearance of the IPL sublamina corresponding to ON-type bipolar cells 1). This structural change is nearly identical to that in congenital stationary night blindness due to TRPM1 mutations (cCSNB), indicating that different disease mechanisms converge on a common downstream target (TRPM1).
The immune response in MAR is divided into two types based on the localization of the target antigen 3).
This immunological heterogeneity explains the variability in MAR outcomes after ICI administration3).
TRPM1 is an ion channel involved in signal transduction of retinal ON bipolar cells. In MAR, autoantibodies against TRPM1 are produced, impairing bipolar cell function1)4). Detection of anti-TRPM1 antibody is useful for definitive diagnosis of MAR.
Tshuva-Bitton et al. (2025) followed a 46-year-old male with cutaneous melanoma-associated MAR for 7 years using multimodal imaging 2). After starting pembrolizumab, the dark-adapted b-wave amplitude improved by over 60%, with increases in macular OCT thickness and improvement in visual field MD values. Thinning of the INL and IPL was the main cause of retinal thickness changes, with no significant changes in the outer retina.
Cohen et al. (2024) reported a case of unilateral MAR developing after nivolumab administration in a patient with melanoma in remission 1). Discontinuation of nivolumab led to improvement in symptoms and electroretinogram findings, and microperimetry confirmed recovery of retinal sensitivity. Structural analysis at the sublamina level of the IPL indicated selective impairment of the ON bipolar cell pathway.
Khaddour et al. (2021) reported the first case of a MAR patient without detectable autoantibodies who achieved complete normalization of electroretinogram and resolution of symptoms with pembrolizumab alone 3). This finding suggests that ICI therapy may be safe and effective in B-cell-mediated pathology.
OCT layer segmentation may allow quantitative evaluation of bipolar cell damage in MAR as changes in INL and IPL thickness 2). Layer analysis has been shown to be more useful than total macular thickness for understanding pathology.
