Fatima Kalabi

Definition and clinical relevance

Cancer-associated retinopathy (CAR) is a paraneoplastic autoimmune retinopathy in which an immune response generated against tumour antigens cross-reacts with retinal antigens, resulting in subacute retinal dysfunction that is often bilateral and may occur with minimal intraocular inflammation (or a clinically quiet eye). In a clinically meaningful proportion of patients, visual symptoms can precede the diagnosis of the underlying malignancy, making CAR a potential ophthalmic “sentinel” presentation of occult cancer (4,7,8).

CAR is typically considered within the broader entity of autoimmune retinopathy (AIR), which includes paraneoplastic and non-paraneoplastic forms; contemporary guidance emphasises careful phenotyping to reduce diagnostic variability and misclassification (1,2).

Epidemiology and associated malignancies

CAR is rare, and most evidence derives from case series and systematic reviews. Small-cell lung carcinoma, breast carcinoma, and gynaecologic malignancies are repeatedly reported as the most common associated primary tumours, although a wide range of solid and haematological malignancies has been described (6,7,8).

Immunopathogenesis

The dominant mechanistic model is immune cross-reactivity: tumour expression of antigens that overlap (directly or immunologically) with retinal proteins stimulates humoral and cellular immune responses that damage photoreceptors and/or other retinal elements. Circulating anti-retinal antibodies are commonly detected in CAR and can support the diagnosis but are not independently diagnostic due to limitations in assay standardisation and imperfect clinical specificity (1,3,4).

Clinical presentation

Symptoms typically include painless, subacute bilateral visual disturbance with: photopsias, progressive visual field loss (often ring scotoma or diffuse constriction), reduced contrast sensitivity, and sometimes nyctalopia (night blindness) (4,8).

Examination may be normal early. Over time, some patients develop retinal pigment epithelium disturbance and vascular attenuation, producing a phenotype that can mimic inherited retinal degeneration (1,4).

Diagnostic evaluation

No single investigation is diagnostic; CAR is a clinicoinvestigative diagnosis requiring congruence between symptoms, objective functional testing, imaging phenotype, and systemic context. A structured framework is recommended by the American Academy of Ophthalmology Task Force guidance for autoimmune retinopathy (1,3).

1) Functional testing (core)

• Full-field electroretinography (ffERG) is central, typically demonstrating generalized rod and cone dysfunction consistent with diffuse retinal disease and supporting distinction from focal maculopathies (1,2,4).
• Formal visual field testing (perimetry) quantifies scotoma patterns and provides longitudinal monitoring of progression and treatment response (1,2,8).

2) Structural and multimodal imaging

• Optical coherence tomography (OCT) commonly shows outer retinal disruption (including ellipsoid zone abnormalities), sometimes with relative early foveal sparing.
• Fundus autofluorescence (FAF) may demonstrate characteristic rings or patchy abnormalities that support an autoimmune retinopathy phenotype while recognising overlap with inherited retinal disease (1,3).

3) Antiretinal antibody testing: interpretive cautions

Antiretinal antibody testing is best used as an adjunct after a compatible clinical phenotype is established. Task Force guidance highlights variability in assays and emphasises that antibody results must be interpreted in clinical context (1,3). Moreover, evidence suggests that repeatedantibody titre/number testing may have limited correlation with visual outcomes and may be unnecessary in many cases after diagnosis is established (5).

4) Exclusion of mimics

The differential diagnosis includes inherited retinal dystrophies, toxic retinopathy, occult inflammatory disease, optic neuropathies, and other causes of rapid retinal dysfunction; careful history, imaging, and objective functional testing are essential to avoid misdiagnosis (1,2).

5) Evaluation for underlying malignancy

When no malignancy is known, a compatible phenotype should prompt urgent liaison with primary care/oncology/acute medicine for malignancy evaluation tailored to patient age, risk profile, and systemic symptoms, because CAR can precede cancer diagnosis (4,6,7).

Management

Evidence remains limited and heterogeneous, and controlled trials are lacking; management is therefore individualised and multidisciplinary (1,7).

1) Oncologic management

Treatment of the underlying malignancy is essential, but ocular outcomes are variable and visual recovery is not assured even with tumour control (4,6,7).

2) Immunomodulatory therapy

Therapeutic strategies reported include systemic corticosteroids, steroid-sparing immunosuppressive agents, intravenous immunoglobulin (IVIG), and plasma exchange (PLEX), selected according to severity, tempo of progression, and systemic constraints (1,4,7).

A systematic review of antibody-proven CAR reported visual acuity improvement in a proportion of treated cases, particularly among patients receiving corticosteroids (with or without plasma exchange), but inference is constrained by publication bias, small numbers, and non-standardised outcome measures (7). Consistent with these limitations, guideline documents recommend objective longitudinal monitoring with functional and imaging endpoints when immunomodulation is used (1,2).

Prognosis and follow-up

CAR often follows a progressive course with persistent field loss and functional impairment. Follow-up should prioritise objective metrics—ffERG and perimetry—supported by OCT and FAF to document progression, therapeutic response, and counselling-relevant structure–function relationships (1,2).

References 

1. Modjtahedi BS, Palestine AG, Jampol LM, Sarraf D, Sen HN, Sobrin L, et al. Guidelines for the Diagnosis, Management, and Study of Autoimmune Retinopathy from the American Academy of Ophthalmology’s Task Force. Ophthalmology Retina. 2025;9(10):1005–1016. doi:10.1016/j.oret.2025.03.024. (Oregon Health & Science University)
2. Fox AR, Gordon LK, Heckenlively JR, Davis JL, Goldstein DA, Lowder CY, et al. Consensus on the Diagnosis and Management of Nonparaneoplastic Autoimmune Retinopathy Using a Modified Delphi Approach. Am J Ophthalmol. 2016;168:183–190. doi:10.1016/j.ajo.2016.05.013. (hsrc.himmelfarb.gwu.edu)
3. American Academy of Ophthalmology. Guidelines for the Diagnosis, Management, and Study of Autoimmune Retinopathy (Clinical Statement). 2025. (AAO)
4. Singh D, Tripathy K. Cancer-Associated Retinopathy. In: StatPearls (Internet). Treasure Island (FL): StatPearls Publishing; Updated 27 Feb 2024. (NCBI)
5. Rujkorakarn P, Margolis MJ, Morvey D, Zhou Y, Foster CS. Limited clinical value of anti-retinal antibody titers and numbers in autoimmune retinopathy. Clin Ophthalmol. 2023;17:749–755. doi:10.2147/OPTH.S404826. (PubMed)
6. Thomas AS, Drenser KA, Francis JH. Paraneoplastic retinopathies: an update on pathogenesis, diagnosis and management. Ann Eye Sci. 2024. (aes.amegroups.org)
7. Brossard-Barbosa N, et al. Treatment of Cancer-Associated Retinopathy: A Systematic Literature Review. Ophthalmology Retina. 2023. (PubMed)
8. Goldstein SM, et al. Cancer-Associated Retinopathy. JAMA Ophthalmol. 1999;117:—. (Accepted for publication July 8, 1999.) (JAMA Network)
9. EyeWiki (American Academy of Ophthalmology). Cancer Associated Retinopathy. Updated 2025. (eyewiki.org)