Introduction: The aim of this study was to differentiate amelanotic choroidal lesions – amelanotic choroidal melanoma, choroidal metastasis, and choroidal granuloma using multimodal imaging. Methods: Retrospective comparative chart review was done. Patients diagnosed with the abovementioned choroidal lesions from 2015 to 2022 were included. Baseline lesion morphology and retinal layer changes on optical coherence tomography (OCT), lesion echogenicity and dimensions on ocular ultrasonography (USG), fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), and indocyanine green angiography (ICG-A) patterns and findings were assessed. Results: Twelve eyes with melanoma, 22 eyes with metastasis, and 9 eyes with granuloma were included. On OCT, 83% of melanomas and 67% of granulomas, and 68% of metastasis had dome-shaped choroidal lesions. Presence of intraretinal fluid (IRF) and shaggy photoreceptors was 94% (95% CI: 79–99%) and 90% (95% CI: 74–98%) specific to differentiate melanomas from other choroidal lesions (AUC >0.75, p < 0.05). Similarly, presence of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) was 77% (95% CI: 55–92%) sensitive and 77% (95% CI: 53–92%) specific (AUC = 0.8, p+ 0.03) and presence of lumpy-bumpy choroid was 55% (95% CI: 32–76%) sensitive and 95% (95% CI: 76–99%) specific (AUC = 0.75, p = 0.04) to distinguish metastasis from other choroidal lesions. Mean height: base ratio was more in melanoma compared to metastasis (0.54 ± 0.22 vs. 0.43 ± 0.12, p = 0.17) and both were hyperechoic on USG. On FAF, 100% metastasis and 60% granulomas were hypoAF, whereas 100% melanomas were hypoAF. Majority choroidal lesions were hyperfluorescent on FFA. Double vascular circulation was observed in melanomas (50%). On ICG-A, all choroidal lesions were hypofluorescent. Conclusion: Clinical and multimodal imaging features such as the presence of IRF, shaggy photoreceptors, iRORA, and lumpy-bumpy choroid can help diagnose and differentiate amelanotic choroidal lesions, thereby avoiding the need for choroidal biopsy. Further larger studies are needed to devise a standard imaging protocol to validate our findings.

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