Dear editors, Choroidal metastases are the most common intraocular malignancies in adults.1 While most originate from breast or lung carcinoma, metastases from cutaneous melanoma are comparatively rare.1, 2 Diagnosis may be challenging, particularly in asymptomatic patients in whom other pigmented choroidal lesions must be considered. We report a case of bilateral pigmented choroidal lesions in metastatic cutaneous melanoma that completely regressed following a single dose of systemic immunotherapy. A 73-year-old man was diagnosed in September 2020 with an ulcerated superficial spreading melanoma on left side of the trunk (Breslow thickness 3.3 mm, pT3b). Sentinel lymph node biopsy in the left axilla was negative. In January 2021, PET–CT revealed metabolic activity in the spleen, liver, and bones (Figure 1a), accompanied by markedly elevated tumor markers (S100 27,300 µg/L; LDH 1,090 U/L). Given the extensive skeletal metabolic activity and exceptionally high LDH and S100, bone marrow infiltration was suspected. Although not routinely performed in metastatic melanoma, bone marrow biopsy was undertaken and confirmed infiltration of the bone marrow with SOX10- and Melan A-positive melanoma cells. Targeted therapy with encorafenib and binimetinib was initiated, achieving partial remission that was maintained for 19 months. In September 2022, during routine ophthalmologic evaluation while still on targeted therapy, new bilateral pigmented choroidal lesions were noted incidentally. The patient was asymptomatic. Visual acuity was finger counting in the right eye due to a macular hole and 20/20 in the left eye. Fundoscopy demonstrated slightly elevated pigmented choroidal lesions in both eyes with associated orange pigment, without subretinal fluid or drusen (Figure 2). The differential diagnosis included primary choroidal melanoma, choroidal metastases, and bilateral diffuse uveal melanocytic proliferation (BDUMP). Primary choroidal melanoma is typically unilateral and associated with subretinal fluid, drusen, lipofuscin deposition, and visual symptoms.3 Although orange pigment initially raised suspicion, the bilateral presentation, absence of subretinal fluid, and lack of symptoms argued against primary melanoma. BDUMP was considered but lacked hallmark findings such as diffuse uveal thickening, reddish retinal pigment epithelial patches, or exudative detachment.2 In the setting of known metastatic melanoma, bilateral choroidal metastases were considered most likely. Although tumor markers had normalized, the new ocular lesions raised concern for emerging metastatic activity. The patient remained immunotherapy-naïve. Given the well-recognized development of acquired resistance to BRAF/MEK inhibition, particularly in patients with high baseline LDH, a transition to immune checkpoint inhibition had been anticipated. After interdisciplinary discussion and intensive discussion with the patient, treatment was escalated to combination immunotherapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg), aiming for durable disease control rather than waiting for overt systemic progression. Shortly after the first dose, the patient developed proximal muscle weakness with markedly elevated creatine kinase (4,970 U/L) and troponin T (674 pg/mL). Acute coronary syndrome was excluded by coronary angiography. Echocardiography and cardiac magnetic resonance imaging did not demonstrate obstructive coronary pathology and were compatible with a non-ischemic inflammatory process. In the absence of coronary artery disease, the biomarker elevation and temporal association with immune checkpoint inhibition were considered consistent with immune checkpoint inhibitor–associated myocarditis with possible myositis overlap. Endomyocardial biopsy was not performed due to the acute presentation. High-dose intravenous methylprednisolone (1,000 mg/day for five days) led to clinical improvement and declining CK levels. After initial clinical stabilization, the patient elected to leave the hospital against medical advice despite persistent troponin elevation. The following day, he was admitted to an external hospital with acute chest pain and was diagnosed with myocardial infarction. Although prior coronary angiography had excluded acute coronary syndrome, a negative evaluation does not preclude a subsequent coronary event, particularly in the context of ongoing myocardial inflammation. Repeated angiography demonstrated a severe distal stenosis of the right coronary artery without visible thrombus. The lesion was not amenable to percutaneous intervention due to its distal location. Recovery was prolonged but ultimately successful. Given the severity of cardiovascular toxicity, immunotherapy was permanently discontinued. Following discontinuation, no further oncologic therapy was administered. PET–CT demonstrated complete metabolic remission (Figure 1b), and tumor markers remained within normal limits. The choroidal lesions, although initially morphologically detectable, showed no metabolic activity and gradually regressed. After three years, complete resolution was documented with only minor retinal pigment epithelium irregularities (Figure 3). Imaging confirmed sustained systemic complete remission. This case underscores the diagnostic complexity of pigmented choroidal lesions in metastatic melanoma and highlights the importance of integrating ocular findings in the systemic oncologic context. It also illustrates the relevance of treatment sequencing in BRAF V600-mutant melanoma. The SECOMBIT trial demonstrated that sequencing strategies influence long-term outcomes.4 In this study, Arm A consisted of targeted therapy until progression followed by combination immunotherapy, whereas Arm B evaluated upfront immunotherapy and Arm C involved a short induction with targeted therapy followed by early immunotherapy. Long-term overall survival was superior in Arms B and C compared with Arm A, suggesting that delaying immunotherapy until progression may compromise durable benefit. Although our patient was transitioned after 19 months rather than according to a predefined early-switch protocol, the decision to initiate immunotherapy prior to overt systemic progression aligns conceptually with the principle of avoiding delayed immunotherapy exposure. Finally, this case demonstrates a complete and sustained remission of metastatic melanoma, including choroidal metastases, following brief systemic immunotherapy. It underscores the importance of early therapeutic intervention and close interdisciplinary collaboration in the diagnosis and management of ocular manifestations of systemic malignancies. Yenny Angela: Honoraria for lectures/advisory boards from Roche, BMS, MSD, Novartis, Amgen, Merck Serono, Almirall Hermal, SUN, Sanofi, Pierre Fabre, Kyowa Kirin, and Takeda. Congress participation supported by Novartis, Pierre Fabre, and UCB. Ralf Gutzmer: Honoraria for lectures/advisory boards from BMS, MSD, Novartis, Merck Serono, Almirall Hermal, SUN Pharma, Sanofi, Regeneron, Pierre Fabre, Immunocore, Delcath, Incyte. Research funding from Amgen, Merck Serono, SUN Pharma, Sanofi, Regeneron, Almirall Hermal, Kyowa Kirin, and Recordati. Congress participation supported by SUN Pharma, Pierre Fabre, Almirall Hermal. Alena Riesmeier, Miltiadis Fiorentzis Nikolaos E. Bechrakis, Carsten Framme, Ekaterina Sokolenko declare no conflicts of interest.
Angela et al. (Tue,) studied this question.