Choroidal naevus regression associated with PD-1 inhibitor monotherapy for metastatic cutaneous malignant melanoma.

Abstract

Nivolumab is a human IgG4 monoclonal antibody directed against the programmed cell death 1 (PD-1) receptor found on the surface of T cells. The antibody induces immune-mediated tumour regression by binding to the PD-1 receptor on activated T cells and thereby blocking its interaction with the PD-L1 ligand expressed by malignant cells and their microenvironment. Nivolumab belongs to the so-called ‘immune checkpoint inhibitors’, which have dramatically improved the outcomes for patients with metastatic cutaneous melanoma and other advanced malignancies. Autoimmune dermatologic side-effects like rash, pruritus, vitiligo and lichenoid skin and mucosal reactions are frequently observed (Belum et al. 2016; Wolner et al. 2018). Vitiligo-like depigmentation in patients with melanoma has been associated with a lower risk of disease progression and death (Teulings et al. 2015). More rarely, fading and disappearance of pigmented skin lesions have been reported among patients receiving immune checkpoint blockade for the treatment of metastatic melanoma (Schwager et al. 2018; Wolner et al. 2018). Herein, we describe a patient who experienced depigmentation of the fundi and regression of a juxtapapillary choroidal naevus during nivolumab therapy for cutaneous metastatic melanoma. A 61-year-old Caucasian male who had undergone resection of a cutaneous malignant melanoma from his back 3 years earlier, presented with multiple metastases to the right axillary lymph nodes and the liver. Fine needle lymph node and liver biopsies confirmed metastatic melanoma with BRAF mutation. The patient underwent a general ophthalmic examination, which was entirely normal except for the presence of a flat choroidal naevus superonasal to the optic disc in his left eye. The naevus had a slate-grey colour with indistinct borders. It was oval in shape, about 2.4 × 1.9 mm in size, and located adjacent to the optic disc rim (Fig. 1A). Visual acuity was 1.2 in both eyes. The patient was started on nivolumab monotherapy at a dose of 240 mg every 2 weeks. After two cycles of nivolumab, he experienced temporary symptoms in the form of muscle pain, tinnitus and reduced hearing. Following completion of the ninth cycle, computed tomography (CT) showed significant regression of the axillary lymph nodes and liver metastases. After 14 months of treatment, the dosing regimen was changed to monthly infusions of 480 mg nivolumab. After a total of 2 years on nivolumab, CT showed complete regression of the liver metastasis and stable remission of the axillary lymph nodes. Nivolumab was discontinued and he was scheduled for regular follow-up. During the course of nivolumab therapy, the patient developed various adverse skin reactions such as rash, photosensitivity and pruritus. He also noticed fading of cutaneous naevi, gradual depigmentation of his body hair and complete poliosis of the eyebrows and eyelashes (Fig. 1D). Repeated ophthalmic examinations revealed that both fundi gradually became less pigmented. The juxtapapillary choroidal naevus diminished in size and became more demarcated with a subtle pale halo (Fig. 1B,C). The patient had no signs or symptoms of intraocular inflammation. Enhanced depth imaging optical coherence tomography showed a normal neural retina and retinal pigment epithelium. The naevus was flat and hyperreflective with optical shadowing of the deeper structures (Fig. 1E). At the last examination, 22 months after initiation of nivolumab, visual acuity was 1.0 OU. Both fundi appeared hypopigmented, and the choroidal naevus had regressed to a size of 0.8 × 0.5 mm (Fig. 1C). Reported ocular side-effects associated with nivolumab therapy include immune retinopathy, anterior uveitis and Vogt–Koyanagi–Harada disease-like posterior uveitis, in addition to various ocular surface and neuro-ophthalmic manifestations (Dalvin et al. 2018). Most recently, a case of fundus hypopigmentation and loss of choroidal naevi pigmentation has been reported in association with nivolumab. However, in contrast to our case, the fundus changes appeared as unilateral yellowish spots around the optic nerve (Sophie et al. 2019). To our knowledge, the present case report is the first to show that PD-1 inhibitor monotherapy can lead to diffuse hypopigmentation of both fundi and regression of a pre-existing choroidal naevus. The gradual choroidal depigmentation without any evidence of concomitant intraocular inflammation indicates that PD-L1 may also be expressed by benign melanocytes within the choroid.