Nivolumab-induced vitiligo in a patient treated for metastatic melanoma

INTRODUCTION

Malignant melanoma represents a neoplastic transformation of melanocytes, the specialized cells responsible for skin pigmentation, with cutaneous manifestations being most prevalent. Accounting for merely 4% of all dermatologic malignancies, this particular cancer nevertheless demonstrates disproportionate aggressiveness and accounts for a substantial proportion of skin cancer mortality.^[1] The therapeutic landscape for melanoma has undergone remarkable transformation with the advent of molecularly targeted agents including V-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, mitogen-activated protein kinase kinase (MEK) inhibitors, and mammalian target of rapamycin inhibitors, complemented by immunotherapeutic strategies such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and programmed cell death protein 1 (PD-1) inhibitors. Nivolumab stands out among these innovations as the Food and Drug Administration (FDA)-approved targeted biological therapy for advanced melanoma. This therapeutic monoclonal antibody, of the immunoglobulin G4 (IgG4) subclass, exerts its pharmacological action through precise binding to the PD-1 receptor, effectively disrupting its engagement with programmed death-ligand 1 (PD-L1) and PD-L2.^[2] This molecular interference liberates immune effector cells from inhibitory regulation, thereby potentiating their capacity to identify and eliminate malignant cells. Despite its clinical efficacy, nivolumab administration frequently precipitates diverse immune-mediated sequelae ranging from cutaneous depigmentation disorders to visceral organ inflammation, including pneumonitis, hepatitis, and thyroiditis.^[3] The current clinical report illustrates a representative case of vitiligo-like hypopigmentation developing secondary to nivolumab treatment in the context of metastatic melanoma management.

CASE REPORT

A 37-year-old female patient presented to the dermatology outpatient department of a tertiary care health center with chief complaints of depigmented lesions for 1 year. The rash predominantly involved bilateral hands, trunk, right side of abdomen, external genitalia, right lower limb, and bilateral feet [Figure 1]. There was no history of any preceding dermatosis or topical drug application before the onset of lesions. She was diagnosed with stage 3 malignant melanoma of the right heel with ipsilateral inguinal lymph node involvement (T3N1M0) 2 years ago. Surgical management with wide local excision and groin node dissection, followed by skin grafting with a plantar artery flap, was done at a tertiary oncology hospital. As an adjunct, she was initiated on postsurgical-targeted therapy with injection nivolumab 240 mg every 2 weeks along with radiotherapy. After 4 doses of injection nivolumab, the patient started developing depigmented lesions, which started from the hands and then progressed to involve the trunk, right leg, and bilateral feet. There was no personal or family history of vitiligo or any other autoimmune disorder. On general physical examination, edema of the right lower limb and right foot was noted. On cutaneous examination, there were well-toill-defined depigmented macules and patches on the abovementioned sites. Further, dermoscopy of the lesions revealed white structureless areas with scalloped margins showing the absence of pigment network (red arrow), leukotrichia (black arrow), and trichrome pattern (blue arrow) [Figure 2]. She was not started on any other medication apart from nivolumab recently and had no other comorbidities. The final diagnosis of vitiligo-like depigmenting rash following nivolumab was made based on the evidence of temporal association and relevant clinical examination.

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Figure 1:

Clinical distribution of vitiligo like depigmenting rash involving (a) bilateral hands, (b) trunk, right side of abdomen and external genitalia, (c) right lower limb and (d) bilateral feet.

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Figure 2:

Dermoscopic image from lesion on the right leg showing white structureless areas with scalloped margins and absence of pigment network (red arrow), leukotrichia (black arrow), and trichrome pattern (blue arrow).

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DISCUSSION

Malignant melanoma, a neoplastic proliferation of melanocytes, is characterized by its aggressive clinical behavior, including high fatality rates, unfavorable outcomes, and marked metastatic potential. Historically, patients with metastatic disease demonstrated particularly dismal survival outcomes, with previous studies reporting median overall survival durations under 12 months.^[4] The therapeutic paradigm has shifted dramatically with the introduction of contemporary immunotherapeutic approaches, which have substantially enhanced clinical outcomes and enabled sustained disease management. Notably, the median survival for advanced melanoma cases has shown remarkable improvement, escalating from the historical range of 6–9 months to approximately 6.5 years with current treatment modalities.^[5]

Nivolumab represents a monoclonal antibody of the IgG4 subclass that functions as an immune checkpoint inhibitor. Its mechanism of action involves specific binding to PD-1 receptors expressed on various immune cells, including T lymphocytes, natural killer cells, regulatory T cells, and B lymphocytes. By competitively blocking the interaction between PD-1 and its ligands – PD-L1 (found on immune cells, malignant cells, vascular endothelium, and antigen-presenting cells) and PD-L2 (primarily located on endothelial cells) – this agent effectively removes immunological brakes.^[6]

Consequently, this molecular interference potentiates T-cell-mediated recognition and destruction of neoplastic cells. Notably, PD-L1 overexpression occurs frequently across multiple malignancies, particularly melanoma, pulmonary, renal, bladder, esophageal, and gastric carcinomas.^[7]

The U.S. FDA has granted approval for nivolumab in multiple therapeutic contexts for melanoma management. These indications include monotherapy or combination therapy with ipilimumab (a CTLA-4-targeted checkpoint inhibitor) for unresectable or metastatic disease. In addition, regulatory approval extends to adjuvant treatment following complete surgical resection in cases with lymph node metastasis or disseminated disease. Although nivolumab’s primary mechanism involves immune system activation against malignant cells, its broad immunostimulatory effects may precipitate various immune-mediated complications. Characteristic adverse reactions associated with checkpoint inhibition encompass cutaneous manifestations, gastrointestinal disturbances, pulmonary inflammation, pituitary dysfunction, and hepatic injury.^[3]

Vitiligo is a chronic autoimmune condition characterized by selective melanocyte destruction, resulting in progressive, patchy skin depigmentation. The presence of circulating CD8+ T-cells that specifically target melanocytes, along with cytotoxic T-lymphocyte infiltrates at lesion borders, strongly supports an autoimmune basis for this disorder.^[8] Research by Schallreuter et al. revealed that melanoma patients exhibit a 7–10 times greater lifetime risk of developing vitiligo compared to the general population, with approximately 20% eventually manifesting vitiligo-like lesions.^[9] Spontaneous leukoderma in melanoma patients has been associated with improved clinical outcomes, suggesting a protective immunological response.^[10] Supporting this, RodrìguezCuevas et al. demonstrated in a Mexican cohort that melanoma patients with leukoderma had significantly better survival rates than those without, reinforcing its role as a positive prognostic indicator.^[11]

Current research indicates that the association between vitiligo and melanoma may stem from immune system targeting of both normal and malignant melanocytes through shared antigen recognition. This phenomenon explains why vitiligo-like hypopigmentation develops not only spontaneously in melanoma patients but also as a cutaneous adverse reaction in those receiving PD-1 inhibitors such as nivolumab and pembrolizumab for melanoma treatment.

Here, we report the case of a 37-year-old female patient who developed vitiligo after undergoing nivolumab therapy for malignant melanoma of the right heel.

The underlying pathophysiological mechanism appears to involve nivolumab-induced activation of cytotoxic T-cells that specifically recognize melanocyte antigens, leading to simultaneous targeting of both neoplastic and healthy melanocytes.^[12] Consequently, the emergence of therapy-induced vitiligo-like depigmentation may serve as a positive clinical marker for treatment efficacy. This immunopathological process involves both cellular (T-cell mediated) and humoral (antibody mediated) responses against shared melanocytic antigens, particularly melanoma antigen recognized by T-cells and gp100.^[13] Current hypotheses suggest that the loss of immune tolerance toward normal melanocytes may occur due to excessive presentation of melanocyte-specific antigens following immunotherapy-mediated tumor cell destruction.

Larsabal et al. conducted a comparative analysis of vitiligo-like lesions induced by immune checkpoint inhibitors versus classical vitiligo.^[14] Their findings revealed distinct clinical differences, demonstrating that anti-PD-1 therapy-associated depigmentation predominantly affects sun-exposed regions with preexisting actinic lentigines (particularly the forehead, facial areas, forearms, and dorsal hands) - a distribution pattern differing from our patient’s presentation. The investigation further identified elevated serum C-X-C motif chemokine ligand 10 concentrations in patients with immunotherapy-related lesions compared to both vitiligo patients and healthy controls. At the cellular level, these treatment-associated lesions exhibited increased populations of cutaneous cluster of differentiation 8 positive T-lymphocytes (CD8+) T lymphocytes secreting interferon-gamma alone or in combination with tumor necrosis factor alpha, a characteristic not observed in either classical vitiligo specimens or normal skin samples.

Classically, the occurrence of vitiligo-like lesions during immunotherapy has been associated with better prognosis in terms of higher objective tumor response rates and significantly improved overall survival in patients with melanoma. Thus, the appearance of vitiligo-like lesions during immunotherapy, although a cosmetic concern, should not be considered a sinister sign.

CONCLUSION

PD-1 inhibitors such as nivolumab and pembrolizumab, although revolutionary for the treatment of melanoma, can lead to a variety of immune side effects such as vitiligo, hepatitis, and thyroiditis. This case report describes the appearance of vitiligo-like depigmenting rash following nivolumab therapy for metastatic malignant melanoma in a 37-year-old female patient. Although cosmetically unacceptable, the development of vitiligo-like lesions during therapy with PD-1 inhibitors has been associated with better overall survival rates and is thus regarded as a good prognostic marker of response to treatment.