Regional vitiligo induced by imiquimod treatment for in-transit melanoma metastases Article Swipe

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Elizabeth Tkachenko , Jennifer Y. Lin , Rebecca I. Hartman · YOU? · · 2019 · Open Access · · DOI: https://doi.org/10.1016/j.jdcr.2019.03.015

Imiquimod is a topical immunomodulator used for the treatment of viral warts and superficial basal cell carcinoma and as an emerging therapy for lentigo maligna and cutaneous melanoma metastases. Vitiligo-like depigmentation has been described as a local adverse effect of topical imiquimod therapy for melanoma1Kim N.H. Lee J.B. Yun S.J. Development of Vitiligo-like depigmentation after treatment of lentigo maligna melanoma with 5% imiquimod cream.Ann Dermatol. 2018; 30: 454-457Google Scholar and at distant sites in patients treated with combination topical monobenzone-imiquimod for metastatic melanoma.2Teulings H.E. Tjin E.P.M. Willemsen K.J. et al.Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial.Oncoimmunology. 2018; 7: e1419113Google Scholar We present a case in which topical imiquimod resulted in both the resolution of in-transit metastatic melanoma and the depigmentation of local and regional skin, suggesting a regional lymphatic effect of this localized topical treatment. A 78-year-old man presented with approximately 100 blue-black papules localized to the scalp that had been increasing in number. Punch biopsy found an atypical intradermal melanocytic proliferation with no intraepidermal component, consistent with in-transit stage IIIC metastatic melanoma. No primary lesion was noted by the patient or on clinical examination. Full-body positron emission tomography/computed tomography (CT) and brain magnetic resonance imaging found no evidence of metastatic disease. Imiquimod was initially chosen as a neoadjuvant treatment prior to surface brachytherapy because some of the patient's raised scalp lesions spontaneously flattened in the weeks after his presentation, suggesting an active immune response that could potentially be amplified. Two skin biopsies of flattened blue-black macules found tumoral melanosis with associated lymphocytic infiltrates and no residual melanoma. He was subsequently treated with topical imiquimod 5% for 8 weeks, applying 1 packet daily for 2 weeks with an associated inflammatory response (Fig 1, A) and then increasing to twice-daily application for the next 6 weeks. All visible lesions were treated and appeared to respond clinically with flattening and reduction in dark coloration, although there were numerous residual blue-black macules on the scalp consistent with tumoral melanosis. Subsequent positron emission tomography/CT imaging found no evidence of malignancy. Brachytherapy was ultimately not required because of the robust response to topical imiquimod alone. Fourteen months after treatment completion, he presented for routine surveillance. Scalp examination found improving blue-black macules, which were smaller and lighter in color compared with prior examinations (Fig 1, B). In addition, there were new well-demarcated depigmented patches on the scalp, neck, and head including the perioral region (Fig 2). Wood's light examination confirmed depigmentation. Full-body skin examination found no other depigmented lesions. There was no evidence of locoregional recurrence, and CT of the chest/abdomen/pelvis 1 month prior showed no evidence of metastatic disease. Three months later, however, seizures developed secondary to a hemorrhagic brain mass that was consistent with melanoma on pathology findings. He is status post–surgical resection and radiation, and currently receiving nivolumab. He has not had any additional cutaneous metastases since initial presentation. The patient has a history of autoimmune hypothyroidism that predated his melanoma diagnosis, which is well controlled with 50 mg levothyroxine daily. He has no family history of autoimmune disease, vitiligo, or skin cancer. Topical imiquimod is a toll-like receptor 7/8 agonist reported to induce localized vitiligo-like depigmentation months after topical use for condyloma acuminata,3Stefanaki C. Nicolaidou E. Hadjivassiliou M. Antoniou C. Katsambas A. Imiquimod-induced vitiligo in a patient with genital warts [14].J Eur Acad Dermatol Venereol. 2006; 20: 755-756Google Scholar superficial basal cell carcinoma,4Burnett C.T. Kouba D.J. Imiquimod-induced depigmentation: report of two cases and review of the literature.Dermatol Surg. 2012; 38: 1872-1875Google Scholar and lentigo maligna.1Kim N.H. Lee J.B. Yun S.J. Development of Vitiligo-like depigmentation after treatment of lentigo maligna melanoma with 5% imiquimod cream.Ann Dermatol. 2018; 30: 454-457Google Scholar Most prior reports of vitiligo-like depigmentation with imiquimod use note depigmentation localized to the site of application, although regional depigmentation has been reported after treatment for condyloma acuminate,3Stefanaki C. Nicolaidou E. Hadjivassiliou M. Antoniou C. Katsambas A. Imiquimod-induced vitiligo in a patient with genital warts [14].J Eur Acad Dermatol Venereol. 2006; 20: 755-756Google Scholar and systemic depigmentation has been reported with combined use of topical monobenzone and imiquimod for cutaneous melanoma metastases.2Teulings H.E. Tjin E.P.M. Willemsen K.J. et al.Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial.Oncoimmunology. 2018; 7: e1419113Google Scholar In the latter report of systemic depigmentation, it was felt the monobenzone provided the systemic effect rather than the imiquimod.2Teulings H.E. Tjin E.P.M. Willemsen K.J. et al.Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial.Oncoimmunology. 2018; 7: e1419113Google Scholar Given this patient's local and regional depigmentation, in conjunction with resolution of his in-transit melanoma metastases, this case likely represents a regional, rather than a purely local, imiquimod-induced immune response. Interestingly, imiquimod monotherapy has been found to induce a local and a sentinel lymph node regional immune response in melanoma patients, which could explain this patient's regional vitiligo.5Narayan R. Nguyen H. Bentow J.J. et al.Immunomodulation by imiquimod in patients with high-risk primary melanoma.J Invest Dermatol. 2012; 132: 163-169Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Importantly, vitiligo-like depigmentation also may be seen following systemic immunotherapy for melanoma and is associated with improved survival.6Teulings H.E. Limpens J. Jansen S.N. et al.Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.J Clin Oncol. 2015; 33: 773-781Crossref PubMed Scopus (405) Google Scholar Despite leading to resolution of in-transit metastasis, locoregional control with imiquimod may not provide systemic control, evidenced by the development of brain metastasis. Indeed, prior research suggests topical imiquimod for melanoma does not produce a peripheral blood response.5Narayan R. Nguyen H. Bentow J.J. et al.Immunomodulation by imiquimod in patients with high-risk primary melanoma.J Invest Dermatol. 2012; 132: 163-169Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar The reason for this finding is unknown but may be owing to different immunologic requirements to treat local versus systemic disease. A murine model of mesothelioma has found that local imiquimod administration induces a local immune response that requires CD8 T cells and natural killer cells, but not CD4 T cells, and is sufficient to retard local, but not distant, tumor growth.7Broomfield S.A. van der Most R.G. Amy C. et al.Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by anti-CD40 immunotherapy.J Immunol. 2009; 182: 5217-5224Google Scholar When CD40 antibody, to simulate CD4 T cells, was added to local imiquimod administration, there was distal tumor growth retardation and enhanced local tumor response.7Broomfield S.A. van der Most R.G. Amy C. et al.Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by anti-CD40 immunotherapy.J Immunol. 2009; 182: 5217-5224Google Scholar We postulate that similar to immunotherapy-induced vitiligo, a vitiligo-like response to topical imiquimod treatment in melanoma patients may portend a positive locoregional prognosis given the possibility of a regional lymphatic treatment effect, although systemic prognosis remains unaffected. Further studies are needed to confirm this hypothesis.

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Regional vitiligo induced by imiquimod treatment for in-transit melanoma metastases

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Elizabeth Tkachenko, Jennifer Y. Lin, Rebecca I. Hartman

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Medicine, Vitiligo, Imiquimod, Dermatology, Melanoma, Cancer research

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