Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2024;14(1):e2024020 1 Diffuse Melanosis Cutis in the Era of Targeted Therapy Fernanda Luiza Staub1, Bruna Ossanai Schoenardie1, Renan Rangel Bonamigo1,2, Juliano Peruzzo1 1 Department of Dermatology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil 2 Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Key words: melanoma, target therapy, hyperpigmentation, metastatic melanoma, pdl-1 inhibitors Citation: Staub F, Ossanai Schoenardie, Rangel Bonamigo R, Peruzzo J. Diffuse Melanosis Cutis in the Era of Targeted Therapy. Dermatol Pract Concept. 2024;14(1):e2024020. DOI: https://doi.org/10.5826/dpc.1401a20 Accepted: November 7, 2023; Published: January 2024 Copyright: ©2024 Staub et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Juliano Peruzzo, Rua Ramiro Barcelos, 2350 - 90035-007 – Porto Alegre – RS, Brazil. Phone: +55 51 33598571 E-mail: julperuzzo@hcpa.edu.br Introduction Metastatic melanoma can rarely present as a diffuse bluish- gray discoloration of the skin, known as diffuse melanosis cutis (DMC) [1,2]. As it can negatively influence quality of life, therapeutic options for hyperpigmentation are crucial. Case Presentation A 47-year-old woman was referred to the dermatology de- partment to investigate a diffuse hyperpigmentation of the skin. She reported starting with progressive skin darkening 5 months prior and having very dark urine 9 months prior to her appointment. She had a diagnosis of cutaneous mel- anoma 6 years earlier and had discovered hepatic metas- tasis 3 years after the melanoma diagnosis. Upon physical examination, the patient presented with a diffuse blue-gray hyperpigmentation, which was more accentuated on the face (Figure 1). Histopathology and Fontana–Masson stain of the skin showed melanophages in a superficial perivascular lo- calization, compatible with dermic melanosis (Figure 2). The diagnosis of diffuse melanosis cutis (DMC) was established. Since the melanoma was positive for BRAF/V600E mutation with indeterminate PDL-1 expression, treatment with dabrafenib and trametinib had been instituted. She re- ported that the urine alterations resolved rapidly after ini- tiating this treatment, but had little improvement in skin hyperpigmentation. As an attempt to attenuate the hyperpigmentation, we prescribed 5% imiquimod for eight weeks, without any im- provement. We also attempted two sessions of Q-Switched laser with no response after two sessions. Conclusions The exact physiopathology of DMC is still unclear [3]. It is postulated that metastatic melanoma releases melanin precursors in the circulation (after cytolysis as a result of rapid turnover of neoplastic deposits, central ischemia, im- munological responses or oncologic therapies), which are converted into melanin in the dermis and may be phagocy- tosed by native histiocytes, causing hyperpigmentation [2]. Melanin precursors can also be excreted in urine causing melanuria [2]. Other theories include the possibility that 2 Research Letter | Dermatol Pract Concept. 2024;14(1):e2024020 melanocyte proliferation might be stimulated by growth fac- tors released by cancer cells or that DMC may be caused by dermal micrometastasis producing melanin [4]. Furthermore, more than one pathway may contribute to the etiopatho- genesis of DMC. Pigmentation is most frequently seen in a photo-distributed pattern [5]. Histologic findings include in- creased melanin in dermal histiocytes, free pigment between collagen stroma and epidermal hyperpigmentation  [2]. Melanophages extending to subcutis and skeletal muscle can also be seen [6]. There is no treatment for DMC. Successful treatment of localized melanosis cutis with imiquimod cream 5% has been described [5], although our patient did not present with the same outcome. DMC is a bad prognosis marker, with a mean life expectancy after developing hyperpigmentation of 4 to 5 months [2]. It is a presentation of metastatic melanoma, considered by some authors as a paraneoplastic condition, that can assist in the diagnosis of advanced melanoma [4]. BRAF-MEK inhibitors have significantly expanded life-expectancy in metastatic melanoma. Our patient died 24 months after first developing DMC. Interestingly, as previ- ously reported, our patient melanuria completely resolved after initiating treatment with dabrafenib and trametinib, although no improvement in skin hyperpigmentation was seen [1]. Even though our attempts to treat DMC were not suc- cessful, we believe this is a field which ought to be studied further. The cosmetic impact of DMC on patients has not been explored as it was associated with a very poor prog- nosis. However, since the advent of targeted therapy and Figure 1. Diffuse blue-gray hyperpigmentation, more accentuated on the face. Figure 2. Histopathology (H&E and Fontana–Masson stains) showing melanin deposition in the superficial dermis with a perivascular distribution. Research Letter | Dermatol Pract Concept. 2024;14(1):e2024020 3 immunotherapy, these patients are living longer, so treat- ments for melanosis might improve their quality of life. References 1. Minocha R, Kefford R, Uribe P, et al. 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