Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(1):e2023022 1 Regression of Multiple Melanocytic Nevi in Two Patients on Nivolumab for Metastatic Melanoma Gloria Baeza-Hernández1, Ricardo Francisco Rubio-Aguilera1, Anastasia Alejandra Garrido-Ríos1, Helena Álvarez-Garrido1, Cristina Martínez-Morán1, Jesús Borbujo1 1 Department of Dermatology. Hospital Universitario de Fuenlabrada, Madrid, Spain Key words: nivolumab, regression, melanocytic nevi, melanoma, dermoscopy Citation: Baeza- Hernández G, Rubio-Aguilera RF, Garrido-Ríos AA, Álvarez-Garrido H, Martínez-Morán C, Borbujo J. Regression Of Multiple Melanocytic Nevi In Two Patients On Nivolumab For Metastatic Melanoma. Dermatol Pract Concept. 2023;13(1):e2023022. DOI: https://doi.org/10.5826/dpc.1301a22 Accepted: May 26, 2022; Published: January 2023 Copyright: ©2023 Baeza- Hernández 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: Gloria Baeza-Hernández, Servicio de Dermatología, Hospital de Fuenlabrada, Camino del Molino 2, 28942 Fuenlabrada, Madrid. E-mail: gloria.baeza@salud.madrid.org Introduction Immunotherapy (anti-PD1 and anti-CTLA4) has been de- scribed to achieve complete regression of non-metastatic melanoma, assessed by reflectance confocal microscopy; however, their effects on benign melanocytic lesions have not been thoroughly studied and may be underreported [1]. Herein we report 2 patients with regression of multiple nevi while on treatment with nivolumab for metastatic melanoma. Case Presentation Two patients, suffering from metastatic melanoma treated with nivolumab (Table 1), attended our outpatient clinic for their annual digital dermoscopic monitoring. They were not aware of any changes or new melanocytic lesions. On phys- ical examination, no new lesions were detected since their last visit one year before; with dermoscopy several of their benign melanocytic nevi had lightened and no atypical or malignant lesions were observed (Figures 1 and 2). Both pa- tients had experienced disease progression despite anti-PD1 treatment. Conclusions Benign melanocytic nevi regression is an emerging sec- ondary effect of anti-PD1 drugs nivolumab and pembroli- zumab. Although these drugs are used on other cancer treatments, this secondary effect seems to be more frequent in patients undergoing treatment for melanoma [2]. In an observational study published in 2017, 11 patients treated 2 Research Letter | Dermatol Pract Concept. 2023;13(1):e2023022 with anti-PD1 for metastatic melanoma (10 with pembroli- zumab and 1 with nivolumab) had more lightened nevi than controls during follow-up (49% versus 19%); nev- ertheless, differences were not statistically significant [3]. Lightening without halo is a known phenomenon, espe- cially in patients treated with pembrolizumab [4,5]. There are few reports regarding regression of melanocytic nevi in patients treated with nivolumab: one similar to our patient, with no inflammation or halo, and another patient who experimented inflammation before regression, with no halo [6,7]. Though some articles suggest that regression of mela- nocytic nevi may be related to the therapeutic effect of the anti-PD1 drug and could be interpreted as a sign of good therapeutical response, our patients both experimented progression despite nivolumab treatment; therefore, more studies are required to shed light on this matter [2,5,7]. One of our patients also had vitiligo-like phenomenon, which has been suggested to be associated with a better prognosis [2]. Furthermore, some other questions remain still unan- swered: it could be asked why some patients experience only lightening without halo, while others have vitiligo-like reactions and halo nevi, and whether the underlying mech- anism is the same [3]; why some patients have clinical inflammation but most of them do not according to the literature. Lastly, it is debatable whether regression of nevi with anti-PD1 is as rare as it seems today, for it may be an unnoticed secondary effect in other cancer patients (lung, Table 1. Patient characteristics. Metastatic melanoma Patient 1 Patient 2 Sex Male Male Age, years 50 60 Location Abdomen Back Mutation BRAF V600E/E2/D Treatment before/after nivolumab Before: dabrafenib-trametinib, which was stopped because metastases spread to his lungs and inguinal and retroperitoneal lymph nodes (lymphadenectomy was performed) No Nivolumab start and end dates/doses mg/weeks 2021 – ongoing/ 240 mg every 2 weeks 2020-2021/ 480 mg every 4 weeks Lightening of nevi observed with digital dermoscopy 2021: > 80% of his nevi. (Previous digital monitoring: 2020) 2022: > 60% of his nevi. (Previous digital monitoring: 2021) Nivolumab secondary effects Yes, vitiligo-like lesions Yes, nivolumab-induced thyrotoxicosis and subsequent hypothyroidism Disease progression while on nivolumab Yes, new lymph node metastases near his melanoma scar on the abdomen and small bowel metastases (2022) Yes, dermal melanoma metastases on the back (2021) Second melanoma while on treatment Yes, melanoma in situ on his back while on dabrafenib- trametinib (2020). Yes, melanoma on his right leg (Breslow thickness 3.4 mm) while on nivolumab (2021). Both were detected in the annual digital dermoscopy monitoring visit. Other - A lung adenocarcinoma was diagnosed while on nivolumab (2021) and later excised. He has developed mediastinal lymph node metastases, awaiting treatment. Research Letter | Dermatol Pract Concept. 2023;13(1):e2023022 3 Figure 1. Clinical images of patient 1: 2020 (left) and 2021 (right). Three examples of lesions registered in digital monitoring of patient 1. (A1-C1) First row shows these benign melanocytic in 2020. (A2-C2) Second row shows the same lesions one year later in 2021, 6 months after starting treatment with nivolumab. kidney, head, and neck, etc.) who are not followed up in a dermatology clinic. One may well wonder about the utility of digital mon- itoring of patients with metastatic melanoma undergoing treatment with immune checkpoint inhibitors (ICI). In a recent single-center retrospective cohort study 42 patients (1.9%) with metastatic melanoma who received treatment with ICI developed new melanomas; thus, prospective stud- ies with longer follow-up are needed to draw a solid con- clusion [8]. While on ICI, both of our patients had a second melanoma that was detected in the digital follow-up; we want to highlight that in case 1, with longer digital moni- toring, melanoma was detected in situ, in line with the find- ings of Lallas et al where almost 70% of second primary melanomas detected during surveillance were in situ [9]. We think that, when available and feasible, monitoring with digital dermoscopy and total body photography should be offered to all melanoma patients, as it helps in the early diag- nosis of melanoma, with some lesions being only diagnosed by dermoscopic changes in the absence of melanoma-specific criteria [9]. Regression of multiple nevi is a scarcely reported second- ary effect of nivolumab we should be aware of, especially in dermoscopic monitoring. It may be an overlooked effect be- cause patients treated with anti-PD1 for cancers other than melanoma are not usually examined by a dermatologist. Its prognostic meaning is still unclear. 4 Research Letter | Dermatol Pract Concept. 2023;13(1):e2023022 4. Wolner ZJ, Marghoob AA, Pulitzer MP, Postow MA, Marchetti MA. A case report of disappearing pigmented skin lesions asso- ciated with pembrolizumab treatment for metastatic melanoma. Br J Dermatol. 2018;178(1):265-269. DOI:10.1111/bjd.15354. PMID: 28132411. PMCID: PMC5533648. 5. Mauzo SH, Tetzlaff MT, Nelson K, et al. Regressed melanocytic nevi secondary to pembrolizumab therapy: an emerging mela- nocytic dermatologic effect from immune checkpoint antibody blockade. Int J Dermatol. 2019;58(9):1045-1052. DOI:10.1111 /ijd.13833. PMID: 29152725. 6. Vazquez B, Velasco R, Martin JM, Gonzalez I, Ramon MD. Regression  of multiple melanocytic nevi associated with nivolumab treatment  for metastatic melanoma. Int J Dermatol. 2019;58(11):1331-1333. DOI:10.1111/ijd.14340. PMID: 30536371. 7. Nakamura Y, Fujino T, Kagamu H, et al. Induction of immune re- action in benign melanocytic nevi without halo during nivolumab therapy in a patient with melanoma. JAMA Dermatology. 2017;153(8):832-834. DOI:10.1001/jamadermatol.2017.0615. PMID: 28492864. References 1. Navarrete-Dechent C, Cordova M, Postow MA, et al. Eval- uation of the Response of Unresectable Primary Cutaneous Melanoma to Immunotherapy Visualized With Reflectance Confocal Microscopy. JAMA Dermatology. 2019;155(3):347. DOI:10.1001/jamadermatol.2018.3688. PMID: 30624578. PM- CID: PMC6440283. 2. Farinazzo E, Zelin E, Agozzino M, et al. Regression of nevi, vitiligo-like depigmentation and halo phenomenon may indi- cate response to immunotherapy and targeted therapy in mel- anoma. Melanoma Res. 2021;31(6):582-585. DOI:10.1097 /CMR.0000000000000776. PMID: 34433200. 3. Zhao CY, Hwang SJE, Wakade D, Carlos G, Anforth R, Fernández-Peñas P. Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced met- astatic melanoma: An observational study. Australas J Der- matol. 2017;58(4):292-298. DOI:10.1111/ajd.12645. PMID: 28707403. Figure 2. Clinical images of patient 2: 2021 (left) and 2022 (right). Three lesions registered in digital monitoring of patient 2. (D1-F1) First row shows these benign melanocytic nevi in 2021, while on nivolumab treatment. (D2-F2) Second row displays the same lesions one year later in 2022, 6 months after finishing treatment with nivolumab. Research Letter | Dermatol Pract Concept. 2023;13(1):e2023022 5 9. Lallas A, Apalla Z, Kyrgidis A, et al. Second primary melanomas in a cohort of 977 melanoma patients within the first 5  years of monitoring. J Am Acad Dermatol. 2020;82(2):398-406. DOI:10.1016/j.jaad.2019.08.074. PMID: 31499156. 8. Nanda JK, Dusza SW, Navarrete-Dechent C, Liopyris K, Marghoob AA, Marchetti MA. Incidence of New Primary Cutaneous Mela- noma in Patients With Metastatic Melanoma Treated With Immune Checkpoint Inhibitors. JAMA Dermatology. 2021;157(1):79. DOI:10.1001/jamadermatol.2020.3671. PMID: 32936222. PMCID: PMC7495326.