Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2025;15(2):4912 1 Significant Nevi Regression Associated with Multiple Non-Metastatic Cutaneous Melanomas: A Case Report Mislav Mokos1, Mirna Šitum1,2,3, Davor Tomas4,5, Sunčica Andrea Rogan6, Marija Buljan1,2 1 University Hospital Center Sestre milosrdnice, Department of Dermatology and Venereology, Zagreb, Croatia 2 University of Zagreb School of Dental Medicine, Zagreb, Croatia 3 Croatian Academy of Sciences and Arts, Zagreb, Croatia 4 University Hospital Center Sestre milosrdnice, Department of Pathology and Cytology, Zagreb, Croatia 5 University of Zagreb School of Medicine, Zagreb, Croatia 6 Polyclinic Medikol, Zagreb, Croatia Key words: Nevi regression, Melanoma, Dermoscopy, Skin neoplasms, Case reports Citation: Mokos M, Šitum M, Tomas D, Rogan SA, Buljan M. Significant Nevi Regression Associated with Multiple Non-Metastatic Cutaneous Melanomas: A Case Report. Dermatol Pract Concept. 2025;15(2):4912. DOI: https://doi.org/10.5826/dpc.1502a4912 Accepted: September 25, 2024; Published: April 2025 Copyright: ©2025 Mokos 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: Professor Marija Buljan, MD, PhD. Department of Dermatology and Venereology, University Hospital Center Sestre milosrdnice, Vinogradska cesta 29, 10000 Zagreb, Croatia. ORCID ID: 0000-0001-9319-9255 E-mail: buljan.marija@gmail.com Introduction Spontaneous regression in melanocytic nevi in patients with a personal history of melanoma is a rare and intriguing phe- nomenon [1]. We present  an extremely rare case of a pa- tient with a history of multiple non-metastatic melanomas and dysplastic nevi syndrome who subsequently experienced sudden regression of nearly all nevi.  Case Presentation A 73-year-old male patient with dysplastic nevi syndrome has been under follow-up at our Department for more than two decades. In 1993, he was diagnosed with an intermediate-thickness melanoma in the right temporal re- gion. Melanoma  in situ was excised from the left abdomi- nal area in 2013, followed by the removal of a superficial spreading melanoma (SSM) (Clark II, Breslow thickness 0.32 mm) from his back in 2014. In August 2023, a super- ficial atypical melanocytic proliferation of uncertain signifi- cance (SAMPUS) was excised from his left upper arm. At the beginning of 2023, signs of initial regression in multiple nevi were observed upon digital dermoscopy. Surprisingly, by September 2023, a routine total body photography follow- up revealed the remarkable disappearance of almost all nevi (Figure 1). At the same time, an SSM was excised from the patient’s back (Clark II, Breslow thickness of 0.56 mm). Three regressed nevi were  removed and showed dysplastic nevi with halo-type inflammatory reaction (Figure 2). The patient’s only current medication was tam- sulosin, prescribed for benign prostatic hyperplasia. Given the notable dermoscopic findings of regressed nevi and the newly identified melanoma, a PET-CT scan was con- ducted, which revealed no pathological metabolic activity 2 Research Letter | Dermatol Pract Concept. 2025;15(2):4912 Figure 1. Clinical presentation before (a, c) and after (b, d) spontaneous regression of dysplastic nevi on the patient’s trunk. Figure 2. (a) Dermoscopic image of one of the three dysplastic nevi, taken on 21 October 2016. (b) Dermoscopic image of the same nevus, taken on 12 December 2022. Regression is clearly visible. (c) Histologic image of dysplastic nevus on the patient’ back (hematoxylin-eosin; 100x). “Halo” type of inflammation indicates early regression. (d) Melan-A staining of the same nevus (x100). (e) CD45 staining, which is specific for lymphocytes, reveals a significant inflammation at the base of the nevus and between the nevus cells in the dermis (x100). Research Letter | Dermatol Pract Concept. 2025;15(2):4912 3 of fluorodeoxyglucose. Additionally, S100 and LDH levels were within normal ranges; thus, there was no indication of an active malignant disease. Conclusions Nevus regression in melanoma patients  is predominantly driven by immune-mediated mechanisms targeting melano- cytes.  Melanocytes and melanoma cells share melanocyte differentiation antigens (MDAs) such as MART-1, gp100, and tyrosinase, which are recognized by the immune system. Cytotoxic T lymphocytes (CTLs) are critical in melanocyte destruction by recognizing tumor-associated antigens pre- sented on MHC class I molecules and inducing apoptosis. Additionally, immune checkpoints such as PD-1/PD-L1 and CTLA-4 regulate immune responses but can be exploited by melanoma cells to evade the immune system [2]. Therefore, it is not surprising that the regression of nevi and vitiligo-like depigmentation has been reported in patients with metastatic melanoma, which has been explained by an increased anti- gen load as melanoma progresses to metastatic disease [3]. Our patient experienced spontaneous regression of nearly all nevi without a diagnosis of metastatic melanoma or receiving immunotherapy, which is an exceptionally rare event since it has  been reported in  the literature in only three patients [1,4,5]. The explanation for the spontaneous regression of nevi in our patient may lie in the fact that he had dysplastic nevus  syndrome, since dysplastic nevi, in comparison with melanocytic nevi, may exhibit higher levels of MDAs, which  are also expressed by melanoma cells. This heightened expression and increased production of lymphocyte-recruiting chemokines and adhesion mole- cules may attract more tumor-infiltrating lymphocytes [4]. Further research is necessary to enhance our understanding of this phenomenon. References 1. Martín JM, Pinazo I, Monteagudo C, Markovic J, Allende A, Jordá E. Spontaneous Regression of Multiple Melanocytic Nevi After Melanoma: Report of 3 Cases. Am J Dermatopathol 2014; 36(11): e183-8. DOI: 10.1097/DAD.0000000000000033. PMID: 25343215. 2. Zindl CL, Chaplin DD. Immunology. Tumor immune evasion. Science 2010; 328(5979): 697-698. DOI: 10.1126/science .1190310. PMID: 20448171. 3. 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 mela- noma. Melanoma Res. 2021; 31(6): 582-5. DOI: 10.1097/CMR .0000000000000776. PMID: 34433200. 4. Speeckaert R, van Geel N, Luiten RM, et al. Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma. Anticancer Res 2011; 31(11): 3697-703. PMID: 22110189. 5. Jaber NF, Paoli J, Jerkovic SG. Rapid regression of multiple me- lanocytic nevi in an individual with history of melanoma with the CDKN2A mutation. JAAD Case Rep 2023; 38: 113-6. DOI: 10.1016/j.jdcr.2023.06.019. PMID: 37484656.