**5. Association with Diseases—What to (Not) Investigate?**

‐ There are many diseases that have been described in individuals with Sutton nevi, such as vitiligo, thyroid diseases, and neoplasia [18,19,37,38]. Among them, vitiligo is the most frequently seen [19]. The association with malignant diseases needs further investigation.

‐ Even though studies have focused on finding out whether patients with halo nevi are susceptible to developing vitiligo, a consensus is lacking. When associated with vitiligo, halo nevi tend to appear earlier in life [18,37]. In other words, the lower the age of the patient with halo nevi, the greater the risk of developing vitiligo. The idea that multiple halo nevi rather than a single lesion associate with vitiligo was suggested by many authors in studies involving children [39] and adults [37]. On the other hand, van Geel et al. considered that the risk of vitiligo decreased when the number of halo nevi was greater than three [18].

Zhou et al. demonstrated that patients with halo nevi and Koebner phenomenon had a greater risk of vitiligo [37]. Moreover, a patient with halo nevi has an increased risk of contracting vitiligo if a member of his family has vitiligo [37].

Great significance was given to studies that involve pediatric patients with vitiligo and halo nevi. A study showed that halo nevi were present in more than a quarter of children with vitiligo [40]. Many of them supported the idea that pediatric patients with vitiligo were more affected by halo nevi than adults with the same disease [39]. The scientific work conducted by Cohen et al. showed that male children with vitiligo were more affected by halo nevi [40]. Moreover, the pediatric patients that had only vitiligo were younger at the moment of the diagnosis than the patients who had both diseases at the same time [40]. A higher incidence of halo nevi was observed in children with generalized vitiligo than in those with more localized forms (segmental and focal) [40]. The idea that children

with generalized vitiligo were more prone to develop halo nevi was highlighted in other articles [41].

Autoimmune diseases, especially Hashimoto's thyroiditis, were more frequently seen in patients with both halo nevi and vitiligo when compared to halo nevi without vitiligo [37]. Considering the fact that vitiligo can be associated with a thyroid pathology, the authors suggested that blood tests should be recommended for patients with Sutton nevi thyroid, in order to estimate the risk of vitiligo [37].

Halo nevi can also appear as an adverse effect of a treatment. Immunotherapy-induced halo nevi was described in patients treated with atezolizumab [42] and ipilimumab [43].

As far as it is known in the literature, the presence of Sutton nevi does not carry an additional risk for the appearance of primary melanoma. However, the link between neoplasia and eruptive Sutton nevi was discussed by Lorentzen in a case series study, where 16 patients with eruptive halo nevi were followed for six years [38]. All the patients were adults and most of their nevi (>80%) had become Sutton nevi [38]. No immunotherapy was administered prior to the appearance of the lesions. During this period, eight patients developed a malignant disease. There was an increased incidence of melanoma (955 times higher than expected) and cancer overall (papillary thyroid cancer, neuroendocrine lung tumor, lung metastases from melanoma) [38].

#### **6. Key Antimelanocyte Immune Reaction Lesson**

The etiology and pathogenesis of halo nevi has not been fully elucidated. There are several mechanisms through which a lymphocytic infiltrate can induce tumoral regression. The marked inflammatory infiltrate seen in the histopathological examination suggests an immune-based mechanism. Two theories have been discussed as pathogenic mechanism: the antibody theory and the cytotoxic T cell response. The antibody theory has been downplayed, because it has been shown that activated and cell proliferating lymphocytes disappeared after excision of the halo nevus [28]. Mononuclear infiltrates in halo nevus consist of about 80% of T cell lymphocytes, mainly CD8 + T cell. Most of the T cells are positive for granzyme B, perforin, and Fas ligand, illustrating their cytotoxic activity [29].

In this review, we aimed to update the knowledge about Sutton nevi starting with the clinical appearance, the dermoscopic features, continuing with information regarding conventional microscopy, immunohistochemistry, and the immunological mechanisms responsible for the occurrence of halo nevi. We also included in the article original unpublished results when discussing dermoscopic, pathologic and immunohistochemical results in halo nevi.

Sutton nevi are valuable models for studying the antitumor reactions that the human body can generate. The slow and effective mechanism against a melanocytic skin tumor can teach us important lessons about both autoimmune diseases and anticancer defenses.

**Author Contributions:** R.N., A.D. (Alexandra Dobre), A.B., I.H., R.A., S.Z., M.B., M.A., L.M., A.C. (Andreea Calinescu), A.C. (Anastasia Coman), F.P., A.D. (Adina Dobritoiu), C.P., R.P., E.B., D.I., G.T. have equal contribution to this paper. They contributed to conceptualization, design of the study, interpretation of the data and revising it critically for important intellectual content. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of UMF (PO-35-F-03 December 2017).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Conflicts of Interest:** The authors declare no conflict of interest.
