{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:07:52Z","timestamp":1784192872967,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health with Ricerca Corrente"},{"name":"5 \u00d7 1000 funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dermatopathology"],"abstract":"<jats:p>Halo nevus (HN), also known as Sutton nevus or leukoderma acquisitum centrifugum, is a melanocytic lesion characterized by a depigmented halo surrounding a central nevus. Although HN is a benign dermatological condition, increasing evidence indicates that HN represents a dynamic in vivo model of melanocyte-directed immune response with relevant implications for autoimmunity, pigmentary disorders, melanoma regression, and tumor immunosurveillance. The pathogenesis is primarily mediated by CD8+ cytotoxic T lymphocytes via interferon-\u03b3-driven pathways, leading to targeted destruction of melanocytes. However, recent studies have highlighted the importance of immune regulatory mechanisms, including PD-L1-expressing neutrophils and FOXP3+ regulatory T cells, which limit excessive immune-mediated damage and may contribute to the self-limited course and repigmentation observed in some lesions. Additional cytotoxic mediators, particularly granulysin, appear to strengthen melanocyte-directed cytotoxicity, while dendritic cells, macrophages, Langerhans cells, neutrophils, and natural killer cells contribute to antigen presentation, tissue remodeling, and immune resolution. HN shares key immunopathogenic features with vitiligo and melanoma regression but differs from both conditions due to its localized, tightly regulated behavior. Moreover, the halo phenomenon is not restricted to melanocytic lesions, supporting the view that it reflects a broader immune pattern rather than a disease-specific entity. This review provides a comprehensive synthesis of the clinical, histopathological, immunological, diagnostic, and translational aspects of halo nevus. Based on the available evidence, we propose a self-limited melanocyte autoimmunity model to explain the characteristic balance between melanocyte destruction, immune regulation, and spontaneous resolution observed in halo nevi.<\/jats:p>","DOI":"10.3390\/dermatopathology13030033","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"33","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Halo Nevus as a Self-Limited Model of Melanocyte Autoimmunity: Bridging Vitiligo, Immune Resolution, and Tumor Immunology\u2014A Narrative Review"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8231-2814","authenticated-orcid":false,"given":"Giulio","family":"Tosti","sequence":"first","affiliation":[{"name":"Dermato-Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.jaad.2011.11.937","article-title":"The natural history of halo nevi: A retrospective case series","volume":"67","author":"Aouthmany","year":"2012","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Nedelcu, R., Dobre, A., Brinzea, A., Hulea, I., Andrei, R., Zurac, S., Balaban, M., Antohe, M., Manea, L., and Calinescu, A. (2021). Current Challenges in Deciphering Sutton Nevi\u2014Literature Review and Personal Experience. J. Pers. Med., 11.","DOI":"10.3390\/jpm11090904"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hla\u010da, N., Vi\u010di\u0107, M., and Prpi\u0107-Massari, L. (2026). Immunological Aspects of Halo Nevus (Sutton\u2019s Nevus). Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1729726"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0140-6736(14)60763-7","article-title":"Vitiligo","volume":"386","author":"Ezzedine","year":"2015","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev-immunol-100919-023531","article-title":"Vitiligo: Mechanisms of Pathogenesis and Treatment","volume":"38","author":"Frisoli","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/pcmr.12949","article-title":"An Update on Vitiligo Pathogenesis","volume":"34","author":"Seneschal","year":"2021","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.det.2016.11.014","article-title":"Vitiligo Pathogenesis and Emerging Treatments","volume":"35","author":"Rashighi","year":"2017","journal-title":"Dermatol. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1111\/exd.13069","article-title":"Targeting CTLA-4, PD-L1 and IDO to Modulate Immune Responses in Vitiligo","volume":"26","author":"Speeckaert","year":"2017","journal-title":"Exp. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.ad.2025.01.011","article-title":"Inflammatory Cell Immunophenotypes in Regressing Melanomas and Halo Nevi: Possible Keys to Distinguish Intensely Inflamed Tumors","volume":"116","author":"Roccuzzo","year":"2025","journal-title":"Actas Dermosifiliogr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1097\/DAD.0000000000000205","article-title":"Study of the Immunophenotype of the Inflammatory Cells in Melanomas with Regression and Halo Nevi","volume":"37","author":"Kutzner","year":"2015","journal-title":"Am. J. Dermatopathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1111\/j.1524-4725.1990.tb00051.x","article-title":"Congenital Melanocytic Nevi with Halo Phenomenon: Report of Two Cases and a Review of the Literature","volume":"16","author":"Langer","year":"1990","journal-title":"J. Dermatol. Surg. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/j.1525-1470.2003.20425.x","article-title":"Halo Congenital Nevus","volume":"20","author":"Kerr","year":"2003","journal-title":"Pediatr. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/DAD.0000000000000683","article-title":"Polypoid Spitz Nevus with a Halo Reaction","volume":"39","year":"2017","journal-title":"Am. J. Dermatopathol."},{"key":"ref_14","first-page":"e74821","article-title":"Benign Nevi Mimicking Melanoma: A Diagnostic Dilemma","volume":"16","author":"Tabassum","year":"2024","journal-title":"Cureus"},{"key":"ref_15","first-page":"e105392","article-title":"Histologic Features of Melanocytic Nevi Secondary to Melanoma Treatment with Immune Checkpoint Inhibitors","volume":"18","author":"Sohail","year":"2026","journal-title":"Cureus"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jdermsci.2017.03.008","article-title":"A Similar Local Immune and Oxidative Stress Phenotype in Vitiligo and Halo Nevus","volume":"87","author":"Yang","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4111","DOI":"10.2147\/JIR.S321672","article-title":"Transcriptome Analysis Reveals the Molecular Immunological Characteristics of Lesions in Patients with Halo Nevi When Compared to Stable Vitiligo, Normal Nevocytic Nevi and Cutaneous Melanoma","volume":"14","author":"Pan","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/416854a","article-title":"Dominant Role of the Niche in Melanocyte Stem-Cell Fate Determination","volume":"416","author":"Nishimura","year":"2002","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/pcmr.12161","article-title":"Melanoma-Associated Leukoderma: Immunology in Black and White?","volume":"26","author":"Rao","year":"2013","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1056\/NEJMoa0908547","article-title":"Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo","volume":"362","author":"Jin","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.det.2016.11.013","article-title":"Genetics of Vitiligo","volume":"35","author":"Spritz","year":"2017","journal-title":"Dermatol. Clin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16580","DOI":"10.1038\/s41598-024-67494-9","article-title":"Analysis of Granulysin Expression in Vitiligo and Halo Nevus","volume":"14","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.1182\/blood-2010-03-273953","article-title":"Granulysin Activates Antigen-Presenting Cells through TLR4 and Acts as an Immune Alarmin","volume":"116","author":"Tewary","year":"2010","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110300","DOI":"10.1016\/j.clim.2024.110300","article-title":"Abnormal Metabolism in Melanocytes Participates in the Activation of Dendritic Cells in Halo Nevus","volume":"265","author":"Jiang","year":"2024","journal-title":"Clin. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2468692","DOI":"10.1080\/03014460.2025.2468692","article-title":"Unravelling the Molecular Mechanisms and Immune Landscape of Vitiligo: A Comprehensive Bioinformatics Study on Melanogenesis-Related Genes","volume":"52","author":"Ma","year":"2025","journal-title":"Ann. Hum. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/j.1365-2133.2010.10154.x","article-title":"Prognostic Value and Clinical Significance of Halo Naevi Regarding Vitiligo","volume":"164","author":"Vandenhaute","year":"2011","journal-title":"Br. J. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.4103\/0366-6999.218011","article-title":"Factors Associated with Development of Vitiligo in Patients with Halo Nevus","volume":"130","author":"Zhou","year":"2017","journal-title":"Chin. Med. J."},{"key":"ref_28","first-page":"e82378","article-title":"Segmental Vitiligo: Rapid Spread from a Halo Nevus","volume":"17","author":"Trevino","year":"2025","journal-title":"Cureus"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Xu, Y., Cui, W., Wang, H., Li, M., and Liu, L. (2025). PD-L1+ Neutrophils Mediate Immune Regulation of CD8+ T Cells in Halo Nevi. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1628913"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1159\/000342757","article-title":"Foxp3+ Regulatory T Cells Are Increased in the Early Stages of Halo Nevi: Clinicopathological Features of 30 Halo Nevi","volume":"225","author":"Park","year":"2012","journal-title":"Dermatology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.immuni.2024.03.002","article-title":"DAMPs and DAMP-Sensing Receptors in Inflammation and Diseases","volume":"57","author":"Ma","year":"2024","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1111\/j.1600-0560.1994.tb00704.x","article-title":"Characterization of the Mononuclear Infiltrate Involved in Regression of Halo Nevi","volume":"21","author":"Akasu","year":"1994","journal-title":"J. Cutan. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3121\/cmr.2.2.89","article-title":"The Immunopathology of Regression in Benign Lichenoid Keratosis, Keratoacanthoma and Halo Nevus","volume":"2","author":"Ivan","year":"2004","journal-title":"Clin. Med. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/1346-8138.70065","article-title":"The Role of Macrophages in Pigmentary Disorders","volume":"53","author":"Yao","year":"2026","journal-title":"J. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ni1582","article-title":"Functions of Natural Killer Cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tharwat, S., Hamdy, F., Hamdy, S., and Nassar, M.K. (2024). Prevalence of Co-Existing Autoimmune and Autoinflammatory Diseases in Vitiligo: A Survey-Based Study from Egypt. BMC Rheumatol., 8.","DOI":"10.1186\/s41927-024-00427-1"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Clemente Hern\u00e1ndez, B., Muelas Rives, I., Gracia Caza\u00f1a, T., \u00c1lvarez Salafranca, M., Poblador-Plou, B., Laguna-Berna, C., Moreno Juste, A., Gimeno-Miguel, A., and Gilaberte, Y. (2025). Comorbidities Associated with Vitiligo: Results from the EpiChron Cohort. J. Clin. Med., 14.","DOI":"10.3390\/jcm14020432"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.jid.2022.10.021","article-title":"Comorbidities in Patients with Vitiligo: A Systematic Review and Meta-Analysis","volume":"143","author":"Lee","year":"2023","journal-title":"J. Investig. Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.jaad.2015.08.063","article-title":"Comorbid Autoimmune Diseases in Patients with Vitiligo: A Cross-Sectional Study","volume":"74","author":"Gill","year":"2016","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.jaad.2016.12.034","article-title":"Vitiligo and Overt Thyroid Diseases: A Nationwide Population-Based Study in Korea","volume":"76","author":"Bae","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_41","first-page":"938257","article-title":"Association between Vitiligo and Thyroid Autoimmunity","volume":"2011","author":"Prohic","year":"2011","journal-title":"J. Thyroid Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1590\/S0365-05962011000200006","article-title":"Vitiligo Epidemiological Profile and the Association with Thyroid Disease","volume":"86","author":"Nunes","year":"2011","journal-title":"An. Bras. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jdermsci.2023.03.004","article-title":"Differences in the Immune Microenvironment between Improved and Non-Improved Cases of Vitiligo after Halo Nevus Excision","volume":"109","author":"Kano","year":"2023","journal-title":"J. Dermatol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jdcr.2024.06.010","article-title":"Halo Angiokeratoma","volume":"51","author":"AlJasser","year":"2024","journal-title":"JAAD Case Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"95","DOI":"10.36849\/JDD.9523","article-title":"Halo Seborrheic Keratosis in a Patient of Color with Vitiligo","volume":"25","author":"Nwaopara","year":"2026","journal-title":"J. Drugs Dermatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"656","DOI":"10.25259\/IJDVL_505_20","article-title":"Halo Phenomenon Is Not Restricted to Melanocytic Lesions","volume":"88","author":"Vural","year":"2022","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_47","first-page":"638","article-title":"Prognostic Role of Histological Regression in Cutaneous Melanoma","volume":"152","author":"Ribero","year":"2017","journal-title":"G. Ital. Dermatol. Venereol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1093\/bjd\/ljaf074","article-title":"Incidence, Stage and Outcome of Malignant Melanoma, Keratinocyte and Other Cancers in Individuals with Vitiligo or Alopecia: Intraindividual or Familial Risks?","volume":"193","author":"Delcoigne","year":"2025","journal-title":"Br. J. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/bjd.12111","article-title":"Decreased Risk of Melanoma and Nonmelanoma Skin Cancer in Patients with Vitiligo: A Survey among 1307 Patients and Their Partners","volume":"168","author":"Teulings","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.jaad.2014.07.050","article-title":"Markedly Reduced Incidence of Melanoma and Nonmelanoma Skin Cancer in a Nonconcurrent Cohort of 10,040 Patients with Vitiligo","volume":"71","author":"Paradisi","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1111\/bjd.16703","article-title":"Risk of Skin Cancer in People with Vitiligo: A Systematic Review and Meta-Analysis","volume":"179","author":"Ban","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.jid.2023.08.012","article-title":"The Risk of Keratinocyte Cancer in Vitiligo and the Potential Mechanisms Involved","volume":"144","author":"Rooker","year":"2024","journal-title":"J. Investig. Dermatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1097\/CMR.0000000000000776","article-title":"Regression of Nevi, Vitiligo-Like Depigmentation and Halo Phenomenon May Indicate Response to Immunotherapy and Targeted Therapy in Melanoma","volume":"31","author":"Farinazzo","year":"2021","journal-title":"Melanoma Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1001\/jamadermatol.2015.2707","article-title":"Association of Vitiligo with Tumor Response in Patients with Metastatic Melanoma Treated with Pembrolizumab","volume":"152","author":"Hua","year":"2016","journal-title":"JAMA Dermatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1196\/annals.1423.043","article-title":"Harnessing Autoimmunity (Vitiligo) to Treat Melanoma: A Myth or Reality?","volume":"1110","author":"Ram","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Israel, T., Kaplan, B., Cohen, N.T., Sherman, S., Kleinstern, G., and Kridin, K. (2025). Is a History of Malignant Melanoma Associated with Subsequent Vitiligo? Insights from a Population-Based Case-Control Study. J. Clin. Med., 14.","DOI":"10.3390\/jcm14155546"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e13556","DOI":"10.1111\/srt.13556","article-title":"Unintended Outcomes: Double Halo Nevus and Vitiligo Following Laser Therapy","volume":"30","author":"Jiang","year":"2024","journal-title":"Skin Res. Technol."},{"key":"ref_58","first-page":"630","article-title":"The Role of Functional Polymorphisms of Apoptotic BAX (-248G>A) and Anti-Apoptotic BCL2 (-938C>A) Genes in the Development of Vitiligo: A Cross-Sectional Study","volume":"50","author":"Daneshparvar","year":"2025","journal-title":"Iran. J. Med. Sci."},{"key":"ref_59","first-page":"e49465","article-title":"Sequential Dermoscopy and Reflectance Confocal Microscopy Paired with Pigmented Lesion Assay Gene Expression Profiling for In Vivo Monitoring of Multiple Halo Nevi on an Adult Patient","volume":"15","author":"Ludzik","year":"2023","journal-title":"Cureus"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jdcr.2025.03.005","article-title":"A Mimicker of a Halo Nevus: A Melanocytic Nevus Superimposed on Idiopathic Guttate Hypomelanosis","volume":"60","author":"Akanji","year":"2025","journal-title":"JAAD Case Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/pcmr.12955","article-title":"The Fate of Melanocyte: Mechanisms of Cell Death in Vitiligo","volume":"34","author":"Wu","year":"2021","journal-title":"Pigment. Cell Melanoma Res."}],"container-title":["Dermatopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2296-3529\/13\/3\/33\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:58:52Z","timestamp":1784192332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2296-3529\/13\/3\/33"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":61,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["dermatopathology13030033"],"URL":"https:\/\/doi.org\/10.3390\/dermatopathology13030033","relation":{},"ISSN":["2296-3529"],"issn-type":[{"value":"2296-3529","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}