[Academic Presentation] Recent Advances in the Study of Halo Nevus

Article reprinted from: Chinese Medical Abstracts – Dermatology

Author: Hu Wenting, Xu Aie

Halonevus, also known as centrifugal acquired leukoderma or Sutton’s nevus, is characterized by a circumscribed area of depigmentation surrounding a pigmented nevus. It is a pigmentary disorder in which cytotoxic T cells serve as the primary effector cells, with multiple cell types contributing to the process. The incidence of halonevus is approximately 1%, and it most commonly affects adolescents; the trunk is the preferred site of involvement. Clinically, solitary halonevuses are more frequently observed. The etiology remains unclear; preexisting pigmented nevi may develop white patches following stimuli such as cryotherapy, laser treatment, or trauma. Exposure to ultraviolet light may also act as an initiating factor in the development of halonevus.

1. Clinical Features

The typical cutaneous feature of halo nevus is a central melanocytic nevus; in a minority of cases, the central lesion may be a dysplastic nevus, a blue nevus, a Spitz nevus, a seborrheic keratosis, a melanoma, a Mongolian spot, or a congenital pigmented nevus, with a surrounding annular white ring. On dermoscopy, the central nevus in most halo nevi exhibits a homogeneous globular architecture with an acellular zone, while the white halo appears as a uniform area of hypopigmentation. Babu et al. reported a case of a 3 cm × 3 cm congenital pigmented nevus in which a white halo accompanied by white hair—a “reverse halo”—developed at the center. Currently, halo nevus is considered a spontaneously regressing, autoimmune‑related condition. Its evolution proceeds through four clinical stages: in the first stage, localized depigmentation appears around the pigmented nevus; in the second stage, the central nevus undergoes pigmentary fading and transforms into a pink papule; in the third stage, the central papule resolves, leaving only an annular depigmented patch; and in the fourth stage, the white patch regains its normal pigmentation. In a follow-up study of 33 halo nevi (lasting 4–61 months, with a mean of 26 months), the authors observed that, over the observation period, the area of the central nevus decreased to varying degrees, averaging a monthly reduction of 2.2%. During the regression phase, the central region may transition from light brown to pink, with punctate vessels occasionally visible. Due to limitations in follow-up conditions, not all halo nevi progress through all four stages clinically; the first stage is the most common and can persist for more than 10 years.

2. Histopathology and Pathophysiology

Under microscopic examination, halo nevi exhibit a loss of melanocytes in the basal layer of the white halo and peritumoral lymphocytic infiltration; the nevi are predominantly compound and intradermal, sometimes showing atypical features. In compound nevi, nevus cells can be seen extending into the dermis in linear strands; in intradermal nevi, nests of nevus cells are observed within the dermis, with a distinct Grenz zone separating them from the epidermis. Microscopically, varying degrees of regression of nevus and melanocytic cells, along with inflammatory cell infiltration, are evident, accompanied by proliferation of newly formed endothelial cells and stromal vascular structures. Currently, the prevailing hypothesis posits that the spontaneous regression of halo nevi is primarily driven by an aberrant state of self‑tolerance toward nevus cells, leading to activation and clonal expansion of antigen‑specific autoreactive T cells and resulting in localized immune damage at the lesion site, with CD8+ T cells serving as the principal effector population. Park et al. performed immunohistochemical analysis on 30 halo nevi and found a marked early increase in Foxp3+ Tregs; moreover, the number of Foxp3+ Tregs correlated positively with the extent of inflammatory infiltrate, suggesting that Foxp3+ Tregs may play a critical role in the pathogenesis of halo nevi.

It was previously believed that humoral immunity played a minor role in the regression of halo nevi; however, circulating anti-melanocyte antibodies can be detected in some patients with halo nevi, and these antibodies disappear following regression or surgical excision. Studies have shown that CD20-positive cells are present around nests of nevus cells both in the early and late stages of regression. Statistical analyses further indicate that, in the late stage of regression, the CD3-to-CD20 ratio is significantly higher than in the early stage, suggesting that during the spontaneous regression of halo nevi, antibody production likely results from T‑lymphocyte–mediated destruction of nevus cells, accompanied by the release of nevus cell antigens that activate B cells. Additionally, research has demonstrated increased expression of CD207-positive cells in halo nevi, implying that Langerhans cells may be activated and participate in the autoimmune response underlying this condition; moreover, the number of macrophages increases in the late phase of regression, potentially contributing to the immune mechanisms driving nevus resolution.

3. Halo Nevus and Associated Diseases and Etiological Factors

3. 1 Nevus of Ota and Vitiligo

Whether halo nevus and vitiligo represent the same disease remains inconclusive; however, the two conditions may share similar immunological mechanisms, in which cytotoxic T lymphocytes and associated antibodies target melanocytes, leading to skin depigmentation. Previous studies have demonstrated differences between halo nevus and vitiligo in HLA subtype expression and molecular expression levels. Moreover, patients with halo nevus exhibit distinct characteristics—such as age at onset, disease duration, the positive rate of the Koebner phenomenon, and the incidence of autoimmune disorders—compared with those with vitiligo, suggesting that halo nevus may be an independent condition with overlapping pathogenic mechanisms to vitiligo.

Halos are often associated with vitiligo, with an unpredictable sequence of onset; epidemiological reports on the incidence of this association vary. Zhang Qian et al. analyzed 106 patients with halos complicated by vitiligo: 29.2% developed vitiligo after the halo, 33.0% before it, and 36.8% concurrently. Moreover, multiple halos were more strongly associated with subsequent vitiligo than solitary halos. Patrizi et al. studied 98 pediatric patients with halos, among whom 27 had concurrent vitiligo, and found that compared with those with a single halo, patients with multiple halos and a personal or family history of autoimmune thyroiditis were at higher risk of developing vitiligo. Geel et al., comparing the medical histories of 40 patients with halos to those of 78 patients with halos and vitiligo, concluded that the longer the duration of the halo—particularly when accompanied by a negative family history of vitiligo and no other autoimmune disorders—the lower the risk of vitiligo. They also noted that halos were more closely linked to vitiligo that manifested before age 12, suggesting indirectly that early‑onset halos may constitute a risk factor for the development of vitiligo. Cohen et al., contrasting 153 children with isolated vitiligo to 55 children with vitiligo complicated by halos, reported that, compared with segmental or localized vitiligo, childhood halos were more strongly associated with generalized vitiligo; however, they found no clear relationship between the extent of disease progression or treatment outcomes and the presence of halos.

3. 2. Nevus of Ota and Melanoma

Hypopigmentation and depigmentation frequently occur during the progression of malignant melanoma; clinically, melanoma associated with halo nevi and postoperative halo nevi have been observed. In some patients with halo nevi, circulating immune antibodies against melanoma cells can be detected in the blood, suggesting a link between halo nevi and melanoma. Previous studies have shown that the two conditions differ in their predominant inflammatory mediators, and that fibrosis is present in the depigmented areas of melanoma lesions. Immunohistochemical analysis further reveals higher expression of proteins such as PD‑1 and TIA‑1 within halo nevus lesions. Certain halo nevi may exhibit atypical features, making it challenging to distinguish benign melanocytic nevi from melanoma. Rodrigo et al. used reflectance confocal microscopy (RCM) to examine nine halo nevus lesions and found that 33.3% of the central nevi displayed atypical architectural patterns under microscopic examination. Combined with previous reports, these findings suggest that the development of halo nevi may be related to malignant melanoma. Moreover, in some cases, disorganized thickening at the dermoepidermal junction (33.3%) and dermal papillary infiltration (33.3%) were observed, also pointing to a possible association with melanoma. Although these lesions were not subjected to histopathological evaluation, the authors classified them as benign based on their clinical characteristics and hypothesized that the atypical structures noted might be attributable to the inflammatory response triggered during the progression of the halo nevus.

Clinically, dermoscopy can be used to differentiate halo nevi from malignant melanoma. On dermoscopic examination, central nevi typically exhibit benign features, with a white halo that is often uniform and symmetrical; in contrast, malignant melanoma may present as an irregular pigmented network, asymmetry, and blue–white structures.

3.3 Halo Nevus and Turner Syndrome

Turner syndrome is a genetic disorder characterized by typical physical features and the complete or partial absence of one X chromosome, and it is associated with cutaneous conditions such as multiple pigmented nevi. Rare cutaneous manifestations reported include pemphigoid‑like lichen planus, halo nevi, and hemangiomas. It was previously believed that patients with Turner syndrome have a higher incidence of halo nevi, and a susceptibility gene for halo nevi in Turner syndrome was proposed to reside within the HLA‑C locus. Bello et al. described an 11‑year‑old patient with Turner syndrome who developed halo nevi among her multiple melanocytic nevi following growth hormone therapy. MIURA et al. reported an 8‑year‑old patient with Turner syndrome who was receiving long‑term anterior pituitary hormone replacement therapy, had a 5‑year history of alopecia areata unresponsive to topical corticosteroids, and, two years earlier, had multiple pigmented nevi accompanied by halo nevi. Histopathologic examination after excision of the lesions revealed perineural infiltration of mononuclear cells around nests of dermal melanocytes, along with loss of HMB‑45‑positive melanocytes in the epidermis; immunohistochemistry demonstrated abundant CD8⁺ T cells, suggesting that immune dysregulation may underlie the increased propensity for halo nevi in Turner syndrome. At present, it remains unclear whether hormonal therapy induces halo nevi or increases their number; previous reports have noted reduced CD4/CD8 ratios and diminished T‑cell immune responses in patients with Turner syndrome, which may be related to the strong association between Turner syndrome and halo nevi.

3.4 Nevus of Ota and Medications

Previous literature has reported that certain drugs used in the treatment of autoimmune diseases and skin tumors can induce halo nevi. Beta‑1a interferon, infliximab, and imatinib mesylate may trigger halo nevi by directly inhibiting melanocytes or by activating CD8+ T cells to elicit an immune response against melanocytes. Ma‑ruthappu et al. described a 30‑year‑old male with ankylosing spondylitis, with no history of hypopigmentary skin disorders or family history, who developed a total of 10 halo nevus lesions on the extremities and trunk after receiving adalimumab 40 mg every other week for six months; these lesions showed no dysplasia or atypical features. The patient continued adalimumab therapy, but the halo nevi did not progress further. Autoantibody formation is one of the adverse effects associated with monoclonal antibody therapies; multiple reports have indicated that anti‑TNFα treatment can lead to vitiligo and halo nevi, suggesting that post‑treatment dysregulation of autoimmune function may be among the mechanisms underlying this phenomenon. Zhou et al. reported a 43‑year‑old female with Graves’ disease who developed vitiligo and halo nevi after three years of oral methimazole; eight months of continued therapy was followed by facial erythema, leading to a clinical diagnosis of Graves’ disease, vitiligo, halo nevi, and lupus. Previous studies have documented that methimazole can cause dermatitis, drug‑induced lupus, and other cutaneous manifestations, while also elevating CD8+ T‑cell levels. Whether a history of thyroid disease and prior methimazole use are associated with the development of halo nevi remains to be confirmed.

3.5 Nevus of Ota and Ultraviolet Radiation

Short-term ultraviolet irradiation can induce apoptosis in various cell types, including melanocytes, via the cytotoxic granule exocytosis pathway. Some researchers have proposed that UV exposure may activate antigens, triggering an inflammatory response and leading to skin damage. Kawaguchi et al. reported a 16-year-old male with no personal or family history of pigmented skin disorders who had been continuously exposed to intense summer sunlight for two weeks; one month later, he developed 18 acrofacial halo nevi over his trunk and extremities. Based on this case, they hypothesized that UV radiation can elicit a cutaneous isomorphic reaction, thereby provoking a localized inflammatory response. Previous studies have suggested that UV exposure may induce melanocyte apoptosis through molecular pathways involving perforin and granzymes. However, clinical data indicate that halo nevi do not predominantly occur on sun-exposed areas such as the face or hands; consequently, the precise association between halo nevi and UV exposure remains unclear.

4. Treatment of Halo Nevus

Currently, there is no consensus on the treatment of halo nevi; laser therapy or surgical excision are the most commonly employed approaches. Some researchers have suggested that, if left untreated, halo nevi may progress to vitiligo, a mechanism that may involve cytotoxic T‑cell–mediated destruction of nevus cells and melanocytes. Zhang Qian et al., after surgically treating 277 patients with halo nevi, concluded that surgical removal can eliminate antigenic stimuli exposed within the lesion, making it an effective therapeutic option. In a small subset of patients with both halo nevi and vitiligo, complete clinical remission of vitiligo was observed following excision of the halo nevi, even in the absence of conventional topical or systemic therapies, suggesting that antigen clearance at the lesion site may lead to a downregulation of circulating autoantibodies and a dampening of the immune response, thereby facilitating repigmentation. However, such reports remain infrequent, and the underlying mechanisms require further investigation. Beyond surgical intervention, Mulekar et al. reported the use of 308‑nm excimer laser therapy in four cases of facial halo nevi, noting favorable repigmentation of the white halo; nevertheless, the safety of excimer laser treatment for halo nevi remains controversial. Additionally, one case has been described in which a patient with both a halo nevus and vitiligo achieved repigmentation of both lesions following topical tacrolimus application. Mouhammad et al. advocate a strategy of close observation and periodic follow-up for benign halo nevi that do not significantly affect appearance and for which patients lack a strong desire for treatment. If clinical findings reveal concerning features—such as advanced age, atypical central nevus morphology, or asymmetric or uneven depigmentation of the halo—prompt excision and histopathological evaluation are warranted.

5. Summary

Clinically, halo nevi have been found to be associated with certain diseases and their treatments. In particular, early‑onset, multiple benign halo nevi are strongly linked to the onset of vitiligo and warrant close follow-up and observation. When a halo nevus is located in areas prone to friction or injury, or when it significantly affects appearance, excision of the central nevus together with the surrounding depigmented halo may be considered; however, the long-term prognosis remains uncertain. To date, there are few reports on the efficacy of large‑scale, multimodal therapeutic approaches, underscoring the need for further clinical and experimental research.

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