Halonevus, also known as leukodermaacquisitumcen-trifugum and Sutton’s moles, is a kind of pigment loss disease in which cytotoxic T cells are the main effector cells and a variety of cells are involved. The incidence of halo nevi is about 1%, mostly occurs in teenagers, the most common site is trunk cadres, clinically, single halo nevi is more common. The cause of the disease is unknown, the original nevus pigmentosa can be induced by freezing, laser treatment or scratching and other stimuli. Light may be one of the causes of halo nevi.
1. Clinical features
The typical skin lesions of halo nevus are central melanocyte nevus, a few central nevus are dysplasia nevus, blue nevus, Spitz nevus, seborrheic keratosis, melanoma, Mongolian spot or congenital nevus pigmentosa, etc., and the peripheral circular or oval white ring lesions. Most of the central nevi under dermoscopy of nevus areus were homogenous spherical with no structural area, and the white halo showed uniform hypochromic area. Babu et al. reported a case of “anti-halo” nevi with white halo and white hair in the center of 3cm by 3cm congenital nevi. At present, it is considered that nevus areola is a kind of spontaneous regressive and autoimmune disease. There are four clinical stages in the evolution of nevus areola: the first stage is the local pigment loss around nevus; In the second stage, the central nevus hypopigmentation evolves into pink papule. In the third stage, the central papule disappeared and only the annular desquamate was left. In the fourth stage, the pigment returned to normal. Some scholars followed up 33 halo nevi (4-61 months, an average of 26 months), and showed that the area of the central nevi decreased in different degrees during the observation period, with an average monthly decrease of 2.2%. In the fading stage, the central area of the nevus can be seen changing from pale brown to pink with dotted vessels. Due to the limitation of follow-up, not all the moles can be seen in four stages in clinical practice, with the first stage being the most common and lasting for more than 10 years.
2. Histopathology and pathophysiology
Under halo ring microscopy, melanocyte loss and lymphocyte infiltration in the basal layer of white halo were observed. Mole is compound mole and intradermal mole more, can have heteromorphic sex expression. Compound nevus showed that the nevus cells were striated to the dermis. Nevi intradermal nevi cells nests can be seen, and Grenz zone between nevi and epidermis is obvious. Microscopically, nevi cells and melanocyte regression and inflammatory cell infiltration were observed with neovascularization and interstitial vascular hyperplasia. At present, it is believed that the main physiological mechanism of spontaneous regress of halo nevus is the abnormal immune tolerance of its own nevus cells, which leads to the activation and proliferation of specific self-reactive T cells and local immune damage at the skin lesions, in which CD8+T cells are the main effector cells. Park et al. conducted immunohistochemical analysis on 30 moles and found that Foxp3+Tregs increased significantly in the early stage of moles, and the number of Foxp3+Tregs was positively correlated with the degree of inflammatory infiltration, indicating that Foxp3+Tregs may play an important role in the development of moles.
Humoral immunity has been considered to play a small role in the process of nevus regression, but circulating anti-melanocyte antibodies can be detected in some patients with nevus, which disappear after nevus regression and resection. Research shows CD20 + cells exist in the halo nevus retreat surrounding the early and late nevus cell nests, statistical analysis shows that fades late CD3 and CD20 ratio is fading early rise obviously, showed that the halo nevus spontaneous regression in the process, the production of antibodies that may well be T cell-mediated damage associated with nevus cell nevus cells release the results of B cell activation antigen. Studies have indicated that CD207 cells are expressed in nevus areus, indicating that langerhans cells may be activated and participate in the autoimmune response of nevus areus during the pathogenesis. The number of macrophages in the late stage of halo nevus regression was higher than that in the early stage, which may be involved in the immune response of halo nevus regression.
3. Nevi areola and related diseases and causes
3.1 nevus areola and vitiligo
Whether nevus areus and vitiligo belong to the same disease has not been determined, but the two may have similar immune mechanism, that is, cytotoxic T lymphocytes and related antibodies act on melanocytes to cause skin pigment loss. Previous studies showed that halo nevus vitiligo in HLA subtypes have different expression and molecular expression level, and halo nevus patients age, disease course, Koebner reaction positive rate and the incidence of autoimmune diseases were significantly different from those of patients with vitiligo, show that halo nevus is probably a with vitiligo in the pathogenesis of overlapping independent disease.
Nevus halo is often accompanied by vitiligo, the order of onset is not fixed, accompanied by the incidence rate of current epidemiological reports vary. Zhang qian et al. counted 106 cases of patients with vitiligo complicated by nevus areolar, and 29.2% of them had nevus areolar before vitiligo, 33.0% had vitiligo later, and 36.8% had vitiligo at the same time. There was a higher correlation between multiple halo nevi and secondary vitiligo than that between single halo nevi and secondary vitiligo. Patrizi et al. studied 98 children with nevi, 27 of whom were associated with vitiligo, and found that patients with multiple nevi, a personal and/or family history of autoimmune thyroiditis were more likely to have vitiligo than patients with single nevi. Geel contrast 40 cases such as halo nevus history with 78 cases of patients with halo nevus with history of vitiligo patients, think more than 3 years, family history of vitiligo negative, factors related to autoimmune diseases, the halo nevus lower risk in patients with vitiligo, and halo nevi associated with 12 before the age of onset of vitiligo, suggests young halo nevus may be a risk factor for complicated with vitiligo. Cohen et al. compared 153 cases of children with vitiligo alone with 55 cases of children with vitiligo and vitiligo halo, and proposed that compared with segmental and localized vitiligo, there was a higher correlation between children with vitiligo halo and generalized vitiligo, but there may be no significant relationship between the progression of vitiligo halo and the treatment effect.
3.2 nevus areola and melanoma
Hypopigmentation and loss of skin pigment often occur in the progression of malignant melanoma. Clinically, melanoma accompanied by nevus areola and postoperative nevus areola can be seen. Circulating immune antibodies of melanoma cells can be found in the blood of some patients with nevus areata, indicating that there is a certain relationship between nevus areus and melanoma. Previous studies have shown that the main inflammatory factors in the course of the two diseases are different, and fibrosis exists in the pigment loss area of melanoma. Immunohistochemistry shows that PD1, tia-1 and other proteins are more expressed in the lesions of nevus areola. Some halo nevi may have atypical morphology, making it difficult to distinguish benign melanocytic nevi from melanoma. Rodrigo et al. observed the skin lesions of 9 cases of nevus areolata using reflection confocal microscope (RCM), and found that 33.3% of the central nevus of nevus areolata could be manifested as atypical structure under the microscope. Combined with previous reports, the occurrence of nevus areolata may be related to malignant melanoma. In addition, dermal papillary infiltration (33.3%) and dermal thickening (33.3%) can be seen at the dermal epidermal junction of some nevus areola, which may also be related to melanoma. Although the above lesions were not pathologically examined, they were all diagnosed as benign according to the clinical characteristics of the lesions, and the atypical structures observed may be related to the inflammatory response caused by the progression of the nevus halo.
Clinical dermoscopy can be used for the differential diagnosis of nevus areola and malignant melanoma. Under dermoscopy, the nevi in the center is benign, and the white halo is more uniform and symmetrical. Malignant melanoma is characterized by irregular pigmented netting, asymmetry, and blue-white structure.
3.3 nevus areola and Turner syndrome
Turner syndrome is a genetic disease with both typical physical signs and complete or partial deletion of secondary sex chromosomes, which is related to skin diseases such as multiple nevus pigmentosa. Rare skin morphological changes reported include pemphigoid lichen planus, moles halo and hemangiomas. Previously, it was believed that the incidence of nevus halo in Turner syndrome patients was higher, and it was proposed that the susceptibility gene of nevus halo in turn-er syndrome was located in the hla-c sequence. Bello et al. reported that one 11-year-old Turner syndrome patient had halo nevi in his multiple melanocyte nevi after growth hormone therapy. Their report a case of 8 patients with Turner syndrome and continuous use of pituitary hormone replacement therapy, with 5 years history of alopecia areata and topical steroid hormone treatment is invalid, multiple pigmented nevus 2 years ago with halo nevus, resection histopathological examination showed the lesion leather upper nest week mononuclear cell infiltrates nevus cells, skin of HMB – 45 positive melanocyte, immunohistochemical display a large number of CD8 + T cells, immune imbalance may be the cause of the Turner syndrome is easy with dizzy mole. At present, it is not clear whether hormone therapy leads to the increase in the number of moles and/or moles. Previously, it has been reported that patients with Turner syndrome showed decreased CD4/CD8 ratio and decreased t-cell immune response level, which may be related to the high correlation between Turner syndrome and moles.
3.4 moles and drugs
Previous literature has reported that some drugs can induce nevus halos in the treatment of autoimmune diseases and skin tumors. Beta-1a interferon, infliximab and imatinib mesylate can induce nevus halo by directly inhibiting melanocyte or activating CD8+ cells to induce melanocyte immune response. Ma-ruthappu et al. reported a 30-year-old male patient with ankylosing spondylitis, who had no history of hypochromic skin or family history. After 6 months of treatment with adamab 40mg every other week, 10 lesions of the nevus areola were found in the limbs and trunk, and no dysplasia or atypical features were found. The patient continued to be treated with atamuzumab but no further progress was made. Autoantibody formation is one of the adverse reactions of monoclonal antibody drugs. Many reports have shown that anti-tnfa treatment can lead to vitiligo and nevus areata, and the disorder of autoimmune function after medication may be one of the causes of nevus areata. Zhou et al. reported a 43-year-old female patient with Graves’ disease who developed vitiligo and nevus areola 3 years after oral administration of methimazole, and developed facial erythema 8 months after continued medication. Clinical diagnosis of Graves’ disease, vitiligo, nevus areola and lupus was made. It has been previously reported that methimazole can cause skin damage such as dermatitis and drug lupus, and increase the level of CD8+ cells. Whether thyroid history and methimazole medication history are related to halo nevi remains to be confirmed.
3.5 moles and ultraviolet rays
Short-term ultraviolet irradiation can induce apoptosis of different types of cells, including melanocytes, by cytotoxic granulocytosis pathway. Some scholars suggest that exposure to ultraviolet light can activate antigens, cause inflammatory reactions and lead to skin damage. Kawaguch et al. reported that a 16-year-old male patient, who had no personal history or family history of pigmented skin, had been exposed to strong summer sun for 2 weeks, and 18 spots of halo nevus lesions were found on the trunk and extremities 1 month later. Therefore, it was speculated that ultraviolet light could induce skin homogeneity and induce local inflammation. Previous studies have suggested that ultraviolet light can induce apoptosis of melanocyte through perforin, granulozyme and other molecular pathways. However, according to clinical statistics, moles do not mainly occur in the face, hands and other exposed parts, so the correlation between moles and ultraviolet rays is not clear.
4. Treatment of halo nevi
The treatment of nevus areus is inconclusive at present, laser or surgical resection is the common treatment. Some scholars have proposed that vitiligo may occur if the nevus halo is not removed in time, and its mechanism may be related to the attack of cytotoxic T cells on nevus cells and melanocytes. After treating 277 cases of nevus areus surgically, zhang qian et al. proposed that surgical treatment can remove the antigen exposed in the skin lesions and is an effective method for the treatment of nevus areus. There are a few patients with vitiligo with halo nevus after the removal of vitiligo, vitiligo without clinical treatment but gradually recolor, presumably due to the skin lesion antigen clearance after the circulation of antibodies down, weakened immune response to vitiligo gradually recolor. At present, there are few reports of this kind, and its mechanism needs to be further explored. In addition to surgical treatment, Mulekar et al. reported that 4 cases of nevus areus were treated with 308nm excimer laser, and the recolor of facial white halo was good, but the safety of excimer laser in the treatment of nevus areus was still controversial. In addition, it has been reported that 1 case of vitiligo patients with nevus halo, external use of tacrolimus after two kinds of skin lesions have recolor. Mouhammad et al. believed that observation and follow-up were the main methods for benign nevi with no severe aesthetic impact and no strong desire for treatment. If clinically observed such as senile nevus areola, central nevus atypical, white halo asymmetrical or uneven and other suspicious manifestations, should be promptly removed and pathological examination.
Clinically, it was found that there was a certain correlation between nevus aureus and some diseases and their treatment. Among them, the benign nevus aureus of low age and multiple occurrence was highly correlated with the pathogenesis of vitiligo, which should be closely followed up and observed. If the nevus areus is located in the area which is easy to be rubbed and damaged or affected by aesthetics, the central nevus and the white spots around the nevus can be resected, but the prognosis has not been determined. At present, the observation of therapeutic effect of large sample and multiple methods is rarely reported, and further clinical and experimental studies are needed.