Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi‐institutional retrospective study

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2–9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression‐free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11–0.55 and 0.03–0.79; P = 0.005, and 0.047, respectively). At the 20‐week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.     

Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression-free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.     

Malignant Melanoma and Vitiligo

Eleven patients suffering from malignant melanoma have been found to have varying degrees of vitiligo. The association of the two conditions may be purely coincidental; however, there are several features both of melanoma and of the vitiligo in these patients which suggest that there could be some relationship between the behaviour of melanoma and the development of vitiligo. The cases are reported with a view to pooling experience of a rare association of events. Depigmentation associated with malignant melanoma may take one of several forms, Milton (1969); the primary lesion may undergo total spontaneous regression leaving an amelanotic scar; all or part of a growing primary lesion may become amelanotic; the skin in the immediate vicinity of a primary melanoma may become amelanotic. Metastatic melanoma can also be associated with depigmentation because the deposits themselves are quite often amelanotic and rarely skin secondaries may show pale halos of depigmentation. The pale halos often develop after successful chemotherapeutic treatment or, on rare occasions, spontaneously. This paper presents eleven cases of depigmentation (vitiligo) which was not closely related to either the primary lesions or to metastases. The clinical course of some of these cases was unusual and a speculation is advanced that vitiligo associated with malignant melanoma may have some bearing on the prognosis of the disease. It is hoped that the publication of this report will stimulate a search for cases in which a possible correlation between vitiligo and malignant melanoma can be either proved or disproved.     

Leucodermia en pacientes con melanoma tratados con interferón

—The association between leucoderma or vitiligo and melanoma has often been described in the literature, and in some cases it has been related with a good prognosis. These achromic lesions may appear before or after the diagnosis of melanoma. The association between leucoderma and interferon has also been described. We present three patients diagnosed of melanoma with lymph node metastasis who developed leucoderma or leucothrichia during treatment with interferon α2b. One of the patients had a melanoma metastasis with an achromic halo before treatment with interferon. The appearance of achromic lesions in patients with melanoma could be the result of a selective immunologic response against pigmented cells. In our three patients there is a sequencial relationship between the treatment with interferon and the appearance of the achromic lesions. This fact suggests that immunotherapy could stimulate this immunological response.     

Hypopigmentation associated with an adenovirus-mediated gp100/MART-1-transduced dendritic cell vaccine for metastatic melanoma

BACKGROUND: Reports of vitiligo associated with metastases and rare cases of spontaneous regression of disease have fueled enthusiasm for immunologic approaches to the treatment of advanced melanoma. More recent strategies have focused on using antigen-presenting dendritic cells as vaccines. OBSERVATIONS: We observed 3 cases of leukoderma associated with a novel adenovirus-mediated gp100/MART-1-transduced dendritic cell (MART indicates melanoma antigen recognized by T cells). All 3 patients had advanced metastatic melanoma. Despite the development of this leukodermic response, all patients experienced disease progression while under treatment. CONCLUSION: We provide the initial evidence for effective induction of a leukodermic response with a gp100/MART-1-transduced dendritic cell vaccine.     

Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod

The pathogenesis of vitiligo was examined for clues to the pigmentary changes that may occur after treatment with topical imiquimod. The literature varies on the pigmentary changes induced by topical use of imiquimod. The US Food and Drugs Administration lists 68 reports of pigmentary changes out of a total of 1257 reports related to imiquimod lodged from 1997 to 2003. Some studies describe vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts (as with the patient described in this report), molluscum contagiosum, basal cell carcinoma, extramammary Paget's disease and murine melanoma. Other studies report hyperpigmentation associated with imiquimod. The possible mechanisms of hypopigmentation associated with imiquimod treatment are discussed, including antibodies found in sera of patients with vitiligo to nonpigment cell antigens, cytoplasmic pigment cell antigens and pigment cell-surface antigens; stimulation by imiquimod of both the innate immune response and cell-mediated adaptive immunity; and increased sensitivity of melanocytes to oxidative stress. The vitiligo-like hypopigmentation following topical imiquimod treatment is in line with the mode of action of this drug.     

Malignant melanoma showing a rapid response to nivolumab

Malignant melanoma is a highly aggressive skin tumour, with a recent rise in incidence. Nivolumab is a recently developed anti‐programmed cell death‐1 immune checkpoint inhibitor and its usage has resulted in a significant improvement in the overall survival of patients with metastatic melanomas. We report a case of advanced melanoma that showed a significant and rapid response to nivolumab treatment. The patient displayed multiple melanoma‐associated vitiligo prior to treatment; this symptom was theorised to indicate potentially immunoreactive melanoma and the need for nivolumab. In addition, interferon‐β was injected prior to nivolumab treatment. The significant rapid response to nivolumab suggested the induction of a marked immune response against melanoma by interferon‐β. Therefore, interferon‐β could be a useful and effective adjuvant for nivolumab therapy.     

Association study between keratinocyte-derived growth factor gene polymorphisms and susceptibility to vitiligo vulgaris in a Taiwanese population: potential involvement of stem cell factor

Background  Vitiligo vulgaris is a depigmentary disorder resulting from the disappearance of functional melanocytes. Currently, the pathogenesis of this disorder remains obscure.
Objectives  Genetic analysis of patients with vitilgo may provide important clues for elucidating the complex pathomechanisms involved in the disease process. Because dysfunctional keratinocytes have recently been implicated in the pathogenesis of vitiligo vulgaris, we conducted a case–control association study to investigate this phenomenon.
Patients and methods  Fifty-one patients with vitiligo vulgaris and 118 healthy controls from Taiwan were recruited to investigate the association between relevant keratinocyte-related genes and the occurrence of vitiligo vulgaris. This study genotyped 11 single-nucleotide polymorphisms (SNPs) in five genes including stem cell factor ( SCF , also known as KITLG ), basic fibroblast growth factor ( bFGF , also known as NuDT6 ), endothelin-1 ( EDN1 ), hepatocyte growth factor ( HGF ) and stem cell growth factor ( SCGF , also known as CLEC11A ).
Results  Our results revealed that the A allele for SNP rs11104947 in the SCF gene and the T allele for SNP rs13866 in the SCGF gene were, respectively, associated with a 1·95- and a 2·14-fold risk of developing vitiligo vulgaris. A higher risk was also detected among subjects who carried the SCF rs995029/rs11104947 C/A haplotype (odds ratio = 2·45). Furthermore, the at-risk alleles for SCF rs11104947 (A allele) and for SCGF SNP rs13866 (T allele) were found to display a 7·92-fold increased gene–gene combined risk. No significant relationship between polymorphic frequency for genes bFGF , EDN1 as well as HGF and occurrence of vitiligo vulgaris was observed.
Conclusions  These novel genetic findings provide new insights in relation to the mechanisms that might be involved in the development of vitiligo vulgaris.     

Response of vitiligo to once- vs. twice-daily topical tacrolimus: a controlled prospective, randomized, observer-blinded trial

Background  A few studies on the treatment of vitiligo with topical tacrolimus have been published and showed promising results. However, most of these trials were uncontrolled.
Objective  This study aims to assess the response of vitiligo to once- or twice-daily treatment with 0.1% tacrolimus in a controlled, randomized, observer-blinded study.
Methods  Seventeen patients with generalized vitiligo were enrolled in this study. In each patient, two lesions were selected and randomized to treatment with either once- or twice-daily application of 0.1% tacrolimus for a total period of 6 months. In 10 patients, a third patch was left untreated to serve as a control.
Results  Fifteen patients with 40 target lesions completed the study. Twice-daily treatment induced excellent (> 75%) repigmentation in two lesions, moderate (> 25–50%) and poor (1–25%) repigmentation in four lesions each, and no response in five lesions. Once-daily treatment resulted in moderate repigmentation in two lesions and poor repigmentation in five lesions, whereas no effect was observed in the remaining eight lesions. One out of 10 control lesions developed moderate spontaneous repigmentation, the other nine remained unchanged. Besides the frequency of tacrolimus application, the treatment outcome was determined by the localization of the affected areas with the facial region showing the best response.
Conclusions  Tacrolimus ointment appears to be an effective treatment option for facial vitiligo. A guarded prognosis is advisable for vitiliginous lesions on other localizations. Treatment must be applied twice daily for optimum response.

Conflict of Interest

None declared.     

Vitiligo and melanoma‐associated hypopigmentation (MAH):shared and discriminative features

Background: It is unclear if differences between melanoma‐associated hypopigmentation (MAH) and classical vitiligo exist. Patients and Methods: Hypopigmented areas and associated lesions (halo nevi, hypopigmented scars) in 15 melanoma patients and 31 patients with classical vitiligo were analyzed by digital photography. The activity of the respective lesions was assessed by the vitiligo disease activity (VIDA) score.Associated diseases were recorded by history and serological tests;genotyping of HLA class I antigens as well as histology/immunohistology were performed. Results: MAH were diagnosed in 12 of 15 melanoma patients;mean onset was 4.8 years after the primary diagnosis of the melanoma. Three melanoma patients reported hypopigmentation more than 15 years before diagnosis of melanoma. In the history and family history of vitiligo patients, autoimmune diseases were much more frequent and haplotype HLA‐A2 was twice as common compared to MAH patients.MAH lesions were most often distributed in a bilateral symmetrical pattern,corresponding to vitiligo.MAH was less progressive compared to classical vitiligo;however,it was more often associated with other acquired leukodermas. In both groups hypopigmentation spread centripetally to the trunk. Histological and immunohistological differences were not found. Conclusions: Whereas differences exist concerning associated autoimmune dis‐eases,MAH and vitiligo shared many common clinical and histological features. Further studies are needed to assess the clinical relevance of vitiligo‐like alterations in melanoma patients.     

Efficacy and safety of tarcrolimus cream 0.1% in the treatment of vitiligo

Background  Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult to treat. Phototherapy and application of topical corticosteroids are most commonly prescribed. However, these therapies are often not effective and use of corticosteroids on the face may lead to cutaneous atrophy, telangiectasia, and ocular complications.
Objective  We sought to assess the efficacy of topical tacrolimus ointment in the treatment of vitiligo.
Methods  A prospective pilot study was performed of 30 patients with vitiligo. Patients were treated with tacrolimus ointment for at least 4 months. Clinical responses were documented during clinic visits, and by pretacrolimus and post-tacrolimus photography.
Results  Twenty-five (83.3%) patients showed some repigmentation at the end of 4 months. Patients with vitiligo for more than 5 years also responded well to tacrolimus ointment. Repigmentation in active vitiligo was superior to that in stable vitiligo. 80% of patients with segmental vitiligo of the head and neck showed some response to tacrolimus, but there was no statistical significance between segmental and vulgaris vitiligo. The mean percentage of repigmentation on the head and neck was greater than that on the trunk and extremities. Four patients initially experienced burning on application.
Conclusions  Topical tacrolimus ointment is an effective and well-tolerated alternative therapy for vitiligo especially involving the head and neck.     

Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up

Background  Melanoma in situ /lentigo maligna (LM) is a potential precursor of LM melanoma. It occurs most commonly in elderly individuals on sun-exposed skin of the head and neck. Although surgical excision is the treatment of choice, this may not be desirable or feasible for large lesions at functionally or cosmetically important sites. Imiquimod is a topical immunomodulator which can generate a local cytotoxic response with potentially antiviral and antitumour effects.
Objectives  To present our experience of LM treated with imiquimod.
Methods  A retrospective review was performed of all patients with facial LM treated in our unit with topical imiquimod between January 2001 and December 2006. Pretreatment diagnostic biopsies were also reviewed and histologically graded.
Results  Forty-eight patients were treated with imiquimod. There were 37 responders and 11 treatment failures (of whom two were 'partial responders'). Of the 37 responders, 31 showed a clinical inflammatory response to imiquimod. One patient in whom treatment failed subsequently developed invasive disease. The mean follow-up duration was 49 months. We could not identify histological features of prognostic significance. However, the ability to develop an inflammatory reaction to imiquimod was a strong predictor of therapeutic benefit.
Conclusions  We consider imiquimod to have a role in the treatment of LM in patients in whom surgery may be contraindicated or for those in whom the cosmetic or functional consequences may be considerable. Until better characterized, its use should probably be confined to centres with experience in the detection and treatment of LM and melanoma.     

Tumor lysis syndrome after transcatheter arterial infusion of cisplatin and embolization therapy for liver metastases of melanoma

Background  Tumor lysis syndrome (TLS) is rare in the treatment of solid tumors, but it may occur in myelolymphoproliferative diseases.
Methods  A 58-year-old man with bulky metastatic melanoma of the liver was treated with transcatheter arterial infusion of cisplatin and embolization therapy. The patient developed classic signs of TLS within 24 h of chemotherapy, including acute renal failure.
Results  The patient was treated with aggressive hydration, allopurinol, and repeated hemodialysis. He gradually improved and his biochemical markers returned to normal.
Conclusion  TLS is an uncommon, but potentially life-threatening, complication in melanoma and other solid tumors. It is important for oncologists to recognize this complication and prevent its development if bulky metastatic disease and several pre-existing risk factors, such as multiple and bulky liver metastases, elevated lactate dehydrogenase, and hyperuricemia, are present.     

中外白癜风诊疗指南及共识比较

本文从白癜风分型、分期、病情评估、药物治疗及非药物治疗等方面比较了欧洲、美国、日本、韩国、中国等地区和国家的白癜风诊疗指南或共识, 概要分析各指南及共识中推荐的白癜风疗法和强调理念的异同, 以帮助临床医生为白癜风患者提供合适的个体化治疗方案。     

The development of guidelines for the treatment of vitiligo. Clinical Epidemiology Unit of the Istituto Dermopatico dell'Immacolata-Istituto di Recovero e Cura a Carattere Scientifico (IDI-IRCCS) and the Archives of Dermatology

OBJECTIVE: To develop and introduce evidence-based guidelines for the treatment of vitiligo in children and in adults. PATIENTS AND SETTING: Patients, residents, and dermatologists from the Department of Dermatology, Academic Medical Center, University of Amsterdam, and the Netherlands Institute for Pigmentary Disorders in Amsterdam. DESIGN: Scientific evidence obtained from 3 systematic reviews of the literature was combined with the results of 2 questionnaires and interviews of potential users of the guidelines, 3 internal expert meetings, and 1 local expert meeting, during which preliminary guidelines were presented and commented on. A final version of the guidelines was synthesized and disseminated among potential users. Six months after the introduction of these guidelines, their use was evaluated. RESULTS: Before the development of the guidelines, there was no uniformity in treatment selection, and there was a variability in estimates of treatment outcome. The metaanalysis showed class 3 corticosteroids and narrowband UV-B to be the most effective and safest therapies for localized and for generalized vitiligo, respectively. From another systematic review, it could be concluded that patients with segmental, stable, or lip-tip vitiligo could be successfully treated with most autologous transplantation methods. For vitiligo universalis, results of the systematic review showed that depigmentation using monobenzone or a Q-switched ruby laser was equally effective. The final version of the guidelines consisted of a treatment scheme together with detailed treatment protocols. Implementation of the guidelines was evaluated in 5 physicians. After the introduction of these guidelines, they were followed in most adult cases with vitiligo (71% of patients with localized vitiligo, 82% with generalized vitiligo, 100% with stable or segmental vitiligo, and 80% with universal vitiligo). In children with vitiligo, the physicians adhered to the guidelines for 52% of the cases. CONCLUSIONS: Guidelines for the treatment of vitiligo can be successfully developed and disseminated for daily clinical practice. The results of the implementation of these guidelines should be confirmed in other centers involving more clinicians.     

Bases inmunológicas de la hipopigmentación vitiligoide asociada a melanoma

Vitiligo is a skin condition characterized by white, hypopigmented macules. Melanocyte loss is a feature of the disease, and it has been hypothesized that an autoimmune mechanism could be responsible for the depigmentation. Melanoma is a malignancy that develops in melanocytes; if not detected and treated early, it is often deadly. Leukoderma, a condition characterized by depigmentation of the skin, is sometimes associated with malignant melanoma. An immune response against melanocyte antigens leading to destruction of either melanoma cells or melanocytes has been observed in both vitiligo and melanoma. Studies in animal models and humans have shown that humoral and cell-mediated immune responses are involved in modulating cytotoxic activity against tumor cells and normal melanocytes. The study of factors associated with anti-tumor immunopathogenic mechanisms —autoimmunity for example— may provide us with tools for the diagnosis and treatment of diseases such as vitiligo and malignant melanoma.     

Do we have to pay more attention to vitiligo patients? Peculiar histopathological features of primary cutaneous melanoma preceded by vitiligo

Vitiligo is an acquired depigmenting skin disease characterized by the loss of functioning epidermal melanocytes. Vitiligo can be associated with an autoimmune disorder. An unusual and important aspect of vitiligo is its relationship to melanoma. We present herein a 34-year-old man who developed regional lymph node metastases of malignant melanoma 2 years after the diagnosis of vitiligo.     

A survey of vitiligo management among dermatologists in Saudi Arabia

Background  There are concerns that there is no uniform approach towards the management of vitiligo.
Objectives  To explore attitudes and strategies for the management of vitiligo among dermatologists.
Methods  A self-administered questionnaire containing 22 questions was distributed to 160 dermatologists attending a national dermatology conference in 2007.
Results  One hundred and twelve dermatologists responded to the questionnaire (70% response rate). We had 105 completed questionnaires (seven were excluded due to incompleteness). Active treatment of vitiligo was recommended by 96% in more than half of patients, while 79% recommended treatment at non-visible sites. Repigmentation was regarded as main treatment goal by 54%. Mid-potent topical steroids were widely prescribed for focal vitiligo (72% in children and 65% in adults). Use of tacrolimus and pimecrolimus was limited. The most common used phototherapy was 'narrowband ultraviolet B' (NBUVB; 36% and 40% for generaliased vitiligo in children and adults, respectively). The use of oral psoralen plus UVA (PUVA) was limited (8% for generalized vitiligo in adults). Few respondents (1–8% for different types of vitiligo) prescribed outdoor topical PUVA. Vitiligo surgery was advised mainly for segmental type (18% in adults and 5% in children). Depigmentation was the first option for universal vitiligo by 50% and 30% in adults and children, respectively.
Conclusions  Most dermatologists are enthusiastic about active treatment of vitiligo even in hidden sites. Overall, the most two common treatment modalities were topical steroids and NBUVB. Vitiligo surgery is underutilized. Development of national practice guidelines is needed.     

Vitiligo: a review of the published work

Vitiligo is a common depigmenting skin disorder, characterized by acquired, idiopathic, progressive, circumscribed hypomelanosis of the skin and hair, with total absence of melanocytes microscopically. It occurs worldwide, with an incidence rate of between 0.1% and 2%. Vitiligo is an important skin disease having a major impact on the quality of life of the patient suffering from it. The causes of this condition are uncertain but seem to be dependent on the interaction of genetic, immunological and neurological factors. Vitiligo coexists with other autoimmune disorders, Sutton or halo nevus, and malignant melanoma. The substantial disfigurement associated with vitiligo can cause serious emotional stress for the patient, which necessitates treatment. Because its pathogenesis is still not understood, there is a plethora of different treatments. Among them, topical steroids and narrowband ultraviolet B monotherapy were the most common as current treatments for localized and generalized vitiligo, respectively. Cosmetic improvement can be achieved by camouflage products and self-tanning dyes. The course of vitiligo is unpredictable, but often progressive. Spontaneous repigmentation may occur in a few people (10–20%), mainly in children, but this tends to be only partial and on sun-exposed areas. In this article, we review vitiligo as a whole, including epidemiology, pathogenesis and etiology, histopathology, clinical manifestations, classification, clinical variants, diagnosis and differential diagnoses, specific investigation, treatment, prognosis, psychosocial view and its association with other disorders.     

Chemical leucoderma: a clinico-aetiological study of 864 cases in the perspective of a developing country

Background  Chemical leucoderma, often clinically mimicking idiopathic vitiligo and other congenital and acquired hypopigmentation, has been increasing rapidly in incidence in developing countries such as India.
Objectives  This study attempts to detect clinical and epidemiological patterns of chemical leucoderma.
Methods  Detailed history-taking, especially of exposure to contributory chemicals, clinical examination, relevant investigations, data recording and analysis were done.
Results  In a total of 864 cases of chemical leucoderma, 65·6% cases started de novo and vitiligo patches were pre-existing in the remaining cases. Patches were limited to the contact area in 73·7% but had spread to remote areas in 26·3% cases. The face (41·1%) and scalp (5·9%) were the commonest and least involved sites. Confetti macules were seen in 89% and pruritus was complained of in 21·8%. Aetiological agents identified were hair dye 27·4% (21% self-use; 6·4% not self-use), deodorant and spray perfume 21·6%, detergent and cleansers 15·4%, adhesive bindi 12%, rubber chappal 9·4%, black socks and shoes 9·1%, eyeliner 8·2%, lipliner 4·8%, rubber condoms 3·5%, lipstick 3·3%, fur toys 3·1%, toothpaste 1·9%, insecticides 1·7%, 'alta' 1·2%, amulet string colour 0·9%. Therapeutic response was much better in 'pure' chemical leucoderma (73·4%) than in those with co-existing vitiligo (20·9%).
Conclusions  Chemical leucoderma, a disease of mostly industrial origin in developed countries, may be induced by common domestic products in developing countries. Diagnosis and differentiation from other causes of hypopigmentation can be done confidently by following the clinical criteria as proposed. The therapeutic response of chemical leucoderma is better than that of vitiligo.