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It can sometimes show a trichrome coloration &#40;band of tan color between the white macule and healthy skin&#41; or quadrichrome coloration &#40;perifollicular or marginal macular hyperpigmentation in cases of repigmenting vitiligo&#41;&#46; Another clinical form is inflammatory vitiligo&#44; with a raised red border similar to pityriasis versicolor&#46; The distribution patterns of vitiliginous lesions include focal vitiligo &#40;isolated lesion&#41;&#44; segmental vitiligo &#40;unilateral macular lesions which generally cover a dermatome&#41;&#44; generalized vitiligo &#40;most common form&#44; disseminated macules of variable size&#44; usually with a symmetric distribution and a certain predilection for extensor surfaces&#41;&#44; and vitiligo universalis &#40;severe form that affects more than 80&#37; of the body surface&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Certain proteins located in melanosomes are required for the synthesis of melanoma&#44; the pigment responsible for color in eyes and skin and its appendages&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> These molecules are denoted melanosomal proteins and are classified into 2 groups&#58;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Tyrosinase and tyrosinase associated protein 1 &#40;encoded by the <span class="elsevierStyleItalic">TYRP-1</span> gene&#41; and protein 2 &#40;encoded by the <span class="elsevierStyleItalic">TYRP-2</span> gene&#41;&#44; which catalyze the biochemical steps in the biosynthesis of melanin</p><p id="par0020" class="elsevierStylePara elsevierViewall">Melanoma-antigen recognized by T cells &#40;MART-1&#41;&#44; Pmel17&#44; Rab7&#44; and Rab27&#44; responsible for retaining the melanosomal structures and&#47;or transporting the melanogenic proteins or melanin pigments</p><p id="par0025" class="elsevierStylePara elsevierViewall">All these proteins are important from the pathogenic&#44; diagnostic&#44; and therapeutic point of view in a large number of pigmentary disorders &#40;vitiligo&#44; piebaldism&#44; melanocytic nevus&#44; and melanoma&#44; among others&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">To date&#44; different theories have been put forward to explain the possible pathogenesis of vitiligo&#44; with the immunology-based theory being the most widely accepted&#46; On the one hand&#44; it has been shown that vitiligo can be associated with other autoimmune disorders&#44; especially autoimmune thyroiditis&#46; On the other&#44; in these patients&#44; antibodies against melanocyte antigens such as tyrosinase&#44; TRYP-1&#44; and TRYP-2 have been detected&#46; In addition&#44; there are studies that show that cellular immunity also has an impact on the development of vitiligo&#46; Infiltrates have been found to contain CD8<span class="elsevierStyleSup">&#43;</span> T cells that are reactive with melanocyte self-antigens such as Melan-A&#47;MART-1&#44; tyrosinase&#44; and gp-100&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment for vitiligo depends on the presence and severity of associated comorbidities&#46; Therapy is based on topical immunosuppressive agents &#40;corticosteroids and calcineurin inhibitors&#41; and phototherapy to induce repigmentation&#46; In cases of extensive depigmentation&#44; depigmentation of healthy skin is indicated using hydroquinone monobenzyl ether&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Melanoma is a fatal mucocutaneous or ocular neoplasm that can be sporadic or familial&#46; The neoplasm is associated with a range of genetic factors&#46; Other predisposing factors are exposure to intense sunlight associated with sunburn and a clear phototype &#40;Fitzpatrick skin type I and II&#44; mainly&#41;&#44; although patients with darker phototypes can also present with the neoplasm&#46; Melanoma accounts for approximately 5&#37; of all cancers in men and 4&#37; in women&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The incidence of cutaneous melanoma among Caucasians is reported to be increasing by between 3&#37; and 7&#37; each year&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical presentations of cutaneous melanoma have been widely reported in dermatology and oncology texts&#44; and so the present review will not cover them in depth&#46; It is however important to mention that lesions are usually macular or nodular&#44; with irregular borders&#44; and generally hyperpigmented with a variety of colors ranging from light coffee to blue and grey&#46; Regions of hypopigmentation &#40;regression&#41; may even be present&#46; Some form of recurrence or metastasis &#40;regional or distant&#41; is reported in between 15&#37; and 36&#37; of patients with early-stage melanoma &#40;I and <span class="elsevierStyleSmallCaps">II</span>&#41; during the clinical course of their disease&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The accepted prognostic factors in the classification of the American Joint Committee on Cancer &#40;AJCC&#41; from 2009 include tumor thickness&#44; level of invasion &#40;only for T1 melanomas&#41;&#44; mitotic rate per mm<span class="elsevierStyleSup">2</span>&#44; ulceration&#44; presence of satellite&#44; lymph node&#44; and pulmonary metastases&#44; high levels of lactate dehydrogenase&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and antitumor lymphoid response&#46; The latter factor specifically refers to tumor-infiltrating lymphocytes&#44; whose density in the infiltrate is directly proportional to improved prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The function of this infiltrate would therefore seem to be to generate an innate antimelanoma immune response&#44; although unfortunately this is insufficient to fully eradicate the neoplasm in many cases&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Other prognostic factors that have also been taken into consideration are age&#44; sex&#44; anatomic site of the tumor&#44; and regional lymph node involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Melanoma is a highly immunogenic neoplasm&#46; In other words&#44; it stimulates the immune system to generate a humoral &#40;antibody-mediated&#41; and essentially cellular &#40;cytotoxic lymphocyte-mediated&#41; response to cytoplasmic antigens as well as to the membrane of melanoma cells&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Melanoma-associated antigens can generally be classified into 2 groups&#58;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Cancer&#47;testicular antigens&#46; These antigens are highly expressed in normal tissue during development&#44; while expression is limited to testicles and the placenta in adults&#46; They are expressed in some types of cancer&#46; This group includes the melanoma antigen family &#40;MAGE&#41;&#44; B antigen family &#40;BAGE&#41;&#44; G antigen family &#40;GAGE&#41;&#44; and New York esophagus &#40;NY-ESO-1&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Differentiation Antigens&#46; These antigens are expressed by both tumor cells and their normal counterparts&#44; but not in other cell types&#46; In turn&#44; this group of antigens is divided into 2 groups&#46; The first group includes melanosomal membrane proteins such as TYRP-1&#44; TYRP-2&#44; Pmel17 &#40;also known as gp100&#41;&#44; and MART-1&#46; Gangliosides &#40;GDs&#41; form the second group&#46; These are widely present in melanoma cells and are thought to play a role in cell-cell and cell-matrix adhesion and in growth factor binding&#44; suggesting that they may be involved in the invasive process of the tumor&#46; This group includes GD3&#44; GD2&#44; GM2&#44; GM3&#44; and O-acetyl GD3&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Melanoma therapy depends on the clinical stage&#46; In early stages&#44; treatment is mainly surgical&#46; Interferon alfa &#40;IFN&#945;&#41; has been used primarily as adjuvant therapy in patients with melanoma who are disease-free after appropriate surgery&#44; but with an intermediate or high risk of recurrence&#46; For advanced stages &#40;disseminated melanoma or inoperable locoregional disease&#41;&#44; chemotherapy&#44; radiotherapy&#44; and chemoimmunotherapy have been used with agents such as interleukin 2 &#40;IL-2&#41;&#44; which enhances the cytotoxicity of antigen-specific T and natural killer &#40;NK&#41; cells in vitro&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The response rates&#44; although less than 20&#37;&#44; are nevertheless promising&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Currently&#44; new treatments against therapeutic targets such as KIT<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> or BRAF<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> are emerging&#46; Another agent that forms part of this generation&#44; the so-called targeted therapy&#44; is the monoclonal antibody denominated ipilimumab &#40;anti-CTLA4&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Effort has also been made to develop immunotherapy regimens with dendritic cells&#44; whether in monotherapy or enhanced with molecules such as the glycoprotein gp100&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and methods such as lymphocyte transfer&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The above approaches reflect the strong interest in melanoma research&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Melanoma-Associated Leukoderma</span><p id="par0070" class="elsevierStylePara elsevierViewall">In certain circumstances&#44; vitiligo &#40;leukoderma&#41; may develop in patients with malignant melanoma&#44; mainly in advanced stages&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The relationship between melanoma and leukoderma is a controversial and fascinating topic&#46; Around 3&#37; of patients with melanoma may present this melanoma-associated vitiliginous depigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Hypopigmentation &#40;leukoderma&#41; in association with benign and malignant melanocytic lesions has been reported frequently with different clinical forms which include regression lesions adjacent to primary melanomas or their metastases &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17</span></a> nevus with halo &#40;Sutton&#41; around preexisting melanocytic nevi&#44; and vitiliginous lesions at sites distant to the melanoma&#44; whether isolated or associated with ocular findings of the Vogt-Koyanagi-Harada syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Distant leukoderma may present during the course of melanoma&#44; particularly in cases of advanced stages &#40;metastasis&#41; and the corresponding therapies &#40;mainly immunotherapy-based treatments with IL-2 or IFN&#945;<span class="elsevierStyleInf">2b</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> Longer survival has been observed in patients who develop leukoderma associated with melanoma in advanced stages compared to patients with advanced melanoma who do not develop it&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> suggesting that this is a reflection of the presence of an antitumor activity in the patient&#46; This melanoma-associated phenomenon presents with a frequency of between 1&#46;4&#37; and 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Unfortunately&#44; as mentioned earlier&#44; the efficacy of this antitumor response is not sufficiently great to increase the chance of complete eradication of melanoma&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Clinically&#44; melanoma-associated leukoderma bears certain similarities with vitiligo&#46; The prevalence of vitiligo among melanoma patients is estimated to be between 3&#37; and 6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In a series of 15 patients with melanoma and hypopigmentation&#44; leukoderma was found to be directly associated with melanoma in 12 cases &#40;80&#37;&#41;&#46; Hypopigmentation was observed on average 4&#46;8 years after initial diagnosis of melanoma&#44; and the age of onset was found to be 56&#46;4<span class="elsevierStyleMonospace">&#40;</span>10&#46;8&#41; years&#44; in comparison with the age in a group of nonmelanoma associated vitiligo of 27&#46;6 &#40;16&#46;5&#41; years&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> There was no difference between sexes in the frequency of the association&#46; In that series of cases&#44; 75&#37; of the patients with melanoma-associated leukoderma had a bilateral and symmetrical distribution of depigmentation similar to disseminated vitiligo&#44; whereas only 25&#37; of the population studied had a focal or asymmetric unilateral distribution of hypopigmentation&#59; no patients with the association had an acrofacial distribution of depigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The progression of melanoma-associated leukoderma is not as fast or progressive as is usually the case with depigmentation in vitiligo&#46; There is no histologic or immunohistochemical difference between the 2 forms of depigmentation&#46; Observations that differentiate between melanoma-associated leukoderma and vitiligo include family history of vitiligo&#44; partial decoloration&#44; and extensive patchy distribution&#46; There is no sufficiently solid evidence to suggest that patients with melanoma are at greater risk of developing vitiligo or vice versa&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Therefore&#44; given the low frequency of the phenomenon&#44; once diagnosis of cutaneous&#44; mucosal&#44; or ocular melanoma has been made&#44; no special follow-up or greater vigilance is required to detect leukoderma&#46; An appropriate physical examination is sufficient to assess whether hypopigmented lesions are present or not&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The association between leukoderma and melanoma is probably the result of a dual immune response against antigens present in both melanocytes and melanoma cells&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;14</span></a> where the primary immunologic effect would be tumor rejection&#44; but with a simultaneous secondary autoimmune effect characterized by hypopigmented macules &#40;leukoderma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Role of Humoral Immunity in Melanoma-Associated Leukoderma</span><p id="par0090" class="elsevierStylePara elsevierViewall">The autoimmune &#40;and even antitumor&#41; effects are largely mediated by antibodies against melanocytic differentiation antigens &#40;tyrosinase&#44; TYRP1&#44; TYRP2&#44; and Pmel17&#41;&#46; For example&#44; Merimsky et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> found significantly higher levels of antityrosinase antibodies in the serum of patients with vitiligo compared to patients with metastatic melanoma&#44; melanoma-associated leukoderma&#44; and healthy controls&#46; They also observed an in vitro inhibition of the proliferation of melanoma cells and a decrease in the incidence and number of metastases in animal models in which animals were treated with immunoglobulin &#40;Ig&#41; G from patients with vitiligo&#46; High titers of anti-TYRP2 IgG antibodies have been found in patients with vitiligo&#44; a similar phenomenon to that observed in patients with melanoma and immunotherapy-induced depigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Antibodies against the Pmel17 antigen were also detected in a population of patients with vitiligo using radioimmunoassay&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In contrast&#44; autoantibodies have not been found in patients with vitiligo&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Further evidence that humoral immunity and melanoma-associated leukoderma play an important role is the finding that the murine monoclonal antibody TA99 &#40;IgG2a&#41; against the TYRP1&#47;7gp75 protein is associated with hypopigmentation in murine models with melanoma &#40;B16 lineage&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Although depigmentation can be considered a cosmetic issue&#44; it is interesting to highlight that the immunologic threshold for depigmentation has been shown to be significantly higher than that required for tumor rejection&#46; This is because antibodies can more readily access solid tumors&#44; which have their own vascularization&#44; than melanocytes&#44; which are located in the basal membrane of the epidermis and follicular epithelia&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In the study conducted by Boasberg et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> in a group of 49 patients with metastatic melanoma who were treated initially with concurrent biochemotherapy &#40;dacarbazine&#44; cisplatinum&#44; vinblastine&#44; IL-2&#44; and IFN&#945;<span class="elsevierStyleInf">2b</span>&#41; and then with maintenance biotherapy based on IL-2 and granulocyte and monocyte colony stimulating factor &#40;GM-CSF&#41;&#44; 21 patients &#40;43&#37;&#41; developed vitiliginous lesions&#46; Survival in this subgroup of patients was close to 18&#46;2 months compared to 8&#46;5 months in patients who did not develop leukoderma&#46; High titers of anti-TYRP2 IgG were found in the group of patients with leukoderma &#40;6 out of 21 patients&#44; 29&#37;&#41; compared to patients without depigmentation &#40;4 out of 28 patients&#44; 14&#37;&#41;&#46; There were no statistically significant differences in the titers of anti-gp100 antibodies between the subgroups of patients&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Role of Cellular Immunity in Melanoma-Associated Leukoderma</span><p id="par0105" class="elsevierStylePara elsevierViewall">As mentioned earlier&#44; vitiligo lesions contain an inflammatory infiltrate composed of macrophages&#44; dendritic cells&#44; and T lymphocytes&#44; mainly of the CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>subpopulation&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> although CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells have also been detected&#46; In peripheral blood of patients with progressive vitiligo&#44; as well as in patients with melanoma &#40;after concurrent development of depigmentation&#41;&#44; CD8&#43;<span class="elsevierStyleHsp" style=""></span>T cells reactive against MART-1 have been detected&#46; In a similar population&#44; it was found that more than 15&#37; of the T cells in peripheral blood were reactive to the 209-217 epitope of the gp100 antigen&#46; These 2 antigens are considered the most immunogenic of melanocytes&#46; Moreover&#44; T cells that infiltrate melanoma tumors are very reactive against these 2 proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Ram&#237;rez-Montagut et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> found that T cells specific for the Melan-A&#47;MART-1 protein were present in 50&#37; of a population of patients with melanoma although there was no correlation with better prognosis&#46; Another study showed the presence of CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells specific for melanocytes in peripheral blood in patients with melanoma&#44; as well as in patients with vitiligo&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Specifically&#44; these cells were reactive against tyrosinase and Melan-A&#47;MART1 in these groups of patients and most expressed HLA-A&#42;0201&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The specificity of epitopes that are targeted by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells suggests that the cells responsible for tumor reduction also cause depigmentation&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In a transgenic melanoma mouse model&#44; almost half the animals &#40;45 out of 88&#41; had permanent leukoderma&#46; In follow-up at 6 months of age&#44; the animals with melanoma-associated leukoderma had significantly fewer facial and dorsal tumors than animals of the same age that had not developed leukoderma&#46; This study also showed that the proportion of peripheral blood lymphocytes specific for melanoma was significantly greater in the subgroup of mice with melanoma-associated leukoderma &#40;1 out of every 680 lymphocytes&#41; than in mice without leukoderma &#40;1 out of every 1000 lymphocytes&#41;&#46; These lymphocytes were predominantly CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>and they also induced secretion of IL-12 and IFN-&#947;&#44; both of which possess antitumor properties&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> The infiltration of immune cells confers a certain degree of protection in this model&#44; as 140 days after the introduction of Melan-<span class="elsevierStyleItalic">ret</span> syngeneic cells&#44; 25&#37; of the transgenic mice with vitiligo were still protected against melanoma&#44; whereas no leukoderma-free mice were protected&#46; The antitumor reactivity is mediated by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells specific for TYRP2 and gp100&#46; The same authors have shown the natural induction of cellular immunity mediated by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T cells in humans during the course of melanoma progression and development of leukoderma&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">It is still subject of debate whether the presence of CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T cells is the cause or a consequence of leukoderma&#44; as reflected in a study by Byrne et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> in which the autoimmune destruction of melanocytes was shown to be necessary for an appropriate and lasting antitumor immune response in a mouse model&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The role of IL-2 is crucial in the development of antitumor cellular immune responses because&#44; in addition to inducing the recruitment of cytotoxic and NK T cells&#44; this cytokine has also been observed to suppress CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CD25<span class="elsevierStyleSup">hi-</span>FoxP3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>regulatory T cells &#40;regulatory T cells that are the first antigen-specific T suppressor cells&#41; in patients with metastatic melanoma who respond favorably to the cytokine&#46; Therefore&#44; IL-2 increases cytotoxic function in CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells responsible for both tumor regression and autoimmunity&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Perspectives</span><p id="par0130" class="elsevierStylePara elsevierViewall">Animal models such as the Sinclair pig are very valuable for understanding the pathogenesis of melanoma-associated entities&#46; This species is born with congenital melanomas that spontaneously regress a few weeks after birth with the concurrent presentation of generalized hypopigmented macules&#46; An increase was observed in the titers of antibodies against pigmentary cells on presentation of leukoderma&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The B16 melanoma cell line has been used in mice models to continue the line of investigation into humoral response against antigens of melanocyte differentiation&#44; and it has even been observed that passive immunization with antibodies against TYRP-1&#47;gp75 results in rejection of the syngeneic melanoma and reduction in pulmonary metastases in animal models of metastatic melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Lengagne et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> established an experimental model in MT&#47;<span class="elsevierStyleItalic">ret</span> transgenic mice with the B6 cell line&#46; The animals in this model develop melanoma lesions at an early age &#40;65&#37; of mice in a 10-month period&#41; and&#44; subsequently&#44; vitiliginous lesions&#46; The authors suggested that the addition of zinc to the water of the mice had induced the development of melanoma&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Cytotoxic T-cell associated antigen 4 &#40;CTLA-4&#41; is responsible for negative regulation of the activated cytotoxic T cells&#46; Blockade of this molecule with a specific anti-CTLA-4 antibody has been demonstrated both in animal models and in humans&#44; with favorable responses&#46; It should be mentioned that the clinical response to treatment is associated with manifestations of autoimmunity&#44; including leukoderma&#44; suggesting that CTLA-4 is important for maintaining peripheral tolerance to antigens&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> These and other molecules will continue to be studied in order to obtain an effective antitumor therapy with limited toxicity&#44; and so improve the quality of life of patients affected by this aggressive malignant neoplasm&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In view of the immunogenic characteristics of melanoma&#44; the development of antitumor vaccines continues to be a challenge&#46; In fact&#44; a vaccine has been developed that contains 6 melanoma-associated peptides&#44; which are derived from the MAGE&#44; MART-1&#47;Melan A&#44; gp100&#44; and tyrosinase proteins&#46; Toxicities associated with immunization include fatigue&#44; headache&#44; myalgia&#44; arthralgia&#44; and nausea&#46; Other types of toxicities were of the autoimmune type&#44; and included elevated rheumatoid factor &#40;10&#37;&#41;&#44; treatment-associated leukoderma &#40;10&#37;&#41;&#44; and antinuclear antibody elevations&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The characteristics of the inductive and effective immune response present in melanoma-associated leukoderma lesions&#44; as well as the selective destruction of pigmentary cells in vitiligo&#44; are the points on which further investigation will focus&#46; In theory&#44; therapy involving transfer of immunoglobulins from patients with vitiligo and administration to patients with melanoma would be possible&#46; Self-transfer may also actually induce an antitumor immune response due to the induction of cross reactivity&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It may even be that the serum of patients with generalized or universal vitiligo could have a more potent antimelanoma effect than that of patients with focal or segmentary vitiligo&#44; and so this is an area of opportunity within the field of immuno-oncology&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that no tests were carried out in humans or animals for the purpose of this study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors obtained the informed consent of patients and&#47;or subjects mentioned in this article&#46; The informed consent form is located in the archives of the corresponding author&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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            1 => "Vitiligo"
            2 => "Leukoderma"
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            2 => "Leucodermia"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Vitiligo is a skin condition characterized by white&#44; hypopigmented macules&#46; Melanocyte loss is a feature of the disease&#44; and it has been hypothesized that an autoimmune mechanism could be responsible for the depigmentation&#46; Melanoma is a malignancy that develops in melanocytes&#59; if not detected and treated early&#44; it is often deadly&#46; Leukoderma&#44; a condition characterized by depigmentation of the skin&#44; is sometimes associated with malignant melanoma&#46; An immune response against melanocyte antigens leading to destruction of either melanoma cells or melanocytes has been observed in both vitiligo and melanoma&#46; 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&#46; The study of factors associated with anti-tumor immunopathogenic mechanisms &#8212;autoimmunity for example&#8212;may provide us with tools for the diagnosis and treatment of diseases such as vitiligo and malignant melanoma&#46;</p>"
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        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El vit&#237;ligo es una patolog&#237;a cut&#225;nea que se manifiesta en forma de manchas hipocr&#243;micas y acr&#243;micas&#46; Se caracteriza por la p&#233;rdida de melanocitos y se ha hipotetizado que un mecanismo autoinmune podr&#237;a estar estrechamente relacionado con este fen&#243;meno de despigmentaci&#243;n&#46; El melanoma es una neoplasia maligna derivada de los melanocitos&#44; que es letal si no se trata oportunamente&#46; La leucodermia es un fen&#243;meno de despigmentaci&#243;n cut&#225;nea&#44; que ocasionalmente se puede asociar a melanoma&#46; Tanto en los pacientes con vit&#237;ligo como con melanoma se ha observado una respuesta inmune contra ant&#237;genos de las c&#233;lulas melanoc&#237;ticas&#44; ya sea para la destrucci&#243;n de los melanocitos normales como de las c&#233;lulas tumorales&#46; A trav&#233;s de diversos estudios en humanos y modelos animales se ha observado que&#44; tanto la inmunidad humoral como la celular tienen un papel inmunorregulador en la citotoxicidad contra el tumor o contra las c&#233;lulas melanoc&#237;ticas&#46; El estudio de los factores asociados a los mecanismos de inmunopatogenicidad antitumoral&#44; as&#237; como a la autoinmunidad es&#44; en potencia&#44; una v&#237;a alternativa para el diagn&#243;stico y tratamiento de patolog&#237;as como el vit&#237;ligo y el melanoma maligno&#46;</p>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gonz&#225;lez R&#44; Torres-L&#243;pez E&#46; Bases inmunol&#243;gicas de la hipopigmentaci&#243;n vitiligoide asociada a melanoma&#46; Actas Dermosifiliogr&#46; 2014&#59;105&#58;122&#8211;127&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Melanoma-associated Leukoderma&#46; Multiple pink macules are observed&#44; in addition to hypochromic plaques&#44; some with a cicatricial appearance&#44; adjacent to tumors of an angiomatous appearance &#40;melanoma metastasis&#41; on the anterior face of the left thigh&#46; This patient has been reported previously by Salas-Alan&#237;s et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p>"
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Review
Immunological Basis of Melanoma-Associated Vitiligo-Like Depigmentation
Bases inmunológicas de la hipopigmentación vitiligoide asociada a melanoma
R. Gonzáleza,
Corresponding author
roger.gonzalez@onderm.com.mx

Corresponding author.
, E. Torres-Lópezb
a Departamento de Introducción a la Clínica, Facultad de Medicina, Universidad Autónoma de Nuevo León, Nuevo León, Mexico
b Departamento de Inmunología, Hospital Universitario Dr. José Eleuterio González, Monterrey, N.L. México, Col. Mitras Centro, Monterrey, Nuevo León, Mexico
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It can sometimes show a trichrome coloration &#40;band of tan color between the white macule and healthy skin&#41; or quadrichrome coloration &#40;perifollicular or marginal macular hyperpigmentation in cases of repigmenting vitiligo&#41;&#46; Another clinical form is inflammatory vitiligo&#44; with a raised red border similar to pityriasis versicolor&#46; The distribution patterns of vitiliginous lesions include focal vitiligo &#40;isolated lesion&#41;&#44; segmental vitiligo &#40;unilateral macular lesions which generally cover a dermatome&#41;&#44; generalized vitiligo &#40;most common form&#44; disseminated macules of variable size&#44; usually with a symmetric distribution and a certain predilection for extensor surfaces&#41;&#44; and vitiligo universalis &#40;severe form that affects more than 80&#37; of the body surface&#41;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Certain proteins located in melanosomes are required for the synthesis of melanoma&#44; the pigment responsible for color in eyes and skin and its appendages&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> These molecules are denoted melanosomal proteins and are classified into 2 groups&#58;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Tyrosinase and tyrosinase associated protein 1 &#40;encoded by the <span class="elsevierStyleItalic">TYRP-1</span> gene&#41; and protein 2 &#40;encoded by the <span class="elsevierStyleItalic">TYRP-2</span> gene&#41;&#44; which catalyze the biochemical steps in the biosynthesis of melanin</p><p id="par0020" class="elsevierStylePara elsevierViewall">Melanoma-antigen recognized by T cells &#40;MART-1&#41;&#44; Pmel17&#44; Rab7&#44; and Rab27&#44; responsible for retaining the melanosomal structures and&#47;or transporting the melanogenic proteins or melanin pigments</p><p id="par0025" class="elsevierStylePara elsevierViewall">All these proteins are important from the pathogenic&#44; diagnostic&#44; and therapeutic point of view in a large number of pigmentary disorders &#40;vitiligo&#44; piebaldism&#44; melanocytic nevus&#44; and melanoma&#44; among others&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">To date&#44; different theories have been put forward to explain the possible pathogenesis of vitiligo&#44; with the immunology-based theory being the most widely accepted&#46; On the one hand&#44; it has been shown that vitiligo can be associated with other autoimmune disorders&#44; especially autoimmune thyroiditis&#46; On the other&#44; in these patients&#44; antibodies against melanocyte antigens such as tyrosinase&#44; TRYP-1&#44; and TRYP-2 have been detected&#46; In addition&#44; there are studies that show that cellular immunity also has an impact on the development of vitiligo&#46; Infiltrates have been found to contain CD8<span class="elsevierStyleSup">&#43;</span> T cells that are reactive with melanocyte self-antigens such as Melan-A&#47;MART-1&#44; tyrosinase&#44; and gp-100&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment for vitiligo depends on the presence and severity of associated comorbidities&#46; Therapy is based on topical immunosuppressive agents &#40;corticosteroids and calcineurin inhibitors&#41; and phototherapy to induce repigmentation&#46; In cases of extensive depigmentation&#44; depigmentation of healthy skin is indicated using hydroquinone monobenzyl ether&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Melanoma is a fatal mucocutaneous or ocular neoplasm that can be sporadic or familial&#46; The neoplasm is associated with a range of genetic factors&#46; Other predisposing factors are exposure to intense sunlight associated with sunburn and a clear phototype &#40;Fitzpatrick skin type I and II&#44; mainly&#41;&#44; although patients with darker phototypes can also present with the neoplasm&#46; Melanoma accounts for approximately 5&#37; of all cancers in men and 4&#37; in women&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The incidence of cutaneous melanoma among Caucasians is reported to be increasing by between 3&#37; and 7&#37; each year&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical presentations of cutaneous melanoma have been widely reported in dermatology and oncology texts&#44; and so the present review will not cover them in depth&#46; It is however important to mention that lesions are usually macular or nodular&#44; with irregular borders&#44; and generally hyperpigmented with a variety of colors ranging from light coffee to blue and grey&#46; Regions of hypopigmentation &#40;regression&#41; may even be present&#46; Some form of recurrence or metastasis &#40;regional or distant&#41; is reported in between 15&#37; and 36&#37; of patients with early-stage melanoma &#40;I and <span class="elsevierStyleSmallCaps">II</span>&#41; during the clinical course of their disease&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The accepted prognostic factors in the classification of the American Joint Committee on Cancer &#40;AJCC&#41; from 2009 include tumor thickness&#44; level of invasion &#40;only for T1 melanomas&#41;&#44; mitotic rate per mm<span class="elsevierStyleSup">2</span>&#44; ulceration&#44; presence of satellite&#44; lymph node&#44; and pulmonary metastases&#44; high levels of lactate dehydrogenase&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and antitumor lymphoid response&#46; The latter factor specifically refers to tumor-infiltrating lymphocytes&#44; whose density in the infiltrate is directly proportional to improved prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The function of this infiltrate would therefore seem to be to generate an innate antimelanoma immune response&#44; although unfortunately this is insufficient to fully eradicate the neoplasm in many cases&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Other prognostic factors that have also been taken into consideration are age&#44; sex&#44; anatomic site of the tumor&#44; and regional lymph node involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Melanoma is a highly immunogenic neoplasm&#46; In other words&#44; it stimulates the immune system to generate a humoral &#40;antibody-mediated&#41; and essentially cellular &#40;cytotoxic lymphocyte-mediated&#41; response to cytoplasmic antigens as well as to the membrane of melanoma cells&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Melanoma-associated antigens can generally be classified into 2 groups&#58;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Cancer&#47;testicular antigens&#46; These antigens are highly expressed in normal tissue during development&#44; while expression is limited to testicles and the placenta in adults&#46; They are expressed in some types of cancer&#46; This group includes the melanoma antigen family &#40;MAGE&#41;&#44; B antigen family &#40;BAGE&#41;&#44; G antigen family &#40;GAGE&#41;&#44; and New York esophagus &#40;NY-ESO-1&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Differentiation Antigens&#46; These antigens are expressed by both tumor cells and their normal counterparts&#44; but not in other cell types&#46; In turn&#44; this group of antigens is divided into 2 groups&#46; The first group includes melanosomal membrane proteins such as TYRP-1&#44; TYRP-2&#44; Pmel17 &#40;also known as gp100&#41;&#44; and MART-1&#46; Gangliosides &#40;GDs&#41; form the second group&#46; These are widely present in melanoma cells and are thought to play a role in cell-cell and cell-matrix adhesion and in growth factor binding&#44; suggesting that they may be involved in the invasive process of the tumor&#46; This group includes GD3&#44; GD2&#44; GM2&#44; GM3&#44; and O-acetyl GD3&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Melanoma therapy depends on the clinical stage&#46; In early stages&#44; treatment is mainly surgical&#46; Interferon alfa &#40;IFN&#945;&#41; has been used primarily as adjuvant therapy in patients with melanoma who are disease-free after appropriate surgery&#44; but with an intermediate or high risk of recurrence&#46; For advanced stages &#40;disseminated melanoma or inoperable locoregional disease&#41;&#44; chemotherapy&#44; radiotherapy&#44; and chemoimmunotherapy have been used with agents such as interleukin 2 &#40;IL-2&#41;&#44; which enhances the cytotoxicity of antigen-specific T and natural killer &#40;NK&#41; cells in vitro&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The response rates&#44; although less than 20&#37;&#44; are nevertheless promising&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Currently&#44; new treatments against therapeutic targets such as KIT<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> or BRAF<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> are emerging&#46; Another agent that forms part of this generation&#44; the so-called targeted therapy&#44; is the monoclonal antibody denominated ipilimumab &#40;anti-CTLA4&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Effort has also been made to develop immunotherapy regimens with dendritic cells&#44; whether in monotherapy or enhanced with molecules such as the glycoprotein gp100&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and methods such as lymphocyte transfer&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The above approaches reflect the strong interest in melanoma research&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Melanoma-Associated Leukoderma</span><p id="par0070" class="elsevierStylePara elsevierViewall">In certain circumstances&#44; vitiligo &#40;leukoderma&#41; may develop in patients with malignant melanoma&#44; mainly in advanced stages&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The relationship between melanoma and leukoderma is a controversial and fascinating topic&#46; Around 3&#37; of patients with melanoma may present this melanoma-associated vitiliginous depigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Hypopigmentation &#40;leukoderma&#41; in association with benign and malignant melanocytic lesions has been reported frequently with different clinical forms which include regression lesions adjacent to primary melanomas or their metastases &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17</span></a> nevus with halo &#40;Sutton&#41; around preexisting melanocytic nevi&#44; and vitiliginous lesions at sites distant to the melanoma&#44; whether isolated or associated with ocular findings of the Vogt-Koyanagi-Harada syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Distant leukoderma may present during the course of melanoma&#44; particularly in cases of advanced stages &#40;metastasis&#41; and the corresponding therapies &#40;mainly immunotherapy-based treatments with IL-2 or IFN&#945;<span class="elsevierStyleInf">2b</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> Longer survival has been observed in patients who develop leukoderma associated with melanoma in advanced stages compared to patients with advanced melanoma who do not develop it&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> suggesting that this is a reflection of the presence of an antitumor activity in the patient&#46; This melanoma-associated phenomenon presents with a frequency of between 1&#46;4&#37; and 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Unfortunately&#44; as mentioned earlier&#44; the efficacy of this antitumor response is not sufficiently great to increase the chance of complete eradication of melanoma&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Clinically&#44; melanoma-associated leukoderma bears certain similarities with vitiligo&#46; The prevalence of vitiligo among melanoma patients is estimated to be between 3&#37; and 6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In a series of 15 patients with melanoma and hypopigmentation&#44; leukoderma was found to be directly associated with melanoma in 12 cases &#40;80&#37;&#41;&#46; Hypopigmentation was observed on average 4&#46;8 years after initial diagnosis of melanoma&#44; and the age of onset was found to be 56&#46;4<span class="elsevierStyleMonospace">&#40;</span>10&#46;8&#41; years&#44; in comparison with the age in a group of nonmelanoma associated vitiligo of 27&#46;6 &#40;16&#46;5&#41; years&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> There was no difference between sexes in the frequency of the association&#46; In that series of cases&#44; 75&#37; of the patients with melanoma-associated leukoderma had a bilateral and symmetrical distribution of depigmentation similar to disseminated vitiligo&#44; whereas only 25&#37; of the population studied had a focal or asymmetric unilateral distribution of hypopigmentation&#59; no patients with the association had an acrofacial distribution of depigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The progression of melanoma-associated leukoderma is not as fast or progressive as is usually the case with depigmentation in vitiligo&#46; There is no histologic or immunohistochemical difference between the 2 forms of depigmentation&#46; Observations that differentiate between melanoma-associated leukoderma and vitiligo include family history of vitiligo&#44; partial decoloration&#44; and extensive patchy distribution&#46; There is no sufficiently solid evidence to suggest that patients with melanoma are at greater risk of developing vitiligo or vice versa&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Therefore&#44; given the low frequency of the phenomenon&#44; once diagnosis of cutaneous&#44; mucosal&#44; or ocular melanoma has been made&#44; no special follow-up or greater vigilance is required to detect leukoderma&#46; An appropriate physical examination is sufficient to assess whether hypopigmented lesions are present or not&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The association between leukoderma and melanoma is probably the result of a dual immune response against antigens present in both melanocytes and melanoma cells&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;14</span></a> where the primary immunologic effect would be tumor rejection&#44; but with a simultaneous secondary autoimmune effect characterized by hypopigmented macules &#40;leukoderma&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Role of Humoral Immunity in Melanoma-Associated Leukoderma</span><p id="par0090" class="elsevierStylePara elsevierViewall">The autoimmune &#40;and even antitumor&#41; effects are largely mediated by antibodies against melanocytic differentiation antigens &#40;tyrosinase&#44; TYRP1&#44; TYRP2&#44; and Pmel17&#41;&#46; For example&#44; Merimsky et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> found significantly higher levels of antityrosinase antibodies in the serum of patients with vitiligo compared to patients with metastatic melanoma&#44; melanoma-associated leukoderma&#44; and healthy controls&#46; They also observed an in vitro inhibition of the proliferation of melanoma cells and a decrease in the incidence and number of metastases in animal models in which animals were treated with immunoglobulin &#40;Ig&#41; G from patients with vitiligo&#46; High titers of anti-TYRP2 IgG antibodies have been found in patients with vitiligo&#44; a similar phenomenon to that observed in patients with melanoma and immunotherapy-induced depigmentation&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Antibodies against the Pmel17 antigen were also detected in a population of patients with vitiligo using radioimmunoassay&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In contrast&#44; autoantibodies have not been found in patients with vitiligo&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Further evidence that humoral immunity and melanoma-associated leukoderma play an important role is the finding that the murine monoclonal antibody TA99 &#40;IgG2a&#41; against the TYRP1&#47;7gp75 protein is associated with hypopigmentation in murine models with melanoma &#40;B16 lineage&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Although depigmentation can be considered a cosmetic issue&#44; it is interesting to highlight that the immunologic threshold for depigmentation has been shown to be significantly higher than that required for tumor rejection&#46; This is because antibodies can more readily access solid tumors&#44; which have their own vascularization&#44; than melanocytes&#44; which are located in the basal membrane of the epidermis and follicular epithelia&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In the study conducted by Boasberg et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> in a group of 49 patients with metastatic melanoma who were treated initially with concurrent biochemotherapy &#40;dacarbazine&#44; cisplatinum&#44; vinblastine&#44; IL-2&#44; and IFN&#945;<span class="elsevierStyleInf">2b</span>&#41; and then with maintenance biotherapy based on IL-2 and granulocyte and monocyte colony stimulating factor &#40;GM-CSF&#41;&#44; 21 patients &#40;43&#37;&#41; developed vitiliginous lesions&#46; Survival in this subgroup of patients was close to 18&#46;2 months compared to 8&#46;5 months in patients who did not develop leukoderma&#46; High titers of anti-TYRP2 IgG were found in the group of patients with leukoderma &#40;6 out of 21 patients&#44; 29&#37;&#41; compared to patients without depigmentation &#40;4 out of 28 patients&#44; 14&#37;&#41;&#46; There were no statistically significant differences in the titers of anti-gp100 antibodies between the subgroups of patients&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Role of Cellular Immunity in Melanoma-Associated Leukoderma</span><p id="par0105" class="elsevierStylePara elsevierViewall">As mentioned earlier&#44; vitiligo lesions contain an inflammatory infiltrate composed of macrophages&#44; dendritic cells&#44; and T lymphocytes&#44; mainly of the CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>subpopulation&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> although CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells have also been detected&#46; In peripheral blood of patients with progressive vitiligo&#44; as well as in patients with melanoma &#40;after concurrent development of depigmentation&#41;&#44; CD8&#43;<span class="elsevierStyleHsp" style=""></span>T cells reactive against MART-1 have been detected&#46; In a similar population&#44; it was found that more than 15&#37; of the T cells in peripheral blood were reactive to the 209-217 epitope of the gp100 antigen&#46; These 2 antigens are considered the most immunogenic of melanocytes&#46; Moreover&#44; T cells that infiltrate melanoma tumors are very reactive against these 2 proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Ram&#237;rez-Montagut et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> found that T cells specific for the Melan-A&#47;MART-1 protein were present in 50&#37; of a population of patients with melanoma although there was no correlation with better prognosis&#46; Another study showed the presence of CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells specific for melanocytes in peripheral blood in patients with melanoma&#44; as well as in patients with vitiligo&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Specifically&#44; these cells were reactive against tyrosinase and Melan-A&#47;MART1 in these groups of patients and most expressed HLA-A&#42;0201&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The specificity of epitopes that are targeted by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells suggests that the cells responsible for tumor reduction also cause depigmentation&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In a transgenic melanoma mouse model&#44; almost half the animals &#40;45 out of 88&#41; had permanent leukoderma&#46; In follow-up at 6 months of age&#44; the animals with melanoma-associated leukoderma had significantly fewer facial and dorsal tumors than animals of the same age that had not developed leukoderma&#46; This study also showed that the proportion of peripheral blood lymphocytes specific for melanoma was significantly greater in the subgroup of mice with melanoma-associated leukoderma &#40;1 out of every 680 lymphocytes&#41; than in mice without leukoderma &#40;1 out of every 1000 lymphocytes&#41;&#46; These lymphocytes were predominantly CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>and they also induced secretion of IL-12 and IFN-&#947;&#44; both of which possess antitumor properties&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> The infiltration of immune cells confers a certain degree of protection in this model&#44; as 140 days after the introduction of Melan-<span class="elsevierStyleItalic">ret</span> syngeneic cells&#44; 25&#37; of the transgenic mice with vitiligo were still protected against melanoma&#44; whereas no leukoderma-free mice were protected&#46; The antitumor reactivity is mediated by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells specific for TYRP2 and gp100&#46; The same authors have shown the natural induction of cellular immunity mediated by CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T cells in humans during the course of melanoma progression and development of leukoderma&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">It is still subject of debate whether the presence of CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>T cells is the cause or a consequence of leukoderma&#44; as reflected in a study by Byrne et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> in which the autoimmune destruction of melanocytes was shown to be necessary for an appropriate and lasting antitumor immune response in a mouse model&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The role of IL-2 is crucial in the development of antitumor cellular immune responses because&#44; in addition to inducing the recruitment of cytotoxic and NK T cells&#44; this cytokine has also been observed to suppress CD4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CD25<span class="elsevierStyleSup">hi-</span>FoxP3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>regulatory T cells &#40;regulatory T cells that are the first antigen-specific T suppressor cells&#41; in patients with metastatic melanoma who respond favorably to the cytokine&#46; Therefore&#44; IL-2 increases cytotoxic function in CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cells responsible for both tumor regression and autoimmunity&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Perspectives</span><p id="par0130" class="elsevierStylePara elsevierViewall">Animal models such as the Sinclair pig are very valuable for understanding the pathogenesis of melanoma-associated entities&#46; This species is born with congenital melanomas that spontaneously regress a few weeks after birth with the concurrent presentation of generalized hypopigmented macules&#46; An increase was observed in the titers of antibodies against pigmentary cells on presentation of leukoderma&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The B16 melanoma cell line has been used in mice models to continue the line of investigation into humoral response against antigens of melanocyte differentiation&#44; and it has even been observed that passive immunization with antibodies against TYRP-1&#47;gp75 results in rejection of the syngeneic melanoma and reduction in pulmonary metastases in animal models of metastatic melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Lengagne et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> established an experimental model in MT&#47;<span class="elsevierStyleItalic">ret</span> transgenic mice with the B6 cell line&#46; The animals in this model develop melanoma lesions at an early age &#40;65&#37; of mice in a 10-month period&#41; and&#44; subsequently&#44; vitiliginous lesions&#46; The authors suggested that the addition of zinc to the water of the mice had induced the development of melanoma&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Cytotoxic T-cell associated antigen 4 &#40;CTLA-4&#41; is responsible for negative regulation of the activated cytotoxic T cells&#46; Blockade of this molecule with a specific anti-CTLA-4 antibody has been demonstrated both in animal models and in humans&#44; with favorable responses&#46; It should be mentioned that the clinical response to treatment is associated with manifestations of autoimmunity&#44; including leukoderma&#44; suggesting that CTLA-4 is important for maintaining peripheral tolerance to antigens&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> These and other molecules will continue to be studied in order to obtain an effective antitumor therapy with limited toxicity&#44; and so improve the quality of life of patients affected by this aggressive malignant neoplasm&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In view of the immunogenic characteristics of melanoma&#44; the development of antitumor vaccines continues to be a challenge&#46; In fact&#44; a vaccine has been developed that contains 6 melanoma-associated peptides&#44; which are derived from the MAGE&#44; MART-1&#47;Melan A&#44; gp100&#44; and tyrosinase proteins&#46; Toxicities associated with immunization include fatigue&#44; headache&#44; myalgia&#44; arthralgia&#44; and nausea&#46; Other types of toxicities were of the autoimmune type&#44; and included elevated rheumatoid factor &#40;10&#37;&#41;&#44; treatment-associated leukoderma &#40;10&#37;&#41;&#44; and antinuclear antibody elevations&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The characteristics of the inductive and effective immune response present in melanoma-associated leukoderma lesions&#44; as well as the selective destruction of pigmentary cells in vitiligo&#44; are the points on which further investigation will focus&#46; In theory&#44; therapy involving transfer of immunoglobulins from patients with vitiligo and administration to patients with melanoma would be possible&#46; Self-transfer may also actually induce an antitumor immune response due to the induction of cross reactivity&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It may even be that the serum of patients with generalized or universal vitiligo could have a more potent antimelanoma effect than that of patients with focal or segmentary vitiligo&#44; and so this is an area of opportunity within the field of immuno-oncology&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that no tests were carried out in humans or animals for the purpose of this study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors obtained the informed consent of patients and&#47;or subjects mentioned in this article&#46; The informed consent form is located in the archives of the corresponding author&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Melanoma-Associated Leukoderma"
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              "titulo" => "Role of Cellular Immunity in Melanoma-Associated Leukoderma"
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        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Vitiligo is a skin condition characterized by white&#44; hypopigmented macules&#46; Melanocyte loss is a feature of the disease&#44; and it has been hypothesized that an autoimmune mechanism could be responsible for the depigmentation&#46; Melanoma is a malignancy that develops in melanocytes&#59; if not detected and treated early&#44; it is often deadly&#46; Leukoderma&#44; a condition characterized by depigmentation of the skin&#44; is sometimes associated with malignant melanoma&#46; An immune response against melanocyte antigens leading to destruction of either melanoma cells or melanocytes has been observed in both vitiligo and melanoma&#46; 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&#46; The study of factors associated with anti-tumor immunopathogenic mechanisms &#8212;autoimmunity for example&#8212;may provide us with tools for the diagnosis and treatment of diseases such as vitiligo and malignant melanoma&#46;</p>"
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        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El vit&#237;ligo es una patolog&#237;a cut&#225;nea que se manifiesta en forma de manchas hipocr&#243;micas y acr&#243;micas&#46; Se caracteriza por la p&#233;rdida de melanocitos y se ha hipotetizado que un mecanismo autoinmune podr&#237;a estar estrechamente relacionado con este fen&#243;meno de despigmentaci&#243;n&#46; El melanoma es una neoplasia maligna derivada de los melanocitos&#44; que es letal si no se trata oportunamente&#46; La leucodermia es un fen&#243;meno de despigmentaci&#243;n cut&#225;nea&#44; que ocasionalmente se puede asociar a melanoma&#46; Tanto en los pacientes con vit&#237;ligo como con melanoma se ha observado una respuesta inmune contra ant&#237;genos de las c&#233;lulas melanoc&#237;ticas&#44; ya sea para la destrucci&#243;n de los melanocitos normales como de las c&#233;lulas tumorales&#46; A trav&#233;s de diversos estudios en humanos y modelos animales se ha observado que&#44; tanto la inmunidad humoral como la celular tienen un papel inmunorregulador en la citotoxicidad contra el tumor o contra las c&#233;lulas melanoc&#237;ticas&#46; El estudio de los factores asociados a los mecanismos de inmunopatogenicidad antitumoral&#44; as&#237; como a la autoinmunidad es&#44; en potencia&#44; una v&#237;a alternativa para el diagn&#243;stico y tratamiento de patolog&#237;as como el vit&#237;ligo y el melanoma maligno&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gonz&#225;lez R&#44; Torres-L&#243;pez E&#46; Bases inmunol&#243;gicas de la hipopigmentaci&#243;n vitiligoide asociada a melanoma&#46; Actas Dermosifiliogr&#46; 2014&#59;105&#58;122&#8211;127&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Melanoma-associated Leukoderma&#46; Multiple pink macules are observed&#44; in addition to hypochromic plaques&#44; some with a cicatricial appearance&#44; adjacent to tumors of an angiomatous appearance &#40;melanoma metastasis&#41; on the anterior face of the left thigh&#46; This patient has been reported previously by Salas-Alan&#237;s et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p>"
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