Melanoma-associated Hypopigmentation Research Articles

Current Challenges in Deciphering Sutton Nevi-Literature Review and Personal Experience.

Halo nevi, known as leukoderma acquisitum centrifugum, Sutton nevus, leukopigmentary nevus, perinevoid vitiligo, or perinevoid leukoderma, together with vitiligo and melanoma-associated hypopigmentation, belong to the group of dermatoses designated as immunological leukodermas. The etiology and pathogenesis of halo nevi has not been fully elucidated. There are several mechanisms through which a lymphocytic infiltrate can induce tumoral regression. In this review, we aimed to update the knowledge about Sutton nevi starting with the clinical appearance and dermoscopic features, continuing with information regarding conventional microscopy, immunohistochemistry, and the immunological mechanisms responsible for the occurrence of halo nevi. We also included in the article original unpublished results when discussing dermoscopic, pathologic and immunohistochemical results in halo nevi. Sutton nevi are valuable models for studying antitumor reactions that the human body can generate. The slow and effective mechanism against a melanocytic skin tumor can teach us important lessons about both autoimmune diseases and anticancer defenses.

DNp73-induced degradation of tyrosinase links depigmentation with EMT-driven melanoma progression

Melanoma is an aggressive cancer with poor prognosis, requiring personalized management of advanced stages and establishment of molecular markers. Melanomas derive from melanocytes, which specifically express tyrosinase, the rate-limiting enzyme of melanin-synthesis. We demonstrate that melanomas with high levels of DNp73, a cancer-specific variant of the p53 family member p73 and driver of melanoma progression show, in contrast to their less-aggressive low-DNp73 counterparts, hypopigmentation in vivo. Mechanistically, reduced melanin-synthesis is mediated by a DNp73-activated IGF1R/PI3K/AKT axis leading to tyrosinase ER-arrest and proteasomal degradation. Tyrosinase loss triggers reactivation of the EMT signaling cascade, a mesenchymal-like cell phenotype and increased invasiveness. DNp73-induced depigmentation, Slug increase and changes in cell motility are recapitulated in neural crest-derived melanophores of Xenopus embryos, underscoring a previously unnoticed physiological role of tyrosinase as EMT inhibitor. This data provides a mechanism of hypopigmentation accompanying cancer progression, which can be exploited in precision diagnosis of patients with melanoma-associated hypopigmentation (MAH), currently seen as a favorable prognostic factor. The DNp73/IGF1R/Slug signature in colorless lesions might aid to clinically discriminate between patients with MAH-associated metastatic disease and those, where MAH is indeed a sign of regression.

Vitiligo‐like depigmentations as the first sign of melanoma: a retrospective case series from a tertiary vitiligo centre

patients with melanoma may develop vitiligo-like skin depigmentation referred to as melanoma-associated leukoderma (MAL), melanoma-associated hypopigmentation (MAH), melanoma-associated depigmentation (MAD) or melanoma-associated vitiligo (MAV) 1-3. Many dermatologists are not aware of the diagnosis MAL and may easily diagnose and treat these patients as having non-segmental vitiligo, thereby overlooking the underlying (metastatic) melanoma. At present, the prevalence of MAL and its clinical characteristics are not well established. This article is protected by copyright. All rights reserved.

Vitiligo, Melanoma Associated Hypopigmentation and Melanoma Incidence and Prognosis: Is There An Association?

Malignant melanoma is considered as the most lethal of all skin cancers. However, it is also one of the most immunogenic, characterized by specific antigen presentation and dense lymphocytic infiltration. Many studies concerning melanoma have reported the concurrent presence of vitiligo or Melanoma Associated Hypopigmentation (MAH). This type of vitiligo can appear before or after MM diagnosis, or in tandem with treatment with immunotherapeutic drugs and has been associated with an improved prognosis and/or better response to immunotherapy treatments. This may be attributed to the fact that activated T cells against antigens found on malignant melanocytes can also recognize normal melanocytes and destroy them. On the other side, very limited data exist on whether classic vitiligo can offer protection against or is associated with a decreased incidence of MM. However, MAH represents an example of a strong link between tumor immunity and autoimmune responses. This unique characteristic may be of use as a biomarker in melanoma patients, allowing prediction of MM prognosis or response to specific treatment regimens. Up to this point only a few studies report patient data regarding classic vitiligo and MM. In this paper, the autoimmune hypothesis in the pathogenesis of vitiligo and MAH are discussed, focusing on similarities, differences and known autoantigens. In addition, the results of studies regarding MM and vitiligo or MAH are also summarized.

The Double Strike Hypothesis of the vitiligo pathomechanism: New approaches to vitiligo and melanoma

Based on current research, we present a consolidated set of theses which explain the pathomechanisms of vitiligo- and melanoma-associated hypopigmentation. The main thesis is the Double Strike Hypothesis, i.e. vitiligo is caused by at least two different major pathomechanisms: an antibody-based pathomechanism and a T-cell-based pathomechanism. The antibody-based pathomechanism is dominant in diffuse vitiligo, while the T-cell based pathomechanism is dominant in localised vitiligo. Based on this main thesis we derive new therapeutical approaches to vitiligo and melanoma by using the different pathomechanisms. Finally we explain why melanoma-associated hypopigmentation as a natural immunotherapy is still in statu nascendi.

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

It is unclear if differences between melanoma-associated hypopigmentation (MAH) and classical vitiligo exist. 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. 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. Whereas differences exist concerning associated autoimmune diseases, 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.

Autoantibodies to tyrosinase: the bridge between melanoma and vitiligo.

Tyrosinase is an enzyme that participates in the process of melanin production in normal melanocytes and melanoma cells. Enzymes are known to be autoantigens in various autoimmune disorders; thus, after the detection of antityrosinase antibodies in patients with vitiligo and melanoma, tyrosinase was defined as an autoantigen in these conditions. In some patients with melanoma the disease is associated with the appearance of "vitiligo-like" white patches on the skin, called melanoma-associated hypopigmentation (MAH). In this article, the authors summarize the recent data related to antityrosinase antibodies and expand on their role in the pathogenesis of vitiligo, melanoma, and MAH. In addition, the beneficial clinical applications of antityrosinase antibodies are presented. An enzyme-linked immunoadsorbent assay to detect the antityrosinase antibodies in the serum of patients and healthy volunteers was established using mushroom tyrosinase. Employing this method, antityrosinase antibodies were analyzed in a diverse group of patients with melanoma and vitiligo and in mice immunized with tyrosinase. In patients with melanoma, those with metastatic disease had a higher titer of antityrosinase antibodies compared with healthy subjects, whereas patients with MAH and those with no evidence of disease had similar titers to the control group. The titer of antityrosinase antibodies in patients with metastatic melanoma treated by vaccination with antiidiotypic antibodies mimicking the high molecular weight melanoma-associated antigen (HMW MAA) initially increased after the vaccination and then decreased. High titers of antityrosinase antibodies were detected in patients with diffuse vitiligo compared with patients with localized disease and with the healthy control group. Mice immunized with tyrosinase generated a high titer of antityrosinase antibodies and after the inoculation of melanoma cells developed a lower number of lung metastases compared with an unvaccinated control group. The appearance of antityrosinase autoantibodies in the serum of patients with metastatic melanoma and diffuse vitiligo is characterized by these two pathologies. The changes in the serum level of these autoantibodies in patients with melanoma after immunization with another antigen (HMW MAA) may have diagnostic and therapeutic implications.

Anti-tyrosinase antibodies participate in the immune response to vaccination with anti-idiotypic antibodies mimicking the high-molecular-weight melanoma-associated antigen

Seven patients with metastatic melanoma were vaccinated with anti-idiotypic monoclonal antibody (mAb) MK2-23 which mimics the high-molecular-weight melanoma-associated antigen (HMW MAA). Sera samples were assayed for anti-anti-idiotypic antibodies, by Ab1-Ab2 complex inhibition test, for anti-B16 epitope antibodies, which are a heterogeneous group against various antigens presented on B16 melanoma cells and for anti-tyrosinase antibodies, which are specific against tyrosinase. Our results pointed to the participation of anti-tyrosinase antibodies in the immune response to vaccination by anti-idiotypic antibodies mimicking the HMW MAA. The anti-tyrosinase antibody kinetic curves presented an initial increase in titres in five cases followed by decreasing titres; in two cases a constant decrease was noted. The inhibition assay demonstrated an increasing percentage of inhibition (range 17-100%) within 100-400 days of treatment. The titre of the anti-tyrosinase antibodies increased following the vaccination, then decreased--probably due to absorption of the antibodies to melanoma cells and normal melanocytes. A positive slope in the percentage of inhibition was roughly associated with a negative slope of anti-tyrosinase antibodies. In one case, a long-standing complete clinical response was accompanied by development of melanoma-associated hypopigmentation. Anti-B16 epitope antibodies had no role in the response to vaccination. The development of anti-tyrosinase antibodies in response to vaccination by anti-idiotypic antibodies mimicking another antigen may be explained by induction of non-specific polyclonal B lymphocytes activation, a well-recognized phenomenon in autoimmune disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitiligo- and melanoma-associated hypopigmentation: a similar appearance but a different mechanism.

The significance of the association between the appearance of hypopigmentation in patients with melanoma and the prognosis is still not clear. It was postulated that, in melanoma, an immune response is responsible for the destruction of the malignant as well as the normal pigmented cells, and that the eventual development of vitiligo-like patches in melanoma patients improves their prognosis. We studied the level of anti-melanoma antibodies in the sera of patients with melanoma with hypopigmentation and compared it to the titer in patients with melanoma only, to the titer of patients with vitiligo, and to that of healthy subjects. Only IgG-type antibodies were found in the sera of patients with vitiligo, with melanoma, or with melanoma with hypopigmentation. No significant differences in the titer of anti-melanoma antibodies could be found between the patients with melanoma when subgrouped according to the initial stage and the status of the disease at the time when the test was carried out. Statistically significantly (P < 0.001) higher titers of antibodies were detected in the sera of patients with vitiligo in comparison to the lower titers in the other groups. Our results point to a similar immunobiological status, which probably does not give any advantage to patients with melanoma with hypopigmentation compared to patients without it. The appearance of hypopigmentary plaques in melanoma patients should be regarded, in our opinion, as a concomitant immunological phenomenon of the disease.

Vitiligo- and melanoma-associated hypopigmentation: a similar appearance but a different mechanism

Vitiligo- and melanoma-associated hypopigmentation: a similar appearance but a different mechanism