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Abstract Background Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. Methods Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. Results This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. Conclusions Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Background: Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. Methods: Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. Results: This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. Conclusions: Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites. [ABSTRACT FROM AUTHOR]

The association between viral infections and both cutaneous and mucosal melanoma (MM) has not been fully investigated. Here, we assessed the prevalence of the DNA of a broad range of viruses in 31 MMs and 15 biopsies of healthy mucosa (HM) using molecular methods. The parvoviruses CuV and B19V, herpesviruses HSV1, HSV2, EBV, HHV6, and HHV8, polyomavirus MCPyV, and α‐HPVs were not detected, or rarely found, in MMs, and in HM, of the digestive, respiratory, and female genital tract. The overall prevalence of β‐HPV in MMs was not significantly higher compared to that in HM (70.9% and 53.3% respectively; p = 0.514). However, the number of MMs positive for β‐HPV types belonging to Species 3 and 5 and for some viral types belonging to Species 1, 2, 3, and 5 were significantly higher compared with HM (p < 0.05). Moreover, compared to HM, the MM samples contained a significantly higher number of β‐HPV types, mainly belonging to Species 1, 3, and 5 (p < 0.05). Our data, although suggesting a role for certain β‐HPV types in MM oncogenesis, require additional investigation in larger populations to support this hypothesis. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides an updated overview about molecular features, clinical advancements and therapeutic directions of the primary mucosal melanoma which represents a rare and heterogeneous malignancy characterized by a poor prognosis. Primary mucosal melanomas (MMs) are uncommon tumors originating from melanocytes located in the mucous membranes at various anatomic sites within the body. MM significantly differs from cutaneous melanoma (CM) regarding epidemiology, genetic profile, clinical presentation, and response to therapies. Despite these differences, that have important implications for both disease diagnosis and prognosis, MMs are usually treated in the same way as CM but exhibit a lower response rate to immunotherapy leading to a poorer survival rate. Furthermore, a high inter-patient variability can be observed in relation to therapeutic response. Recently, novel "omics" techniques have evidenced that MM lesions have different genomic, molecular, and metabolic landscapes as compared with CM lesions, thus explaining the heterogeneity of the response. Such specific molecular aspects might be useful to identify new biomarkers aimed at improving the diagnosis and selection of MM patients who could benefit from immunotherapy or targeted therapy. In this review, we have focused on relevant molecular and clinical advancements for the different MM subtypes in order to describe the updated knowledge relating to main diagnostic, clinical, and therapeutic implications as well as to provide hints on likely future directions. [ABSTRACT FROM AUTHOR]

Gynecologic melanomas are uncommon and malignant mucosal melanomas with vaginal origin are extremely rare, treatment strategies are limited and extrapolated from those of cutaneous melanoma. A better understanding of the vulvovaginal melanoma's biology and its risk factors is needed. Therapeutic strategies include surgery, systemic therapy and radiotherapy. For vulvovaginal melanoma, surgery is selected as the primary treatment. Immunotherapy and target treatment have recently enhanced the systemic therapy for cutaneous melanoma (CM). Immunotherapy and new target agents demonstrated a better survival of melanoma and might be considered as treatment of vulvovaginal melanoma. Radiotherapy is included in the therapeutic arsenal for mucosal melanoma and may be performed on selected patients who may receive concurrent checkpoints and inhibition neoadjuvant radiotherapy with the purpose of reducing morbidity and mortality. [ABSTRACT FROM AUTHOR]

Gynecologic melanomas are uncommon and malignant mucosal melanomas with vaginal origin are extremely rare, treatment strategies are limited and extrapolated from those of cutaneous melanoma. A better understanding of the vulvovaginal melanoma’s biology and its risk factors is needed. Therapeutic strategies include surgery, systemic therapy and radiotherapy. For vulvovaginal melanoma, surgery is selected as the primary treatment. Immunotherapy and target treatment have recently enhanced the systemic therapy for cutaneous melanoma (CM). Immunotherapy and new target agents demonstrated a better survival of melanoma and might be considered as treatment of vulvovaginal melanoma. Radiotherapy is included in the therapeutic arsenal for mucosal melanoma and may be performed on selected patients who may receive concurrent checkpoints and inhibition neoadjuvant radiotherapy with the purpose of reducing morbidity and mortality.

Background: Head and neck mucosal melanomas (MMs) are rare tumors with adverse outcomes and poorer prognoses than their more common cutaneous counterparts (cutaneous melanomas-CMs). Few studies have compared the expression of mitochondrial dynamic markers in these tumors. This study aimed to assess the correlations of mitochondrial markers with melanoma progression and their potential as predictors of lymph node involvement and distant metastasis.Methods: Immunohistochemistry against anti-mitochondrial (AMT), dynamin-related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), mitofusin-1 (MFN1), and mitofusin-2 (MFN2) antibodies was performed in 112 cases of head and neck CM and MM. A Cox regression multivariate model was used to assess the correlation of AMT, FIS1, and MFN2 expressions considering the risk for nodal and distant metastasis.Results: All markers studied presented higher staining in tumor cells than normal adjacent tissues. Higher mitochondrial content was observed in MM than in CM, and it was significantly associated with nodal metastasis in oral melanomas. Both FIS1 and DRP1 expressions were related to advanced Clark's levels in CM, and they were overexpressed in oral melanomas. Moreover, increased immunoexpression of MFN2 was significantly associated with a higher risk of metastasis in CM, and it was also overexpressed in sinonasal melanomas.Conclusions: Our results suggest that mitochondrial fission and fusion processes can play an important role during multiple stages of tumorigenesis and the development of nodal and distant metastasis in cutaneous and mucosal melanomas. [ABSTRACT FROM AUTHOR]

INTRODUÇÃO E OBJETIVOS: O melanoma é uma neoplasia maligna que pode acometer a pele e as mucosas. A taxa de incidência do melanoma cutâneo de forma geral tem aumentado nos últimos anos. Esta pesquisa realizou uma análise retrospectiva de melanomas cutâneos e mucosos no período de 30 anos em um serviço do Rio Grande do Norte, enfatizando características clínicas, conduta e evolução dos melanomas mucosos orais. MATERIAL E MÉTODO: Nos prontuários clínicos, foram coletadas informações sobre idade, raça, sexo, localização o tipo de comprometimento da lesão, se primária ou metastática. RESULTADOS: Um total de 397 casos de melanoma foi diagnosticado, sendo 332 cutâneos (83,6%) e 46 mucosos (11,6%). O tronco foi mais acometido (27,7%), seguido por membros inferiores (24,7%) e cabeça e pescoço (18,9%). Entre os melanomas mucosos, a maioria era de cabeça e pescoço (76,1%). De forma geral, 52,4% ocorreram em indivíduos do sexo masculino e 47,6%, no feminino. A idade média foi de 54,9 anos. Nos homens esteve mais presente nas sétima e oitava décadas de vida, e nas mulheres, nas quinta e sexta décadas. Seis casos (1,5%) acometeram a mucosa oral e estes ocorreram mais em indivíduos do sexo feminino, acima de 55 anos. CONCLUSÃO: O perfil epidemiológico dos casos de melanomas avaliados se assemelha aos poucos estudos epidemiológicos publicados, apesar de alguns dados, no tocante a sexo e idade em determinadas localizações anatômicas, terem variado e a incidência de melanomas orais ter sido bem mais baixa do que a relatada na maioria das pesquisas.INTRODUCTION AND OBJECTIVES: Melanoma is a malignant neoplasm that occurs in the skin and mucosae. Overall, the incidence rate of cutaneous melanoma has increased in the last years. It was performed a retrospective analysis of cutaneous and mucosal melanomas diagnosed within a period of 30 years in one health care institution of Rio Grande do Norte, highlighting clinical features, approach and evolution of oral mucosal melanomas. METHODS: Data as to age, race, gender, tumor topography and lesion involvement (metastatic or primary) were collected from clinical records. RESULTS: A total of 397 cases of melanoma were diagnosed, 332 of them were cutaneous (83.6%) and 46 of them were mucosal (11.6%). The trunk was the most affected area (27.7%), followed by lower limbs (24.7%) and head/neck (18.9%). Within the mucosal melanomas, most cases were on head and neck (76.1%). By and large, 52.4% affected male individuals and 47.6% affected female patients. The mean age was 54.9. Among men it was more prevalent in the 7th and 8th decades of life, whereas among women it was more prevalent in the 5th and 6th decades of life. A total of 6 cases (1.5%) occurred in the oral mucosa, with more prevalence among female individuals over 55 years of age. CONCLUSIONS: The epidemiological profile of the analyzed cases of melanoma was similar to the few published epidemiological studies, although some data on gender and age in certain anatomical sites varied and the incidence of oral melanoma was much lower than that reported in most investigations.

Cancer heterogeneity has been proposed to be one of the main causes of metastatic dissemination and therapy failure. However, the underlying mechanisms of this phenomenon remain poorly understood. Melanoma is an aggressive malignancy with a high heterogeneity and metastatic potential. Therefore, the present study investigated the possible association between cancer heterogeneity and metastasis in melanoma. In total, two novel Chinese oral mucosal melanoma (COMM) cell lines, namely COMM‑1 and COMM‑2, were established for exploring methods into preventing the loss of cellular heterogeneity caused by long‑term cell culture. Each cell line was grown under two different models of culture, which yielded two subtypes, one exhibited an adhesive morphology (COMM‑AD), whereas the other was grown in suspension (COMM‑SUS). Compared with the COMM‑AD cells, the COMM‑SUS cells exhibited higher metastatic capacities and autofluorescence. Further investigations indicated that the COMM‑SUS cells exhibited metabolic reprogramming by taking up lactate produced by COMM‑AD cells at increased levels to accumulate NADH through monocarboxylate transporter 1, whilst also increasing NADPH levels through the pentose phosphate pathway (PPP). Additionally, increased NADH and NADPH levels in the COMM‑SUS cells, coupled with the upregulation of the anti‑ferroptotic proteins, glutathione peroxidase 4 and ferrop-tosis suppressor protein 1, enabled them to resist ferroptotic cell death induced by oxidative stress during hematogenous dissemination. The inhibition of ferroptosis was found to substantially increase the metastatic capacity of COMM‑AD cells. Furthermore, suppressing lactate uptake and impairing PPP activation significantly decreased the metastatic potential of the COMM‑SUS cells. Thus, the present study on metabolic heterogeneity in COMM cells potentially provides a novel perspective for exploring this mechanism underlying cancer metastasis.

Abstract: This work provides descriptive epidemiological data of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe as defined as in the RARECARE project. We analysed 8669 incident cases registered in the period 1995–2002 by 76 population-based cancer registries (CRs), and followed up for vital status to 31st December 2003. Age-standardised incidence to the European standard population was obtained restricting the analysis to 8416 cancer cases collected by 64 not specialised CRs or with information available only for some anatomical sites. Period survival rates at 2000–2002 were estimated on 45 CRs data. Twenty-two CRs which covered the period 1988–2002 were analysed to obtain the 15-year prevalence (1st January 2003 as reference date). Complete prevalence was calculated by using the completeness index method which estimates surviving cases diagnosed prior to 1988 (‘unobserved’ prevalence). The expected number of new cases per year and of prevalent cases in Europe was then obtained multiplying the crude incidence and complete prevalence rates to the European population at 2008. We estimated 5204 new cases per year (10.5per million) to occur in Europe, of which 48.7% were melanomas of uvea, 24.8% melanomas of mucosa and 26.5% adnexal carcinomas of the skin. Five-year relative survival was 40.6% and 68.9% for mucosal and uveal melanomas, respectively. Adnexal skin carcinomas showed a good prognosis with a survival of 87.7% 5years after diagnosis. Northern Europe, United Kingdom (UK) and Ireland showed the highest 5-year survival rate for uveal melanomas (72.6% and 73.4%), while Southern Europe showed the lowest rate (63.7%). More than 50,000 persons with a past diagnosis of one of these rare cancers were estimated to be alive at 2008 in Europe, most of them (58.8%, n =29,676) being patients with uveal melanoma. Due to the good prognosis and high incidence of uveal melanomas, these malignancies are highly represented among the long-term survivors of the studied rare cancer types. Therefore, maximising quality of life is particularly important in treatment of uveal melanoma. As regards mucosal melanomas, the centralisation of treatment to a select number of specialist centres as well as the establishment of expert pathology panels should be promoted. The geographical differences in incidence and survival should be further investigated analysing the centre of treatment, the stage at diagnosis and the treatment. [Copyright &y& Elsevier]

Mitochondrial dysfunction is caused by an imbalance in the fission and fusion processes, and it has been implicated in the pathogenesis of several human cancers. However, the role of mitochondrial markers in melanomas still remains poorly understood. In this study, the authors assessed the expression of 3 mitochondrial markers (antimitochondrial, fission protein 1 [FIS1], and mitofusin 2 [MFN2]) in a series of head and neck mucosal and cutaneous melanomas. Patients with cutaneous (n = 56) and mucosal (oral, n = 30, sinonasal, n = 26) melanomas of the head and neck region were enrolled in this study. Clinical and follow-up data were retrieved from medical records. The expression of 3 mitochondrial markers was assessed by the immunohistochemistry, and then digitally quantified and correlated with clinicopathological data and outcome information. In the multivariate model, high mitochondrial content was identified as an independent prognostic value for disease-free survival (DFS) in cutaneous melanomas and overall survival in oral melanomas. FIS1 expression was significantly associated with lower overall survival rates in patients with oral melanomas and strictly correlated with vascular invasion in mucosal melanomas. MFN2 was associated with high risk of distant metastasis in patients with cutaneous melanomas. In summary, the authors demonstrated that mitochondrial content, along with FIS1 and MFN2 expressions, is correlated with important clinicopathological characteristics in patients with cutaneous and mucosal head and neck melanomas., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Melanomas are highly aggressive tumours derived from melanocytes, which occur most commonly in the skin. Occasionally, these tumours may appear in oral and sinonasal mucous membranes. In this study, we performed a comparative analysis of the Phosphorylated Akt1 (p-Akt1) expression in 144 patients affected by cutaneous (CM), 34 oral cavity (OM), and 31 sinonasal melanomas (SNM). Similar to the metastatic cutaneous melanomas, p-Akt1 was overexpressed in 17/34 of the oral cavity and 20/31 of the sinonasal melanomas. In addition, the p-Akt1-nuclear expression was associated with poorer cancer-specific survival in cutaneous ( P < .0001), oral ( P < .0001), and sinonasal ( P = .001) melanomas. Multivariate analysis showed p-Akt1 to be an independent prognostic marker in oral ( P = .041) and sinonasal ( P < .0001) melanomas patients. In conclusion, p-Akt1 overexpression is an independent prognostic marker in mucosal melanomas and is significantly up-regulated in sinonasal melanomas. As both mucosal and metastatic cutaneous melanomas showed high frequency of p-Akt1 expression, these findings suggest that mucosal melanomas have a biological behaviour, similar to the aggressive cutaneous melanomas., Competing Interests: CONFLICTS OF INTEREST The authors have not conflicts of interest to disclose.

Melanoma of the skin is the fifth leading new cancer diagnosis, having accounted for almost 77,000 cases and more than 9000 deaths in the United States in 2013. Although cutaneous neoplasms of this type are relatively common, their mucosal counterparts are not. Mucosal melanomas comprise approximately 1.3% of all melanocytic malignancies. Although they are rare, these lesions present at an advanced stage with more adverse prognoses. In addition, at a molecular level, they have proven to be distinct entities because they possess genetic mutations not usually seen in their cutaneous counterparts. Conversely, a sizable proportion of mucosal melanomas lack the gene aberrations seen in cutaneous melanomas. Such findings indicate different pathways in tumorigenesis for the two subtypes. Because melanomas arising from the mucosae are not often encountered, very little has been published on staging guidelines and prognostic factors. This causes dilemmas for both patients and physicians. Further work is necessary to define staging systems for all mucosal locations, so that accurate prognoses can be assigned to such lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mucosal melanomas of the head and neck are rare pathological entities that correlate with poor prognosis due to their high propensity for local failure and distant metastases. The exact role of radiation therapy in the management of mucosal melanoma patients has not yet been fully proven, even though in everyday clinical practice these patients are referred for radiotherapy, in an effort to improve locoregional control. The guidelines of various societies on the role of radiation therapy for the treatment of mucosal melanoma of the head and neck region are very limited. We reviewed and analyzed the guidelines developed in the U.S.A. (National Comprehensive Cancer Network), Canada (Cancer Care Ontario and Canadian Medical Association), Europe (European Society for Medical Oncology and European Society for Radiotherapy and Oncology) and Australia and New Zealand (Cancer Council Australia) and isolated evidence for the management of mucosal melanomas of the head and neck region with radiation therapy worldwide., (Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)