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Competing Interests: The authors declare no conflicts of interest.

Competing Interests: The authors declare no conflicts of interest.

Several studies have focused on identifying microRNAs involved in the pathogenesis of melanoma. However, its association with clinicopathological features has been scarcely addressed. The aim of this study is to identify microRNAs expression profiles related to aggressive clinicopathological and molecular features, and to analyze the association with melanoma survival. A retrospective and observational study was performed in a series of 179 formalin-fixed paraffin embedded primary cutaneous melanomas. First, a screening analysis on a discovery set (n = 22) using miRNA gene chip array (Affymetrix, Santa Clara, California, USA) was performed. Differentially expressed microRNAs were detected employing the software Partek Genomic Suite. Validation of four microRNAs was subsequently performed in the entire series (n = 179) by quantitative real time PCR (qRT-PCR). MicroRNAs expression screening analysis identified 101 microRNAs differentially expressed according to Breslow thickness (≤1 mm vs. >1 mm), 79 according to the presence or absence of ulceration, 78 according to mitosis/mm2 (<1 mitosis vs. ≥1 mitosis) and 97 according to the TERT promoter status (wt vs. mutated). Six microRNAs (miR-138-5p, miR-130b-3p, miR-30b-5p, miR-34a-5p, miR-500a-5p, miR-339-5p) were selected for being validated by qRT-PCR in the discovery set (n = 22). Of those, miR-138-5p, miR-130b-3p, miR-30b-5p, miR-34a-5p were selected for further analysis in the entire series (n = 179). Overexpression of miR-138-5p and miR-130b-3p was significantly associated with greater Breslow thickness, ulceration, and mitosis. TERT mutated melanomas overexpressed miR-138-5p. Kaplan-Meier survival analysis showed poorer survival in melanomas with miR-130b-3p overexpression. Our findings provide support for the existence of a microRNA expression profile in melanomas with aggressive clinicopathological features and poor prognosis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The growth rate (GR) of melanomas is not uniform. A fast-growing subtype has been identified and seems to have a role in the stabilization of the mortality rates because of melanoma. To examine features associated with fast-growing melanomas (FGMs) and to determine the relationship between the GR and well-recognized prognostic factors of melanoma, a series of 386 new invasive cutaneous melanomas seen during 2004-2009 were retrieved from our database. The GR was calculated according to earlier published studies. FGMs were defined as those whose GR was greater than 0.49 mm per month. Differences in clinical, epidemiological, and pathological features were evaluated. Correlations between the GR, tumor thickness, and mitotic rate were also analyzed. FGMs were significantly more prevalent among patients aged over 65 years and with a higher rate of past personal history of nonmelanoma skin cancer. This subtype was over-represented among melanomas located on both nonexposed and usually exposed skin and was less related to earlier sunburns. Patients with FGMs presented with more aggressive pathological features and had more advanced disease with sentinel node analysis affected in up to 35% of cases. There was a strong positive correlation between the GR and tumor thickness (r=0.762), and mitotic rate (r=0.542). This study was limited by being retrospective in nature. FGMs are a highly aggressive subtype of melanomas that seem to develop after at least two routes, one related to chronic sun exposure and another unrelated to the sun. Older patients have a higher predisposition to develop this kind of tumor. This variant warrants specific strategies to improve primary and secondary prevention.

We explored the presence of germline alterations in CDK4 exon 2, CDKN2A and MC1R in a hospital-based study of 89 melanoma cases from 89 families with at least two members affected by cutaneous melanoma. A total of 30% of the melanoma kindreds studied were carriers of CDKN2A variants, and three of these variants were known predominant alleles that have been identified earlier in Mediterranean populations (p.G101W, p.V59G and c.358delG). We observed a higher frequency of nonsynonymous MC1R variants in these Spanish melanoma kindreds (72%) with respect to the general population (60%). We observed a higher frequency of nonsynonymous MC1R variants in this Spanish melanoma kindred (72%) respect to general population (60%). A new classification of MC1R variants based on their functional effects over melanocortin-1 receptor, including the dominant-negative effect of some of them in heterozygotes, suggested an association of loss of function MC1R variants and multiple primary melanoma cases from melanoma kindred (odds ratio: 6.07, 95% confidence interval: 1.35-27.20). This study proposes the relevance of loss of function MC1R variants in the risk of melanoma in multiple primary melanoma cases with family history from areas with low melanoma incidence rate.

Bilateral periorbital edema and swelling are frequent in clinical practice and are commonly attributed to orbital contact dermatitis due to different drugs and cosmetic products. However, when there is a background of a solid cancer, the possibility of eyelid metastasis should be also considered. Metastases to the eyelids are rare, and in most cases, these lesions are unilateral. Because only a few cases of bilateral involvement have been reported in the literature, clinical and morphological data of this variant are under recognized. We report the clinical and histopathological characteristics of 2 patients with 4 eyelid metastasis and review the previous cases reported in the literature.

Carriers of mutations in the melanoma susceptibility gene, CDKN2A, exhibit a higher than expected risk of breast cancer. In this study, we aimed to determine mutations in the CDKN2A gene in patients with melanoma and additional breast cancer. Thirty-one women with histologically confirmed melanoma and breast cancer were studied for CDKN2A/ARF gene mutations by direct sequencing analysis. We identified four CDKN2A germline mutations. Two patients harbored the A148T polymorphism, one of them with family history of breast cancer. Another patient, with a melanoma diagnosed at 77 years, a breast cancer diagnosed at 66 and a family history of melanoma, had the V59G mutation. The fourth patient had a melanoma diagnosed at 54 years, a breast cancer at 46, and a strong family history of breast cancer (mother and grandmother), and presented the A85T mutation. The epidemiologic link between cutaneous melanoma and breast cancer is not mainly related to CDKN2A mutations. However, some mutations might have a role in this association or even in familial breast cancer, as it could be inferred from the patient with the A85T mutation.

The aim of this study was to determine independent clinical and pathological prognostic factors for overall and disease-free survival in Spanish melanoma patients. Eight hundred and twenty-three patients with localized melanoma and complete clinical and pathological information were evaluated. The age at diagnosis, gender, location, tumour thickness, invasion level, ulceration, histological subtype, inflammatory infiltrate, mitotic rate, vascular invasion, microscopic satellitosis, regression and cell type were all included. Univariate and multivariate Cox regression analyses were performed for overall and disease-free survival. Gender, histological subtype, tumour thickness, invasion level, ulceration, inflammatory infiltrate, microscopic satellitosis, vascular invasion and mitotic rate were related to overall and disease-free survival in univariate analysis. Age and location were only related to disease-free survival. Only tumour thickness, vascular invasion and gender exhibited independent significance for overall survival in multivariate analysis. For disease-free survival, tumour thickness, location, mitotic rate, vascular invasion and microscopic satellitosis were the sole independent factors. It can be concluded that the Breslow thickness remains the most significant prognostic factor for the survival of patients with localized cutaneous melanoma. Our results support the inclusion of microscopic satellitosis and vascular invasion in the current American Joint Committee on Cancer (AJCC) staging system, although further studies evaluating their separate influence are needed. Mitotic rate is confirmed as an objective and independent predictor of disease-free survival for melanoma patients that should be considered in further revisions of the mentioned staging system.

The sentinel lymph node (SLN) is the first draining node from the area in which a tumour is located. The presence or absence of SLN micrometastasis is an important prognostic factor for melanoma. As the first dissemination route for melanoma is lymphatic and we know that the immune system plays an important role in melanoma response, we hypothesize that melanoma and its corresponding SLN should constitute an immunological unit. Small portions of 54 SLNs from 37 patients undergoing selective lymphadenectomy were subjected to quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to quantify messenger RNA (mRNA) transcripts of the following genes: tyrosinase, telomerase, cyclooxygenase-1 (COX-1), COX-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4, IL-10 and IL-12. In addition, 11 non-sentinel lymph nodes (NSLNs) were excised from 11 of the 37 patients and the same study was performed. Immunohistochemistry with different antibodies against dendritic cells (DCs) was performed in 10 pairs of SLNs and NSLNs. Significantly higher mRNA expression of COX-2, GM-CSF, IFN-gamma and IL-10 was found in SLNs compared with NSLNs in the overall group. DCs, as labelled by S-100 and CD1a, were significantly decreased in NSLNs compared with SLNs. These data suggest that the initial increase in GM-CSF observed in SLNs could lead to the attraction of a high number of DCs to SLNs. However, the presence of certain immunosuppressive molecules, such as IL-10 and COX-2, could block their maturation and their ability to become efficient antigen presenters.

Benign lymphangioendothelioma (BL) is a rare vascular neoplasm that can histopathologically mimic a low-grade angiosarcoma or the patch stage of Kaposi sarcoma. We report on the case of a 49-year-old man with a benign lymphangioendothelioma on the right thigh that evolved on a vascular birthmark after a trauma. Because of constant pain and the slow but progressive growth of the lesion, we decided to excise the tumor. Three stages of surgery were needed to obtain negative margins. We review the reports of BL to date, with special attention to those that developed after trauma and those that had a preexistent vascular lesion, and expound on the histopathologic differential diagnosis with low-grade angiosarcoma.