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Hypoxia affects tumor aggressiveness and activates pathways associated with epithelial mesenchymal transition (EMT) which are crucial for tumor progress. In this study, the correlation of hypoxia and EMT with sentinel lymph node status and tumor-specific survival was investigated in primary melanomas. CD34 for capillary count and Hypoxia inducible factor-1α (HIF-1α) as hypoxia indicators as well as Ezrin and L1-Cell Adhesion Molecule (L1CAM), both critical proteins contributing to EMT, were analyzed using immunohistochemistry in 49 melanoma patients with long follow-up (F/U, mean 110 months; range 12−263 months). We found a significant correlation between Breslow tumor thickness and Ezrin expression (p = 0.018). L1CAM expression in primary melanoma was significantly associated with HIF-1α expression (p < 0.0001) and sentinel lymph node metastasis (p = 0.011). Furthermore, low capillary count, reflecting hypoxic condition, was significantly associated with Ezrin expression (p = 0.047) and decreased tumor-specific survival (p = 0.035). In addition, patients with high Ezrin expression in their primary melanoma had a dramatic loss of life early in their F/U period (mean survival time 29 months; range 15−44 month). Our results highlight the relevance of Ezrin, L1CAM and HIF-1α as prognostic markers in melanoma patients. Additionally, we demonstrate that hypoxia in primary melanoma affects EMT and is at least partly responsible for early metastatic dissemination.

Background: The negative pigment network (NPN) is seen as a negative of the pigmented network and it is purported to be a melanoma-specific structure., Objectives: We sought to assess the frequency, sensitivity, specificity, and odds ratios (ORs) of NPN between melanoma cases and a group of control lesions., Methods: Digitalized images of skin lesions from 679 patients with histopathological diagnosis of dermatofibroma (115), melanocytic nevus (220), Spitz nevus (139), and melanoma (205) were retrospectively collected and blindly evaluated to assess the presence/absence of NPN., Results: The frequency of occurrence of NPN was higher in the melanoma group (34.6%) than in Spitz nevus (28.8%), melanocytic nevus (18.2%), and dermatofibroma (11.3%) groups. An OR of 1.8 emerged for the diagnosis of melanoma in the presence of NPN as compared with nonmelanoma diagnosis. Conversely, for melanocytic nevi and dermatofibromas the OR was very low (0.5 and 0.3, respectively). For Spitz nevi the OR of 1.1 was not statistically significant. When comparing melanoma with dermatofibroma, melanocytic nevus, and Spitz nevus, we observed a significantly higher frequency of multicomponent pattern (68.1%), asymmetric pigmentation (92.9%), irregularly distributed NPN (87.3%), and peripheral location of NPN (66.2%) in melanomas., Limitations: Further studies can provide the precise dermoscopic-histopathologic correlation of NPN in melanoma and other lesions., Conclusions: The overall morphologic pattern of NPN, such as the irregular distribution and the peripheral location of NPN, along with the multicomponent pattern and the asymmetric pigmentation could be used as additional features in distinguishing melanoma from Spitz nevus and other benign lesions., (Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Serum 25-hydroxyvitamin D3 (Vitamin D) insufficiency and single-nucleotide polymorphisms (SNPs) on its receptor, Vitamin D receptor (VDR), have been reported to be involved in melanoma susceptibility in populations mostly from northern countries., Objective: To investigate 25-hydroxyvitamin D3 levels and VDR SNPs in melanoma patients from sunny area of Barcelona, two studies were carried out. The first study evaluated the levels of Vitamin D at time of melanoma diagnosis and the second one analyzed the association between VDR genetic variants and risk of having a high nevus number, the strongest phenotypic risk factor for melanoma., Methods: The levels of 25-hydroxyvitamin D3 in 81 melanoma patients at diagnosis were measured. In a second group of melanoma patients, including 150 with low and 113 with high nevus number, 11 VDR SNPs were analyzed for their association with nevus number., Results: In the first study, 68% of patients had insufficient levels of 25-hydroxyvitamin D3 (<25 ng/ml). Autumn-winter months and fair phototype were associated with 25-hydroxyvitamin D3 insufficiency; after multivariate analysis, season of sampling remained the only independent predictor of 25-hydroxyvitamin D3 levels. In the second study, VDR variant rs2189480 (P = 0.006) was associated with risk of high nevus number whereas rs2239179 (P = 0.044) and rs7975128 (P = 0.0005) were protective against high nevus number. After Bonferroni adjustment only rs7975128 remained significant. In stratified analysis, SNP rs7975128 was found protective against multiple melanomas (P = 0.021)., Conclusion: This study showed that even in Barcelona, a sunny Mediterranean area, 25-hydroxyvitamin D3 levels were sub-optimal in the majority of melanoma patients at diagnosis. The involvement of VDR in nevi and, in turn, in melanoma susceptibility has also been suggested. Larger studies are needed to confirm our findings.

Background: The 'gold standard' for the diagnosis of melanocytic lesions is dermatopathology. Although most of the diagnostic criteria are clearly defined, the interpretation of histopathology slides may be subject to interobserver variability., Objectives: The aim of this study was to determine the variability among dermatopathologists in the interpretation of clinically difficult melanocytic lesions., Methods: This study used the database of MelaFind®, a computer-vision system for the diagnosis of melanoma. All lesions were surgically removed and sent for independent evaluation by four dermatopathologists. Agreement was calculated using kappa statistics., Results: A total of 1,249 pigmented melanocytic lesions were included. There was a substantial agreement among expert dermatopathologists: two-category kappa was 0.80 (melanoma vs. non-melanoma) and three-category kappa was 0.62 (malignant vs. borderline vs. benign melanocytic lesions). The agreement was significantly greater for patients ≥40 years (three-category kappa = 0.67) than for younger patients (kappa = 0.49). In addition, the agreement was significantly lower for patients with atypical mole syndrome (AMS) (kappa = 0.31) than for patients without AMS (kappa = 0.76)., Limitations: The data were limited by the inclusion/exclusion criteria of the MelaFind® study. This might represent a selection bias. The agreement was evaluated using kappa statistics. This is a standard method for evaluating agreement among pathologists, but might be considered controversial by some statisticians., Conclusions: Expert dermatopathologists have a high level of agreement when diagnosing clinically difficult melanocytic lesions. However, even among expert dermatopathologists, the current 'gold standard' is not perfect. Our results indicate that lesions from younger patients and patients with AMS may be more problematic for the dermatopathologists, suggesting that improved diagnostic criteria are needed for such patients., (Copyright © 2012 S. Karger AG, Basel.)

The skin is the most affected organ by cancer. The incidence rates of skin cancer are steadily increasing, both for melanoma and non-melanoma skin cancers (squamous cell carcinoma, basal cell carcinoma). Over 90 % of the death cases from skin cancers attribute to melanoma. Survival from melanoma is strongly related to tumour thickness. Therefore early detection is the most important step to improve prognosis. In the last years a number of new non invasive techniques for the early diagnosis of melanoma have been developed which are superior to the naked eye examination. In this overview article we present some non-invasive diagnostic techniques like total body photography, digital dermoscopy and confocal microscopy which in addition to dermoscopy assist the dermatologist in differentiating nevi from early melanomas.Non-melanoma skin cancer can be prevented by accurate sun protection. Early squamous cell carcinomas and basal cell carcinomas can be treated either invasively or non-invasively with excellent prognosis.

It is well known that dermoscopy improves the diagnostic accuracy of pigmented skin lesions. Many dermoscopic criteria can be found both in nevi and in melanoma. For the correct interpretation of those criteria, formal training and clinical experience in dermoscopy is needed. This paper reviews the global and local dermoscopic features seen both in nevi and melanoma and focuses on the interpretation of those findings in order to differentiate between benign and malignant melanocytic skin tumors.

In the last years a number of new non invasive techniques for the early diagnosis of melanoma have become very popular. In addition to dermoscopy, total body photography and digital dermoscopy frequently assist the dermatologist in differentiating nevi from early melanomas. A new promising technique for the non invasive diagnosis of melanoma might be confocal microscopy.

Background: The presence of at least one MC1R gene variant is associated with a reduction in age at melanoma diagnosis in families with CDKN2A mutations., Objectives: To describe dermoscopic features of early melanoma in CDKN2A gene mutation-positive Spanish individuals and to evaluate the possibility of a correlation between particular dermatoscopic pattern and MC1R gene variants., Methods: Patients in whom a melanoma was diagnosed during specific follow up of high-risk individuals carrying CDKN2A mutations (with familial or personal history of previous melanoma) were included in this study. The decision to remove such melanomas was taken on the basis of history, clinical and dermoscopic evaluations including total body photography and digital dermoscopy., Results: Of the nine patients included in this study, three were noncarriers of the red hair MC1R polymorphism, three patients had one red hair MC1R polymorphism and three patients had two red hair MC1R polymorphisms. On dermoscopic analysis of suspect melanocytic lesions we found that the mean +/- SD ABCD total dermoscopy score (TDS) was significantly higher in noncarriers of red hair MC1R polymorphisms than in carriers of two MC1R gene red hair variants (6.8 +/- 0.4 vs. 4.4 +/- 0.9; P = 0.014)., Conclusions: Early melanomas in patients with two MC1R red hair variants may be difficult to diagnose definitively by dermoscopy because, in our limited experience, they show fewer colours and structures and have a lower TDS. In such melanomas, subtle atypical vessels and other changes detected by digital image follow up may be useful to confirm the diagnosis of melanoma. An integrated approach including clinical history and dermoscopic data (also considering additional information, such as the presence of atypical vessels) should be utilized in evaluating these high-risk patients. Further studies are necessary to confirm our suggestion.

Dermoscopy has been described as a useful tool for the early diagnosis of melanoma and the differential diagnosis of pigmented lesions of the skin. This has been proven by three independent meta analyses of the literature. Dermoscopy is a fast evolving field with a high number of new publications every year. Initially, the use of dermoscopy was limited to pigmented lesions, but it is used more and more in other situations. It has become an important tool for the diagnosis of nail pigmentations, hair and scalp disorders, and so forth. In this article we try to provide an update on recent trends and developments in dermoscopy.

Background: Dermoscopy is a helpful tool that can assist experienced users improve the diagnostic accuracy for pigmented lesions in acral sites. As a simplification, one can assume that if pigment is found predominantly in the furrows, the lesion can be considered benign, and if the pigmentation is present predominantly on the ridges, the lesion should be considered malignant. The differentiation between furrows and ridges is the main clue for the diagnosis, but this can sometimes be difficult to discern. For this reason, we describe a simple in vivo technique that makes this task much easier for the clinician., Observations: Liquid ink (ie, from a fountain pen) should be applied directly onto the lesion. The ink should be left on the skin for a few seconds to allow the ink to penetrate into the furrows. The excess ink should then be wiped off. The ink will at first diffusely color the entire skin surface. The subsequent cotton swab wiping will only remove the ink on the skin overlying the ridges. The furrows will retain the stain and become clearly visible on dermoscopic examination as thin inked lines. This in turn will make it easy to evaluate whether the melanin pigmentation follows the ink lines (benign pattern) or if the pigmentation is located in between these ink lines (malignant pattern). Conclusion The furrow ink test is a quick and easy method to facilitate the correct identification of furrows and ridges on volar skin and facilitates dermoscopic diagnosis of pigmented lesions in acral sites.

The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had > or =2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered.

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