Multiple primary melanomas: Our experience.

Patients with melanoma have an increased risk of having other neoplasms, and particularly other melanomas and non-melanoma skin cancers. The study aimed to describe multiple primary melanomas in a large medical university centre from Romania (Cluj-Napoca) from 2004 to 2020. Out of 699 patients with melanoma included in the study, 26 (3.71%) developed multiple tumours. The 26 patients developed a total of 59 melanomas, corresponding to a mean of 2.3 melanomas per patient. The site and histological subtype of the first and second melanomas were not consistent. The proportion of subsequent melanomas that were in situ (51.5%) or thin melanomas (<1 mm, 24.2%) was higher compared with first melanomas (7.7%, respectively 11.5%). The median and mean time to diagnosis was 2.75 months, respectively, 28.09 months. In total, 76.92% of second melanomas were detected within three years, but we were able to document a subsequent melanoma more than ten years after the first diagnosis. The study highlights the importance of follow-up in patients diagnosed with melanoma, not only in the first years after the primary diagnoses but for the entire life.

Assessment of sun-related behavior and serum vitamin D in basal cell carcinoma: Preliminary results.

Ultraviolet radiation (UV), mainly from sunlight, is the main risk factor of the most common human skin cancer, basal cell carcinoma (BCC). A positive effect of UV on the skin is its contribution to the synthesis of vitamin D, which is important in sustaining general health, but having high levels of vitamin D is considered a risk factor for BCC. However, vitamin D receptor has antagonistic effects to UV radiation in regulating Sonic Hedgehog pathway. This is a pilot study aimed at characterizing the sun-related behavior and vitamin D status of 52 BCC patients and 59 controls from our geographical area. Patients were included in 4 subgroups: Single, multiple, recurrent, and both multiple and recurrent BCCs. Patients, more than controls, had at least one sunburn in childhood and lentigines (P<0.001). Also, they spent daily, on average, more time in the sun than controls (P<0.001) (3.00-8.00 and 1.50-4.00 h respectively). Outdoor work was similar in both groups. Participants had lower vitamin D serum levels than expected. Due to the small number of cases, no statistically significant differences were found between the subgroups but some tendencies were noted. Patients with only one recurrent BCC had less sunburns than the ones who also developed tumors at multiple sites (P=0.2). Patients with multiple and recurrent tumors had slightly lower vitamin D levels compared with single BCC patients (P=0.1) although they used more vitamin D supplements after the BCC diagnosis (P=0.2). Having a diagnosis of BCC, made patients more compliant to the use of sunscreen cream, but even so, half of them still did not use it. In conclusion, more effort should be invested in sun-related education and public health actions should focus on vitamin D deficiencies.

A Recurrent Case of Targetoid Hemosiderotic Hemangioma: A Case Report and a Comprehensive Review of the Literature.

Targetoid hemosiderotic hemangioma is an acquired vascular malformation of unknown origin. We report the case of a 31-year-old man with a recurrent and spontaneous regressive targetoid hemosiderotic hemangioma. Diagnosis relied on clinical and histological findings. Physical examination revealed presence of an approximately 2 cm targetoid lesion located on the left arm, and associated with pain after pressure. No trigger agent (trauma, insect sting) was reported. Dermoscopy showed a group of red lacunae centrally, encircled by an intermediate yellow circular homogenous area and a red violaceous homogenous ring in the periphery. The histopathological examination and the immunohistochemical staining of the lesion were characteristic for a hemangioma-like proliferation of vessels in the upper part of the dermis, similar to a targetoid hemosiderotic angioma. We also review epidemiological, clinical, and histopathological findings in 6 similar cases presented in the literature. Spontaneous regression and recurrence have rarely been described in this type of skin lesion.

Risk factors for melanoma and skin health behaviour: An analysis on Romanian melanoma patients.

In contrast to Western Europe, in Central and Eastern Europe reports show higher rates of advanced melanoma and lower survival. Our aim was to document and compare melanoma risk factors and skin health behaviour in patients diagnosed with melanoma and people not affected by this disease in a large medical university centre from Romania (Cluj-Napoca). Two hundred and forty-seven melanoma patients followed-up in the Department of Dermatology at the Cluj-Napoca Emergency County Hospital and 956 people not affected by melanoma completed a paper-based questionnaire regarding melanoma risk factors, risk behaviour and self-protecting measures, after giving informed consent. People with melanoma had significantly higher personal risk and protective behaviour, and lower risk behaviour than those not affected. Although our data suggest that melanoma patients are better educated about how to avoid a second primary melanoma, our results are concerning when compared with studies from other countries. The low incidence of self and clinical skin-examination together with the relatively low percentage of participants which would consult a doctor in the case of new/changing mole could be one of the explanations for the late diagnosis of melanoma in the studied population. According to our findings, there is an urgent need for population health campaigns regarding not only primary but also secondary melanoma prevention.

Vitamin D receptor polymorphisms and melanoma.

Melanoma represents the most aggressive skin cancer, with an unpredictable and often treatment resistant behavior. The etiology of melanoma is multifactorial and includes both environmental and genetic factors. Recent evidence indicates that vitamin D has a role in the development and progression of melanoma. The biologically active form of vitamin D/1,25-dihydroxyvitamin D3 acts by binding to a intranuclear receptor; vitamin D receptor (VDR). Single nucleotide polymorphisms (SNPs) in the vitamin D receptor gene may alter the expression or the function of the VDR protein leading to various diseases, including melanoma. More than 600 SNPs have been identified in the VDR gene, but only a few have been analyzed in relation to melanoma risk: FokI, TaqI, BsmI, ApaI, Cdx2, EcoRV, and BglI. Individual studies carried on small cohorts of patients reported controversial results. In an attempt to clarify the available data in the literature on this subject, we elaborated a systematic review in which we analyzed the relationship between VDR gene polymorphisms and melanoma risk and progression. We concluded that vitamin D pathway is important for the pathogenesis and the progression of cutaneous melanoma, illustrating the gene-environment interactions, but well-designed prospective studies that include data on both genotypes and phenotypes of vitamin D metabolism are essential in order to understand the mechanisms underlying the association between vitamin D and melanoma.

Complete regression of primary melanoma associated with nevi involution under BRAF inhibitors: A case report and review of the literature.

Melanoma is one of the most immunogenic tumors among human neoplasms, with numerous clinical observations of partial or completely regressed tumors. It is an aggressive tumor, with the greatest reported number of somatic mutations, BRAF mutation being the most common one. BRAF mutation is also present in a higher percentage in benign nevi. Complete regression of primary tumor and involution of nevi are, however, rare phenomenon in melanoma that can appear in relation with UV exposure, surgical trauma, target therapy in melanoma, pregnancy or host immune response to an evolving melanoma tumor. We present the case of a 58-year-old man with a completely regressed metastatic melanoma who developed a second melanoma with concomitant involution of papillomatous nevi under BRAF inhibitors treatment. In reviewed literature we have found 53 cases of completely regressed primary melanomas, neither of them reporting nevi involution. Complete regression of primary tumor can occur as an immune response to tumor progression. Nevi can involute under BRAF inhibitor therapy, but development of new malignant lesions under BRAF inhibitors is linked to BRAF wild-type. Documentation of primary tumor and dynamic changes in nevi highlight the need of a good clinical skin examination and increase the utility of baseline and sequential dermoscopy in melanoma.

Regression and Sentinel Lymph Node Status in Melanoma Progression.

BACKGROUND The purpose of this study was to assess the role of regression and other clinical and histological features for the prognosis and the progression of cutaneous melanoma. MATERIAL AND METHODS Between 2005 and 2016, 403 patients with melanoma were treated and followed at our Department of Dermatology. Of the 403 patients, 173 patients had cutaneous melanoma and underwent sentinel lymph node (SLN) biopsy and thus were included in this study. RESULTS Histological regression was found in 37 cases of melanoma (21.3%). It was significantly associated with marked and moderate tumor-infiltrating lymphocyte (TIL) and with negative SLN. Progression of the disease occurred in 42 patients (24.2%). On multivariate analysis, we found that a positive lymph node and a Breslow index higher than 2 mm were independent variables associated with disease free survival (DFS). These variables together with a mild TIL were significantly correlated with overall survival (OS). The presence of regression was not associated with DFS or OS. CONCLUSIONS We could not demonstrate an association between regression and the outcome of patients with cutaneous melanoma. Tumor thickness greater than 2 mm and a positive SLN were associated with recurrence. Survival was influenced by a Breslow thickness >2 mm, the presence of a mild TIL and a positive SLN status.

Junctional Epidermolysis Bullosa: Allelic Heterogeneity and Mutation Stratification for Precision Medicine.

Junctional epidermolysis bullosa (JEB) is a hereditary blistering disease caused by reduced dermal-epidermal adhesion due to deficiencies of one of the proteins, laminin-332, type XVII collagen, integrin α6ß4 or integrin α3. Significant progress has been achieved in the development of therapies for EB, such as bone-marrow transplantation, local or systemic injections with fibroblasts or mesenchymal stromal cells, readthrough of premature termination codons, or exon skipping. These were tailored in particular for dystrophic EB, which is caused by type VII collagen deficiency and have not yet reached broad clinical practice. Recently, pioneering combined gene and stem cell therapy was successful in treating one boy with junctional EB. Beside these exclusive approaches, no specific therapy to amend the major clinical features, skin and mucosal blistering and non-healing wounds is available to date. Here we extend the mutational spectrum of junctional EB, provide a stratification of COL17A1 mutations and discuss potential molecular therapeutic approaches.

The role of lymph node ultrasound evaluation in melanoma - review of the literature.

Melanoma is an aggressive tumour, resistant to treatment, derived from melanocytes, with an increasing incidence in the last years in the majority of countries. The most important prognostic factor in the initial stages (I/II) is the presence of metastases at the level of lymph nodes. Ultrasound (US) is a non-invasive method, used in the pre- and post-operative node evaluation due to its high availability, the reduced cost and easy reproducibility. The US accuracy is however dependent on operator expertise. The present article proposes a presentation of the US role in the evaluation of lymph nodes in melanoma patients.

Clinico-pathologic, dermoscopic and ultrasound examination of a rare acral tumour involving the nail - case report and review of the literature.

There is a large spectrum of tumors presenting as nodular lesions that may affect the subungual space. We report the case of a 62-year-old woman presenting with a rapidly growing nodular lesion under the nail of the first left toe. Non-invasive examinations using dermoscopy, ultrasonography and elastography were performed for the preoperative assessment of the lesion. The biopsy of the lesion revealed superficial acral fibromyxoma, a benign tumor with predisposition for acral sites. The patient underwent radical surgery with wide resection margins. This is the first case report of a superficial acral fibromyxoma affecting the subungual region characterized by dermoscopic, ultrasonographic and elastographic features. We also performed a short review of the literature.

Assessment of Cutaneous Melanoma by Use of Very- High-Frequency Ultrasound and Real-Time Elastography.

OBJECTIVE: The primary objective of this study was to evaluate the usefulness of very-high-frequency ultrasound as tool for assessment of skin melanoma by investigation of the correlation between the ultrasound measurement of the thickness of a melanoma and the histopathologically measured Breslow index. The secondary objective was to assess the potential role of real-time elastography in the preoperative evaluation of skin melanoma. SUBJECTS AND METHODS: The study included 42 cutaneous melanoma lesions in 39 adult subjects examined in the division of ultrasound of a department of radiology between September 2011 and January 2015. Gray-scale sonographic features at 40 MHz (thickness, echogenicity, contour) and real-time strain elastographic (qualitative and semiquantitative, strain ratio) characteristics were evaluated and compared with the pathologic results. RESULTS: The melanoma lesions had a homogeneous hypoechoic appearance with a regular contour and stiff or medium consistency. The mean difference between Breslow index and ultrasound thickness was -0.05 mm (95% CI, -0.24 to 0.13 mm), sustaining the absence of significant differences between these two measurements. A strong relation was identified between real-time elastographic appearance and strain ratio for the relations between lesion and hypodermis and between lesion and neighboring dermis (p < 0.002) or hypodermis. CONCLUSION: Our study showed that very-high-frequency ultrasound and real-time elastography can be useful examinations for comprehensive preoperative evaluation of cutaneous melanoma.

Doppler ultrasound and strain elastography in the assessment of cutaneous melanoma: preliminary results.

AIM: To study the usefulness of color or power Doppler ultrasound (US) in the pre-surgical evaluation of skin melanoma, and to correlate the Doppler characteristics with the appearance on high frequency ultrasound strain elastography (SE) in the preoperative evaluation of cutaneous melanoma. MATERIALS AND METHOD: The study included 42 cutaneous melanoma lesions in 39 adult subjects examined between September 2011 and January 2015. Doppler US features (the presence and aspect of vascularization, and the number of vascular pedicles) and elasticity by strain elastography were evaluated together with the pathological results. RESULTS: The melanoma lesions presented hyper-vascularization, with multiple vascular pedicles and stiff appearance. Significant correlations between the thickness of the tumor, measured histopathologically by the Breslow index, and the degree of vascularization (p=0.0167), and number of vascular pedicles (p=0.0065) were identified. Strong correlations between the SE appearance and vascularization on one hand, and SE and the number of vascular pedicles were also identified (p<0.001). CONCLUSION: Our study demonstrates that Doppler US and SE offer useful information for THE preoperative evaluation of cutaneous melanoma and may contribute to better defining the long term prognosis.

Patterns of Change During the Dermoscopic Follow-Up of Melanocytic Lesions in High Risk Patients.

BACKGROUND: Melanomas and melanocytic nevi that change over time display different change patterns, correlated with histopathological features. METHODS: We performed a retrospective analysis of the dermoscopic images corresponding to 86 lesions excised due to the changes occurred during the follow-up period in patients at high risk for melanoma, and we drew a comparison between the changes occurring in melanomas and those occurring in melanocytic nevi. RESULTS: There were significant differences between the models of dermoscopic change characteristic to melanoma and those characteristic to melanocytic nevi. We observed changes with high specificity for the diagnosis of melanoma - asymmetric growth (Sp=90%), new structureless grey-blue areas (Sp=97.5%) or new grey-blue network (Sp=96.25%), new pseudopods or radial streaks (Sp=95%). CONCLUSION: Our study highlights highly specific changes whose presence should raise the suspicion of melanoma and lead to the excision of the lesion.

Desmoplakin mutations with palmoplantar keratoderma, woolly hair and cardiomyopathy.

Mutations in genes encoding for desmosomal components are associated with a broad spectrum of phenotypes comprising skin and hair abnormalities and account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy. Today, more than 120 dominant and recessive desmoplakin (DSP) gene mutations have been reported to be associated with skin, hair and/or heart defects. Here we report on 3 cases with yet unreported DSP mutations, c.7566_7567delAAinsC, p.R2522Sfs*39, c.7756C>T, p.R2586*, c.2131_2132delAG and c.1067C>A, p.T356K, that were associated with variable woolly hair or hypotrichosis, palmoplantar keratoderma, and cardiac manifestations. In addition, we review and summarise the clinical features and DSP mutations of the patients described in the literature, which illustrates the complexity of this group of disorders and of their genotype-phenotype correlations, which cannot be easily predicted. Early diagnosis is crucial and cardiac examinations have to be performed on a regular basis.

Active and inactive forms of matrix metalloproteinases 2 and 9 in cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is the most aggressive type of skin cancer, with high implications on the morbidity and mortality of patients. Matrix metalloproteinases (MMP) 2 and 9 have been involved in melanoma progression because they degrade important components of the basement membrane. We studied the relationship between the levels of active and inactive MMP 2, MMP 9, and clinicopathological parameters. MATERIALS AND METHODS: Expression of both active and latent forms of MMP 2 and MMP 9 was evaluated by zymography in 21 melanoma tissue samples and 19 benign melanocytic nevi samples. RESULTS: In the melanoma group, inactive MMP 2 was detected in 100% of samples and active MMP 2 in 95%. Inactive MMP 9 was detected in 85% of samples and active MMP 9 in 38%. In the nevi group, 78.9% of samples expressed inactive MMP 2, 5.26% active MMP 2, 21% inactive MMP 9, and 0% active MMP 9. Both forms of MMP 2 and MMP 9 were found to be correlated with skin tumor malignancy. Expression of active and latent MMP 9 was higher in tumors >2 mm thick (P = 0.03, P = 0.014). A correlation was also found between positive lymph node metastasis, inactive MMP 9, and active MMP 9 expression (r = 0.59 P < 0.01, r = 0.668, P < 0.01). The amount of active and latent form of MMP 2 did not have an impact on lymph node metastasis. CONCLUSIONS: Our study demonstrates that active and latent MMP 2 and MMP 9 correlate with melanoma, and both forms of MMP 9 correlate with positive lymph node metastasis.

Correlation of dermatoscopy with the histopathological changes in the diagnosis of thin melanoma.

UNLABELLED: Dermatoscopy is a non-invasive technique that enables the early diagnosis of melanoma. The purpose of the present study is to identify the dermatoscopic structures or changes that can indicate the presence of thin melanoma and their correlation with the histopathological aspect. MATERIALS AND METHODS: Twenty-four thin melanomas diagnosed at the Department of Dermatology in Cluj-Napoca, Romania, have been assessed from the point of view of the presence of dermatoscopic structures likely to indicate malignancy. The lesions have been excised and serially sectioned to identify the histopathological correspondent of the various dermatoscopic structures. RESULTS: The dermatoscopic analysis has indicated the following characteristics that suggest the presence of thin melanoma: irregular dots or globules, small white or grey-blue areas, some peripheral pseudopods or radial streaming, red dots at the level of the lesion or the presence of an atypical vascular pattern. As far as lesions under dermatoscopic follow-up are concerned, the following may be signs of malignant transformation: changes of the pigment network, newly appeared small white or red-blue areas or irregularly distributed dots or globules. All these structures are correlated with the histopathological changes that characterize thin melanoma. CONCLUSIONS: Slight dermatoscopic changes are extremely important in diagnosing thin melanomas as they correlate with the histopathological aspect.

Photodamaging effects of porphyrins and chitosan on primary human keratinocytes and carcinoma cell cultures.

BACKGROUND: Photodynamic therapy (PDT) is a non-surgical method for treating non-melanoma skin cancer and precancerous lesions which involves the activation of a photosensitizer by visible light to produce activated oxygen species within target cells, resulting in the destruction of the latter. The present study evaluates the effect of PDT on primary normal and basal cell carcinoma cultures in vitro. METHODS: Primary human keratinocytes and carcinoma cell cultures were exposed to various concentrations of 5,10,15,20-tetra-(para-methoxyphenyl) porphyrin (TMP) and its zinc compound (Zn-TMP) for 24 hours, with or without chitosan, and then irradiated using a PDT lamp (630 nm, 6 J/cm(2)). The effects of PDT were assessed using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay and an immunocytochemical method with Annexin V-FITC for detecting apoptosis. RESULTS: Both tested substances, TMP and Zn-TMP, had a phototoxic effect on primary human carcinoma cell cultures in concentrations of 1-100 µg/ml, which positively correlated with the concentration of the photosensitizer. There was no phototoxic effect on primary keratinocytes, probably because of the preferential accumulation of photosensitizing substances in tumoral cells. Administration of chitosan in association with photosensitizing substances increased cell viability compared with photosensitizers alone, exerting a cytoprotective effect. CONCLUSIONS: The study demonstrates that the photodynamic activity of TMP and its metalloporphyrin derivative is limited to primary human carcinoma cells and suggests that these porphyrins could be efficiently used in PDT in vivo.