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Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist–based trials.

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Background Although polychlorinated biphenyls (PCBs) have been classified as human carcinogens for their association with melanoma, few data are available for other skin lesions. Objectives To investigate the prevalence of skin disorders in a highly PCB polluted area in northern Italy, with locally produced food as the main source of human contamination, and evaluate the association between skin lesions and PCB serum levels, taking account of possible confounders. Materials & methods Thirty-three PCB congeners were quantitatively assessed and a total of 189 subjects were equally divided into three groups using the tertiles of total PCB serum concentrations. All subjects underwent a clinical examination and were interviewed on their risk factors and history of skin diseases. Results No statistically significant difference was found in the prevalence of skin cancer, nevi, pigmentary disorders as well as inflammatory and infectious skin diseases among the three PCB exposure groups. It should be noted that the use of questionnaires to assess subjects' past sun exposure and photoprotection is intrinsically flawed due to random error. Conclusions Our study does not support the hypothesis that chronic PCB exposure, through the ingestion of contaminated food, determines an increased risk of developing skin diseases.

Naevi typically involute after the fourth decade of life and are rare in the elderly. However, the rate at which naevi disappear with age varies greatly with some individuals still having large numbers of naevi in late middle age. A small subset of compound naevi in adolescence exhibits a peripheral rim of small brown clods. These naevi enlarge symmetrically with time, accompanied by a progressive development of reticular pattern until the disappearance of the peripheral clods that indicates their growth stabilization. On the other hand, a melanocytic lesion that shows a growth after the age of 30 should raise the doubt of being a melanoma and should thereafter be considered as candidate for excision. In a clinical setting, common behaviour is to excise a melanocytic lesion that shows growing parameters (like a peripheral rim of clods) after 35 years old.

The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs).To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders.This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014.62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors.Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients.We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents.One-hundred-twenty-three patients (21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated.Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi.Our results confirm the scarce involvement of the major high-risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8+ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34+ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist–based trials.

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Background: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. Patients and Methods: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. Results: Median follow-up was 126 months (interquartile range, 104–157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node–negative and 3 patients who were sentinel node–positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%–99.2%) and 82.2% (95% CI, 77.3%–87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. Conclusions: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.

PURPOSE Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB. PATIENTS AND METHODS The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram. RESULTS Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines. CONCLUSION We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.

Polychlorinated biphenyls (PCB) have been classified by the International Agency for Research on Cancer (IARC) in Group 1 as carcinogenic to human, based on sufficient evidence in humans of an increased risk of cutaneous malignant melanoma (CMM), however few studies have been done in the general population. This study examined the relationship between PCB plasma levels and risk of CMM adjusting for sun sensitivity and sun exposure in a province of Northern Italy (Brescia), where a chemical factory produced PCBs from 1938 to 1984 causing human contamination. A case–control study of 205 CMM patients and 205 control subjects was conducted. Cases and controls were assayed for plasma levels of 33 PCB congeners. No associations was found between risk of CMM and plasma levels of total PCB (OR = 0.81; 95% CI: 0.34–1.96 for highest vs lowest quartile) or specific congeners. The study confirmed the association with light skin colour (OR = 3.00; 95% CI: 1.91–4.73), cumulative lifetime UV exposure (OR = 2.56; 95% CI: 1.35–4.85) and high level of education (OR = 1.45; 95% CI: 1.03–2.05). This case-control study does not support the hypothesis of an association between current plasma levels of PCBs and CMM development in the general population. Keywords: Melanoma, Polychlorinated biphenyls, Environmental risk factors