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Background: Cutaneous malignant melanoma (CMM) accounts for the highest mortality rate among all skin cancers. Traditional histopathologic diagnosis may be limited by the pathologists' subjectivity. Second-opinion strategies and multidisciplinary consultations are usually performed to overcome this issue. An available solution in the future could be the use of automated solutions based on a computational algorithm that could help the pathologist in everyday practice. The aim of this pilot study was to investigate the potential diagnostic aid of a machine-based algorithm in the histopathologic diagnosis of CMM., Methods: We retrospectively examined excisional biopsies of 50 CMM and 20 benign congenital compound nevi. Hematoxylin and eosin (H&E) stained WSI were reviewed independently by two expert dermatopathologists. A fully automated pipeline for WSI processing to support the estimation and prioritization of the melanoma areas was developed., Results: The spatial distribution of the nuclei in the sample provided a multi-scale overview of the tumor. A global overview of the lesion's silhouette was achieved and, by increasing the magnification, the topological distribution of the nuclei and the most informative areas of interest for the CMM diagnosis were identified and highlighted. These silhouettes allow the histopathologist to discriminate between nevus and CMM with an accuracy of 96% without any extra information., Conclusion: In this study we proposed an easy-to-use model that produces segmentations of CMM silhouettes at fine detail level., Competing Interests: Conflict of interest statement The authors have no conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Basal cell carcinoma can simulate melanoma and specific dermoscopic criteria have not yet been defined in a large cohort., Objective: To identify dermoscopic "trump" characteristics for differential diagnosis, identify cluster groups and assess the clinical impact of this study's findings., Methods: Retrospective, multicentric comparative study of atypical, non-facial basal cell carcinoma (≥1 seven-point checklist criteria) and melanoma (with at least one BCC criteria) at dermoscopy. Observed dermoscopic features were used to develop a proposed score. Lesion clusters were defined with hierarchical analysis. Clinical impact was assessed with a blinded reader study following this study's results., Results: A total of 146 basal cell carcinoma and 76 melanoma were included. Atypical vascular pattern was common to most lesions (74.5%). Twelve trump features were included in the proposed score (sensitivity 94.1% and specificity 79.5%). Cluster analysis identified 3 basal cell carcinoma and 3 melanoma clusters. Findings improved overall diagnostic accuracy and confidence (26.8% and 13.8%, respectively; p < 0.001)., Conclusions: These findings support the notion that atypical vascular pattern should be considered a shared feature of both melanoma and atypical basal cell carcinoma. Our proposed score improves diagnostic accuracy and confidence. Absence of pigmented features was associated with lower diagnostic accuracy and confidence., (© 2022 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: The incidence of cutaneous melanoma (cM) has increased in the last decades. Germline mutations in the high-penetrance melanoma susceptibility gene CDKN2A (Cyclin-dependent kinase inhibitor 2A) are associated with a younger age at diagnosis and an increased risk to develop pancreatic cancer., Methods: We retrospectively analyzed the data of patients with prior diagnosis of cM referring to our service from January 2005 to May 2017. The aim was to investigate the rate of multiple cMs (MPM), assessing their clinical/pathological features. Moreover, the genetic tests of patients who had undergone CDKN2A/CDKN2B, CDK4 and MITF screening were evaluated., Results: One hundred fifteen patients (9.26%) were diagnosed with MPMs: 70 males (60.87%) and 45 women (39.13%). 75 patients (43 males and 32 females) underwent genetic screening for germline mutations. The screening revealed that 4/75 patients (5.33%) were carriers of the non-synonymous missense variation c.442G>A (p.Ala148Thr) in CDKN2A exon 2 in heterozygosis, 3 of whom had at least one in-situ melanoma. In 1 patient (1.33%) we detected the variation c.249C>A, p.His83Gln in CDKN2A exon 2 in heterozygosis and in 1 patient (1.33%) the mutation c.952G>A (p.Glu318Lys) in MITF gene was found., Conclusions: This study confirms the need for a full body skin examination and a prolonged surveillance in patients affected by cM, as MPMs were detected in up to 10% of total cases in our series and synchronous lesions in 1/5. Moreover, it reflects the great variability of cM high-susceptibility genes mutational status within the Italian territory. Patients carrying c.952G>A (p.Glu318Lys) MITF mutation have a higher risk to develop a nodular cM.

Malignant cutaneous melanoma (CM) is a potentially lethal form of skin cancer whose worldwide incidence has been constantly increasing over the past decades. During their lifetime, about 8% of CM patients will develop multiple primary melanomas (MPMs), usually at a young age and within 3 years from the first tumor/diagnosis. With the aim of improving our knowledge on MPM biology and pathogenesis, we explored the miRNome of 24 single and multiple primary melanomas, including multiple tumors from the same patient, using a small RNA-sequencing approach. From a supervised analysis, 22 miRNAs were differentially expressed in MPM compared to single CM, including key miRNAs involved in epithelial-mesenchymal transition. The first and second melanoma from the same patient presented a different miRNA profile. Ten miRNAs, including miR-25-3p, 149-5p, 92b-3p, 211-5p, 125a-5p, 125b-5p, 205-5p, 200b-3p, 21-5p, and 146a-5p, were further validated in 47 single and multiple melanoma samples. Pathway enrichment analysis of miRNA target genes revealed a more differentiated and less invasive status of MPMs compared to CMs. Bioinformatic analyses at the miRNA isoform (isomiR) level detected a panel of highly expressed isomiRs belonging to miRNA families implicated in human tumorigenesis, including miR-200, miR-30, and miR-10 family. Moreover, we identified hsa-miR-125a-5p|0|-2 isoform as tenfold over-represented in melanoma than the canonical form and differentially expressed in MPMs arising in the same patient. Target prediction analysis revealed that the miRNA shortening could change the pattern of target gene regulation, specifically in genes implicated in cell adhesion and neuronal differentiation. Overall, we provided a putative and comprehensive characterization of the miRNA/isomiR regulatory network of MPMs, highlighting mechanisms of tumor development and molecular features differentiating this subtype from single melanomas.

Background: Lentigo maligna (LM) and lentigo maligna-melanoma (LMM) are histotypes of melanoma arising in skin with cumulative solar radiation damage. The extension of atypical melanocytes to the hair follicle (folliculotropism) is a histopathological feature of LM/LMM. Its role has not been totally clarified, but it may be correlated to treatment response in LM or to progression in LMM., Objective: This retrospective, multicentric study aims to identify dermatoscopic features associated with folliculotropism in LMs/LMMs., Patients and Methods: We analyzed cases of head and neck LMs/LMMs diagnosed between 2005-2014 at Melanoma Units, University of Bologna/Modena/Florence/Siena (Italy), Nice (France): 25 LMs and 73 LMMs were included., Results: Grey circles (44 %) indicated an isthmic/bulb level of involvement, which were completely absent in the infundibular LM lesions (P = 0.041). In the group of LMMs, light/dark brown pseudonetwork and light brown structureless areas were an indicator of diffuse distribution of malignant melanocytes in the follicular units (P < 0.001 and P = 0.001, respectively), while grey circles indicated focal or diffuse distribution (P < 0.001)., Conclusions: A better understanding of the extension of malignant melanocytes is helpful, aiding clinicians in their decision to perform a radical excision or obtaining a biopsy in the most invasive area of the lesion, which includes potential folliculotropism., (© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Background: Some risk factors for malignant melanoma (MM) are recognized., Objective: To compare the strength of association between MM and eruptive cherry angiomas (CAs) with that of other well-known associations., Methods: This cross-sectional study included all subjects referred to the Outpatient Dermatology-Oncology and Dermoscopy Units of the Universities of Ferrara and Bologna, Italy, over a 5-month period and submitted to total body skin examination. We recorded: age, sex, cutaneous and non-cutaneous malignancies, presence of CAs, arbitrarily considered as "eruptive" when >10, >40 common melanocytic naevi or >2 clinically atypical naevi. The strength of association between the possible risk factors and MM was calculated by odds ratio in both the whole population and age quartiles. Variables associated with MM were included in multiple logistic regression analysis., Results: 1,190 subjects were included; 615 had malignant skin tumours, 462 MM, 85 extracutaneous tumours. Five hundred and eighty-seven subjects had eruptive CAs, 485 subjects >40 melanocytic naevi and 368 more than 2 atypical melanocytic naevi. Eruptive CAs, especially in subjects younger than 70, and >2 atypical melanocytic naevi, mostly in subjects older than 50, were significantly associated with MM. The strength of these 2 associations was similar. The presence of >40 melanocytic naevi was not associated with MM., Conclusions: These findings confirmed an association between MM and eruptive CAs, which was as strong as the one between MM and >2 atypical melanocytic naevi. CAs seem an intriguing model of interaction between heterogeneous variables, like immunocompetence, stimuli inducing endothelial cell proliferation, and oncogenesis, which deserves further investigation., (© 2020 S. Karger AG, Basel.)

Breslow thickness (BT) is the most important histopathologic factor for primary melanoma staging. BT determines the margins for wide local excision whether sentinel lymph node biopsy should be performed and subsequent melanoma staging, and patient management. The correct determination of a 0.8-mm cutoff in melanoma is important for pathologists because discrepancies leading to a change in stage can have significant clinical implications, including incorrect and/or inappropriate prognostic information, investigation, management, and follow-up. Difficulties in BT determination are mostly represented by the presence of regression or melanoma associated with a pre-existing nevus. This study aimed at investigating a molecular parameter, namely microRNA (miRNA) expression, in reference to BT assessment. Melanoma cell proliferation is influenced by miRNA dysregulation. Indeed, some miRNAs sustain and induce proliferative signals or repress growth-suppressive pathways, thereby promoting melanoma carcinogenesis. To identify the miRNAs correlating with BT, we analyzed our global miRNA expression data of 20 thin melanomas and identified two potential candidates, miR-21-5p and miR-146a-5p. We assessed the expression of these two specific miRNAs in 90 archive formalin-fixed and paraffin-embedded samples of superficially spreading melanomas (SSMs) and 25 nodular melanomas from two independent cohorts and correlated the individual and combined miRNA expression with BT and other tumor characteristics. The individually normalized expression of miR-21-5p and miR-146a-5p showed a highly significant and linear correlation with BT in SSM, and their combined expression value was more strongly correlated (Pearson's r = 0.799, 95% CI = 0.71-0.86) than their individual expressions. This correlation was not significant in nodular melanoma. In SSM, we observed that the combined miRNA expression above or below 1.5 was significantly associated with overall survival and successfully identified all patients with relapsing SSM. We concluded that the combined assessment of miR-21-5p and miR-146a-5p expression in superficially spreading melanoma, in association with BT measurement, could aid pathologists in SSM staging., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite of the emerging new systemic and local oncologic treatments (immunotherapy and checkpoint inhibitors, oncolytic viral treatments and injected immunostimulants) the management of skin melanoma metastasis can be still challenging. The main aim of this review was to assess the efficacy and the role of imiquimod in local metastatic melanoma disease. An extensive literature review was performed from September 2000 to March 2020 using PubMed, MEDLINE, Embase, and Cochrane Library databases. Selected articles regarded topical imiquimod, its mode of action as an antitumoral agent and its applications in melanoma metastases treatment. We analyzed a total of 18 published article of clinical cases and small case series and five studies: two retrospective large case series, two Phase I and II clinical trials and one cohort non randomized study. Generally, the treatment is safe and well tolerated. Imiquimod lead to an unstable locoregional control. The use of topical imiquimod for the treatment of MM cutaneous metastases should be considered in selected cases and in palliative settings., (© 2020 Wiley Periodicals LLC.)

Objectives: Malignant acral melanoma (AM) is relatively infrequent in white patients. Molecular investigations have returned variable results regarding the mutational pattern. We sought to describe the mutation profile and clinicopathologic features of AM., Methods: We investigated BRAF, KIT, and NRAS mutational status in a series of 31 AM samples from white patients., Results: Nodular melanoma was the most common histopathologic subtype (48.4%), followed by acral lentiginous melanoma (25.8%) and superficial spreading melanoma (25.8%). BRAF, KIT, and NRAS mutational rates were 12.9%, 17.2%, and 30.0%, respectively. We observed significant associations between KIT mutational status and a thinner Breslow thickness compared with wild-type (WT) status (P = .002), NRAS mutation status and younger age compared with WT. In patients presenting at least one mutation, triple-WT patients presented metastases most frequently., Conclusions: Although these data represent preliminary results, better knowledge of tumor biology and prognosis of AM can support the clinical approach and follow-up., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In the last three decades cutaneous melanoma has been widely investigated as a steroid hormone-sensitive cancer. Following this hypothesis, many epidemiological studies have investigated the relationship between estrogens and melanoma. No evidence to date has supported this association due to the great complexity of genetic, external and environmental factors underlying the development of this cancer. Molecular mechanisms through which estrogen and their receptor exert a role in melanoma genesis are still under investigation with new studies increasingly focusing on the discovery of new molecular targets for therapeutic treatments.

Antibodies directed against programmed death receptor 1 emerged as beneficial immune-checkpoint inhibitor therapy in many different types of cancer. However, programmed death receptor 1 is critical in promoting self-tolerance and the most common toxicities of checkpoint inhibitors are immune-related adverse events. We present a 48-year-old woman affected by metastatic uveal melanoma treated with nivolumab (3 mg/kg every 2 weeks). The patient had no previous history of autoimmune disease or dermatologic conditions. At the fourth month of treatment, on cutaneous examination, she presented multiple whitish vitiligo-like patches on the trunk, axillae, hands and face. Diagnosis of melanoma-associated leukoderma vitiliginous reaction was made. Over the following months, the melanoma-associated leukoderma lesions slowly progressed with cigarette paper-like appearance and indurated texture. A skin biopsy leaded the diagnosis of extragenital lichen sclerosus. To the best of our knowledge, this is the first reported case of extragenital lichen sclerosus on previous melanoma-associated leukoderma lesions related to nivolumab monotherapy. The increase in clinical experience with anti programmed death receptor 1 enhances the knowledge about adverse effects associated with these immunotherapies and allows to compare therapeutic strategies.

Acral lentiginous melanoma (ALM) is the most common type of malignant melanoma (MM) in Asians, Afro-Americans and Middle-Easterners. It represents 1.5-10% of all MM cases, being the most common histological type of MM arising on palms, soles and nail apparatus, which is more generically defined as acral MM. To date no risk factors have been officially established, however a history of trauma may be involved in the pathogenesis of acral MM. This shows heterogeneous clinical features and frequently presents with advanced stage and aggressive behavior, often as a result of misdiagnosis or delayed identification. Dermoscopy is helpful for an early diagnosis of ALM: the most characteristic dermoscopic patterns are the parallel ridge and the irregular diffuse pigmentation. On histopathology ALM displays a lentiginous growth pattern, with melanocytes arranged as solitary units along the basilar epidermis, without notable pagetoid growth in the early stage. Not all acral MMs present a lentiginous pattern: superficial spreading melanoma and nodular melanoma patterns are also possible. Novel studies investigating the biologic characteristics of acral MM reported variable results: the overall mutational rates ranged respectively between 8.5% and 23% for KIT, between 3.6% and 33.3% for BRAF and between 3% and 47% for NRAS in ALMs. Increasing attention has been recently given to other genes, such as telomerase reverse transcriptase, platelet-derived growth factor receptor alfa and cyclin D1. Larger molecular investigations urge to describe the molecular profile of acral MM, to allow the development of specific targeted therapies.

Objectives: The extension of atypical melanocytes to the hair follicle, also termed melanoma folliculotropism, is poorly evaluated and its role is contradictory. We performed an observational study focusing on anatomical areas rich in follicles, such as the head and neck region., Methods: Primary head and neck melanomas diagnosed in the Melanoma Unit, Policlinic Sant'Orsola-Malpighi, University of Bologna were analyzed. Folliculotropism was evaluated with a quantitative and morphologic parameter. Statistical analyses were performed correlating patients' prognosis with folliculotropism and other clinical and histopathologic factors., Results: The study was carried out on a sample of 62 patients. The diffuse distribution (atypical melanocytes present in more than three contiguous follicular units) correlated with scalp localization, nodular subtype, higher Breslow thickness, and a poorer prognosis., Conclusions: We believe that folliculotropism should be further investigated and reported by pathologists during the histologic diagnosis of melanoma., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aim of the study was to assess the association between eruptive cherry angiomas (CAs) and malignant melanoma (MM). Secondary objectives included investigating (i) this association in different age subgroups, and (ii) the association of eruptive CAs with other variables such as malignant tumours, in general, and immunosuppressive treatments. This cross-sectional study involved all patients referred to the outpatient Dermatology-Oncology Units of the universities of Ferrara and Bologna, Italy, and submitted to total body skin examination. These patients were included in a previously collected series. We recorded age, sex, cutaneous and noncutaneous malignancies, immunosuppressive treatments, and presence of CAs. CAs were arbitrarily considered as 'eruptive' when more than or equal to 10. Variables significantly associated with eruptive CAs were included in the logistic regression analysis, also stratified by age. A total of 1693 patients were included in the present study: 500 patients had malignancies, 460 malignant skin tumours, 263 had MM; 150 patients were immunosuppressed; 804 (47.49%) patients had eruptive CAs. In the whole study population, age, immunosuppressive treatment, MM, other skin and nonskin malignant tumours were significantly associated with eruptive CAs at the multivariate analysis. Multivariate analysis in each age subgroup revealed that the association between MM and eruptive CAs was highly significant in younger patients (≤50 years), significant in the 51-70 year-old subgroup, whereas it lost significance in older patients. These findings suggest an association between MM and eruptive CAs, particularly in the lower and intermediate age groups. Both the nature of this association and its possible impact in clinical practice, especially in MM screening, are yet to be established.

Background: Targeted therapies in melanoma have shown clinical benefit in incrementing the overall survival of metastatic patients. However, cutaneous adverse events have been frequently associated with these drugs., Methods: We report our experience in the management of patients treated with dabrafenib for metastatic melanoma, focusing on the monitoring of pigmented lesions. Dermatologic evaluation was performed during the first visit, at the start of each treatment and subsequently after every four weeks. Global nevi count, videodermoscopy of suspected lesions, and surgical excisions when necessary were performed at the beginning of the treatment and every fourth week. All other cutaneous adverse events (cAEs) were noted and documented. Eleven patients were included., Results: The most important cAEs included palmo-plantar hyperkeratosis, diffuse xerosis and pigmented lesion changes. Regarding the latter, in 6 patients, especially in the first months of treatment, we observed hyperpigmentation and hyperkeratosis of the nevi, of the pigmented mucosae and, in one patient, hyperkeratotic changes on a cutaneous metastasis. Histopathology of the excised lesions showed one ex novo melanoma occurrence and benign changes to pre-existing nevi., Conclusions: The awareness of the importance of sequential monitoring of pigmented lesions, with particular attention to the lesions of new onset, is crucial for the best management of these complex patients.

Background: Melanoma is an infrequent neoplasm in children and adolescents. The number of consultancies for melanocytic nevi control in the pediatric population is increased by the major anxiety of parents and pediatricians., Methods: A retrospective chart review was performed in order to evaluate the incidence rate of melanoma, Spitz nevi, congenital and acquired melanocytic nevi in patients aged 14 years or less and referred to our institution from April 2010 to September 2015., Results: A total of 32,755 dermatologic pediatric consultancies were performed in the considered 66 months period, including 4260 patients referred for mole control (13%). During the same period, a total of 5193 excisions of melanocytic lesions were performed (adults and pediatric patients), 259 of which were performed in 250 patients aged 14 years or less (4.98%). Only 1 in situ melanoma of the nail matrix was detected in a 12-year-old female patient (0.38% of surgical excisions). The number needed to excise (NNE) in our pediatric population, calculated by comparing the total number of excised lesions and the number of melanomas found, was 259., Conclusions: Our data leads to 3 major observations: 1) the rarity of melanoma in patients with 14 years of age or less is confirmed; 2) the number of excisions performed in this pediatric population is extremely high; 3) neither the cases of melanoma and atypical Spitz neoplasm (ASN) nor the majority of Spitz nevi were referred to us for a generic mole control. Mole controls in the pediatric population should be properly addressed, incrementing the attention on specific suspicious cutaneous lesions.

Background: The prognosis of cutaneous melanoma is correlated to histopathologic parameters such as Breslow thickness, the presence of mitosis, ulceration and lymphatic involvement at the moment of the diagnosis. On the other hand, the prognostic value of parameters such as age, sex, and tumor localization are still a matter of debate. We evaluated herein the prognostic factors in melanoma patients during a long-term follow-up (60 months)., Methods: Melanoma patients presenting stage IB-III at diagnosis were included. Breslow thickness, ulceration, lymphatic involvement, patients' age, sex and tumor localization were correlated to patients' prognosis. Univariate Cox regressions and multivariate Cox proportional-hazards regression were performed. Successively, Kaplan-Meier was used for variables significantly associated with overall melanoma survival., Results: A total of 115 melanoma patients were included in this study. During follow-up 82 (72.17%) patients survived and 33 (28.7%) died. In our dataset, Breslow thickness >2 mm (P=0.0007), patients age >50 years (P=0.005) and positive sentinel lymph node (P=0.0003) seem to be the most important variables correlated with the presence of metastases at 5 years follow-up. However distant metastases were also observed during follow-up in 14/26 patients presenting negative sentinel lymph node at diagnosis., Conclusions: Given the vital importance of target drugs and the newly introduced immunotherapies in cutaneous melanoma management, we would suggest that mutational analyses should also be extended to the subgroup of patients presenting microstaging parameters related to a poor prognosis in a long-term follow-up of 60 months.

The introduction of dermoscopy has improved the accuracy of diagnosis of melanoma. However, early stage melanoma can be difficult to diagnose. Eighty-nine cases of thin melanoma with a Breslow thickness ≤1 mm located on the lower limb and diagnosed between 2008 and 2016 were assessed using 4 dermoscopic algorithms: (i) modified pattern analysis; (ii) ABCD rule of dermoscopy; (iii) 7-point checklist; and (iv) Menzies' method. Two groups of early stage melanomas of the legs were identified: "difficult to diagnose melanomas" (DDM) and "non-difficult to diagnose melanomas" (NDDM). In our series the dermoscopic features of DDM were difficult to differentiate from melanocytic naevi, and the reticular pattern was the most frequently observed. "Depigmentation" was the only specific criterion associated with DDM. The sensitivity of diagnostic systems for thin melanomas of the lower limbs was lower than in previous studies. This result could be related to the lower mean Breslow thickness of the invasive melanomas in our sample and the high number of melanomas in situ. In conclusion, early stage melanoma of the legs may be difficult to detect at clinical examination or with dermoscopic examination alone. Focusing on depigmentation in dermoscopy associated with anamnestic features could be a useful tool to detect difficult thin melanomas. In addition, sequential dermoscopy is recommended for high-risk patients with previous melanomas or atypical mole syndrome.

Ipilimumab is an immunomodulatory antibody directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which is administered to patients with advanced melanoma, with a proven positive effect on overall survival. The cutaneous adverse effects (AEs) of ipilimumab are relatively frequent, although described as usually mild and rarely life threatening. To describe a three-year experience of a single institute in detecting and managing cutaneous AEs. A cohort of patients (n = 41) treated with ipilimumab (3 mg/kg/three weeks) for metastatic melanoma, from 2013 to 2016, was investigated for adverse cutaneous events. On dermatological evaluation, 34.1% of the patients in our series developed cutaneous AEs: rash (7.3%; n = 3), folliculitis (7.3%; n = 3), mucositis (2.4%; n = 1), rosacea (2.4%; n = 1), eczema (2.4%; n = 1), acneiform eruption (2.4%; n = 1), syringometaplasia mucinosa (2.4%; n = 1), Stevens-Johnson syndrome (2.4%; n = 1), and vitiligo (4.9%; n = 2). These were all Grade 1 and 2 AEs, except for the case of Stevens-Johnson syndrome (Grade 4). On a patient-reported scale, 4.9% (n = 2) and 9.8% (n = 4) of the patients complained of severe xerosis and pruritus, respectively. Ipilimumab was relatively well tolerated in our series, mainly causing mild cutaneous AEs, which, in our experience, responded satisfactorily to conventional therapies. Only in one case was the treatment discontinued, due to Grade 4 side effects.

The effect of hormonal stimulation and fertility treatments, on the development of malignant melanoma (MM) remains to be determined. The aim of this study was to investigate the presence of oestrogen receptor alpha (ERα) and progesterone receptor (PR) in MM and nevi after hormonal stimulation. Immunohistochemical analyses were performed utilizing antibodies specifically directed against ERα and PR in MM and atypical nevi specimens from patients: (1) diagnosed during pregnancy, (2) diagnosed in the six months following delivery, or (3) who had undergone repetitive cycles of hormonal stimulation for in vitro fertilization (IVF) in the year that preceded MM diagnosis. Controls were atypical nevi and MM specimens of female patients of the same age group who had received no hormonal therapies and reported no pregnancies in the five years before diagnosis. Twenty-eight female patients at childbearing age were selected for this study. Strong cytoplasmic positivity of ERα and PR was detected in atypical melanocytes of two MM specimens of patients who had undergone repetitive cycles of hormonal stimulation during IVF procedures. All other specimens showed no expression of ERα or PR. Since our results represent preliminary findings, conclusions regarding a possible correlation between IVF therapy and melanoma occurrence cannot be ascertained. Larger laboratory studies should be performed to investigate reproductive hormone receptor expression in MM in women following IVF, pregnancy, prolonged contraceptive use, or hormone replacement therapy.

Background: Actinic keratoses (AKs) are the most common type of keratinocytic lesions worldwide. The skin areas affected by the so-called "field cancerization" harbor mutagenetic risks for the development of squamous cell carcinoma (SCC)., Methods: We retrospectively investigated the histopathological reports and clinical charts of 672 patients affected by multiple AKs, presenting at least 5 years of follow-up. The frequency of non-melanoma skin cancers (NMSC, namely SCC and basal cell carcinoma [BCC]) and malignant melanomas (MMs) in patients affected by multiple AKs were analyzed., Results: More than 40% of patients with a previous diagnosis of multiple AKs developed an NMSC (SCC or BCC), or an MM, during a follow-up period of 5 to 11 years. The risk of developing another skin malignancy appeared to be higher in the age range between 61 and 80 years. The relative risk of developing a BCC and/or an MM in patients with a previous AK diagnosis was found to be 4.52., Conclusions: The presence of multiple AKs and "field cancerization" seems to be associated with a high risk not only of NMSC such as SCC and BCC, but also of MM. An adequate follow-up is required in these groups of patients.

Targeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed. Patients treated with BRAF and MEK inhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute's Common Terminology Criteria. Of the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1. Hair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.

Introduction and Objectives: Nail apparatus melanoma (NAM) is an uncommon tumor, especially in Caucasians. The prognosis of patients affected by NAM was analyzed and correlated with the histopathological criteria and the surgical management of the tumors., Materials and Methods: We collected data regarding NAM referred to the Skin Cancer Unit of the Dermatology Department of the University of Bologna, from 1992 to January 2012., Results: Out of 1,327 melanoma cases diagnosed between 1992 and 2012, 42 patients were affected by NAM (2.93%). All the patients were Caucasian. Two deceased patients with insufficient medical records and 1 woman with a personal history of breast cancer were excluded. Thirty-nine cases entered this study: 24 were women (67%) and 15 men (33%). The mean age at diagnosis of NAM was 57.3 years (range 29-88 years). Statistical analyses showed that prognosis was significantly correlated with the Breslow thickness (≥/<2 mm; p = 0.02), regression (p < 0.0001) and ulceration (p = 0.04). Regarding surgical management, Kaplan-Meier's test pointed out that performing functional surgery compared to disarticulation did not correlate with a better prognosis of patients (p = 0.08)., Conclusions: In our experience, the surgical management (disarticulation with respect to functional surgical excision) did not influence the prognosis of NAM patients. The latter was affected by the histopathological characteristics (Breslow thickness, regression and mitoses) and location (fingers vs. foot)., (© 2016 S. Karger AG, Basel.)

Spitzoid neoplasms may represent a difficult diagnosis in the practice of dermatopathology. We evaluated the concordance of the fluorescence in-situ hybridization (FISH) assay, histopathology, and dermoscopy in a group of adults and in a group of children with spitzoid neoplasms. The FISH assay, designed to detect the copy number of the RREB1 (6p25), MYB (6q23), and CCND1 (11q13) genes and of centromere 6 (Cep 6), was performed in a group of children and in a group of adults with a histopathologic diagnosis of spitzoid neoplasms. FISH data were compared with dermoscopy and histopathology. Fifteen spitzoid neoplasms were collected from 13 patients (five children and eight adults): nine lesions were histologically diagnosed as typical Spitz nevi; three lesions were melanomas and three were atypical Spitz nevi. The conventional FISH criteria were concordant with the clinical and histopathologic diagnosis of Spitz nevi in four adults and in three children. FISH criteria of the other neoplasms showed a concordance with the histopathologic diagnosis in three cases. Discordant results were obtained in five cases (two children, three adults). The FISH melanoma assay proved more reliable in spitzoid lesions found in adults than in children. This assay should be interpreted carefully in pediatric patients with Spitz nevi in the context of histological features as melanomas in the pediatric population may show distinct chromosomal aberrations., (Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.)

Thirteen melanocytic skin neoplasms with a consultation diagnosis by A. Bernard Ackerman were submitted to immunohistochemistry for HMB-45, Ki67, cyclin D1, e-cadherin, and p16; 9/13 cases underwent fluorescence in situ hybridization (FISH) test targeting 6p25 (RREB1), 6q23 (MYB), centromere 6 (Cep6), and 11q13 (CCND1), as well as the centromere 7 (Cep7). A "consensus diagnosis" among 3 experts was also advocated both before and after morphomolecular information. Three neoplasms with a consultation diagnosis of Spitz nevus showed at least 3 abnormal immunohistochemical patterns; 2 of these cases were also FISH-positive for CCND1 gain, but none of them had a final consensus diagnosis of melanoma. Two neoplasms with a consultation diagnosis of congenital nevus received a consensus diagnosis of melanoma. Molecular morphology techniques can highlight the atypical features of melanocytic neoplasms and support existence of a morphobiologic "spectrum": This should be mirrored in the final report by abandoning the dichotomic (benign vs malignant) diagnostic approach.

Malignant melanoma (MM) is a significant cause of morbidity and mortality worldwide. The MM-related incidence and mortality have been increasing at an alarming rate over at least the past four decades. Malignant melanoma has been thought to be related mainly to exposure to the sun or UV radiation. A review of the scientific literature reveals many significant correlations between chemical exposure in the workplace and the occurrence of malignant melanoma, particularly in cutaneous areas that have never been exposed to sunlight. Discrepant findings are reported by independent studies concluding that MM is causally related to employment-related chemical exposures and to investigators with industry affiliations. More studies are needed to define a correlation of chemical exposure as a co-factor on the pathogenesis in some melanoma patients. We propose further investigation by dermatologists working in Melanoma Centers, using a simple questionnaire on chemical exposure among patients, that have previously been diagnosed and are followed up for melanoma comparing with appropriate matched controls. Collecting the data and results from the questionnaire will help us understand the initiation events in melanoma and prevention health issues.

Summary: Background: Narrowband‐ultraviolet B (NB‐UVB) is widely used for the treatment of several dermatological diseases. A cutaneous carcinogenic effect has been hypothesized, but not proved. Methods: We retrospectively reviewed the data of patients treated with NB‐UVB between January 1998 and December 2013 at the Dermatology Unit of our University Hospital, to evaluate the cutaneous carcinogenic risk of NB‐UVB. Results: In all, 375 patients were included, each receiving a mean follow‐up of 6.9 years. Vitiligo and psoriasis were the most common diseases. In total, 19 non‐melanoma skin cancers (NMSCs) were diagnosed in eight patients, after a mean latency of 5.2 years after the first radiation. No malignant melanoma (MM) was observed. The incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were 620.2/100 ̇000 p/y and 116.3/100 ̇000 p/y. NMSCs were more frequent in patients affected by psoriasis (P = .0232), with older age at the first radiation (mean = 68.8 years, P = .0001). Conclusion: Despite the small number of patients and limited follow‐up, our data suggest that NB‐UVB may trigger cutaneous carcinogenesis, mainly in patients at risk for NMSCs, increasing their personal risk for single and multiple neoplasms, usually superficial BCCs. MM risk does not seem to be enhanced. [ABSTRACT FROM AUTHOR]

Congenital melanotic macules of the tongue (CMMT) are a rare and benign condition that is probably underestimated. We report the case of an African infant with multiple congenital hyperpigmented macules of the tongue. To avoid a difficult-to-perform procedure such as a tongue biopsy, focused clinical monitoring was performed every 3 months for 30 months to detect significant changes. A clinical diagnosis of CMMT was made in the absence of concomitant systemic diseases using the clinical findings, the location on the tongue, the negative family history for melanoma, and the absence of drugs and toxic exposure. Clinical follow-up may be sufficient to monitor CMMT rather than performing a tongue biopsy. [ABSTRACT FROM AUTHOR]

We describe the occurrence of a giant squamous cell carcinoma in a patient receiving vemurafenib for the treatment of late melanoma mestastases. Although the development of keratoacanthomas and squamous cell carcinomas (SCC) has been described during vemurafenib therapy, most of the reported cases are treated with surgical excision. In the present case, SCC regressed after drug withdrawal. [ABSTRACT FROM AUTHOR]

Melanomas arising at uncommon sites include a group of lesions related to unusual localizations in specific ethnic groups. The rarity of the disease often represents a limit to the participation of patients in specific trials. However, this peculiar genetic scenario has important therapeutic implications regarding new oncologic therapies. The aim of this article is to review the clinical features, somatic alterations and therapeutic options for melanomas of uncommon sites. They can be classified as cutaneous and mucosal lesions affecting the nail apparatus, palms/soles, oral mucosa, genital area and scalp. The prognosis may be worse compared to melanomas of other districts, and a prompt diagnosis may dramatically influence the outcome. Dermatologists and oncologists should therefore distinguish this melanoma subgroup in terms of surgical intervention and medical treatment. Due to the lack of mutations in genes usually found in cutaneous melanomas, the discovery of novel targets is required to develop new strategies and to change the prognosis of non-responders or wild-type patients. [ABSTRACT FROM AUTHOR]