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Spitz tumors are a subset of melanocytic neoplasms characterized by epithelioid or spindled melanocytes(1). The benign nature of the "Spitz nevus" has since been clarified, but the debate regarding Spitzoidtumors (STs) is still ongoing. Spitzoid tumors encompass a wide spectrum of cutaneous lesions ranging from benign Spitz nevus (SN) to Spitzoid melanoma (SM), the latter displaying capacity for widespread metastasis and a potentially lethal outcome (2). The term atypical Spitz tumors (ASTs) refers to melanocytic tumors exhibiting the morphological features of SN, as well as some features associated with malignancy, but not sufficient to classify them as SMs. Currently, histopathology is the gold standard for the diagnosis of STs and cutaneous MM. However, the differential diagnosis between benign and malignant melanocytic lesions with spitzoid features remains challenging (3-6). In order to facilitate the work of clinicians and pathologists, we attempted a comparative clinical and demographic study comparing ASTs and MMs of patients referred to two Italian institutes. Patient data were obtained from two different Italian dermatological centers (Melanoma Registry of the Instituto Dermopaticodell'Immacolata IDI-IRCCS Rome, Lazio and the Skin Cancer Unit of Dermatology, Hospital Sant'Orsola-Malpighi, University of Bologna), from January 2007 to December 2017. Histological reports presenting pre-operative queries of both "atypical Spitz nevi" or "malignant melanoma" and a final diagnosis confirming one of the queries were included in the study. The chi-square test or Mann-Whitney U-test were applied to analyze differences between the groups for categorical variables such as sex, diagnosis, and continuous variables (age). The "anatomic site" variable was classified into three categories as follows: the limbs, trunk, and head/neck. A multivariate binary logistic model was used to investigate if the anatomic site was an independent predictor of MM. Age and sex were considered confounding factors. A total of 504 patients (51.8% men; 48.2% women) met the inclusion study criteria (mean age 52 years, SD = 22.8) (Table 1). 373 were cases of MM and 131 were cases of AST. Mean age of MM cases and AST were 61.2 years old (SD = 17.6) and 25.8 years old (SD = 13.8), respectively. Subjects with MM were predominantly men (58.2% versus 33.6%) (P<0.0001) and older (median age 62 years versus 25 years) (P=0.0001) than subjects with AST. The most frequent anatomic site for MM was the trunk (39.7 %), while the lower limb was the most frequent anatomic site for AST (48.1 %) (P<0.0001). Table 2 shows the multivariable analysis used to assess if anatomic site was an independent predictor of cutaneous melanoma. Multivariate analysis confirmed an increased risk for MM in comparison with AST for both localization on the trunk (OR:2.78; 95 %CI: 1.74-4.45) (P<0.0001) and head/neck (OR:3.20; 95% CI: 1.60-6.38) (P=0.0001). After introducing age (model 1, OR: 2.11; 95% CI: 1.08-4.12) (P=0.003) and sex into the model, the only anatomic site that remained statistically significant was the trunk (model 2, OR: 2.03; 95% CI: 1.0.3-3.99) (P=0.04). The results show that if the lesion was located on the trunk, the probability of being a MM was two times higher than that of AST, independent of sex, age, or center. After stratifying for sex, the effect was stronger for women (OR: 2.72; 95% CI: 1.14-6.50). After stratifying for age, the effect was stronger for younger subjects (<40 years) (OR: 2. 59; 95% CI: 1.20-5.60) (P=0.02). In this study, we focused on the clinical-epidemiological data in an attempt to improve the identification of nodular melanocytic lesions by providing clinicians with further information in order to reduce the rate of misdiagnosis and assist in providing critical clinical information to surgeons and pathologists. Consistently with the literature, ASTs were mainly found in young-adult patients (mean age was 25.8 years), in the female sex (66.4%), and were typically located on the lower limbs (48.1%) (3,7-10). MM were found to be slightly more common in male patients (58.2%) in the overall patient group; the mean age at the time of the diagnosis was 61.2 years old, and the majority of lesions were located on the trunk (39.7%). These data were similar to those reported by other authors (11-13). ASTs cases were mainly women and younger than MM cases, and were typically located on the lower limbs (Figure 3 and Figure 4). Nodules located on the trunk resulted in a two times greater risk of MM in comparison with AST. In summary, distinguishing ASTs from MMs is often challenging, and histopathology remains the diagnostic gold standard for melanocytic neoplasms, but a specific clinical framework may help surgeons, pathologists, and clinicians to correctly diagnose and manage these lesions in children and adults.

The lentiginous spread of melanocytes into the hair follicle can be observed in a number of benign melanocytic neoplasms such as in nevi but also in sun-induced melanocytic hyperplasia and melanoma. The follicular colonization by melanocytes in melanoma is classified into three distinct patterns: primary follicular melanoma, melanoma with folliculotropism, and invasive melanoma arising from melanoma in situ with folliculotropism. The role of follicular colonization in melanoma pathologic staging is still a matter of debate though the description of the latter has been recommended by the International Collaboration on Cancer Reporting. In this review, we will discuss the role of follicular colonization in melanoma and melanocytic nevi as well as the facts and controversies regarding this topic., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: One of the most relevant genetic alterations in cutaneous melanoma (CM) is the biallelic inactivation/loss-of-heterozygosis (LOH) of cyclin-dependent kinase inhibitor 2 A (CDKN2A), which results in the immunohistochemical loss of p16 frequently found in CM. However, we recently described a rare case of dermal/deep-seated melanoma arising in giant congenital nevus (DDM-GCN) with p16 overexpression combined with p53 loss and tumor protein 53 (TP53) mutation. Herein, we reported a case series of CM with p16 overexpression and analyzed their clinicopathologic features, immunohistochemical expression of the cell cycle regulatory molecules (CCRM: p53, p21, Cyclin D1, Rb), and mutational landscape., Methods: We retrospectively tested for p16 all cases of CM diagnosed at our institution between January 1st 2019-April 1st 2022. In CM with p16 overexpression, we reported clinicopathologic features, immunohistochemical results for melanocytic markers and CCRM, and mutational landscape investigated with a next-generation sequencing (NGS) panel. In cases with zonal p16 overexpression, the immunohistochemical assessment for melanocytic markers and CCRM, as well as the NGS analysis have been performed in both components {with and without p16 overexpression [p16(+)c and p16(-)]}., Results: Overexpression of p16 was found in 10/2879 (0.35%) CM [5/10 (50%) diffuse and 5/10 (50%) zonal]. We combined the immunohistochemical results for CCRM and molecular data to classify the cases as follows: a) Group 1 with altered expression of at least one CCRM but no TP53 mutations [3/10 (30%), all with Rb altered/lost]; b) Group 2 with altered expression of at least one CCRM and TP53 mutations [4/10 (40%), all with p53 altered]; c) Group 3 with normal expression of CCRM and no TP53 mutations [3/10 (30%), all with mutations in MAPK pathway genes (NRAS and BRAF)]. In CM with zonal p16 overexpression, the histologic appearance of p16(+)c was heterogeneous, whereas combining CCRM profiles and molecular data the cases could be categorized as follows: a) cases with the same CCRM and molecular profiles in both p16(+)c and p16(-)c; b) cases with p16(+)c showing additional genetic mutations and/or modifications of CCRM expression., Conclusions: p16 overexpression is a rare event, occurring in advanced-stage, clinically- and histologically-heterogeneous CM. These lesions may be classified into three different groups based on CCRM expression and mutational profiles (including TP53 mutation). The analysis of CM with zonal p16 overexpression suggests that, at least in a subset of cases, this phenomenon could represent a sign of "molecular progression" due to the acquisition of additional genetic mutations and/or modifications of the CCRM profile., Competing Interests: Declaration of Competing Interest All the Authors present in this article declare no conflicts of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma., Methods: Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events., Results: A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab., Conclusion: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Genova reported receipt of Grants from Italian Ministry of Health and BMS, and Honoraria from AstraZeneca, BMS, Eli Lilly, MSD, Roche, Sanofi, Takeda, ThermoFisher. Prof. Del Mastro reported receipt of speaker Honoraria from Roche, Novartis, Eli Lilly and MSD; Travel Grants from Roche, Pfizer and Celgene; participation on Advisory Board for Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Eli Lilly, Seattle Genetics, Eisai, Pierre Fabre, and Daiichi Sankyo. Prof. Lambertini reported receipt of personal fees (advisory role and/or speaker honoraria) from Roche, Takeda, Sandoz, Eli Lilly, Pfizer, AstraZeneca, Novartis Exact Sciences and Ipsen. Prof. Spagnolo reported receipt of Honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merk, Sun Pharma, MSD, Pierre Fabre; participation on Advisory Board for Novartis, Philogen SunPharma, and MSD. The remaining authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Epidemiologic data highlight sex differences in melanoma outcome. A putative role of sex hormones is still under investigation. Very few laboratory investigations have focused on the level of expression of estrogen receptors in melanoma. We evaluated the presence of estrogen receptors alpha (ERα) and beta (ERβ) in melanoma specimens from female patients with a previous history of breast carcinoma (BC). Moreover, another group of female patients undergoing ovarian stimulation (OS) were also compared to two control groups matched for age and melanoma staging. The study was performed at the IRCCS Policlinico di Sant'Orsola Hospital's Melanoma Unit from January 2017 to December 2019. The nuclear and cytoplasmatic immunohistochemical staining was evaluated and scored by the percentage of stained tumour cells: 0 (≤20%), 1 (21-50%) or 2 (≥50%). Twenty-eight specimens were analysed. ERβ nuclear presence was detected in all cases of women with a history of breast cancer. Cytoplasmatic ERβ was clearly expressed with a score of 2 in seven cases. In the respective control group, nuclear and cytoplasmatic ERβ expression was much lower. A cytoplasmatic ERα positivity was also detected in almost all cases. In the second group of women who experienced ovarian stimulation for Assisted Reproductive Technology (ART), a lower abundance of nuclear ERs was detected. Conversely, cytoplasmatic ERβ and α expression ranged widely. Melanoma of women treated with anti-estrogen therapy is generally more prone to express estrogen receptors compared with women of the same age and CM staging but also compared with women in fertile age with and without a history of OS., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: dysplastic nevi (DN) share some clinical and histological features with melanoma and have been considered intermediate lesions toward malignant transformation. However, scientific evidence of DN representing melanoma precursors is still incomplete, and many observations pointed toward their being a distinct biological entity. The current definition of DN is also confusing and the practical consequence of this uncertainty is the excessive excision of DN with severe atypia. MicroRNAs (miRNAs) are small RNAs that regulate gene expression and whose global expression can classify normal and pathological tissues., Objectives: given these considerations, we decided to perform a small RNA profiling study in a group of DN and invasive melanomas obtained from the same patient, to assess tumor evolution according to the global microRNA expression., Methods: we performed a small-RNA sequencing of 6 DN, 2 congenital nevi and 4 cutaneous melanomas obtained from 4 subjects and evaluated the global miRNA expression correlation between samples., Results and Conclusions: the hierarchical clustering and principal component analyses of global miRNA expression, independently grouped together DN and their matching congenital nevi and showed a divergence of DN miRNA profile from melanoma. Our study suggests that DN have a peculiar and different miRNA expression profile compared to melanomas developed in the same patient, thus supporting the hypothesis that DN are distinct biological entities and not melanoma precursors., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: A number of mutations related to malignant melanoma (MM) have been identified, and of the mutated genes, BRAF has been found to be altered in > 50% of cases. Most of these have been BRAF V600E mutations, whereas the incidence of BRAF V600K may vary from 10% to 30%. Little is known about the clinical prognostic correlations of BRAF V600K MMs. We evaluated the clinical and dermoscopic features, incidence, therapy response and outcomes in the medium to long term., Aim: To compare the clinical and dermoscopic characteristics, the response to systemic therapies and the prognosis among MMs with BRAF V600E and BRAF V600K mutations., Methods: We retrieved the data of patients tested in our centre for MM from 2012 to 2015, including clinical features, dermoscopic pictures, clinical history and tumour mutations. Only patients with BRAF V600E and BRAF V600K mutations were included. Any MMs positive for BRAF V600K mutation were collected, and the number of V600K cases and their features were used to extract the same number of patients with BRAF V600E from our database using a matching method. The clinical and dermoscopic presentation, therapy response and disease progression of the two groups were then evaluated., Results: In total, 132 cases of BRAF V600E-mutated MMs were identified, and then randomized with a propensity-score method to match the 10 retrieved cases of BRAF V600K mutation. Both groups had a nodular appearance to the tumours and an advanced disease stage, and no significant differences in dermoscopic features were highlighted. During the follow-up period, four patients with BRAF V600K died of disease-specific causes. Moreover, we found a higher frequency of metastasis, a faster disease progression and more rapid mortality in patients with BRAF V600K., Conclusion: Despite the small size of this study, the results show similar clinical and dermoscopic characteristics between V600E and V600K mutations, but compared with BRAF V600E MMs, BRAF V600K MMs seem to be less responsive to therapy and have a worse prognosis., (© 2022 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Introduction: Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a 'cold' tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes., Areas Covered: This review examines the available evidence on the use of immunotherapeutic strategies in early and advanced TNBC, discusses the pitfalls and limitations often encountered in clinical research, and summarizes data on novel promising immunomodulatory approaches that have been explored in early-phase trials., Expert Opinion: PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1-positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution towards a more personalized approach, and extended clinical benefit in TNBC. Abbreviations: Triple-negative breast cancer (TNBC); breast cancers (BCs); estrogen receptor (ER); progesterone receptor (PgR); human epidermal growth factor-2 (HER-2); basal-like 1 (BL1), basal-like 2 (BL2); mesenchymal (MES); mesenchymal stem-like (MSL); immunomodulatory (IM); luminal androgen receptor (LAR); basal-like immunosuppressed (BLIS); basal-like immune-activated (BLIA); tumor-infiltrating lymphocytes (TILs); tumor mutational burden (TMB); immune cells (ICs); immunohistochemistry (IHC); overall response rate (ORR); overall survival (OS); progression-free survival (PFS); intention-to-treat (ITT); hazard ratio (HR); confidence interval (CI); Food and Drug Administration (FDA); European Medicines Agency (EMA); immune checkpoint inhibitors (ICI); Combined Positive Score (CPS); disease control rate (DCR); neoadjuvant chemotherapy (NACT); pathological complete response (pCR); event-free survival (EFS); disease-free survival (DFS); residual cancer burden (RCB); San Antonio Breast Cancer Symposium (SABCS); antibody-drug conjugates (ADCs); PARP inhibitors (PARPi); clinical benefit rate (CBR); Histone deacetylase inhibitors (HDACi); Dendritic cell (DC); talimogene laherparepvec (TVEC); granulocyte-macrophage colony-stimulating factor (GM-CSF); mismatch repair deficiency (dMMR).

Cutaneous melanoma (cM) is the deadliest of all primary skin cancers. Its prognosis is strongly influenced by the stage at diagnosis, with early stages having a good prognosis and being potentially treatable with surgery alone; advanced stages display a much worse prognosis, with a high rate of recurrence and metastasis. For this reason, the accurate and early diagnosis of cM is crucial-misdiagnosis may have extremely dangerous consequences for the patient and drastically reduce their chances of survival. Although the histological exam remains the "gold standard" for the diagnosis of cM, a continuously increasing number of immunohistochemical markers that could help in diagnosis, prognostic characterization, and appropriate therapeutical choices are identified every day, with some of them becoming part of routine practice. This review aims to discuss and summarize all the data related to the immunohistochemical analyses that are potentially useful for the diagnosis of cM, thus rendering it easier to appropriately applicate to routine practice. We will discuss these topics, as well as the role of these molecules in the biology of cM and potential impact on diagnosis and treatment, integrating the literature data with the experience of our surgical pathology department.

Background: The diagnosis of nodal nevi (NN) is challenging as they mimic melanoma metastases (MM), with a detection rate mostly ranging between 1% and 11% in sentinel lymph node biopsy (SLNB). Herein, we assessed the incidence of NN and the association with the clinical-pathological features of primary melanoma, adopting the updated European Organisation for Research and Treatment of Cancer (EORTC) protocol for SLNB., Methods: All cases of paired melanoma and SLNB were retrospectively evaluated (April 2019-May 2020). Appropriate statistical tests were adopted, with significant variables included in the logistic regression model., Results: 81 patients and a total of 186 lymph nodes (LNs) were included. Eleven patients had only NN and 4 had both NN and MM (18.5%); 29 LNs (15.6%) showed at least one NN and 12 (6.5%) showed more than one NN (a total amount of 43 NN was detected). All NN and none MM stained for p16. NN were associated with age < 60 years (p: 0.042), no ulceration (p: 0.025) and nevus-associated melanoma (NAM) (p: 0.018), with this latter being the only predictor at the logistic regression model (p: 0.022)., Conclusions: The updated EORTC protocol shows a high number of NN and highlights a strong association with NAM., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Lymphovascular invasion (LVI) is considered an unfavorable prognostic factor in cutaneous melanoma (CM). However, its detection by hematoxylin and eosin (H&E) is challenging, with discordant data about its association with clinical-pathological features and no previous studies investigating the inter- (IrOA) and intra-observer (IaOA) agreement. Herein, we tested H&E and double staining (DS) for CD34/SOX10 to detect the LVI in a cohort of 92 CMs, evaluating the IrOA, the IaOA, and the association with the other clinical-pathological features., Methods: Five authors independently evaluated 92 consecutive and retrospectively enrolled cases of CMs. We assessed the IrOA (Fleiss's Kappa/FK and intraclass correlation coefficient/ICC) and the IaOA (Cohen's Kappa/CK) with both H&E and CD34/SOX10. Furthermore, we compared the LVI assessment with the two stains and analyzed the association with other clinical-pathological features [χ 2 tests for dichotomous and categorical data; Student t-test (normal distribution) and Mann-Whitney U-test (non-normal distribution) for continuous data]., Results: The IrOA was almost identical with H&E (FK=0.446; ICC=0.805) and CD34/SOX10 (FK=0.454; ICC=0.810); by contrast, the IaOA was higher with H&E for one pathologist (CK: 0.809) and with CD34/SOX10 for the other one (CK: 0.563). Applying previously defined criteria, LVI was detected in 10 (9.2%) and 11 (10.1%) cases with H&E and CD34/SOX10, respectively (p = 1.000). Both H&E and CD34/SOX10 were significantly associated with vertical growth phase (H&E, p: 0.014; CD34/SOX10, p: 0.010), mitosis ≥ 1/mm2 (H&E, p: 0.000; CD34/SOX10, p: 0.004), pT (H&E, p: 0.000; CD34/SOX10, p: 0.001), Breslow thickness (H&E, p: 0.000; CD34/SOX10, p: 0.001), and lymph node and/or distant metastasis (H&E, p: 0.005; CD34/SOX10, p: 0.000); only H&E was associated with ulceration (p: 0.002) and distant metastasis (p: 0.000), conversely, only CD34/SOX10 was associated with lymph node metastasis (p: 0.003)., Conclusions: CD34/SOX10 does not improve the IrOA and the IaOA of the LVI assessment in CM; furthermore, H&E and CD34/SOX10 show a similar profile of association with the other unfavorable clinical-pathological features of CM. As result, CD34/SOX10 could be a redundant diagnostic tool if applied for the prognostic characterization of not-selected CM in a routine diagnostic scenario., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

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.

Immune checkpoint inhibitors (i.e. anti-PD1, anti-PDL1, and anti-CTLA4) have revolutionized the therapeutic approach of several cancer types. In a subset of metastatic patients, the duration of the response is so long that a cure might be hypothesized, and a treatment discontinuation strategy could be proposed. Considering that long-term efficacy, some patients could also plan to have a child. Moreover, immunotherapy is moving to the early setting in several diseases including melanoma and breast cancer that are common cancers in young patients. However, there is a paucity of data about their potential detrimental effect on fertility, pregnancy, or sexuality. Herein, we conducted a systematic review with the aim to comprehensively collect the available evidence about fertility, pregnancy, and sexual adverse effects of checkpoint inhibitors in order to help clinicians in daily practice and trialists to develop future studies., Competing Interests: Disclosure MG is on the advisory boards of Novartis, Eli Lilly, Pierre-Fabre, all outside the submitted work. ML acted as a consultant for Roche, AstraZeneca, Eli Lilly, and Novartis and received speaker honoraria from Roche, Sandoz, Takeda, Pfizer, Eli Lilly, and Novartis outside the submitted work; also acknowledges the support from the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health 5×1000 funds 2017 (no grant number) for pursuing in his research efforts in the field of oncofertility. FP is on the advisory board of Amgen; reports research fundings from AstraZeneca; travel grants from Celgene; research funding from and is on the advisory board of Eisai; advisory board of Eli Lilly; honoraria from Ipsen; is on the advisory board of and honoraria from MSD; is on the advisory boards of Novartis, Pierre-Fabre, and Pfizer; is on the advisory board and received travel grants and research funding from Roche; and honoraria from Takeda, all outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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: Scalp melanomas are usually thicker and show worse prognosis than other sites and other head and neck melanomas. One hypothesis to explain this aggressive behavior could be diagnosis delay attributed to hair concealment of lesions., Methods: Primary melanomas of the scalp diagnosed over two decades at four reference centers in Australia and Italy were included. Hair coverage and visibility of the lesions were assessed on preoperative photographic documentation by two investigators and correlated with some prognostic factors (Breslow thickness, mitotic rate, and ulceration). Patients records and pathology reports provided clinical and histological data., Results: The majority of 113 melanomas included were located on easily visible areas of the scalp - hairless scalp (49%) or hairline (15%). The remaining ones (36%), considered to be hair-covered, showed more frequently thinning of hair (63%) than a dense hair coverage (37%). Melanomas of "hairy scalps" were more frequently invasive (81%) and had higher median Breslow (0.8 ± 1.3 mm) than those arising on bald scalps or areas with thinning of hair (43%; 0 ± 0.6 mm), P = 0.004. However, when considering only the invasive cases (n = 55), Breslow thickness and mitotic rate were not statistically different between concealed and easily visible areas. Melanomas detected by a doctor were thinner than those first noticed by the patient, relatives, or a hairdresser (P < 0.001)., Conclusions: Most scalp melanomas arose on easily visible areas, which are more prone to ultraviolet damage. Hair-covered ones, despite rare, could be overlooked during examination. Proactive screening of the scalp area should be encouraged., (© 2020 the International Society of Dermatology.)

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.)

Melanoma in giant congenital nevus (M-GCN) is a rare and potentially lethal neoplasm. In children, M-GCN appears as a dermal/deep-seated melanoma (DDM-GCN) with histopathologic features difficult to distinguish from proliferative nodules (PNs-GCN). DDM-GCN in adults is an anecdotal entity and only 8 cases have been described and genetically characterized. We report the first case of DDM-GCN in a 34-year-old man characterized with a large-panel next-generation sequence (NGS) highlighting a TP53 mutation with a UV-signature (C>T substitution) in DDM but not in PNs-GCN and GCN. Curiously, DDM showed an aberrant p16 overexpression without detection of CDKN2A mutation at NGS. In line with previous studies, it supports a different pathway in children and adults: UV-induced mutations may be involved in the latter not only by CDKN2A but also by TP53 mutations, with a potentially confusing overexpression of p16 protein. While these data need to be confirmed in larger cases series, our results show that NGS could be an additional genetic diagnostic tool in DDM-GCN., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

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.)

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.)

Dermatofibroma (BFH), atypical fibroxanthoma (AFX) and dermal pleomorphic sarcoma (DPS) are skin-based soft-tissue neoplasms of uncertain lineage. They are classified as "fibrohistiocytic" neoplasms, even if the World Health Organization stated that this term connotes a polymorphic group of lesions that histologically resemble fibroblasts and histiocytes. It is well-known that this group of lesions shows a "fibro-histiocytic-dendritic" and/or a "myofibroblastic" phenotype, even within the same lesion. We studied the expression of cathepsin-k in 34 cases (25 BFH, 5 AFX, 4 DPS) with a broad panel of antibodies. 20 cases (5 dermatofibrosarcoma protuberans, 5 melanomas, 5 basal cell carcinomas, 5 squamous cell carcinomas) were chosen as controls. Although our results need to be validated, they support a myofibroblastic and/or partial myofibroblastic ("proto-myofibroblastic") phenotype and the lineage-plasticity of these neoplasms, highlighting the potential role of cathepsin-k in myofibroblastic trans-differentiation. Cathepsin-k proved to be an additional immunoistochemical marker potentially useful in the diagnostic algorithm., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

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.

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.)

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.

Mohs micrographic surgery (MMS) is a good treatment option for epithelial neoplasms, especially when localized in areas where tissue conservation is crucial, such as the nail unit (NU). MMS is a method of radical excision offering high cure rates due to the margin control and functional preservation. Our aim is to provide a review on the use of MMS for the treatment of the most common nail tumours. We revised the current literature on the use of MMS to treat malignant neoplasms (Bowen's disease, squamous cell carcinoma, melanoma, basal cell carcinoma, keratoacanthoma, carcinoma cuniculatum) and benign neoplasms (onychomatricoma and glomus tumour). MMS represents a successful surgical option for nail tumours, firstly in terms of tissue conservation: the NU anatomy is complex and the preservation of the component structures is imperative for its functionality. Secondly, due to the surgical radicality, which is essential not only for the clearing of malignant tumours, but also for benign cases, in order to reduce recurrences. Although a conservative treatment of NU melanoma with MMS has been proposed, in our experience, the conservative approach with functional surgery is a good option for the treatment of non-invasive melanoma (in situ and Ia)., (© 2018 European Academy of Dermatology and Venereology.)

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.

Oral pigmentations (OPs) are often neglected, although a meticulous examination of the oral cavity is important not only in the diagnosis of oral melanoma, but also for the detection of important clinical findings that may indicate the presence of a systemic disease. OPs may be classified into two major groups on the basis of their clinical appearance: focal and diffuse pigmentations, even though this distinction may not appear so limpid in some cases. The former include amalgam tattoo, melanocytic nevi, melanoacanthoma and melanosis, while the latter include physiological/racial pigmentations, smoker's melanosis, drug-induced hyperpigmentations, postinflammatory hyperpigmentations and OPs associated with systemic diseases. We will discuss the most frequent OPs and the differential diagnosis with oral mucosal melanoma (OMM), underlining the most frequent lesions that need to undergo a bioptic examination and lesions that could be proposed for a sequential follow-up., (© 2017 European Academy of Dermatology and Venereology.)

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.

Background: The incidence of brain metastases (BM) in melanoma patients is common and associated with poor prognosis. MAP-kinase inhibitors and immunologic checkpoint blockade antibodies led to improved survival of metastatic melanoma patients; however, patients with BM are under-represented or excluded from the majority of clinical trials and the impact of new drugs on their survival is less clear. With the present systematic review, we aimed to analyze outcomes of patients with melanoma BM treated with the new drugs, both in the setting of phase I-II-III clinical trials and in the "real world"., Methods: An electronic search was performed to identify studies reporting survival outcomes of patients with melanoma BM treated with MAP-kinase inhibitors and/or immunologic checkpoint blockade antibodies, regardless of study design., Results: Twenty-two studies were included for a total of 2153 patients. Median OS was 7.9 months in phase I-II-III trials and 7.7 months in "real world" studies. In clinical trials, median OS was 7.0 months for patients treated with immunotherapy and 7.9 months for patients treated with BRAF inhibitors. In "real world" studies, median OS was 4.3 months and 7.7 months for patients treated with immunotherapy and BRAF inhibitors, respectively. Evidence of clinical activity exists for both immunotherapy and MAP-kinase inhibitors., Conclusions: MAP-kinase inhibitors and immunologic checkpoint blockade antibodies have clinical activity and may achieve improved OS in patients with metastatic melanoma and BM. These results support the inclusion of patients with BM in investigations of new agents and new treatment regimens for metastatic melanoma., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The patient provided written informed consent to publication of the case details and photographs. A 59-year-old male patient presented to the Melanoma Unit for a dermatological consultation because of the eruptive onset of multiple hyperpigmented naevi 1 month after beginning medical therapy with cetuximab for metastatic colorectal cancer. Regular sequential dermoscopic monitoring should be performed for these patients, as suggested for other targeted therapies,5 in order to detect changes in melanocytic lesions at an early stage and prevent the onset of melanoma. [Extracted from the article]

The article presents a case study of a 24-year-old white female with congenital skin lesion in her right scapular area. It is noted that she was diagnosed with large plaque-type blue naevus with cellular nodules (LPTBN-CN). The article adds that LPTBN-CN patients should be advised on the potential oncologic transformation, the importance of follow-ups should be emphasized and, whenever possible, a preventive complete surgical removal should be evaluated before subcutaneous nodules develop.