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Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS., Objectives: To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting., Methods: We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS., Results: In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression., Conclusions: PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR., Competing Interests: Conflicts of interest E.H. has received honoraria for consulting and/or lectures from Helsinn, Takeda, Vidac, Recordati and Rafa; and support for travel/meeting participation from Rafa. C.J. has received honoraria for consulting and/or lectures and support for travel/meeting participation from Takeda, Kyowa Kirin and Recordati. J.N. has received honoraria for consulting and/or lectures from Kyowa Kirin, Takeda, Recordati/Helsinn and Mallinckrodt/Therakos; and research funding from Kyowa Kirin. P.Q. has received honoraria for consulting and/or lectures from Takeda, Kyowa Kirin, Recordati/Helsinn, Mallinckrodt and 4SC. J.C.-M. has received honoraria for lectures from Takeda and Janssen. P.O. has received honoraria for lectures from Kyowa, Helsinn, Recordati, Mallinkrodt and 4SC; and support for travel/meeting participation from Kyowa, Almirall and LEO Pharma., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce., Objectives: To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP., Methods: This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation., Results: Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3 years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5 years available for 33 patients and at 15 years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19 years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19 years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99)., Conclusions: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

is missing (Short communication).

Cutaneous squamous cell carcinoma (CSCC) accounts for ∼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management., Competing Interests: Disclosure PQue reported consulting or advisory role for Roche/Genentech, Novartis, MSD, Bristol Myers Squibb, Pierre Fabre, Sanofi, Sun Pharma Advanced Research Company, Merck Serono; travel, accommodations, expenses from MSD Oncology, Sanofi/Regeneron. FB reported advisory role for SunPharma; speaker fee, travel/accommodations for presentations or lectures for Sanofi/Regeneron; honoraria as consultant for Roche, Novartis. PB reported consulting or advisory role for Merck, Sanofi, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol-Myers Squibb, GSK; research funding by GSK, MSD, Sanofi, BMS. MDV reported consulting or advisory role for Novartis, MSD, Bristol Myers Squibb, Pierre Fabre, Immunocore. KP reported advisory board roles with Abbvie, LEO Pharma, Janssen, Almirall, Eli Lilly, Galderma, Novartis, Pierre Fabre, Sun Pharma, and Sanofi. PQua reported advisory board and speaker fee from Sanofi, SunPharma, IGEA. IZ reported advisory board and speaker fee from Sanofi, SunPharma, Philogen, Regeneron, Novartis, MSD, Cieffe Derma, La Roche Posay, BMS, Almirall. FS reported 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. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Current treatment guidelines for cutaneous T cell lymphoma (CTCL) advocate a stage-driven approach, considering clinical presentation, symptom burden, and patient comorbidities. Therapy selection hinges on factors like disease subtype, severity, and treatment availability. The primary goal is to enhance the quality of life by mitigating symptoms, as achieving lasting complete remission is infrequent., Areas Covered: Over the past decade (2013-2023), the therapeutic landscape of CTCL has experienced substantial transformation with the introduction of innovative therapies. This review explores the main pivotal developments in traditional treatment schedules and recently introduced drugs, aiming to offer clinicians and researchers a thorough perspective on the decade's progress in the field., Expert Opinion: Despite the progress made in CTCL therapeutics, ranging from topical chemotherapeutics to immunomodulatory agents, several unmet needs persist. Firstly, there is a pressing need for the incorporation of readily available predictors for treatment response, encompassing clinical, pathological, and molecular features. Secondly, a more profound comprehension of the tumor microenvironment is imperative to optimize the landscape of targetable molecules. Lastly, the undertaking of studies on combination regimens should be encouraged as it enhances therapy efficacies by synergistically combining agents with diverse modes of action.

Introduction: Immunomodulating therapies harness the power of the immune system to combat disease. In advanced melanoma, immune checkpoint inhibitors have significantly improved survival outcomes by activating the immune system to recognize and eliminate cancer cells. In psoriasis, interleukin inhibitors effectively suppress inflammation and improve disease symptoms., Areas Covered: We provide a meta-opinion-based consensus paper on the analogies and differences in treatment mechanisms, duration, frequency between immunotherapy for advanced melanoma and biologics for psoriasis. Combining the current scientific evidence with expert insights, we provide valuable guidance for future research and decision-making processes., Expert Opinion: The development of immunological treatments in melanoma and psoriasis has revolutionized dermatology, but the quest for tailored therapies that maximize efficacy continues. Managing cutaneous exacerbations during melanoma immunotherapy in psoriatic patients remains challenging. Similarly, treating oncologic psoriasis patients resistant to traditional therapies requires individualized approaches. Research is needed to identify response predictors in both conditions and address the sustainability of healthcare systems due to the high cost of biologics. Drug delay studies for psoriasis and longer follow-up evaluations after immunotherapy discontinuation in melanoma are essential for optimizing treatment outcomes and resource allocation.

Introduction: Over the past two years, the scientific community has witnessed an exponential growth in research focused on identifying prognostic biomarkers for melanoma, both in pre-clinical and clinical settings. This surge in studies reflects the need of developing effective prognostic indicators in the field of melanoma., Areas Covered: The aim of this work is to review the scientific literature on the most recent findings on the development or validation of prognostic biomarkers in melanoma, in the attempt of providing both clinicians and researchers with an updated broad synopsis of prognostic biomarkers in cutaneous melanoma., Expert Opinion: While the field of prognostic biomarkers in melanoma appears promising, there are several complexities and limitations to address. The interdependence of clinical, histological, and molecular features requires accurate classification of different biomarker families. Correlation does not imply causation, and adjustments for confounding factors are often overlooked. In this scenario, large-scale studies based on high-quality clinical trial data can provide more reliable evidence. It is essential to avoid oversimplification by focusing on a single biomarker, as the interactions among multiple factors contribute to define the disease course and patient's outcome. Furthermore, implementing well-supported evidence in real-life settings can help advance prognostic biomarker research in melanoma.

Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners., (© 2023 John Wiley & Sons Ltd.)

Melanoma is a rare but highly lethal type of skin cancer whose incidence is increasing globally. Melanoma is characterized by high resistance to therapy and relapse. Despite significant advances in the treatment of metastatic melanoma, many patients experience progression due to resistance mechanisms. Epigenetic changes, including alterations in chromatin remodeling, DNA methylation, histone modifications, and non-coding RNA rearrangements, contribute to neoplastic transformation, metastasis, and drug resistance in melanoma. This review summarizes current research on epigenetic mechanisms in melanoma and their therapeutic potential. Specifically, we discuss the role of histone acetylation and methylation in gene expression regulation and melanoma pathobiology, as well as the promising results of HDAC inhibitors and DNMT inhibitors in clinical trials. We also examine the dysregulation of non-coding RNA, particularly miRNAs, and their potential as targets for melanoma therapy. Finally, we highlight the challenges of epigenetic therapies, such as the complexity of epigenetic mechanisms combined with immunotherapies and the need for combination therapies to overcome drug resistance. In conclusion, epigenetic changes may be reversible, and the use of combination therapy between traditional therapies and epigenetically targeted drugs could be a viable solution to reverse the increasing number of patients who develop treatment resistance or even prevent it. While several clinical trials are underway, the complexity of these mechanisms presents a significant challenge to the development of effective therapies. Further research is needed to fully understand the role of epigenetic mechanisms in melanoma and to develop more effective and targeted therapies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cutaneous adverse events (CAEs) related to oncological therapies are a common scenario in daily clinical practice., Methods: This is a retrospective observational study collecting the data regarding CAEs of patients treated with immune checkpoints inhibitors (ICIs) in four different Italian centers., Results: Of 323 patients included, 305 were evaluable for this analysis; 182 patients (59.7%) had metastatic cutaneous melanoma (CM), 99 (32.5%) non-small cell lung cancer (NSCLC) and 24 (7.8%) renal cell carcinoma (RCC). The most frequent CAEs that we found, considering all the 305 patients, were pruriginous maculopapular rash (10.2% of the patients), vitiligo-like areas (7.2% of the patients), psoriasiform rash (6.2% of the patients), asymptomatic maculopapular rash (4.6% of the patients), and lichenoid rash (4.3% of the patients). Vitiligo-like areas occurred more frequently in patients with CM, while a lichenoid rash was more frequently observed in patients with RCC. Treatment interruption was related to drug-induced CAEs in 15.4% of melanoma patients and 0.0% of lung and kidney patients. Patients developing a cutaneous adverse event had better overall response rate and higher progression free survival and overall survival than the patients without CAEs., Conclusions: Our study brings new information on the characteristics of CAEs related to ICIs treatment in three different types of cancers, CM, NSCLC and RCC.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Johanna Latzka: speakers fees and travel support from Kyowa Kirin. Chalid Assaf: Advisory board: 4SC, Takeda, Helsinn, Innate Pharma, Recordati Rare Diseases, Kyowa Kirin. Martine Bagot: Advisory boards: Helsinn, Recordati, Innate Pharma, Kyowa Kirin, Takeda. Antonio Cozzio: Advisory activity for Kyowa Kirin, Takeda. Reinhard Dummer: has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. Emmanuella Guenova: member of the scientific advisory board of Scailyte AG; received grants and personal fees from Helsinn Healthcare SA and Takeda Pharmaceutical Company, personal fees from Mallinckrodt Pharmaceuticals, Kyowa Hakko Kirin Co., Ltd., Novartis, and Sanofi. Robert Gniadecki: reports carrying out clinical trials for Bausch Health, AbbVie and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma and Sanofi. Emmilia Hodak: received consulting and lecture fees from Takeda, consulting and lecture fees and travel support from Helsinn, lecture fees and travel support from Rafa. Constanze Jonak: received personal fees from Kyowa Kirin, Recordati Rare Diseases, and Takeda; Investigator for Innate Pharma and 4SC (grant paid to institution). Claus-Detlev Klemke: received travel support, lecture and consultancy fees from Actelion, Innate Pharma, Kyowa Kirin, Recordati Rare Diseases, Stemline and Takeda. Robert Knobler: Speaker for Mallinckrodt. Stephen Morris: none. Jan Peter Nicolay: received consulting and lecture fees from Actelion, Innate Pharma, Kyowa Kirin, Recordati, Takeda, TEVA; received a research grant from Kyowa Kirin paid to institution. Pablo Luis Ortiz Romero: received fees for Advisory committees from 4SC, Takeda, Kyowa Kirin, Actelion, Recordati rare diseases, Miragen, Bioprofarma, Mallinckrodt. Innate Pharma. Evangelia Papadavid: Advisory, speaker and grants: Recordati, Mallinckrodt, Takeda, UCB. Nicola Pimpinelli: received consulting fee from Actelion, lecture and advisory board fees from Kyowa Kirin, Recordati Rare Diseases, Takeda. Pietro Quaglino: participation to advisory board; received speaker fees from Therakos, Kyowa Kirin, Takeda, Cellgene, Helsinn-Recordati, 4SC. Annamari Ranki: none. Julia Scariscbrick: Takeda, Mallinckrodt, Kyowa Kirin, Recordati, Helsinn. Rudolf Stadler: received consult fees from Kyowa Kirin, Therakos, 4SC, Actelion. Liisa Väkevä: none. Marten Vermeer: unrestricted grants from: Kyowa, Takeda, Recordati, safety board: Innate; advisory board: Kyowa Kirin, Galderma, Speakers fee: Takeda, Kyowa. Ulrike Wehkamp: Consultancies for Takeda, Kyowa Kirin, Helsinn Healthcare, Mundipharma, Stemline and Galderma, and lectured at educational events sponsored by MSD, Takeda, Galderma, Kyowa Kirin, Stemline and Helsinn Healthcare all outside of the submitted work. Sean Whittaker: advisory boards for Kyowa Kirin and Recordati. Rein Willemze: none. Franz Trautinger: received consulting and lecture fees from Kyowa Kirin, Recordati Rare Diseases and Takeda., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Introduction: The CheckMate 238 randomised study demonstrated the relevant benefit in terms of recurrence-free survival (RFS) of nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma patients with a tolerable safety profile., Materials and Methods: From November 2018 to June 2019, 611 patients with stage III and IV resected melanoma were enroled to receive nivolumab as part of an Italian Expanded Access Programme (EAP). According to stages, 77% were stage III while 141 (23%) were stage IV with no evidence of disease (NED). Among stage III, 121 patients had IIIA (19.8%)., Results: After a median follow-up of 23 months, the RFS in the Intention-to-Treat (ITT) population was 76.6% at 1 year and 59.6% at 2 years; 1- and 2-year distant metastasis-free survival were 83.7% and 71.2%, respectively. The overall survival rate in the ITT population was 93.8% at 1 year and 85.5% at 2 years. No significant differences in RFS were observed according to BRAF status. Treatment-related adverse events of grades 3-4 occurred in 11.5% of patients., Conclusion: This paper reports the results of the Italian Nivolumab EAP in the adjuvant setting of stage III and IV NED melanoma patients. Our results confirm in a real-life setting the clinical activity and safety of nivolumab reported in the CheckMate238 registrative/pivotal. The enroled cohort of 611 patients highlights the relevant clinical need in this setting, also confirmed by the very short accrual time, representing one of the largest series reported as adjuvant EAP with the longest follow-up., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Among primary cutaneous T-cell lymphomas (CTCL), mycosis fungoides (MF) is the most frequent and, along with Sézary syndrome (SS), the best-studied subtype. Most available studies on epidemiology of MF and SS are based on small cohorts or different inclusion criteria. Moreover, although this has become a hot topic, most studies show limitations, such as selection bias and lack of clinical information or follow-up data. Therefore, no reliable conclusions can be drawn. This paper reviews the current data underpinning our understanding of the epidemiology of MF and SS, and presents some original findings based on data retrieved from the cutaneous lymphoma registry of the Italian Marche region. The Marche Regional Cutaneous Lymphoma Registry is a multidisciplinary team founded 27 years ago to share the management of these rare disorders. All patients with a clinical and histologically confirmed diagnosis of primary cutaneous lymphoma are centralized in Ancona (Italy) at the Haematology Clinic, Polytechnic University of Marche, for clinical evaluation, staging, treatment, and follow-up. This paper emphasizes the need for a national registry of pCLs in Italy, as no detailed epidemiological information is available in the country except for the Marche Regional Cutaneous Lymphoma Registry. A national registry would allow for more comprehensive data collection from all over Italy and could provide more accurate information on incidence and epidemiology. This would be beneficial for understanding the pathogenesis and diagnostic procedures of these diseases and could improve patient outcomes. Therefore, we advise the creation of a national registry of pCLs in Italy.

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: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking., Objectives: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate., Methods: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment., Results: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition., Conclusions: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters., (© 2023 European Academy of Dermatology and Venereology.)

Competing Interests: Conflicts of interest None disclosed.

Background: Advanced basal cell carcinoma (aBCC) represents a complex and clinically heterogeneous group of lesions for which curative surgery and/or radiotherapy is unlikely. Systemic therapy with hedgehog pathway inhibitors (HHIs) changed the treatment landscape for this complex patient population., Objectives: The aims of the present study are to describe the clinical characteristics of a real-life Italian cohort diagnosed with aBCC and to investigate effectiveness and safety of HHI., Methods: A multicenter observational study was performed by twelve Italian centers in the period January 1, 2016 - October 15, 2022. Patients aged ≥18 years and diagnosed with aBCC (locally advanced [laBCC] and metastatic BCC [mBCC]) were eligible for the study. Methods for investigating tumor response to HHI included clinical and dermatoscopic evaluation, radiological imaging, and histopathology. For HHI safety assessment, therapy-related adverse events (AEs) were reported and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: We enrolled 178 patients under treatment with HHI: 126 (70.8%) and 52 patients (29.2%) received sonidegib and vismodegib, respectively. Comprehensive data on HHI effectiveness and disease outcome were available for 132 (74.1%) of 178 patients: 129 patients had a diagnosis of laBCC (n = 84, sonidegib; n = 45, vismodegib) and 3 patients of mBCC (n = 2, vismodegib; n = 1, sonidegib, off-label). Objective response rate was 76.7% (95% confidence interval [CI]: 82.3-68.7) and 33.3% (95% CI: 88.2-1.7) for laBCC (complete response [CR]: 43/129; PR: 56/129) and mBCC (CR: 0/3; PR: 1/3), respectively. High-risk aBCC histopathological subtypes and occurrence of &gt;2 therapy-related AEs were significantly associated with nonresponse to HHI therapy ([OR: 2.61; 95% CI: 1.09-6.05; p: 0.03] and [OR: 2.74; 95% CI: 1.03-7.9; p: 0.04]), respectively. Majority of our cohort (54.5%) developed at least 1 therapy-related AE, most of which were mild-moderate in severity., Conclusions: Our results demonstrate the effectiveness and safety profile of HHI and confirm the reproducibility of pivotal trial results in real-life clinical setting., (© 2023 S. Karger AG, Basel.)

Background: Advanced cutaneous squamous cell carcinoma (aCSCC) represents an area of unmet clinical need, with no standardized treatments until the recent approval of immune checkpoint inhibitors (ICIs)., Objectives: The aim of the study was to describe clinical characteristics and therapeutic strategies of a real-life Italian cohort of aCSCC patients managed at the beginning of cemiplimab approval as compassionate use in Italy., Methods: A multicenter retrospective study was performed by 10 Italian centers in the period January 1, 2018-May 31, 2020. Patients aged ≥18 years and diagnosed with aCSCC (locally aCSCC and metastatic CSCC) were eligible for the study. Analysis of patients' characteristics and treatment strategies was performed., Results: 239 patients were initially recruited in the study: 19 patients were excluded due to incomplete data collection, yielding a final cohort of 220 patients, of which 191 and 220 were included for patients' clinical characteristics and therapeutic intervention analysis, respectively. Median age at the time of diagnosis was 81 years (range: 72-86); nodal metastases were detected in 64/220 (29%) patients, and distant metastatic spread was reported in 33/220 (15%) patients. Most of our patients referred chronic occupational and/or recreational sun exposure, experienced ≥1 sunburn during their lifetime, never wore hats or used photoprotective filters, and presented with signs of cumulative sun damage (solar lentigines and/or actinic keratosis). Majority of our cohort received at least one intervention directed to the primary tumor (n = 212, 96.3%); surgery and radiotherapy were the most common therapeutic choices. Immunotherapy was administered to a small number of patients as compassionate use, especially in the metastatic setting., Conclusions: Our study outlines the complex and heterogeneous clinical and therapeutic landscape of aCSCC patients at the beginning of ICI era, highlighting the need of a standardized care for this fragile and high-need patient population., (© 2023 S. Karger AG, Basel.)

Importance: Primary cutaneous lymphomas (PCL) are rare diseases, but the indolent course makes their prevalence high. Although there are many treatment options, no hierarchy is recommended., Objective: To identify the burden of PCL and describe clinical-pathologic features; associated comorbidities; analyse treatment approaches in real-life and the parameters associated with the achievement of complete response (CR)., Design, Setting and Participants: In this study, all the PCL patients (384 patients) consecutively seen at the Dermatologic Clinic of the University of Turin from January 1, 2019 to December 31, 2019, with follow-up updated to December 2020, were included., Main Outcomes and Measures: Subtype of PCL, demographic data, time elapsed between first lesions and diagnosis, associated symptoms, comorbidities, staging at diagnosis, high-grade transformation, blood involvement, stage progression, therapies used and response were assessed., Results: 247 were cutaneous T-cell lymphomas (CTCL, 64.3%), 137 cutaneous B-cell lymphomas (CBCL, 35.7%) and the most frequent subtype was MF (48.4%). 62.3% of CTCL patients showed at least one comorbidity, mainly cardiovascular (28.7%), 20.2% show other not cutaneous neoplasms. The main approaches were skin-directed therapies (topical steroids 65.6%; phototherapy 50.2%). 39.3% patients achieved a CR during the disease course. Pruritus, the presence of comorbidities and high-grade transformation were factors associated with failure to achieve CR, whereas stage IA of MF was associated with greater achievement of CR., Conclusions and Relevance: The Th2 cytokine related development of pruritus could justify increased resistance to treatment, while the presence of associated comorbidities could reduce treatment options as well as treatment compliance., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies., (© 2022 by The American Society of Hematology.)

This prospective registry-based study aims to describe electrochemotherapy (ECT) modalities in basal cell carcinoma (BCC) patients and evaluate its efficacy, safety, and predictive factors. The International Network for Sharing Practices of Electrochemotherapy (InspECT) multicentre database was queried for BCC cases treated with bleomycin-ECT between 2008 and 2019 (n = 330 patients from seven countries, with 623 BCCs [median number: 1/patient; range: 1-7; size: 13 mm, range: 5-350; 85% were primary, and 80% located in the head and neck]). The procedure was carried out under local anaesthesia in 68% of cases, with the adjunct of mild sedation in the remaining 32%. Of 300 evaluable patients, 242 (81%) achieved a complete response (CR) after a single ECT course. Treatment naïvety (odds ratio [OR] 0.35, 95% confidence interval [C.I.] 0.19-0.67, p = 0.001) and coverage of deep tumour margin with electric pulses (O.R. 5.55, 95% C.I. 1.37-21.69, p = 0.016) predicted CR, whereas previous radiation was inversely correlated (O.R. 0.25, p = 0.0051). Toxicity included skin ulceration (overall, 16%; G3, 1%) and hyperpigmentation (overall, 8.1%; G3, 2.5%). At a 17-month follow-up, 28 (9.3%) patients experienced local recurrence/progression. Despite no convincing evidence that ECT confers improved outcomes compared with standard surgical excision, it can still be considered an opportunity to avoid major resection in patients unsuitable for more demanding treatment. Treatment naïvety and coverage of the deep margin predict tumour clearance and may inform current patient selection and management.

Background: Chlormethine gel was approved for treatment of mycosis fungoides, the most common cutaneous T-cell lymphoma, on the basis of results from study 201 and study 202. A post-hoc analysis of study 201 found interesting trends regarding improved efficacy of chlormethine gel vs ointment and noted a potential association between dermatitis and clinical response., Objective: To expand these results by performing a post-hoc analysis of study 202., Patients and Methods: Patients received chlormethine gel or ointment during study 201 (12 months) and higher-concentration chlormethine gel during study 202 (7-month extension). Response was assessed using Composite Assessment of Index Lesion Severity (CAILS). Associations between treatment frequency, response, and skin-related adverse events (AEs) were assessed using multivariate time-to-event analyses. Time-to-response and repeated measures analyses were compared between patients who only used chlormethine gel and those who switched from ointment to gel., Results: No associations were seen between treatment frequency and improved skin response (CAILS) or AE occurrence within the 201/202 study populations. However, an association was observed specifically between contact dermatitis and improved CAILS response at the next visit (p < 0.0001). Patients who used chlormethine gel during both studies had a significantly (p < 0.05) shorter time to response and higher overall response rates than patients who initiated treatment with ointment., Conclusions: This post-hoc analysis shows that patients who initiated treatment using chlormethine gel had faster and higher responses compared with patients who initially used chlormethine ointment for 12 months. The development of contact dermatitis may be a potential prognostic factor for response., Trial Registration Numbers and Dates of Registration: Study 201: NCT00168064, September 14, 2002; Study 202: NCT00535470, September 26, 2007., (© 2022. The Author(s).)

Mycosis fungoides (MF) and Sézary syndrome (SS) are the best-studied subtypes of cutaneous T-cell lymphoma, a rare non-Hodgkin lymphoma that primarily presents in the skin but can also involve blood, lymph nodes and viscera. The role of blood involvement in the assessment and staging of MF and SS has evolved in recent years from being classed as simply 'present' or 'absent', with no impact on staging, to full analysis of abnormal peripheral blood T cells using flow cytometry (FC) to detect and quantify aberrant T-cell phenotypes and polymerase chain reaction (PCR) to characterize T-cell receptor gene rearrangements. These sensitive peripheral blood assessments are replacing manual Sézary cell counts and have become an important part of clinical workup in MF and SS, providing the potential for more accurate prognosis and appropriate management. However, although international recommendations now include guidelines for FC analysis of peripheral blood markers for staging purposes, many clinics only perform these analyses in patients with advanced-stage lymphoma, if at all, and there is still a need for standardized use of validated markers. Standardization of a single effective multiparameter FC panel would allow for accurate identification and quantification of blood tumour burden for diagnosis, staging, assessment of therapeutic response, and monitoring of disease progression at all stages of disease. Once defined, validation of an MF/SS biomarker FC panel will enable uptake into clinical settings along with associated standardization of protocols and reagents. This review discusses the evolution of the role of FC in evaluating blood involvement in MF and SS, considers recently published international guidelines and identifies evidence gaps for future research that will allow for standardization of FC in MF and SS., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest Dr Querfeld received a research grant from Celgene; is a clinical investigator for Celgene, Trillium, miRagen, Bioniz, Kyowa Kirin; and is on Steering Committees/Boards for Helsinn, miRagen, Bioniz, Trillium, Kyowa Kirin, and Medivir. Dr Kim is on a Steering Committee for and has received research funding from Eisai; has received research funding from Forty Seven; is an Advisory Board member for Seattle Genetics; is a Steering Committee member and Advisory Board member for, and received research funding from, Kyowa Hakko Kirin; received research funding from Portola, Horizon; received research funding from Soligenix; is on a Steering Committee and Advisory Board for, and received research funding from, Innate; received research funding from Elorac; is on an Advisory Board for, and received research funding from, Galderma; is on a Steering Committee for, and received research funding from, Corvus; and received research funding from Trillium. Dr Guitart received research support from Galderma and Soligenix and is on Scientific Advisory Boards for Helsinn, Kyowa Kirin, miRagen, and Leo Pharma. Dr Scarisbrick is a consultant for Takeda, Helsinn, Recordati, 4SC, Kyowa, Mallinckrodt, and miRagen and has received a research grant from Kyowa. Dr Quaglino is on Advisory Boards for 4SC, Takeda, Actelion, Innate Pharma, Recordati Rare Diseases, Kyowa, and Therakos.

Background: The management of melanoma patients with metastatic melanoma in the sentinel nodes (SN) is evolving based on the results of trials questioning the impact of completion lymph node dissection (CLND) and demonstrating the efficacy of new adjuvant treatments. In this landscape, new prognostic tools for fine risk stratification are eagerly sought to optimize the therapeutic path of these patients., Methods: A retrospective cohort of 2,086 patients treated with CLND after a positive SN biopsy in thirteen Italian Melanoma Centers was reviewed. Overall survival (OS) was the outcome of interest; included independent variables were the following: age, gender, primary melanoma site, Breslow thickness, ulceration, sentinel node tumor burden (SNTB), number of positive SN, non-sentinel lymph nodes (NSN) status. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model., Results: The 3-year, 5-year and 10-year OS rates were 79%, 70% and 54%, respectively. At univariate analysis, all variables, except for primary melanoma body site, were found to be statistically significant prognostic factors. Multivariate Cox regression analysis indicated that older age (P < 0.0001), male gender (P = 0.04), increasing Breslow thickness (P < 0.0001), presence of ulceration (P = 0.004), SNTB size (P < 0.0001) and metastatic NSN (P < 0.0001) were independent negative predictors of OS., Conclusion: The above results were utilized to build a nomogram in order to ease the practical implementation of our prognostic model, which might improve treatment personalization., (© 2022. The Author(s).)

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts., Competing Interests: Competing interests: PAA—received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, Sanofi; had a consultant role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna; participated to Advisory Board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. PB—Advisory board or conference honoraria: Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol Myers Squibb, GSK, Nestlè. CC—Participation to scientific meetings provided by Novartis, Sun, Pierre-Fabre, Bristol Meyers Squibb; Advisory board participation Novartis, MSD. VCS—Participation to scientific meetings provided by Novartis, Sun, Pierre-Fabre, Bristol Meyers Squibb; Advisory board participation Merck-Serono, Pierre-Fabre, Novartis; Invited speaker: Pierre-Fabre, Novartis, Bristol Meyers Squibb. APDT—Advisory Boards Bayer, Roche, Novartis, PharmaMar. NF—Personal financial interest Advisory board: AAA, Merck, MSD, Novartis, Pfizer; Public speaking: AAA, Ipsen. Institutional financial interest Grant: Ipsen, AAA, Merck. Clinical trials (local PI): 4SC, Astellas, Beigene, Fibrogen, Incyte, Ipsen, MSD, Nucana. GG—Participation to board: Merck, Glaxo, Pharmamar, Novartis, Bayer, EISAI. MM—Honoraria for serving as a speaker from MSD, Roche, Bristol Myers Squibb (BMS), Sanofi, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GlaxoSmithKline (GSK), Sciclone, Alfasigma, and Merck Serono; Personal fees for advisory boards from Merck Sharp & Dohme Corp., Roche, BMS, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, Sanofi, GSK, Alfasigma, and Merck Serono; Stockholder in Epigen Therapeutics and Theravance. PQua—Invited speaker and advisory board participation: BMS, Merck, MSD; Novartis, Pierre Fabre, Sanofi, Roche. PQue—Advisory board participation: Roche, Novartis, Pierre Fabre, Merk Sharp and Dome, BMS, Sanofi, Sun Pharma, Merck. FS—Personal financial interests Advisory board, public speaking: Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, Merck, Hutchison Medipharma Limited—Institutional financial interests Clinical trials (PI): GETNE, Incyte, MSD, Hutchison Medipharma Limited—Non financial interests AIOM: coordinator of neuroendocrine neoplasms guidelines, ITANET: executive board member ESMO: member of the NETs and endocrine tumors faculty Panelists MB reports honoraria for consulting, advisory role, speakers’ bureau, travel, accommodation, expenses from MSD, Roche/Genertech, AstraZeneca, Thermo Fisher Scientific, Illumina. FB reports participation to Advisory Klox Technologies, Smith And Nephew, Acelity 3m, Urgo Medical, Decomed, Mimedx. RB reports donors to the Hospital and/or participation to Advisory Boards AZ, BI, Novartis, MSD, Otsuka, Lilly, Roche, Amgen, GSK, Eisai. AB reports advisory board: Janssen, IPSEN, Novartis AAA, AMGEN - Public speaking: Novartis AAA, AMGEN. DC reports consultant/advisory role for Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, Merck. FC reports advisory board or conference honoraria for BMS, MSD, Pierre Fabre, Novartis. RD reports participation as advisor and speaker for BMS, Novartis, MSD, Sanofi, Pierre Fabre. AMDG has served as a consultant and/or advisor to Incyte, Pierre Fabre, Glaxo Smith Kline, Bristol Myers Squibb, Merck Sharp Dohme, and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre and Sanofi. GF reports AbbVie Srl, Ag Global Event, Allmiral, Amgen, Atenapoli, Bb & C. Srl, Boehringer Ingelheim Italia Spa, Casa Di Cura Ruesh Spa, Collage Spa, Cosmetica Srl, Defhaforum Srl, Dialecticon Srl, Dynamico Education Srl, Editamed Srl, Edizioni Minerva Medica, Effetti Srl, Eli Lilly Italy Spa, F.C. Congressi Srl, Galderma Italia Spa, General Topica Srl, Havas Life Italy Srl, Havas Pr Milan Srl, Health Publishing, Healthware Group, Hippocrates Sintech Srl, Hps Health Publishing & Service Srl, Icim International Srl, Infomedica Srl, Intramed Comunication, Iqvia Solution Srl, Janssen Cilag Srl, La Fonderie, Ldv Srl, Leo Pharma Spa, Maghia Srl, Medica Editoria, Medicoop Vesevo, Mertz Pharma Italia Spa, Micom Srl, Non Solo Meeting Srl, Novartis Pharma Ag, Palazzo Della Salute Srl, Perrigo Italia Srl, Pierre Fabre Dermo Cosmetique, Plannig Congressi, Prex Srl, Qbggroup Srl, Sidemast Srl, Sifarma Spa con socio unico, Sifarma Spa, Sintesi Infomedica Srl, Tecniche Nuove Spa, Thenewway Srl, Triumph Italy Srl, Uvet Gbt Spa, Valetudo Srl, Vyvalife Srl, Vyvamed Srl, Winch ‐ Srl. MCF has served on advisory boards and received honoraria for lectures from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi and Sun Pharma. MTF reports participation to scientific meetings provided by Novartis, Pierre-Fabre, Bristol Meyers, Lilly, AbbVie. FG received honoraria for speaker/advisory role from Servier, Eli Lilly, Iqvia, Merck Serono, Amgen and Bristol Myers Squibb. DG reports Pfizer, Ipsen, Merck. PG reports lecture fees and Advisory Board: AstraZeneca, Roche, Pfizer, MSD, Novartis, Eli Lilly, Boehringer Ingelheim, AMGEN. MG reports participation to scientific meetings provided by Merck Sharp & Dohme, Novartis, Sun, Pierre-Fabre, Bristol Meyers Squibb; advisory board participation for Pierre-Fabre, Novartis, Merck Sharp & Dohme, Bristol Meyers Squibb; invited speaker: Pierre-Fabre, Novartis, Merck Sharp & Dohme, Bristol Meyers Squibb. DM reports honoraria or Advisory Board for Novartis, Bayer HealthCare Pharmaceuticals, Pierre-Fabre, Sanofi Genzyme, MSD Italia S.r.l., Roche, Skyline Dx B.V. LM reports participation to board Astellas and Ipsen. AMM reports Novartis, BMS, MSD, Pierre Fabre, Gilead, Sunpharma, Merck’s, Sanofi. FM reports consultant in events organized by Bristol Meyers Squibb, MSD, Sanofi, Sunpharma, Novartis e Pierre-Fabre, honoraria for participation to events MSD, Sanofi, Sunpharma, Novartis e Pierre-Fabre, participation to meetings: Pharmar, BMS, Novartis - Advisory Board Bristol Meyers Squibb, MSD, Sanofi, Sunpharma, Novartis e Pierre-Fabre. GP reports invited speaker and advisory board participation: BMS, MSD, Incyte, Novartis, Pierre Fabre, Roche, Sanofi. GP reports AbbVie; Almirall; Janssen Cilag; Leo-Pharma; Merck Serono, Novartis, Pfizer, Pierre Fabre, Sanofi Genzyme. JP reports participation to advisory board BMS, MSD. NP reports Kyowa Kirin, Merck Serono, MSD, Novartis, Pierre Fabre, Recordati Rare Diseases, Sanofi, Takeda. FS reports lecture fees: BMS, Novartis, MSD, Pierre Fabre, Sun Pharma, Sanofi, Merck, advisory board: MSD, Novartis, Philogen, Sun Pharma. LT reports financial support with the following subjects with commercial interests in the health sector: Elekta, Igea Medical, Sun Farma, Sanofi, Roche, Molipharma, Nanobiotix AB, HNS GEC-ESTRO WG, AIRO. IZ reports Advisory Board or speakers fee from Novartis, Sanofi Genzyme, Sunpharma, Philogen, MSD, La Roche Posay, Biogena. GCAC, LA, GB, AB, PB, LB, VB, FB, AC, VF, FF, MG, CG, RM, PM, RP, FP, PP, LR, GR, PR, GR, ET, MCT, MT, MV, BV have declared no significant conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series., (© 2022. The Author(s).)

Background: The etiopathogenesis of MF remains obscure. CD27 is a member of the tumor necrosis factor receptor superfamily (TNFRS) that regulates lymphocyte function. Expression of CD27 protein and mRNA has been reported in B-cell lymphomas and adult T-cell leukemia/lymphoma. In this study, we examined the expression of CD27 in the skin of MF patients by real time PCR. The amount of CD27 was measured in MF patients and healthy controls., Methods: A total of 98 skin biopsies were analyzed: 12 obtained from healthy donors and 86 obtained cryostatic sections OCT-embedded affected by MF. Relative quantification of mRNA CD27 expression was achieved by means of TaqMan (Thermo Fisher Scientific, Waltham, MA, USA) amplification and normalization to glyceraldehyde-3-phosphate dehydrogenase (GAPDH)., Results: Housekeeping gene was detectable in all skin samples and there is no difference between healthy control and MF P value =0.1564. CD27 mRNA sequences were found in 3 of 12 (25%) of skin obtained from healthy donors and in 59 of 86 (68%) of skin obtained from cryostatic sections OCT-embedded affected by MF. The χ 2 statistic with Yates correction is 6.8413 and the P value is 0.0089. When we compared the CD27 expression in MF and controls the RQ analysis showed a value of 9.12±14.13. A RQ of 9.12 means that this gene is 9.12 times more expressed in MF skin samples then in the healthy skin samples. No difference was observed in the MF clustered by stages., Conclusions: Our findings indicates that CD27 can be used as diagnostic/prognostic markers, and whether anti-CD27 antibodies can be used in therapy.

Immunotherapy and target therapy have revolutionized treatment of stage III/IV melanoma. Both treatments show a favorable toxicity profile even if cutaneous adverse events (AEs) are frequent (30%-40% of cases). This is a retrospective single center cohort study that included patients with stage IV or inoperable stage III metastatic melanoma (AJCC 8th) who received BRAFi + MEKi therapy or immunotherapy with Checkpoint inhibitors. All cutaneous AEs were ascertained by a dermatologist based on clinical and histological findings. The primary outcome was to provide a detailed clinical dermatological classification of cutaneous adverse events and an evaluation of the incidence of skin toxicity in the two arms of therapy (immunotherapy and target therapy). A total of 286 patients with stages III-IV metastatic melanoma were included: 146 received immunotherapy and 140 target therapy. In the immunotherapy cohort, 63 (43.1%) cutaneous reactions were observed while 33 skin reactions (23.6%) were identified in patients treated with target therapy. All the skin toxicities observed were grade I, excepted four cases: an erythema multiforme-like eruption, a grade III psoriasis and two grade III maculopapular rashes. Immunotherapy in older age resulted statistically related to skin toxicities (p = 0.011), meanly in metastatic setting (p = 0.011). Cumulative incidence of skin toxicities was 65.63% in immunotherapy cohort (p = 0.001). Also multivariate logistic regression shows a significant association between skin adverse events and immunotherapy (odds ratio [OR] = 0.50; 95% confidence interval [CI]: 0.29-0.85, p: 0.01) and between cutaneous AEs and metastatic setting (OR = 1.97; 95% CI: 1.04-3.74, p: 0.04). We have also shown that as the age of initiation of therapy increases the probability of developing skin toxicity grows. However, stratifying by type of therapies the effect of age persists only in immunotherapy (OD: 1.04; CI: 1.01-1.06; p: 0.04) while for target therapy age does not affect the onset of skin toxicity (OD 1.01; CI 0.98-1.04; p = 0.42). No differences were shown between patients on target therapy and immunotherapy regarding gender. Patients were also evaluated regarding concomitant therapies and seems that Levotyroxine may be involved in AEs during immunotherapy treatment. More studies are needed to deepen this aspect, also considering the medical history and diverse drug associations. Cutaneous adverse events are characterized by heterogeneous manifestations, are more often seen in patients on immunotherapy and dermatologists can play a crucial role in multidisciplinary care., (© 2022 The Authors. Dermatologic Therapy published by Wiley Periodicals LLC.)