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Hypopigmentation disorders pose significant diagnostic challenges in dermatology, sometimes reflecting underlying hematological conditions. This review explores the clinical presentations related to hypopigmentation in hematological disorders, focusing on vitiligo, morphea, and syndromic albinism. Vitiligo, an autoimmune disorder targeting melanocytes, involves interactions between genetic polymorphisms and immune responses, particularly regarding CD8+ T cells and IFN-γ. Drug-induced vitiligo, notably by immune checkpoint inhibitors and small-molecule targeted anticancer therapies, underscores the importance of immune dysregulation. Morphea, an inflammatory skin disorder, may signal hematological involvement, as seen in deep morphea and post-radiotherapy lesions. Syndromic albinism, linked to various genetic mutations affecting melanin production, often presents with hematologic abnormalities. Treatment approaches focus on targeting the immune pathways specific to the condition, and when that is not possible, managing symptoms. Understanding these dermatological manifestations is crucial for the timely diagnosis and management of hematological disorders.

The discovery of the role of Bruton’s Tyrosine Kinase (BTK) in inflammation and autoimmunity has recently led to the development of BTK inhibitors for the treatment of autoimmune diseases, including pemphigus vulgaris. We herein present the case of a patient affected by pemphigus vulgaris, refractory to conventional immunosuppressive therapies and to multiple courses of rituximab, who was treated with rilzabrutinib and achieved disease control, but whose immunological profile switched from pemphigus vulgaris to pemphigus foliaceus after drug discontinuation. Furthermore, we review the literature in order to better characterize the phenotypic transitions from pemphigus vulgaris to pemphigus foliaceus reported so far. The factors underlying this transition are largely unknown, although it has been postulated that immunosuppressive therapies may be more effective against anti-desmoglein 3 antibodies compared to anti-desmoglein 1. However, further studies are needed to better define the effect of rilzabrutinib (and immunosuppressive therapies in general) on anti-desmoglein 1 and anti-desmoglein 3 antibodies.

Abstract Background Primitive location of melanoma could be a relevant prognostic factor. As regards the scalp, some studies indicate a particularly aggressive biological behaviour for this anatomical localisation. Objectives In this multicentric study, data regarding head–neck melanoma (HNM) have been revised. Methods The design of the study included two main phases. In this retrospective study, data regarding HNM have been collected and analysed. Results In summary, our data suggest that the posterior neck is the area most affected by thicker melanomas. Cheeks and neck melanoma are associated with reduced disease‐free years of life and overall survival compared with all other sites of HNM. Conclusions This study provides useful information in defining the clinical features of HNM, thus improving diagnosis and treatment strategies.

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies.

Severe mucormycosis is a fatal disease rarely complicating chronic lymphoproliferative disorders. We present a fulminant and fatal case of a 74-year-old Caucasian woman suffering from CLL treated with second-generation BTK inhibitor zanubrutinib. After a first septic episode a month prior, originating from the lung with later systemic involvement by an unidentified agent and treated with large-spectrum antibiotics and fluconazonle, a slow-onset enlarging tender warm and erythematous nodular swollen cutaneous lesion appeared in her lower limbs and spread subsequently to her upper limbs, progressing towards central ulceration with a necrotic core. Suspecting a mycotic dissemination from an unknown agent, a skin punch biopsy was performed, and intraconazole was started. Due to spread of the skin lesions, the patient was hospitalized and intravenous liposomal ampthotericin B was started. Histopathology showed an atypical sporangium-rich mycotic angioinvasion of the small vessels. Only the increase of BDG and GM could corroborate the hypothesis of mycotic infection. However, long-term CLL, immunosuppressive therapies, neutropenia, and prior use of azoles and other antimycotic agents were risk factors for mucormycosis; BTK inhibitor could also be added as another novel risk factor. Despite all therapeutic efforts, the patient died. Post-mortem molecular exams confirmed the diagnosis of disseminated mucormycosis.

Primary cutaneous B-cell lymphomas (PCBCLs) constitute a rare subset of non-Hodgkin lymphoma (NHL), with distinctive clinical and biological characteristics. The risk of autoimmune or neoplastic comorbidities in subjects with NHL has been extensively reported in the literature, but the data available are not directly applicable to PCBCLs. The aim of our study was to determine the frequency of relevant medical conditions, with a primary focus on autoimmune and neoplastic disorders, in subjects with PCBCL. We performed a retrospective observational study involving 56 patients diagnosed histologically with PCBCL and 54 sex- and age-matched controls. Our results show a statistically significant association for neoplastic comorbidities in general (41.1% vs. 22.2%, p = 0.034) and hematological malignancies specifically (19.6% vs. 1.9%, p = 0.0041) with PCBCL compared to controls. We did not highlight a statistically significant difference in the frequency of autoimmune comorbidities (21.4% vs. 9.3%, p = 0.1128) and of chronic viral hepatitis (7.1% vs. 0, p = 0.1184). Finally, type 2 diabetes (19.6% vs. 1.9%, p = 0.0041) was significantly associated with PCBCL. Our preliminary data supporting the association between PCBCLs and neoplastic disorders suggest that altered immune surveillance may be a common predisposing mechanism.

Abstract Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals which could be associated with cancer development, such as kidney and testicular cancers, pancreatic and hepatocellular carcinoma and thyroid tumor. Available scientific literature offers no information on the role of PFAS in melanoma development/progression. Since 1965, a massive environmental contamination by PFAS has occurred in northeastern Italy. This study compared histopathology and prognosis between melanoma patients exposed (n = 194) and unexposed (n = 488) to PFAS. All patients were diagnosed and/or treated for melanoma at the Veneto Oncological Institute and the University Hospital of Padua (Italy) in 1998–2014. Patients were categorized in exposed or unexposed groups according to their home address and the geographical classification of municipalities affected by PFAS contamination as provided by Veneto Government in 2018. Presence of mitoses was found in 70.5% of exposed patients and 58.7% of unexposed patients (p = 0.005). Median follow-up was 90 months (IQR 59–136). 5-year overall survival was 83.7% in exposed patients and 88.0% in unexposed patients (p = 0.20); 5-year disease-specific survival was 88.0% in exposed patients and 90.9% in unexposed patients (p = 0.50); 5-year disease-free survival was 83.8% in exposed patients and 87.3% in unexposed patients (p = 0.20). Adjusting for imbalanced characteristics at baseline (presence of mitoses), survival was not statistically different between exposed and unexposed patients (overall survival: HR 1.10, 95% CI 0.77 to 1.58, p = 0.57; disease-specific survival: HR 0.99, 95% CI 0.62 to 1.59, p = 0.99; disease-free survival: HR 1.10, 95% CI 0.74 to 1.64, p = 0.62). Although the magnitude of PFAS exposure was not quantifiable, our findings suggested that exposure to PFAS was associated with higher level of mitosis in melanoma patients, but this did not translate into a survival difference. Further studies are required to investigate this relationship and all effects of PFAS on prognosis.

Background: A higher risk for COVID-19 infection and severity for men compared to women has been described since the beginning of the pandemic. The role of androgens has been recently highlighted as they control two key steps of coronavirus infection mediated through the transmembrane protease serin 2 (TMPRRS2) and the angiotensin-converting enzyme 2 (ACE2) receptor in the lung tissue. Furthermore, a high incidence of androgenic alopecia among males with COVID-19 disease have been reported.Objective: This study aims to evaluate the telogen effluvium (TE) prevalence and its relationship with clinical and immunologic parameters in a sample of patients consecutively evaluated after recovery from COVID-19 pneumonia in Northern Italy.Methods: Overall 104 patients were recruited within three months from COVID-19 pneumonia recovery; 80 (77%) had been hospitalized in a Respiratory Intensive Care Unit and the remaining ones had been treated at home. The extent of TE was assessed with a visual analogic scale for thick bundle of hairs. Demographic and clinical data and systemic inflammation biomarkers were also evaluated.Results. Thirty-two patients reported a history of TE and their mean TE-VAS score was 5.78 ± 1.72 (range 3–9). Women had about a 5-fold higher risk (odds) of complaining of TE compared to males (OR = 4.69, 95%CI: 1.91, 11.49; p = .001), and the association became stronger when adjusted for COVID-19 severity (hospital admission vs home care: OR = 6.09, 95%CI: 2.34, 15.88; p < .001). Levels of C-reactive protein >1.90 mg/l (ORadj: 2.43, 95%CI 0.85, 7.05, p = 0.096) or IL 1β > 5 ng/l (ORadj 4.72, 95%CI: 1.31, 23.19, p = .03) were also significantly associated with TE.Conclusion: This exploratory study raises the hypothesis that hair shedding is more strictly related to the severity of COVID-19 disease and the underlying inflammation rather than to patients' hormonal status. KEY MESSAGESThe presence of Telogen effluvium (TE) was significantly more common in women.Higher severity of the Covid-19 disease seems to play a critical role, more important than the hormonal influence, in the development of TE.The severity of inflammation related to TE and Covid-19 could also play a role as suggested by the higher levels of CRP and platelets and IL1β.

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Primary cutaneous B-cell lymphomas (PCBCLs) account for 25% of all cutaneous lymphomas: the main subtypes within this group are primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone B-cell lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Biopsy with histological examination and immunohistochemistry is the gold standard for the diagnosis of PCBCLs. A clinically oriented approach to PCBCLs classifies these entities according to their clinical behavior into indolent or intermediate to aggressive subtypes. While PCFCL and PCMZL are indolent diseases, PCDLBCL, LT has an aggressive course spreading to extracutaneous sites in approximately 45% of cases. Therefore, instrumental staging for extracutaneous disease is not performed following a diagnosis of PCMZL and PCFCL, while it is recommended for PCDLBCL, LT. Finally, dermatoscopy, under the guide of a strong clinical suspicion, may provide a novel diagnostic tool to enhance the clinical recognition of different subtypes of PCBCL.

The interleukins IL-4 and IL-13 are increasingly recognized contributors to the pathogenesis of cutaneous T cell lymphomas (CTCLs), and their role in disease-associated pruritus is accepted. The prevailing Th2 profile in advanced CTCL underscores the significance of understanding IL-4/IL-13 expression dynamics from the early stages of disease, as a shift from Th1 to Th2 may explain CTCL progression. Targeted agents blocking key cytokines of type 2 immunity are established therapeutics in atopic disorders and have a promising therapeutic potential in CTCL, given their involvement in cutaneous symptoms and their contribution to the pathogenesis of disease. IL-4, IL-13, and IL-31 are implicated in pruritus, offering therapeutic targets with dupilumab, tralokinumab, lebrikizumab, and nemolizumab. This review analyzes current knowledge on the IL-4/IL-13 axis in mycosis fungoides and Sezary syndrome, the most common types of CTCL, examining existing literature on the pathogenetic implications with a focus on investigational treatments. Clinical trials and case reports are required to shed light on novel uses of medications in various diseases, and ongoing research into the role of IL-4/IL-13 axis blockers in CTCL therapy might not only improve the management of disease-related pruritus but also provide in-depth insights on the pathophysiologic mechanisms of CTCL.

Rituximab is currently approved for patients affected by moderate-to-severe pemphigus vulgaris, a severe autoimmune blistering skin disease that can be life-threatening. The standard rituximab dosing regimens, originally established for B-cell non-Hodgkin’s lymphomas, have been recognized to exceed the effective dose required for inducing B-cell depletion, considering that the B-cell burden in pemphigus vulgaris is considerably lower than in lymphoproliferative disorders. We herein report our experience with very ultra-low-dose rituximab in two patients affected by pemphigus vulgaris.

Abstract Recently, the zebrafish has been established as one of the most important model organisms for medical research. Several studies have proved that there is a high level of similarity between human and zebrafish genomes, which encourages the use of zebrafish as a model for understanding human genetic disorders, including cancer. Interestingly, zebrafish skin shows several similarities to human skin, suggesting that this model organism is particularly suitable for the study of neoplastic and inflammatory skin disorders. This paper appraises the specific characteristics of zebrafish skin and describes the major applications of the zebrafish model in dermatological research.

Since the 1970s, human monkeypox (Mpox) has been referred to as a zoonotic endemic disease of specific regions of Africa until early 2022, when a worldwide epidemic outbreak developed. There are many hypotheses on how Mpox could spread to non-endemic regions; the dominant theory is that it spread from the UK and Spain among men who have sex with men (MSM). Therefore, the first clinical case in the Veneto region (Northeast of Italy) was analyzed—which represented a typical case report of the ongoing outbreak—with lesions located mainly in the areas associated with sexual behaviors (genital and oral). This case report highlights the new challenges of Mpox, as it seems to differ from the previous classic manifestation. Indeed, although the patient achieved restitution ad integrum of lesions and complete recovery from the disease, it is deemed necessary to offer communication strategies to involve a heterogeneous audience based on different risks of exposure but without stigmatizing attitudes, avoiding the mistakes made with HIV. The need for broad public involvement is demonstrated by identifying Mpox even in “anomalous cases.” Stigma could be an obstacle in engaging patients in proper care and in getting honest answers while contact tracing, as happened in our patient's case; thus, WHO recently renamed monkeypox as Mpox. Abnormal outbreaks in non-endemic countries, with no causal links, must become a warning signal for governments and health policies to design national plans for managing unexpected outbreaks. For an effective public health response, health institutions must communicate effectively, focus on changes and prevention measures, and formulate a plan based on equity and inclusion of the most vulnerable groups.

HLA class II molecules are key factors determining susceptibility to autoimmune disorders, and their role in immune-mediated skin conditions such as psoriasis has been extensively investigated. However, there is currently little understanding of their role in antibody-mediated skin diseases such as autoimmune blistering disorders. We researched the available literature using PubMed to narratively review the current knowledge on HLA associations in antibody-mediated blistering skin pathologies. Our results summarized the risk alleles that are identified in the literature, together with certain known protective alleles: in the pemphigus group, alleles HLA-DQB1*0503 and HLA-DRB1*0402 are most commonly associated with disease; in the pemphigoid group, the most studied allele is HLA-DQB1*0301; in epidermolysis bullosa acquisita, few genetic studies are available; in dermatitis herpetiformis, the association with haplotypes HLA-DQ2 and HLA-DQ8 is strongly established; finally, in linear IgA bullous disease, specific HLA alleles may be responsible for pediatric presentations. Our current pathogenic understanding of this group of disorders assigns a key role to predisposing HLA class II alleles that are able to bind disease autoantigens and therefore stimulate antigen-specific autoreactive T cells. The latter engage B lymphocytes that will produce pathogenic autoantibodies. The distribution of HLA alleles and their disease associations are variable across demographics, and an in-depth pathogenetic understanding is needed to support associations between HLA alleles and disease phenotypes. Additionally, in a personalized medicine approach, the identification of HLA alleles associated with the risk of disease may become clinically relevant in identifying susceptible subjects that should avoid exposure to known triggers, such as medication, when possible.

Immuno-mediated skin diseases are a common and clinically heterogeneous group of cutaneous conditions [...]

Introduction: Omalizumab has been recently registered as a third-line therapy for chronic spontaneous urticaria. Objectives: In this study, we aimed to provide real life data by reporting our experience with omalizumab in the treatment of chronic spontaneous urticaria. Methods: A retrospective data analysis was conducted on 40 patients affected by chronic spontaneous urticaria and treated with omalizumab at the Dermatology Unit of University of Padua, Italy.Demographic, anthropometric, and clinical data have been collected. Results: Overall, the majority of patients (23 patients, 57.5%) achieved complete recovery by taking omalizumab and 17.5% (7 patients) had a partial response. The majority of patients who did not have a response to omalizumab had a BMI> 25 kg/m2. Conclusions: Our study suggests that omalizumab is a safe and effective treatment for chronic spontaneous urticaria. We identified BMI as a critical biological factor that significantly impacts the outcomes of omalizumab treatment. Our findings also suggest a potential use of BMI as a predictive biomarker for omalizumab treatment. An updosing of omalizumab may be proposed in patients with high BMI to achieve a better control of the disease.

The introduction of monoclonal antibodies such as rituximab to the treatment of cancer has greatly advanced the treatment scenario in onco-hematology. However, the response to these agents may be limited by insufficient efficacy or resistance. Antibody–drug conjugates are an attractive strategy to deliver payloads of toxicity or radiation with high selectivity toward malignant targets and limited unwanted effects. Primary cutaneous lymphomas are a heterogeneous group of disorders and a current area of unmet need in dermato-oncology due to the limited options available for advanced cases. This review briefly summarizes our current understanding of T and B cell lymphomagenesis, with a focus on recognized molecular alterations that may provide investigative therapeutic targets. The authors reviewed antibody-directed therapies investigated in the setting of lymphoma: this term includes a broad spectrum of approaches, from antibody–drug conjugates such as brentuximab vedotin, to bi-specific antibodies, antibody combinations, antibody-conjugated nanotherapeutics, radioimmunotherapy and, finally, photoimmunotherapy with specific antibody–photoadsorber conjugates, as an attractive strategy in development for the future management of cutaneous lymphoma.

Psoriasis is a chronic immune-mediated inflammatory skin disease, characterized by well-demarcated scaly, erythematous, infiltrated plaques. The cutaneous-to-systemic expansion of the inflammation in psoriasis leads to the concept of “psoriatic march” or “inflammatory skin march”. Accordingly, psoriasis is thought to be a systemic inflammatory disease associated with numerous comorbidities. Indeed, it’s currently considered an independent risk factor for cardiovascular diseases. Here, we discuss the current knowledge on TNF-α and IL-23/IL-17 mediated pathways linking the psoriatic plaque to the cardiovascular compartment. We further argue the possible involvement of the endothelial compartment in the psoriatic plaque- cardiovascular system crosstalk.

BackgroundMerkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC.MethodsA retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens.Results143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor.ConclusionsAutoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient.

Introduction: Subjects with erythropoietic protoporphyria rely on broad-spectrum sunscreens with high sun protection factor, which is not informative on efficacy in the absorption spectrum of protoporphyrin IX, spanning visible radiation and peaking around 408 nm. Photoactivation of protoporphyrin IX is responsible for painful skin photosensitivity in erythropoietic protoporphyria.The authors assessed the protective efficacy of six sunscreens in vitro in the absorption spectrum of protoporphyrin IX.Method: Transmittance measurements were performed in the 300–850 nm wavelengths on samples of six photoprotective products applied to polymethyl methacrylate plates. Porphyrin protection factor was calculated in the 300–700 nm region to provide a measurement for the efficacy of each product based on the action spectrum of protoporphyrin IX.Results: Product A showed the highest porphyrin protection factor among tested products with a median value of 4.22. Product A is a sunscreen containing organic filters, titanium dioxide and synthetic iron oxides, pigmentary grade active ingredients that absorb visible radiation. Other products showed inefficient protection in the visible, with transmittance between 75 and 95% at 500 nm. The low porphyrin protection factor of inorganic filter product B was attributed to particle micronization, as declared by the manufacturer.Conclusion: Adding porphyrin protection factor to sunscreen labeling could help patients with erythropoietic protoporphyria and other photosensitivity disorders identify products tailored on their specific needs. The development of sunscreens providing protection from visible radiation and excellent cosmetical tolerability could improve the lifestyle of patients with erythropoietic protoporphyria.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignant tumor with neuroendocrine differentiation, with a rapidly growing incidence rate, high risk of recurrence, and aggressive behavior. The available therapeutic options for advanced disease are limited and there is a pressing need for new treatments. Tumors harboring fusions involving one of the neurotrophin receptor tyrosine kinase (NTRK) genes are now actionable with targeted inhibitors. NTRK-fused genes have been identified in neuroendocrine tumors of other sites; thus, a series of 76 MCCs were firstly analyzed with pan-TRK immunohistochemistry and the positive ones with real-time RT-PCR, RNA-based NGS, and FISH to detect the eventual underlying gene fusion. Despite 34 MCCs showing pan-TRK expression, NTRK fusions were not found in any cases. As in other tumors with neural differentiation, TRK expression seems to be physiological and not caused by gene fusions.

The “Veneto Cancer Registry” records melanoma as the most common cancer diagnosed in males and the third common cancer in females under 50 years of age in the Veneto Region (Italy). While melanoma is rare in children, it has greater incidence in adolescents and young adults (AYA), but literature offers only few studies specifically focused on AYA melanoma. The aim of this study was to describe the characteristics, surgical treatment, and prognosis of a cohort of AYA melanoma in order to contribute to the investigation of this malignancy and provide better patient care. This retrospective cohort study included 2,752 Caucasian patients (702 AYA and 2,050 non-AYA patients) from the Veneto Region who were over 15 years of age at diagnosis, and who received diagnosis and/or treatment from our institutions between 1998 and 2014. Patients were divided in adolescents and youth (15-25 years), young adults (26-39 years) and adults (more than 39 years) for the analysis. We found statistically significant differences in gender, primary site, Breslow thickness, ulceration, pathologic TNM classification (pTNM) stage and tumor subtype among the age groups. Disease-specific survival and disease-free survival were also different among the age groups. Our findings suggest that the biological behavior of melanoma in young people is different to that in adults, but not such as to represent a distinct pathological entity. Additional and larger prospective studies should be performed to better evaluate potential biological and cancer-specific differences between AYAs and the adult melanoma population.

In the field of advanced melanoma, there is an urgent need to investigate novel approaches targeting specific components of the cancer–immunity cycle beyond immune checkpoint inhibitors. The authors reviewed the basic understanding of the role of neutrophils in cancer biology, and the latest clinical evidence supporting the correlation between cancer-associated neutrophils and the prognosis and response to the immunotherapy of advanced melanoma. Finally, they propose that granulocyte and monocyte apheresis, an emerging non-pharmacological treatment in current dermatology, could become an investigative treatment targeting melanoma-associated neutrophils which could be potentially used in combination with the usual immune checkpoint inhibitors.

EGFR tyrosine kinase inhibitors (TKIs) are the front-line treatment in EGFR mutation positive advanced non-small cell lung cancer (aNSCLC) patients. Generally, they are well-tolerated but skin toxicity is common (45–100% of patients) and may adversely affect quality of life. Pathogenesis of cutaneous side effects is usually linked to EGFR expression in normal cells of the epidermis and not immune-related. Subacute cutaneous lupus erythematosus (SCLE) is an autoimmune disease and about 40% of SCLE cases are drug related, but no reports are available involving osimertinib. Our report depicts a drug induced-SCLE (DI-SCLE) caused by erlotinib and worsened by osimertinib. The adverse event is characterized by the absence of systemic symptoms. Diagnosis has been performed by skin biopsy and the conditions improved with systemic steroids administration and EGFR-TKIs discontinuation. The report underlines the importance of a complete dermatologic diagnosis of skin lesions induced by EGFR inhibitors, according to symptom severity and timing of improving with standard clinical management. The diagnosis of immune-related skin toxicity in this context affects the treatment and the outcome of skin toxicity and must be taken into account when planning subsequent treatments, potentially including immune checkpoint inhibitors (ICIs).

BackgroundMelanoma of unknown primary (MUP), accounts for up to 3% of all melanomas and consists of a histologically confirmed melanoma metastasis to either lymph nodes, (sub)cutaneous tissue, or visceral sites without any evidence of a primary cutaneous, ocular, or mucosal melanoma. This study aimed to investigate the characteristics, treatment strategies, and prognostic factors of MUP patients, in order to shed some light on the clinical behavior of this malignancy.MethodsAll the consecutive patients with a diagnosis of MUP referring to our institutions between 1985 and 2018 were considered in this retrospective cohort study. The records of 173 patients with a suspected diagnosis of MUP were retrospectively evaluated for inclusion in the study. Patient selection was performed according to the Das Gupta criteria, and a total of 127 MUP patients were finally included in the study, representing 2.7% of the patients diagnosed with melanoma skin cancer at our institutions during the same study period. A second cohort of all consecutive 417 MKP patients with AJCC stages IIIB–IV, referring tions in the period considered (1985–2018), was included in the study to compare survival between MUP and MKP patients. All the diagnoses were based on histopathologic, cytologic and immunohistochemical examination of the metastases. All tumors were re-staged according to the 2018 American Joint Committee on Cancer (AJCC) 8th Edition.ResultsMedian follow-up was 32 months (IQR: 15–84). 3-year progression-free survival (PFS) was 54%, while 3-year overall survival (OS) was 62%. Worse OS and PFS were associated with older age (P = 0.0001 for OS; P = 0.008 for PFS), stage IV (P < 0.0001 for OS; P = 0.0001 for PFS) and higher Charlson Comorbidity Index (P < 0.0001 for OS and P = 0.01 for PFS). Patients with lymph node disease showed longer PFS (P = 0.001) and OS (P = 0.0008) than those with (sub)cutis disease. Complete lymph node dissection (CLND) was the most common surgical treatment; a worse OS in these patients was associated with the number of positive lymph nodes (P = 0.01), without significant association with the number of retrieved lymph nodes (P = 0.79). Survival rates were lower in patients undergoing chemotherapy (CT) and target therapy (TT), and higher in those receiving immunotherapy (IT). 417 patients with AJCC stages IIIB–IV of Melanoma Known Primary (MKP) were included for the survival comparison with MUP. 3-year PFS rates were 54 and 58% in MUP and MKP, respectively (P = 0.30); 3-year OS rates were 62 and 70% in MUP and MKP, respectively (P = 0.40).ConclusionsThe most common clinical scenario of our series was a male patient around 59 years with lymph node disease. We report that CLND associated with IT was the best treatment in terms of survival outcome. In the current era of IT and TT for melanoma, new studies have to clarify the impact of novel drugs on MUP.

The incidence of cutaneous melanoma has been increasing in the last decades among the fair-skinned population. Despite its complex and multifactorial etiology, the exposure to ultraviolet radiation (UVR) is the most consistent modifiable risk factor for melanoma. Several factors influence the amount of UVR reaching the Earth’s surface. Our study aimed to explore the relationship between melanoma and altitude in an area with mixed geographic morphology, such as the Veneto region (Italy). We included 2752 melanoma patients who were referred to our centers between 1998 and 2014. Demographics, histological and clinical data, and survival information were extracted from a prospectively maintained local database. Head/neck and acral melanoma were more common in patients from the hills and the mountains, while limb and trunk melanoma were more common in patients living in plain and coastal areas. Breslow thickness, ulceration and mitotic rate impaired with increased altitude. However, the geographical area of origin was not associated with overall or disease-free survival. The geographical area of origin of melanoma patients and the “coast-plain-hill gradient” could help to estimate the influence of different sun exposure and to explain the importance of vitamin D levels in skin-cancer control.

In the complex pathogenesis of vitiligo, the exact mechanism of the dermatosis is still to be clarified. We previously demonstrated that a protein called melanoma inhibitory activity (MIA) is present in non-segmental vitiligo skin and seems to cause the detachment of melanocytes, consequently creating the depigmented macules. In this study, we present an animal model of vitiligo on the basis of the ability of the MIA protein to induce vitiligo-like lesions. Twenty pigmented mice were chosen for the experiments and received injections in the tail with saline (control group) or with saline + MIA protein (treated group). The control group did not show any sign of depigmentation. The treated group showed, instead, clear zones of complete depigmentation in the injected areas in each mouse, with the appearance of white patches with whitening of the hair and a clear-cut edge. Histological examination of the tail in the treated zone showed the absence of melanocytes, without the presence of any inflammatory cell or any sign of skin inflammation patterns, confirming the detachment of the melanocyte operated by the MIA protein. These data seem to confirm a possible role played by the MIA protein in the pathogenesis of vitiligo and may support the development of treatments able to inhibit its action as an alternative therapeutic strategy for this disorder.

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin. Due to its rarity, the management of MCC is not standardized across centers. In this article, we present the experience of the Veneto region in the North-East of Italy, where a committee of skin cancer experts has proposed a clinical pathway for the diagnosis and treatment of MCC. Putting together the evidence available in the international literature, we outlined the best approach to the management of patients affected with this malignancy step- by- step for each possible clinical situation. Crucial in this pathway is the role of the multidisciplinary team to deal with the lack of robust information on each aspect of the management of this disease.

Langerhans cells represent the first immune cells that sense the entry of external molecules and microorganisms at the epithelial level in the skin. In this pilot case-study, we evaluated Langerhans cells density and progression of epidermal atrophy in permanent spinal cord injury (SCI) patients suffering with either lower motor neuron lesions (LMNSCI) or upper motor neuron lesions (UMNSCI), both submitted to surface electrical stimulation. Skin biopsies harvested from both legs were analyzed before and after 2 years of home-based Functional Electrical Stimulation for denervated degenerating muscles (DDM) delivered at home (h-bFES) by large anatomically shaped surface electrodes placed on the skin of the anterior thigh in the cases of LMNSCI patients or by neuromuscular electrical stimulation (NMES) for innervated muscles in the cases of UMNSCI persons. Using quantitative histology, we analyzed epidermal thickness and flattening and content of Langerhans cells. Linear regression analyses show that epidermal atrophy worsens with increasing years of LMNSCI and that 2 years of skin electrostimulation reverses skin changes, producing a significant recovery of epidermis thickness, but not changes in Langerhans cells density. In UMNSCI, we did not observe any statistically significant changes of the epidermis and of its content of Langerhans cells, but while the epidermal thickness is similar to that of first year-LMNSCI, the content of Langerhans cells is almost twice, suggesting that the LMNSCI induces an early decrease of immunoprotection that lasts at least 10 years. All together, these are original clinically relevant results suggesting a possible immuno-repression in epidermis of the permanently denervated patients.

Abstract Background Nodular melanoma (NM) accounts for most thick melanomas and because of their frequent association with ulceration, fast growth rate and high mitotic rate, contribute substantially to melanoma-related mortality. In a multicentric series of 214 primary melanomas including 96 NM and 118 superficial spreading melanoma (SSM), histopathological features were examined with the aim to identify clinicopathological predictors of recurrence. Methods All consecutive cases of histopathologically diagnosed primary invasive SSM and NM during the period 2005–2010, were retrieved from the 12 participating Italian Melanoma Intergroup (IMI) centers. Each center provided clinico-pathological data such as gender, age at diagnosis, anatomical site, histopathological conventional parameters, date of excision and first melanoma recurrence. Results Results showed that NM subtype was significantly associated with Breslow thickness (BT) at multivariate analysis: [BT 1.01–2 mm (OR 7.22; 95% CI 2.73–19.05), BT 2.01–4 mm (OR 7.04; 95% CI 2.54–19.56), and BT > 4 mm (OR 51.78; 95% CI 5.65–474.86) (p 5 mitoses/mm2 (OR 4.87; 95% CI 1.77–13.40) (p = 0.002)]. The risk of recurrence was not significantly associated with NM histotype while BT [BT 1.01–2.00 mm (HR 1.55; 95% CI 0.51–4.71), BT 2.01–4.00 mm (HR 2.42; 95% CI 0.89–6.54), BT > 4.00 mm. (HR 3.13; 95% CI 0.95–10.28) (p = 0.05)], mitotic rate [MR > 2 mitoses/mm2 (HR 2.34; 95% CI, 1.11–4.97) (p = 0.03)] and the positivity of lymph node sentinel biopsy (SNLB) (HR 2.60; 95% CI 1.19–5.68) (p = 0.007) were significantly associated with an increased risk of recurrence at multivariate analysis. Conclusions We found that NM subtype was significantly associated with higher BT and MR but it was not a prognostic factor since it did not significantly correlate with melanoma recurrence rate. Conversely, increased BT and MR as well as SNLB positivity were significantly associated with a higher risk of melanoma recurrence.

Abstract Background Electrochemotherapy (ECT), by combining manageable cytotoxic agents with short electric pulses, represents an effective palliative skin-directed therapy. The accumulated evidence indicates that ECT stands out as a safe and well-tolerated alternative treatment for patients with multiple or large basal cell carcinoma (BCC), who are not suitable for conventional treatments. However, long-term data and shared indications are lacking. Methods In this observational study, we retrospectively analyzed 84 prospectively collected patients with multiple, recurrent or locally advanced BCC who were not candidate for standard therapies and received bleomycin-based ECT according to the European Standard Operative Procedures of ECT, from 2006 to 2016. Results Disease extent was local, locally advanced and metastatic in 40 (48%), 41 (49%) and 3 (3%), respectively. Forty-four (52%) individuals had multiple BCCs. Grade 3 skin toxicity after ECT was observed in 6% of cases. Clearance rate was 50% (95% CI 39–61%). Primary presentation (p = 0.004), tumor size

Psoriasis is a chronic immune-mediated inflammatory disease. Up to 40% of patients with psoriasis may develop psoriatic arthritis. Currently, interleukin (IL)-17/IL-23 pathways are identified as key factors in the immunopathogenesis of both conditions. Here we describe the case of a patient who developed psoriasiform skin lesions 10 months after the initiation of anti-IL17 therapy for psoriatic arthritis. The underlying disease had responded well to the therapy, but the patient developed a striking pustular eruption at the fingers with nail involvement, onycholysis, yellow discoloration, and subungual keratosis. Clinical and histological findings were consistent with an acrodermatitis continua of Hallopeau-like eruption. Skin lesions subsided after discontinuation of the responsible anti-IL17 agent. The interpretation of this paradoxical side effect of biological therapies remains unclear but may relate to an unbalanced inflammatory cytokine response induced by the inhibition of TNF activity. It is likely that patients, who are genetically prone, may respond exaggeratedly to a cytokine imbalance. The identification of this kind of patient, in the future, could be useful in order to choose the correct therapy.

Abstract In the original version of this article [1], published on 7 November 2017, affiliation 18 has been incorrectly assigned to the authors Serena Magi and Laura Mazzoni. They are only affiliated to the Skin Cancer Unit, Istituto Tumori Romagna (IRST), Meldola, Italy (affiliation 5).

Erosive pustular dermatosis of the scalp (EPDS) is a rare condition characterized by sterile pustules, erosions, and crusted lesions on the scalp of elderly patients. This inflammatory disorder has an unknown origin and it could develop into areas of alopecia that tend to be atrophic. An 84-year-old Caucasian man presented with a several months history of painful erythematous erosions and crusts on his scalp. The lesions appeared after treatment with imiquimod cream for actinic keratoses. Previous therapies included topical antibiotics and topical steroids. Physical examination revealed the presence of extensive erosions and crusts on the scalp, with minute pustules on the sides. The clinical features and the medical history led us to the diagnosis of EPDS. Treatment with systemic steroid was administered with improvement observed after ten days. The clinical manifestations of EPDS completely resolved after 2 months, without clinical relapses.

Sarcoidosis is a multisystemic inflammatory disorder with cutaneous lesions present in about one-quarter of the patients. Cutaneous lesions have been classified as specific and nonspecific, depending on the presence of nonnecrotizing epithelial cell granulomas on histologic studies. The development and progression of specific cutaneous sarcoidosis involves a complex interaction between cells of the adaptive immune systems, notably T-lymphocytes and dendritic cells. In this paper, we will discuss the role of T-cells and skin dendritic cells in the development of primary cutaneous sarcoidosis and comment on the potential antigenic stimuli that may account for the development of the immunological response. We will further explore the contributions of selected cytokines to the immunopathological process. The knowledge of the adaptive immunological mechanisms operative in cutaneous sarcoidosis may subsequently be useful for identifying prevention and treatment strategies of systemic sarcoidosis.