Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

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.

Concordance of in vivo reflectance confocal microscopy and horizontal-sectioning histology in skin tumours.

BACKGROUND: In vivo reflectance confocal microscopy (RCM) enables the study of architectural and cytological aspects in horizontal sections, which closely correlate with histologic features. However, traditional histopathological vertical sections cannot totally reproduce the image of the in vivo RCM horizontal section. OBJECTIVE: To evaluate the concordance between in vivo RCM and histopathologic transverse sections for melanocytic lesions, basal cell carcinoma and seborrheic keratoses. METHODS: Prospectively collected benign melanocytic and non-melanocytic tumours diagnosed by dermoscopy were evaluated for common RCM features and compared to histopathology in horizontal sections with haematoxylin and eosin staining. RESULTS: A total of 44 skin tumours including 19 melanocytic lesions (nine compound, five junctional and five intradermal nevi), 12 basal cell carcinomas and 13 seborrheic keratoses were collected in the Department of Dermatology of Hospital Clinic of Barcelona. The RCM features that had statistically significant agreement with the histopathological horizontal sections were the preserved and visible honeycomb pattern, well defined DEJ, small bright particles, dermal nests, tumour islands and dark silhouettes, clefting, collagen bundles, thickened collagen bundles and cytologic atypia. CONCLUSIONS: Histopathology evaluation of horizontal sections of skin tumours can be correlated with main RCM findings. The results of this study have improved the understanding and interpretation of RCM features in relation to skin tumours, thus reinforcing the utility of RCM as a diagnostic tool.

Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

Surgery after sonidegib treatment achieves complete response in locally advanced basal cell carcinoma of the face.

Basal cell carcinoma accounts for 75% of skin cancers worldwide and is the most common malignancy in Caucasians. Since chronic ultraviolet exposure is the major risk factor for its development, sun-exposed areas such as the face are frequently affected. The gold-standard treatment is surgical excision. Radiotherapy may be considered in selected cases such as unresectable primary tumors. In some patients, when the risk of a significant functional/cosmetic deficit advises against both surgery and radiotherapy, target therapy (hedgehog pathway inhibitors) can be administered alone or in a neoadjuvant setting, to reduce the tumor size and make it eligible for surgery. Vismodegib as a neoadjuvant treatment before surgery has been investigated in a single, multicentre, open-label, phase II trial (VISMONEO); however, sonidegib has not yet been evaluated in this setting. We report the cases of two patients with locally advanced basal cell carcinoma of the face who achieved complete remission with sonidegib followed by a more limited surgical excision than would have been needed without target therapy.

Gender differences in adult atopic dermatitis and clinical implication: Results from a nationwide multicentre study.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease that affects both children and adults. However, limited research has been conducted on gender differences in AD. OBJECTIVES: This study aimed to assess gender differences in adult AD patients, focusing on demographic and clinical features, comorbidities and treatment approaches. METHODS: In this multicentre, observational, cross-sectional study, we enrolled 686 adult patients with AD (357 males and 329 females). For each patient, we collected demographic data (age and sex), anthropometric measurements (weight, height, hip circumference, waist circumference and waist-to-hip ratio), clinical information (onset age, disease duration, severity, itching intensity, impact on quality of life) and noted comorbidities (metabolic, atopic and other). We recorded past and current topical and systemic treatments. We analysed all collected data using statistical techniques appropriate for both quantitative and qualitative variables. Multiple correspondence analysis (MCA) was employed to evaluate the relationships among all clinical characteristics of the patients. RESULTS: We found no differences in age at onset, disease duration, severity and quality of life impact between males and females. Males exhibited higher rates of hypertriglyceridaemia and hypertension. No significant gender differences were observed in atopic or other comorbidities. Treatment approaches were overlapping, except for greater methotrexate use in males. MCA revealed distinct patterns based on gender, disease severity, age of onset, treatment and quality of life. Adult males with AD had severe disease, extensive treatments and poorer quality of life, while adult females had milder disease, fewer treatments and moderate quality of life impact. CONCLUSIONS: Our study reveals that gender differences in adult AD patients are largely due to inherent population variations rather than disease-related disparities. However, it highlights potential undertreatment of females with moderate AD and quality of life impact, emphasizing the need for equitable AD treatment. JAK inhibitors may offer a solution for gender-based therapeutic parity.

Current treatment goals are achieved by the majority of patients with atopic dermatitis treated with tralokinumab: results from a multicentric, multinational, retrospective, cohort study.

BACKGROUND: Tralokinumab is a human monoclonal antibody targeting interleukin-13 that is approved for the treatment of moderate-severe atopic dermatitis. Studies analyzing the efficacy and safety of tralokinumab in a real-world setting are scarce. RESEARCH DESIGN AND METHODS: A European, multicentric, real-world, retrospective cohort study was defined to assess the effectiveness and safeness profile of tralokinumab, investigating the achievement of pre-specified treatment goals; and to detect potential differences in terms of effectiveness and safeness across some selected patient subcohorts. RESULTS: A total of 194 adult patients were included in this study. A significant improvement in physician-assessed disease severity was detected at each follow-up visit as compared with baseline and similar trend was observed for patient-reported outcomes and quality of life. No meaningful difference in effectiveness was found when considering patient age (<65 versus ≥65 years), neither dissecting patient cohort in dupilumab-naive vs dupilumab-treated subjects. Among tralokinumab-treated patients, 88% achieved at least one currently identified real-world therapeutic goal at week 16. CONCLUSIONS: This retrospective multicenter study confirmed the effectiveness and safeness of tralokinumab throughout 32 weeks of observation, showing the achievement of therapeutic goals identified in both trial and real-world settings in a large proportion of tralokinumab-treated patients.

Guidelines for the diagnosis and treatment of basal cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

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.

High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Dupilumab-associated ocular adverse events are predicted by low tear break-up time and correlate with high IL-33 tear concentrations in patients with atopic dermatitis.

Dupilumab, blocking IL-4 and IL-13 signals, improves atopic dermatitis and Quality of Life but might be also associated with the occurrence of ocular adverse events (OAEs). The main objective of our prospective study was to characterize the cytokine and chemokine profile in the tear fluid of dupilumab-treated patients with moderate-to- severe atopic dermatitis and to identify biomarkers predicting the occurrence of ocular adverse events. Patients with moderate-to-severe AD underwent dermatological and ophthalmological evaluation at the baseline (T0) and week 16 or at the time of an eventual ocular adverse events (T1). A multiplex immunoassay measuring multiple cytokines and chemokines in the tear fluid extracted during ocular examination at both T0 and T1 was performed. Thirty-nine patients with moderate-to-severe AD and treated with dupilumab were included in the study. Baseline tear fluid levels revealed a significantly higher concentration of type 2 cytokines and chemokines in AD patients than healthy controls. The occurrence of ocular adverse events during dupilumab therapy was associated with a significant increase of IL-33 tear fluid levels and a significantly lower tear break-up time, this latter also identified as predictive factor. Our findings suggest that the ophthalmological examination should be considered a valid support to identify patients at risk of developing OAEs and to provide their appropriate management.

Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients-The European MelSkinTox study.

BACKGROUND: Checkpoint inhibitors provide an effective approach for the melanoma treatment. They prolong lymphocyte effects, which explains the cytotoxicity underlying immune-related adverse events (IrAEs). Cutaneous IrAEs affect nearly 40% of PD-1i and 50% of CTLA4i-treated patients. Severe cutaneous irAE do not often occur but could be life-threatening and may persist despite treatment discontinuation. METHODS: We aimed to investigate cutaneous IrAEs in a cohort of patients treated with ICI across Europe in an effort to characterize the reactions in a real-world, phase IV, post-marketing study using a follow-up questionnaire. Data since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow-up of melanoma and cutaneous adverse events, supported by EADO. The dermatoses reported were pooled into four categories: inflammatory dermatosis, bullous diseases, drug-related eruptions and pigmentary diseases. RESULTS: Inflammatory benign dermatoses (n = 63) represented the most common group of reactions (52.5%), followed by drug-related eruptions (n = 24, 20%), pigmentary diseases (n = 23, 19.2%) and bullous diseases (n = 10, 8.3%). Grade II (n = 41, 34.2%) are represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis-like rash, urticarial eruption and vitiligo. Grade III (n = 18, 15.0%) are represented by bullous pemphigoid, lichenoid eruption and rashes. Grade IV (n = 2, 1.7%) is only represented by bullous disease. Most cutaneous IrAEs led to immunotherapy continuation (n = 95, 88.0%). CR is associated with more severe the cutaneous irAEs. We report an average time-to-onset of 208 days and some late-onset events. CONCLUSION: Our study has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. Grade I-II cutaneous IrAE are easily managed allowing ongoing anticancer treatment. Severe late-onset cutaneous irAE are not uncommon. A dermatological follow-up helps mitigate the risk of life-threatening adverse events. These findings highlight the importance of oncodermatological involvement in management of patients with melanoma receiving immunotherapy.

Line-field confocal optical coherence tomography of cutaneous vascular lesions: Morphological assessment and histopathological correlations.

BACKGROUND: Cutaneous vascular lesions (VLs) are benign or malignant processes involving blood and/or lymphatic vessels, usually readily diagnosed with dermoscopy. However, cases showing unclear clinical/dermoscopic findings may require further investigations. Line-field confocal optical coherence tomography (LC-OCT) is a new, non-invasive imaging technique displaying high resolution and deep penetration. The aim of this study was to describe the LC-OCT features of the most common benign and malignant VLs and to correlate them with histopathological substrates. METHODS: Clinical, dermoscopic, LC-OCT and histopathological images of VLs were retrospectively collected. Detailed LC-OCT description and histopathological correlations were produced for different types of VLs. RESULTS: The study included 71 VLs belonging to 50 caucasian patients [31 (62%) females; median age 56.8 (30-83) years] study lesions included 25 cherry haemangiomas, 15 angiokeratomas, 10 thrombosed haemangiomas, six pyogenic granulomas, five venous lakes, four targetoid haemosiderotic haemangiomas, four Kaposi's sarcomas and two extraungual glomus tumours. LC-OCT detected increased dermal vascularity, assuming different size and shape according to the particular type of VLs. LC-OCT criteria correlated well to established histopathologic findings. CONCLUSION: The results of our preliminary observations indicate that in vivo evaluation with LC-OCT may provide practical clues for the identification of the vascular nature of a lesion and its differential diagnosis.

Real-life experience with ixekizumab in plaque psoriasis: a multi-center, retrospective, 3-year study.

BACKGROUND: Confirmatory data on the long-term effectiveness and safety of ixekizumab in psoriatic patients from real-world studies are needed. OBJECTIVES: The primary aim was to evaluate the 3-year drug survival of ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis, in a multicenter real-world setting. The secondary aim was to assess the influence of predictive factors on the drug survival of ixekizumab. METHODS: A retrospective analysis was performed on a cohort of patients with chronic plaque psoriasis, who received at least one dose of ixekizumab before December 2018. The drug survival analysis was performed and descriptively analyzed using Kaplan-Meier survival curves. Multivariable Cox regression analyses were carried out including variables considered to be of clinical importance. RESULTS: A total of 306 patients were enrolled. The overall drug survival at 12, 24, and 36 months of treatment with ixekizumab was 92.11%, 83.85%, and 80.19%, respectively. A higher probability (HR 2.34) of drug withdrawal was found among patients who had already received an anti-IL-17 agent compared with bio-naive patients (p 0.017). CONCLUSIONS: We found that ixekizumab is a biological agent characterized by long-term effectiveness, not influenced by several clinical factors and associated with a good safety profile.

Moderate-to-severe atopic dermatitis in adolescents treated with dupilumab: A multicentre Italian real-world experience.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) in the adolescence is a high burden disease, and its treatment can be very challenging due to paucity of approved systemic drugs for this age and their side-effects. Dupilumab was recently approved for treatment of adolescent AD. OBJECTIVES: A multicentre, prospective, real-world study on the effectiveness and safety of dupilumab in adolescents (aged from ≥12 to <18 years) with moderate-to-severe AD was conducted. The main AD clinical phenotypes were also examined. METHODS: Data of adolescents with moderate-to-severe AD treated with dupilumab at label dosage for 16 weeks were collected. Treatment outcome was assessed by EASI, NRS itch, NRS sleep loss and CDLQI scores at baseline and after 16 weeks of treatment. The clinical scores were also evaluated according to clinical phenotypes. RESULTS: One hundred and thirty-nine adolescents were enrolled in the study. Flexural eczema and head and neck eczema were the most frequent clinical phenotypes, followed by hand eczema and portrait-like dermatitis. Coexistence of more than 1 phenotype was documented in 126/139 (88.5%) adolescents. Three patients (2.1%) contracted asymptomatic SARS-CoV-2 infection and 1 of the discontinued dupilumab treatment before the target treatment period. A significant improvement in EASI, NRS itch, NRS sleep loss and CDLQI was observed after 16 weeks of treatment with dupilumab. This outcome was better than that observed in clinical trials. Dupilumab resulted effective in all AD phenotypes, especially in diffuse eczema. Twenty-eight (20.1%) patients reported adverse events, conjunctivitis and flushing being the most frequent. None of patients discontinued dupilumab due to adverse event. CONCLUSIONS: Dupilumab in adolescent AD showed excellent effectiveness at week 16 with consistent improvement of all clinical scores. Moreover, dupilumab showed a good safety profile also in this COVID-19 pandemic era.

The role of postoperative radiotherapy in eccrine porocarcinoma: a multidisciplinary systematic review.

OBJECTIVE: Eccrine porocarcinoma (EPC) is a malignant adnexal tumor accounting for about 0.005% of skin tumors. The standard treatment of EPC is the complete surgical excision of the primary lesion and of the clinically involved lymph nodes. There is limited evidence regarding the role of radiotherapy (RT) in managing EPC after surgery. Therefore, the aim of this multidisciplinary systematic review is to analyze the available evidence about postoperative RT in the curative treatment of EPC. MATERIALS AND METHODS: A systematic search strategy was launched trough the main scientific databases including PubMed, Scopus and Cochrane. An additional manual search and a chain citation were performed about potentially relevant papers. The key words used for the search included "eccrine porocarcinoma", "porocarcinoma", "radiotherapy", "radiation therapy", "adjuvant radiotherapy" and "postoperative radiotherapy". RESULTS: A total of 104 publications were identified and 14 papers were included in the final analysis. The only articles found on adjuvant RT in EPC were case reports published between 1996 and 2019. There was a slight female prevalence (57% female/43% male) with a mean age of 65 years (range 37-85). Head-and-neck region was the most frequently involved anatomical site followed by legs. CONCLUSIONS: Adjuvant radiotherapy after surgical removal of EPC could be considered in cases with positive or close margins and in cases with unfavorable histological features. In view of limited literature data and the rarity of EPC the best treatment sequence should always be discussed within the frame of a multidisciplinary setting. ADVANCES IN KNOWLEDGE: adjuvant radiotherapy after surgical removal of EPC could be considered in cases with positive or close margins and in cases with unfavorable histological features.

Line-field confocal optical coherence tomography of basosquamous carcinoma: a case series with histopathological correlation.

BACKGROUND: Basosquamous carcinoma (BSC) is a rare and potentially aggressive cutaneous neoplasm combining histopathological features of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Line-field confocal optical coherence tomography (LC-OCT) is a new, non-invasive imaging technique featuring excellent resolution and penetration. To date, studies about the use of LC-OCT in the BCC and SCC fields are available, but similar investigations are lacking in the BSC field. OBJECTIVE: The goal of the present study was to identify/describe LC-OCT criteria of BSC. METHODS: Consecutively enrolled BSCs were imaged with dermoscopy and LC-OCT prior to surgical excision. Dermoscopic and LC-OCT images were evaluated, and histopathological slides were reviewed. RESULTS: Six BSCs from six patients [four (66.7%) males and two (33.3%) females; mean age 76.5 (62-96) years] were included. Identified LC-OCT criteria for BSC included BCC-associated (dermal lobules with millefeuille pattern, dilated vessels, bright cells within the epidermis, bright cells within lobules, stromal stretching, stromal brightness) and SCC-associated features (acanthosis, hyperkeratosis, disarranged epidermal architecture, broad strands, elastosis and glomerular vessels). Interruption of the dermal-epidermal junction and ulceration represented overlapping criteria. CONCLUSION: Line-field confocal-OCT is a new promising technique that may support the non-invasive recognition of BSC through the simultaneous detection of BCC-associated and SCC-associated features. We hypothesize that the use of LC-OCT might be helpful not only in the diagnostic setting but also in the follow-up surveillance for an early identification of recurrences. Further larger studies are needed to prove this hypothesis.

Treatment approaches of advanced cutaneous squamous cell carcinoma.

Common primary cutaneous squamous cell carcinoma (CSCC) accounts for 20% of keratinocyte cancers that is usually successfully treated with surgery or radiotherapy. In a minority of cases, CSCC lesions may progress to locally advanced or metastatic disease that may be difficult to be treated causing significant morbidity and mortality. Chemotherapies and targeted therapy with anti-epidermal growth factor receptor antibodies have been used off-label in small studies and case reports of advanced CSCC, but data are scarce and response short-lived. Recently, two PD-1 immune checkpoint inhibitors, cemiplimab and pembrolizumab, have been approved for the treatment of advanced CSCC; specifically the former can be administered in patients with locally advanced and metastatic tumours, while the latter in case of recurrent metastatic CSCC. The introduction of immune checkpoint inhibitors represents a breakthrough in the treatment of CSCC, since numerous clinical trials showed that these agents may provide remarkable clinical benefit with an acceptable safety profile, in a high-need population who had no standard of care. In addition, real-world studies are needed to validate the results observed in clinical trials and numerous clinical trials in the neoadjuvant or adjuvant setting are ongoing. Finally, further studies should investigate predictive biomarkers useful to better select patients to maximize the treatment efficacy.