Diagnosis of invasive cutaneous squamous cell carcinoma, imaging and staging.

The assessment of patients with a lesion raising the suspicion of an invasive cutaneous squamous cell carcinoma (cSCC) is a frequent clinical scenario. The management of patients with cSCC is a multistep approach, starting with the correct diagnosis. The two main diagnostic goals are to differentiate from other possible diagnoses and correctly recognize the lesion as cSCC, and then to determine the tumor spread (perform staging), that is if the patient has a common primary cSCC or a locally advanced cSCC, or a metastatic cSCC (with in-transit, regional lymph nodal, or rarely distant metastasis). The multistep diagnostic approach begins with the clinical characteristics of the primary cSCC, it is complemented with features with dermoscopy and, if available, reflectance confocal microscopy and is confirmed with histopathology. The tumor spread is assessed by physical examination and, in some cases, ultrasound and/or computed tomography or magnetic resonance imaging, mainly to investigate for regional lymph node metastasis or for local infiltration into deeper structures. In the last step, the clinical, histologic and radiologic findings are incorporated into staging systems.

A retrospective study of diameter and Breslow thickness in invasive melanomas.

INTRODUCTION: A diameter larger than 6 millimeters is included in the criteria used in public health messages to detect a cutaneous melanoma. We aim to investigate the independent association of Breslow thickness with the melanoma diameter. METHODS: A retrospective study was performed in patients with invasive melanomas of the nodular melanoma or superficial spreading melanoma subtype. The quartiles of the diameter (lower, median, upper) were studied in non-parametric quantile regression model. RESULTS: In total, 537 cases of invasive melanomas were included and 60% had Breslow thickness ≤ 1.0 mm. There were 429 SSM (79.9%) and 108 NM (20.1%). Although NMs were significantly thicker (median Breslow thickness: 2.7 mm versus 0.7 mm respectively, p<0.0001), they were not associated with larger diameter compared to SSMs (p:0.71). After adjustment for age and sex, melanoma location and subtype, having Breslow thickness ≤ 1.0 mm was not significantly associated with the lower quartile, median and upper quartile of the diameter (p-values: 0.063, 0.083, and 0.791, respectively). CONCLUSION: In our study including melanomas of the NM or SSM subtype, Breslow thickness was not associated with the diameter, adding evidence to support the limitations of using diameter larger than 6 mm for the detection of invasive melanomas and indicating the potential of smaller melanomas to be thicker tumors.

Expert Agreement on the Presence and Spatial Localization of Melanocytic Features in Dermoscopy.

Dermoscopy aids in melanoma detection; however, agreement on dermoscopic features, including those of high clinical relevance, remains poor. In this study, we attempted to evaluate agreement among experts on exemplar images not only for the presence of melanocytic-specific features but also for spatial localization. This was a cross-sectional, multicenter, observational study. Dermoscopy images exhibiting at least 1 of 31 melanocytic-specific features were submitted by 25 world experts as exemplars. Using a web-based platform that allows for image markup of specific contrast-defined regions (superpixels), 20 expert readers annotated 248 dermoscopic images in collections of 62 images. Each collection was reviewed by five independent readers. A total of 4,507 feature observations were performed. Good-to-excellent agreement was found for 14 of 31 features (45.2%), with eight achieving excellent agreement (Gwet's AC >0.75) and seven of them being melanoma-specific features. These features were peppering/granularity (0.91), shiny white streaks (0.89), typical pigment network (0.83), blotch irregular (0.82), negative network (0.81), irregular globules (0.78), dotted vessels (0.77), and blue-whitish veil (0.76). By utilizing an exemplar dataset, a good-to-excellent agreement was found for 14 features that have previously been shown useful in discriminating nevi from melanoma. All images are public (www.isic-archive.com) and can be used for education, scientific communication, and machine learning experiments.

Immunotherapy and Its Timing in Advanced Basal Cell Carcinoma Treatment.

For patients with advanced basal cell carcinoma (BCC), including locally advanced or metastatic BCC not amenable to curative surgery or radiotherapy, hedgehog pathway inhibitors (HHI) vismodegib and sonidegib are approved as first-line systemic treatment. Results from clinical trials highlight that the overall discontinuation rate of HHI treatment varies from 88% to 92% with vismodegib and is approximately 92% with sonidegib, and half of patients will discontinue HHI after approximately 8 to 12 months. The main factors weighing in on the decision to discontinue HHI include efficacy (tumor response), adverse events and patient decision. In clinical practice, some of the patients that stop HHI may be re-evaluated if the tumor becomes amenable to surgery, or restart HHI at a later time, while others will need to switch to immunotherapy, depending on the reasons for HHI discontinuation. In this review, we revisit the therapeutic decisions considering a switch from HHI to immunotherapy with anti-PD-1 agent cemiplimab and we highlight the place of cemiplimab in the therapeutic ladder for patients with advanced BCC. We discuss the evidence on the efficacy and safety of anti-PD-1 agents as second-line systemic monotherapy, or in combination with other treatments, and the emergence of checkpoint immunotherapy as a neoadjuvant treatment.

European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma. Part 1: Diagnostics and prevention-Update 2023.

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in white populations, accounting for 20% of all cutaneous malignancies. Overall, cSCC mostly has very good prognosis after treatment, with 5-year cure rates greater than 90%. Despite the overall favourable prognosis and the proportionally rare deaths, cSCC is associated with a high total number of deaths due to its high incidence. A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV) and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update recommendations on cSCC, based on current literature and expert consensus. Part 1 of the guidelines addresses the updates on classification, epidemiology, diagnosis, risk stratification, staging and prevention in immunocompetent as well as immunosuppressed patients.

European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma: Part 2. Treatment-Update 2023.

In order to update recommendations on treatment, supportive care, education, and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV), and the European Organisation of Research and Treatment of Cancer (EORTC) was formed. Recommendations were based on an evidence-based literature review, guidelines, and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic cSCC. For common primary cSCC, the first-line treatment is surgical excision with postoperative margin assessment or micrographically controlled surgery. Achieving clear surgical margins is the most important treatment consideration for patients with cSCCs amenable to surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with clear surgical margins, current evidence has not shown significant benefit for those with at least one high-risk factor. Radiotherapy should be considered as the primary treatment for non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed regional nodal metastasis, lymph node dissection is recommended. For patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drugs Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC, include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiotherapy. Multidisciplinary board decisions are mandatory for all patients with advanced cSCC, considering the risks of toxicity, the age and frailty of patients, and co-morbidities, including immunosuppression. Patients should be engaged in informed, shared decision-making on management and be provided with the best supportive care to improve symptom management and quality of life. The frequency of follow-up visits and investigations for subsequent new cSCC depends on underlying risk characteristics.

Clinical and Dermoscopic Findings of Nevi after Photoepilation: A Review.

Atypical clinical and dermoscopic findings, or changes in pigmented melanocytic lesions located on body areas treated with lasers or intense pulsed light (IPL) for hair removal (photoepilation), have been described in the literature. There are three prospective studies in a total of 79 individuals with 287 melanocytic nevi and several case reports reporting the dermoscopic findings and changes after photoepilation. Clinical changes have been reported in 20-100% of individuals, while dermoscopic changes have been observed in 48% to 93% of nevi. More frequent dermoscopic changes included bleaching, the development of pigmented globules, and irregular hyperpigmented areas and regression structures, including gray areas, gray dots/globules, and whitish structureless areas. The diagnostic approach for pigmented lesions with atypical dermoscopic findings and changes after photo-epilation included reflectance confocal microscopy, sequential digital dermoscopy follow-up, and/or excision and histopathology. Challenges pertaining to these diagnostic steps in the context of photoepilation include the detection of findings that may warrant a biopsy to exclude melanoma (ugly duckling, irregular hyperpigmented areas, blue-gray or white areas, and loss of pigment network), the potential persistence of changes at follow-up, and that a histopathologic diagnosis may not be possible due to the distortion of melanocytes or complete regression of the lesion. Furthermore, these diagnostic approaches can be time-consuming, require familiarization of the physician with dermoscopic features, may cause anxiety to the individual, and highlight that avoiding passes of the laser or IPL devices over pigmented lesions is key.

Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.

The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.

European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.

Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients" International Study.

BACKGROUND: The introduction of cyclin-dependent kinase inhibitors (CDK4/6i) was a great advance in therapeutics for patients with estrogen receptor+/human epidermal growth factor receptor (HER2) locally advanced and metastatic breast cancer. Despite the increasing use of these agents, their adverse drug-related events have not yet been fully characterized. We describe the spectrum of cutaneous adverse reactions occurring in advanced breast cancer patients treated with cyclin-dependent kinase inhibitors, analyzing types, severity, time to onset, and possible treatment outcomes. METHODS: We performed a multicentric retrospective study including patients with advanced breast cancer who developed cutaneous lesions during treatment with CDK4/6i in the period from June 2020 to June 2021. Patients > 18 years were recruited at eleven onco-dermatology units located in Albania (1), Argentina (1), France (1), Greece (3), Italy (3), and Spain (2). We evaluated patients' epidemiological and clinical characteristics, types of cutaneous adverse events, their time to onset, and treatment outcomes. The severity of the skin reactions was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 score. RESULTS: Seventy-nine patients (median age: 62.3 years; range 39-83 years) were included in the study, and, collectively, we recorded a total of 165 cutaneous adverse events during follow-up visits. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and eczematous lesions (24/79). Cutaneous toxicities were usually mild in severity (>65%) and occurred after a median of 6.5 months. Only four patients (5%) required treatment discontinuation due to the severity of the skin lesions. The majority of the skin reactions were managed with topical treatments. CONCLUSIONS: To the best of our knowledge, we present the largest case series of cutaneous adverse events developing in advanced breast cancer patients treated with CDK4/6i. We showed that cutaneous toxicities are usually mild in severity, and manageable with standard supportive care; however, in selected cases, they can lead to treatment discontinuation with possible implications for patients' clinical outcomes.

The Association of Nevus-Associated Melanoma with Common or Dysplastic Melanocytic Nevus: A Systematic Review and Meta-Analysis.

Background: Cutaneous melanoma has an adjacent nevus remnant upon histological examination in 30% of cases (nevus-associated melanoma, NAM), while it appears de novo for 70% of tumors. Regarding NAM arising in acquired melanocytic nevus, currently there is no evidence on whether NAM more frequently develops in association with a dysplastic or common melanocytic nevus. Objectives: To conduct a systematic review and meta-analysis to investigate the proportion of dysplastic or common melanocytic nevus in NAM associated with acquired nevus. Methods: A systematic literature search is conducted using PubMed, Scopus, and the Cochrane Library. The PRISMA checklist is used. Studies reporting patients diagnosed with NAM arising in an acquired common or dysplastic melanocytic nevus are included. A meta-analysis of proportions is performed using the random-effects model. The magnitude of heterogeneity is assessed with the I2 statistic. Results: A total of 22 studies with 2174 NAMs with an acquired nevus (dysplastic or common) are included. The proportion of dysplastic nevus in NAM varies considerably in the included studies, ranging from 0% to 100%. In the meta-analysis, the overall estimate of the proportion of having a dysplastic nevus in NAM is 51% (95% CI: 39-63%) with high heterogeneity at I2: 95.8% (p < 0.01). A sensitivity meta-analysis of 12 studies that included 30 or more acquired nevus-NAMs (2023 cases) shows that 65% of the NAMs developed in a dysplastic nevus (95% CI: 51-77%). In a meta-analysis of 4 studies reporting invasive-only acquired nevus-NAMs (764 cases), the proportion of dysplastic nevus is 56% (95% CI: 36-75%). Only 2 studies are found reporting in situ NAMs with an acquired nevus, and the pooled estimated proportion of dysplastic nevus is 71% (95% CI: 63-78%). Conclusions: The results of this meta-analysis suggest a higher proportion of dysplastic nevus in acquired nevus-NAM; however, there is considerable uncertainty and high heterogeneity, highlighting the need for future well-designed studies with uniform histopathological definitions for dysplastic nevus remnants which report the type of nevus in NAM separately for invasive melanomas, thin tumors, and by histological subtype.

A dermatologic assessment of 101 mpox (monkeypox) cases from 13 countries during the 2022 outbreak: Skin lesion morphology, clinical course, and scarring.

BACKGROUND: In the 2022 mpox (monkeypox) outbreak, 79,000 global cases have been reported. Yet, limited dermatologic data have been published regarding lesion morphology and progression. OBJECTIVE: The objective of this study was to characterize skin lesion morphology, symptomatology, and outcomes of mpox infection over time. METHODS: The American Academy of Dermatology/International League of Dermatological Societies Dermatology COVID-19, Mpox, and Emerging Infections Registry captured deidentified patient cases of mpox entered by health care professionals. RESULTS: From August 4 to November 13, 2022, 101 cases from 13 countries were entered, primarily by dermatologists (92%). Thirty-nine percent had fewer than 5 lesions. In 54% of cases, skin lesions were the first sign of infection. In the first 1-5 days of infection, papules (36%), vesicles (17%), and pustules (20%) predominated. By days 6-10, pustules (36%) were most common, followed by erosions/ulcers (27%) and crusts/scabs (24%). Crusts/scabs were the predominant morphology after day 11. Ten cases of morbilliform rash were reported. Scarring occurred in 13% of the cases. LIMITATIONS: Registry-reported data cannot address incidence. There is a potential reporting bias from the predilection to report cases with greater clinical severity. DISCUSSION: These findings highlight differences in skin findings compared to historical outbreaks, notably the presence of skin lesions prior to systemic symptoms and low overall lesion counts. Scarring emerged as a major possible sequela.

Epidemiological trends in cutaneous lymphomas in Greece.

Primary cutaneous lymphomas (PCLs) are a heterogenous group of non-Hodgkin lymphomas arising in the skin from T- or B-lymphocytes, for which there is limited epidemiological data available. To describe the disease characteristics and estimate annual incidence rates (IRs) and temporal trends of PCLs and their subtypes in Attica, Greece. A retrospective analysis of all PCL patients, diagnosed in Attica's main haemopathology referral centre from 2009 to 2021, was conducted. In total, 1,189 patients were included; 725 males and 464 females (males__females=1.56). The median age at diagnosis was 62 years. The annual IR was 2.2 new cases per 100,000 individuals. Most patients (n=979, 82.3%) were diagnosed with cutaneous T-cell lymphoma (CTCL) with a crude IR of 1.8 new cases per 100,000 person-years. Mycosis fungoides (MF) was the most common subtype (n=817, 68.7%), followed by lymphomatoid papulosis (LyP) (n=59, 5.0%). The crude IR for MF was 1.5 new cases per 100,000 person-years. Cutaneous B-cell lymphomas (CBCLs) accounted for 17.6% (n=210) of all PCLs (IR: 0.4 new cases per 100,000 person-years). PCL, CTCL and MF incidence rates increased from 2009 to 2019, followed by a decrease in 2020-2021. The incidence rate of CBCL increased steadily during the study period. The annual IRs of PCL in Greece were higher than those reported in other studies from Europe, America and Asia. The increase in IRs from 2009 to 2019 may reflect physicians' improved diagnostic efficiency. The COVID-19 pandemic may be the reason for the decline in PCL, CTCL and MF diagnoses from 2020 to 2021.

An Epidemiological Update on Indoor Tanning and the Risk of Skin Cancers.

Indoor tanning (sunbeds, solarium) uses artificial ultraviolet radiation (UVR) to stimulate cosmetic tanning of the skin. Indoor tanning has been officially classified as a human carcinogen in 2009 by the International Agency for Research on Cancer of the World Health Organization (WHO). The differences in the prevalence of sunbed use across countries and over the years highlight underlying legislative, climatic, and cultural differences. Indoor tanning-seeking behaviors may be driven by motivations for an appealing appearance, largely influenced by gender and age, and several misconceptions that a prevacation tan safeguards the skin, that sunbeds can be used to treat acne or to increase vitamin D, or that tanning is a healthy habit. This review provides an epidemiological update on the prevalence of sunbed use, who tends to use sunbeds and why, and details the current evidence on the association of sunbeds with skin cancers, including cutaneous melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC). A statistically significant higher risk of cutaneous melanoma, BCC and cSCC with the use of sunbeds has been consistently demonstrated. This risk of skin cancer is even higher with the more frequent use of sunbeds, underscoring a dose-response relationship, and in those first exposed to sunbeds at a younger age. Preventive measures against sunbed use include legislation restricting sunbed use, educational campaigns to inform and discourage from indoor tanning, as well as using the internet, online advertising messages and the social media to reach larger audiences and to promote an untanned appearance.