Tracking the risk factors associated with high-risk cSCC: A 10-year, Two-Institution, Greek study.

PURPOSE: We sought to identify independent risk factors for positive sentinel lymph node biopsy (SLNB), local recurrence (LR), metastasis (M) and death caused by cutaneous squamous cell carcinoma (cSCC) (DCS) in high-risk cSCC patients. Moreover, we compared the Brigham and Women's Hospital (BWH) system with the previous used in Greece (based on tumor size) and proposed a new classification system. METHODS: 1,524 cSCC patients were enrolled between January 2004 and December 2014, from two medical institutions. Potential risk factors for SLNB (local recurrence/LR, metastasis/M, death caused by SCC/DCS) were analyzed by univariate and multivariate Cox logistic regression models. RESULTS: Of the included patients with a median follow-up of 60 months 107 developed local recurrence (7%) while 84 developed metastases (5.5%). Among 36 patients undergoing sentinel lymph node biopsy (SLNB), 25% showed a positive SLNB with a false-negative result (11%). On multivariate analysis, key prognostic factors for LR were tumor diameter ≥2 cm, poor differentiation, incomplete excision and perineural invasion and for M were high-risk tumor site, tumor diameter ≥2 cm, poor differentiation, invasion beyond subcutaneous tissue, incomplete excision, perineural invasion and recurrence. DCS seems to be affected by tumor diameter ≥ 2 cm, poor differentiation, invasion beyond subcutaneous tissue, incomplete excision, perineural invasion and recurrence independently. CONCLUSIONS: These suggest the determined role of tumor diameter of cSCCs. Harnessing knowledge and collecting the up-to-date data along the clinical journey of high-risk cSCC, the future looks bright (development of new clinical trials, adjuvant therapies and tumor staging with SLNB).

Cutaneous Vasculopathy in a COVID-19 Critically Ill Patient: A Histologic, Immunohistochemical, and Electron Microscopy Study.

We describe a critically ill, SARS-CoV-2 positive patient with respiratory failure and thrombotic/livedoid skin lesions, appearing during the course of the disease. The biopsy of the lesions revealed an occlusive, pauci-inflammatory vasculopathy of the cutaneous small vessels characterized by complement and fibrinogen deposition on vascular walls, pointing to a thrombotic vasculopathy. Transmission electron microscopy of the affected skin failed to reveal any viral inclusions. Clinical evaluation and laboratory findings ruled out systemic coagulopathies and disseminated intravascular coagulation, drug-induced skin reaction, and common viral rashes. Our hypothesis is that the, herein evidenced, microvascular occlusive injury might constitute a significant pathologic mechanism in COVID-19, being a common denominator between cutaneous and pulmonary manifestations.

Advanced cutaneous squamous cell carcinoma: how is it defined and what new therapeutic approaches are available?

PURPOSE OF REVIEW: Despite the overall excellent survival rates in patients with cutaneous squamous cell carcinoma (cSCC), advanced cutaneous SCCs are associated with high patient morbidity and mortality. Therefore, important unmet clinical needs persist: identifying high risk patients and choosing optimal treatment approaches. RECENT FINDINGS: In recent years, a better understanding of the biology of cSCC and its clinical progression have led to improved staging systems and new promising treatments for advanced disease. Such treatments include PD1 inhibitors, such as cemiplimab, which was recently approved for the treatment of cutaneous SCC, and pembrolizumab whose efficacy in the treatment cSCC is still being investigated. Other treatments, such as epidermal growth factor receptor inhibitors have also been used in the treatment of cSCC with moderate success. Several clinical and histological risk factors are considered key in estimating the risk or recurrence or metastasis in cSCCs and, therefore, influence the appropriate treatment choice and patient monitoring. SUMMARY: The present study reviews the current definition of advanced cSCC and discusses the new systemic approaches, including checkpoint inhibitors.

A Practical Guide for the Follow-Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors.

The Hedgehog pathway inhibitors (HPIs), vismodegib and sonidegib, are increasingly employed in the treatment of patients with advanced basal cell carcinoma (BCC). The aim of this review is to create a synthesis of available information in the literature regarding the follow-up of patients with advanced BCC treated with HPIs and to provide the treating physician with a structured practical guide to standardize clinical practice. Several challenges during treatment are addressed: to optimally evaluate tumor responses, to differentiate between resistance (HPI rechallenge not possible) and recurrence (HPI rechallenge may be possible) in case of BCC regrowth, to readily assess for toxicity and tolerability issues, to provide patients with practical ways and behaviors to effectively cope with adverse events, and to improve patient adherence and quality of life. IMPLICATIONS FOR PRACTICE: This is a practical guide for clinical practice regarding the monitoring and follow-up of patients with advanced basal cell carcinoma (BCC) during treatment with the Hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib. This review aims to bridge the gap in knowledge of assessing tumor response for BCC with both an externally visible component and an infiltrating component measurable with imaging. Furthermore, it addresses the follow-up for adverse events as a challenging multistep process involving practices aiming to readily assess new-onset symptoms of HPI toxicity, perform total-body skin examination, and improve patient adherence and quality of life.

Use of vismodegib for the treatment of multiple basal cell carcinomas in a patient with xeroderma pigmentosum.

A female patient with xeroderma pigmentosum and multiple basal cell carcinomas was treated with a hedgehog pathway inhibitor (vismodegib), which successfully treated the majority of her basal cell carcinomas while preventing the appearance of new lesions. The sum diameter of lesions showed a 61% decrease after 16.5 months of treatment, although after 18.5 months of treatment, a persistent lesion showed progression and metatypical characteristics; adverse events included persistent alopecia muscle cramps, dysgeusia, and amenorrhea. Despite these limitations, vismodegib may have a role in the treatment of some patients with xeroderma pigmentosum.

An update on molecular alterations in melanocytic tumors with emphasis on Spitzoid lesions.

Significant progress in the molecular pathology of melanocytic tumors have revealed that benign neoplasms, so-called nevi, are initiated by gain-of-function mutations in one of several primary oncogenes, such as BRAF in acquired melanocytic nevi, NRAS in congenital nevi or GNAQ/GNA11 in blue nevi, with consequent MAPK and PI3K/AKT/mTOR activation. Secondary genetic alterations overcome tumor suppressive mechanisms and allow the progression to intermediate lesions characterized by TERT-p mutation or to invasive melanomas displaying disruption of tumor suppressor genes. Currently, melanoma is molecularly regarded as four different diseases, namely BRAF, NRAS, NF1 and the "triple wild type" subtypes, which are associated with particular clinicopathological features. Melanocytic Spitzoid lesions include benign Spitz nevus, atypical Spitz tumor (AST) and Spitzoid melanoma. This is a challenging diagnostic group, particularly with regard to the distinction between AST and Spitzoid melanoma on clinical and histological grounds. Molecular analysis has identified the presence of HRAS mutation, BAP1 loss (often accompanying by BRAF mutations) or several kinase fusions in distinct categories of Spitz tumors. These aberrations account for the rapid growth characteristic of Spitz nevi. Subsequent growth is halted by various tumor suppressive mechanisms abrogation of which allow the development of AST, now better classified as low-grade melanocytic tumor. Although at present ancillary genetic techniques have not been very helpful in the prediction of biological behavior of AST, they have defined distinct tumor subsets differing with regard to biology and histology. Finally, we discuss how novel molecular markers may assist the differential diagnosis of melanoma, particularly from malignant peripheral nerve sheath tumor (MPNST). It is anticipated that the significant progress in the field of molecular pathology regarding the various types of melanocytic tumors, will eventually contribute to a more accurate histologic categorization, prediction of biologic behavior and personalized treatment.

MelaNostrum: a consensus questionnaire of standardized epidemiologic and clinical variables for melanoma risk assessment by the melanostrum consortium.

BACKGROUND: Many melanoma observational studies have been carried out across different countries and geographic areas using heterogeneous assessments of epidemiologic risk factors and clinical variables. AIM: To develop a consensus questionnaire to standardize epidemiologic and clinical data collection for melanoma risk assessment. METHODS: We used a stepwise strategy that included: compilation of variables from case-control datasets collected at various centres of the MelaNostrum Consortium; integration of variables from published case-control studies; consensus discussion of the collected items by MelaNostrum members; revision by independent experts; addition of online tools and image-based charts; questionnaire testing across centres and generation of a final draft. RESULTS: We developed a core consensus questionnaire (MelanoQ) that includes four separate sections: A. general and demographic data; B. phenotypic and ultraviolet radiation exposure risk factors and lifestyle habits; C. clinical examination, medical and family history; and D. diagnostic data on melanoma (cases only). Accompanying online tools, informative tables, and image-based charts aid standardization. Different subsections of the questionnaire are designed for self-administration, patient interviews performed by a physician or study nurse, and data collection from medical records. CONCLUSIONS: The MelanoQ questionnaire is a useful tool for the collection and standardization of epidemiologic and clinical data across different studies, centres, cultures and languages. This will expedite ongoing efforts to compile high-quality data for pooled analyses or meta-analyses and offer a solid base for the design of clinical, epidemiologic and translational studies on melanoma.

Vismodegib persistence and discontinuation patterns in Greek patients from a real world setting.

Hedghehog pathway inhibitors have been successfully used for patients with locally advanced basal cell carcinomas. However, these treatments have been associated with various adverse events that may limit patient compliance. In this study, an association of patient and disease characteristics with drug compliance in a real clinical setting was made. 18 patients were included in the study. The average patient age was 78.39 years. The time that patients remained to treatment was, on average, 8.73 months. 72.2% of patients experienced at least one adverse event. At study cut-off, 11 out of 18 patients had discontinued treatment. The most common reason for discontinuation was reported "fatigue" from the treatment due to the type of AEs experienced (37.4%) and patient's choice after complete response achievement (30.8%). Factors that were associated with treatment discontinuation was: number of previous treatments, severity of AEs and patient age.

Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.

Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal.

Pharmacologic treatment options for advanced epithelial skin cancer.

INTRODUCTION: Epithelial skin cancers (ESCs), namely basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), are considered common skin malignancies, with rising incidence rates over the past few decades. A subgroup of patients with ESC present with advanced and 'difficult'-to-treat tumours, including locally advanced and metastatic tumours. Currently, there is no widely accepted staging system for locally advanced ESCs, while metastatic BCCs and SCCs share a staging system. Therefore, selecting an appropriate therapeutic regimen for these patients may be difficult. AREAS COVERED: The purpose of this review is to highlight the pharmacologic treatment options for advanced ESCs. These include 'conventional' chemotherapeutic regimens such as 5-fluorouracil, cisplatin, vincristine, bleomycin and doxorubicin and newer, more 'targeted' therapies. EXPERT OPINION: Vismodegib, a Hedgehog (Hh) inhibitor, was recently approved for the treatment of advanced BCC showing a good efficacy rate and a relatively well-tolerated safety profile in clinical studies. In addition, a number of hedgehog inhibitors are now in Phase I and II trials of advanced BCC demonstrating encouraging results. Phase II studies with epithelial growth factor receptor inhibitors, such as cetuximab, gefitinib, panitimumab and erlotinib have been conducted in patients with advanced SCCs, used either as monotherapy or in combination with chemotherapy. However, there is still much knowledge to be gained about the treatment efficacies, optimal treatment durations, mechanisms of drug tolerance, adverse events and the ways in which these therapies influence patient outcomes and quality of life.

A double-blind vehicle-controlled study of a preparation containing undecylenoyl phenylalanine 2% in the treatment of melasma in females.

BACKGROUND: Undecylenoyl phenylalanine is a novel skin-lightening agent, probably acting as α-melanocyte-stimulating hormone (α-MSH) and beta-adrenergic receptor (ß-ADR) antagonist. OBJECTIVES: The objective of this double-blind randomized comparative study was to evaluate the efficacy and safety of a preparation containing undecylenoyl phenylalanine 2% in the topical treatment of melasma in females. METHODS: Forty female patients with melasma were randomly assigned to apply either the active preparation or the vehicle alone, twice daily for 12 weeks. Patients were evaluated monthly for efficacy and safety. RESULTS: In all, 37 patients completed the study. Of the 20 patients on active treatment, no one responded completely, but 17 (85%) had partial response. Of them, 11 had moderate improvement and six had marked improvement. Lightening of the lesions was evident from the first follow-up visit at 4 weeks. A statistically significant difference (P < 0.001) in efficacy between the active preparation and the vehicle was documented. Using patient assessment ratings, 80% were extremely satisfied or satisfied with the result. The reported side effects were minor and included erythema and itching or burning at the site of application. CONCLUSIONS: Undecylenoyl phenylalanine 2% achieved a significant lightening of melasma lesions with minimal side effects.