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.

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.

The presence of eccentric hyperpigmentation should raise the suspicion of melanoma.

BACKGROUND: Melanocytic lesions with eccentric hyperpigmentation (EH), even though without other dermatoscopic features of melanoma, are often excised. OBJECTIVE: Aiming to understand whether the EH in a pigmented lesion is an accurate criterion of malignancy, we evaluated the capability of two evaluators, with different expertise, to correctly diagnose a melanoma when analysing a given lesion in toto versus a partial analysis, with only the EH or the non-hyperpigmented portion (non-EH) visible. METHODS: Dermatoscopic images of 240 lesions (107 melanomas and 133 nevi) typified by EH were selected. Facial, acral, mucosal lesions and lesions showing clear-cut features of melanoma (except for atypical network) were excluded. Clinical and dermoscopic features (main pattern and numbers of colours) were described for all cases. Each image was split in two through a software so that only the EH or the non-EH was visible. Two blinded evaluators examined three sets of images, two with customized images and one with the non-modified ones: they were asked to give a dichotomous diagnosis (melanoma or nevus) for each image. RESULTS: Melanomas were significantly more frequently typified by colour variegation (3 colours in 44.8% and 4 colours in 41.1% of cases) and atypical network (88.1% in the EH). No significant differences in diagnostic accuracy emerged between the two evaluators. Sensitivity improved in the evaluation of the whole lesions (mean sensitivity 89.7%) in comparison with the evaluation of EH or non-EH alone (72.7-62.6%). Specificity increased when evaluating the EH (54.1%). Positive predictive value (PPV) and likelihood ratio (LR+) of EH resulted 52.3% and 1.4, meaning that in one case out of two with EH is a melanoma. CONCLUSIONS: Lesions with EH are challenging, regardless of dermoscopic experience. The EH is a robust criterion for malignancy, since the evaluation of the whole lesion, through an intralesional comparative approach, increases sensitivity.

Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies.

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all skin cancers. Although primary cSCCs can be successfully treated with surgery, a subset of highly aggressive lesions may progress to advanced disease, representing a public healthcare problem with significant cancer-related morbidity and mortality. A complex network of genes (TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) have been shown to play an important role in the pathogenesis of cSCC. The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH-activating agents capable to restore its tumour-suppressor function. EGFR inhibitors including both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors (erlotinib, gefitinib and dasatinib) have been used in clinical trials for the treatment of advanced cSCC, achieving only partial clinical benefit. Recently, an immune-modulatory drug (cemiplimab) has been introduced for the treatment of advanced cSCC with good clinical results and a favourable safety profile, while other PD1/PD-L1 inhibitors, either as monotherapy or in combination with targeted therapies, are currently under investigation. This review focuses on molecular findings involved in the pathogenesis of cSCC and their implications for the future development of new treatment strategies. In addition, current and ongoing treatments on targeted therapies and/or immunotherapy are illustrated.

Topical and systemic medical treatments of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common non melanoma skin cancer (NMSC) in white individuals over the age of 40 years. BCCs usually grow slowly and rarely metastasize, but can be locally invasive if neglected or of an aggressive subtype. The local tissue destruction caused by an untreated BCC can be extensive, therefore optimal treatment should lead to tumour clearance. Surgery and topical medical treatments are successful therapeutic options for most superficial and nodular BCC. Systemic medical treatments may be considered when surgical procedures are not recommended on the basis of the anatomical site and tumor extension, and patients' associated comorbidities. Expected cure rates and cosmetic outcome should be also carefully considered. A better understanding of the molecular mechanisms of BCC pathogenesis can lead to new developing target medical therapies, and data on their efficacy seem encouraging.