Skin Cancer Microenvironment: What We Can Learn from Skin Aging?

Aging is a natural intrinsic process associated with the loss of fibrous tissue, a slower cell turnover, and a reduction in immune system competence. In the skin, the continuous exposition of environmental factors superimposes extrinsic damage, mainly due to ultraviolet radiation causing photoaging. Although not usually considered a pathogenic event, photoaging affects cutaneous biology, increasing the risk of skin carcinogenesis. At the cellular level, aging is typified by the rise of senescence cells a condition characterized by reduced or absent capacity to proliferate and aberrant hyper-secretory activity. Senescence has a double-edged sword in cancer biology given that senescence prevents the uncontrolled proliferation of damaged cells and favors their clearance by paracrine secretion. Nevertheless, the cumulative insults and the poor clearance of injured cells in the elderly increase cancer incidence. However, there are not conclusive data proving that aged skin represents a permissive milieu for tumor onset. On the other hand, tumor cells are capable of activating resident fibroblasts onto a pro-tumorigenic phenotype resembling those of senescent fibroblasts suggesting that aged fibroblasts might facilitate cancer progression. This review discusses changes that occur during aging that can prime neoplasm or increase the aggressiveness of melanoma and non-melanoma skin cancer.

Clinical management of very small pigmented lesions: Improved clinical outcome through dermoscopy and reflectance confocal microscopy combination.

INTRODUCTION: Small-sized pigmented lesions (SSPL) <3 mm in diameter are common pitfall in the daily dermatology practice. Dermoscopy alone is hampered by the lack of specific features inversely proportional to the diameter of the lesions and its performance is highly operator-dependent. Reflectance confocal microscopy (RCM) has been demonstrated to be effective in the diagnosis of several difficult lesions where dermoscopy lacks to provide conclusive information. MATERIALS AND METHODS: A total of 179 lesions with uncertain or equivocal clinical and dermoscopy appearance were selected. Dermoscopist has been requested to express a diagnostic suspect when possible. Equivocal lesions underwent RCM performed by expert for second-level evaluation before surgical excision for histological diagnosis. Results have been later statistically analysed. RESULTS: Dermoscopy was not diagnostic in large number of lesions with low concordance histology (39.1%) instead of a much high concordance when combined with RCM (93.9%). CONCLUSIONS: Small-sized pigmented lesions were more likely to be located on the face area. Diagnosis of pigmented BCC was relatively easy on dermoscopy and also in the case of small lesions showing typical signs of BCC. LM and MM have been seen to be particularly difficult to be diagnosed using only dermoscopy. The combination of digital dermoscopy and RCM represents the correct approach of SSPL.

A Single Center Retrospective Review of Patients from Central Italy Tested for Melanoma Predisposition Genes.

BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes. OBJECTIVE: This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy. METHODS: From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: "low significance" and "high significance" cases. RESULTS: 128 patients (72% belonging to the "high significance" category, 28% belonging to the "low significance" category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS. CONCLUSIONS: It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.

A novel CDKN2A in-frame deletion associated with pancreatic cancer-melanoma syndrome.

Pancreatic cancer-melanoma syndrome (PCMS) is an inherited condition in which mutation carriers have an increased risk of malignant melanoma and/or pancreatic cancer. About 30% of PCMS cases carry mutations in CDKN2A. This gene encodes several protein isoforms, one of which, known as p16, regulates the cell-cycle by interacting with CDK4/CDK6 kinases and with several non-CDK proteins. Herein, we report on a novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) found in an Italian family with PCMS. By segregation analysis, the c.52_57delACGGCC was proven to segregate in kindred with cutaneous melanoma (CM), in kindred with CM and pancreatic cancer, and in a single case presenting only with pancreatic cancer. In the literature, duplication mapping in the same genic region has been already reported at the germline level in several unrelated CM cases as a variant of unknown clinical significance. A computational approach for studying the effect of mutational changes over p16 protein structure showed that both the deletion and the duplication of the c.52_57 nucleotides result in protein misfolding and loss of interactors' binding. In conclusion, the present results argue that the quantitative alteration of nucleotides c.52_57 has a pathogenic role in p16 function and that the c.52_57delACGGCC is associated with PCMS.

Lentigo maligna of the face: A quantitative simple method to identify individual patient risk probability on dermoscopy.

BACKGROUND/OBJECTIVES: The clinical and dermoscopic differential diagnosis of flat pigmented facial lesions represents a great challenge for the clinicians. Our aim was to report a quantitative method based on dermoscopic features to better classify pigmented facial lesions. METHODS: This is a retrospective case-series study that analysed the dermoscopic features of 582 pigmented facial lesions. RESULTS: The individual patient probability of lentigo maligna (LM) was predicted by a multivariate model, with an accuracy of 0.72. According to the odds ratio at the multivariate analysis, an individual scoring index was assigned to each criterion, and a value of 4.56 was identified as optimal cut-off point. Up to a score of 2.5, the probability that a lesion is an LM is 0. The probability increases from 10 to 50% for a score ranging between 4.5 and 6. It is about 90% for a score of 7. CONCLUSION: The optimal cut-off point obtained and the curve that identifies the probability of a patient having a LM could improve the classification and the management strategies of equivocal pigmented facial lesions.

Persistent ß-Hexachlorocyclohexane Exposure Impacts Cellular Metabolism with a Specific Signature in Normal Human Melanocytes.

BACKGROUND: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of ß-hexachlorocyclohexane (ß-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. METHODS: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. RESULTS: We demonstrated that ß-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/ß-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. CONCLUSIONS: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk.

Effectiveness of ixekizumab for the treatment of moderate-to-severe plaque psoriasis with involvement of difficult-to-treat areas: A 52-week multicenter retrospective study.

Biological drugs have dramatically changed the approach to treating moderate-to-severe plaque psoriasis, achieving excellent skin clearance and safety outcomes. However, the management of difficult-to-treat areas (e.g., scalp, palms/soles, nails, and genitalia) still represents a challenge in psoriasis treatment. Data in the literature on difficult-to-treat sites are limited and, frequently, no specific analysis is performed during clinical trials. We conducted a 52-week, retrospective study to evaluate the effectiveness of ixekizumab in 120 patients with moderate-to-severe plaque psoriasis of at least one difficult-to-treat area (scalp, palmoplantar surfaces, nails, and genitalia). Ninety-nine patients had scalp psoriasis, 35 had involvement of the palms or soles, 27 were affected by genital psoriasis, and 22 patients reported involvement of the nails. After 1 year of treatment, 96% of patients with scalp involvement, 95.6% of patients with palmoplantar psoriasis, 95.2% of patients with genital psoriasis, and 85% of patients with nail involvement achieved a site-specific Physician's Global Assessment of 0 or 1 (clear or almost clear). No serious adverse events were observed during the study. Our study supports the effectiveness of ixekizumab in plaque psoriasis involving difficult-to-treat sites.

Efficacy and safety of tildrakizumab in elderly patients: real-world multicenter study (ESTER - study).

Purpose of the article: Interleukin-23 inhibitors, such as tildrakizumab, have emerged as safe and effective options for the management of psoriasis. Yet their efficacy in elderly patients (aged 65 years or more), particularly in those with difficult-to-treat areas involvement, remains insufficiently explored. We conducted this real-life retrospective multicentric observational study to assess the effectiveness of tildrakizumab in elderly patients with moderate-to-severe psoriasis, with involvement of difficult-to-treat areas.Materials and methods: We enrolled forty-nine patients aged 65 years old or more (mean age 73.1 ± 6.0), all treated with tildrakizumab for at least 28 weeks. The effectiveness of tildrakizumab was assessed by Static Physician's Global Assessment of Genitalia (sPGA-G), fingernail-PGA (f-PGA), palmoplantar PGA (pp-PGA), scalp-specific PGA (sc-PGA), and Psoriasis Area and Severity Index (PASI) scores.Results: Significant improvements in PASI scores were observed within 28 weeks of treatment, with 77.5%, 60%, and 45.2% of patients achieving PASI75, PASI90, and PASI100, respectively. The mean PASI decreased significantly from baseline (13.6 ± 9.9) to 1.3 ± 1.7 at week 28. More than 90% of patients had clear sPGA-G and pp-PGA scores and over 70% had clear f-PGA and sc-PGA scores after 28 weeks.Conclusions: Our findings suggest that tildrakizumab could be a valuable option for the treatment of elderly patients, including those with difficult-to-treat areas involvement.

Melanoma molecular classes and prognosis in the postgenomic era.

Gene expression profiling is a powerful method to classify human tumours on the basis of biological aggressiveness, response to therapy, and outcome for the patient, but its application in melanoma lags behind that of other cancers. From more than 100 articles available on the topic, we selected 14 focusing on patients' outcome. We review and briefly discuss salient findings, and list ten reasons why melanoma molecular classes are not yet used in clinical diagnosis and prognosis. The available evidence suggests that we are on the verge of creating a framework for the use of melanoma molecular classes in prognosis, but so far there is little consensus to put together informative diagnostic and prognostic gene sets.

Rapidly and successful improvement of nail psoriasis with risankizumab.

This clinical case demonstrates quick resolution of nail psoriasis in a patient treated with risankizumab, highlighting the role of IL-23 in the pathogenesis of nail psoriasis.

Long-term management of pediatric psoriasis with ixekizumab: a case report.

Psoriasis in pediatric patients is uncommon and the management of moderate-to-severe cases can be challenging. We report the case of a 17-year-old girl who presented with severe plaque psoriasis unresponsive to UVB phototherapy. The Psoriasis Area Severity Index (PASI) was 18 and the Dermatology Life Quality Index was 24. We decided to prescribe ixekizumab, observing complete skin clearance after only 8 weeks. The patient is still on treatment with no reported adverse events after two years.

Effectiveness of risankizumab in plaque psoriasis with involvement of difficult-to-treat areas: a real-world experience from two referral centers.

The management of plaque psoriasis that affects difficult-to-treat areas can be challenging. Biologics have become the treatment of choice for moderate-to-severe plaque psoriasis. However, there are limited data on their efficacy in difficult-to-treat sites (including scalp, palms/soles, nails and genitalia). We conducted a 52-week retrospective study to evaluate the effectiveness of risankizumab in 202 patients with moderate-to-severe involvement of at least one difficult-to-treat area. One hundred and sixty-five patients had scalp psoriasis, 21 had involvement of palms or soles, 72 were affected by genital psoriasis, and 50 patients reported the involvement of the fingernails. After one year of treatment, 97.58% of patients with scalp involvement, 95.28% of patients with palmoplantar psoriasis, 100% of patients with genital psoriasis and 82% of patients with nail involvement achieved a site-specific Physician's Global Assessment of 0 or 1 (clear or almost clear). No serious adverse events were observed during the study. Our study supports the effectiveness of risankizumab in plaque psoriasis involving difficult-to-treat sites.

Artificial Intelligence and Advanced Melanoma: Treatment Management Implications.

Artificial intelligence (AI), a field of research in which computers are applied to mimic humans, is continuously expanding and influencing many aspects of our lives. From electric cars to search motors, AI helps us manage our daily lives by simplifying functions and activities that would be more complex otherwise. Even in the medical field, and specifically in oncology, many studies in recent years have highlighted the possible helping role that AI could play in clinical and therapeutic patient management. In specific contexts, clinical decisions are supported by "intelligent" machines and the development of specific softwares that assist the specialist in the management of the oncology patient. Melanoma, a highly heterogeneous disease influenced by several genetic and environmental factors, to date is still difficult to manage clinically in its advanced stages. Therapies often fail, due to the establishment of intrinsic or secondary resistance, making clinical decisions complex. In this sense, although much work still needs to be conducted, numerous evidence shows that AI (through the processing of large available data) could positively influence the management of the patient with advanced melanoma, helping the clinician in the most favorable therapeutic choice and avoiding unnecessary treatments that are sure to fail. In this review, the most recent applications of AI in melanoma will be described, focusing especially on the possible finding of this field in the management of drug treatments.

Treatment adherence with diclofenac 3% gel among patients with multiple actinic keratoses: an integrated low-intensity intervention program versus standard-of-care.

BACKGROUND: Diclofenac 3% gel is a widely used topical treatment with proven efficacy in reducing the burden of actinic keratosis (AK); however, clinical benefit might not fully translate in clinical practice as nonadherence is substantial for prolonged treatment regimens. We evaluated the efficacy of an integrated low-intensity intervention program versus standard-of-care on treatment adherence among patients with multiple AK receiving diclofenac in hyaluronic acid gel 3%. METHODS: We designed an open label, randomized, parallel group, interventional, multicenter, longitudinal cohort study including patients with multiple, grade I/II AKs. Visits were scheduled for end of treatment (T4), follow-up 1 (T5) and follow-up 2 (T6) at 90, 180 and 365 days from baseline, respectively. Patients in the intervention group received additional visits at 30 and 60 days from baseline, a brief health education intervention, an enhanced patient-physician communication, a weekly SMS reminder to medication prescriptions. RESULTS: Patients were equally allocated between intervention (intervention group [IG], N.=86) and control group ([CG] N.=86); at baseline, both groups had similar socio-demographic and clinical characteristics. Change scores from baseline showed a slight increment in quality of life related to AK in both groups (CG: ΔT4-T1=-0.079; IG: ΔT4-T1=-0.006; P=0.39) and in quality of physician-patient interaction reported by IG (ΔT3-T2=0.18; P<0.0001). Adherence rate was not statistically different between IG and CG (28.4% vs. 40.7%; P=0.11). Patients reported similar satisfaction for effectiveness, convenience and side effects of treatment. Clinical conditions improved over time and results did not differ between groups; complete clearance rate at 1 year was 18% and 29% for CG and IG, respectively. CONCLUSIONS: Our findings showed no difference in adherence rate between the two groups, suggesting that enhanced follow-up interventions and health care education may not be sufficient drivers to promote adherence among this clinical population. Further studies are needed to explore barriers to adherence with treatments for AKs.

Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?

Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the PTCH1 gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/ß-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3ß axis and consequent increase of ß-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.

Enlarging melanocytic lesions with peripheral globular pattern: a dermoscopic and confocal microscopy study.

BACKGROUND: Enlarging melanocytic lesions with peripheral globular pattern (EMLPGP) are a pitfall in dermoscopy. Our aim was to evaluate the meaning of EMLPGP and to assess the use of dermoscopy and reflectance confocal microscopy (RCM) in order to improve the clinical management of this subtype of melanocytic lesions. METHODS: A total of 135 EMLPGP were recruited and, accordingly to the dermoscopy features, were removed; later, an expert dermoscopist reviewed the lesions blinded to histology. Moreover, a subgroup of 63 lesions who underwent also to RCM, were reviewed by an expert confocalist. RESULTS: Patients had a median age of 41 years old and a female prevalence (61.5%). The main anatomic site was the trunk (86%). Histology of the 135 excised EMLPGP disclosed 116 nevi (86%; P<0.0001) and 19 melanomas (14%). On dermoscopy, statistical significance was detected for small globules that were observed in 106 cases (78.5%; P<0.0001), while globules distribution and color did not impact the diagnosis prediction, as well as age, sex or any other patient profile. Considering the RCM, atypical cytology and irregular architecture were detected in 100% of melanomas (P<0.0001). CONCLUSIONS: Our study shows that EMLPGPs are detectable in every age and can be a pitfall in especially in high risk patients with an over-excision of lesions. The presence of peripheral globules should be evaluated considering the overall dermoscopic features. RCM can contribute significantly in the management of lesions trough the detection of cyto-architectural atypia. Therefore, RCM in combination with dermoscopy can optimize the reduction of harmless lesions.

Daylight photodynamic therapy: experience in the treatment of actinic keratosis in the San Gallicano Institute (Rome) and a review of literature.

BACKGROUND: Actinic keratosis (AK) is a photo-induced skin lesion. It has been considered by several authors as in-situ squamous cell carcinoma (SCC), that can evolve to invasive SCC (iSCC). Given the malignant potential and because it is impossible predict which AK will evolve in iSCC, it is necessary to treat each lesion. Multiple therapeutic approaches have been described to treat AKs. In addition to the topical drugs, photodynamic therapy (PDT) has become an established therapeutic modality for grade I and II of AKs of face and scalp. Recently the daylight photo-dynamic therapy (DL-PDT) has found extensive use in the care of the AK and in the field cancerization. METHODS: The study included 101 patients, 90 males and 11 females, mean age 71, phototype I-II, with multiple AK I and II of the face and the scalp, treated with DL-PDT. Patients were clinically evaluated for 3 months. The aim of this study was to show our experience in Daylight Photodynamic Therapy, to confirm the validity in term of efficacy and safety of DL-PDT for I and II AK of face and scalp and to underline the patient's higher satisfaction for this type of treatment and his availability to be retreated with the DL-PDT. RESULTS: The efficacy was complete in 16 patients (15.8%), in 71 patients (70.3%) was much improved or improved and only in 14 (13.9%) subjects were minimal, while nobody had worsened or changed. The majority of patients (84.2%) patients were satisfied of the efficacy as well of the cosmetic results, only 15 (14.9%) were low satisfied and one patient was not satisfied. CONCLUSIONS: This study confirms that the DL-PDT is a good alternative to c-PDT for the treatment of grade I and II AK of the face and scalp and in Rome, as in Southern Europe, it is possible to perform the DL-PDT in almost every month of year.

Correction to: Actinic keratoses: when and how to treat a single lesion.

This corrects the article DOI: 10.23736/S0392-0488.18.06082-0.

Clinicopathological and dermoscopic features of amelanotic and hypomelanotic melanoma: a retrospective multicentric study.

BACKGROUND: Amelanotic and hypomelanotic melanoma (AHM) has a higher risk of delayed diagnosis and a significant lower 5-year melanoma-specific survival compared to pigmented melanoma. Our aim was the evaluation of the clinicopathological/dermoscopic features of amelanotic melanoma (AM) and hypomelanotic melanoma (HM). METHODS: All participants had a personal history of AHM. We defined HM as showing clinical/dermoscopic pigmentation in < 25% of the lesion's surface and histopathological focal pigmentation, while AM as melanomas with clinical/dermoscopic and histopathological absence of pigmentation. RESULTS: The most common phenotypic traits among the 145 AHM patients were as follows: phototype II, blue-grey eyes, and dark brown hair. Red hair was present in 23.8% AHM cases (AM = 22.60%; HM = 25.80%). The most affected area was the back (29.5%). A total of 67.1% were classified as AM and 32.9% as HM. The most represented hair colors in AM and HM were, respectively, blonde and dark brown hair. Median Breslow thickness was 1.7 mm, superficial spreading melanoma (SSM) and nodular melanoma (NM) were the most represented histotypes, and mitotic rate > 1 × mm2 was reported in 73.3% cases, and regression was significantly more present in HM. Dermoscopy showed high prevalence of white structureless zones (63.4%), linear looped vessels (58.8%), linear irregular vessels (50.0%), and arborizing vessels (47.2%). Multivariate logistic regression confirmed the association between the presence of pigmentation and the following: histological regression, dermoscopic globules, and arborizing vessels. CONCLUSIONS: Predominance of red hair in AHM patients was not confirmed. AHM affects mostly intermittent sun-exposed body areas. The deeper median Breslow thickness (versus pigmented melanoma), the association of AM with the nodular histotype, and the high mitotic rate highlight the AHM's aggressiveness. HM's higher levels of regression can be explained by the presence of pigmentation, driving the underlying immune response. AHM showed a polymorphous vascular pattern and significant presence of arborizing vessels (especially HM).