The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview.

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous "pre-activated state" due to PTCH1 mutations to those of skin tumor stroma.

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.

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.

Bleomycin Electrochemotherapy of Dermal Cylindroma as an Alternative Treatment in a Rare Adnexal Neoplasm: A Case Report and Literature Review.

BACKGROUND: Brooke-Spiegler syndrome is a rare autosomal dominant disorder characterized by the continuous development of multiple benign skin appendage tumors. It is treated usually by repeated standard surgery. Here, we present a case study where electrochemotherapy (ECT) with bleomycin was used as an effective alternative approach in treating advanced dermal cylindromatosis of the head and neck in a patient with Brooke-Spiegler syndrome. PATIENTS AND METHODS: A 45-year-old woman presented with multiple recurrent dermal cylindroma lesions on her scalp. Previous treatment consisted of several surgical excisions that resulted in psychological deterioration due to the formation of numerous scars and extensive alopecic areas. ECT was offered to provide tumor removal and disease control and to improve the patient's quality of life. RESULTS: The treatment was well tolerated, and a significant reduction in neoplastic tissue was achieved. Importantly, scalp skin condition significantly improved, regaining a fair follicular density on the margins. CONCLUSION: This report suggests the feasibility of bleomycin ECT as a less invasive alternative option for controlling multiple scalp cylindroma lesions with cosmetically acceptable results, and improving quality of life.

Dermoscopy of pigmented lesions of the vulva: a retrospective morphological study.

BACKGROUND: The dermoscopic patterns of pigmented skin tumors are influenced by the body site. OBJECTIVE: To evaluate the clinical and dermoscopic features associated with pigmented vulvar lesions. METHODS: Retrospective analysis of clinical and dermoscopic images of vulvar lesions. The χ² test was used to test the association between clinical data and histopathological diagnosis. RESULTS: A total of 42 (32.8%) melanocytic and 86 (67.2%) nonmelanocytic vulvar lesions were analyzed. Nevi significantly prevailed in younger women compared with melanomas and melanosis and exhibited most commonly a globular/cobblestone (51.3%) and a mixed (21.6%) pattern. Dermoscopically all melanomas showed a multicomponent pattern. Melanotic macules showed clinical overlapping features with melanoma, but their dermoscopic patterns differed significantly from those observed in melanomas. CONCLUSION: The diagnosis and management of pigmented vulvar lesions should be based on a good clinicodermoscopic correlation. Dermoscopy may be helpful in the differentiation of solitary melanotic macules from early melanoma.

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.

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

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

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.

Vulvar melanoma: a report of 10 cases and review of the literature.

Despite its low incidence, vulvar melanoma carries a poor prognosis and shows a high tendency to metastasize because the diagnosis is often delayed. Although it is very well known that ultraviolet radiation is an important aetiological factor for cutaneous melanomas in adults, this cannot be considered true for vulvar melanoma. Chronic inflammatory disease, viral infections, irritant agents are the main factors suspected to induce mucosal melanoma. We report 10 cases of vulvar malignant melanoma observed in our institute from 1990 to 2005 and a review of the literature.

Giant and large basal cell carcinoma treated with topical photodynamic therapy.

Basal cell carcinoma (BCC) is the most common cancer affecting Caucasians and, due to its large size or to the poor condition of the patient, it can be difficult to treat it with conventional therapies: in these cases photodynamic therapy with methyl aminolevulinate (MAL-PDT) may represent a good option. A retrospective non-comparative follow-up study was performed to test the response of giant and large BCC to MAL-PDT. Twelve patients with 14 giant BCC (> or = 5 cm) and 5 patients with 5 large BCC (4-5 cm) were treated with MAL-PDT; they were evaluated 6 months after the end of the treatment to define the initial cure rate, and then at 12 and 36 months for the follow-up. At 6 months the initial cure rate for the 19 BCCs was 95% and at 36 months the overall long-term cure rate was 66%. The follow-up will last up to 5 years. MAL-PDT is a valid option for the treatment of giant and large BCC.

Familial melanoma and multiple primary melanoma.

Cutaneous melanoma (CM) has the highest mortality rates among the most common skin cancers, and its incidence is rising worldwide, thus representing a significant health care burden. CM is considered the most lethal skin cancer if not detected and treated during its early stages. Susceptibility to CM is also associated with an increased presence of atypical nevi and the occurrence of multiple primary melanoma. Personal history of CM increases the risk of developing a second melanoma by 5-8%. A family history of melanoma has also been strongly associated with an increased risk of melanoma. Approximately 5-10% of melanoma cases occur in a familial context. The main genes involved are CDKN2A, CDK4 and MC1R. The recent technological advances have allowed the identification of new genes involved in melanoma susceptibility: breast cancer 1 (BRCA1), BRCA1-associated protein 1 (BAP1), and telomerase reverse transcriptase (TERT).Tests on these genes allow to identify a larger number of high-risk individuals with a potential of developing familial melanoma and primary multiple melanomas. These patients also have a high risk of developing internal organ malignancies, especially pancreatic cancer. It is essential that these individuals receive adequate management along with frequent dermatological examinations, dermoscopic evaluation, genetic counselling and instrumental examinations aimed at the early identification of other tumors associated with CM.

Malignant melanoma and pregnancy.

The occurrence of cancer in pregnant women is not a common phenomenon and the real incidence of malignant melanoma during this period is unknown. Many authors reported a poor prognosis in pregnant women with melanoma compared with non-pregnant women's tumour. Several retrospective reviews reported a worsened prognosis in pregnant women with melanoma and found that progesterone and oestrogen receptors can be detected in melanoma tissue. Other data are in conflict with these opinions; several studies demonstrated that the timing of the disease diagnosis during pregnancy did not appear to influence the risk of mortality. In our report, we reviewed data on women with malignant melanoma who were diagnosed during pregnancy in our institute from 1991 to 2000. We have considered the following parameters: age at diagnosis, histological type and tumour thickness, stage of disease and surgical management and we have compared the clinical and biological behaviour of these melanomas with melanoma in non-pregnant women observed in the same period and in a follow-up of 5 years. In our study, there is no significant difference in outcome and survival rate between pregnant and non-pregnant women with melanoma. During pregnancy, melanocytic skin lesions show a transient modification of dermoscopic pattern; consequently, a close follow-up of pigmented lesions, both clinical and instrumental, is very important during pregnancy and care must be taken in revealing the presence of other risk factors for melanoma.

The role of Wnt/ß-catenin signaling pathway in melanoma epithelial-to-mesenchymal-like switching: evidences from patients-derived cell lines.

Deregulations or mutations of WNT/ß-catenin signaling have been associated to both tumour formation and progression. However, contradictory results concerning the role of ß-catenin in human melanoma address an open question on its oncogenic nature and prognostic value in this tumour. Changes in WNT signaling pathways have been linked to phenotype switching of melanoma cells between a highly proliferative/non-invasive and a slow proliferative/metastatic condition. We used a novel panel of cell lines isolated from melanoma specimens, at initial passages, to investigate phenotype differences related to the levels and activity of WNT/ß-catenin signaling pathway. This in vitro cell system revealed a marked heterogeneity that comprises, in some cases, two distinct tumour-derived subpopulations of cells presenting a different activation level and cellular distribution of ß-catenin. In cells derived from the same tumor, we demonstrated that the prevalence of LEF1 (high ß-catenin expressing cells) or TCF4 (low ß-catenin expressing cells) as ß-catenin partner for DNA binding, is associated to the expression of two distinct profiles of WNT-responsive genes. Interestingly, melanoma cells expressing relative low level of ß-catenin and an invasive markers signature were associated to the TNF-α-induced pro-inflammatory pathway and to the chemotherapy resistance, suggesting that the co-existence of melanoma subpopulations with distinct biological properties could influence the impact of chemo- and immunotherapy.

Dermoscopy of patients with multiple nevi: Improved management recommendations using a comparative diagnostic approach.

OBJECTIVE: To assess the outcome on management recommendations of a comparative approach vs a morphologic approach in evaluating dermoscopic images of lesions from a series of patients with multiple nevi. DESIGN: In a 2-step study, 6 experienced dermoscopists were asked to provide management recommendations (excision or follow-up) for a series of lesions from patients with multiple nevi based on dermoscopic images of the lesions. In the first step, participating dermoscopists evaluated individual images of lesions based only on morphologic structure (morphologic approach). In the second step, the same lesions were grouped by patient, allowing the participants to evaluate the lesions in the context of other nevi from the same patient (comparative approach). SETTING: Academic referral center. PATIENTS: Seventeen patients with 190 lesions (184 monitored nevi, 4 excised nevi, and 2 excised melanomas). MAIN OUTCOME MEASURE: Using pooled data from each step, excision recommendation rates for the comparative approach and the morphologic approach were calculated. RESULTS: Using the morphologic approach, 55.1% of overall recommendations favored excision; using the comparative approach, the rate decreased to 14.1%. The 2 melanomas included in the study were correctly judged to merit excision by all participants in step 1 and in step 2. Conclusion Among patients with multiple nevi, evaluation of equivocal lesions in the context of a patient's other nevi results in a lower rate of excision recommendations compared with evaluation of individual lesions based on morphologic structure alone.

Human Papillomaviruses, p16INK4a and Akt expression in basal cell carcinoma.

BACKGROUND: The pathogenic role of beta-HPVs in non melanoma skin cancer (NMSC), is not still completely understood, and literature data indicate that they might be at least cofactors in the development of certain cutaneous squamous cell carcinomas. However, only few reports contain data on basal cell carcinoma (BCC). The HPVs interact with many cellular proteins altering their function or the expression levels, like the p16INK4a and Akt. Our study aimed to determine the presence of different beta -HPV types and the expression of p16INK4a and Akt in BCC, the commonest NMSC, in the normal appearing perilesional skin and in forehead swab of 37 immunocompetent patients. METHODS: The expression of p16INK4a and Akt, by immunohistochemistry, and the HPV DNA, by nested PCR, were investigated in each sample. RESULTS: No correspondence of HPV types between BCC and swab samples was found, whereas a correspondence between perilesional skin and BCC was ascertained in the 16,7% of the patients. In BCC, 16 different types of beta HPV were found and the most frequent types were HPV107 (15,4%), HPV100 (11,5%) and HPV15 (11,5%) all belonging to the beta HPV species 2. Immunohistochemistry detected significant p16INK4a expression in almost all tumor samples (94,3%) with the highest percentages (> 30%) of positive cells detected in 8 cases. A statistically significant (p = 0,012) increase of beta HPV presence was detected in p16INK4a strongly positive samples, in particular of species 2. pAkt expression was detected in all tumor samples with only 2 cases showing rare positive cells, whereas Akt2 expression was found in 14 out of 35 BCC (40%); in particular in HPV positive samples over-expressing p16INK4a. CONCLUSIONS: Our data show that p16INK4a and pAkt are over-expressed in BCC and that the high expression of p16INK4a and of Akt2 isoform is often associated with the presence of beta-HPV species 2 (i.e. HPV 15). The association of these viruses with the up-regulation of p16INK4a and Akt/PI3K pathway suggests that in a subtype of BCC these viruses may exert a role in the carcinogenesis or in other, still undefined, biological property of these tumors. If this particular type of BCC reflects a different biology it will remain undisclosed until further studies on a larger number of samples will be performed.

Clinical features predicting identification of CDKN2A mutations in Italian patients with familial cutaneous melanoma.

CDKN2A is the most common, most penetrant gene whom germline mutations predisposing to cutaneous familial melanoma (FAM). Multiple primary melanoma (MPM), early age at onset, >2 affected members and pancreatic cancer are consistent features predicting positive test. However, the impact that cumulative clinical features have on the likelihood of molecular testing is unknown. In this work, genotype-phenotype correlations focused on selected clinical features were performed in 100 Italian FAM unrelated patients. Molecular studies of CDKN2A mutations were performed by direct sequencing. Statistical study included multiple correspondence analysis, uni- and multivariate analyses, and individual patient's probability calculation. MPM, >2 affected family members, Breslow thickness >0.4mm, and age at onset ≤41 years were the unique independent features predicting positive CDKN2A screening. The rate of positive testing ranged from 93.2% in the presence of all of them, to 0.4% in their absence. The contribution of each of them was quantified accordingly, with MPM being the most significant. These findings confirm previous data and add novel insights for the role of accurate patients' selection in CDKN2A screening.

Eccrine poroma: a clinical-dermoscopic study of seven cases.

Eccrine poroma can mimic benign and malignant melanocytic and non-melanocytic lesions. To date, little is known about the dermoscopic features of this condition. Seven histopathologically proven cases of eccrine poroma were examined using dermoscopy by three independent dermatologists. Both glomerular and hairpin vessels were observed in 71% of cases, whereas linear irregular vessels were observed in 43% of cases. A white-to-pink halo surrounding the vessels and multiple pink-white structureless areas were also frequently found (in 86% and 71% of cases, respectively). Three dermoscopic "profiles" were identified, all characterized by the presence of a white-to-pink halo surrounding the vessels, as well as by the association of two additional different features, namely: glomerular vessels and pink-white structureless areas, glomerular and linear irregular vessels, hairpin vessels and linear irregular vessels. However, due to the small number of lesions studied so far, we suggest that these profiles should be considered as likely, but not definitely pathognomonic signs of eccrine poroma.