Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Tumor-Infiltrating Lymphocyte Recognition in Primary Melanoma by Deep Learning Convolutional Neural Network.

The presence of tumor-infiltrating lymphocytes (TILs) is associated with a favorable prognosis of primary melanoma (PM). Recently, artificial intelligence (AI)-based approach in digital pathology was proposed for the standardized assessment of TILs on hematoxylin and eosin-stained whole slide images (WSIs). Herein, the study applied a new convolution neural network (CNN) analysis of PM WSIs to automatically assess the infiltration of TILs and extract a TIL score. A CNN was trained and validated in a retrospective cohort of 307 PMs including a training set (237 WSIs, 57,758 patches) and an independent testing set (70 WSIs, 29,533 patches). An AI-based TIL density index (AI-TIL) was identified after the classification of tumor patches by the presence or absence of TILs. The proposed CNN showed high performance in recognizing TILs in PM WSIs, showing 100% specificity and sensitivity on the testing set. The AI-based TIL index correlated with conventional TIL evaluation and clinical outcome. The AI-TIL index was an independent prognostic marker associated directly with a favorable prognosis. A fully automated and standardized AI-TIL appeared to be superior to conventional methods at differentiating the PM clinical outcome. Further studies are required to develop an easy-to-use tool to assist pathologists to assess TILs in the clinical evaluation of solid tumors.

Spatial Proximity and Relative Distribution of Tumor-Infiltrating Lymphocytes and Macrophages Predict Survival in Melanoma.

Tumor microenvironment plays a crucial role in primary cutaneous melanoma (CM) progression. Although the role of tumor-infiltrating lymphocyte (TIL) density has been known for a long time, its spatial distribution and impact with or without tumor-associated macrophages (TAMs) remain controversial. Herein, we investigated spatial proximity between tumor cells and immune cells in 113 primary CM and its correlation with disease-free (DFS) and overall survival (OS). The study cohort included clinical stage II (n = 79) and stage III (n = 34) primary CM with a Breslow thickness of >2 mm (with a median age of 64 years, including 72 men and 41 women). In univariate models, patients with SOX10+ melanoma cells with high proximity to CD8+ TILs in a 20 µm radius showed longer DFS (hazard ratio [HR], 0.58; 95% CI, 0.36-0.93; P = .025) and OS (HR, 0.55; 95% CI, 0.32-0.92; P = .023). Furthermore, at multivariate combined analysis, patients with SOX10+ melanoma cells with high proximity to CD8+ TILs or low proximity to CD163+ TAMs in a 20 µm radius showed an increased OS (aHR, 0.37; 95% CI, 0.14-0.96; P = .04) compared with melanoma patients with low proximity to CD8+ TILs or high proximity to CD163+ TAMs. In a subgroup analysis including 92 patients, a significant negative impact on DFS (aHR, 4.49; 95% CI, 1.73-11.64; P = .002) and OS (aHR, 3.97; 95% CI, 1.37-11.49; P = .01) was observed in sentinel lymph node (SLN)-negative patients with a high proximity of CD163+ TAMs to CD8+ TILs. These findings could help identify high-risk patients in the context of thick melanoma and a negative SLN. Our study suggests the importance of quantifying not only the density of immune cells but also the individual and combined relative spatial distributions of tumor cells and immune cells for clinical outcomes in SLN-negative primary CM patients.

BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

BACKGROUND: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear. MATERIALS AND METHODS: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. RESULTS: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively. CONCLUSIONS: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients.

Fluorescence-advanced videodermatoscopy (FAV) for the differential diagnosis of suspicious facial lesions: A single-centre experience with pattern analysis and histopathological correlation.

BACKGROUND: Fluorescence-advanced videodermatoscopy (FAV) is a new non-invasive high-resolution skin imaging technique to assess pigmented lesions in conjunction with the clinical examination and dermatoscopy. OBJECTIVES: This is the first prospective study to identify morphologic descriptors and standardized terminology to examine facial pigmented lesions using FAV. The objectives were to identify FAV indicators, which can assist physicians in diagnosing suspicious flat facial pigmented lesions. METHODS: Consecutive equivocal pigmented lesions were retrospective analysed. Histopathological examination was performed for all the lesions. The main cytomorphological and cytoarchitectural FAV features were described and correlated with histopathological characteristics. RESULTS: From January to October 2020, 21 consecutive clinically suspected pigmented lesions in 20 patients were analysed using dermatoscopy and FAV and then surgically excised. Histopathological examination identified lentigo maligna (LM), lentigo maligna melanoma (LMM), solar lentigo (SL), flat seborrheic keratosis (SK) and pigmented actinic keratosis (PAK). Thirteen malignant melanocytic lesions were removed (11 LM, 2 LMM), two were diagnosed as PAK, and the remaining six pigmented lesions were SL-SKs. With FAV, large ovoid pleomorphic and dendritic cells arranged in the intrafollicular disposition, are typical of most malignant melanocytic lesions (12/13, 92.3%). No benign lesions displayed these features. In dermatoscopy, this folliculotropism corresponded to the presence of an annular-granular pattern with slate grey dots that were aggregated asymmetrically around follicular openings. CONCLUSIONS: FAV features can provide an improved diagnostic approach in the differential diagnosis of flat pigmented facial lesions.

Cutaneous immune-related adverse events and photodamaged skin in patients with metastatic melanoma: could nicotinamide be useful?

Cutaneous immune-related adverse events (irAEs) occur in more than one-third of patients treated with immune checkpoint inhibitors; they are often the first clinical manifestation, although they may occur months after initiation of therapy. We noticed that our patients usually have these cutaneous AEs on photodamaged skin. In fact, out of 19 patients being treated for metastatic melanoma, 8 (42%), all of whom had significant cutaneous actinic damage, developed cutaneous irAEs earlier and in a more serious form than those without such damage. Thus, we gave a high oral dose of nicotinamide (500 mg twice daily) to the patients with metastatic melanoma who had photodamaged skin, and continued this for the entire duration of the immunotherapy. The appearance of the first signs of cutaneous irAEs was 180 days after starting therapy in nicotinamide-treated patients, compared with 65 days for patients not treated with nicotinamide.

Atypical Spitz tumours: an epidemiological, clinical and dermoscopic multicentre study with 16 years of follow-up.

BACKGROUND: Atypical Spitz tumours (ASTs) are regarded as an intermediate category distinguished from prototypical Spitz naevus by presenting one or more atypical features and often by an uncertain malignant potential. Clinical and dermoscopic features may play a relevant role in the diagnostic approach. AIM: To evaluate the clinical and dermoscopic features of ASTs, and their evolution over time. METHODS: This was a descriptive, multicentre study of the clinical and dermoscopic characteristics of ASTs. Data on clinical and dermoscopic characteristics, histopathology, local extension, therapy and follow-up, lymph node staging, complete lymph node dissection, and outcome were collected from the databases of four Italian Dermatology Units for the period 2004-2021. RESULTS: The study population consisted of 99 patients (62 female, 37 male) with a histologically confirmed diagnosis of AST, including age at presentation ranged from 2 to 70 years (mean 28.1 years, median 24 years). Of the 99 patients, 29 (29.3%) underwent sentinel lymph node biopsy, which showed evidence of micrometastases in three cases (10.3%); all three patients underwent complete lymph node dissection with no evidence of further metastasis. Considering the whole study population, the clinical outcome was excellent, as all of the patients have no evidence of recurrence or distant metastasis. The follow-up period ranged from 6 to 216 months (mean 81.6 months, median 78 months). In addition, we collected data on the clinical and dermoscopic features of 26 lesions. The most frequent dermoscopic pattern observed was the multicomponent pattern (34.6%), followed by homogeneous (26.9%) and nonspecific (23.2%). In 66.7% of amelanotic ASTs, we observed glomerular (coiled) vessels uniformly distributed within the entire lesion, without asymmetry. CONCLUSION: The results of our study with a long follow-up show no recurrence or distant metastases, confirming the good clinical outcome, even in the case of sentinel lymph node positivity. From a diagnostic point of view, our series identified a typical dermoscopic picture for amelanotic ASTs, with a glomerular vascular pattern throughout the lesion in the absence of other dermoscopic parameters, making the correct diagnosis possible.

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.

The surgical treatment of non-metastatic melanoma in a Clinical National Melanoma Registry Study Group (CNMR): a retrospective cohort quality improvement study to reduce the morbidity rates.

BACKGROUND: Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry. METHODS: Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated. RESULTS: Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure. CONCLUSIONS: Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.

Clinical and dermoscopic polymorphisms in agminated Spitz nevi: Ugly presentation but benign behavior.

Agminated Spitz nevi are an uncommon entity, and their management is challenging due not only the young age of the patients but also the tumor's uncertain malignant potential and the variability in the dermoscopic and clinical presentation. We report a case of a 6-year-old boy with multiple agminated Spitz nevi on a café au lait macule with different atypical clinical patterns and dermoscopic features.

NTRK Gene Fusion Detection in Atypical Spitz Tumors.

Atypical Spitz tumors (AST) deviate from stereotypical Spitz nevi for one or more atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Activating NTRK1/NTRK3 fusions elicit oncogenic events in Spitz lesions and are targetable with kinase inhibitors. However, their prevalence among ASTs and the optimal approach for their detection is yet to be determined. A series of 180 ASTs were screened with pan-TRK immunohistochemistry and the presence of NTRK fusions was confirmed using FISH, two different RNA-based NGS panels for solid tumors, and a specific real time RT-PCR panel. Overall, 26 ASTs showed pan-TRK immunostaining. NTRK1 fusions were detected in 15 of these cases showing cytoplasmic immunoreaction, whereas NTRK3 was detected in one case showing nuclear immunoreaction. Molecular tests resulted all positive in only two ASTs (included the NTRK3 translocated), RNA-based NGS and real time RT-PCR were both positive in three cases, and FISH and real time RT-PCR in another two cases. In seven ASTs NTRK1 fusions were detected only by FISH and in two cases only by real time RT-PCR. The frequency of NTRK fusions in ASTs is 9%, with a clear prevalence of NTRK1 compared to NTRK3 alterations. Pan-TRK immunohistochemistry is an excellent screening test. Confirmation of NTRK fusions may require the use of different molecular techniques.

Folliculotropism in head and neck lentigo maligna and lentigo maligna melanoma.

BACKGROUND: Lentigo maligna (LM) and lentigo maligna-melanoma (LMM) are histotypes of melanoma arising in skin with cumulative solar radiation damage. The extension of atypical melanocytes to the hair follicle (folliculotropism) is a histopathological feature of LM/LMM. Its role has not been totally clarified, but it may be correlated to treatment response in LM or to progression in LMM. OBJECTIVE: This retrospective, multicentric study aims to identify dermatoscopic features associated with folliculotropism in LMs/LMMs. PATIENTS AND METHODS: We analyzed cases of head and neck LMs/LMMs diagnosed between 2005-2014 at Melanoma Units, University of Bologna/Modena/Florence/Siena (Italy), Nice (France): 25 LMs and 73 LMMs were included. RESULTS: Grey circles (44 %) indicated an isthmic/bulb level of involvement, which were completely absent in the infundibular LM lesions (P = 0.041). In the group of LMMs, light/dark brown pseudonetwork and light brown structureless areas were an indicator of diffuse distribution of malignant melanocytes in the follicular units (P < 0.001 and P = 0.001, respectively), while grey circles indicated focal or diffuse distribution (P < 0.001). CONCLUSIONS: A better understanding of the extension of malignant melanocytes is helpful, aiding clinicians in their decision to perform a radical excision or obtaining a biopsy in the most invasive area of the lesion, which includes potential folliculotropism.

The use of cisplatin electrochemotherapy in nonmelanoma skin cancers: A single-center study.

Electrochemotherapy (ECT) is a well-known nonconventional skin cancer ablative method that was shown to be safe and effective for treating both locoregional disease spreading and disseminated cutaneous and subcutaneous lesions from different types of cancer. The most common medications used are bleomycin and cisplatin. In the last years many studies were performed on ECT, lead it to be a valid therapeutic option in many international guidelines. Nevertheless, there are still no clear indications regarding timing of its use. The main aim of this study was first to assess the safety and effectiveness of intralesional cisplatin ECT for treating different types of nonmelanoma skin cancer in a group of eligible patients. The second endpoint was to assess patients' tolerability and symptoms improvement through the treatment. A single-center prospective study was performed. Patients with squamous cell carcinoma, basal cell carcinoma, or skin metastases were selected during 1 month. The ideal setting was the presence of two or three lesions with a maximum diameter of 2 cm. Both primary, recurrent, and metastatic lesions were included. Before and 8 weeks after treatment, all patients were evaluated to assess the number, measurement, and anatomical site of skin lesions using photography and metric notation. The medical device for membrane electroporation was the CLINIPORATOR EPS02 model. The cisplatin concentration was at least 1 mg/mL. The dose for each single lesion was calculated based on its volume, as is the standard procedure for ECT. Local or systemic adverse events and changes in symptoms were evaluated with a questionnaire based on a visual analog scale that was administrated before and after ECT. Eight patients with a total of 18 lesions underwent the procedure (six men and two women). Four out of eight (50%) patients had a complete response to the treatment. However, all eight patients had an overall tumor response (100%), experiencing an improvement in symptoms including less pain and bleeding from the tumor. Our study clearly show that ECT with intralesional cisplatin is a valuable and safety procedure for nonmelanoma skin cancer and cutaneous tumor metastasis. ECT with cisplatin was able to achieve a good local disease control leading to complete response in an half of cases. The results were stable after 1 year of follow-up. The outer ear area displayed a really good response, due to both ear's anatomical configuration and intralesional cisplatin pharmacological characteristics.

Italian expert consensus paper on the management of patients with actinic keratoses.

Two round tables involving experts were organized in order to reach a consensus on the management of patients with actinic keratosis (AK). In the first, seven clinical questions were selected and analyzed by a systematic literature review, using a Population, Intervention, Control, and Outcomes framework; in the second, the experts discussed relevant evidences and a consensus statement for each question was developed. Consensus was reached among experts on how to best treat AK patients with respect to different clinical scenarios and special populations. Lesion-directed treatments are preferred in patients with few AKs. Patients with multiple AKs are challenging, with more than one treatment usually needed to achieve complete lesion clearance or a high lesion response rate, therapy should be personalized, based on previous treatments, patient, and lesion characteristics. Methyl aminolevulinate-PDT, DL (day light) PDT, and imiquimod cream were demonstrated to have the lowest percentage of new AKs after post treatment follow-up. For IMQ 5% and 3.75%, a higher intensity of skin reactions is associated with higher efficacy. Photodynamic therapy (PDT) is the most studied treatment for AKs on the arms. Regular sunscreen use helps preventing new AKs. Oral nicotinamide 500 mg twice daily, systemic retinoids and regular sunscreen use were demonstrated to reduce the number of new squamous cell carcinomas in patients with AKs. Limited evidence is available for the treatment of AKs in organ transplant recipients. There is no evidence in favor or against the use of any of the available treatments in patients suffering from hematological cancer.

A clinical, pathological and immunohistochemical series of 9 cases of primary cutaneous apocrine carcinomas of the head and neck.

BACKGROUND/OBJECTIVES: Primary cutaneous apocrine carcinoma is a rare malignant adnexal skin tumour that can recur locally, spread to regional lymph nodes and metastatize to visceral organs. Wide dissemination and death from disease are much less common. The axilla is the most common site of presentation. It is infrequently reported in the head and neck region. METHODS: All cases diagnosed as primary cutaneous apocrine carcinoma of the head and neck were retrospectively collected from the archives of the Division of Pathological Anatomy, University of Florence from 1996 to 2016. There was no history or clinical evidence of breast cancer. Clinical data and follow-up were collected by the clinicians. RESULTS: Nine cases were found, with a mean age of 76 years, ranging in size between 0.3 and 3.5 cm. Clinically, they were frequently mistaken for basal cell carcinomas. Histopathologically, all the tumours showed decapitation secretion, a tubular, solid or mixed (tubulo-papillary and solid-tubular) growth pattern and were predominantly classified as grade 2 tumours. GCDFP-15 and hormone receptors were variably expressed. HER2 and podoplanin were negative in all cases. In one case, spreading to regional lymph nodes was observed. No cases were associated with death due to the disease. CONCLUSION: As immunohistochemical analysis lacks specificity in distinguishing primary cutaneous apocrine carcinoma from a cutaneous metastasis of breast carcinoma, detailed clinical history, breast examination, adequate treatment and follow-up are necessary to confirm a diagnosis of primary cutaneous apocrine carcinoma.

Germline and somatic mutations in patients with multiple primary melanomas: a next generation sequencing study.

INTRODUCTION: Multiple primary melanomas (MPM) occur up to 8% of patients with cutaneous malignant melanoma (CMM). They are often sporadic harbouring several somatic mutations, but also familial cases harbouring a CDKN2A germline mutation have been describe in Caucasian populations. The aim of this study was to investigate the incidence, the distribution patterns and the impact of known and unknown germline and somatic mutations in patients with MPM from Italy. MATERIALS AND METHODS: One-hundred and two MPM patients were enrolled for germline mutation analysis, and five patients with at least four MPMs were identified for somatic mutation analysis. The demographic, pathologic and clinical features were retrieved from medical records. Molecular analysis for both germline and somatic mutations was performed in genomic DNA from peripheral blood and tissue samples, respectively, through a next generation sequencing approach, using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup for somatic analysis and a commercial cancer hotspot panel for somatic analysis. RESULTS: CDKN2A mutations were detected in 6/16 (37.5%) and 3/86 (3.5%) MPM cases with and without family history for melanoma, respectively. Furthermore, multiple MC1R and, to a lesser extent, ATM variants have been identified. BAP1 variants were found only in MPM patients from southern Italy. The most frequent somatic variants were the pathogenic BRAFV600E and TP53, followed by KIT, PIK3CA, KDR, and NRAS. Single APC, ERBB4, MET, JAK3 and other variants with unknown function were also detected. CONCLUSIONS: CDNK2A mutation is the most relevant susceptibility mutation in Italian patients with MPM, especially those with a family history for CMM. The prevalence of this mutation and other sequence variants identified in this study varies among specific sub-populations. Furthermore, some heterogeneity in driver somatic mutations between sporadic MPMs has been observed, as well as in a number of associated sequence variants the clinical impact of which needs to be further elucidated.

Appearance of cutaneous melanoma and subcutaneous metastases in metastatic gastric carcinoma undergoing chemotherapy with oral 5-fluorouracil prodrug.

Metastatic skin lesions of gastric cancers usually appear as nonspecific, firm, and hyperpigmented nodules. However, they occasionally present as unusual skin manifestations that mimic other skin disorders. We describe a case of multiple cutaneous metastases from gastric cancer resembling sebaceous cysts with a synchronous melanoma, in a patient after fluoropyrimidine-based systemic chemotherapy. Melanoma occurring as a second cancer has been recognized in patients having undergone previous chemotherapy or radiation for another cancer. We can assume that the capecitabine-based chemotherapy may have played a role in the development of the melanocytic neoplasm. Our observation adds extra evidence to the link between fluoropyrimidine-based immunosuppression and the induction of melanocytes' proliferation and transformation. For these reasons, it is advisable to require dermatological checkups for patients undergoing chemotherapy treatments in order to identify suspicious melanocytic lesions as soon as possible.

Prognostic impact of regression in patients with primary cutaneous melanoma >1 mm in thickness.

BACKGROUND: The impact of histologic regression on sentinel lymph node biopsy (SLNB) status and on clinical outcome is uncertain. OBJECTIVE: To investigate whether and to what extent regression <75% is able to predict SLNB status and clinical outcome of patients with melanoma >1-mm thick. METHODS: The study included patients with diagnoses given at 4 centers of the Italian Melanoma Intergroup. Univariate and multivariate Cox proportional hazard models stratified by center were used to analyze the effect of regression on disease-free interval and melanoma-specific survival. RESULTS: Out of 1182 patients given primary cutaneous melanoma diagnoses during 1998-2015 with a Breslow thickness >1 mm, 954 (304 with and 650 without regression) were included in the analysis. The proportion of patients with a positive SLNB was lower in patients with regression than without (24.4% vs 31.6%, chi-squared test P = .0368). At multivariate analysis, no association was detected between regression and disease-free interval (hazard ratio 1.11, 95% confidence interval 0.85-1.46; P = .4509) or melanoma-specific survival (hazard ratio 1.05, 95% confidence interval 0.77-1.44; P = .7600). LIMITATION: Retrospective analysis. CONCLUSION: In our series, regression was not an independent prognostic factor in primary cutaneous melanoma patients with Breslow thickness >1 mm whereas it was associated with a lower incidence of SLNB positivity.

Fluorescence-advanced videodermatoscopy: A promising and potential technique for the in vivo evaluation of vitiligo.

Fluorescence advanced videodermatoscopy (FAV) has been proposed recently to be a new, noninvasive method for in vivo skin examination at high magnification. The working principle underlying FAV relates to the ability of endogenous molecules to absorb specific wavelengths and emit fluorescence. Herein we report our experience with FAV in the study of active, non-segmental vitiligo treated with narrowband UVB. Our findings indicate that FAV has the potential for application in the clinical follow-up, disease prognosis, and therapeutic monitoring of vitiligo.