Dermoscopy and reflectance confocal microscopy of solitary flat pink lesions: A new combined score to diagnose amelanotic melanoma.

BACKGROUND: Differential diagnosis of amelanotic/hypomelanotic melanoma among solitary flat pink lesions is challenging, due to limited clinical and dermoscopic clues. Dermoscopy and reflectance confocal microscopy assessments improve diagnostic accuracy, but their combined capacity among solitary flat pink lesions is yet to be defined. OBJECTIVES: To determine (i) whether diagnostic accuracy is improved with combined dermoscopy and reflectance confocal microscopy, (ii) a model to estimate probability of flat amelanotic/hypomelanotic melanoma among solitary flat pink lesions. METHODS: A retrospective single-centre study of solitary flat pink lesions, excised for suspected malignancy between 2011 and 2022 was performed. Images were independently evaluated by two dermatologists, blinded to histopathological diagnosis. Diagnostic performance was evaluated on the receiver operating characteristic curve and the area under the curve. Predictive features were identified by univariate and multivariate logistic regression analyses. A final predictive nomogram of independent risk factors was calculated by backward likelihood ratio. Hypothesis being tested was formulated before data collection. RESULTS: A total of 184 patients (87 females, 47.3%) were included; mean age was 57.6 years (19-95). Combined dermoscopy and reflectance confocal microscopy was more sensitive (83%, CI 69.2-92.4 and 91.5%, CI 79.6-97.6) than dermoscopy alone (76.6%, CI 62.0-87.7 and 85.1%, CI 71.7-93.8). Predictive features defined the new model, including linear irregular vessels (4.26-folds, CI 1.5-12.1), peripheral pigment network (6.07-folds, CI 1.83-20.15), remnants of pigmentation (4.3-folds, CI 1.27-14.55) at dermoscopy and atypical honeycomb (9.98-folds, CI 1.91-51.96), disarranged epidermal pattern (15.22-folds, CI 2.18-106.23), dendritic pagetoid cells in the epidermis (3.77-folds, CI 1.25-11.26), hypopigmented pagetoid cells (27.05-folds, CI 1.57-465.5), and dense and sparse nests (3.68-folds, CI 1.24-10.96) in reflectance confocal microscopy. Diagnostic accuracy of the model was high (AUC 0.91). CONCLUSIONS: Adjunctive reflectance confocal microscopy increases diagnostic sensitivity of flat amelanotic/hypomelanotic melanoma differential diagnosis. The proposed model requires validation.

Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients' management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place. METHODS: We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis. RESULTS: Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability. CONCLUSIONS: Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease.

Dermoscopy of cutaneous adnexal tumours: a systematic review of the literature.

Cutaneous adnexal tumours (ATs) encompass a variegated group of hamartomas and benign or malignant tumours, originating from the hair follicle, sebaceous, eccrine or apocrine glands that may simulate other cutaneous neoplasms. This study aims to provide a comprehensive overview of the spectrum of clinical and dermoscopic features of ATs, to better define these lesions and assist in the differential diagnosis. We performed a two-step systematic search of the literature in PubMed, Embase and Cochrane Library databases from inception until 4 September 2020. In the first step, we aimed to define histological variants of ATs with descriptions of dermoscopic criteria. The second step included a search for the name of each previously identified AT variants in the same databases adding 'AND (epilum* or dermosc* or dermatosc*)'. All study types in English language reporting dermoscopic images of ATs were included. Collisions between ATs and other inflammatory or neoplastic skin lesions were excluded, with the exception of collisions with a sebaceous nevus. The protocol of this study was prospectively registered in PROSPERO (CRD42021244677). In total, 206 articles met our inclusion criteria, encompassing 372 ATs in 365 patients. Most ATs were apocrine-eccrine (n = 217, 58.3%, n = 173 benign) with a prevalence of poromas (n = 82), followed by follicular ATs (n = 88, 23.7%, n = 83 benign) and sebaceous ATs (n = 67, 18.0%, n = 49 benign). Most patients had a single AT lesion (320, 86.0%), while 42 (11.3%) had multiple ATs. A syndrome causing multiple ATs was identified in 15 patients. Histopathological analysis revealed 82% benign (n = 305) and 18.0% malignant (n = 67). ATs were classified according to their ability to mimic four groups of more common skin tumours: basal cell carcinoma, squamous cell carcinoma, melanocytic lesions and benign cutaneous lesions. Moreover, we have highlighted the ability of malignant variants of ATs to simulate benign skin lesions. This systematic review offers a comprehensive overview of the common clinical and dermoscopic features of follicular, sebaceous and apocrine-eccrine ATs and details possible differential dermoscopic features.

Flat scalp melanoma dermoscopic and reflectance confocal microscopy features correspond to histopathologic type and lesion location.

BACKGROUND: Dermoscopy and Reflectance Confocal Microscopy (RCM) features of scalp melanoma according to lesion location and histopathology have not been fully investigated. OBJECTIVES: To reveal dermoscopic and RCM features of scalp melanoma according to lesion location and histopathology. METHODS: We retrospectively retrieved images of suspicious, atypical excised, flat melanocytic lesions of the scalp, assessed on dermoscopy and RCM at five centres, from June 2007 to April 2020. Lesions were classified according to histopathological diagnoses of nevi, lentigo maligna melanoma (LM/LMM) or superficial spreading melanoma (SSM). Clinical, dermoscopic and RCM images were evaluated; LM/LMM and SSM subtypes were compared through multivariate analysis. RESULTS: Two hundred forty-seven lesions were included. In situ melanomas were mostly LM (81.3%), while invasive melanomas were mostly SSM (75.8%). Male sex, baldness and chronic sun-damaged skin were associated with all types of melanomas and in particular with LM/LMM. LMs were mostly located in the vertex area and SSM in the frontal (OR: 8.8; P < 0.05, CI 95%) and temporal (OR: 16.7; P < 0.005, CI 95%) areas. The dermoscopy presence of pseudo-network, pigmented rhomboidal structures, obliterated hair follicles and annular-granular pattern were associated with LM diagnoses, whereas bluish-white veil was more typical of SSM. Observations on RCM of atypical roundish and dendritic cells in the epidermis were associated with SSM (42.4%) and dendritic cells with LM (62.5%) diagnoses. Folliculotropism on RCM was confirmed as a typical sign of LM. CONCLUSIONS: Flat scalp melanomas reveal specific dermoscopic and RCM features according to histopathologic type and scalp location.

Sclerosing nevus with pseudomelanomatous features: dermoscopic and confocal aspects.

BACKGROUND: Sclerosing nevus with pseudomelanomatous features (SNPFs) is a clinical and pathologic entity that mimics melanoma both clinically and histologically. The lesion is a melanocytic nevus, histologically characterized by fibrosis and a pseudomelanomatous proliferation. It is typically seen in young to middle-aged individuals, mainly on the back, where microtrauma or inflammatory changes are more frequent. Dermoscopic description of SNPF has been reported so far in one case series. OBJECTIVE: The aim of our study was to describe the dermoscopic and confocal features of SNPF. METHODS: Histopathologically confirmed cases of SNPF were retrospectively collected from three referral centres in Italy. Only lesions with available clinical, dermoscopic and histopathological data were included; confocal images were also retrieved, when available. Lesions were evaluated for the presence of 12 dermoscopic and five confocal criteria previously described. RESULTS: The study population included 93 lesions in as many patients (71 men and 22 women; median age: 38 years). Dermoscopically, we found a predominance of dark colours, in particular brown and blue, which were found in all lesions and the vast majority of the lesions (86/93; 92.5%) displayed at least one structureless area. By the combination of colours and structures, we observed that the majority of the lesions (67/92; 72%) were characterized by more than one structure and more than one colour. Confocal evaluation was performed on a subset of 24/93 lesions showing a regular architecture pattern (19/24 cases, 79%), with a predominance of the ringed pattern. The presence of focal cytologic atypia at the dermal-epidermal junction was present in 12/24 cases (50%) with a prevalent dendritic-shaped cell proliferation. CONCLUSIONS: The current study demonstrated that SNPF was frequently characterized, on dermoscopic examination, by more than one structure and more than one colour and on confocal microscopy by a regular ringed pattern with focal dendritic atypical cells.

Diagnostic accuracy of ex vivo fluorescence confocal microscopy in Mohs surgery of basal cell carcinomas: a prospective study on 753 margins.

BACKGROUND: Frozen histological sections are used for intraoperative margin assessment during Mohs surgery. Fluorescence confocal microscopy (FCM) is a new tool that offers a promising and faster alternative to frozen histology. OBJECTIVES: To evaluate prospectively in a clinical setting the accuracy of FCM vs. frozen sections in margin assessment of basal cell carcinoma (BCC). METHODS: Patients with BCC scheduled for Mohs surgery were prospectively enrolled. Freshly excised surgical specimens were examined by FCM and then frozen sections were evaluated. Permanent sections were obtained, in order to validate the sample technique. A blind re-evaluation was also performed for discordant cases. Sensitivity and specificity levels, as well as positive and negative predictive values (PPV and NPV, respectively), were calculated and receiver-operating characteristic curves generated. RESULTS: We enrolled 127 BCCs in as many patients (40·2% females). Seven hundred and fifty-three sections were examined. All BCCs were located in the head and neck area. In evaluating the performance of FCM vs. frozen sections, sensitivity was 79·8%, specificity was 95·8%, PPV was 80·5% and NPV was 95·7% [area under the curve 0·88, 95% confidence interval 0·84-0·92 (P < 0·001)]. Forty-nine discordant cases were re-evaluated; 24 were false positive and 25 false negative. The performance of FCM and frozen sections was also evaluated according to the final histopathological assessment. CONCLUSIONS: We found high levels of accuracy for FCM vs. frozen section evaluation in intraoperative BCC margin assessment during Mohs surgery. Some technical issues prevent the wide use of this technique, but new devices promise to overcome these limitations.

Integration of dermoscopy and reflectance confocal microscopy for distinguishing melanomas from nevi of the breast area.

BACKGROUND: Nevi of special sites encompass a class of benign lesions characterized by the presence of atypical clinical and histopathological features that can be difficult to distinguish from melanoma. Dermoscopy and reflectance confocal microscopy may improve the clinical assessment of melanocytic lesions to avoid unnecessary excisions. OBJECTIVES: The aim of this study was to assess the value of specific dermoscopic and confocal criteria in distinguishing melanomas from nevi of the breast area. METHODS: Dermoscopic and confocal images from consecutive patients with at least one clinically and/or dermoscopically equivocal melanocytic skin lesion of the breast area were retrospectively evaluated. In this case-control study, only histopathologically proven melanomas (cases) and nevi (controls) were included. Spearman's coefficients were first calculated to flag significant correlation; then univariate and multivariate logistic regression analyses were performed to assess which factors were independently associated with the histopathological diagnosis. Finally, a mixed dermoscopic/confocal score was created to distinguish nevi from melanomas on the breast area. RESULTS: The study population included 55 skin lesions of the breast area, 34 (61.8%) nevi and 21 (38.2%) melanomas. Among dermoscopic criteria, atypical network and irregular pigmentation resulted independently associated with melanoma diagnosis (OR: 11.1; 95% CI 1.0-119.9; P:0.048 and OR: 6.5; 95% CI 1.1-37.5; P:0.037, respectively). Furthermore, on RCM examination, the presence of pagetoid cells was an independent positive predictor for melanoma (OR: 38.5; 95% CI 3.9-379.6; P:0.002). The mixed score showed high levels of sensitivity and specificity, 95.2% and 82.4%, respectively, which were higher than dermoscopic and confocal evaluations alone. CONCLUSION: The combined use of dermoscopy and confocal microscopy in the triage of pigmented lesions of the breast area may help in increasing the diagnostic accuracy and avoiding unnecessary excisions.

Dermoscopic and reflectance confocal microscopy features of cutaneous squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the skin is a highly prevalent neoplasm. The management and the prognosis of this tumour are dependent on its invasiveness and its grade of differentiation. OBJECTIVES: To evaluate whether specific dermoscopic and reflectance confocal microscopy (RCM) criteria can predict the diagnosis of invasive SCC vs. in situ SCC and poorly differentiated compared with well- and moderately differentiated SCC. METHODS: Dermoscopic and RCM images of SCC were retrospectively evaluated for the presence of predefined criteria. RESULTS: Among 143 SCCs, 121 cases had a complete set of images and thus were included in the study set. The head and neck area was the most frequently involved body site (74/121; 61.1%) followed by extremities (36/121, 29.7%) and trunk (11/121, 9.1%). Seventy tumours were in situ (57.8%), while 51 were invasive (42.1%), of these 11 were poorly differentiated (21.5%), 16 were moderately differentiated (31.3%), and 24 were well differentiated (47.0%). Chi-squared analysis demonstrated that invasive SCCs were characterized by polymorphic vessels, erosion/ulceration, architectural disarrangement, speckled nucleated cells in the dermis, irregularly dilated vessels and absence of hyperkeratosis. Buttonhole vessels, white structureless areas and dotted or glomerular vessels were significantly associated with in situ lesions. Poorly differentiated SCCs were typified by red areas, erosion/ulceration and architectural disarrangement. Well- or moderately differentiated SCCs were associated with white areas and speckled nucleated cells in the epidermis. CONCLUSION: Clinical, dermoscopic and RCM images provide useful information that should be integrated in order to achieve the optimal therapeutic management for the patient.

Dermoscopic features predicting the presence of mitoses in thin melanoma.

BACKGROUND: The latest AJCC classification has included the number of mitoses as a factor for upstaging thin melanomas. Meanwhile, while dermoscopy has often been used to predict melanoma thickness, its value in predicting number of mitoses remains unknown. OBJECTIVE: Our aim is to evaluate the correlation between dermoscopic features and the presence of mitoses in a consecutive cohort of thin melanomas. METHODS: A case control study has been performed to identify specific dermoscopic parameters that could differentiate thin melanomas with 1 or more mitoses per mm2 from those without mitoses. RESULTS: Of 177 melanomas equal to or thinner than 1mm, 131 (74%) lesions had no mitoses and 46 (36%) lesions had at least 1 mitosis×mm2. Dermoscopic features associated with the presence of 1 or more mitoses were the following: peripheral streaks (OR 4.11; 95% CI 1.94-8.71) and black colour (OR 4.70; 95% CI; 2.28-9.68). In contrast, atypical pigment network (OR (0.30; 95% CI 0.15-0.61)) and brown colour (OR 0.36; 95% CI 0.18-0.75) were associated to melanomas without mitoses. The same variables were also associated to the increasing number of mitoses at linear regression. CONCLUSION: Black colour and peripheral streaks can predict the presence of mitoses in thin melanoma, while atypical pigment network and brown colour are associated to thin melanoma without mitoses.

Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy.

The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer. We recently showed that CDH6 is a TGFß target and an EMT marker in thyroid cancer, suggesting a role for this protein in the progression of this type of tumor. Papillary thyroid carcinomas (PTCs) are usually indolent lesions. However, metastatic spreading occurs in about 5% of the cases. The identification of molecular markers that could early predict the metastatic potential of these lesions would be strategic to design more tailored approaches and reduce patients overtreatment. In this work, we assessed the role of CDH6 in the metastatic progression of thyroid cancer. We showed that loss of CDH6 expression profoundly changes cellular architecture, alters the inter-cellular interaction modalities and attenuates EMT features in thyroid cancer cells. Using a yeast two-hybrid screening approach, based on a thyroid cancer patients library, we showed that CDH6 directly interacts with GABARAP, BNIP3 and BNIP3L, and that through these interactions CDH6 restrains autophagy and promotes re-organization of mitochondrial network through a DRP1-mediated mechanism. Analysis of the LIR domains suggests that the interaction with the autophagic machinery may be a common feature of many cadherin family members. Finally, the analysis of CDH6 expression in a unique cohort of human PTCs showed that CDH6 expression marks specifically EMT cells. and it is strongly associated with metastatic behavior and worse outcome of PTCs.

Association between dermoscopic and reflectance confocal microscopy features of cutaneous melanoma with BRAF mutational status.

BACKGROUND: Melanomas harbouring common genetic mutations might share certain morphological features detectable with dermoscopy and reflectance confocal microscopy. BRAF mutational status is crucial for the management of metastatic melanoma. OBJECTIVES: To correlate the dermoscopic characteristics of primary cutaneous melanomas with BRAF mutational status. Furthermore, a subset of tumours has also been analysed for the presence of possible confocal features that might be linked with BRAF status. METHODS: Retrospectively acquired dermoscopic and confocal images of patients with melanoma in tertiary referral academic centres: Skin Cancer Unit in Reggio Emilia and at the Melanoma Unit in Barcelona. Kruskal-Wallis test, logistic regressions, univariate and multivariate analyses have been performed to find dermoscopic and confocal features significantly correlated with BRAF mutational status. RESULTS: Dermoscopically, the presence of irregular peripheral streaks and ulceration were positive predictors of BRAF-mutated melanomas with a statistically significance value, while dotted vessels were more represented in wild-type melanomas. None of the evaluated reflectance confocal microscopy features were correlated with genetic profiling. CONCLUSIONS: Ulceration and irregular peripheral streaks represent dermoscopic feature indicative for BRAF-mutated melanoma, while dotted vessels are suggestive for wild-type melanoma.

Efficacy of allergen immunotherapy in reducing the likelihood of developing new allergen sensitizations: a systematic review.

BACKGROUND: Guidelines and position papers indicate that allergen immunotherapy (AIT) is the only disease-modifying treatment, including prevention of the onset of new allergen sensitizations. However, this preventive effect was shown by only a few observational studies. Our aim was to systematically review the efficacy of AIT in preventing the onset of new allergen sensitizations. METHODS: Computerized bibliographic searches of Medline, EMBASE, and the Cochrane Library (through June 2015) were supplemented with manual searches of reference lists. Observational studies or randomized controlled trials with a long-term observation period were included. Paired reviewers extracted data about study characteristics and assessed biases. The end point was the risk difference in the onset of new allergen sensitizations between patients treated with AIT and pharmacotherapy. The strength of the evidence was graded based on the risk of bias, consistency, and magnitude of effect, according to the GRADE Working Group's guide. RESULTS: Eighteen studies (1049 children, 10 057 adults) met the inclusion criteria. The risk of bias was high in all but one study. Low evidence supports the position that AIT prevents the onset of new allergen sensitizations, with 10 of 18 studies reporting a reduction in the onset of new sensitizations in patients treated with AIT vs placebo. Small studies and studies with a shorter follow-up showed the highest benefit of AIT. CONCLUSIONS: The overall evidence provides a low-grade level of the evidence supporting the efficacy of AIT in preventing the onset of new allergen sensitizations, but high-quality studies could change this estimate.

Clinical and dermoscopic clues to differentiate pigmented nail bands: an International Dermoscopy Society study.

BACKGROUND: Longitudinal melanonychia might be difficult to differentiate and the use of dermoscopy can be useful for the preoperative evaluation and management decision. OBJECTIVES: The aim of our study was to investigate clinical and dermoscopic criteria of acquired longitudinal melanonychia in adults to identify the best predictors of melanoma using a multivariate analysis and to explore eventual new dermoscopic criteria for nail melanoma diagnosis. METHODS: In this retrospective observational study, 82 histopathologically diagnosed, acquired nail pigmented bands were collected and examined. All variables were included in the analysis and examined as possible predictors of nail melanoma. Both univariate and multivariable analyses have been performed. RESULTS: Among 82 cases, 25 were diagnosed as nail melanoma and 57 as benign lesions (including 32 melanocytic nevi and 25 benign melanocytic hyperplasia). Melanoma cases were significantly associated with a width of the pigmented band higher than 2/3 of the nail plate, grey and black colours, irregularly pigmented lines, Hutchinson and micro-Hutchinson signs, and nail dystrophy. Granular pigmentation, a newly defined dermoscopic criterion, was found in 40% of melanomas and only in 3.51% of benign lesions. CONCLUSIONS: Dermoscopic examination of longitudinal melanonychia provides useful information that could help clinicians to improve melanoma recognition.