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Background/Objectives: There is currently no guidance on how to interpret the global degrees of activity (worsening) and repigmentation (improvement) in vitiligo. Stratification into global degrees can be completed for static evaluations (e.g., visible disease activity signs) and dynamic assessments (e.g., evolution over time). For the latter, the Vitiligo Disease Activity Score (VDAS 15&60 ) and Vitiligo Disease Improvement Score (VDIS 15&60 ) were recently validated. Methods : In the current study, a Physician Global Assessment (PGA) for disease activity (worsening) and repigmentation (improvement) was evaluated for validity (construct) and reliability (inter- and intrarater) based on a photo set of 66 patients. Subsequently, the PGA activity (worsening) and repigmentation (improvement) were used to stratify the Vitiligo Extent Score plus (VESplus), VDAS 15&60 or VDIS 15&60 into three global categories (slightly, moderately and much worse/improved), based on ROC analysis. Results : For the VESplus, cut-off values for the categories 'slightly, moderately and much worse' were >0.3%, >27.71% and >128.75% BSA (relative changes in the affected total BSA), respectively. For the categories 'slightly, moderately and much improved', they were >0%, >4.87% and >36.88% BSA (relative changes in the affected total BSA), respectively. The optimal cut-off values of the number of active (VDAS 15 ) body areas were >0 areas for slightly worse, >2 areas for moderately worse and >7 for much worse. For VDIS 15 , the cut-off values for slightly improved and moderately improved were >0 and >1. For VDAS 60 and VDIS 60 , the cut-off points were >0.5, >3, >9.5 and >0.5 and >1.5, respectively. The results should be interpreted with caution in patients with extensive vitiligo due to the rather limited disease extent of the included patient population (VESplus (median: 3.2%)). Conclusions : This research will aid in the development of more detailed international definitions.

Background: The assessment of the individual evolution of vitiligo is important for therapeutic decision making in daily practice. A fast, simple and validated physician-reported score to assess clinical changes in depigmentation over time in separate parts (activity and improvement) is currently missing., Objective: The main objective of the study was to develop and validate the Vitiligo Disease Activity Score (VDAS) and Vitiligo Disease Improvement Score (VDIS)., Methods: The Vitiligo Disease Activity Score (VDAS) and Vitiligo Disease Improvement Score (VDIS) were evaluated based on a photo set of 66 patients with two different time points. In the first (short) version, only the number of changing body regions was counted based on 15 predefined areas (VDAS 15 and VDIS 15 ), while in the second (extensive) version the degree of worsening or improvement from +4 to -4 for each body area was added for a more detailed assessment (VDAS 60 and VDIS 60 ). Content and construct validity were tested. In addition inter-, intrarater reliability and feasibility were evaluated by 7 (test) and 5 (retest) physicians., Results: Evidence for content and construct validity was provided. Overall, VDAS 15 , VDIS 15 , VDAS 60 and VDIS 60 demonstrated good to excellent inter-rater reliability [intraclass correlation (ICC): VDAS: range = 0.797-0.900; VDIS: range = 0.726-0.798]. The intrarater reliability ICCs were 0.865 and 0.781 for the VDAS 15 and VDIS 15 , respectively. Similar results were obtained for the VDAS 60 and VDIS 60 (ICC = 0.913 and 0.800, respectively). Completion time was short (median: 122 s/patient (first round); 95 s/patient (second round)]., Limitations: Single tertiary centre mainly of skin phototype 2 to 3., Conclusion: The VDAS and VDIS appear to be valid, reliable and feasible instruments to score the evolution of vitiligo lesions. This accommodates the current urgent need for a simple, standardized and practical assessment of vitiligo activity and improvement over time., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Ectodysplasin receptor EDAR is seen as a typical Tumor Necrosis Factor receptor (TNFR) family member known to interact with its ligand Eda-A1, and signaling mainly through the nuclear factor-kappaB (NF-κB) and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in EDAR transduction cascade cause anhidrotic ectodermal dysplasia. Here, we report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-κB pathway. Contrarily to other death receptors, EDAR does recruit caspase-8 to trigger apoptosis but solely upon ligand withdrawal, thereby behaving as the so-called dependence receptors. We propose that pro-apoptotic activity of unbound EDAR confers it a tumor suppressive activity. Along this line, we identified loss-of-pro-apoptotic function mutations in EDAR gene in human melanoma. Moreover, we show that the invalidation of EDAR in mice promotes melanoma progression in a B-Raf mutant background. Together, these data support the view that EDAR constrains melanoma progression by acting as a dependence receptor.

Background: Subungual squamous cell carcinoma (SSCC) and subungual melanoma (SUM) are rare tumors. Several case reports of association of SSCC with SUM (SSCC-SUM) have been published., Objective: We sought to document the clinical, dermoscopic, and histologic features in a case series of SSCC-SUMs and describe their relative frequency compared with those of SSCC and SUM., Methods: All patients who underwent surgical exploration of the nail apparatus with a dermatopathologic examination from 2012 to 2015 were reviewed retrospectively to identify all cases of SSCC, SUM, and SSCC-SUM. For patients with SSCC-SUM, clinical characteristics were obtained from electronic medical records. All histologic specimens were reviewed by 3 dermatopathologists., Results: The medical records of 456 patients were reviewed. SSCC was diagnosed in 78 (17%), SUM was diagnosed in 63 (14%), and SSCC-SUM was diagnosed in 9. Patients with SSCC-SUM accounted for 11% of those with a diagnosis of SSCC (9 of 78) and 14% of those with a diagnosis of SUM (9 of 63)., Limitations: This was a single-institution retrospective study., Conclusion: The association of SSCC and SUM is relatively frequent in patients with SUM and warrants further consideration to understand the underlying mechanisms involved., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: Liquid-based (LB)-FNA is widely recognized as a reliable diagnostic method to evaluate thyroid nodules. However, up to 30% of LB-FNA remain indeterminate according to the Bethesda system. Use of molecular biomarkers has been recommended to improve its pathological accuracy but implementation of these tests in clinical practice may be difficult. Here, we evaluated feasibility and performance of molecular profiling in routine practice by testing LB-FNA for BRAF, N/HRAS and TERT mutations., Methods: We studied a large prospective cohort of 326 cases, including 61 atypia of undetermined significance, 124 follicular neoplasms, 72 suspicious for malignancy and 69 malignant cases. Diagnosis of malignancy was confirmed by histology on paired surgical specimen., Results: Mutated LB-FNAs were significantly associated with malignancy regardless of the cytological classification. Overall sensitivity was 60% and specificity 89%. Importantly, in atypia of undetermined significance and follicular neoplasm patients undergoing surgery according to the Bethesda guidelines, negative predictive values were 85.4% and 90% respectively. TERT promoter mutation was rare but very specific for malignancy (5.5%) suggesting that it could be of interest in patients with indeterminate cytology., Conclusions: Mutation profiling can be successfully performed on thyroid LB-FNA without any dedicated sample in a pathology laboratory. It is an easy way to improve diagnostic accuracy of routine LB-FNA and may help to better select patients for surgery and to avoid unnecessary thyroidectomies., (© 2017 John Wiley & Sons Ltd.)

Background: Cutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized., Objectives: To study the cutaneous histopathological changes associated with MPE, sMPE and DRESS., Methods: A retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013., Results: The number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS., Limitations: This was a retrospective study., Conclusions: Numerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS., (© 2016 European Academy of Dermatology and Venereology.)

Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAF V 600 -mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITF low /p75 high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Acral lentiginous melanoma (ALM) can be difficult to differentiate from acral nevus. Reflectance confocal microscopy (RCM) is widely used for the diagnosis of melanocytic tumours, but the RCM features of ALM and acral nevus have not been described yet., Objective: To determine the RCM features of ALM and acral nevus, and their correlation with clinical and histological characteristics., Methods: Retrospective study of 17 cases of ALM and 26 acral nevi., Results: Pagetoid cells were present in all ALMs with a visible epidermis and in three nevi. A proliferation of atypical melanocytes at the dermal-epidermal junction (DEJ) and/or in the dermis was visible in nine ALMs but not in nevi. The histopathological examination of initial skin biopsies was unable to diagnose ALM in four cases, differing from RCM that could identify malignant tumour cells by exploring the whole lesions., Conclusion: Reflectance confocal microscopy can help in the differentiation of ALM and acral nevus, and to guide the biopsy., (© 2015 European Academy of Dermatology and Venereology.)

Introduction: Diffuse malignant mesothelioma (MMD) is a rare disease. The diagnosis is difficult and needs an antibody panel. The tumor suppressor gene BRCA1 associated protein 1 (BAP1) is involved in several cancers, including MMD. Loss of BAP1 expression is correlated with BAP1 somatic or constitutional genetic defects. Our work assesses the value of integrating BAP1 in the panel of antibodies used for the diagnosis of MMD., Materials and Methods: Immunohistochemical techniques were performed on cytological and histological specimens of MMD and adenocarcinoma pleural metastasis., Results: Of the 26 patients with MMD and the 24 patients with adenocarcinoma pleural metastasis, loss of BAP1 expression was observed in 11 (48%) and one adenocarcinoma (6%) on cytological specimens and in 12 MMD (48%) and in one adenocarcinoma (5%) on biopsy specimens. The concordance between immunocytochemistry and immunohistochemistry was 100%. The specificity of BAP1 was 100% on cytological and biopsy specimen for the diagnosis of malignancy in case of mesothelial proliferation., Discussion and Conclusion: Loss of BAP1 expression is an indicator of MMD in a context of mesothelial proliferation. This immunohistochemistry could be integrated in the panel of immunostaining used for MMD diagnosis, either on histological or cytological samples. Furthermore, loss of BAP1 expression guides the patient to an oncology genetic counseling in order to eliminate a MMD developed as part of a constitutional genetic defect., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe adverse drug reaction. Large detailed studies of histopathological features of DRESS are sparse and suggest an association between keratinocyte damage and the severity of visceral involvement., Objectives: To describe the dermatopathological features in a large series of DRESS and their possible association with clinical features and the severity of the disease., Methods: A retrospective analysis of the clinicobiological and dermatopathological features in a monocentric cohort of patients with DRESS., Results: From January 2005 to January 2013, 45 patients were validated as probable or definite cases of DRESS. The median age was 64 years (range 3-87). The most frequent clinical and biological features included: fever ≥38.5°C (95%), facial oedema (72%), enlarged lymph nodes (51%), visceral involvement (75%), blood eosinophilia (97%) and atypical lymphocytes (82%). Severe DRESS occurred in 24% and a fatal outcome in 6% of patients. Histopathological analysis showed that no specific histopathological pattern was characteristic for DRESS. However, several changes in different cutaneous compartments were observed in 2 of 3 of cases. Spongiosis (55%) and keratinocyte damage (53%) were the most common epidermal changes. Spongiosis was associated with non-severe DRESS (P = 0.041) whereas confluent keratinocyte necrosis correlated with severe DRESS (P = 0.011). Vascular changes were frequent (88%). A moderate dermal perivascular lymphocytic infiltrate was invariably present, containing eosinophils, neutrophils and/or atypical lymphocytes in 57% of cases., Conclusions: Epidermal changes are indicative for the severity of DRESS., (© 2015 European Academy of Dermatology and Venereology.)

Background: Depigmentation therapy can be an option in adults with extensive and refractory vitiligo. Remaining pigmented patches can be removed using depigmentation creams (monobenzyl ether of hydroquinone 20%), laser therapy or cryotherapy. In contrast to cream treatment, laser therapy and cryotherapy are fast and targeted methods, capable of destroying melanocytes selectively on one specific area. Up till now, controlled trials comparing laser and cryotherapy as depigmenting treatment in vitiligo are lacking., Material and Methods: We performed a retrospective comparative study in 22 generalized vitiligo patients. Thirty-one pigmented test regions were exposed to cryotherapy and 20 to 755 nm laser therapy. The mean surface area per test region was 3.55 cm2 and number of treatments per test region was limited to one single session in 84.3% and varied up to four sessions (2.0%)., Results: Overall no significant difference in the capacity to induce depigmentations was observed between cryotherapy (46.7%) and laser therapy (42.9%) after one treatment. The percentage of induced depigmentation was significantly different according to the body location (P = 0.005) with best results on the trunk, followed by the arms, face, neck and less on the hands. Variables that positively influenced depigmentation results were a younger age of vitiligo onset (P = 0.012), skin type V (P < 0.001) and clinical presence of Koebner's phenomenon (P = 0.039). Despite initial failure after one treatment, repetitive treatment sessions on eight test areas resulted in successful depigmentation. Side-effects were restricted to cryotherapy and concerned mainly hyperpigmentation in the face., Conclusion: To our knowledge, this is the first study comparing head-to-head depigmentation strategies intra- and inter-individually. We could demonstrate that in general laser and cryotherapy are equally effective in inducing depigmentations in generalized vitiligo patients. Retreatment of the same area may be required in case of initial failure., (© 2014 European Academy of Dermatology and Venereology.)

Background: Ex vivo fluorescence confocal microscopy (FCM) permits real-time imaging of freshly excised skin tissues. Its usefulness as a time-sparing alternative to frozen sections in Mohs surgery of basal cell carcinoma is well documented., Objectives: The purpose of this study was to describe the ex vivo FCM features of a series of benign and malignant nonpigmented tumours of the nail unit, and to correlate them with conventional histopathology., Patients and Methods: Nail apparatus tumours from 10 patients were imaged during surgical exploration using ex vivo FCM after immersion in acridine orange. Confocal mosaics of the freshly performed biopsies were evaluated in real time and retrospectively compared with haematoxylin and eosin sections., Results: Our series included two invasive epithelial tumours (Group 1), four in situ or minimally invasive squamous cell carcinomas (SCC) (Group 2), three benign epithelial tumours (Group 3) and one nodular melanoma (Group 4). The correlation was excellent for malignant epithelial tumours exhibiting marked cytological and architectural atypias (Bowen disease, invasive SCC and onycholemmal carcinoma). Onychomatricomas exhibited a very peculiar aspect with densely cellular papillae. The correlation was less favourable for minimally invasive well-differentiated SCCs with slight cytological atypias. The correlation was poor for our case of amelanotic invasive subungual melanoma., Conclusions: Ex vivo FCM could be a useful tool to shorten management of nonpigmented nail tumours: in the case of a malignant tumour, it could indeed lead to performing wide excision during the same surgical procedure and possibly assessing the surgical margins., (© 2014 British Association of Dermatologists.)

Background: Although most mucosal pigmented macules are benign, it can be clinically challenging to rule out an early melanoma. Reflectance confocal microscopy (RCM) is a noninvasive imaging technique useful in discriminating between benign and malignant skin lesions., Objectives: To describe the confocal aspects of benign and malignant mucosal pigmented macules with histopathological correlations., Methods: We retrospectively reviewed the confocal images of 56 labial or genital pigmented macules including 10 macular melanomas. According to the retrospective nature of the study, we evaluated the recorded images chosen by the physicians that performed the RCM examination for each case., Results: In benign macules, the most frequently observed pattern was a ringed pattern characterized by round or polycyclic papillae, with a hyper-reflective basal layer; another pattern was characterized by sparse bright dendritic cells in the basal layer, the basal epithelial cells being otherwise less reflective. Roundish cells, a high density of dendritic cells with atypias and intraepithelial bright cells were clues to the presence of malignancy., Conclusions: Reflectance confocal microscopy seems to be a valuable tool to noninvasively differentiate benign from malignant mucosal pigmented macules and target biopsies in cases of equivocal features., (© 2013 British Association of Dermatologists.)

Second primary melanomas (SPMs) induced by vemurafenib have been recently described. The aim of this study was to define the dermoscopical signs of melanoma in this context. Patients underwent a total body examination before receiving vemurafenib. Each single melanocytic lesion was registered before therapy by digital dermoscopy (DD), and then repeated monthly until therapy disruption. Forty-two patients were included, the mean duration of follow-up was 6.7 months, and a mean number of 51 lesions per patients were captured and followed. A total number of 2,155 lesions were recorded, of which 56.1% presented at least one change during the study. More common changes concerned the color of the lesions (up to 15%) and appearance or disappearance of globules (14.6%). Thirty-six of the melanocytic lesions were surgically excised, 21 were classified as a nevus, 1 was a lentigo, and 14 as a second new primary melanoma (occurring in 21% of our patients). DD allowed us to excise only 36/2,155 (1.6%) of the lesions and permitted us to detect 14 SPM in the 42 patients with a highly efficient malignant/benign ratio of 63.6%. Although vemurafenib is now tested in an adjuvant setting DD should be systematically used in order to accurately detect SPM and reduce the number of unnecessary excisions.

Background: Other than the classic skin necrosis induced by oral anticoagulants (OAC) in patients with protein C and S deficiencies, other types of OAC induced-skin ulcers are little known. Herein, we describe an original case of recurrent pyoderma gangrenosum (PG)-like ulcers induced by OAC., Patients and Methods: A 70-year-old female heart-transplant recipient presented deep, hyperalgesic and quickly-spreading necrotic ulceration of the right leg 6 weeks after starting oral anticoagulant therapy with fluindione. Histological analysis revealed dermal infiltrate containing polynuclear neutrophils, which accords with the histopathological diagnosis of leukocytoclastic vasculitis or PG. Infectious, autoimmune and thrombophilic causes were ruled out. Fluindione was withdrawn and the ulcer healed completely within a month. Six months later, right leg ulceration recurred two weeks after the patient resumed fluindione but healed within 1 month of discontinuation of the drug. An OAC from another chemical family (warfarin) was then introduced, with further recurrence of ulceration after 2 weeks of treatment., Discussion: The chronology of events and the negativity of aetiological explorations allowed a diagnosis to be made of OAC-induced skin ulcer, a rare complication of which the pathophysiology is unclear. This is the first case of PG-like ulcers induced by OAC., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: New primary melanomas arising in patients with stage IV melanoma and receiving BRAF inhibitors have recently been reported. This raises the question of the nature of the earliest cellular events identifiable within pre-existing moles., Objectives: To use reflectance confocal microscopy (RCM) to investigate changing moles in patients using vemurafenib., Methods: In the first part of the study 23 lesions were examined by RCM before excision (performed because of digital dermoscopy changes) and histopathological examination. In the second part, 10 randomly chosen lesions in two patients were examined before and after 3 months of vemurafenib treatment., Results: The first step permitted the highlighting of an unusual RCM pattern identified in five lesions characterized by areas of marked atypia in otherwise nondysplastic lesions. In the second step, four initially nondysplastic lesions developed focal or multifocal areas of marked atypia under treatment, which were not always correlated with digital dermoscopy changes, but did correlate with histopathology. All four lesions were finally diagnosed as melanomas., Conclusions: Although the clinical relevance of such findings remains questionable, RCM allowed us to observe, at the cellular level, the earliest events occurring within vemurafenib-induced changing moles. Moreover, repeated RCM examinations permitted to confirm that microscopic marked atypia that led to the histopathological diagnosis of melanoma appeared under treatment and were not pre-existing., (© 2013 The Authors. BJD © 2013 British Association of Dermatologists.)

Background: The 'dermoscopic island' is a term that was recently proposed to design an area of a pigmented lesion with a uniform dermoscopic pattern different from the remainder of the lesion. The positive predictive value of this sign for the diagnosis of melanoma is about 50%., Objective: The purpose of our study was to see if reflectance confocal microscopy (RCM) permitted to accurately distinguish between nevi and melanoma in such lesions., Methods: Five lesions of five consecutive unselected patients, with a dermoscopic island but no feasible clear cut diagnosis on the basis of dermoscopy alone were examined by RCM before excision for histopathological evaluation., Results: Two lesions corresponded to nevi, and three lesions were early melanomas arising on a benign naevus in one case, and on a dysplastic naevus in two cases. In all five cases, RCM permitted to make the correct diagnosis, with a very good correlation with conventional histopathology., Conclusion: Reflectance confocal microscopy appears as a promising tool not only to enhance the early diagnosis of melanoma but also to avoid unnecessary excisions of lesions with a dermoscopic island., (© 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.)