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In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITWe performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITWe showed that up-regulated genes in FHITThese data suggest that ICI might not be a relevant option for NSCLC patients with FHIT

BACKGROUND The prognosis of unresectable cutaneous squamous cell carcinomas is very poor. OBJECTIVE To evaluate the efficacy and safety of panitumumab alone or in association with radiotherapy in the treatment of unresectable cutaneous squamous cell carcinoma. METHODS This was a monocentre retrospective study of all consecutive patients having received at least two courses of panitumumab, alone or in association with radiotherapy, between 2016 and 2019. The primary endpoint was the rate of best overall response, evaluated according to the RECIST 1.1 criteria. The secondary endpoints were the response and disease control rates at 6 weeks and 6 months, progression-free survival, overall survival and safety. RESULTS A total of 25 patients were included; their median age was 86 years, and 17 (86%) had a WHO performance status over 2. The best overall response rate was 52%, including four complete responses (16%) and nine partial responses (36%). All patients with complete response and five out of nine patients with partial response had received concurrent radiotherapy, in most cases in moderate to low doses (

Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by inactivating mutations in the MEN1 gene. In the literature, few cases of MEN1 have been reported because of mosaic MEN1 mutations. Objective We performed an extensive molecular characterization in several lesions and blood samples, including plasmatic circulating cell-free DNA (ccfDNA) in an exceptional case of a patient with MEN1 mosaicism causing primary hyperparathyroidism, multiple pancreatic neuroendocrine tumors (NETs), and a metastatic thymic NET. Methods Blood, ccfDNA and multiple tissue analysis were performed by next-generation sequencing. Results MEN1 mosaicism was confirmed by multiple tissue analysis. Somatic analysis of the largest pancreatic NET revealed the same MEN1 second-hit mutation as found in the thymic lesion, demonstrating its metastatic origin from the thymic lesion. Moreover, in ccfDNA we found the mosaic MEN1 mutation but also the somatic second-hit mutation found in the thymic primary tumor, revealing the presence of circulating tumor DNA (ctDNA). After surgical removal of the pancreatic metastasis, the mutated fraction of both mutations decreased, before increasing again several weeks before a new clinical relapse, suggesting that thymic ctDNA may be used as an early tumor biomarker. Conclusion This exceptional MEN1 case highlighted (1) the importance of looking for MEN1 mosaicism, (2) that MEN1 mosaicism can cause very aggressive disease, and (3) the interest in analyzing ccfDNA for confirming MEN1 mosaicism but also as a potential tumor biomarker for NET.

To prospectively assess the impact of expert pathological review of skin adnexal carcinoma diagnosis in France.From 2014 to 2019, 2573 samples from patients with newly diagnosed or suspected skin adnexal carcinomas were reviewed prospectively by expert pathologists through the national CARADERM (CAncers RAres DERMatologiques) network. Changes in diagnosis between referral and expert review were analysed regarding their potential impact on patient care or prognosis.The samples comprised 2205 newly diagnosed adnexal carcinomas, 129 benign adnexal tumours, 136 basal cell carcinomas, 74 squamous cell carcinomas, six cutaneous metastases and 13 other malignancies. There were 930 (42%) sweat gland carcinomas, of which porocarcinoma (261; 11.8%), microcystic adnexal carcinoma (125; 5.7%) and hidradenocarcinoma (109; 4.9%) were the most frequent subtypes; 778 (35%) hair follicle carcinomas, 238 (11%) sebaceous carcinomas and 212 (10%) extramammary Paget diseases/mammary-like anogenital gland adenocarcinomas. A diagnostic change between referral and expert review occurred in 503 (21.3%) patients, significantly higher for cases sent with a provisional diagnosis seeking an expert second opinion (45.7%) than for cases sent with a formal diagnosis (2.8%) (p .0001). Sweat gland carcinomas were more prone to diagnostic discrepancies than other tumours (p .0001), including 1.8% of patients with sweat gland carcinoma subtype misclassification with predicted clinical impact. Changes between benign and malignant conditions occurred in 117 samples (5% of patients).The study provides a unique description of the distribution of skin adnexal carcinomas and highlights the importance of expert review for these rare cancers. Optimal clinical management was impacted in a significant proportion of patients.

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Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.

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International audience; Rationale: Lymphoid interstitial pneumonia is a rare benign pulmonary lymphoproliferative disorder usually presenting with a subacute or chronic condition and frequently associated with autoimmune disorders, dysgammaglobulinemia, or infections. Patient concerns: A 74-year-old woman with no past medical history presented with acute dyspnea, nonproductive cough, hypoxemia (room air PaO 2 : 48 mmHg) and bilateral alveolar infiltrates with pleural effusion. Antibiotics and diuretics treatments did not induce any improvement. No underlying condition including cardiac insufficiency, autoimmune diseases, immunodeficiency, or infections was found after an extensive evaluation. Bronchoalveolar lavage revealed a lymphocytosis (60%) with negative microbiological findings. High-dose intravenous corticosteroids induced a mild clinical improvement only, which led to perform a surgical lung biopsy revealing a lymphoid interstitial pneumonia with no sign of lymphoma or malignancies. Diagnoses: Acute severe idiopathic lymphoid interstitial pneumonia. Interventions: Ten days after the surgical lung biopsy, the patient experienced a dramatic worsening leading to invasive mechanical ventilation. Antibiotics and a new course of high-dose intravenous corticosteroids did not induce any improvement, leading to the use of rituximab which was associated with a dramatic clinical and radiological improvement allowing weaning from mechanical ventilation after 10 days. Outcomes: Despite the initial response to rituximab, the patient exhibited poor general state and subsequent progressive worsening of respiratory symptoms leading to consider symptomatic palliative treatments. The patient died 4 months after the diagnosis of lymphoid interstitial pneumonia. Lessons: Idiopathic lymphoid interstitial pneumonia may present as an acute severe respiratory insufficiency with a potential transient response to rituximab. Abbreviations: EBV = Epstein-Barr virus, HIV = human immunodeficiency virus, HTLV-1 = human T-cell lymphotropic virus-1, LIP = lymphoid interstitial pneumonia.

International audience; Skin involvement in Waldenström's macroglobulinaemia is poorly described, and diagnosis of this disorder may be difficult. Many differential diagnoses are possible (other lymphomas, primary cutaneous lymphoma, etc.). Describing 2 aspects of Waldenström's macroglobulinaemia (infiltration by lymphoplasmacytic tumour cells or histological transformation into diffuse large B-cell lymphoma) allows the identification of clinical, histological and immunohistochemical diagnostic aids. Detection of the MYD88 L265P mutation is of interest. This study identified a characteristic clinical picture in non-transformed cases, and was able to distinguish between transformed and non-transformed cases by their severity and poor prognosis. Cutaneous involvement in Waldenström's macroglobulinaemia (WM) has been poorly characterized. To describe this involvement, a retrospective study of 19 patients with WM and cutaneous involvement of tumour B cells was performed. Twelve patients (group 1) had lymphoplasmacytic, non-transformed cutaneous proliferation, while in 7 cases (group 2) cutaneous involvement corresponded to histological transformation. In group 1, skin involvement was inaugural in 6 cases. The lesions were infiltrated plaques (83%), papules (25%) and tumours (42%). Four patients had a similar clinical picture (purplish, bilateral and symmetrical infiltration on the face). MYD88 L265P mutation was detected in the skin biopsy in all 6 cases tested. The 3-year specific survival rate was 88%. In group 2, cutaneous transformation occurred during the followup of the WM (71%). Lesions presented as ulcerated tumours (86%) of the trunk (57%) and lower limbs (57%). The 3-year specific survival rate was 22%. Skin involvement in WM has distinctive characteristics (e.g. clinical, histological, immunohistochemical, MYD88 L265P mutation).

is missing (Short communication)

Introduction Le granulome actinique d’O’Brien est une affection granulomateuse chronique, affectant les personnes d’âge moyen, survenant sur les zones photoexposees. La survenue de granulome actinique au cours de la prise de doxycycline, molecule connue pour sa photosensibilisation, a ete rapportee. Nous rapportons une observation originale de granulome actinique induit par la prise de statines. Materiel et methodes Une femme de 74 ans consultait pour une eruption cutanee a type de lesions erythemateuses annulaires, avec bordure papuleuse, d’extension centrifuge, situees en regions photoexposees (visage, avant-bras, bras et decollete). Les lesions etaient survenues durant l’ete 2020, et persistaient lors de la consultation en novembre, avec un debut d’amelioration spontanee. Le bilan biologique trouvait une NFS normale, des anticorps anti-nucleaires positifs a 1/160 sans specificite, notamment anti-ADN natif et anti-SSA/SSB negatifs, le bilan phosphocalcique et le taux d’enzyme de conversion etaient normaux, de meme que la fonction renale. La biopsie cutanee montrait un epiderme d’architecture normale, un infiltrat granulomateux dans le derme moyen avec des cellules geantes multinucleees et focalement des images d’elastophagocytose, apres coloration a l’orceine. L’IFD etait negative. La patiente rapportait une eruption cutanee d’aspect similaire survenue 7 ans auparavant, quelques semaines apres la mise sous atorvastatine pour une hypercholesterolemie. Le traitement avait alors ete arrete et les lesions avaient regresse. Or, un traitement par pravastatine avait ete debute quelques mois avant l’eruption actuelle. L’ensemble de ces elements nous a conduit a retenir le diagnostic de granulome actinique d’O’Brien, possiblement induit par la prise de statines. La pravastatine a ete arretee en decembre et des consignes de photoprotection ont ete donnees a la patiente. L’evolution a ensuite ete favorable en quelques mois avec regression complete des lesions. La reprise accidentelle de la statine en mars et avril, sans exposition solaire associee, ne s’est pas accompagnee de rechute et une remission complete etait constatee en mai 2021. Discussion Il s’agit a notre connaissance du premier cas de granulome actinique survenu sous statines, classe medicamenteuse a l’origine d’environ 5,7 % des photosensibilisations d’origine medicamenteuse, volontiers declenchees dans les UVA. L’evolution a ici ete favorable a l’arret du traitement et en l’absence de toute nouvelle photoexposition. Conclusion Devant des lesions cutanees annulaires, avec histologie granulomateuse, en zones photo-exposees, le diagnostic de granulome actinique doit etre evoque. Cette observation souligne l’importance de rechercher la prise de medicament photosensibilisant. Le traitement repose principalement sur une photoprotection stricte et l’arret du traitement favorisant si cela est possible.

Rationale Thoracic endometriosis is a rare disorder that can involve airways, pleura and lung parenchyma. It is the most frequent form of extra-abdominopelvic endometriosis. Multiple lung cavitations are a rare feature of thoracic endometriosis. Patient concerns A 46-year-old woman was referred to our hospital after incidental finding of multiple pulmonary cavitations with surrounding areas of ground glass opacity on a thoraco-abdominal computed tomography-scan performed for abdominal pain. Retrospectively, the patient also reported mild hemoptysis occurring 4 months ago. Diagnoses Positron emission tomography-computed tomography scan revealed moderate and homogeneous [18F] fluoro-2-deoxy-D-glucose (18F-FDG) uptake in pulmonary cavitations (maximum standardized uptake value 5.7). The diagnosis of thoracic endometriosis was confirmed by histological examination of surgical resection of a left lower lobe cavitation. Interventions and outcome Gonadotropin-releasing hormone analogues associated with add-back therapy was started. Four months after initiating pharmacological treatment, the chest computed tomography-scan showed a dramatic decrease in lung cavitations size. Lessons Thoracic endometriosis is a rare disorder requiring a multidisciplinary management including gynaecologist, pulmonologist, radiologist, nuclear physician, pathologist and thoracic surgeon for early diagnosis and treatment. Our case report highlights that an increased 18F-FDG uptake can be found in thoracic endometriosis syndrome presenting as multiple lung cavitations.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease in Western countries. Although topical and/or systemic glucocorticoids treatment efficacy is widely recognized, up to 30% of patients with BP may undergo a relapse during the first year of treatment. We investigated the protein expression of the total glucocorticoid receptor and GRβ isoform in the skin biopsy specimens from patients with BP and wondered whether such investigation at baseline provided a tool to predict disease outcome. Total GR and GRβ protein expressions were detected by immunohistochemistry at baseline on 12 patients who later relapse and 11 patients who remained on remission in comparison with 14 control patients. The expression of GRβ in the epidermis of patients with BP who later relapse was significantly higher than that in the epidermis of patients with BP controlled upon corticosteroid treatment, which was also higher than control patients. Thus, our results suggest that increased protein expression of GRβ in skin epithelial cells is predictive of reduced steroid treatment efficacy, and therefore of increased risk of disease relapse in patients with BP.

Plaque-like myofibroblastic tumor of infancy was first characterized in 2007 by Clarke et al. In the first 2 cases described, large plaque-like tumors presented in the first 3 months of life exhibited microscopic features consistent with dermatofibroma but with immunohistochemical features of myofibroblastic lineage. In 2013, Marqueling et al reported 3 additional cases, 2 of which presented in early childhood, prompting the authors to recommend that the name of this condition be shortened to plaque-like myofibroblastic tumor. We present here 4 additional cases to better characterize clinical and histopathological features of this newly recognized entity. This benign lesion is of myofibroblastic lineage and demonstrates features consistent with multiple clustered dermatofibroma.

Introduction Le mogamulizumab (MOGA) est un anticorps antiCCR4, indique dans le mycosis fongoide (MF) ou le syndrome de Sezary (SS). De 27 % a 62 % des patients ont sous MOGA une toxicite cutanee mal decrite : prurit, rash maculopapuleux,1 Steven–Johnson, 1 phenomene de rappel apres radiotherapie. Nous rapportons chez 3 patients une toxicite cutanee particuliere et discutons sa valeur pronostique. Observations Une femme de 62 ans, en echec de photopherese, interferon et bexarotene pour un SS de stade T4N0M0B1b, etait traitee par MOGA, avec une excellente reponse des 1 mois. A 6 mois, elle restait en reponse cutanee et sanguine subtotale, mais on notait des lesions squameuses en casque du cuir chevelu et des plaques infiltrees pre-auriculaires, bilaterales et symetriques. L’examen histologique montrait un infiltrat granulomateux dermique profond sans cellules residuelles de lymphome. Une femme de 65 ans etait traitee par MOGA pour un SS T4N3M0B2 apres echec du methotrexate, avec une reponse quasi complete. A 5 mois, apparaissaient un casque psoriasiforme du cuir chevelu et des plaques infiltrees pre-auriculaires bilaterales. L’examen histologique montrait le meme aspect de granulomes gigantocellulaires avec infiltrat histiocytaire et eosinophilique, sans lymphome residuel. Un homme de 56 ans, en echec de plusieurs lignes therapeutiques (interferon-photopherese, gemcitabine, doxorubicine) pour un SS T4N3M0B2, etait traite par MOGA. A 3 mois, on notait une reponse cutanee > 90 % et une remission sanguine complete. A 5 mois, apparaissaient des plaques infiltrees pre-auriculaires et un casque squameux. Les patientes 1 et 2 avaient aussi des plaques du tronc dont l’histologie montrait un aspect granulomateux (P1) ou inflammatoire riche en eosinophiles (P2) Discussion Ces 3 patients ont developpe sous MOGA une eruption cutanee cliniquement stereotypee et histologiquement granulomateuse, associee a une excellente reponse. Dans la litterature, 6 patients issus de l’essai princeps MAVORIC ont developpe apres un delai comparable a celui de notre serie (4,6 mois), parallelement a une bonne reponse au MOGA, une dermatose nommee par les auteurs « CGDE » (cutaneous granulomatous drug eruption),constituee de plaques erythemato-squameuses du tronc, des bras, du visage et du cuir chevelu. Histologiquement, l’infiltrat etait granulomateux, compose d’histiocytes, lymphocytes, eosinophiles et/ou cellules geantes multinucleees. Nous rapportons 3 cas histologiquement similaires a cette nouvelle entite, avec un aspect clinique tres particulier et facilement reconnaissable, caracterise par des lesions erythemato-squameuses en casque et des plaques inflammatoires pre-auriculaires, et parfois des plaques du tronc mal distinguables cliniquement de plaques de MF. La valeur pronostique favorable de cette eruption devra etre confirmee par des etudes prospectives.

Introduction Les anticorps anti-PD1 (anti-PD1) sont indiques pour les melanomes (M) de stade III inoperables ou de stade IV. Exceptionnellement, des M de stade I ou II ne sont pas accessibles a la chirurgie en raison de leur siege (souvent muqueux ou acral) et/ou de leur surface d’extension (visage), celle-ci etant non realisable ou inacceptable par son caractere mutilant ou delabrant. Nous rapportons 11 patients traites dans cette situation par un anti-PD1. Materiel et methodes Ont ete inclus tous les patients traites par un anti-PD1 entre janvier 2018 et avril 2020 pour un M de stade I ou II (AJCC8) pour lequel la reunion de concertation pluridisciplinaire avait exclu une intervention chirurgicale. Le critere de jugement principal etait le taux de reponse. Les criteres secondaires la survie globale, la survie sans progression et la toxicite. La date de point etait le 30/05/2020. Resultats Onze patients (8 femmes et 3 hommes), d’âge moyen 72 ans (extremes (E) : 49–90), ont ete inclus. Cinq ont recu du nivolumab, 5 du pembrolizumab, 1 du cemiplimab en raison d’un carcinome epidermoide cutane inoperable d’un membre qui constituait l’indication premiere. Le M etait cervico-facial dans 6 cas, plantaire dans 1 cas, muqueux dans 4 cas (endo-nasal : 2 ; pharynge : 1 ; vulvaire : 1). La surface lesionnelle variait de 5 a 44 cm2 (mediane :15). Un M etait in situ (femme jeune avec recidive tres etendue de la joue et du pourtour de l’oeil de part d’autre d’une greffe), les 10 autres invasifs, d’epaisseur 0,35 a 13 mm (mediane : 3 mm) mesuree sur des biopsies partielles (7 cas) ou une IRM (1 cas) (non evaluable : 2 cas). Tous les M etaient BRAF sauvage et exprimaient faiblement PDL1 en immunohistochimie ( Discussion Les anti-PD1 sont une alternative therapeutique interessante pour des M de stade I–II inoperables, incluant les M muqueux, pourtant moins sensibles a ces traitements au stade metastatique que les M cutanes. Le taux de reponse complete parait superieur a celui obtenu aux stades plus avances, independamment de l’expression de PDL1. Une etude prospective avec des criteres stricts de non operabilite pourrait etre proposee.

Introduction Les lymphomes cutanes primitifs sont un groupe heterogene de lymphomes T cutanes (LTC) et de lymphomes B cutanes (LBC). Nous avons peu dinformations sur les caracteristiques des patients atteints de ces maladies et leurs stades initiaux. Malgre plusieurs publications nationales europeennes il existe peu de donnees sur ĺevolution de leur epidemiologie au cours du temps. Le but de cette etude etait de comparer ĺepidemiologie, les caracteristiques et la demographie des patients atteints dun lymphome cutane primitif au cours des quinze dernieres annees et dinvestiguer d’eventuels changements. Materiel et methodes Nous avons inclus les patients ayant eu un diagnostic de lymphome cutane primitif selon les criteres de ĺEORTC-OMS entre 2005 et 2019. Les patients ont ete tries en 3 groupes definis par leur periode d’inclusion (2005–2009, 2010–2014 et 2015–2019) pour les comparer. Resultats Le nombre total de patients inclus a augmente annuellement. Ĺincidence calculee des lymphomes cutanes primitifs etait de 1,06/100 000 habitants en France, ce qui est plus eleve que ce qui a ete decrit dans la litterature. La majorite des lymphomes cutanes etaient plus frequents chez les hommes a un âge moyen de 60 ans. La frequence relative des LTC etait stable, la proportion du mycosis fongoide classique avait diminue et la proportion des autres variants etait croissante (par exemple le mycosis fongoide folliculotrope). Des tendances similaires ont ete observees pour les lymphomes B cutanes, la frequence relative des lymphomes B de la zone marginale etait croissante. Discussion Les changements de frequence des lymphomes cutanes peuvent etre expliques par ĺemergence de nouveaux criteres diagnostiques et des definitions plus precises de ces maladies dans la nouvelle classification. Cest la premiere etude a demontrer des changements de ĺepidemiologie des lymphomes cutanes primitifs au cours du temps.

Introduction La peri-arterite noueuse (PAN) est une vascularite necrosante des vaisseaux de moyen calibre, associant nouures, livedo, anevrysmes coeliomesenteriques et renaux. Des formes familiales sont liees a des mutations du gene adenosine deaminase 2 (ADA2). Nous rapportons une famille avec PAN de presentation proche d’un deficit en ADA2 (DADA2), sans variation pathogene d’ADA2 ni diminution de l’activite enzymatique. Observations Un homme de 70 ans presentait des papulo-nodules des membres et du tronc apparus recemment, avec arthralgies des inter-phalangiennes proximales. Il avait depuis l’enfance un syndrome de Raynaud et un livedo ramifie du tronc, avec extension progressive aux membres. Ses antecedents comportaient une HTA, un IDM et un episode de pneumopathie bacterienne. La biologie montrait : CRP a 12,9 mg/L, lymphopenie a 0,6 g/L, hypogammaglobulinemie (5,7 g/L), FAN+ a 1/400, negativite des ANCA, et des serologies virales. La biopsie d’un nodule montrait une vascularite non necrosante des vaisseaux de petit et moyen calibre. L’angioscanner aortique etait normal. L’IRM cerebrale revelait des sequelles ischemiques et des microsaignements. Sa niece et petite niece (46 et 13 ans) presentaient depuis l’enfance un livedo des membres et du tronc, des nodules des membres inferieurs evoluant par poussees, un rhumatisme inflammatoire distal, avec lymphopenie et diminution isolee des IgM chez la niece. Un DADA2 etant evoque, l’etanercept 25 mg/semaine etait debute chez le patient, permettant la disparition des nodules et des arthralgies, l’attenuation du livedo et la normalisation de la CRP. La mesure enzymatique de l’ADA2 etait normale, le sequencage complet du gene ADA-2 ne montrait pas de mutation pathogene. Le sequencage de l’exome montrait que les patients partageaient 2 variants rares, dans ALPK1 et USP34. Discussion Nos patients ont une presentation clinique et biologique proche du DADA2 : debut precoce, livedo, nodules cutanes, arthralgies, AVC, deficit de l’immunite cellulaire et humorale, reponse favorable aux anti-TNF. Cependant, la transmission du DADA-2 est autosomique recessive, une diminution de l’activite enzymatique et des mutations du gene sont mises en evidence. USP34 et ALPK1, mutes heterozygotes chez les patients, sont les genes candidats, USP34 etant implique dans l’ubiquitination et la voie de l’auto-inflammation et des mutations d’ALPK1 ayant ete decrites dans 2 syndromes auto-inflammatoires, ROSAH (« retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, headache ») et PFAPA (« periodic fever, aphtous stomatitis, pharyngitis, adenitis »). En conclusion, il s’agit des premiers cas de PAN de transmission autosomique dominante de penetrance incomplete, non liee a un DADA2. Cette entite est importante a connaitre en raison du risque probable d’atteinte vasculaire cerebrale et de la reponse aux anti-TNF. L’implication d’ALPK1 et USP34 est en cours d’etude.

Background Primary cutaneous lymphomas (PCLs) are a heterogeneous group of T-cell (CTCL) and B-cell (CBCL) malignancies. Little is known about their epidemiology at initial presentation in Europe and about potential changes over time. Objectives The aim of this retrospective study was to analyse the frequency of PCLs in the French Cutaneous Lymphoma Registry (GFELC) and to describe the demography of patients. Methods Patients with a centrally validated diagnosis of primary PCL, diagnosed between 2005 and 2019, were included. Results The calculated incidence was unprecedently high at 1·06 per 100 000 person-years. The number of included patients increased yearly. Most PCL subtypes were more frequent in male patients, diagnosed at a median age of 60 years. The relative frequency of rare CTCL remained stable, the proportion of classical mycosis fungoides (MF) decreased, and the frequency of its variants (e.g. folliculotropic MF) increased. Similar patterns were observed for CBCL; for example, the proportion of marginal-zone CBCL increased over time. Conclusions Changes in PCL frequencies may be explained by the emergence of new diagnostic criteria and better description of the entities in the most recent PCL classification. Moreover, we propose that an algorithm should be developed to confirm the diagnosis of PCL by central validation of the cases.

Tumour necrosis factor-α [TNF-α] inhibitors have revolutionised the management of chronic inflammatory conditions. A number of cutaneous adverse events have been reported with TNF inhibition, including vasculitis. Most reactions are mild and rarely warrant treatment withdrawal. Here we describe a patient with Crohn’s disease treated with adalimumab in whom severe multivisceral Henoch-Schönlein purpura developed, including neurological involvement, requiring definitive TNF blocker withdrawal.

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In non-metastatic non-small-cell lung cancer (NSCLC), outcomes remain poor. Adjuvant chemotherapies provide a limited improvement in disease-free survival. Recent exploratory studies on early-stage NSCLC show that immunotherapy given according to Programmed Death&ndash, Ligand 1 expression generates variable results, emphasizing a need to improve tumor characterization. We aimed to conjointly assess NSCLC, the expression of PD&ndash, L1, and epithelial&ndash, mesenchymal transition, frequently involved in tumor aggressiveness. 188 resected NSCLCs were analyzed. Among 188 patients with curatively resected NSCLC, 127 adenocarcinomas and 61 squamous cell carcinomas were stained for PD&ndash, L1 and vimentin expression. Overall survival has been compared regarding PD&ndash, L1 and vimentin statuses both separately and conjointly in Tumor Cancer Genome Atlas databases. PD&ndash, L1 and vimentin higher expressions were strongly associated (OR = 4.682, p &lt, 0.0001). This co-expression occurred preferentially in tumors with lymph node invasion (p = 0.033). PD&ndash, L1 was significantly associated with high EMT features. NSCLC harboring both PD&ndash, L1high/vimentinhigh expressions were significantly associated with poor overall survival (p = 0.019). A higher co-expression of vimentin and PD&ndash, L1 was able to identify patients with worse outcomes. Similar to an important prognostic marker in NSCLC, this tandem marker needs to be further presented to anti-PD&ndash, L1 immunotherapies to improve outcome.

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Introduction Le pronostic des carcinomes epidermoides cutanes (CEC) inoperables est sombre. Le but de cette etude est d’evaluer l’efficacite et la tolerance de l’anticorps anti-EGFR panitumumab, peu utilise en France, seul ou associe a la radiotherapie dans les CEC inoperables. Materiel et methodes Il s’agissait d’une etude retrospective et monocentrique de tous les patients consecutifs ayant recus au moins 2 cures de panitumumab seul ou en association avec la radiotherapie, entre 2016 et 2019, quels que soient les traitements anterieurs recus a l’exclusion d’anti-EGFR en monotherapie. Le critere de jugement principal etait le taux de meilleure reponse globale selon RECIST 1.1. Les criteres de jugement secondaires etaient les taux de reponse et de controle a 6 semaines et 6 mois, la survie sans progression, la survie globale et la tolerance. Resultats Vingt-cinq patients d’âge median 86 ans (extremes : 48–97) etaient inclus. Dix-sept (68 %) avaient un indice OMS ≥ 2. Le taux de meilleure reponse globale etait de 52 % avec 4 reponses completes (16 %) et 9 reponses partielles (36 %). Tous les patients en reponse complete et 5 sur 9 en reponse partielle avaient recu un traitement concomitant par radiotherapie, dans la plupart des cas a des doses moderees a faibles ( Discussion Malgre ses limites liees a son caractere monocentrique et retrospectif et a un nombre limite de patients, notre etude fournit pour la premiere fois des donnees « en vie reelle » sur l’efficacite et la securite du panitumumab dans le traitement des CEC inoperables. Ces resultats suggerent que le traitement des CEC inoperables par panitumumab reste pertinent, en particulier en association avec la radiotherapie, malgre l’apport recent des anticorps anti-PD1. Il presente plusieurs avantages : il peut etre utilise chez des patients tres âges ou fragiles comme dans notre serie ; il ne provoque pas de risque anaphylaxique comme le cetuximab, ni effets secondaires potentiellement irreversibles ou menacant le pronostic vital ; des reponses a long terme ont ete observees dans notre etude. Des etudes prospectives evaluant les anti-EGFR en association avec les anticorps anti-PD1 et/ou la chimiotherapie seraient utiles.

Introduction Le brentuximab vedotin (BV) est un conjugue anticorps monoclonal anti-CD30–medicament, liberant un poison du fuseau de facon selective dans les cellules CD30+. Son utilisation dans certains lymphomes T cutanes (LTC) exprimant le CD30 est validee par l’etude de phase III ALCANZA. Nous rapportons 2 observations exceptionnelles de LTC CD30+ a grandes cellules anaplasiques (LTCGCA) monomeliques, a tres forte masse tumorale, traites avec succes par BV. Observations Cas 1 : un homme de 84 ans etait hospitalise pour d’innombrables nodules et tumeurs ulcerees d’apparition rapide sur la jambe droite. L’examen histologique montrait un infiltrat dermique massif de grandes cellules CD4+/CD30+/ALK−/CD3−/CD20−/Ki67 a 100 %. Le bilan d’extension etait negatif. Le diagnostic de LTCGCA monomelique de stade T2cN0M0 etait retenu. Devant cette cinetique et un etat pulmonaire precaire, le BV 1,8 mg/kg/21 jours etait administre en 1ere ligne, permettant une remission complete (RC) des la 4e cure. L’apparition au TEP scanner d’un ganglion iliaque moderement hypermetabolique justifiait d’une radiotherapie a ce niveau, le BV etant arrete pour des paresthesies. La reponse clinique se maintenait a 6 mois. Cas 2 : une femme de 76 ans etait traitee en 2e ligne par BV, dans le cadre de l’essai therapeutique ALCANZA, pour un LTCGCA monomelique du membre inferieur droit a tres forte masse tumorale et cinetique rapide, de stade T2cN0M0. Une RC etait obtenue apres 3 cures. Le BV etait arrete apres 12 cures en raison d’une neuropathie peripherique (NP) de grade III, regressive en 8 mois. La RC se maintenait sans traitement avec 5 ans de recul. Discussion Ces 2 observations sont exceptionnelles par : 1) Cette presentation monomelique tres extensive et agressive tres rarement decrite au cours des LTCGCA et faisant craindre une dissemination rapide. 2) La reponse spectaculaire au BV. La litterature rapporte une observation analogue, chez un patient bulgare dont le LTCGCA monomelique progressait apres radiotherapie et methotrexate. Une regression tumorale > 80 % etait obtenue apres 4 cures. La duree optimale du traitement chez les patients repondeurs au BV pour une LTCGCA n’a pas ete evaluee. La limite principale de son utilisation prolongee est l’apparition de NP chez environ deux tiers des patients, regressive apres arret dans 82 % des cas. L’absence de recidive a tres long terme dans notre second cas suggere qu’un traitement de quelques mois pourrait suffire a assurer une reponse complete et durable. Conclusion Les formes monomeliques agressives de LTCGCA peuvent simuler cliniquement un lymphome B de type jambe. Leur agressivite contraste avec le resultat remarquable du BV chez ces 3 patients, faisant discuter sa place en 1ere ligne dans ces formes rares.

International audience

International audience; Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle, associated with considerable tissue remodelling. Although abnormal cytokine expression was detected both in perilesional and in uninvolved skin, up to now there is no model allowing a better understanding of the implicit inflammatory mechanisms in HS. The aim of this study was to investigate the inflammatory response in HS skin by mean of an ex vivo model culture. To that purpose, nine skin biopsy specimens from patients suffering from HS and controls were cultured up to 4 days. Microscopy imaging investigations showed variations of collagen I and III organization, and an increase in elastin fibres fragmentation in HS skin after 4 days of culture. The HS matrix structure remodelling was associated with high level of MMP-2 and MMP-9 in HS lesional skin. After 4 days of culture, the MMP expression in HS perilesional skin reached the level observed in HS lesional skin. Concomitantly, an increase in IL-1β concentration was observed in all skin samples after 4 days of culture, although IL-1β concentrations remained significantly higher in HS lesional skin as compared with control skin. Meanwhile, neither IL-17 concentrations nor the inflammasome components NLRP3 and caspase-1 varied. Thus, our HS skin model culture showed that MMP-induced matrix alteration could participate in HS inflammation by releasing biological active peptides and inflammatory factors from the extracellular matrix (ECM), and open new opportunities to investigate the regulation of the inflammatory mechanism associated with HS.

Background A distinctive eruption referred to as 'insect bite-like reaction' or 'eosinophilic dermatosis of haematological malignancy' has been described during the course of haematological B-cell malignancies (BCM). However, its clinical evolution, histopathological features and pathogenesis remain unclear. Objectives To characterize this eruption and to investigate its pathogenesis and relationship with the underlying BCM. Methods In this multicenter retrospective study of the French Study Group on Cutaneous Lymphomas, 37 patients with a BCM and a cutaneous eruption consisting in chronic and/or recurrent papules, papulo-vesicles and/or nodules were included. Clinical, histopathological, immunohistochemical and molecular data were reviewed. Results No significant insect bite history or seasonal predominance was recorded. Patients had pruritic papules (81%), papulo-vesicles (43%) and nodules (38%), often predominated in the head and neck region (84%), without complete remission periods in most cases (57%). The predominant associated BCM was chronic lymphocytic leukaemia (73%). Histological and immunohistochemical review showed a dense dermal lymphocytic infiltrate predominantly composed of T lymphocytes (100%), with frequent eosinophils (77.6%); a perivascular and periadnexal (most often folliculotropic) pattern (77.6%), sometimes suggestive of a folliculotropic mycosis fungoides; clusters of tumour B cells were identified in 47% of cases using appropriate phenotyping markers. In 10/14 cases (71.4%) tested for B-cell IgH gene rearrangement, a B-cell clone was identified in skin lesions (identical to the blood clone in nine cases), whereas no T-cell clone was present. Conclusion We propose the denomination 'T-cell papulosis associated with B-cell malignancy' (TCP-BCM) for this distinctive eruption. Although resulting in various histopathological pictures, it can be easily recognized by clinicians and may be identified by informed pathologists relying on some key features. An extravasation of tumour B cells with skin-homing properties associated with a secondary, predominant, T-cell immune reaction could explain the clinicopathologic aspect and the prolonged regressive and recurrent course of the disease.

Summary Introduction Prurigo pigmentosa is a rare inflammatory, pruriginous skin disease seen predominantly in young Asian women, with average age of onset in the mid-20s. Observation A 25-year-old fair-skinned European woman presented with a two-year history of pruriginous skin lesions recurring fortnightly. The initial lesions were inflammatory papules, which first emerged on the back of the neck before spreading to the shoulders, below the breasts and the back. The papules resolved leaving a reticular hyperpigmented network that gradually worsened after each episode. The clinical presentation and histopathological findings were consistent with a diagnosis of prurigo pigmentosa. Doxycycline 200 mg/day was initiated, with rapid resolution, absence of any further flare-ups and gradual regression of the reticular pigmentation. Discussion Prurigo pigmentosa is a skin disease of stereotypical presentation marked by frequent inflammatory flare-ups involving the trunk that are followed by periods of remission with residual hyperpigmentation. Herein we report a case observed in a fair-skinned French female subject. It is important that dermatologists are able to recognize it and distinguish it from other forms of pruriginous papular dermatosis, owing to the dramatic efficacy of tetracyclines in controlling the inflammatory flares and in reducing the adverse aesthetic impact of hyperpigmentation.

Introduction L’angiomatose dermique diffuse (ADD) est une angioendotheliomatose reactionnelle peu connue caracterisee par la proliferation de cellules endotheliales dans le derme reticulaire. Le plus souvent unifocale, elle touche surtout les membres inferieurs mais aussi l’abdomen et les seins. Nous rapportons un cas d’ADD multifocale. Observations Une femme de 61 ans, obese, aux antecedents d’HTA et d’AOMI, traitee par antiagregant plaquettaire et IEC sans statine, avait consulte pour des lesions ulcerees abdominales superficielles pustuleuses a bordures telangiectasiques, apparues suite a une cure d’eventration ( Fig. 1A ). L’histologie en bordure d’ulceration etait aspecifique et le diagnostic retenu etait alors celui de pyoderma gangrenosum superficiel, traite efficacement par dermocorticoides. Deux ans plus tard, elle reconsultait pour des lesions douloureuses telangiectasiques et livedoides du sein droit, avec ulcerations superficielles et cicatrisation atrophique ( Fig. 1B ) evoluant depuis 3 mois, associees depuis peu a des telangiectasies du sein controlateral. L’histologie du sein droit montrait une proliferation dermique de cellules endotheliales se disposant entre les faisceaux de collagene ( Fig. 2A ). Il s’y associait quelques telangiectasies. Les cellules n’avaient pas d’atypie et etaient marquees par le CD31 ( Fig. 2B ). La prise en charge initiale privilegiee etait une reduction ponderale, un bon controle tensionnel et l’introduction d’une statine. Discussion L’ADD est rare et survient sur un terrain atheromateux, notamment en cas d’obesite. La localisation mammaire est souvent associee a une macromastie. L’hypothese physiopathologique est celle d’un evenement ischemique initial favorise par un traumatisme local. L’ADD est caracterisee par des lesions en nappes erythemato-violacees, livedoides, parfois indurees, pouvant evoluer vers une necrose seche ou des ulcerations superficielles. Certains cas de calciphylaxie associee ont ete rapportes, celle-ci etant un diagnostic differentiel dans les formes a evolution ulceree, comme le pyoderma gangrenosum, la maladie de Degos ou la pathomimie. L’histologie est necessaire et montre une proliferation dermique de cellules endotheliales exprimant les CD31 et CD34, se disposant entre les fibres de collagene. Le traitement n’est pas codifie et repose principalement sur la prise en charge des facteurs de risque d’atherome. En cas d’atteinte mammaire, l’isotretinoine a ete proposee pour son role anti-angiogenique avec une bonne efficacite ; une chirurgie de reduction mammaire peut aussi etre envisagee. L’efficacite de la corticotherapie systemique, la revascularisation ou l’anticoagulation efficace a aussi ete rapportee. Conclusion L’ADD doit etre mieux connue et evoquee devant des lesions telangiectasiques avec ulcerations superficielles, survenant sur un terrain atheromateux qu’il faudra prendre en charge. Une atteinte multifocale est possible et ne doit pas faire remettre en cause le diagnostic.

Lymphomatoid papulosis (LyP) is considered as an indolent CD30+ lymphoproliferative cutaneous disorder. 1,2 Nevertheless, 10%–20% up to 50% of patients with LyP have coexistent lymphoma. 1, 3–7 The most frequently associated malignancies are mycosis fungoides, primary cutaneous anaplastic large cell lymphoma, or Hodgkin's disease. There are only seven reported cases of an association between LyP and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 5, 7-9 Herein, we report and analyze three new cases. This article is protected by copyright. All rights reserved.

International audience; Rationale: Pyoderma gangrenosum (PG), like other neutrophilic dermatosis, may be associated with a variety of systemic disorders including inflammatory bowel diseases, rheumatoid arthritis, and hematologic disorders. Conversely, the association between PG and systemic lupus erythematosus (SLE) has rarely been reported.Patient concerns: We report here 2 cases of this association.Diagnoses: The first case involves a 32-year-old woman who developed, 1 year after SLE diagnosis, 3 painful nodular lesions of PG on her face, and cervical area. The second case was observed in a 37-year-old woman referred for ulcerative nodular papules of PG on her legs, whereas she had been diagnosed with SLE 10 years before. SLE was inactive in the first case, whereas PG occurred during a lupus flare up in the second one.Interventions: We found 23 previous cases of SLE and PG in the literature with most cases (12/20) occurring during a lupus flare.Outcomes: Although rare, this association may be supported by common innate immunity dysregulation and abnormal neutrophil activation.Lessons: PG and other neutrophilic diseases reported in patients with SLE may be added to the large clinical spectrum of cutaneous lesions observed in SLE.

Background: ELISA-BP180 values and direct immunofluorescence (DIF) are prognostic factors for relapse after treatment cessation in bullous pemphigoid (BP). Objective: To determine the relevance of ELISA-BP230 antibodies for predicting relapse 6 months after treatment cessation. Methods: We retrospectively selected patients with BP and available data from ELISA-BP180 and -BP230 and DIF performed at treatment cessation. The rate of relapse was calculated at 6 months. We compared ELISA-BP180 and -BP230 values and DIF in patients with relapse and remission. Results: We included 97 patients. At 6 months, 25.6% of patients showed relapse. The proportion of patients with an ELISA-BP230 value ≥27 UA/ml was higher, but not significantly, for those with relapse than for those with remission (p = 0.11). The frequency of positive DIF findings was significantly higher for patients with relapse (p = 0.005). Conclusion: DIF is of better value than ELISA-BP180 and -230 tests to predict relapse after treatment cessation in BP.

Resume Introduction Le meropeneme (carbapeneme) est un antibiotique rarement prescrit. Des effets secondaires cutanes ont ete rapportes a type d’exantheme, de prurit, d’urticaire et de syndromes de Lyell ou de Stevens–Johnson. La levofloxacine (fluoroquinolone), antibiotique largement prescrit, partage les memes effets secondaires cutanes, auxquels s’ajoute une action photosensibilisante. Nous rapportons un cas d’hyperpigmentation cutanee noirâtre induite par l’association de meropeneme et de levofloxacine. Observation Un homme de 67 ans etait traite par meropeneme (1 g × 4/j), levofloxacine (500 mg × 2/j) et amikacine (500 mg/j) pendant 2 semaines, puis meropeneme, levofloxacine et rifampicine (600 mg × 2/j) pendant 4 semaines, pour une osteite du cinquieme metatarsien. Trois semaines apres le debut de l’antibiotherapie, une pigmentation noirâtre apparaissait, predominant a la face anterieure des jambes. La biopsie cutanee revelait un depot noirâtre du derme superficiel et moyen, perivasculaire et interstitiel, colore par les colorations de Fontana et de Perls. L’etude en microspectroscopie infrarouge permettait d’identifier la molecule de meropeneme dans le derme. Apres arret des antibiotiques, la pigmentation regressait lentement. Discussion Des cas similaires d’hyperpigmentation cutanee noirâtre ont ete rapportes apres utilisation de minocycline. Dans ces cas, l’analyse histologique montrait egalement des depots dermiques de fer et/ou de melanine, mais la nature du pigment responsable restait incertaine. Dans notre cas, l’analyse en spectroscopie infrarouge a permis de localiser le meropeneme dans le derme. Deux cas d’hyperpigmentation cutanee ont ete rapportes apres utilisation de la levofloxacine, avec une analyse histologique similaire.