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Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X-inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus Paecilomyces lilacinus as the first manifestation of CGD. Dihydrorhodamine 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs-albeit by different mechanisms-are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p 0.0001, LHR + = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p 0.001, LHR + = 3.1).These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC.

Introduction Les anti-interleukine-17 (IL-17), comme l’ixekizumab, sont de plus en plus utilises pour traiter le psoriasis. Paradoxalement, les anticorps monoclonaux peuvent induire des reactions inflammatoires. Nous rapportons un nouveau cas de reaction granulomateuse sous ixekizumab. Materiel et methodes Il s’agissait d’un patient de 53 ans, suivi pour un psoriasis cutanee severe, evoluant depuis l’âge de 15 ans sans atteinte articulaire associee. Il n’y avait pas d’autre antecedent notable. Apres echec d’une phototherapie par UVB, du methotrexate et de l’adalimumab, le patient etait mis sous ixekizumab. Apres les 3 mois d’induction, on notait une excellente efficacite (PASI et DLQI a 0). Apres 7 mois de traitement, malgre un psoriasis toujours blanchi, il avait de nouvelles lesions principalement du haut du dos et des bras. Ces lesions etaient legerement infiltrees, arrondies et asymptomatiques suggerant une lesion dermique. La biopsie cutanee mettait en evidence des granulomes dans le derme constitues de cellules epithelioides et gigantocellulaires, sans necrose caseeuse. Il n’y avait pas de germes aux colorations speciales. Nous avons donc conclu a une localisation cutanee de sarcoidose induite par l’ixekizumab. Une exploration comprenant un bilan biologique, un electrocardiogramme, des explorations fonctionnelles respiratoires, un scanner pulmonaire et une consultation ophtalmologique etait strictement normale et confortait le diagnostic de sarcoidose cutanee. Apres 6 mois d’arret de l’ixekizumab, on notait une legere regression des lesions de sarcoidose mais une recidive du psoriasis motivant l’introduction du guselkumab. A 3 mois de la nouvelle biotherapie, on notait une franche amelioration du psoriasis et une nette regression des lesions de sarcoidose. Discussion Nous rapportons un cas de sarcoidose cutanee sans atteinte systemique survenu sous ixekizumab. Six cas de sarcoidose sous anti-IL-17 ont precedemment ete decrits dans la litterature. Il s’agit soit d’aggravation soit de cas de novo. D’autres observations de reaction granulomateuse ont ete rapportees sous anti-IL-17. En effet, les inhibiteurs de l’IL-17 sont connus pour induire ou aggraver la maladie de Crohn. Trois cas de granulome annulaire ont egalement ete decrits. L’evolution de ces differents cas a ete favorable a l’arret du traitement. La production d’IL-17 par les lymphocytes CD4+ Th17 est fortement impliquee dans la formation des granulomes tout comme l’INF-γ. Il existe un equilibre de ce milieu cytokinique pouvant etre perturbe lorsqu’une de ces voies est modifiee. Ce desequilibre pourrait expliquer l’apparition des reactions paradoxales sous anti-IL17. Il existe un cas d’aggravation d’uveite sarcoidosique sous anti-IL23 (cytokine activatrice des Th17). Cependant, dans notre cas, les lesions de sarcoidose regressaient sous guselkumab.

Introduction Le carcinome epidermoide cutane (CEC) est le 2e cancer cutane le plus frequent. Aux stades localement avance et metastatique, le pronostic est defavorable. Parmi les traitements proposes lorsque la chirurgie et la radiotherapie ne sont plus curatives, les anti-EGFR et la chimiotherapie standard ont une efficacite souvent non durable dans le temps et une toxicite non negligeable. Le cemiplimab a obtenu l’AMM en France en mars 2020 mais avec un service medical rendu juge insuffisant compte tenu des donnees disponibles encore limitees. Notre objectif principal etait d’estimer l’efficacite du cemiplimab dans le traitement des CEC localement avances et metastatiques en situation de vie reelle en Nouvelle-Aquitaine. Materiel et methodes Notre etude observationnelle retrospective a porte sur 71 patients traites par cemiplimab dans le cadre de CEC localement avances ou metastatiques au sein de 5 centres hospitaliers de Nouvelle-Aquitaine (La Rochelle, Poitiers, Bordeaux, Limoges et Niort) entre aout 2018 et juin 2020. Le critere de jugement principal etait le taux de meilleure reponse, defini comme la proportion de patients ayant obtenu une reponse complete ou partielle selon les criteres RECIST et/ou cliniques. Parmi les criteres de jugement secondaires, nous avons evalue le profil de securite selon la classification CTCAE v5.0. Resultats Nous rapportons un taux de meilleure reponse de 45 % avec 15 remissions completes, 17 remissions partielles, 22 stabilisations et 17 progressions. Le taux de meilleur controle de la maladie etait de 76 %. La mediane de survie sans progression etait estimee a 10,5 mois pour une duree mediane de suivi de 8.9 mois. Soixante-dix-neuf pour cent des patients ont eu des effets secondaires (ES) mais, non severes dans la majorite des cas, 17 % ont eu des ES de grades ≥ 3. Les ES les plus rapportes etaient par ordre decroissant: asthenie, cytolyse hepatique, perte de poids, cholestase hepatique, anorexie, prurit et diarrhee. Un seul patient est decede a cause d’un ES et le traitement a ete arrete de facon definitive chez 12 patients (17 %) a cause d’effets secondaires. Discussion Cette etude confirme les taux de reponse importants suggerant que le cemiplimab en vraie vie confere une efficacite similaire a celle observee dans les essais cliniques. La duree de reponse pouvait etre prolongee dans le temps et maintenue apres l’arret du cemiplimab mais les donnees de suivi sont limitees dans cette etude retrospective. Le profil de securite est rassurant et semble plus favorable que celui des anti-EGFR et de la chimiotherapie chez une population cible âgee. Toutefois, compte tenu des effets secondaires parfois severes, il serait interessant de trouver des facteurs predictifs de l’efficacite. L’heliodermie, reflet du taux de charge mutationnelle, semble etre un facteur a etudier.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus, Paecylomyces lilacinus as the first manifestation of CGD. Dihydrorhodamin 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis of undetermined potential (CHIP) could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

International audience; While virus-negative Merkel cell carcinoma (MCC) is characterized by high frequency of UV-induced mutations, expression of two viral oncoproteins is regarded as key mechanism driving Merkel cell polyomavirus (MCPyV)-positive MCC. The cells in which these molecular events initiate MCC oncogenesis have yet not been identified for both MCC subsets. A considerable proportion of virus-negative MCC is found in association with squamous cell carcinoma (SCC) suggesting (i) coincidental collision, (ii) one providing a niche for the other or (iii) one evolving from the other. Whole exome sequencing of four combined tumors consisting of SCC in situ and MCPyV-negative MCC demonstrated in all cases many mutations shared between SCC and MCC indicating a common ancestry and thereby a keratinocytic origin of these MCCs. Moreover, analyses of the combined cases as well as of pure SCC and MCC suggests that RB1 inactivation in SCC facilitates MCC development and that epigenetic changes may contribute to the SCC/MCC transition.

Background: Acne vulgaris of adult females has increased over the past 10 years; it affects currently 20 to 30% of adult females. The physiopathology of adult female acne is distinguished from that of teenagers essentially by two factors: hormonal and inflammatory. On a therapeutic plan, in female acne, four types of systemic treatment approved in this indication include: cyclines (leading to bacterial resistance); zinc salts (less effective than cyclines); and antiandrogens (risks of phlebitis). The last alternative is represented by isotretinoin, but its use in women of childbearing potential is discouraged because of the teratogen risks.In this context, spironolactone could represent an interesting alternative. It blocks the 5-alpha-reductase receptors at the sebaceous gland and inhibits LH production at the pituitary level. It has no isotretinoin constraints and does not lead to bacterial resistance. Currently, a very few studies have been performed on a limited number of patients. They showed that at low doses (lower than 200 mg/day), spironolactone can be effective against acne.In that context, it seemed clearly interesting to perform the first double-blind randomized study of spironolactone vs cyclines, which remains the moderate acne reference treatment, and to demonstrate the superiority of spironolactone’s efficacy in order to establish it as an alternative to cyclines.Methods: Two hundred female patients will be included. They will have acne vulgaris with at least ten inflammatory lesions and no more than three nodules. After randomization, the patients will be treated by spironolactone or doxycycline for three months and after placebo. The study will be blind for the first six months and open for the last six months. Discussion: The treatment frequently used in female acne is systemic antibiotics with many courses as it is a chronic inflammatory disease. In the context of the recent WHO revelation about the serious, worldwide threat to public health of antibiotic resistance, this trial could give the physician another alternative for adult female acne before using isotretinoin, whose management is more complex. Trial registration: On ClinicalTrials.gov, registration number NCT03334682, first published on 7 November, 2017. Recruitment is still ongoing.

Background Acne vulgaris of adult woman has increased over the past 10 years; it affects currently 20 to 30% of adult women. The physiopathology of adult woman acne is distinguished from the teenager one essentially by 2 factors: hormonal one with a peripheral hyperandrogeny coupled with an hypersensibility of cutaneous androgens receptors and an inflammatory one linked with Cutibacterium acnes. On a therapeutic plan, in female acne, four types of systemic treatment, approved in this indication are: cyclines which are problematic for the bacterial resistance; zinc salts which target only the inflammatory lesions and are less effective as cycline; antiandrogens, with acetate of cyproterone associated with risks of phlebitis and pulmonary embolism and recently meningioma. The last alternative is represented by isotretinoin but the use in women of childbearing potential is binding because of the teratogen risks and in addition, peripheral hyperandrogenia represents an identified risk of relapse. In this context, the spironolactone could represent an interesting alternative. It blocks the 5-alpha-reductase receptors at sebaceous gland and inhibits LH production at the pituitary level. It has not isotretinoin constraints, does not lead to bacterial resistance and targets the peripheral hyperandrogenia. Currently, very few studies have been performed on a weak number of patients. They showed that at low doses (lower than 200mg/day), spironolactone can be effective against acne. Methods: In that context, it seemed clearly interesting to perform the first double-blind randomized study spironolactone vs cyclines, which remains the moderate acne reference treatment and to demonstrate the superiority of spironolactone’s efficacy in order to establish it as an alternative way to cyclines. Discussion: Acne’s treatment frequently used in female acne is systemic antibiotics with many courses as it is a chronic inflammatory disease. In the context of recent WHO revelation about serious, worldwide threat to public health about antibiotic resistance, this trial could permit to give to the physician another alternative in adult female acne before using isotretinoin whose management is more complex. Trial registration : On ClinicalTrials.gov, registration number NCT03334682, first published on 7 November, 2017. Recruitment is still ongoing. Keywords : acne vulgaris, spironolactone, cycline

Introduction Le carcinome a cellules de Merkel (CCM) est un carcinome neuroendocrine cutane rare et agressif. En 2008, Feng et coll. identifiaient l’integration du polyomavirus a cellules de Merkel (MCPyV) comme l’evenement oncogenique responsable de 80 % de ces tumeurs. Les cas de CCM depourvus de virus sont consideres comme des tumeurs induites par les UV. Ce second groupe est associe a un pronostic plus pejoratif. Objectif comparer les caracteristiques morphologiques et immunohistochimiques des CCM en fonction du statut viral des tumeurs. Materiel et methodes L’inclusion des cas etait realisee a partir d’une cohorte multicentrique de CCM. Le statut viral etait determine par PCR en temps reel. Au total, 80 CCM viro-positifs et de 21 cas viro-negatifs ont ete inclus. L’evaluation microscopique a ete realisee par deux pathologistes en aveugle du statut viral. Les criteres morphologiques suivants ont ete etudies : la forme du noyau, la presence d’un nucleole, la taille de la cellule, le volume cytoplasmique, la presence d’un cytoplasme clair, d’une architecture en rosettes, d’un epidermotropisme, d’un contingent d’une autre ligne de differenciation (tumeurs composites) ou l’association a une maladie de Bowen ou a une keratose actinique. L’expression des marqueurs immunohistochimiques suivants a egalement ete etudiee : ATOH1, CD99, cytokeratines (CK) 7, 8, 18 et 20, EMA, grand antigene T, neurofilament, PAX5, p53, SATB2, TDT et TTF- 1. Resultats L’evaluation microscopique ( Figure 1 ) a montre que des noyaux allonges, fusiformes etaient plus frequemment observes dans les tumeurs viro-negatives (p = 0,005). De plus, ces dernieres presentaient parfois un phenotype de type « carcinome neuroendocrine a grandes cellules » avec une plus grande taille cellulaire (p = 0,0026), un cytoplasme abondant (p = 10−7) et des nucleoles proeminents (p = 0,002). Un epidermotropisme, et l’association avec une maladie de Bowen/keratose actinique n’etaient jamais observes pour les tumeurs viro-positives. En immunohistochimie, les tumeurs viro-negatives montraient une frequente positivite de TTF1, de la CK7, une surexpression de p53, ainsi qu’une frequente negativite des neurofilaments. En revanche, une expression intense de MUC1, une expression en dot des cytokeratines 8, 18 et 20 ainsi que du CD99 ont ete identifies comme des caracteristiques des CCM viro-positifs. L’expression en dot du CD99 etait notamment associee a la presence du polyomavirus de Merkel (sensibilite = 81 %, specificite = 90 %, rapport de vraisemblance positif = 8,08). Conclusion Notre etude confirme l’existence de caracteristiques morphologiques et immunohistochimiques distinctes entre les CCM viro-positifs et viro-negatifs. De maniere interessante, notre etude a identifie le pattern d’expression en dot du CD99 comme un marqueur associe au statut viro-positif.

Supplementary information : https://static-content.springer.com/esm/art%3A10.1038%2Fs41379-019-0288-7/MediaObjects/41379_2019_288_MOESM1_ESM.pdf; International audience; In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei-similar to the spindle-shape variant of small cell lung cancer-were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p = 0.005). Moreover, virus-negative cases more frequently displayed a "large-cell neuroendocrine carcinoma" phenotype with larger cell size (p = 0.0026), abundant cytoplasm (p = 4×10-7) and prominent nucleoli (p = 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.

Electronic supplementary material : https://static-content.springer.com/esm/art%3A10.1038%2Fs41379-018-0155-y/MediaObjects/41379_2018_155_MOESM1_ESM.docx; International audience; Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n = 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.

Introduction Le carcinome a cellules de Merkel (CCM) est un carcinome neuroendocrine cutane primitif, principalement induit par l’integration du polyomavirus de Merkel. L’expression de la cytokeratine 20 (CK20) est actuellement utilisee pour distinguer les CCM des carcinomes neuroendocrines d’autres organes. Cependant, cette distinction reste difficile dans les cas de CCM CK20-negatifs et dans les carcinomes a cellules de Merkel ganglionnaires sans primitif cutane. L’objectif de la presente etude est d’evaluer les performances diagnostiques des marqueurs precedemment decrits dans la litterature pour le diagnostic de CCM, notamment dans les cas de variantes difficiles a diagnostiquer (tumeurs CK20-negatives et CCM sans primitif cutane). Materiel et methodes Cent dix-huit cas de CCM (dont 9 MCC CK20-negatif et 15 MCC sans primitif cutane) ont ete compares a 85 cas de CNE extra-cutanes. Apres inclusion de l’ensemble des prelevements dans un tissu micro array, les marqueurs immunohistochimiques suivants ont ete realises : cytokeratine 20, TTF-1, ATOH1, neurofilament (NF), SATB2, PAX5, TdT, CD99, MUC1 et antigene Large T (CM2B4). L’evaluation a ete realisee en double insu. De plus, la presence d’ADN de MCPyV a ete recherchee par PCR quantitative. Apres la determination de seuils de positivite optimaux dans une premiere serie de validation (30 cas), les performances diagnostiques de chaque marqueur ont ete evaluees en utilisant un rapport positif de vraisemblance (seuil > 10). Dans les cas de CCM difficiles a diagnostiquer, la methode « CHi-squared Automatic Interaction Detector » (CHAID) a ete appliquee pour proposer un arbre de decision en utilisant une combinaison de marqueurs. Resultats SATB2, NF et la detection du Polyomavirus de Merkel apparaissent comme les marqueurs les plus robustes pour le diagnostic positif de MCC (rapports de vraisemblance : 36,6 ; 44,4 et 28,2, respectivement) ( Tableau 1 ). Alors que les CCM ganglionnaires sans primitif cutane avaient un phenotype prototypique de CCM, les cas CK20-negatifs presentaient frequemment une absence d’expression des marqueurs immunochimiques SATB2 et Neurofilament (37,5 et 44 % de cas positifs respectivement). Cependant le genome du Polyomavirus de Merkel etait frequemment present dans ces cas CK20-negatifs MCPyV (78 % par qPCR). Par consequent, dans cette derniere population, l’utilisation d’un arbre de decision combinant la detection des marqueurs immunohistochimiques SATB2, NF et la detection du Polyomavirus est proposee. Conclusion SATB2, le neurofilament et la detection du polyomavirus de Merkel permettent, en complement de la cytokeratine 20, de distinguer les CCM des carcinomes neuroendocrines extra-cutanes.

Merkel cell carcinoma (MCC) is a rare tumor of the skin that has an aggressive behavior. Immunity is the main regulator of MCC development, and many interactions between lymphocytes and tumor cells have been proven. However, the impact of tumor-infiltrating myeloid cells needs better characterization.To characterize tumor-infiltrating myeloid cells in MCC and their association with other immune effectors and patient outcome.MCC cases were reviewed from an ongoing prospective cohort study. In all, 103 triplicate tumor samples were included in a tissue microarray. Macrophages, neutrophils, and myeloid-derived suppressor cells were characterized by the following markers: CD68, CD33, CD163, CD15, CD33, and human leukocyte antigen-DR. Associations of these cell populations with programmed cell death ligand 1 expression, CD8 infiltrates, and vascular density were assessed. Impact on survival was analyzed by log-rank tests and a Cox multivariate model.The median density of macrophages was 216 cells/mmSampling bias and the retrospective design were potential study limitations.Infiltration of CD33

Background Merkel cell carcinoma (MCC) can present as a cutaneous tumor or a lymph node metastasis without a primary tumor. MCC presenting without a primary tumor (MCCWOPT) can be misinterpreted on histologic examination as lymph node metastasis (LNM) from another neuroendocrine carcinoma (LNMNEC). However, this distinction is crucial for therapeutic management. Objective To determine the discriminative criteria for the differential diagnosis of MCCWOPT, LNM from cutaneous MCC, and LNMNECs. Methods Clinical, morphologic, and immunohistochemical data (expression of cytokeratins AE1, AE3, 7, 19, and 20; chromogranin A, synaptophysin, thyroid transcription factor-1 [TTF-1]), as well as the presence of Merkel cell polyomavirus (by immunohistochemistry and PCR) were compared in patients with MCCWOPT (n = 17), LNM from a cutaneous MCC (n = 11), and LNMNEC (n = 20; 8 lung, 7 thyroid, 3 digestive tract, 2 other). Results MCC (including MCCWOPT and LNM from a cutaneous MCC) differed from LNMNEC by 7 discriminative criteria: 1) elderly age, 2) location of the tumor, 3) extent of the disease, 4) cytokeratin expression, 5) TTF-1 expression, 6) histologic type, and 7) Merkel cell polyomavirus detection, summarized under the acronym ELECTHIP. All MCC patients had ≥5 of the ELECTHIP criteria, whereas all patients with LNMNEC (except 1) had Limitations The discriminant ability of the ELECTHIP criteria should be validated in a second independent set. Conclusion MCCWOPT can be distinguished from other LNMNEC by the ELECTHIP criteria.

Background Merkel cell carcinoma (MCC) is a rare tumor of the skin that has an aggressive behavior. Immunity is the main regulator of MCC development, and many interactions between lymphocytes and tumor cells have been proven. However, the impact of tumor-infiltrating myeloid cells needs better characterization. Objective To characterize tumor-infiltrating myeloid cells in MCC and their association with other immune effectors and patient outcome. Methods MCC cases were reviewed from an ongoing prospective cohort study. In all, 103 triplicate tumor samples were included in a tissue microarray. Macrophages, neutrophils, and myeloid-derived suppressor cells were characterized by the following markers: CD68, CD33, CD163, CD15, CD33, and human leukocyte antigen-DR. Associations of these cell populations with programmed cell death ligand 1 expression, CD8 infiltrates, and vascular density were assessed. Impact on survival was analyzed by log-rank tests and a Cox multivariate model. Results The median density of macrophages was 216 cells/mm 2 . CD68 + and CD33 + macrophage densities were associated with CD8 + T-cell infiltrates and programmed cell death ligand 1 expression. In addition, MCC harboring CD8 + T cell infiltrates and brisk CD33 + myeloid cell infiltrates were significantly and independently associated with improved outcomes (recurrence-free and overall survival). Limitations Sampling bias and the retrospective design were potential study limitations. Conclusion Infiltration of CD33 + myeloid cells and CD8 + T lymphocytes defines a subset of MCC associated with improved outcome.

International audience; This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.