Contributors: Service de Pathologie CHRU Tours; Centre Hospitalier Régional Universitaire de Tours (CHRU Tours); Infectiologie et Santé Publique (ISP); Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); University Hospital of Würzburg; Julius-Maximilians-Universität Würzburg = University of Würzburg Würsburg, Germany (JMU); Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Département de Pathologie CHU Marseille; CHU Marseille; Plateforme de Génétique moléculaire des cancers (PGMC); Centre Hospitalier Universitaire d'Angers (CHU Angers); PRES Université Nantes Angers Le Mans (UNAM); University Hospital Essen (AöR); German Cancer Consortium Heidelberg (DKTK); Universität Duisburg-Essen = University of Duisburg-Essen Essen; Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy); Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL); Ruprecht-Karls Universität Heidelberg = Ruprecht-Karls University = Universität Heidelberg = Heidelberg University; Service de dermatologie (CHRU de Tours); The authors thank Fondation ARC pour la recherche contre le cancer, Interdisziplinares Zentrum fur Klinische Forschung Wurzburg (IZKF B-343) the German Research Foundation (SCHR 1178/3-2), the Ligue Nationale Contre le Cancer, Comites 16, 18, 28, HUGO Grant. German Cancer Consortium (DKTK), ED003, Illumina Grant.
نبذة مختصرة : International audience ; Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas.
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