Analyses of combined Merkel cell carcinomas with neuroblastic components suggests that loss of T antigen expression in Merkel cell carcinoma may result in cell cycle arrest and neuroblastic transdifferentiation.

Autor: Kervarrec T; Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France.; 'Biologie des infections à polyomavirus' team, UMR INRAE ISP 1282, Université de Tours, Tours, France.; CARADERM Network., Appenzeller S; Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany., Gramlich S; Institute of Pathology, University of Würzburg, Würzburg, Germany., Coyaud E; PRISM INSERM U1192, Université de Lille, Lille, France., Bachiri K; PRISM INSERM U1192, Université de Lille, Lille, France., Appay R; Department of Pathology, Université de Marseille, Assistance publique des Hopitaux de Marseille, Marseille, France., Macagno N; CARADERM Network.; Department of Pathology, Université de Marseille, Assistance publique des Hopitaux de Marseille, Marseille, France., Tallet A; Platform of Somatic Tumor Molecular Genetics, Centre Hospitalier Universitaire de Tours, Tours, France., Bonenfant C; Platform of Somatic Tumor Molecular Genetics, Centre Hospitalier Universitaire de Tours, Tours, France., Lecorre Y; Dermatology Department, LUNAM Université, CHU Angers, Angers, France., Kapfer J; Cap Orléans Laboratory, Orléans, France., Kettani S; IHP Group, Angers, France., Srinivas N; Department of Translational Skin Cancer Research and Dermatology, University Hospital Essen, Essen, Germany., Lei KC; Department of Translational Skin Cancer Research and Dermatology, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ), Heidelberg, Germany., Lange A; Bioinformatics & Computational Biophysics, University Duisburg-Essen, Essen, Germany., Becker JC; Department of Translational Skin Cancer Research and Dermatology, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ), Heidelberg, Germany., Sarosi EM; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany., Sartelet H; Laboratoire de Biopathologie, CHRU de Nancy, Nancy, France.; INSERM U1256, Université de Lorraine, Nancy, France., von Deimling A; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany., Touzé A; 'Biologie des infections à polyomavirus' team, UMR INRAE ISP 1282, Université de Tours, Tours, France., Guyétant S; Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France.; 'Biologie des infections à polyomavirus' team, UMR INRAE ISP 1282, Université de Tours, Tours, France., Samimi M; 'Biologie des infections à polyomavirus' team, UMR INRAE ISP 1282, Université de Tours, Tours, France.; CARADERM Network.; Department of Dermatology, Université de Tours, Centre Hospitalier Universitaire de Tours, Tours, France., Schrama D; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany., Houben R; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Jazyk: angličtina
Zdroj: The Journal of pathology [J Pathol] 2024 Sep; Vol. 264 (1), pp. 112-124. Date of Electronic Publication: 2024 Jul 25.
DOI: 10.1002/path.6304
Abstrakt: 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. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
(© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
Databáze: MEDLINE
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