title: Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry.
abstract: Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine nonmelanoma skin cancer, which is associated with the Merkel cell polyoma virus (MCPyV). Recently, expression of the terminal deoxynucleotidyl transferase (TdT) and the paired box gene 5 (PAX 5) has been consistently reported in the majority of MCCs. We tested 21 MCCs for the expression of MCPyV, TdT, PAX5, IgG, IgM, IgA, kappa, and lambda by immunohistochemistry and assessed IgH and Igk rearrangement in all 21 MCCs. All of the MCCs revealed specific expression of PAX5 and 72.8% of the MCCs expressed TdT. In addition, most of the MCCs revealed specific expression of one or more Ig subclasses and kappa or lambda. One MCC did reveal monoclonal IgH and Igk rearrangement next to two other MCCs showing Igk rearrangement. As coexpression of TdT and PAX5 under physiologic circumstances is restricted to pro/pre- and pre-B cells we propose, on the basis of our results, that the cell of origin of MCCs is a pro/pre- or pre-B cell rather than the postmitotic Merkel cells. MCPyV infection and transformation of pro-/pre-B cells are likely to induce the expression of simple cytokeratins as has been shown for SV40 in other nonepithelial cells. This model of cellular ancestry of MCCs might impact therapy and possibly helps to understand why approximately 20% of MCCs are MCPyV-negative.
authors.affiliation: Authors' Affiliations: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; and Department of Internal Medicine IV, University Hospital Aachen, Aachen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Zur Hausen
authors.forename: Dorit
authors.initials: D
authors.lastname: Rennspiess
authors.forename: Veronique
authors.initials: V
authors.lastname: Winnepenninckx
authors.forename: Ernst-Jan
authors.initials: EJ
authors.lastname: Speel
authors.forename: Anna Kordelia
authors.initials: AK
authors.lastname: Kurz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015266:Carcinoma, Merkel Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002454:Cell Differentiation / Q000502:physiology; D004253:DNA Nucleotidylexotransferase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008297:Male; D059965:Merkel cell polyomavirus / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D027601:Polyomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D007136:Immunoglobulins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D004253:DNA Nucleotidylexotransferase