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Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma

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Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as “combined” or “conventional.” Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of the combined MCC cases suggests similar routes of carcinogenesis for combined and conventional MCC.

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Funding

This work was funded by project POCAME, Axe Immunothérapies, Cancéropole Grand Ouest-Région Centre Val de Loire (France) and by the Fond de recherche de la société française de Pathologie 2016.

Author information

Authors and Affiliations

  1. Department of Pathology, Université de Tours, Centre Hospitalier Universitaire de Tours, 37044, Tours Cedex 09, France

    Thibault Kervarrec, Gaëlle Fromont & Serge Guyétant

  2. Biologie des infections à polyomavirus team, UMR INRA ISP 1282, Université de Tours, 31, Avenue Monge, 37200, Tours, France

    Thibault Kervarrec, Mahtab Samimi, Pauline Gaboriaud, Antoine Touzé & Serge Guyétant

  3. Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080, Würzburg, Germany

    Thibault Kervarrec, Roland Houben & David Schrama

  4. Department of Dermatology, Université François Rabelais, Centre Hospitalier Universitaire de Tours, 37044, Tours Cedex 09, France

    Mahtab Samimi & Massimo Tommasino

  5. Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69008, Lyon, France

    Tarik Gheit

  6. Université de Poitiers, 2RCT “Récepteurs et régulation des cellules tumorales” team, 1 rue Georges Bonnet, 86073, Poitiers, France

    Agnès Beby-Defaux

  7. Department of Virology, Université de Poitiers, Centre Hospitalier Universitaire de Poitiers, 2 rue de la Milétrie, 86021, Poitiers, France

    Agnès Beby-Defaux

  8. Department of Dermatology, LUNAM Université, Centre Hospitalier Universitaire d’Angers, 4 rue Larrey, 49933, Angers, France

    Yannick Le Corre

  9. Department of Dermatology, Université de Poitiers, Centre Hospitalier Universitaire de Poitiers, 2 rue de la Milétrie, 86021, Poitiers, France

    Eva Hainaut-Wierzbicka

  10. Department of Dermatology, Université de Franche Comté, Centre Hospitalier Universitaire de Besançon, EA3181, IFR133, 2 boulevard Fleming, 25030, Besançon, France

    Francois Aubin

  11. Department of Dermatology, Centre Hospitalier Régional d’Orléans, 14 avenue de l’Hôpital, CS 86709, 45067, Orléans cedex 2, France

    Guido Bens

  12. Department of Dermatology, Centre Hospitalier Régional du Mans, 194 avenue Rubillard, 72037, Le Mans, France

    Hervé Maillard

  13. Department of Pathology, Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux, Avenue de Magellan, 33604, Pessac, France

    Adeline Furudoï

  14. Department of Pathology, Centre Hospitalier Régional d’Orléans, 14 avenue de l’Hôpital, CS 86709, 45067, Orléans cedex 2, France

    Patrick Michenet

Authors
  1. Thibault Kervarrec
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  2. Mahtab Samimi
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  3. Pauline Gaboriaud
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  4. Tarik Gheit
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  5. Agnès Beby-Defaux
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  6. Roland Houben
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  7. David Schrama
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  8. Gaëlle Fromont
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  9. Massimo Tommasino
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  10. Yannick Le Corre
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  11. Eva Hainaut-Wierzbicka
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  12. Francois Aubin
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  13. Guido Bens
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  14. Hervé Maillard
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  15. Adeline Furudoï
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  16. Patrick Michenet
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  17. Antoine Touzé
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  18. Serge Guyétant
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Corresponding author

Correspondence to Thibault Kervarrec.

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Conflict of interest

The authors declare no conflict of interest.

Institutional review board

The local Ethics Committee of Tours (France) approved the study (no. RCB2009-A01056-51)

Electronic supplementary material

Supplemental table S1

Antibodies and dilution used for immunohistochemistry (DOCX 66 kb)

Supplemental table S2

Primers used (DOCX 59 kb)

Supplemental table S3

Univariate analysis of factors associated with Merkel cell carcinoma recurrence and death (DOCX 14 kb)

Supplemental table S4

Detection of beta papillomavirus (DOCX 48 kb)

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Kervarrec, T., Samimi, M., Gaboriaud, P. et al. Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma. Virchows Arch 472, 825–837 (2018). https://doi.org/10.1007/s00428-018-2342-0

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  • DOI: https://doi.org/10.1007/s00428-018-2342-0

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