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Virchows Archiv

, Volume 472, Issue 5, pp 825–837 | Cite as

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

  • Thibault Kervarrec
  • Mahtab Samimi
  • Pauline Gaboriaud
  • Tarik Gheit
  • Agnès Beby-Defaux
  • Roland Houben
  • David Schrama
  • Gaëlle Fromont
  • Massimo Tommasino
  • Yannick Le Corre
  • Eva Hainaut-Wierzbicka
  • Francois Aubin
  • Guido Bens
  • Hervé Maillard
  • Adeline Furudoï
  • Patrick Michenet
  • Antoine Touzé
  • Serge Guyétant
Original Article
  • 174 Downloads

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.

Keywords

Merkel cell carcinoma Merkel cell polyomavirus Combined merkel cell carcinoma Squamous carcinoma Polyomavirus Papillomavirus 

Notes

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.

Compliance with ethical standards

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)

Supplementary material

428_2018_2342_MOESM1_ESM.docx (66 kb)
Supplemental table S1 Antibodies and dilution used for immunohistochemistry (DOCX 66 kb)
428_2018_2342_MOESM2_ESM.docx (59 kb)
Supplemental table S2 Primers used (DOCX 59 kb)
428_2018_2342_MOESM3_ESM.docx (14 kb)
Supplemental table S3 Univariate analysis of factors associated with Merkel cell carcinoma recurrence and death (DOCX 14 kb)
428_2018_2342_MOESM4_ESM.docx (49 kb)
Supplemental table S4 Detection of beta papillomavirus (DOCX 48 kb)

References

  1. 1.
    Lemos BD, Storer BE, Iyer JG, Phillips JL, Bichakjian CK, Fang LC, Johnson TM, Liegeois-Kwon NJ, Otley CC, Paulson KG, Ross MI, Yu SS, Zeitouni NC, Byrd DR, Sondak VK, Gershenwald JE, Sober AJ, Nghiem P (2010) Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 63:751–761.  https://doi.org/10.1016/j.jaad.2010.02.056 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    LeBoit PE, World Heath Organisation, International Agency for Research on Cancer (eds) (2007) Pathology and genetics of skin tumours: [... reflects the views of a working group that convened for an editorial and consensus conference in Lyon, France, September 22 - 25, 2003]. Reprinted. IARC Press, LyonGoogle Scholar
  3. 3.
    Feng H, Shuda M, Chang Y, Moore PS (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–1100.  https://doi.org/10.1126/science.1152586 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Touzé A, Gaitan J, Maruani A, Le Bidre E, Doussinaud A, Clavel C et al (2009) Merkel cell polyomavirus strains in patients with Merkel cell carcinoma. Emerg Infect Dis 15:960–962.  https://doi.org/10.3201/eid1506.081463 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Houben R, Adam C, Baeurle A, Hesbacher S, Grimm J, Angermeyer S, Henzel K, Hauser S, Elling R, Bröcker EB, Gaubatz S, Becker JC, Schrama D (2012) An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells. Int J Cancer 130:847–856.  https://doi.org/10.1002/ijc.26076 CrossRefPubMedGoogle Scholar
  6. 6.
    González-Vela MDC, Curiel-Olmo S, Derdak S, Beltran S, Santibañez M, Martínez N et al (2017) Shared oncogenic pathways implicated in both virus-positive and UV-induced Merkel cell carcinomas. J Invest Dermatol 137:197–206.  https://doi.org/10.1016/j.jid.2016.08.015 CrossRefPubMedGoogle Scholar
  7. 7.
    Paulson KG, Iyer JG, Tegeder AR, Thibodeau R, Schelter J, Koba S, Schrama D, Simonson WT, Lemos BD, Byrd DR, Koelle DM, Galloway DA, Leonard JH, Madeleine MM, Argenyi ZB, Disis ML, Becker JC, Cleary MA, Nghiem P (2011) Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol Off J Am Soc Clin Oncol 29:1539–1546.  https://doi.org/10.1200/JCO.2010.30.6308 CrossRefGoogle Scholar
  8. 8.
    Moshiri AS, Doumani R, Yelistratova L, Blom A, Lachance K, Shinohara MM, Delaney M, Chang O, McArdle S, Thomas H, Asgari MM, Huang ML, Schwartz SM, Nghiem P (2016) Polyomavirus-negative Merkel cell carcinoma: a more aggressive subtype based on analysis of 282 cases using multimodal tumor virus detection. J Invest Dermatol 137:819–827.  https://doi.org/10.1016/j.jid.2016.10.028. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M, Bini J, Arora R, Hanson NC, Tassello JA, Frosina D, Moore P, Chang Y (2009) Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathol 33:1378–1385.  https://doi.org/10.1097/PAS.0b013e3181aa30a5 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Martin B, Poblet E, Rios JJ, Kazakov D, Kutzner H, Brenn T, Calonje E (2013) Merkel cell carcinoma with divergent differentiation: histopathological and immunohistochemical study of 15 cases with PCR analysis for Merkel cell polyomavirus. Histopathology 62:711–722.  https://doi.org/10.1111/his.12091 CrossRefPubMedGoogle Scholar
  11. 11.
    Carter MD, Gaston D, Huang W-Y, Greer WL, Pasternak S, Ly TY, Walsh NM (2017) Genetic profiles of different subsets of Merkel cell carcinoma show links between combined and pure MCPyV-negative tumors. Hum Pathol 71:117–125.  https://doi.org/10.1016/j.humpath.2017.10.014. CrossRefPubMedGoogle Scholar
  12. 12.
    Chou T-C, Tsai K-B, Wu C-Y, Hong C-H, Lee C-H (2016) Presence of the Merkel cell polyomavirus in Merkel cell carcinoma combined with squamous cell carcinoma in a patient with chronic arsenism. Clin Exp Dermatol 41:902–905.  https://doi.org/10.1111/ced.12954 CrossRefPubMedGoogle Scholar
  13. 13.
    Mitteldorf C, Mertz KD, Fernández-Figueras MT, Schmid M, Tronnier M, Kempf W (2012) Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients. Am J Dermatopathol 34:506–510.  https://doi.org/10.1097/DAD.0b013e31823b9b4e CrossRefPubMedGoogle Scholar
  14. 14.
    Bishop JA, Westra WH (2011) Human papillomavirus-related small cell carcinoma of the oropharynx. Am J Surg Pathol 35:1679–1684.  https://doi.org/10.1097/PAS.0b013e3182299cde CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gardair C, Samimi M, Touzé A, Coursaget P, Lorette G, Caille A et al (2015) Somatostatin receptors 2A and 5 are expressed in Merkel cell carcinoma with no association with disease severity. Neuroendocrinology 101:223–235.  https://doi.org/10.1159/000381062 CrossRefPubMedGoogle Scholar
  16. 16.
    Asgari MM, Sokil MM, Warton EM, Iyer J, Paulson KG, Nghiem P (2014) Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma. JAMA Dermatol 150:716–723.  https://doi.org/10.1001/jamadermatol.2013.8116 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Watanabe G, Ishida T, Furuta A, Takahashi S, Watanabe M, Nakata H, Kato S, Ishioka C, Ohuchi N (2015) Combined immunohistochemistry of PLK1, p21, and p53 for predicting TP53 status: an independent prognostic factor of breast cancer. Am J Surg Pathol 39:1026–1034.  https://doi.org/10.1097/PAS.0000000000000386 CrossRefPubMedGoogle Scholar
  18. 18.
    Rodig SJ, Cheng J, Wardzala J, DoRosario A, Scanlon JJ, Laga AC, Martinez-Fernandez A, Barletta JA, Bellizzi AM, Sadasivam S, Holloway DT, Cooper DJ, Kupper TS, Wang LC, DeCaprio JA (2012) Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 122:4645–4653.  https://doi.org/10.1172/JCI64116 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liu W, Yang R, Payne AS, Schowalter RM, Spurgeon ME, Lambert PF, Xu X, Buck CB, You J (2016) Identifying the target cells and mechanisms of Merkel cell polyomavirus infection. Cell Host Microbe 19:775–787.  https://doi.org/10.1016/j.chom.2016.04.024 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rollison DE, Giuliano AR, Messina JL, Fenske NA, Cherpelis BS, Sondak VK, Roetzheim RG, Iannacone MR, Michael KM, Gheit T, Waterboer T, Tommasino M, Pawlita M (2012) Case-control study of Merkel cell polyomavirus infection and cutaneous squamous cell carcinoma. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 21:74–81.  https://doi.org/10.1158/1055-9965.EPI-11-0764 CrossRefGoogle Scholar
  21. 21.
    Hampras SS, Michel A, Schmitt M, Waterboer T, Kranz L, Gheit T, Fisher K, Sondak VK, Messina J, Fenske N, Cherpelis B, Tommasino M, Pawlita M, Rollison DE (2015) Merkel cell polyomavirus (MCV) T-antigen seroreactivity, MCV DNA in eyebrow hairs, and squamous cell carcinoma. Infect Agent Cancer 10:35.  https://doi.org/10.1186/s13027-015-0030-0 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gheit T, Billoud G, de Koning MNC, Gemignani F, Forslund O, Sylla BS, Vaccarella S, Franceschi S, Landi S, Quint WGV, Canzian F, Tommasino M (2007) Development of a sensitive and specific multiplex PCR method combined with DNA microarray primer extension to detect Betapapillomavirus types. J Clin Microbiol 45:2537–2544.  https://doi.org/10.1128/JCM.00747-07 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Iannacone MR, Gheit T, Pfister H, Giuliano AR, Messina JL, Fenske NA, Cherpelis BS, Sondak VK, Roetzheim RG, Silling S, Pawlita M, Tommasino M, Rollison DE (2014) Case-control study of genus-beta human papillomaviruses in plucked eyebrow hairs and cutaneous squamous cell carcinoma. Int J Cancer 134:2231–2244.  https://doi.org/10.1002/ijc.28552 CrossRefPubMedGoogle Scholar
  24. 24.
    Di Bonito P, Libera SD, Petricca S, Iaconelli M, Accardi L, Muscillo M et al (2015) Frequent and abundant Merkel cell polyomavirus detection in urban wastewaters in Italy. Food Environ Virol 7:1–6.  https://doi.org/10.1007/s12560-014-9168-y. CrossRefPubMedGoogle Scholar
  25. 25.
    Gheit T, Landi S, Gemignani F, Snijders PJF, Vaccarella S, Franceschi S, Canzian F, Tommasino M (2006) Development of a sensitive and specific assay combining multiplex PCR and DNA microarray primer extension to detect high-risk mucosal human papillomavirus types. J Clin Microbiol 44:2025–2031.  https://doi.org/10.1128/JCM.02305-05 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Harms KL, Healy MA, Nghiem P, Sober AJ, Johnson TM, Bichakjian CK, Wong SL (2016) Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann Surg Oncol 23:3564–3571.  https://doi.org/10.1245/s10434-016-5266-4 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Czapiewski P, Majewska H, Kutzner H, Kazakov D, Renkielska A, Biernat W (2016) TTF-1 and PAX5 are frequently expressed in combined Merkel cell carcinoma. Am J Dermatopathol 38:513–516.  https://doi.org/10.1097/DAD.0000000000000464 CrossRefPubMedGoogle Scholar
  28. 28.
    Lai JH, Fleming KE, Ly TY, Pasternak S, Godlewski M, Doucette S, Walsh NM (2015) Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors. Hum Pathol 46:1290–1296.  https://doi.org/10.1016/j.humpath.2015.05.008 CrossRefPubMedGoogle Scholar
  29. 29.
    Pulitzer MP, Brannon AR, Berger MF, Louis P, Scott SN, Jungbluth AA, Coit DG, Brownell I, Busam KJ (2015) Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma. Mod Pathol Off J U S Can Acad Pathol Inc 28:1023–1032.  https://doi.org/10.1038/modpathol.2015.60 CrossRefGoogle Scholar
  30. 30.
    Chen C-H, Wu Y-Y, Kuo K-T, Liau J-Y, Liang C-W (2015) Combined squamous cell carcinoma and Merkel cell carcinoma of the vulva: role of human papillomavirus and Merkel cell polyomavirus. JAAD Case Rep 1:196–199.  https://doi.org/10.1016/j.jdcr.2015.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Iwasaki T, Kodama H, Matsushita M, Kuroda N, Yamasaki Y, Murakami I, Yamamoto O, Hayashi K (2013) Merkel cell polyomavirus infection in both components of a combined Merkel cell carcinoma and basal cell carcinoma with ductal differentiation; each component had a similar but different novel Merkel cell polyomavirus large T antigen truncating mutation. Hum Pathol 44:442–447.  https://doi.org/10.1016/j.humpath.2012.08.022 CrossRefPubMedGoogle Scholar
  32. 32.
    Leroux-Kozal V, Lévêque N, Brodard V, Lesage C, Dudez O, Makeieff M, Kanagaratnam L, Diebold MD (2015) Merkel cell carcinoma: histopathologic and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus large T antigen correlated with viral load. Hum Pathol 46:443–453.  https://doi.org/10.1016/j.humpath.2014.12.001 CrossRefPubMedGoogle Scholar
  33. 33.
    Eid M, Nguyen J, Brownell I (2017) Seeking standards for the detection of Merkel cell polyomavirus and its clinical significance. J Invest Dermatol 137:797–799.  https://doi.org/10.1016/j.jid.2016.12.024 CrossRefPubMedGoogle Scholar
  34. 34.
    Houben R, Grimm J, Willmes C, Weinkam R, Becker JC, Schrama D (2012) Merkel cell carcinoma and Merkel cell polyomavirus: evidence for hit-and-run oncogenesis. J Invest Dermatol 132:254–256.  https://doi.org/10.1038/jid.2011.260 CrossRefPubMedGoogle Scholar
  35. 35.
    Tommasino M (2017) The biology of beta human papillomaviruses. Virus Res 2016.  https://doi.org/10.1016/j.virusres.2016.11.013
  36. 36.
    Mehrad M, Carpenter DH, Chernock RD, Wang H, Ma X-J, Luo Y, Luo J, Lewis JS Jr, el-Mofty SK (2013) Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus. Am J Surg Pathol 37:1349–1356.  https://doi.org/10.1097/PAS.0b013e318290427d CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ostrowski SM, Wright MC, Bolock AM, Geng X, Maricich SM (2015) Ectopic Atoh1 expression drives Merkel cell production in embryonic, postnatal and adult mouse epidermis. Dev Camb Engl 142:2533–2544.  https://doi.org/10.1242/dev.123141 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Thibault Kervarrec
    • 1
    • 2
    • 3
  • Mahtab Samimi
    • 2
    • 4
  • Pauline Gaboriaud
    • 2
  • Tarik Gheit
    • 5
  • Agnès Beby-Defaux
    • 6
    • 7
  • Roland Houben
    • 3
  • David Schrama
    • 3
  • Gaëlle Fromont
    • 1
  • Massimo Tommasino
    • 4
  • Yannick Le Corre
    • 8
  • Eva Hainaut-Wierzbicka
    • 9
  • Francois Aubin
    • 10
  • Guido Bens
    • 11
  • Hervé Maillard
    • 12
  • Adeline Furudoï
    • 13
  • Patrick Michenet
    • 14
  • Antoine Touzé
    • 2
  • Serge Guyétant
    • 1
    • 2
  1. 1.Department of PathologyUniversité de Tours, Centre Hospitalier Universitaire de ToursTours Cedex 09France
  2. 2.Biologie des infections à polyomavirus team, UMR INRA ISP 1282Université de ToursToursFrance
  3. 3.Department of Dermatology, Venereology and AllergologyUniversity Hospital WürzburgWürzburgGermany
  4. 4.Department of DermatologyUniversité François Rabelais, Centre Hospitalier Universitaire de ToursTours Cedex 09France
  5. 5.Infections and Cancer Biology Group, International Agency for Research on CancerLyonFrance
  6. 6.Université de Poitiers, 2RCT “Récepteurs et régulation des cellules tumorales” teamPoitiersFrance
  7. 7.Department of VirologyUniversité de Poitiers, Centre Hospitalier Universitaire de PoitiersPoitiersFrance
  8. 8.Department of DermatologyLUNAM Université, Centre Hospitalier Universitaire d’AngersAngersFrance
  9. 9.Department of DermatologyUniversité de Poitiers, Centre Hospitalier Universitaire de PoitiersPoitiersFrance
  10. 10.Department of DermatologyUniversité de Franche Comté, Centre Hospitalier Universitaire de BesançonBesançonFrance
  11. 11.Department of DermatologyCentre Hospitalier Régional d’OrléansOrléans cedex 2France
  12. 12.Department of DermatologyCentre Hospitalier Régional du MansLe MansFrance
  13. 13.Department of PathologyUniversité de Bordeaux, Centre Hospitalier Universitaire de BordeauxPessacFrance
  14. 14.Department of PathologyCentre Hospitalier Régional d’OrléansOrléans cedex 2France

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