Epstein-Barr virus is absent in gastric superficial neoplastic lesions

  • Joana RibeiroEmail author
  • Mariana Malta
  • Ana Galaghar
  • Luís Pedro Afonso
  • Diogo Libânio
  • Rui Medeiros
  • Mario Dinis-Ribeiro
  • Pedro Pimentel-Nunes
  • Hugo SousaEmail author
Original Article


Epstein-Barr virus (EBV) has been associated with about 9% of all gastric carcinomas, but its role in gastric carcinogenesis remains unclear since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa. This study intends to determine the prevalence of EBV in gastric dysplasia and superficial neoplasia to clarify whether EBV infection is an early or late event in gastric cancer development. This retrospective study included a total of 242 gastric lesions from 199 consecutive patients who were referred for endoscopic resection. The histological classification of lesions includes 137 low- and high-grade dysplasia and 105 superficial carcinomas. EBV infection was investigated by EBER-ISH. Results showed that EBV was not detected in any epithelial cells of any case with dysplasia or superficial carcinomas, although we observed the presence of a small number of EBV-infected lymphocytes in 2.1% of all lesions. These results showed that EBV is not present in gastric dysplasia neither in superficial carcinomas suggesting that EBV carcinogenesis is a late event in well/moderately differentiated gastric carcinogenesis.


Gastric dysplasia Neoplastic lesion Gastric cancer Epstein-Barr virus (EBV) EBVaGC 



Authors would like to acknowledge the support of Portuguese League Against Cancer (LPCC-NRNorte) for the development of this project.

Author contributions

JR, HS, PPN, RM, conception and design of the study; JR and MM, EBV detection and data analysis; AG and LPA, histological review of cases and results; DL, MDR and PPN, cases selection and clinical data collection; JR, analysis and interpretation of data, drafting the manuscript, final approval; JR and HS, analysis and interpretation of data, manuscript writing; all authors were able to review the article and give final approval.

Funding Information

Joana Ribeiro was granted with a PhD Scholarship (SFRH/BD/107740/2015) from FCT-Fundação para Ciência e Tecnologia.

Compliance with ethical standards

All procedures were approved by the Ethical Committee of Portuguese Oncology Institute of Porto (CES IPO 80/2014).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Burke AP, Yen TS, Shekitka KM, Sobin LH (1990) Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol 3:377–380PubMedGoogle Scholar
  2. 2.
    Camargo MC, Kim KM, Matsuo K, Torres J, Liao LM, Morgan DR, Michel A, Waterboer T, Zabaleta J, Dominguez RL, Yatabe Y, Kim S, Rocha-Guevara ER, Lissowska J, Pawlita M, Rabkin CS (2016) Anti-helicobacter pylori antibody profiles in Epstein-Barr virus (EBV)-positive and EBV-negative gastric cancer. Helicobacter 21:153–157. CrossRefPubMedGoogle Scholar
  3. 3.
    Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, Yu J, Sung JJ, Herrera-Goepfert R, Meneses-Gonzalez F, Kijima Y, Natsugoe S, Liao LM, Lissowska J, Kim S, Hu N, Gonzalez CA, Yatabe Y, Koriyama C, Hewitt SM, Akiba S, Gulley ML, Taylor PR, Rabkin CS (2014) Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 63:236–243. CrossRefPubMedGoogle Scholar
  4. 4.
    Camargo MC, Murphy G, Koriyama C, Pfeiffer RM, Kim WH, Herrera-Goepfert R, Corvalan AH, Carrascal E, Abdirad A, Anwar M, Hao Z, Kattoor J, Yoshiwara-Wakabayashi E, Eizuru Y, Rabkin CS, Akiba S (2011) Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis. Br J Cancer 105:38–43. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209. CrossRefGoogle Scholar
  6. 6.
    Chen ZM, Shah R, Zuckerman GR, Wang HL (2007) Epstein-Barr virus gastritis: an underrecognized form of severe gastritis simulating gastric lymphoma. Am J Surg Pathol 31:1446–1451. CrossRefPubMedGoogle Scholar
  7. 7.
    de Souza CR, de Oliveira KS, Ferraz JJ, Leal MF, Calcagno DQ, Seabra AD, Khayat AS, Montenegro RC, Alves AP, Assumpcao PP, Smith MC, Burbano RR (2014) Occurrence of Helicobacter pylori and Epstein-Barr virus infection in endoscopic and gastric cancer patients from Northern Brazil. BMC gastroenterology 14:179–179. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Dinis-Ribeiro M, Areia M, de Vries AC, Marcos-Pinto R, Monteiro-Soares M, O'Connor A, Pereira C, Pimentel-Nunes P, Correia R, Ensari A, Dumonceau JM, Machado JC, Macedo G, Malfertheiner P, Matysiak-Budnik T, Megraud F, Miki K, O'Morain C, Peek RM, Ponchon T, Ristimaki A, Rembacken B, Carneiro F, Kuipers EJ, European Society of Gastrointestinal E, European Helicobacter Study G, European Society of P, Sociedade Portuguesa de Endoscopia D (2012) Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 44:74–94. CrossRefPubMedGoogle Scholar
  9. 9.
    Dixon MF (2002) Gastrointestinal epithelial neoplasia: Vienna revisited. Gut 51:130–131CrossRefGoogle Scholar
  10. 10.
    Dixon MF, Genta RM, Yardley JH, Correa P (1996) Classification and grading of gastritis. The updated Sydney System. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol 20:1161–1181CrossRefGoogle Scholar
  11. 11.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase no. 11 [internet]. Accessed 31/12/2016Google Scholar
  12. 12.
    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374–1403. CrossRefPubMedGoogle Scholar
  13. 13.
    Gulley ML, Pulitzer DR, Eagan PA, Schneider BG (1996) Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Hum Pathol 27:20–27CrossRefGoogle Scholar
  14. 14.
    Hirano A, Yanai H, Shimizu N, Okamoto T, Matsubara Y, Yamamoto K, Okita K (2003) Evaluation of epstein-barr virus DNA load in gastric mucosa with chronic atrophic gastritis using a real-time quantitative PCR assay. Int J Gastrointest Cancer 34:87–94. CrossRefPubMedGoogle Scholar
  15. 15.
    Hungermann D, Muller S, Spieker T, Lisner R, Niedobitek G, Herbst H (2001) Low prevalence of latently Epstein-Barr virus-infected cells in chronic gastritis. Microsc Res Tech 53:409–413. CrossRefPubMedGoogle Scholar
  16. 16.
    Iizasa H, Nanbo A, Nishikawa J, Jinushi M, Yoshiyama H (2012) Epstein-Barr virus (EBV)-associated gastric carcinoma. Viruses 4:3420–3439CrossRefGoogle Scholar
  17. 17.
    Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49CrossRefGoogle Scholar
  18. 18.
    Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS (2009) Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 24:354–365. CrossRefPubMedGoogle Scholar
  19. 19.
    Luqmani YA, Linjawi SO, Shousha S (2001) Detection of Epstein-Barr virus in gastrectomy specimens. Oncol Rep 8:995–999PubMedGoogle Scholar
  20. 20.
    Martinez-Lopez JL, Torres J, Camorlinga-Ponce M, Mantilla A, Leal YA, Fuentes-Panana EM (2014) Evidence of Epstein-Barr virus association with gastric cancer and non-atrophic gastritis. Viruses 6:301–318. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Matsusaka K, Funata S, Fukayama M, Kaneda A (2014) DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World J Gastroenterol 20:3916–3926. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Minoura-Etoh J, Gotoh K, Sato R, Ogata M, Kaku N, Fujioka T, Nishizono A (2006) Helicobacter pylori-associated oxidant monochloramine induces reactivation of Epstein-Barr virus (EBV) in gastric epithelial cells latently infected with EBV. J Med Microbiol 55:905–911. CrossRefPubMedGoogle Scholar
  23. 23.
    Murai K, Kakushima N, Sugino T, Yoshida M, Kawata N, Tanaka M, Takizawa K, Muramatu K, Kusafuka K, Bando E, Ono H (2018) Epstein-Barr virus positivity among surgically resected intramucosal gastric cancer. Dig Endosc 30:667–671. CrossRefPubMedGoogle Scholar
  24. 24.
    Nogueira C, Mota M, Gradiz R, Cipriano MA, Caramelo F, Cruz H, Alarcão A, Castro F, Oliveira F, Martinho F, Pereira JM, Figueiredo P, Maximino L (2017) Prevalence and characteristics of Epstein–Barr virus-associated gastric carcinomas in Portugal. Infect Agent Cancer 12:1–8. CrossRefGoogle Scholar
  25. 25.
    Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, Yamada G, Azuma T, Hatakeyama M (2008) Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci U S A 105:1003–1008. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ribeiro J, Malta M, Galaghar A, Silva F, Afonso LP, Medeiros R, Sousa H (2017) P53 deregulation in Epstein-Barr virus-associated gastric cancer. Cancer Lett 404:37–43. CrossRefPubMedGoogle Scholar
  27. 27.
    Ribeiro J, Oliveira A, Malta M, Oliveira C, Silva F, Galaghar A, Afonso LP, Neves MC, Medeiros R, Pimentel-Nunes P, Sousa H (2017) Clinical and pathological characterization of Epstein-Barr virus-associated gastric carcinomas in Portugal. World J Gastroenterol 23:7292–7302. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Takada K (2000) Epstein-Barr virus and gastric carcinoma. Mol Pathol 53:255–261CrossRefGoogle Scholar
  29. 29.
    Tan VP, Wong BC (2011) Helicobacter pylori and gastritis: untangling a complex relationship 27 years on. J Gastroenterol Hepatol 26(Suppl 1):42–45. CrossRefPubMedGoogle Scholar
  30. 30.
    Tokunaga M, Land CE, Uemura Y, Tokudome T, Tanaka S, Sato E (1993) Epstein-Barr virus in gastric carcinoma. Am J Pathol 143:1250–1254PubMedPubMedCentralGoogle Scholar
  31. 31.
    Tsang CM, Yip YL, Lo KW, Deng W, To KF, Hau PM, Lau VM, Takada K, Lui VW, Lung ML, Chen H, Zeng M, Middeldorp JM, Cheung AL, Tsao SW (2012) Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells. Proc Natl Acad Sci U S A 109:E3473–E3482. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Tsang CM, Zhang G, Seto E, Takada K, Deng W, Yip YL, Man C, Hau PM, Chen H, Cao Y, Lo KW, Middeldorp JM, Cheung AL, Tsao SW (2010) Epstein-Barr virus infection in immortalized nasopharyngeal epithelial cells: regulation of infection and phenotypic characterization. Int J Cancer 127:1570–1583. CrossRefPubMedGoogle Scholar
  33. 33.
    Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, European Society for Medical O, European Society of Surgical O, European Society of R, Oncology (2014) Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol 40:584–591. CrossRefPubMedGoogle Scholar
  34. 34.
    Yanai H, Takada K, Shimizu N, Mizugaki Y, Tada M, Okita K (1997) Epstein-Barr virus infection in non-carcinomatous gastric epithelium. J Pathol 183:293–298.<293::AID-PATH937>3.0.CO;2-C CrossRefPubMedGoogle Scholar
  35. 35.
    Young LS, Yap LF, Murray PG (2016) Epstein-Barr virus: more than 50 years old and still providing surprises nature reviews. Cancer 16:789–802. CrossRefPubMedGoogle Scholar
  36. 36.
    Zur Hausen A, van Rees BP, van Beek J, Craanen ME, Bloemena E, Offerhaus GJ, Meijer CJ, van den Brule AJ (2004) Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis. J Clin Pathol 57:487–491CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Molecular Oncology & Viral Pathology Group (CI-IPOP)Portuguese Oncology Institute of PortoPortoPortugal
  2. 2.Faculty of Medicine of Porto UniversityFMUPPortoPortugal
  3. 3.Research Department, Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte)PortoPortugal
  4. 4.Department of PathologyPortuguese Oncology Institute of PortoPortoPortugal
  5. 5.Gastroenterology DepartmentPortuguese Oncology Institute of PortoPortoPortugal
  6. 6.CINTESIS - Center for Health Technology and Services Research (Centro de Investigação Médica, Faculdade de MedicinaUniversidade do PortoPortoPortugal
  7. 7.Virology ServicePortuguese Oncology Institute of PortoPortoPortugal
  8. 8.Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of Minho, Campus de GualtarBragaPortugal
  9. 9.ICVS/3B’s - PT Government Associate LaboratoryBraga/GuimarãesPortugal

Personalised recommendations