Skip to main content

Advertisement

SpringerLink
Log in

Epstein-Barr virus associated gastric dysplasia: a new rare entity?

  • Brief Report
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Epstein-Barr virus (EBV) infection characterizes a portion of gastric adenocarcinomas. However, since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa, the etiologic role of EBV in gastric carcinogenesis is still debated. We report an unusual case of an EBV-associated foveolar gastric dysplasia associated with a focus of EBV-positive low-grade tubular adenocarcinoma, arisen in the context of a lymphocytic-like (EBV-positive) gastritis. The present case offers the unique opportunity to determine whether EBV is an early or late event in gastric cancer development and to evaluate its prevalence in patients with gastric dysplasia. To properly address this question, we investigated EBER expression in a large mono-institutional series of gastric and gastro-esophageal cancers (n = 594) and associated precursor lesions (n = 84). All the selected gastric dysplastic lesions (n = 43) resulted EBV negative. In most cases, EBV is present only in gastric and gastroesophageal junction adenocarcinomas, but not in their precursor lesions. However, the reported case indicates that non-conventional EBV-associated dysplasia may represent a novel histopathological entity in the gastric dysplasia scenario and that EBV could play an early direct role in gastric carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52(24):6735–6740

    CAS  PubMed  Google Scholar 

  2. Gullo I, Grillo F, Mastracci L et al (2020) Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica 112(3):166–185. https://doi.org/10.32074/1591-951X-166

    Article  PubMed  PubMed Central  Google Scholar 

  3. Polk DB, Peek RMJ (2010) Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer 10(6):403–414. https://doi.org/10.1038/nrc2857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Saraggi D, Fassan M, Bornschein J, Farinati F, Realdon S, Valeri N, Rugge M (2016) From Barrett metaplasia to esophageal adenocarcinoma: the molecular background. Histol Histopathol 31(1):25–32

    CAS  PubMed  Google Scholar 

  5. WHO (2019) Classification of Tumours Editorial Board. Digestive system tumours, 5th edn. IARC, Lyon

    Google Scholar 

  6. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–9. https://doi.org/10.1038/nature13480

    Article  CAS  Google Scholar 

  7. Sun K, Jia K, Lv H, et al (2020) EBV-positive gastric cancer: current knowledge and future perspectives. Front Oncol 10:583463. Published 2020 Dec 14. https://doi.org/10.3389/fonc.2020.583463

  8. Coati I, Lotz G, Fanelli GN et al (2019) Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. Br J Cancer 121(3):257–263. https://doi.org/10.1038/s41416-019-0508-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Derks S, Liao X, Chiaravalli AM et al (2016) Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers. Oncotarget 7(22):32925–32932. https://doi.org/10.18632/oncotarget.9076

    Article  PubMed  PubMed Central  Google Scholar 

  10. Xie T, Liu Y, Zhang Z et al (2020) Positive status of Epstein-Barr virus as a biomarker for gastric cancer immunotherapy: a prospective observational study. J Immunother 43(4):139–144. https://doi.org/10.1097/CJI.0000000000000316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim ST, Cristescu R, Bass AJ et al (2018) Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 24(9):1449–1458. https://doi.org/10.1038/s41591-018-0101-z

    Article  CAS  PubMed  Google Scholar 

  12. Young LS, Yap LF, Murray PG (2016) Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer 16(12):789–802. https://doi.org/10.1038/nrc.2016.92

    Article  CAS  PubMed  Google Scholar 

  13. Zhang W (2014) TCGA divides gastric cancer into four molecular subtypes: implications for individualized therapeutics. Chin J Cancer 33(10):469–470. https://doi.org/10.5732/cjc.014.10117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Genitsch V, Novotny A, Seiler CA, Kröll D, Walch A, Langer R (2015) Epstein-barr virus in gastro-esophageal adenocarcinomas - single center experiences in the context of current literature. Front Oncol 26(5):73. https://doi.org/10.3389/fonc.2015.00073

    Article  Google Scholar 

  15. Lee J-H, Kim S-H, Han S-H, An J-S, Lee E-S, Y.-S, (2009) Kim, “Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis.” J Gastroenterol Hepatol 24(3):354–365. https://doi.org/10.1111/j.1440-1746.2009.05775.x

    Article  PubMed  Google Scholar 

  16. Beek Van, J,zurHausen A, Klein Kranenbarg E, et al (2004) EBV-positive gastric adenocarcinomas a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol 22(4):664–670. https://doi.org/10.1200/JCO.2004.08.061

    Article  PubMed  Google Scholar 

  17. Koriyama C, Akiba S, Corvalan A et al (2004) Histology-specific gender, age and tumor-location distributions of Epstein-Barr virus-associated gastric carcinoma in Japan. Oncol Rep 12(3):543–547

    PubMed  Google Scholar 

  18. Ryan JL, Morgan DR, Dominguez RL et al (2009) High levels of Epstein-Barr virus DNA in latently infected gastric adenocarcinoma. Lab Invest 89(1):80–90. https://doi.org/10.1038/labinvest.2008.103

    Article  CAS  PubMed  Google Scholar 

  19. Vanoli A, Di Sabatino A, Martino M et al (2017) Epstein-Barr virus-positive ileal carcinomas associated with Crohn’s disease. Virchows Arch 471(4):549–552. https://doi.org/10.1007/s00428-017-2209-9

    Article  PubMed  Google Scholar 

  20. Hungermann D, Müller 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(6):409–413. https://doi.org/10.1002/jemt.1109

    Article  CAS  PubMed  Google Scholar 

  21. Zur Hausen A, van Rees BP, van Beek J et al (2004) Epstein-Barr virus in gastric carcinomas and gastric stump carcinomas: a late event in gastric carcinogenesis. J Clin Pathol 57(5):487–491. https://doi.org/10.1136/jcp.2003.014068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ribeiro J, Malta M, Galaghar A et al (2019) Epstein-Barr virus is absent in gastric superficial neoplastic lesions. Virchows Arch 475(6):757–762. https://doi.org/10.1007/s00428-019-02670-1

    Article  PubMed  Google Scholar 

  23. Hirano A, Yanai H, Shimizu N et al (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(2–3):87–94. https://doi.org/10.1385/IJGC:34:2-3:087

    Article  CAS  PubMed  Google Scholar 

  24. Martínez-López JLE, Torres J, Camorlinga-Ponce M, Mantilla A, Leal YA, Fuentes-Pananá EM (2014) Evidence of Epstein-Barr virus association with gastric cancer and non-atrophic gastritis. Viruses 6(1):301–318. https://doi.org/10.3390/v6010301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tanabe H, Mizukami Y, Takei H, Tamamura N, Omura Y, Kobayashi Y, Murakami Y, Kunogi T, Sasaki T, Takahashi K, Ando K, Ueno N, Kashima S, Yuzawa S, Hasegawa K, Sumi Y, Tanino M, Fujiya M, Okumura T (2021) Clinicopathological characteristics of Epstein-Barr virus and microsatellite instability subtypes of early gastric neoplasms classified by the Japanese and the World Health Organization criteria. J Pathol Clin Res 7(4):397–409. https://doi.org/10.1002/cjp2.209

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chang MS, Kim HS, Kim CW, Kim YI, Lan Lee B, Kim WH (2002) Epstein-Barr virus, p53 protein, and microsatellite instability in the adenoma-carcinoma sequence of the stomach. Hum Pathol 33(4):415–420. https://doi.org/10.1053/hupa.2002.124718

    Article  CAS  PubMed  Google Scholar 

  27. Kim L, Kim JM, Hur YS et al (2012) Extended gastritis cystica profunda associated with Epstein-Barr virus-positive dysplasia and carcinoma with lymphoid stroma. Pathol Int 62(5):351–355. https://doi.org/10.1111/j.1440-1827.2012.02806.x

    Article  CAS  PubMed  Google Scholar 

  28. Choi MG, Jeong JY, Kim KM, Bae JM, Noh JH, Sohn TS, Kim S (2012) Clinical significance of gastritis cystica profunda and its association with Epstein-Barr virus in gastric cancer. Cancer 118(21):5227–5233. https://doi.org/10.1002/cncr.27541

    Article  PubMed  Google Scholar 

Download references

Funding

This work was partly supported by a grant from the Italian Health Ministry and Veneto region research program NET-2016–02363853 to MF. The funding agencies had no role in the design and performance of the study.

Author information

Authors and Affiliations

  1. Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, via Gabelli 61, 35121, Padua, Italy

    Valentina Angerilli, Francesca Galuppini, Gianmaria Pennelli, Angelo Paolo Dei Tos & Matteo Fassan

  2. Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Giuseppe Nicolo’ Fanelli

  3. Anatomia Patologica 1, Department of Laboratory Medicine, Pisa University Hospital, Pisa, Italy

    Giuseppe Nicolo’ Fanelli

  4. Department of Pathology, San Bortolo Hospital, Vicenza, Italy

    Emanuele S. G. d’Amore

  5. Surgical Pathology Unit, University Hospital of Padua, Padua, Italy

    Mauro Michelotto

  6. Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Castelfranco Veneto, Italy

    Pierluigi Pilati

  7. Department of Surgical Oncology and Gastroenterology Sciences (DiSCOG), Surgery Unit, University of Padua, Padua, Italy

    Gaya Spolverato, Salvatore Pucciarelli & Marco Scarpa

  8. Department of Surgical Oncology and Gastroenterology Sciences (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy

    Fabio Farinati & Edoardo Savarino

  9. Gastroenterology Unit, Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy

    Stefano Realdon

  10. Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Castelfranco Veneto, Veneto, Italy

    Sara Lonardi

  11. Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy

    Sara Lonardi

  12. Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy

    Francesca Bergamo & Fotios Loupakis

  13. Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Alessandro Vanoli

  14. Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy

    Matteo Fassan

Authors
  1. Valentina Angerilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Galuppini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gianmaria Pennelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giuseppe Nicolo’ Fanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emanuele S. G. d’Amore
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mauro Michelotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pierluigi Pilati
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gaya Spolverato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Salvatore Pucciarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marco Scarpa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fabio Farinati
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Edoardo Savarino
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stefano Realdon
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Sara Lonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Francesca Bergamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Fotios Loupakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Angelo Paolo Dei Tos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alessandro Vanoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Matteo Fassan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study conception and design: VA, FG, GP, AV, MF. Material preparation, data collection, and analysis: VA, GNF, ESd’A, MM, PP, GS, SP, MS, FF, ES, SR, SL, FB, FL, APDT, MF. Financial support: APDT, MF. The first draft of the manuscript was written by VA, FG, AV, MF. All authors contributed to and approved the final manuscript.

Corresponding author

Correspondence to Matteo Fassan.

Ethics declarations

Ethics approval

The study was approved by our Institutional Review Board and was included in the observational retrospective study “GAS-ALL-IN—GAStric cancers a retrospective analysis of ALL major prognostic and prective determINants” (IOV CE 2020/140).

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Angerilli, V., Galuppini, F., Pennelli, G. et al. Epstein-Barr virus associated gastric dysplasia: a new rare entity?. Virchows Arch 480, 939–944 (2022). https://doi.org/10.1007/s00428-021-03206-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-021-03206-2

Keywords

Search

Navigation