Epstein–Barr virus status is a promising biomarker for endoscopic resection in early gastric cancer: proposal of a novel therapeutic strategy

  • Hiroki Osumi
  • Hiroshi Kawachi
  • Toshiyuki YoshioEmail author
  • Satoshi Ida
  • Noriko Yamamoto
  • Yusuke Horiuchi
  • Akiyoshi Ishiyama
  • Toshiaki Hirasawa
  • Tomohiro Tsuchida
  • Naoki Hiki
  • Kengo Takeuchi
  • Junko Fujisaki
Original Article—Alimentary Tract



Epstein–Barr virus-positive gastric cancer (EBVGC) is associated with a low prevalence of lymph node metastasis (LNM); however, EBV status is not considered in the indication of endoscopic resection (ER). We aimed to clarify the implication of EBV status for ER of pT1b GC.


Consecutive cases of pT1b GCs treated with surgery between 2005 and 2014 were retrospectively analyzed. Clinicopathological factors and LNM status were compared between EBVGC and non-EBVGC groups.


EBVGC accounted for 7.9% (71 of 898) cases. Compared to non-EBVGC, EBVGC was more frequent in males (p = 0.0055), the upper third region (p < 0.0001), showed elevated growth features (p = 0.0059), and was associated with a lower frequency of accompanying ulceration (p = 0.002), greater depth of submucosal invasion (p = 0.017), and lower frequency of lymphatic invasion (p < 0.0001). Frequency of LNM was significantly lower in EBVGC than in non-EBVGC (4.2% vs. 21.9%, p < 0.0001). In EBVGC, tumors without lymphovascular invasion showed significantly lower frequency of LNM than those with lymphovascular invasion (0 of 50, 0%; vs 3 of 21, 14.3%; p = 0.023). Histologically, 84.5% (60 of 71) of EBVGC included carcinomas with lymphoid stroma and/or lace pattern components.


pT1b EBVGC is a convincing candidate for ER, regardless of risk factors other than lymphovascular invasion.


Gastric carcinoma pT1b Epstein–Barr virus Lymph node metastasis 



We are grateful to Ms. Miyuki Kogure, Mr. Motoyoshi Iwakoshi, Ms. Tomoyo Kakita, Ms. Miki Hatta, Mr. Shuhei Ishii, and Ms. Naoko Takahashi for their excellent technical support. We also thank Dr. Maki Kobayashi for strong support and advice regarding the histologic analysis.

Author contributions

Conception and design: HO, HK, TY and JF; acquisition of data: HO; analysis and interpretation of data: HO, HK, TY; writing, review and/or revision of the manuscript: all authors; administrative, technical or material support: HK and NY; study supervision: JF.


This research was supported by the Daiwa Securities Health Foundation and JSPS KAKENHI Grant number JP16K08661.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Institutional Review Board, approval number 2017-1078) and with the Helsinki Declaration.

Supplementary material

535_2019_1562_MOESM1_ESM.tiff (10 mb)
Figure S1: Typical endoscopic image of EBVGC. Superficial depressed type (0-IIc) are the most common macroscopic EBVGC (A). EBVGC with invasion to the deep submucosa results in submucosal tumor-like protrusions due to the prominent proliferation of lymphoid tissue around poorly cohesive cancer tissue (carcinoma with lymphoid stroma) (B). Abbreviations: EBV, Epstein–Barr virus; EBER-ISH, EBV-Encoded RNA in situ hybridization; EBVGC, EBV gastric cancer (TIFF 6594 kb)
535_2019_1562_MOESM2_ESM.xlsx (10 kb)
Supplementary material 2 (XLSX 10 kb)
535_2019_1562_MOESM3_ESM.xlsx (10 kb)
Supplementary material 3 (XLSX 10 kb)


  1. 1.
    Muto M, Yao K, Kaise M, et al. Magnifying endoscopy simple diagnostic algorithm for early gastric cancer (MESDA-G). Dig Endosc. 2016;28:379–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20:1–19.CrossRefGoogle Scholar
  3. 3.
    Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer. 2000;3:219–25.CrossRefPubMedGoogle Scholar
  4. 4.
    Ito H, Gotoda T, Oyama T, et al. Long-term oncological outcomes of submucosal manipulation during non-curative endoscopic submucosal dissection for submucosal invasive gastric cancer: a multicenter retrospective study in Japan. Surg Endosc. 2018;32:196–203.CrossRefPubMedGoogle Scholar
  5. 5.
    Hoteya S, Iizuka T, Kikuchi D, et al. Clinicopathological outcomes of patients with early gastric cancer after non-curative endoscopic submucosal dissection. Digestion. 2016;93:53–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRefGoogle Scholar
  7. 7.
    Camargo MC, Kim WH, Chiaravalli AM, et al. Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis. Gut. 2014;63:236–43.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu X, Liu J, Qiu H, et al. Prognostic significance of Epstein–Barr virus infection in gastric cancer: a meta-analysis. BMC Cancer. 2015;15:782.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    van Beek J, zur Hausen A, Klein Kranenbarg E, et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol. 2004;22:664–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Tokunaga M, Land CE. Epstein-Barr virus involvement in gastric cancer: biomarker for lymph node metastasis. Cancer Epidemiol Biomark Prev. 1998;7:449–50.Google Scholar
  11. 11.
    Fukayama M, Hino R, Uozaki H. Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma. Cancer Sci. 2008;99:1726–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Park JH, Kim EK, Kim YH, et al. Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer. Gastric Cancer. 2016;19:1041–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Participants in the Paris Workshop. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc. 2003;58:S3–43.CrossRefGoogle Scholar
  14. 14.
    Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14:101–12.CrossRefGoogle Scholar
  15. 15.
    Nakamura K, Sugano H, Takagi K. Carcinoma of the stomach in incipient phase: its histogenesis and histological appearances. Gan. 1968;59:251–8.PubMedGoogle Scholar
  16. 16.
    Bosman FT, Carneiro F, Hruban RH, et al. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC press; 2010.Google Scholar
  17. 17.
    Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histoclinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.CrossRefPubMedGoogle Scholar
  18. 18.
    Uemura Y, Tokunaga M, Arikawa J, et al. A unique morphology of Epstein-Barr virus-related early gastric carcinoma. Cancer Epidemiol Biomarkers Prev. 1994;3:607–11.PubMedGoogle Scholar
  19. 19.
    Burke AP, Yen TS, Shekitka KM, et al. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 1990;3:377–80.PubMedGoogle Scholar
  20. 20.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Murphy G, Pfeiffer R, Camargo MC, et al. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Akiba S, Koriyama C, Herrera-Goepfert R, et al. Epstein-Barr virus associated gastric carcinoma: Epidemiological and clinicopathological features. Cancer Sci. 2008;99:195–201.CrossRefPubMedGoogle Scholar
  23. 23.
    Koriyama C, Akiba S, Minakami Y, et al. Environmental factors related to Epstein-Barr virus-associated gastric cancer in Japan. J Exp Clin Cancer Res. 2005;24:547–53.PubMedGoogle Scholar
  24. 24.
    Arikawa J, Tokunaga M, Satoh E, et al. Morphological characteristics of Epstein-Barr virus-related early gastric carcinoma: a case-control study. Pathol Int. 1997;47:360–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Nishikawa J, Iizasa H, Yoshiyama H, et al. Clinical importance of Epstein-Barr virus-associated gastric cancer. Cancers. 2018;10:E167.CrossRefPubMedGoogle Scholar
  26. 26.
    Lim H, Park YS, Lee JH, et al. Features of gastric carcinoma with lymphoid stroma associated with Epstein-Barr virus. Clin Gastroenterol Hepatol. 2015;13:1738–44.CrossRefPubMedGoogle Scholar
  27. 27.
    Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976;38:232–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Nakamura S, Ueki T, Yao T, et al. Epstein-Barr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer. 1994;73:2239–49.CrossRefPubMedGoogle Scholar
  29. 29.
    Yanai H, Nishikawa J, Mizugaki Y, et al. Endoscopic and pathologic features of Epstein–Barr virus-associated gastric carcinoma. Gastrointest Endosc. 1997;45:236–42.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2019

Authors and Affiliations

  • Hiroki Osumi
    • 1
  • Hiroshi Kawachi
    • 2
  • Toshiyuki Yoshio
    • 1
    Email author
  • Satoshi Ida
    • 3
  • Noriko Yamamoto
    • 2
  • Yusuke Horiuchi
    • 1
  • Akiyoshi Ishiyama
    • 1
  • Toshiaki Hirasawa
    • 1
  • Tomohiro Tsuchida
    • 1
  • Naoki Hiki
    • 3
  • Kengo Takeuchi
    • 2
  • Junko Fujisaki
    • 1
  1. 1.Department of GastroenterologyThe Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR)TokyoJapan
  2. 2.Department of PathologyThe Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR)TokyoJapan
  3. 3.Department of Gastroenterological SurgeryThe Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR)TokyoJapan

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