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Risk stratification for lymph node metastasis using Epstein–Barr virus status in submucosal invasive (pT1) gastric cancer without lymphovascular invasion: a multicenter observational study

  • Hiroki Osumi
  • Hiroshi Kawachi
  • Katsuyuki Murai
  • Kimihide Kusafuka
  • Shuntaro Inoue
  • Masaki Kitamura
  • Toshiyuki YoshioEmail author
  • Naomi Kakusima
  • Ryu Ishihara
  • Hiroyuki Ono
  • Noriko Yamamoto
  • Takashi Sugino
  • Shinichi Nakatsuka
  • Satoshi Ida
  • Souya Nunobe
  • Etsuro Bando
  • Takeshi Omori
  • Kengo Takeuchi
  • Junko Fujisaki
Original Article

Abstract

Background

Lymphovascular invasion (LVI) is a strong predictive factor for lymph node metastasis (LNM) in early gastric cancer (GC). This study investigated the risk for LNM in pT1b GC without LVI based on Epstein–Barr virus (EBV) status in addition to conventional clinicopathological parameters.

Methods

In total, 847 consecutive patients of pT1b GC without LVI who underwent surgery at three high-volume centers between 2005 and 2014 were retrospectively analyzed. Clinicopathological parameters and EBV status were evaluated, and univariate and multivariate analyses were performed to estimate LNM risk. With regard to the presence of those three parameters, risk stratification for LNM was performed and compared with a previously proposed risk classification that included low-risk (LNM < 3.0%), intermediate-risk (LNM ≥ 3.0 and < 19.6%), and high-risk (LNM ≥ 19.6%) groups.

Results

EBV-positive GC (EBVGC) accounted for 11.3% (96 of 847) of cases; LNM was lower in EBVGC than in non-EBVGC (1 of 96, 1.0% vs. 71/751, 9.5%). In the multivariate analysis, non-EBVGC [odds ratio (OR) 10.8, 95% confidence interval (CI) 1.48–78.9], age < 65 years (OR 2.13, 95% CI 1.30–3.48), and tumor diameter > 3 cm (OR 2.26, 95% CI 1.36–3.74) were independent risk factors for LNM. Patients with EBVGC were at low risk for LNM whereas those with all of three independent risk factors were at high risk (36 of 168, 21.4%, 95% CI 15.5–28.4).

Conclusion

LNM risk stratification that includes EBV status is useful for clinical decision-making in pT1b GC cases without LVI.

Keywords

Gastric cancer pT1b Lymphovascular invasion Epstein–Barr virus Lymph node metastasis 

Notes

Acknowledgments

The authors thank Ms. Miyuki Kogure, Mr. Motoyoshi Iwakoshi, Ms. Tomoyo Kakita, Ms. Miki Hatta, Mr. Shuhei Ishii, and Ms. Naoko Takahashi for excellent technical support; and Dr. Maki Kobayashi for support and advice with the histological analysis.

Funding

This research was supported by the Daiwa Securities Health Foundation, Takeda Japan Medical Office Funded Research Grant 2019, and a Japan Society for the Promotion of Science KAKENHI grant (no. JP16K08661).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Institutional Review Board; approval no. 2017-1078) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The protocol was described in the Web site of the hospital, and the subjects were provided with the opportunity to opt out, and therefore, no new consent was required from the patients.

Supplementary material

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Supplementary file1 (XLSX 12 kb)
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Supplementary file2 (XLSX 10 kb)
10120_2019_963_MOESM3_ESM.xlsx (10 kb)
Supplementary file3 (XLSX 9 kb)

References

  1. 1.
    Muto M, Yao K, Kaise M, Kato M, Uedo N, Yagi K, et al. Magnifying endoscopy simple diagnostic algorithm for early gastric cancer (MESDA-G). Dig Endosc. 2016;28:379–93.CrossRefGoogle Scholar
  2. 2.
    Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T, 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.CrossRefGoogle Scholar
  3. 3.
    Hirasawa T, Gotoda T, Miyata S, Kato Y, Shimoda T, Taniguchi H, et al. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer. Gastric Cancer. 2009;12:148–52.CrossRefGoogle Scholar
  4. 4.
    Hatta W, Gotoda T, Oyama T, Kawata N, Takahashi A, Yoshifuku Y, et al. A scoring system to stratify curability after endoscopic submucosal dissection for early gastric cancer: “eCura system”. Am J Gastroenterol. 2017;112:874–81.CrossRefGoogle Scholar
  5. 5.
    Hasuike N, Ono H, Boku N, Mizusawa J, Takizawa K, Fukuda H, et al. A non-randomized confirmatory trial of an expanded indication for endoscopic submucosal dissection for intestinal-type gastric cancer (cT1a): the Japan Clinical Oncology Group study (JCOG0607). Gastric Cancer. 2018;21:114–23.CrossRefGoogle Scholar
  6. 6.
    Takizawa K, Takashima A, Kimura A, Mizusawa J, Hasuike N, Ono H, et al. A phase II clinical trial of endoscopic submucosal dissection for early gastric cancer of undifferentiated type: Japan Clinical Oncology Group study JCOG1009/1010. Jpn J Clin Oncol. 2013;43:87–91.CrossRefGoogle Scholar
  7. 7.
    Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 2017; 20: 1–19.Google Scholar
  8. 8.
    Sekiguchi M, Oda I, Taniguchi H, Suzuki H, Morita S, Fukagawa T, et al. Risk stratification and predictive risk-scoring model for lymph node metastasis in early gastric cancer. J Gastroenterol. 2016;51:961–70.CrossRefGoogle Scholar
  9. 9.
    Tokunaga M, Land CE. Epstein–Barr virus involvement in gastric cancer: biomarker for lymph node metastasis. Cancer Epidemiol Biomarkers Prev. 1998;7:449–50.Google Scholar
  10. 10.
    Fukayama M, Hino R, Uozaki H. Epstein–Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma. Cancer Sci. 2008;99:1726–33.CrossRefGoogle Scholar
  11. 11.
    Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein–Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33.CrossRefGoogle Scholar
  12. 12.
    Park JH, Kim EK, Kim YH, Kim JH, Bae YS, Lee YC, 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.CrossRefGoogle Scholar
  13. 13.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRefGoogle Scholar
  14. 14.
    Osumi H, Kawachi H, Yoshio T, Ida S, Yamamoto N, Horiuchi Y, et al. Epstein-Barr virus status is a promising biomarker for endoscopic resection in early gastric cancer: proposal of a novel therapeutic strategy. J Gastroenterol. 2019.  https://doi.org/10.1007/s00535-019-01562-0.Google Scholar
  15. 15.
    Sano T, Aiko T. New Japanese classifications and treatment guidelines for gastric cancer: revision concepts and major revised points. Gastric Cancer. 2011;14:97–100.CrossRefGoogle Scholar
  16. 16.
    Nakamura K, Sugano H, Takagi K. Carcinoma of the stomach in incipient phase: its histogenesis and histological appearances. Gan. 1968;59:251–8.Google Scholar
  17. 17.
    Sasako M, Kinoshita T, Maruyama K. Prognosis of early gastric cancer (in Japanese with English abstract). Stomach Intestine. 1993;28:139–46.Google Scholar
  18. 18.
    Sano T, Kobori O, Muto T. Lymph node metastasis from early gastric cancer: endoscopic resection of tumour. Br J Surg. 1992;79:241–4.CrossRefGoogle Scholar
  19. 19.
    Ono H, Yao K, Fujishiro M, Oda I, Nimura S, Yahagi N, et al. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer. Dig Endosc. 2016;28:3–15.CrossRefGoogle Scholar
  20. 20.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.CrossRefGoogle Scholar
  21. 21.
    Habu H, Endo M. Gastric cancer in elderly patients–results of surgical treatment. Hepatogastroenterology. 1989;36:71–4.Google Scholar
  22. 22.
    Fujimoto S, Takahashi M, Ohkubo H, Mutou T, Kure M, Masaoka H, et al. Comparative clinicopathologic features of early gastric cancer in young and older patients. Surgery. 1994;115:516–20.Google Scholar
  23. 23.
    Maehara Y, Emi Y, Tomisaki S, Oshiro T, Kakeji Y, Ichiyoshi Y, et al. Age-related characteristics of gastric carcinoma in young and elderly patients. Cancer. 1996;77:1774–800.CrossRefGoogle Scholar
  24. 24.
    Wang JY, Hsieh JS, Huang CJ, Huang YS, Huang TJ. Clinicopathologic study of advanced gastric cancer without serosal invasion in young and old patients. J Surg Oncol. 1996;63:36–40.CrossRefGoogle Scholar
  25. 25.
    Inoshita N, Yanagisawa A, Arai T, Kitagawa T, Hirokawa K, Kato Y. Pathological characteristics of gastric carcinomas in the very old. Jpn J Cancer Res. 1998;89:1087–92.CrossRefGoogle Scholar
  26. 26.
    Arai T, Esaki Y, Inoshita N, Sawabe M, Kasahara I, Kuroiwa K, et al. Pathologic characteristics of gastric cancer in the elderly: a retrospective study of 994 surgical patients. Gastric Cancer. 2004;7:154–9.CrossRefGoogle Scholar
  27. 27.
    Kitamura K, Yamaguchi T, Taniguchi H, Hagiwara A, Yamane T, Sawai K, et al. Clinicopathological characteristics of gastric cancer in the elderly. Br J Cancer. 1996;73:798–802.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  • Hiroki Osumi
    • 1
  • Hiroshi Kawachi
    • 2
  • Katsuyuki Murai
    • 3
  • Kimihide Kusafuka
    • 4
  • Shuntaro Inoue
    • 5
  • Masaki Kitamura
    • 6
  • Toshiyuki Yoshio
    • 1
    Email author
  • Naomi Kakusima
    • 3
  • Ryu Ishihara
    • 5
  • Hiroyuki Ono
    • 3
  • Noriko Yamamoto
    • 2
  • Takashi Sugino
    • 4
  • Shinichi Nakatsuka
    • 6
  • Satoshi Ida
    • 7
  • Souya Nunobe
    • 7
  • Etsuro Bando
    • 8
  • Takeshi Omori
    • 9
  • Kengo Takeuchi
    • 3
  • Junko Fujisaki
    • 1
  1. 1.Department of GastroenterologyThe Cancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  2. 2.Department of PathologyThe Cancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  3. 3.Division of EndoscopyShizuoka Cancer CenterShizuokaJapan
  4. 4.Division of PathologyShizuoka Cancer CenterShizuokaJapan
  5. 5.Department of Gastrointestinal OncologyOsaka International Cancer InstituteOsakaJapan
  6. 6.Department of PathologyOsaka International Cancer InstituteOsakaJapan
  7. 7.Department of Gastroenterological SurgeryThe Cancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  8. 8.Division of Gastric SurgeryShizuoka Cancer CenterShizuokaJapan
  9. 9.Department of Gastroenterological SurgeryOsaka International Cancer InstituteOsakaJapan

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