Poor prognosis in Epstein–Barr virus-negative gastric cancer with lymphoid stroma is associated with immune phenotype

  • Charles J. Cho
  • Hyo Jeong Kang
  • Yeon-Mi Ryu
  • Young Soo Park
  • Hui Jeong Jeong
  • Young-Mi Park
  • Hyun Lim
  • Jeong Hoon Lee
  • Ho June Song
  • Hwoon-Yong Jung
  • Sang-Yeob Kim
  • Seung-Jae Myung
Original Article

Abstract

Background

Gastric cancer with lymphoid stroma (GCLS) is pathologically characterized by poorly developed tubular structures with a prominent lymphocytic infiltration. Its clinical and prognostic features differ in patients positive and negative for Epstein–Barr virus (EBV) infection. This study analyzed the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and the density of tumor-infiltrating lymphocytes (TILs) including CD3+ and CD8+ T cells, as well as their prognostic significance in patients with GCLS.

Methods

The study included 58 patients with GCLS (29 EBV+ and 29 EBV−) who underwent curative resection. Expression of CD3, CD8, PD-1, and PD-L1 in tumor cells and TILs was analyzed using a quantitative multispectral imaging system (Opal™), with these results validated by immuno-histochemical assays for PD-L1 on whole slide sections.

Results

The proportion of tumors overexpressing PD-L1 (31.0 vs. 0%, P = 0.002), TIL density (4548 vs. 2631/mm2, P < 0.001), and intra-tumoral CD8+ T-cell density (2650 vs. 1060/mm2, P < 0.001) were significantly higher in EBV+ than in EBV− GCLS. In addition, CD8+/CD3+ T-cell ratio was higher in EBV+ than in EBV− GCLS (55.3 vs. 35.8%, P < 0.001). Lower TIL density, defined as < 1350/mm2, was a significant negative factor of survival.

Conclusions

Despite histopathological similarity, quantitative multispectral imaging revealed differences in the tumor immune micro-environment between EBV+ and EBV− GCLS, indicating that the underlying pathogenesis differs in these two disease entities. TIL density may be a prognostic marker in patients with GCLS.

Keywords

Gastric cancer with lymphoid stroma Immune checkpoint Tumor-infiltrating lymphocyte Epstein–Barr virus 

Notes

Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C3078).

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Human rights statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent to be included in the study, or the equivalent, was obtained from all patients.

Supplementary material

10120_2018_820_MOESM1_ESM.docx (607 kb)
Supplementary material 1 (DOCX 607 kb)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Charles J. Cho
    • 1
  • Hyo Jeong Kang
    • 2
  • Yeon-Mi Ryu
    • 3
  • Young Soo Park
    • 2
  • Hui Jeong Jeong
    • 2
  • Young-Mi Park
    • 3
  • Hyun Lim
    • 1
  • Jeong Hoon Lee
    • 1
  • Ho June Song
    • 1
  • Hwoon-Yong Jung
    • 1
  • Sang-Yeob Kim
    • 3
    • 4
  • Seung-Jae Myung
    • 5
  1. 1.Department of GastroenterologyUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulKorea
  2. 2.Department of PathologyUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulKorea
  3. 3.Asan Institute for Life SciencesUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulKorea
  4. 4.Department of Convergence MedicineUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulKorea
  5. 5.Department of Gastroenterology and Convergence MedicineUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulKorea

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