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Crohn’s-Like Lymphoid Reaction is Associated with Oncological Prognosis and Nutritional Status in Patients with Pathological Stage II/III Gastric Cancer

  • Peritoneal Surface Malignancy
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Peritumoral lymphoid aggregates, termed Crohn’s-like lymphoid reaction (CLR), are markers of an antitumor immune response, which is an important predictor of patient outcome. In this study, we investigated the prognostic utility of CLR and its relationship with nutritional status in patients with gastric cancer (GC).

Methods

The study included 170 patients who underwent curative surgery for pathological stage (pStage) II/III GC. The maximum diameters of peritumoral and normal mucosal CLR aggregates were measured, and the median peritumoral diameter (0.57 mm) was used to stratify patients into two groups (large-CLR and small-CLR). The relationships between CLR size and preoperative nutritional status (body mass index, body composition status, Onodera’s prognostic nutritional index), tumor-infiltrating CD8+ T-lymphocyte count, and survival were evaluated.

Results

Peritumoral CLR aggregates were significantly larger than aggregates in the normal mucosa. Clinicopathological variables were not significantly different between the two patient groups; however, the large-CLR group had better cancer-specific survival (p = 0.018) and recurrence-free survival (p = 0.03) than the small-CLR group. Multivariate analysis revealed that CLR size was an independent prognostic factor for cancer-specific survival [hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.3–3.56, p = 0.002] and recurrence-free survival (HR 1.96, 95% CI 1.22–3.19, p = 0.005). Nutritional status markers were significantly poorer for the small-CLR group than the large-CLR group. CD8+ T-cell tumor infiltration was positively correlated with CLR size but not with patient survival.

Conclusions

CLR size correlated with patient nutritional status and prognosis and may be helpful in identifying high-risk populations of pStage II/III GC patients.

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Acknowledgment

The authors thank Yuki Orito and Amphone Okada for excellent technical assistance, and Anne M. O’Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

Part of this study was supported by a Grant-in-Aid for Scientific Research (16K10533) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Authors and Affiliations

  1. Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Japan

    Yusuke Omura MD, Yuji Toiyama MD, PhD, FACS, Yoshinaga Okugawa MD, PhD, Akira Yamamoto MD, Chengzeng Yin MD, Kurando Kusunoki MD, Yukina Kusunoki MD, Tsunehiko Shigemori MD, Shozo Ide MD, Takahito Kitajima MD, PhD, Hiroyuki Fujikawa MD, PhD, Hiromi Yasuda MD, PhD, Junichiro Hiro MD, PhD, Shigeyuki Yoshiyama MD, PhD, Masaki Ohi MD, PhD & Masato Kusunoki MD, PhD

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  1. Yusuke Omura MD
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  2. Yuji Toiyama MD, PhD, FACS
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Contributions

Study conception and design: YuO, YT, YoO, and MK. Acquisition and analysis of the data: YuO, YT, YoO, AY, CY, KK, YK, TS, SI, TK, HF, HY, JH, SY, and MO. Interpretation of the data: YuO, YT, and YoO. Drafting of the manuscript: YuO, YT, YoO, and MK. Critical revision of the manuscript: YuO, YT, YoO, AY, CY, KK, YK, TS, SI, TK, HF, HY, JH, SY, MO, and MK.

Corresponding authors

Correspondence to Yuji Toiyama MD, PhD, FACS or Yoshinaga Okugawa MD, PhD.

Ethics declarations

Yusuke Omura, Yuji Toiyama, Yoshinaga Okugawa, Akira Yamamoto, Chengzeng Yin, Kurando Kusunoki, Yukina Kusunoki, Tsunehiko Shigemori, Shozo Ide, Takahito Kitajima, Hiroyuki Fujikawa, Hiromi Yasuda, Junichiro Hiro, Shigeyuki Yoshiyama, Masaki Ohi, and Masato Kusunoki have no conflicts of interest to disclose.

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Supplementary material 1 (DOCX 16 kb)

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Supplementary Fig.

 1 Histology of CLR and lymphoid aggregates and CD8+ T-cell infiltration. (a–c) Representative H&E-stained sections of gastric cancer showing LAs not included in the definition of CLR (arrows): (a) LAs associated with mucous membrane; (b) LAs considered parts of the small lymph nodes; and (c) irregularly shaped or long and narrow non-nodular LAs. (d) Immunohistochemical staining of CD8+ T lymphocytes (red) in the tumor margin. Original magnification × 100. CLR Crohn’s-like lymphoid reaction, H&E hematoxylin and eosin, LAs lymphoid aggregates (TIFF 7235 kb)

Supplementary Fig.

 2 Kaplan–Meier analysis of patient survival according to CLR size. (a–d) Kaplan–Meier (a, b) overall survival curves and (c, d) disease-free survival for GC patients, stratified based on the median maximum CLR diameter in normal mucosa (a, c: 0 mm) and gastric cancer (b, d: 0.57 mm). (e) Cancer-specific survival stratified by CLR size for 70 patients with pStage II disease and 91 patients with pStage III disease. CLR Crohn’s-like lymphoid reaction (TIFF 853 kb)

Supplementary Fig.

 3 Correlation between peritumoral CD8+ T-cell count, CLR size, and patient survival. (a, b) Correlation between CD8+ T-cell count in the tumor margin and CLR size (p < 0.0001, R = 0.66). (c–f) Kaplan–Meier survival curves for (c) cancer-specific survival, (d) recurrence-free survival, (e) overall survival, and (f) disease-free survival in GC patients based on a cut-off value of median CD8+ T cells present in the tumor margin. CLR Crohn’s-like lymphoid reaction, GC gastric cancer (TIFF 945 kb)

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Omura, Y., Toiyama, Y., Okugawa, Y. et al. Crohn’s-Like Lymphoid Reaction is Associated with Oncological Prognosis and Nutritional Status in Patients with Pathological Stage II/III Gastric Cancer. Ann Surg Oncol 27, 259–267 (2020). https://doi.org/10.1245/s10434-019-07709-w

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  • DOI: https://doi.org/10.1245/s10434-019-07709-w

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