Retrospective Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2024; 16(6): 2487-2503
Published online Jun 15, 2024. doi: 10.4251/wjgo.v16.i6.2487
Association between Helicobacter pylori infection, mismatch repair, HER2 and tumor-infiltrating lymphocytes in gastric cancer
Carlos A Castaneda, Miluska Castillo, Luis A Bernabe, Joselyn Sanchez, Matteo Fassan, Katherine Tello, Ignacio Ivan Wistuba, Ivan Chavez Passiuri, Eloy Ruiz, Juvenal Sanchez, Fernando Barreda, Daniel Valdivia, Yaqueline Bazan, Milagros Abad-Licham, Claudio Mengoa, Hugo Fuentes, Paola Montenegro, Ebert Poquioma, Raul Alatrista, Claudio J Flores, Luis Taxa
Carlos A Castaneda, Faculty of Health Sciences, Universidad Cientifica del Sur, Lima 15038, Peru
Carlos A Castaneda, GECO PERU, Grupo de Estudios Clinicos Oncologicos del Peru, Lima 15038, Peru
Miluska Castillo, Luis A Bernabe, Joselyn Sanchez, Katherine Tello, Raul Alatrista, Department of Research, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
Joselyn Sanchez, Faculty of Human Medicine, Universidad Ricardo Palma, Lima 15039, Peru
Matteo Fassan, Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua 35121, Italy
Ignacio Ivan Wistuba, Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
Ivan Chavez Passiuri, Eloy Ruiz, Department of Abdominal Surgery, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
Juvenal Sanchez, Yaqueline Bazan, Luis Taxa, Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
Fernando Barreda, Daniel Valdivia, Department of Medical Specialties, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
Milagros Abad-Licham, Department of Pathology, Instituto Regional de Enfermedades Neoplasicas del Norte, Trujillo 13001, Peru
Milagros Abad-Licham, Faculty of Human Medicine, Universidad Privada Antenor Orrego, Trujillo 13008, Peru
Claudio Mengoa, Department of Surgery, Instituto Regional de Enfermedades Neoplasicas del Sur, Arequipa 04002, Peru
Hugo Fuentes, Paola Montenegro, Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
Ebert Poquioma, Department of Epidemiology, Instituto Nacional de Enfermedades Neoplasicas, Lima 15038, Peru
Claudio J Flores, Unidad de Investigación Básica y Traslacional, Oncosalud-AUNA, Lima 15038, Peru
Luis Taxa, Faculty of Medicine, Universidad San Martin de Porres, Lima 15008, Peru
Author contributions: Castaneda CA and Castillo M contributed to the conception and design of the study; Castaneda CA, Castillo M and Flores CJ performed data analysis and interpretation; Bernabe LA, Sanchez J, Tello K, Fassan M, Bazan Y, Alatrista R, Poquioma E and Taxa L performed data acquisition, as well as providing technical support; Chavez Passiuri I, Barreda F, Ruiz E, Wistuba II, Abad-Licham M, Mengoa C, Fuentes H, Montenegro P and Valdivia D provided administrative and material support; all authors drafted the article, made critical revisions and approved the final version of the manuscript.
Supported by Ministerio de la Produccion de Peru, No. 317-PNICP-EC-2014, and No. 430-PNICP-PIAP-2014; Consejo Nacional de Ciencia Tecnologia e Innovacion Tecnologica, No. 196-2015-FONDECYT, No. 197-2015-FONDECYT, and No. 204-2015-FONDECYT.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Institutional of Instituto Nacional de Enfermedades Neoplasicas (Approval No. 025-2016-DI-DICON/INEN).
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Carlos A Castaneda, MD, MSc, Assistant Professor, Faculty of Health Sciences, Universidad Cientifica del Sur, Panamericana Sur 19, Villa El Salvador, Lima 15038, Peru. ccastaneda@gecoperu.org
Received: February 7, 2024
Revised: April 4, 2024
Accepted: April 11, 2024
Published online: June 15, 2024
Processing time: 135 Days and 14.5 Hours
Abstract
BACKGROUND

The influence of Helicobacter-pylori (H. pylori) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.

AIM

To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC.

METHODS

Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 immune cells, and dMMR and HER2-status were determined by immunohistochemistry (IHC). H. pylori infection was evaluated by routine histology and quantitative PCR (qPCR) in a subset of samples.

RESULTS

dMMR was found in 34.4%, HER2+ in 5% and H. pylori-positive in 55.7% of samples. High IT-TIL was associated with grade-3 (P = 0.038), while ST-TIL with grade-1 (P < 0.001), intestinal-histology (P < 0.001) and no-recurrence (P = 0.003). dMMR was associated with high TIL levels in the ST (P = 0.019) and IB (P = 0.01) compartments, and ST-CD3 (P = 0.049) and ST-CD8 (P = 0.05) densities. HER2- was associated with high IT-CD8 (P = 0.009). H. pylori-negative was associated with high IT-TIL levels (P = 0.009) when assessed by routine-histology, and with high TIL levels in the 3 compartments (P = 0.002-0.047) and CD8 density in the IT and ST compartments (P = 0.001) when assessed by qPCR. A longer overall survival was associated with low IT-CD163 (P = 0.003) and CD8/CD3 (P = 0.001 in IT and P = 0.002 in ST) and high IT-CD3 (P = 0.021), ST-CD3 (P = 0.003) and CD3/CD163 (P = 0.002).

CONCLUSION

TIL levels were related to dMMR and H. pylori-negativity. Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Keywords: Lymphocytes; Macrophages; Gastric cancer; Helicobacter pylori; HER2; Mismatch repair

Core Tip: Absence of Helicobacter pylori was associated with high tumor-infiltrating lymphocyte (TIL) levels and CD8 density. Deficient mismatch-repair was associated with high TIL levels, and CD3 and CD8 density. Longer overall survival was associated with a low CD8/CD3 ratio, and high CD3 and CD3/CD163 ratio.