Clinical and Translational Research
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2020; 26(20): 2618-2631
Published online May 28, 2020. doi: 10.3748/wjg.v26.i20.2618
Clinicopathological features of early gastric cancers arising in Helicobacter pylori uninfected patients
Chiko Sato, Kingo Hirasawa, Yoko Tateishi, Yuichiro Ozeki, Atsushi Sawada, Ryosuke Ikeda, Takehide Fukuchi, Masafumi Nishio, Ryosuke Kobayashi, Makomo Makazu, Hiroaki Kaneko, Yoshiaki Inayama, Shin Maeda
Chiko Sato, Kingo Hirasawa, Yuichiro Ozeki, Atsushi Sawada, Ryosuke Ikeda, Takehide Fukuchi, Masafumi Nishio, Ryosuke Kobayashi, Makomo Makazu, Endoscopy Division, Yokohama City University Medical Center, Yokohama 232-0024, Japan
Yoko Tateishi, Department of Histopathology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
Hiroaki Kaneko, Shin Maeda, Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
Yoshiaki Inayama, Division of Pathological Diagnosis, Yokohama City University Medical Center, Yokohama 232-0024, Japan
Author contributions: Sato C and Hirasawa K contributed to conception and design. Sato C, Hirasawa K, Ikeda R, Sawada A, Nishio M, Fukuchi T, Kobayashi R, Makazu M, and Kaneko H contributed to acquisition of data. Hirasawa K and Sato C contributed to the analysis and interpretation of data. Tateishi Y and Inayama Y contributed to histopathological evaluation. Hirasawa K contributed to the drafting of the article. Hirasawa K and Maeda S contributed to the critical revisions of the article. Hirasawa K and Maeda S approved the final version of the article. All authors contributed to experimental design, data collection, and data analysis. All authors read and approved the final manuscript.
Institutional review board statement: The study protocol was approved by the Ethics Committee of Yokohama City University Medical Center Hospital (Approval number: D1602024).
Informed consent statement: Patients were not required to provide informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All authors declare no conflicts of interest related to the manuscript.
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:
Corresponding author: Kingo Hirasawa, MD, PhD, Associate Professor, Chief Doctor, Endoscopy Division, Yokohama Medical University Center Hospital, 4-57, Urafune-cho, Minami-ku, Yokohama 232-0024, Japan.
Received: January 28, 2020
Peer-review started: January 28, 2020
First decision: February 27, 2020
Revised: March 25, 2020
Accepted: May 14, 2020
Article in press: May 14, 2020
Published online: May 28, 2020

Persistent Helicobacter pylori (H. pylori) infection causes chronic inflammation, atrophy of the gastric mucosa, and a high risk of developing gastric cancer. In recent years, awareness of eradication therapy has increased in Japan. As H. pylori infections decrease, the proportion of gastric cancers arising from H. pylori uninfected gastric mucosa will increase. The emergence of gastric cancer arising in H. pylori uninfected patients though rarely reported, is a concern to be addressed and needs elucidation of its clinicopathological features.


To evaluate the clinicopathological features of early gastric cancer in H. pylori-uninfected patients.


A total of 2462 patients with 3375 instances of early gastric cancers that were treated by endoscopic submucosal dissection were enrolled in our study between May 2000 and September 2019. Of these, 30 lesions in 30 patients were diagnosed as H. pylori-uninfected gastric cancer (HpUIGC). We defined a patient as H. pylori-uninfected using the following three criteria: (1) The patient did not receive treatment for H. pylori, which was determined by investigating medical records and conducting patient interviews; (2) Lack of endoscopic atrophy; and (3) The patient was negative for H. pylori after being tested at least twice using various diagnostic methods, including serum anti-H. pylori-IgG antibody, urease breath test, rapid urease test, and microscopic examination.


The frequency of HpUIGC was 1.2% (30/2462) for the patients in our study. The study included 19 males and 11 females with a mean age of 59 years. The location of the stomach lesions was divided into three sections; upper third (U), middle third (M), lower third (L). Of the 30 lesions, 15 were U, 1 was M, and 14 were L. Morphologically, 17 lesions were protruded and flat elevated type (0-I, 0-IIa, 0-IIa + IIc), and 13 lesions were flat and depressed type (0-IIb, 0-IIc). The median tumor diameter was 8 mm (range 2-98 mm). Histological analysis revealed that 22 lesions (73.3%) were differentiated type.The HpUIGC lesions were classified into fundic gland type adenocarcinoma (7 cases), foveolar type well-differentiated adenocarcinoma (8 cases), intestinal phenotype adenocarcinoma (7 cases), and pure signet-ring cell carcinoma (8 cases). Among 30 HpUIGCs, 24 lesions (80%) were limited to the mucosa; wherein, the remaining 6 lesions showed submucosal invasion. One of the submucosal invasive lesions showed more than 500 μm invasion. The mucin phenotype analysis identified 7 HpUIGC with intestinal phenotype and 23 with gastric phenotype.


We elucidated the clinicopathological characteristics of HpUIGC, revealing recognition not only undifferentiated-type but also differentiated-type. In addition, intestinal phenotype tumors were also observed and could be an important tip.

Keywords: Early gastric cancer, Helicobacter pylori, Un-infection, Negative, Clinicopathological features, Endoscopic submucosal dissection, Mucins, Phenotype

Core tip: Chronic Helicobacter pylori (H. pylori) infection is a major risk factor for gastric cancer. Historically, gastric cancers in Japan were related to H. pylori infection, and the frequency of H. pylori uninfected gastric cancer (HpUIGC) was very rare. However, the rarity of gastric cancer in H. pylori negative patients may be partly owing to underreporting, and the mechanisms behind the development and progression of this type of gastric cancer must be elucidated. This study elucidated the clinicopathological features of H. pylori uninfected gastric cancer from 30 gastric cancer patients. Differentiated-type gastric cancers without submucosal invasion were most prominent.