
==== Front
Intern Med
Intern Med
Internal Medicine
0918-2918
1349-7235
The Japanese Society of Internal Medicine

38220193
10.2169/internalmedicine.2955-23
Original Article
Prevalence of Gastric Epithelial Tumors in Helicobacter pylori-uninfected Individuals Undergoing a Medical Checkup
Okimoto Eiko 1
Adachi Kyoichi 1
Ebisutani Yuri 1
Ishimura Norihisa 2
Ishihara Shunji 2
1 Health Center, Shimane Environment and Health Public Corporation, Japan
2 Second Department of Internal Medicine, Shimane University Faculty of Medicine, Japan
Correspondence to Kyoichi Adachi, adachi@kanhokou.or.jp

13 1 2024
15 8 2024
63 16 22512258
21 9 2023
26 11 2023
Copyright © 2024 by The Japanese Society of Internal Medicine
https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Objective

This study investigated the prevalence of gastric epithelial tumor in Helicobacter pylori-uninfected subjects who underwent esophagogastroduodenoscopy (EGD) as part of an annual checkup.

Methods

A total of 20,540 EGD examinations of H. pylori-uninfected individuals (12,917 men, 7,623 women; mean age 51.5±9.2 years old) were performed between April 2016 and March 2023. The prevalence of gastric epithelial tumor discovery and the size and location of each lesion type were analyzed.

Results

According to 20,540 examinations, 61 gastric epithelial tumors were endoscopically and histologically diagnosed in 58 of the subjects, with a prevalence rate of 0.28%. These tumors included signet-ring carcinoma (n=10, 0.05%), gastric adenocarcinoma of fundic-gland type (n=10, 0.05%), intestinal-type well-differentiated adenocarcinoma (n=2, 0.01%), and raspberry-type gastric foveolar tumors (n=36, 0.18%). One subject had two intestinal-type well-differentiated adenocarcinomas, and two each had two raspberry-type gastric foveolar tumors. The mean sizes of the signet-ring carcinomas, gastric adenocarcinoma of fundic-gland type, intestinal-type well-differentiated adenocarcinomas, and raspberry-type gastric foveolar tumors were 6.4, 4.7, 5.0, and 3.4 mm, respectively. Each lesion was located at a specific site in the stomach characteristic of its type.

Conclusion

In the present H. pylori-uninfected subjects, the prevalence of gastric epithelial tumors found on an EGD examination was 0.28%. Endoscopic examination should be performed in H. pylori-uninfected individuals to detect such tumors in characteristic locations.

Helicobacter pylori-uninfected
gastric cancer
gastric tumor
etiology
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pmcIntroduction

Helicobacter pylori infection is a well-known risk factor for gastric cancer development, while the occurrence of such cancer is considered rare in H. pylori-uninfected cases (1-5). However, the development of gastric cancer in H. pylori-uninfected individuals in Japan has recently been frequently reported, and there is an increasing awareness of such cases (6-19). Thus, the detection of gastric cancer in individuals not infected with H. pylori is important for endoscopists who perform esophagogastroduodenoscopy (EGD).

Among the various types of gastric epithelial tumors, undifferentiated signet-ring cell carcinoma, gastric adenocarcinoma of fundic-gland type, conventional and raspberry-type gastric foveolar tumors, intestinal-type well-differentiated adenocarcinomas, and pyloric gland type adenomas have been reported in H. pylori-uninfected cases (6-19). In the present study, hyperplastic polyps were not included as gastric epithelial tumors because endoscopic or surgical treatment for this polyp is usually considered unnecessary.

Reports of gastric epithelial tumor occurrence in H. pylori-uninfected cases have mainly been presented by specialized facilities where endoscopic and/or surgical treatment is actively performed. However, these facilities are unable to use their findings to determine the prevalence of this type of tumor in the general population, since the majority of their patients are introduced from another medical institution for a detailed examination and/or treatment.

The present study investigated the prevalence of gastric epithelial tumors in H. pylori-uninfected individuals who underwent EGD as part of an annual checkup at our facility, as the results were considered similar to those of the general population.

Materials and Methods

The subjects were selected from among individuals who visited the Health Center of Shimane Environment and Health Public Corporation for a medical checkup between April 2016 and March 2023. Raspberry-type gastric foveolar-type tumors and gastric adenocarcinoma of fundic-gland type have been recognized in our institute since 2016. A total of 34,327 EGD examinations were performed during the study period. After excluding individuals who had undergone gastrectomy, those who were H. pylori-uninfected were selected as study subjects (Fig. 1).

Figure 1. Selection of study subjects. EGD: esophagogastroduodenoscopy, GMA (C1-O3): endoscopic gastric mucosal atrophy classification reported by Kimura and Takemoto (28), *: H. pylori-eradicated group, **: H. pylori-positive group, and ***: H. pylori-uninfected group

Undifferentiated signet-ring cell carcinomas are named because of their histological resemblance to signet rings, which result from the formation of large vacuoles full of mucin that displaces the nucleus to the periphery of the cell. This type of tumor in H. pylori-uninfected subjects is usually shown by endoscopy as a slightly depressed or flat whitish lesion, mainly in the non-atrophic fundic gland area from the antrum to the lower body. In addition, signet-ring cell carcinoma accounts for a large proportion of uninfected gastric cancer cases (6,7).

Gastric adenocarcinomas of fundic-gland type are well-differentiated adenocarcinomas composed of pale gray-blue, basophilic columnar cells with mild nuclear atypia, resembling chief cells that are positive for immunohistochemical staining of pepsinogen-I and/or H+K+-ATPase. This type of tumor endoscopically appears as a whitish submucosal tumor with branching architecture of dilated vessels, and it was reported to be mainly located in the non-atrophic fundic gland area of the upper third of the stomach (8-12). Intestinal-type well-differentiated adenocarcinomas are endoscopically detected in the antrum as depressed lesions with mild surrounding elevation, although these are rarely noted in patients negative for H. pylori (13,14). Pyloric gland type adenomas detected in H. pylori-uninfected subjects are endoscopically detected as elevated lesions in non-atrophic fundic gland areas and those with an immunohistochemically gastric phenotype (15).

Shibagaki et al. reported H. pylori-uninfected patients with a raspberry-type gastric foveolar-type tumor that showed a reddish fine granular surface located in the upper third of the stomach (17). Histology of this tumor has been reported to show tubular or papillary growth with structural atypia and round or cuboidal neoplastic nuclei with loss of polarity, and immunohistochemical studies have revealed that this tumor has a gastric phenotype (17). Based on the Japanese classification of gastric carcinoma, this type of lesion was diagnosed as well-differentiated carcinoma. However, recent reports have noted that this tumor, in the absence of H. pylori infection, should be termed foveolar-type adenoma, as it is clinically and pathologically different from similar tumors in H. pylori-positive cases (20,21). Therefore, the prevalence of raspberry-type gastric foveolar-type tumors without division into adenocarcinoma and adenoma was analyzed in the present study.

Patients diagnosed with an undifferentiated signet-ring cell carcinoma, gastric adenocarcinoma of fundic-gland type, intestinal-type well-differentiated adenocarcinoma, or raspberry-type gastric foveolar-type tumor during the study period based on endoscopic and histological findings were analyzed. Subjects with a conventional gastric foveolar-type tumor or pyloric gland adenoma were not diagnosed during the study period.

H. pylori infection status (uninfected, positive, post-eradication) was comprehensively determined based on a detailed medical history obtained during an interview conducted by a public health nurse, the results of diagnostic testing for H. pylori infection, and EGD findings (Fig. 1). During the study period, the serum anti-H. pylori IgG antibody assays for determining H. pylori infection were performed using the SphereLight H. pylori antibody JⓇ kit or L-type Wako H. pylori antibody JⓇ kit (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan) (22-24). The antibody titer was automatically determined using a chemiluminescent enzyme immunoassay method or latex agglutination turbidimetric immunoassay, with a value ≥4.0 U/mL defined as positive according to the manufacturer's instructions. The sensitivity and specificity of these two kits were reported to be 94.4-97.5% and 94.4-98.6%, respectively (23,24). Patients who had undergone therapy without successful eradication were not included in the post-eradication group. When eradication therapy could not be confirmed successful, the individual was recommended to undergo an H. pylori stool antigen test at our institution.

All EGD examinations were performed by experienced licensed endoscopists using an EG-L580NW endoscope (FUJIFILM, Tokyo, Japan). Two endoscopists were certified by the Japan Society of Gastroenterological Endoscopy (JGES), while the others underwent EGD examinations for more than 5 years. The degree of endoscopic gastric mucosal atrophy (GMA) and endoscopic findings indicating positivity for H. pylori infection, such as nodular gastritis, spotty and/or diffuse redness of the fundic gland mucosa, and sticky mucous (25-27), were carefully examined in all subjects. When GMA was endoscopically observed, the degree was evaluated using the classification of Kimura and Takemoto, in which GMA is classified into six grades (C1, C2, C3, O1, O2, O3) (28). Mucosal atrophy progresses successively from C1 to O3, and this classification has been proven to correlate well with the histological features of atrophy (28). The degree of GMA was divided into seven groups (no atrophy and grades noted above). All endoscopic images from each subject were simultaneously reviewed by three expert endoscopists to determine the degree of GMA and to diagnose findings indicating positivity for H. pylori infection, with decisions made by consensus. When there were inconsistencies in the judgment concerning the endoscopic images among the experts, the final diagnosis was decided by the lead endoscopist (K.A.).

As shown in Fig. 1, the subjects with endoscopic GMA (C2-O3) and negative results of H. pylori-testing were assigned to the H. pylori-eradicated group in this study. The subjects with positive results of H. pylori-testing were assigned to the H. pylori-positive group, as were the subjects with endoscopic GMA (C2-O3) and/or endoscopic H. pylori-positive findings even though H. pylori-testing was not performed. Similarly, subjects with no medical history of eradication therapy for H. pylori and endoscopic GMA (no atrophy and C1) were assigned to the H. pylori-uninfected group, even if H. pylori-testing was not performed.

The numbers of EGD examinations performed in H. pylori-eradicated subjects, H. pylori-positive subjects, and H. pylori-uninfected subjects were 11,992 (7,979 men, 4,013 women; mean age 52.7±10.5 years old), 1,585 (1,068 men, 517 women; mean age 57.0±9.4 years old), and 20,540 (12,917 men, 7,623 women; mean age 51.5±9.2 years old), respectively. Regular use of a proton pump inhibitor or H2 receptor antagonist at the time of EGD was also determined by interview, although details related to the duration or dosage of anti-secretory drugs were not obtained.

The prevalence of gastric epithelial tumors in H. pylori-uninfected subjects was analyzed, and the size and location of each detected lesion were investigated. Tumor size was estimated by comparison with the size of the biopsy forceps tip or by examination of a specimen obtained by endoscopic mucosal resection. Findings indicating the presence of a fundic gland polyp (FGP) were also analyzed, as they have been reported to be frequently observed in cases of raspberry-type gastric foveolar-type tumors (17,18). In addition, time-course changes in tumor size were investigated by a comparison with endoscopic findings of previous EGD examinations, although we were unable to diagnose these lesions at that time.

Statistical analyses were performed using the chi-squared test, Fisher's exact probability test, and Mann-Whitney U test. The chi-square test was used for the analysis of categorical variables. Fisher's exact probability test was applied when the number of categorical variables was five or fewer. The Mann-Whitney U test was used to analyze continuous variables. All calculations were performed using the StatView software program (version 5.0; Abacus Concepts Inc., Berkeley, USA), with a p-value ＜0.05 considered to indicate statistical significance.

This study was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Shimane Environment and Health Public Corporation. Written informed consent indicating that the obtained clinical data would be used for the study without the release of individual information was received from all subjects before performing the medical checkups. In addition, each participant was allowed to opt out of this retrospective investigation at any time by informing the study manager.

Results

Among the 20,540 EGD examinations of H. pylori-uninfected individuals conducted during the study period, 61 gastric epithelial tumors were endoscopically and histologically diagnosed in 58 patients. All subjects with gastric epithelial tumors were confirmed to be uninfected by H. pylori based on the results of multiple diagnostic tests, such as serological tests, urea-breath tests, and histological examinations. A gastric epithelial tumor was found in 0.28% of the H. pylori-uninfected subjects. There was no significant difference in the detection rate of gastric epithelial tumors between the first four years (between April 2016 and March 2020) and the second three years of the study period (between April 2020 and March 2023) (0.25% vs. 0.33%, p=0.285). During the same study period, gastric epithelial tumors were diagnosed in 9 cases among 1,585 H. pylori-positive individuals (0.57%) and in 47 cases among 11,992 H. pylori-eradicated individuals (0.39%). There was a significant difference in the detection rate of gastric epithelial tumors between H. pylori-uninfected and H. pylori-positive individuals (p=0.046).

Typical endoscopic images of gastric epithelial tumors detected during the study period are shown in Figure 2～6 (Fig. 2, 3: undifferentiated signet-ring cell carcinoma, Fig. 4: gastric adenocarcinoma of fundic-gland type, Fig. 5: intestinal-type well-differentiated adenocarcinoma, and Fig. 6: raspberry-type gastric foveolar-type tumor).

Figure 2. Endoscopic image of undifferentiated signet-ring cell carcinoma. Representative endoscopic image of the greater curvature of the antrum showing a slightly depressed whitish lesion, 4 mm in size. Histology findings obtained following endoscopic mucosal resection revealed a mucosal cancer lesion.

Figure 3. Endoscopic image of advanced undifferentiated signet-ring cell carcinoma. Representative endoscopic image of the greater curvature of the lower body (a) and upper body and fornix (b) showing scirrhous type advanced cancer. Histology findings obtained following gastrectomy after undergoing chemotherapy revealed signet-ring cell carcinoma accompanied by a poorly differentiated component. In this case, the uninfected status of H. pylori was confirmed by a serum antibody test, urea breath test, and histology.

Figure 4. Endoscopic image of gastric adenocarcinoma of fundic-gland type. Representative endoscopic image of the fornix showing a flat elevated submucosal tumor-like lesion, 3 mm in size. Histology findings obtained following endoscopic mucosal resection revealed submucosal invasion.

Figure 5. Endoscopic image of intestinal-type well-differentiated adenocarcinoma. Representative endoscopic image of the greater curvature of the antrum obtained using indigo carmine contrast dye showing two depressed lesions, 5 and 2 mm in size. Histology findings obtained following endoscopic mucosal resection revealed that both lesions were mucosal cancer with an immunohistochemically intestinal phenotype.

Figure 6. Endoscopic image of raspberry-type gastric foveolar-type tumor. Representative endoscopic image of fornix showing a reddish raspberry-like lesion, 3 mm in size. Histology findings obtained following a biopsy procedure revealed a foveolar-type adenoma tumor. The lesion was not detected in an EGD examination performed at another clinic as part of a detailed investigation, but follow-up EGD is considered necessary in such cases to confirm complete disappearance.

The characteristics of the positive cases are listed in Table 1. Signet-ring carcinoma, gastric adenocarcinoma of fundic-gland type, intestinal-type well-differentiated adenocarcinoma, and raspberry-type gastric foveolar tumors were found in 10, 10, 2, and 36 subjects, respectively. One subject was diagnosed with two intestinal-type well-differentiated adenocarcinoma lesions, and two were diagnosed with two raspberry-type gastric foveolar tumors. Among the three lesions of intestinal-type well-differentiated adenocarcinoma, two lesions in one case were determined to have a pure intestinal phenotype by immunohistochemical staining, and the other lesion showed a mixed gastrointestinal phenotype. None of the subjects showed heterochronous tumor development during the study period.

Table 1. Prevalence of Gastric Epithelial Tumors in \H. pylori-uninfected Subjects.

	Signet-ring cell carcinoma	Gastric adenocarcinoma of fundic-gland type	Intestinal-type well-differentiated adenocarcinoma	Raspberry-type gastric foveolar tumor	Total	No gastric epithelial tumor	
Number of cases	10	10	2	36	58	20,482	
Prevalence (%)	0.05	0.05	0.01	0.18	0.28	99.72	
Male/female	5/5	9/1	1/1	26/10	41/17	12,876/7,606	
Age (mean±SD)	50.0±6.6	58.1±9.4*	50.0±14.1	56.5±8.8*	55.5±8.8*	51.5±9.2	
Age range	40-59	46-72	40-60	35-73	35-73	22-86	
Anti-secretory drug usage							
Vonoprazan	0	0	0	1 (2.8)	1 (1.7)	123 (0.6)	
Conventional PPI	0	0	0	3 (8.3)	3 (5.2)	655 (3.2)	
H2RA	0	0	0	0	0	110 (0.5)	
Accompanied with FGP	6 (60)	8 (80)	1 (50)	25 (69)	40 (69)*	11,397 (56)	
*Significantly different in comparison with subjects without gastric epithelial tumors. Numbers in parentheses indicate percentage. PPI: proton pump inhibitor, H2RA: histamine 2 receptor antagonist

In the present H. pylori-uninfected subjects, the prevalence rates were 0.05% for signet-ring carcinoma, 0.05% for gastric adenocarcinoma of fundic-gland-type, 0.01% for intestinal-type well-differentiated adenocarcinoma, and 0.18% for raspberry-type gastric foveolar tumors. There were no significant differences in the ratio of men to women or anti-secretory drug use between subjects with and without gastric epithelial tumors. However, those with such tumors were significantly older than those without (p＜0.001), and patients with gastric adenocarcinomas of the fundic-gland type and raspberry-type gastric foveolar tumors were significantly older than those without gastric epithelial tumors (p＜0.001 and 0.036, respectively). In addition, the prevalence of FGP was higher in patients with gastric epithelial tumors than in those without them (p=0.042).

Details of the 61 gastric epithelial tumors in H. pylori-uninfected subjects are shown in Table 2. The mean sizes for signet-ring carcinoma, gastric adenocarcinoma of fundic-gland type, intestinal-type well-differentiated adenocarcinoma, and raspberry-type gastric foveolar tumors were 6.4, 4.7, 5.0, and 3.4 mm, respectively. All four types of endoscopically detected tumors were at least 2 mm in size. Signet-ring carcinoma and intestinal-type well-differentiated adenocarcinoma lesions were located from the antrum to the lower body, whereas gastric adenocarcinomas of fundic-gland type and raspberry-type gastric foveolar tumors were mainly located in the area from the middle body to the fornix. Based on cancer depth, signet-ring carcinoma, intestinal-type well-differentiated adenocarcinoma, and raspberry-type gastric foveolar tumor cases were histologically diagnosed as mucosal cancer, except for one case of scirrhous advanced signet-ring cell carcinoma. In contrast, submucosal invasion was histologically observed in 8 of the 10 cases of gastric adenocarcinoma of fundic-gland type.

Table 2. Size and Site of Gastric Epithelial Tumors in H. pylori-uninfected Subjects

	Signet-ring cell carcinoma	Gastric adenocarcinoma of fundic-gland type	Intestinal-type well- differentiated adenocarcinoma	Raspberry-type gastric foveolar-type tumor	
Number of lesions	10	10	3	38	
Size, mm, mean±SD	6.4±3.7*	4.7±2.3	5.0±3.0	3.4±1.8	
Size, mm, range	2-11*	2-10	2-8	2-10	
Site, number of lesions*					
Cardia	0	1	0	0	
Fornix	0	6	0	9	
Upper body	0	2	0	17	
Middle body	0	1	0	10	
Lower body	1	0	0	2	
Angular portion	1	0	0	0	
Antrum	7	0	3	0	
Cancer depth					
M	9	2	3	38	
Sm	0	8	0	0	
Advanced	1	0	0	0	
*One subject with a scirrhous type signet-ring cell carcinoma who underwent a gastrectomy after undergoing chemotherapy was excluded. M: mucosal cancer, Sm: submucosal invasion, Advanced: invasion to muscularis propria or greater

The time-course changes in tumor size were able to be investigated in 42 lesions, since those appeared in the same location noted in a previous EGD examination (Table 3). The lesion could not be identified by the images of previous EGD examinations in one case of scirrhous-type signet-ring cell carcinoma. The tumor size did not change in cases of signet-ring cell carcinoma, except in one case of scirrhous type cancer. The size of seven of the eight gastric adenocarcinomas of fundic-gland type was endoscopically unchanged, although one lesion was endoscopically estimated to be enlarged. In contrast, all three intestinal-type well-differentiated adenocarcinomas were enlarged in comparison with the lesions observed at previous EGD examinations. In addition, one-third of the raspberry-type gastric foveolar tumors were endoscopically determined to be enlarged by a comparison with the findings of previous EGD examinations.

Table 3. The Time-course Change of Gastric Epithelial Tumor Size by Comparison with Previous EGD Findings in H. pylori-uninfected Subjects.

	Signet-ring cell carcinoma	Gastric adenocarcinoma of fundic-gland type	Intestinal-type well- differentiated adenocarcinoma	Raspberry-type gastric foveolar-type tumor	
Number of lesions	7	8	3	24	
Enlarged	1* (14)	1 (13)	3 (100)	9 (37)	
No change in size	6 (86)	7 (88)	0	15 (63)	
Comparison was performed by the endoscopic findings of previous EGD, in which the same gastric tumor could be pointed out. Values in parentheses indicate percentage. * The lesion could not be pointed out by the images of previous EGD examinations in one case with scirrhous type signet-ring cell carcinoma

Discussion

Recently, various histological-types of gastric epithelial tumors have been diagnosed in H. pylori-uninfected patients (6-18). The endoscopic features of gastric epithelial tumors in individuals without H. pylori infection are understood by EGD endoscopists (19) and have been frequently reported (6-18). The present study was conducted to determine the prevalence of gastric epithelial tumors in H. pylori-uninfected subjects who underwent an EGD examination as part of a scheduled medical check-up. During the seven-year study period, four different types of gastric epithelial tumors were diagnosed in individuals who underwent such testing at our institute.

In the present H. pylori-uninfected subjects, raspberry-type gastric foveolar-type tumors were the most frequently diagnosed type of gastric epithelial tumor, with a prevalence rate of 0.18%. The second-most prevalent were signet-ring carcinomas and gastric adenocarcinomas of fundic-gland type, each with a prevalence of 0.05%. Overall, the prevalence of gastric epithelial tumors, including intestinal-type well-differentiated adenocarcinoma, was found to be 0.28%. To our knowledge, this is the first report on the prevalence of gastric epithelial tumors in H. pylori-uninfected subjects who underwent an EGD examination as part of a scheduled medical check-up; thus, it was not possible to evaluate whether the rates of prevalence were high or low. Nevertheless, these findings demonstrate the importance of EGD for the detection of gastric epithelial tumors in H. pylori-uninfected cases, since EGD examinations of H. pylori-uninfected Japanese individuals are thought to be rapidly increasing in frequency.

In this study, 60% of study subjects were H. pylori-uninfected individuals, and half of gastric epithelial tumors were diagnosed in these subjects. The proportion of H. pylori-uninfected gastric epithelial tumors was markedly higher than previously reported (5-7). The concepts of gastric adenocarcinoma of fundic-gland type and raspberry-type gastric foveolar tumors were recently established (8-12,16-19), and we have been able to diagnose these tumors frequently in H. pylori-uninfected subjects. However, raspberry-type gastric foveolar tumors were not diagnosed in H. pylori-positive and post-eradication subjects in this study, reportedly being generated only in H. pylori-uninfected subjects (16-18). Raspberry-type gastric foveolar tumors made up 62% of H. pylori-uninfected gastric epithelial tumors in this study. Thus, the diagnosis of raspberry-type gastric foveolar tumors in many H. pylori-uninfected subjects is considered the most important factor in explaining the high proportion of H. pylori-uninfected gastric epithelial tumors.

Except for one subject with scirrhous advanced signet-ring cell carcinoma, the gastric epithelial tumors were diagnosed at a relatively small size. The locations of each tumor type were not different from those previously reported in several studies (6-14,16-18). In examinations of individuals negative for H. pylori infection, a careful EGD examination should be performed to detect gastric epithelial tumors with knowledge of the typical location and endoscopic characteristics. In addition, the possibility of advanced gastric cancer should be considered even if an EGD examination is performed in H. pylori-uninfected patients (29).

The analysis of time-course changes in lesion size showed that almost all signet-ring cell carcinomas and gastric adenocarcinomas of the fundic-gland type were not enlarged. In contrast, time-course enlargement was observed in intestinal-type well-differentiated adenocarcinomas and one-third of raspberry-type gastric foveolar tumors. Therefore, the proliferative ability is thought to differ among the different types of gastric epithelial tumors observed in H. pylori-uninfected individuals. In Japan, the number of EGD examinations for population-based screening, which are performed to reduce the rate of mortality due to gastric cancer, has been increasing. However, the significance of gastric epithelial tumor detection in population-based screening of H. pylori-uninfected cases could not be determined at present, as the influence of these tumor occurrences on the mortality rate has not been fully clarified.

This study has several limitations, including its retrospective design and the findings being obtained from examinations performed at a single center. H. pylori infection status was determined based on the medical history of H. pylori infection, EGD findings, and/or results of diagnostic tests for H. pylori infection. Thus, the status of H. pylori infection might not have been correctly determined in some of the study subjects. In addition, an H. pylori-uninfected status should be diagnosed by histological clarification of the absence of GMA and gastric metaplasia (6). Our institution was established to perform medical checkups; thus, individuals with evidence of gastric tumors require detailed examinations and treatments at other medical centers. We were therefore unable to perform detailed histological investigations, including immunohistochemical staining, for the determination of tumor characteristics and proliferative ability. In addition, the classification of gastric adenocarcinoma of fundic-gland type with submucosal invasion could not be performed, since histological examinations with immunohistochemical staining are needed to classify this type of tumor into gastric adenocarcinoma of fundic-gland type and gastric adenocarcinoma of fundic-gland mucosal-type (11). A large-scale multicenter study will be necessary to more clearly examine the prevalence and other factors related to the occurrence of gastric epithelial tumors in H. pylori-uninfected individuals.

In conclusion, the present study found the rate of prevalence of gastric epithelial tumor incidence in H. pylori-uninfected individuals to be 0.28%. Careful EGD examinations should be performed with an understanding of the characteristic tumor locations and endoscopic findings in patients without H. pylori infection.

The authors state that they have no Conflict of Interest (COI).

Acknowledgement

We wish to thank Marie Ishida, Mizuki Kawamoto, Noriko Yamauchi, Nanaho Nakanishi, Yumi Yamamoto, Kenichi Takuwa, Dai Takahashi, and Masatomo Aoki of the Shimane Environment and Health Public Corporation and Keiko Masuzaki of the Second Department of Internal Medicine, Shimane University Faculty of Medicine, for their helpful technical support.
==== Refs
1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 61 : 177-240, 1994.7715070
2. Uemura N , Okamoto S , Yamamoto S , et al . Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345 : 784-789, 2001.11556297
3. Ohata H , Kitauchi S , Yoshimura N , et al . Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer 109 : 138-143, 2004.14735480
4. Kato S , Matsukura N , Tsukada K , et al . Helicobacter pylori infection-negative gastric cancer in Japanese hospital patients: incidence and pathological characteristics. Cancer Sci 98 : 790-794, 2007.17470129
5. Matsuo T , Ito M , Takata S , Tanaka S , Yoshihara M , Chayama K . Low prevalence of Helicobacter pylori-negative gastric cancer among Japanese. Helicobacter 16 : 415-419, 2011.22059391
6. Yamamoto Y , Fujisaki J , Omae M , Hirasawa T , Igarashi M . Helicobacter pylori-negative gastric cancer: characteristics and endoscopic findings. Dig Endosc 27 : 551-561, 2015.25807972
7. Yamada A , Kaise M , Inoshita N , et al . Characterization of Helicobacter pylori-naïve early gastric cancers. Digestion 98 : 127-134, 2018.29719284
8. Ueyama H , Yao T , Nakashima Y , et al . Gastric adenocarcinoma of fundic gland type (chief cell predominant type): proposal for a new entity of gastric adenocarcinoma. Am J Surg Pathol 34 : 609-619, 2010.20410811
9. Ueyama H , Matsumoto K , Nagahara A , Hayashi T , Yao T , Watanabe S . Gastric adenocarcinoma of the fundic gland type (chief cell predominant type). Endoscopy 46 : 153-157, 2014.24338239
10. Benedict MA , Lauwers GY , Jain D . Gastric adenocarcinoma of the fundic gland type: update and literature review. Am J Clin Pathol 149 : 461-473, 2018.29648578
11. Ueyama H , Yao T , Akazawa Y , et al . Gastric epithelial neoplasm of fundic-gland mucosa lineage: proposal for a new classification in association with gastric adenocarcinoma of fundic-gland type. J Gastroenterol 56 : 814-828, 2021.34268625
12. Akazawa Y , Ueyama H , Hayashi T , et al . Clinicopathological and molecular characterization of early gastric adenocarcinoma in Helicobacter pylori-uninfected patients: emphasis on differentiated gastric adenocarcinoma. J Gastroenterol 57 : 725-734, 2022.35939123
13. Yoshii S , Hayashi Y , Takehara T . Helicobacter pylori-negative early gastric adenocarcinoma with complete intestinal mucus phenotype mimicking verrucous gastritis. Dig Endosc 29 : 235-236, 2017.27977882
14. Shibagaki K , Itawaki A , Miyaoka Y , et al . Intestinal-type gastric dysplasia in Helicobacter pylori-naïve patients. Virchows Arch 480 : 783-792, 2022.34787713
15. Nakazawa K , Yoshinaga S , Okuda N , et al . Endoscopic characteristics of adenoma of gastric phenotype (pyloric gland adenoma). I To Cho (Stomach and Intestine) 55 : 1036-1042, 2020 (in Japanese).
16. Isono Y , Baba Y , Mukai K , et al . Gastric adenocarcinoma coexisting with a reddish semipedunculated polyp arising from Helicobacter pylori-negative normal gastric mucosa: a report of two cases. Clin J Gastroenterol 11 : 481-486, 2018.30022297
17. Shibagaki K , Fukuyama C , Mikami H , et al . Gastric foveolar-type adenomas endoscopically showing a raspberry-like appearance in the Helicobacter pylori-uninfected stomach. Endosc Int Open 7 : E784-E791, 2019.31198840
18. Sakamoto U , Adachi K , Kishi K , et al . Prevalence of raspberry-type gastric foveolar-type tumor in individuals undergoing medical checkups. Intern Med 62 : 2775-2781, 2023.36823084
19. Ishibashi F , Hirasawa T , Ueyama H , Minato Y , Suzuki S . Exploring quality indicators for the detection of Helicobacter pylori-naïve gastric cancer: a cross-sectional nationwide survey. Clin Endosc 56 : 460-469, 2023.37011917
20. Sekine S , Montgomery E , Vieth M . Foveolar-type adenoma. In: WHO Classification of Digestive System Tumours. 5th ed. 2019: 79-80.
21. Kushima R . Introduction of “gastric-type neoplasia in the stomach and duodenum”. I To Cho (Stomach and Intestine) 57 : 1495-1498, 2022 (in Japanese).
22. Adachi K , Kishi K , Notsu T , et al . Serum anti-Helicobacter pylori IgG antibody titer in H. pylori-negative cases with a different gastric mucosal atrophy status. Intern Med 59 : 2817-2823, 2020.32713919
23. Aoyama N , Shigeta S , Yokozaki H . Evaluation of 6 H. pylori antibody serological diagnosis kits using the same samples strictly diagnosed the status of H. pylori infection. Nihon Helicobacter Gakkaishi (Jpn J Helicobacter Res) 21 : 112-120, 2020 (in Japanese).
24. Tokai Y , Fujisaki J , Ishizuka N , et al . Usefulness of the l-type Wako Helicobacter pylori antibody J test. JGH Open 5 : 673-678, 2021.34124385
25. Haruma K, Ed. Kyoto Classification of Gastritis. Nihon Medical Center, Tokyo, 2017: .
26. Watanabe K , Nagata N , Nakashima R , et al . Predictive findings for Helicobacter pylori-uninfected, -infected and -eradicated gastric mucosa: validation study. World J Gastroenterol 19 : 4374-4379, 2013.23885149
27. Kato M , Terao S , Adachi K , et al . Changes in endoscopic findings of gastritis after cure of H. pylori infection: multicenter prospective trial. Dig Endosc 25 : 264-273, 2013.23369104
28. Kimura K , Takemoto T . An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy 1 : 87-97, 1969.
29. Yoshida Y , Kurahara K , Yaita H , et al . Clinicopathological characteristics of Helicobacter pylori-uninfected advanced gastric cancer. I To Cho (Stomach and Intestine) 55 : 1061-1076, 2020 (in Japanese).
