Ohno K, Nakatani E, Kurokami T, Kawai A, Itai R, Matsuda M, Masui Y, Satoh T, Ikeda S, Hirata T, Takeda S, Suzuki M, Haruma K. Relationship between gastric mucosal atrophy by endoscopy and non-ampullary duodenal epithelial tumors. World J Gastrointest Oncol 2025; 17(2): 100545 [DOI: 10.4251/wjgo.v17.i2.100545]
Corresponding Author of This Article
Ken Haruma, PhD, Researcher, Department of General Internal Medicine 2, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 700-8505, Japan. kharuma@med.kawasaki-m.ac.jp
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Ohno K and Nakatani E contributed equally; Ohno K designed and performed the experimental studies and drafted the manuscript; Nakatani E designed the research and contributed to the analysis; Kurokami T, Kawai A, Itai R, Matsuda M, Masui Y, Satoh T, Ikeda S, Hirata T, and Takeda S contributed to appropriate endoscopic diagnosis and accumulation of cases; Suzuki M contributed to specimen preparation and pathological diagnosis; Haruma K designed the experimental studies and supervised the study.
Institutional review board statement: This study was approved by the ethics committee of Shizuoka General Hospital (No. SGHIRB #2021033) and conducted in compliance with the Declaration of Helsinki.
Informed consent statement: Personal information was strictly managed, and patients provided consent to participate in the study using an opt-out method. The study was conducted at an institution; therefore, patients who did not wish to participate could be excluded. The data were analyzed anonymously and did not contain personally identifiable information.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: Ken Haruma, PhD, Researcher, Department of General Internal Medicine 2, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 700-8505, Japan. kharuma@med.kawasaki-m.ac.jp
Received: August 20, 2024 Revised: October 21, 2024 Accepted: November 14, 2024 Published online: February 15, 2025 Processing time: 151 Days and 20.6 Hours
Abstract
BACKGROUND
The pathogenesis of non-ampullary duodenal epithelial tumors (NADETs) is not fully understood. NADETs that express gastric-type mucin phenotypes (G-NADETs) are noteworthy because of their high malignancy. Gastric foveolar metaplasia, from which G-NADETs originate, protects the duodenal mucosa from gastric acidity. As gastric acid secretion is affected by endoscopic gastric mucosal atrophy (EGMA), we hypothesized that EGMA would be associated with G-NADETs.
AIM
To evaluate the association between EGMA and the occurrence of G-NADETs.
METHODS
This cross-sectional retrospective study investigated the relationship between EGMA and NADETs in 134 patients. The duodenum was divided into parts 1 (bulb), 2 (superior duodenal angle to the papilla), and 3 (anal side of the papilla to the horizontal part). The effects of gastric acidity and presence of Brunner’s glands were considered. EGMA was divided into types C (no or mild atrophy) and O (severe atrophy). Mucin phenotype expressions in NADETs were divided into gastric, intestinal, gastrointestinal, and unclassifiable.
RESULTS
When NADETs were classified according to EGMA, 105 were classified as type C and 29 as type O. G-NADETs were present in 11.9% (16 cases) of all cases, and all 16 cases were of type C. Among G-NADETs, 93.8% (15 cases) were present in part 1 or 2. There was an association between G-NADETs and type C in part 1, and 50.0% (eight of 16 cases) of G-NADETs were associated with a current or previous Helicobacter pylori infection status. Additionally, all eight cases occurred in part 1.
CONCLUSION
G-NADETs were significantly associated with type C. Gastric acidity and Brunner's gland growth may be associated with G-NADETs.
Core Tip: This retrospective study evaluated effects of endoscopic gastric mucosal atrophy (EGMA) on the occurrence of highly malignant gastric-type non-ampullary duodenal epithelial tumors (G-NADETs). G-NADETs were observed in 16 patients with no or mild EGMA (type C). On dividing NADETs into parts 1 (bulb), 2 (superior duodenal angle to the papilla), and 3 (anal side of the papilla), type C and G-NADETs were mainly observed in part 1. Half of the G-NADETs had a history of Helicobacter pylori infection and were found in part 1. These results suggest that G-NADET occurrence is related to gastric acidity.
Citation: Ohno K, Nakatani E, Kurokami T, Kawai A, Itai R, Matsuda M, Masui Y, Satoh T, Ikeda S, Hirata T, Takeda S, Suzuki M, Haruma K. Relationship between gastric mucosal atrophy by endoscopy and non-ampullary duodenal epithelial tumors. World J Gastrointest Oncol 2025; 17(2): 100545
Non-ampullary duodenal epithelial tumors (NADETs), which are rare tubular adenomas and carcinomas, occur in 1%-2% of all gastrointestinal tumors of the small intestine[1]. However, more cases have been reported because of increased disease occurrence and advances in endoscopic equipment[2]. The only definite risk factor for NADETs is familial adenomatous polyposis[3]. Other risk factors include animal protein and fat intake[4], bile acid[5], smoking, history of colorectal cancer, and Helicobacter pylori (H. pylori) infection[6]. In contrast, some studies have reported that gastric fundic gland polyps and Barrett’s esophagus have been more frequently observed with non-atrophic gastric mucosa without H. pylori infection[7].
Non-ampullary duodenal adenocarcinomas have a poor prognosis, with a 5-year survival rate of approximately 30%[8,9]. NADETs that express the gastric-type mucin phenotype (G-NADETs) are highly malignant. G-NADETs are most frequently observed in the proximal duodenum and on the oral side of the duodenal papilla, particularly in the bulb[10]. The gastric foveolar metaplasia, which is the primary source of G-NADETs, differentiates from Brunner’s glands to protect the duodenal mucosa from gastric acidity[11]. Gastric acid secretion is associated with endoscopic gastric mucosal atrophy (EGMA)[12]. Therefore, we aimed to investigate the relationship between EGMA and NADETs to elucidate the pathogenesis of G-NADETs.
MATERIALS AND METHODS
Study population
This retrospective cross-sectional study included pathologically diagnosed NADETs between January 2015 and August 2021 at Shizuoka General Hospital. Patients with biopsy-only disease (where only diagnosis was made and no treatment was administered), familial adenomatous polyposis, previous upper gastrointestinal surgery, an unknown H. pylori infection status, and unclassifiable mucin phenotypes were excluded, while those who underwent endoscopic resection or surgical removal were included. Additionally, the lesion with the largest diameter was selected for patients with multiple NADETs.
Classification of EGMA and location of NADETs
EGMA was evaluated based on the Kyoto classification of gastritis[13]. This classification was derived from the Kimura-Takemoto classification[14], which defines EGMA from the antrum to the cardia as the closed type (C-1 to C-3) and advanced EGMA that progresses from the cardia to the greater curvature of the stomach as the open type (O-1 to O-3). Additionally, C-0, in which EGMA is absent, and O-p, in which atrophic demarcation is obscured because of advanced atrophy, were added to the classification (Figure 1)[15]. Compared with the open type, the closed type increased gastric acid secretion[12]; therefore, EGMA was divided into types C (C-0 to C-3) and O (O-1 to O-p). EGMA was endoscopically diagnosed by two independent gastrointestinal endoscopists at Shizuoka General Hospital. When disagreement occurred, another specialist certified by the Japanese Society of Gastrointestinal Endoscopy from the same hospital was consulted, and his opinion was adopted.
Figure 1 Endoscopic gastric mucosal atrophy according to the Kyoto classification of gastritis and effect of gastric acidity on the duodenum.
Part 1 comprises the bulb. Part 2 comprises the region from the superior duodenal angle to the papilla. Part 3 comprises the region from the anal side of the papilla to the horizontal part. Type C (C-0 to C-3) comprises no or mild endoscopic gastric mucosal atrophy. Type O (O-1 to O-p) comprises severe endoscopic gastric mucosal atrophy. Type C comprises normal to high acidity in the stomach and part 1. Type O comprises low acidity. Dark orange areas indicate highly acidic environments. Purple areas indicate the growth of Brunner’s glands.
The NADET location was divided into three parts based on the distribution of Brunner’s glands and the effect of gastric acid: Part 1 (bulb), where Brunner’s glands are abundant and strongly affected by gastric acid; part 2 (superior duodenal angle to the duodenal papilla), where Brunner’s glands have a normal volume and the effect of gastric acid is reduced by duodenal juice reflux; and part 3 (anal side of the duodenal papilla to the duodenal horizontal part), where Brunner’s glands are rare and not affected by gastric acid (Figure 1).
Definitions of the H. pylori infection status
The H. pylori infection status was classified as infected, uninfected, and previously infected. These were diagnosed comprehensively using H. pylori antigen or antibody tests (serum immunoglobulin G antibody test, urea breath test, and stool antigen assay), the EGMA status according to the Kyoto classification of gastritis, and the patient’s H. pylori eradication history. Current H. pylori infections were defined as one or more positive antigen or antibody tests that supported the endoscopic findings. Uninfected cases were defined as one or more negative antigen or antibody tests that supported the endoscopic findings. Patients who received H. pylori eradication therapy and those who experienced spontaneous eradication were not distinguished. The time from H. pylori eradication to detection varied among cases: 1 year in one case, 5 years in one case, 6 years in two cases, and > 10 years in one case for the gastric type. For the gastrointestinal type, the durations were 2 years in five cases, 3 years in one case, 5 years in one case, 9 years in one case, and > 10 years in one case. In the intestinal type, the timeframes were 1 year in five cases, 2 years in three cases, 3 years in three cases, 5 years in two cases, and > 10 years in nine cases. One case was deemed to have spontaneously eradicated H. pylori from the gastric type, while two cases from the intestinal type had unknown courses after eradication.
Pathological evaluation of NADETs
The major carcinogenic pathway of non-ampullary duodenal adenocarcinomas is the adenoma-carcinoma sequence[16]. NADETs are defined as adenocarcinomas, tubular adenomas, and precancerous lesions. Macroscopic types are evaluated according to the Paris endoscopic classification[17]. We histologically classified the lesions as category 3 (mucosal low-grade neoplasia) or 4/5 (non-invasive high-grade neoplasia/invasive neoplasia) according to the Vienna classification[18]. Resected NADET specimens were fixed in 40 g/L buffered formalin solution immediately after removal. Endoscopically resected specimens were cut at 2 mm intervals, and surgically resected specimens were cut at intervals of 2-4 mm according to the Japanese classification of gastric carcinoma. After hematoxylin and eosin staining, a diagnosis was made by a pathologist at our hospital. The mucin phenotype was diagnosed using the following four immunohistochemical stains: MAC5AC (45M1; Thermo Fisher Scientific, Waltham, MA, United States) and MUC6 (CLH5; Abnova, Taipei City, Taiwan) as gastric-type markers and MUC2 (CCP58; Dako, Glostrup, Denmark) and CD10 (56C6; Leica, London, United Kingdom) as intestinal-type markers. These mucin phenotypes were considered positive when the percentage of cells positive for each marker in the tumor was ≥ 10%[19,20]. A tumor was defined as gastric when at least one gastric marker was positive, as intestinal when at least one intestinal marker was positive, as mixed gastrointestinal when both markers were positive, and as unclassifiable when both markers were negative (Table 1).
Table 1 Classification of the mucin phenotype according to immunohistochemical stains.
CD10 (+) or MUC2 (+)
CD10 (-) or MUC2 (-)
MUC5AC (+) or MUC6 (+)
Gastrointestinal type
Gastric type
MUC5AC (-) or MUC6 (-)
Intestinal type
Unclassified
Statistical analysis
Continuous variables are presented as means ± SD, and categorical variables are presented as frequencies (percentages). Regarding group comparisons, t-tests (two-group comparison) were performed for continuous variables and χ2 tests were performed for categorical variables. These data were not complementary. P < 0.05 indicated a significant difference, and two-tailed tests were performed for all analyses. Multiple comparisons were not considered during the exploratory studies. All statistical analyses were performed using EZR (R Software for Statistical Computing, Vienna, Austria)[21], a statistical software application that extends the capabilities of R and R Commander.
RESULTS
During the study period, 178 NADETs were pathologically diagnosed in 174 patients at Shizuoka General Hospital. Four patients had two NADETS, and the lesion with the largest diameter was used. Fifteen patients underwent biopsy alone, five had familial adenomatous polyposis, seven had a history of upper gastrointestinal surgery, eight had an unknown H. pylori infection status, and five had a pathologically unclassifiable mucin phenotype; all these patients were excluded from this study. A total of 134 patients met the inclusion criteria. NADETs were observed in parts 1, 2, and 3 in 24, 62, and 48 patients, respectively (Figure 2). These NADETs were divided according to EGMA into 105 type C cases and 29 type O cases. Patients with type O were elderly. Both groups comprised more male than female patients. NADETs in part 3 were more likely to occur in patients with type C. The G-NADETs and five cases involving submucosal or deeper invasion were all classified as type C (Figure 3). Most patients with type C had an uninfected H. pylori status (62.9%), whereas most patients with type O had an infected H. pylori status (72.4%). The presence or absence of a proton pump inhibitor did not affect the incidence of NADETs in either group (Table 2).
Type C and G-NADETs were independently associated with NADETs in part 1, whereas EGMA was not associated with NADETs in parts 2 and 3.
All 16 G-NADETs were observed in patients with type C, and 93.5% (15 cases) of G-NADETs were observed in parts 1 and 2 (Table 3).
Table 3 Relationship between the non-ampullary duodenal epithelial tumors position and mucin phenotype, n (%).
NADET position
Part 1
Part 2
Part 3
Variable
Category
Gastric atrophy
P value
Gastric atrophy
P value
Gastric atrophy
P value
Type C, n = 17
Type O, n = 7
Type C, n = 44
Type O, n = 18
Type C, n = 44
Type O, n = 4
Mucin phenotype
Gastric type
11 (64.7)
0 (0.0)
0.006
4 (9.1)
0 (0.0)
0.158
1 (2.3)
0 (0.0)
1
GI type
4 (23.5)
3 (42.9)
15 (34.1)
3 (16.7)
11 (25.0)
1 (25.0)
Intestinal type
2 (11.8)
4 (57.1)
25 (56.8)
15 (83.3)
32 (72.7)
3 (75.0)
When patients with a current or previous H. pylori infection status and patients with an uninfected H. pylori status were compared, 50.0% (eight of 16 cases) of G-NADETs were observed in the patients with a current or previous H. pylori infection status, and all eight of them occurred in part 1 (Table 4).
Table 4 Relationship between the Helicobacter pylori infection status and gastric-type non-ampullary duodenal epithelial tumors position, n (%).
Variable
Category
Helicobacter pylori
P value
Previous or current, n = 8
Uninfected, n = 8
Atrophy
C-0 to C-3
8 (100.0)
8 (100.0)
O-1 to O-p
0 (0.0)
0 (0.0)
Position
Part 1
8 (100.0)
3 (37.5)
0.026
Part 2
0 (0.0)
4 (50.0)
Part 3
0 (0.0)
1 (12.5)
DISCUSSION
This study divided NADETs into three locations and examined their relationship with EGMA. During most previous studies, the duodenum was divided into two parts according to the papilla, and G-NADETs occurred more frequently in the proximal duodenum, especially in the bulb[10]. During this study, the proximal duodenum was divided into part 1, which comprised the bulb and was strongly affected by gastric acid, and part 2, which comprised the region from the superior duodenal angle to the papilla, where the effect of gastric acid was reduced because of duodenal fluid reflux. If the occurrence of G-NADETs is dependent on only Brunner’s gland growth, then there should be no difference in the incidence of G-NADETs at each site with EGMA. However, G-NADETs occurred more frequently in patients with type C disease than in patients with type O tumors in part 1 during this study. Furthermore, no difference in the incidence of G-NADETs was observed in part 2, regardless of the degree of EGMA. These results suggest that the occurrence of G-NADETs may be influenced by the growth of Brunner’s glands and by gastric acidity.
Of the 16 G-NADETs, 50.0% (eight of 16 cases) were associated with a current or previous H. pylori infection status, and all eight of them were of type C and occurred in part 1. These cases could be considered type B gastritis with high gastric acid secretion, and the environment of part 1 was extremely likely to be highly acidic. These results support the possibility that gastric acidity is associated with the occurrence of G-NADETs.
In Western countries, most NADETs have a poor prognosis and are considered invasive carcinomas, and only 10%-22% of NADETs have intramucosal lesions[22,23]. In Japan, endoscopy is widely used; therefore, 56.4% of NADETs are considered intramucosal lesions and 48.0% are treated with endoscopy[24]. Endoscopic resection of NADETs and endoscopic submucosal dissection involve a high risk of perforation, and surgical procedures such as pancreatoduodenectomy are highly invasive. However, cases in which intestinal NADETs exhibit no tendency to invade the duodenal wall during long-term follow-up have been observed[25]. Although G-NADETs are highly malignant, the proportion of G-NADETs among all NADETs is low, accounting for only 11.9% of cases in this study. Therapeutic interventions for NADETs should be determined after considering their mucin phenotypes. Mutations in GNAS and KRAS have been observed in non-papillary duodenal invasive carcinomas that express a gastric-type phenotype. Gastric foveolar metaplasia with prominent papillary proliferation and ectopic gastric mucosa have the same mutation and are considered precancerous lesions of G-NADETs[18].
The Updated Sydney System[26] determines the pathological diagnosis based on biopsy results; however, the Kyoto classification of gastritis determines the endoscopic diagnosis and was used to diagnose EGMA during this study. Although there are no reports comparing the degree of EGMA and gastric acid secretion according to the Kimura-Takemoto classification, this classification reflects histological atrophic gastritis of the mucosa of the gastric body. It is known that gastric acid secretion decreases as the gastritis progresses[27,28]. The Kyoto classification is simple, minimally invasive, and has a sensitivity of 98.7% and specificity of 98.4% for the diagnosis of histological gastritis[29]. Therefore, the Kyoto classification is an excellent diagnostic tool. Patients with type C have relatively higher acid secretion than patients with type O[12]. Gastric foveolar metaplasia, which occurs as a biological defense mechanism of the duodenal mucosa against gastric acid, is more likely to occur in patients with type C[11]. The stomach is in a hyperacidic state in patients with H. pylori and type B gastritis. Therefore, we hypothesized that EGMA would be associated with the occurrence of G-NADETs.
The Japanese clinical practice guidelines for duodenal cancer 2021[3] introduced two studies; Kakushima et al[6] cited H. pylori infection as a positive risk factor for the occurrence of NADETs, while Matsuzaki et al[7] reported Barrett’s esophagus and fundic gland polyps as positive risk factors. The latter is a typical finding in H. pylori-negative cases; therefore, these two studies seem contradictory. However, the studies had key methodological differences. Specifically, unlike our study, Kakushima et al[6] did not report the mucin phenotypes or the relationships between EGMA and cancer locations. Moreover, the study by Matsuzaki et al[7] included patients without cancer, and considered EGMA and NADETs in the bulb and descending regions separately.
During this study, no relationship was observed between intestinal NADETs and EGMA. This may be because intestinal NADETs originate from the small intestinal mucosa and are not affected by gastric acidity. The number of type C and G-NADETs may increase in the future because of the increasing number of patients with an uninfected H. pylori status and patients who experienced H. pylori eradication at a young age.
This study has few limitations. First, it was a single-center, retrospective study; therefore, selection bias and information bias were possible, limiting the generalizability of the results. Second, as this was a cross-sectional study, an assessment of causality over time was not possible. Third, the relationship between EGMA and gastric acid secretion was not evaluated quantitatively because gastric acid secretion was not directly measured during this study.
CONCLUSION
A significant association was observed between G-NADETs and type C. The higher incidence of G-NADETs in patients with type C compared with that in patients with type O in part 1 suggested that gastric acidity, in addition to Brunner’s gland growth, may contribute to the occurrence of G-NADETs. Based on the validation of this study’s results in future multicenter studies, it may be recommended that patients with C-type be carefully searched for G-NADETs at the bulb. Particularly, the relationship between G-NADETs and the bulb should be closely monitored in C-type patients with current or previous H. pylori infection.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Japan
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade C
Creativity or Innovation: Grade C
Scientific Significance: Grade C
P-Reviewer: Kinami S S-Editor: Li L L-Editor: A P-Editor: Yu HG
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