Development of gastric cancer in nonatrophic stomach with highly active inflammation identified by serum levels of pepsinogen and Helicobacter pylori antibody together with endoscopic rugal hyperplastic gastritis

Abstract

This study aimed to elucidate groups at high risk of developing cancer among patients with serologically identified Helicobacter pylori infection and nonatrophic stomach. Annual endoscopy was performed for a mean of 5.4 years in 496 asymptomatic middle-aged men who were H. pylori antibody-positive and pepsinogen (PG) test-negative. Subjects were stratified according to the activity of H. pylori-associated gastritis measured by serum levels of PG and H. pylori antibody, and/or by endoscopic findings of rugal hyperplastic gastritis (RHG), and cancer development was investigated. During the study period, seven cases of cancer developed in the cohort (incidence rate, 261/100,000 person-years), with 85.7% developing in the group showing a PGI/II ratio 3.0, reflecting active inflammation-based high PGII levels. Cancer incidence was significantly higher in this group (750/100,000 person-years) than in groups with less active gastritis. Furthermore, cancer incidence for this group was significantly higher in the subgroup with high H. pylori antibody titers than in the lowtiter subgroup. Meanwhile, endoscopic findings revealed that 11.7% of subjects showed RHG reflecting localized highly active inflammation, and cancer risk was significantly higher in patients with RHG than in patients without. Combining the two serum tests and endoscopic examination for RHG allowed identification of subjects with more active gastritis and higher cancer risk. No cancer development was observed in these high-risk subjects after H. pylori eradication. Subjects with highly active gastritis identified by the two serological tests and endoscopic RHG constitute a group at high risk of cancer development with H. pylori-infected nonatrophic stomach.Gastric cancer is one of the leading causes of cancer-related deaths in Japan, with 50,017 deaths attributed to this cancer in 2009. 1 Helicobacter pylori infection is now widely accepted as playing a major role in the development of gastric cancer in areas showing high-risk for this cancer, including Japan. 2-5 H. pylori triggers chronic inflammation in the gastric mucosa, leading to a series of molecular and morphological events known as the atrophy-metaplasia-dysplasia-cancer sequence. [3][4][5] This carcinogenic sequence is considered to represent a major route of stomach carcinogenesis, and previous studies, including our own, have identified positive correlations between extent of chronic atrophic gastritis (CAG) and risk of gastric cancer. 6-13 Our longitudinal cohort study clearly indicated that progression of H. pylori-associated chronic gastritis increases cancer risk in a stepwise manner, and that patients with metaplastic gastritis, an end result of chronic H. pylori infection, show the highest annual cancer incidence rate of around 1% among asymptomatic middle-aged Japanese men. 11 Other

Altered mucosal DNA methylation in parallel with highly active Helicobacter pylori-related gastritis

“…In contrast, diffuse-type cancer develops in the stomach following chronic active inflammation without passing through the intermediate steps of atrophic gastritis or intestinal metaplasia. Of particular note, the activity of mucosal inflammation is proposed for a risk of diffuse-type cancer [9,10,38]. To date, studies about DNA methylation in gastric carcinogenesis have been mainly focused on the intestinal type [22,23,28,39].…”

Finding out Serologically Active Gastritis Subjects by Conventional Endoscopy and Picking out Subjects Who might be Benefit from Helicobacter pylori Eradication as a Primary Prevention for Gastric Cancer

“…There have been efforts to identify these subgroups, actually Kiyohira et al [18] showed gastritis severity and gastric mucosal status could be well documented by serum PG. Recent Japanese studies [1,19] uncovered some groups of atrophy free subject showed GC risk equivalent to extensive atrophic gastritis especially diffuse type GC, the main characteristics of these subgroups were elevated PG II. Considering Hunter et al [20] that H.pylori infection contribute more to PG II elevation than to PG I, and Iranian study [21] suggesting that PG II could be good surrogate marker for body morphological change after H.pylori infection, and major portion of PG II was originated from the active gastritis by neutrophil cell infiltration, we could come to conclusion that H.pylori infected active gastritis creating more neutrophil infiltration would cause more PG II elevation.…”

“…and actually when we made the protocol we referred to watanabe et al [27] reporting that all cancers in high H.pylori titer group belonged to Group B-γ, inevitably some portion of active gastritis subjects in Group B might be omitted and performing genuine Korean active gastritis study would be the way to go. Because we depend on CLO test for H.pylori identification, some H.pylori positive subjects might be exempted from the study, however we used EAB and various endoscopic findings: we must have tried to find out H.pylori by other methods if we had confronted abnormal mucosal findings with negative CLO test (actually all of four subjects who showed no visible EAB had abnormal mucosal patterns), consequently most of the exempted cases might be Group D not Group B and thinking of our main purpose they would not be considered as candidate for primary GC prevention.…”

Development of diffuse carcinomas in the gastric corpus in patients with rugal hyperplastic gastritis

“…Watanabe et al 1 have recently described development of gastric cancers of Laurens diffuse type in patients with rugal hyperplastic (enlarged fold) gastritis, all located in the gastric corpus. We have read their publication with interest.…”

“…4 Furthermore, gastric carcinomas of the diffuse type in patients with atrophic gastritis have neuroendocrine differentiation and have been suggested to develop from ECL cells. 5 Altogether, there is a large number of studies suggesting that gastrin may be pivotal for gastric mucosal hyperplasia and carcinogenesis and serum gastrin should have been measured in the study by Watanabe et al 1 The serum concentrations of PGs do not necessarily reflect gastric acidity or degree of atrophy and particularly some persons with reduced gastric acid secretion and, thus, presumed hypergastrinemia may have serum PGI in the normal range. 6,7 Yours sincerely, Reidar Fossmark and Helge Waldum…”