Characteristics Associated With Spontaneous Helicobacter pylori Clearance After Subtotal Gastrectomy in Patients With Gastric Cancer
Article information
Abstract
Objectives
Helicobacter pylori eradication treatment typically occurs after gastrectomy; however, the specific criteria for eradication treatment have not been reported. This study aimed to evaluate the rates and locations of spontaneous clearance, as well as the accompanying histological changes.
Methods
Patients with H. pylori-positive status at the time of gastric cancer diagnosis and who underwent subtotal gastrectomy at a tertiary care center in Seoul (South Korea) were prospectively enrolled in this study. H. pylori infection status and histological features (presence of mononuclear cells, neutrophils, atrophy, and intestinal metaplasia) were evaluated pre- and postoperatively at different locations in the stomach.
Results
Sixteen patients with H. pylori-positive gastric cancer underwent subtotal gastrectomy. Of these, 13 (81.3%) showed spontaneous clearance at least once during the follow-up. Half of the patients (8, 50.0%) had cleared their infections within 6 months after surgery. Histological factors, such as neutrophil and mononuclear cell counts, atrophy, and intestinal metaplasia, did not differ according to H. pylori clearance status. The spontaneous clearance rates of H. pylori were 69.2% in the cardia, 46.1% in the fundus, 38.4% in the lesser curvature of the mid-body, and 41.6% in the greater curvature of the mid-body; the differences in clearance rates were not significant (p=0.149).
Conclusions
The rate of spontaneous H. pylori clearance was high in patients with gastric cancer who underwent subtotal gastrectomy. Postoperative H. pylori status should be re-evaluated to confirm the presence of infection prior to considering eradicating therapy.
INTRODUCTION
Helicobacter pylori infection is closely associated with gastric cancer development [1], which remains a major cause of death, especially in East Asian countries [2-4]. Epidemiological data from Asia show that H. pylori-positive individuals have at least twice the risk of developing stomach cancer as do those with negative results [5,6]. Infections with these bacteria often cause chronic gastritis, which can lead to precancerous changes such as atrophic gastritis and intestinal metaplasia [7,8]. The eradication of H. pylori can alleviate atrophic gastritis and intestinal metaplasia in the general population [9,10]. Consequently, most guidelines recommend screening for and eradicating these infections in high-risk patients to reduce the incidence of gastric cancer [11-14].
However, clear guidelines have not been established for H. pylori eradication following gastric cancer surgery as the postoperative gastric physiology may differ from that of the intact stomach [15]. Although the growth of these bacteria can be suppressed by bile reflux after surgery, there is a view that the bacteria can proliferate due to changes in acid secretion [16,17], making the prediction of post-gastrectomy infection status difficult.
In this study, we investigated the effect of gastric cancer surgery on H. pylori status and the accompanying histological changes. We also analyzed the differences in H. pylori infection status according to the position of the remnant stomach to determine if there was an association with gastric acid levels.
METHODS
Patients
Between March 2016 and January 2018, 93 patients underwent gastric cancer surgery at a tertiary care center in Seoul, Korea, at the time of their cancer diagnosis. These patients, eligible to participate in this study, tested to determine their H. pylori status. Among them, 16 were diagnosed with H. pylori infection and underwent distal gastrectomy; these patients were prospectively enrolled in this study. Of those ineligible to participate, some were excluded due to undergoing total or near-total gastrectomy, undergoing pre-operative endoscopic submucosal dissection, not returning for follow-up evaluations receiving postoperative chemotherapy, and undergoing prior H. pylori eradication therapy (Fig. 1). This study was approved by the Institutional Review Board of the Asan Medical Center, and written informed consent was obtained from all participants (IRB number: 2015-0823).
Evaluation of H. pylori infection
Patient H. pylori status was evaluated using the rapid urease test (RUT) and histopathological diagnosis of biopsy specimens; the presence of H. pylori in a biopsy specimen was confirmed using Wright-Giemsa staining. The RUT was considered positive when a color change from yellow to pink or red was observed within 24 hours using a urease reaction kit (CKD Hp kitTM; ChongKunDang BiO).
Ten biopsy specimens for Sydney scoring and H. pylori diagnosis were obtained during preoperative endoscopic examinations, with two specimens taken from each of five sites (antrum, cardia, fundus, and lesser and greater curvatures of the mid-body of the stomach) using standard-sized biopsy forceps. Additional preoperative biopsy specimens for RUT were obtained from the antrum and greater curvature of the mid-body. Biopsies were performed preoperatively and 6 and 12 months after surgery. Postoperatively, 10 biopsy specimens for Sydney scoring and H. pylori diagnosis were obtained from the anastomosis site, cardia, fundus, and lesser and greater curvatures of mid-body of the stomach (two samples per site) using standard-sized biopsy forceps during the endoscopic examination. If either the RUT or the histology of the biopsy specimen was positive, the preoperative H. pylori status was considered positive. Postoperatively, the presence of H. pylori was evaluated using only biopsy specimens.
Histology
The histological features of the gastric mucosa were examined by an experienced gastrointestinal pathologist using hematoxylin-eosin and Wright-Giemsa staining. Histological markers, including numbers of neutrophils and mononuclear cells, atrophy, and intestinal metaplasia, were assessed and scored from 0 to 3 based on the updated Sydney scoring system (0=none, 1=mild, 2=moderate, and 3=severe) [18].
Definition
In this study, non-clearance was defined as H. pylori identified at any postoperative biopsy site; if bacteria were not found at any of the postoperative sites without eradication treatment, spontaneous clearance was assumed. These definitions were based on pathological evaluations.
Statistical analysis
All statistical analyses were performed using SPSS software (version 20.0; IBM Corp.). Baseline characteristics were compared using the Mann–Whitney U-test and Fisher’s exact test. Differences in histological features between individuals with a persistently positive H. pylori status and those demonstrating spontaneous clearance were calculated using the Mann–Whitney U-test. Wilcoxon’s signed-rank test was used to compare the baseline and follow-up histological findings within each group. Statistical significance was set at p<0.05.
RESULTS
Baseline characteristics
A summary of the baseline postoperative H. pylori status of the enrolled patients is shown in Table 1. The mean ages of patients with persistent H. pylori infections (non-clearance group) and those exhibiting spontaneous resolution of their infections (spontaneous clearance group) were 48.7 years and 58.4 years, respectively. Both groups predominantly included men. The non-clearance group had high percentages of individuals who were current smokers and drinkers (66.7% and 100%, respectively). All enrolled patients underwent subtotal gastrectomy involving Billroth I (B-I) reconstruction. The baseline characteristics were not significantly different between the two groups (Table 1).
Spontaneous clearance rates depending on postoperative periods
Preoperatively, all 16 patients had positive RUT results, and the histological results determined using Giemsa staining showed 81.3% (13/16) with bacteria present at the cardia, fundus, greater curvature of mid body, and antrum; 75.0% (12/16) demonstrated bacteria at the lesser curvature of mid-body. Of the 16 patients, 13 (81.3%) showed spontaneous clearance at least once during the follow-up period, with half (eight patients, 50.0%) clearing their infection within six postoperative months (Table 2).
Histological changes during follow-up
Tables 3-6 show the changes in histological factors, including numbers of neutrophils and mononuclear cells, atrophy, and intestinal metaplasia, at different stomach locations. The postoperative neutrophil and mononuclear cell counts decreased over time, albeit without showing any statistical significance between the non-clearance and spontaneous clearance groups.
In the spontaneous clearance group, the neutrophil counts in the cardia were significantly decreased (p=0.021) at 12 months postoperatively; in the lesser curvatures of the mid-bodies, the counts were significantly decreased at 6 months postoperatively (p=0.038) (Table 3). Additionally, the mononuclear cell counts were significantly decreased in the cardia and in the lesser curvatures of the mid-body at 6 and 12 months after surgery (cardia p=0.020 and 0.014, respectively; lesser curvatures of the mid-body p=0.030 and 0.016, respectively) (Table 4).
In both groups, postoperative atrophy and intestinal metaplasia tended to decrease relative to the baseline. In the spontaneous clearance group, there were significant decreases in atrophy and intestinal metaplasia by postoperative month 12 in the lesser curvatures of the mid-bodies (p=0.033 and 0.026, respectively) (Tables 5 and 6). None of the other histological factors showed significant differences between the two groups.
Spontaneous clearance rate according to stomach anatomy
The spontaneous clearance rates of H. pylori were 69.2% in the cardia, 46.1% in the fundus, 38.4% in the greater curvature of the mid-body, and 41.6% in the lesser curvature of the mid-body; the clearance rates did not differ significantly according to location (p=0.149) (Table 7).
DISCUSSION
In this prospective, single-center study, we evaluated the spontaneous eradication of H. pylori in patients 6 and 12 months after undergoing subtotal gastrectomies. The spontaneous clearance rate was high (81.3%, 13/16 patients). Notably, eight patients (50.0%) spontaneously cleared their infections within 6 months of surgery. After surgery, histological factors, specifically neutrophil and mononuclear cell counts, decreased relative to preoperative levels. The spontaneous clearance group showed significant reductions in neutrophil and mononuclear cell counts in the cardia and lesser curvature of the mid body by 12 months post-operatively.
Although the changes in H. pylori status after subtotal gastrectomy are not yet fully understood, several studies have shown spontaneous clearance of H. pylori after subtotal gastrectomies for peptic ulcers or early gastric cancer. In one study, 60 of 140 (42.9%) postoperative patients showed spontaneous clearance of these bacteria at least once during follow-up [19]. In another study, the rate of H. pylori spontaneous clearance after partial gastrectomy was 43% (13/30) [20]. Although previous studies have shown spontaneous clearance rates in the range of 40%, our study showed a higher rate (81.3%). In our study, we specifically analyzed patients who underwent B-I reconstructions. Considering that bile reflux is less commonly associated with patients undergoing B-I than those undergoing B-II reconstructions, factors other than bile reflux are believed to contribute to spontaneous clearance [21,22]. Additionally, directly comparing our study with other studies may be difficult because other studies targeted patients undergoing gastrectomies due to peptic ulcers [20].
Following a gastrectomy, the loss of the pyloric ring in the remnant stomach increases bile reflux, which worsens atrophy and intestinal metaplasia [23]. H. pylori is also known to contribute to residual-stomach gastritis after gastrectomy [24]. Some researchers believe that bile reflux is the main contributing factor, whereas others believe that bile reflux and H. pylori are interrelated contributors [25,26]. In our study, atrophy and intestinal metaplasia decreased after surgery; however, these differences were not statistically significant. Only the spontaneous clearance group showed significant improvements in atrophy and intestinal metaplasia in the lesser curvature of mid-body by 12 postoperative months. The tendency of atrophy and intestinal metaplasia to improve despite increased bile reflux during the postoperative period suggests that bile reflux is not the only factor affecting atrophy and intestinal metaplasia. In addition, significant improvements in atrophy and intestinal metaplasia in the lesser curvature of the mid-body were seen in the spontaneous clearance group, suggesting that H. pylori may also affect atrophy and intestinal metaplasia.
Neutrophils and mononuclear cells are associated with chronic inflammation of the digestive tract [27]. Histological evaluations, using the updated Sydney system revealed, that inflammatory cell infiltration increased in the presence of gastritis [28]. Gastritis caused by H. pylori infection and chronic inflammation are closely related [29]. Although some studies suggest that bile reflux and H. pylori exacerbate remnant gastritis and increase histological inflammation, others have shown an association with H. pylori, but not with bile reflux and inflammation [21,30]. In our study, the numbers of mononuclear cells and neutrophils decreased after gastrectomy in the spontaneous clearance group, suggesting suggests that the loss of H. pylori after gastrectomy is a major contributor to improvements in inflammation.
This study investigated whether the location of each remnant stomach (cardia, fundus, greater and lesser curvatures of the mid-body) impacted the spontaneous bacterial clearance rates; however, no differences were observed. We also evaluated histological factor differences at each location. All four factors (neutrophil and mononuclear cell numbers, atrophy, and intestinal metaplasia) showed significant improvement in the lesser curvatures of mid-bodies in the spontaneous clearance group, which is worthy of further study. Such studies might examine differences such as the degree of bile reflux among the locations.
This study has several limitations. It was conducted at a single center, involved a small number of patients, and had a relatively short follow-up period. Although atrophy and intestinal metaplasia tended to decrease over the postoperative follow-up period, a statistical significance was not observed, possibly because of the small number of patients and short follow-up period. Additionally, we could not assess postoperative antibiotic use. Although we could not investigate the impact of bile reflux differences because only patients undergoing B-I reconstruction were included, the high rate of spontaneous clearance suggests that there is a major cause other than bile reflux. Also, unlike other studies that included patients receiving adjuvant chemotherapy, we excluded such patients to control for the effect of chemotherapy on H. pylori clearance [19]. This study serves as a foundation for future large-scale studies. Furthermore, this study involved multiple comparisons of different histological factors, locations, and time points. Due to the exploratory nature of the study and the small sample size, we could not apply formal adjustments for multiple testing, such as Bonferroni correction. Therefore, the findings, especially those with marginal p-values, should be cautiously interpreted. Future studies involving larger sample sizes and statistical models that incorporate corrections for multiple testing are required to validate these preliminary observations.
In conclusion, we observed a high rate of spontaneous H. pylori clearance after subtotal gastrectomy (81.3%), with the highest incidence occurring within six postoperative months. This suggests that patient postoperative H. pylori status should be re-evaluated before starting eradication therapy.
Notes
Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
This work was supported by IL-YANG Pharmaceutical Co., Ltd.
Acknowledgements
The authors thank Yang Soon Park for the histological examination and assessment.
Authors’ Contribution
Conceptualization: Ji Yong Ahn, Byung Sik Kim, So Young Byun, Hee Sung Kim. Data curation: all authors. Funding acquisition: Ji Yong Ahn. Investigation: all authors. Methodology: Ji Yong Ahn, Byung Sik Kim, So Young Byun, Hee Sung Kim. Project administration: Ji Yong Ahn, Byung Sik Kim, So Young Byun, Hee Sung Kim. Resources: So Young Byun, Hee Sung Kim. Software: So Young Byun, Hee Sung Kim. Supervision: Ji Yong Ahn. Validation: So Young Byun, Hee Sung Kim. Visualization: So Young Byun, Hee Sung Kim. Writing—original draft: So Young Byun. Writing—review & editing: So Young Byun. Approval of final manuscript: all authors.
