Gastric cancer diagnosed after Helicobacter pylori eradication in diabetes mellitus patients

To evaluate the incidence and characteristics of gastric cancer diagnosed after H. pylori eradication in DM patients, 991 patients who underwent successful H. pylori eradication therapy at our institution between January 1996 and March 2013 and were followed up for over 6 months (the follow-up period was defined as the period from the day of commencement of eradication therapy to the day of the last endoscopy performed at our institution) were analyzed retrospectively. Then, we excluded patients who met the following criteria: i) those in whom endoscopy before eradication was not conducted at our institution (n = 18) and ii) those with a previous history of gastrectomy (n = 8). Therefore, a total of 965 patients were included in the analysis.

Patients were divided into DM and non-DM groups. DM was diagnosed according to the 2010 Japan Diabetes Society (JDS) criteria [14]. The diagnoses of hypertension (HT), hyperlipidemia (HL), and hyperuricemia (HU) were based on the need for medical treatment. The study design was approved by the Ethics Committee at the Institute for Adult Diseases, Asahi Life Foundation and conformed to the Declaration of Helsinki. The patients’ records were anonymized prior to analysis. Written informed consent was obtained from all participants.

H. pylori infection was defined by a positive result for at least one of the following: rapid urease test (Helicocheck, Otsuka Pharmaceuticals, Tokyo, Japan), serological testing for anti-H. pylori IgG, ¹³C-urea urea breath test, or pathological analysis by hematoxylin and eosin or Giemsa staining. Patients in whom H. pylori infection was confirmed underwent eradication therapy. Patients in whom eradication therapy had failed received additional treatment: the first-line regimen comprised a proton pump inhibitor (PPI), amoxicillin, and clarithromycin [15]; the second-line regimen comprised a PPI, amoxicillin, and metronidazole; and the third-line regimen comprised a PPI, amoxicillin, and sitafloxacin [16]. The success or failure of eradication therapy was determined by a ¹³C-urea breath test performed at least 4 weeks after treatment.

At our institution, patients who receive eradication therapy are recommended to undergo esophagogastroduodenoscopy annually. The upper gastrointestinal endoscopies were performed by experienced endoscopists. Gastric mucosal atrophy was evaluated using the endoscopic scale described by Kimura and Takemoto [17], which has been reported to concord with the histological results [18]. Patients were classified into three groups according to their endoscopic atrophic gastritis grade: the mild (C-I and C-II), moderate (C-III and O-I), and severe atrophic gastritis (O-II and O-III) groups.

Biopsy specimens were taken from the neoplastic lesion, and the final diagnosis of gastric cancer was based on the pathology results. Gastric cancers were classified pathologically according to Lauren’s classification as intestinal or diffuse type [19]. A lesion identified by endoscopy prior to eradication was not counted as gastric cancer after eradication in this study.

All statistical analyses were performed using the JMP10 software (SAS Institute, Cary, NC, USA). Welch’s t-test was used to compare the means of continuous variables. Comparisons of nominal variables were performed by χ ² test or Fisher’s exact test, as appropriate. The incidence of gastric cancer in patients with and without DM was evaluated using the Kaplan–Meier method, and the statistical significance of the differences was evaluated by log-rank test. The diagnosis of gastric cancer was the primary endpoint, and data were censored at the last endoscopy. The risk of gastric cancer after eradication was assessed using Cox’s proportional-hazards model. Since no gastric cancer was detected in the mild atrophic gastritis group, this group served as the control. Odds ratios (OR) with 95 % confidence intervals (CI) were used as a measure of association and were adjusted using unconditional logistic regression models. A two-sided p-value of less than 0.05 was considered to indicate statistical significance.

The baseline characteristics of the patients are provided in Table 1. In total, 965 patients (729 males and 236 females, mean age 62.9 years, and mean body mass index (BMI) 23.2 kg/m²) underwent successful H. pylori eradication therapy as the first-, second-, and third-line regimens in 782 (81.0 %), 178 (18.4 %), and 5 (0.52 %) patients, respectively. The 965 patients comprised 518 DM patients (13 type 1 DM and 505 type 2 DM patients) and 447 non-DM patients. Patients were followed-up for up to 16.2 years (mean 4.5 years). In terms of the endoscopic atrophic gastritis grade, 173 (17.9 %), 422 (43.7 %), and 370 (38.3 %) patients were categorized as having mild, moderate, and severe atrophic gastritis, respectively.

Non-DM patients who underwent eradication therapy were significantly younger than DM patients (60.7 and 64.8 years, respectively). The mean follow-up period (4.18 years for non-DM patients and 4.78 years for DM patients) and mean endoscopy interval (1.37 years for non-DM patients and 1.61 years for DM patients) of the non-DM patients were significantly shorter than those of the DM patients. The mean BMI (23.1 kg/m² for non-DM patients and 23.4 kg/m² for DM patients) was not significantly different between non-DM and DM patients. The proportion of patients who received medications for HT and HL was higher in DM than in non-DM patients.

During the follow-up period, 21 gastric cancers [9 in non-DM patients (0.482 %/year) and 12 in DM patients (0.485 %/year)] were diagnosed after H. pylori eradication (Table 2). No gastric cancer was found in the mild atrophic gastritis group, while 8 (38.1 %) gastric cancers were diagnosed in the moderate atrophic gastritis group and 13 (61.9 %) in the severe atrophic gastritis group. Among these 21 gastric cancers, there were no cardiac cancers. Eleven (52.4 %) gastric cancers had a depth of invasion limited to the mucosa; the remainder [10 (47.6 %)] exhibited submucosal or deeper invasion.

The mean age (69.4 years for non-DM patients and 70.6 years for DM patients), the proportion of males (77.8 % for non-DM patients and 91.7 % for DM patients), mean follow-up duration (4.59 years for non-DM patients and 3.95 years for DM patients), mean endoscopy interval (1.93 years for non-DM patients and 1.62 years for DM patients), mean BMI (23.4 kg/m² for non-DM patients and 22.6 kg/m² for DM patients) and atrophic gastritis grade were not significantly different between the gastric cancer patients with versus without DM.

In total, 16 (76.2 %) intestinal-type gastric cancer and 5 (23.8 %) diffuse-type gastric cancer cases were diagnosed. Among the non-DM gastric cancer patients, 88.9 % (8/9) were of the intestinal type, compared with 66.7 % (8/12) of the DM gastric cancer patients. Regarding gastric cancer treatment modalities, 11 (52.4 %) patients underwent curative endoscopic treatment. The remaining 10 (47.6 %) patients received curative surgical treatment. There were no significant differences in the pathology, diameter (22.1 mm for non-DM patients and 25.0 mm for DM patients), depth, location, or treatment of the gastric cancers between patients with and without DM.

Kaplan–Meier analysis of the proportions of patients free of gastric cancer after H. pylori eradication with and without DM is shown in Fig. 1. No significant difference was found in the incidence of gastric cancer after eradication between non-DM and DM patients by log-rank test (p = 0.8754).

We next analyzed the risk factors for gastric cancer after H. pylori eradication using Cox’s proportional hazards model (Table 3). Age, sex, BMI, DM, HT, HL, and HU were not found to be risk factors for gastric cancer after H. pylori eradication in either univariate or multivariate analysis. Severe atrophic gastritis before eradication was identified as a significant risk factor for gastric cancer after H. pylori eradication in the multivariate analysis (OR 2.56, 95 % CI 1.03–6.77, p = 0.0424), in accordance with a previous report [9].