Patients with a corpus predominant or pangastritis have a much higher stomach cancer risk than those with an antral predominant gastritis

[ginfreely]

 

[ginfreely]

 

[ginfreely]

Abstract​

Background and aims​

The incidence of gastric cancer in Japan is four times higher than in the UK. It usually arises in a stomach with corpus predominant or pangastritis that has undergone extensive atrophy and intestinal metaplasia. We hypothesised that a Japanese population would have a more severe gastritis with a corpus predominant or pangastritis pattern and a greater degree of atrophy and intestinal metaplasia than that found in the UK. To test this we designed a comparative trial.

Methods​

A total of 252 age matched consecutive patients were recruited from the endoscopy services in Leeds and Tokyo. In each centre, 21 patients were prospectively selected from each decennial, between the ages of 20–80 years. All had epigastric discomfort as their predominant symptom. Patients with peptic ulcer, cancer, and oesophagitis were excluded. Five gastric biopsies were examined by two histopathologists using the updated Sydney system. Helicobacter pylori infection was assessed by histology and culture of biopsies and enzyme linked immunosorbent assay and immunoblot of plasma.

Results​

Gastritis was found by both pathologists in 59 (47%) UK and 76 (60%) Japanese patients (χ2 test, p = 0.04). In those patients with gastritis, corpus predominant or pangastritis was commoner in the Japanese (63% Japan v 36% in the UK (χ2 test, p = 0.003) Atrophy and intestinal metaplasia were more extensive and severe (Mann‐Whitney U test, p<0.001) and chronic inflammation and polymorph activity were also greater, especially in the corpus (Mann‐Whitney U test, p<0.001). Fifty three of 59 UK gastritis patients (90%) and 67/76 (88%) (χ2 test, p = 1) Japanese gastritis patients were positive for H pylori. Using a previously described “gastric cancer risk index” among H pylori positive patients, there were significantly more Japanese than UK subjects with a “high risk” score.

Conclusion​

In Japanese as opposed to English patients, gastritis is more prevalent and severe with more corpus predominant atrophy and intestinal metaplasia. These differences may partially explain the higher incidence of gastric cancer in Japan.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860129/#

 

[ginfreely]

The incidence of gastric cancer varies throughout the world. It is four times more common in Japan than in the UK and occurs at a younger age.1 A variety of aetiological factors have been put forward to account for these differences, including Helicobacter pylori prevalence2 and virulence3as well as dietary4 and genetic5 variations between different populations.

The Correa hypothesis postulates a progression from chronic gastritis to gastric atrophy and intestinal metaplasia (IM), leading to dysplasia and finally cancer.6 Histologically, gastric cancer is classified as either “intestinal” or “diffuse”. Intestinal cancer is commoner and is associated with atrophy and IM while diffuse cancer tends to arise in areas of active inflammation. Both are strongly associated with H pylori infection. The severity and histological appearances of the gastritis are therefore relevant but the pattern of the gastritis seems to be even more important. Patients with a corpus predominant or pangastritis (gastritis affecting the corpus more than the antrum or affecting both equally) have a much higher cancer risk than those with an antral predominant gastritis.7 Corpus gastritis that is associated with loss of parietal cell mass (atrophy) and hypo‐ or achlorhydria allows faecal‐type bacterial species to colonise the stomach and it is thought that these organisms may convert ingested nitrate to nitrite and then to carcinogenic N nitroso compounds.6

It is unclear which factors are responsible for the increased risk of cancer in Japan compared with the UK but it would seem a reasonable hypothesis that whatever the underlying cause the Japanese population should have a more severe gastritis, occurring at an earlier age, and with a corpus, rather than an antral, predominant pattern. Therefore, the aim of this study was to evaluate the pattern and severity of gastritis in patients complaining of dyspepsia in the UK and Japan, matched for age.

 

[ginfreely]

hypo‐ or achlorhydria

 

[ginfreely]

Patients and methods​

This was a cross sectional comparative study carried out at the General Infirmary at Leeds and the National Cancer Centre Hospital, Tokyo. Three endoscopists (T Gotoda in Tokyo and L Gatta and G Naylor in Leeds) spent two months training together ensuring concordance of patient selection, recruitment and biopsy sites, processing of histological and microbiological specimens, blood sampling, and storage.

Ethics approval for the study was obtained from the local ethics committees. In Leeds, patients were recruited from a “one stop” dyspepsia clinic. Patients gave written consent on the day if they agreed to enter the trial. In Tokyo, patients attending the National Cancer Centre Hospital endoscopy department specifically for investigation of dyspepsia were similarly approached.

In order to calculate sample size, we identified existing data on gastritis for the UK and Japan. Results from a previous Japanese biopsy study8 had shown normal findings (that is, no evidence of gastritis) in 9.5% of an asymptomatic population aged 20–60+ years. Unpublished data from a Leeds population showed 50.5% of patients in a routine endoscopy series to have normal stomachs. No asymptomatic Western population data existed but as previous studies9,10have demonstrated a lack of correlation between symptoms and histological findings in patients with gastritis, we concluded that this comparison was valid for the purpose of our power calculation. This gave a prevalence of 90.5% and 49.5% for gastritis (of any type) for Japan and Leeds, respectively. Therefore, to detect a difference of 41% in prevalence between the Japanese and English patients with a power of 0.80 and a significance level of 0.05 (alpha two sided), at least 126 patients had to be enrolled from each centre. Twenty one patients from each decennial from 20 to 80 years were therefore recruited from Leeds and Tokyo between May 2000 and April 2002. Inclusion criteria were as follows: age 20–80 years, predominant symptom of epigastric pain and no endoscopic evidence of reflux oesophagitis, peptic ulcer disease, or malignancy (“non ulcer dyspepsia”). Patients were excluded if they had received H pylori eradication therapy in the past or any non‐steroidal anti‐inflammatory drugs, proton pump inhibitors, antibiotics, or bismuth containing compounds in the previous two weeks or H2receptor antagonists in the previous two days. At endoscopy, five gastric mucosal biopsies were taken as detailed below. Further antral and body biopsies were taken for H pylori culture. Blood was also taken for H pylori serology.

 

[ginfreely]

 

[ginfreely]

 

[ginfreely]

Samples were placed in 10% formalin and then embedded in paraffin for sectioning. Three sets of slides were made in each centre; one set was stained with haematoxylin and eosin. These were then assessed by the histopathologist in each centre (Professor M Dixon (MD) in Leeds and Professor T Shimoda (TS) in Tokyo). A second set was sent unstained to the other centre where haematoxylin‐eosin staining took place and the slides were assessed. The pathologists were blinded as to the age and sex of the subjects but because of differences in laboratory identification of the slides, they were aware of their origin. The graded features were scored as absent, mild, moderate, or severe (0–3) according to the updated Sydney system for polymorph activity, chronic inflammation, IM, and atrophy. Thus two sets of histological data were produced on all of the material from Leeds and Tokyo, one from a Japanese pathologist and one from a “Western” pathologist. In addition, two further sets of slides (one each from Leeds and Tokyo) were stained in Leeds by a modified Giemsa for detection of H pylori(MD). Patients were considered positive for histological gastritis (consensus gastritis) only if it was diagnosed by both pathologists.

 

[ginfreely]

Helicobacter pylori​

Three methods were used to detect H pylori: histology, culture, and antibody testing. Antral and body biopsy samples were placed immediately into culture medium and then frozen to −70°C. They were cultured on 10% (vol/vol) blood agar at 37°C in variable atmosphere incubators under microaerobic conditions in the separate centres. Cultures (Tokyo) or biopsies (Leeds) where then transported to a single centre (London) to be typed for CagA status and VacA genotype.

Two serological tests were performed on samples from all patients. Firstly, an enzyme linked immunosorbent assay of IgG antibodies against H pylori (HM‐CAP; Enteric Products Inc., Westbury, New York, USA) with a value of 1.8 taken as positive (sensitivity 98.7%, specificity 100%). Secondly, an immunoblot kit assay that included VacA and CagA antibody testing as well as diagnosing infection (Helocoblot 2.1; Genelabs Diagnostics, Singapore) (sensitivity 96%, specificity 95%).

 

[ginfreely]

Statistical analysis​

Demographic data and pattern of gastritis were compared using Pearson's χ2 test. The Sydney system approach generates four sets of categorical data each, with four possible grades for the five biopsies from individual patients. Statistical analysis of the gastritis data was restricted to those patients in whom both pathologists had agreed the presence of gastritis (consensus gastritis). In order to carry out the statistical comparisons, we converted the grades to numerical values (0–3) and used medians and non‐parametric testing, namely the Mann‐Whitney U test. Interobserver agreement between the two pathologists was examined using kappa statistics, a chance corrected coefficient of agreement. Differences between proportions and their 95% confidence interval (CI) were calculated using the method recommended by Newcombe and Altman.12 Values of p<0.05 were considered significant. These criteria were determined before commencement of the study. Standard statistical packages were used for the analyses (SPSS version 10.1 (SPSS Science, Chicago, Illinois, USA) and Statsdirect (Statsdirect, Cheshire, UK)).

 

[ginfreely]

Results​

Demographics​

Sex, age, and smoking characteristics of the two patient groups are illustrated in table 11.. There was no significant difference in age between the two groups. However, the prevalence of female patients was higher in the Japanese (64.3% (95% CI 55.6–72.1)) than in the UK groups (50% (95% CI 41.4–58.6)), with a difference in prevalence equal to 14.3% (95% CI 2.1–25.9).

 

[ginfreely]

Prevalence of gastritis​

There was consensus agreement between the two pathologists that 76 (60.3% (95% CI 51.6–68.4)) Japanese and 59 (47.6% (95% CI 39.1–56.3)) UK patients had gastritis, with a difference in prevalence equal to 12.7% (95% CI 0.04–24.5; p = 0.0432). Demographic details for these patients are shown in table 11 and details of the consensus diagnosis per decennial in table 22.

 

[ginfreely]

Interobserver agreement between the pathologists​

Sydney system scores were compared. Mean kappa coefficients varied from 0.376 to 0.632 (table 33).). Agreement was poorest for atrophy and greatest for chronic inflammation. Landis and Koch13 suggest that kappa values >0.20 represent “fair” and >0.40 “moderate” agreement. A previous assessment of interobserver variation in the assessment of gastritis,14 using a comparable scoring system, found kappa scores of 0.1–0.29 for atrophy.

 

[ginfreely]

Sydney system

 

[ginfreely]

View attachment 199249

 

[ginfreely]

 

[ginfreely]

 

[ginfreely]

Severity of gastritis​

Total median scores from all five biopsies were compared between the two patient groups for atrophy, IM, activity, and chronic inflammation in subjects with gastritis. The Japanese median atrophy score was 9 compared with 2 in the UK (median difference 6 (95% CI 5–8); Mann‐Whitney U test, p<0.001). Median scores for IM were 1.5 for Japan and 0 for the UK (median difference 0 (95% CI 0–3); Mann‐Whitney U test, p<0.01). Median scores for polymorph activity were 8 for Japan and 4 for UK (median difference 4 (95% CI 2–5); Mann‐Whitney U test, p<0.001). Median scores for chronic inflammation were 13 for Japan and 9 for the UK (median difference 4 (95% CI 2–5); Mann‐Whitney U test, p<0.001). Medians for each decennial are illustrated in fig 22.. It can be seen that for each parameter there was a trend to a greater degree of pathological change in each of the age decennials, except for IM in the 20s and 30s where they were the same.

 

[ginfreely]

Pattern of gastritis​

Cumulative scores for each patient with gastritis were analysed to assess the pattern of inflammation (antral predominant or corpus/pangastritis). The updated Sydney system11 suggests that chronic inflammation (mononuclear cell infiltration) should be used as the principal tool to assess pattern. The reasoning is that this represents the “degree” of gastritis and also does not have the sampling errors that atrophy and IM are prone to.

Therefore, scores from both pathologists for chronic inflammation were added together for biopsies 1 and 2 (antrum) and compared with the equivalent scores from biopsies 4 and 5 (corpus). If the cumulative scores were 2 or more points greater in the antrum biopsies compared with the corpus biopsies, gastritis was classified as “antral predominant”; if they were 2 or more points greater in the corpus it was classified as “corpus predominant”; or if they were within one point of each other as “pangastritis”.

Sixty three per cent of Japanese patients with gastritis had a corpus predominant or pangastritis compared with 36% in the UK (χ2 test, p = 0.003) (fig 33,, table 44)