We found that the proportion of gastrectomies with carcinoma showing EIM was higher among populations with a higher gastric cancer risk (Japanese and Chileans in the Pacific basin) than in those with a lower cancer risk (North Americans, Mexicans, and Swedes in the Atlantic basin). The percentage of cases with EIM was significantly higher in specimens with IC than in those with DC in all cities investigated, indicating that EIM is mostly associated with the development of gastric carcinoma of that particular phenotype in both basins. Nonetheless, 13% of the specimens in elderly patients with DC in the Atlantic basin, in addition to 46% of elderly patients with DC in the Pacific basin, also had EIM. Thus, the possibility that EIM may also precede the development of a substantial number of gastric carcinomas of diffuse type (particularly in high cancer incidence areas) should be entertained. This possibility has not received much attention in the literature.
It should be stressed that in the Atlantic basin 25.0% of the gastrectomies with carcinoma had no IM and that 7.2% of the specimens with miscellaneous diseases showed EIM. As a comparison, 10.8% of the specimens with carcinoma in the Pacific basin had no IM, whereas 10.6% of gastrectomies with miscellaneous diseases displayed EIM. These results clearly indicate that the growing tumour does not elicit EIM, and that some carcinomas evolve in the absence of IM. Whether patients with miscellaneous gastric diseases having EIM are at future risk of developing gastric carcinoma could not be answered by our study.
To investigate the validity of the results obtained in patients with carcinoma, one important confounding factor was explored; namely, the number of sections obtained for each gastrectomy specimen. The mean number of sections obtained in specimens with carcinoma was higher in the Pacific basin (mean, 21.0 sections/specimen) than in the Atlantic basin (mean, 10.5). Consequently, it is possible that the higher number of sections obtained at some hospitals bordering the Pacific basin may have contributed to detecting a higher proportion of specimens with EIM. However, the higher number of sections in specimens from cities with a high gastric cancer incidence cannot totally explain the differences found, because a high proportion of specimens with EIM was found in cities with a relatively low number of sections/specimen (table 2). Environmental factors could be an explanation. In this respect, it has been postulated that environmental carcinogens encourage the development of gastric carcinoma.2,3,29–32
Hot food and/or hot fluids, bacteria, or viruses could induce chronic inflammatory changes in susceptible individuals and subsequently IM, thus rendering the gastric mucosa more vulnerable to environmental carcinogens. It is not unconceivable that environmental carcinogens might alter the gastric mucosa and contribute to the development of EIM before cancer ensues. Because gastric carcinoma is more frequent in the Pacific basin, it is possible that environmental carcinogens are either more powerful in that area, or that for unknown reasons the gastric mucosa of their inhabitants is more vulnerable to carcinogens. Ethnicity appears not to influence the presence of EIM; specimens from populations of different ethnicity dwelling in the same oceanic basin, such as Chileans and Japanese had the highest frequency of EIM in the entire survey.
Some authors have reported that IM is found in biopsies taken exclusively from endoscopically abnormal areas,33
whereas other authors recommend harvesting gastric biopsies from pre-established mucosal sites.34
In this respect, the Sydney system35
for the grading of gastritis has provided practical guidelines for optimal biopsy sampling of the gastric mucosa. However, using the Sydney system’s recommendations, El-Zimaity and Graham9
found that IM was missed in more than 50% of biopsies from “Sydney” sites in patients with confirmed gastric IM on multiple site sampling. They showed that the detection of IM increased from 48% to 75% when the biopsy sites were changed from the Sydney system.9
In addition, they concluded that the minimum number of biopsies needed to identify IM should probably be eight, and emphasised that current and future studies using the Sydney system as a basis for detecting gastric IM are probably not reliable.9
More recently Khakoo and colleagues36
and Dursun and colleagues37
also found that the endoscopic division of the Sydney classification was unable to clarify the reporting of gastritis and IM. From the above, it appears that sampling gastric biopsies from endoscopically abnormal areas,33,38
or from pre-established mucosal sites,34
may be insufficient for calculating the prevalence of IM and estimating the possible cancer risk of IM in long follow up studies.39
The conflicting results may partly be explained by confounding factors, such as the focal distribution of IM in many cases, and by the difficulty in diagnosing IM at gross examination, as shown by Stemmermann and Hayashi10
and by Kumagae et al
Another confounding factor not mentioned in the literature is the difference in proficiency among endoscopists in various countries in detecting gastric IM. Because endoscopists are instrumental in providing the material for histological evaluation, it is conceivable that the conflicting findings at histology could partly be explained by differences in the skill of endoscopists in detecting IM areas. Moreover, the protocols received at the pathology department are often incomplete, providing no information on whether the biopsies were taken from a single “spot”, from one of many spots, or from one or several extensive mucosal areas. The difficulty in calculating the risk of IM in biopsy specimens can be exemplified as follows: patients showing at histology either a minimal spot of IM (with or without histochemically abnormal mucins7,8
) or with extensive IM areas will be classified as having IM. The question arises: which patients are at risk of developing carcinoma; those with a single, minimal spot of IM, perhaps with histochemically abnormal mucins, or those with extensive IM? At this stage, it should be pointed out that recently the importance of the histochemical constituents of the mucin in IM in gastric biopsies7,8
has repeatedly been challenged.39–41
Hence, the limitations of gastric biopsies in assessing: (1) the extension of gastric IM and (2) the possible cancer risk in long term follow up studies have been emphasised in our study.
Therefore, we planned our present investigation with an awareness of the limitations of gastric biopsies in assessing the magnitude of IM in the gastric mucosa in individual patients. For that purpose, gastrectomy specimens with carcinoma and with miscellaneous diseases (control cases) were investigated. We soon realised that the method had several pitfalls because the size of the resected specimens varied with the topographical location of the tumour, with the size of the tumour removed, and with the resection technique used by individual surgeons within the same hospital, between different hospitals, and between different countries. In addition, the number of blocks taken from the resected specimens by pathologists at various hospitals also varied. Nevertheless, despite these limitations, the method described herein enabled us to compare the prevalance of gastric IM in populations dwelling in disparate geographical regions at the rim of the Atlantic and the Pacific basins.
It should be mentioned that this work was initiated in 1981—before the discovery of H pylori
by Warren and Marshall.42
In our subsequent studies, we did not investigate H pylori
, mainly because H pylori
specific stains were not performed in the hospitals contributing to this survey. In addition, the organism is known to be absent in cases with IM for a variety of reasons, namely: alterations in the pH of the mucosa (from neutral mucin to acid mucins secreted by goblet cells), mucosal atrophy, and mucosal hypoacidity (often found in patients with gastric cancer). Another factor known to influence the presence of H pylori
after resection is the flushing of the specimen with saline, followed (in the past) by the intense light exposure required for photographic documentation. This leads to autolytic necrosis (as a result of a heating and drying effect) of the superficial cell layer of the mucosa, where H pylori
“The differences in the prevalence of extensive intestinal metaplasia in gastrectomies appear to be unrelated to ethnicity but linked to the patient’s geographical habitat”
Shousha and colleagues43
found a significantly higher prevalence of IM in gastric biopsies from British patients than in those from Yemeni patients, despite the fact that the Yemeni patients had a significantly higher prevalence of H pylori.
Our own studies of gastric biopsies from elderly Swedish patients with H pylori
showed only occasional foci of IM. It has been shown that a particular combination of bacterial and host genotypes is required to define high cancer risk in H pylori
More recent developments have shown that there are ethnic differences in H pylori
induced gastritis between Asian and Western populations.46
Working with a transgenic mouse system we recently found that gastric tumours concurred with antral IM.47
Apparently, particular alterations in the genome in transgenic mice are able to induce gastric IM without the participation of H pylori
Thus, the relation between H pylori
and the development of IM has not yet been fully clarified. The mere presence of H pylori
is not sufficient to infer that these bacteria are responsible for gastric carcinogenesis. In retrospect, and based on the aforementioned pitfalls in the handling and processing of resected specimens, and on more recent knowledge, searching for H pylori
in our survey would probably have led to questionable results and to unreliable suppositions.
In the Pacific basin, a similarly high prevalence of EIM was found in gastrectomies from Japanese and Chilean individuals (who have different ethnicities). In the Atlantic basin, populations such as those of London and Florence had a similar prevalence of cases with EIM to that of Iceland (a population with a purer ethnicity). However, these populations in the Atlantic basin had a much lower percentage of cases with EIM than was seen in Japan or in Chile in the Pacific basin. Interestingly, the proportion of gastrectomies with EIM was significantly higher in Vancouver than in New York and in Santiago de Chile than in Buenos Aires, despite the fact that these populations reside at approximately the same geographical latitude, but in different basins. Hence, the differences appear to be unrelated to ethnicity but linked to the patient’s geographical habitat.
Take home messages
- The following differences in the occurrence of gastric intestinal metaplasia (IM) were found in our survey between dwellers of the Pacific and the Atlantic basins
- The proportion of gastrectomies with extensive IM (EIM) was significantly higher in the Pacific than in the Atlantic basin, despite the fact that patients undergoing surgery for gastric carcinoma were older in the Atlantic than in the Pacific basin
- The proportion of specimens with EIM among the elderly was significantly higher in those with intestinal carcinoma (IC) than in those with diffuse carcinoma (DC)
- EIM in the Pacific basin was more widely spread in the gastric mucosa from individual specimens with IC than those with DC
- The proportion of gastrectomies with EIM in Vancouver was higher than in New York and in Santiago de Chile than in Buenos Aires, despite the fact that those populations reside at approximately the same geographical latitude, but in different basins
- IM was totally absent in nearly 22% of specimens with carcinoma, but it was present in 11% of specimens with miscellaneous gastric diseases, strongly suggesting that EIM is not initiated by a synchronously growing carcinoma
- The Japanese (the population with the highest incidence of gastric cancer) had atypical mitoses in areas with EIM far from the tumour. This important histological parameter has been ignored in discussions aimed at disclosing the gastric cancer risk of IM. It remains to be elucidated whether atypical mitoses are one of the alterations required for the evolution of EIM towards gastric dysplasia and carcinoma in populations at risk
A pertinent question would be: does EIM per se increase the gastric cancer risk or are other parameters also involved? During the course of our work, we noticed atypical mitoses in gastrectomies from Japanese patients.49,50
These were found in areas with EIM far from the carcinoma. Because atypical mitoses reflect mutated cells, it appears that cellular mutation(s) are important in the evolution of EIM towards dysplasia/carcinoma in the Japanese. Those speculations fit well with the hypothesis of gastric carcinogenesis proposed by Correa,51
who suggested that mutagenic carcinogens in the microenvironment trigger the sequence of cellular mutations leading to gastric carcinoma.