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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

Gastric intestinal metaplasia, an intermediate step in Correa's cascade of gastric carcinogenesis, is generally regarded as a pre-malignant lesion. Epidemiological studies suggest that patients with intestinal metaplasia have more than a 10-fold increased risk of developing gastric cancer. Within the subclassification of intestinal metaplasia, incomplete or type III intestinal metaplasia appears to be associated with even higher malignant potential. The topographical distribution of intestinal metaplasia may also have prognostic implications. Certain genetic and epigenetic alterations have been demonstrated in gastric intestinal metaplasia which straddle into gastric cancer. These findings suggest that genetic changes occur early in the multistep gastric carcinogenesis process. Unlike Barrett's oesophagus and colonic polyp, which have well-defined surveillance guidelines, there is no widely accepted surveillance programme for gastric intestinal metaplasia. An annual surveillance programme may allow early detection of gastric cancer, which theoretically may improve survival. It remains elusive whether the treatment of Helicobacter pylori infection may reverse gastric intestinal metaplasia or reduce the subsequent risk of cancer development. Further controlled studies with longer follow-up are needed to resolve this controversy. The role of chemo-prophylactic agents, e.g. cyclo-oxygenase-2 inhibitor, should be investigated.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

Gastric cancer is generally believed to develop from a multistep progression from chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and subsequently to cancer. This series of changes in gastric carcinogenesis, often called Correa's cascade,1 is often initiated by Helicobacter pylori infection. In this regard, atrophic gastritis and intestinal metaplasia are considered to be the precursors of gastric cancer, especially for the intestinal type of gastric malignancy. However, not all individuals with intestinal metaplasia will progress to gastric cancer, and the factors governing this progression remain unknown. This review discusses the aetiology, genetic alterations and potential treatment options for gastric intestinal metaplasia.

Histology of intestinal metaplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

Intestinal metaplasia is defined as the replacement of the gastric mucosa by epithelium that resembles the small bowel mucosa (Figure 1). The recognition of small intestinal mucosa in the stomach dates back to the 19th century.2 Intestinal metaplasia results from gastric stem cells that are diverted from proliferation into cells specific to the stomach towards those of the small intestine, such as absorptive cells, goblet cells and Paneth cells. This is usually triggered by persistent irritation to the gastric mucosa, with H. pylori infection being the most important triggering factor.

image

Figure 1. Gastric intestinal metaplasia with prominent goblet cells replacing the normal gastric epithelium. (a) Haematoxylin and eosin stain of gastric intestinal metaplasia. (b) Periodic acid–Schiff–Alcian blue stain with goblet cells highlighted.

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By using various histological and histochemical techniques, intestinal metaplasia can be classified into different subtypes. Several classification systems have been used, but that most widely employed is that proposed by Jass & Filipe.3 In this classification, intestinal metaplasia is classified into complete and incomplete types. The complete type, or type I, is characterized by the presence of absorptive cells, Paneth cells and goblet cells secreting sialomucins, which corresponds to the small intestine phenotype. The incomplete type, which encompasses types II and III, is characterized by the presence of columnar and goblet cells secreting sialomucins and/or sulphomucins. Type II secretes neutral and acidic sialomucins and type III produces sulphomucins. Sulphomucins can be differentiated from sialomucins using high iron diamine/Alcian blue staining. Other features associated with type III intestinal metaplasia include prominent glandular distortion and the absence of Paneth cells.

Recently, it has been found that the expression of mucin core proteins (MUC) is altered in different types of intestinal metaplasia. Whilst all types of intestinal metaplasia show de novo expression of MUC2,4 the expression of MUC1, MUC5AC and MUC6 is decreased in the complete type of intestinal metaplasia, but preserved in the incomplete type.5

Epidemiology of intestinal metaplasia and gastric cancer

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

The classification of intestinal metaplasia into different subtypes carries prognostic significance. Based on retrospective data,6, 7 complete or type I intestinal metaplasia is associated with a low risk of gastric cancer, whereas type III (colonic) intestinal metaplasia has the strongest association with cancer. In a large cohort study from Slovenia with 10 years of follow-up, patients with intestinal metaplasia had an overall 10-fold increased risk of gastric cancer compared with those without intestinal metaplasia.7 Patients with type III intestinal metaplasia had a four-fold increased risk of cancer development compared with those with type I. In a cohort study from China that involved more than 3000 subjects with a follow-up of 4–5 years, the odds ratio of progression from intestinal metaplasia to gastric cancer varied from 17 to 29. The risk was particularly high for those with more advanced baseline histological lesions, such as the presence of dysplasia.8 In a recent Japanese study, the relative risk of progression from intestinal metaplasia to cancer was 6.4 (95% confidence interval, 2.6–16.1).9

However, the association between the risk of gastric cancer development and intestinal metaplasia subtypes is not universally accepted.10 The subtyping of intestinal metaplasia is sometimes difficult in superficial endoscopic biopsy. Alternatively, it has been proposed that the distribution of intestinal metaplasia, rather than the intestinal metaplasia subtype, may be of higher predictive value of the cancer risk. In this regard, Cassaro et al. showed that intestinal metaplasia involving the lesser curvature from the cardia to the pylorus or the entire stomach was associated with a higher risk of gastric cancer than focal or antral-predominant intestinal metaplasia.11 Moreover, they noticed that the presence of incomplete-type metaplasia correlated with the extent of intestinal metaplasia in the stomach.

Aetiology of intestinal metaplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

The emergence of intestinal metaplasia in the gastric mucosa is believed to be the result of an adaptive response and selection pressures as a reaction to an adverse environment.12H. pylori infection, smoking and high salt intake are often implicated as aetiological factors. Nonetheless, the mechanisms leading to these phenotypic changes remain contentious.

There is little doubt that chronic H. pylori infection is the most important aetiological agent for the development of intestinal metaplasia. On the other hand, H.pylori infection has been causally related to the development of peptic ulcers. It is well-recognized that patients with duodenal ulcer are at a lower risk of developing gastric cancer.9, 13 Along the same line, it was found in a cross-sectional study that those with duodenal ulcer disease were less likely to have intestinal metaplasia and glandular atrophy.14 Thus, H. pylori infection appears to produce two divergent clinical outcomes, namely duodenal ulcer or gastric ulcer/cancer. These divergent clinical outcomes in response to the same infection can be reconciled by the understanding of the topographical distribution of H. pylori-associated gastritis. Duodenal ulcer patients are characterized by the antral-predominant, non-atrophic type of gastritis, whereas gastric cancer patients tend to develop multifocal or extensive corpus atrophic gastritis. Nonetheless, the exact reason leading to these two phenotypic characteristics remains elusive.

Recently, El-Omar et al. have demonstrated that the polymorphisms in interleukin-1β, a pro-inflammatory cytokine as well as a potent inhibitor of gastric acid secretion, may underlie the predisposition to atrophic gastritis development, and hence the risk of gastric cancer in susceptible individuals.15 However, this finding needs to be confirmed in other ethnic groups. On the other hand, environmental factors, diet in particular, have been extensively studied. It has been shown in both human and animal studies that a high-salt diet is associated with a higher risk of atrophic gastritis.16, 17 Salt has been shown to facilitate the colonization of H.pylori in mice and may therefore perpetuate chronic active gastritis and glandular atrophy.18 Bacterial genotypes may also influence H. pylori colonization. In a study from Portugal and Columbia, H. pylori cagA+, vacA s1 and m1 genotypes were associated with a higher bacterial density, higher degrees of lymphocytic infiltrates, atrophy and intestinal metaplasia.19 Furthermore, the presence of H. pylori adherence factor blood group antigen binding adhesin (babA2) is detected more frequently in patients with intestinal metaplasia.20 All in all, the interplay between host, environmental and bacterial factors determines the gastric histology.

Cellular kinetic changes in intestinal metaplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

The disruption of cellular kinetics plays an instrumental role in cancer development. Inhibition of apoptosis and/or increased proliferation leads to cellular accumulation and the development of neoplasms. H. pylori infection induces cellular apoptosis and proliferation in normal gastric epithelium.21–23 This alteration is reversed by the eradication of H. pylori infection. However, we have recently demonstrated that the apoptotic index is significantly attenuated in H. pylori-associated intestinal metaplasia.24 Whilst proliferation was increased in both intestinal metaplasia and non-intestinal metaplasia regions, the level of apoptosis was significantly lower in the former. Thus, the apoptotic index/proliferation index ratio was markedly reduced in intestinal metaplasia, favouring cellular accumulation and possibly neoplasm formation.

Genetic alterations in intestinal metaplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

The imbalance in the cellular kinetics of gastric intestinal metaplasia could be attributed to genetic and epigenetic changes. Mutation in p53 is one of the most common genetic alterations found in human cancer, including gastric cancer. Shiao et al. examined 12 cases of gastric cancer and reported p53 mutations in 50% of the adjacent intestinal metaplasia.25 Apart from sequencing of the p53 gene, mutant p53 can also be detected by immunohistochemistry due to its long half-life. Using immunohistochemistry techniques, the accumulation of p53 proteins has been demonstrated in intestinal metaplasia, particularly in type III.26

Another reason accounting for the inhibition of apoptosis in gastric intestinal metaplasia may be related to the expression of cyclo-oxygenase-2. Cyclo-oxygenase is a key enzyme responsible for the conversion of arachidonic acid into prostaglandins. The cyclo-oxygenase-1 isoform is believed to be constitutively expressed, whereas the cyclo-oxygenase-2 isoform is inducible, particularly in the presence of inflammation. Interestingly, over-expression of cyclo-oxygenase-2 is also observed in many neoplastic conditions, including colon, breast, pancreas and stomach.27In vitro experiments have shown that cyclo-oxygenase-2 expression is associated with resistance to apoptosis and an increase in metastatic potential.28, 29 The expression of cyclo-oxygenase-2 is negligible in normal human stomach. However, cyclo-oxygenase-2 expression is up-regulated in H. pylori-associated gastritis.30 By using immunohistochemistry and in situ hybridization, we have shown that cyclo-oxygenase-2 is strongly expressed in intestinal metaplasia.31 One might argue that cyclo-oxygenase-2 expression is merely a result of H. pylori-induced inflammation in the gastric epithelium. Yet, even after successful H. pylori eradication, cyclo-oxygenase-2 expression persisted in the gastric foveolar epithelium.31 As cyclo-oxygenase-2 expression has been implicated in various neoplastic diseases, including colorectal cancer and pancreatic cancer, its role in gastric carcinogenesis deserves further investigation.

Microsatellite instability is a form of genetic aberration typically found in patients with hereditary, non-polyposis, colorectal cancer syndrome. Most of these patients suffer from germline mutation of the DNA mismatch repair genes, including hMLH1 and hMSH2. Apart from colorectal cancer, microsatellite instability has also been demonstrated in a subgroup of gastric cancers.32 Moreover, microsatellite instability can be detected in gastric intestinal metaplasia obtained from both cancer and non-cancer patients.33 In contrast to patients with hereditary, non-polyposis, colorectal cancer syndrome, germline mutation is rarely detected in gastric carcinoma with microsatellite instability. Instead, the instability can be accounted for by the transcriptional silencing of the DNA mismatch repair gene (hMLH1) by promoter hypermethylation.34 In addition to gastric cancer, Kang et al. recently demonstrated the presence of promoter hypermethylation of hMLH1 in gastric intestinal metaplasia.35 In addition, they detected hypermethylation of other genes, including p16, DAP-kinase, THBS1 and TIMP-3, in gastric intestinal metaplasia. Their findings suggest that hypermethylation occurs early in the multistep gastric carcinogenesis pathway and may play an instrumental role in gastric cancer development.

Gastric cancer cells express a broad spectrum of growth factors and cytokines. Of these, transforming growth factor-α and epidermal growth factor receptor-I have been reported in pre-neoplastic gastric lesions. Filipe et al. found an increased expression of these two growth factors in the intestinal metaplasia of patients with gastric cancer by immunohistochemistry and western blotting.36 Cyclins, cyclin-dependent kinases and their inhibitors regulate cell growth, differentiation, survival and cell death. We have recently demonstrated that the over-expression of cyclin D2 and diminished p27 expression are detected in H. pylori-associated intestinal metaplasia37(Figure 2). Notably, these aberrant expressions could be restored by H. pylori eradication.

image

Figure 2. The multistep gastric carcinogenesis pathway. Helicobacter pylori infection is believed to trigger this cascade. The genetic and epigenetic alterations demonstrated in various stages of the gastric carcinogenesis pathway are shown. COX-2, cyclo-oxygenase-2 ; EGFR, epidermal growth factor receptor; MSI, microsatellite instability ; TGF, transforming growth factor.

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Is there a need for surveillance?

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

Unlike Barrett's oesophagus and colonic adenoma, there are no guidelines on the surveillance for gastric intestinal metaplasia. The potential benefit of any surveillance programme has yet to be proven. This is further complicated by the variable gastric cancer incidences in different geographical regions, which render the formulation of recommendations difficult. Moreover, gastric intestinal metaplasia may be difficult to recognize endoscopically when compared with pre-malignant oesophageal and colonic lesions (Figure 3). Even with the chromoendoscopic technique, e.g. by using methylene blue (methylthioninium chloride) or indigocarmine, identification of intestinal metaplasia in the stomach can be difficult.38

image

Figure 3. Endoscopic appearance of extensive intestinal metaplasia in the angular incisura.

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Although the diagnosis and surveillance of intestinal metaplasia in the non-cancerous stomach can be difficult, the diagnosis of early cancer in patients known to have intestinal metaplasia seems to be a different issue. In a recent report from the UK,39 it was found that annual endoscopic surveillance could potentially detect most new gastric cancers at an early stage. The 5-year survival of gastric cancer detected by surveillance was significantly higher than that detected at open access endoscopy (50% vs. 10%). These promising results support the implementation of structured screening in those individuals with intestinal metaplasia that is at risk of developing into cancer. Nonetheless, in most developed countries which could potentially provide the infrastructure for the endoscopic surveillance of gastric cancer, the incidence of the disease has probably decreased so much that any screening programme is difficult to justify.

Is intestinal metaplasia reversible?

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

If an intensive surveillance programme for early gastric cancer is not feasible, what of chemo-prevention therapy with the aim to halt the progression of intestinal metaplasia into gastric cancer? Despite the strong causality link between H. pylori infection and gastric cancer, evidence to show that the treatment of H. pylori infection could actually prevent gastric cancer is lacking. These studies are extremely difficult to perform due to the long lead time in gastric cancer development. In order to examine the potential benefits of H. pylori eradication, studies were designed to investigate the regression of pre-cancerous changes, such as intestinal metaplasia and atrophy, as surrogate end-points of treatment success. Nonetheless, there are conflicting data in the literature due to the inconsistency in the interpretation of histological grading, sampling errors and different study populations. A summary of these results is presented in Table 1.40–44 Most Japanese studies reported a favourable outcome. Uemura et al. reported a significant improvement of antral and corpus intestinal metaplasia 6 months after the eradication of H. pylori infection in 65 patients with early gastric cancer who had received endoscopic mucosal resection.40 Another uncontrolled study from Japan compared the histological changes of 163 dyspeptic patients who had received anti-Helicobacter therapy.44 Of the 115 patients who had successful eradication of H. pylori, the severity of intestinal metaplasia in the antrum improved in 28 (61%) of 46 patients after 1 year. However, this improvement was based on the result of a single biopsy specimen that was subject to a major sampling error.

Table 1.  Effect of Helicobacter pylori eradication on changes of intestinal metaplasia (IM)
ReferenceCountryNo. of patientsDesignFollow-up (months)IM changes
  1. RR, relative risk.

Van der Hulst et al.41The Netherlands155 (122 cagA+ vs. 33 cagA–)Uncontrolled12No change (regardless of cagA status)
Ohkusa et al.44Japan163 (115 H. pylori-eradicated vs. 46 failed eradication)Uncontrolled12IM improved in 28/46
Uemura et al.40Japan132 early gastric cancer Non-randomized (65 eradicated vs. 67 no eradication) 6Significant improvement in antrum (from 1.3 to 0.9) and corpus (from 0.7 to 0.46)
Sung et al.43China587Randomized control (eradication vs. placebo)12No change
Correa et al.42Columbia976 (631 completed trial)Randomized control (eight treatment groups)72RR for IM regression = 3.1 (1.0–9.3)

Recently, the results of two large-scale randomized controlled studies have been published. Correa et al. reported their 6-year follow-up results in Colombian patients.42 In their study, 976 patients were randomized to receive eight different treatments that included vitamin supplements and anti-Helicobacter therapy alone or in combination vs. placebo. Of the 631 patients who completed the trial, 79 received anti-Helicobacter therapy and there was a borderline regression of intestinal metaplasia when compared with placebo (15% vs. 6%; relative risk, 3.1; 95% confidence interval, 1.0–9.3). Interestingly, supplementation with β-carotene or ascorbic acid resulted in a similar degree of improvement in intestinal metaplasia (20% and 19%). However, the combinations of anti-H. pylori therapy and vitamins conferred no extra benefits to gastric histology. On the other hand, the progression rate of intestinal metaplasia was comparable irrespective of the treatment received. The progression rate was 23% for placebo, whereas 17% of eradicated patients showed progression of intestinal metaplasia. This inconsistent result suggests that anti-Helicobacter treatment may not necessarily halt intestinal metaplasia progression. Therefore, as stated in the editorial accompanying this paper, these results should be interpreted with caution.45 We have conducted another interventional study in the Shandong Province of northern China in which 587 H. pylori-infected subjects were randomized to receive anti-Helicobacter therapy or placebo.43 At 1 year, we found that there was no significant improvement in intestinal metaplasia with anti-Helicobacter therapy compared with placebo. However, patients with persistent infection had significant deterioration of corpus atrophy at 1 year. It thus appears that the eradication ofH. pylori infection may at least slow down the progression of atrophy, but fails to reverse these changes at 1 year. Recently, we have completed our 5-year follow-up of these patients and have found that patients who had successful eradication of H. pylori had significantly reduced progression of intestinal metaplasia than those with persistent infection. Gastric atrophy also regressed after the eradication of H. pylori.46 These results thus favour the eradication of H. pylori in the prevention of intestinal metaplasia progression.

In a small randomized trial, it was found that patients given 6 months of ascorbic acid following H. pylori eradication showed significant improvement of intestinal metaplasia when compared with those given placebo.47 Apart from H. pylori eradication and vitamin supplementation, another attractive chemo-preventive agent is non-steroidal anti-inflammatory drugs (NSAIDs). Epidemiological data suggest a negative correlation between the use of NSAIDs or aspirin and gastric cancer. A recent case–control study showed that the continuous use of NSAIDs was associated with a reduction in the risk of gastric cancer (odds ratio, 0.51; 95% confidence interval, 0.33–0.79).48 Due to the gastric toxicity associated with conventional NSAIDs, this approach may not be clinically feasible. With the recent availability of cyclo-oxygenase-2 inhibitors, it is tempting to test whether this agent can be used in the chemo-prevention of gastric cancer. Preliminary data on the use of cyclo-oxygenase-2 inhibitors in patients with familial adenomatous polyposis have provided encouraging results.49 However, whether this can be translated into the chemo-prevention of gastric intestinal metaplasia awaits further study.

If intestinal metaplasia is perceived as an altered gastric phenotype resulting from the somatic mutation of stem cells or epigenetic changes in progenitor cells, it would be anticipated that these changes may not be reversible at all despite the eradication of H. pylori. Future studies with a longer follow-up and a larger sample size may be able to deliver the final verdict on whether intestinal metaplasia has in fact passed the ‘point of no return’. Nonetheless, the changes in the gastric environment associated with the eradication of H. pylori, such as the resolution of inflammation, elimination of DNA damage50 and reduction of proliferation,24 may be more important in the prevention of gastric cancer than the actual reversal of intestinal metaplasia.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References

Based on compelling epidemiological data and molecular changes detected in gastric intestinal metaplasia, there is little doubt that intestinal metaplasia is a pre-malignant gastric lesion. However, not all patients with intestinal metaplasia will progress to gastric cancer. Future research should be directed at the identification of those who are at risk of further development, so that intensive surveillance programmes can be implemented. Although the use of anti-Helicobacter therapy in the treatment of intestinal metaplasia appears to be promising, long-term results are lacking. The role of other chemo-preventive agents should be determined.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Histology of intestinal metaplasia
  5. Epidemiology of intestinal metaplasia and gastric cancer
  6. Aetiology of intestinal metaplasia
  7. Cellular kinetic changes in intestinal metaplasia
  8. Genetic alterations in intestinal metaplasia
  9. Is there a need for surveillance?
  10. Is intestinal metaplasia reversible?
  11. Conclusions
  12. Acknowledgements
  13. References
  • 1
    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52: 673540.
  • 2
    Stemmermann GN. Intestinal metaplasia of the stomach. Cancer 1994; 74: 55664.
  • 3
    Jass JR, Filipe MI. Sulphomucins and precancerous lesions of the human stomach. Histopathology 1980; 4: 2719.
  • 4
    Ho SB, Shekels LL, Toribara NW, et al. Mucin gene expression in normal, pre-neoplastic and neoplastic human gastric epithelium. Cancer Res 1995; 55: 268190.
  • 5
    Reis CA, David L, Correa P, et al. Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC and MUC6) expression. Cancer Res 1999; 59: 10037.
  • 6
    Matsukura N, Suzuki K, Kawachi T, et al. Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas. J Natl Cancer Inst 1980; 65(2): 23140.
  • 7
    Filipe MI, Munoz N, Matko I, et al. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 1994; 57: 3249.
  • 8
    You WC, Li JY, Blot WJ, et al. Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer. Int J Cancer 1999; 83(5): 6159.
  • 9
    Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001; 345: 7849.
  • 10
    Genta RM, Rugge M. Review article: pre-neoplastic states of the gastric mucosa—a practical approach for the perplexed clinician. Aliment Pharmacol Ther 2001; 15(Suppl. 1): 4350.
  • 11
    Cassaro M, Rugge M, Gutierrez O, et al. Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol 2000; 95: 14318.
    Direct Link:
  • 12
    Dixon MF. Prospects for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia. Gut 2001; 49: 24.
  • 13
    Hansson LE, Nyren O, Hsing AW, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. NEngl J Med 1996; 335: 2429.
  • 14
    Tsukui T, Kashiwagi R, Sakane M, et al. Aging increase and duodenal ulcer reduce the risk of intestinal metaplasia of the gastric corpus in Japanese patients with dyspepsia. J Gastroenterol Hepatol 2001; 16: 1521.
  • 15
    El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000; 404: 398402.DOI: 10.1038/35006081
  • 16
    Correa P, Haenszel W, Cuello C, et al. A model for gastric cancer epidemiology. Lancet 1975; 2(7924): 5860.
  • 17
    De Koster E, Buset M, Fernandes E, et al. Helicobacter pylori: thelink with gastric cancer. Eur J Cancer Prev 1994; 3: 24757.
  • 18
    Fox JG, Dangler CA, Taylor NS, et al. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res 1999; 59: 48238.
  • 19
    Nogueira C, Figueiredo C, Carneiro F, et al. Helicobacter pylori genotypes may determine gastric histopathology. Am J Pathol 2001; 158: 64754.
  • 20
    Prinz C, Schoniger M, Rad R, et al. Key importance of the Helicobacter pylori adherence factor blood group antigen binding adhesin during chronic gastric inflammation. Cancer Res 2001; 61: 1903–9.
  • 21
    Moss SF, Calam J, Agarwal B, et al. Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 1996; 38: 498501.
  • 22
    Peek RM, Moss SF, Tham KT, et al. Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst 1997; 89: 8638.
  • 23
    Leung WK, To KF, Chan FKL, Lee TL, Chung SCS, Sung JJY. Interaction of H. pylori and NSAID on gastric epithelial cell apoptosis and proliferation: implications on ulcerogenesis. Aliment Pharmacol Ther 2000; 14: 87985.
  • 24
    Leung WK, Yu J, To KF, et al. Apoptosis and proliferation in Helicobacter pylori-associated gastric intestinal metaplasia. Aliment Pharmacol Ther 2001; 15: 146772.
  • 25
    Shiao YH, Rugge M, Correa P, et al. p53 alteration in gastric precancerous lesions. Am J Pathol 1994; 144: 5117.
  • 26
    Wu MS, Shun CT, Lee WC, et al. Overexpression of p53 in different subtypes of intestinal metaplasia and gastric cancer. Br J Cancer 1998; 78: 9713.
  • 27
    Dubois RN. Review article: cyclooxygenase—a target for colon cancer prevention. Aliment Pharmacol Ther 2000; 14(Suppl. 1): 647.
  • 28
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2. Cell 1995; 83: 493501.
  • 29
    Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997; 94: 333640.
  • 30
    Chan FK, To KF, Ng YP, et al. Expression and cellular localization of COX-1 and -2 in Helicobacter pylori gastritis. Aliment Pharmacol Ther 2001; 15: 18793.
  • 31
    Sung JJY, Leung WK, Go MYY, et al. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol 2000; 157: 72935.
  • 32
    Yamamoto H, Perez-Piteira J, Yoshida T, et al. Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features. Gastroenterology 1999; 116: 134857.
  • 33
    Leung WK, Kim JJ, Kim JG, et al. Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol 2000; 156(2): 53743.
  • 34
    Leung SY, Yuen ST, Chung LP, et al. hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 1999; 59: 15964.
  • 35
    Kang GH, Shim YH, Jung HY, et al. CpG island methylation in premalignant stages of gastric carcinoma. Cancer Res 2001; 61: 284751.
  • 36
    Filipe MI, Osborn M, Linehan J, et al. Expression of transforming growth factor alpha, epidermal growth factor receptor and epidermal growth factor in precursor lesions to gastric carcinoma. Br J Cancer 1995; 71: 306.
  • 37
    Yu J, Leung WK, Ng EKW, et al. Effect of H. pylori eradication on expression of cyclin D2 and p27 in gastric intestinal metaplasia. Aliment Pharmacol Ther 2001; 15: 150512.
  • 38
    Morales TG, Sampliner RE, Camargo E. Inability to noninvasively diagnose gastric intestinal metaplasia in Hispanics or reverse the lesion with Helicobacter pylori eradication. J Clin Gastroenterol 2001; 32: 4004.DOI: 10.1097/00004836-200105000-00008
  • 39
    Whiting JL, Sigurdsson A, Rowlands DC, et al. The long term results of endoscopic surveillance of premalignant gastric lesions. Gut 2002; 50: 37881.DOI: 10.1136/gut.50.3.378
  • 40
    Uemura N, Mukai T, Okamoto S, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev 1997; 6: 63942.
  • 41
    Van der Hulst RWM, Van Der Ende A, Dekker FW, et al. Effect of Helicobacter pylori eradication on gastritis in relation to cagA: a prospective 1-year follow-up study. Gastroenterology 1997; 113: 2530.
  • 42
    Correa P, Fontham ETH, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter therapy. J Natl Cancer Inst 2000; 92: 18818.
  • 43
    Sung JJY, Lin SR, Ching JYL, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology 2000; 119: 714.
  • 44
    Ohkusa T, Fujiki K, Takashimizu I, et al. Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Ann Intern Med 2001; 134: 3806.
  • 45
    Blot WJ. Preventing cancer by disrupting progression of precancerous lesions. J Natl Cancer Inst 2000; 92: 18689.
  • 46
    Sung JJY, Lin SR, Leung WK, et al. Does eradication of H.pylori prevent deterioration of gastric atrophy and intestinal metaplasia? A 5-year follow-up. Gastroenterology 2002; 122: Abstract.
  • 47
    Zullo A, Rinaldi V, Hassan C, et al. Ascorbic acid and intestinal metaplasia in the stomach: a prospective randomized study. Aliment Pharmacol Ther 2000; 14: 13039.DOI: 10.1046/j.1365-2036.2000.00841.x
  • 48
    Langman MJ, Cheng KK, Gilman EA, et al. Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database. Br Med J 2000; 320: 16426.
  • 49
    Steinbach G, Lynch PM, Philips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 194652.
  • 50
    Nardone G, Staibano S, Rocco A, et al. Effect of Helicobacter pylori infection and its eradication on cell proliferation, DNA status, and oncogenic expression in patients with chronic gastritis. Gut 1999; 44: 78999.