Intestinal metaplasia and gastric carcinogenesis

Review article: intestinal metaplasia and gastric carcinogenesis

W. K. LEUNG & J. J . Y. SUNG

Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital,

The Chinese University of Hong Kong, Hong Kong, China

Accepted for publication 1 April 2002

SUMMARY

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 survi-

val. It remains elusive whether the treatment of

Helicobacter pylori infection may reverse gastric intesti-

nal 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-oxyge-

nase-2 inhibitor, should be investigated.

INTRODUCTION

Gastric cancer is generally believed to develop from a

multistep progression from chronic gastritis, atrophic

gastritis, intestinal metaplasia, dysplasia and subse-

quently 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 con-

sidered 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

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.

� 2002 Blackwell Science Ltd 1209

Correspondence to: Professor J. J. Y. Sung, Department of Medicine and

Therapeutics, Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin,

Hong Kong, China.E-mail: [email protected]

Aliment Pharmacol Ther 2002; 16: 1209–1216.

By using various histological and histochemical tech-

niques, 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 differen-

tiated from sialomucins using high iron diamine ⁄Alcian

blue staining. Other features associated with type III

intestinal metaplasia include prominent glandular dis-

tortion 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

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 intesti-

nal 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 invol-

ving 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

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.

1210 W. K. LEUNG & J. J . Y. SUNG

� 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 1209–1216

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

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.12 H. 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 develop-

ment 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 ⁄ can-

cer. 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 multi-

focal 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-1b, 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 find-

ing 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 infil-

trates, atrophy and intestinal metaplasia.19 Further-

more, 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

The disruption of cellular kinetics plays an instrumental

role in cancer development. Inhibition of apoptosis

and ⁄or increased proliferation leads to cellular accu-

mulation and the development of neoplasms. H. pylori

infection induces cellular apoptosis and proliferation in

normal gastric epithelium.21–23 This alteration is re-

versed by the eradication of H. pylori infection. How-

ever, we have recently demonstrated that the apoptotic

index is significantly attenuated in H. pylori-associated

intestinal metaplasia.24 Whilst proliferation was in-

creased in both intestinal metaplasia and non-intestinal

metaplasia regions, the level of apoptosis was signifi-

cantly lower in the former. Thus, the apoptotic

index ⁄proliferation index ratio was markedly reduced

in intestinal metaplasia, favouring cellular accumula-

tion and possibly neoplasm formation.

GENETIC ALTERATIONS IN INTESTINAL

METAPLASIA

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-oxyge-

nase is a key enzyme responsible for the conversion of

REVIEW: INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS 1211


arachidonic acid into prostaglandins. The cyclo-oxyge-

nase-1 isoform is believed to be constitutively expressed,

whereas the cyclo-oxygenase-2 isoform is inducible,

particularly in the presence of inflammation. Interest-

ingly, over-expression of cyclo-oxygenase-2 is also

observed in many neoplastic conditions, including

colon, breast, pancreas and stomach.27 In vitro experi-

ments 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 immuno-

histochemistry 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-oxyg-

enase-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-polyp-

osis, 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 carci-

noma with microsatellite instability. Instead, the insta-

bility 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 meta-

plasia. 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-a 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 expres-

sions could be restored by H. pylori eradication.

IS THERE A NEED FOR SURVEILLANCE?

Unlike Barrett’s oesophagus and colonic adenoma, there

are no guidelines on the surveillance for gastric

Figure 2. The multistep gastric carcino-

genesis pathway. Helicobacter pylori infec-

tion is believed to trigger this cascade. The

genetic and epigenetic alterations demon-

strated 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.



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

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 surveil-

lance was significantly higher than that detected at

open access endoscopy (50% vs. 10%). These promising

results support the implementation of structured screen-

ing 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?

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 inconsis-

tency 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.

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 random-

ized 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 regres-

sion of intestinal metaplasia when compared with

placebo (15% vs. 6%; relative risk, 3.1; 95% confidence

interval, 1.0–9.3). Interestingly, supplementation withFigure 3. Endoscopic appearance of extensive intestinal

metaplasia in the angular incisura.



b-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 irrespect-

ive 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 treat-

ment 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. How-

ever, patients with persistent infection had significant

deterioration of corpus atrophy at 1 year. It thus

appears that the eradication of H. 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 eradica-

tion of H. pylori had significantly reduced progression of

intestinal metaplasia than those with persistent infec-

tion. 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 intesti-

nal 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 intesti-

nal metaplasia awaits further study.

Table 1. Effect of Helicobacter pylori eradication on changes of intestinal metaplasia (IM)

Reference Country

No. of

patients Design

Follow-up

(months)

IM

changes

Van der Hulst et al.41 The Netherlands 155 (122 cagA+

vs. 33 cagA–)

Uncontrolled 12 No change

(regardless

of cagA status)

Ohkusa et al.44 Japan 163 (115 H.

pylori-eradicated vs.

46 failed eradication)

Uncontrolled 12 IM improved

in 28 ⁄46

Uemura et al.40 Japan 132 early gastric

cancer

Non-randomized

(65 eradicated

vs. 67 no eradication)

6 Significant

improvement in

antrum (from 1.3

to 0.9) and corpus

(from 0.7 to 0.46)

Sung et al.43 China 587 Randomized control

(eradication vs. placebo)

12 No change

Correa et al.42 Columbia 976

(631 completed trial)

Randomized control

(eight treatment groups)

72 RR for IM

regression

¼ 3.1 (1.0–9.3)

RR, relative risk.



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 dam-

age50 and reduction of proliferation,24 may be more

important in the prevention of gastric cancer than the

actual reversal of intestinal metaplasia.

CONCLUSIONS

Based on compelling epidemiological data and molecu-

lar 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 prom-

ising, long-term results are lacking. The role of other

chemo-preventive agents should be determined.

ACKNOWLEDGEMENTS

The work described in this paper was supported by a

grant from the Research Grants Council of Hong Kong

Special Administrative Region, China (Project No.

CUHK 4061 ⁄01M).

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Intestinal metaplasia and gastric carcinogenesis