Pathogenesis and potential reversibility of intestinal metaplasia − a milestone in gastric carcinogenesis

The global burden of gastric cancer remains high, ranking fifth for incidence and third for cancer-related mortality worldwide. Early recognition of the disease can lead to potentially successful treatment; however, most patients are diagnosed at a late stage.¹(1) H. pylori is the main risk factor for non-cardia gastric cancer development. Although most H. pylori-positive individuals remain asymptomatic, the infection predisposes them to the development of chronic gastritis², which can be followed by the inflammation–atrophy–metaplasia–dysplasia–carcinoma sequence, known as the Correa cascade.³ Both chronic atrophic gastritis and intestinal metaplasia are considered precancerous conditions, as they independently confer risk for the development of dysplasia and gastric cancer.⁴

H. pylori infection is associated with a 3-fold increase in the lifetime risk for developing non-cardia gastric cancer, and H. pylori infection is believed to cause at least 75% of all gastric cancer.⁵ The eradication reduces the risk of gastric cancer in patients with non-atrophic and atrophic gastritis and effectively heals non-atrophic chronic gastritis. It may also lead to the regression of atrophic gastritis.⁶ On the other hand, short-term cancer risk in patients with established intestinal metaplasia does not seem to change significantly with H. pylori eradication^7,8, and intestinal metaplasia has thus been considered irreversible. This concept has been challenged in recent years by studies with longer follow up, in which regression of intestinal metaplasia has been observed after H. pylori eradication.^9,10 This short review summarizes the role of H. pylori in intestinal metaplasia and non-cardia gastric cancer, reviews gastric intestinal metaplasia pathogenesis, and briefly discusses evidence regarding its reversibility.

The following keywords and MeSH terms were used for online searches: [(gastric) AND (metaplasia) OR (intestinal) AND ((regression) OR (reversibility) OR (reversible))]. Reference lists of suitable studies and related previous review articles were reviewed manually to increase search yield and identify other related studies. All searches were restricted to original studies published in the English language.

Gastric intestinal metaplasia is defined as the replacement of normal gastric epithelium in the antral or oxyntic mucosa with intestinal epithelium, consisting of intestinal cell types including Paneth, goblet, and absorptive cells.⁵⁶ These metaplastic glands are characterized by modification of the surrounding stroma and by reorganization of the crypts, with displacement of the proliferative zone from the neck region to the base of the crypts.⁵⁷ Intestinal metaplasia can be classified as either limited (when confined to one anatomical region) or extensive, if two gastric regions are involved (Figure 1).

FIGURE 1.

Complete intestinal metaplasia is characterized by small intestinal-type mucosa with mature absorptive cells, and a brush border, with a notable loss of gastric mucin markers (MUC1, MUC5AC, MUC6) and an acquisition of the intestinal mucin MUC2. On the other hand, incomplete intestinal metaplasia is characterized by columnar “intermediate” cells at various differentiation stages, irregular mucin droplets, and a lack of a brush border, while still maintaining gastric mucin markers alongside the presence of intestinal mucin MUC2.^58,59 Earlier gastric metaplasia classifications relied on traditional mucin staining methods (such as periodic acid-Schiff, Alcian blue, and high iron diamine) and cell morphology. This methodology defined three intestinal metaplasia grades: Type I, which encompasses absorptive cells, Paneth cells, and goblet cells that secrete sialomucins; Type II, consisting of goblet and columnar cells secreting sialomucins; and Type III, involving goblet and columnar cells secreting sulfomucins. Presently, Type I aligns with the complete type, while Types II and III correspond to the incomplete type in the contemporary classification.⁵⁸

The Correa cascade is a widely accepted model of the pathogenesis of gastric cancer (Figure 2).³ This cascade commences with the emergence of chronic mucosal inflammation, mediated by polymorphonuclear and mononuclear cells. It evolves through a multifactorial process, steered by various factors including H. pylori, host genetics, environmental elements, and diet, propelling further alterations in the gastric mucosa towards atrophy, metaplasia, and ultimately, cancer.^60,61,62

FIGURE 2.

Annually, an estimated 0.1%, 0.25%, 0.6%, and 6% of Western patients with atrophic gastritis, intestinal metaplasia, and mild-to-moderate or severe dysplasia, respectively, progress to gastric cancer.⁶² In contrast, East Asian populations demonstrate a higher risk, with about 1.8%, 10%, and 73% of patients with atrophic gastritis, intestinal metaplasia, and dysplasia, respectively, progressing to gastric cancer each year.⁶³ Patients with incomplete intestinal metaplasia encounter a 3.3-fold higher relative risk of developing gastric cancer compared to those with complete intestinal metaplasia. Furthermore, extensive intestinal metaplasia is linked with a 2.1-fold higher relative risk of progression compared to limited gastric metaplasia.^64,65

Host factors that are associated with higher risk for non-cardia gastric cancer are similar to risk factors for development of intestinal metaplasia (Table 1) and include advanced age, male sex, family history, and smoking. More than two thirds of all gastric cancers are diagnosed after the age of 55, and roughly two thirds of non-cardia cancers are found in male patients.⁶⁶ The reason for the latter observation is most likely multifactorial. The difference can be partly attributed to smoking (which is more prevalent in men) and partly to the protective role of estrogen, since increased fertility and late menopause both reduce the risk of gastric cancer in women.⁶⁷ Individuals with blood type A have a 20% higher chance of developing gastric cancer when compared to other blood types, according to a prospective blood donor cohort study.⁶⁸

Ethnicity also plays an important role in gastric cancer risk. The incidence of non-cardia gastric cancer in individuals of African-American, East Asian, or Pacific Islander descent is almost twice that observed in Caucasians.⁶⁹ A similar pattern was seen in the analysis of intestinal metaplasia prevalence. A study that reviewed 800,000 gastric biopsies taken in the United States showed 20% prevalence of gastric metaplasia in people of East Asian descent, 12% prevalence in Hispanics, and 8% in all other ethnic backgrounds.⁶²

Tobacco smoking is the second most important environmental factor in gastric cancer pathogenesis, accounting for 11% of all cases.⁷⁰ Tobacco use increases the risk of intestinal metaplasia and doubles the risk of its progression to dysplasia, according to a large Chinese population-based study.⁷¹

Bile acid reflux into the gastric lumen produces repetitive gastric mucosal injury, which predisposes patients to intestinal metaplasia and gastric cancer in H. pylori-positive patients.⁷² Bile acids increase the expression of CDX2, an intestinal-specific transcription factor that directs and maintains intestinal differentiation in gastric mucosa⁷³, and indirectly damage cellular DNA by induction of oxidative stress and production of reactive oxygen species⁷⁴, which promote intestinal metaplasia and the further accumulation of mutations, leading to increased cancer risk.

The role of diet (being an obvious potential factor in gastric disorders) has been extensively studied in gastric cancer pathogenesis. High salt consumption is associated with increased risk of H. pylori infection and upregulation of cagA expression.^75,76 Dietary use of processed or preserved meat using smoke or salt is positively and dose-dependently associated with non-cardia gastric cancer.⁷⁷ Nitrite and nitrate additives form N-nitroso carcinogenic compounds when they combine with amino acids.

Similar carcinogens are formed by ingestion of haem (and meat) in the human gastrointestinal tract.⁷⁸ Vegetables and fruits in the diet have a protective role⁷⁹, and folic acid supplementation has been shown to reduce H. pylori related gastric inflammation and dysplasia in murine models.⁸⁰

Large prospective trials of H. pylori eradication for non-cardia gastric cancer prevention failed to show a reduction in gastric cancer incidence after eradication in a subpopulation of patients with pre-existing gastric intestinal metaplasia or extensive atrophic gastritis.^7,81 Intestinal metaplasia has thus been considered irreversible, and its occurrence is considered to be the histological point of no return in the carcinogenic cascade.

These assumptions appeared to be confirmed by prospective studies designed to evaluate the effect of H. pylori eradication on intestinal metaplasia and atrophic gastritis in eradicated subjects. A marked regression of histologic changes associated with acute and chronic gastritis was observed after eradication in one of these studies; however, the level of mucosal atrophy and intestinal metaplasia remained unchanged one year after H. pylori eradication.⁸² Similar results with no regression in intestinal metaplasia were reported in a more recent detailed histological analysis of 88 antral biopsies taken in patients with intestinal metaplasia prior to and several months after H. pylori eradication.⁸³ Several other smaller studies, all with short intervals of observation, reported similar results.^84,85 On the other hand, a number of prospective studies with longer observation intervals report the partial regression of intestinal metaplasia.^10,86–87 Hwang et al. postulated that the reason for this apparent discrepancy might stem simply from the slow pace of the process under observation.¹⁰ The partial reversibility of intestinal metaplasia after H. pylori eradication is also indirectly supported by a meta-analysis that confirmed reduced gastric cancer incidence in all levels of baseline risk, including patients with gastric metaplasia.⁸⁸ Another recent meta-analysis directly addressed the natural course of intestinal metaplasia. Its regression was observed in 32%, and its persistence in 43%, of 20 relevant studies.⁸⁹

A recent study of genomic and epigenomic profiling of intestinal metaplasia by Huang et al.⁹⁰ also addressed the regression of intestinal metaplasia. Eighty-two eradicated patients with intestinal metaplasia were included in an assessment of correlates between molecular features and clinical outcome. At the end of surveillance period, 6 patients had developed dysplasia or cancer, 61 showed no change, and regression of intestinal metaplasia was observed in 15 patients. The level of DNA methylation changes correlated with the tendency to progress and was highest among progressors, intermediate in the stable group, and low in patients with intestinal metaplasia regression. Furthermore, H. pylori burden correlated with DNA methylation levels only in the intermediate group, but not in the methylation-high group, which could explain the failure of H. pylori eradication to stabilize or reverse intestinal metaplasia in these patients. Levels of aberrant DNA methylation could thus indicate the point of no return within the scope of intestinal metaplasia.

Folate is water soluble vitamin that acts a as a methyl group donor in DNA methylation and plays an important role in epigenetic regulation.⁹¹ Folic acid (FA) supplementation has been shown to reduce the risk of gastric cancer in 7-year prospective randomized trial of 216 patients with chronic atrophic gastritis.⁹² All 5 observed gastric cancer cases occurred outside the group of FA-treated patients. Furthermore, the use of FA for 12 months was associated with more frequent reversal of both, atrophy and intestinal metaplasia in comparison to patients receiving placebo. These observations were confirmed by recent meta-analysis of the role of FA supplementation in reversal of gastric precancerous conditions.⁹³ Daily doses of 20–30 mg of FA in the duration of 3–6 months were associated with significant reversal of both, atrophic gastritis and intestinal metaplasia (RR: 1.77, 95% CI: 1.32–2.37).⁹³

The long-held belief that intestinal metaplasia of the gastric mucosa represents an irreversible precursor to cancer has increasingly been questioned in recent years. The concept of a ‘point of no return’ in the progression toward gastric cancer is now understood to be more complex than histomorphological changes alone. Consequently, the histological subtypes of gastric intestinal metaplasia must be considered during the planning of patient surveillance due to their varying potential for neoplastic transformation. Additionally, epigenomic alterations and molecular profiling could prove valuable in identifying the pro-carcinogenic transformation of intestinal metaplasia in patients without established risk factors. The eradication of H. pylori remains a critical step towards the potential reversibility of intestinal metaplasia; however, identifying patients at high risk of progression to cancer continues to be essential. The question of intestinal metaplasia progression despite H. pylori eradication could be addressed by examining changes in DNA methylation levels. Furthermore, non-H. pylori related host risk factors in the pathogenesis of gastric cancer are under thorough investigation. Significant challenges remain, such as accurately quantifying these factors and determining their exposure duration to assess their actual impact on intestinal metaplasia progression accurately. Recent studies highlighting the role of bile acids, N-nitroso–containing compounds, and deficiencies in vitamin C and folate have shown promise, yet their clinical relevance remains to be fully elucidated. An enduring unresolved issue is the long-term monitoring of these individuals, where the patchy nature of intestinal metaplasia could lead to sampling errors and potentially incorrect assessments of intestinal metaplasia reversibility.