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. Author manuscript; available in PMC: 2019 Dec 16.
Published in final edited form as: Curr Opin Gastroenterol. 2018 Nov;34(6):458–464. doi: 10.1097/MOG.0000000000000472

Guilt by association: intestinal metaplasia does not progress to gastric cancer

David Y Graham 1, Winnie Y Zou 1
PMCID: PMC6913177  NIHMSID: NIHMS1061636  PMID: 30138135

Abstract

Purpose of review

This review integrates the new thinking about relationships between gastric cancer and intestinal metaplasia/pseudopyloric metaplasia (SPEM). We address whether recent studies have closed or widened the knowledge gap regarding gastric cancer pathogenesis in mice or humans.

Recent findings

Recent studies in mouse models have provided a variety of new insights into the cellular origin and progression of events resulting in gastric cancer. Many suggest a direct transformation from intestinal metaplasia/pseudopyloric metaplasia/SPEM to gastric cancer. However, results from different investigator and models are conflicting and often describe events not present in studies in humans.

Summary

Both Helicobacter pylori-associated and autoimmune gastritis may produce gastric atrophy with extensive intestinal metaplasia and an abnormal gastric microbiome. However, only H. pylori gastritis carries a risk for adenocarcinoma. The differences reported with mouse models can best be explained as the results of different models of regeneration and repair rather than as models of gastric cancer. Overall, the data remains consistent with the original hypothesis that gastric cancer results from increased genetic instability of gastric stem cells rather than a direct transition from metaplasia to cancer. Intestinal metaplasia, pseudopyloric metaplasia, and SPEM have all been falsely accused based on guilt by association.

Keywords: autoimmune gastritis, gastric cancer, Helicobacter pylori, intestinal metaplasia, pseudopyloric metaplasia, risk assessment, spasmolytic polypeptide-expressing metaplasia, stem cells, transdifferentiation

INTRODUCTION

There has been a flurry of new observations and reviews regarding the origin and significance of intestinal metaplasia and its relation to gastric cancer [1■,2■■,3■■,4■,5■,6,7■■,8■,9■■,10,11■,12■]. The majority of new exciting information has come from studies involving experimental animals [1■,2■■,3■■,4■,5■,7■■,8■,9■■,10,11■,12■,13■■]. Observations are also starting to appear using gastric organoids [10,14]. Although these new findings have overall advanced knowledge, their interpretation has often widened the gap between existing concepts regarding the pathogenesis of gastric adenocarcinoma and intestinal metaplasia in humans and the observations from studies in mice. Both mice and humans share a common reparative process for glandular injury, which results in what has been termed pseudopyloric or mucus metaplasia in man and spasmolytic polypeptide-expressing metaplasia (SPEM) in mice. This reparative response is present throughout the intestine [15–17] and provides a niche allowing Helicobacter pylori to colonize the duodenum and cause duodenal ulcers [18,19].

Pseudopyloric metaplasia was first used by Stoerk to describe the appearance of histological regeneration of the stomach after diphtheria-associated gastric injury [20]. Early pathologists, who worked with resected or autopsy specimens used the Swiss-roll technique to clearly visualize the progression of atrophic gastritis into the proximal stomach via the expansion of pseudopyloric metaplasia. The phenomena of the antral–corpus junction moving proximally to replace the fundic gland mucosa was repeatedly described by early investigators [21,22] and also formed the basis of the Kimura-Takemoto endoscopic classification of the extent of gastric atrophy, which remains in common use today [23,24].

Pseudopyloric metaplasia was also identified in experimental models and in gastric remnants of humans [25,26]. In the stomach, it was identified clinically by its location that is, antral-appearing mucosa in the anatomic location of the corpus. This became more difficult when endoscopists placed all biopsy specimens in the same bottle making the origin of any specific biopsy unknown. The corpus location of antral-appearing mucosa could, however, be identified by the presence of pepsinogen I-containing cells on immunohistochemical staining as these cells are not present in the antrum [27]. The discovery that pseudopyloric mucosa exhibited positive staining for SPEM simplified the task of pathologists in identifying pseudopyloric metaplasia and has also become the basis for a proposed new cancer risk stratification system that is fundamentally a histologic correlate of the Kimura-Takemoto endoscopic classification system [28]. However, as cells staining for SPEM are not restricted to pseudopyloric metaplasia, the pathologist remains dependent on the endoscopist to confirm that the biopsy was obtained from the gastric corpus. Although SPEM is the currently preferred nomenclature for studies in experimental animals, we prefer pyloric or pseudo- pyloric metaplasia for studies in humans; pseudopyloric mucosa is unambiguous in relation to appearance and location. Spasmolytic polypeptide-expressing metaplasia or mucosa can occur anywhere in the gastrointestinal tract, whereas pseudopyloric mucosa unambiguously denotes a mucosa that appears similar to that of normal gastric antrum presenting in the corpus.

INTESTINAL METAPLASIA

The advance of antral–corpus border produces a lawn of pseudopyloric mucosa onto which islands or patches of intestinal metaplasia may appear and over time expand and even coalesce [27]; both are also potentially reversible. Morphologically, intestinal metaplasia appears similar to normal small intestinal mucosa replete with goblet, Paneth, and absorptive as well as displacement of the proliferative zone to the base of the crypts. It is considered as a tissue rather than a cellular transdifferentiation [29]. Regression of intestinal metaplasia has been demonstrated in experimental animals using adenosine diphosphate ribosylation inhibitors, such as olaparib and with prostaglandin E2 [30,31]. Regression has also been demonstrated in humans with H. pylori-induced atrophy-receiving tamoxifen [32]. Striking regression has also been observed in pernicious anemia patients receiving steroids [33–37] and following spontaneous loss of parietal cell auto-anti-bodies [38].

SUBTYPES OF INTESTINAL METAPLASIA

In H. pylori-associated gastritis, the extent and severity of damage correlates with cancer risk [39]. It has also been suggested that the type of intestinal metaplasia also may serve as a biomarker for risk [40]. There are three types of intestinal metaplasia: Type 1 (complete) is characterized by small intestinal type epithelium, Type II (incomplete) is characterized by colonic type epithelium with sialomucins, and Type III (incomplete) is characterized by colonic type epithelium with sulphomucins [40,41]. Type I intestinal metaplasia is usually the first to appear and in autoimmune gastritis may be the primary and only type present; Type II and Type III may appear late in the process when mucosal atrophy is extensive [40]. Type II and Type III likely reflect the presence of increasing genetic instability such as in methylation [41].

PYLORIC METAPLASIA, INTESTINAL METAPLASIA, AND GASTRIC CANCER

Both pyloric metaplasia and intestinal metaplasia are frequently described as precancerous conditions with an arrow drawn between intestinal metaplasia and intraepithelial neoplasia (previously termed dysplasia). However, gastric cancers can occur in areas without intestinal metaplasia [27,42] and detailed mapping of the mucosa in patients with gastric cancer demonstrates multifocal intraepithelial neoplasia in areas without intestinal metaplasia distant from the original tumor [27]. Intestinal metaplasia may also be present at the edges of gastric ulcers [21] and in nonatrophic mucosa at sites of prior mucosal damage; the latter is probably the basis of small intestinal patches observed in what otherwise would be considered normal stomachs. It may also be present in patients with duodenal ulcer disease, a disorder rarely associated with development of gastric cancer [43,44]. Duodenal ulcer disease is characterized by a normal or nearly normal corpus mucosa, and slow or lack of spread of atrophic changes from the antrum into the corpus. This protection is mediated by high-acid secretion and can be abolished by anything that reduces acid secretion such as vagotomy, antisecretory drugs, vitamin deficiency, fever, and so forth [45–48]. Even temporary suppression of the acid pump allows H. pylori access to the proliferative zone, resulting in inflammation and secretion of IL1β, which can further reduce acid secretion and can potentially become self perpetrating [47,48].

NEITHER INTESTINAL METAPLASIA NOR PSEUDOPYLORIC METAPLASIA PROGRESSES TO CANCER

One exception will falsify a hypothesis. The most important and serious challenge to the hypothesis that pseudopyloric metaplasia or intestinal metaplasia leads to adenocarcinoma is exemplified in the natural history of autoimmune gastritis (Table 1) [49]. Table 1 shows that both H. pylori-associated gastritis and autoimmune gastritis may eventually develop corpus atrophy with extensive pseudopyloric and intestinal metaplasia and achlorhydria. In autoimmune gastritis, antral atrophy is absent unless the disease is complicated by an H. pylori gastritis [49]. In addition, achlorhydria in either condition results in acquisition of a new diverse gastric microbiome containing intestinal bacteria in which carcinogens are produced [50–52]. However, the two conditions differ markedly in terms of cancer risk producing adenocarcinoma in H. pylori gastritis versus neuroendocrine tumors in autoimmune gastritis [49]. Data in autoimmune gastritis confirms that neither intestinal metaplasia nor pseudopyloric metaplasis alone carry a significant risk of gastric adenocarcinoma. However, in H. pylori and probably other infectious causes of atrophic gastritis [e.g. Epstein–Barr virus (EBV) infection], the extent and severity of metaplasia serve as a surrogate risk marker as reflected in the OLGA gastric cancer staging system [53].

Table 1.

Comparison between the histological features of autoimmune and Helicobacter pylori-associated gastritis and their risk of cancer development

Autoimmune
gastritis		 H. pylori-associated
gastritis
Achlorhydria Yes Yes
Atrophy Yes Yes
Intestinal metaplasia Yes Yes
Microbiome change Yes Yes
Cancer type Carcinoid Adenocarcinoma
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HUMAN HELICOBACTER PYLORI- ASSOCIATED GASTRIC ADENOCARCINOMA

H. pylori-associated gastric cancer is an inflammation-associated cancer occurring as a complication of chronic H. pylori infection [54,55] (Figs. 1 and 2) [56■]. The population risk of gastric cancer correlates with the ability of H. pylori to increase the inflammatory response (e.g. virulence) [55]. The cancer risk with the most virulent H. pylori strain (e.g. cagA, vacA s1m1-positive) is only about double that of the least virulent strain [55,56■]. The risk is further modulated by environmental factors, especially diet [47,56■,57]. The traditional paradigm is that malignancy results from progressive genetic instability of stem cells, which eventually develop into cancer stem cells. H. pylori infection contributes indirectly to carcinogenesis by inducing inflammation and eliminating the acid barrier, which prevents growth of most bacteria in the stomach. H. pylori also contributes directly by a variety of mechanisms including breakage of double stranded DNA and promoting abnormal methylation, and so forth (Fig. 2) [54]. The immune system interacts with potential cancer stem cells to govern whether the putative cancer stem cells persist and multiply or are eliminated [58]. The importance of the H. pylori–host interaction is best exemplified by the marked fall in metachronous cancers after cure of the H. pylori infection [59,60]. It remains unclear whether the risk reduction is primarily related to the reduction in inflammation, the elimination of H. pylori–host interactions, or both.

FIGURE 1.

FIGURE 1.

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Role of Helicobacter pylori in development of gastric stem cell genetic instability. Reproduced with permission from [54].

FIGURE 2.

FIGURE 2.

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Role of inflammation in the pathogenesis of Helicobacter pylori-associated gastric carcinogenesis. Reproduced with permission from [56■].

THE CELLS OF ORIGIN OF GASTRIC CANCER

Modern lineage tracing methods and unbiased transcriptome sequencing have allowed the identification of gastric cancer stem cell markers. Lgr5+ stem cells have been identified as the active antral stem cells capable of multilineage differentiation [61], whereas the Villin+ population represents the quiescent stem cells that specifically reside within the lesser curvature of the antrum [62]. In mice, deletion of Apc transforms the Lgr5+ stem cells into gastric cancer stem cells and the mice develop microscopic adenomas within 5 weeks [61,63–65].

Analysis of human malignant corpus tumors have also shown high levels of Lgr5 expression [66■]. Similarly, Klf4 deletion in Villin+ gastric stem cells results in pronounced hypertrophy within 35–50 weeks and spontaneous gastric adenoma formation by 80 weeks [67]. In addition, recent studies have also identified the transdifferentiation ability of chief cells, marked by Mist1, in the corpus, in which both gastric-type as well as intestinal-type cancers can be directly driven via genetic alterations in the chief cells [5■,68]. Knockout of Cdh1 gene in Mist1 cells, in combination of Helicobacter felis infection can generate diffuse-type gastric cancer, and aberrant Notch activation can yield intestinal-type cancers [68]. Together, these studies are consistent with the traditional concept that the tumor-initiation potential of gastric stem cell populations is acquired via genetic mutations and that gastric stem and progenitor cell types can likely serve as direct sources of cancer transformation without the intermediate step of SPEM or intestinal metaplasia.

From epidemiological studies, SPEM and intestinal metaplasia are certainly correlated with chronic gastric atrophy and gastric cancer [69,70]. However, the direct experimental evidence of metaplasia to gastric cancer transition is minimal. Some mouse models have shown invasive submucosal glands, but failed to demonstrate important signs of cancer, such as nuclear atypia and dysplasia [71■■]. Studies using animal models have focused on identifying the stem cells involved in regeneration and repair resulting in erroneous conclusions that a prominent component (e.g. SPEM or intestinal metaplasia) is responsible for cancer transformation. We, in term, align with the traditional belief that cancers directly arise from the genetic instability of stem cells, rather than via metaplasia.

SUMMARY OF ANIMAL AND HUMAN DATA REGARDING SPASMOLYTIC POLYPEPTIDE-EXPRESSING METAPLASIA AND INTESTINAL METAPLASIA

SPEM is a tissue reparative response following glandular injury in intestine and pancreas [2■■]. It is generally reversible and often disappears upon compete healing. Intestinal metaplasia can produce a mucosa replete with a characteristic intestinal brush border containing brush border enzymes. It is unclear, but likely, that intestinal metaplasia is also a reparative response to tissue injury. However, its presence is difficult or impossible to discern outside the stomach as it is nearly indistinguishable from normal intestinal mucosa.

Many experimental animal models, such as Helicobacter spp. infection, DMP-777 injury, or tamoxifen injection, have been developed to study gastric neoplasia. As SPEM or intestinal metaplasia have been considered preneoplastic, the development of metaplasia has often been considered an end-point of cancer studies. However, none of these commonly used preneoplastic mouse models results in what would be considered the equivalent of gastric adenocarcinoma in humans [7■■,54] and metaplasia has not been shown to be a direct precursor of adenocarcinoma transformation. The disease called dysplasia in animals has been described as exuberantly proliferative metaplastic or reactive lesions rather than as intraepithelial neoplasia, which is the definition of dysplasia in humans [7■■]. Further confirmation of its benign nature comes from experiments where organoids were made from three mouse models of gastric cancer and in a xenograft model failed to cause tumors whereas the control of carcinogen-treated gastric mucosa did. It is also not known whether the experimental animal disease resolves after cure of Helicobacter spp. infection [7■■,54].

CONCLUSION

Overall, current preneoplastic mouse models represent models for regeneration and repair rather than for development of gastric cancer. There is no compelling reason to discard the prior conclusions that intestinal metaplasia is not the direct precursor to gastric adenocarcinoma but rather the presence, extent, and possibly the type of intestinal metaplasia in H. pylori gastritis is an easily recognizable biomarker useful for risk-stratification for development of gastric cancer [72].

KEY POINTS.

  • Gastric cancer remains one of the most common and lethal human cancers.

  • Experiments using mice models of gastric injury that produce SPEM and intestinal metaplasia have reported conflicting results regarding the origin and fate of metaplastic epithelium and the cell type responsible for producing cancer. The models do not appear to mimic the development of gastric cancer in humans.

  • Data are insufficient to support the hypothesis that intestinal metaplasia transforms into gastric cancer in humans as only pseudopyloric and intestinal metaplasia associated with H. pylori infection is associated with gastric cancer.

Acknowledgements

Financial support and sponsorship

D.Y.G. is in part by the Research Service Department of Veterans Affairs and by Public Health Service grant DK56338, which funds the Texas Medical Center Digestive Diseases Center. W.Y.Z. is part of the Medical Scientist Training Program at Baylor College of Medicine, supported by F30 DK107173.

Footnotes

Conflicts of interest

D.Y.G. is a consultant for RedHill Biopharma regarding novel H. pylori therapies and has received research support for culture of Helicobacter pylori and is the PI of an international study of the use of antimycobacterial therapy for Crohn’s disease. He is also a consultant for BioGaia in relation to probiotic therapy for H. pylori infection and for Takeda in relation to H. pylori therapies. W.Y.Z. has no interests to declare.

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