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Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer.

Park YH, Kim N - J Cancer Prev (2015)

Bottom Line: The prevalence of AG and IM vary depending on countries, even it represents diverse results in the same nation.Helicobacter pylori infection has been proved as the most important cause of AG and IM.However, the reversibility of AG and IM by eradication of H. pylori which was assumed to be certain by meta-analysis is; however, controversial now.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam.

ABSTRACT
Atrophic gastritis (AG) and intestinal metaplasia (IM) are the main precursor lesions of gastric cancer as the incidence of gastric cancer increases in the gastric mucosa involved with AG and IM. The prevalence of AG and IM vary depending on countries, even it represents diverse results in the same nation. Usually AG is antecedent of IM but the etiologies of AG and IM are not always the same. The sensitivity and specificity of diagnostic methods to detect AG and IM are different. Furthermore, the management strategy of AG and IM has not been established, yet. Helicobacter pylori infection has been proved as the most important cause of AG and IM. Thus the eradication of H. pylori is very important to prevent the progression to gastric cancer which is still placed in the high rank in morbidity and mortality among cancers. However, the reversibility of AG and IM by eradication of H. pylori which was assumed to be certain by meta-analysis is; however, controversial now. Therefore, the understanding and early diagnosis of AG and IM are very important, especially, in high incidence area of gastric cancer such as Republic of Korea.

No MeSH data available.


Related in: MedlinePlus

Correa’s theory regarding human gastric carcinogenesis: a multistep and multifactorial process. Gastritis begins from superficial gastritis and progresses into atrophic gastritis, metaplasia, dysplasia and gastric cancer. Adapted from Correa et al.15
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f1-jcp-20-25: Correa’s theory regarding human gastric carcinogenesis: a multistep and multifactorial process. Gastritis begins from superficial gastritis and progresses into atrophic gastritis, metaplasia, dysplasia and gastric cancer. Adapted from Correa et al.15

Mentions: Chronic inflammation can damage inflamed cells and trigger a multistep process of carcinogenesis. In premalignant tissues associated with chronic inflammation, tumor cells and leukocytes of various kinds such as neutrophils, macrophages, monocytes, mast cells, eosinophils, dendritic cells, and lymphocytes are present.12,13 These inflammatory cells contribute to cancer initiation, promotion and metastasis by producing cytokines, reactive oxygen species, and reactive nitrogen species. Various oxidant products can damage cellular DNA, RNA, and proteins by chemical reactions such as oxidation, nitration, nitrosation, and halogenation. Damages of cellular components result in increased mutations and altered functions of important enzymes and proteins in premalignant tissues, so contributing to the multistage carcinogenesis process.14 According to the Correa model, chronic inflammation of gastric mucosa triggers a pathway of chronic active gastritis, multifocal atrophy, IM, gastric dysplasia and finally invasive gastric adenocarcinoma (Fig. 1).15 The pathogenesis of intestinal type gastric cancer can be explained by a multistep process from chronic gastritis through AG, IM, and dysplasia to cancer. The presence of AG, which has been traditionally defined as the loss of glands,16 is well known as a risk factor of gastric cancer. The risk of gastric cancer increases with greater extent and higher degree of gastric mucosal atrophy.17 Gastric IM is defined as the replacement of the surface, foveolar, and glandular epithelium in the gastric mucosa by intestinal epithelium with the presence of Paneth cells, goblet cells and absorptive cells.17 Several studies suggest that AG and IM are major precursor lesions of gastric cancer.18–20 These relationships were observed before the identification of H. pylori infection in 1982.21 Gastric cancer divides into 2 major histologic types, intestinal-type and diffuse-type, by Lauren classification.22 The intestinal-type cancers are believed to arise secondary to AG and IM.23 On the contrary, diffuse-type gastric cancer usually arises independently of IM. This raised doubts about the association between IM and gastric cancer development.24 It is thought that diffuse type is more likely to have a primary genetic etiology, and the involvement of H. pylori is probably limited to a subset of sporadic cases.23,24 However, many studies suggest that both intestinal and diffuse types of gastric carcinoma are associated with H. pylori infection.25,26 Compared with other risk factors of gastric cancer, AG and IM increase the risk of intestinal type gastric cancer exponentially. The risk of gastric cancer in subjects with severe fundal AG was 5.76 times higher than that in those having little or no fundal AG.27 In addition, the subjects with IM have more than a 10-fold increased risk of developing gastric cancer.28 In addition, several groups have reported the correlation between H. pylori infection and gastric cancer. Moreover AG and IM, precursors of gastric cancer, elevate the risk of gastric cancer.18,19 In a prospective study of 1,526 subjects, 1,246 patients had H. pylori infection and 280 did not.18 During mean follow-up of 7.8 years, gastric cancer developed in individuals (36 patients, 2.9%) infected with H. pylori but not in the uninfected persons.18 Histological description of severe gastric atrophy, corpus-predominant gastritis, or IM are increasing risk factors of gastric cancer.18 In addition, in a cohort of 4,655 healthy asymptomatic subjects, the risk of gastric cancer increased stepwise from chronic atrophic gastritis (CAG)-free gastritis [H. pylori(+)/CAG (−) group] (hazard ratio [HR], 7.13; 95% confidence interval [CI], 0.95 to 53.33) to CAG [H. pylori(−)/CAG(+) group] (HR, 14.85; 95% CI, 1.96 to 107.7) and finally to severe CAG with extensive IM [H. pylori(−)/CAG(+) group] (HR, 61.85; 95% CI 5.6 to 682.64) in which H. pylori is lost. So it is probable that H. pylori alone is not directly associated with gastric carcinogenesis,19 but H. pylori – induced chronic inflammation can provide the seed of cascade leading to gastric cancer, which can progress continuously even in the absence of H. pylori.29 The patients with H. pylori infection and IM have more than 6.4-fold increased risk of gastric cancer than the subjects of infected with H. pylori infection but without IM.18 In a cohort study of 2,224 subjects conducted in Republic of Korea, the group with IM have 10.9-fold increased risk of gastric cancer.20 Therefore, each lesion of AG or IM will increase the incidence of gastric cancer, and if both lesions are combined, the incidence of gastric cancer will increase even more. As mentioned above, H. pylori infection triggers a multistep progression from chronic gastritis, gastric atrophy, IM and finally into gastric cancer.30H. pylori was identified in 1982 by Marshall and Warren.31H. pylori is a gram-negative, flagellated bacterium about 3 μm long with a diameter of about 0.5 μm.31H. pylori became the first bacterium to be classified as a type I carcinogen by International Agency for Research on Cancer (IARC) working group in 1994,32 and now it is considered the most common etiologic bacterium of gastric cancer.1 Evidences supporting that came out from several meta-analyses. In a meta-analysis of 19 cohort or case-control studies, the summary odds ratio for gastric cancer in H. pylori-infected subjects is 1.92 (95% CI, 1.32 to 2.78).33 In another meta-analysis of 42 cohort or case-control studies, the summary odds ratio for H. pylori infection in relation to gastric carcinoma was 2.04 (95% CI, 1.69 to 2.45).34 So, these studies show the clear association between H. pylori and gastric adenocarcinomas.33,34 However, among H. pylori-positive patients, only 1% to 2% subjects will develop gastric cancer,17 suggesting that the final effects of H. pylori infection could be determined by prevalence, environmental factors, bacterial factors and host factors.35 Despite the clear relationship between H. pylori infection and gastric adenocarcinomas through AG and IM, especially in intestinal-type of gastric cancer, the mechanisms of process about chronic inflammation and developing gastric cancer are under investigation. The enhanced production of free radicals by chronic H. pylori infection causes mutations in target cells so the neoplastic clones are established.36 And tumor necrosis factor alpha from plays major roles in the growth, invasion and metastasis of neoplasm. This mechanism was called ‘a perigenetic pathway’.36 Another study suggested that the TNF-α inducing protein (Tipα) from H. pylori binds to and enters the nucleus through a specific biding molecule, act as a carcinogen of gastric cancer.37


Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer.

Park YH, Kim N - J Cancer Prev (2015)

Correa’s theory regarding human gastric carcinogenesis: a multistep and multifactorial process. Gastritis begins from superficial gastritis and progresses into atrophic gastritis, metaplasia, dysplasia and gastric cancer. Adapted from Correa et al.15
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384712&req=5

f1-jcp-20-25: Correa’s theory regarding human gastric carcinogenesis: a multistep and multifactorial process. Gastritis begins from superficial gastritis and progresses into atrophic gastritis, metaplasia, dysplasia and gastric cancer. Adapted from Correa et al.15
Mentions: Chronic inflammation can damage inflamed cells and trigger a multistep process of carcinogenesis. In premalignant tissues associated with chronic inflammation, tumor cells and leukocytes of various kinds such as neutrophils, macrophages, monocytes, mast cells, eosinophils, dendritic cells, and lymphocytes are present.12,13 These inflammatory cells contribute to cancer initiation, promotion and metastasis by producing cytokines, reactive oxygen species, and reactive nitrogen species. Various oxidant products can damage cellular DNA, RNA, and proteins by chemical reactions such as oxidation, nitration, nitrosation, and halogenation. Damages of cellular components result in increased mutations and altered functions of important enzymes and proteins in premalignant tissues, so contributing to the multistage carcinogenesis process.14 According to the Correa model, chronic inflammation of gastric mucosa triggers a pathway of chronic active gastritis, multifocal atrophy, IM, gastric dysplasia and finally invasive gastric adenocarcinoma (Fig. 1).15 The pathogenesis of intestinal type gastric cancer can be explained by a multistep process from chronic gastritis through AG, IM, and dysplasia to cancer. The presence of AG, which has been traditionally defined as the loss of glands,16 is well known as a risk factor of gastric cancer. The risk of gastric cancer increases with greater extent and higher degree of gastric mucosal atrophy.17 Gastric IM is defined as the replacement of the surface, foveolar, and glandular epithelium in the gastric mucosa by intestinal epithelium with the presence of Paneth cells, goblet cells and absorptive cells.17 Several studies suggest that AG and IM are major precursor lesions of gastric cancer.18–20 These relationships were observed before the identification of H. pylori infection in 1982.21 Gastric cancer divides into 2 major histologic types, intestinal-type and diffuse-type, by Lauren classification.22 The intestinal-type cancers are believed to arise secondary to AG and IM.23 On the contrary, diffuse-type gastric cancer usually arises independently of IM. This raised doubts about the association between IM and gastric cancer development.24 It is thought that diffuse type is more likely to have a primary genetic etiology, and the involvement of H. pylori is probably limited to a subset of sporadic cases.23,24 However, many studies suggest that both intestinal and diffuse types of gastric carcinoma are associated with H. pylori infection.25,26 Compared with other risk factors of gastric cancer, AG and IM increase the risk of intestinal type gastric cancer exponentially. The risk of gastric cancer in subjects with severe fundal AG was 5.76 times higher than that in those having little or no fundal AG.27 In addition, the subjects with IM have more than a 10-fold increased risk of developing gastric cancer.28 In addition, several groups have reported the correlation between H. pylori infection and gastric cancer. Moreover AG and IM, precursors of gastric cancer, elevate the risk of gastric cancer.18,19 In a prospective study of 1,526 subjects, 1,246 patients had H. pylori infection and 280 did not.18 During mean follow-up of 7.8 years, gastric cancer developed in individuals (36 patients, 2.9%) infected with H. pylori but not in the uninfected persons.18 Histological description of severe gastric atrophy, corpus-predominant gastritis, or IM are increasing risk factors of gastric cancer.18 In addition, in a cohort of 4,655 healthy asymptomatic subjects, the risk of gastric cancer increased stepwise from chronic atrophic gastritis (CAG)-free gastritis [H. pylori(+)/CAG (−) group] (hazard ratio [HR], 7.13; 95% confidence interval [CI], 0.95 to 53.33) to CAG [H. pylori(−)/CAG(+) group] (HR, 14.85; 95% CI, 1.96 to 107.7) and finally to severe CAG with extensive IM [H. pylori(−)/CAG(+) group] (HR, 61.85; 95% CI 5.6 to 682.64) in which H. pylori is lost. So it is probable that H. pylori alone is not directly associated with gastric carcinogenesis,19 but H. pylori – induced chronic inflammation can provide the seed of cascade leading to gastric cancer, which can progress continuously even in the absence of H. pylori.29 The patients with H. pylori infection and IM have more than 6.4-fold increased risk of gastric cancer than the subjects of infected with H. pylori infection but without IM.18 In a cohort study of 2,224 subjects conducted in Republic of Korea, the group with IM have 10.9-fold increased risk of gastric cancer.20 Therefore, each lesion of AG or IM will increase the incidence of gastric cancer, and if both lesions are combined, the incidence of gastric cancer will increase even more. As mentioned above, H. pylori infection triggers a multistep progression from chronic gastritis, gastric atrophy, IM and finally into gastric cancer.30H. pylori was identified in 1982 by Marshall and Warren.31H. pylori is a gram-negative, flagellated bacterium about 3 μm long with a diameter of about 0.5 μm.31H. pylori became the first bacterium to be classified as a type I carcinogen by International Agency for Research on Cancer (IARC) working group in 1994,32 and now it is considered the most common etiologic bacterium of gastric cancer.1 Evidences supporting that came out from several meta-analyses. In a meta-analysis of 19 cohort or case-control studies, the summary odds ratio for gastric cancer in H. pylori-infected subjects is 1.92 (95% CI, 1.32 to 2.78).33 In another meta-analysis of 42 cohort or case-control studies, the summary odds ratio for H. pylori infection in relation to gastric carcinoma was 2.04 (95% CI, 1.69 to 2.45).34 So, these studies show the clear association between H. pylori and gastric adenocarcinomas.33,34 However, among H. pylori-positive patients, only 1% to 2% subjects will develop gastric cancer,17 suggesting that the final effects of H. pylori infection could be determined by prevalence, environmental factors, bacterial factors and host factors.35 Despite the clear relationship between H. pylori infection and gastric adenocarcinomas through AG and IM, especially in intestinal-type of gastric cancer, the mechanisms of process about chronic inflammation and developing gastric cancer are under investigation. The enhanced production of free radicals by chronic H. pylori infection causes mutations in target cells so the neoplastic clones are established.36 And tumor necrosis factor alpha from plays major roles in the growth, invasion and metastasis of neoplasm. This mechanism was called ‘a perigenetic pathway’.36 Another study suggested that the TNF-α inducing protein (Tipα) from H. pylori binds to and enters the nucleus through a specific biding molecule, act as a carcinogen of gastric cancer.37

Bottom Line: The prevalence of AG and IM vary depending on countries, even it represents diverse results in the same nation.Helicobacter pylori infection has been proved as the most important cause of AG and IM.However, the reversibility of AG and IM by eradication of H. pylori which was assumed to be certain by meta-analysis is; however, controversial now.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam.

ABSTRACT
Atrophic gastritis (AG) and intestinal metaplasia (IM) are the main precursor lesions of gastric cancer as the incidence of gastric cancer increases in the gastric mucosa involved with AG and IM. The prevalence of AG and IM vary depending on countries, even it represents diverse results in the same nation. Usually AG is antecedent of IM but the etiologies of AG and IM are not always the same. The sensitivity and specificity of diagnostic methods to detect AG and IM are different. Furthermore, the management strategy of AG and IM has not been established, yet. Helicobacter pylori infection has been proved as the most important cause of AG and IM. Thus the eradication of H. pylori is very important to prevent the progression to gastric cancer which is still placed in the high rank in morbidity and mortality among cancers. However, the reversibility of AG and IM by eradication of H. pylori which was assumed to be certain by meta-analysis is; however, controversial now. Therefore, the understanding and early diagnosis of AG and IM are very important, especially, in high incidence area of gastric cancer such as Republic of Korea.

No MeSH data available.


Related in: MedlinePlus