|Year : 2018 | Volume
| Issue : 10 | Page : 1232-1239
Gastric Cancer Screening by Combined Determination of Serum Helicobacter pylori Antibody and Pepsinogen Concentrations: ABC Method for Gastric Cancer Screening
Xian-Zhe Chen1, Cheng-Zhi Huang2, Wei-Xian Hu1, Ying Liu3, Xue-Qing Yao1
1 Second Clinical Medical College, Southern Medical University, Guangzhou, Guangdong 510515; Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
2 Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080; Medical College, Shantou University, Shantou, Guangdong 515063, China
3 Reproductive Department, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
|Date of Submission||23-Jan-2018|
|Date of Web Publication||30-Apr-2018|
Dr. Xue-Qing Yao
Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, No. 106 Zhongshan Second Road, Guangzhou, Guangdong 510080
Source of Support: None, Conflict of Interest: None
Objective: Gastroscopy combined with gastric mucosa biopsies is currently regarded as a gold standard for diagnosis of gastric cancer. However, its application is restricted in clinical practice due to its invasive property. A new noninvasive population screening process combining the assay of anti-Helicobacter pylori antibody and serum pepsinogen (PG) (ABC method) is adopted to recognize the high-risk patients for further endoscopy examination, avoiding the unnecessary gastroscopy for most population and saving the cost consumption for mass screening annually. Nevertheless, controversies exist for the grouping of ABC method and the intervals of gastroscopy surveillance for each group. In this review, we summarized these popular concerned topics for providing useful references to the healthcare practitioner in clinical practice.
Data Sources: The PubMed databases were systematically searched from the inception dates to November 22, 2017, using the keywords “Helicobacter pylori,” “Pepsinogens,” and “Stomach Neoplasms.”
Study Selection: Original articles and reviews on the topics were selected.
Results: Anti-H. pylori antibody and serum PG concentration showed significant changes under the different status of H. pylori infection and the progression of atrophic gastritis, which can be used for risk stratification of gastric cancer in clinic. In addition, anti-H. pylori antibody titer can be used for further risk stratification of gastric cancer contributing to determine better endoscopy surveillance interval.
Conclusions: The early detection and diagnosis of gastric cancer benefit from the risk stratification, but the cutoff values for H. pylori antibody and serum PG concentration require further modification.
Keywords: Gastroscopy Surveillance; Helicobacter pylori Antibody; Pepsinogens; Risk Stratification; Stomach Neoplasms
|How to cite this article:|
Chen XZ, Huang CZ, Hu WX, Liu Y, Yao XQ. Gastric Cancer Screening by Combined Determination of Serum Helicobacter pylori Antibody and Pepsinogen Concentrations: ABC Method for Gastric Cancer Screening. Chin Med J 2018;131:1232-9
|How to cite this URL:|
Chen XZ, Huang CZ, Hu WX, Liu Y, Yao XQ. Gastric Cancer Screening by Combined Determination of Serum Helicobacter pylori Antibody and Pepsinogen Concentrations: ABC Method for Gastric Cancer Screening. Chin Med J [serial online] 2018 [cited 2018 Jul 18];131:1232-9. Available from: http://www.cmj.org/text.asp?2018/131/10/1232/231512
| Introduction|| |
Gastric cancer is still the leading cause of cancer-related deaths all over the world, especially in the countries of East Asia, such as Japan and China.,, Correa  pointed out that the human gastric carcinogenesis is a slow progressive, multistep, and multifactorial pathology process. The multistep process is composed of chronic superficial gastritis, atrophy gastritis, intestinal metaplasia (IM), dysplasia, and adenocarcinoma. Pathologically, gastric cancer is divided as intestinal type or diffuse type according to Lauren's classification. Similarly, multifactorial process involves Helicobacter pylori infection and excessive ingestion of salt and nitrate. Two significant risk factors of H. pylori infection and atrophic gastritis are considered to contribute to the development and deterioration of gastric cancer., What's worse, the most patients with gastric cancer at early stage (EGC) are insidious and asymptomatic. Due to lack of standardized screening system, many patients were advanced to the late stage of gastric carcinoma even at the time the endoscopy was first performed in clinical setting. At that time, the prognosis becomes very poor and the 5-year survival rate after surgery is only 20–30% compared with 90% in patient with EGC. Therefore, it is important to establish an efficient and better cost-effective screening method for early detection of gastric cancer in regular mass survey.
Compare to any other country in the world, as a high risk nation of gastric cancer, Japan has established a relatively better screening system and shown the obvious achievements., In Japan, a gastric cancer screening program, named photofluorography, was launched in 1960. Together with other traditional screening methods including double-contrast barium X-rays or panendoscopy, it has been wildly adopted throughout the country. However, these traditional methods leave much more to be desired. They require further efforts in aspects of detection rate and economic cost improvement.
Gastroscopy in combination with gastric mucosa biopsies is regarded as a gold standard model for diagnosis of gastric cancer. However, it is hesitantly accepted by patients because it is an invasive procedure and may induce the discomfort. In addition, it is not suitable for large-scale survey as well due to the high cost consumption. On the contrary, it is advisable to make the risk stratification for gastric cancer first by other noninvasive tests. In recent years, a number of noninvasive diagnosis tests are developed, such as reevaluation of conventional serum markers, new biomarkers, circulating tumor cell and cell-free nucleic acids, tumor-associated autoantibodies, and exhaled breath analysis. A new mass screening named ABC method which incorporates the assay of H. pylori antibody and serum pepsinogen (PG) has been implemented in Nishitokyo city from 2011 on the initiative of Nishitokyo Medical Association. In comparison of the conventional mass screening, the ABC method not only increases the EGC detection rate but also reduces the screening cost.,,
| Helicobacter Pylori Infection|| |
Discovered by Marshall and Warren in 1982, H. pylori is regarded as a strong cancerogen and a trigger of gastric cancer cascade. Approximately 70% of gastric cancers are related to H. pylori infection which is called H. pylori-positive gastric cancer (HPPGC), while about 30% of gastric cancers are not correlated with H. pylori, called H. pylori-negative gastric cancer (HPNGC), but in association with the factors of demographic feature, life style, Epstein-Barr virus infection, and so on., Actually, the proportion of HPNGC varied from 10% to 40% among GC in the literatures,,, because of the prevalence and the differences in the definition of H. pylori status. For example, Tsai et al. reported that the posteradicated patients may have negative tests for H. pylori and Yoon et al. proposed that as progression of gastric atrophy and IM drives H. pylori out of the gastric mucosa, the possibility of false-negative H. pylori test results could significantly increase resulting in the different proportion of HPNGC. In other word, 70% of gastric cancer can be prevented potentially by removal of H. pylori infection.
When infected by H. pylori, the bacteria can colonize the gastric mucosa and stimulate a series of inflammatory reactions. The H. pylori antibody titers are related to the immune response intensity of each host and the density of H. pylori colonization. The stronger immune response is, the higher antibody titers are. However, the controversy is raised whether immune suppression in advanced cancer impacts the titers of antibody. The relationship between antibody titer and the density of H. pylori colonization is clear. The titer of H. pylori antibody is significantly declined when the bacteria are successfully eradicated or spontaneously subsided. Accordingly, H. pylori antibody titer can be used to evaluate the density of H. pylori colonization and the status of H. pylori infection. Patients with H. pylori antibody titer ≥10 U/ml (E-plate “Eiken” Hp antibody: enzyme immunoassay method) were categorized as the H. pylori infection-positive group based on manufacturer's recommended cutoff value, with 91.2% sensitivity and 97.4% specificity.
| Serum pepsinogen|| |
As an inactive precursor of pepsin, PG has two isoforms including PG I and PG II. Both PG I and PG II are produced by the principal cells and mucous neck cells located at fundic glands, while PG II can be secreted by pyloric glands and Brunner's glands., Approximately 99% PG secretes into the gastric cavity, only 1% enters into the bloodstream., According to this concept, many previous studies advocated that the serum PG levels can represent the morphologic and functional status of gastric mucosa., For example, in H. pylori-infected patients, with the progress of atrophic gastritis from the antrum to the corpus mucosa, the amount of PG I is considerably reduced or abolished owing to the damage of principal cells and parietal cells, while the level of serum PG II increases because the infiltration model of neutrophils and mononuclear cells is toward the upper stomach from the antrum., One study concluded that PG II is independently associated with risk of gastric cancer. This evidence indicated that the serum PG level was closely correlated with the progression of atrophic gastritis. Meantime, it indirectly reflected the status of H. pylori infection as well. It is widely accepted that patients with both serum PG I levels ≤70 ng/ml and PG I/II ratio ≤3.0 were classified as PG-seropositive type and all other situations were classified as PG-seronegative type, using a commercial RIA kit (PG I/II RIA bead kit; Dainabot Co., Tokyo, Japan) with 70.5% sensitivity and 97% specificity.,,
| Risk Stratification of Gastric Cancer with ABC Method|| |
Several prospective studies have confirmed that the ABC method is an effective and convenient risk stratification pattern for gastric cancer through joint assay of H. pylori antibody and serum PG simultaneously.,,,, By the aid of ABC method, patients are stratified into four categories: Group A [Hp(−)PG(−)], noninfected cases; Group B [Hp(+) PG(−)], free or mild chronic atrophic gastritis (CAG) with active or acute H. pylori infection; Group C [Hp(+) PG(+)], CAG with chronic inactive H. pylori infection; and Group D [Hp(−)PG(+)], severe CAG with extensive IM and spontaneous diminishment of H. pylori infection. It is generally believed that the risk of gastric cancer is the highest in Group D, followed by Groups C, B, and A in order. Thus, it is recommended that periodic endoscopic examination should be taken for patients in Group B, C, and D at the interval of 3, 2, and 1 year, respectively, except Group A.
Many studies considered previously H. pylori serology was a categorical variable only, either positive or negative. However, Kishikawa et al. proposed that H. pylori serology was not a categorical variable, it is a consecutive variable, such as the antibody titer levels.
Kishikawa et al. pointed out that the risk stratification of all patients within each group is actually different. They suggested that the severity of H. pylori infection should be divided into four subgroups based on the titers of IgG anti-H. pylori antibody: low negative (<3 U/ml), high negative (3–10 U/ml), low positive (10–50 U/ml), and high positive (>50 U/ml), respectively.
Infected by H. pylori, the bacteria can colonize in the gastric mucosa and stimulate a series of inflammatory reactions, which result to the development of atrophic gastritis and impair the gastric secret function. It is generally believed that the eradication of H. pylori can reduce the risk of subsequent cancer development. However, it is unclear whether a critical irreversible point exists during the development of gastric cancer. CAG is considered as the first step in the process of gastric mucosal degeneration. When the disease progresses, the gastric intra-environment eventually becomes inhospitable for the bacteria survival, resulting in H. pylori diminished spontaneously. Nevertheless, it should be noticed that severe CAG and IM may be an irreversible gastric mucosal changes despite whether H. pylori is eradicated or not., Therefore, it is quite important to eliminate H. pylori infection before the irreversible changes occur, in particular for the patients in Group C and D.,
| Group A: [Hp(−)PG(−)]|| |
Theoretically, patients in Group A (H. pylori antibody titer <10 U/ml, PG I >70 ng/ml or I/II ratio >3) have no history of H. pylori infection in fact. It is considered as the lowest risk group for gastric cancer development and is excluded from regular endoscopy requirement. In H. pylori-noninfected cases, the function of the gastric mucosal remains intact, whereas the PG I secretion and PG II secretion increase because of inflammation of gastric mucosal. The intragastric environment becomes hyperacidity, leading to the appearance of gastritis commonly seen under endoscopy, including chronic superficial gastritis and erosive gastritis. The endoscopic findings in this group include the exhibitions of regular configuration of collecting venules under gastric mucosa. Chronic superficial gastritis may show several hyperemic strips at greater curvature side of antrum. Erosive gastritis may present with multiple hyperemic erosions on the antrum. These characteristics of gastric mucosa alterations are also observed in Group B.
However, some studies reported that about 2–10% cases of gastric cancer were classified into Group A. Although 30% cases of gastric cancer were not correlated with H. pylori infection (called HPNGC ,), it was possible that patients had taken the eradicative treatment for H. pylori before, whether it was intentional or unintentional. The patients were then misclassified to Group A because of the negative H. pylori antibody. Actually, Group A can be subdivided into two subtypes. One is true H. pylori infection-negative cases and the other one is infection-positive case, but the bacteria were successfully eradicated. A study  once reported that in 345 patients classified to Group A by ABC method, 10 cases were found suffering from gastric neoplasia (gastric cancer and adenoma). This study suggested that patients who were classified as Group A by ABC method, with H. pylori antibody titer ≥3 U/ml and a PG I/II ratio ≤4.3, should take the endoscopic examination. As pointed out by Kishikawa et al., patients with high-negative antibody in a Subgroup A were considered as the posteradicated cases. These patients possess elevated risk for developing of intestinal-type gastric cancer., Besides, some studies considered that the risk for gastric cancer in these patients is comparable to those in Group non-A. Moreover, the patients with high-negative antibody in Group A are strongly recommended to have the reevaluation by other assays. If the result is positive, the patients should receive the antibiotic therapy. Hence, a high-negative H. pylori antibody may be helpful to distinguish these patients from others in Group A. These patients need a careful follow-up at the interval of 3 years.,
| Group B: [Hp(+)PG(−)]|| |
Patients with active or acute H. pylori infection in Group B (H. pylori antibody titer ≥10 U/ml, PG I >70 ng/ml or I/II ratio >3) usually show an increased risk of diffuse gastric cancer. It is recommended to take the regular endoscopy for these patients every 3 years. Typical endoscopic findings in this group include antrum nodules, hemorrhagic spots on the fundus, and thickened gastric folds. The excretory function of gastric mucosa cells remains intact, no matter they were actively infected or not. The PG secretion increases, especially PG II, which was a good marker for active H. pylori infection in stomach., In addition, the intragastric environment becomes more acid due to inflammation. Therefore, at the stage with progressive deterioration of H. pylori infection, it is strongly recommended to eradicate the bacteria before the occurrence of irreversible lesions in stomach. In the study of Watanabe et al., no cancer development was observed in this group after H. pylori eradication. Although there is no significant progression of gastric mucosa damage in Group B, the high-positive antibody indicates the progressive mucosal inflammation, which has a higher risk for diffuse cancer in comparison to the patients with low-positive antibody titer. Consequently, it is recommended that for the patients with high-positive antibody in Group B, endoscopic examination is required at the interval of each 2 years.
| Group C: [Hp(+)PG(+)]|| |
Patients with chronic inactive H. pylori infection in Group C (H. pylori antibody titer ≥10 U/ml, and PG I ≤70 ng/ml, and I/II ratio ≤3) have an increased risk of intestinal-type gastric cancer. It is recommended to take a follow-up with regular endoscopy surveillance every 2 years. In patients with long-term H. pylori infection, the endoscopic findings show the appearance of atrophic gastritis, with or without IM extending from the gastric antrum toward the corpus and cardia. However, less atrophic and metaplastic damage were shown at the sites of greater curvature side of the upper corpus, where H. pylori can survive for the longest time before spontaneous regression. According to the statistics, about 90% of new cases of noncardia gastric cancer worldwide are attributed to the infection of these bacteria., With the evolution of atrophic lesion, the secretion of PG I and PG II decreases significantly and the intragastric environment becomes hypoacidic. Sung et al. reported that the mean pH of gastric juice was higher in the H. pylori-positive group (n = 17) than that in the H. pylori-negative group (n = 29) (4.54 vs. 2.46, P = 0.002). Similarly, the amount of H. pylori was lower in the group at pH <3 (21.4%) than that in the group pH ≥3 (61.1%) (P = 0.007). Due to inhospitable survival environment, the amount and density of H. pylori are significantly reduced but still alive in the stomach, which result to the facts that although the titer of H. pylori antibody decreases, it remains at the level ≥10 U/ml. Thus, the low-positive antibody titer cases in Group C, representing advanced atrophy and/or metaplasia gastritis (MG), has a higher risk for intestinal-type cancer than the high-positive antibody titer ones. Thus, the patients in Group C require urgently the antibiotic treatment to eradicate H. pylori infection before reaching the irreversible stage., After treatment, it is possible the test results both in histology and serology can return to normal ranges followed by the decrease of cancer risk correspondently. Meanwhile, it has been reported that in some patients with severe corpus MG and low PG level, the damages were still reversible. At present, there is no consensus on the irreversible damage of stomach mucosa,, but regular endoscopic screening is necessary. The experts suggest that the annual endoscopy is required for the patients with low-positive antibody in Group C because the patients in Group D may originate from them who are with the spontaneous disappearance of H. pylori from the gastric mucosa.
| Group D: [Hp(−)PG(+)]|| |
Patients with spontaneous regression of H. pylori in Group D (H. pylori antibody titer <10 U/ml, PG I ≤70 ng/ml and I/II ratio ≤3) are considered with the highest risk for intestinal-type gastric cancer. It is recommended to take the careful follow-up and regular endoscopy surveillance annually. The endoscopic findings in this group are similar to those in Group C with low-positive antibody titer; however, it is more severe in patients with spontaneous diminishment of H. pylori. In such advanced cases, most damage of gastric mucosa is irreversible, which will further develop into carcinoma in accordance with Correa's hypothesis. It is rare to diagnose the patients with extremely atrophy of gastric mucosa and spontaneously H. pylori vanishment. About 99% of H. pylori-infected patients are classified into Groups A, B, and C; only 1% patients are defined to Group D. The separate reports by Miki  and Yoshida et al. revealed that the individuals enrolled to Group D were merely 0.66% (33 of 5209 individuals) and 0.71% (33 of 4655 individuals), respectively. With spontaneous diminishment of H. pylori, gastric cancer in Group D also may be misclassified as HPNGC. According to the hypothesis of Correa's cancer progressive cascade, it indicates that no matter HPNGC or HPPGC, its development of gastric cancer must go through atrophic gastritis. In other words, according to the risk stratification of ABC method, before gastric cancer occurrence in these HPNGC patients, they may be allocated to Group A before gastric atrophy appearance or to Group D with gastric atrophy appearance. In addition, there is no particular prevention and treatment for HPNGC. But, no matter being allocated to Group A or to Group D according to the ABC method, all these patients are suggested to receive corresponding periodic endoscopy examination with different surveillance interval. Accordingly, HPNGC can be detected at the early stage and even receive corresponding intervention treatments during precancerosis. In Group D, the efficiency of antibiotic therapies is very limited. However, effective therapy and regular endoscopy are vital to prevent the patients in other groups evolving to Group D before the disease reaches irreversible stage.
No matter HPPGC or HPNGC, the early detection rate and the prognosis can be improved using the risk stratification of ABC method, but in order to increase the risk stratification precision, it is suggested that combination with the histological change information of gastric mucosa is required to modify the cutoff values of H. pylori antibody and serum PG concentration in the future. Meanwhile, the level of anti-H. pylori antibody titer should be applied for further risk stratification of gastric cancer to determine better endoscopy surveillance interval for different risk stratified groups.
| Discussion|| |
According to the hypothesis of Correa's cancer progressive cascade, atrophic gastritis and IM are considered as preneoplastic gastric lesions, which will develop to dysplasia and adenocarcinoma spontaneously. With H. pylori infection, the bacteria can colonize in gastric mucosa and stimulate a series of inflammatory reactions, leading to the deterioration of atrophic gastritis and the impairment of gastric secretory function. CAG is considered as the first step of a sequence of mucosal changes in the stomach, which finally results to the changes of intragastric environment inhospitable for H. pylori survival. Therefore, H. pylori infection has an indirect association with gastric carcinogenesis via atrophic gastritis. During this process, H. pylori antibody and serum PG concentration showed significant changes, which can be used for risk stratification of gastric cancer in clinic.,,
Since gastric cancer is a potentially curable disease if diagnosed early, it is advisable to make risk stratification first for patients before taking invasive examinations such as gastroscopy, regardless in the disease high-incidence or low-incidence areas. A new mass screening named ABC method was developed for risk stratification of gastric cancer in Japan. However, the optimal PG cutoff value for atrophic gastritis remains controversial. The criteria of PG-seropositive levels (PG I ≤70 ng/ml, and PG I/II ratio of ≤3.0) proposed by Miki are widely accepted at present time. Nonetheless, Park et al. disagreed because this criteria were only based on the data from endoscopy diagnosis for atrophic gastritis rather than histological information. In fact, the cytological changes of minor gastric atrophy appear before the morphological changes of stomach mucosa endoscopically. Therefore, the criteria proposed by Miki et al. seem hysteretic. In other word, the best PG cutoff value for gastric atrophy may be higher based on histological examination.
Furthermore, certain previous studies supported that H. pylori infection would impact on PG level., The reliable PG cutoff values may differ from the differences of various bacteria infection status., Park et al. concluded that the optimal cutoff values of the PG I/PG II ratio for predicting gastric neoplasms were 3.1 for H. pylori antibody negative patients and 4.1 for H. pylori antibody positive patients.
For patients with H. pylori infection, it is urgent to take proper antibiotic treatment before the disease reaching the irreversible “critical point,” particularly at the stage of chronic inactive H. pylori infection.,, There is no standard available for the severity of CAG at the irreversible stage. Serum PG assay may be a good selection as PG level can indicate the severity of CAG and the efficancy of H. pylori eradication.,, Osumi et al. proposed that a significant increase of PG I/II ratio is a reliable biomarker for evaluation of successful H. pylori eradication, with 93.1% sensitivity and 93.8% specificity. Thus, further studies are required to define the optimal PG cutoff values of gastric atrophy on the basis of histology and a PG serum level on the irreversible stage of gastric mucosa impairment.
Based on the original ABC method, the risk of gastric cancer is the highest in Group D, followed by Groups C, B, and A consecutively. Accordingly, it is recommended that patients in Groups B, C, and D requiring gastroscopy at the interval of each 3 years, 2 years and 1 year, respectively. Group A is excluded from endoscopic surveillance requirement because of unnecessary. However, further risk stratification by anti-H. pylori antibody titer was introduced for the early detection of gastric cancer. Kishikawa et al. believed that the interval of endoscopic surveillance should be shorten, for instances, to every 3 years for patients with a high-negative antibody titer in Group A, to every 2 years for patients with a high-positive antibody titer in Group B and to every 1 year for patients with a low-positive antibody titer in Group C.
They proposed to set up the cutoff value for H. pylori-seropositive patients at the point where H. pylori positive patients are averagely distributed into each subgroup. Whilie in H. pylori-seronegative patients, antibody titer 3–10 U/ml is considered as the high-negative titer. Patients with titer less than 3 U/ml is considered as a low-negative titer case. However, there is no consensus currently on the cutoff value of antibody titer. It is generally believed that lowering the cutoff value of H. pylori antibody titer is helpful to precisely recognize the high-risk patients for further endoscopic surveillance periodically and administrate the antibiotic therapy. Specifically, it is important to recognize the patients with positive H. pylori infection but was successfully eradicated in Group A because these patients still have a chance to develop the intestinal-type gastric cancer., In this aspect, it is always ignored. Haneda et al. suggested that the optimal cutoff value of PG I/II in posteradication is 4.5, including more gastric cancer cases compared with the traditional PG method. All in all, the prognosis improvement of gastric cancer depends on the early detection and diagnosis. In order to receive accurate risk stratification, further studies are required in the recent future.
Financial support and sponsorship
This work was supported by grants from the Natural Science Foundation of Guangdong Province, China (No. S2011010001430), the Science and Technology Planning Project of Guangdong Province, China (No. 2017A030223006, 2016A020215128, 2014A020212636, and 2013B021800161), the Science and Technology Planning Project of Guangzhou, China (No. 201704020077), the Research Fund of Guangdong General Hospital (No. y012015338), the Yuexiu Science and Information Center of Guangzhou Scientific Foundation (No. 2012-GX-046).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, et al.
Recent patterns in gastric cancer: A global overview. Int J Cancer 2009;125:666-73. doi: 10.1002/ijc.24290.
Peleteiro B, Severo M, La Vecchia C, Lunet N. Model-based patterns in stomach cancer mortality worldwide. Eur J Cancer Prev 2014;23:524-31. doi: 10.1097/CEJ.0b013e328364f2b6.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al.
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86. doi: 10.1002/ijc.29210.
Correa P. A human model of gastric carcinogenesis. Cancer Res 1988;48:3554-60.
Nakajima N, Ito Y, Yokoyama K, Uno A, Kinukawa N, Nemoto N, et al.
The expression of murine double minute 2 (MDM2) on Helicobacter pylori
-infected intestinal metaplasia and gastric cancer. J Clin Biochem Nutr 2009;44:196-202. doi: 10.3164/jcbn.08-254.
Lauren P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31-49. doi: 10.1111/apm.19188.8.131.52.
Zhong C, Li KN, Bi JW, Wang BC. Sodium intake, salt taste and gastric cancer risk according to Helicobacter pylori
infection, smoking, histological type and tumor site in China. Asian Pac J Cancer Prev 2012;13:2481-4. doi: 10.7314/APJCP.2012.13.6.2481.
Takahashi S. Long-term Helicobacter pylori
infection and the development of atrophic gastritis and gastric cancer in Japan. J Gastroenterol 2002;37 Suppl 13:24-7. doi: 10.1016/j.gie.2011.08.030.
Vohlonen I, Pukkala E, Malila N, Härkönen M, Hakama M, Koistinen V, et al.
Risk of gastric cancer in Helicobacter pylori
infection in a 15-year follow-up. Scand J Gastroenterol 2016;51:1-9. doi: 10.1080/00365521.2016.1183225.
Tsukuma H, Oshima A, Narahara H, Morii T. Natural history of early gastric cancer: A non-concurrent, long term, follow up study. Gut 2000;47:618-21. doi: 10.1136/gut.47.5.618.
Lu J, Huang CM, Zheng CH, Li P, Xie JW, Wang JB, et al.
Consideration of tumor size improves the accuracy of TNM predictions in patients with gastric cancer after curative gastrectomy. Surg Oncol 2013;22:167-71. doi: 10.1016/j.suronc.2013.05.002.
Suzuki H, Gotoda T, Sasako M, Saito D. Detection of early gastric cancer: Misunderstanding the role of mass screening. Gastric Cancer 2006;9:315-9. doi: 10.1007/s10120-006-0399-y.
Oshima A, Hirata N, Ubukata T, Umeda K, Fujimoto I. Evaluation of a mass screening program for stomach cancer with a case-control study design. Int J Cancer 1986;38:829-33. doi: 10.1002/ijc.2910380608.
Fukao A, Tsubono Y, Tsuji I, HIsamichi S, Sugahara N, Takano A, et al.
The evaluation of screening for gastric cancer in Miyagi Prefecture, Japan: A population-based case-control study. Int J Cancer 1995;60:45-8. doi: 10.1002/ijc.2910600106.
Hamashima C, Shibuya D, Yamazaki H, Inoue K, Fukao A, Saito H, et al.
The Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol 2008;38:259-67. doi: 10.1093/jjco/hyn017.
Miki K. Gastric cancer screening using the serum pepsinogen test method. Gastric Cancer 2006;9:245-53. doi: 10.1007/s10120-006-0397-0.
Ichinose M, Yahagi N, Oka M, Ikeda H, Miki K, Omata M. Screening for gastric cancer in Japan. Humana Press, Totowa, NJ; 2002.
Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, Goh KL, et al.
Screening for gastric cancer in Asia: Current evidence and practice. Lancet Oncol 2008;9:279-87. doi: 10.1016/S1470-2045(08)70072-X.
Wan QS, Zhang KH. Noninvasive detection of gastric cancer. Tumour Biol 2016;37:1-11. doi: 10.1007/s13277-016-5129-4.
Yamaguchi Y, Nagata Y, Hiratsuka R, Kawase Y, Tominaga T, Takeuchi S, et al.
Gastric cancer screening by combined assay for serum anti-Helicobacter pylori
IgG antibody and serum pepsinogen levels – The ABC method. Digestion 2016;93:13-8. doi: 10.1159/000441742.
Kodashima S, Miki K, Fujishiro M, Yahagi N. Gastric cancer risk A, B, C, D gastritis screening (ABC screening) using the combination assay of serum anti-Helicobacter pylor
i IgG antibody and the serum pepsinogen levels. Am J Gastroenterol 2011:106:S44-S44.
Saito S, Azumi M, Muneoka Y, Nishino K, Ishikawa T, Sato Y, et al.
Cost-effectiveness of combined serum anti-Helicobacter pylori
IgG antibody and serum pepsinogen concentrations for screening for gastric cancer risk in Japan. Eur J Health Econ 2017;1-11. doi: 10.1007/s10198-017-0901-y.
Asaka M, Kato M, Graham DY. Strategy for eliminating gastric cancer in Japan. Helicobacter 2010;15:486-90. doi: 10.1111/j.1523-5378.2010.00799.x.
Marshall BJ. One Hundred Years of Discovery and Rediscovery of Helicobacter pylori
and Its Association with Peptic Ulcer Disease – Helicobacter pylori
– NCBI Bookshelf. Washington (DC): Asm Press; 2001.
Tsai KF, Liou JM, Chen MJ, Chen CC, Kuo SH, Lai IR, et al.
Distinct clinicopathological features and prognosis of Helicobacter pylori
negative gastric cancer. PLoS One 2017;12:e0170942. doi: 10.1371/journal.pone.0170942.
Kato S, Matsukura N, Tsukada K, Matsuda N, Mizoshita T, Tsukamoto T, et al. Helicobacter pylori
infection-negative gastric cancer in Japanese hospital patients: Incidence and pathological characteristics. Cancer Sci 2007;98:790-4. doi: 10.1111/j.1349-7006.2007.00478.x.
Matsuo T, Ito M, Takata S, Tanaka S, Yoshihara M, Chayama K, et al.
Low prevalence of Helicobacter pylori
-negative gastric cancer among Japanese. Helicobacter 2011;16:415-9. doi: 10.1111/j.1523-5378.2011.00889.x.
Yoon H, Kim N, Lee HS, Shin CM, Park YS, Lee DH, et al. Helicobacter pylori
-negative gastric cancer in South Korea: Incidence and clinicopathologic characteristics. Helicobacter 2011;16:382-8. doi: 10.1111/j.1523-5378.2011.00859.x.
Yamamoto Y, Fujisaki J, Omae M, Hirasawa T, Igarashi M. Helicobacter pylori
-negative gastric cancer: Characteristics and endoscopic findings. Dig Endosc 2015;27:551-61. doi: 10.1111/den.12471.
Fock KM, Ang TL. Epidemiology of Helicobacter pylori
infection and gastric cancer in Asia. J Gastroenterol Hepatol 2010;25:479-86. doi: 10.1111/j.1440-1746.2009.06188.x.
Hui PK, Chan WY, Cheung PS, Chan JK, Ng CS. Pathologic changes of gastric mucosa colonized by Helicobacter pylori
. Hum Pathol 1992;23:548-56. doi: 10.1016/0046-8177(92)90132-M.
Hsu PI, Lai KH, Tseng HH, Liu YC, Yen MY, Lin CK, et al.
Correlation of serum immunoglobulin G Helicobacter pylori
antibody titers with histologic and endoscopic findings in patients with dyspepsia. J Clin Gastroenterol 1997;25:587-91. doi: 10.1097/00004836-199712000-00007.
Wang L, Chang EW, Wong SC, Ong SM, Chong DQ, Ling KL, et al.
Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins. J Immunol 2013;190:794-804. doi: 10.4049/jimmunol.1202088.
Koizumi W, Tanabe S, Imaizumi H, Hibi K, Kida M, Ohida M,et al
. Effect of anti-Helicobacter pylori
IgG antibody titer following eradication of Helicobacter pylori
infection. Hepatogastroenterology 2003;50:293-6.
Gritti I, Banfi G, Roi GS. Pepsinogens: Physiology, pharmacology pathophysiology and exercise. Pharmacol Res 2000;41:265-81. doi: 10.1006/phrs.1999.0586.
Samloff IM. Cellular localization of group I pepsinogens in human gastric mucosa by immunofluorescence. Gastroenterology 1971;61:185-8.
Samloff IM, Liebman WM. Cellular localization of the group II pepsinogens in human stomach and duodenum by immunofluorescence. Gastroenterology 1973;65:36-42.
Ichinose M, Miki K, Furihata C, Kageyama T, Niwa H, Oka H, et al.
Radioimmunoassay of group II pepsinogen in human serum. Clin Chim Acta 1982;122:61-9. doi: 10.1016/0009-8981(82)90095-X.
Ichinose M, Miki K, Furihata C, Kageyama T, Hayashi R, Niwa H, et al.
Radioimmunoassay of serum group I and group II pepsinogens in normal controls and patients with various disorders. Clin Chim Acta 1982;126:183-91. doi: 10.1016/0009-8981(82)90034-1.
Samloff IM, Varis K, Ihamaki T, Siurala M, Rotter JI. Relationships among serum pepsinogen I, serum pepsinogen II, and gastric mucosal histology. A study in relatives of patients with pernicious anemia. Gastroenterology 1982;83:204-9.
Shafaghi A, Mansour-Ghanaei F, Joukar F, Sharafkhah M, Mesbah A, Askari K, et al.
Serum gastrin and the pepsinogen I/II ratio as markers for diagnosis of premalignant gastric lesions. Asian Pac J Cancer Prev 2013;14:3931-6. doi: 10.7314/APJCP.2013.14.6.3931.
Cao XY, Jia ZF, Jin MS, Cao DH, Kong F, Suo J, et al.
Serum pepsinogen II is a better diagnostic marker in gastric cancer. World J Gastroenterol 2012;18:7357-61. doi: 10.3748/wjg.v18.i48.7357.
Nejadi-Kelarijani F, Roshandel G, Semnani S, Ahmadi A, Faghani B, Besharat S,et al
. Diagnostic values of serum levels of pepsinogens and gastrin-17 for screening gastritis and gastric cancer in a high risk area in Northern Iran. Asian Pac J Cancer Prev 2014;15:7433-6. doi: 10.7314/APJCP.2014.15.17.7433.
Kitamura Y, Yoshihara M, Ito M, Boda T, Matsuo T, Kotachi T, et al.
Diagnosis of Helicobacter pylori
-induced gastritis by serum pepsinogen levels. J Gastroenterol Hepatol 2015;30:1473-7. doi: 10.1111/jgh.12987.
Miki K. Gastric cancer screening by combined assay for serum anti-Helicobacter pylori
IgG antibody and serum pepsinogen levels – “ABC method”. Proc Jpn Acad Ser B Phys Biol Sci 2011;87:405-14. doi: 10.2183/pjab.87.405.
Miki K. Usefulness of gastric cancer screening using the serum pepsinogen test method. Am J Gastroenterol 2002;97:245-53. doi: 10.1016/S0002-9270(03)00128-X.
Watanabe Y, Kurata JH, Mizuno S, Mukai M, Inokuchi H, Miki K, et al. Helicobacter pylori
infection and gastric cancer. A nested case-control study in a rural area of Japan. Dig Dis Sci 1997;42:1383-7.
Park CH, Kim EH, Jung DH, Chung H, Park JC, Shin SK, et al.
The new modified ABCD method for gastric neoplasm screening. Gastric Cancer 2016;19:128-35. doi: 10.1007/s10120-015-0473-4.
Inoue K. Gastric cancer screening using ABC classification. Nihon Rinsho 2012;70:1790-4.
Watabe H, Mitsushima T, Yamaji Y, Okamoto M, Wada R, Kokubo T, et al.
Predicting the development of gastric cancer from combining Helicobacter pylori
antibodies and serum pepsinogen status: A prospective endoscopic cohort study. Gut 2005;54:764-8. doi: 10.1136/gut.2004.055400.
Kudo T, Kakizaki S, Sohara N, Onozato Y, Okamura S, Inui Y, et al.
Analysis of ABC (D) stratification for screening patients with gastric cancer. World J Gastroenterol 2011;17:4793-8. doi: 10.3748/wjg.v17.i43.4793.
Kishikawa H, Kimura K, Takarabe S, Kaida S, Nishida J. Helicobacter pylori
antibody titer and gastric cancer screening. Dis Markers 2015;2015:156719. doi: 10.1155/2015/156719.
Ikeda F, Shikata K, Hata J, Fukuhara M, Hirakawa Y, Ohara T, et al.
Combination of Helicobacter pylori
antibody and serum pepsinogen as a good predictive tool of gastric cancer incidence: 20-year prospective data from the Hisayama study. J Epidemiol 2016;26:629-36. doi: 10.2188/jea.JE20150258.
Lee SY. Future candidates for indications of Helicobacter pylori
eradication: Do the indications need to be revised? J Gastroenterol Hepatol 2012;27:200-11. doi: 10.1111/j.1440-1746.2011.06961.x.
Liu KS, Wong IO, Leung WK. Helicobacter pylori
associated gastric intestinal metaplasia: Treatment and surveillance. World J Gastroenterol 2016;22:1311-20. doi: 10.3748/wjg.v22.i3.1311.
Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT, et al.
Early Helicobacter pylori
eradication decreases risk of gastric cancer in patients with peptic ulcer disease. Gastroenterology 2009;137:1641-80. doi: 10.1053/j.gastro.2009.07.060.
Take S, Mizuno M, Ishiki K, Nagahara Y, Yoshida T, Yokota K, et al.
Baseline gastric mucosal atrophy is a risk factor associated with the development of gastric cancer after Helicobacter pylori
eradication therapy in patients with peptic ulcer diseases. J Gastroenterol 2007;42 Suppl 17:21-7. doi: 10.1007/s00535-006-1924-9.
Lee SY. Endoscopic gastritis, serum pepsinogen assay, and Helicobacter pylori
infection. Korean J Intern Med 2016;31:835-44. doi: 10.3904/kjim.2016.166.
Miura K, Okada H, Kouno Y, Kanzaki H, Iwamuro M, Hori K, et al.
Actual status of involvement of Helicobacter pylori
infection that developed gastric cancer from group A of ABC (D) stratification – Study of early gastric cancer cases that underwent endoscopic submucosal dissection. Digestion 2016;94:17-23. doi: 10.1159/000446771.
Matsuo T, Ito M, Tatsugami M, Boda T, Takata S, Tanaka S, et al.
Gastric cancer development after Helicobacter pylori
eradication therapy: A new form of gastric neoplasia. Digestion 2012;85:61-7. doi: 10.1159/000335260.
Boda T, Ito M, Yoshihara M, Kitamura Y, Matsuo T, Oka S, et al.
Advanced method for evaluation of gastric cancer risk by serum markers: Determination of true low-risk subjects for gastric neoplasm. Helicobacter 2014;19:1-8. doi: 10.1111/hel.12101.
Take S, Mizuno M, Ishiki K, Yoshida T, Ohara N, Yokota K, et al.
The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori
. J Gastroenterol 2011;46:318-24. doi: 10.1007/s00535-010-0347-9.
Kobayashi M, Sato Y, Terai S. Endoscopic surveillance of gastric cancers after Helicobacter pylori
eradication. World J Gastroenterol 2015;21:10553-62. doi: 10.3748/wjg.v21.i37.10553.
Watanabe M, Kato J, Inoue I, Yoshimura N, Yoshida T, Mukoubayashi C, et al.
Development of gastric cancer in nonatrophic stomach with highly active inflammation identified by serum levels of pepsinogen and Helicobacter pylori
antibody together with endoscopic rugal hyperplastic gastritis. Int J Cancer 2012;131:2632-42. doi: 10.1002/ijc.27514.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A, et al.
Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108. doi: 10.3322/caac.21262.
Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to Helicobacter pylori
. Int J Cancer 2015;136:487-90. doi: 10.1002/ijc.28999.
Sung J, Kim N, Lee J, Hwang YJ, Kim HW, Chung JW, et al.
Associations among gastric juice pH, atrophic gastritis, intestinal metaplasia and Helicobacter pylori
infection. Gut Liver 2018; 12:158-64. doi: 10.5009/gnl17063.
Kodama M, Murakami K, Okimoto T, Abe H, Sato R, Ogawa R, et al.
Histological characteristics of gastric mucosa prior to Helicobacter pylori
eradication may predict gastric cancer. Scand J Gastroenterol 2013;48:1249-56. doi: 10.3109/00365521.2013.838994.
Osborn JF, Cattaruzza MS, Ferri AM, De Angelis F, Renzi D, Marani A, et al.
How long will it take to reduce gastric cancer incidence by eradicating Helicobacter pylori
infection? Cancer Prev Res (Phila) 2013;6:695-700. doi: 10.1158/1940-6207.CAPR-12-0428.
Rugge M. Gastric cancer risk in patients with Helicobacter pylori
infection and following its eradication. Gastroenterol Clin North Am 2015;44:609-24. doi: 10.1016/j.gtc.2015.05.009.
Asaka M, Mabe K, Matsushima R, Tsuda M. Helicobacter pylori
eradication to eliminate gastric cancer: The Japanese strategy. Gastroenterol Clin North Am 2015;44:639-48. doi: 10.1016/j.gtc.2015.05.010.
Tatemichi M, Sasazuki S, Inoue M, Tsugane S; JPHC Study Group. Clinical significance of IgG antibody titer against Helicobacter pylori
. Helicobacter 2009;14:231-6. doi: 10.1111/j.1523-5378.2009.00681.x.
Yoshida T, Kato J, Inoue I, Yoshimura N, Deguchi H, Mukoubayashi C, et al.
Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori
antibody titer. Int J Cancer 2014;134:1445-57. doi: 10.1002/ijc.28470.
Chen HN, Wang Z, Li X, Zhou ZG. Helicobacter pylori
eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: Evidence from a meta-analysis. Gastric Cancer 2016;19:166-75. doi: 10.1007/s10120-015-0462-7.
Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori
-induced gastric inflammation and gastric cancer. Cancer Lett 2014;345:196-202. doi: 10.1016/j.canlet.2013.08.016.
Loor A, Dumitraşcu DL. Helicobacter pylori
infection, gastric cancer and gastropanel. Rom J Intern Med 2016;54:151-6. doi: 10.1515/rjim-2016-0025.
Mizuno S, Miki I, Ishida T, Yoshida M, Onoyama M, Azuma T, et al.
Prescreening of a high-risk group for gastric cancer by serologically determined Helicobacter pylori
infection and atrophic gastritis. Dig Dis Sci 2010;55:3132-7. doi: 10.1007/s10620-010-1154-0.
Toyoda K, Furusyo N, Ihara T, Ikezaki H, Urita Y, Hayashi J, et al.
Serum pepsinogen and Helicobacter pylori
infection – A Japanese population study. Eur J Clin Microbiol Infect Dis 2012;31:2117-24. doi: 10.1007/s10096-011-1543-0.
Huang RG, Xiao HL, Zhou B, Song XH, Zhang J, Wang CM, et al.
Serum pepsinogen levels are correlated with age, sex and the level of Helicobacter pylori
infection in healthy individuals. Am J Med Sci 2016;352:481-6. doi: 10.1016/j.amjms.2016.08.005.
Cao Q, Ran ZH, Xiao SD. Screening of atrophic gastritis and gastric cancer by serum pepsinogen, gastrin-17 and Helicobacter pylori
immunoglobulin G antibodies. J Dig Dis 2007;8:15-22. doi: 10.1111/j.1443-9573.2007.00271.x.
Bölükbaş C, Bölükbaş FF, Ovünç O, Kiliç G, Dalay R, Güven H, et al.
Relationship between Helicobacter pylori
status and serum pepsinogens as serologic markers in atrophic gastritis. Turk J Gastroenterol 2006;17:172-6.
Veenendaal RA, Biemond I, Peña AS, van Duijn W, Kreuning J, Lamers CB, et al.
Influence of age and Helicobacter pylori
infection on serum pepsinogens in healthy blood transfusion donors. Gut 1992;33:452-5. doi: 10.1136/gut.33.4.452.
Watari J, Chen N, Amenta PS, Fukui H, Oshima T, Tomita T, et al. Helicobacter pylori
associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol 2014;20:5461-73. doi: 10.3748/wjg.v20.i18.5461.
Tahara T, Shibata T, Horiguchi N, Kawamura T, Okubo M, Ishizuka T, et al.
Apossible link between gastric mucosal atrophy and gastric cancer after Helicobacter pylori
eradication. PLoS One 2016;11:S870-71. doi: 10.1371/journal.pone.0163700.
Katicić M, Banić M, Urek MC, Gasparov S, Krznarić Z, Prskalo M, et al.
Croatian guidelines for gastric cancer prevention by eradication of Helicobacter pylori
infection. Lijec Vjesn 2014;136:59-68.
Dinis-Ribeiro M, Areia M, Vries AC, Marcos-Pinto R, Monteiro-Soares M, O'Connor A, et al
. Management of precancerous conditions and lesions in the stomach (MAPS): Guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Virchows Arch 2012;460:19-46. doi: 10.1007/s00428-011-1177-8.
Leja M, Lapina S, Polaka I, Rudzite D, Vilkoite I, Daugule I, et al.
Pepsinogen testing for evaluation of the success of Helicobacter pylori
eradication at 4 weeks after completion of therapy. Medicina (Kaunas) 2014;50:8-13. doi: 10.1016/j.medici.2014.05.001.
Osumi H, Fujisaki J, Suganuma T, Horiuchi Y, Omae M, Yoshio T, et al.
Asignificant increase in the pepsinogen I/II ratio is a reliable biomarker for successful Helicobacter pylori
eradication. PLoS One 2017;12:e0183980. doi: 10.1371/journal.pone.0183980.
Choi HS, Lee SY, Kim JH, Sung IK, Park HS, Shim CS, et al.
Combining the serum pepsinogen level and Helicobacter pylori
antibody test for predicting the histology of gastric neoplasm. J Dig Dis 2014;15:293-8. doi: 10.1111/1751-2980.12144.
Kotachi T, Ito M, Yoshihara M, Boda T, Kiso M, Masuda K, et al.
Serological evaluation of gastric cancer risk based on pepsinogen and Helicobacter pylori
antibody: Relationship to endoscopic findings. Digestion 2017;95:314-8. doi: 10.1159/000477239.
Kishikawa H, Kimura K, Ito A, Arahata K, Takarabe S, Kaida S,et al
. Predictors of gastric neoplasia in cases negative for Helicobacter pylor
i antibody and with normal pepsinogen. Anticancer Res 2015;35:6765-71.
Haneda M, Kato M, Ishigaki S, Suzuki M, Takahashi M, Nakagawa M, et al.
Identification of a high risk gastric cancer group using serum pepsinogen after successful eradication of Helicobacter pylori
. J Gastroenterol Hepatol 2013;28:78-83. doi: 10.1111/j.1440-1746.2012.07285.x.