The Impact of Endoscopic Surveillance of Atrophic Gastritis With and Without Intestinal Metaplasia on a High-risk Population for Gastric Cancer in Latin America: The ECHOS Cohort Study.
Conditions: Gastric Cancer, Dysplasia Stomach, Atrophic Gastritis, Helicobacter Pylori Infection
Sponsor: Pontificia Universidad Catolica de Chile

 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan: 
 
The impact of endoscopic surveillance of 
atrophic gastritis with and without intestinal 
metaplasia on a high-risk population for 
gastric cancer in Latin America: The 
ECHOS cohort study 
 
 
 
 
 
 
 
 
 
NCT: not assigned 
July 10, 2023 
 
 

INTRODUCTION 
 
Gastric cancer is the 5th most common cancer and the 4th leading cause of cancer-related deaths 
worldwide.1 Chronic atrophic gastritis (CAG) is part of a sequential histopathological cascade that 
precedes the development of gastric adenocarcinoma (GA).2 Chronic Helicobacter pylori (H. 
pylori) infection is the primary trigger of this cascade and leads to chronic inflammatory changes 
in the gastric mucosa which can lead to CAG, intestinal metaplasia (IM), dysplasia and eventually 
GA.3,4 
 
Multiple strategies have been suggested for GA prevention.5-8 Primary prevention is based on the 
recognition and treatment of H. pylori as the main risk factor for GA.9-12 Secondary prevention 
relies on endoscopic surveillance of high-risk patients for the detection of early-stage GA with 
potentially curative resection. CAG and IM can be accurately identified and graded through gastric 
mapping biopsies obtained according to the updated Sydney System biopsy protocol (USSBP).13 
Staging of preneoplastic conditions with Operative Link on Gastritis Assessment (OLGA) or 
Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) scales14 has demonstrated 
to accurately predict the risk of progression to GA in some populations;15-18 however, the value of 
these systems for risk stratification has not been comprehensively evaluated in a high-risk Latin 
American population.  
 
In Chile, gastric cancer is the leading cause of cancer-related deaths in men and the 3rd in females, 
with mortality rates of 25 and 12.2 per 100,000 inhabitants, respectively. Risk stratification of 
patients with CAG/IM would help with prioritization of EGDs for those with CAG/IM at highest 
risk of progression and minimizing endoscopic burden. However, there are limited data in Latin 
America regarding risk factors associated with progression of gastric preneoplasia, and 
specifically, the performance of OLG/OLGIM staging for risk stratification.24  
 
Accordingly, our objective was to evaluate the risk factors associated with incident high grade 
dysplasia (HGD)/GA in patients with CAG with or without IM who are enrolled in endoscopic 
surveillance, as well as to compare HGD/GA incidence according to the OLGA and OLGIM 

scales. As an exploratory analysis, we also evaluated the stage of GA among those enrolled in 
endoscopic surveillance, given that most GA in Chile are diagnosed in the advanced stage. 
 
METHODS 
 
Study design and settings 
 
The Endoscopic Cohort and Histological OLGA staging (ECHOS) study is a retrospective 
longitudinal cohort developed in the Pontificia Universidad Católica de Chile health care system, 
an open health care system with 3 endoscopic units in Santiago, Chile. Patients 18 years or older 
were eligible for the study if they had at least one non-urgent outpatient EGD with gastric biopsies 
collected following the USSBP between June 2015 and June 2021. The baseline EGD was defined 
as the earliest examination conducted between this time frame that met inclusion criteria. 
Participants were included in the cohort if they underwent a subsequent "surveillance" EGD. In 
order for the subsequent EGD to qualify as surveillance, it needed to occur at least 6 months after 
the baseline EGD and include gastric biopsies collected according to the USSBP; one exception 
to the USSBP requirement was if HGD or GA was detected on the surveillance (i.e. non-baseline) 
EGD. Patients with prior history of HGD or any type of gastric malignancy, gastrectomy or non-
gastric active malignancy were excluded. Also, patients with HGD or GA on the baseline EGD 
were excluded. Patients with indefinite (IND) or low-grade dysplasia (LGD) on the baseline EGD 
were considered for the cohort (see below).  
 
Demographic variables, medical comorbidities, and first-degree family history of gastric cancer 
were recorded from clinical records. The baseline and follow-up endoscopic findings were 
abstracted from the procedure reports, including the presence of any overt lesions or abnormalities. 
The baseline and follow-up histological findings, including H. pylori status (as defined by 
histologic findings), CAG and IM anatomical extent, IM histologic type, and OLGA/OLGIM stage 
(detailed below) were recorded. Although EGD surveillance schedules were determined by the 
endoscopist, these generally followed the published Chilean guideline recommendations for CAG 
and IM endoscopic surveillance—namely, surveillance annually for OLGA III/IV, IND, or LGD, 
every 3 years for OLGA I/II and every 5 years if OLGA 0 with persistent H. pylori infection.21  

Endoscopic follow-up of all individuals with their baseline EGD between June 2015-2021 was 
captured through the end of the study period, March 6, 2023. The composite primary outcome was 
defined as incident HGD or GA, as confirmed based on histology. Secondary outcomes were 
incident GA alone, incident LGD, global histopathological progression (defined as a progression 
from one global stage in the precancerous cascade to another, e.g. from chronic superficial gastritis 
(CSG) to CAG or from CAG without IM to IM), progression or regression of OLGA and OLGIM 
stages (defined as an increase or decrease of at least one point in the scales, e.g. OLGA II to III). 
We also captured the stage of GA. A flow chart of the study is illustrated in Supplementary 
Figure 1.  
 
Procedures were performed according to ethical standards established in the Helsinki Declaration. 
The study protocol was approved by the Ethics Committee of Hospital Clínico Universidad 
Católica de Chile (ID 16-341). All patients signed written informed consent for the EGD prior to 
the procedure. 
 
EGD and gastric biopsies sampling method 
 
All baseline and surveillance EGDs were performed by experienced endoscopists using the same 
equipment across the 3 endoscopic units (Olympus (GIF-H190/GIF-H170 or Fujinon EC-600ZW). 
Gastric biopsies were obtained following the USSBP as described in supplementary methods and 
additional gastric biopsies were collected and stored in a different jar if there were any additional 
concerning findings during the EGD.  
 
Histological classification of gastric biopsies 
 
Gastric samples were evaluated at one centralized pathology laboratory by two independent 
experienced pathologists (JT and JCR). Biopsies were hematoxylin and eosin (H&E) and Giemsa 
stained. Evaluation of CAG was performed according to the OLGA scale (stages 0 to IV).13 IM 
was classified for clinical purposes by the anatomical extent (antrum-restricted vs. corpus-
extended) and the histological subtype (complete type vs. incomplete type) based on H&E. All 
slides were retrospectively reviewed by the pathologists (JT and JCR) to confirm the baseline 

presence or absence of CAG/IM and to provide a corresponding OLGIM stage.25 Agreement 
between the pathologists for OLGA groups, OLGIM groups and IM were Kappa 0.73, 0.78 and 
0.86, respectively. In all discrepant cases, an agreement was reached between the pathologists with 
no need for a third pathologist as an arbiter. Gastric dysplasia was categorized as IND, LGD or 
HGD according to the Vienna classification.26 The most advanced discrete histology observed in 
the set of biopsies was used as the global diagnosis for analysis purposes. Antrum-restricted IM 
was defined as IM located only in the antrum or incisura angularis without evidence of corpus 
involvement, while corpus-extended IM was defined as IM located in the corpus irrespective of 
the findings in the antrum or incisura angularis.  
 
Active H. pylori infection was determined based on Giemsa staining in any of the gastric samples. 
Presence of H. pylori at both baseline and surveillance EGD was considered as persistent H. pylori 
infection; whereas positive H. pylori at baseline and negative at follow-up was considered H. 
pylori eradication, as long as treatment occurred in between. Autoimmune gastritis (AIG) 
histologic features were also assessed and recorded (further described in supplementary 
methods).27  
 
Statistical Analysis Plan 
 
Patients were categorized based on OLGA and OLGIM stage as low-risk (OLGA/OLGIM 0-I), 
intermediate-risk (OLGA/OLGIM II) and high-risk (OLGA/OLGIM III-IV).15-18 Demographic 
and clinical characteristics were compared between the OLGA/OLGIM groups. Categorical 
variables were expressed as percentages (%) and continuous variables were expressed as mean and 
95% confidence interval (95%CI) or median and interquartile range (IQR) as appropriate. The Chi-
square test was used to compare categorical variables and differences in continuous variables were 
evaluated with t-test or Mann-Whitney U test, as appropriate. 
 
For the primary analysis, we analyzed the rate of progression to HGD/GA in each of the defined 
OLGA/OLGIM groups, expressed as incidence rate per 100 person-year with 95%CI. Also, given 
that OLGA/OLGIM II is potentially an intermediate-risk category,15-18 we conducted a subgroup 
analysis evaluating factors associated with progression of OLGA II vs. OLGA 0/I. For the models 

evaluating cumulative HGD/GA risk, follow-up time started at the baseline EGD and continued 
until the earliest of the following: last available surveillance EGD, occurrence of HGD/GA or 
death. Cumulative risk of the composite primary outcome was estimated from Kaplan-Meier 
functions. 
 
Univariate and multivariable Cox proportional hazards models were used to assess factors 
associated with HGD/GA, expressed as hazard ratio (HR) and 95%CI. Given the expected low 
number of primary outcome events (HGD/GA), Poisson regression models were used as a 
sensitivity analysis to estimate the adjusted incidence rate ratio (aIRR) by OLGA and OLGIM 
staging. Separate models for OLGA and OLGIM staging were performed, given the high 
correlation and collinearity of this variables. Models were adjusted for age, sex, active H. pylori 
infection, and the number of surveillances EGDs during the study period.  
 
Secondary analyses included 1) differences in progression to HGD/GA based on anatomic extent 
and IM subtype, according to the following subgroups: antral-restricted complete-type IM, antral-
restricted incomplete-type IM, corpus-extended complete-type IM and corpus-extended 
incomplete-type IM, using the log-rank test for equality survival function. Patients with 
unavailable IM histological subtype were excluded from these analyses (i.e. “IM unavailable, 
10.9%”); 2) change in a global histological category with respect to either histopathological 
progression or regression; 3) changes in OLGA and OLGIM stages during the follow-up. 
Multivariable logistic regression analyses, adjusted for age, sex and H. pylori infection, were used 
to evaluate factors associated with histopathological or OLGA/OLGIM progression and regression 
(binary outcome), and expressed as adjusted odds ratios (aOR) and 95%CI. We also evaluated the 
stage of GA among patients enrolled in endoscopic surveillance. 
 
As an exploratory analysis, we characterized the demographic and histopathological characteristics 
of those patients who had baseline EGD with USSBP but who did not undergo subsequent 
surveillance EGD (and thus did not meet inclusion criteria for the primary analytic cohort). 
 

An a priori two-sided p-value threshold of 0.05 was established for statistically significant results. 
All statistical analyses were conducted using STATA v14.2 (Statacorp, College Station, TX, 
USA). 
 
REFERENCES 
1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021.  
2. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–First American 
Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 
1992;52:6735-6740. 
3. International Agency for Research on Cancer. Schistosomes, liver flukes and Helicobacter 
pylori. Lyon, France: IARC, 1994.  
4. Correa P. A human model of gastric carcinogenesis. Cancer Res. 1988;48:3554-60.  
5. Gupta S, Li D, El Serag HB, et al. AGA Clinical Practice Guidelines on Management of Gastric 
Intestinal Metaplasia. Gastroenterology 2020; 158(3):693-702. 
6. Pimentel-Nunes P, Libânio D, Marcos-Pinto R, et al. Management of epithelial precancerous 
conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal 
Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European 
Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) 
guideline update 2019. Endoscopy 2019;51(4):365-388.  
7. Banks M, Graham D, Jansen M, et al. British Society of Gastroenterology guidelines on the 
diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. 2019 
Sep;68(9):1545-1575.  
8. Matysiak-Budnik T, Camargo MC, Piazuelo MB, et al. Recent Guidelines on the Management 
of Patients with Gastric Atrophy: Common Points and Controversies. Dig Dis Sci 
2020;65(7):1899-1903. 
9. Yan L, Chen Y, Chen F, et al. Effect of Helicobacter pylori Eradication on Gastric Cancer 
Prevention: Updated Report From a Randomized Controlled Trial With 26.5 Years of Follow-
up. Gastroenterology. 2022 Mar 29:S0016-5085(22)00338-9.  
10. Choi IJ, Kook M-C, Kim Y-I, et al. Helicobacter pylori therapy for the prevention of 
metachronous gastric cancer. N Engl J Med 2018;378:1085-1095. 

11. Choi IJ, Kim CG, Lee JY, et al. Family History of gastric cancer and Helicobacter pylori 
treatment. N Engl J Med 2020;382:427–436.  
12. Chiang TH, Chang WJ, Chen SL, et al. Mass eradication of Helicobacter pylori to reduce 
gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands. Gut. 2021 
Feb;70(2):243-250.  
13. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading of gastritis. The updated 
Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am 
J Surg Pathol 1996;20(10):1161-81. 
14. Capelle LG, de Vries AC, Haringsma J, et al. The staging of gastritis with the OLGA system 
by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointest 
Endosc. 2010 Jun;71(7):1150-8.  
15. Rugge M, Genta RM, Fassan M, et al. OLGA Gastritis Staging for the Prediction of Gastric 
Cancer Risk: A Long-term Follow-up Study of 7436 Patients. Am J Gastroenterol 2018; 
113(11):1621-1628. 
16. Lee JWJ, Zhu F, Srivastava S, et al. Severity of gastric intestinal metaplasia predicts the risk of 
gastric cancer: a prospective multicentre cohort study (GCEP). Gut. 2021 May 11:gutjnl-2021-
324057.  
17. Yue H, Shan L, Bin L. The significance of OLGA and OLGIM staging systems in the risk 
assessment of gastric cancer: a systematic review and meta-analysis. Gastric Cancer. 2018 
Jul;21(4):579-587.  
18. den Hollander WJ, Holster IL, den Hoed CM, et al. Surveillance of premalignant gastric lesions: 
a multicentre prospective cohort study from low incidence regions. Gut. 2019 Apr;68(4):585-
593. 
19. Torres-Roman JS, Alvarez CS, Guerra-Canchari P, et al. Sex and age differences in mortality 
trends of gastric cancer among Hispanic/Latino populations in the United States, Latin America, 
and the Caribbean. Lancet Reg Health Am. 2022 Oct 7;16:100376.  
20. Ministry of Health of Chile. Mortality statistics. In: Information. DoHSa, editor. [cited 2022 
Jan 15]. Available from: https://deis.minsal.cl. 
21. Rollán A, Cortés P, Calvo A, et al. Recommendations of the Chilean Association for Digestive 
Endoscopy for the management of gastric pre-malignant lesions. Rev Med Chile 2014; 142: 
1181-92.  

22. Latorre G, Álvarez  J, Ivanovic-Zuvic D, et al. Coverage of diagnostic upper gastrointestinal 
endoscopy for the prevention of gastric cancer in Chile: results from the 2009-2010 National 
Health Survey. Rev Med Chil. 2015 Sep;143(9):1198-205. 
23. González N, Parra-Blanco A, Arantes V, Mönkemüller. Current status of endoscopic 
submucosal dissection in Latin America. Acta Gastroenterol Latinoam 2016;46:213-219.  
24. Piazuelo MB, Bravo LE, Mera RM, et al. The Colombian Chemoprevention Trial: 20-Year 
Follow-Up of a Cohort of Patients with Gastric Precancerous Lesions. Gastroenterology. 2021 
Mar;160(4):1106-1117.e3. 
25. Gawron AJ, Shah SC, et al. AGA Technical Review on Gastric Intestinal Metaplasia-Natural 
History and Clinical Outcomes. Gastroenterology. 2020 Feb;158(3):705-731.e5. 
26. Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut. 2002 Jul;51(1):130-1.  
27. Lenti MV, Rugge M, Lahner E, et al. Autoimmune gastritis. Nat Rev Dis Primers 2020; 6(1):56. 
28. Shichijo S, Hirata Y, Niikura R et al. Histologic intestinal metaplasia and endoscopic atrophy 
are predictors of gastric cancer development after Helicobacter pylori eradication. Gastrointest 
Endosc 2016; 84: 618 – 624. 
29. Li D, Bautista MC, Jiang SF, et al. Risks and Predictors of Gastric Adenocarcinoma in Patients 
with Gastric Intestinal Metaplasia and Dysplasia: A Population-Based Study. Am J 
Gastroenterol. 2016 Aug;111(8):1104-13.  
30. Reddy KM, Chang JI, Shi JM, Wu BU. Risk of Gastric Cancer Among Patients With Intestinal 
Metaplasia of the Stomach in a US Integrated Health Care System. Clin Gastroenterol Hepatol. 
2016 Oct;14(10):1420-5. 
31. Song H, Ekheden IG, Zheng Z, Ericsson J, Nyrén O, Ye W. Incidence of gastric cancer among 
patients with gastric precancerous lesions: observational cohort study in a low risk Western 
population. BMJ. 2015 Jul 27;351:h3867.  
32. Matysiak-Budnik T, Camargo MC, Piazuelo MB, Leja M. Recent Guidelines on the 
Management of Patients with Gastric Atrophy: Common Points and Controversies. Dig Dis Sci. 
2020 Jul;65(7):1899-1903.  
33. Isajevs S, Liepniece-Karele I, Janciauskas D, et al. Gastritis staging: interobserver agreement 
by applying OLGA and OLGIM systems. Virchows Arch. 2014;464:403–407. 

34. González CA, Sanz-Anquela JM, Companioni O, et al. Incomplete type of intestinal metaplasia 
has the highest risk to progress to gastric cancer: results of the Spanish follow-up multicenter 
study. J Gastroenterol Hepatol. 2016 May;31(5):953-8. 
35. Whiting JL, Sigurdsson A, Rowlands DC, Hallissey MT, Fielding JW. The long term results of 
endoscopic surveillance of premalignant gastric lesions. Gut. 2002 Mar;50(3):378-81.  
36. Sano T, Katai H, Sasako M, Maruyama K. The management of early gastric cancer. Surg Oncol. 
2000 Jul;9(1):17-22.  
37. Bollschweiler E, Berlth F, Baltin C, Mönig S, Hölscher AH. Treatment of early gastric cancer 
in the Western World. World J Gastroenterol. 2014;20(19):5672-5678. 
38. Coppelli L, Díaz LA, Riquelme A, Waeger C, Rollán A, Bellolio E, et al. La derivación 
protocolizada a endoscopía asociada a la detección de Helicobacter pylori mediante antígeno 
en deposiciones disminuye lista de espera para endoscopía y optimiza la detección de lesiones 
premalignas y cáncer gástrico incipiente. Rev Med Chil. 2019;147:1382-9. 
39. de Vries AC, van Grieken NC, Looman CW et al. Gastric cancer risk in patients with 
premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology 
2008; 134: 945 – 952.  
40. Simone A, Casadei A, De Vergori E et al. Rescue endoscopy to identify site of gastric dysplasia 
or carcinoma found at random biopsies. Dig Liver Dis 2011; 43: 721 – 725.  
41. Zhao G, Xue M, Hu Y, Lai S, Chen S, Wang L. How Commonly Is the Diagnosis of Gastric 
Low Grade Dysplasia Upgraded following Endoscopic Resection? A Meta-Analysis. PLoS 
One. 2015 Jul 16;10(7):e0132699. 
42. Usui Y, Taniyama Y, Endo M, et al. Helicobacter pylori, Homologous-Recombination Genes, 
and Gastric Cancer. N Engl J Med. 2023 Mar 30;388(13):1181-1190.  
43. Rugge M, Bricca L, Guzzinati S, Sacchi D, Pizzi M, Savarino E, Farinati F, Zorzi M, Fassan 
M, Dei Tos AP, Malfertheiner P, Genta RM, Graham DY. Autoimmune gastritis: long-term 
natural history in naïve Helicobacter pylori-negative patients. Gut. 2023 Jan;72(1):30-38.