FROM PREMALIGNANT LESIONSTO EARLY GASTRIC CANCER
WHAT IS CLINICALLY RELEVANT?
ed, Tamara Matysiak-Budnik

FROM PREMALIGNANT LESIONSTO EARLY GASTRIC CANCER
WHAT IS CLINICALLY RELEVANT?
ed, Tamara Matysiak-Budnik

SUMMARY
1 FOREWORD
Tamara Matysiak-Budnik
3 EPIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE?
Jin Young Park, Melina Arnold
15 SCREENING FOR GASTRIC CANCER IN EUROPE: IS IT FEASIBLE AND USEFUL?
Wladyslaw Januszewicz, Peter Malfertheiner, Jaroslaw Regula
25 HISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW?
Maria Blanca Piazuelo
39 HELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS:DON’T BE TOO LATE TO ERADICATE!
Francis Mégraud, Christine Varon
47 NON INVASIVE TESTS FOR DETECTION OF GASTRIC ATROPHY
Marcis Leja, Francesco Di Mario
59 HOW TO RECOGNIZE AND CHARACTERIZE INTESTINAL METAPLASIA IN THE STOMACHAT ENDOSCOPY: SHOULD WE CHANGE OUR PRACTICE?
Marta Rodriguez-Carrasco, Emmanuel Coron, Mário Dinis-Ribeiro,
Pedro Pimentel-Nunes
71 MANAGEMENT OF GASTRIC PREMALIGNANT LESIONS:WHAT SHOULD CLINICIAN DO TODAY?
Nicolas Chapelle, Estelle Cauchin, Tamara Matysiak-Budnik
81 ENDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER
Inês Pita, Mário Dinis-Ribeiro, Pedro Pimentel-Nunes
93 ORGANIZATION OF EXPERT CENTERS
Driffa Moussata
101 GLOSSARYHE OFTEN ACTS UNJUSTLY WHO DOES NOT DO A CERTAIN
THING; NOT ONLY HE WHO DOES A CERTAIN THING....
MARCUS AURELIUS (IX,5)F OREWORD

Foreword
Dear Reader,
It is our great pleasure to introduce this book whose main objective is to present
the current knowledge on gastric premalignant lesions and early gastric cancer, andthe clinical approaches for patients with these lesions. Gastric cancer is a deadly
neoplasm with dismal prognosis if diagnosed at an advanced stage, and the best
way to reduce the mortality from this cancer is to diagnose it at an early, curable
stage, allowing for an effective and conservative, endoscopic treatment. This implies
our capacity to identify the patients at risk of gastric cancer, i.e. harboring gastricprecancerous lesions, to follow them up correctly, and to be able to detect and treat
early gastric cancer. Our knowledge on pathogenesis and evolution of gastric precancerous lesions, like atrophic gastritis, gastric intestinal metaplasia and dysplasia,
has improved considerably in the last decades. At the same time, great progress has
been made in the field of endoscopy, leading to the introduction of novel and more
efficient techniques for the detection and even possible treatment of gastric lesions.
Our objective is to bring all this knowledge to our Reader, by presenting it in a veryclear and practical way, thus allowing the incorporation of this knowledge into dailyclinical practice. This book covers different aspects of gastric cancer and gastric precancerous lesions, including the latest data on epidemiology and screening of gastriccancer, histological aspects and pitfalls in histological diagnosis of gastric precancerous lesions, an update on the role of Helicobacter pylori and the place of non-invasive
methods in the diagnosis of gastric precancerous lesions, the latest recommendations
on the surveillance of patients with these lesions, and the role of endoscopy and new
endoscopic techniques in the detection of gastric intestinal metaplasia and treatmentof early gastric cancer. The authors of this book are well recognized world experts inthis field, who put effort into addressing all these topics in a simple and didactic way,underligning the practical information that is important for Clinicians.
We do hope that this book will bring useful information and become a practicalguide for our Colleagues.
Professor Tamara Matysiak-Budnik

Matysiak-Budnik T

1

F OREWORD

2

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

Epidemiology of gastric cancer:
New trends of increasing incidence?
Jin Young Park 1, Melina Arnold 1
1International Agency for Research on Cancer (IARC), Lyon, France

CURRENT GLOBAL BURDEN
With over 1 million new cases and close to 800,000 deaths in 2018, gastric cancer is the fifth most frequently diagnosed cancer and the third-leading
cause of cancer death worldwide 1,2. From a global perspective, it therefore remains an important cause of cancer-related incidence and mortality. Incidence
rates vary substantially across countries and world regions, ranging from 22
per 100,000 person-years in Eastern Asia to less than 5 per 100,000 in Africa,
North America and Northern Europe. Countries with the highest incidence
rates of gastric cancer include the Republic of Korea, Mongolia and Japan (figure 1). Patterns in mortality are closely aligned with those of incidence, given
the frequently late detection of the tumour and high cancer-related fatality(figure 2). Yet, while gastric cancer ranks among the top causes of cancer-related
death in many transitioning countries, a proportionally lower share of deaths
from the disease can be observed in highly developed countries. Incidence rates
are generally two-fold higher in men relative to women (figure 3) and have been
observed to disproportionally affect certain population subgroups, such as persons of lower socioeconomic status, ethnic and indigenous populations andimmigrants from high-risk areas 3-5. For example, gastric cancer incidence andmortality were shown to be elevated in almost all indigenous peoples relative
to corresponding non-indigenous populations in the same regions or countries,
particularly among Inuit residing in the circumpolar region and among Maori 4.
A comprehensive systematic review and meta-analysis published recently also
showed that immigrants from regions with a high incidence of gastric cancer
living in regions with low incidence maintain a higher risk of gastric cancer andrelated mortality 6.

Park JY, Arnold M

3

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

4

FIGURE 1. Age-standardized incidence rates (World Standard Population) fromgastric cancer in 2018, both sexes combined.
Source: GLOBOCAN 2018 (gco.iarc.fr/today)

FIGURE 2. Age-standardized mortality rates (World Standard Population) fromgastric cancer in 2018, both sexes combined.
Source: GLOBOCAN 2018 (gco.iarc.fr/today)

Park JY, Arnold M

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

Republicof Korea

13.2

32.1

Eastern Asia
Eastern Europe
South America
Western Asia

12.7
11.3
10.4
10.1
8.7
8.2
8.1
7,9
7.8
7.2
6,4
6,2
5.6
5.4

Southern Asia
Melanesia
Carribean
Western Europe
Central America
Micronesia/Polynesia
South-Eastern Asia
South Central Asia
Australia/New Zealand
Northern Europe
Northern America
Middle Africa
Southern Africa
Western Africa
Eastern Africa
Northern Africa
60

6.9
6,0
5.0
6.4
5.1
3.7
6.3
4.1
4.0
3.5
2.9
3.1
2.8
4.0

5.4
4.9
4.7
4.7
50

40

30

Republicof Korea

7.5

17.1

20

10

5

2.6
3.8
4.0
3.0
0

10

20

30

40

50

Age-standardized incidence rate per 100,000
Males

Females

FIGURE 3. Age-standardized incidence rates (World Standard Population) fromgastric cancer in 2018 by world region in males and females.
Source: GLOBOCAN, 2018 (gco.iarc.fr/today)

Park JY, Arnold M

60

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

6

Although often reported as a single entity, gastric cancers can be broadlyclassified into two major topographical subsites, the cardia and non-cardia. The
cardia gastric cancer arises in the area of the stomach adjoining the oesophageal-gastric junction, while non-cardia gastric cancer develops from more distal
regions of the stomach, and the two entities differ in terms of aetiology, risk
factors and geographical patterns. While cardia gastric cancer is associated withobesity and gastroesophageal reflux disease in Western populations (resembling
etiological factors attributed to oesophageal adenocarcinoma), the vast majority of non-cardia gastric cancer cases are associated with Helicobacter pylori
infection. According to recent estimates for the year 2018, an estimated 18%(or 181,000 cases) of all gastric cancer cases occurred in the cardia and 82%(853,000 cases) occurred in non-cardia regions of the stomach 7. However,the contributions of non-cardia gastric cancer and cardia gastric cancer to theoverall burden from gastric cancer vary greatly across world regions (figure 4).
Tthe proportion of cardia gastric cancers tends to be highest in highly developed countries and relatively low in most high-risk populations, such as China
or Japan, exceptions include a high proportion of cardia gastric cancers in thehigh-incidence regions of Iran 8-10 . Risks for each subsite also differ acrossethnic groups, with, for example, cardia gastric cancer being more common in
non-Hispanic whites in the United States (US) than in other ethnic groups 3.

TRENDS IN INCIDENCE AND MORTALITY
Figure 5 shows the trends in overall age-standardized gastric cancer incidence and mortality rates in various countries across world regions since thebeginning of cancer registration using the data from the International Agency
on Cancer’s (IARC) Cancer Incidence in Five Continents (CI5) plus Database
and the World Health Organization (WHO) Mortality Database 11. Due toits delayed detection in most countries, mortality and incidence show similar,
consistently decreasing trends over time with the exception of a few countries,
such as Japan and the Republic of Korea, where the incidence rates have historically been high and have remained largely stable over time, even thoughmortality has been decreasing. Both countries have a national gastric cancer
screening program in place and opportunistic upper endoscopic screening is
widely accepted, likely contributing to the observed patterns in incidence andmortality. The decreasing rates of gastric cancer have been attributed to improved socio-economic status, improved sanitation, changes in diet and lifestyle, widespread antibiotic use, and, predominantly, the decreasing prevalenceof Helicobacter pylori infection 12-14.
Despite the overall decrease in gastric cancer incidence and mortality rates overthe last decades, increasing incidence rates of gastric cancer have been observed inPark JY, Arnold M

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

Eastern Asia
Eastern Europe
South America
Western Asia
Southern Europe
Carribean + South America
South-Eastern Asia
South Central Asia
Western Europe
Sub-Saharan Africa
Northern Africa
Oceania
Northern Europe
Northern America

4.4

1.2
0.7
1.6
0.9
0.9
0.4
0.8
1.6
0.2
0.4
1.7
1.2
1.4
5

6.9
6.5
6.1
5.3
4.5
4.2
4.1
3.4
3.4
3.3
2.8
0

5

17.9

10.2
8.8

CGC
NCGC
10

15

20

Age standardized rate per 100,000(both sexes combined)

FIGURE 4. Age-standardized incidence rates from cardia (CGC) and non-cardia(NCGC) gastric cancer in 2018 by world region, both sexes combined. 7

7

Age-standardized (World) rate
per 100,000
40
30
20
10
7
5
3
2

North America

North-West Europe

South-East Europe
Slovakia

Denmark
USA Black

Denmark

USA White

Austria

Canada

Korea

Japan
Belarus
Italy
Spain
Hongkong
Slovakia

Netherlands
UK
Netherlands
UK

CanadaUSA

Belarus

Italy
Spain

Austria

East Asia
Korea
Japan

Hongkong
Philippines
Philippines

1
0.7
1960

1990

2020

1960

Latin America
40
30
20
10
7
5
3
2

Costa-Rica

1990

2020

Africa

1960

1990

2020

1960

South-West Asia

1990

2020

Oceania

Costa-Rica

Colombia
EcuadorEcuadorColombia

BrazilIsraelIsrael
KuweitUgandaAustralia
NewZealandAustralia

ThailandKuweitSouth Africa

1
0.7

New-ZealandTurkeyTurkeyThailand

1960

1990

2020

1960

1990

2020

1960

1990

Incidence

2020

1960

1990

2020

Mortality

FIGURE 5. Trends in age-standardized incidence and mortality rates (World
Standard Population) from gastric cancer in 2018 by country (source: CI5plus
and WHO mortality database, reprinted from "Global Burden of 5 Major Types of
Gastrointestnal Cancer"). 11
Park JY, Arnold M

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

8sub-populations of several countries. Using the data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) from 19772006, significantly increasing incidence rates of gastric cancer were reported in US
whites aged 25-39 years old (estimated annual percentage change (EAPC)=2.7%)15.
This observation was largely driven by a significant increase in the incidence rates
of gastric corpus cancer among younger and middle-aged whites and non-Hispanic
whites (EAPC between 1999 and 2007 = 4.5% in whites and 5.7% for non-Hispanic
whites for 25-39 years old, respectively)16. More recently, rising incidence patterns
among persons below the age of 50 were confirmed using more recent data in theUS, contrasted by a significant decrease in incidence in their older counterparts(EAPC for 1995-2013 = 1.3% for age <50 y vs.-2.6% for age >50y, respectively) 17.
Analysing the trends by anatomical subsite in non-Hispanic whites, increased rates
for corpus gastric cancer in younger birth cohorts and falling rates in older cohorts
were observed (EAPC 4.6% for age<50y vs. -0.5% for age < 50y, respectively). The
increases were more pronounced among women than men and largely limited to
non-Hispanic whites 17.
The stable or increasing incidence rates of gastric cancer in younger birthcohorts were also observed in several countries outside the US, such as Brazil,
Denmark, India and Israel 18. In Korea, despite the overall, moderate decreasing
trends in the incidence of gastric cancer, an increasing trend was reported between
1999 and 2010 especially in women between 40 and 54 years of age 19. An updated analysis of data between 1999 and 2014 in Korea confirmed the non-decreasing, stable incidence rates of gastric cancer for those who are under 50 years old.
The study reported an EAPC of 3.7 % for non-cardia tumours localized to thegastric corpus compared to cardia/fundus (EAPC 1.3%) or antrum (EAPC 1.3%)
20. Similarly, more recent stable trends in incidence of corpus and pylorus sites
have been observed in the Netherlands despite the overall decreasing trend 21. Together, such trends may lead to a deceleration or a reversal of the overall declining
gastric cancer rates in the future.
These increasing trends of corpus-dominant, young age–dominant, female-dominant, so-called “CYF” gastric cancers observed in the US and othercountries were assumed to resemble or follow a pattern of oesophageal cancer,
which began in highly developed countries 22. Several hypotheses for changing
trends include changing gastric microecology, with disappearance of Helicobacter
pylori and auto-immunity, with increasing trend of cancers in the corpus of thestomach where the autoimmune type of gastritis predominates 22,23. Continued
efforts are warranted to investigate whether such changes in trends are observed
elsewhere and involve different aetiology.
At the same time, a careful interpretation is required when interpreting trends
by cancer subsite given an often large proportion of tumours with unspecified

Park JY, Arnold M

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE
location. Increasing incidence rates in a known subsite of gastric cancer therefore
might not be an accurate reflection of actual increases, with some of the increases
being potentially attributable to the increasingly better attribution of the previously
unspecified category.

SURVIVAL AND PROGNOSTIC FACTORS
Although advances in the clinical management of gastric cancer have led tosmall improvements in outcomes over the past years, five-year survival remains
poor, in the range of 20-30% in most countries worldwide 24-26. Recent analysesof population-based cancer registry data from high-income countries with similar access to health care indicated that while progress has been made, specificallyamong patients aged below 75, international survival disparities in gastric cancer
continue to persist 25. Patients with gastric cancer are diagnosed at an earlier stage
in countries where established screening programs exist compared to the US orother countries where no screening programs are in place (table 1). In the Republicof Korea, for example, where gastric cancer incidence is amongst the highest in theworld, the implementation of national screening programs using endoscopic and/or radiographic methods has led to an increasing number of cases diagnosed at an
early, curable stage and high five-year survival rates of over 76% between 20132017 27.The most important prognostic factor determining survival from gastriccancer is stage at diagnosis, with 5-year net survival of above 60% for early gastriccancer in contrast to approximately 5% for advanced disease 28,29. Survival fromgastric cancer may furthermore depend on the anatomical subsite and histologicaltype. Proximal gastric cancers as well as cancers of the diffuse Lauren type histology 30 have a worse prognosis when compared to distal (non-cardia) and intestinal
types 31,32.

FUTURE BURDEN
According to recent estimates, the number of gastric cancer cases is set out to growfrom just over 1 million in 2018 to more than 1.7 million in 2040 as a result of demographic changes, i.e. population aging and growth 2. Recent country-level analyses
showed that the absolute number of new gastric cancer cases is expected to further
increase in the next decades in many of the countries included in the study despite thedecreasing trend of incidence rates 12. In addition, while generally decreases or stabilisation of incidence rates were observed in those aged 50 years and above, this was notalways the case in the younger age groups. Increases in incidence in those younger than
50 years were predicted in 15 out of 34 countries with both low- and high-incidence,
including Belarus, Chile, the Netherlands, Canada and the UK, using the IARC’shigh-resolution cancer registry data 12.

Park JY, Arnold M

9Park JY, Arnold M

26

36

10

Regional

Distant

Unknown

23.4

5.5

32

69.5

5-years
NS

7.2

18.3

20.7

53.9

% of all
cases

N/A

6.6

51.9

96.7

5-yearsNS

2009-2011

Japan 2

11.9

38.7

28.8

32.5

% of all
cases

37.8

4.5

32.8

54.1

5-yearsNS

2012-2014

Australia 3

1

41.7

18.8

38.5

% of all
cases

10.5

1.5

25.5

37

5-yearsNS

2010-2014

Netherlands 4

11

12

26

51

% of all
cases

49.2

5.5

55.7

92.4

5-yearsNS

2006-2010

Republicof Korea 5

Sources: 1SEER 18 (2010-16); 2 personal comm. (2009-11); 3 NSW, ICBP SURVMARK-2 (2012-14); 4 cijfersoverkanker.
nl (2010-14); 5Korea National Cancer Incidence Database data 33; 5-yr NS: 5-year net survival; N/A: not available.

28

USA 1

2010-2016% of allcases

Localized

Stage atdiagnosis

Years

10

TABLE 1. Comparison of gastric cancer stage at diagnosis and 5-year net survival in various countries.

E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCEE PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE
CONCLUSION
In 2018, more than 1 million gastric cancer cases occurred globally of which
853,000 were at non-cardia sites. The main burden continues to fall in many
countries globally, however gastric cancer remains a major challenge to publichealth on a global scale. This is mainly due to the absolute number of new cases
which will stay stable or continue to grow in the foreseeable future, driven by
population growth and aging as well as the increases seen in the incidence rates
in younger generations in some countries. While these potential changes in theepidemiology of gastric cancer warrant continuing examinations and further
research, urgent action in terms of cancer control is required from all countries given its substantial global burden, by, for example, including it in theirnational cancer control programmes with detailed assessments of human andeconomic impacts of prevention strategies.

REFERENCES
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2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA Cancer J Clin 2018; 68: 394-424.
2. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon, France:
International Agency for Research on Cancer (IARC), 2018. https://gco.iarc.fr/today
3. Gupta S, Tao L, Murphy JD, et al. Race/Ethnicity-, Socioeconomic Status-, and Anatomic
Subsite-Specific Risks for Gastric Cancer. Gastroenterology 2019; 156: 59-62 e4.
4. Arnold M, Moore SP, Hassler S, Ellison-Loschmann L, Forman D, Bray F. The burdenof stomach cancer in indigenous populations: a systematic review and global assessment.
Gut 2014; 63: 64-71.
5. Arnold M, Aarts MJ, Siesling S, Aa M, Visser O, Coebergh JW. Diverging breast andstomach cancer incidence and survival in migrants in The Netherlands, 1996-2009. Acta
Oncol 2013; 52: 1195-201.
6. Pabla BS, Shah SC, Corral JE, Morgan DR. Increasing Incidence and Mortality of Gastric Cancer in Immigrant Populations from High to Low Regions of Incidence: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2019: 18: 347-59. DOI:
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DOI: 10.1136/gutjnl-2020-321600
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patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut 2015; 64: 1881-8.
9. Taghavi N, Nasrollahzadeh D, Merat S, et al. Epidemiology of upper gastrointestinal can-Park JY, Arnold M

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12cers in Iran: a sub site analysis of 761 cases. World J Gastroenterol 2007; 13: 5367-70.
10. Babaei M, Pourfarzi F, Yazdanbod A, et al. Gastric cancer in Ardabil, Iran--a review andupdate on cancer registry data. Asian Pac J Cancer Prev 2010; 11: 595-9.
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12. Arnold M, Park JY, Camargo MC, Lunet N, Forman D, Soerjomataram I. Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035.
Gut 2020; 69: 823-9.
13. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric Cancer:
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14. Etemadi A, Safiri S, Sepanlou SG, et al. The global, regional, and national burden of
stomach cancer in 195 countries, 1990–2017: a systematic analysis for the Global Burdenof Disease study 2017. Lancet Gastroenterol Hepatol 2020; 5: 42-54.
15. Anderson WF, Camargo MC, Fraumeni JF, Jr., Correa P, Rosenberg PS, Rabkin CS.
Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 2010;
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16. Camargo MC, Anderson WF, King JB, et al. Divergent trends for gastric cancer incidenceby anatomical subsite in US adults. Gut 2011;60:1644-9.
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18. Luo G, Zhang Y, Guo P, Wang L, Huang Y, Li K. Global patterns and trends in stomach
cancer incidence: Age, period and birth cohort analysis. Int J Cancer 2017; 141: 1333-44.
19. Song M, Kang D, Yang JJ, et al. Age and sex interactions in gastric cancer incidence andmortality trends in Korea. Gastric Cancer 2015; 18: 580-9.
20. Eom BW, Jung K-W, Won Y-J, Yang H, Kim Y-W. Trends in Gastric Cancer Incidence According to the Clinicopathological Characteristics in Korea, 1999-2014. Cancer Res Treat
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21. Holster IL, Aarts MJ, Tjwa ETTL, Lemmens VEPP, Kuipers EJ. Trend breaks in incidenceof non-cardia gastric cancer in the Netherlands. Cancer Epidemiol 2014; 38: 9-15.
22. Blaser MJ, Chen Y. A New Gastric Cancer Among Us. J Natl Cancer Inst 2018;110: 54950.
23. Song M, Rabkin CS, Camargo MC. Gastric Cancer: an Evolving Disease. Curr Treat Options Gastroenterol 2018; 16: 561-9.
24. Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival
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25. Arnold M, Rutherford MJ, Bardot A, et al. Progress in cancer survival, mortality, andPark JY, Arnold M

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incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol 2019; 20: 1493-505.
26. De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999-2007 bycountry and age: results of EUROCARE--5-a population-based study. Lancet Oncol 2014;
15: 23-34.
27. Hong S, Won Y-J, Park YR, Jung K-W, Kong H-J, Lee ES. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2017. Cancer Res Treat 2020; 52: 335-50.
28. Pasechnikov V, Chukov S, Fedorov E, Kikuste I, Leja M. Gastric cancer: prevention,screening and early diagnosis. World J Gastroenterol 2014; 20: 13842-62.
29. Jim MA, Pinheiro PS, Carreira H, Espey DK, Wiggins CL, Weir HK. Stomach cancer
survival in the United States by race and stage (2001-2009): Findings from the CONCORD-2 study. Cancer 2017; 123 Suppl 24: 4994-5013.
30. Lauren P. The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called
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31. Anderson LA, Tavilla A, Brenner H, et al. Survival for oesophageal, stomach and small
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32. Bringeland EA, Wasmuth HH, Mjones P, Myklebust TA, Gronbech JE. A population-based study on incidence rates, Lauren distribution, stage distribution, treatment,
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E PIDEMIOLOGY OF GASTRIC CANCER: NEW TRENDS OF INCREASING INCIDENCE

14

S CREENING FOR GASTRIC CANCER IN EUROPE

Screening for gastric cancer
in Europe: Is it feasible and useful?
Wladyslaw Januszewicz 1,2 , Peter Malfertheiner 3 Jaroslaw Regula 1
1
Department of Oncological Gastroenterology, Maria Sklodowska-Curie
National Research Institute of Oncology, Warsaw, Poland
2
Department of Gastroenterology, Hepatology and Clinical Oncology,
Centre of Postgraduate Medical Education, Warsaw, Poland
3
Otto-von-Guericke Universität, Klinik für Gastroenterologie, Hepatologie undInfektiologie & LMU Universitätsklinikum, Med. Klinik II, München, Germany

15
BACKGROUND
Despite a uniform decrease in the incidence of gastric cancer (GC) in the lastfew decades, it remains one of the leading causes of cancer-related deaths worldwide 1. In Europe, in 2012 alone, nearly 140,000 cases of GC were diagnosed,
and approximately 107,000 people died of GC, according to the European
Network of Cancer Registries (ENCR)2. GC diagnosis is related to poor survival(5-year survival <30% in most European countries) because at the time of presentation, most patients are diagnosed with advanced-stage disease. In contrast,
early-stage GC has an excellent prognosis (5-year survival rates of >90%) and
can often be treated with minimally-invasive, organ-sparing modalities, such as
endoscopic resection 3.
Non-cardia GC (NCGC) subdivded into two histological subtypes - intestinaland diffuse according to Lauren’s classification 4 - accounts for the vast majority ofcancer cases within the stomach. Helicobacter pylori (H. pylori) infection is the mostsignificant risk factor for GC, regardless of its histological class. Other conditions,such as older age, high salt intake, a diet low in fruits and vegetables, smoking, andfamily history, are additive risk factors if concomitant with H. pylori gastritis 5.
The development of intestinal-type NCGC is characterized by a stepwise progression described by the Correa cascade - an inflammatory-driven pathway typically initiated by the H. pylori infection. The inflamed gastric mucosa then undergoes
several premalignant stages: from chronic atrophic gastritis to intestinal metaplasia,

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S CREENING FOR GASTRIC CANCER IN EUROPE
dysplasia, and eventually, intramucosal cancer 6. This multistage process provides aunique opportunity for screening and timely intervention when the disease is still ata benign stage.
On the contrary, the diffuse-type of NCGC does not offer a similar opportunity,
as no such stepwise process in the oncogenic cascade has been documented. Despite a less well understood pathogenesis, the development of these tumors can also
be attributed to H. pylori infection, which makes this organism a common groundin gastric carcinogenesis 7. Overall, H. pylori is responsible for ~90% of the global
burden of NCGC 8 and is increasingly recognized as the primary target of GC prevention strategies. However, in order to adopt and implement such strategies, a series
of individual considerations need to be made.

THE RATIONALE FOR GASTRIC CANCER SCREENING

16

A variety of factors must be considered when the implementation of a population-wide cancer screening program is posited, the most important of which are thecountry’s demographic profile and the local burden of the disease of interest. In thiscontext, the age-standardized incidence rate (ASR) is a commonly used parameter
9. As any screening program must be tailored to disease burden, ASR characterizes
the different risk levels in a given population. In terms of GC, three risk areas can be
determined (table 1):2 High-risk areas: ASR ≥20 per 100,000 person-years (p-y); e.g., Japan, Korea,
China;
2 Intermediate risk areas: ASR ≥10 and <20 per 100,000 p-y; e.g., Portugal, Lithuania, Romania, Slovenia;
2 Low-risk areas: ASR <10 per 100,000 p-y; e.g. USA, UK, Sweden, Germany.
At present, population-wide screening for GC is performed only in high-risk areas, such as Japan and South Korea. In Japan, with an estimated ASR for NCGC
of 25.5 per 100,000 p-y 1, health authorities introduced the first national screening
program in 1983. Initially, the program was based on barium gastrography; however,since 2017, it also includes annual endoscopy in individuals ≥50 years of age 10.
Similarly, in Korea, the National Cancer Screening Program recommends biennial
upper gastrointestinal series or endoscopy for adults aged 40 years and older 11.
Although there is little evidence showing the influence of these programs on the outcome of GC, a recent meta-analysis indicated that endoscopic screening could leadto a 40% risk reduction in GC mortality (RR, 0.60; 95% CI, 0.49–0.73) in high-risk
Asian countries 12.
On the contrary, in countries with a low GC incidence, there is no rationale forendoscopic screening, and it remains debatable in countries with intermediate risk.
This raises the question: what should the appropriate GC screening strategy be, ifany, in Europe?

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S CREENING FOR GASTRIC CANCER IN EUROPE

TABLE 1. Summary table of established and postulated screening strategies for
gastric cancer in different risk areas.
Low-risk areas(ASR <10 per 100,000)

Intermediate risk areas(ASR ≥10 and <20
per 100,000)

High-risk areas(ASR ≥20 per 100,000)

Targeted GC screening for at-risk individuals(postulated and potentially cost-effective)

Primary GC screening(established and cost-effective)

H. pylori "Screen-and-treat" within at-risk individuals(e.g., family history of GC, precancerous gastriclesions)

H. pylori "screen-and-treat"
within general population

Serological testing (serum
pepsinogen) in high-risk
individuals (e.g., smoking
men over 50 years of age)Primary imaging screening(upper GI endoscopy /gastrography) in individuals≥40(50) years old.

Upper GI endoscopy
in FOBT-positive CRC
screening individuals

Stool antigen H. pylori testing combinedwith a FOBT-based CRC screening program
Serological testing (serum pepsinogen)coupled with CRC screening program
ASR: age-standardized ratio, CRC: colorectal cancer, GC: gastric cancer, FOBT: fecal
occult blood test.

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S CREENING FOR GASTRIC CANCER IN EUROPE

18

Applying a uniform screening strategy to Europe as a region presents challenges,
as there is significant heterogeneity of the disease burden among individual country
members, ranging from low to intermediate GC risk 13. For instance, a recent systematic analysis showed that the ASR for GC varies from 10.5 cases per 100,000 (uncertainty intervals [UI]: 10.0-11.0) in Western Europe, to 17.7 cases per 100,000 (UI:
17.2–18.3) in the Eastern part of the continent 14. On an individual country level, theincidence rate can vary from as high as 29.0 and 26.6 per 100,000 in Albania and Belarus to as low as 5.6 and 6.2 per 100,000 in Sweden and Switzerland, respectively 2.
There have been some initiatives in Europe to seek a feasible screening strategy
in countries with an intermediate risk for GC. In particular, a recent cost-utility
analysis has postulated that upper GI endoscopic screening can be cost-effective if
combined with a screening colonoscopy in individuals between 50 to 75 years of age
13. This is an interesting concept; however, most colorectal cancer (CRC) screening
programs in Europe are based on fecal occult blood (FOBT) testing 15. Therefore,
this would be highly limiting, as the upper endoscopy screening would be available
only to those who are offered a colonoscopy after a positive FOBT test. Moreover,as previously mentioned, it could only be cost-effective in countries where the incidence of GC is in the intermediate risk range. Only a few countries carry such a highburden of GC in Europe.
In practice, GC screening can be applied at different phases of disease evolution,from the earliest – H. pylori infection, through intermediate precancerous changes of
the gastric mucosa – atrophic gastritis and intestinal metaplasia, to early-stage cancer
itself. As with any population healthcare strategy, at-risk individuals should be identified with the least invasive, cheapest, and most patient-tolerable test possible. Currently, several screening strategies aiming to fulfill these criteria are being debated.

H. PYLORI TESTING
H. pylori is categorized as a class I carcinogen according to the World HealthOrganization (WHO), and remains the primary risk factor for GC worldwide 16.
There are several non-invasive tests available in clinical routine for the detection ofthis pathogen, including H. pylori stool antigen test (HPSA), urea breath test (UBT),
and serological tests (e.g., IgG to H. pylori). With these assays, a "screen-and-treat"approach is easily accessible, making this strategy a method of choice for primary
GC prevention in high incidence areas 17. Successful eradication therapy has been
proven to decrease the degree of mucosal inflammation and prevent its progression
to preneoplastic lesions 5. In fact, the latest recommendations from the Kyoto consensus for high-risk regions support active and early screening for H. pylori infection
before the consequences of chronic inflammation occur 18. Overall, the recommendations generally propose that all individuals found to be infected should be offered
eradication therapy unless there are competing considerations 18.

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S CREENING FOR GASTRIC CANCER IN EUROPE
Furthermore, a very recent report from Taiwan has shown that HPSA testing
could be successfully coupled with a CRC screening program 19. In this nationwide
study, eligible individuals were invited in a randomized fashion either to receive thestandard fecal immunochemical test (FIT) or a FIT supplemented with an HPSA
test. A positive HPSA result was followed by an eradication therapy, which was successful in 91.9% (95%CI 91.1 – 92.7%) patients (intention-to-treat [ITT] analysis).
Interestingly, the addition of the HPSA test increased the screening program’s participation rate by 13.9% (95%CI 13.4 – 14.4%), compared to FIT-only testing. It
is also worth noting that H. pylori carriers had a higher rate of colorectal adenomas
than non-carriers (adjusted RR: 1.15; 95%CI 1.03 – 1.28, P=0.01) 19. Although
the baseline results did not show any difference in the detection rates of early-stage
GC between the groups, the long-term outcomes (e.g., the study’s effect on GC
mortality) are awaited. As most existing CRC screening programs in Europe arebased on FOBT (particularly FIT) testing, this approach could be easily adaptable
in a European setting.

SEROLOGICAL BIOMARKERS
Both atrophic gastritis and intestinal metaplasia are associated with an increased
risk of GC development. The prevalence and malignant potential of these conditions
remain poorly characterized in Europe; however, a nationwide cohort study in the
Netherlands has shown an annual progression rate of 0.1% and 0.25% for atrophic gastritis and intestinal metaplasia, respectively 20. So far, endoscopy remains
the mainstay for the diagnosis and surveillance of precancerous gastric conditions.
In fact, European guidelines recommend endoscopic monitoring every three years
for patients with the presence of extensive atrophy or intestinal metaplasia 21,22.
Emerging serological biomarkers, however, might provide a promising alternative for
identifying precancerous gastric conditions.
Pepsinogen I (PGI) and pepsinogen II (PGII), both precursors of pepsin, areproduced by the gastric mucosa and released into the gastric lumen and peripheral
circulation 23. PGI is secreted mostly by the chief and mucous neck cells in the fundic glands while PGII is also secreted in diverse types of glands all over the stomach”.
When atrophic changes develop in the gastric corpus, the level of PGI decreases
while PGII levels remain relatively stable or may even increase. Hence, low serum
pepsinogen PGI and/or PGI/PGII ratio is an accurate indicator of chronic atrophic
gastritis and more advanced premalignant conditions, such as intestinal metaplasia,
dysplasia, and even GC. Most studies on the utility of pepsinogen testing originate
from high-risk areas for GC. Indeed, pepsinogen testing is already an establishednon-invasive GC screening method in Japan 24.
More recently, a few studies on the topic from low-risk areas have also been undertaken. A report from the USA showed that non-invasive screening with serum

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S CREENING FOR GASTRIC CANCER IN EUROPE

20

pepsinogen could reduce gastric cancer mortality in high-risk individuals (actively
smoking men aged > 50 years) and remain cost-effective 25.
In a German study, serum pepsinogen as a GC screening modality was assessedin patients undergoing colonoscopy (from various indications) 26. A positive (i.e. abnormally low) serum pepsinogen result was significantly correlated with gastric atrophic changes, with a relative risk (RR) for this condition of 12.2 (95%CI: 6.3–23.5).
Moreover, patients with a high-risk GC profile according to the Operative Link of
Gastritis Assessment (OLGA; stages III and IV, respectively) 27 could be identified
by serum pepsinogen assessment with a sensitivity of 75.0%, and a specificity of
82.2%, respectively 26. The authors postulated that serological GC screening could
be combined with a CRC screening program. Individuals with a positive pepsinogentest should be proposed an additional upper GI endoscopy in addition to screeningcolonoscopy 26.
Lastly, a multi-center study from the Netherlands and Norway showed that pepsinogen combined with a Gastrin-17 serological panel could be useful in stratifying
patients with premalignant conditions of the stomach into those at either a higher
risk or lower risk for malignant progression 28. This study hints at the promising roleof serological markers in tailoring endoscopic surveillance programs for high-risk
individuals in low GC incidence areas.
Further studies on the topic have shown that serum levels of trefoil factor family
proteins (TFF) may also be useful in serological GC screening. The best marker
candidate from this group - TFF3 - showed a sensitivity of 80.9% and specificity of
81.0% for GC diagnosis and was superior to pepsinogen testing alone in the samecohort. Combining TFF3 with pepsinogen I/II testing may provide a more accurate
non-invasive screening modality with increased accuracy for GC screening 29. However, although promising, TFF testing as a screening method has not yet entered into
clinical practice.

CONCLUSION
As a region, Europe is rather heterogeneous in terms of GC burden with a gradually increasing incidence rate (general trend) in its Eastern parts, albeit with some
exceptions (e.g., Portugal). Therefore, implementing a uniform GC screening program for the whole region could lead to an uneven allocation of resources. However,this should not discourage the active pursuit of prevention strategies since GC affects
over 140,000 individuals in Europe every year and carries a dismal prognosis due toits advanced-stage presentation in most cases.
The "screen-and-treat" strategy for H. pylori infection has already been established in Europe and may have contributed to the continuing decrease of GC incidence in the region. So far, this strategy is mostly applied to patients with dyspeptic
symptoms and has been proven to reduce the costs of dyspepsia work-up in general

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S CREENING FOR GASTRIC CANCER IN EUROPE
healthcare 30. Considering this, more generalized testing (also including asymptomatic individuals) could remain cost-neutral for the healthcare segment. However,such a wide-ranged approach should be wisely balanced with potential pitfalls, suchas increasing antibiotic resistance and possible adverse effects.
So far, the available evidence suggests that screening for GC in Europe could
benefit specific populations and individuals. Those include patients with previous
or active H. pylori infection, a positive family history for GC, or known gastric premalignant conditions 5. Emerging non-invasive serological markers and tests could
help identify at-risk individuals and constitute a more patient-friendly alternative toreplace endoscopy as a primary diagnostic modality.
Europe sorely lacks interventional healthcare studies on this topic. This critical
medical and social demand could surely be the prelude to an exciting era of research,
furthering the fight against a disease that remains a persistent threat to a large subsetof the population throughout the continent.

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6. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer
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7. Hansson LE, Engstrand L, Nyrén O, Lindgren A. Prevalence of Helicobacter pylori infection in subtypes of gastric cancer. Gastroenterology 1995; 109: 885-8. doi: 10.1016/00165085(95)90398-4
8. De Martel C, Ferlay J, Franceschi S, et al.Global burden of cancers attributable to infections in 2008: A review and synthetic analysis. Lancet Oncol 2012; 13: 607-15. doi:
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gastric cancer screening. Jpn J Clin Oncol, 2018; 48: 673-83.
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crt.2011.43.2.83
12. Zhang X, Li M, Chen S, et al. Endoscopic Screening in Asian Countries Is AssociatedWith Reduced Gastric Cancer Mortality: A Meta-analysis and Systematic Review. Gastroenterology 2018; 155: 347-54.e9. doi: 10.1053/j.gastro.2018.04.026
13. Areia M, Spaander MCWC, Kuipers EJ, Dinis-Ribeiro M. Endoscopic screening for gastric cancer: A cost-utility analysis for countries with an intermediate gastric cancer risk.
United Eur Gastroenterol J 2017; 6: 205064061772290. doi: 10.1177/2050640617722902
14. Etemadi A, Safiri S, Sepanlou SG, et al. The global, regional, and national burden of
stomach cancer in 195 countries, 1990–2017: a systematic analysis for the Global Burdenof Disease study 2017. Lancet Gastroenterol Hepatol 2020; 5: 42-54. doi: 10.1016/S24681253(19)30328-0
15. Cardoso R, Guo F, Heisser T, Hoffmeister M, Brenner H. Utilisation of colorectal cancer
screening tests in european countries by type of screening offer: Results from the european
health interview survey. Cancers (Basel) 2020; 12 : epub. doi: 10.3390/cancers12061409
16. Vogiatzi P, Cassone M, Luzzi I, Lucchetti C, Otvos L, Giordano A. Helicobacter pylori asa class I carcinogen: Physiopathology and management strategies. J Cell Biochem 2007 ;102: 264-73. doi: 10.1002/jcb.21375
17. Liou JM, Malfertheiner P, Lee YC, et al. Screening and eradication of Helicobacter pylori
for gastric cancer prevention: The Taipei global consensus Gut 2020; 69: 2093-112. doi:
10.1136/gutjnl-2020-322368
18. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori
gastritis. Gut 2015; 64: 1353-67. doi: 10.1136/gutjnl-2015-309252
19. Lee Y-C, Chiang T-H, Chiu H-M, Wu M-S, Yeh Y-P, Chen TH-H. Community-based
Gastric Cancer Screening Coupled with a National Colorectal Cancer Screening Program: Baseline Results. Gastroenterology 2021; epub. doi: 10.1053/j.gastro.2021.01.008
20. de Vries AC, van Grieken NCT, Looman CWN, et al. Gastric Cancer Risk in Patients
With Premalignant Gastric Lesions: A Nationwide Cohort Study in the Netherlands.
Gastroenterology 2008; 134: 945-52. doi: 10.1053/j.gastro.2008.01.071.
21. 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 Port. Endoscopy 2019;51: 365-88. doi: 10.1055/a-0859-1883.
22. Dinis-Ribeiro M, Areia M, De Vries AC, 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 Soci-

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ety of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).
Endoscopy 2012; 44: 74-94. doi: 10.1055/s-0031-1291491
23. Samloff IM, Liebman WM. Cellular localization of the group II pepsinogens in humanstomach and duodenum by immunofluorescence. Gastroenterology 1973; 65: 36-42.
24. Miki K, Ichinose M, Kakei N, et al. The clinical application of the serum pepsinogen I and
II levels as a mass screening method for gastric cancer. In: Advances in Experimental Medicine and Biology. Adv Exp Med Biol 1995 ; 139-43. doi: 10.1007/978-1-4615-1871-6_17.
25. Yeh JM, Hur C, Ward Z, Schrag D, Goldie SJ. Gastric adenocarcinoma screening andprevention in the era of new biomarker and endoscopic technologies: A cost-effectivenessanalysis. Gut 2016; 65: 563-74. doi: 10.1136/gutjnl-2014-308588
26. Selgrad M, Bornschein J, Kandulski A, et al. Combined gastric and colorectal cancer
screening—A new strategy. Int J Mol Sci 2018; 19. doi: 10.3390/ijms19123854.
27. 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;
21: 579-87. doi: 10.1007/s10120-018-0812-3
28. Den Hollander WJ, Holster IL, Den Hoed CM, et al. Surveillance of premalignant gastriclesions: A multicentre prospective cohort study from low incidence regions. Gut 2019; 68:
585-93. doi: 10.1136/gutjnl-2017-314498.
29. Aikou S, Ohmoto Y, Gunji T, et al. Tests for serum levels of trefoil factor family proteins
can improve gastric cancer screening. Gastroenterology 2011; 141: 837-45. doi: 10.1053/j.
gastro.2011.05.040.
30. Ford AC, Forman D, Hunt RH, Yuan Y, Moayyedi P. Helicobacter pylorieradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: Systematic
review and meta-analysis of randomised controlled trials. BMJ 2014; 348 :g3174. doi:
10.1136/bmj.g3174 Table 1. Summary table of established and postulated screening
strategies for gastric cancer in different risk areas.

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW

Histology
of gastric precancerous lesions
What clinicians should know
Maria Blanca Piazuelo 1
1Vanderbilt University Medical Center, Nashville, USA

The vast majority of non-cardia gastric adenocarcinomas are related to Helicobacter
pylori (H. pylori) infection. It is believed that most adenocarcinomas of the intestinal type 1 develop after a decades-long process of injury to the gastric mucosa
through a sequence of phenotypic alterations known as the Correa cascade 2,3(figure 1). It is also likely that a significant proportion of non-syndromic diffuse-typeadenocarcinomas follow this pathway. Multifocal atrophic gastritis (non-metaplastic
and metaplastic variants) and dysplasia are well-recognized precancerous lesions(table 1), with corresponding increasing risks of progression to cancer 4,5. Theselesions may be considered the ‘field of cancerization’ in which gastric cancer develops 6, and therefore, they should not be understood as mutually exclusive entities,
but as morphological manifestations of the same precancerous condition. Althoughlargely recognized as cancer precursors, their molecular alterations remain underintense investigation. The long-term nature of the gastric precancerous processoffers an excellent period of opportunity for early detection of neoplastic lesions
and ultimately for reduction of gastric cancer mortality. This chapter aims to summarize the most relevant concepts in histopathology of the precancerous process
initiated by the two main etiologic factors of chronic atrophic gastritis: H. pylori
infection and autoimmunity. This chapter excludes precursor lesions of cardia carcinomas, syndromic gastric carcinomas, and neuroendocrine neoplasms.

THE CORREA PRECANCEROUS CASCADE
Non-atrophic chronic gastritis
Upon colonization of the mucosa, H. pylori elicits an inflammatory reaction (gastritis) that may last decades unless successfully treated. The presence of polymorphonuclear neutrophils characterizes the acute inflammation episodes (acute gastritis or
active gastritis) and is strongly associated with the presence of H. pylori. Lympho-

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW

ORI

YL
H. P

Normal Mucosa

Non atrophic
gastritis

Atrophic gastritis
without metaplasia

Intestinal
metaplasia

Dysplasia

Adenocarcinoma

26

FIGURE 1. The Correa precancerous cascade.

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW
cytes and plasma cells are the main components of the mononuclear leukocyte infiltrate in chronic gastritis, and lymphoid follicles are also frequently observed. H. pylori infection also stimulates epithelial proliferation, leading to elongation of glandular
necks and foveolar hyperplasia. The infection occurs initially in the antropyloric
region due to the less acidic environment being more favorable for the bacterium.
Over time, or due to the effects of proton pump inhibitors in reducing gastricacidity, H. pylori may spread proximally colonizing the corpus mucosa. Despite
inflammatory and epithelial proliferative alterations, the term non-atrophic gastritis reflects that the normal glandular epithelium is preserved, and this stage is notconsidered precancerous.

Multifocal atrophic gastritis
Gastric atrophy is the loss of native glands and it represents a fundamental change
reflecting chronic injury. When the inflammatory process persists over years or decades, individual glands or small groups of glands may become smaller in size or may
completely disappear. They may be replaced by fibrotic tissue in the lamina propria(non-metaplastic atrophy) or by metaplastic epithelium (i.e. pseudopyloric metaplasia and/or intestinal metaplasia) (table 1). This entire process is called multifocal
atrophic gastritis because occurs in a patchy fashion. It starts at the junction between
the antrum and the corpus, mainly at the incisura angularis, as independent foci thatcoalesce and spread first along the lesser curvature and then to other parts of thestomach. Over time, larger areas of the antral and corporal mucosa may be affected 3.
Advanced stages of atrophic gastritis typically present a mixture of non-metaplastic
and metaplastic areas in a patchy fashion.
TABLE 1. Gastric precancerous lesions.
1

Multifocal atrophic gastritis
a. Non-metaplastic: Shrunk/vanishing glands or loss of glands,
b. Pseudopyloric metaplasia (only in oxyntic mucosa),c. Intestinal metaplasia:
i. Complete type (type I),
ii. Incomplete type (types II and III);2

Dysplasia (non-invasive neoplasia, intraepithelial neoplasia)
a. Indefinite for dysplasia,
b. Low-grade,c. High-grade.

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW
Pseudopyloric metaplasia

28

By definition, pseudopyloric metaplasia (also called antralization), only occurs in
the oxyntic mucosa. It is characterized by loss of parietal and chief cells, which are
replaced by epithelium with mucous phenotype, resembling the antropyloric glands(figure 2). In advanced stages of oxyntic atrophy, the specialized (parietal and chief)cells may be completely lost. Although pseudopyloric metaplasia may be easily identified in routine hematoxylin and eosin (H&E)-stained sections, in absence of a proper documentation of the anatomic location of a corpus biopsy specimen, this typeof metaplasia may be overlooked. In such instances, a gastrin immunohistochemical
stain may be useful in differentiating oxyntic from antral mucosa by demonstrating
an absence of G cells in metaplastic oxyntic mucosa. A lesion resembling pseudopyloric metaplasia has been described in rodent models of human gastric disease andnamed spasmolytic polypeptide-expressing metaplasia. Spasmolytic polypeptide is
the trefoil factor 2 (TFF2), which is normally expressed in the human mucosecreting
glands in the antropyloric mucosa, in the Brunner glands, and in the mucous neckcells in the oxyntic mucosa. Pseudopyloric metaplasia consistently expresses TFF2 7.

Intestinal metaplasia
Intestinal metaplasia, on the other hand, is a lesion much easier to recognize inroutine histological sections and can be observed in any area of the gastric mucosa.
It is defined as the replacement of native gastric epithelium by epithelium resembling
intestinal morphology. It has long been recognized that intestinal metaplasia is a very
heterogeneous lesion, and multiple classifications have been proposed 8-11. Oneof the most frequently used classifications recognizes two types: complete (or small
intestinal) and incomplete (or colonic). Although initially based on the complete
or incomplete presence of small intestinal digestive enzymes 10,11, discrimination
between these two types has been widely adopted by pathologists on the basis ofmorphology on H&E-stained sections 12 (figure 3). The complete type is characterized by well-developed goblet cells alternating with eosinophilic enterocytes withwell-defined brush border (representing absorptive microvilli), and Paneth cells areobserved at the base of the crypts. Incomplete metaplasia shows goblet cells of varying size alternating with columnar cells containing intracytoplasmic mucin droplets,
and absence of a brush border. In addition, the incomplete type tends to show amore irregular architecture.
Another classification, developed by Jass and Filipe 8,9, recognizes three typesof intestinal metaplasia based on the mucins expressed: type I corresponds tothe complete type, and types II and III are subclassifications of the incomplete
type (figure 4). Special histochemical stains are required: the Alcian blue pH
2.5/periodic acid–Schiff (AB/PAS) technique discriminates between gastric andintestinal mucins. In turn, intestinal mucins can be sialic or sulfated, and are dif-

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW

A

29
B

FIGURe 2. Chronic atrophic gastritis with pseudopyloric metaplasia. A) Corpus
mucosaA showing disorganized architecture andBglandular structures with antral
phenotype (pseudopyloric metaplasia; asterisks). There is severe loss of parietal
and chief cells. Arrows show remaining chief cells at the base of the glands;
B) at higher magnification, pseudopyloric metaplasia (asterisk) and scarce parietal cells (arrowheads) are observed. Hematoxylin and eosin; original magnifications, ×200 (a) and ×400 (b).

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW

A

B

30
FIGURE 3. Intestinal metaplasia. A) Complete type, with well-defined goblet
cells alternating with eosinophilic enterocytes displaying a brush border (inset) and Paneth cells at the bottom of the crypts (arrow); B) incomplete type,showing goblet cells and intracytoplasmic mucin droplets of varying sizes andshapes, and absence of a brush border. Hematoxylin and eosin; original magnification, ×400; inset, ×1,000. Reproduced from original publication 12, withpermission.

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW
AB/PAS

HID/AB

Type I

Type II

31

Type IIIFIGURE 4. Intestinal metaplasia classification by Jass and Filipe 8. Type I: with AB/
PAS, goblet cells show a mixture of neutral (magenta) and acid (blue) mucins
in goblet cells (yielding a purple color); in this image (left upper corner) a few
normal gastric glands are stained magenta (asterisks). With HID/AB, the type I
shows only sialomucins (blue) in goblet cells. Incomplete types II and III with AB/
PAS show a mixture of gastric (magenta) and intestinal (blue) mucins in goblet
and columnar cells. With HID/AB, the type II shows only sialomucins (blue) ingoblet and columnar cells, and the type III displays predominantly sulfomucins(brown mucin droplets) in columnar cells. AB/PAS, Alcian blue (pH 2.5)/periodic
acid-Schiff; HID/AB, high-iron diamine/Alcian blue; original magnification, ×200.
Reproduced from original publication 33 with permission.

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW

32

ferentiated with the high-iron diamine (HID)/AB technique. The type I displays
mucins only in goblet cells; the type II may display sialomucins or a mixture ofgastric and sialomucins in goblet cells and intermediate columnar cells; and thetype III is characterized by the predominant presence of sulfomucins in the columnar intermediate cells. Any combination of the three types may be observedin a single biopsy.
The significance of these classifications is based on their utility to predict the riskof gastric cancer. A large body of evidence supports that the incomplete type is associated with higher synchronous or prospective gastric cancer risk than the complete
type 8,13-17. Therefore, the presence of incomplete type was proposed as a moreadvanced step in the precancerous cascade 2. Using Jass and Filipe classification, thetype III has shown the highest association with gastric cancer 8,13. However, the HID/AB technique involves potentially toxic diamine reagents and has been discontinued inmany laboratories worldwide, being reserved exclusively for research purposes.
For practical purposes, the differentiation between complete and incomplete
may be useful, and in most cases can be made using routine H&E-stained sections.
It should be clarified, though, that the images in figure 3 are very well-defined examples, but as mentioned, intestinal metaplasia is a very heterogeneous lesion andsometimes subtyping based on routine staining is not possible due to ambiguous/
unclear features. In such instances, the AB/PAS technique (which is performed withrelative regularity in histopathology laboratories) may be useful for differentiatingcomplete versus incomplete types. Extensive intestinal metaplasia usually presents a
combination of complete and incomplete subtypes. Despite the evidence, the utilityof intestinal metaplasia subtyping as a marker of gastric cancer risk has not been
widely adopted in clinical practice. It has been observed that the extent of atrophic
changes is directly related with the presence of the incomplete type 13,17,18. Therefore, when the extent of atrophy can be assessed applying staging systems for risk assessment (see below), subtyping of intestinal metaplasia may not provide additional
useful information.

ASSESSMENT OF GASTRIC CANCER RISKBASED ON THE EXTENT OF ATROPHIC CHANGESThe updated Sydney system for the classification of gastritis 19 was widely accepted in clinical practice and has provided guidance for grading of histopathological variables and information regarding the etiology of gastritis according to
the topography. It also proposed a 5-biopsy protocol (2 antrum and 2 corpus,
from lesser and greater curvature each, and one from the incisura angularis) for
an adequate representation of the gastric mucosa 19. Biopsy samples should besubmitted in at least 2 separate containers: antrum (including incisura biopsy)
and corpus. Subsequently, based on the consensus that the extent of atrophic

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW
changes is related with the gastric cancer risk, a group of pathologists and gastroenterologists created the Operative Link on Gastritis Assessment (OLGA)
staging system. The risk of developing neoplasia is categorized in stages: 0-II are
low-risk, and III-IV are high-risk. Stages are assigned by combining the extent of
antrum and corpus atrophic changes (including all variants of atrophy: non-metaplastic, pseudopyloric and intestinal metaplasia) (figure 5) 20,21. A second system, the Operative Link on Gastritis Assessment based on Intestinal Metaplasia(OLGIM), was then proposed based on the high interobserver agreement for the
diagnosis of intestinal metaplasia 22. The OLGIM system uses the same stages,
but with intestinal metaplasia as the only histopathology parameter. Althoughboth systems have been validated 17,23,24, it has been observed that by focusing
on intestinal metaplasia alone, the OLGIM system is less sensitive in identifying
individuals at high risk, by down-staging some patients who should be offeredfollow-up 25.

Antrum

ATROPHY SCORECORPUS
Score 1

Score 2

Score 3

Score 4No atrophy (score O) *Stage 0Stage I

Stage II

Stage II

Mild atrophy (score 1) *Stage I

Stage I

Stage II

Stage III

Moderate atrophy (score 2) *Stage II

Stage II

Stage III

Stage IV

Severe atrophy (score 3) *Stage III

Stage III

Stage IV

Stage IVFIGURE 5. The OLGA staging system. Reproduced from original publication
20 with permission. * including incisura angularis.
Some caveats in the application of these systems are:
1. In the OLGA system, the perpendicular orientation and full thickness of themucosa is required, specifically for the scoring of atrophy without metaplasia,
although not so critical for scoring the metaplastic variants. In the OLGIM
system, the orientation or full thickness of the biopsy is less critical.
2. The OLGA stage of an individual cannot be lower than the OLGIM stage sinceintestinal metaplasia is also included in the OLGA system 26. The misinterpretation of OLGA as only assessing atrophy without metaplasia has caused
considerable confusion in the literature.
3. Both systems use an average (although antrum and corpus separately) of theextent of the atrophic lesions, so the OLGA or OLGIM stage of an individual
should not be used as the only parameter for endoscopic surveillance decision. As an example, an individual with intestinal metaplasia in each of the fivebiopsy samples still could be classified in a low-risk OLGIM stage.

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOWDYSPLASIA
Gastric dysplasia (synonyms: intraepithelial neoplasia, non-invasive neoplasia, adenoma) is a neoplastic process limited to the epithelial layer and is associated with ahigher risk of synchronous or metachronous gastric cancer than the previously discussed lesions 4,5. Dysplasia arises most frequently in the antral compartment, but inthe presence of extensive atrophic changes, dysplastic lesions may occur in any gastriclocation 27. Morphological features include both cytological and architectural abnormalities without disruption of the epithelial basement membrane and without invasion
to the lamina propria. Multiple classification systems exist, but as a consensus, dysplasia is mainly graded as: indefinite for dysplasia, low-grade, or high-grade 27-30.

Indefinite for dysplasia

34

One of the major challenges in the diagnosis of dysplasia is the differentiationfrom reactive or regenerative epithelial changes. The term indefinite for dysplasia isused when atypical epithelial changes cannot be definitively categorized as dysplastic. Cytological atypia (without or with architectural alterations) may be observedin the presence of erosions, ulcerations, or marked inflammation. In addition, thePadova classification 29 describes two specific lesions in this category: hyperproliferative intestinal metaplasia and foveolar hyperproliferation. Although both lesions
may be observed in the setting of H. pylori-induced gastritis, the latter may also arise
as a reactive change to a variety of chemical agents, such as bile acid or nonsteroidal
anti-inflammatory drugs. Furthermore, certain technical issues, such as cautery artefact or poor tissue fixation can make interpretation difficult. In all these situations,indefinite for dysplasia is an appropriate temporary diagnosis, and a repeat biopsy(after medical therapy, if necessary) is indicated29.

Low-and high-grade dysplasias
In low-grade dysplasia, the nuclei are enlarged and hyperchromatic, frequently with ‘cigar-like’ appearance and pseudostratification. There is mucin
depletion, increased nuclear/cytoplasmic ratio, and occasional mitosis. The
nuclei are basally located and maintain the polarity with respect to the basement membrane, and there are minimal architectural changes (figure 6A and B).
High-grade dysplasia shows a more disorganized epithelium, with larger, plump,and more irregular nuclei of variable size, some of them occupying the upper
halves of the cells. (figure 6C and D) Other characteristics are prominent amphophilic nucleoli, loss of cell polarity and increased mitotic activity. Architecturalchanges may consist of irregular or branched tubular structures, or a cribriform
pattern. No stromal invasion is allowed in the diagnosis of dysplasia. It has beenlong recognized that discrepancies exist in nomenclature of neoplastic lesions

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW
between western and Japanese pathologists. For western pathologists, invasionis the hallmark of carcinoma. In Japan, carcinoma is diagnosed based on definitive neoplastic epithelium, even without invasion 30. The diagnosis and gradingof dysplasia is subject to significant interobserver variation; therefore, a second
opinion is strongly advisable.
According to the recent WHO classification of tumors of the digestive system,27
although the terms ‘dysplasia’ and ‘intraepithelial neoplasia’ are still considered acceptable for lesions in certain anatomical locations, the term dysplasia is preferred
for lesions in the tubal gut, whereas intraepithelial neoplasia is preferred for thosein the pancreas, gallbladder and biliary tree. The term ‘carcinoma in situ’ is not recommended, instead this term is included in the category of high-grade dysplasia 27.

A

B

35

C

D

FIGURE 6. A-B) Low-grade dysplasia. At lower magnification (A), a small focus
of low-grade dysplasia is observed in a background of intestinal metaplasia.
B) Higher magnification of the dysplastic glands, with hyperchromatic, basally located nuclei, with ‘cigar-like’ appearance and pseudostratification. C-D)
High-grade dysplasia replacing most of the epithelium observed (C) with the
exception a few metaplastic glands in the lower right area. At higher magnification (D), larger and plump nuclei of variable size are observed, some of themoccupying the upper halves of the cells and displaying prominent nucleoli. Hematoxylin and eosin; original magnification, ×200 (A, C); ×400 (B, D).

Piazuelo MB

H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOWAUTOIMMUNE GASTRITIS

36

Autoimmune gastritis is a type of immune-mediated chronic atrophic gastritis of
the oxyntic mucosa where the parietal cells are the primary target. It is characterized by
the presence of antibodies against parietal cells and/or intrinsic factor 31.The pathogenesis of this condition is not completely understood, but there is evidence that H.
pylori infection may represent a trigger of autoimmunity in some cases. Autoimmune
gastritis represents a preneoplastic condition, as patients with pernicious anemia (itsmost recognized late-stage clinical manifestation) have a high risk of developing either
type 1 gastric neuroendocrine tumors 27 or gastric adenocarcinomas 32. The typical
histological manifestation of autoimmune gastritis is a corpus-predominant atrophic
gastritis, a pattern different from the most common antral involvement in H. pylori-associated gastritis. Histopathological features vary according to the stage of the disease
and include a predominantly lymphoplasmacytic infiltrate in the lamina propria andpresence of foci of lymphocytes infiltrating glands. Atrophic changes include a variable degree of loss of parietal and chief cells, and epithelial metaplastic transformation(pseudopyloric, intestinal, and pancreatic acinar). In advanced stages, there may beenterochromaffin-cell-like hyperplasia and type 1 neuroendocrine tumors, indicatinga state of hypergastrinemia. In the corresponding antral mucosa, hyperplasia of gastrin-producing (G) cells is usually observed 27.

REFERENCES
1. 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.
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;52:6735-40.
3. Correa P, Haenszel W, Cuello C, et al. A model for gastric cancer epidemiology. Lancet
1975;2:58-60.
4. 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;134:945-52.
5. Song H, Ekheden IG, Zheng Z, et al. Incidence of gastric cancer among patients withgastric precancerous lesions: observational cohort study in a low risk Western population.
BMJ 2015;351:h3867.
6. Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization.
Nat Rev Cancer 2018;18:19-32.
7. Rugge M, Sacchi D, Genta RM,, et al. Histological assessment of gastric pseudopyloric

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H ISTOLOGY OF GASTRIC PRECANCEROUS LESIONS: WHAT CLINICIANS SHOULD KNOW
metaplasia: Intra- and inter-observer consistency. Dig Liver Dis 2020.
8. Filipe MI, Munoz N, Matko I, et al. Intestinal metaplasia types and the risk of gastriccancer: a cohort study in Slovenia. Int J Cancer 1994;57:324-9.
9. Jass JR, Filipe MI. The mucin profiles of normal gastric mucosa, intestinal metaplasia andits variants and gastric carcinoma. Histochem J 1981;13:931-9.
10. Matsukura N, Suzuki K, Kawachi T, et al. Distribution of marker enzymes and mucin in
intestinal metaplasia in human stomach and relation to complete and incomplete typesof intestinal metaplasia to minute gastric carcinomas. J Natl Cancer Inst 1980;65:231-40.
11. Teglbjaerg PS, Nielsen HO. “Small intestinal type” and “colonic type” intestinal metaplasia of the human stomach, and their relationship to the histogenetic types of gastricadenocarcinoma. Acta Pathol Microbiol Scand A 1978;86A:351-5.
12. Correa P, Piazuelo MB, Wilson KT. Pathology of gastric intestinal metaplasia: clinicalimplications. Am J Gastroenterol 2010;105:493-8.
13. Cassaro M, Rugge M, Gutierrez O, et al. Topographic patterns of intestinal metaplasia
and gastric cancer. Am J Gastroenterol 2000;95:1431-8.
14. Gawron AJ, Shah SC, Altayar O, et al. AGA Technical Review on Gastric Intestinal Metaplasia-Natural History and Clinical Outcomes. Gastroenterology 2020;158:705-731 e5.
15. Gonzalez 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;31:953-8.
16. Gonzalez CA, Sanz-Anquela JM, Gisbert JP, et al. Utility of subtyping intestinal metaplasia as marker of gastric cancer risk. A review of the evidence. Int J Cancer 2013;133:102332.
17. Mera RM, Bravo LE, Camargo MC, et al. Dynamics of Helicobacter pylori infection as adeterminant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 2018;67:1239-1246.
18. Rugge M, Fassan M, Pizzi M, et al. Operative Link for Gastritis Assessment gastritis staging incorporates intestinal metaplasia subtyping. Hum Pathol 2011;42:1539-44.
19. 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;20:1161-81.
20. Rugge M, Correa P, Di Mario F, et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis
2008;40:650-8.
21. Rugge M, Meggio A, Pennelli G, et al. Gastritis staging in clinical practice: the OLGA
staging system. Gut 2007;56:631-6.
22. 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;71:1150-8.
23. 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

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38

2018;113:1621-1628.
24. Rugge M, Meggio A, Pravadelli C, et al. Gastritis staging in the endoscopic follow-up forthe secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients.
Gut 2019;68:11-17.
25. Rugge M, Fassan M, Pizzi M, et al. Operative link for gastritis assessment vs operative linkon intestinal metaplasia assessment. World J Gastroenterol 2011;17:4596-601.
26. 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;65:1899-1903.
27. WHO Classification of Tumors Editorial Board. Digestive system tumours. Lyon (France):
International Agency for Research on Cancer, 2019 (WHO Classification of tumours
series, 5th ed; vol. 1).
28. Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut 2002;51:130-1.
29. Rugge M, Correa P, Dixon MF, et al. Gastric dysplasia: the Padova international classification. Am J Surg Pathol 2000;24:167-76.
30. Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47:251-5.
31. Hall SN, Appelman HD. Autoimmune Gastritis. Arch Pathol Lab Med 2019;143:13271331.
32. Song M, Latorre G, Ivanovic-Zuvic D, et al. Autoimmune Diseases and Gastric Cancer
Risk: A Systematic Review and Meta-Analysis. Cancer Res Treat 2019;51:841-850.
33. Shah SC, Gawron AJ, Mustafa RA, et al. Histologic Subtyping of Gastric Intestinal Metaplasia: Overview and Considerations for Clinical Practice. Gastroenterology 2020;158:745750.

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H ELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS

Helicobacter pylori infection
and gastric precancerous lesions
Don’t be too late to eradicate!

Francis Mégraud, Christine Varon 1
1
Inserm U1053, University of Bordeaux,Bordeaux, France

In the past, it was thought that in contrast to other organs, the stomach was
evolving histologically and physiologically over the years , leading to the opinion
that it was a normal evolution. The different steps were well described by Correa 1 and later the essential cause of this evolution was discovered: the bacterial
infection by Helicobacter pylori.
However, this cascade of events does not apply to the evolution of cardia
gastric cancer (GC) or the diffuse type non-cardia GC according to the Laurén
histological classification.
In this chapter, we will review the role of H. pylori in the different steps thatlead to gastric precancerous lesions, the other factors that contribute to this evolution, and the impact of H. pylori eradication, including the treatment used andthe cost-effectiveness of this approach.

EVOLUTION OF HELICOBACTER PYLORI INFECTION
From epidemiology to etiologic discovery
As early as 1975, i.e. before the discovery of H. pylori, Correa et al. proposeda model for GC pathogenesis, which could apply to most GC, those of theintestinal type.
The different steps were chronic gastritis, gastric atrophy, intestinal metaplasia(IM) followed by dysplasia and early GC. They anticipated that the first step alreadybegan in the first decade of life and that the mutagen involved could be a nitroso
compound. This sequence of histological events was named the Correa cascade 1.
Later H. pylori was discovered and shown to be the essential cause of this cascadeof events 2.

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H ELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS
The role of Helicobacter pylori

40

H. pylori is indeed acquired early in life, essentially but not exclusively in thefamily, mainly by oral-oral contamination or vomit, and provokes an acute gastritis which evolves to chronic gastritis 3.
Most individuals are not able to get rid of the bacteria spontaneously as thesebacteria are located “outside” of the body, in the mucus layer lining the gastricepithelium.
This infection induces limited or no symptoms and, given its occurrence at a
young age, most people consider the few symptoms that they may have as normal.
Indeed, H. pylori is even considered to be beneficial in childhood because it contributes to the maturation of the immune system 4. Only a few children develop
ulcers, necessitating a treatment 5.
After several years and sometimes decades, the gastric mucosa tends to become
atrophic, altering the physiology of the stomach, and intestinal cells may appear focally.
H. pylori, and especially its oncoprotein CagA, are able to reprogram epithelial cells and activate properties of stemness of progenitor and stem cells 6.
Accumulation of DNA damage can happen during the close contact between H.
pylori and host cells 7. When IM occurs, the role of H. pylori which cannot colonize these cells becomes of secondary importance compared to other additional
factors which will lead to dysplasia and GC.

Other factors
While the role of H. pylori is essential, and at the origin of around 90% of GC
8, the remaining 10% are caused by the Epstein Barr virus 9, and other factors,
both genetic and environmental, are important contributors.
First, it must be underlined that even if all H. pylori strains are able to induce
chronic gastritis, they are not equal with regard to their pathogenicity factors.
Among these factors, there are variations in the attachment factors, the amountof cytotoxin production ranging from none to a lot according to the genotype 10,
and even more importantly a pathogenicity island, namely cag, which has important proinflammatory properties and is not present in all strains, or is partly deleted 11. Moreover, in the last steps of the carcinogenic process, the importance ofgastric microbiota is crucial. Different bacteria can colonize the stomach which
is now less acidic, including bacteria that produce N-nitroso compounds 12 andacetaldehyde 13, which are well known carcinogens.
It has also been shown that the host genotype, especially with regard to IL-1b
and other cytokines 14, may influence the degree of inflammation and gastricacid inhibition.
Finally, dietary factors and drugs have an important impact. A salty diet may
itself induce gastric atrophy, consequently acting as a synergistic factor with H.
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H ELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS
pylori infection 15. Iron deficiency and a lack of vitamins and anti-oxidants havealso been implicated 16. In contrast, a diet rich in vitamins is considered to beprotective. Regarding drugs, long term use of proton pump inhibitors (PPI),
which permanently decrease the acidity, are also possible risk factors.
The first progress in terms of histological evaluation of gastric lesions was
the publication of the Sydney system, which grades the activity, inflammation,
atrophy, IM and the presence of H. pylori, separately. 17. Another crucial step
was the development of the OLGA 18 and OLGIM 19 staging systems, whichhave an important clinical value because they provide information on the risk ofevolution of premalignant lesions to GC.
Another point is the risk related to the so-called incomplete IM (Type III).
This typing, based on the mucin profile 20, is not used systematically but may be
an important factor as observed in some studies 21.

HELICOBACTER PYLORI ERADICATION AND ITS IMPACT
Helicobacter pylori eradication
Since H. pylori is a bacterium, it is possible to eradicate it with antibiotics, but
it is not easy. It is necessary to add antisecretory drugs, namely PPI, to increase
the gastric pH to allow the activity of most antibiotics or, even better when available, potassium-competitive acid blockers (P-CAB), such as vonoprazan 22.
Clinical trials performed in the 1990s showed that a combination of two antibiotics was necessary, i.e. clarithromycin and amoxicillin or clarithromycin andmetronidazole 23. This triple therapy (with a PPI) has been used worldwide but
its success decreased progressively at the beginning of the century, due to anincrease in clarithromycin resistance 24. To continue giving empiric treatment,
quadruple therapies using either clarithromycin-amoxicillin-metronidazole +PPI 25 or tetracycline-metronidazole-bismuth salts + PPI 26 have therefore been
recommended. However, they are not in line with the WHO recommendations
for prudent use of antibiotics 27 and the treatment generates more immediate
adverse events than triple therapies. In addition, mid- and long-term effects likeselection of antibiotic resistance in other bacteria and changes in the gut microbiota are greater than with triple therapies. Therefore, the current policy, whenpossible, is to use the triple therapy, guided by antimicrobial susceptibility testing(AST) 28.
Commercially available kits exist today, allowing for the detection of H. pylori andits eventual resistance to clarithromycin, the most crucial antibiotic in this respect.
These kits are based on real-time PCR, which is convenient to use and gives quick
and precise results 29. Based on the AST result, clarithromycin can still be administered in 70-80% of the cases according to the region in Europe 24. However, thisMégraud F, Varon C

41

H ELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS
guided triple therapy has to be optimized, i.e. it must include: 1) the most effective
PPI: esomeprazole or rabeprazole, which are not modified by the hepatic enzyme:
CYP2C19, and prescribed at a higher dose than before, 2) the prescription of 1g
amoxicillin three times a day instead of two to avoid a time lapse without amoxicillinin the gastric mucus, given the pharmacokinetics of the antibiotic 30, and 3) thetreatment must be prolonged to two weeks (table 1).
In case of failure which should not exceed 10% of the cases, there is still the possibility to use a quadruple therapy, preferably one using bismuth. For those allergic
to penicillin, amoxicillin must be replaced by metronidazole in the triple therapy.
TABLE 1. Proposition of eradication treatment for Helicobacter pylori.
First line treatment
guided by AST for clarithromycinA

if clarithromycin susceptible (or absence of 23S rDNA mutation detectedby RT-PCR)
esomeprazole or rabeprazole (double dose) - clarithromycin (500 g x 2) amoxicillin (1 g x 3) for 14 daysB

if clarithromycin resistantPylera® - omeprazole for 10 days

42

Second line treatment
after guided treatment A: Pylera®* - omeprazole for 10 days
after treatment B - test for levofloxacinC

if levofloxacin susceptible
esomeprazole or rabeprazole (double dose) - amoxicillin (1 g x 3) levofloxacin (500 mg x 2) for 14 daysD

if levofloxacin resistantesomeprazole or rabeprazole (double dose) - amoxicillin (1 g x 3) - metronidazole(500 mg x 2) for 14 days
Third line treatment
consider Talicia®
AST: antimicrobial susceptibility testing.
* Pylera® contains per capsule: tetracycline 125mg-metronidazole 125mgbismuth sub citrate 140mg. Recommended 3 capsules 4 times per day.
**Talicia contains per capsule omeprazole 10mg - amoxicillin 250mg - rifabutin
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H ELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS
Impact of H. pylori eradication according to the mucosal status
When the eradication treatment is given at the chronic gastritis stage, a quick
improvement in histology occurs. The bacteria and the inflammatory activity disappear, but it may take months to observe the disappearance of the inflammatorycomponents and the re-establishment of a normal mucosa. In a mouse experiment, we observed that resveratrol, with its anti-inflammatory properties, speeds
up the process 31.
When the treatment is given at the gastric atrophy stage, the process is muchslower and may take years. Rokkas et al. carried out the first systematic review
and meta-analysis on the reversibility of gastric atrophy after H. pylori eradication. They found 8 studies with an at least one-year follow-up, with the majority
being less than ten years. There was a beneficial effect both on the antrum andthe corpus, the pooled OR with a 95% confidence interval (CI) being 0.554[0.372-0.825), p=0.004 for antrum atrophy and 0.209 [0.081-0.538], p <0.001
for corpus atrophy 32.
In a second meta-analysis that included 26 studies 33, they found the same
results on GC prevention , without significant heterogeneity. One limitation ofthis study was that 24 of the studies were performed in East Asian countries.
However, H. pylori eradication did not have an effect on the evolution towards
GC in either publication, when the histological examination at baseline showedeither IM or dysplasia.
More recently, very long term follow-ups studies are appearing in the literatureand show that even under such circumstances it is possible to see a regression of
the GC risk, and so a controversy was born. If we take the analogy of smoking
as a risk factor for lung cancer, it is possible to see a decrease in the risk of lungcancer to the baseline level only after more than 20 years of not smoking 34. It
is therefore conceivable that such a long delay without H. pylori infection may
also be necessary to decrease the risk of GC to the baseline level, and more longterm follow-ups studies are needed to provide a definitive answer to the question.

How to manage H. pylori eradication at the population level?
A remaining question is whether an organized screening for H. pylori infection
and its associated lesions in the general population would be beneficial. The current status is that it can be cost effective only in countries with a high prevalenceof infection and a high incidence of GC, essentially in East Asia. Furthermore,
the benefit of an immediate expense will only be seen a long time afterward 35.
The pragmatic approach in most European countries is to test for H. pylori inall patients undergoing upper digestive endoscopy that are older than 50, and totreat them if positive. In some countries a test and treat approach using non-inva-

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H ELICOBACTER PYLORI INFECTION AND GASTRIC PRECANCEROUS LESIONS
sive tests is proposed for younger patients. The limitation is that GC can develop
with minimal symptoms and therefore H. pylori eradication may occur too late.
In this situation, there are recommendations to perform an endoscopy follow up
at regular intervals.
In other situations the proposal was to combine the colorectal cancer detection program with screening for H. pylori and premalignant lesions. A non-invasive test using H. pylori serology and evaluation of the Pepsinogen I/II ratio isused to select those for whom an upper digestive endoscopy will be performed.

CONCLUSION44

We can conclude that H. pylori eradication is always beneficial but to bringthe most benefit, it must not be carried out too late in life. However, the current recommendation is not to eradicate during childhood, but ideally in young
adults, before they have children. This, in turn, would limit the transmission to
the younger generations. It can obviously be performed later but the risk is thatit takes decades for the mucosa to get back to normal, especially when it attains
the grade of IM, so the sooner the better!

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1. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer
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2. Warren R, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic
gastritis. Lancet 1983 ; 1 : 1273.
3. Mentis A, Lehours P, Mégraud F. Epidemiology and diagnosis of Helicobacter pylori infection. Helicobacter 2015; 20 (Suppl 1): 1-7.
4. Arnold IC, Hitzler I, Müller A. The immunomodulatory properties of Helicobacter pylori
confer protection against allergic and chronic inflammatory disorders. Front Cell InfectMicrobiol 2012; 2: 10.
5. Jones NL, Koletzko S, Goodman K, et al. Joint ESPGHAN/NASPGHAN guidelines forthe management of Helicobacter pylori in children and adolescents (Update 2016). J Pediatr Gastroenterol Nutr 2017; 64: 991-1003
6. Amieva M, Peek RM Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology 2016; 150: 64-78.
7. Koeppel M, Garcia-Alcalde F, Glowinski F, Schlaermann P, Meyer TF. Helicobacter pylori
infection causes characteristic DNA damage patterns in human cells. Cell Rep 2015; 11:1703-13.
8. González CA, Megraud F, Buissonniere A, et al. Helicobacter pylori infection assessed by
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Eurogast-EPIC project. Ann Oncol 2012; 23(5):1320-1324.
9. Cancer Genome Atlas Research Network. Comprehensive molecular characterization ofgastric adenocarcinoma. Nature 2014; 513: 202-9.
10. Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism invacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types withcytotoxin production and peptic ulceration. J Biol Chem 1995; 270: 17771-7.
11. Hatakeyama M. Helicobacter pylori and gastric carcinogenesis. J Gastroenterol 2009; 44 :239-48.
12. Jakszyn P, Gonzalez CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence. World J Gastroenterol
2006; 12: 4296-303.
13. Salaspuro M. Acetaldehyde and gastric cancer. J Dig Dis 2011; 12: 51-9.
14. Troost E, Hold GL, Smith MG, et al. The role of interleukin-1beta and other potential
genetic markers as indicators of gastric cancer risk. Can J Gastroenterol 2003;17 (Suppl
B): 8B-12B.
15. Gaddy JA, Radin JN, Loh JT, et al. High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis. Infect Immun 2013; 81: 2258-67.
16. Cover TL, Peek RM Jr. Diet, microbial virulence, and Helicobacter pylori-induced gastriccancer. Gut Microbes 2013; 4: 482-93.
17. Price AB, The Sydney System: histological division. J Gastroenterol Hepatol 1991; 6: 20922.
18. Rugge M, Genta RM; OLGA Group. Staging gastritis: an international proposal. Gastroenterology 2005; 129: 1807-8.
19. 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; 71: 1150-58.
20. Filipe MI, Potet F, Bogomoletz WV, et al. Incomplete sulphomucin-secreting intestinal
metaplasia for gastric cancer. Preliminary data from a prospective study from three centres. Gut 1985; 26: 1319-26.
21. 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; 31: 953-58.
22. Kagami T, Sahara S, Ichikawa H, et al. Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype. Aliment Pharmacol Ther
2016; 43: 1048-59
23. Lind T, Mégraud F, Unge P, et al. The MACH2 study: role of omeprazole in eradication of
Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999; 116: 248-53.
24. Megraud F, Coenen S, Versporten A, et al. Helicobacter pyloriresistance to antibiotics inEurope and its relationship to antibiotic consumption. Gut 2013; 62: 34-42.
25. De Francesco V, Pontone S, Bellesia A, et al. Quadruple, sequential, and concomitantMégraud F, Varon C

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first-line therapies for H. pylori eradication: a prospective, randomized study. Dig Liver
Dis 2018; 50: 139-41.
26. Malfertheiner P, Bazzoli F, Delchier JC, et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, methonidazole, and tetracylcine given withomeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011; 377: 905-13.
27. Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Prevalence of antibiotic resistance in Helicobacter pylori: A systematic review and meta-analysis in World Health Organization Regions. Gastroenterology 2018; 155: 1372-82.
28. Choi YI, Chung JW, Park DK, et al. Tailored eradication vs empirical bismuth-containing
quadruple therapy for first-line Helicobacter pylori eradication: A comparative, open trial .
World J Gastroenterol 2019; 25: 6743-51.
29. Bénéjat L, Ducournau A, Lehours P, Mégraud F. Real-time PCR for Helicobacter pylori
diagnosis. The best tools available. Helicobacter 2018; 23: e12512.
30. Matysiak-Budnik T, Heyman M, Candalh C, Lethuaire D, Mégraud F. In vitro transfer ofclarithromycin and amoxicillin across the epithelial barrier: effect of Helicobacter pylori. J
Antimicrob Chemother 2002; 50: 865-872.
31. Mayo K, Castagnino C, Chèze C, Vercauteren J, de Mascarel A, Mégraud F. Ameliorationof gastric inflammation by polyphenols from red wine: a mouse model using Helicobacter
felis. Gut 2000;47 (Suppl 1):A61
32. Rokkas T, Pistiolas D, Sechopoulos P, Robotis I, Margantinis G. The long-term impact ofHelicobacter pylori eradication on gastric histology: a systematic review and meta-analysis.
Helicobacter 2007;12 (Suppl 2): 32-8.
33. Rokkas T, Rokka A, Portincasa P. A systematic review and meta-analysis of the role ofHelicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol 2017; 30:
414-23.
34. Kenfield SA, Stampfer MJ, Rosner BA, Colditz GA. Smoking and smoking cessation in
relation to mortality in women. JAMA 2008; 299: 2037-47.
35. Ford AC, Yuan Y, Forman D, Hunt R, Moayyedi P. Helicobacter pylori eradication for theprevention of gastric neoplasia. Cochrane Database Syst Rev 2020; 7: CD005583.

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N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?

Non-invasive tests for the detection ofgastric atrophy: What is really useful?
Mãrcis Leja 1,2, Francesco Di Mario3
1
Faculty of Medicine & Institute of Clinical and Preventive Medicine,
University of Latvia
2
Digestive Diseases Centre GASTRO
3
Department of Medicine and Surgery, University of Parma, Italy

THE APPLICATION OF NON-INVASIVE TESTSFOR GASTRIC ATROPHY
The ‘gold standard’ for the detection of gastric mucosal atrophy is endoscopy –either with detailed biopsy assessment (the Western approach) or by thorough visualinspection (the typical approach in the East). The clinical application of non-invasive
testing for the detection of gastric atrophy generally includes one of the following:
1) for selecting symptomatic patients for endoscopy, and therefore avoiding unnecessary procedures, or 2) as a general population-based screening of asymptomatic
individuals to identify those at an increased risk. Although non-invasive testing for
atrophy has been available for decades, numerous guidelines and recommendations
have indicated the rationale for the use of such tests (mainly pepsinogen testing). At
this stage, no country has yet introduced population-based testing. The available evidence and guideline recommendations will be reviewed in this chapter; in addition,a brief discussion of emerging testing modalities will be provided.

THE RELEVANCE AND APPROACHESFOR PEPSINOGEN DETECTION
Pepsinogens are the most studied indirect markers for gastric mucosal atrophy.
In 1982, Michael Samloff was the first to propose the clinical use of serum
pepsinogen I as “a serological biopsy for gastric mucosa” 1. Pepsinogens are
pepsin pro-enzymes that can be measured in blood as indirect markers of gastric mucosal changes 2. Two isozymogens, pepsinogen I (PgI) and pepsinogen

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47

N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?
II (PgII), are produced in different parts of the stomach 3. PgI production
is exclusively limited to acid-secreting glands of the gastric corpus (proximal
stomach), whereas PgII production is widespread in diverse types of glands
throughout the stomach, as well as Brunner glands of the duodenum 4. Figure
1 summarizes the physiology and anatomical site of production of pepsinogenI, pepsinogen II and gastrin 17. Thus, mucosal atrophy affecting the gastriccorpus leads to decreased levels of PgI, while PgII levels tend to be relatively
stable. In particular, the presence of mucosal inflammation, also related to H.
pylori infection, may increase the levels of both PgI and PgII 5, 6 and thus insome cases result in normal PgI values when both atrophy and inflammation
are present 7. To account for this draw-back, a decreased ratio of PgI to PgII
(PgI/PgII) is considered to be the best serologic marker of gastric atrophy 8.

48

Pepsinogen I (body and fundus) :marker of acid secretion
Pepsinogen II (whole stomach) :marker of inflammation

Gastrin 17 (antrum) :2 negative feedback with acid secretion,
2 marker for the antral G-cell fonction.

FIGURE 1. Functional anatomy of serological markers of gastric mucosa.
It should be noted, that different methods can be used for pepsinogen detection (latex-agglutination, ELISA, chemiluminescent enzyme immune assay).
While there is a good correlation between results obtained with different methods 9, the results may appear different when absolute values are considered.
Therefore, the cut-off values have to be decided specifically for the method
used, and potentially, also adjusted in different populations.
Several meta-analyses have addressed the issue of the accuracy of pepsinogen testing for the detection of precancerous gastric lesion.
The initial meta-analysis by Dinis-Ribeiro et al. 2 included 42 data sets, including population-based screening studies accounting for 296,553 individuals.

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N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?
Multiple studies from Asia (predominantly Japan) were included. Eight studies
were considered in the evaluation of the performance of pepsinogens for corpus
atrophic gastritis detection. However, because of heterogeneity, in particular,
the use of different cut-offs, pooled analysis was not possible.
The meta-analysis by Huang et al. 10 in 2015 demonstrated good correlation between decreased pepsinogen levels and atrophic gastritis, and the authors succeededin calculating a pooled sensitivity of 69% (95% CI 55 – 80) and specificity of 88%(95% CI 77 – 94), and ROC AUC of 0.83 (95% CI: 0.80-0.86) for PgI/PgII to detect atrophy. The authors concluded that serum pepsinogen levels have a potentiallysignificant role in the identification of populations at high risk of gastric cancer andcould be used for mass screening. It was also noted that there was great heterogeneity between studies, in particular using different methods for the quantification of
pepsinogen levels.
The third metanalysis was published by Zagari et al. 2 in 2017, and in addition to pepsinogens it has addressed the role of the pepsinogen, gastrin-17 andH.pylori antibody combination for the detection of atrophic gastritis. Twenty
studies that have used this detection panel (GastroPanel ®) with a total of 4241
subjects assessed the performance of the serological marker test for the diagnosis of atrophic gastritis regardless of the site in the stomach. The sensitivity was
at 74.7% (95% CI: 62.0-84.3) and specificity at 95.6% (95%, CI: 92.6-97.4).
With a prevalence of atrophic gastritis of 27% (median prevalence across thestudies), the negative predictive value was at 91%. The authors have suggested
that the sensitivity and specificity of the panel is higher than for pepsinogen andgastrin-17 serum assays separately.
The most recent meta-analysis has been published by Bang et al. 11 showing
a sensitivity of 59%, specificity of 89%, odds ratio of 12, and 0. area under the
curve at 0.81 for the cut-off values of PG I ≤70 ng/mL and PG I/PG II ratio ≤3
for the detection of corpus atrophic gastritis.
Thus, the accumulated evidence suggests moderate sensitivity, but relatively
high specificity for pepsinogen tests to detect atrophic gastritis.
BOX.

Practical hints

2

The PgI/PgII ratio should be used for diagnostic purposes instead of PgI alone because
the use of a ratio compensates for the increase in pepsinogen levels caused by mucosal
infection, in particular by H. pylori.

2

Different methods are currently used for pepsinogen detection in clinical practice, including latex-agglutination, ELISA, CLEIA (chemiluminescent enzyme immune assay).

2

Cut-off levels for either PgI of Pg I/II depend on the test-system (method) used, andshould not be transposed between different methods (a common mistake), and may be
adapted to the studied population.

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49

N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?
ABC (D) METHOD
Combined evaluation of pepsinogen levels and detection of the presenceof H. pylori has been suggested by Miki and colleagues in Japan for population-based testing. Typically, serological detection of antibodies against H. pylori has been suggested for this purpose. Accordingly, patients are divided into
the following groups (ABCD) (table 1).
TABLE 1. ABC(D) group definitions.

50

A

B

C

D

Pepsinogens

NormalNormalDecreased

Decreased

H. pylori

AbsentPresent

Present

AbsentAs demonstrated by Watabe et al. 12 in a 4.5 year follow-up of 7,000 patients, the highest risk score was in the “D” group, which could be explained by
the fact that in the natural course of H. pylori infection, this bacteria may disappear from gastric mucosa, and accordingly, patients at more advanced stages ofatrophy have a higher risk of developing gastric cancer (figure 2).
The acquired evidence on the ABC method has been recently summarized
in a book edited by K. Miki 13.
However, there are certain limitations related to the method, see the hints
below.
BOX.

Practical hints

2 A positive H. pylori serology may be a false-positive in patients with a past infection; most of the recommendations require an additional confirmatory test (suchas 13C-urea breath test) to confirm the presence of the infection.
2

Prior eradication therapy should be considered when applying the ABC method.
Otherwise successful eradication therapy could be the reason for misplacing apatient to a higher risk-group (e.g. from group C to group D).

2

It should be mentioned that a significant proportion of subjects (up to 20%) witha positive H. pylori serology do not have an active infection even when not self-reporting previous eradication therapy. Therefore, for treatment purposes and to
avoid overtreatment, it is recommended that a positive serology be confirmed byan additional test like 13C-urea breath test.

Leja M, Di Mario F

N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?
GASTRIN-17
Recently, an additional marker has been suggested for the characterizationof atrophy in the antral part of the stomach – amidated gastrin-17 (G-17) since
it is secreted exclusively by the G-cells in this part of the organ 4, 14, 15.
Theoretically, there could be an additional advantage of adding G-17 to thepepsinogen biomarker panel mainly for two reasons: 1) high G-17 and the presenceof decreased pepsinogens would confirm the presence of atrophy in the corpus; 2)
low G-17 could be indicative of atrophy in the antral part of the stomach.
G-17 levels in the circulation increase after food intake; therefore the measurements of G-17 following a provocation with a protein-rich meal are considered to be the best indicator of antral G-cell function 15, 16. However, theuse of a provocation test is impractical and inconvenient in a screening setting,therefore fasting G-17 is instead being used in many studies 17.
In addition to diet, amidated G-17 levels in the circulation are sensitive toother physiological stimuli, including drug intake (e.g. proton pump inhibitors) 4. This decreases the value of the test for detecting atrophy in the antral
part of the stomach to sensitivity levels far below the acceptable levels for ascreening test (15.8% when fasting and 36.8% after stimulation) 18. No difference in G-17 levels was found between proximally and distally localized gastriccancer 19, 20. Therefore, currently there seems to be a limited benefit frominvestigating this parameter.
BOX.

Practical hints

2

Amidated gastrin-17 ( G-17) can show a compensatory increase under the conditionsof corpus atrophy with normal antral mucosa, making it difficult to judge the presenceof antral atrophy.

2

Although better G-17 results are demonstrated after a food stimulation, performing
such a test is not easy in routine practice.

RECOMMENDATIONS BY THE CURRENT GUIDELINES
Several national, regional and international recommendations and consensus statements have suggested the role of serology in atrophic gastritis and/or
gastric cancer risk stratification.
The role of serological tests (pepsinogen I, II, I/II, anti-H. pylori antibodies) in
gastric cancer risk stratification has been elucidated by the Kyoto Global Consensus(Statement 15; Level of evidence high, Grade of recommendation strong) 21.
Maastricht V/Florence Consensus indicates that the available data consistently recognise pepsinogen serology as the most useful non-invasive test to explore

Leja M, Di Mario F

51

N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?

GROUP Apatients= 3 324(2 260 males, 1064 females;
median age: 47.1; HR= 1)
6 983 PATIENTSGROUP Bpatients= 2 134(1 489 males, 645 females;
median age: 49.2; HR= 1.1)

GROUP D

52

GROUP C

patients= 443

patients= 1 082(320 males, 123 females;
median age: 53.3; HR= 8.29)(713 males, 369 females;
median age: 52.0; HR= 6.0)

A

B

C

D

Pepsinogen
index

N

N

↓

↓

IgG anti HP

-

-

+

-

= SPGI < 70 mg/mL and PGI/PGII ratio < 3.0 ng/mL;
N= all other cases

Leja M, Di Mario F

N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?

Proportion of gastric cancer development
0,05Groupe D

0,04Groupe C

0,03

0,02

0,01

Groupe B
Groupe A

0,00

0

1

2

3

4

5

6

7

53

8

Follow-up (years) *Numbers at risk
0

1

2

3

4

5

6

7

Group A

3324

3217

2997

2997

2734

2448

1950

950

Group B

2134

2071

1904

1904

1726

1537

1229

579

Group C

1084

1050

950

950

866

761

610

298

Group D

443

420

384

384

345

305

237

105

Figure 2. Pepsinogen index and gastric cancer cancer risk. * Follow-up average:
4.7 years. SPGI : serum levels of pepsinogens. 12

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N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?

54

the status of the gastric mucosa (non-atrophic vs atrophic). The PGI/PGII ratio
cannot be considered as a biomarker of gastric neoplasia. (Recommendation 9;
Level of evidence 2A, Grade of recommendation A) 8.
MAPS II update is generally in agreement with the above, stating that low
pepsinogen I serum levels and/or a low PGI/II ratio can be used to identify patients with advanced stages of atrophic gastritis (Recommendation 11; Qualityof evidence moderate, Grade of recommendation strong) 22.
The Brazilian recommendations state that serological analysis of gastric atrophy using pepsinogen I (PGI) and pepsinogen II (PGII), combined with antibodies against H. pylori and gastrin-17, can be used to identify populations
at risk of gastric cancer (Recommendation 19; Level of evidence 3A, Grade ofrecommendation B). However, they also state that further studies are necessary
to validate this approach in Brazil and other countries of Latin America 23.
Controversially, the British Society of Gastroenterology guidelines on the
diagnosis and management of patients at risk of gastric adenocarcinoma do notrecommend the use of biomarkers as a screening tool in areas with a low incidence of gastric adenocarcinoma, such as the UK (evidence level: low quality;
grade of recommendation: weak; level of agreement: 93%) 24.

AUTOIMMUNE GASTRITIS:
THE RELEVANCE AND SEROLOGICAL METHODSPatients with autoimmune gastritis (AIG) are reported to have an increased riskof developing gastric cancer. Very recently, in 2020, Weise et al. compared a cohort ofgastric cancer patients with or without autoimmune gastritis in a case-control studyin Germany. They showed that subjects with autoimmune gastritis were detected atearlier stages of cancer which translated into a significantly better 5-year survival 25.
The prevalence of oxyntic gastric atrophy is high in patients with autoimmune
thyroid disease, and testing for serum pepsinogens should be included in theclinical assessment of these patients. In 2015, Venerito et al. performed a case-control
study confirming the accuracy of PGI and PGII for screening of autoimmune gastritis in subjects affected by autoimmune thyroiditis 26.
The presence of antibodies against gastric parietal cells (APCA) that target thea- and b- subunits of the proton pump, have also been suggested as markers for atrophy in the stomach mucosa 17. APCA is considered to be a marker of autoimmune
gastritis. The presence of APCA correlates with atrophy in the corpus part of thestomach 27; they may precede clinical manifestations of corpus gastritis as pernicious anemia 28.
The intrinsic factor (IF) is a glycoprotein produced by the parietal cells (oxyntic
cells) located in the gastric body and fundus 29. Anti-intrinsic factor antibodies(anti-IFA) have been regarded as a marker of pernicious anaemia and appear at later

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N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?
stages of atrophic gastritis 4. Anti-IFA appear to be very specific, but with low sensitivity for the detection of atrophic corpus gastritis.
BOX.

Practical hints

2 Both the detection of antibodies against gastric parietal cells (APCA) and anti-intrinsic factor antibodies (anti-IFA) have a place in autoimmune gastritis (AIG) detection,
however none of the tests is perfect.
2 At this stage, we are still lacking a “ gold standard” for serological detection of AIG.

OTHER EMERGING TESTING MODALITIESOther promising serological markers for the detection of gastric atrophy exist,
such as ghrelin and trefoil factor 3 (TFF3), however they have been less studied.
Ghrelin is a gastric hormone involved in the regulation of hunger and satiety. Ghrelin positive cells can physiologically be detected in all parts of the stomach, but they are mainly distributed in the proximal parts, i.e. the fundus and theproximal corpus region 30, 31. There is an inverse correlation between ghrelin
expression and the degree of inflammation present in the stomach 32. However,the number of ghrelin positive cells, as well as ghrelin levels in the serum decrease
with the progression of preneoplastic and neoplastic alterations of the gastric mucosa 33, 34. Serum ghrelin is significantly lower in atrophic gastritis compared toearly stages of H. pylori-induced gastric inflammation. In gastric cancer, ghrelinis almost not expressed at all. Low baseline concentrations of ghrelin in the serum
are associated with a higher risk for gastric cancer (OR 1.75; 95% CI 1.49-2.01)
35. Furthermore, the detected ghrelin levels may depend on preanalytical factors(such as collection and storage of samples).
The TFF family consists of three thermostable and protease-resistant proteins,
TFF1, TFF2, and TFF3; these proteins are thought to play a pivotal role in mucosal protection against damage. TFF3 is expressed in goblet cells of the intestine
and also at lower levels in other organs, such as the breast, salivary glands, therespiratory tract and the hypothalamus 36.
TFF3 has been suggested as a promising non-invasive biomarker for gastricatrophy and gastric cancer, whether alone or in combination with pepsinogens. A
study from China has suggested a better performance of TFF3 (0.81) compared toPg I/II (0.78) for the detection of corpus atrophic gastritis, and combination of theabove may have an even better predictive power 36.
Finally, there are other markers, including micro-RNA panels and volatile
markers in the breath that have been studied and demonstrated promising results
for the detection of premalignant gastric lesions, including atrophy. However, there
is still a long way to go before these biomarkers reach clinical practice.

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N ON-INVASIVE TESTS FOR THE DETECTION OF GASTRIC ATROPHY: WHAT IS REALLY USEFUL?
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19. Bornschein J, Selgrad M, Wex T, et al. Serological assessment of gastric mucosal atrophy
in gastric cancer. BMC Gastroenterol 2012; 12: 10.
20. Hansen S, Vollset SE, Derakhshan MH, et al. Two distinct aetiologies of cardia cancer;
evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori
status. Gut 2007; 56: 918-25.
21. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori
gastritis. Gut 2015; 64: 1353-67.
22. Pimentel-Nunes P, Libanio 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: 365-88.
23. Coelho LGV, Marinho JR, Genta R, et al. IVth Brazilian consensus conference on Helicobacter pylori infection. Arquivos de Gastroenterologia 2018; 55: 97-121.
24. 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;
68: 1545-75.
25. Weise F, Vieth M, Reinhold D, et al. Gastric cancer in autoimmune gastritis: A case-control study from the German centers of the staR project on gastric cancer research. United
European Gastroenterol J 2020; 8: 175-84.
26. Venerito M, Radunz M, Reschke K, et al. Autoimmune gastritis in autoimmune thyroid
disease. Aliment Pharmacol Ther 2015; 41: 686-93.
27. Lo CC, Hsu PI, Lo GH, et al. Implications of anti-parietal cell antibodies and anti-Helicobacter pylori antibodies in histological gastritis and patient outcome. World J Gastroenterol 2005; 11: 4715-20.
28. Betterle C, Mazzi PA, Pedini B, et al. Complement-fixing gastric parietal cell autoantibodies. A good marker for the identification of type A chronic atrophic gastritis. Autoimmunity
1988; 1: 267-74.
29. Al-Awami HM, Raja A, Soos MP. Physiology, Intrinsic Factor (Gastric Intrinsic Factor). In :StatPearls, Treasure Island (FL), 2020.
30. Kim HH, Jeon TY, Park DY, et al. Differential Expression of Ghrelin mRNA According to
Anatomical Portions of Human Stomach. Hepatogastroenterology 2012; 59.
31. Tanaka-Shintani M, Watanabe M. Distribution of ghrelin-immunoreactive cells in humanLeja M, Di Mario F

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gastric mucosa: comparison with that of parietal cells. J Gastroenterol 2005; 40: 345-9.
32. Takiguchi S, Adachi S, Yamamoto K, et al. Mapping analysis of ghrelin producing cells in
the human stomach associated with chronic gastritis and early cancers. Dig Dis Sci 2012;57: 1238-46.
33. Zub-Pokrowiecka A, Rembiasz K, Konturek SJ, et al. Ghrelin in diseases of the gastric mucosa associated with Helicobacter pylori infection. Med Sci Monit 2010; 16:
CR493-500.
34. Mottershead M, Karteris E, Barclay JY, et al. Immunohistochemical and quantitative
mRNA assessment of ghrelin expression in gastric and oesophageal adenocarcinoma. J
Clin Pathol 2007; 60: 405-9.
35. Murphy G, Kamangar F, Dawsey SM, et al. The relationship between serum ghrelin andthe risk of gastric and esophagogastric junctional adenocarcinomas. J Natl Cancer Inst2011; 103: 1123-29.
36. Huang Z, Zhang X, Lu H, et al. Serum trefoil factor 3 is a promising non-invasive biomarker for gastric cancer screening: A monocentric cohort study in China. BMC Gastroenterol 2014; 14: 74.

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H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACH

How to recognize and characterizeintestinal metaplasia in the stomach
at endoscopy
Should we change our practice ?

Marta Rodriguez-Carrasco1, Emmanuel Coron2,
Mário Dinis-Ribeiro1,3, Pedro Pimentel-Nunes 1,3,4
1
Gastroenterology Department, Portuguese Oncology Institute of Porto, Porto, Portugal
2
Institut des maladies de l’appareil digestif (Imad),CHU & Faculty of Medicine of Nantes, Nantes, France
3
MEDCIDS - Department of Community Medicine, Health Information
and Decision, Faculty of Medicine, University of Porto, Porto, Portugal
4Surgery and Physiology Department, Faculty of Medicine, University of Porto,
Porto, Portugal

Gastric cancer is a major health problem worldwide responsible for one third ofcancer deaths, and represents the fifth most frequent cancer in terms of incidence.
Because most gastric cancers are still diagnosed at symptomatic and advanced
stage, their prognosis is poor despite treatment. Therefore, every effort should bemade to prevent gastric cancer and to permit earlier detection of the disease atpremalignant stages, since patients with chronic atrophic gastritis (AG) or gastricintestinal metaplasia (GIM) are at risk for gastric cancer.
The European Society of Gastrointestinal Endoscopy (ESGE) introduced
the first international guidelines on the management of precancerous conditions and lesions of the stomach in 2012, which was updated in 2019 1. These
guidelines, that are based on new evidence using the Delphi process, provide
clear definitions and algorithms to detect and characterize precancerous conditions of the stomach. In fact, gastric carcinogenesis is a multistep process,beginning with AG usually induced by infection with Helicobacter pylori (Hp),

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which may evolve into GIM, then, to low grade dysplasia, high grade dysplasia, and eventually invasive adenocarcinoma. This “perfect” sequence of events
leading to the development of gastric cancer through different steps of precancerous gastric conditions is known as the “Correa’s cascade”.
GIM can be found in 10-30 % of patients undergoing endoscopy for any
indication. Among patients with preneoplastic conditions, GIM is by far themost frequently observed finding (in around 80%) 2. However, the risk of progression from GIM to gastric cancer is low, and it was estimated to be approximately 3 cases per 1,000 person-years in a recent meta-analysis 3. In contrast,
the risk of progression from GIM to dysplasia is slightly higher, at around 12
cases per 1,000 person-years. This risk may be higher in patients with incomplete and/or extensive GIM 4, 5.
For these reasons, a precise risk stratification for gastric cancer encompasses
not only the endoscopic identification but also the extension of preneoplasticchanges. It is therefore crucial for endoscopists to be aware of the different
patterns that gastric mucosa may exhibit in the presence of AG or GIM. It is
important to bear in mind that most of the preneoplastic conditions are foundin the antrum, followed by the corpus and a pangastric location, not only inwestern countries but also in other populations 4. Combining better knowledgeof gastric patterns with advanced endoscopy and the multistep process of carcinogenesis should therefore help in the detection and treatment of patients at
an earlier stage.

WHITE LIGHT ENDOSCOPY DETECTION
OF GASTRIC INTESTINAL METAPLASIAWhite light endoscopy (WLE) remains the first step for endoscopic examination because of the additional information that it provides for diagnosis,
namely for the detection of gastric lesions and prediction of deep submucosal
invasion 6. Similarly, different findings related to the presence of GIM havebeen described over the years. Initially, GIM was described as whitish, flat orslightly elevated areas (figure 1) 7. Later, a different pattern named “mottled
patchy erythema” was reported, which are depressed reddish areas 8. Nevertheless, the colour of GIM under WLE can also be similar to the surrounding
mucosa 6, so the diagnosis of GIM under WLE can be challenging since it canshow subtle changes.
Results from studies addressing conventional WLE for GIM detection,
showed a poor correlation between endoscopic findings and histological diagnosis 9. Despite the improvements of diagnostic accuracy with the introductionof high-definition (HD)-WLE, its sensitivity and interobserver agreement still
remain low 10-12.
Rodriguez-Carrasco M, Coron E, Dinis-Ribeiro M, Pimentel-Nunes P

H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACHHigh magnification HD-WLE may improve the endoscopic accuracy becauseof its ability to characterize microsurface patterns. Gastric mucosa of normal
antrum shows a groove-type structure and normal corpus has a foveolar-typeappearance. However, in the presence of GIM, the microsurface appearancechanges to groove-type or villiform structures, mimicking the normal antral orintestinal mucosa 6. High magnification can be useful for the characterizationof the microsurface pattern but it is still unavailable in several endoscopic units
worldwide. Moreover, there is scarce data regarding its real impact in terms of
diagnostic accuracy for GIM detection 13.
Accordingly, the diagnosis of GIM under WLE remains unsatisfactory, andthe diagnostic accuracy relies mostly on the endoscopist´s experience, but evenin those situations, biopsies are still necessary.

B

A

61

C

FIGURE 1. Examples of gastric intestinal metaplasia under white light endoscopy. Whitish elevated areas (a) showing tubulovillous pattern (b) can be seenin the incisura.

CHROMOENDOSCOPY DETECTION AND STAGINGOF GASTRIC INTESTINAL METAPLASIAIn order to increase the diagnostic accuracy of gastrointestinal endoscopy, new techniques have been developed in the past few years. Among them,
image-enhanced endoscopy is an emerging technique, which comprises twomodalities, conventional chromoendoscopy and virtual chromoendoscopy (divided into optical-digital, and digital according to the enhancement image processing). Conventional chromoendoscopy improves the contrast of the mucosa
by applying different kinds of dyes, and its use showed an increase in overall
accuracy for the diagnosis of preneoplastic conditions 14. However, it has notbeen universally adopted because it is a cumbersome technique. Converse-

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H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACH
ly, virtual chromoendoscopy has the additional advantage of simplicity of use(“push-button technology”) and higher image quality.
Previous studies reported different endoscopic descriptors for GIM according to the type of image-enhanced endoscopy technology, with narrow-band
imaging (NBI) being the most evaluated. With this technology, the two mostassessed markers were the presence of bluish-whitish patches 15 and areas witha tubulovillous pattern 16 (figure 2). With NBI under high magnification (MENBI), a fine blue-white line can be present on the crests of the epithelial surface
or gyri, named light blue crest (LBC) 17.

A

B

62

FIGURE 2. Examples of gastric intestinal metaplasia under narrow-band imaging. Slightly elevated areas showing tubulovillous pattern can be seen in thelesser curvature of the corpus (a) and the greater curvature of the antrum (b).
The high diagnostic yield of NBI and ME-NBI for the diagnosis of GIM havebeen reported in several studies, showing an accuracy of over 90% 10, 11. However, slight differences have been observed according to the type of endoscopic marker
evaluated. Without high magnification, tubulovillous pattern was demonstrated to behighly accurate and reproducible 10, 16, and under ME-NBI, the presence of LBC
demonstrated high performance 17. Nevertheless, discrepancies in LBC definition
have been noticed which may influence its reproducibility 18. A recent meta-analysis
assessing different image-enhanced endoscopy technologies and endoscopic markers obtained the best results with tubulovillous pattern, even without using high magnification (sensitivity of 88%, specificity 97%) 18. As a result, tubulovillous pattern has
been suggested as the most reliable marker for the detection of GIM.
Despite the fact that NBI has been the most validated technology for the diagnosis
of GIM, the accuracy of other image-enhanced endoscopy technologies has also
been evaluated. With autofluorescence imaging (AFI), antrum GIM appears as multiple purplish areas on a green background, and fundic GIM as homogeneous green

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H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACH
areas on a purple background. In spite of the additional value of AFI over WLE, specificity of AFI is still low 19, for this reason, the use of AFI as a “red flag” tool followed by
ME-NBI was proposed, which is known as trimodal imaging (TMI). However, although
TMI seems to substantially improve the diagnosis of dysplastic lesions, its specificity forpreneoplastic conditions remains low 20. Fewer studies have addressed the performanceof flexible spectral imaging color enhancement (FICE), and the most evaluated markers
were LBC, tubulovillous pattern and large long crest (a combination of linear dark andlight areas that differed from the normal gastric epithelium). However, this image-enhanced endoscopy technology also seems to be suboptimal for GIM identification, only
improved by its combination with high magnification and/or probe-based confocal laser
endomicroscopy (pCLE) 21. Better results have been recently reported regarding linked
colour imaging (LCI) and blue laser imaging/blue light imaging (BLI). With LCI, GIM
has been described as lavender colour areas (“lavender colour sign”), and its high accuracy has been recently reported 22. Nonetheless, the most promising results have beenobtained with BLI. Owing to the similarities between NBI and BLI (both technologies
are based on the same physical principle), the images produced are similar. Consequently, the same endoscopic markers for GIM with BLI and NBI have been considered(figure 3). One study evaluating blue laser imaging under high magnification obtained an
accuracy of 94%, which is comparable to that previously reported with ME-NBI 23. The
recent multi-LED technology (BLI) has also been evaluated in a prospective study, anddespite the small cohort, it demonstrated a high accuracy for advanced stages of GIM as
well as interobserver agreement 24. Although more studies are necessary to reach consistent conclusions, it is expected that NBI and BLI will be equally effective.

A

B

FIGURE 3. Examples of gastric intestinal metaplasia. The presence of slightly
elevated bluish-whitish areas (a) showing tubulovillous pattern (b) can be seenin the antrum under blue light imaging, with and without bright mode, respectively.

Rodriguez-Carrasco M, Coron E, Dinis-Ribeiro M, Pimentel-Nunes P

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64

No additionnalrisk factors **H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACH

Targeted biopsies
from irregular areas(1 or 2 samples)

Irregular mucosaland vascular patterns(suspicion of dysplasia)

Targeted biopsies from antrum/incisuraand corpus in separate vials(2-3 samples from each area)+
Consider targeted biopsies
from normal areas(test Helicobacter pylori)

Resection/surveillanceaccording to MAPS II *GIM only in antrum OR in corpus(EGGIM≥ 5)

Surveillance according to MAPS II*

Tubulovillous mucosal pattern(suspicion of GIM)

Additionnalrisk factors **Targeted biopsies from the area with GIM
in one single vial+
Biopsies from the other gastric area
without GIM
in one different vial
(test Helicobacter pylori)

GIM only in antrum OR in corpus(EGGIM 1-4)

FIRST TIME DIAGNOSTIC WHITE LIGHT ENDOSCOPY AND VIRTUAL CHROMOENDOSCOPYH OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACH

Normal mucosaland vascularpatterns

Random biopsies
from antrum and corpus
in one single vial
(test Helicobacter pylori)

No surveillance *Targeted biopsies
only if irregular pattern is identified(suspicion of dysplasia)

Rodriguez-Carrasco M, Coron E, Dinis-Ribeiro M, Pimentel-Nunes P

FIGURE 4. Suggested endoscopic approach for the detection and follow-up of gastric intestinal metaplasia (GIM). * Eradication of Helicobacter pylori if positive; ** family history ofgastric cancer, incomplete type GIM, autoimmune gastritis, or persistent Helicobacter pylori infection. MAPS: MAnagement of epithelial Precancerous conditions and lesions in the
Stomach.
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H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACHSHOULD WE CHANGE OUR PRACTICE?

66

The benefits of image-enhanced endoscopy technologies vs. HD-WLE forthe detection of GIM seem obvious, but histological confirmation is still necessary. Accordingly, current ESGE guidelines recommend guiding biopsies byvirtual chromoendoscopy 1. One of the reasons to challenge the benefit of targeted biopsies instead of mapping (according to updated Sidney protocol), is
the fact that the patchy and multifocal presentation of GIM can affect thedetection rate. In this context, two comparative studies of the two strategies
concluded that they are complementary as their combination achieved the best
detection rate of GIM 25, 26. One of the studies added that a high proportionof missed NBI cases (48%) corresponded to mild GIM 26. Although NBI willprobably have a limited ability to detect focal and mild GIM, the clinical impact
does not seem to be significant, as those cases will not benefit from endoscopic
surveillance.
Altogether, these results led to a new approach for endoscopic staging of
GIM and a new NBI staging classification has been proposed, the Endoscopic
Grading of Gastric Intestinal Metaplasia (EGGIM) 10. The main advantageof this classification is the possibility to endoscopically assess the entire gastric mucosa instead of the histological assessment of tiny areas. Furthermore,
it was recently validated in a multicentre study, and it was demonstrated thatwith EGGIM of between 5-10, the sensitivity and specificity to detect extensive
stages of GIM (OLGIM III/IV) were 89% and 95%, respectively 27. Moreover,in a recently published study EGGIM was shown to be strongly correlated togastric cancer risk even without biopsies, validating this tool as an independentrisk factor for gastric cancer 28.
Accordingly, a new strategy to detect and stage GIM has been proposed 29.
This approach focusses on the importance of a high-quality examination to
obtain a more accurate diagnosis, and optimize the biopsy protocol instead of
relying only on random biopsies. The decision to perform targeted biopsies by
NBI should be based on different clinical scenarios which includes the findings
at initial endoscopy along with personal risk factors for gastric cancer (figure 4).
The first scenario would involve the detection of a normal mucosa under WLE
and EGGIM 0 under NBI. Considering the excellent negative predictive valueof NBI for detecting advanced stages of GIM, biopsies performed according to
the updated Sydney System but put in one single vial are enough to confirm
endoscopic diagnosis (absence of GIM) and to check for H. pylori infection
30. The second scenario would involve the detection of AG under WLE and/or
EGGIM 1-4 observed under NBI. In these situations, the possible risk of under- or overestimation of gastritis makes it difficult to rely solely on endoscopic

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H OW TO RECOGNIZE AND CHARACTERIZE INTESTINAL DYSPLASIA IN THE STOMACH
diagnosis. Targeted biopsies should be taken from GIM areas, as well as fromnormal areas (in separate vials according to the gastric area), so OLGIM stage
can be confirmed and H. pylori tested. The third scenario would involve the detection of extensive GIM. Targeted biopsies in at least 2 separate vials (antrum
and corpus) should be taken to confirm the diagnosis, as well as from normal
areas in case of H. pylori testing. In contrast, endoscopic surveillance biopsies
would not be necessary unless an area suspicious for dysplasia is seen (targetedbiopsy, 1 or 2 fragments) or if we want to check the H. pylori status (in this case,biopsies should be taken from the normal mucosa, most commonly colonizedby this bacterium).

CONCLUSION
The benefits of virtual chromoendoscopy over WLE for the diagnosis of
GIM have been demonstrated in numerous studies, and NBI seems to be themost accurate technology for this purpose. Although different endoscopic
markers have been evaluated, the presence of the tubulovillous pattern is probably the most reliable marker for the identification of GIM areas. The improvements in endoscopic imaging is changing the diagnostic approach, grading andfollow-up of patients with different stages of GIM. This new approach allows
endoscopists to increasingly rely on endoscopic imaging and consider biopsies
as a complementary and still necessary part on the diagnostic process, but not
the fundamental one.

REFERENCES
1. 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: 365-88.
2. Chapelle N, Péron M, Mosnier JF, et al. Prevalence, Characteristics and Endoscopic
Management of Gastric Premalignant Lesions in France. Dig Dis 2019 : 1-7.
3. Akbari M, Tabrizi R, Kardeh S, Kamran B. Lankarani Gastric cancer in patients with gastric atrophy and intestinal metaplasia: A systematic review and meta-analysis. PLoS One
2019; 14: e0219865. DOI: 10.1371/journal.pone.0219865
4. Mera RM, Bravo LE, Camargo MC, et al. Dynamics of Helicobacter pylori infection as adeterminant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 2018; 67: 1239-46.
5. Lahner E, Esposito G, Pilozzi E, et al. Occurrence of gastric cancer and carcinoids in atrophic

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gastritis during prospective long-term follow up. Scand J Gastroenterol 2015; 50: 856-65.
6. Muto M, Yao K, Kaise M, et al. Magnifying endoscopy simple diagnostic algorithm forearly gastric cancer (MESDA-G). Dig Endosc 2016; 28: 379-93.
7. Stathopoulos G, Goldberg RD, Blackstone MO. Endoscopic diagnosis of intestinal metaplasia. Gastrointest Endosc 1990; 36: 544-5.
8. Nagata, N, Shimbo T, Akiyama J, et al. Predictability of Gastric Intestinal Metaplasia byMottled Patchy Erythema Seen on Endoscopy. Gastroenterology Res 2011; 4: 203-9.
9. Lim JH, Kim N, Lee HS, et al. Correlation between Endoscopic and Histological Diagnoses of Gastric Intestinal Metaplasia. Gut Liver 2013; 7: 41-50.
10. Pimentel-Nunes P, Libânio D, Lage J, et al. A multicenter prospective study of the real-time use of narrow-band imaging in the diagnosis of premalignant gastric conditions
and lesions. Endoscopy 2016; 48: 723-30.
11. Ang TL, Pittayanon R, Lau JYW, et al. A multicenter randomized comparison between
high-definition white light endoscopy and narrow band imaging for detection of gastriclesions. Eur J Gastroenterol Hepatol 2015; 27: 1473-8.
12. Yil Sik Hyun, Han DS, Bae JH, Park HS, Eun CS. Interobserver variability and accuracyof high-definition endoscopic diagnosis for gastric intestinal metaplasia among experienced and inexperienced endoscopists. J Korean Med Sci 2013; 28: 744-9.
13. Anagnostopoulos GK, Yao K, Kaye P, et al. High-resolution magnification endoscopy
can reliably identify normal gastric mucosa, Helicobacter pylori-associated gastritis, andgastric atrophy. Endoscopy 2007; 39: 202-7.
14. Zhao Z,Yin Z, Wang S, et al. Meta-analysis: The diagnostic efficacy of chromoendoscopy
for early gastric cancer and premalignant gastric lesions. J Gastroenterol Hepatol 2016; 31:
1539-45.
15. Capelle LG, Haringsma J, de Vries AC, et al. Narrow band imaging for the detectionof gastric intestinal metaplasia and dysplasia during surveillance endoscopy. Dig Dis Sci
2010; 55: 3442-8.
16. Pimentel-Nunes P, Dinis-Ribeiro M, Soares JB, et al. A multicenter validation of an endoscopic classification with narrow band imaging for gastric precancerous and cancerous
lesions. Endoscopy 2012; 44: 236-46.
17. Uedo N, Ishihara R, Iishi H, et al. A new method of diagnosing gastric intestinal metaplasia: narrow-band imaging with magnifying endoscopy. Endoscopy 2006; 38: 819-24.
18. Rodriguez-Carrasco M., Gianluca Esposito G, Libânio D, Pimentel-Nunes P, Dinis-Ribeiro M. Image-enhanced endoscopy for gastric preneoplastic conditions and neoplastic
lesions: a systematic review and meta-analysis. Endoscopy 2020; epub. 52: 1048-65. DOI:
10.1055/a-1205-0570
19. Inoue, T, Uedo N, Ishihara R, et al. Autofluorescence imaging videoendoscopy in the
diagnosis of chronic atrophic fundal gastritis. J Gastroenterol 2010; 45: 45-51.
20. So J, Rajnakova A, Chan YH, et al. Endoscopic tri-modal imaging improves detection ofgastric intestinal metaplasia among a high-risk patient population in Singapore. Dig Dis

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Sci 2013; 58: 3566-75.
21. Pittayanon R, Rerknimitr R, Wisedopas N, et al. Flexible spectral imaging color enhancement plus probe-based confocal laser endomicroscopy for gastric intestinal metaplasia
detection. J Gastroenterol Hepatol 2013; 28: 1004-9.
22. Ono S, Kato M, Momoko Tsuda M, et al. Lavender Color in Linked Color Imaging Enables Noninvasive Detection of Gastric Intestinal Metaplasia. Digestion 2018; 98: 222-30.
23. Chen H, Liu Y , Lu Y, et al. Ability of blue laser imaging with magnifying endoscopy forthe diagnosis of gastric intestinal metaplasia. Lasers Med Sci 2018; 33: 1757-62.
24. Castro R, Rodriguez M , Libânio D, et al. Reliability and accuracy of blue light imaging
for staging of intestinal metaplasia in the stomach. Scand J Gastroenterol 2019; 54: 1301-5.
25. Buxbaum JL, Hormozdi D, Dinis-Ribeiro M, et al. Narrow-band imaging versus whitelight versus mapping biopsy for gastric intestinal metaplasia: a prospective blinded trial.
Gastrointest Endosc 2017; 86: 857-65.
26. Xirouchakis E, Laoudi F, Tsartsali L, et al. Screening for gastric premalignant lesions
with narrow band imaging, white light and updated Sydney protocol or both? Dig Dis Sci
2013; 58: 1084-90.
27. Esposito G, Pimentel-Nunes P, Angeletti S, et al. Endoscopic grading of gastric intestinal
metaplasia (EGGIM): a multicenter validation study. Endoscopy 2019; 51: 515-21.
28. Marcos P, Brito-Gonçalves G , Libânio D, et al. Endoscopic grading of gastric intestinal
metaplasia on risk assessment for early gastric neoplasia: can we replace histology assessment also in the West? Gut 2020; 69:1762-8. DOI: 10.1136/gutjnl-2019-320091.
29. Rodriguez-Carrasco M, Libânio D, Dinis-Ribeiro M, Pimentel-Nunes P. Where should
gastric biopsies be performed when areas of intestinal metaplasia are observed? Endosc Int
Open 2019; 7: e1636-9. DOI: 10.1055/a-0953-2247.
30. Castro R, Esposito G, Libânio D, et al. A single vial is enough in the absence of endoscopic suspected intestinal metaplasia - less is more! Scand J Gastroenterol 2019; 54: 673-7.

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M ANAGEMENT OF GASTRIC PREMALIGNANT LESIONSManagementof gastric premalignant lesions
What should clinicians do today?
Nicolas Chapelle 1, Estelle Cauchin 1, Tamara Matysiak-Budnik 1
1Institut des maladies de l’appareil digestif (IMAD),
Hépato-gastroentérologie & Oncologie digestive,
CHU de Nantes, France

Gastric precancerous lesions (GPL), which include chronic atrophic gastritis,
gastric intestinal metaplasia (IM), and dysplasia, are associated with an increased
risk of gastric cancer (GC) 1. This risk depends on the type of the lesion (lower
for atrophic gastritis, higher for IM and the highest for dysplasia), the severity of thelesions expressed by different histopathological scores (OLGA for atrophic gastritis,
OLGIM for IM, and low or high grade for dysplasia), the extension of the lesions
within the stomach (focal or patchy distribution, exclusive antrum or corpus involvement, or extended pangastritis), and on some specific characteristics of the lesions
like the type of IM (complete or incomplete) 1-6.
A detailed histological description of the different types and stages of GPL isprovided in another chapter of this book, but here it is important to underline thatspecific anatomical and histological patterns of GPL confer, together with other factors, a specific risk of evolution to GC and therefore should be evaluated and taken
into account while considering the surveillance modalities 7–9.
Given an increased risk of GC in patients with GPL, the surveillance of thesepatients seems to be a logical approach to prevent the risk of advanced GC. Thisapproach has shown its efficacy in countries with a high risk of incidence of GC, likesome Asian countries 10-13, and it has also been tested in Europe 1,14.
In Singapore, endoscopic surveillance of patients with GPL has been shown to beefficient and cost-effective with a recommended surveillance interval of 1 to 2 years
15,16. In Portugal, a country considered as intermediate GC incidence area, thesystematic endoscopic surveillance of patients with GPL has also been shown to becost-effective with a proposed surveillance interval of every 3 years 17.
Although most European countries are classified as low or intermediate GC
risk areas, it is now considered that surveillance of patients with GPL is indicat-

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ed and several European guidelines on the management of patients with theselesions have been published in the past few years 18-21. (figure 1).
Other guidelines have also been elaborated, and in particular by the American
Gastroenterology Association (AGA Guidelines, 22), as well as by the Chilean
Association for Digestive Endoscopy 23.
There are differences among these guidelines, some of them specifically addressing particular aspects, like the surveillance of gastric IM only in the AGA
guidelines, and some covering the entire spectrum of the different aspects of histological diagnosis, surveillance and treatment of patients with all types of GPL.
There are also some differences in the recommendations proposed, in particularwith respect to the surveillance, reflecting the differences in the epidemiologicalcontext and healthcare systems in different countries. However, despite thesedifferences, there are two common points highlighted by all of the guidelines:
1. The necessity to search for Helicobacter pylori (H. pylori) infection in all patientswith GPL and eradicate this infection if present.
2. The indication of stratifying the risk according to the histological results (severity and extension of gastric atrophy and IM), as well as other factors like persistent H. pylori infection, family history of GC, or ethnic origin of the patient.
In Europe, in addition to some national guidelines 20,21, international European guidelines have been published (so called “MAPS” guidelines, for Management of precancerous conditions and lesions in the stomach), elaborated byseveral European Societies, with participation of experts representing the majority of European countries, and thus globally adapted to the European context.
The first version of these guidelines was published in 2012 18 and more recently,
a new, updated version was published, integrating the recent advances in our
knowledge on diagnosis and evolution of GPL, as well as the progress in endoscopy (MAPS II, 19)
The recommendations given below are mainly based on the MAPS guidelines,
but a referral to other guidelines is made as well.

INITIAL DIAGNOSIS AND “STAGING” OF GPL
Endoscopy
The importance of a good quality endoscopic assessment is underlined. This
aspect is addressed in more detail in a dedicated chapter of this book. In general, endoscopic evaluation should be performed using high-resolution endoscopy
and whenever possible with chromoendoscopy (virtual or dye-based), which issuperior to standard endoscopy and allows for a better evaluation of the gastricmucosa and identification of areas suspected of atrophy or IM, thus allowing theimplementation of targeted rather than random biopsies.

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M ANAGEMENT OF GASTRIC PREMALIGNANT LESIONS
Performing biopsies is necessary, and at least 4 biopsies (2 from the antrum
and 2 from the corpus), and if possible an additional biopsy from the incisura,should be obtained and placed into two separate vials (from the antrum and incisura in one vial, and from the corpus in the second vial).
In case of an initial diagnosis made “accidentally”, on the basis of histologicalanalysis of a gastric biopsy obtained for other reasons and without a correct endoscopic protocol, a second endoscopy should be proposed within a short interval period (<6 months) in order to obtain a correct endoscopic and histologicalevaluation. This recommendation is included in the British guidelines, and although it is not explicitly stated in the MAPS guidelines, it seems logical since it
is clearly indicated that a correct endoscopic evaluation and histological analysis
of at least 4 biopsies, from the antrum and from the corpus, are necessary, which
is usually not the case during an average endoscopic procedure.

Histology
The histological evaluation is described in detail in the dedicated chapter. It
should be preferentially performed by a Pathologist who has experience in gastricpathology. It should include the evaluation of the type and severity of the lesions
according to the OLGA and OLGIM score, and, if possible, the evaluation of thetype of IM (complete or incomplete type).

Non-invasive markers of gastric atrophy
All guidelines recognize the usefulness of measuring serum pepsinogen (PG)
I and II, which allows for a global evaluation of the state of the gastric mucosa,
and in particular of its secretory capacities, which are impaired in case of gastricatrophy. Indeed, in case of marked destruction of the gastric glands, there is an
impairment of pepsinogen secretion, and in particular decreased levels of PGIand decreased PGI/PGII ratio are observed.
Although this dosage is not performed routinely, and is not reimbursed in the
majority of European countries, it could be recommended whenever possible. If
it cannot be currently performed, it is recommended to obtain a blood sample
from the patient and store the serum frozen for a potential future analysis.

Helicobacter pylori
The search for H. pylori infection is mandatory, and should be performed in all patients with GPL and in case of a positive test, the bacteria should be eradicated 24-26.
The positive effect of H. pylori eradication on the evolution of GPL is reflected by several findings: 1) H. pylori eradication reduces inflammation, it may
reverse the atrophy and in some cases even IM 27, 2) H. pylori eradication afterendoscopic resection of early gastric cancer (usually associated with pre-existing

Chapelle N, Cauchin E, Matysiak-Budnik T

73

74

M ANAGEMENT OF GASTRIC PREMALIGNANT LESIONSNOM ANAGEMENT OF GASTRIC PREMALIGNANT LESIONS

Low grade
dysplasia

Endoscopic
reassesssment<12 months

High grade
dysplasia

NO

Visible lesion

Confirmation by expert Pathologist

Dysplasia/Indefinite for dysplasia

Fortuitous diagnosis of GPL, standard endoscopy/no chromoendoscopy/
insufficient number of biopsies
Dedicated endoscopy < 6 months

YES

First degree family
history of gastriccancerNO

Every 1-2 year

No visible lesions : follow-up according
to stage of gastritis

Endoscopic
reassesssment<12 months

Endoscopic evaluation(high definition endoscopy, chromoendoscopy, biopsies)

YES

AG or IM
Antrum + Corpus
OLGA/OLGIM III/IV

H pylori detection and eradication if positive

Every 3 year

Family history of gastric cancer
Incomplete IM
Autoimmune gastritis
Persistent H. pylori infection
Ethnic factor (Eastern Europe,
Eastern Asia, South America)IM
Antrum-limitedor Corpus-limited

Atrophic gastritis (AG) or Intestinal Metaplasia (IM)AG
Antrum-limited
mild to moderate

No surveillance

Place for non-invasive markers ?
(Pepsinogen ...)YES

Resection

Yearlysurveillance

Chapelle N, Cauchin E, Matysiak-Budnik T

FIGURE 1. Algorithm for the surveillance of patients with Gastric precancerous lesions (GPL) adapted from Pimentel Nunes et al 19. AG: Atrophic
Gastritis, OLGA: Operative Link on Gastritis Assessment, OLGIM: Operative Link on Gastritis Assessment based on Intestinal Metaplasia ; IM:
Intestinal Metaplasia.
Chapelle N, Cauchin E, Matysiak-Budnik T

75

M ANAGEMENT OF GASTRIC PREMALIGNANT LESIONSGPL) leads to a significant decrease in the risk of metachronous GC 28, 3) H.
pylori eradication leads to a significant decrease in GPL prevalence, as well as GC
incidence and mortality at a population-level 29.
The bacterium can be detected by histology, but in case of negative histology,
serology should be performed to confirm the absence of the bacteria. Indeed, incase of gastric atrophy, the sensitivity of biopsy-based methods, as well as theurea-breath test, is decreased, and serology seems to be the most sensitive method, the only one not affected by the status of the gastric mucosa, and therefore
recommended in this setting.
The eradication regimen should be preferably proposed according to the resultsof antimicrobial susceptibility testing, performed either by real-time PCR directly
on gastric biopsies (for clarithromycin), or by classical antibiogram after bacterial
culture (for all antibiotics). If pre-treatment testing is not possible, the empiricaltreatment should be applied according to validated local recommendations.

Family history

76

Family history is important, and in particular the history of GC, as well as
information on the ethnic origin of the patients, and this information should berecorded. Indeed, even when living in low incidence countries, individuals originating from high GC incidence area, like Asian or South American countries, areconsidered to be at an increased risk of GC 30,31. However, whether the ethnic
factor confers an independent increased risk of evolution from GPL to GC remains still unproven.

SURVEILLANCE OF GPL
Dysplasia
Among all GPL, dysplasia, and in particular high grade dysplasia, is associated with the highest risk of evolution to GC with an annual rate of 6% 1, and it isestimated that one out of 19 patients with dysplasia will develop GC within 20
years 3. In case of dysplasia, found on the gastric mucosa without an endoscopically defined lesion, an immediate high quality endoscopic reassessment withchromoendoscopy and multiple gastric biopsies should be performed. Although
the exact number of biopsies is not specified, it can be reasonably proposed thatat least 3 biopsies from the antrum, 3 from the corpus and 2 biopsies from theincisura region should be obtained. If the histopathological analysis confirms ahigh-grade dysplasia, the control endoscopy with multiple biopsies should be
performed within 6 months, while in case of low grade dysplasia, within 12
months.

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M ANAGEMENT OF GASTRIC PREMALIGNANT LESIONS
Intestinal metaplasia
Intestinal metaplasia confers an intermediate risk of evolution to GC, evaluated at 0.25% per year 1, and it is estimated that one out of 39 patients will develop
GC within 20 years 3. This risk may vary depending on the severity and extensionof the lesions, as well as according to the type of IM (complete or incomplete). It
is now well established, that patients with extended IM and incomplete IM, havea higher risk of GC. However, some studies suggest that even IM limited to theantrum may confer an increased risk of GC if the incomplete type is present 32.
In case of IM at a single location (limited to the antrum or the corpus), without severe atrophy and without any other particular risk factors, no systematicsurveillance is indicated. However, this surveillance should be proposed in caseof incomplete type of IM, family history of GC, or persistent H. pylori infection
with a control endoscopy with guided biopsies every 3 years.
In case of IM extended to both the antrum and the corpus (score OLGIM III/IV), independently of the existence of other risk factors, endoscopic surveillanceshould be proposed every 3 years. In the presence of additional risk factors (advanced atrophy, family history of GC, incomplete type of IM), stricter surveillance should be proposed (surveillance endoscopy every 1 to 2 years).

Atrophic gastritis
Patients with chronic atrophic gastritis have a higher risk of GC compared to thegeneral population, with the annual risk varying from 0.1 to 0.25% in different studies
1,21. This risk depends on the severity and extension of gastric atrophy. In case of mild
or moderate gastric atrophy restricted to the antrum, without IM, there is no evidence
to support the recommendation of surveillance endoscopy.
In case of advanced atrophic gastritis with severe atrophic changes extended toboth the antrum and the corpus (OLGA III/IV), associated or not with IM, endoscopic surveillance every 3 years is recommended. In the presence of additional risk
factors, like family history of GC, these patients may benefit from stricter surveillance (every 1 to 2 years).
Patients with autoimmune gastritis may also benefit from endoscopic surveillance
every 3 to 5 years. We should keep in mind that in these patients, the risk of developing
neuroendocrine tumors greatly outweighs the risk of developing adenocarcinoma.

FUTURE DIRECTIONSIn the future, better stratification of patients with GPL according to theirindividual risk of evolution to GC will allow for the application of more efficientand cost-effective surveillance strategies. Better assessment of the individual risk
level will be achieved thanks to the progress in endoscopic techniques, blood

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77

M ANAGEMENT OF GASTRIC PREMALIGNANT LESIONS
markers as well as molecular markers, currently under study 33-35. The appropriate organization of the detection/surveillance health system adapted to the
local context will also be helpful 1.

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2. Spence AD, Cardwell CR, McMenamin ÚC, et al. Adenocarcinoma risk in gastric atrophy and intestinal metaplasia: a systematic review. BMC Gastroenterol 2017;17:157.
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3. Song H, Ekheden IG, Zheng Z, et al. Incidence of gastric cancer among patients withgastric precancerous lesions: observational cohort study in a low risk Western population.
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4. Zullo A. Follow-up of intestinal metaplasia in the stomach: When, how and why. World J
Gastrointest Oncol 2012;4:30. doi:10.4251/wjgo.v4.i3.30
5. Olmez S, Aslan M, Erten R, et al. The Prevalence of Gastric Intestinal Metaplasia andDistribution of Helicobacter pylori Infection, Atrophy, Dysplasia, and Cancer in Its Subtypes. Gastroenterol Res Pract 2015;2015:1–6. doi:10.1155/2015/434039
6. Sung JK. Diagnosis and management of gastric dysplasia. Korean J Intern Med
2016;31:201–9. doi:10.3904/kjim.2016.021
7. Quach DT, Hiyama T, Gotoda T. Identifying high-risk individuals for gastric cancer surveillance from western and eastern perspectives: Lessons to learn and possibility to develop an integrated approach for daily practice. World J Gastroenterol 2019;25:3546–62.
doi:10.3748/wjg.v25.i27.3546
8. Dinis-Ribeiro M, Kuipers EJ. How to Manage a Patient With Gastric Intestinal Metaplasia: An International Perspective. Gastroenterology 2020;158:1534–7. doi:10.1053/j.
gastro.2020.01.008
9. 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;65:1899–903. doi:10.1007/s10620-020-06272-9
10. 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; 84:618–24. doi:10.1016/j.gie.2016.03.791
11. Hamashima C, Shabana M, Okada K, et al. Mortality reduction from gastric cancer
by endoscopic and radiographic screening. Cancer Sci 2015;106:1744–9. doi:10.1111/
cas.12829

1

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12. Hamashima C, Ogoshi K, Narisawa R, et al. Impact of endoscopic screening on mortality reduction from gastric cancer. World J Gastroenterol 2015;21:2460–6. doi:10.3748/wjg.v21.i8.2460
13. Zhang X, Li M, Chen S, et al. Endoscopic Screening in Asian Countries Is AssociatedWith Reduced Gastric Cancer Mortality: A Meta-analysis and Systematic Review. Gastroenterology 2018;155:347-354.e9. doi:10.1053/j.gastro.2018.04.026
14. Whiting JL. The long term results of endoscopic surveillance of premalignant gastric lesions. Gut 2002;50:378–81. doi:10.1136/gut.50.3.378
15. Wu JT, Zhou J, Naidoo N, et al. Determining the cost-effectiveness of endoscopic surveillance for gastric cancer in patients with precancerous lesions. Asia Pac J Clin Oncol
2016;12:359–68. doi:10.1111/ajco.12569
16. Zhou HJ, Dan YY, Naidoo N, et al. A cost-effectiveness analysis evaluating endoscopic
surveillance for gastric cancer for populations with low to intermediate risk. PloS One
2013;8:e83959. doi:10.1371/journal.pone.0083959
17. Areia M, Dinis-Ribeiro M, Rocha Gonçalves F. Cost-Utility Analysis of Endoscopic Surveillance of Patients with Gastric Premalignant Conditions. Helicobacter 2014;19:425–36.
doi:10.1111/hel.12150
18. Dinis-Ribeiro M, Areia M, de Vries A, et al. Management of precancerous conditions andlesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal
Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Societyof Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).
Endoscopy 2012;44:74–94. doi:10.1055/s-0031-1291491
19. 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;51:365–88. doi:10.1055/a-0859-1883
20. 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;68:1545–75. doi:10.1136/gutjnl-2018-318126
21. Lahner E, Zagari RM, Zullo A, et al. Chronic atrophic gastritis: Natural history, diagnosis
and therapeutic management. A position paper by the Italian Society of Hospital Gastroenterologists and Digestive Endoscopists [AIGO], the Italian Society of Digestive Endoscopy [SIED], the Italian Society of Gastroenterology [SIGE], and the Italian Society ofInternal Medicine [SIMI]. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver
2019;51:1621–32. doi:10.1016/j.dld.2019.09.016
22. Gupta S, Li D, El Serag HB, et al. AGA Clinical Practice Guidelines on Managementof Gastric Intestinal Metaplasia. Gastroenterology 2020;158:693–702. doi:10.1053/j.gastro.2019.12.003
23. Rollán A, Cortés P, Calvo A, et al. Diagnóstico precoz de cáncer gástrico: Propuesta de detección y seguimiento de lesiones premalignas gástricas: protocolo ACHED. Rev Médica

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Chile 2014;142:1181–92. doi:10.4067/S0034-98872014000900013
24. Liou J-M, Malfertheiner P, Lee Y-C, et al. Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus. Gut 2020;69:2093–112.
doi:10.1136/gutjnl-2020-322368
25. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report. Gut 2017;66:6–30. doi:10.1136/
gutjnl-2016-312288
26. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori
gastritis. Gut 2015;64:1353–67. doi:10.1136/gutjnl-2015-309252
27. Hwang Y-J, Kim N, Lee HS, et al. Reversibility of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication - a prospective study for up to 10 years. Aliment
Pharmacol Ther 2018;47:380–90. doi:10.1111/apt.14424
28. 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;378:1085–95. doi:10.1056/NEJMoa1708423
29. Chiang T-H, Chang W-J, Chen SL-S, et al. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands.
Gut 2020;:gutjnl-2020-322200. doi:10.1136/gutjnl-2020-322200
30. Choi CE, Sonnenberg A, Turner K, et al. High Prevalence of Gastric Preneoplastic Lesions in East Asians and Hispanics in the USA. Dig Dis Sci 2015;60:2070–6. doi:10.1007/
s10620-015-3591-2
31. Choi AY, Strate LL, Fix MC, et al. Association of gastric intestinal metaplasia and East
Asian ethnicity with the risk of gastric adenocarcinoma in a U.S. population. Gastrointest
Endosc 2018;87:1023–8. doi:10.1016/j.gie.2017.11.010
32. Chapelle N, Péron M, Mosnier J-F, et al. Prevalence, Characteristics and Endoscopic Management of Gastric Premalignant Lesions in France. Dig Dis 2019;:1–7.
doi:10.1159/000503748
33. Wei N, Mulmi Shrestha S, Shi RH. Markers of gastric intestinal metaplasia under digitalchromoendoscopy: systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2020 :epub. doi:10.1097/MEG.0000000000001834
34. Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet 2020; 396: 635–48.
doi:10.1016/S0140-6736(20)31288-5
35. Thapa S, Fischbach LA, Delongchamp R, et al. Using Machine Learning to Predict Progression in the Gastric Precancerous Process in a Population from a Developing Country Who Underwent a Gastroscopy for Dyspeptic Symptoms. Gastroenterol Res Pract
2019;2019:1–8. doi:10.1155/2019/8321942

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E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

Endoscopic treatmentof early gastric cancerInês Pita1, Mário Dinis-Ribeiro1,2, Pedro Pimentel-Nunes1,2,3
1
Gastroenterology Department, Instituto Português
de Oncologia do Porto, Porto, Portugal
2
MEDCIDS, Department of Community Medicine, Health Information
and Decision, Faculty of Medicine, University of Porto, Porto, Portugal
3
Surgery and Physiology Department, Faculty of Medicine,
University of Porto, Porto, Portugal

81
Gastric cancer is one of the most common and lethal malignancies worldwide,with over a million incident cases and accounting for 8% of all cancer deathsin 2018 1,2. While traditionally diagnosed at advanced stages, especially in theWest, the more widespread use of upper endoscopy has increased the detectionof early gastric neoplasms. These are defined as adenocarcinoma restricted tothe mucosa or submucosa, irrespective of lymph node status (i.e. T1, any N). 3
Gastrectomy with lymphadenectomy was the standard treatment for gastric cancer. However, early gastric cancer has a low probability of lymph node spread andmay be appropriately treated with endoscopic resection. Based on surgical series of
pT1 gastric cancers, factors associated with higher risk of lymph node involvement
include larger lesion size, ulceration, undifferentiated histology, depth of invasion
and lymphovascular or perineural invasion 4. After endoscopic resection, histopathological evaluation of the lesion must assess these features in order to define thelikelihood of an endoscopic cure; in lesions with high-risk criteria, gastrectomy andlymphadenectomy should be considered.
In this chapter we review the different techniques for endoscopic resection of early gastric cancer, discuss the pre-treatment lesion evaluation andthe post-resection histological assessment and follow-up. An algorithm for the
management of early gastric neoplasms is proposed in figure 1.

Pita I, Dinis-Ribeiro M, Pimentel-Nunes P :E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

Early gastric cancer suspected(visible lesions / dysplasia on random biopsies)

High-definition endoscopy with chromoendoscopy(HD-CE) at expert center
Endoscopically
non-resectable lesion

Endoscopicallyresectable lesion

Surgery

ESD(EMR is an alternative
for <15mm differentiatednon-ulcerated lesions)

LOW-RISK RESECTIONLOCAL-RISK RESECTION

HIGH-RISK RESECTION

En bloc, R0 and:- pTis/pT1a, G1-2,
UL- LV- pT1a, G1, UL+, LV-,
≤30 mm
- pT1b sm1 (<500 µm),
G1, UL-, LV-, ≤30 mm- pT1a, G3, UL-, LV-, ≤20mm

Piecemeal / HM+ANDno high-risk criteria

VM+
LV+
Sm2 (>500 µm) >30mm
UL >30mm
Undifferentiated >20mm

HD-CE at 3-6 mo,
12 mo,
then annually
CT in expanded
indication

HD-CE at 3-6 mowith scar biopsies
Consider more frequent
follow-up
Re-ESD if recurrence

MDT discussion
Weight risk of surgery
vs LNM (eCura system)

82

FIGURE 1. Algorithm for early gastric cancer management. EMR, endoscopic
mucosal resection; ESD, endoscopic submucosal dissection (G1-2, well/moderately differentiated lesions; G3, undifferentiated lesion); HM, horizontal margin; LV,
lymphovascular invasion; LNM, lymph node metastasis; MDT, multidisciplinary
team; mo, months; R0, free margin resection; UL, ulceration; VM, vertical margin.
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E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER
PRE-TREATMENT LESION EVALUATION
When an early gastric neoplasm is suspected (either as a visible lesion or as
neoplasia in random biopsies), endoscopy is the most informative diagnostic andstaging procedure. This endoscopic assessment is important to detect previously
unrecognized lesions (including synchronous neoplasms) and to predict the resectability and curability of the lesion, allowing a more informed decision on the besttreatment option for each individual lesion and patient.
Early gastric cancer can present as a polypoid protrusion, slightly raised plaque,mucosal discoloration, depression, erosion or an ulcer; subtle, small and flat lesions
may be missed by endoscopy. In fact, high-definition white-light endoscopy (WLE)
shows poor to modest sensitivity in the detection of early gastric cancer 5,6 andthe miss-rate for upper gastrointestinal cancers can be as high as 11% 7. This may
be due to inadequate inspection, failure to recognize a lesion, sampling error or
pathologist error. However, a careful endoscopic observation paired with chromoendoscopy by an experienced user can increase early gastric cancer detection 6,8,9
and should be offered after any diagnosis of gastric neoplasia, even if no lesion was
described.
Endoscopic evaluation can predict the T stage (including distinction between
T1a and T1b) with 78% accuracy 10. Lesion size, location and morphology are
predictors of resectability and curability and should be carefully assessed 11.
Lesion morphology should be described using the Paris classification and otherfeatures associated with submucosal invasion should be noted: irregular/nodular
surface protrusion, irregular depression, and clubbing, fusion or abrupt cutting of
convergent folds. In contrast, mucosal lesions more often show smooth protrusion,
shallow and even depression, flat/superficial spread, and erosion with slightly raised
margins 10. Dye-based or digital chromoendoscopy should ideally be employed to
improve diagnosis, staging and margin delineation, as they have been associatedwith improved detection of lesions and diagnosis of dysplasia compared to WLE. 6
Although abdominal CT is part of gastric cancer staging, early neoplastic lesions
for which endoscopic resection is considered have a very low risk of lymph nodemetastasis. In this situation, CT is not deemed mandatory, as it is more likely toshow benign findings which may lead to unfounded doubts regarding endoscopic
resection. In the West, endoscopic ultrasonography (EUS) is usually recommended
before endoscopic resection, as it is believed to be the most accurate method for T
staging. However, the use of EUS to determine the resectability of a lesion is controversial. Its accuracy is lower for early gastric cancer stages (T1-T2) 12,13 andin one comparative study resulted in a high rate of over-staging when compared to
endoscopic evaluation 10. Moreover, if endoscopic resection is deemed feasible,
histological specimen analysis represents the most accurate staging method andPita I, Dinis-Ribeiro M, Pimentel-Nunes P :83

E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER
does not preclude subsequent surgery if a higher risk lesion is found. Accordingly,
European guidelines suggest that an expert endoscopic assessment is enough todetermine the feasibility of endoscopic resection in the majority of lesions, withfurther staging procedures reserved for selected cases 14.

ENDOSCOPIC RESECTION

84

Endoscopic mucosal resection (EMR) was the first endoscopic alternative togastrectomy for the treatment of early gastric cancer, with early Asian series reporting disease-specific survival of 99% at 5 and 10 years after a complete en
bloc resection of select small mucosal lesions 15. Subsequent Western series also
reported high rates (97%) of long-term remission after EMR of small (<30 mm),
intramucosal, differentiated tumors without lymphovascular invasion; however,these results were limited by low en bloc and R0 resections and high recurrence
rates (up to 30%) 16. Several EMR techniques have been described, namely
injection-, cap- or band-assisted EMR (figure 2); however, all are limited by thesize of the snare in terms of en bloc resection.
Endoscopic submucosal dissection (ESD) was developed in Japan to allow en
bloc resection of gastric lesions regardless of size (figure 3) 17. Several meta-analyses
comparing both techniques demonstrated higher en bloc and R0 resection rates
for ESD, with lower resection rates and similar post-procedural bleeding. Theseadvantages are maintained even in lesions <10mm, but are counterbalanced bylonger procedure times and a higher perforation risk 18-23. Many recent Western series have replicated the earlier good outcomes reported in the East, with>90% of en bloc and complete resections, 70-80% curative resection rates, local
recurrence of <5% and acceptable adverse event rates (post-procedural bleedingin 5-10% and perforation in <3%) 24-27.
When compared with gastrectomy in meta-analyses, ESD shows significantly
lower procedural time, length of hospital stay, adverse event rates and procedure-related mortality. Overall and disease-specific survival rates are comparable (>95%and >99%, respectively), although recurrence and metachronous lesions are morecommon after ESD (2 vs 0.2% and 7 vs 0.4%, respectively) 28–31. ESD is also associated with a better quality of life at 1 year when compared with gastrectomy 26.
Based on this evidence, European guidelines recommend ESD as the firstline endoscopic procedure for early gastric cancer treatment, with EMR being analternative for small (<15 mm) elevated lesions in which en bloc R0 resection isdeemed likely 14. Nevertheless, the pros and cons of endoscopic resection versus
surgical treatment should always be disclosed to the patient, especially the risk of
non-curative (i.e. high risk of lymph node metastasis [LNM]) resection even after
successful endoscopic excision.

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E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

A

B

C

FIGURE 2. Gastric cap-assisted endoscopic mucosal resection (in this case, ofa grade 1 neuroendocrine tumor). A) Lesion delineation using coagulation
current; B) the endoscope is removed and the cap is fitted onto its tip. After
submucosal injection, the snare is positioned into the cap loop and the lesion
aspirated into the cap. All the margin marks should be visible inside the cap;C) the snare is closed around the lesion and blended current is used to resect
the lesion.

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E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

A

B

C

D

E

F

86

Pita I, Dinis-Ribeiro M, Pimentel-Nunes P

E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

G

H

87
FIGURE 3. Endoscopic submucosal dissection technique. A) Prior to resection,
careful lesion inspection to assess margins: in this case, a IIa lesion in the greater curvature of the antrum; B) the lesion margins are marked using the needle knife and coagulation current. Virtual chromoendoscopy is employed tofacilitate mucosal pattern inspection and lesion delineation; C) the lesion islifted away from the muscularis propria with submucosal injection; D) one orseveral access points to the submucosa are created around the lesion, using aneedle-knife and blended current; E) et F) using the previously created accesspoints, the IT-Knife is used to create a circumferential incision; G) the IT-knife
is used to dissect the submucosal layer underneath the lesion; H) after complete
resection, a coagulation forceps is used to coagulate the larger vessels in themucosal defect.

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88

The histopathological evaluation of the endoscopic resection specimen is the basis for the final decision between accepting endoscopic treatment as curative or proposing further surgery. To improve accurate assessment, specimens should ideallybe pinned on cork or thick paper with pins to avoid shrinkage artifacts before being
fixed in 4% formalin. The minimal requirements for the pathology report are:2 lesion size,
2 histological type,2 grade: well-differentiated (G1), moderately differentiated (G2) and undifferentiated/diffuse type (G3)
2 invasion depth: intraepithelial neoplasia (pTis), intramucosal adenocarcinoma(pTia) or submucosal adenocarcinoma (pT1b), and in the latter, submucosal invasion depth in µm should be measured (sm1 if ≤500 µm; sm2 if >500 µm)
2 lymphovascular invasion,
2 ulceration,
2 vertical and horizontal resection margins.
Initial curative criteria for endoscopic resection were based on the limitations of
EMR and included only differentiated adenocarcinomas of <20mm without ulceration or lymphovascular invasion. With the possibilities brought on by ESD, thesecriteria were found to be too strict, resulting in unnecessary surgery, as large surgicalseries of pT1 cancers found additional groups of lesions with very low risk of LNM.
These were termed “expanded criteria” for endoscopic cure (providing en bloc andR0 resection):
2 differentiated non-ulcerated intramucosal adenocarcinoma without lymphovascular invasion, of any size (LNM risk <0.5%);
2 differentiated ulcerated intramucosal adenocarcinoma without lymphovascularinvasion, ≤30 mm (LNM risk <0.5%);
2 differentiated non-ulcerated superficial submucosal adenocarcinoma (≤500 µm
invasion depth) without lymphovascular invasion, ≤30 mm (LNM risk <3%);
2 undifferentiated non-ulcerated intramucosal adenocarcinoma without lymphovascular invasion, ≤20 mm (LNM risk <1%).
A particular situation is the case of a piecemeal resection or positive horizontal
margin, as these cases do not increase the risk of LNM but have a high risk of local
recurrence 32, which can in the majority of cases be re-treated with ESD.
Any patient who does not meet these criteria should be informed of the 2.5-20%
risk of lymph node disease and gastrectomy with lymphadenectomy should be proposed, unless advanced age or significant comorbidities are a concern, in which casesurgical morbi-mortality must be weighed against the risk of recurrence. In this regard, a scoring system based on non-curative resections submitted to surgery (eCura

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E NDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER
system) was proposed, dividing patients into low-, medium- and high-risk groups for
LNM based on lymphatic invasion, tumor size, deep submucosal invasion, venous invasion and positive vertical margins 33. The system was validated and these subgroups
are associated with differences in 5-year disease-specific survival (99.6, 96 and 91%,
respectively). More importantly, in the low-risk group, 5-year disease-specific survival
was very similar whether patients were operated or surveilled (99.7 vs 99.6%) 34,
suggesting that in fragile patients, surveillance may be an option as long as the patient
is informed of the risks and poor prognosis in the event of disease recurrence.

FOLLOW-UP AFTER ENDOSCOPIC RESECTION
After a curative resection, the main concern during follow-up is the risk of metachronous lesions (10-20%); this is higher in older patients, those with multiple lesions and those with extensive pre-neoplastic conditions 27,35. Helicobacter pylori
should be eradicated when present as its eradication can reduce the incidence of newlesions (36). Since there are currently no other strategies proven to decrease the riskof metachronous lesions, management of these patients relies on regular endoscopic
follow-up, as >85% of new lesions are amenable to endoscopic resection.
Most centers schedule a first endoscopy 3-6 months after ESD (to confirm scarhealing and absence of residual/synchronous lesions) and annually thereafter, as
there is evidence that longer intervals are associated with larger, more advanced
lesions and higher rates of gastrectomy 37. Given the low risk of LNM, in expanded
criteria resections, staging baseline and follow-up CTs should also be considered.
In the case of local-risk resection (positive horizontal margins or piecemeal resection),scar biopsies and more frequent endoscopies in the first two years should be considered.

CONCLUSION
Due to the widespread use of endoscopy and advanced imaging techniques, gastric cancer is increasingly being diagnosed at early stages associated with low LNM
risk and potentially amenable to curative endoscopic resection.
Careful endoscopic evaluation by an experienced endoscopist is the main staging
procedure before treatment, with other imaging techniques (CT or EUS) having acontroversial role. ESD is the first-line technique for endoscopic resection of earlygastric cancer, as it has a high rate of en bloc, R0, curative resections, with an acceptable safety profile and a positive impact on the quality of life compared to surgery.
Accurate histopathological assessment of the resection specimen is paramountfor adequate post-resection management, since in lesions with high-risk criteria for
LNM surgical lymphadenectomy must be considered. After a curative endoscopic
resection, there is a considerable risk of developing metachronous lesions and endoscopic follow-up is necessary for early detection.

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Hruban RH, et al, eds 4th edn Lyon: IARC. 2010;48–58.
4. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from earlygastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer
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5. Ang TL, Pittayanon R, Lau JYW, et al. A multicenter randomized comparison between
high-definition white light endoscopy and narrow band imaging for detection of gastriclesions: European Journal of Gastroenterology & Hepatology 2015; 27: 1473–8.
6. Pimentel-Nunes P, Libânio D, Lage J, et al. A multicenter prospective study of the real-time use of narrow-band imaging in the diagnosis of premalignant gastric conditions
and lesions. Endoscopy 2016; 48: 723–30.
7. Menon S, Trudgill N. How commonly is upper gastrointestinal cancer missed at endoscopy? A meta-analysis. Endosc Int Open 2014; 2 : e46–50.
8. Zhao Z, Yin Z, Wang S, et al. Meta-analysis: The diagnostic efficacy of chromoendoscopy
for early gastric cancer and premalignant gastric lesions. J Gastroenterol Hepatol 2016; 31:
1539–45.
9. Kikuste I, Marques-Pereira R, Monteiro-Soares M, et al. Systematic review of the diagnosis of gastric premalignant conditions and neoplasia with high-resolution endoscopic
technologies. Scand J Gastroenterol 2013; 48: 1108–17.
10. Choi J, Kim SG, Im JP, Kim JS, Jung HC, Song IS. Endoscopic prediction of tumor invasion depth in early gastric cancer. Gastrointest Endosc 2011; 73: 917–27.
11. Hirasawa K, Kokawa A, Oka H, et al. Risk assessment chart for curability of early gastriccancer with endoscopic submucosal dissection. Gastrointest Endosc 2011; 74 : 1268–75.
12. Cardoso R, Coburn N, Seevaratnam R, et al. A systematic review and meta-analysis of theutility of EUS for preoperative staging for gastric cancer. Gastric Cancer 2012; 15 Suppl
1: S19-26.
13. Mocellin S, Marchet A, Nitti D. EUS for the staging of gastric cancer: a meta-analysis.
Gastrointest Endosc 2011; 73: 1122–34.
14. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy(ESGE) Guideline. Endoscopy 2015; 47: 829-54.
15. doi: 10.1055/s-0034-1392882. Uedo N, Iishi H, Tatsuta M, et al. Longterm outcomes
after endoscopic mucosal resection for early gastric cancer. Gastric Cancer 2006; 9: 88–92.
16. Manner H, Rabenstein T, May A, et al. Long-term results of endoscopic resection in early

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gastric cancer: the Western experience. Am J Gastroenterol 2009; 104: 566–73.
17. Ono H. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;
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18. Park Y-M, Cho E, Kang H-Y, Kim J-M. The effectiveness and safety of endoscopic submucosal dissection compared with endoscopic mucosal resection for early gastric cancer:a systematic review and metaanalysis. Surg Endosc 2011; 25: 2666–77.
19. Lian J, Chen S, Zhang Y, Qiu F. A meta-analysis of endoscopic submucosal dissection and
EMR for early gastric cancer. Gastrointest Endosc 2012; 76: 763–70.
20. Facciorusso A, Antonino M, Di Maso M, Muscatiello N. Endoscopic submucosal dissection vs endoscopic mucosal resection for early gastric cancer: A meta-analysis. World J
Gastrointest Endosc 2014; 6: 555–63.
21. Tao M, Zhou X, Hu M, Pan J. Endoscopic submucosal dissection versus endoscopic
mucosal resection for patients with early gastric cancer: a meta-analysis. BMJ Open 2019;9: e025803.
22. Zhao Y, Wang C. Long-Term Clinical Efficacy and Perioperative Safety of Endoscopic
Submucosal Dissection versus Endoscopic Mucosal Resection for Early Gastric Cancer:
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24. Manta R, Galloro G, Pugliese F, et al. Endoscopic Submucosal Dissection of Gastric Neoplastic Lesions: An Italian, Multicenter Study. J Clin Med 2020 ; 9 : 737. doi: 10.3390/
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25. Probst A, Schneider A, Schaller T, Anthuber M, Ebigbo A, Messmann H. Endoscopic
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27. Libânio D, Pimentel-Nunes P, Afonso LP, Henrique R, Dinis-Ribeiro M. Long-Term
Outcomes of Gastric Endoscopic Submucosal Dissection: Focus on Metachronous andNon-Curative Resection Management. GE Port J Gastroenterol 2017; 24: 31-9.
28. Liu Q, Ding L, Qiu X, Meng F. Updated evaluation of endoscopic submucosal dissection
versus surgery for early gastric cancer: A systematic review and meta-analysis. Int J Surg
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29. Gu L, Khadaroo PA, Chen L, et al. Comparison of Long-Term Outcomes of Endoscopic
Submucosal Dissection and Surgery for Early Gastric Cancer: a Systematic Review andMeta-analysis. J Gastrointest Surg 2019; 23:1493–501.
30. Li H, Feng L-Q, Bian Y-Y, et al. Comparison of endoscopic submucosal dissection withsurgical gastrectomy for early gastric cancer: An updated meta-analysis. World J Gastroin-

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31. Abdelfatah MM, Barakat M, Ahmad D, et al. Long-term outcomes of endoscopic submucosal dissection versus surgery in early gastric cancer: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2019;31:418–24.
32. Figueiredo PC, Pimentel-Nunes P, Libânio D, Dinis-Ribeiro M. A systematic review andmeta-analysis on outcomes after Rx or R1 endoscopic resection of superficial gastric cancer. Eur J Gastroenterol Hepatol 2015;27:1249–58.
33. Hatta W, Gotoda T, Oyama T, et al. A Scoring System to Stratify Curability after Endoscopic Submucosal Dissection for Early Gastric Cancer: “eCura system.” Am J Gastroenterol 2017;112:874–81.
34. Hatta W, Gotoda T, Oyama T, et al. Is the eCura system useful for selecting patients who
require radical surgery after noncurative endoscopic submucosal dissection for early gastric cancer? A comparative study. Gastric Cancer 2018; 21:481–9.
35. Park W-Y, Lee S-J, Kim Y-K, et al. Occurrence of metachronous or synchronous lesions
after endoscopic treatment of gastric epithelia dysplasia- impact of histologic features ofbackground mucosa. Pathol Res Pract 2018; 214: 95–9.
36. Zhao B, Zhang J, Mei D, et al. Does Helicobacter pylori Eradication Reduce the Incidenceof Metachronous Gastric Cancer After Curative Endoscopic Resection of Early Gastric
Cancer: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2020; 54: 235-41.
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O RGANIZATION OF EXPERT CENTERS

Organization of expert centers
Driffa Moussata1
1
Tours Hospital, France

An expert center is defined as a working group of different specialists who have an experience in the field of gastric cancer and gastric carcinogenesis, capable of providing
multidisciplinary care coordination with the aim of assuring an optimal outcome forpatients with an increased risk of gastric cancer 1. This working group mainly includes
gastroenterologists/endoscopists, experts in the detection and resection of gastric lesions, pathologists and biologists. This team has to take care of patients presenting low
or high risk of gastric cancer or already presenting preneoplastic lesions. However, thestrategy is to coordinate the different specialities and create a cohort of patients, whichis the first step for creating a research network. This group of experts standardizes theprocess of care and develops the methods of teaching. According to the according
to the European Cancer Organization (ECCO) 2, the essential requirements for theorganization of an expert care center encompass multidisciplinary teamwork, patientcare pathways, professional education and enrolment in clinical trials.

MULTIDISCIPLINARY TEAM
A multidisciplinary team (MDT) should encompass different specialists in one
center, including a gastroenterologist/endoscopist, bacteriologist, geneticist, surgeon
and pathologist, who have experience in chronic gastritis and gastric preneoplastic
lesions. This team will take care of the patients and discuss each case at regularmeetings, use the most recent technologies and adequate treatment based on recent
published guidelines. According to the ECCO recommendations, MDT members
should see at least 200 cases with oeso-gastric cancer lesions annually 2.
Several studies have demonstrated the effectiveness of MDTs in improving efficiency of care delay and clinical outcome 3-5, as well as in reducing the numberof unnecessary tests 6. The MDT organization prioritizes the resources in order todecrease the delay of treatment initiation. Clinical prioritization for referrals is aform of time scheduling. Prioritization can improve both the effectiveness and theequity in accessing health care. This approach has to be developed in close interac-

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tion between primary care physicians and different specialists. It has been reported
that almost one third of gastroscopies are inappropriate referrals 7-10. In a recent
retrospective study 8, as much as 43% of almost 86,000 repeated gastroscopies were
inappropriately prescribed. A recent review showed that the prevalence of relevant
findings was significantly higher in case of “appropriate” than “inappropriate” gastroscopies 9. Likewise, data by Meggio et al. 10 seems to demonstrate that appropriateness was the main variable predicting the risk of relevant endoscopic finding(OR 9.29, p<0.0001), secondary to priority agreement between the primary care
physicians and the specialists (OR 1.911, p=0.03). Another issue implicated in theuse of this model was to guarantee timely high-priority referrals without affecting thenormal supply of services.
Interventional endoscopy is also a part of the management of patients with earlyneoplastic gastric tumors. The gastroenterologist/endoscopist must be trained andaccredited in diagnostic upper GI endoscopy 2. Chromoendoscopy and high-definition video endoscopy must be used for diagnosis and treatment. The endoscopic
resection techniques have to be mastered and the endoscopy unit must be subjected
to appropriate regular audit. Among quality criteria, resection margin or right correct histological analysis highlight the close interaction between the endoscopist andthe pathologist.
Pathology, especially using techniques of molecular pathology, plays a critical rolein the diagnosis of gastric preneoplastic and neoplastic lesions 11. Pathologists musthave an expertise in the evaluation of gastric biopsies as well as EMR (endoscopic
mucosal resection) /ESD (endoscopic submucosal dissection) specimens. Over theyears, there has been a disagreement between the Western and the Japanese pathologists regarding the diagnosis of superficial gastric lesions, with a lack of inter-observer agreement in the differential diagnosis between reactive and dysplastic changes,
between undefined or high-grade dysplasia and intramucosal carcinoma 12. The
pathologist reports have to detail the analysis of the resected tumor or the biopsies
and must contain a list of items as recommended by professional organizations andinternationally recognized classification used for histopathological diagnosis 13. Incase of indefinite OK dysplasia or suspicion of cancer, a second analysis must be
performed internally or externally by national experts.
The development of professional relationships with ancillary services increases theuse of evidence-based assessment. Improved standardization and less variability wereseen after implementation of the MDT 6. The responsibility for coordination of studies
and diagnostic tests was consolidated within a single service with the greatest capacity.

ORGANIZATION OF THE PATIENT CARE PATHWAY
In Western countries, screening programs targeting only the high-risk population(figure 1) seem to be more cost-effective than general screening programs, irrespec-

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Histopathology

Bacteriology

PATIENT COHORT
Individual screening,
predisposition, syndrome

95

Gastroscopy/
Endoscopy

Clinical pathway

Genetics

Research

FIGURE 1. Patient care pathway in expert center.

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96

tive of age or risk factors 14. A risk-based approach to endoscopic screening of theupper gastro-intestinal tract (GIT) may be more cost-effective than general screening of asymptomatic low-risk individuals. Indeed, it is important to distinguish thegeneral population from the patients with inherited cancer predisposition syndromes
or first-degree relatives of gastric cancer patients, who also have to be managed byexperts in genetic testing and counselling, working together with gastroenterologists.
For this reason, it is important to stratify the risk of gastric cancer depending on theclinical criteria (sex, personal and family history, ethnic background, H. pylori infection, …) as well as on endoscopic and histological findings (atrophy, intestinal metaplasia, ...) in order to establish specific patient care pathways. Identification of thesubjects at a very high risk of upper GIT cancer and the appropriate surveillance of
these patients is the main objective. Once a patient is identified with preneoplastic lesions or cancer predisposition, an appropriate surveillance has to be initiated in orderto prevent the development of cancer. For genetic predisposition syndromes, guidelines have been established recommending upper endoscopy as part of management
15, 16. Patients with cancer predisposition have an increased risk for various tumor
types, many of which could be detected early or even prevented through specialized
screening and surveillance. Identification of individuals with genetic predisposition
to cancer affects treatment of both the patients with cancer and their relatives. Geneticists are expected to use family history and tumor molecular data to performgenetic assessments for every patient with preneoplastic lesions (dysplasia, polyps)
and be familiar with the diagnosis and management of individuals with hereditarycancer syndromes 17. Individuals who carry associated mutations should benefit
from consultation with multidisciplinary care teams composed of oncologist, geneticist, surgeon and gastroenterologist advisers. Furthermore, the expert center may
collaborate with certified patient associations who represent users, particularly withgenetic diseases. The involvement of patients in therapeutic programs is another way
of favoring a care approach. This improves the care of patients and their families bydeveloping community-hospital networks and collaboration between physicians andpatient associations.
An expert center has to fulfill some quality criteria. Firstly, the center has to bewell identified and easily available to the patients and to the professionals. Secondly,
for a proper and detailed endoscopic assessment of the upper GIT, some performance measures need to be considered as described by the European Society of GI
Endoscopy (ESGE), including key performance measures and minor performancemeasures (table 1). Certain standards, such as accurate photo-documentation, accurate terminology and nomenclature, as well as correct documentation, seem tobe paramount for achieving a high-quality upper GIT endoscopic examination 18.
In the meta-analysis by Menon et al. 19, they have demonstrated a pooled missed
rate of upper GIT cancer of 11.3%. Even in Japan, Shimodate et al. 20 showed that

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75% of the newly diagnosed gastric cancers were evident in retrospectively analyzed
images of prior gastroscopies of the same patients. Thirdly, time to treatment is also
an important criterion of care quality, which is modified by various factors like institutional resources and regional practice patterns. Treatment strategies are decided
on after a consensus among the MDT members during regular meetings. All MDT
decisions must be documented and recorded in the patient’s data. The core andextended MDTs must meet regularly to review the activity of the previous period
based on the audited metrics, discuss changes in protocols and procedures and improve the performance of the unit/center. The MDT performance must be quality
assured both internally and by external review with demonstration of cost-effectiveness of quality improvements. The essential requirements of the ECCO for a quality
cancer care group strongly recommend participation in national or international accreditation programs 21.
TABLE 1. Major and minor criteria of quality of health care.
Key performance measures

Minor performance measures

Instructions prior to UGI endoscopy

Minimum 7 min procedure timefor first diagnostic UGI endoscopy
and follow-up of preneoplastic lesions

Documentation of procedure duration

Minimum 1 min inspection time per cm

Accurate photodocumentation

Use of chromoendoscopy

Application of recommendations

Endoscopic resection

Accurate registration of complications
after therapeutic UGI endoscopy

Prospective registration

UGI endoscopy: Upper Gastrointestinal endoscopy.

EDUCATION
An expert center should also play a central role in education. In endoscopy, thecurrent trend in teaching before practical application on the patient is knowledgebased training, simulation followed by practical courses. These different types oftraining can involve mechanical models, live animal models, ex vivo (hybrid involving plastic and animal organs), practical training like e-learning and, more recently,
computerized virtual reality simulators. These different models offer the possibilityof acquiring technical or non-technical skills 22. A Cochrane study concluded thatthese different types of training improve the skills, particularly of fellows 23.
Learning platforms, especially e-learning, have the advantage of allowing several
gastroenterologists to be trained simultaneously in different parts of the world andMoussata D97

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could therefore become an important tool for training, quality improvement andfuture developments in the field of endoscopy. In Japan, this endoscopic learning
has already been shown to improve the detection of superficial gastric cancers 2426. The Portuguese teams have demonstrated the contribution of e-learning in theteaching and validation of endoscopic classification systems 27, 28. Some studies
have shown that web-based training significantly improves knowledge in chromoendoscopic characterization of the preneoplastic lesions in fellows as well as in MD
groups. Significant average improvement rates of 21% 24 and 12% 25 have been
demonstrated in the histological prediction of the main gastric lesions by white lightand NBI with magnification through e-learning 24, 25. The role of expert centers is
to promulgate and spread the different ways of teaching to the medical community.

RESEARCH CENTER98

An expert center should be involved in clinical research programs, either throughtheir own research or in programs supported by other centers included in research
networks. The MDT meeting is an opportunity to assess all new patients for theireligibility to be included in academic or industry sponsored clinical trials. Collaboration between high volume centers and community hospitals is needed to identify
the patients who could be included in clinical trials. Innovative study designs can be
developed more efficiently by elaborating new diagnostic or therapeutic targets inthe future 2. Correlative biomarker research is a crucial part of all phases of clinicalstudies and requires close cooperation among the different physicians and pathologists/biologists and biobanks within research networks. The link between basic andclinical research is fundamental in order to develop new technologies or treatments,
and this mission should also be supported by expert centers.
In conclusion, an expert center in the management of gastric precancerous lesions is based on a multidisciplinary team with high expertise in the field, and should
combine the missions of optimal patient care using the best methods of diagnosis
and treatment and dedicated patient pathways, education and research.

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28. Dias-Silva D, Pimentel-Nunes P, Magalhães J, et al. The learning curve for narrow-band
imaging in the diagnosis of precancerous gastric lesions by using Web-based video. Gastrointest Endosc 2014; 79: 910-20.

Moussata D

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Abbreviation

Meaning

AFI

Autofluorescence Imaging

AG

Atrophic gastritis

AIG

Autoimmune gastritis

Anti-IFA

Anti-Intrisic Factor Antibodies

APCA

Antibodies against gastric parietal cells

ASR

Age-Standardized Rate

AST

Antimicrobial Susceptibility Testing

EGGIM

Endoscopic grading of gastric intestinal metaplasia

EMR

Endoscopic Mucosal Resection

ESD

Endoscopic Submucosal Dissection

EUS

Endoscopic ultrasonography

FIT test

Fecal Immunochemichal Test

GC

Gastric Cancer

GPL

Gastric precancerous lesions

GIM

Gastric Intestinal Metaplasia

GIT

Gastro-Intestinal tract

H&E

Hematoxylin and Eosin

HPSA test

Helicobacter pylori stool antigen test

IEE

Image-enhanced endoscopy

IM

Intestinal Metaplasia

IF

Intrisic factor

LBC

Light blue crest

101

G LOSSARY

102

Abbreviation

Meaning

LNM

Lymph node Metastatis

MAPS

MAnagement of epithelial Precancerous conditions and lesions
in the Stomach

NBI

Narrow band imaging

NCGC

Non-cardia Gastric Cancer

OLGA

Operative Link on Gastritis Assessmenton

OLGIM

Operative Link on Gastritis Assessment based on Intestinal Metaplasia

pCLE

Probe-based confocal laser endomicroscopy

PGI

Pepsinogen I

PGII

Pepsinogen II

PPI

Proton pump inhibitors

SPGI

Serum levels of pepsinogens

TMI

Trimodal Imaging

TFF

Trefoil factor

WLE

White Light Endoscopy

GastroPanel®

Test before referral!

Innovative test for primary care to improve
productivity
GastroPanel® is a cost-effective tool for generalpractitioners for the management of dyspeptic patients.
The patient-friendly blood test is especially useful fordyspeptic patients of over 40 years of age.

 Accurately identify patients requiring referral for
gastroscopy Get reliable information on the status and functionof stomach mucosa including H. pylori
 Reduce unnecessary referrals to gastroscopy andimprove productivity

 Identify risk patients for gastric cancer

www.gastropanel.com

CRITÈRES DE QUALITÉ DE LA COLOSCOPIEENGLISH VERSION REVISEDBY ZUZANA SAIDAKPUBLISHED AND COMPOSED BY
LE GRAND MÉTIER (LGM): ROUEN (FRANCE), 2021.

THE AUTHORS

Melina ARNOLD
Estelle CAUCHIN
Nicolas CHAPELLE
Emmanuel CORON
Francesco DI MARIO
Mário DINIS-RIBEIRO
Wladyslaw JANUSZEWICZMarcis LEJAPeter MALFERTHEINER
Tamara MATYSIAK-BUDNIKFrancis MÉGRAUD
Driffa MOUSSATAJin Young PARKMaria Blanca PIAZUELO
Pedro PIMENTEL-NUNES
Inês PITA
Jaroslaw REGULA
Marta RODRIGUES-CARRASCO
Christine VARON