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1. Gastritis staging as a clinical priority
Claudia Mescolia
, Aly Gallo Lopezc
, Luis Taxa Rojasd
, Walker Jove Oblitase
, Matteo Fassana
and Massimo Ruggea,b
The elective background for gastric adenocarcinoma is the atrophic transformation of the gastric mucosa. The extent of mucosal
atrophy basically parallels the risk of developing gastric cancer. This means that either noninvasive (serology) or invasive
(endoscopy/histology) methods enabling the atrophic transformation to be quantified can be used theoretically to assess a given
patient’s gastric cancer risk. This review aims to focus on the reliability of histology gastritis Operative Link for Gastritis
Assessment -staging system for assessing the ‘personalized’ cancer risk in individuals with (atrophic) gastritis. Eur J
Gastroenterol Hepatol 00:000–000
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
Before the year is out, more than one million new cases of
gastric cancer (GC) will have been diagnosed worldwide,
and the patients’ overall 5-year survival rate will not
exceed 30%, mainly because of the advanced stage of their
disease [1–3].
GC, one of the most typical inflammation-associated
epithelial malignancies, is usually the result of a multistep
accumulation of genotypic and phenotypic changes
triggered by a longstanding gastritis. Longstanding (not
self-limiting) gastritis is epidemiologically, clinically, and
biologically linked to Helicobacter pylori, which has been
qualified as a class I carcinogen. The oncogenic role of
other inflammatory gastric diseases is more elusive,
although autoimmune gastritis has been considered a
precancerous condition since the latter half of the last
century.
Assessment of gastritis-related cancer risk in individual
patients is far from easy as it depends on the confounding
shared responsibilities of several etiologic factors, both
environmental and host related. Once we have excluded the
(rare) cases of syndromic GC because of hereditary mechanisms
[4], the elective background for gastric adenocarcinoma is the
atrophic transformation of the gastric mucosa (the so-called
‘cancerization field’ for GC). The extent of mucosal atrophy
basically parallels the risk of developing GC. This means that
either noninvasive (serology) or invasive (endoscopy/histology)
methods enabling the atrophic transformation to be quantified
can be used theoretically to assess a given patient’s GC risk
[5,6].
This review aims to focus on the reliability of histology
for assessing the ‘personalized’ cancer risk in individuals
with gastritis.
The natural history of gastric mucosal atrophy
In most cases, gastric mucosal atrophy is the outcome of
longstanding inflammatory conditions. Among the etio-
logies of atrophy, H. pylori infection is the most prevalent
worldwide. Because of the antral location of the earliest
H. pylori-associated inflammatory lesions, the gastric
antrum (including its cranial ‘atrophic’ border) is the
gastric compartment that is exposed the soonest to the risk
of atrophy [7].
In the natural history of H. pylori-related gastritis, the
progressive distal-to-cranial spread of the inflammatory
lesions may involve the oxyntic mucosa, eventually
resulting in a patchily atrophic gastritis. This phenotype,
originally described by Correa [8] as ‘multifocal atrophic
gastritis’, is the elective substrate in which more severe
(neoplastic) lesions may develop, first as intraepithelial
neoplasia, and ultimately as invasive cancer (Fig. 1).
Less commonly, gastric atrophy may result from a
primary autoimmune disease, targeting the (oxyntic) par-
ietal cells [9–11].
This ‘autoimmune atrophy-variant’ is also a non-self-
limiting inflammatory disease, which may result in two
basic glandular changes, that is, a numerical loss of
glandular units and/or a ‘phenotypic remodulation’ of the
oxyntic glands, which lose their native acid-secreting
commitment and acquire the metaplastic morphology of
pyloric glands (pseudopyloric metaplasia). Both these
conditions are consistent with the current definition of
mucosal atrophy (see below).
A third route to mucosal atrophy involves the pathogenic
combination of a H. pylori infection with a ‘secondary’,
H. pylori-triggered autoimmunity. The assumption of this
‘secondary autoimmunity’ is based on the assumption of a
molecular mimicry between H. pylori antigens and structural
proteins of the gastric parietal cells. This hypothesis has been
supported by evidence of longstanding H. pylori infection
a
Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED),
University of Padova, b
Veneto Tumor Registry (RTV), Veneto Regional Authority,
Padova, Italy, c
Proyecta Diagnostico Scientific Research Center-CONCYTEC
Instituto de Investigación de la Facultad de Medicina Humana de la Universidad
de San Martín de Porres, d
Department of Pathology, Instituto Nacional de
Enfermedades Neoplásicas INEN, Lima and e
Gastroenterology Division, Honorio
Delgado Hospital, Arequipa, Peru
Correspondence to Massimo Rugge, Surgical Pathology and Cytopathology
Unit, Department of Medicine (DIMED), University of Padova, Via A. Gabelli, 61,
35121 Padova, Italy
Tel: + 39 049 821 8990; fax: + 39 049 827 2277;
e-mail: massimo.rugge@unipd.it
Received 26 August 2017 Accepted 5 September 2017
European Journal of Gastroenterology & Hepatology 2017, 00:000–000
Keywords: atrophic gastritis, gastric oncogenesis, intestinal metaplasia,
Operative Link for Gastritis Assessment staging
’Review article
0954-691X Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001015 1
Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Edson Guzman
Firmado digitalmente porEdson Guzman
Nombre dereconocimiento (DN): cn=Edson Guzman, o, ou, email=edson_guzman@hotmail.com,c=PE
Fecha: 2017.12.12 23:57:12 -05'00'

2. triggering the emergence of gastric CD4+ T-cells that
cross-react with epitopes shared by gastric H/K ATPase and
H. pylori proteins [12]. It is not known whether this
H. pylori-induced gastric autoimmunity is influenced by a
given host’s immunological profile or by a peculiar biological
trait of the H. pylori strain involved, or both. It is also
unclear whether eradicating the H. pylori can also extinguish
the subordinate autoimmune disease and/or its putative
associated cancer risk.
Atrophy: definition and histological phenotypes
Gastric atrophy is defined as ‘loss of appropriate glands’ [13].
This definition includes two phenotypes of atrophic transfor-
mation (Table 1): (i) the disappearance of glandular units,
replaced by fibrotic lamina propria (i.e. a reduced glandular
mass, but no change in the native glandular phenotype), or
(ii) the replacement of the native glands by metaplastic glands
featuring a new commitment (this is called ‘metaplastic
atrophy’) involving intestinal metaplasia (IM) and/or pseudo-
pyloric metaplasia (also known as spasmolytic polypeptide-
expressing metaplasia). The spasmolytic polypeptide-expressing
metaplasia variant (only affecting the oxyntic mucosa) can be
(more) easily assessed by exploiting its positive immunostaining
with TFF2 antibodies (Fig. 2) [14–19].
Unlike nonmetaplastic atrophy, the metaplastic variant
does not necessarily feature a reduction in the number of
glandular units. It is simply that the metaplastic replacement
of the original glands ultimately results in a decreasing
number of ‘native’ glandular structures being ‘appropriate’
for the compartment concerned.
In each biopsy sample, atrophic transformation can be
graded as a percentage of the atrophic transformation.
Including a score of 0 (i.e. no atrophy), a four-tiered scale
has been proposed, where a score of 1 = global atrophy
affecting 1–30% of the biopsy sample; 2 = global atrophy
affecting 31–60% of the biopsy sample; and 3 = global
atrophy affecting more than 60% of the biopsy sample. This
global score of all the (frequently coexisting) histological
variants of mucosal atrophy enables a consistent assessment
of the level of atrophy in a biopsy set obtained from both
the antral mucosa (including the incisura angularis) and the
oxyntic mucosa (Fig. 3).
Endoscopy and biopsy sampling for the histological
assessment of gastric mucosal atrophy
The biological rationale behind any endoscopy protocol
for obtaining biopsies is based on the following well-
established conviction: ‘the greater the extent of atrophy,
the higher the risk of GC’.
Generally, a gastrointestinal endoscopy procedure can
never be considered ‘complete’ unless some biopsy samples
are obtained (with the obvious exception of cases of
bleeding). Different biopsy sampling protocols have been
proposed, which rightly differ depending on the clinical
setting and the main purpose of the endoscopy procedure
(clinical practice vs. clinical research). Both the oxyntic
and the antral mucosa should be explored histologically
because of the potentially different diseases affecting the
two compartments.
Apart from the procedures requiring extensive mucosal
mapping (to seek endoscopically silent focal lesions)
and those performed for clinical research purposes, the
biopsy sampling protocol suggested by the Sydney System
should consistently satisfy most clinical diagnostic needs.
ATROPHY
Inflammation Inflammation
H. pylori
infection
“Primary”
Autoimmune
Gastritis
Fig. 1. Nonself-limiting gastritis: etiology and topography. The H. pylori infection initially results into nonatrophic antral inflammation, followed by mucosal
atrophy. At the same time, corpus-inflammation also develops, which progresses to atrophy (multifocal atrophic gastritis, according to Correa). Primary
autoimmune gastritis initially results in corpus-restricted (nonatrophic) inflammation, which ultimately progresses to corpus-restricted atrophic gastritis. Dark
grey color = inflammation; medium grey = Atrophy.
Table 1. Nosology, histology phenotypes, and score method for gastric mucosa atrophy
Site/type of lesions
Atrophy Histological type
Antral mucosa including the incisura
angularis Oxyntic mucosa Histology score
Absent Score 0
Indefinite High-grade inflammation High-grade inflammation Not assessable
Present Nonmetaplastic (decline in the number of native
glands)
Glands vanishing/shrinking
Fibrosis/inflammation of the lamina propria
Glands vanishing/shrinking
Fibrosis/inflammation of the lamina
propria
Score 1 = 1–30%
Score 2 = 31–60%
Score 3 = > 60%
Metaplastic (metaplasia of native glands) Intestinal metaplasia Pseudopyloric metaplasia (SPEM)
Intestinal metaplasia
SPEM, spasmolytic polypeptide-expressing metaplasia.
2 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00
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3. According to the Sydney System recommendations, two
biopsy samples should be obtained from the antral mucosa,
one from the so-called atrophic border (and specifically
from the angularis incisura), and two from the oxyntic
mucosa (the corpus/fundus area) [20]. The biopsy samples
should be submitted to the Pathology Department in two
separate vials: one containing the antral and angularis
samples, and the other containing the oxyntic biopsies. The
angularis incisura has been considered a ‘sentinel’ site where
atrophic modifications are assessable soonest. Sampling
the angularis mucosa is time-consuming, however, and
many gastroenterologists would prefer to skip this sampling
step. Additional samples should be obtained from any
focal lesions, including ulcers (especially in the proximal
stomach).
From a descriptive diagnostic approach to the staging-
frame of histology reporting
Our current understanding of the natural history of gas-
tritis and the established criteria for the histological
examination of atrophy together lay the foundations for a
new framework for reporting gastritis histology. This new
approach replaces the traditional, descriptive ‘Sydney
model’ with a histological report in terms of the stage and
the grade of gastritis [20]. Grading is used to determine the
cumulative intensity of the inflammation, whereas staging
provides information on the topographical extent of the
atrophic-metaplastic changes identified and their extent is
considered the main determinant of the gastritis-associated
cancer risk.
This grading and staging approach was proposed for-
mally in March 2005 by an international group of gastric
pathologists and other experts [the Operative Link for
Gastritis Assessment (OLGA)] [21,22]. Briefly, the OLGA
system includes two ‘compartmental’ scores for atrophy:
one based on the antral/angularis biopsy samples and the
other on the oxyntic samples (each scored as: 0/1/2/3).
Combining the antral with the oxyntic scores results in an
OLGA gastritis stage theoretically associated with different
levels of GC risk (Table 2). Preliminary studies carried out
in different epidemiological contexts consistently asso-
ciated only stages III and IV with a risk of progression to
GC. In other words, the OLGA stage indicates the indi-
vidual likelihood of a patient developing a malignancy and
can be adopted as a ‘personalized’ rationale for guiding the
endoscopic follow-up of patients at a higher risk of cancer.
The stage of the organic lesions correlates significantly
with ‘functional’ gastric mucosa parameters and with
serum pepsinogen levels, thus providing support for the
clinical feasibility of reserving endoscopy and biopsy pro-
cedures for a limited subgroup of patients whose ser-
ological profile is consistent with gastric mucosal atrophy.
Because IM scoring was judged more consistent than
atrophy scoring, an alternative staging system (OLGIM)
was subsequently proposed, which only considers the IM
score [23]. More studies are needed to compare the two
Fig. 2. Tff2 immunostaining significantly increases the specificity in the his-
tology detection of pseudopyloric metaplasia [SPEM; Tff2 polyclonal anti-
body; Proteintech (Chicago, Illinois, USA); working dilution 1 : 180]. Biopsy
sample obtained from the oxyntic mucosa: pseudopylorized glands show
intense cytoplasmic immunoreaction.
A3
A2
A1
B2
B1
VIAL 1:
Samples A1-A2-A3
VIAL 2:
Samples B1-B2
B2
B1
ATROPHY PREVALENCE AT
EACH SINGLE BIOPSY SAMPLE LEVEL
0%
10%
MEAN ATROPHY AT EACH
COMPARTMENT LEVEL
OLGA
STAGE
10%
0%
50%
20%
I
II
III
A1
20%
35%
50%
A2
20%
40%
60%
A3
25%
50%
90%
BODY
5%=
score 1
5%=
score 1
5%=
score 1
ANTRUM
21%=
score 1
42%=
score 1
67%=
score 3
CASE 1
CASE 2
CASE 3
1 2 3 4
Fig. 3. Simulations of the gastritis staging process: (1) atrophy score (%) at each single biopsy sample level as obtained by the antral (a) mucosa: percentages;
(2) atrophy score (%) at each single biopsy sample level as obtained by the body (b) mucosa: percentages; (3) mean of the atrophy score as obtained from the
antral and body’s biopsy samples; and (4) by combining the score values as obtained from the antrum and the body, Table 1 allows to finalize the gastritis
staging.
OLGA staging for gastritis Mescoli et al. www.eurojgh.com 3
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4. staging proposals, but both are consistent with the aim to
identify unequivocally as to which gastritis patients should
be placed under surveillance.
‘Gastric serology’ in gastric cancer secondary prevention
strategies
The invasiveness and cost of endoscopy and biopsy pro-
cedures limit their extensive use as part of GC secondary
prevention strategies. Serological tests have therefore been
proposed as a first-line (noninvasive) method for identi-
fying the patients with atrophic gastritis who warrant
endoscopic investigation.
The serological assessment of gastric atrophy is based
largely on two main proenzymes produced by the gastric
mucosa, pepsinogen I (PgI) and pepsinogen II (PgII), and
on their ratio (PgI/PgII). Although PgII is produced by the
antral and corpus mucosa, PgI is produced almost exclu-
sively by the oxyntic chief cells. This means that any
atrophy-induced loss of oxyntic glands results in lower PgI
levels and a lower PgI/PgII ratio [24].
In the setting of H. pylori-related gastritis, a normal PgI/
PgII ratio virtually rules out any presence of gastric
mucosal atrophy (with a high negative predictive value),
enabling a patient to be confidently excluded from any
further invasive (endoscopic) diagnostic procedures.
Patients with H. pylori infection and a low PgI/PgII ratio
should be considered at a higher risk of GC and a second-
level diagnostic procedure(endoscopy and histological
examination) could be warranted. The cut-off for distin-
guishing patients ‘at risk’ on serology may differ depend-
ing on the population-related cancer risk.
Gastritis staging in international guidelines
In 2002, an expert consensus statement suggested that
H. pylori eradication therapy can prevent GC [25]. A few
years later, the Asia-Pacific consensus guidelines recommended
an eradication strategy in countries with a high incidence of
GC [26]. In 2012, an international consensus document on the
‘Management of precancerous conditions and lesions in the
stomach (MAPS)’ stated that: ‘Systems for histopathological
staging… may be useful for identifying subgroups of patients
with different risks of progression to gastric cancer (recom-
mendation grade C), namely those with extensive lesions
(i.e., atrophy and/or intestinal metaplasia in both antrum and
corpus)’. Gastritis staging was not mentioned, however,
among the crucial variables for distinguishing atrophic gastritis
by different levels of cancer risk [27].
In the same year, the ‘Maastricht IV/Florence Consensus
Report’, addressing the use of gastritis staging in the routine
management of gastritis patients, simply reported: ‘The
gastritis OLGA staging conveys useful information on the
potential clinicopathological outcome (including cancer
progression). The adoption of this system is therefore useful
for patient management. According to OLGA staging and
H. pylori status, patients with gastritis can be confidently
stratified and managed according to their cancer risk’ [28].
In February 2014, the Kyoto Global Consensus Conference
unanimously recognized that the risk of developing GC par-
allels the extent and location of atrophy and IM, as assessed
by gastritis staging. To be precise, according to statement no. 4
(consensus level: 100%): ‘new staging systems for the char-
acterization of gastritis have been introduced to assess the GC
risk. They are used in clinical practice and are either based on
the severity of atrophy in various gastric subsites (OLGA) or
on IM (OLGIM)’ [29]. The same document (statement no. 14)
qualifies the histological staging of gastritis as ‘useful for risk
stratification (grade of recommendation: strong; evidence level:
low; consensus level: 97.3%)’.
The adoption of gastritis staging for orienting patient
management was addressed more recently both in the
‘Guidelines for the management of H. pylori infection in Italy:
the III Working Group Consensus Report 2015’ and in the
subsequent ‘Maastricht V/Florence Consensus Report’. The
Italian document includes OLGA staging among the criteria
to consider when scheduling the follow-up of patients with
atrophic gastritis (i.e. no follow-up for patients with stage
0–I–II gastritis; endoscopy/biopsy follow-up for those with
stage III–IV gastritis) [30]. As for the ‘Maastricht V/Florence
Consensus Report’, statement no. 14 reads: ‘the selection of
patients for follow-up should be based on histological classi-
fication criteria (OLGA/OLGIM) [31]’.
Conclusion
Less than 30% of GC patients survive more than 3 years after
the disease has been diagnosed clinically. This unacceptable
mortality rate is because of the neoplastic dissemination that
has already occurred by the time the cancer becomes clinically
apparent.
More than 40 years ago, Pelayo Correa described the
natural history of gastric epithelial malignancies, also providing
the biological rationale for secondary prevention strategies. The
subsequently emerging evidence of H. pylori being responsible
for triggering the GC inflammatory–neoplastic cascade also
made a new primary cancer prevention scenario theoretically
possible.
Leaving aside the imperative of cleansing the world of
H. pylori infection (by improving lifestyles, and providing
anti-H. pylori vaccination, and anti-H. pylori therapies),
Table 2. Operative Link for Gastritis Assessment staging frame
Atrophy (any subtype) at the single biopsy level:
Mean percentage of atrophy as assessed in two specimens obtained from the oxyntic mucosa
Score 1 = 1–30%
Score 2 = 31–60%
Score 3 = > 60% Score 0 Score 1 Score 2 Score 3
Mean percentage of atrophy as assessed in three specimens obtained
from the antral mucosa (including the incisura angularis)
Score 0 0 I II II
Score 1 I II II III
Score 2 II II III IV
Score 3 III III IV IV
4 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00
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5. this review focused on the secondary prevention of GC. The
strategy basically requires a task force comprising a trio
of specialists (gastroenterologist, endoscopist, pathologist).
The endoscopists and pathologists are responsible for
assessing precancerous diseases, and play a fundamental
role in improving the present state of affairs. Sophisticated
digital endoscopy can now capture minute mucosal lesions
that were invisible 15 years ago. Pathologists are now asked
to deliver diagnostic messages (i.e. to stage cases of gastritis)
that can be used consistently to rank a given patient’s cancer
risk. Gastroenterologists are in charge of providing appropriate
anti-H. pylori therapies (where necessary) and establishing
patient-tailored follow-up protocols [32,33]. By combining
these complementary competences optimally, GC will become
(it already is!) a preventable disease.
Acknowledgements
This work was partly supported by grants from the Italian
Association for Cancer Research (AIRC regional grant
no. 6421 to MR).
Conflicts of interest
There are no conflicts of interest.
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OLGA staging for gastritis Mescoli et al. www.eurojgh.com 5
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