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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
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0954-691X Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001015 1
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2 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00
triggering the emergence of gastric CD4 + T-cells that Including a score of 0 (i.e. no atrophy), a four-tiered scale
cross-react with epitopes shared by gastric H/K ATPase and has been proposed, where a score of 1 = global atrophy
H. pylori proteins [12]. It is not known whether this affecting 1–30% of the biopsy sample; 2 = global atrophy
H. pylori-induced gastric autoimmunity is influenced by a affecting 31–60% of the biopsy sample; and 3 = global
given host’s immunological profile or by a peculiar biological atrophy affecting more than 60% of the biopsy sample. This
trait of the H. pylori strain involved, or both. It is also global score of all the (frequently coexisting) histological
unclear whether eradicating the H. pylori can also extinguish variants of mucosal atrophy enables a consistent assessment
the subordinate autoimmune disease and/or its putative of the level of atrophy in a biopsy set obtained from both
associated cancer risk. the antral mucosa (including the incisura angularis) and the
oxyntic mucosa (Fig. 3).
Atrophy: definition and histological phenotypes
Endoscopy and biopsy sampling for the histological
Gastric atrophy is defined as ‘loss of appropriate glands’ [13].
assessment of gastric mucosal atrophy
This definition includes two phenotypes of atrophic transfor-
mation (Table 1): (i) the disappearance of glandular units, The biological rationale behind any endoscopy protocol
replaced by fibrotic lamina propria (i.e. a reduced glandular for obtaining biopsies is based on the following well-
mass, but no change in the native glandular phenotype), or established conviction: ‘the greater the extent of atrophy,
(ii) the replacement of the native glands by metaplastic glands the higher the risk of GC’.
featuring a new commitment (this is called ‘metaplastic Generally, a gastrointestinal endoscopy procedure can
atrophy’) involving intestinal metaplasia (IM) and/or pseudo- never be considered ‘complete’ unless some biopsy samples
pyloric metaplasia (also known as spasmolytic polypeptide- are obtained (with the obvious exception of cases of
expressing metaplasia). The spasmolytic polypeptide-expressing bleeding). Different biopsy sampling protocols have been
metaplasia variant (only affecting the oxyntic mucosa) can be proposed, which rightly differ depending on the clinical
(more) easily assessed by exploiting its positive immunostaining setting and the main purpose of the endoscopy procedure
with TFF2 antibodies (Fig. 2) [14–19]. (clinical practice vs. clinical research). Both the oxyntic
Unlike nonmetaplastic atrophy, the metaplastic variant and the antral mucosa should be explored histologically
does not necessarily feature a reduction in the number of because of the potentially different diseases affecting the
glandular units. It is simply that the metaplastic replacement two compartments.
of the original glands ultimately results in a decreasing Apart from the procedures requiring extensive mucosal
number of ‘native’ glandular structures being ‘appropriate’ mapping (to seek endoscopically silent focal lesions)
for the compartment concerned. and those performed for clinical research purposes, the
In each biopsy sample, atrophic transformation can be biopsy sampling protocol suggested by the Sydney System
graded as a percentage of the atrophic transformation. should consistently satisfy most clinical diagnostic needs.
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
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OLGA staging for gastritis Mescoli et al. www.eurojgh.com 3
According to the Sydney System recommendations, two From a descriptive diagnostic approach to the staging-
biopsy samples should be obtained from the antral mucosa, frame of histology reporting
one from the so-called atrophic border (and specifically Our current understanding of the natural history of gas-
from the angularis incisura), and two from the oxyntic tritis and the established criteria for the histological
mucosa (the corpus/fundus area) [20]. The biopsy samples examination of atrophy together lay the foundations for a
should be submitted to the Pathology Department in two new framework for reporting gastritis histology. This new
separate vials: one containing the antral and angularis approach replaces the traditional, descriptive ‘Sydney
samples, and the other containing the oxyntic biopsies. The model’ with a histological report in terms of the stage and
angularis incisura has been considered a ‘sentinel’ site where the grade of gastritis [20]. Grading is used to determine the
atrophic modifications are assessable soonest. Sampling cumulative intensity of the inflammation, whereas staging
the angularis mucosa is time-consuming, however, and provides information on the topographical extent of the
many gastroenterologists would prefer to skip this sampling atrophic-metaplastic changes identified and their extent is
step. Additional samples should be obtained from any considered the main determinant of the gastritis-associated
focal lesions, including ulcers (especially in the proximal cancer risk.
stomach). 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.
Fig. 2. Tff2 immunostaining significantly increases the specificity in the his-
tology detection of pseudopyloric metaplasia [SPEM; Tff2 polyclonal anti-
Because IM scoring was judged more consistent than
body; Proteintech (Chicago, Illinois, USA); working dilution 1 : 180]. Biopsy atrophy scoring, an alternative staging system (OLGIM)
sample obtained from the oxyntic mucosa: pseudopylorized glands show was subsequently proposed, which only considers the IM
intense cytoplasmic immunoreaction. score [23]. More studies are needed to compare the two
B1
A1 A2 A3 B1 B2 ANTRUM BODY
B2
A3 21%= 5%=
CASE 1 20% 20% 25% 10% 0% I
A1 score 1 score 1
A2
42%= 5%=
VIAL 1: CASE 2 35% 40% 50% 0% 10% II
Samples A1-A2-A3
score 1 score 1
VIAL 2:
Samples B1-B2 67%= 5%=
CASE 3 50% 60% 90% 20% 50% III
score 3 score 1
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.
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4 European Journal of Gastroenterology & Hepatology Month 2017 • Volume 00 • Number 00
staging proposals, but both are consistent with the aim to management of gastritis patients, simply reported: ‘The
identify unequivocally as to which gastritis patients should gastritis OLGA staging conveys useful information on the
be placed under surveillance. potential clinicopathological outcome (including cancer
progression). The adoption of this system is therefore useful
‘Gastric serology’ in gastric cancer secondary prevention for patient management. According to OLGA staging and
strategies H. pylori status, patients with gastritis can be confidently
stratified and managed according to their cancer risk’ [28].
The invasiveness and cost of endoscopy and biopsy pro-
In February 2014, the Kyoto Global Consensus Conference
cedures limit their extensive use as part of GC secondary
unanimously recognized that the risk of developing GC par-
prevention strategies. Serological tests have therefore been
allels the extent and location of atrophy and IM, as assessed
proposed as a first-line (noninvasive) method for identi-
by gastritis staging. To be precise, according to statement no. 4
fying the patients with atrophic gastritis who warrant
(consensus level: 100%): ‘new staging systems for the char-
endoscopic investigation.
acterization of gastritis have been introduced to assess the GC
The serological assessment of gastric atrophy is based
risk. They are used in clinical practice and are either based on
largely on two main proenzymes produced by the gastric
the severity of atrophy in various gastric subsites (OLGA) or
mucosa, pepsinogen I (PgI) and pepsinogen II (PgII), and
on IM (OLGIM)’ [29]. The same document (statement no. 14)
on their ratio (PgI/PgII). Although PgII is produced by the
antral and corpus mucosa, PgI is produced almost exclu- qualifies the histological staging of gastritis as ‘useful for risk
sively by the oxyntic chief cells. This means that any stratification (grade of recommendation: strong; evidence level:
atrophy-induced loss of oxyntic glands results in lower PgI low; consensus level: 97.3%)’.
levels and a lower PgI/PgII ratio [24]. The adoption of gastritis staging for orienting patient
In the setting of H. pylori-related gastritis, a normal PgI/ management was addressed more recently both in the
PgII ratio virtually rules out any presence of gastric ‘Guidelines for the management of H. pylori infection in Italy:
mucosal atrophy (with a high negative predictive value), the III Working Group Consensus Report 2015’ and in the
enabling a patient to be confidently excluded from any subsequent ‘Maastricht V/Florence Consensus Report’. The
further invasive (endoscopic) diagnostic procedures. Italian document includes OLGA staging among the criteria
Patients with H. pylori infection and a low PgI/PgII ratio to consider when scheduling the follow-up of patients with
should be considered at a higher risk of GC and a second- atrophic gastritis (i.e. no follow-up for patients with stage
level diagnostic procedure(endoscopy and histological 0–I–II gastritis; endoscopy/biopsy follow-up for those with
examination) could be warranted. The cut-off for distin- stage III–IV gastritis) [30]. As for the ‘Maastricht V/Florence
guishing patients ‘at risk’ on serology may differ depend- Consensus Report’, statement no. 14 reads: ‘the selection of
ing on the population-related cancer risk. patients for follow-up should be based on histological classi-
fication criteria (OLGA/OLGIM) [31]’.
Gastritis staging in international guidelines
Conclusion
In 2002, an expert consensus statement suggested that
H. pylori eradication therapy can prevent GC [25]. A few Less than 30% of GC patients survive more than 3 years after
years later, the Asia-Pacific consensus guidelines recommended the disease has been diagnosed clinically. This unacceptable
an eradication strategy in countries with a high incidence of mortality rate is because of the neoplastic dissemination that
GC [26]. In 2012, an international consensus document on the has already occurred by the time the cancer becomes clinically
‘Management of precancerous conditions and lesions in the apparent.
stomach (MAPS)’ stated that: ‘Systems for histopathological More than 40 years ago, Pelayo Correa described the
staging… may be useful for identifying subgroups of patients natural history of gastric epithelial malignancies, also providing
with different risks of progression to gastric cancer (recom- the biological rationale for secondary prevention strategies. The
mendation grade C), namely those with extensive lesions subsequently emerging evidence of H. pylori being responsible
(i.e., atrophy and/or intestinal metaplasia in both antrum and for triggering the GC inflammatory–neoplastic cascade also
corpus)’. Gastritis staging was not mentioned, however, made a new primary cancer prevention scenario theoretically
among the crucial variables for distinguishing atrophic gastritis possible.
by different levels of cancer risk [27]. Leaving aside the imperative of cleansing the world of
In the same year, the ‘Maastricht IV/Florence Consensus H. pylori infection (by improving lifestyles, and providing
Report’, addressing the use of gastritis staging in the routine anti-H. pylori vaccination, and anti-H. pylori therapies),
Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
OLGA staging for gastritis Mescoli et al. www.eurojgh.com 5
this review focused on the secondary prevention of GC. The reevaluation of metaplasias and the origins of gastric cancer.
strategy basically requires a task force comprising a trio Gastroenterology 2010; 138:2207–2210.
15 Rugge M, Pennelli G, Pilozzi E, Fassan M, Ingravallo G, Russo VM, et al.
of specialists (gastroenterologist, endoscopist, pathologist).
Gruppo Italiano Patologi Apparato Digerente (GIPAD); Società Italiana di
The endoscopists and pathologists are responsible for Anatomia Patologica e Citopatologia Diagnostica/International Academy
assessing precancerous diseases, and play a fundamental of Pathology, Italian division (SIAPEC/IAP). Gastritis: the histology report.
role in improving the present state of affairs. Sophisticated Dig Liver Dis 2011; 43 (Suppl 4):S373–S384.
digital endoscopy can now capture minute mucosal lesions 16 Rugge M, de Boni M, Pennelli G, de Bona M, Giacomelli L, Fassan M,
et al. Gastritis OLGA-staging and gastric cancer risk: a twelve-year
that were invisible 15 years ago. Pathologists are now asked clinico-pathological follow-up study. Aliment Pharmacol Ther 2010;
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that can be used consistently to rank a given patient’s cancer 17 Rugge M, Correa P, Di Mario F, El-Omar E, Fiocca R, Geboes K, et al.
risk. Gastroenterologists are in charge of providing appropriate OLGA staging for gastritis: a tutorial. Dig Liver Dis 2008; 40:650–658.
18 Farinati F, Cardin R, Cassaro M, Bortolami M, Nitti D, Tieppo C, et al.
anti-H. pylori therapies (where necessary) and establishing
Helicobacter pylori, inflammation, oxidative damage and gastric cancer:
patient-tailored follow-up protocols [32,33]. By combining a morphological, biological and molecular pathway. Eur J Cancer Prev
these complementary competences optimally, GC will become 2008; 17:195–200.
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This work was partly supported by grants from the Italian Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996;
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22 Rugge M, Genta RM. OLGA Group. Staging gastritis: an international
Conflicts of interest proposal. Gastroenterology 2005; 129:1807–1808.
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There are no conflicts of interest. Bruno MJ, et al. The staging of gastritis with the OLGA system by using
intestinal metaplasia as an accurate alternative for atrophic gastritis.
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