Gastric cancer (GC) remains a major health problem worldwide, with a poor 5-year survival
rate, partly due to its late diagnosis. Early detection can significantly increase
survival and, therefore, identification of patients with higher GC risk (e. g. premalignant
conditions) who may benefit from surveillance is essential for decreasing its mortality
[1]. Intestinal-type adenocarcinoma, the most frequent histological type, is preceded
by a cascade of precancerous lesions such as atrophic gastritis and gastric intestinal
metaplasia (IM). Thus, in the absence of screening strategies in European countries,
the MAPS II Guideline recommends opportunistic identification and follow-up of individuals
at high risk [1], namely those with advanced stages of atrophic gastritis.
Because the correlation between white light endoscopy (WLE) and histological findings
is poor and use of chromoendoscopy is cumbersome, two classifications of advanced
atrophic changes based on random biopsies have been proposed: Operative Link for Gastritis
Assessment (OLGA) and Operative Link on Gastritis/Intestinal Metaplasia (OLGIM). Some
reports have shown that IM is the most reliable marker for this purpose due to its
higher interobserver agreement, besides the lack of validated endoscopic pattern of
atrophic gastritis. Hence, OLGIM to OLGA is preferable, under European Society of
Gastrointestinal Endoscopy Guideline MAPS II, for staging gastritis [1]. However, to improve endoscopic diagnostic accuracy, different real-time techniques
using imaging-enhanced endoscopy (IEE) emerged. The major advantages are that they
are easy to employ and allow precise observation of the entire gastric mucosa and
microvascular pattern. Prior reports evaluated the diagnostic efficacy of these technologies,
most of them focusing on narrow-band imaging (NBI). A systematic review showed a pooled
sensitivity and specificity of NBI of 0.87 and 0.77, respectively, for IM diagnosis,
and 0.90 and 0.83 for dysplasia/cancer diagnosis [2]. More recently, our group reported excellent results in diagnostic yield of NBI
in addition to high resolution-WLE (HR-WLE), achieving a global accuracy superior
to 90 % in detection of IM and dysplasia [3].
In fact, the concept of random biopsies is now arguable with widespread use of virtual
chromoendoscopy (CE) which, at the touch of a button, has been shown to significantly
improve endoscopic-histological concordance. Due to the multifocal and patchy distribution
presented in most cases of IM, biopsy samples (which represent only a very small part
of the entire mucosa) are prone to sampling error, and for these reasons, it seems
more logical to rely on endoscopic assessment of the entire mucosa to stratify GC
risk instead of depending on random biopsies. But are CE-targeted-biopsies better
than Sydney-Houston random biopsies for mapping? Results from some reports suggest
that targeted biopsies are not inferior, but random biopsies may detect some cases
of IM that are not identified with only NBI [4]. However, this difference does not appear to have a significant clinical meaning
because most NBI missed areas will be mild and focal IM, so without necessity of surveillance
in most cases. In fact, Buxbaum et al analyzed the diagnostic yield of mapping (biopsies
according to the updated Sidney protocol) + WLE vs. NBI + WLE vs. NBI + mapping and
the best results were with NBI + mapping (100 % detection of patients with IM and
94.7 % of gastric locations of IM [4]).
Consequently, considering the diagnostic yield of random biopsies and the possibility
of missing important changes in the mucosa, this approach is being increasingly questioned
and the possibility of replacing random with targeted biopsies is being suggested
more and more. In this context, a new endoscopic classification of IM (Endoscopic
Grading of Gastric Intestinal Metaplasia [EGGIM classification]) was proposed by our
group, and recently validated in a multicenter study, showing a sensitivity of 89.4 %
for identifying extensive IM (OLGIM III/IV) if EGGIM > 4 and > 99 % accuracy for excluding
advance stages of gastritis if EGGIM 0 [5]. In fact, the MAPS II guideline recommends that whenever possible, virtual CE be
used to target biopsies instead of performing random biopsies [1]. It would be reasonable to use a combined approach in which WLE would be followed
by NBI examination, with exhaustive inspection of the mucosa and EGGIM calculation,
in addition to targeted biopsies from suspicious areas for neoplasia; and if no endoscopic
suspicion of IM, random biopsies can be performed (only) for Helicobacter pylori (Hp) diagnosis if applicable. This strategy would vary in accordance with different scenarios.
Focal changes with WLE
Independently of the stage of gastritis, focal gastric lesions may be found with WLE.
If some lesions always deserve biopsies (e. g. ulcers) most in fact will be benign
changes of the mucosa. In most cases, even though biopsies may still be needed, we
recommend always doing CE. With CE, we are able to evaluate mucosal and vascular patterns
and endoscopic diagnosis of benignity can be made with more certainty (e. g. fundic
glands polyps, papules with foveolar hyperplasia). Therefore, the decision to do biopsies
or not depends on the clinical scenario, but commonly at least, fewer biopsies will
be needed (while increasing our endoscopic diagnostic confidence).
Normal with WLE, absent IM with virtual CE (EGGIM 0)
Normal with WLE, absent IM with virtual CE (EGGIM 0)
It has been previously reported that in the absence of a typical pattern of IM by
NBI, the predictive negative value for extensive IM is excellent independent of prevalence
of IM [3]
[5]. In this context, we believe that random biopsies to confirm absence of preneoplastic
conditions could be spared unless testing for Hp status is indicated. (in that case, random biopsies according to Sydney System are
advised because Hp may be only in the antrum or only in the corpus, although in these cases, a single
vial for all the biopsy samples seems adequate). In fact, we have shown that in patients
with EGGIM 0, when sending antrum and corpus biopsies in the same vial, no cases of
advanced-stage gastritis would be missed without biopsies while only 5 % had OLGA
I/II and 2 % OLGIM I/II and in all cases, the pathologist was able to differentiate
antrum from corpus mucosa (Castro et al., under revision).
Normal/AG with WLE, focal/moderate IM with virtual CE (EGGIM 1 – 4)
Normal/AG with WLE, focal/moderate IM with virtual CE (EGGIM 1 – 4)
When a mucosal pattern B (IM in Pimentel-Nunes classification) is identified but restricted
to only one gastric compartment, NBI-targeted-biopsies of that area should be taken
in one vial and biopsies from the normal mucosa compartment in a separate vial (so
we can confirm the diagnosis and OLGIM stage and also test for Hp) ([Fig. 1]).
Fig. 1 NBI examples of EGGIM classification. a A patchy tubular mucosal pattern is identified in the context of atrophic changes.
This is a case of focal GIM affecting < 30 % on this area, which corresponds to EGGIM
1 (and probably a global EGGIM 1 – 4). b Extensive areas with tubular mucosal pattern without irregularity. This is a case
of GIM affecting > 30 % of mucosa on this area (therefore, EGGIM 2, and probably global
EGGIM ≥ 5).
Nevertheless, we have to acknowledge that these are the cases that we will miss more
endoscopically, by underestimating and mostly by overestimating gastritis (for instance,
foveolar hyperplasia can overestimate EGGIM because it can be confounded with IM,
and patients with severe atrophy without significant IM can be substaged). Thus, relying
solely on endoscopic staging in patients with focal/moderate IM is less reliable.
On the other hand, Hp infection does not seem to affect this endoscopic staging system although Hp status should be investigated because these patients probably will benefit most from
eradication [5]. In our personal experience, NBI-targeted biopsies from IM suspected areas will
probably be enough for detection of Hp status and no additional biopsy from normal area will be needed, because targeted
biopsy nearly always includes normal mucosa.
For example, if some focal tubular mucosa is seen only in the antrum/incisura (EGGIM
1 – 4a), targeted biopsies should be done of these areas (2 to 3 targeted-biopsies
in the same vial – antrum vial) and then two random biopsies from the corpus (corpus
vial) ([Fig. 2]).
Fig. 2 Proposed mapping biopsies protocol at initial examination and during follow-up. IM,
intestinal metaplasia; EGGIM, endoscopic grading of gastric intestinal metaplasia.
1 In case of Hp infection, eradication is recommended. 2 Family history of gastric cancer, incomplete IM, autoimmune gastritis, or persistent
Hp infection
With this approach, individuals who do not benefit from endoscopic surveillance will
be identified while at the same time, their Hp status is investigated. However, if additional risk factors are present (e. g. family
history of gastric cancer, incomplete IM, autoimmune gastritis, or persistent Hp infection), surveillance is recommended [1].
Extensive IM (EGGIM 5 – 10)
Extensive IM (EGGIM 5 – 10)
When a mucosal pattern B is extensively identified, the question of when and where
to do biopsies depends on the specific clinical scenario ([Fig. 1]).
For diagnosis (patient not previously known to have IM), NBI-targeted biopsies should
be taken in separate vials from each location (antrum/incisura and corpus) to identify
individuals at high risk. The exception could be in countries with IM prevalence > 25 %,
where EGGIM positive predictive value for extensive IM is ≥ 85 % and, therefore, in
theory biopsies could be avoided [5]. However, in our opinion, in most diagnostic cases, biopsies from the more representative
areas in the antrum and in the corpus should be taken in separate vials to also confirm
the histological diagnosis. Given the fact that Hp status should be investigated, and that metaplastic glands are frequently not colonized
by Hp, taking additional targeted-biopsies from normal areas (e. g. one from the antrum
and one from the body) could be considered. These patients do, however, benefit less
from Hp eradication, although some reports suggest that Hp eradication can halt progression) ([Fig. 2]).
However, for surveillance, we believe that biopsies are unnecessary in patients with
extensive IM but no irregular/pattern C/suspicious areas. Even though some authors
recommend extensive biopsies in patients under surveillance, in our opinion, most
of these biopsies will not alter management. We prefer careful endoscopic evaluation
of the entire mucosa, first with WLE and then with virtual CE, and only perform biopsies
if pattern C is identified/suspected. If a clear neoplastic lesion is detected, one
or two fragments should be taken from the most suspicious areas. If diminutive areas
of mucosa with a slightly irregular pattern are seen but with no clearly defined lesion,
targeted biopsies of these areas (labelled in separate vials) should be taken. In
most cases, these areas will only present IM, but some of them will have focal dysplasia
of the epithelium. These patients may benefit from a shorter-interval endoscopic surveillance
(in 6 to 12 months, depending if high- or low-grade dysplasia, respectively; [1]).
Conclusions
In our opinion, because virtual CE has been proven to optimize the benefit of biopsies,
with the proper endoscopic technology, biopsies can be avoided in some circumstances
(EGGIM 0 in the initial examination if no Hp status is needed, potentially if EGGIM ≥ 5 in countries with high IM prevalence,
and during surveillance of extensive IM). However, biopsy-based protocols are still
necessary in other situations, but we recommend changing the approach from random
to targeted biopsies whenever possible.
For these reasons, NBI-targeted-biopsies are advised in the following cases:
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To confirm low-risk individuals (EGGIM 1 – 4 without any other risk factors) who will
not benefit in most cases from endoscopic surveillance but who will benefit most from
Hp eradication;
-
For initial diagnosis of those at high risk (EGGIM ≥ 5);
-
And, of course, when a dysplastic area is suspected.
It is also important to note that the majority of CE studies were conducted in tertiary
centers with former CE experience. Thus, evaluation of diagnostic capability of IEE
in community settings is still lacking and IEE needs to be disseminated to better
identify patients with high risk of gastric cancer and improve their outcomes. Nevertheless,
we believe the focus should be on obtaining a better/high-quality examination with
an exhaustive evaluation of mucosal changes and attempt to make a real-time diagnosis,
rather than increasing biopsy samples, which sometimes are not representative nor
cost-effective. Indubitably, currently we cannot dispense with histological examination,
but perhaps in the near future with constant improvement in IEE, it may be possible
to restrict biopsies only to confirm dysplastic areas, optimizing performance of our
procedures as well as decreasing costs and improving our self-diagnostic yield as
endoscopists, which at the same time, could constitute a quality measurement for upper
gastrointestinal procedures. In conclusion, not always more biopsies mean better endoscopy!
