Introduction
The gastric carcinogenic sequence involves subsequent changes inf the mucosa from
normal to chronic gastritis, atrophic gastritis (AG), intestinal metaplasia (IM),
dysplasia, and gastric cancer (GC) [1 ]. The development of IM is an important step in the precancerous cascade of gastric
adenocarcinoma, and it has been reported that patients with IM have a 10-fold increased
risk of GC [2 ]. Therefore, identification of gastric IM during esophagogastroduodenoscopy (EGD)
is very important to recognize high-risk individuals who may benefit from being enrolled
in surveillance for GC [3 ]. A light blue crest (LBC) is an endoscopic sign used to detect metaplasia. Although
IM can be observed using white light, its sensitivity and specificity is lower compared
to narrow band imaging (NBI).
IM appears during white light imaging as slightly elevated or flat whitish areas,
without contrast (color) with the surrounding mucosa, or as depressed reddish areas
of shallow depth. Conventional endoscopic identification of IM has a high rate of
interobserver variability and correlates poorly with histological findings.
Although the current standard for diagnosis for IM is histological assessment of a
biopsy specimen, high-quality image-enhanced endoscopy enables detection and characterization
of premalignant and malignant gastric lesions and determination of how far they extend
[4 ]. NBI with magnifying endoscopy (NBI-ME) visualizes a particular endoscopic sign
of IM, LBC, which is defined as a thin, blue-white line on the crest of the epithelial
surface, showing high diagnostic accuracy [5 ]
[6 ]
[7 ]
[8 ]: sensitivity of 90 % and specificity of 90 % [8]. Use of NBI increases sensitivity
of endoscopy for diagnosing IM compared to white light endoscopy (WLE) diagnosis (87 %
vs. 53 %, P < 0.001) [7 ].
The i-scan (Pentax Medical, HOYA Corporation, Tokyo, Japan) is a computerized digital
image processing system that improves the visibility of vessels, crypts, and surface
structures of the superficial mucosa [9 ]. The OE i-scan-Mode System (Pentax Medical) is a new, computerized, dynamic, digital
image processor that provides high-resolution enhanced images. i-SCAN combines high-resolution
endoscopy with three adjustable modes of image enhancement: 1) surface enhancement,
which delimits the edges of the structures; 2) CE, which shows the areas of low density
in color (depressed lesions), sharpening the appearance of the vessels and the texture
of the surface; and 3) TE, which modifies the colors of each pixel by accentuating
the mucosal (MS) and vascular (MV) pattern. As an example, this technology is reported
to be useful for improving detection of dysplasia in Barrett's esophagus with a high
diagnostic yield [10 ]. However, the usefulness of this system for diagnosing gastric IM has not been investigated.
Actual diagnostic criteria for IM are not pathognomonic, nor reproducible using WLE,
which may be the reason for the low rate of agreement among examiners. We suggest
that with NBI and i-scan, used in combination with histology, it is possible to detect
more cases. The aim of this study, therefore, was to evaluate the diagnostic yield
of the i-scan system with magnifying endoscopy for detection of gastric IM in clinical
practice.
Patients and methods
Study design and settings
This was a prospective cohort study conducted in a private endoscopic center in Mexico
City from July 2018 to September 2019. All patients received extensive information
about the objective of the study, including benefit of histological confirmation of
GC risk and potential increase of risk of bleeding associated with biopsy, and provided
consent for study participation. The study protocol was approved by the Ethics and
Research Committee of the Hospital Ángeles del Pedregal in Mexico City (HAP 2557).
Participants
Eligibility criteria were: 1) history of peptic ulcer; 2) symptoms of dyspepsia or
gastroesophageal reflux disease; 3) age over 18 years old; and 4) provision of written
informed consent for study participation. Exclusion criteria were: 1) poor performance
status; 2) bleeding tendency; 3) past history of gastrectomy or stenosis; 4) suspected
symptom or clinical information for perforation, intestinal obstruction, advanced
GC, gastrointestinal bleeding, or portal hypertension; and 5) dimethicone allergy.
Endoscopic equipment and procedure
A magnifying videoendoscope (Magniview EG-2990Zi HD, Pentax Medical) and an EPK-i7010
processor (Pentax Medical) that works in WLE and i-scan OE modes were used in this
study. We used Mode 2 Pentax Medical (similar NBI-Olympus) and i-scan 2 to detect
LBC sign. A distal attachment (OE-A58, Pentax Medical) was placed over the tip of
the gastroscope to maintain adequate distance to the mucosa during magnifying observation.
The EGD procedures were performed by two endoscopists separately, and two others (blinded)
evaluated the endoscopic images who had experience in NBI-ME diagnosis to determined
the presence of IM according to the LBC sign. An anesthesiologist administered intravenous
propofol sedation to the patients and monitored their vital signs continuously.
Following a systematic alphanumeric-coded endoscopic (SACE) method [11 ], gastric mucosa was systematically examined to detect any definite or suspicious
neoplastic lesions. Then, after thorough observation of the gastric mucosa, magnifying
endoscopic images of WLE and i-scan OE Mode 1 were captured at the two predetermined
biopsy sites (antrum and pyloric regions) ([Fig. 1 ], [Fig. 2 ]): the antral lesser and greater curvature (approximately 2–3 cm proximal to the
pylorus), the corpus lesser and greater curvature (approximately 4 cm proximal to
the gastric angle), and the incisura angulus [12 ]
[13 ]. Even though, biopsies were taken from five areas, only two sites were evaluated
(one in the antrum and one in the body) to determine the extent of IM. Immediately
after observation in each mode, the endoscopic findings were documented in the medical
notes and they could not be modified. Finally, biopsy specimens were taken from each
site. All procedures were recorded with a high-definition video recorder.
Fig. 1 Images coded by region and area (systematic alphanumeric-coded endoscopy) using i-scan
OE Mode 2 (pentax system). a Close-up of pyloric area (A6) and b lower curvature in distal body (L12).
Fig. 2 Images by i-scan coded by region and area (alphanumeric system) using OE i-scan mode
1 (pentax system). We observed a contrast color difference as shown by the white opaque
substance in a the pyloric area (A6), and b the greater curvature in distal body (L14).
Diagnostic criteria for IM in WLE and magnifying i-scan OE images
The diagnosis of IM in WLE was made according to presence of irregularly clustered
whitish mucosa, mucosa with a rough or uneven surface, a villous appearance, and patchy
redness [14 ]. The mucosa was diagnosed as IM when it had any of the above-mentioned endoscopic
findings, while it was diagnosed as non-IM when it had none of the findings.
The diagnosis of IM in magnifying i-scan OE images was made according to presence
of an endoscopic finding of LBC. LBC was defined as a fine, blue-white line on crests
of the epithelial surfaces/gyri [5 ]. It was initially described in NBI-ME images, but we confirmed that the same finding
is seen in magnifying i-scan OE images. When the mucosa showed LBC in any part of
the image fields, it was diagnosed as IM, while I fthere was no LBC in the endoscopic
image field, it was diagnosed as non-IM.
Each biopsy specimen was deposited in a separate pod that contained 10 % formaldehyde
and labeled. After fixation, the biopsy specimens were embedded into a paraffin block,
sectioned, and stained with hematoxylin and eosin (H & E) and Giemsa. In the case
of presence of IM, they were also stained with Alcian blue (pH 2.5) and periodic acid
Schiff (PAS) [15]. Diagnosis of complete and incomplete type IM was made according
to Updated Sydney System criteria [12 ]. Pathologists were blinded to clinical and endoscopic findings. Presence of histological
IM in the biopsy specimen was used as a reference standard for calculation of diagnostic
accuracy.
Grade of IM, and Helicobacter pylori was evaluated according to the updated Sydney system [12 ]. The Operative Link for Gastric Intestinal Metaplasia Assessment (OLGIM) was used
for staging of histological severity and topography of IM [16 ].
Measured outcomes and statistical analyses
Descriptive statistics were used out for frequencies and proportions. For comparisons
of demographic data, Pearson’s chi-square tests and Student's t tests were used for
categorical and continuous variables, respectively. The prevalence of IM was reported.
For evaluation of diagnostic yield, the sensitivity, specificity, positive predictive
values (PPVs), negative predictive values (NPVs), positive likelihood ratios (LR +),
and negative (LR –) and diagnostic accuracy of each endoscopic diagnostic method were
calculated. Differences in diagnostic yield between WLE and magnifying i-scan OE were
compared using MacNemar’s test. The interobserver kappa concordance test between endoscopists
was calculated. To measure internal consistency, we also calculated the Cronbach’s
alpha.
Results
A total of 328 patients were included in this study. Demographic characteristics are
shown in [Table 1 ]. IM was histologically detected in 111 individuals (30.1 %). For patients over 45
years old, IM was noted in 111 of 302 subjects (36.7 %). There were statistically
significant differences in mean age (P < 0.001), intake of proton pump inhibitors, tobacco (P < 0.0001), alcohol (P < 0.0001), nonsteroidal anti-inflammatory drugs (0.0005), family history of GC (P < 0.0005), and H. pylori infection (0.0001) between patients with IM and those without IM.
Table 1
Demographic characteristics of the study participants.
Variables
Total
Intestinal metaplasia
Absent
Present
P value
Age, mean years (SD)
53 (17)
61 (13)
< 0.001
Sex (men/women)
116/212
72/145
44/67
0.070
BMI mean (SD)
24.5 (0.4)
25.8 (0.4)
0.075
Cigarette smoking (% > 20/day)
39 (11.9)
25 (11.5 %)
14 (12.6 %)
0.00001
Drinking habit, n (%)
57 (17.3)
41 (18.9 %)
16 (14.4 %)
0.00001
Regular NSAID intake, n (%)
99 (30.1)
51 (23.5)
48 (43.2 %)
< 0.00001
Family history of GC in first-degree relatives
34 (10.3)
21 (9.6 %)
13 (11.7 %)
0.0005
H. pylori infection, n (%)
52 (15.8)
35 (16.1 %)
17 (15.3 %)
0.00001
Indication of EGD
118 (44.0 %)
68 (43.3 %)
50 (45.0 %)
0.014
72 (26.8 %)
40 (25.4 %)
30 (27.0 %)
0.072
58 (21.6 %)
36 (22.9 %)
22 (19.8 %)
0.014
18 (6.7 %)
12 (7.64 %)
6 (5.4 %)
0.962
2 (1.7 %),
1 (0.63 %)
3 (2.7 %)
0.080
BMI, body mass index; NSAID, bonsteroid antiinflammatory drug; GC, gastric cancer;
CI, confidence interval; SD, standard deviation.
Histological characteristics of IM patients are shown in [Table 2 ]. IM was more predominant in the antrum (106 patients, 95.4 %) than in the corpus
(45 patients, 40.5 %). According to the OLGIM staging system, patients were stratified
as stage I, II, III, and IV in 25 (7.62 %), nine (2.74 %), one (0.3 %), and one (0.3 %),
respectively. Only two of them (0.6 %) were classified as have high risk for GC.
Table 2
Histological characteristics of IM patients.
Intestinal metaplasia
N = 111
Prevalence
106 (95)
45 (41)
27 (24.3)
Subtype
4 (3.2)
107 (96)
Distribution
94 (85)
17 (15)
OLGIM stage
25 (22.5)
9 (8.1)
1 (0.9)
1 (0.9)
IM, intestinal metaplasia; OLGIM, Operative Link for Gastric Intestinal Metaplasia
Assessment.
Antrum and pyloric regions were observed using WLE ([Fig. 1 ]) and i-scan OE Mode 2 ([Fig. 2 ]) with magnification ([Fig. 3 ]). Sn, Sp, PPV, NPV, LR + , LR-, and diagnostic accuracy of both methods for histological
IM are shown in [Table 3 ]. The kappa concordance was calculated as 0.67. The reliability coefficient was calculated
as 0.7407.
Fig. 3 Close-up Mode 2 images of the antrum using OE Ii-scan mode (pentax system). a , b , c , A mucosal pattern with light blue crest sign is visible.
Table 3
Diagnostic accuracy for detecting the endoscopic sign of the light blue crest by combining
Magniview EG-2990Zi HD and i-scan OE mode.
Method
White light endoscopy
Magnifying i-scan OE
Sensitivity
50 (41–60)
96 (90–99)
Specificity
55 (48–62)
91 (86–94)
Positive predictive value
36 (31–42)
84 (78–89)
Negative predictive value
68 (63–73)
98 (94–99)
Positive likelihood ratio
1.12 (0.9–1.4)
10.4 (6.8–16)
Negative likelihood ratio
0.9 (0.7–1.1)
0.05 (0.02–0.12)
Diagnostic accuracy
53 (43–60)
93 (89–95)
Data are presented with percentage (95 % confidence interval). OE, optical enhancement.
Discussion
This prospective study provided evidence that magnifying i-scan OE imaging improved
diagnosis of GIM compared to only WLE diagnosis in Mexican patients.
H. pylori was classified as a definite carcinogen in 1994 [17 ]. However, it is known that H. pylori infection is a necessary but not sufficient causal factor for GC [18 ], and having only H. pylori infection does not increase GC risk substantially [19 ]. Persistent infection with H. pylori causes subsequent AG and IM in the gastric mucosa, which signify high risk of GC
[20 ]. In particular, the risk of GC increases significantly when IM is present in the
gastric mucosa [21 ]. We found the prevalence of IM in our study subjects was 33.8 %, but according to
the OLGIM staging system, only two of the study subjects (2 %) were classified as
high risk for GC. Accordingly, identification of IM and surveillance for patients
with IM enables detection of GC in an early stage [22 ] and would improve mortality from GC in our country.
In 1964, Takemoto described the presence of white-grayish elevations dispersed in
the antrum and the angularis incisura as a specific finding of IM [23 ]. Although this finding is highly specific (specificity of 98 %-100 %) for histological
IM, the sensitivity was quite low (6 %-13 %) [24 ] because IM exists in not only white-grayish elevated areas but also areas without
color difference, or in shallow, depressed, reddish areas [25 ]. Fukuta, et al. included several endoscopic findings of IM other than whitish slight
elevation and showed good diagnostic values: sensitivity of 86.1 % to 94.6 % and specificity
of 65.9 % to 69.1 % [14 ]. Although the same endoscopic findings were used for the diagnostic criteria of
WLE for IM in this study, the diagnostic ability of WLE (sensitivity of 50 % and specificity
of 55 %) was not as good as that in the previous Japanese study [14 ]. A recent online survey and imaging test indicated that the accuracy for endoscopic
diagnosis of IM was significantly higher among Japanese and Korean endoscopists compared
to the rest of the world [26 ], and it may be attributed to training and routine practice of endoscopic diagnosis
of IM in East Asian countries.
Usefulness of NBI for diagnosis of gastric IM was first reported in a Japanese study
with sensitivity of 89 % and specificity of 93 % [5 ]. An American study described sensitivity and specificity of 89 % and 93 %, respectively,
for detection of gastric IM with NBI endoscopy [27 ]. Our previous study demonstrated that non-magnifying NBI imaging had sensitivity,
specificity, PPV, NPV, and diagnostic accuracy for diagnosing gastric IM as 80%, 96 %,
84 %, 95 %, 93 %, and 87 %, respectively [12]. Moreover, we found that i-scan OE showed
good LR (LR + of 10.4 [95 %CI 6.8–16] and LR- of 0.05 [95 %CI 0.02–0.12]), which is
the ratio between the probability of observing an alteration in patients with disease
versus the probability of this result in healthy patients [28 ]. Values of LR greater than 10 have a higher probability of disease and close to
0 to rule it out. According to the meta-analysis, NBI has the pooled LR + of 8.98
(95 % CI 6.42–12.58) and LR- of 0.12 (95 % CI 0.09–0.16 [8 ]. Unlike sensitivity, specificity, and predictive values, LR incorporates both sensitivity
and specificity, and is not influenced by the prevalence of the disease [28]. The
use of LR enables an evaluation closer to reality because the combination of such
optical technology using band limited lights and digital image processing technology
is reported to yield improved diagnostic accuracy for not only gastric IM but also
other diseases in the upper gastrointestinal tract compared to WLE [29 ].
In this study, we focused on one representative endoscopic finding of gastric IM:
LBC. In normal gastric mucosa, the microsurface structure has been described as the
foveola type in the body and the groove type in the antrum [30 ]. MS structure of IM shows a groove type or villiform structures that mimics the
normal antral or intestinal mucosa. As in NBI, the LBC was observed on the edge of
the ridged or villiform MS of the gastric IM. Kanemitsu et al. reported that the sensitivity
and specificity of white opaque substance (WOS) for histologically diagnosed IM were
50.0 % (95 % IC 40.0 %–50.0 %) and 100.0 % (95 %CI 85.0 %–100.0 %), respectively [31 ]. In our study, the sensitivity and specificity of WOS to diagnose IM were poor (data
not shown). The different diagnostic values of MTB and WOS in this study may be a
result of differences in endoscopy systems and ethnic backgrounds of study subjects.
The white light anomalies reported as IM [14 ] have an area under the receiver operating curve between 0.55 to 0.8 in this paper,
different among each anomaly and different in the antrum and gastric body. We observed
that i-scan sensitivity and specificity do not differ between the antrum and corpus.
Using the diagnostic criteria, there were no differences in sensitivity or specificity.
Although the structural characteristics of the mucosa differ between the antrum and
the gastric body, the diagnostic criteria for IM are considered to be the same.
Finally, American Gastroenterological Association guidelines do not recommend routine
surveillance for GIM, and it should be reconsidered in patients with any potential
risk.
This study has some limitations. It was conducted by only two operators and both experienced
difficulties while trying to focus the mucosa, even using an endoscopic cap. Furthermore,
this study only used i-scan, and even though NBI and i-scan have similar diagnostic
accuracies for histological prediction, they are not identical [32 ]. A comparative study between NBI and i-scan could be very informative for validating
our findings across these two techniques, but such a study would require a larger
group of patients. Therefore, refinement of endoscopic technology and provision of
adequate training is necessary before this method can be widely used.
Conclusions
In conclusion, our study demonstrated that the accuracy of magnifying i-scan OE by
means of identification of the LBC sign was better than WLE for diagnosis of gastric
IM in a Mexican clinical practice.
