Introduction
Upper gastrointestinal endoscopy mainly detects neoplastic lesions in the pharynx,
esophagus, and stomach. However, conventional white light imaging (WLI) is disadvantageous
because it is likely to overlook early-stage lesions [1 ]
[2 ]
[3 ]. A new image processing technique, linked color imaging (LCI), was developed for
the LASEREO system using laser beams (Fujifilm Corporation, Tokyo, Japan). LCI is
an image-enhanced endoscopic observation method in which conventional white light
and short-wavelength narrowband light are applied simultaneously in an appropriately
balanced manner to emphasize slight color differences of the membrane by making reddish
colors appear redder and whitish colors whiter through simultaneous enhancement and
weakening of colors. Although the usefulness of LCI in the qualitative diagnosis of
upper gastrointestinal lesions has been reported [4 ]
[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ]
[11 ]
[12 ]
[13 ]
[14 ]. There has been no large-scale clinical trial focused on detection and diagnosis
of upper gastrointestinal lesions. We previously conducted a large-scale randomized
controlled clinical trial–the LCI-Further Improving Neoplasm Detection in upper gastrointestinal
(LCI-FIND) trial–and demonstrated the capability of LCI for detecting neoplastic lesions
in the upper gastrointestinal tract [15 ].
Endoscopes used for observation of the upper gastrointestinal tract are divided into
two types: ultraslim and standard with a relatively larger caliber. Whereas standard
endoscopes can only be inserted transorally, ultraslim endoscopes can be inserted
transorally and transnasally, causing less burden on the patient undergoing endoscopic
examination. However, because of the small caliber, ultraslim endoscopy has a risk
of producing lower-quality images and decreased operability compared with standard
endoscopy. There is, however, a recent report documenting that ultraslim endoscopy
is equivalent to standard endoscopy in terms of diagnostic capability.[16 ] The LCI-FIND trial used both ultraslim and standard endoscopic instruments. Hence,
we performed a sub-analysis using data from the LCI-FIND trial to examine whether
the ability of ultraslim endoscopy to detect neoplastic lesions is no-inferior to
that of standard endoscopy.
Patients and methods
Since the methods used in the LCI-FIND trial have been described in detail in a previous
report on the results of the primary endpoint [15 ], only an outline of the methods is shown here.
Patients
The subjects were patients aged 20 to 89 years who were scheduled for upper gastrointestinal
endoscopy in 19 major hospitals in Japan. All of them were known to have a history
or current diagnosis of gastrointestinal cancer (pharyngeal, esophageal, gastric,
or colorectal).
This study was performed after obtaining approval from the institutional review boards
of all participating institutions. This study is registered under the UMIN Clinical
Trial Registry (UMIN000023863). Written informed consent was obtained from all subjects.
This study received the provision of medical equipment and financial support from
Fujifilm Corporation, but an agreement was made that the company would not influence
the content and results of the study.
Methods
This study was conducted after patient recruitment as a post-hoc analysis of the LCI
study. The minimization method was used for the random assignment of the patients.
The following four stratification factors were used: facility, age (≥ 70 or < 70 years),
presence/absence of current cancer, and presence/absence of surgical history of gastric
or esophageal resection.
The endoscopic devices used included LASEREO, LASEREO 7000 system, and upper gastrointestinal
endoscopes (EG-L580NW, EG-L590WR, EG-L590ZW, EG-L600ZW, EG-L580NW7, EG-L600WR7, and
EG-L600ZW7) (Fujifilm Corporation, Tokyo, Japan). The choice of endoscopic equipment
was left to the free will of the endoscopists. In this study, patients in whom EG-L580NW
or EG-L580NW7 were used were in the group subjected to ultraslim endoscopy, and those
in whom other endoscopes with greater calibers were used were in the group subjected
to standard endoscopy.
The image resolution of endoscopy was evaluated by the United States Air Force (USAF)
resolution test chart ([Fig. 1 ]) on a monitor of the endoscopy system at distances of 50 mm and 70 mm between the
distal end of the endoscopy and the chart. Evaluated endoscopes were EG-L580NW7 categorized
as ultraslim-scope, EG-L590WR and EG-L600WR7 as standard-scope. EG-L580NW used in
this study has the same optical specification as L580NW7. Also, EG-L590ZW was the
same as EG-L590WR and EG-L600ZW7 were the same as EG-600WR7 in optical specification,
respectively. Image resolution was defined by the maximal resolvable lines per mm
of the USAF test chart. The results are shown in [Table 1 ]. The EG-L580NW7 and EG-L590WR had almost the same resolution and the EG-L600WR7
had higher resolution than two scopes.
Fig. 1 The images shown are a comparison of resolution chart at a 50-mm distance between
the scope and the resolution chart. The distinguishable lines are 1 to 2 for the ultraslim
endoscopy (left) and 1 to 3 for the normal-diameter endoscopy (right), which when
converted to resolution are 2.24 LP/mm and 2.52 LP/mm, respectively.
Table 1
Results of image resolution evaluation on the ultraslim-scope and the standard scopes
using the USAF test chart.
Endoscope
Resolution (lines/mm)
50 mm
70 mm
EG-L580NW7
2.24
1.41
EG-L590WR
2.52
1.59
EG-L600WR7
3.56
2.52
USAF, United States Air Force.
During the endoscopic procedure, each location was observed with WLI followed by LCI
(WLI group) or with LCI followed by WLI (LCI group). The number of detected lesions,
neoplastic/nonneoplastic, and the degree of endoscopist’s confidence (high/low) about
the malignant potential were recorded for each observation of each location. The degree
of endoscopist confidence was rated as high when the endoscopist judged the lesion
as being definitely cancer, whereas it was rated as low when the endoscopist judged
that the possibility of cancer was not deniable for the lesion. The time required
for observation of the esophagus and stomach was calculated from the recorded time
data on photographs taken at the beginning and end of the observation of each location.
Biopsy specimens were obtained from all diagnosed lesions. Neoplastic lesions were
defined as high-grade dysplasia and carcinoma of the pharynx, intraepithelial neoplasia
(IN), carcinomas of the esophagus, and adenoma and carcinoma of the stomach. Duodenal
lesions were not included in this study because of their low frequency.
Endpoints included the percentage of patients diagnosed with pharyngeal, esophageal,
or gastric neoplastic lesions observed by WLI and LCI in the primary mode; the percentages
of patients diagnosed with a neoplastic lesion observed by WLI and LCI in the primary
mode by location, size, morphology type, and degree of endoscopist confidence; and
neoplastic lesions detected by WLI and LCI in the secondary mode.
The presence of Helicobacter pylori infection was not assessed in this study.
Statistical analysis
Patients who underwent standard endoscopy and those who underwent ultraslim endoscopy
were analyzed separately. Since this was an exploratory study that used data after
the confirmatory analysis of the primary endpoint, the percentage and 95 % confidence
interval (CI) were calculated and presented for each item. The 95 % CI was calculated
by exact binomial distribution. As for relative risk, the crude risk ratio without
adjustment, odds ratio adjusted for age, presence/absence of current cancer, and presence/absence
of surgical history using a logistic model, and 95 % CI were calculated.
Results
A total of 1,508 patients were recruited between November 2016 and July 2018, and
1,504 patients who gave consent to the study were registered and randomized to the
WLI (753 patients) and the LCI groups (752 patients). The final population for evaluation
comprised 751 patients in the WLI group and 750 patients in the LCI group, excluding
two patients: one patient in the WLI group who underwent standard endoscopy because
of a large amount of residue and another patient in the LCI group who underwent standard
endoscopy because of stenosis caused by pharyngeal neoplasm ([Fig. 2 ]).
Fig. 2 Consort diagram.
Ultraslim endoscopes were used in 223 patients, and standard endoscopes were used
in 1,279 patients. Standard endoscopes were inserted transorally in all the 1,279
patients, whereas ultraslim endoscopes were inserted transorally in 44 (19.7 %) patients
and transnasally in the remaining patients. The number of examinations for each type
of endoscopy by medical facility are shown in [Table 2 ].
Table 2
Number of examinations for each type of endoscope by medical facility.
Facility
Ultraslim
endoscope
Standard
endoscope
Total
A
21
471
492
B
0
344
344
C
145
1
146
D
1
90
91
E
1
71
72
F
3
68
71
G
0
57
57
H
43
11
54
I
0
44
44
J
2
29
31
K
1
20
21
L
0
21
21
M
0
16
16
N
0
13
13
O
0
10
10
P
0
8
8
Q
6
0
6
R
0
4
4
S
0
1
1
Total
223
1279
1502
Baseline characteristics of the study subjects are shown in [Table 3 ]. Among the patients who underwent ultraslim endoscopy, the presence of current cancer
was slightly more frequent in the LCI group, and the history of radiation therapy
was slightly more frequent in the WLI group. Sedation was performed in 28 of 223 patients
(12.6 %) in the ultraslim group and 502 of 1279 patients (39.2 %) in the standard
group, with a significantly higher rate in the standard group (P < 0.001).
Table 3
Baseline characteristics of the study subjects.
Ultraslim endoscopy (N = 223)
Standard endoscopy (N = 1279)
WLI group
(N = 117)
LCI group
(N = 106)
WLI group
(N = 635)
LCI group
(N = 644)
Age
73 (66–77)
71 (67–76)
71 (66–77)
72 (66–77)
Age < 70 years
44 (37.6; 28.8–47.0)
40 (37.7; 28.5 –47.7)
255 (40.2; 36.3–44.1)
259 (40.2; 36.4–44.1)
Male
95 (81.2; 72.9–87.8)
86 (81.1; 72.4–88.1)
483 (76.1; 72.6–79.3)
496 (77.0; 73.6–80.2)
Surgical history
16 (13.7; 8.0–21.3)
13 (12.3; 6.7–20.1)
62 (9.8; 7.6–12.3)
72 (11.2; 8.9–13.9)
Current cancer
16 (13.7; 8.0–21.3)
19 (17.9; 11.2–26.6)
103 (16.2; 13.4–19.3)
102 (15.8; 13.1–18.9)
History of radiation therapy
32 (27.4; 19.5–36.4)
24 (22.6; 15.1–31.8)
56 (8.8; 6.7–11.3)
63 (9.8; 7.6–12.3)
Data are shown as medians (25 %–75 %) or numbers (percentage; 95 % confidence interval).
WLI, white-light imaging; LCI, linked color imaging.
Neoplastic lesions were detected in 48 of 530 patients (9.06%) in the sedation group
and 77 of 972 patients (7.92 %) in the non-sedation group, with a slight but not significant
difference in the sedation group (P = 0.447).
[Fig. 3 ] shows the LCI and WLI endoscopic images of representative cancer lesions in the
esophagus obtained by ultraslim endoscopy.
Fig. 3 Typical case of early esophageal cancer detected by ultraslim endoscopy with linked
color imaging. The white light imaging image on the left shows only a slight reddening
of the arrowhead area, whereas the linked color imaging on the right shows a well-defined,
reddish depression, which is recognizable as a depressed early-stage esophageal cancer
[Table 4 ] shows the numbers of neoplastic lesions and patients with neoplastic lesions detected
by ultraslim endoscopy or standard endoscopy with WLI and LCI in the primary and secondary
modes. The primary endpoint of the LCI-FIND trial was the percentage of patients diagnosed
with a neoplastic lesion using WLI or LCI in the primary mode. Among patients who
underwent ultraslim endoscopy, the corresponding percentage in primary mode was significantly
higher in LCI than in WLI group; the crude risk ratio was 2.21 (95 % CI: 1.06–4.67),
and the adjusted odds ratio was 2.46 (95 % CI: 1.07–5.63). In secondary mode, the
percentage of patients diagnosed with a neoplastic lesion tended to be lower in LCI;
the crude risk ratio was 0.28 (95 % CI: 0.04–2.45), and the adjusted odds ratio was
0.27 (95 % CI: 0.04–1.83). In contrast, among patients who underwent standard endoscopy,
the percentage of patients diagnosed with a neoplastic lesion in primary mode was
higher in LCI than in WLI; the crude risk ratio was 1.53 (95 % CI: 0.96–2.45), and
the adjusted odds ratio was 1.57 (95 % CI: 0.96–2.57), while the corresponding percentage
in secondary mode was significantly lower in the LCI group; the crude risk ratio was
0.18 (95% CI: 0.07–0.49), and the adjusted odds ratio was 0.17 (95% CI: 0.06–0.49).
Table 4
Patient-based results (primary results): neoplastic lesions detected using WLI and
LCI in primary and secondary modes.
Ultraslim endoscopy (N = 223)
Standard endoscopy (N = 1279)
WLI group
(N = 117)
LCI group
(N = 106)
Risk ratio
Adjusted odds ratio
WLI group
(N = 635)
LCI group
(N = 644)
Risk ratio
Adjusted odds ratio
Total
Patient
12
(10.3; 5.4–17.2)
19
(17.9; 11.2–26.6)
1.75
(0.90–3.42)
1.91
(0.89–4.10)
48
(7.6; 5.6–9.9)
46
(7.1; 5.3–9.4)
0.95
(0.64–1.39)
0.94
(0.62–1.43)
Lesion
14
21
–
–
49
50
–
–
Detected by primary mode
Detected by WLI
Detected by LCI
Detected by WLI
Detected by LCI
Patient
9
(7.7; 3.6–14.1)
18
(17.0; 10.4–25.5)
2.21
(1.06–4.67)
2.46
(1.07–5.63)
27
(4.3; 2.8–6.1)
42
(6.5; 4.7–8.7)
1.53
(0.96–2.45)
1.57
(0.96–2.57)
Lesion
10
20
–
–
27
46
–
–
Detected by secondary mode
Detected by LCI
Detected by WLI
Detected by LCI
Detected by WLI
Patient
4
(3.4; 0.9–8.5)
1
(0.9; 0.0–5.1)
0.28 (0.04–1.81)
0.27
(0.04–1.83)
22
(3.5; 2.2–5.2)
4
(0.6; 0.2–1.6)
0.18
(0.07–0.49)
0.17
(0.06–0.49)
Lesion
4
1
–
–
22
4
–
–
Data are shown as numbers (percentages; 95 % confidence interval), ratios (95 % confidence
interval), or numbers.
WLI, white-light imaging; LCI, linked color imaging
Odds ratios for the neoplastic lesions detected, obtained from a logistic regression
analysis, were adjusted according to age, presence or absence of current cancer, and
surgical history.
[Table 5 ] shows the number of neoplastic lesions detected in the primary mode according to
location, size, and morphological type of the lesion. Among patients who underwent
ultraslim endoscopy, the number of neoplastic lesions detected by LCI was greater
than that detected by WLI in all cases, except for pharyngeal lesions and lesions
measuring 11–20 mm, in which the number of lesions detected by WLI and LCI were comparable
and diffuse lesions in which the number of detected lesions by LCI was one-third of
that detected by WLI. In particular, the ability of LCI to detect esophageal lesions
and depressed lesions was suggested to be higher in ultraslim endoscopy than in standard
endoscopy.
Table 5
Lesion-based results (descriptive results): clinicopathological features of lesions,
including their number, detected in the WLI and LCI groups and endoscopic confidence
prediction using WLI and LCI (only the first endoscopic procedure in each group).
Ultraslim endoscopy
Standard endoscopy
Detected by WLI in the WLI group
(9 patients/10 lesions)
Detected by LCI in the LCI group
(18 patients/20 lesions)
Detected by WLI in the WLI group
(27 patients/27 lesions)
Detected by LCI in the LCI group
(42 patients/46 lesions)
Lesion location
Pharynx
2 (20.0)
2 (10.0)
0 (0)
5 (10.9)
SCC
2
2
0
5
Esophagus
6 (60.0)
13 (65.0)
4 (14.8)
5 (10.9)
SCC
6
11
4
5
IN
0
2
0
0
Stomach
2 (20.0)
5 (25.0)
23 (85.2)
36 (78.3)
Adenocarcinoma
2
4
20
34
Intestinal type
1
4
20
31
Diffuse type
1
0
0
3
Adenoma
0
1
3
2
Lesion size
≤ 10 mm
6 (60.0)
14 (70.0)
18 (66.7)
25 (54.3)
10 to ≤ 20 mm
4 (40.0)
4 (20.0)
7 (25.9)
17 (37.0)
> 20 mm
0 (0)
2 (10.0)
2 (7.4)
3 (6.5)
Median size (mm)
13 (7–16)
13 (9–25)
11 (7–17)
11 (8–19)
Lesion morphology
Unidentified or untreated
0 (0)
0 (0)
0 (0)
1 (2.2)
Mass
1 (10.0)
2 (10.0)
11 (40.7)
13 (28.3)
Diffuse infiltrative
6 (60.0)
2 (10.0)
3 (11.1)
9 (20.0)
Depressed
Total
3 (30.0)
16 (80.0)
13 (48.1)
24 (52.2)
Data are shown as numbers (percentages), numbers, or medians (25 %–75 %).
WLI, white-light imaging; LCI, linked color imaging; SCC, squamous cell carcinoma;
IN, intraepithelial neoplasia
[Table 6 ] shows the number of lesions biopsied for suspicion of tumor and the number of detected
tumors by location. Among patients examined by ultraslim endoscopy, the proportion
of detected tumors to all biopsied lesions was higher for LCI than for WLI. The superiority
of LCI was more prominent in these patients than in those examined by standard endoscopy.
Table 6
Proportion of detected tumors versus all lesions biopsied for the number of lesions
detected and tumors in the pharynx, esophagus, and stomach with WLI and LCI.
Ultraslim endoscopy
Standard endoscopy
WLI
LCI
WLI
LCI
Pharynx
2/5
(40.0; 5.3–85.3)
2/6
(33.3; 4.3–77.7)
0/1 (0)
5/11
(45.5; 16.8–76.6)
Esophagus
6/13
(46.2; 19.2–74.9)
13/22
(59.1; 36.4–79.3)
4/8
(50.0; 15.7–84.3)
5/17
(29.4; 10.3–56.0)
Stomach
2/13
(15.4; 1.9–45.5)
5/19
(26.3; 9.2–51.2)
23/81
(28.4; 18.9–39.5)
36/110
(32.7; 24.1–42.3)
Total
10/31
(32.3; 16.7–51.4)
20/47
(42.6; 28.3–57.8)
27/90
(30.0; 20.8–40.6)
46/138
(33.3; 25.5–41.9)
Data are shown as number of tumor lesions detected/number of lesions detected (percentage;
95 % confidence interval).
WLI, white-light imaging; LCI, linked color imaging.
Discussion
The previously reported LCI-FIND trial [15 ] demonstrated that LCI detected neoplastic lesions significantly better, by 1.67
times, than WLI. In this regard, the superiority of LCI to WLI in the diagnostic ability
when used in ultraslim endoscopy was examined in this study. The results showed that
the potential of ultraslim endoscopy with LCI was comparable to that of standard endoscopy
with LCI. In particular, the results suggested that ultraslim endoscopy would be superior
to standard endoscopy in detecting esophageal and depressed lesions. Based on these
findings, it seems that the results of the LCI-FIND trial can be extrapolated to examination
by ultraslim endoscopy. The use of ultraslim endoscopes should be further promoted
in screening and surveillance tests, considering the lower burden of this modality
on patients. As the results of this study show, the sedation rate was significantly
lower in the ultraslim endoscopy group than in the standard endoscopy group, and one
advantage of ultraslim endoscopy is that it avoids the need for sedation.
When observing the esophagus, the procedure time tended to be longer for ultraslim
endoscopy than for standard endoscopy. This may be because ultraslim endoscopy allows
closer observation of the esophagus owing to the small caliber of the endoscope, which
is unlikely to cause a vomiting reflex in patients. The reason for the higher detection
rate of neoplastic lesions with the Ultraslim endoscopy is not clear, but it may be
possible that there was a difference in detection rates between endoscopists who used
it primarily on a daily basis and those who had less experience using it.
The limitations of this study are as follows. This was not a confirmatory study, but
an exploratory study that was performed after completion of the main analysis. In
addition, the frequency of use of ultraslim endoscopes and standard endoscopes varied
greatly among medical facilities, and it is not deniable that the results of this
analysis were influenced by facilities or endoscopists associated with the heavy use
of ultraslim endoscopy. In this regard, an endoscopist in one facility used ultraslim
endoscopy most frequently, and there was the possibility that the data obtained from
this endoscopist had high influence on the overall results. However, the analysis
of data excluding those from this endoscopist showed the same tendency as that observed
in the present study (data not shown). Therefore, the results of this study were unlikely
to be affected by the characteristics of the practice of this endoscopist. Also, the
proportion of patients with previous surgical and radiotherapy was slightly higher
in the group with ultraslim endoscopy.
Thus, it was apparent that the detection rate of neoplastic lesions was about two-fold
higher with LCI than with WLI in ultraslim endoscopy of the upper gastrointestinal
tract. Based on this finding, use of ultraslim endoscopy with LCI should be encouraged
for screening tests and surveillance tests. The BLI mode is also useful in the diagnosis
of neoplastic lesions. It is recommended that screening observations are made in LCI,
and when a lesion is visible, close and detailed observations are made in BLI [17 ]
[18 ].
Conclusions
In conclusion, an exploratory analysis of data from the LCI-FIND trial showed that
LCI was very useful for identifying neoplastic lesions in the pharynx, esophagus,
and stomach, even when used in ultraslim endoscopy. Therefore, it is recommended that
ultraslim endoscopy with LCI be used for screening tests and surveillance tests of
the upper gastrointestinal tract.
