ORIGINAL ARTICLE: Clinical Endoscopy

Impact of submucosal saline solution injection for cold snare

polypectomy of small colorectal polyps: a randomized
controlled study
Yuichi Shimodate, MD,1 Junya Itakura, MD, PhD,2 Hiroshi Takayama, MD,1 Masayuki Ueno, MD,1
Rio Takezawa, MD,1 Naoyuki Nishimura, MD,1 Hirokazu Mouri, MD, PhD,1 Tomohiko Sunami, MD,1
Ryosuke Hirai, MD,1 Shumpei Yamamoto, MD,1 Muneaki Miyake, MD,1 Kazuhiro Matsueda, MD, PhD,1
Yoshiharu Yamamoto, BS,3 Motowo Mizuno, MD, PhD1

Okayama, Japan

Background and Aims: Cold snare polypectomy (CSP) of small colorectal polyps is widely used. However, the
technique is still troubled by insufficient resection depth, which may prevent precise pathologic evaluation. In this
study, we investigated whether submucosal injection of saline solution helps to achieve deeper resection in CSP.
Methods: The study was a single-center, prospective, randomized trial. Patients with small (3- to 10-mm diam-
eter) nonpedunculated adenomatous or sessile serrated colorectal polyps were randomly allocated to either con-
ventional CSP (C-CSP) or CSP with submucosal injection (CSP-SI). Primary outcome was the rate of complete
muscularis mucosae (MM) resection, defined by the proportion of MM under the tumor more than 80% of the
tumor’s horizontal dimension. Secondary outcomes were the rates of negative lateral and vertical margins, frag-
mentation of resected specimens, conversion to hot snare mucosal resection, intraprocedural bleeding, delayed
bleeding, and perforation.
Results: Two hundred fourteen patients were randomly assigned to the CSP-SI (n Z 107) or C-CSP (n Z 107)
group. The rate of complete MM resection was 43.9% in the CSP-SI group and 53.3% in the C-CSP group, a sta-
tistically insignificant difference. The rates of negative lateral margin and vertical margin (42.3% and 56.7%,
respectively) in the CSP-SI group were significantly lower than those (58% and 76%) in the C-CSP group (P Z
.03 and P Z .006, respectively). There was no polypectomy-related major bleeding or perforation.
Conclusions: Saline solution injection into the submucosa did not improve the resection depth of CSP of small
colorectal polyps, and the method resulted in lower rates of negative lateral and vertical margins of resected le-
sions. (Clinical trial registration number: UMIN000037980.) (Gastrointest Endosc 2020;92:715-22.)

Colorectal adenoma is a precursor lesion for colorectal snare polypectomy (CSP) of small colorectal polyps.
cancer,1 and colonoscopic removal of the tumors can Accordingly, the new European Society of Gastrointestinal
prevent death from the disease. Several reports, Endoscopy clinical guideline7 recommends CSP for
including ours,2-6 have demonstrated the safety of cold resection of diminutive polyps (
5 mm) and suggests

Abbreviations: CSP, cold snare polypectomy; C-CSP, conventional cold
snare polypectomy; CSP-SI, cold snare polypectomy with submucosal in-
jection; MM, muscularis mucosae.
DISCLOSURE: All authors disclosed no financial relationships.
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Copyright ª 2020 by the American Society for Gastrointestinal Endoscopy
0016-5107/$36.00
https://doi.org/10.1016/j.gie.2020.05.039
Received January 16, 2020. Accepted May 17, 2020.
Current affiliations: Department of Gastroenterology and Hepatology (1),
Department of Pathology (2), and Kurashiki Clinical Research Institute
(3), Kurashiki Central Hospital, Okayama, Japan.
Reprint requests: Yuichi Shimodate, MD, Department of Gastroenterology
and Hepatology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki,
Okayama 710-8602, Japan.

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Saline solution injection for deeper resection in CSP
CSP for 6- to 9-mm sessile polyps. We have reported cases
of CSP-resected polyps found to have advanced histology
and unclear vertical margins,8 indicating the possibility of
unexpected and incomplete removal of malignant polyps
with CSP. This mishap may occur despite careful
endoscopic observation before resection. It is reported
that 5.2% of colorectal polyps <10 mm in diameter had
advanced histology.9 Although up to 90% negative
predictive value with advanced imaging such as narrow-
band imaging has been established for diagnosis of invasive
cancer,10 small polyps with advanced histology can still be
unexpectedly removed by CSP. Thus, complete resection
of tumors that enables accurate histologic assessment is
essential to avoid local recurrence of tumor even in CSP
for small colorectal polyps.
We also reported that insufficient resection of muscula-
ris mucosae (MM) at CSP was associated with difficulty in
precise histopathologic evaluation of CSP-excised tissues.8
In a randomized controlled study from Europe,11 the rate
of histologic complete resection was 92.8% in cold snare
EMR with submucosal injection of normal saline solution
for nonpedunculated colorectal polyps of 6 to 10 mm
and was not inferior to that with hot snare EMR. Thus,
we hypothesized that submucosal injection of normal
saline solution would result in resection of submucosal
tissues and improve the rate of complete resection of
tumor tissues in CSP. In the present study, we
investigated the efficacy of CSP with submucosal saline
solution injection (CSP-SI) by comparing the rate of
submucosal resection with that of conventional CSP (C-
CSP).
METHODS
Study design
This study was a single-center, prospective, randomized
trial (allocation ratio, 1:1) to compare the efficacy and safety
between CSP-SI and C-CSP. The study was carried out at
Kurashiki Central Hospital according to the Consolidated
Standards of Reporting Trials (CONSORT) guideline, and
the study protocol was approved by the institutional review
board of the hospital (October 25, 2017). The study was
registered with UMIN Clinical Trials Registry (www.umin.
ac.jp/ctr/index/htm; UMIN000037980) on October 27, 2017.
Eligibility criteria for participants
The study included patients who had undergone colo-
noscopy mostly for screening within 5 years before the
study period and had been found to have 1 nonpeduncu-
lated colorectal polyp with endoscopic diagnosis of ade-
noma or sessile serrated adenoma/polyp of 3 to 10 mm
in diameter. Polyps had not been removed at that
time, a common practice in Japan before the use of
CSP. When they visited our hospital for scheduling of
endoscopic removal of their polyps (the targeted
716 GASTROINTESTINAL ENDOSCOPY Volume 92, No. 3 : 2020
Shimodate et al
polyps), the study protocol was explained to them.
Then, written informed consent for colonoscopy, poly-
pectomy, and participation in this study was obtained,
and the patients were randomly allocated to either
CSP-SI or C-CSP. Exclusion criteria were pregnancy, his-
tory of inflammatory bowel disease or familial polyposis,
bleeding tendency (platelet count <80,000/mL, prothrom-
bin percentage activity <40%, or international normal-
ized ratio of prothrombin time (PT-INR) >3.0 in
patients taking warfarin), multiple antithrombotic ther-
apy, or lesions suspected as advanced neoplasia at colo-
noscopy before this study.
Interventions
Colonoscope model PCF-Q260AZI or PCF-H290ZI
(Olympus Medical Systems, Tokyo, Japan) was used in all
patients. For bowel preparation, 2 L polyethylene glycol
with ascorbic acid (Moviprep; Ajinomoto Pharmaceutical
Co, Tokyo, Japan) was used. A transparent or short hood
was attached to the tip of the colonoscope. Carbon dioxide
insufflation was used during the procedure. When targeted
polyps were detected, real-time endoscopic magnifying
narrow-band imaging and magnifying chromoendoscopy
(when needed) were performed to determine again the
possible presence of advanced neoplasia.
For the diagnosis of advanced neoplasia with deep sub-
mucosal invasion, the criteria of the Japan NBI Expert
Team classification (types 2B and 3, for which the negative
predictive value for deep submucosal invasion was re-
ported at over 90%)10 or Kudo’s pit pattern classification
(VI and VN pit)12 was used. When such polyps were
detected, they were treated by hot snare EMR and
classified into invalidated polys for per-protocol analysis.
The size of polyps was re-estimated by comparing them
with the diameter of the snare catheter or of an opened
snare placed along the polyps.
All lesions were removed by CSP, ensnaring about 1 to
2 mm of the normal mucosa around the base of the polyp
with a dedicated cold polypectomy snare (Exacto cold
snare [U.S. Endoscopy, Mentor, Ohio, USA] or SnareMaster
plus [Olympus Medical Systems]; SnareMaster plus was
used for most polyps). In CSP-SI patients, normal saline so-
lution mixed with indigo carmine (.04%) and epinephrine
(1:10,000) was injected just before CSP was performed.
Excised polyps were retrieved by suctioning through the
colonoscope’s biopsy channel into a polyp trap. Endoscop-
ists confirmed the retrieved specimens and classified them
as “unfragmented” or “fragmented.” All unfragmented and
retrieved specimens were stretched and mounted onto
plates with pins. Endoscopic hemostasis was performed if
spurting or massive oozing that continued for more than
30 seconds occurred.
All patients taking antiplatelet or anticoagulant drugs
underwent cold polypectomy without cessation of the
medication. In cases where lesion(s) other than the
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Shimodate et al
Figure 1. Definition of complete muscularis mucosae (MM) resection.
Resection was defined as complete when MM was present under the tu-
mor along more than 80% of its horizontal axis, ie, (b þ c þ d)/a  .8.
targeted lesion was found accidentally at colonoscopy in
this study, CSP or hot snare EMR was performed for these
polyps; these lesions were not included in the analysis of
the outcomes except for adverse events. Patients were
permitted to go home after an hour of rest in the hospital.
Two weeks after polypectomy, patients visited our outpa-
tient clinic, where they were informed of the histopatholo-
gy of their resected lesions and were interviewed about
postpolypectomy adverse events.
Outcomes
The primary outcome was the rate of complete resec-
tion of the MM. MM resection was considered completely
arbitrarily when MM was present under the tumor along
more than 80% of the tumor’s horizontal dimension
(Fig. 1).8 Because the definition of complete MM
resection was not established in previous studies,8,13 we
performed additional sensitivity analysis with various
definitions of complete MM resection, according to the
following proportion of MM under the tumor along the
tumor’s horizontal dimension: 95%, 80%, and 60%.
Fragmented polyps at retrieval and polyps resected
with hot snare EMR because of difficulty of resection
with CSP were classified into incomplete MM resection.
Fragmentation was defined as fragmentation of resected
specimens at retrieval to the degree in which retrieved
pieces could not be reconstructed for pathologic
evaluation; specimens that were fragmented into 2 or 3
pieces at retrieval but were easily reconstructed were not
categorized into the fragmentation.
Secondary outcomes were the rates of conversion to
hot snare EMR because of difficulty of CSP resection, en
bloc resection, fragmentation of specimens at retrieval, his-
tologically evaluated resection of the submucosal layer, his-
tologically evaluated negative lateral and vertical margins
for neoplasia, and any adverse events related to the pro-
cedure. For adverse events, intraprocedural bleeding was
defined as spurting or oozing that continued more than
30 seconds. Major delayed bleeding was defined as hema-
tochezia requiring emergent endoscopic hemostasis within
2 weeks after the procedure. Emergent endoscopy was
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Saline solution injection for deeper resection in CSP
performed for hematochezia that recurred at least twice,
hematochezia with unstable vital signs (blood
pressure <100 mm Hg or heart rate >90 beats/min), or
hematochezia with a more than 2-g/dL decrease of hemo-
globin. Pathologic diagnosis was made in accordance with
the Japanese classification of colorectal carcinomas.14
Sample size calculation
Reported rates of complete MM resection with C-CSP
were 72% to 73%,8,13 and in our pilot study with the
CSP-SI technique it was 87.8% (all lesions were removed
by Y.S.; unpublished observation). Thus, we hypothesized
that CSP-SI would achieve a 16% increase (88%) in the
complete MM resection rate over that of C-CSP (72%).
The sample size was based on detecting a difference in
proportions at the 5% level of significance with a power
of 80% for the rate of complete MM resection; therefore,
at least 97 patients were required in each group. Consid-
ering 10% of invalidated cases, 107 patients in each group
and a total of 214 patients were required. The sample size
was calculated with Power and Sample Size Calculation
version 3.1.2, 2014 (PS; Department of Biostatistics, Van-
derbilt School of Medicine, Nashville, Tennessee, USA).
Randomization and allocation
Randomization of participants was carried out with a
simple randomization prepared by Excel 2010 (Microsoft
Corporation, Redmond, Wash, USA) by the independent
statistician (Y.Y.). Participants were allocated with the
envelop method (allocation ratio was 1:1) to C-CSP or
CSP-SI groups. All retrieved specimens were evaluated his-
topathologically in a blinded manner by a board-
certificated pathologist (J.I.) who had no clinical informa-
tion of the lesions, but endoscopists and patients were
not blinded to the CSP procedures because they were al-
lowed to see the endoscopy monitor during the
procedure.
Statistical analysis
The primary outcome was evaluated with intention-to-
treat analysis and per-protocol analysis. For secondary out-
comes, adverse events were analyzed with intention-to-
treat analysis, and the other outcomes were evaluated
with per-protocol analysis. Excluded cases for per-
protocol analysis were poor bowel preparation, polyps
not detected, polyps with endoscopically diagnosed
advanced neoplasia, polyps not retrieved, polyps diag-
nosed as normal colonic mucosa pathologically, and devia-
tion from the allocated procedure.
Data are presented as mean  standard deviation. Cat-
egorical variables were compared with the Fisher exact
test. The Student t test or Mann-Whitney U test was used
to compare continuous variables where appropriate. As
an ancillary analysis, we performed multivariate logistic
regression analysis to identify predictive factors associated
with incomplete MM resection. For the statistical analysis,
Volume 92, No. 3 : 2020 GASTROINTESTINAL ENDOSCOPY 717
Saline solution injection for deeper resection in CSP
214 patients enrolled
107 patients randomized
to CSP-SI group
5 not detected
2 not retrieved
1 protocol violation*
2 normal mucosae
Per-protocol analysis
N=97
Figure 2. Flow diagram of patient enrollment. *One lesion in the cold snare polypectomy with submucosal injection (CSP-SI) group was removed with
conventional cold snare polypectomy (C-CSP) because of the endoscopist’s mistake, and 1 lesion in the C-CSP group was removed with CSP-SI because of
the endoscopist’s decision.
we used EZR (Saitama Medical Center, Jichi Medical Uni-
versity, Saitama, Japan), which is a graphic user interface
for R (The R Foundation for Statistical Computing, Vienna,
Austria).
RESULTS
Participants flow
The flow of participants is illustrated in Figure 2. From
November 2017 to September 2019, we enrolled 214
patients and randomly assigned them to the CSP-SI group
(n Z 107) or the C-CSP group (n Z 107). Five lesions in
the CSP-SI group and 1 lesion in the C-CSP group were
not identified during colonoscopy. In the remaining 208
patients, the targeted polyps were found, and CSP was per-
formed (102 patients in the CSP-SI group and 106 in the C-
CSP group). Two lesions in the CSP-SI group and 1 lesion
in the C-CSP group could not be retrieved. One lesion in
the CSP-SI group was removed with C-CSP because of
the endoscopist’s mistake, and 1 lesion in the C-CSP group
was removed with CSP-SI by the endoscopist’s decision,
which was a protocol violation. Two lesions in CSP-SI
group and 4 lesions in C-CSP group were diagnosed path-
ologically as normal colonic mucosae. No case was
excluded because of poor bowel preparation or polyp
with endoscopic diagnosis of advanced neoplasia. The re-
maining 197 targeted lesions (100 lesions in the C-CSP
group and 97 lesions in the CSP-SI group) were analyzed
by per-protocol analysis. In the intention-to-treat analysis
for the primary outcome, all excluded polyps were catego-
rized as incomplete MM resection.
718 GASTROINTESTINAL ENDOSCOPY Volume 92, No. 3 : 2020
Shimodate et al
107 patients randomized
to C-CSP group
1 not detected
1 not retrieved
1 protocol violation
4 normal mucosae
Per-protocol analysis
N=100
Baseline characteristics of participants and
polyps
Baseline characteristics of patients and targeted lesions
were similar in the C-CSP group and the CSP-SI group
(Table 1). Most lesions were present in the ascending
colon or sigmoid colon. Median polyp size was 5 mm in
both groups. Fifty-three patients (49.5%) in the C-CSP
group and 37 patients (34.6%) in the CSP-SI group had pol-
ypectomy for accidentally detected polyps other than the
targeted lesion (P Z .04; median number of resected le-
sions was 1). Characteristics of the targeted lesions for
per-protocol analysis were also similar between the groups
(Table 2). Most lesions were resected with SnareMaster
plus. One intramucosal carcinoma (well-differentiated
adenocarcinoma) was resected in a CSP-SI patient.
Outcomes
Complete MM resection, the primary outcome, was
achieved in 47 lesions (43.9%) in the CSP-SI group and in 57
lesions (53.3%) in the C-CSP group, a statistically insignificant
difference (P Z .22) (intention-to-treat analysis, Table 3). In
the per-protocol analysis, there was also no significant differ-
ence, with a complete MM resection rate of 48.5% in the CSP-
SI group and 57% in the C-CSP group (P Z .26). In the addi-
tional sensitivity analysis with various definitions of complete
MM resection, there was no significant difference between
the 2 groups (Table 3, Supplementary Table 1, available
online at www.giejournal.org).
A summary of the secondary outcomes is presented in
Table 4. C-CSP was converted to hot snare EMR in 2
lesions because of difficulty of resection. All lesions were
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Shimodate et al Saline solution injection for deeper resection in CSP

TABLE 1. Baseline characteristics of participants and polyps

Cold snare polypectomy with Conventional cold snare

submucosal injection (n [ 107) polypectomy (n [ 107) P value

Endoscopist, nonexpert 54 (50.5) 52 (48.6) .89

Median age, y 68 65 .57
Sex, male 60 (56.1) 61 (57) 1
Antithrombotic drug 10 (9.3) 16 (15) .3
Cardiovascular disease 9 (8.4) 16 (15) .2
Stroke 4 (3.7) 6 (5.6) .75
Diabetes mellitus 9 (8.4) 5 (4.7) .41
Liver cirrhosis 1 (.9) 0 1
Renal failure 1 (.9) 0 1
Polyp location*
Cecum 7 (6.5) 6 (5.6) .77
Ascending 25 (23.4) 27 (25.2)
Transverse 23 (21.5) 15 (14)
Descending 13 (12.1) 15 (14)
Sigmoid 30 (28) 36 (33.6)
Rectum 9 (8.4) 8 (7.5)
Morphology, protruded 76 (71) 64 (59.8) .11
Median polyp size, mm 5 5 .33
Additional EMR for other polypsy 37 (36.3) 53 (50) .04
Median no. of other polyps 1 1 .79
Values are n (%) unless otherwise defined. Nonexpert endoscopists had experienced fewer than 1000 screening colonoscopies.
*Accidentally detected polyps other than the targeted lesion were included.
yEndoscopic resection of accidentally detected polyps other than the targeted lesion.

resected en bloc. Six lesions (6.2%) in the CSP-SI group
and 4 lesions (4%) in the C-CSP group were fragmented
during retrieval, an insignificant difference in the rates of
fragmentation. Resection of lesions with submucosal tissue
was observed histologically in only 17 lesions (17.5%) in
the CSP-SI group and 23 lesions (23%) in the C-CSP group;
among those lesions, the median resection depth of the
submucosal layer was 200 mm in both groups. The rates
of histologically evaluated negative lateral or vertical mar-
gins for neoplasia were 42.3% and 56.7%, respectively, in
the CSP-SI group and 58% and 76%, respectively, in the
C-CSP group; polyps removed by hot snare EMR because
of difficulty of CSP resection and fragmented polyps at
retrieval were classified into not negative lateral and verti-
cal margins. The rates of negative lateral margin and verti-
cal margin were significantly lower in the CSP-SI group
than in the C-CSP group (P Z .03 and P Z .006, respec-
tively). In contrast, there was no polyp with histologically
evaluated positive lateral or vertical margins in either the
CSP-SI or C-CSP group, implicating that destruction of tis-
sue margins caused such rates of negative margins and that
remnant of neoplasia was unlikely.
In this study, there was no perforation or intraproce-
dural bleeding. Major delayed bleeding, because of diver-
ticular hemorrhage, occurred in 1 patient in the C-CSP
group, who was on antithrombotic therapy with a thieno-
pyridine derivative, 18 days after polypectomy. Minor de-
layed bleeding occurred in 4 patients (3.7%) in the CSP-
SI group and 3 patients (2.8%) in the C-CSP group, all of
which spontaneously ceased without intervention.
Ancillary analysis
No significant predictive factors associated with an
incomplete MM resection was identified by multivariate lo-
gistic regression analysis (Supplementary Table 2, available
online at www.giejournal.org).
DISCUSSION
In this prospective randomized study, submucosal injec-
tion with indigo carmine, epinephrine, and normal saline
solution did not increase the rate of complete MM resec-
tion. The rates of histologically negative lateral and vertical
margins were lower in the CSP-SI group than in the C-CSP
group. We had expected that submucosal injection would
improve the quality of CSP-resected specimens for patho-
logic evaluation, but it did not.
We have no convincing explanation for the negative
impact of submucosal injection in CSP. Elevation of

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Saline solution injection for deeper resection in CSP Shimodate et al

TABLE 2. Characteristics of the targeted polyps in per-protocol analysis

Cold snare polypectomy with Conventional cold snare

submucosal injection (n [ 97) polypectomy (n [ 100) P value

Endoscopist, nonexpert 49 (50.5) 48 (48) .78

Snares, SnareMaster plus 94 (97) 95 (95) .72
Median polyp size, mm 5 5 .19
Location
Cecum 4 (4.1) 5 (5) .9
Ascending 23 (23.7) 24 (24)
Transverse 23 (23.7) 15 (15)
Descending 10 (10.3) 14 (14)
Sigmoid 30 (30.9) 34 (34)
Rectum 7 (7.2) 8 (8)
Morphology, protruded sessile (Is) 67 (69.1) 59 (59) .18
Pathologic diagnosis
Low-grade adenoma 92 (94.8) 95 (95) .91
High-grade adenoma 0 1 (1)%
Well-differentiated adenocarcinoma 1 (1.0) 0
Inflammatory polyp 1 (1.0) 2 (2)
Hyperplastic polyp 1 (1.0) 1 (1)
Sessile serrated adenoma/polyp 2 (2.1) 1 (1)
Values are n (%) unless otherwise defined. Nonexpert endoscopists had experienced fewer than 1000 screening colonoscopies.

TABLE 3. Primary outcome: complete MM resection rate

Cold snare Conventional cold snare

polypectomy with polypectomy P
submucosal injection with submucosal injection) value

Complete MM resection (
80%)

Intention-to-treat analysis (n Z 107) (n Z 107)
47 (43.9) 57 (53.3) .22
Per-protocol analysis (n Z 97) (n Z 100)
47 (48.5) 57 (57) .26
MM resection at various definitions(intention-to-treat analysis)
<60% 32 (30) 26 (24.3) .44

60% and <80% 12 (11.2) 11 (10.3) 1

80% and <95% 21 (19.6) 17 (15.9) .59

95% 26 (24.3) 40 (37.4) .54
Values are n (%).
MM, Muscularis mucosae.

lesions by the injection allowed the snare to more easily
grasp lesions, but the CSP snare without electrocautery
could have slipped over the elevated stiff MM layer. Su-
zuki et al15 reported that the submucosal layer was
obtained more often with hot snare polypectomy than
with CSP (81% vs 24%). Ito et al16 reported that the
resection depth from the MM in CSP versus hot snare
EMR was 76 mm versus 338 mm and that resection of
the submucosa was achieved in 9% versus 92%,
respectively. Recently, the efficacy of underwater CSP
for resection of small colorectal adenomas has been
reported.17 In that method, significantly higher rates of
R0 resection and the proportion of area containing MM
were achieved than with C-CSP, suggesting that
underwater CSP may be better than CSP-SI for complete
MM resection. Strategies other than submucosal injection,

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Shimodate et al
TABLE 4. Secondary outcomes
Cold snare polypectomy with
submucosal injection (n [ 97)
Secondary outcomes: per-protocol analysis
Conversion to hot snare EMR
Evaluation of specimen
En bloc resection
Fragmentation*
Resection of submucosal layer
Median resection depth of
submucosal layer, mm
Negative lateral marginy
Negative vertical margin
Adverse events: intention-to-treat analysis
Perforation
Intraprocedural bleeding
Major delayed bleeding
Minor delayed bleeding
Values are n (%) unless otherwise defined.
*Fragmentation was defined as fragmentation of resected specimens at retrieval to the degree in which retrieved pieces could not be reconstructed for pathologic evaluation;
specimens that were fragmented into 2 or 3 pieces at retrieval but were easily reconstructed were not categorized into fragmentation.
yHistologically evaluated margins. There was no polyp with histologically positive lateral or vertical margins.
such as underwater CSP, may be needed to improve the
quality of CSP resection.
The finding that the rates of histologically negative
lateral and vertical margins were lower in the CSP-SI group
than in the C-CSP group was unexpected and is concern-
ing. If injection increases the likelihood of leaving adeno-
matous tissue, it may result in increased recurrence of
polyps and, in the rare circumstance of a small polyp being
an adenocarcinoma, leaving residual malignant tissue. The
reason for the difference between CSP-SI and C-CSP in
rates of lateral and vertical margin negativity is not clear
to us, but it is further reason to be skeptical of the ade-
quacy of CSP-SI.
Fragmentation of the resected specimens is another fac-
tor associated with insufficient pathologic evaluation.8 We
suspected that saline solution injection might reduce the
rate of fragmentation, already low (about 4%) without
injection, but it did not. Barge et al18 reported that polyp
fragmentation occurred at retrieval with suction through
the suction valve button, a narrow channel in the button
is suspected to damages the tissues. To avoid fragmentation,
we have to devise a way to retrieve CSP-resected specimens
without going through the suction valve button.
In this study, there was no polypectomy-related major
bleeding in either the CSP-SI or C-CSP groups, even
though nonexperts performed many of the procedures
and patients taking anticoagulants or antiplatelet therapy
underwent polypectomy without cessation of these drugs.
Thus, CSP, with or without saline solution injection, ap-
pears to a safe procedure, as reported by others.2-6
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Saline solution injection for deeper resection in CSP
Conventional cold snare
polypectomy (n [ 100) P value
0 (0) 2 (2) .5
97 (100) 100 (100) 1
6 (6.2) 4 (4) .5
17 (17.5) 23 (23) .38
200 200
41 (42.3) 58 (58) .03
55 (56.7) 76 (76) .006
(n Z 107) (n Z 107)
0 0
0 0
0 1 (.9) 1
4 (3.7) 3 (2.8) 1
There are several limitations of our study. First, this is a
single-center, open-label study. Although histologic evalua-
tion of specimens was performed in blinded manner, pa-
tients and endoscopists knew the treatment methods.
Second, safety of CSP-SI may not be conclusively shown
because of the small sample size. Third, epinephrine
used for submucosal injection in the CSP-SI group might
have played a role in the outcomes, but the issue was
not addressed in this study. Fourth, resection depth of
the submucosal layer was the same in both groups; no
advantage of an additional submucosal injection was
observed in polyps <10 mm. However, if CSP indication
is expanded to larger polyps, the effects of submucosal in-
jection may still need to be investigated. Finally, procedure
time was not recorded. In a previous study, a longer pro-
cedure time for hot snare EMR was reported compared
with CSP for small colorectal polyps.4 Thus, CSP-SI may
also increase the procedure time.
In conclusion, injection of epinephrine and normal sa-
line solution into the submucosa did not increase the
depth of resection of small colorectal polyps removed
with CSP. Moreover, there is doubt about the thorough-
ness of polyp resection because we found lower rates of
negativity of lateral and vertical polyp margins with saline
solution injection than without injection. Saline solution in-
jection did not decrease the rate of fragmentation of re-
sected specimens. Considering these findings, in addition
to the expense and time that saline solution injection im-
poses, the technique cannot be recommended for removal
of small colorectal polyps with CSP. Better methods are
Volume 92, No. 3 : 2020 GASTROINTESTINAL ENDOSCOPY 721
Saline solution injection for deeper resection in CSP
needed to achieve sufficiently deep resection in CSP; un-
derwater CSP warrants validation, and improvements in
the CSP snare may also be necessary for helping to easily
grasp lesions together with the submucosal layer.
ACKNOWLEDGMENT
We thank to Akira Doi, Sho Ishikawa, Takafumi Kanada-
ni, Mariko Minami, Shintaro Hino, Kousuke Iwane, and Hir-
oshi Yamamoto for provision of study patients and also
Hironobu Tokumasu for assistance building the concept
of this trial.
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Shimodate et al Saline solution injection for deeper resection in CSP

SUPPLEMENTARY TABLE 1. Sensitivity analysis with various definitions of complete MM resection

Definition of complete MM resection No. of cases Odds ratio (95% confidential interval) P value

60%
C-CSP 68 Ref
CSP-SI 59 .7 (.4-1.3) .29

80%
C-CSP 57 Ref
CSP-SI 47 .7 (.4-1.2) .23

95%
C-CSP 40 Ref
CSP-SI 26 .5 (.3-1.0) .051
C-CSP, Conventional cold snare polypectomy; CSP-SI, cold snare polypectomy with submucosal injection; MM, muscularis mucosae.

SUPPLEMENTARY TABLE 2. Multivariate analysis of risk factors for incomplete MM resection

Univariate Multivariate
Odds (95% confidential interval) P value Odds (95% confidential interval) P value

Endoscopist
Nonexpert Ref Ref
Expert .4 (.2-0.8) .004 .5 (.3-1.1) .09
Procedure
Cold snare polypectomy Ref Ref
Cold snare polypectomy 1.4 (.8-2.5) .23 1.2 (.6-2.2) .47
with submucosal injection
Location
Left Ref Ref
Right 1.6 (.9-2.79) .11 1.7 (.9-3.0) .09
Morphology
Flat Ref Ref
Protruded 2.6 (1.4-4.8) .002 2.0 (1.0-4.2) .05
Polyp size

5 mm Ref Ref
5 mm 1.2 (.7-2.1) .53 1.5 (.8-2.8) .21
Nonexpert endoscopists had experienced fewer than 1000 screening colonoscopies, whereas expert endoscopists had experienced more than 1000 screening colonoscopy.
Location: left, sigmoid, descending colon and rectum; right, cecum, ascending and transverse colon.

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