Keywords Endoscopy Lower GI Tract - Polyps / adenomas / ... - Colorectal cancer - Endoscopic
resection (polypectomy, ESD, EMRc, ...) - CRC screening
Introduction
Colorectal Cancer (CRC) is still ranked as the third highest in terms of cancer mortality
[1 ]
[2 ] and, therefore, an important subject in the medical field. Since the knowledge of
the adenoma carcinoma sequence [3 ], screening colonoscopies as well as polypectomies for detected adenomas have been
the gold standard of CRC prevention [4 ]
[5 ]. The standard procedure for polypectomies to remove larger polyps in the colon is
currently snare polypectomy or endoscopic mucosal resection (EMR) [6 ]. EMR of larger colonic lesions often requires resection in piecemeal technique and,
thus, carries a recurrence rate of up to 20% [7 ].
On the other hand, endoscopic submucosal dissection (ESD) developed by eastern endoscopists,
originally for en bloc resection of gastric cancers, has been gaining more prominence
in treatment of colorectal lesions in recent years in Asia. Japanese data show a high
en bloc rate and a low recurrence rate of 0.5% in a 5-year follow-up after ESD of
broad-based colonic lesions larger than 20 mm [8 ]. Due to this success, this method is also increasingly being used in western countries
for removal of lateral spreading colonic lesions [9 ]. However, snare resection remains the standard for removal of broadly pedunculated
colonic polyps classified by the Paris classification system as 0-Ip lesions. 0-Ip
lesions are histologically described using the Haggitt classification system. The
Haggitt classification system categorizes carcinomas as low risk or high risk depending
on depth of submucosal infiltration [10 ]. Patients with a carcinoma categorized as Haggitt level 1 to 3 are typically treated
by local excision unless risk factors such as lymphatic invasion and budding dictate
otherwise. However, a patient classified with Haggitt level 4 requires surgical treatment
[10 ]. A prerequisite for proper assessment is complete evaluation of the polyp and stalk,
ideally en bloc. We, therefore, retrospectively analyzed the ESD technique for resection
of large or broadly pedunculated polyps concerning en bloc resection rate, histological
outcome, recurrence, and adverse event (AE) rate.
Patients and methods
This was a single-center retrospective study at the University Hospital Marburg, Germany,
investigating patients undergoing ESD for removal of pedunculated colonic polyps classified
after the Paris classification system as a 0-Ip lesion between 2019 and 2022.
Inclusion criteria were 0-Ip lesions with a polyp diameter ≥ 20 mm and/or a broad
stalk > 5 mm. Polyp and stalk diameter were estimated endoscopically in comparison
with the knife and forceps diameter. All consecutive 0-Ip lesions that met the inclusion
criteria were resected with ESD. All resected specimens were histologically examined
and finally measured by the university’s pathology institute.
Initial endoscopic follow-up was scheduled routinely 3 to 6 months after resection.
In addition to endoscopic evaluation, a biopsy was taken from the former resection
site or scar.
The data were analyzed for size, polyp localization, histology, en bloc resection
rate, intra-procedure and postprocedural AEs, procedure time, and recurrence rate
of the adenomas. Procedure time was counted starting from injection into the base
until full removal of the lesion. Final polyp size, stalk diameter, and stalk length
were measured on the histological preparation after formalin fixation. Statistical
correlations between polyp size, stalk diameter, and malignancy or resection time
were analyzed.
A regression analysis was performed and the results were calculated using a product-based
biserial correlation (Pearson) and a biserial correlation (Spearman), each with a
one-sided significance test. P < 0.05 was considered statistically significant.
The study was approved by the local ethics committee of the Medical Faculty of the
Philipps University Marburg, Germany (No. RS 22/45).
ESD technique
ESD procedures were performed with a 1.5-mm or 2.0-mm ESD knife (Dualknife, Olympus
Co.), using either a therapeutic gastroscope or a colonoscope, each with a transparent
spacer cap. After submucosal injection of gelofusin/indigo carmine at the base of
the stalk, the stalk was dissected with ESD. For ESD, either a complete circumferential
incision or, alternatively, a half circumferential incision was made on the anal side.
Endoscopic dissection from the anal to the oral side of the polyp stalk was then performed.
In the associated video, a visual representation of the described technique can be
seen ([Video 1 ]) as well as in [Fig. 1 ], [Fig. 2 ], [Fig. 3 ], and [Fig. 4 ]. If needed, the clip line method was applied for stabilization through traction
during resection.
Chromoendoscopy and magnification showing J-NET classification 2b and 3. Submucosal
injection at the basis of the polyp stalk. Incision starting on the anal side. Dissection
was undertaken from anal to oral side first. Then circumferential incision of the
oral side was completed in retroflexion. Vessel coagulation using swift coag mode.
Clip line was attached for traction. Further dissection on the muscle surface. Prophylactic
forceps coagulation of vigorous vessels in the residual stalk (soft coag mode, 60
W). Final dissection with arterial bleeding treated with a hemoclip. Final cut. Prophylactic
clip closure of the resection area.
Stretched resectate. Final histology: G2, pT1(sm1), L0, V0, R0, Haggit level 1.Video
1
Fig. 1
a Broad and short pedunculated sigmoid adenoma. b Injection at the base of the polyp stalk. c Incision starting at the anal side with dissection to oral side. d After two-thirds dissection, attachment of a clip line for traction. e Subsequent, dissection of the remaining polyp stalk. f Prophylactic clipping of the resection base. g Resectate removed en bloc. h Histology revealed a tubulovillous adenoma focally with HG-EIN resected R0 (1.25x,
HE stain), i detail magnification (4x, H&E stain).
Fig. 2
a Broad pedunculated adenoma. b
Injection of the stalk at its base. c Semi-circumferential
incision from the anal side. d Endoscopic dissection from the
anal to the oral side using the pocket technique. e Finally,
application of a clip line and f dissection of the residual
stalk under traction. g Resection site. h Stretched resectate now relatively flat. i
Histology staining and detailed magnification showing HG-EIN with transition to
adenocarcinoma in situ. Lamina muscularis mucosae is intact (1.25 x, H&E stain);
j detailed magnification (4x, H&E stain).
Fig. 3
a Pedunculated adenoma in the sigmoid colon. b Incision of the polyp stalk after injection. c Endoscopic submucosal dissection from anal to oral is performed. d In this case, with a relatively long pedicle, positioning with a spacer cap is sufficient.
e Clean resection area. f Resected polyp Paris classification Ip. g Histology shows adenocarcinoma G1 in the polyp stalk (1.25x, H&E stain), the section
magnification illustrates tumor cell association in the submucosa of the polyp stalk
resulting in a final tumor stage G1 pT1 Sm1 R0, L0, V0, Haggitt level 3 (4x, H&E stain).
Fig. 4
a Broad pedunculated adenoma. b Chromoendoscopy and magnification showing J-NET classification 2b and 3. c Injection of the stalk. d Incision and dissection was undertaken from anal to the oral side first. e Then circumferential incision of the oral side was completed in retroflexion. f Clip line was attached for traction. g Further course of the endoscopic dissection. h Vigorous vessels at the base of the polyp stalk require prophylactic coagulation
with coagulation forceps (Coag mode 60 W) prior to dissection. i Nevertheless, a vigorous arterial hemorrhage occurred at the end, j which was treated with a hemoclip k before the final resection. l Resection side. m Prophylactic clipping of resection side. n Stretched resectate. o Histology revealed HG-EIN with adenocarcinoma (1.25x, H&E stain), p the detailed magnification shows tumor cell association in the submucosa still in
the polyp head (4x, H&E stain). Final tumor stage is G2, pT1(sm1), L0, V0, R0, Haggit
level 1.
Intraprocedural bleeding was routinely stopped using a coagulation forceps (Radial
Jaw 4 Hot, Boston Scientific Co), as well as adrenaline injections, as needed. Larger
resection areas were closed with hemoclips in cases of suspected higher risk of postoperative
bleeding for patients receiving anticoagulation medication (vitamin K antagonists
and mainly direct oral anticoagulants [DOACs]). DOACs were paused 48 hours prior to
ESD and were resumed within 48 to 72 hours after resection.
Patients were informed about the procedures and gave written consent. All ESDs were
performed by the same experienced endoscopist.
Results
The sample consisted of 25 patients (7 female and 18 male). [Table 1 ] shows basic demographic, procedure, and outcomes data. The median patient age was
67 years (range, 48–93 years).
Table 1 Patient data and initial and follow-up results.
Patient
Age
Sex
Site cm anocutaneous
Procedure time (min)
Stalk length (mm)
Stalk width (mm)
Ø polyp (max mm)
Histology
Haggit level
Resection (R0/R1)
Follow-up (d)
Recurrence
HG-EIN, high-grade intraepithelial neoplasia; LG-EIN, low-grade intraeplithelial neoplasia.
1
58
M
18
41
4
5
47
pTis L0, V0
0
R0
90
None
2
69
M
15
36
8
4
26
LG-IEN
R0
88
None
3
63
M
25
35
6
3
22
LG-IEN
R0
4
83
F
22
29
12
7
28
LG-IEN
R0
5
61
F
25
45
12
9
40
pT1 L0, V0, G1
3
R0
563
None
6
59
M
25
45
7
5
24
LG-IEN
R0
104
None
7
59
M
20
130
10
15
38
HG-IEN
R0
81
None
8
51
M
28
130
10
20
42
Hyperplastic Mucosa
R0
9
77
M
15
48
14
10
25
LG-IEN
R0
10
48
M
20
35
10
5
25
HG-IEN
R0
248
None
11
67
M
25
57
7
18
25
HG-IEN
R0
309
None
12
65
M
12
100
12
4
47
LG-IEN
R0
13
70
M
12
34
7
6
42
pT1 L0, V0, G2
3
R0
113
None
14
59
F
70
96
19
3
52
HG-IEN
R0
92
None
15
82
M
10
96
6
7
51
HG-IEN
R0
16
62
F
20
21
9
15
30
HG-IEN
R0
228
None
17
76
F
30
19
11
11
23
pTis, L0, V0, G2
0
R0
138
None
18
68
F
20
68
13
5
40
pT1, Bd3, V1, G3
4
R0
19
73
M
20
32
9
3
27
LGIN
R0
151
None
20
67
M
50
61
9
12
28
pT1, L0, V0, G1
3
R0
84
None
21
93
F
8
55
12
3
23
pTis, L0, V0, G2
0
R0
22
91
M
14
80
16
15
40
pT1, L0, V0, G2
3
R0
89
None
23
70
M
40
132
18
4
47
HG-EIN
R0
229
None
24
52
M
40
20
5
15
27
LG-EIN
R0
179
None
25
63
M
35
162
4
15
50
LG-EIN
R0
100
None
ESD was mainly performed under propofol sedation and in one case under general anesthesia
due to preexisting cardiopulmonary disease. Most of the 0-Ip polyps (n = 19/25, 76%)
were located in the sigmoid.
All 0-Ip lesions could be resected completely en bloc using ESD, resulting in an en
bloc resection rate of 100%. Median endoscopic resection time was 48 minutes (range,
19–162).
The statistical tests to determine correlation between the various parameters showed
a significant correlation (P < 0.01) between polyp size and examination time (r=0.694) (P = 0.002). However, stalk size did not seem to play a role in procedure duration (r
= 0.12, P = 0.28).
Histological results and R0 resection rate
Median size of the resected lesions/polyps was 30 × 25 × 17 mm shown in length x width
x height. Median stalk diameter was 7 mm and median stalk length was 10 mm. [Fig. 1 ], [Fig. 2 ], [Fig. 3 ], and [Fig. 4 ] show various examples of polyps resected in our study.
Histologic examination revealed one hyperplastic polyp and 64% adenomas (16/25), of
which nine were low-grade intraepithelial neoplasia (LG-IEN) and seven were high-grade
intraepithelial neoplasia (HG-IEN) as shown in [Fig. 5 ]. Thirty-two percent (8/25) of the removed 0-Ip lesions were carcinomas. Histological
staging resulted in seven low-risk carcinomas (pTis: 3; pT1-Haggitt level 3: 4) and
one high-risk carcinoma (pT1, pNx, Bd3, V1, G3, Haggitt level 4), which subsequently
were treated with surgery as illustrated in [Table 2 ].
Fig. 5 Overview of histological results of polyps.
Table 2 Overview of histological results of carcinomas.
Histological staging
Histological grading
Haggitt level
HG-EIN- pTis, L0, V0
Haggitt 0
pTis, L0, V0
G2
Haggitt 0
pTis, L0, V0, Bd1
G2
Haggitt 0
pT1, L0, V0,
G1
Haggitt 3
pT1, L0, V0,
G2
Haggitt 3
pT1, L0, V0,
G1
Haggitt 3
pT1, L0, V0
G2
Haggitt 3
pT1, pNx, Bd3, V1
G3
Haggitt 4
Statistically, there appeared to be a slight to moderate correlation between neoplastic
histology (LG-IEN vs HG-IEN + cancer) and polyp size and width r = 0.286, but this
correlation was not significant (P = 0.088), nor was stalk diameter with r = 0.153, also not significant (P = 0.237).
The histologic R0 resection rate was 100% with no marginal adenoma or carcinoma cells.
Adverse events
Minimal intraprocedural bleeding occurred in 11 cases (44%) and was mainly treated
using either the coagulation function of the ESD knife (swift coag 30W) or coagulation
forceps (soft coag 80W).
At the end of the procedure, the resection area was clipped in 20 (80%) of 25 patients
for bleeding prophylaxis. No post-procedural bleeding occurred.
In one of the 25 patients, an incomplete perforation was suspected, showing a deep
muscle defect of the sigmoid resection area without pneumoperitoneum. Successful treatment
consisted of antibiotic coverage and endoscopic vacuum therapy (Endosponge, Braun)
for 7 days, including one sponge exchange.
Follow up and curative resection rate
Seventeen of 25 patients returned for endoscopic follow-up, 11 of whom had adenomas
and six carcinomas. Median total follow-up time was 113 days (range, 81–563). Five
patients refused endoscopic follow-up due to advanced age and existing concomitant
diseases, four of whom had adenomas and one carcinoma. One patient died 7 months after
ESD of small cell lung cancer diagnosed at that time with multiple metastases.
The patient with a high-risk adenocarcinoma (pT1, pNx, Bd3, V1, G3, Haggitt 4) underwent
surgical resection of the sigmoid colon and, therefore, dropped out of endoscopic
follow up.
Endoscopic follow-up of resection sites revealed no recurrences either endoscopically
or in histologic examination of the biopsies taken.
The follow-up group included six patients with adenocarcinoma (pTis: 2; pT1 L0, V0,
G1, Haggitt 3; pT1 L0, V0, G2, Haggitt 3; pT1 L0, V0, G1, Haggitt3; pT1, L0,V0, G2,
Haggitt 3) with a median follow-up of 101.5 days (range, 84–563) and no recurrence
after ESD resection.
The curative resection rate was 96% (24/25).
Discussion
Our retrospective study of ESD resections of large and/or broad pedunculated polyps
resulted in an en bloc and R0 resection rate of 100%. Histologically, 32% of polyps
were
already classified as carcinomas, including seven low-risk carcinomas in eight cases.
The
curative resection rate was 96% using ESD.
In the eight cases of carcinoma, we decided to include three cases in which the cancer
was in its earliest stage, which is carcinoma in situ. That has the characteristic
feature of lateral expansion within the mucosa, which is an indicator that these tumor
cells have acquired invasive capacity, in contrast to HG-IEN. Therefore, we included
these lesions (n = 3) in the group of cancerous lesions. It should be emphasized,
however, that due to the lack of contact with lymphatic vessels, these early intramucosal
invasive lesions have no metastatic capacity.
Data on ESD resection of colonic lesions primarily analyze the treatment of flat,
laterally spreading lesions. In comparison, there are few data available on ESD resection
of Ip lesions. Some case reports and mainly eastern retrospective multicenter studies
examined feasibility for ESD on pedunculated polyps [11 ]
[12 ]
[13 ]
[14 ]
[15 ]. Choi et al. [11 ] described ESD resection of 23 difficult Ip lesions in 2013 as an alternative to
snare resection. They achieved an en bloc resection rate of 100% with a cancer incidence
of 87% in this selected group. The study of Chiba et al. [13 ] included a sample size (29 patients) similar to our respective study. The curative
resection rate was 85.7% and the cancer incidence was 20.6% [13 ]. The latest retrospective study by Inagaki et al. [14 ] investigated 36 Ip lesions. En bloc, complete en bloc, and curative resection rates
were 97%, 97% and 81%, respectively. Cancer incidence was 25% in this study. These
studies did not report on any follow ups and, therefore, the possible recurrence of
the lesions, an aspect we observed further.
The latest recommendation from the European Society of Gastrointestinal Endoscopy
committee is use of ESD to selectively treat lesions with higher risk of submucosal
invasive cancer. They identify lesions with a higher risk as mainly “nongranular lateral
spreading types (LST-NGs), particularly if pseudo depressed 0-IIc; granular nodular
mixed LSTs, particularly if more than 2 cm in size; especially lesions in the rectosigmoid
area; and those showing an irregular pattern with CE” [16 ]. A meta-analysis including 48 studies, which was published in 2018, described a
submucosal invasion risk in overall LST adenomas of 8.1%. Whereas they emphasize that
non-granular pseudo depressed LSTs had a submucosal invasion rate of 31.6% [17 ]. A different multicenter study, which was published in 2020, described submucosal
invasion as high as 36% in LST non-granular pseudo depressed adenomas [18 ].
In our study, 32% of all assessed lesions (8/25), namely large-diameter Ip polyps,
were
cancerous. Here our data showed a slight to moderate yet not statistically significant
correlation of polyp size and stalk diameter with neoplasia (HG-IEN and cancer). The
cancer
risk would match the estimated risk in LST non-granular pseudo depressed adenomas.
In addition
to polyp size, endoscopic criteria for malignancy in pedunculated polyps may include
ulceration of the polyp head and interrupted vascular pattern [19 ].
Endoscopic oncologic resection in these cases requires complete en bloc removal, taking
the polyp stalk at the base while avoiding a marginal or incomplete resection. Only
this allows for valid histopathological evaluation of submucosal infiltration depth
and is vital for an accurate differentiation between low-risk and high-risk carcinomas.
In our study cohort, the majority of carcinomas consisted of histologically staged
low-risk carcinomas with no further indication of necessary oncologic surgical resection.
It is debatable whether a certain polyp size, stalk diameter, or both, are the decisive
factors in the decision to use ESD as an alternative to snare resection.
In our study we included polyps with a size ≥ 20 mm and/or broad stalk ≥ 5 mm. All
Ip lesions had a final histological polyp size ≥ 20 mm (median polyp size: 30 mm),
but not all had a stalk size over 5 mm (median stalk size: 7 mm). This may be due
to inaccurate endoscopic size estimation with limited visibility of the stalk in cases
with a big polyp head. Another point to consider may be tissue shrinkage after formalin
fixation. Polyp size alone can impede visualization and snare positioning with risk
of fractional resection. This may be the reason that published data on ESD resection
of Ip lesions have not determined a certain stalk diameter in the indication. Choi
et al. [11 ] included difficult Ip lesions, which were defined as polyp size ≥ 3 cm and included
poor visualization of the stalk, technical difficulties in snare positioning for en
bloc resection, or need for trimming of the polyp head. Chiba et al. [13 ] used nearly the same inclusion criteria. Inagaki et al. [14 ] defined inclusion criteria as the endoscopist’s determination of difficult snare
positioning and/or an estimated high risk for bleeding due to a thick polyp stalk
without specifying numerical limits. If stricter inclusion criteria were applied to
our data (polyp size ≥ 30 mm and/or polyp stalk ≥ 10 mm), 18 of 25 lesions would still
have fulfilled the ESD indication.
Looking more closely at the cancerous polyps in our study, polyp size ranged between
27 and 47 mm (median polyp size: 40 mm) and polyp stalks between 5 and 15 mm (median
stalk size: 7.5 mm). This is in accordance with data from Choi et al. [11 ], who resected 20 cancerous polyps, of which only five had a polyp stalk ≥ 10 mm.
Stalk length varied between short and long. Four of six cancerous polyps resected
by Chiba et al. [13 ] had a wide stalk between 20 and 30 mm. The study by Inagaki et al. [14 ] did not mention stalk width and length of Ip polyps. Their resected cancerous lesions
had a polyp size between 20 and 50 mm, similar to our data.
Based on our data, it is likely that resection of difficult pedunculated polyps with
ESD enables a higher en bloc rate with entrainment of the polyp stalk, which is especially
crucial for cancerous polyps.
For non-pedunculated colonic adenoma, ESD has proven to result in high en bloc rates
as well has low recurrence rates [20, 23, 22]. The literature reports en bloc rates
as high as 91% and recurrence rates as low as 1% to 2%, whereas some studies show
that EMR results in recurrence rates up to 12% to 19% [20 ].
Our analysis also showed en bloc resection rates as high as 100% and R0 resection
rate as low as 0% using ESD. Our calculated results include 17 of 25 patients who
have been assessed in the follow up. Currently, prospective randomized studies are
lacking to finally clarify which Ip lesions benefit from ESD resection. The retrospective
comparison of ESD and snare resection from 2013 [11 ] resulted in an advantage for ESD resection with an en bloc resection rate of 100%
versus 90%. In this study, difficult Ip lesions with a higher proportion of short
and thick polyp stalks without numerical minimum were selected for resection in the
ESD group. Nevertheless, snare resection of the supposedly easier Ip lesions achieved
a lower en bloc resection rate. Although prospective randomized data are lacking,
this supports using ESD for en bloc resection of difficult Ip lesions.
Another important aspect when evaluating medical treatments are their AE rates. In
2005, the Munich Polypectomy study analyzed over 3000 snare polypectomies, which included
treatment of 27.8% pedunculated polyps [21 ]. They reported an overall AE rate of 9.7%, 75% of which were classified as minor
[21 ]. However, the authors highlighted that size, location, and configuration (sessile
vs pedunculated) played an important role, with the lowest AE rate of 0.4% occurring
in pedunculated left-sided polyps smaller than 2 cm. The perforation rate was reported
as only 1.1% and it is not clearly stated to which kind of lesions it applied. ESD
has a reported perforation rate of approximately 4.8% and is often said to be associated
with higher risk of AEs than EMR [1 ]
[22 ]
[23 ]. In our case study, there were no perforations, but there was one suspected perforation
which equated to 3% and matches the reported rates. Nonetheless, this AE was treated
endoscopically and did not require any further interventions such as transfusions
and/or surgery.
Another common AE of snare resection of broadly pedunculated polyps is bleeding from
the well-vascularized polyp stalk. A randomized trial comparing prophylactic clipping
of the base with prophylactic endoloop application prior to snare resection still
resulted in 5% direct bleeding events on resection and 1% post-resection bleeding
in both groups [24 ]. An advantage of ESD is that it allows slow transection of the polyp stalk with
targeted coagulation of vessels using either the ESD knife or coagulation forceps.
This aspect is illustrated in a current case report [12 ]. Published data [11 ]
[13 ]
[14 ] report no delayed bleeding using ESD, which is in accordance with our data. No postoperative
bleeding occurred in our study, and minor intraprocedural bleeding was stopped with
targeted vascular coagulation during resection.
There are a few limitations to our study. The main one is it that it was retrospective,
single-center, and had a relatively small sample size. Also, the lack of a direct
comparison between ESD and EMR is another limitation that needs to be addressed. In
the future, a prospective randomized trial comparing both methods should be conducted
to verify our findings. Next would be measuring the stalks. Although all of our stalks
were measured by the pathology institute, some of them were not measured until after
formalin treatment, which led to shrinkage. Therefore, initial assessment of stalk
width was subject to examiner judgment.
In the future, for more exact evaluation, the stalks should be measured after resection,
before formalin exposure, or using a standardized measurement technology, e.g., with
artificial intelligence.
Conclusions
To conclude, it can be said that in our case study, ESD was an effective and safe
treatment for larger colonic pedunculated lesions with en bloc resection rate and
R0 resection rate both being 100% and recurrence rate being as low as 0%. Thirty-three
percent of resected 0-Ip lesions were staged as adenocarcinomas. Here, complete en
bloc resection allowed full patho-oncological staging in all cases. Of those adenocarcinomas,
more than 50% were staged as Haggitt level 3 or higher. In seven of eight carcinoma
patients, ESD was curative and patients did not have to undergo any further treatment.
Whenever ESD is performed, its higher technical complexity as well as longer procedure
times have to be considered. Given this, our study showed a significant correlation
between polyp size but not stalk diameter with ESD resection time. Prospective comparative
data are the next step to analyze the increased complexity of ESD resection versus
snare resection against the exact benefit in terms of increased R0 and lower recurrence
rate. However, even if comparative studies defining exact eligibility criteria are
lacking so far, ESD can be recommended and should be discussed when treating large
pedunculated lesions due to their higher carcinoma risk.
