- Email: [email protected]
Efficacy and safety of endoscopic submucosal dissection for superficial colorectal tumors more than 50 mm in diameter
ORIGINAL ARTICLE: Clinical Endoscopy
Efficacy and safety of endoscopic submucosal dissection for superficial colorectal tumors more than 50 mm in diameter Yoshikazu Hayashi, MD, PhD,1 Satoshi Shinozaki, MD, PhD,1,4 Keijiro Sunada, MD,1 Hiroyuki Sato, MD, PhD,1 Yoshimasa Miura, MD,1 Yuji Ino, MD,1 Hisanaga Horie, MD, PhD,2 Noriyoshi Fukushima, MD, PhD,3 Alan K. Lefor, MD, PhD, MPH,2 Hironori Yamamoto, MD, PhD1 Tochigi, Japan
Background and Aims: The feasibility of endoscopic submucosal dissection (ESD) for large superficial colorectal tumors is undefined. The aim of this study was to assess the outcomes for patients undergoing ESD of superficial colorectal tumors larger than 50 mm. Methods: A total of 472 patients who underwent ESD for superficial colorectal tumors from 2010 to 2014 were enrolled. We retrospectively reviewed their records. Results: We compared patients with 20-mm to 50-mm lesions and those with lesions >50 mm regarding demographics, the ESD procedure, and histopathology. Among patients with lesions >50 mm, laterally spreading tumors nongranular and protruded types were uncommon. Histopathologically, deeply invasive (1000 mm) submucosal carcinomas were more frequent in lesions >50 mm (14% [10/70] vs 5% [20/402], P < .01). Technically, en bloc resection was successfully accomplished in 99% of patients (69/70). Although the total dissection time for lesions >50 mm was significantly longer than for lesions 20 mm to 50 mm (mean SD, 157 114 minutes vs 68 50 min; P < .01), dissection speed for lesions >50 mm was significantly faster than for lesions 20 mm to 50 mm (P < .01). There were no significant differences in en bloc R0 resection rate comparing both groups (>50 mm, 83% vs 20 mm to 50 mm, 87%; P Z .31). No perforations or postoperative bleeding occurred in patients with lesions >50 mm. Post-ESD colorectal strictures requiring intervention did not develop in any patient. Conclusions: ESD for superficial colorectal tumors >50 mm is feasible. ESD of these lesions had a high R0 resection rate and a low adverse event rate. En bloc resection by ESD provides adequate pathological specimens and may limit the need for surgical intervention. (Gastrointest Endosc 2016;83:602-7.)
At the end of the 20th century, we began performing endoscopic submucosal dissection (ESD) for colorectal neoplasms.1,2 Our institution is a pioneer in performing colorectal ESD. Colorectal ESD is considered more difficult than gastric ESD because the colon wall is thinner than the stomach. It is even more difficult when the tumor is located on a prominent fold and/or an area with sharp bending, which can result in loss of control of the endoscope.3 These factors may increase the rate of adverse events. A recent prospective study4 revealed that
colorectal lesions >50 mm are an independent risk factor for the occurrence of adverse events. We performed ESD for 1223 colorectal lesions from June 1998 to October 2014. Colorectal ESD was recognized as an advanced medical treatment by the Japanese government in April 2010. We have treated large tumors regardless of their size as long as a curative resection was expected. Technological improvements in the devices used to perform ESD over the past decade have led to a safe and reliable procedure. In our experience, ESD for colorectal lesions
Abbreviations: LST-G, laterally spreading tumor–granular type; LST-NG, laterally spreading tumor–nongranular type; PEG, polyethylene glycol.
Received March 26, 2015. Accepted August 2, 2015.
DISCLOSURE: Dr Yamamoto has received honoraria, grants, and royalties from and holds a patent for a double-balloon endoscope with Fujifilm. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2016 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.08.037
602 GASTROINTESTINAL ENDOSCOPY Volume 83, No. 3 : 2016
Current affiliations: Department of Medicine, Division of Gastroenterology (1), Departments of Surgery (2), and Pathology (3), Jichi Medical University, Shinozaki Medical Clinic (4), Tochigi, Japan. Reprint requests: Hironori Yamamoto, MD, PhD, Division of Gastroenterology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
www.giejournal.org
Hayashi et al
>50 mm in size is feasible. The aim of this study was to assess the safety and outcomes of patients undergoing ESD for superficial colorectal tumors, especially focusing on tumors >50 mm in diameter. The hypothesis of this study was that the resection rates are lower for lesions >50 mm.
METHODS We retrospectively reviewed all of the consecutive colorectal lesions treated by ESD between April 2010 and October 2014 at the Division of Gastroenterology of Jichi Medical University. To perform an up-to-date analysis, we used data from procedures after the recognition of colorectal ESD by the Japanese government. We reviewed patient records, operative records, and pathological findings. This study was approved by our institutional review board. Full written informed consent for ESD of the colorectal lesions was obtained from all patients. The indications for ESD of colorectal lesions included lesions considered difficult to treat with EMR in an en bloc fashion and image-enhanced magnifying endoscopy and magnifying chromoendoscopy not demonstrating submucosal invasion of 1000 mm. EUS using a miniprobe was performed for lesions with findings suspicious for invasive carcinoma by magnified endoscopy. When EUS clearly demonstrated tumor invasion to the muscularis propria, surgical resection was indicated. We did not preclude ESD due to technical difficulties such as large size, location, or endoscopic instability. To analyze the colorectal ESD results for a more homogeneous group of lesions, we included only superficial neoplastic lesions (adenomas and early carcinomas) with a diameter of 20 mm in this retrospective study. Bowel preparation was routinely performed by using oral sodium picosulfate 0.75% 10 mL on the night before the procedure and 2 L of polyethylene glycol (PEG) solution on the day of the ESD procedure. When the stool became watery and clear, bowel preparation was complete even if the dose of PEG solution had not reached 2 L. If the stool was not watery and clear after the routine preparation, another 1 to 2 L of PEG solution or 0.9 to 1.8 L of isotonic magnesium citrate solution were administered. Midazolam and pethidine were used for sedation in most patients, and butyl scopolamine or glucagon were used to decrease colonic peristalsis. An endoscope with a water jet instrument (EC-580RD/M; Fujifilm, Tokyo, Japan), carbon dioxide insufflation, and a small-caliber tip transparent (ST) hood (DH-15GR or DH-28GR; Fujifilm, Tokyo, Japan) fitted to the tip of the endoscope were used. When we could not maintain adequate maneuverability using a standard colonoscope, we used a balloon-assisted endoscope (EC-450BI5 and TS-13101; Fujifilm).5 Mucosal incision and submucosal dissection were performed by using a Flush knife BT (DK2618JB-15; Fujifilm) or a DualKnife (KD-650Q; Olympus, Tokyo, Japan) with an www.giejournal.org
ESD of colorectal tumors larger than 50 mm
electrosurgical generator (VIO300D; ERBE Elektromedizin Ltd, Tübingen, Germany). Hot hemostasis forceps (HOYA Corporation, Tokyo, Japan) were used to control bleeding. We divided the resected colorectal tumors into 2 groups based on size (20 mm-50 mm and >50 mm). We analyzed the size, shape, location, dissection time, and pathological findings for each lesion. The area of the resected specimen (mm2) was calculated using the following formula: major axis (mm)/2 minor axis (mm)/2 3.14. The dissection time (minutes) was defined from the start of cutting the mucosa to completion of the resection. The dissection speed (mm2/min) was calculated by using the area of resected specimen (mm2)/dissection time (minutes). For submucosal injection, 0.4% sodium hyaluronate (MucoUp; Seikagaku, Tokyo, Japan) was used. En bloc resection was defined as resection of the entire specimen in a single piece. En bloc R0 resection was pathologically defined by fulfilling an en bloc resection, with tumor-free vertical and horizontal margins. En bloc curative resection was pathologically defined by fulfilling en bloc R0 resection, a differentiated carcinoma or adenoma, with <1000 mm of submucosal invasion and no lymphovascular invasion, based on the 2014 Japanese Society for Cancer of the Colon and Rectum Guidelines for the treatment of colorectal cancer.6 The definition of perforation includes perforations during and after the ESD procedure. Postoperative bleeding was defined as overt bleeding within 14 days after ESD requiring endoscopic hemostasis.
Statistical analysis Sample size was calculated by estimating R0 resection rates of 90% and 70% for lesions 20 mm to 50 mm and >50 mm, respectively. The R0 resection rate for lesions 20 mm to 50 mm was estimated referring to previous literature showing an 88% en bloc resection rate and an 89% histopathological curative resection rate for carcinoma portions of lesions.4 The R0 resection rate limited to lesions >50 mm was estimated to be lower (70%), considering the technical difficulties. The calculated sample size was 150 for lesions 20 mm to 50 mm and 30 for lesions >50 mm determined with an allocation ratio of 5:1, an a error of 5%, and a power of 80%. Statistical analysis was performed by using Microsoft Excel 2013 (Microsoft Corp, Redmond, Wash) with add-in software Statcel 3 (OMS Publishing Inc, Saitama, Japan). Data are expressed as the median. Independent continuous variables were compared using the Mann– Whitney U test. Categorical data were compared using the c2 test or the Fisher exact test. Differences were considered statistically significant with a P value <.05.
RESULTS A total of 583 colorectal ESD procedures in 540 patients were performed during the study period. For the final Volume 83, No. 3 : 2016 GASTROINTESTINAL ENDOSCOPY 603
ESD of colorectal tumors larger than 50 mm
analysis, 111 lesions were excluded from the 583 lesions for the following reasons: (1) nonneoplastic lesions (n Z 18), (2) carcinoid tumor (n Z 24), (3) mucosaassociated lymphoid tissue lymphoma (n Z 1), (4) advanced cancer (n Z 3), (5) discontinuation of ESD during an earthquake (n Z 1), and (6) tumor size <20 mm in diameter (n Z 64). The remaining 472 lesions, including lesions 20 mm to 50 mm (n Z 402) and lesions >50 mm (n Z 70), were included in this study (Table 1). The study groups were large enough for statistical analysis according to the sample size calculation. The ESD procedures were carried out by 9 fully trained endoscopists (A, B, C, D, E, F, G, H, and I) and 7 advanced endoscopy trainees (Table 2). We compared the 2 groups of lesions with regard to their demographic, ESD procedure–specific, and pathological data (Table 1). Compared with smaller lesions, lesions >50 mm were located more often in the rectum (33/70 [47%] vs 102/402 [25%]; P < .01). Laterally spreading tumors–nongranular type (LST-NG) and protruded type tumors were fewer in number among the larger lesions. Histopathologically, deeply invasive (1000 mm) submucosal carcinomas were more frequent in the >50-mm group. Technically, en bloc resection was successfully accomplished in 99% of patients in both groups. Although total dissection time in the >50 mm group was significantly longer than that in the 20-mm to 50-mm group (P < .01), dissection speed in the >50-mm group was significantly faster than that in the 20-mm to 50-mm group (P < .01). There were no significant differences in en bloc R0 resection rate comparing both groups (>50-mm group, 83% vs 20-mm to 50–mm group, 87%; P Z .31). Although the curative resection rates in both groups were comparatively high, the rate for the >50-mm group was significantly lower than that of the 20-mm to 50-mm group (74% vs 84%, P Z .04). We compared rectal lesions (n Z 135) with other lesions (n Z 337) with regard to en bloc R0 resection rate and curative resection rate. The en bloc R0 resection rates were, respectively, 85% (n Z 115) versus 87% (n Z 294) without a significant difference (P Z .55). The curative resection rates were, respectively, 79% (n Z 107) versus 84% (n Z 284) without a significant difference (P Z .19). No perforation or postoperative bleeding occurred in the >50-mm group. No immediate bleeding with a decrease of >2 g/dL in hemoglobin level compared with preprocedure levels occurred during ESD in either group. Post-ESD colorectal stricture requiring intervention did not develop in any of the patients. After ESD, 18 of 70 patients in the >50-mm group (26%) were considered to have undergone a noncurative resection. The details of these 18 patients are shown in Table 3. All 4 adenomas with positive margins were observed without further resection. Deeply invasive submucosal carcinoma was present in 10 of the 18 patients (56%). Eight of these 10 patients underwent 604 GASTROINTESTINAL ENDOSCOPY Volume 83, No. 3 : 2016
Hayashi et al
laparoscopic resection, and the remaining 2 patients (patients 15 and 18 in Table 3) were carefully followed without resection because of severe comorbidities. For patient 6, the ESD specimen was intentionally cut by snaring without cauterization during the procedure because the large resected portion interfered with visibility during the remaining ESD procedure. Overall, 9 of the 18 patients (50%) underwent subsequent surgical resection, and 2 (22%) had lymph node metastases.
DISCUSSION After we began performing ESD for colorectal lesions, the ESD technique became widely accepted and is used in many institutions to resect large superficial colorectal tumors. In the past, performing ESD for colorectal tumors >50 mm was considered relatively difficult with increased risk.4 Because of technical challenges including lesion size, many large superficial colorectal tumors continue to be referred for surgical resection.7 In this study, we present data that support the feasibility and safety of performing ESD for superficial colorectal tumors >50 mm based on the experience at our institution. A 99% en bloc resection rate and a curative resection rate >70% based on histological evaluation is acceptable considering it is a less invasive procedure compared with surgical resection. The rate of adverse events in patients with lesions >50 mm is similar to that in patients with lesions 20 mm to 50 mm. The use of ESD for the resection of colorectal neoplasms >50 mm was limited due to concerns regarding the curability and safety of these lesions. In general, surgical resection and piecemeal EMR are used for large colorectal neoplasms. However, based on the data in this study, we believe that ESD is feasible for the treatment of superficial colorectal tumors >50 mm. ESD should result in a curative resection, considering the rather benign pathological nature of these superficial lesions. It benefits patients by avoiding surgical resection. The risk of lymph node metastases is considered negligible in patients with submucosal invasion <1000 mm and without lymphatic or vascular invasion, regardless of the lesion size based on studies of surgically resected specimens.8 In this study, the dissection time for lesions >50 mm is w2 hours, which is not longer than surgical resection under general anesthesia. The en bloc R0 resection rate was 83% for lesions >50 mm in this study. This R0 resection rate is a good outcome without surgical resection. Piecemeal EMR is another viable option, with the advantages of short procedure time and simple technique.9 However, precise pathological examination is limited due to the specimen being obtained in a piecemeal fashion, and an inadequate examination may lead to difficulty in www.giejournal.org
Hayashi et al
ESD of colorectal tumors larger than 50 mm
TABLE 1. Clinical characteristics of patients and treatment results >50-mm group
20-mm to 50-mm group No. of lesions Age, y, median SD (range)
P value
402
70
68 10 (35-94)
67 11 (38-88)
.68
161:241
40:30
<.01
217 (54)
32 (46)
.2
Sex, female:male, no. Tumor location, no. (%) Right side of colon Left side of colon
83 (21)
5 (7)
<.01
Rectum
102 (25)
33 (47)
<.01
LST-G
184 (46)
60 (86)
<.01
LST-NG
135 (34)
7 (10)
<.01
Protruded type
83 (21)
3 (4)
<.01
30 8 (20-50)
63 19 (51-133)
Adenoma
172 (43)
18 (26)
Intramucosal carcinoma
171 (43)
36 (51)
.17
Slightly invasive (<1000 mm) submucosal carcinoma
39 (10)
6 (9)
.77
Macroscopic type, no. (%)
Tumor diameter, mm, median SD (range) Pathological findings, no. (%)
Deeply invasive (1000 mm) submucosal carcinoma
20 (5)
10 (14)
<.01
394 (98)
69 (99)
1.00
40 9 (16-67)
73 22 (44-140)
En bloc resection, no. (%) Resected specimen diameter, mm, median SD (range) Dissection time, min, median SD (range) Dissection speed, mm2/min, median SD (range)
<.01
54 50 (7-425)
121 114 (22-634)
<.01
18.4 12.1 (2.9-71.4)
28.2 16.8 (9.4-83.4)
<.01
En bloc R0 resection, no. (%)
351 (87)
58 (83)
.31
En bloc curative resection, no. (%)
339 (84)
52 (74)
.04
Perforation, no. (%)
14 (4)
0 (0)
.24
Postoperative bleeding, no. (%)
9 (2.2)
0 (0)
.37
LST-G, Laterally spreading tumors, granular type; LST-NG, laterally spreading tumors, nongranular type.
identifying focal or deep submucosal invasion. A high local recurrence rate after piecemeal EMR (10%-23.5%) has been reported.10-15 The en bloc resection rate in the current study was 99% in patients with lesions >50 mm. Larger tumors are more likely to contain focal submucosal invasion. In this study, large en bloc ESD specimens enabled precise pathological evaluation of minute findings. These pathological results contribute to differentiating noncurative resections into the following categories: (1) deep submucosal invasion, (2) lymphatic or vascular invasion, and (3) unclear or positive margin. Detailed pathological evaluation helped to determine the need for additional treatment (Table 3). Although unclear or positive horizontal margins suggest an increased risk of local recurrence, focal deep submucosal and/or lymphovascular invasion indicate an increased risk of lymph node metastases, which necessitates consideration of the need for additional surgery. These important findings may be overlooked in a specimen obtained in a piecemeal fashion. Therefore, we believe that en bloc resection using ESD is the treatment of choice for large superficial colorectal tumors. www.giejournal.org
TABLE 2. Procedural experience of each endoscopist Experience, no.*
20-mm to 50-mm lesions, no. (%)
>50-mm lesions, no. (%)
A
238
42 (10)
11 (16)
B
226
67 (17)
10 (14)
C
222
18 (4)
6 (9)
D
73
50 (12)
7 (10)
E
68
46 (11)
15 (21)
F
99
73 (18)
8 (11)
G
69
45 (11)
11 (16)
H
35
25 (6)
2 (3)
I
46
36 (9)
0 (0)
1076
402y
70z
Endoscopist
Total
*Experience Z total number of colorectal endoscopic submucosal dissections performed between 1998 and October 2014. yTwenty-four of 402 lesions were resected by 7 advanced endoscopy trainees with attending endoscopists (A, B, D, E, F, G). zFour of 70 lesions were resected by 3 advanced endoscopy trainees with attending endoscopists (B, G).
Volume 83, No. 3 : 2016 GASTROINTESTINAL ENDOSCOPY 605
ESD of colorectal tumors larger than 50 mm
Hayashi et al
TABLE 3. Details of patients undergoing noncurative resection of lesions >50 mm in diameter
Pt
Sex Age, y Location
Endoscopic growth type
Tumor size, mm
Pathology
ly
v
Submucosal invasion En bloc pVM pHM depth, mm resection
After ESD
Surgical pathology
1
F
72
Rb
LST-G-M
72
Adenoma
ND ND
0
X
0
EB
FU
ND
2
F
61
A
LST-G-M
58
Adenoma
ND ND
0
1
0
EB
FU
ND
3
F
64
A
LST-G-H
59
Adenoma
ND ND
0
1
0
EB
FU
ND
4
F
83
Rb
LST-G-M
71
Adenoma
ND ND
1
0
0
EB
FU
ND
5
M
78
Rb
LST-G-M
66
Intramucosal
0
0
X
0
0
EB
FU
ND
6
F
88
Rb
LST-G-M
101
Intramucosal
0
0
1
1
0
P
FU
ND
7
F
68
A
LST-G-M
51
Slight
1
0
0
0
500
EB
FU
ND
8
F
51
A
LST-G-M
103
Slight
0
1
X
X
100
EB
Lap-C
NT, N0
9
M
52
C
LST-G-M
52
Deep
0
0
0
0
2000
EB
Lap-C
NT, N0
10
F
67
A
LST-G-M
71
Deep
0
0
0
0
4000
EB
Lap-C
NT, N0
11
F
62
C
LST-G-M
64
Deep
0
1
0
0
1600
EB
Lap-C
NT, N0
12
F
53
Rb
LST-G-M
56
Deep
0
1
0
0
5000
EB
Lap-C
NT, N0
13
F
58
S
LST-G-M
58
Deep
0
1
0
0
12,000
EB
Lap-C
NT, N2
14
M
60
Rb
LST-G-M
78
Deep
0
2
0
0
3,000
EB
Lap-C
NT, N0
15
M
76
Rb
LST-G-M
96
Deep
0
2
1
0
18,000
EB
FU
ND
16
M
70
Rb
LST-G-M
62
Deep
1
1
0
X
7,000
EB
Lap-C
NT, N1
17
F
75
Ra
Protruded type
90
Deep
0
0
X
0
1,800
EB
Lap-C
NT, N0
18
F
85
Ra
Protruded type
51
Deep
0
1
1
0
ND
EB
FU
ND
Pt, Patient; ly, lymphatic invasion (0, negative; 1, mildly positive); v, venous invasion (0, negative; 1, mildly positive; 2, moderately positive); pVM, pathological vertical margin (X, obscure; 0, negative; 1, positive); pHM, pathological horizontal margin (X, obscure; 0, negative; 1, positive); ESD, endoscopic submucosal dissection; F, female; Rb, lower rectum; LST-G-M, laterally spreading tumor (granular, mixed-nodular type); ND, no data; M, male; EB, en bloc resection; FU, follow-up observation; A, ascending colon; LST-G-H, laterally spreading tumor (granular, homogeneous type); IC, intramucosal; P, piecemeal resection; Slight, slightly invasive (<1000 mm) submucosal carcinoma; Lap-C, laparoscopy-assisted colectomy; NT, no tumor remaining; N0, no lymph node metastasis; C, cecum; Deep, deeply invasive (1000 mm) submucosal carcinoma; N2, number of lymph node metastasis 4; S, sigmoid colon; N1, number of lymph node metastases 3; Ra, upper rectum.
The safety of ESD for the resection of colorectal tumors >50 mm has not been confirmed. Saito et al4 reported that ESD for lesions >50 mm was an independent risk factor for the occurrence of adverse events. However, Nawata et al16 reported the safety of ESD followed by complete closure using clips for patients with large colorectal tumors, with a rate of adverse events similar to that for 20-mm to 50-mm lesions and lesions >50 mm. However, the number of lesions >50 mm in that series was comparatively small. In the current study, we successfully treated 70 colorectal lesions >50 mm safely, with a rate of adverse events similar to that in patients with 20-mm to 50- mm lesions. In addition, the dissection speed for lesions >50 mm was faster than that for 20-mmto 50-mm lesions. Nawata et al16 reported a similar result by using a scissor-type knife. There are several possible explanations for this observation. First, many of the lesions in the 20-mm to 50-mm group were LST-NG or a protruded type, whereas most lesions in the >50-mm group were laterally spreading tumors–granular type (LST-G). Fibrosis of the submucosal layer, which is often associated with LST-NG but not with LST-G, makes ESD difficult.17,18 Toyonaga et al19 reported that dissection during ESD for LST-NG was slower than that for LST-G. Therefore, the dissection speed was faster in the larger group. In this study, submucosal
invasive carcinomas were more frequent in lesions >50 mm (16 lesions). However, 14 of the 16 lesions were LST-G with limited submucosal fibrosis under the large nodules. As a result, submucosal invasion in the larger lesions did not affect the dissection speed significantly because the majority of the area of the larger lesions was intramucosal without submucosal fibrosis. The submucosal layer in protruded type lesions also has severe fibrosis at the center more frequently than is seen in LST-G lesions. Second, the dissection speed was faster in the larger lesions because longer and repetitive dissection strokes can be carried out in the larger lesions. Third, it is relatively easy to create a submucosal pocket in the case of large lesions. As we described previously,20-22 the pocket creation method is a new strategy to facilitate difficult colorectal ESD. A submucosal pocket is easier to create for large tumors than for small tumors. The pocket creation method provides good traction by getting into the submucosal layer and prevents leakage of injected sodium hyaluronate. The pocket creation method facilitates submucosal dissection just above the muscularis layer, resulting in a high-quality pathological specimen with a thick submucosal layer under the tumor. The pocket creation method is our standard approach for performing ESD throughout the alimentary tract. We
606 GASTROINTESTINAL ENDOSCOPY Volume 83, No. 3 : 2016
www.giejournal.org
Hayashi et al
believe that the difficulty of performing ESD for colorectal lesions is not only determined by tumor size but also macroscopic findings relating to severe submucosal fibrosis or in locations with unstable endoscopic maneuvering. There may be some concern regarding stricture formation after colorectal ESD. Stricture formation after esophageal ESD has been an important issue. ESD of large colorectal tumors is sometimes circumferential. However, the current study and other studies4,16 did not report the development of severe strictures. Jung et al23 reported the feasibility of ESD for lesions >10 cm and reported no strictures after ESD. Thus far, postprocedure strictures after ESD of large superficial colorectal lesions have not been reported. Further studies with more patients and longer follow-up are necessary to confirm this issue. We recognize that this study has some limitations, including (1) the retrospective nature of the study, (2) all patients were treated at a single center, and (3) there was no evaluation of long-term outcomes. These 3 issues all support the need for new large-scale, multicenter studies of ESD for large colorectal lesions. In conclusion, ESD for superficial colorectal tumors >50 mm is feasible and safe. Patients in this study had a high curative resection rate and a low adverse event rate. En bloc resection by ESD provides curative treatment and may reduce the need for surgical intervention.
REFERENCES 1. Yamamoto H, Koiwai H, Yube T, et al. A successful single-step endoscopic resection of a 40 millimeter flat-elevated tumor in the rectum: endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc 1999;50:701-4. 2. Yamamoto H, Kawata H, Sunada K, et al. Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood. Endoscopy 2003;35:690-4. 3. Yamamoto H. Endoscopic submucosal dissection for colorectal tumors. interventional and therapeutic gastrointestinal endoscopy. Front Gastrointest Res 2010;27:287-95. 4. Saito Y, Uraoka T, Yamaguchi Y, et al. A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video). Gastrointest Endosc 2010;72:1217-25. 5. Hayashi Y, Sunada K, Yamamoto H. Prototype holder adequately supports the overtube in balloon-assisted endoscopic submucosal dissection. Dig Endosc 2014;26:682. 6. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol 2015;20:207-39.
www.giejournal.org
ESD of colorectal tumors larger than 50 mm 7. Mounzer R, Das A, Yen RD, et al. Endoscopic and surgical treatment of malignant colorectal polyps: a population-based comparative study. Gastrointest Endosc 2015;81:733-40.e2. 8. Kitajima K, Fujimori T, Fujii S, et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol 2004;39:534-43. 9. Tanaka S, Terasaki M, Hayashi N, et al. Warning for unprincipled colorectal endoscopic submucosal dissection: accurate diagnosis and reasonable treatment strategy. Dig Endosc 2013;25:107-16. 10. Tanaka S, Haruma K, Oka S, et al. Clinicopathologic features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointest Endosc 2001;54:62-6. 11. Higaki S, Hashimoto S, Harada K, et al. Long-term follow-up of large flat colorectal tumors resected endoscopically. Endoscopy 2003;35: 845-9. 12. Hurlstone DP, Sanders DS, Cross SS, et al. Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection. Gut 2004;53:1334-9. 13. Hotta K, Fujii T, Saito Y, et al. Local recurrence after endoscopic resection of colorectal tumors. Int J Colorectal Dis 2009;24:225-30. 14. Saito Y, Fukuzawa M, Matsuda T, et al. Clinical outcome of endoscopic submucosal dissection versus endoscopic mucosal resection of large colorectal tumors as determined by curative resection. Surg Endosc 2010;24:343-52. 15. Terasaki M, Tanaka S, Oka S, et al. Clinical outcomes of endoscopic submucosal dissection and endoscopic mucosal resection for laterally spreading tumors larger than 20 mm. J Gastroenterol Hepatol 2012;27:734-40. 16. Nawata Y, Homma K, Suzuki Y. Retrospective study of technical aspects and adverse events of endoscopic submucosal dissection for large superficial colorectal tumors. Dig Endosc 2014;26:552-5. 17. Sato K, Ito S, Kitagawa T, et al. Factors affecting the technical difficulty and clinical outcome of endoscopic submucosal dissection for colorectal tumors. Surg Endosc 2014;28:2959-65. 18. Mizushima T, Kato M, Iwanaga I, et al. Technical difficulty according to location, and risk factors for perforation, in endoscopic submucosal dissection of colorectal tumors. Surg Endosc 2015;29:133-9. 19. Toyonaga T, Man-i M, Fujita T, et al. Retrospective study of technical aspects and adverse events of endoscopic submucosal dissection for laterally spreading tumors of the colorectum. Endoscopy 2010;42: 714-22. 20. Hayashi Y, Sunada K, Takahashi H, et al. Pocket-creation method of endoscopic submucosal dissection to achieve en bloc resection of giant colorectal subpedunculated neoplastic lesions. Endoscopy 2014;46(Suppl 1):E421-2. 21. Yamamoto H, Hayashi Y, Sunada K. How to conquer difficult ESD: duodenum, fibrosis, and more. In: Fukami N, ed. Endoscopic submucosal dissection–principles and practice. Heidelberg (Germany): Springer; 2015. p. 115-28. 22. Hayashi Y, Miura Y, Yamamoto H. Pocket-creation method for the safe, reliable, and efficient endoscopic submucosal dissection of colorectal lateral spreading tumors. Dig Endosc 2015;27:534-5. 23. Jung da H, Youn YH, Kim JH, et al. Endoscopic submucosal dissection for colorectal lateral spreading tumors larger than 10 cm: Is it feasible? Gastrointest Endosc 2015;81:614-20.
Volume 83, No. 3 : 2016 GASTROINTESTINAL ENDOSCOPY 607
Efficacy and safety of endoscopic submucosal dissection for superficial colorectal tumors more than 50 mm in diameter Yoshikazu Hayashi, MD, PhD,1 Satoshi Shinozaki, MD, PhD,1,4 Keijiro Sunada, MD,1 Hiroyuki Sato, MD, PhD,1 Yoshimasa Miura, MD,1 Yuji Ino, MD,1 Hisanaga Horie, MD, PhD,2 Noriyoshi Fukushima, MD, PhD,3 Alan K. Lefor, MD, PhD, MPH,2 Hironori Yamamoto, MD, PhD1 Tochigi, Japan
Background and Aims: The feasibility of endoscopic submucosal dissection (ESD) for large superficial colorectal tumors is undefined. The aim of this study was to assess the outcomes for patients undergoing ESD of superficial colorectal tumors larger than 50 mm. Methods: A total of 472 patients who underwent ESD for superficial colorectal tumors from 2010 to 2014 were enrolled. We retrospectively reviewed their records. Results: We compared patients with 20-mm to 50-mm lesions and those with lesions >50 mm regarding demographics, the ESD procedure, and histopathology. Among patients with lesions >50 mm, laterally spreading tumors nongranular and protruded types were uncommon. Histopathologically, deeply invasive (1000 mm) submucosal carcinomas were more frequent in lesions >50 mm (14% [10/70] vs 5% [20/402], P < .01). Technically, en bloc resection was successfully accomplished in 99% of patients (69/70). Although the total dissection time for lesions >50 mm was significantly longer than for lesions 20 mm to 50 mm (mean SD, 157 114 minutes vs 68 50 min; P < .01), dissection speed for lesions >50 mm was significantly faster than for lesions 20 mm to 50 mm (P < .01). There were no significant differences in en bloc R0 resection rate comparing both groups (>50 mm, 83% vs 20 mm to 50 mm, 87%; P Z .31). No perforations or postoperative bleeding occurred in patients with lesions >50 mm. Post-ESD colorectal strictures requiring intervention did not develop in any patient. Conclusions: ESD for superficial colorectal tumors >50 mm is feasible. ESD of these lesions had a high R0 resection rate and a low adverse event rate. En bloc resection by ESD provides adequate pathological specimens and may limit the need for surgical intervention. (Gastrointest Endosc 2016;83:602-7.)
At the end of the 20th century, we began performing endoscopic submucosal dissection (ESD) for colorectal neoplasms.1,2 Our institution is a pioneer in performing colorectal ESD. Colorectal ESD is considered more difficult than gastric ESD because the colon wall is thinner than the stomach. It is even more difficult when the tumor is located on a prominent fold and/or an area with sharp bending, which can result in loss of control of the endoscope.3 These factors may increase the rate of adverse events. A recent prospective study4 revealed that
colorectal lesions >50 mm are an independent risk factor for the occurrence of adverse events. We performed ESD for 1223 colorectal lesions from June 1998 to October 2014. Colorectal ESD was recognized as an advanced medical treatment by the Japanese government in April 2010. We have treated large tumors regardless of their size as long as a curative resection was expected. Technological improvements in the devices used to perform ESD over the past decade have led to a safe and reliable procedure. In our experience, ESD for colorectal lesions
Abbreviations: LST-G, laterally spreading tumor–granular type; LST-NG, laterally spreading tumor–nongranular type; PEG, polyethylene glycol.
Received March 26, 2015. Accepted August 2, 2015.
DISCLOSURE: Dr Yamamoto has received honoraria, grants, and royalties from and holds a patent for a double-balloon endoscope with Fujifilm. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2016 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.08.037
602 GASTROINTESTINAL ENDOSCOPY Volume 83, No. 3 : 2016
Current affiliations: Department of Medicine, Division of Gastroenterology (1), Departments of Surgery (2), and Pathology (3), Jichi Medical University, Shinozaki Medical Clinic (4), Tochigi, Japan. Reprint requests: Hironori Yamamoto, MD, PhD, Division of Gastroenterology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
www.giejournal.org
Hayashi et al
>50 mm in size is feasible. The aim of this study was to assess the safety and outcomes of patients undergoing ESD for superficial colorectal tumors, especially focusing on tumors >50 mm in diameter. The hypothesis of this study was that the resection rates are lower for lesions >50 mm.
METHODS We retrospectively reviewed all of the consecutive colorectal lesions treated by ESD between April 2010 and October 2014 at the Division of Gastroenterology of Jichi Medical University. To perform an up-to-date analysis, we used data from procedures after the recognition of colorectal ESD by the Japanese government. We reviewed patient records, operative records, and pathological findings. This study was approved by our institutional review board. Full written informed consent for ESD of the colorectal lesions was obtained from all patients. The indications for ESD of colorectal lesions included lesions considered difficult to treat with EMR in an en bloc fashion and image-enhanced magnifying endoscopy and magnifying chromoendoscopy not demonstrating submucosal invasion of 1000 mm. EUS using a miniprobe was performed for lesions with findings suspicious for invasive carcinoma by magnified endoscopy. When EUS clearly demonstrated tumor invasion to the muscularis propria, surgical resection was indicated. We did not preclude ESD due to technical difficulties such as large size, location, or endoscopic instability. To analyze the colorectal ESD results for a more homogeneous group of lesions, we included only superficial neoplastic lesions (adenomas and early carcinomas) with a diameter of 20 mm in this retrospective study. Bowel preparation was routinely performed by using oral sodium picosulfate 0.75% 10 mL on the night before the procedure and 2 L of polyethylene glycol (PEG) solution on the day of the ESD procedure. When the stool became watery and clear, bowel preparation was complete even if the dose of PEG solution had not reached 2 L. If the stool was not watery and clear after the routine preparation, another 1 to 2 L of PEG solution or 0.9 to 1.8 L of isotonic magnesium citrate solution were administered. Midazolam and pethidine were used for sedation in most patients, and butyl scopolamine or glucagon were used to decrease colonic peristalsis. An endoscope with a water jet instrument (EC-580RD/M; Fujifilm, Tokyo, Japan), carbon dioxide insufflation, and a small-caliber tip transparent (ST) hood (DH-15GR or DH-28GR; Fujifilm, Tokyo, Japan) fitted to the tip of the endoscope were used. When we could not maintain adequate maneuverability using a standard colonoscope, we used a balloon-assisted endoscope (EC-450BI5 and TS-13101; Fujifilm).5 Mucosal incision and submucosal dissection were performed by using a Flush knife BT (DK2618JB-15; Fujifilm) or a DualKnife (KD-650Q; Olympus, Tokyo, Japan) with an www.giejournal.org
ESD of colorectal tumors larger than 50 mm
electrosurgical generator (VIO300D; ERBE Elektromedizin Ltd, Tübingen, Germany). Hot hemostasis forceps (HOYA Corporation, Tokyo, Japan) were used to control bleeding. We divided the resected colorectal tumors into 2 groups based on size (20 mm-50 mm and >50 mm). We analyzed the size, shape, location, dissection time, and pathological findings for each lesion. The area of the resected specimen (mm2) was calculated using the following formula: major axis (mm)/2 minor axis (mm)/2 3.14. The dissection time (minutes) was defined from the start of cutting the mucosa to completion of the resection. The dissection speed (mm2/min) was calculated by using the area of resected specimen (mm2)/dissection time (minutes). For submucosal injection, 0.4% sodium hyaluronate (MucoUp; Seikagaku, Tokyo, Japan) was used. En bloc resection was defined as resection of the entire specimen in a single piece. En bloc R0 resection was pathologically defined by fulfilling an en bloc resection, with tumor-free vertical and horizontal margins. En bloc curative resection was pathologically defined by fulfilling en bloc R0 resection, a differentiated carcinoma or adenoma, with <1000 mm of submucosal invasion and no lymphovascular invasion, based on the 2014 Japanese Society for Cancer of the Colon and Rectum Guidelines for the treatment of colorectal cancer.6 The definition of perforation includes perforations during and after the ESD procedure. Postoperative bleeding was defined as overt bleeding within 14 days after ESD requiring endoscopic hemostasis.
Statistical analysis Sample size was calculated by estimating R0 resection rates of 90% and 70% for lesions 20 mm to 50 mm and >50 mm, respectively. The R0 resection rate for lesions 20 mm to 50 mm was estimated referring to previous literature showing an 88% en bloc resection rate and an 89% histopathological curative resection rate for carcinoma portions of lesions.4 The R0 resection rate limited to lesions >50 mm was estimated to be lower (70%), considering the technical difficulties. The calculated sample size was 150 for lesions 20 mm to 50 mm and 30 for lesions >50 mm determined with an allocation ratio of 5:1, an a error of 5%, and a power of 80%. Statistical analysis was performed by using Microsoft Excel 2013 (Microsoft Corp, Redmond, Wash) with add-in software Statcel 3 (OMS Publishing Inc, Saitama, Japan). Data are expressed as the median. Independent continuous variables were compared using the Mann– Whitney U test. Categorical data were compared using the c2 test or the Fisher exact test. Differences were considered statistically significant with a P value <.05.
RESULTS A total of 583 colorectal ESD procedures in 540 patients were performed during the study period. For the final Volume 83, No. 3 : 2016 GASTROINTESTINAL ENDOSCOPY 603
ESD of colorectal tumors larger than 50 mm
analysis, 111 lesions were excluded from the 583 lesions for the following reasons: (1) nonneoplastic lesions (n Z 18), (2) carcinoid tumor (n Z 24), (3) mucosaassociated lymphoid tissue lymphoma (n Z 1), (4) advanced cancer (n Z 3), (5) discontinuation of ESD during an earthquake (n Z 1), and (6) tumor size <20 mm in diameter (n Z 64). The remaining 472 lesions, including lesions 20 mm to 50 mm (n Z 402) and lesions >50 mm (n Z 70), were included in this study (Table 1). The study groups were large enough for statistical analysis according to the sample size calculation. The ESD procedures were carried out by 9 fully trained endoscopists (A, B, C, D, E, F, G, H, and I) and 7 advanced endoscopy trainees (Table 2). We compared the 2 groups of lesions with regard to their demographic, ESD procedure–specific, and pathological data (Table 1). Compared with smaller lesions, lesions >50 mm were located more often in the rectum (33/70 [47%] vs 102/402 [25%]; P < .01). Laterally spreading tumors–nongranular type (LST-NG) and protruded type tumors were fewer in number among the larger lesions. Histopathologically, deeply invasive (1000 mm) submucosal carcinomas were more frequent in the >50-mm group. Technically, en bloc resection was successfully accomplished in 99% of patients in both groups. Although total dissection time in the >50 mm group was significantly longer than that in the 20-mm to 50-mm group (P < .01), dissection speed in the >50-mm group was significantly faster than that in the 20-mm to 50-mm group (P < .01). There were no significant differences in en bloc R0 resection rate comparing both groups (>50-mm group, 83% vs 20-mm to 50–mm group, 87%; P Z .31). Although the curative resection rates in both groups were comparatively high, the rate for the >50-mm group was significantly lower than that of the 20-mm to 50-mm group (74% vs 84%, P Z .04). We compared rectal lesions (n Z 135) with other lesions (n Z 337) with regard to en bloc R0 resection rate and curative resection rate. The en bloc R0 resection rates were, respectively, 85% (n Z 115) versus 87% (n Z 294) without a significant difference (P Z .55). The curative resection rates were, respectively, 79% (n Z 107) versus 84% (n Z 284) without a significant difference (P Z .19). No perforation or postoperative bleeding occurred in the >50-mm group. No immediate bleeding with a decrease of >2 g/dL in hemoglobin level compared with preprocedure levels occurred during ESD in either group. Post-ESD colorectal stricture requiring intervention did not develop in any of the patients. After ESD, 18 of 70 patients in the >50-mm group (26%) were considered to have undergone a noncurative resection. The details of these 18 patients are shown in Table 3. All 4 adenomas with positive margins were observed without further resection. Deeply invasive submucosal carcinoma was present in 10 of the 18 patients (56%). Eight of these 10 patients underwent 604 GASTROINTESTINAL ENDOSCOPY Volume 83, No. 3 : 2016
Hayashi et al
laparoscopic resection, and the remaining 2 patients (patients 15 and 18 in Table 3) were carefully followed without resection because of severe comorbidities. For patient 6, the ESD specimen was intentionally cut by snaring without cauterization during the procedure because the large resected portion interfered with visibility during the remaining ESD procedure. Overall, 9 of the 18 patients (50%) underwent subsequent surgical resection, and 2 (22%) had lymph node metastases.
DISCUSSION After we began performing ESD for colorectal lesions, the ESD technique became widely accepted and is used in many institutions to resect large superficial colorectal tumors. In the past, performing ESD for colorectal tumors >50 mm was considered relatively difficult with increased risk.4 Because of technical challenges including lesion size, many large superficial colorectal tumors continue to be referred for surgical resection.7 In this study, we present data that support the feasibility and safety of performing ESD for superficial colorectal tumors >50 mm based on the experience at our institution. A 99% en bloc resection rate and a curative resection rate >70% based on histological evaluation is acceptable considering it is a less invasive procedure compared with surgical resection. The rate of adverse events in patients with lesions >50 mm is similar to that in patients with lesions 20 mm to 50 mm. The use of ESD for the resection of colorectal neoplasms >50 mm was limited due to concerns regarding the curability and safety of these lesions. In general, surgical resection and piecemeal EMR are used for large colorectal neoplasms. However, based on the data in this study, we believe that ESD is feasible for the treatment of superficial colorectal tumors >50 mm. ESD should result in a curative resection, considering the rather benign pathological nature of these superficial lesions. It benefits patients by avoiding surgical resection. The risk of lymph node metastases is considered negligible in patients with submucosal invasion <1000 mm and without lymphatic or vascular invasion, regardless of the lesion size based on studies of surgically resected specimens.8 In this study, the dissection time for lesions >50 mm is w2 hours, which is not longer than surgical resection under general anesthesia. The en bloc R0 resection rate was 83% for lesions >50 mm in this study. This R0 resection rate is a good outcome without surgical resection. Piecemeal EMR is another viable option, with the advantages of short procedure time and simple technique.9 However, precise pathological examination is limited due to the specimen being obtained in a piecemeal fashion, and an inadequate examination may lead to difficulty in www.giejournal.org
Hayashi et al
ESD of colorectal tumors larger than 50 mm
TABLE 1. Clinical characteristics of patients and treatment results >50-mm group
20-mm to 50-mm group No. of lesions Age, y, median SD (range)
P value
402
70
68 10 (35-94)
67 11 (38-88)
.68
161:241
40:30
<.01
217 (54)
32 (46)
.2
Sex, female:male, no. Tumor location, no. (%) Right side of colon Left side of colon
83 (21)
5 (7)
<.01
Rectum
102 (25)
33 (47)
<.01
LST-G
184 (46)
60 (86)
<.01
LST-NG
135 (34)
7 (10)
<.01
Protruded type
83 (21)
3 (4)
<.01
30 8 (20-50)
63 19 (51-133)
Adenoma
172 (43)
18 (26)
Intramucosal carcinoma
171 (43)
36 (51)
.17
Slightly invasive (<1000 mm) submucosal carcinoma
39 (10)
6 (9)
.77
Macroscopic type, no. (%)
Tumor diameter, mm, median SD (range) Pathological findings, no. (%)
Deeply invasive (1000 mm) submucosal carcinoma
20 (5)
10 (14)
<.01
394 (98)
69 (99)
1.00
40 9 (16-67)
73 22 (44-140)
En bloc resection, no. (%) Resected specimen diameter, mm, median SD (range) Dissection time, min, median SD (range) Dissection speed, mm2/min, median SD (range)
<.01
54 50 (7-425)
121 114 (22-634)
<.01
18.4 12.1 (2.9-71.4)
28.2 16.8 (9.4-83.4)
<.01
En bloc R0 resection, no. (%)
351 (87)
58 (83)
.31
En bloc curative resection, no. (%)
339 (84)
52 (74)
.04
Perforation, no. (%)
14 (4)
0 (0)
.24
Postoperative bleeding, no. (%)
9 (2.2)
0 (0)
.37
LST-G, Laterally spreading tumors, granular type; LST-NG, laterally spreading tumors, nongranular type.
identifying focal or deep submucosal invasion. A high local recurrence rate after piecemeal EMR (10%-23.5%) has been reported.10-15 The en bloc resection rate in the current study was 99% in patients with lesions >50 mm. Larger tumors are more likely to contain focal submucosal invasion. In this study, large en bloc ESD specimens enabled precise pathological evaluation of minute findings. These pathological results contribute to differentiating noncurative resections into the following categories: (1) deep submucosal invasion, (2) lymphatic or vascular invasion, and (3) unclear or positive margin. Detailed pathological evaluation helped to determine the need for additional treatment (Table 3). Although unclear or positive horizontal margins suggest an increased risk of local recurrence, focal deep submucosal and/or lymphovascular invasion indicate an increased risk of lymph node metastases, which necessitates consideration of the need for additional surgery. These important findings may be overlooked in a specimen obtained in a piecemeal fashion. Therefore, we believe that en bloc resection using ESD is the treatment of choice for large superficial colorectal tumors. www.giejournal.org
TABLE 2. Procedural experience of each endoscopist Experience, no.*
20-mm to 50-mm lesions, no. (%)
>50-mm lesions, no. (%)
A
238
42 (10)
11 (16)
B
226
67 (17)
10 (14)
C
222
18 (4)
6 (9)
D
73
50 (12)
7 (10)
E
68
46 (11)
15 (21)
F
99
73 (18)
8 (11)
G
69
45 (11)
11 (16)
H
35
25 (6)
2 (3)
I
46
36 (9)
0 (0)
1076
402y
70z
Endoscopist
Total
*Experience Z total number of colorectal endoscopic submucosal dissections performed between 1998 and October 2014. yTwenty-four of 402 lesions were resected by 7 advanced endoscopy trainees with attending endoscopists (A, B, D, E, F, G). zFour of 70 lesions were resected by 3 advanced endoscopy trainees with attending endoscopists (B, G).
Volume 83, No. 3 : 2016 GASTROINTESTINAL ENDOSCOPY 605
ESD of colorectal tumors larger than 50 mm
Hayashi et al
TABLE 3. Details of patients undergoing noncurative resection of lesions >50 mm in diameter
Pt
Sex Age, y Location
Endoscopic growth type
Tumor size, mm
Pathology
ly
v
Submucosal invasion En bloc pVM pHM depth, mm resection
After ESD
Surgical pathology
1
F
72
Rb
LST-G-M
72
Adenoma
ND ND
0
X
0
EB
FU
ND
2
F
61
A
LST-G-M
58
Adenoma
ND ND
0
1
0
EB
FU
ND
3
F
64
A
LST-G-H
59
Adenoma
ND ND
0
1
0
EB
FU
ND
4
F
83
Rb
LST-G-M
71
Adenoma
ND ND
1
0
0
EB
FU
ND
5
M
78
Rb
LST-G-M
66
Intramucosal
0
0
X
0
0
EB
FU
ND
6
F
88
Rb
LST-G-M
101
Intramucosal
0
0
1
1
0
P
FU
ND
7
F
68
A
LST-G-M
51
Slight
1
0
0
0
500
EB
FU
ND
8
F
51
A
LST-G-M
103
Slight
0
1
X
X
100
EB
Lap-C
NT, N0
9
M
52
C
LST-G-M
52
Deep
0
0
0
0
2000
EB
Lap-C
NT, N0
10
F
67
A
LST-G-M
71
Deep
0
0
0
0
4000
EB
Lap-C
NT, N0
11
F
62
C
LST-G-M
64
Deep
0
1
0
0
1600
EB
Lap-C
NT, N0
12
F
53
Rb
LST-G-M
56
Deep
0
1
0
0
5000
EB
Lap-C
NT, N0
13
F
58
S
LST-G-M
58
Deep
0
1
0
0
12,000
EB
Lap-C
NT, N2
14
M
60
Rb
LST-G-M
78
Deep
0
2
0
0
3,000
EB
Lap-C
NT, N0
15
M
76
Rb
LST-G-M
96
Deep
0
2
1
0
18,000
EB
FU
ND
16
M
70
Rb
LST-G-M
62
Deep
1
1
0
X
7,000
EB
Lap-C
NT, N1
17
F
75
Ra
Protruded type
90
Deep
0
0
X
0
1,800
EB
Lap-C
NT, N0
18
F
85
Ra
Protruded type
51
Deep
0
1
1
0
ND
EB
FU
ND
Pt, Patient; ly, lymphatic invasion (0, negative; 1, mildly positive); v, venous invasion (0, negative; 1, mildly positive; 2, moderately positive); pVM, pathological vertical margin (X, obscure; 0, negative; 1, positive); pHM, pathological horizontal margin (X, obscure; 0, negative; 1, positive); ESD, endoscopic submucosal dissection; F, female; Rb, lower rectum; LST-G-M, laterally spreading tumor (granular, mixed-nodular type); ND, no data; M, male; EB, en bloc resection; FU, follow-up observation; A, ascending colon; LST-G-H, laterally spreading tumor (granular, homogeneous type); IC, intramucosal; P, piecemeal resection; Slight, slightly invasive (<1000 mm) submucosal carcinoma; Lap-C, laparoscopy-assisted colectomy; NT, no tumor remaining; N0, no lymph node metastasis; C, cecum; Deep, deeply invasive (1000 mm) submucosal carcinoma; N2, number of lymph node metastasis 4; S, sigmoid colon; N1, number of lymph node metastases 3; Ra, upper rectum.
The safety of ESD for the resection of colorectal tumors >50 mm has not been confirmed. Saito et al4 reported that ESD for lesions >50 mm was an independent risk factor for the occurrence of adverse events. However, Nawata et al16 reported the safety of ESD followed by complete closure using clips for patients with large colorectal tumors, with a rate of adverse events similar to that for 20-mm to 50-mm lesions and lesions >50 mm. However, the number of lesions >50 mm in that series was comparatively small. In the current study, we successfully treated 70 colorectal lesions >50 mm safely, with a rate of adverse events similar to that in patients with 20-mm to 50- mm lesions. In addition, the dissection speed for lesions >50 mm was faster than that for 20-mmto 50-mm lesions. Nawata et al16 reported a similar result by using a scissor-type knife. There are several possible explanations for this observation. First, many of the lesions in the 20-mm to 50-mm group were LST-NG or a protruded type, whereas most lesions in the >50-mm group were laterally spreading tumors–granular type (LST-G). Fibrosis of the submucosal layer, which is often associated with LST-NG but not with LST-G, makes ESD difficult.17,18 Toyonaga et al19 reported that dissection during ESD for LST-NG was slower than that for LST-G. Therefore, the dissection speed was faster in the larger group. In this study, submucosal
invasive carcinomas were more frequent in lesions >50 mm (16 lesions). However, 14 of the 16 lesions were LST-G with limited submucosal fibrosis under the large nodules. As a result, submucosal invasion in the larger lesions did not affect the dissection speed significantly because the majority of the area of the larger lesions was intramucosal without submucosal fibrosis. The submucosal layer in protruded type lesions also has severe fibrosis at the center more frequently than is seen in LST-G lesions. Second, the dissection speed was faster in the larger lesions because longer and repetitive dissection strokes can be carried out in the larger lesions. Third, it is relatively easy to create a submucosal pocket in the case of large lesions. As we described previously,20-22 the pocket creation method is a new strategy to facilitate difficult colorectal ESD. A submucosal pocket is easier to create for large tumors than for small tumors. The pocket creation method provides good traction by getting into the submucosal layer and prevents leakage of injected sodium hyaluronate. The pocket creation method facilitates submucosal dissection just above the muscularis layer, resulting in a high-quality pathological specimen with a thick submucosal layer under the tumor. The pocket creation method is our standard approach for performing ESD throughout the alimentary tract. We
606 GASTROINTESTINAL ENDOSCOPY Volume 83, No. 3 : 2016
www.giejournal.org
Hayashi et al
believe that the difficulty of performing ESD for colorectal lesions is not only determined by tumor size but also macroscopic findings relating to severe submucosal fibrosis or in locations with unstable endoscopic maneuvering. There may be some concern regarding stricture formation after colorectal ESD. Stricture formation after esophageal ESD has been an important issue. ESD of large colorectal tumors is sometimes circumferential. However, the current study and other studies4,16 did not report the development of severe strictures. Jung et al23 reported the feasibility of ESD for lesions >10 cm and reported no strictures after ESD. Thus far, postprocedure strictures after ESD of large superficial colorectal lesions have not been reported. Further studies with more patients and longer follow-up are necessary to confirm this issue. We recognize that this study has some limitations, including (1) the retrospective nature of the study, (2) all patients were treated at a single center, and (3) there was no evaluation of long-term outcomes. These 3 issues all support the need for new large-scale, multicenter studies of ESD for large colorectal lesions. In conclusion, ESD for superficial colorectal tumors >50 mm is feasible and safe. Patients in this study had a high curative resection rate and a low adverse event rate. En bloc resection by ESD provides curative treatment and may reduce the need for surgical intervention.
REFERENCES 1. Yamamoto H, Koiwai H, Yube T, et al. A successful single-step endoscopic resection of a 40 millimeter flat-elevated tumor in the rectum: endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc 1999;50:701-4. 2. Yamamoto H, Kawata H, Sunada K, et al. Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood. Endoscopy 2003;35:690-4. 3. Yamamoto H. Endoscopic submucosal dissection for colorectal tumors. interventional and therapeutic gastrointestinal endoscopy. Front Gastrointest Res 2010;27:287-95. 4. Saito Y, Uraoka T, Yamaguchi Y, et al. A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video). Gastrointest Endosc 2010;72:1217-25. 5. Hayashi Y, Sunada K, Yamamoto H. Prototype holder adequately supports the overtube in balloon-assisted endoscopic submucosal dissection. Dig Endosc 2014;26:682. 6. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin Oncol 2015;20:207-39.
www.giejournal.org
ESD of colorectal tumors larger than 50 mm 7. Mounzer R, Das A, Yen RD, et al. Endoscopic and surgical treatment of malignant colorectal polyps: a population-based comparative study. Gastrointest Endosc 2015;81:733-40.e2. 8. Kitajima K, Fujimori T, Fujii S, et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol 2004;39:534-43. 9. Tanaka S, Terasaki M, Hayashi N, et al. Warning for unprincipled colorectal endoscopic submucosal dissection: accurate diagnosis and reasonable treatment strategy. Dig Endosc 2013;25:107-16. 10. Tanaka S, Haruma K, Oka S, et al. Clinicopathologic features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointest Endosc 2001;54:62-6. 11. Higaki S, Hashimoto S, Harada K, et al. Long-term follow-up of large flat colorectal tumors resected endoscopically. Endoscopy 2003;35: 845-9. 12. Hurlstone DP, Sanders DS, Cross SS, et al. Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection. Gut 2004;53:1334-9. 13. Hotta K, Fujii T, Saito Y, et al. Local recurrence after endoscopic resection of colorectal tumors. Int J Colorectal Dis 2009;24:225-30. 14. Saito Y, Fukuzawa M, Matsuda T, et al. Clinical outcome of endoscopic submucosal dissection versus endoscopic mucosal resection of large colorectal tumors as determined by curative resection. Surg Endosc 2010;24:343-52. 15. Terasaki M, Tanaka S, Oka S, et al. Clinical outcomes of endoscopic submucosal dissection and endoscopic mucosal resection for laterally spreading tumors larger than 20 mm. J Gastroenterol Hepatol 2012;27:734-40. 16. Nawata Y, Homma K, Suzuki Y. Retrospective study of technical aspects and adverse events of endoscopic submucosal dissection for large superficial colorectal tumors. Dig Endosc 2014;26:552-5. 17. Sato K, Ito S, Kitagawa T, et al. Factors affecting the technical difficulty and clinical outcome of endoscopic submucosal dissection for colorectal tumors. Surg Endosc 2014;28:2959-65. 18. Mizushima T, Kato M, Iwanaga I, et al. Technical difficulty according to location, and risk factors for perforation, in endoscopic submucosal dissection of colorectal tumors. Surg Endosc 2015;29:133-9. 19. Toyonaga T, Man-i M, Fujita T, et al. Retrospective study of technical aspects and adverse events of endoscopic submucosal dissection for laterally spreading tumors of the colorectum. Endoscopy 2010;42: 714-22. 20. Hayashi Y, Sunada K, Takahashi H, et al. Pocket-creation method of endoscopic submucosal dissection to achieve en bloc resection of giant colorectal subpedunculated neoplastic lesions. Endoscopy 2014;46(Suppl 1):E421-2. 21. Yamamoto H, Hayashi Y, Sunada K. How to conquer difficult ESD: duodenum, fibrosis, and more. In: Fukami N, ed. Endoscopic submucosal dissection–principles and practice. Heidelberg (Germany): Springer; 2015. p. 115-28. 22. Hayashi Y, Miura Y, Yamamoto H. Pocket-creation method for the safe, reliable, and efficient endoscopic submucosal dissection of colorectal lateral spreading tumors. Dig Endosc 2015;27:534-5. 23. Jung da H, Youn YH, Kim JH, et al. Endoscopic submucosal dissection for colorectal lateral spreading tumors larger than 10 cm: Is it feasible? Gastrointest Endosc 2015;81:614-20.
Volume 83, No. 3 : 2016 GASTROINTESTINAL ENDOSCOPY 607