Does submucosal fibrosis affect the results of endoscopic submucosal dissection of early gastric tumors?

ORIGINAL ARTICLE: Clinical Endoscopy

Does submucosal fibrosis affect the results of endoscopic submucosal dissection of early gastric tumors? Jae Yoon Jeong, MD,1 Young-Ha Oh, MD,2 Yeon Hwa Yu, MD,1 Hye Sun Park, MD,1 Hang Lak Lee, MD,1 Chang Soo Eun, MD,1 Dong Soo Han, MD1 Seoul, Korea

Background: Endoscopic submucosal dissection (ESD) is an effective treatment of early gastric tumors, but submucosal fibrosis can be an obstacle to successful ESD. Objective: To examine the association between endoscopic and pathologic factors and submucosal fibrosis in early gastric tumors, and to measure the association between degree of submucosal fibrosis and outcomes of ESD. Design: A retrospective study. Setting: An academic medical center. Patients: From November 2006 to April 2011, 161 patients with 167 early gastric tumors treated by ESD. Intervention: ESD. Main Outcome Measurements: Endoscopic and pathologic factors related to submucosal fibrosis. Procedure time, en bloc resection rate, and complications according to degree of submucosal fibrosis. Results: In univariate analysis, the presence of endoscopic submucosal fibrosis was significantly related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Multivariate analysis for these factors showed that endoscopic submucosal fibrosis was independently associated with lesions in tumor size greater than 30 mm, in the proximal portion of the stomach, and more common in adenocarcinomas than in adenomas. After correction for multiple testing, only the middle of the stomach as a locational risk factor retains statistical significance. Also, the more advanced the endoscopic submucosal fibrosis, the longer the time required for ESD (P ⬍ .0001). The severity of endoscopic submucosal fibrosis was associated with a lower en bloc resection rate and with abundant immediate bleeding. Limitations: Retrospective, single-center study. Conclusion: Submucosal fibrosis of early gastric tumors is closely related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Moreover, the greater the degree of submucosal fibrosis the longer the time taken for the ESD procedure and the higher the frequency of complications such as perforation and immediate bleeding. (Gastrointest Endosc 2012;76:59-66.)

Endoscopic submucosal dissection (ESD) is an effective treatment for early gastric tumors.1,2 ESD has the advantage over conventional EMR of a lower rate of recurrence because of the en bloc resection of a larger lesion. However, because of its technical difficulty, it takes longer, and

there is a greater risk of complications such as bleeding and perforation.3,4 The success rate of ESD depends on the technical proficiency of the endoscopist and the condition of the gastric tumor. Even for a skilled endoscopist, however, submu-

Abbreviations: CI, confidence interval; ESD, endoscopic submucosal dissection; IQR, interquartile range; ORs, odds ratios.

Received October 27, 2011. Accepted March 10, 2011.

DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. Copyright © 2012 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2012.03.172

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Current affiliations: Department of Internal Medicine (1), Department of Pathology (2), Hanyang University College of Medicine, Seoul, Korea. Reprint requests: Dong Soo Han, MD, PhD, Internal Medicine, Hanyang Univesity Guri Hospital, 249-1 Gyomoon-dong, Guri-si, Gyunggi-do 471-701, Seoul, Korea.

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cosal fibrosis can be an obstacle to success.5-8 Submucosal fibrosis, which usually results from inflammation or tumor invasion,9 makes it harder to lift the tumor tissue from the muscle layer. This in turn lengthens the procedure time, creates risk of complications such as perforations, and reduces the success rate of complete en bloc resection.1,8 Despite its importance, there has been little or no investigation of the relationship between the degree of submucosal fibrosis and outcomes of ESD in early gastric tumors. Accordingly, the objectives of this study were first, to examine the association between endoscopic and pathologic factors and submucosal fibrosis in early gastric tumors; second, to examine the association between degree of submucosal fibrosis and outcomes of ESD; and third, to measure the agreement between endoscopic observation of submucosal fibrosis and actual histologic findings.

METHODS Patients We retrospectively assessed cases at Hanyang University Guri hospital, Gyunggi-do, South Korea, from November 2006 to April 2011, during which period 167 neoplasms in 161 patients with gastric adenoma or early gastric cancer were treated with ESD out of a total of 175 neoplasms in 169 patients (median age, 67 years; interquartile range [IQR], 58-72 years; men:women ⫽ 113:48). The 8 neoplasms that were excluded comprised 5 that had no tumor in the ESD tissue and 3 gastrointestinal stromal tumors. All ESDs were performed by 2 experienced endoscopists (D.S.H, C.S.E), and the study was approved by the Institutional Review Board of Hanyang University Guri hospital.

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Take-home Message ●

●

Submucosal fibrosis of early gastric tumors is closely related to tumor size, location, ulceration, histologic finding, and submucosal invasion. The greater the extent of submucosal fibrosis, the longer the time taken to perform the endoscopic submucosal dissection (ESD) and the higher the frequency of complications, such as perforation and immediate bleeding. When findings associated with submucosal fibrosis are seen, the endoscopist needs extra caution because the chance of complication encountered through ESD may be higher.

impossible, direct dissection with mainly the Flex knife through the fibrotic portions was performed. Visible nonbleeding vessels were cauterized with hemostatic forceps (Coagrasper, Olympus) during the submucosal dissection, and prophylactic hemostasis was performed with hemostatic forceps or by argon plasma coagulation. A Roth net (US Endoscopy Group, Mentor, OH, USA) was used to retrieve the lesions.

Definitions

The ESD procedures were performed only on patients who agreed to the treatment after receiving full explanations. The patients were sedated with intravenous midazolam (0.1 mg/kg), propofol (0.5 mg/kg), and pethidine (25 mg) just before the procedures, and oxygen saturation and electricardiograms were monitored. We used a singlechannel endoscope (GIF-Q260 or GIF-H260; Olympus Optical Co, Ltd, Tokyo, Japan) attached to a transparent hood. After circumference of the lesion was marked with a Flex knife, a mixture of saline solution, indigo carmine, and diluted epinephrine (1:10,000) was injected into the submucosal layer. Circumferential incisions were made with a Flex knife (Olympus or Kachu Technology, Korea) or an insulation-tipped knife (Olympus). Submucosal dissection was carried out with an insulation-tipped or Flex knife, after repeated submucosal injection, until complete removal of the lesion. In cases with mild submucosal fibrosis, dissection was attempted trying as much as possible to penetrate under the fibrotic portions, while avoiding the portions with submucosal fibrosis. In cases with submucosal fibrosis so severe that such attempts were

Endoscopically, the degree of submucosal fibrosis was classified as follows, based on the findings obtained after a solution including indigo carmine was injected under the submucosal layer (Fig. 1): F0, no fibrosis, which appeared as a blue transparent layer; F1, mild fibrosis, which appeared as a white web-like structure in the blue submucosal layer; and F2, severe fibrosis, which appeared as a white muscle-like structure without a blue transparent layer.10 Histologically, the degree of submucosal fibrosis was evaluated by an expert pathologist (Y.H.O.) using slides stained with hematoxylin and eosin and with Masson’s trichrome, without knowledge of any clinical data. The intensity of histologic submucosal fibrosis was scored as 0 (negative stain, no fibrosis, nearly normal appearance), 1 (weak fibrosis), and 2 (dense fibrosis). The extent of fibrosis on the same slides was assessed from the percentage of the total area that was stained with Masson’s trichrome stain, as follows: 0 (0%-10%), 1 (11%-50%), and 2 (51%-100%). The final staining score was obtained as the sum of the intensity and extent scores. Fibrosis with a final score of 0 was considered as no fibrosis (F0), 1 and 2 as mild fibrosis (F1), and 3 and 4 as severe fibrosis (F2) (Fig. 2). Ulceration included open ulcer and ulcer scar. Immediate bleeding was defined as spurting or oozing of blood from a vessel during ESD. Delayed bleeding was defined as changes in hematologic laboratory test results, or clinical symptoms such as hematemesis and melena, which indicate gastrointestinal bleeding after ESD. Finally, procedure time was defined as the time from insertion of the

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ESD procedure

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Figure 1. Degrees of endoscopic submucosal fibrosis in early gastric tumors. A, F0, no fibrosis, which manifests as a blue transparent layer. B, F1, mild fibrosis, which appears as a white web-like structure in the blue submucosal layer. C, F2, severe fibrosis, which appears as a white muscle-like structure without a blue transparent layer.

endoscope to complete resection of the lesion. It included any time taken for hemostasis during the dissection.

Statistics

Figure 2. Sections of endoscopic submucosal dissections, showing representative findings of submucosal fibrosis. A, F0, no fibrosis. B, F1, mild fibrosis. C, F2, severe fibrosis. (Masson’s trichrome stain, orig. mag. ⫻40.)

Although some of the patients studied had more than 1 neoplasm treated by ESD procedures, quantities observed in different ESD procedures were assumed to constitute statistically independent observations for the purposes of data analysis. Statistical analyses were carried out with PASW 18.0

Software for Windows (Chicago, Ill). Quantitative data were summarized by the mean and SD presented as “mean (SD)” or by the median and the interquartile range (IQR) presented as “median (IQR).” Endoscopic and pathologic factors that affected endoscopic submucosal fibrosis were analyzed by using Pearson’s ␹2 test or the Fisher exact test.

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We subsequently performed multivariate logistic regression analysis, taking as candidate variables for the analysis the factors that showed significant associations with endoscopic submucosal fibrosis in the univariate analyses. That analysis produced estimated odds ratios (ORs) and their 95% confidence intervals, where the ORs refer to the following baseline categories: ⱕ10 mm in size of tumor, lower in location, ulceration (-), adenoma in histologic finding, and mucosa in depth, respectively. For predictors with more than 2 categories, dummy variables were used to index the different values. Also, we used 1-way analysis of variance and Pearson’s ␹2 test or the Fisher exact test to analyze the association between the degree of endoscopic submucosal fibrosis and the outcomes of ESD. In addition, analysis of covariance was used to evaluate the relationship between the degree of endoscopic submucosal fibrosis and procedure time, where the covariate adjusted in the analysis was the size of the lesions. An overall P value ⬍.05 was required for statistical significance. Because it is recognized that there was multiple testing of outcome data arising from individual lesions and procedures, using the method of Bonferroni, P values should be taken as significant only if they have nominal values (P ⬍ .01) to help avoid spurious, artifactual significance. Furthermore, the P values for the univariate statistical tests of association between submucosal fibrosis and lesion/procedure characteristics were not corrected for multiple testing, because those tests were taken as exploratory for the subsequent multivariate logistic regression analysis. The kappa statistic was used to measure the agreement between estimates of endoscopic submucosal fibrosis and histologic submucosal fibrosis. It quantifies agreement over and above what might occur by chance alone. A kappa value of 0 means that agreement was no more than what could be expected by chance alone, whereas perfect agreement is shown by a kappa value equal to 1. When kappa is greater than 0.60, but no more than 0.80, there is said to be substantial agreement. The P value given with a kappa statistic refers to rejection of the null hypothesis of only chance agreement.

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imal portion of the stomach, and to adenocarcinomas rather than adenomas (Table 2). After correction for multiple testing, only the middle of the stomach as a locational risk factor retained statistical significance.

Endoscopic submucosal fibrosis and outcomes of ESD The mean (SD) procedure time was 89.8 (68.7) minutes. The types of resection done on the lesion by means of ESD were as follows: en bloc resections 156 (93.4%), piecemeal resections 11 (6.6%), and complete resections 135 (80.8%). The mean procedure time of the ESD in relation to the degree of endoscopic submucosal fibrosis were as follows: F0 63.0 minutes (57.0-69.0 minutes, 95% CI), F1 128.6 minutes (107.2-150.0 minutes, 95% CI), and F2 242.0 minutes (193.0-291.0 minutes, 95% CI). Clearly, the more advanced the endoscopic submucosal fibrosis, the longer the ESD procedure (Fig. 3, P ⬍ .0001). After adjustment for the size of the lesion, an important determinant factor for procedure time, the mean procedure time according to the degree of endoscopic submucosal fibrosis were as follows: F0 64.2 minutes (56.4-72.1 minutes, 95% CI), F1 126.0 minutes (110.1-142.0 minutes, 95% CI), and F2 235.6 minutes (213.1-260.1 minutes, 95% CI), showing significant difference between groups (P ⬍ .0001). Also, the severity of endoscopic submucosal fibrosis was associated with lower en bloc resection rates and with abundant immediate bleeding. However, delayed bleeding was not significantly related to the degree of endoscopic submucosal fibrosis (Table 3). Both of the cases of perforation had endoscopic submucosal fibrosis of grade F2.

Comparison between endoscopic and histologic estimates of submucosal fibrosis The results of a comparison between endoscopic and histologic grading of submucosal fibrosis are summarized in Table 4. The concordance was 86.8% (Kendall’s tau-b and ␬ coefficients were 0.776 and 0.711, respectively) (P ⬍ .0001).

DISCUSSION RESULTS

The mean (SD) size of the lesions in the 167 cases was 19.1 (10.6) mm. Lesions with endoscopic submucosal fibrosis were found in 44 of the 167 cases (26.3%). In univariate analysis of endoscopic and pathologic factors, tumors with endoscopic submucosal fibrosis differed significantly from those without endoscopic submucosal fibrosis with respect to tumor size, location, ulceration, histologic findings, and submucosal invasion (Table 1). Multivariate analysis for these factors showed that endoscopic submucosal fibrosis was independently related to lesions in tumor size greater than 30 mm, in the prox-

We have demonstrated that submucosal fibrosis during ESD is significantly correlated with tumor size, location, ulceration, histologic type, and submucosal invasion. In multivariate analysis, it was shown that the frequency of submucosal fibrosis was higher in lesions larger than 30 mm, in the proximal portion of the stomach, and classified as adenocarcinomas. Also, the more advanced the endoscopic submucosal fibrosis was, the longer the ESD took and the more complications occurred. In most previous studies it was accepted that the larger the lesions and the closer they were to the proximal portion of the stomach, the greater were the dangers of bleeding, incomplete resection, and delays in procedure.1,3,8,11,12 However, those studies, unlike ours, could

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Endoscopic submucosal dissection of early gastric tumors

TABLE 1. Univariate analysis of factors anticipated to be associated with endoscopic submucosal fibrosis Total (n ⴝ 167)

No submucosal fibrosis (n ⴝ 123)

Submucosal fibrosis (n ⴝ 44)

Size of tumor, mm

.015

ⱕ10

33 (19.8%)

29 (23.6%)

4 (9.1%)

11-20

86 (51.5%)

66 (53.6%)

20 (45.4%)

21-30

32 (19.2%)

20 (16.3%)

12 (27.3%)

ⱖ31

16 (9.5%)

8 (6.5%)

8 (18.2%) ⬍.0001

Location Lower

104 (62.3%)

91 (74.0%)

13 (29.5%)

Middle

53 (31.7%)

26 (21.1%)

27 (61.4%)

Upper

10 (6.0%)

6 (4.9%)

4 (9.1%)

Endoscopic findings

.790

Elevated

52 (31.1%)

39 (31.7%)

13 (29.5%)

Flat or depressed

113 (68.9%)

84 (68.3%)

31 (70.5%)

Ulceration

.026

No

130 (77.8%)

101 (82.1%)

29 (65.9%)

Yes

37 (22.2%)

22 (17.9%)

15 (34.1%)

Time from diagnosis to ESD, days

.936

ⱕ10

29 (17.4%)

23 (18.7%)

6 (13.6%)

11-20

65 (38.9%)

47 (38.2%)

18 (40.9%)

21-30

39 (23.4%)

29 (23.6%)

10 (22.7%)

31-40

8 (4.8%)

6 (4.9%)

2 (4.6%)

ⱖ41

26 (15.5%)

18 (14.6%)

8 (18.2%)

Histologic findings

.011

Adenoma

99 (59.3%)

80 (65.0%)

19 (43.2%)

Adenocarcinoma

68 (40.7%)

43 (35.0%)

25 (56.8%)

Depth Mucosa Submucosa

P value

.022 157 (94.0%)

119 (96.7%)

37 (84.1%)

10 (6.0%)

4 (3.3%)

6 (15.9%)

ESD, Endoscopic submucosal dissection.

not establish whether submucosal fibrosis in early gastric tumors was related to the size or location of the lesions. It seems likely that the reason submucosal fibrosis is more common in the proximal portion of the stomach is related to the structural difference between the regions. There are median longitudinal oblique muscles in the innermost portions of the anterior and posterior walls of the body where perforation vessels divide to form a network, and we suggest that layers of fasciae, formed by fibrosis around the transverse vasoganglia, render the fibrosis more intense in those regions than in any others.13 As

other studies have shown, procedure time are extended and the frequency of complications is higher for lesions in the body rather than in the antrum.1,3,8 We believe that this is due, in part, to differences in the difficulty of dissection resulting from the regional differences in structure, as well as to the technical difficulty resulting from the effects of gravity on the efficiency of submucosal dissection. Adenocarcinomas were more closely related to submucosal fibrosis than were adenomas, including high-grade dysplasias. We believe that this results from the fact that fibroblasts and myofibroblasts cause fibrosis of the sub-

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TABLE 2. Multivariate analysis of factors predictive of endoscopic submucosal fibrosis Odds ratio (95% CI)

P value

Size of tumor, mm ⱕ10

1

11-20

1.915 (0.537-6.830)

.316

21-30

3.333 (0.808-13.754)

.096

ⱖ31

6.308 (1.208-32.946)

.029*

Location Lower

1

Middle

8.679 (3.532-21.324)

⬍.0001

Upper

5.548 (1.184-26.009)

.030*

Figure 3. Procedure times for cases of endoscopic submucosal fibrosis of different severities: F0, no fibrosis; F1, mild fibrosis, F2, severe fibrosis. Boxplots summarize the procedure times for each severity classification. For each boxplot, the box gives the interquartile range, that is, the 25th to 75th percentiles of times, with the line inside the box denoting the median, the 50th percentile of data. The limits indicate the range other than outliers, and the outliers are shown with circles.

Ulceration

mucosal layer as a result of the desmoplastic response to cancers.14 Previous studies have shown that cancer invasion causes submucosal fibrosis,9 and the present study also indicates that submucosal invasion is likely to cause submucosal fibrosis. But, as also shown in this study, it is difficult to establish the depth of invasion when submucosal fibrosis is accompanied by cancer invasion. Therefore, in such cases we suggest that a more stringent standard than a depth of 500 ␮m should be adopted for ESD.15 We found that the more severe the submucosal fibrosis, the longer the time taken for the ESD procedure. Likewise, recent studies have shown that submucosal fibrosis is a predictor of delayed ESD procedure.1,8 In addition, we showed that procedure time varied according to the extent of submucosal fibrosis. As suggested in a previous study,1 the en bloc resection rate is low in cases of submucosal fibrosis. Also, the seriousness of the submucosal fibrosis is related to the frequency of immediate bleeding, and in the 2 cases in which perforation occurred, the submucosal fibrosis was classified as F2. These prolonged procedure times, low en bloc resection rate, and high frequency of

complications result from the technical difficulty of dissecting deeper tissue to obtain complete resection where there is fibrosis. Therefore, it is necessary to perform ESD more carefully, or even to stop, when serious submucosal fibrosis of grade F2 is encountered. Until now, almost no study has evaluated an efficient ESD method for lesions with submucosal fibrosis. In general, to perform resection with fibrotic portions, lesions around the fibrotic portions should first be dissected to evaluate the anatomic relationship between the muscle and submucosal layer. Dissection toward the fibrotic portion should then be performed. In addition, a knife with a firm body would be more helpful in dissecting these portions. For example, a fixed Flex knife is more convenient than an ordinary Flex knife in such situations.16 Submucosal injection with normal saline solution may not achieve adequate lifting in cases with submucosal fibrosis. However, sodium hyaluronate may be a good choice in ESD cases with submucosal fibrosis because it does not cause tissue damage, and it has an ability to maintain submucosal lifting compared with other injection fluids because of its high viscosity.17 We evaluated the concordance between the endoscopic and histologic classifications of submucosal fibrosis. To our knowledge, no study of the extent of agreement between these measures has been published. We found a high degree of concordance, which suggests that endoscopic assessment of submucosal fibrosis is an objective measure of submucosal fibrosis. This study had several limitations. First, it was a retrospective study involving quite a limited number of cases from a single center. As a result, we could not clearly demonstrate significant relationships between submucosal fibrosis and differentiation and perforation. However, because the baseline characteristics of the cases in this study, such as age, sex, tumor size, and location were qualitatively similar to those obtained in larger studies of ESD,1,3,8

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No

1

Yes

2.002 (0.773-5.190)

.153

Histologic findings Adenoma Adenocarcinoma

1 2.536 (1.024-6.277)

.044*

Depth Mucosa Submucosa

1 3.647 (0.726-18.334)

.116

CI, confidence interval. *Nominally significant for a single test of hypothesis; however, correction for multiple testing of data removes this significance.

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Endoscopic submucosal dissection of early gastric tumors

TABLE 3. Resection methods, immediate bleeding, and delayed bleeding according to degree of endoscopic submucosal fibrosis Endoscopic submucosal fibrosis

No (F0)

Mild (F1)

Severe (F2)

⬍.0001

Resection methods En bloc resection (n ⫽ 156) Piecemeal resection (n ⫽ 11)

120 (76.9%)

25 (16.0%)

11 (7.1%)

3 (27.3%)

5 (45.4%)

3 (27.3%) ⬍.0001

Immediate bleeding No (n ⫽ 130)

110 (84.6%)

13 (10%)

7 (5.4%)

Yes (n ⫽ 37)

13 (35.2%)

17 (45.9%)

7 (18.9%)

Delayed bleeding

.247

No (n ⫽ 158) Yes (n ⫽ 9)

115 (72.8%)

29 (18.3%)

14 (8.9%)

8 (88.9%)

1 (11.1%)

0 (0%)

TABLE 4. Agreement between endoscopic and histologic estimates of severity of submucosal fibrosis Histologic submucosal fibrosis Endoscopic submucosal fibrosis

No (n ⴝ 111)

Mild (n ⴝ 46)

Severe (n ⴝ 10)

No (n ⫽ 123)

108

15

0

Mild (n ⫽ 30)

3

27

0

Severe (n ⫽ 14)

0

4

10

␬ ⫽ 0.711 (P ⬍ .0001).

we consider the outcomes of this study to be significant. Second, in comparison with other previous studies, the incidence of submucosal fibrosis in the present study was higher, which may have led to a possible selection bias. The reason for this, we presume, is the larger number of ulcerations that included scar, which induces submucosal fibrosis, than in other studies.8 In addition, because there is no concrete definition of submucosal fibrosis observed through an endoscopic view, a subjective classification of a submucosal fibrosis from the observer’s point of view may have caused a difference from other previous studies. To complement this limitation, we have evaluated the concordance between the endoscopic submucosal fibrosis and the histologic submucosal fibrosis, which ultimately resulted in a significant consistency. Third, even though ESD was performed by 2 experienced endoscopists, their procedure times were longer than those in recent larger studies.1,8 This may have been because of the higher proportion of cases of submucosal fibrosis in this study, and we succeeded in having fewer complications such as delayed bleeding. In other words, the cases in this study were very difficult, and ESD was performed in a very careful manner to minimize complications. Finally, addiwww.giejournal.org

P value

tional endoscopic predictive factors, such as the expertise of the endoscopist, and injection fluid, were not included in the present study. In summary, we found that submucosal fibrosis of early gastric tumors was closely related to tumor size, location, ulceration, histologic features, and submucosal invasion. Also, more severe submucosal fibrosis was associated with prolonged ESD and with complications such as perforation and immediate bleeding. This study is significant in that it appears to be the first that seeks to identify factors related to submucosal fibrosis during ESD, as well as associations between the degree of submucosal fibrosis and ESD outcomes. When such findings associated with submucosal fibrosis are seen, the endoscopist needs extra caution because the chances of complication encountered through ESD may be higher. However, we think that a large prospective study is needed to confirm the associations between submucosal fibrosis and the various associated factors. REFERENCES 1. Chung IK, Lee JH, Lee SH, et al. Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study. Gastrointest Endosc 2009; 69:1228-35. 2. Onozato Y, Ishihara H, Iizuka H, et al. Endoscopic submucosal dissection for early gastric cancers and large flat adenomas. Endoscopy 2006;38: 980-6. 3. Mannen K, Tsunada S, Hara M, et al. Risk factors for complications of endoscopic submucosal dissection in gastric tumors: analysis of 478 lesions. J Gastroenterol 2010;45:30-6. 4. Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009; 58:331-6. 5. Yamamoto S, Uedo N, Ishihara R, et al. Endoscopic submucosal dissection for early gastric cancer performed by supervised residents: assessment of feasibility and learning curve. Endoscopy 2009;41:923-8. 6. Imagawa A, Okada H, Kawahara Y, et al. Endoscopic submucosal dissection for early gastric cancer: results and degrees of technical difficulty as well as success. Endoscopy 2006;38:987-90.

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7. Kim ES, Cho KB, Park KS, et al. Factors predictive of perforation during endoscopic submucosal dissection for the treatment of colorectal tumors. Endoscopy 2011;43:573-8. 8. Ahn JY, Choi KD, Choi JY, et al. Procedure time of endoscopic submucosal dissection according to the size and location of early gastric cancers: analysis of 916 dissections performed by 4 experts. Gastrointest Endosc 2011;73:911-6. 9. Fu K, Sano Y, Kato S, et al. Hazards of endoscopic biopsy for flat adenoma before endoscopic mucosal resection. Dig Dis Sci 2005;50:1324-7. 10. Matsumoto A, Tanaka S, Oba S, et al. Outcome of endoscopic submucosal dissection for colorectal tumors accompanied by fibrosis. Scand J Gastroenterol 2010;45:1329-37. 11. Lee TH, Cho JY, Chang YW, et al. Appropriate indications for endoscopic submucosal dissection of early gastric cancer according to tumor size and histologic type. Gastrointest Endosc 2010;71:920-6. 12. Goto O, Fujishiro M, Kodashima S, et al. Is it possible to predict the procedural time of endoscopic submucosal dissection for early gastric cancer? J Gastroenterol Hepatol 2009;24:379-83.

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13. Park J. Endoscopic submucosal dissection in anatomically difficult lesion [in Korean]. Korean J Gastrointest Endosc 2010;40(Suppl 1): 256-61. 14. Semba S, Kodama Y, Ohnuma K, et al. Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells. Br J Cancer 2009;101: 1365-73. 15. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219-25. 16. Jang JS. Submucosal dissection technique [in Korean]. Korean J Gastrointest Endosc 2011;43(Suppl 1):25-7. 17. Fujishiro M, Yahagi N, Nakamura M, et al. Successful outcomes of a novel endoscopic treatment for GI tumors: endoscopic submucosal dissection with a mixture of high-molecular-weight hyaluronic acid, glycerin, and sugar. Gastrointest Endosc 2006;63:243-9.

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