2/49; 4.1% 7/41; PATIENTS AND METHODS

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1 A new technique for endoscopic mucosal resection with an insulated-tip electrosurgical knife improves the completeness of resection of intramucosal gastric neoplasms Received July 6, For revision August 27, Accepted October 17, From the Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital, East Chiba, Japan. Supported in part by a Grant-in-Aid for Cancer Research (12-2) from the Ministry of Health and Welfare of Japan. Reprint requests: Manabu Muto, MD, Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Chiba , Japan. Copyright 2002 by the American Society for Gastrointestinal Endoscopy /2002/$ /69/ doi: /mge Shin ichi Miyamoto, MD, Manabu Muto, MD, Yasuo Hamamoto, MD, Narikazu Boku, MD, Atsushi Ohtsu, MD, Satoshi Baba, MD, Motoki Yoshida, MD, Masana Ohkuwa, MD, Kouichi Hosokawa, MD, Hisao Tajiri, MD, Shigeaki Yoshida, MD Background: En bloc resection is optimal for the cure of gastric neoplasms by endoscopic mucosal resection (EMR). A new technique was developed for EMR by using an insulated-tip electrosurgical knife (IT-EMR). This is a report on the clinical application of IT-EMR. Methods: IT-EMR of 123 gastric tumors was performed in 120 patients. The en bloc resection rate, completeness of resection, and associated complications were evaluated. The local recurrence rate was studied for 90 intramucosal lesions followed for more than 6 months without further treatment. Results: The en bloc resection rate for all lesions was 54% (67/123 lesions). The en bloc resection rates were 82% (27/33) for lesions 10 mm or less in size, 54% (29/54) for those between 11 mm and 20 mm, and 31% (11/36) for those of over 20 mm. Complete resection rates in the cases with en bloc resection were 78% (21/27) for lesions 10 mm or less in size, 76% (22/29) for those between 11 mm and 20 mm, and 73% (8/11) for those over 20 mm. There were no episodes of major bleeding that required blood transfusion or surgical intervention; minor bleeding including oozing occurred in 38% (47/123). Perforation occurred in 1 case (1/123; 0.8%). The local recurrence rate for lesions resected en bloc was significantly lower than that for lesions resected as multiple fragments (respectively, 2/49; 4.1% vs. 7/41; 17%: p = 0.041). Conclusions: IT-EMR is feasible in clinical practice and has a high en bloc resection rate. En bloc resection may reduce the rate of local recurrence. Endoscopic mucosal resection (EMR) is a standard treatment for mucosal gastric neoplasms because of its minimal invasiveness and excellent results in terms of survival after treatment. 1,2 It is generally accepted in Japan that EMR can be performed for mucosal gastric cancers that are 20 mm or less in diameter. However, studies have shown that the frequency of lymph node metastasis with mucosal gastric cancers less than 30 mm in diameter without histologic ulceration or lymphatic permeation is extremely low (0.36%). 3 This evidence encouraged us to perform EMR for much larger mucosal cancers. For curative treatment, the most important issue is completeness of the resection. However, conventional techniques of EMR such as the strip biopsy, originally developed based on the snare-biopsy method by Tada et al., 4,5 are thought to be inadequate for en bloc resection of large lesions. The multiple fragments that result from this form of resection make it difficult to evaluate the completeness of the excision histologically, which may lead to incomplete therapy and local tumor recurrence. 6 Therefore, en bloc resection with an adequate tumor cell-negative margin is essential for a successful outcome. For the purpose of en bloc resection, Hosokawa and Yoshida 7 developed a new device for EMR: the insulated-tip electrosurgical knife (IT-knife). It was reported that EMR with an IT-knife (IT-EMR) made it possible to perform en bloc resections of larger early stage gastric cancers with a reduction in the recurrence rate. 8 These encouraging results led us to use this method as a standard technique for larger gastric mucosal neoplasms. The aim of this retrospective study with a larger number of cases was to evaluate the feasibility of IT-EMR as a standard technique for EMR. PATIENTS AND METHODS A total of 123 lesions in 120 patients (88 men, 32 women; median age 67 years, range years) were treated with IT-EMR between July 1994 and December These consisted of 91 early stage gastric cancers and 32 adenomas. Because the main aim of the study was to evaluate the feasibility of IT-EMR for the treatment of gastric neoplasm, both cancers and adenomas were included. For all lesions, the following criteria were fulfilled: (1) histopathologic diagnosis by biopsy of intestinaltype adenocarcinoma or adenoma; (2) endoscopic diagnosis of an intramucosal lesion; and (3) absence endoscopically of macroscopic ulceration and fold convergence. For the definition and macroscopic typing of early stage gastric cancers, the Japanese Classification of Gastric Carcinoma was used. 9 IT-EMR was performed as previously described (Fig. 1). 7,8,10,11 The procedure was performed by using a conventional single-channel endoscope (GIF-Q230,GIF-Q240; Olympus Optical Co., Ltd., Tokyo, Japan). In this method, several spots were marked 5 to 10 mm outside the margin of the target lesion by using a marking tip device (type CD-IL, Olympus) and electrosurgical coagulation current. 576 GASTROINTESTINAL ENDOSCOPY VOLUME 55, NO. 4, 2002

2 Gastric neoplasms: endoscopic mucosal resection with insulated-tip diathermic knife S Miyamoto, M Muto, Y Hamamoto, et al. If endoscopy subsequent to IT-EMR disclosed that the marked spots remained, further resection was carried out to ensure complete removal of the lesion. Histologic assessment Resected specimens were cut into 2-mm slices according to the Japanese Classification of Gastric Carcinoma 9 and were evaluated histologically as to whether tumorous glandular tissue was present or absent at the margin of each slice. Definition of complete and incomplete resection When en bloc resection could be performed, it was easy to evaluate the completeness of the resection histologically. Efficacy of resection was determined according to the completeness of resection: when the tumor was resected as a single fragment, was contained within the mucosal layer, and when the margin was definitely free of tumorous glands histologically, resection was considered to be complete. If the lesion was resected as 2 or more fragments, resection was also defined as complete if the margin of the fragment containing an intramucosal tumor was free from tumorous glands and the additional fragments did not contain any tumorous glands histologically. However, with resection of multiple fragments it is difficult to reconstruct the lesion accurately and to evaluate the resected margin histologically. Therefore, multifragment resections were defined as incomplete when the tumorous glands were present in 2 or more fragments histologically, even if endoscopically the lesion was completely removed. If the lateral margin of a lesion could not be evaluated histologically because of the effects of the electrosurgical current or mechanical damage, the resection was defined as incomplete. Complications Bleeding was classified as being of 2 types: minor and major. Minor bleeding was defined as bleeding that was stopped by endoscopic treatment by using methods such as hemoclip application, 12 hypertonic saline solution/epinephrine injection, 13 ethanol injection, 13 heat probe coagulation, 14 or argon plasma coagulation. 15 Major bleeding was defined as bleeding that required transfusion or surgical intervention. Perforation was diagnosed endoscopically just after resection and/or by the presence of free air on a plain abdominal radiograph or CT. Recurrence after EMR Endoscopic examinations were carried out every 3 to 4 months during the first year after EMR, every 6 months during the second year, and annually thereafter. Biopsy specimens were taken from any ulcerative lesions identified to confirm the presence of residual tumor and local recurrence histologically. US and/or CT were carried out at least once per year in patients who had malignant lesions resected to search for lymphadenopathy or distant metastases. To investigate whether the recurrence rate decreased, data were analyzed for 90 intramucosal lesions resected by IT-EMR and observed for more than 6 months A B C D E F G H Figure 1. Schematic drawing of IT-EMR. A, Indigo carmine dye spraying to clearly demarcate target lesion. B, Several spots marked outside lesion using marking tip device. C, Saline solution with diluted epinephrine (0.02 mg/ml) injected into submucosal layer around lesion to lift it from muscle layer. D, Initial incision of mucosa made with conventional needle knife to allow insertion of insulated-tip of IT-knife. E, Circumferential incision completed with IT-knife just outside marked spots with repeated injection of saline solution/epinephrine. F, Additional injection of enough saline solution/epinephrine made before snaring to prevent perforation. G, Raised lesion resected with standard snare with combination of cutting and coagulation electrosurgical current. H, Resected specimen removed with grasping forceps. (median 20 months; range 6-59 months) without additional treatment. Of the 33 patients excluded from this analysis, 30 had been observed for less than 6 months, and 3 required additional surgical resection. One of these patients proved to have invasion of the submucosa by cancer on histologic examination after EMR and 2 had a major complication (bleeding and perforation) during EMR. Statistical analysis All statistical analysis was done with the Stat View software package for Macintosh (version 5; Abacus Concepts, Inc., Berkeley, Calif.). The chi-square test was used for categorical variables. For statistical comparisons of discrete variables responsible for local recurrence after IT-EMR, a logistic-regression analysis was used to examine the odds ratio. A p value less than 0.05 was considered statistically significant. RESULTS Clinicopathologic features The size of lesions treated by EMR was estimated by reviewing photographs of the endoscopic lesions and assigning each lesion to 1 of 3 categories: 10 mm or less, between 11 mm and 20 mm, and over 20 mm. As shown in Table 1, about one-third (36/123; 29%) of the lesions were over 20 mm in diameter. En bloc resection rate The en bloc resection rate according to the tumor size is shown in Table 2. Regardless of the size, the en bloc IT-EMR rate was high: lesions 10 mm or less, 82% (27/33); between 10 mm and 20 mm, 54% (29/54); and over 20 mm, 31% (11/36). The en bloc VOLUME 55, NO. 4, 2002 GASTROINTESTINAL ENDOSCOPY 577

3 S Miyamoto, M Muto, Y Hamamoto, et al. Gastric neoplasms: endoscopic mucosal resection with insulated-tip diathermic knife Table 1. Characteristics of the lesions n = 123 No. (%) Size (27) (44) (29) Macroscopic type Elevated 88 (72) Flat and depressed 35 (28) Histology Cancer 91 (74) Adenoma 32 (26) Table 2. En bloc resection rate and complete resection rate of IT-EMR Size (mm) En bloc resection Complete resection 10 82% (27/33) 64% (21/33) % (29/54) 41% (22/54) 21 31% (11/36) 22% (8/36) Total 54% (67/123) 41% (51/123) Table 3. Complete resection rate of IT-EMR Complete resection rate Figure 2. En bloc resection rate for IT-EMR according to location of tumor. L, Lower third of stomach; M, middle third of stomach; U, upper third of stomach; AW, anterior wall; LC, lesser curvature; PW, posterior wall; GC, greater curvature. resection rate according to location is shown in Figure 2. Location of the lesion was determined with the Japanese Classification of Gastric Cancer 9 by dividing the longitudinal axis of the stomach in thirds and the cross-sectional circumference into 4 equal sections (Fig. 2). Even for tumors located in the proximal third and on the posterior wall of the stomach, locations in which it is technically difficult to perform en bloc resection, the en bloc resection rate was high: respectively, 60% (6/10) and 65% (15/23). Complete resection rate The complete resection rate according to tumor size is also shown in Table 3. For lesions less than 20 mm in size, the complete resection rate was 49% (43/87). As shown in Table 3, when en bloc resection was successful the complete resection rate was 73% (8/11), which includes lesions over 20 mm in size, whereas resection of lesions as multiple fragments had an extremely low rate of complete resection, even for lesions less than 20 mm in size (19%, 6/31). Complications Complications in relation to tumor size are shown in Table 4. Multi- Size (mm) En bloc resection fragment resection p Value 10 74% (20/27) 17% (1/6) < % (17/29) 25% (5/25) < % (8/11) 0% (0/25) < Total 67% (45/67) 11% (6/56) < Table 4. Complications of IT-EMR % of bleeding Size (mm) Minor bleeding Major bleeding % of perforation (10/33) 0 (0/33) 3 (1/33) (20/54) 0 (0/54) 0 (0/54) (17/36) 0 (0/36) 0 (0.36) Total 38 (47/123) 0 (0/123) 0.8 (1/123) There was no major bleeding; minor bleeding occurred in 38% (47/123). There was one perforation (1/123; 0.8%). Recurrence after IT-EMR The overall local recurrence rate was 10% (9/90). A logistic-regression analysis was carried out to determine which variables correlated with local recurrence after IT-EMR. The variables were classified into 2 categories: lesional factors (size, macroscopic type, location) and technical factors (endoscopic and histologic evaluations for completeness of resection). The statistical analysis is summarized in Table 5. Analysis based on the lesional factors showed that tumor size larger than 20 mm was significantly associated with local recurrence (odds ratio 5.36: 95% CI [1.23, 23.33], p = 0.02), whereas macroscopic type and 578 GASTROINTESTINAL ENDOSCOPY VOLUME 55, NO. 4, 2002

4 Gastric neoplasms: endoscopic mucosal resection with insulated-tip diathermic knife S Miyamoto, M Muto, Y Hamamoto, et al. Table 5. Predictors of local recurrence after IT-EMR by univariate logistic regression analysis (n = 90) Variables associated with lesional factors Odds ratio 95% CI p Value Tumor size (mm) 20* vs. > , Macroscopic type Depressed* vs. elevated , Location 1 L* vs. M + U , Location 2 AW + LC* vs. PW + GC , Variables associated with technical factors Endoscopic evaluation En bloc* vs. multifragment resection , Histologic evaluation Complete* vs. incomplete resection , L, Lower third of stomach; M, middle third of stomach; U, upper third of stomach; AW, anterior wall; LC, lesser curvature; PW, posterior wall; GC, greater curvature. *Reference category. Table 6. Local recurrence rate after IT-EMR (n = 90) Size Endoscopic evaluation Histologic evaluation (mm) En bloc resection Multifragment resection Complete resection Incomplete resection 10 0% (0/20) 20% (1/5) 0% (0/17) 13% (1/8) % (0/20) 12% (2/17) 0% (0/14) 9% (2/23) 21 22% (2/9) 21% (4/19) 13% (1/8) 25% (5/20) Total 4.1%* (2/49) 17% (7/41) 2.6%* (1/39) 16% (8/51) *p < location were not associated. Analysis based on the technical factors showed that both multifragment resections and incomplete resections were closely associated with local recurrence (odds ratio 4.84: 95% CI [0.95, 24.75], p = 0.04; odds ratio 7.07: 95% CI [0.85, 59.16], p = 0.03, respectively). Table 6 shows the relationship between tumor size and endoscopic and histologic evaluations for completeness of resection. The local recurrence rate in cases of en bloc resection was significantly lower than that for multifragment resections (2/49; 4.1% vs. 7/41; 17%, p = 0.041). In particular, no local recurrence was observed in patients with tumors less than 20 mm in size if en bloc resection was achieved. As expected, similar findings were observed in the cases of complete resection. In addition, no lymph node metastases or distant metastases were observed in any patient. DISCUSSION EMR has become a standard treatment for mucosal gastric neoplasm because it is less invasive and provides better quality of life for patients when compared with surgical resection. However, incomplete resection results in residual or recurrent lesions. To achieve cure by EMR, en bloc resection is optimal for all lesions because it may reduce the local recurrence rate. 5,8,16 Conventional EMR with a double-channel endoscope is technically easy, but proves to be difficult for en bloc resection of lesions over 20 mm in size. To achieve complete resection, several new techniques based on the original strip-biopsy method have been developed including EMR with a cap-fitted endoscope (EMRC), 17 endoscopic aspiration mucosectomy, 18,19 and EMR with a ligating device. 20,21 However, even if these methods are indicated for larger tumors, it might be difficult to perform en bloc resection with a sufficient tumor cell-negative margin because the actual size of the resected specimen will be much larger than the tumor itself. In fact, Noda et al. 22 found that all patients with tumors larger than 30 mm had incomplete resections after conventional EMR. In the present study, the en bloc resection rate with IT-EMR was high for large lesions, including those over 30 mm. Moreover, when en bloc resection was performed by IT-EMR, the complete resection rate was high, regardless of lesion size. Even for lesions more than 20 mm in size, the complete resection rate was 73% if en bloc resection was performed by IT-EMR. In contrast, in the series of Miyata et al., 16 the complete resection rate was only 30% for tumors of the same size. This indicates that complete resection can be achieved for a larger proportion of mucosal gastric neoplasms with IT-EMR. Tumor location is the other important factor that affects the success of en bloc resection. En bloc resection by conventional EMR may be especially difficult for lesions in the proximal body and the posterior wall of the stomach because geometrically they lie tangential to the endoscope. However, even for such lesions, the en bloc resection rate for IT- EMR was high (6/10; 60% and 15/23; 65%, respectively). Therefore, IT-EMR may resolve the technical difficulty of resection in relation to tumor location. Tumor size larger than 20 mm and resection as multiple fragments were significant risk factors for VOLUME 55, NO. 4, 2002 GASTROINTESTINAL ENDOSCOPY 579

5 S Miyamoto, M Muto, Y Hamamoto, et al. Gastric neoplasms: endoscopic mucosal resection with insulated-tip diathermic knife local recurrence in the present study. Indeed, if en bloc resection was performed, no local recurrence was observed with tumors less than 20 mm in size, and the frequency of local recurrence was low even with lesions larger than 20 mm. This indicates that en bloc resection should be performed to reduce the possibility of local recurrence. Based on the results of the current study, IT-EMR reduces the rate of local recurrence because the en bloc resection rate with IT-EMR is high, even for large lesions, compared with conventional EMR. In addition, the local recurrence rate in the cases of incomplete resection in the present series (8/51; 16%) was low by comparison with the rate noted in previous studies (63/178; 35%). 2 In IT-EMR, the target lesion including an adequate tumor cell-negative margin is accurately identified with the circumferential incision line before snare excision. Therefore, even in the cases defined as incomplete resection based on uncertainty as to the histological status of the lateral margin, the tumor may actually have been completely resected. Safety in addition to cure is an important issue. The major complications of EMR are bleeding and perforation. Bleeding occurs on average in 1.6% in all EMR cases, 2 although definitive criteria for bleeding have not been established. In the present study, all cases of bleeding, even if minor, were analyzed because this reflects clinical practice. The explanation for the relatively high frequency of bleeding in patients undergoing IT-EMR might be in part related to the criteria for bleeding. With regard to severity, oozing was present in most cases of bleeding; spurting bleeding was rare. As reported by Ono et al., 11 even spurting bleeding can be stopped by endoscopic treatment, which obviates the need for blood transfusion. Moreover, the bleeding rate seems to differ according to the treatment techniques. For example, the bleeding rate for EMRC was reported to be 11.6% by Tani et al. 23 and 7.0% by Chonan et al. 24 The high bleeding rate associated with IT-EMR might be related to the circumferential incision rather than from a lack of technical experience on our part. 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