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Clinical outcomes of endoscopic submucosal dissection for superficial Barrett's adenocarcinoma
ORIGINAL ARTICLE
Clinical outcomes of endoscopic submucosal dissection for superficial Barrett’s adenocarcinoma Kenichi Kagemoto, MD,1 Shiro Oka, MD, PhD,2 Shinji Tanaka, MD, PhD,2 Tomohiro Miwata, MD,1 Yuji Urabe, MD, PhD,1 Yoji Sanomura, MD, PhD,2 Shigeto Yoshida, MD, PhD,1 Toru Hiyama, MD, PhD,3 Koji Arihiro, MD, PhD,4 Kazuaki Chayama, MD, PhD1 Hiroshima, Japan
Background: Advances in diagnostic techniques have allowed early stage detection of superficial Barrett’s adenocarcinoma (SBA) as well as resection by endoscopic submucosal dissection (ESD). Few reports exist, however, on the safety and efficacy of ESD for SBA. Objective: To analyze outcomes of ESD for SBA in relation to clinicopathological features of the lesions. Design: Retrospective study. Setting: University hospital. Patients: Twenty-three patients (21 men, 2 women; mean age, 63 years) with 26 SBAs. Intervention: ESD. Main Outcome Measurements: We examined outcomes of ESD in relation to the clinicopathological features of SBAs. The main outcomes assessed were en bloc resection rate, operation time, adverse event rates, additional resection rate, and time between ESD and any recurrence. Results: Twenty lesions (87%) derived from short-segment Barrett’s esophagus, and 3 lesions (13%) derived from long-segment Barrett’s esophagus. The majority of SBAs (54%) were located in the 0 to 3 o’clock circumferential quadrant. Median tumor size was 15 mm (range 5-60 mm). Macroscopic types were flat elevated (n Z 13, 50%), depressed (n Z 12, 46%), and protruded (n Z 1, 4%). The SBAs appeared red (n Z 23, 88%) or normally pale (n Z 3, 12%). Under magnifying narrow-band imaging, all SBAs showed an irregular mucosal pattern and an irregular vascular pattern. The endoscopic en bloc resection rate was 100% (26/26), and the pathological en bloc resection rate was 85% (22/26). The median procedure time was 95 minutes (range, 30-210 minutes). Delayed bleeding occurred in 1 case, but there was no perforation. The SBAs were of the differentiated type (n Z 25, 96%) or poorly differentiated type (n Z 1, 4%). The tumor had invaded the superficial muscularis mucosa (n Z 3, 12%), lamina propria mucosa (n Z 5, 19%, deep muscularis mucosa (n Z 9, 34%), SM1 (n Z 3, 12%), and SM2 (n Z 6, 23%). Additional surgical resection after ESD was performed in 9 cases, and there were no residual tumors, but 1 lymph node metastasis was found. There were no recurrent tumors; however, 1 metachronous adenocarcinoma was diagnosed 42 months after ESD. Limitations: Single-center, retrospective study. Conclusions: ESD appears to be a safe and effective treatment strategy for early stage SBA. (Gastrointest Endosc 2014;-:1-7.)
Abbreviations: BE, Barrett’s esophagus; ESD, endoscopic submucosal dissection; LSBE, long-segment Barrett’s esophagus; NBI, narrow-band imaging; RFA, radiofrequency ablation; SBA, superficial Barrett’s adenocarcinoma; SSBE, short-segment Barrett’s esophagus. DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.01.022
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Received September 20, 2013. Accepted January 9, 2014. Current affiliations: Department of Gastroenterology and Metabolism, Graduate School of Biomedical Sciences, Hiroshima University (1), Departments of Endoscopy (2), Health Service Center (3), and Pathology (4), Hiroshima University Hospital, Hiroshima, Japan. Reprint requests: Shiro Oka, MD, PhD, Department of Endoscopy, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 7348551, Japan.
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ESD for superficial Barrett’s adenocarcinoma
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The incidence of superficial Barrett’s adenocarcinoma (SBA) has increased steadily in Western countries.1 In Japan, most esophageal cancers are squamous cell carcinomas. SBAs are few, reportedly accounting for only 0.9% of all esophageal cancers in Japan.2 However, the incidence of Barrett’s esophagus (BE) and thus SBA is expected to increase in Japan because of a decrease in Helicobacter pylori infection rates and the westernization of the Japanese diet, both of which are thought to promote GERD.3-5 With advances in endoscopic technologies, it has become possible to detect SBA in the early stage2 and then go on to treat these cases by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). However, few reports exist regarding ESD for SBA.6,7 ESD has become a standard treatment in Japan for both early gastric cancer and superficial esophageal cancer.8-13 ESD involves circumferential mucosal incision and direct submucosal dissection, making it possible to safely resect even large tumors en bloc and obtain endoscopically clear margins. We conducted a retrospective analysis of the clinicopathological features and outcomes of SBA resected by ESD in our hospital.
Take-home Message All superficial Barrett’s adenocarcinomas (SBAs) had irregular mucosal and vascular patterns under magnifying narrow-band imaging (NBI); thus, NBI is useful for diagnosing SBA. En bloc resection was achieved in all cases, and clear resection margins were pathologically confirmed in 85% of cases. Endoscopic submucosal dissection for early stage SBAs appears to be a safe and effective treatment strategy.
high-contrast imaging of the vascular and mucosal patterns within the BE segment. We use a simplified classification system to assess BE and SBAs.14 According to this system, NBI descriptors (mucosal and vascular patterns) are classified as regular for nondysplastic BE and irregular for dysplastic BE/early adenocarcinoma.14 All procedures were performed with the use of a magnifying endoscope (GIF- Q240Z or -Q260Z; Olympus Medical Systems, Tokyo, Japan) in combination with the NBI system.
ESD procedure PATIENTS AND METHODS Patients The study group comprised 23 patients with 26 SBAs resected by ESD at Hiroshima University Hospital between April 2006 and June 2013. All lesions had been detected by endoscopic screening for GI carcinoma or by endoscopic surveillance after treatment for GI disease. All 26 SBAs had been diagnosed endoscopically as intramucosal carcinoma by standard observation, magnifying observation, and EUS before ESD. During the same period, surgery for SBAs was performed in 10 cases because these lesions were clinically diagnosed as submucosal massive carcinoma. No SBA was treated by EMR during this period. All patients had been informed of the benefits and risks of ESD before providing written consent for the procedure. The patients were identified through a search of our hospital endoscopy records, and patients’ records were accessed so that pertinent information could be obtained for the study. The ESD procedures and assessment of the study data are described in the following. The study was conducted with approval from the institutional review board of Hiroshima University.
Narrow-band imaging assessment and procedure Narrow-band imaging (NBI) is a noninvasive optical technique that uses reflected light to visualize the superficial structure of the organ surface. It has been used to visualize morphologic changes in the structure of esophageal lesions because it allows detailed high-resolution and 2 GASTROINTESTINAL ENDOSCOPY Volume
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For ESD, each patient was placed in the left lateral position, and the operator and assistant stood on the left side of the examination table and in front of the patient. A single-channel endoscope (GIF-Q260J or -H260Z; Olympus or EG-450RD5 or EG-590WR; FUJIFILM, Tokyo, Japan) or 2-channel endoscope (GIF-2TQ260M; Olympus) was used for conventional endoscopic observation. The circumference of the lesion was marked with argon plasma coagulation. Local injection and incision were first performed from the distal side. The injection solution consisted of a 10% glycerin solution with 0.025% epinephrine and 0.005% indigo carmine. The solution was injected under the epithelium to produce a cushion of adequate elevation. The marks were checked, and the elevated area was incised with a Hook-knife (Olympus) in the VIO300D cut mode. Injection and incision were repeated from the proximal side, thus extending the incision circumferentially around the entire lesion. A soft, transparent hood was attached to the tip of the endoscope before incision so that adequate tension for dissection would be achieved. The HookKnife, ITknife nano (Olympus), and/or SB knife (Sumitomo Bakelite, Tokyo, Japan) was used to exfoliate the submucosa in the VIO300D cut or coagulation mode. Injection of 10% glycerin solution and sodium hyaluronate with 0.0025% epinephrine into the submucosa was performed as needed, and further resection was carried out to ensure total removal of the lesion. Post-ESD bleeding was defined as bleeding after the procedure as manifested by a decrease in the hemoglobin level of 2 g/dL or greater below the most recent preoperative level, observation of any bleeding source, or massive melena. Perforation was diagnosed endoscopically just www.giejournal.org
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after resection or by the presence of free air on a plain abdominal radiograph or CT image.
Histological assessment after ESD Resected specimens were stretched and pinned to polystyrene foam boards and fixed in 10% formalin for 24 hours. After fixation, all resected specimens were cut into longitudinal slices 2 mm in width. The tissue specimens were embedded in paraffin, sectioned at 4 mm, and stained with hematoxylin and eosin. Histological evaluation was performed by 2 experienced pathologists according to World Health Organization criteria.
Surveillance after ESD Follow-up surveillance endoscopy was performed at our hospital 3 to 12 months after ESD according to the type of resection. In cases of complete resection, endoscopic examination was performed 12 months after the procedure and once every 12 months thereafter. In cases of incomplete resection, endoscopic examination was performed 3, 6, and 12 months after the procedure during the first year, and every 12 months thereafter. A tumor detected in close proximity to the scar resulting from ESD was regarded as a local recurrent tumor, whereas 1 or more primary tumors detected more than 1 cm from the ESD scar were regarded as metachronous tumors. CT scanning was performed annually to detect any lymph node or other organ metastasis.
Study data For the purpose of the study, the following data were obtained: patient age and sex; BE classification (shortsegment BE [SSBE] or long-segment BE [LSBE]); length of the BE segment; presence of esophageal hiatal hernia, reflux esophagitis, or atrophic gastritis; lesion characteristics (circumferential location, size, color, and gross type); NBI features (mucosal and vascular patterns); outcome of ESD (en bloc resection rates; operation time; adverse events including bleeding, perforation, and stenosis; additional surgical resection rate, followup time after ESD, and recurrence (assessed in cases that were followed for more than 12 months); and histological findings (histology, tumor depth, and lymphovascular invasion). We adhered to the Japanese Classification of Esophageal Cancer15 for histological assessment. En bloc resection was defined as removal of the lesion in a single piece for which the margin appeared endoscopically tumor free. Pathological en bloc resection was defined as removal of the lesion in a single piece for which the horizontal and vertical margins were shown to be free of both carcinoma and dysplasia (R0 resection). SM1 and SM2 invasion was also defined according to the Japanese Classification of Esophageal Cancer.15 www.giejournal.org
ESD for superficial Barrett’s adenocarcinoma
RESULTS Characteristics of the patients who underwent ESD for SBAs are shown in Table 1. The male/female sex ratio was 21/2, and the mean age of the patients was 63 years (range 45-84 years). The SSBE/LSBE ratio was 20/3. Twenty patients (87%) had an esophageal hiatal hernia. Atrophic gastritis was absent in 14 patients; closed-type atrophic gastritis was present in 8 patients and open-type atrophic gastritis in 1 patient (4%). Four patients (17%) had a reflux esophagitis. Characteristics of SBAs are shown in Table 2. The SBAs were located in the 4 circumferential quadrants as follows: 0 to 3 o’clock quadrant, 14 lesions (54%); 3 to 6 o’clock quadrant, 7 lesions (27%); 9 to 12 o’clock quadrant, 7 lesions (27%); and 6 to 9 o’clock quadrant, 4 lesions (15%). (Note that the percentages are not mutually exclusive because some lesions occupied 2 or more quadrants.) The median tumor diameter was 15 mm (range 5-60 mm). The red/normal pale appearance ratio was 23/2. Macroscopic types of SBAs were as follows: flat elevated type (0-II), 13 lesions (50%); depressed type (0-IIc), 12 lesions (46%); and protruded type (0-I), 1 lesion (4%). Under magnifying NBI, all lesions had both irregular mucosal and vascular patterns. Representative endoscopic and histological images of SBA are shown in Figure 1. The outcomes of ESD are shown in Table 3. The average standard deviation operation time was 93 48 minutes (range 30-210 minutes). En bloc resection was achieved in all cases and clear resection margins were pathologically confirmed in 22 specimens (85%). Thus, en bloc resection was considered pathologically incomplete in 4 specimens: 3 with a positive vertical margin and 1 with a positive horizontal margin. Bleeding after ESD occurred in 1 case (4%), and this bleeding was controlled by endoscopic electrocoagulation. No perforation occurred. Stenosis occurred in 4 cases (15%), and all stenoses were treated by balloon dilation. Histological findings are shown in Table 2. All but 1 lesion (ie, 25/26 or 96%) was of the differentiated type. No lymphovascular invasion was found. The depths of tumor invasion were as follows: to the superficial muscularis mucosa, 3 lesions (12%); to the lamina propria mucosa, 5 lesions (19%); to the deep muscularis mucosa, 9 lesions (34%); to SM1, 3 lesions (12%); and to SM2, 6 lesions (23%). Additional surgical resection was performed in 9 (35% of lesions) cases (tumor invasion to the submucosa in 8 cases and undifferentiated type tumor in 1 case). There were no residual tumors, but 1 lymph node metastasis was found in the following metachronous case after surgical resection. Additional surgical resection was not performed in 1 SM1 case and in 1 horizontal margin-positive case. The average standard deviation follow-up period after ESD was 33 24 months. In 24 cases that we could follow for more than 12 months, the recurrence rate was 0%. There was no Volume
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TABLE 2. Lesion characteristics (N [ 26)
TABLE 1. Clinical characteristics of study patients (N [ 23)
Location, no. (%)
Age, y Mean SD Median (range)
0-3 o’clock
14 (54)
63 10
3-6 o’clock
7 (27)
61 (45-84)
6-9 o’clock
4 (15)
9-12 o’clock
7 (27)
Sex, no. (%) Male
21 (91)
Female
Circulation, no. (%)
2 (9)
Barrett’s esophagus, no. (%) SSBE
20 (87)
LSBE
3 (13)
w1/4
19 (73)
1/4–1/2
5 (19)
1/2–3/4
1 (4)
3/4–all
1 (4)
Tumor diameter, mm
Esophageal hiatal hernia, no. (%) Present
20 (87)
Absent
3 (13)
Mean SD Median (range)
19.0 13.6 15 (5-60)
Color, no. (%)
Reflux esophagitis, no. (%) Present
4 (17)
Absent
19 (83)
Red
23 (88)
Pale
3 (12)
Macroscopic type, no. (%)
Atrophic gastritis, no. (%)
0-I
1 (4)
Absent
14 (61)
0-II
13 (50)
Closed type
8 (35)
0-IIb
0 (0)
Open type
1 (4)
0-IIc
12 (46)
SD, Standard deviation; SSBE, short-segment Barrett’s esophagus; LSBE, long-segment Barrett’s esophagus.
treatment-related or SBA-related death. However, 1 metachronous adenocarcinoma was found 42 months after ESD. In this patient, ESD was thus performed again, and en bloc resection was achieved. However, the tumor had invaded the submucosa, and additional surgical resection was performed. There was no residual tumor, but 1 metastatic lymph node was found. Since the surgical treatment, there has been no local or metastatic recurrence in this case.
Mucosal pattern, no. (%) Regular
0 (0)
Irregular
26 (100)
Vascular pattern, no. (%) Regular
0 (0)
Irregular
26 (100)
Histology, no. (%) Well differentiated
18 (69)
Moderately differentiated
7 (27)
Poorly differentiated
1 (4)
Tumor depth, no. (%)
DISCUSSION We assessed 26 SBAs resected by ESD in 23 patients. Sixty percent (n Z 14) of the patients had no atrophic gastritis, and 8 of the 9 patients with atrophic gastritis had the closed type. However, only 17% of our patients had reflux esophagitis. A very large general population (N Z 3000) study conducted in Sweden found no relationship with symptoms such as heartburn and BE.16 In addition, BE has been reported to occur even after total gastrectomy.17 These findings cast doubt on the proposed role of stomach acid reflux in the gradual enlargement of
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Superficial muscularis mucosa
3 (12)
Lamina propria mucosa
5 (19)
Deep muscularis mucosa
9 (34)
SM1
3 (12)
SM2
6 (23)
Lymphovascular invasion, no. (%) Negative
26 (100)
Positive
0 (0)
SD, Standard deviation.
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Kagemoto et al
ESD for superficial Barrett’s adenocarcinoma
Figure 1. Endoscopic and histological images of superficial Barrett’s adenocarcinoma. A, Mucosal changes are apparent from the 11 o’clock to 2 o’clock position. Note in particular the red, flat mucosal elevation in the 1 o’clock position. B, Reversed endoscopic view reveals a lesion involving the entire circumference of Barrett’s esophagus. C, The lesion is more clearly depicted after the spreading of indigo carmine. D, Irregular mucosal and vascular patterns are observed under magnifying endoscopy and narrow-band imaging. E, Resected specimen. F, Histopathological findings showing Barrett’s adenocarcinoma in the submucosa. The lesion was completely resected (ly0, v0, HM0, VM0).
BE and suggest the involvement of other causal factors.4 Sixteen patients (70%) included in our study had taken proton pump inhibitors, which may explain why there were so few cases of reflux esophagitis. The 0 to 3 o’clock quadrant was the most common SBA location in our study patients, and the same location has been reported as most common (with statistical significance) in at least 1 fairly large group of patients (N Z 119).18 It is not clear why SBAs occur or are found most frequently at this location. It is possible that there is a detection bias. The 0 to 3 o’clock quadrant is the most visible quadrant. This position also favors mucosal breaks, which may ultimately lead to SBA.19 It is important to carefully observe the 0 to 3 o’clock quadrant. In this study, SBAs tended to appear red, and all had irregular mucosal and vascular patterns under magnifying NBI. Thus, we consider NBI to be useful for diagnosing SBA. Goda et al20 also reported the usefulness of magnifying NBI for the detection of intestinal metaplasia and SBA. They grouped the fine mucosal patterns and the capillary patterns observed under NBI into 5 categories each, and all adenocarcinomas in their study were characterized by both irregular mucosal and capillary patterns. Amano et al21 reported the usefulness of chromoendoscopy with crystal violet for detecting SBAs. Because crystal violet stains superficial epithelial cells, the pit patterns of Barrett’s epithelium can be clearly identified. A very recent report also described the usefulness of chromoendoscopy and magnifying NBI in cases of BE-associated adenocarcinoma.22 A reddened mucosal lining found during endoscopic screening or surveillance for BE calls for careful examination, not only by white-light www.giejournal.org
TABLE 3. Outcomes of ESD for superficial Barrett’s adenocarcinoma (26 lesions) Operation time, min Mean SD
93 48
Median (range) En bloc resection, no. (%) Pathological en bloc resection
95 (30-210) 26 (100) 22 (85)
Procedure-related adverse events, no. (%) Delayed bleeding
1 (4)
Perforation
0 (0)
Stenosis
4 (15)
Additional surgical resection
9 (35)
Follow-up after ESD, mo Mean SD
33 24
Median (range)
35 (2-85)
Recurrence, no. (%)
0 (0)
ESD, Endoscopic submucosal dissection; SD, standard deviation.
endoscopy but also by other modalities including magnifying NBI. There have been reports of lymph node metastasis from early stage SBA, such as intramucosal adenocarcinoma.23 Such metastasis results from the abundant lymph and Volume
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blood vessels that develop between the duplicated mucosa-muscle plates.23 In Japan, the incidence of lymph node metastasis of SBA has not been sufficiently examined in relation to invasion depth, so the criteria for endoscopic therapy have not yet been established. Among our study patients, there were 9 cases of tumor invasion into the submucosa, and additional surgical resection was performed in 9 cases (including 8 of the 9 cases of invasion into the submucosa). In our study group, there were no residual tumors, but lymph node metastasis was found in 1 case. Data from a large number of cases of SBA in Japan are needed before the criteria for endoscopic therapy can be established. In Western countries, EMR is widely accepted as treatment for dysplasia and adenocarcinoma in BE, and complete local remission achieved by EMR has been reported in 96.6% to 99% of cases.24-26 However, piecemeal resection and repeated resection are also reported, and recurrent and metachronous lesions occurred in 11% to 21.5% of these cases.24-26 All SBAs included in our study were resected by ESD, which requires a more advanced technique and takes more time than EMR. We think that ESD is preferred over EMR because large esophageal lesions can be resected en bloc, allowing for accurate histological assessment. Neuhaus et al27 reported safe performance of ESD for SBA, but they did not achieve sufficient R0 resection rates to warrant its recommended use over piecemeal EMR. However, in combination with radiofrequency ablation (RFA) and ESD, yielded complete eradication of neoplastic lesions. It has also been reported that intestinal metaplasia and dysplasia in BE can be effectively and safely treated with the combination of EMR and RFA.28 Pathological en bloc resection was achieved in 85% of the lesions in this study, and it was higher rate than any reported previously. We were able to achieve accurate histological assessment of the resected specimens and thus performed additional surgical resection in cases in which ESD was not curative. We did not perform RFA for BE. During follow-up, there was no local or metastatic recurrence and no treatment-related or SBA-related deaths. One metachronous adenocarcinoma (4%) was found. LSBE is reported to be a risk factor for metachronous adenocarcinoma,26 and the metachronous tumor in our patient was associated with LSBE. There were only 3 cases of LSBE in this study; all others were SSBE cases. This might explain the low incidence of metachronous adenocarcinoma without RFA. We think that careful surveillance is necessary after ESD. In Western countries, endoscopic surveillance once every 2 or 3 years is recommended when there is no dysplasia, twice yearly in cases of low-grade dysplasia, and every 3 months in cases of high-grade dysplasia.29,30 The criterion standard is random endoscopic biopsies from 4 directions at 2-cm intervals (1-cm intervals if dysplasia is present).31 After endoscopic therapy in highrisk patients with LSBE who had piecemeal resection of 6 GASTROINTESTINAL ENDOSCOPY Volume
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the neoplasia and/or multifocal neoplasia, endoscopic surveillance every 3 months during the first 2 years and then twice annually is suggested.26 In Japan, targeted biopsy is common for suspected BE-associated dysplasia or adenocarcinoma.32 A recent prospective, randomized, controlled trial that compared standard endoscopy with random biopsies with NBI target biopsies for BE was reported. Dysplasia was detected more frequently with targeted biopsies using NBI.33 On the other hand, there has been a report that neither indigo carmine chromoendoscopy nor NBI improves the sensitivity for detection of high-grade dysplasia and early cancer.34 Thus, further studies are needed to establish a post-ESD surveillance program in Japan and to confirm the clinical usefulness of NBI for detecting dysplasia.
CONCLUSIONS We investigated the outcomes of ESD for SBA in relation to clinicopathological features. ESD for early stage SBA appears to be a safe and effective treatment strategy. However, the histopathological criteria after ESD of SBA have not been established, and it will be necessary to understand the long-term prognosis after ESD for SBA before we can establish such criteria. REFERENCES 1. Cameron AJ. Epidemiology of Barrett’s esophagus and adenocarcinoma. Dis Esophagus 2002;15:106-8. 2. Makuuchi H. The present state of Barrett’s cancer in Japan and views on the future. Jpn J Gastroenterol 2008;105:1299-308. 3. Koike T, Ohara S, Shimosegawa T, et al. Role of gastric acid secretion in the pathogenesis of Barrett’s esophageal cancer in a Japanese population. Clin J Gastroenterol 2009;2:143-8. 4. Oryu M, Mori H, Kobara H, et al. Differences in the characteristics of Barrett’s esophagus and Barrett’s adenocarcinoma between the United States and Japan. ISRN Gastroenterol 2013;840690. 5. Inomata Y, Koike T, Ohara S, et al. Preservation of gastric acid secretion may be important for the development of gastroesophageal junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status. Am J Gastroenterol 2006;101:926-33. 6. Ikeda K, Isomoto H, Oda H, et al. Endoscopic dissection of a minute intramucosal adenocarcinoma in Barrett’s esophagus. Dig Endosc 2009;21:34-6. 7. Hoteya S, Matsui A, Iizuka T, et al. Comparison of the clinicopathological characteristics and results of endoscopic submucosal dissection for esophagogastric junction and non-junctional cancers. Digestion 2013;87:29-33. 8. Oka S, Tanaka S, Kaneko I, et al. Advantage of endoscopic submucosal dissection compared with EMR for early gastric cancer. Gastrointest Endosc 2006;64:877-83. 9. Urabe Y, Hiyama T, Tanaka S, et al. Advantages of endoscopic submucosal dissection versus endoscopic oblique aspiration mucosectomy for superficial esophageal tumors. J Gastroenterol Hepatol 2011;26: 275-80. 10. Higashimaya M, Oka S, Tanaka S, et al. Outcome of endoscopic submucosal dissection for gastric neoplasm in relationship to endoscopic classification of submucosal fibrosis. Gastric Cancer 2013;16:404-10. 11. Oda I, Saito D, Tada M, et al. A multicenter retrospective study of endoscopic resection for early gastric cancer. Gastric Cancer 2006;9:262-70.
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Kagemoto et al 12. Oyama T, Tomori A, Hotta K, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol 2005;3: S67-70. 13. Fujishiro M, Yahagi N, Kakushima N, et al. Endoscopic submucosal dissection of esophageal squamous cell neoplasms. Clin Gastroenterol Hepatol 2006;4:688-94. 14. Singh M, Bansal A, Curvers WL, et al. Observer agreement in the assessment of narrow-band imaging system surface patterns in Barrett’s esophagus: a multicenter study. Endoscopy 2011;43:745-51. 15. Shimoda T. Japanese classification of esophageal cancer, the 10th edition-pathological part. Nihon Rinsho 2011;69:109-20. 16. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129:1825-31. 17. Westhoff BC, Weston A, Cherian R, et al. Development of Barrett’s esophagus six months after total gastrectomy. Am J Gastroenterol 2004;99:2271-7. 18. Enestvedt BK, Lugo R, Guarner-Argente C, et al. Location, location, location: does early cancer in Barrett’s esophagus have a preference? Gastrointest Endosc 2013;13:382-9. 19. Katsube T, Adachi K, Furuta K, et al. Difference in localization of esophageal mucosal breaks among grades of esophagitis. J Gastroenterol Hepatol 2006;21:1656-9. 20. Goda K, Tajiri H, Ikegami M, et al. Usefulness of magnifying endoscopy with narrow band imaging for the detection of specialized intestinal metaplasia in columnar-lined esophagus and Barrett’s adenocarcinoma. Gastrointest Endosc 2007;65:36-46. 21. Amano Y, Komazawa Y, Ishimura N, et al. Two cases of superficial cancer in Barrett’s esophagus detected by chromoendoscopy with crystal violet. Gastrointest Endosc 2004;59:143-6. 22. Yamashina T, Uedo N, Matsui F, et al. Usefulness of chromoendoscopy and magnifying narrow band imaging endoscopy for diagnosis of demarcation of adenocarcinoma in Barrett’s esophagus. Dig Endosc 2013;25:173-6. 23. Faragalla HF, Marcon NE, Yousef GM, et al. Immunohistochemical staining for smoothelin in the duplicated versus the true muscularis mucosae of Barrett esophagus. Am J Surg Pathol 2011;35:55-9.
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ESD for superficial Barrett’s adenocarcinoma 24. Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 2007;65:3-10. 25. Behrens A, May A, Gossner L, et al. Curative treatment for high-grade intraepithelial neoplasia in Barrett’s esophagus. Endoscopy 2005;37: 999-1005. 26. Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s esophagus. Gut 2008;57:1200-6. 27. Neuhaus H, Terheggen G, Rutz EM, et al. Endoscopic submucosal dissection plus radiofrequency ablation of neoplastic Barrett’s esophagus. Endoscopy 2012;44:1105-13. 28. Pouw RE, Wirths K, Eisendrath P, et al. Efficacy of radiofrequency ablation combined with endoscopic resection for Barrett’s esophagus with early neoplasia. Clin Gastroenterol Hepatol 2010;8:23-9. 29. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 1998;93: 1028-32. 30. Garud SS, Keilin S, Cai Q, et al. Diagnosis and management of Barrett’s esophagus for the endoscopist. Ther Adv Gastroenterol 2010;3:227-38. 31. Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002;97:1888-95. 32. Goda K, Singh R, Oda I, et al. Current status of endoscopic diagnosis and treatment of superficial Barrett’s adenocarcinoma in Asia-Pacific region. Dig Endosc 2013;25:146-50. 33. Sharma P, Hawes RH, Bansal A, et al. Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett’s esophagus: a prospective, international, randomised controlled trial. Gut 2013;62:15-21. 34. Kara MA, Peters FP, Rosmolen WD, et al. High-resolution endoscopy plus chromoendoscopy or narrow-band imaging in Barrett’s esophagus: a prospective randomized crossover study. Endoscopy 2005;37: 929-36.
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Clinical outcomes of endoscopic submucosal dissection for superficial Barrett’s adenocarcinoma Kenichi Kagemoto, MD,1 Shiro Oka, MD, PhD,2 Shinji Tanaka, MD, PhD,2 Tomohiro Miwata, MD,1 Yuji Urabe, MD, PhD,1 Yoji Sanomura, MD, PhD,2 Shigeto Yoshida, MD, PhD,1 Toru Hiyama, MD, PhD,3 Koji Arihiro, MD, PhD,4 Kazuaki Chayama, MD, PhD1 Hiroshima, Japan
Background: Advances in diagnostic techniques have allowed early stage detection of superficial Barrett’s adenocarcinoma (SBA) as well as resection by endoscopic submucosal dissection (ESD). Few reports exist, however, on the safety and efficacy of ESD for SBA. Objective: To analyze outcomes of ESD for SBA in relation to clinicopathological features of the lesions. Design: Retrospective study. Setting: University hospital. Patients: Twenty-three patients (21 men, 2 women; mean age, 63 years) with 26 SBAs. Intervention: ESD. Main Outcome Measurements: We examined outcomes of ESD in relation to the clinicopathological features of SBAs. The main outcomes assessed were en bloc resection rate, operation time, adverse event rates, additional resection rate, and time between ESD and any recurrence. Results: Twenty lesions (87%) derived from short-segment Barrett’s esophagus, and 3 lesions (13%) derived from long-segment Barrett’s esophagus. The majority of SBAs (54%) were located in the 0 to 3 o’clock circumferential quadrant. Median tumor size was 15 mm (range 5-60 mm). Macroscopic types were flat elevated (n Z 13, 50%), depressed (n Z 12, 46%), and protruded (n Z 1, 4%). The SBAs appeared red (n Z 23, 88%) or normally pale (n Z 3, 12%). Under magnifying narrow-band imaging, all SBAs showed an irregular mucosal pattern and an irregular vascular pattern. The endoscopic en bloc resection rate was 100% (26/26), and the pathological en bloc resection rate was 85% (22/26). The median procedure time was 95 minutes (range, 30-210 minutes). Delayed bleeding occurred in 1 case, but there was no perforation. The SBAs were of the differentiated type (n Z 25, 96%) or poorly differentiated type (n Z 1, 4%). The tumor had invaded the superficial muscularis mucosa (n Z 3, 12%), lamina propria mucosa (n Z 5, 19%, deep muscularis mucosa (n Z 9, 34%), SM1 (n Z 3, 12%), and SM2 (n Z 6, 23%). Additional surgical resection after ESD was performed in 9 cases, and there were no residual tumors, but 1 lymph node metastasis was found. There were no recurrent tumors; however, 1 metachronous adenocarcinoma was diagnosed 42 months after ESD. Limitations: Single-center, retrospective study. Conclusions: ESD appears to be a safe and effective treatment strategy for early stage SBA. (Gastrointest Endosc 2014;-:1-7.)
Abbreviations: BE, Barrett’s esophagus; ESD, endoscopic submucosal dissection; LSBE, long-segment Barrett’s esophagus; NBI, narrow-band imaging; RFA, radiofrequency ablation; SBA, superficial Barrett’s adenocarcinoma; SSBE, short-segment Barrett’s esophagus. DISCLOSURE: All authors disclosed no financial relationships relevant to this publication. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.01.022
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Received September 20, 2013. Accepted January 9, 2014. Current affiliations: Department of Gastroenterology and Metabolism, Graduate School of Biomedical Sciences, Hiroshima University (1), Departments of Endoscopy (2), Health Service Center (3), and Pathology (4), Hiroshima University Hospital, Hiroshima, Japan. Reprint requests: Shiro Oka, MD, PhD, Department of Endoscopy, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 7348551, Japan.
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ESD for superficial Barrett’s adenocarcinoma
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The incidence of superficial Barrett’s adenocarcinoma (SBA) has increased steadily in Western countries.1 In Japan, most esophageal cancers are squamous cell carcinomas. SBAs are few, reportedly accounting for only 0.9% of all esophageal cancers in Japan.2 However, the incidence of Barrett’s esophagus (BE) and thus SBA is expected to increase in Japan because of a decrease in Helicobacter pylori infection rates and the westernization of the Japanese diet, both of which are thought to promote GERD.3-5 With advances in endoscopic technologies, it has become possible to detect SBA in the early stage2 and then go on to treat these cases by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). However, few reports exist regarding ESD for SBA.6,7 ESD has become a standard treatment in Japan for both early gastric cancer and superficial esophageal cancer.8-13 ESD involves circumferential mucosal incision and direct submucosal dissection, making it possible to safely resect even large tumors en bloc and obtain endoscopically clear margins. We conducted a retrospective analysis of the clinicopathological features and outcomes of SBA resected by ESD in our hospital.
Take-home Message All superficial Barrett’s adenocarcinomas (SBAs) had irregular mucosal and vascular patterns under magnifying narrow-band imaging (NBI); thus, NBI is useful for diagnosing SBA. En bloc resection was achieved in all cases, and clear resection margins were pathologically confirmed in 85% of cases. Endoscopic submucosal dissection for early stage SBAs appears to be a safe and effective treatment strategy.
high-contrast imaging of the vascular and mucosal patterns within the BE segment. We use a simplified classification system to assess BE and SBAs.14 According to this system, NBI descriptors (mucosal and vascular patterns) are classified as regular for nondysplastic BE and irregular for dysplastic BE/early adenocarcinoma.14 All procedures were performed with the use of a magnifying endoscope (GIF- Q240Z or -Q260Z; Olympus Medical Systems, Tokyo, Japan) in combination with the NBI system.
ESD procedure PATIENTS AND METHODS Patients The study group comprised 23 patients with 26 SBAs resected by ESD at Hiroshima University Hospital between April 2006 and June 2013. All lesions had been detected by endoscopic screening for GI carcinoma or by endoscopic surveillance after treatment for GI disease. All 26 SBAs had been diagnosed endoscopically as intramucosal carcinoma by standard observation, magnifying observation, and EUS before ESD. During the same period, surgery for SBAs was performed in 10 cases because these lesions were clinically diagnosed as submucosal massive carcinoma. No SBA was treated by EMR during this period. All patients had been informed of the benefits and risks of ESD before providing written consent for the procedure. The patients were identified through a search of our hospital endoscopy records, and patients’ records were accessed so that pertinent information could be obtained for the study. The ESD procedures and assessment of the study data are described in the following. The study was conducted with approval from the institutional review board of Hiroshima University.
Narrow-band imaging assessment and procedure Narrow-band imaging (NBI) is a noninvasive optical technique that uses reflected light to visualize the superficial structure of the organ surface. It has been used to visualize morphologic changes in the structure of esophageal lesions because it allows detailed high-resolution and 2 GASTROINTESTINAL ENDOSCOPY Volume
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For ESD, each patient was placed in the left lateral position, and the operator and assistant stood on the left side of the examination table and in front of the patient. A single-channel endoscope (GIF-Q260J or -H260Z; Olympus or EG-450RD5 or EG-590WR; FUJIFILM, Tokyo, Japan) or 2-channel endoscope (GIF-2TQ260M; Olympus) was used for conventional endoscopic observation. The circumference of the lesion was marked with argon plasma coagulation. Local injection and incision were first performed from the distal side. The injection solution consisted of a 10% glycerin solution with 0.025% epinephrine and 0.005% indigo carmine. The solution was injected under the epithelium to produce a cushion of adequate elevation. The marks were checked, and the elevated area was incised with a Hook-knife (Olympus) in the VIO300D cut mode. Injection and incision were repeated from the proximal side, thus extending the incision circumferentially around the entire lesion. A soft, transparent hood was attached to the tip of the endoscope before incision so that adequate tension for dissection would be achieved. The HookKnife, ITknife nano (Olympus), and/or SB knife (Sumitomo Bakelite, Tokyo, Japan) was used to exfoliate the submucosa in the VIO300D cut or coagulation mode. Injection of 10% glycerin solution and sodium hyaluronate with 0.0025% epinephrine into the submucosa was performed as needed, and further resection was carried out to ensure total removal of the lesion. Post-ESD bleeding was defined as bleeding after the procedure as manifested by a decrease in the hemoglobin level of 2 g/dL or greater below the most recent preoperative level, observation of any bleeding source, or massive melena. Perforation was diagnosed endoscopically just www.giejournal.org
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after resection or by the presence of free air on a plain abdominal radiograph or CT image.
Histological assessment after ESD Resected specimens were stretched and pinned to polystyrene foam boards and fixed in 10% formalin for 24 hours. After fixation, all resected specimens were cut into longitudinal slices 2 mm in width. The tissue specimens were embedded in paraffin, sectioned at 4 mm, and stained with hematoxylin and eosin. Histological evaluation was performed by 2 experienced pathologists according to World Health Organization criteria.
Surveillance after ESD Follow-up surveillance endoscopy was performed at our hospital 3 to 12 months after ESD according to the type of resection. In cases of complete resection, endoscopic examination was performed 12 months after the procedure and once every 12 months thereafter. In cases of incomplete resection, endoscopic examination was performed 3, 6, and 12 months after the procedure during the first year, and every 12 months thereafter. A tumor detected in close proximity to the scar resulting from ESD was regarded as a local recurrent tumor, whereas 1 or more primary tumors detected more than 1 cm from the ESD scar were regarded as metachronous tumors. CT scanning was performed annually to detect any lymph node or other organ metastasis.
Study data For the purpose of the study, the following data were obtained: patient age and sex; BE classification (shortsegment BE [SSBE] or long-segment BE [LSBE]); length of the BE segment; presence of esophageal hiatal hernia, reflux esophagitis, or atrophic gastritis; lesion characteristics (circumferential location, size, color, and gross type); NBI features (mucosal and vascular patterns); outcome of ESD (en bloc resection rates; operation time; adverse events including bleeding, perforation, and stenosis; additional surgical resection rate, followup time after ESD, and recurrence (assessed in cases that were followed for more than 12 months); and histological findings (histology, tumor depth, and lymphovascular invasion). We adhered to the Japanese Classification of Esophageal Cancer15 for histological assessment. En bloc resection was defined as removal of the lesion in a single piece for which the margin appeared endoscopically tumor free. Pathological en bloc resection was defined as removal of the lesion in a single piece for which the horizontal and vertical margins were shown to be free of both carcinoma and dysplasia (R0 resection). SM1 and SM2 invasion was also defined according to the Japanese Classification of Esophageal Cancer.15 www.giejournal.org
ESD for superficial Barrett’s adenocarcinoma
RESULTS Characteristics of the patients who underwent ESD for SBAs are shown in Table 1. The male/female sex ratio was 21/2, and the mean age of the patients was 63 years (range 45-84 years). The SSBE/LSBE ratio was 20/3. Twenty patients (87%) had an esophageal hiatal hernia. Atrophic gastritis was absent in 14 patients; closed-type atrophic gastritis was present in 8 patients and open-type atrophic gastritis in 1 patient (4%). Four patients (17%) had a reflux esophagitis. Characteristics of SBAs are shown in Table 2. The SBAs were located in the 4 circumferential quadrants as follows: 0 to 3 o’clock quadrant, 14 lesions (54%); 3 to 6 o’clock quadrant, 7 lesions (27%); 9 to 12 o’clock quadrant, 7 lesions (27%); and 6 to 9 o’clock quadrant, 4 lesions (15%). (Note that the percentages are not mutually exclusive because some lesions occupied 2 or more quadrants.) The median tumor diameter was 15 mm (range 5-60 mm). The red/normal pale appearance ratio was 23/2. Macroscopic types of SBAs were as follows: flat elevated type (0-II), 13 lesions (50%); depressed type (0-IIc), 12 lesions (46%); and protruded type (0-I), 1 lesion (4%). Under magnifying NBI, all lesions had both irregular mucosal and vascular patterns. Representative endoscopic and histological images of SBA are shown in Figure 1. The outcomes of ESD are shown in Table 3. The average standard deviation operation time was 93 48 minutes (range 30-210 minutes). En bloc resection was achieved in all cases and clear resection margins were pathologically confirmed in 22 specimens (85%). Thus, en bloc resection was considered pathologically incomplete in 4 specimens: 3 with a positive vertical margin and 1 with a positive horizontal margin. Bleeding after ESD occurred in 1 case (4%), and this bleeding was controlled by endoscopic electrocoagulation. No perforation occurred. Stenosis occurred in 4 cases (15%), and all stenoses were treated by balloon dilation. Histological findings are shown in Table 2. All but 1 lesion (ie, 25/26 or 96%) was of the differentiated type. No lymphovascular invasion was found. The depths of tumor invasion were as follows: to the superficial muscularis mucosa, 3 lesions (12%); to the lamina propria mucosa, 5 lesions (19%); to the deep muscularis mucosa, 9 lesions (34%); to SM1, 3 lesions (12%); and to SM2, 6 lesions (23%). Additional surgical resection was performed in 9 (35% of lesions) cases (tumor invasion to the submucosa in 8 cases and undifferentiated type tumor in 1 case). There were no residual tumors, but 1 lymph node metastasis was found in the following metachronous case after surgical resection. Additional surgical resection was not performed in 1 SM1 case and in 1 horizontal margin-positive case. The average standard deviation follow-up period after ESD was 33 24 months. In 24 cases that we could follow for more than 12 months, the recurrence rate was 0%. There was no Volume
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TABLE 2. Lesion characteristics (N [ 26)
TABLE 1. Clinical characteristics of study patients (N [ 23)
Location, no. (%)
Age, y Mean SD Median (range)
0-3 o’clock
14 (54)
63 10
3-6 o’clock
7 (27)
61 (45-84)
6-9 o’clock
4 (15)
9-12 o’clock
7 (27)
Sex, no. (%) Male
21 (91)
Female
Circulation, no. (%)
2 (9)
Barrett’s esophagus, no. (%) SSBE
20 (87)
LSBE
3 (13)
w1/4
19 (73)
1/4–1/2
5 (19)
1/2–3/4
1 (4)
3/4–all
1 (4)
Tumor diameter, mm
Esophageal hiatal hernia, no. (%) Present
20 (87)
Absent
3 (13)
Mean SD Median (range)
19.0 13.6 15 (5-60)
Color, no. (%)
Reflux esophagitis, no. (%) Present
4 (17)
Absent
19 (83)
Red
23 (88)
Pale
3 (12)
Macroscopic type, no. (%)
Atrophic gastritis, no. (%)
0-I
1 (4)
Absent
14 (61)
0-II
13 (50)
Closed type
8 (35)
0-IIb
0 (0)
Open type
1 (4)
0-IIc
12 (46)
SD, Standard deviation; SSBE, short-segment Barrett’s esophagus; LSBE, long-segment Barrett’s esophagus.
treatment-related or SBA-related death. However, 1 metachronous adenocarcinoma was found 42 months after ESD. In this patient, ESD was thus performed again, and en bloc resection was achieved. However, the tumor had invaded the submucosa, and additional surgical resection was performed. There was no residual tumor, but 1 metastatic lymph node was found. Since the surgical treatment, there has been no local or metastatic recurrence in this case.
Mucosal pattern, no. (%) Regular
0 (0)
Irregular
26 (100)
Vascular pattern, no. (%) Regular
0 (0)
Irregular
26 (100)
Histology, no. (%) Well differentiated
18 (69)
Moderately differentiated
7 (27)
Poorly differentiated
1 (4)
Tumor depth, no. (%)
DISCUSSION We assessed 26 SBAs resected by ESD in 23 patients. Sixty percent (n Z 14) of the patients had no atrophic gastritis, and 8 of the 9 patients with atrophic gastritis had the closed type. However, only 17% of our patients had reflux esophagitis. A very large general population (N Z 3000) study conducted in Sweden found no relationship with symptoms such as heartburn and BE.16 In addition, BE has been reported to occur even after total gastrectomy.17 These findings cast doubt on the proposed role of stomach acid reflux in the gradual enlargement of
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Superficial muscularis mucosa
3 (12)
Lamina propria mucosa
5 (19)
Deep muscularis mucosa
9 (34)
SM1
3 (12)
SM2
6 (23)
Lymphovascular invasion, no. (%) Negative
26 (100)
Positive
0 (0)
SD, Standard deviation.
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Kagemoto et al
ESD for superficial Barrett’s adenocarcinoma
Figure 1. Endoscopic and histological images of superficial Barrett’s adenocarcinoma. A, Mucosal changes are apparent from the 11 o’clock to 2 o’clock position. Note in particular the red, flat mucosal elevation in the 1 o’clock position. B, Reversed endoscopic view reveals a lesion involving the entire circumference of Barrett’s esophagus. C, The lesion is more clearly depicted after the spreading of indigo carmine. D, Irregular mucosal and vascular patterns are observed under magnifying endoscopy and narrow-band imaging. E, Resected specimen. F, Histopathological findings showing Barrett’s adenocarcinoma in the submucosa. The lesion was completely resected (ly0, v0, HM0, VM0).
BE and suggest the involvement of other causal factors.4 Sixteen patients (70%) included in our study had taken proton pump inhibitors, which may explain why there were so few cases of reflux esophagitis. The 0 to 3 o’clock quadrant was the most common SBA location in our study patients, and the same location has been reported as most common (with statistical significance) in at least 1 fairly large group of patients (N Z 119).18 It is not clear why SBAs occur or are found most frequently at this location. It is possible that there is a detection bias. The 0 to 3 o’clock quadrant is the most visible quadrant. This position also favors mucosal breaks, which may ultimately lead to SBA.19 It is important to carefully observe the 0 to 3 o’clock quadrant. In this study, SBAs tended to appear red, and all had irregular mucosal and vascular patterns under magnifying NBI. Thus, we consider NBI to be useful for diagnosing SBA. Goda et al20 also reported the usefulness of magnifying NBI for the detection of intestinal metaplasia and SBA. They grouped the fine mucosal patterns and the capillary patterns observed under NBI into 5 categories each, and all adenocarcinomas in their study were characterized by both irregular mucosal and capillary patterns. Amano et al21 reported the usefulness of chromoendoscopy with crystal violet for detecting SBAs. Because crystal violet stains superficial epithelial cells, the pit patterns of Barrett’s epithelium can be clearly identified. A very recent report also described the usefulness of chromoendoscopy and magnifying NBI in cases of BE-associated adenocarcinoma.22 A reddened mucosal lining found during endoscopic screening or surveillance for BE calls for careful examination, not only by white-light www.giejournal.org
TABLE 3. Outcomes of ESD for superficial Barrett’s adenocarcinoma (26 lesions) Operation time, min Mean SD
93 48
Median (range) En bloc resection, no. (%) Pathological en bloc resection
95 (30-210) 26 (100) 22 (85)
Procedure-related adverse events, no. (%) Delayed bleeding
1 (4)
Perforation
0 (0)
Stenosis
4 (15)
Additional surgical resection
9 (35)
Follow-up after ESD, mo Mean SD
33 24
Median (range)
35 (2-85)
Recurrence, no. (%)
0 (0)
ESD, Endoscopic submucosal dissection; SD, standard deviation.
endoscopy but also by other modalities including magnifying NBI. There have been reports of lymph node metastasis from early stage SBA, such as intramucosal adenocarcinoma.23 Such metastasis results from the abundant lymph and Volume
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blood vessels that develop between the duplicated mucosa-muscle plates.23 In Japan, the incidence of lymph node metastasis of SBA has not been sufficiently examined in relation to invasion depth, so the criteria for endoscopic therapy have not yet been established. Among our study patients, there were 9 cases of tumor invasion into the submucosa, and additional surgical resection was performed in 9 cases (including 8 of the 9 cases of invasion into the submucosa). In our study group, there were no residual tumors, but lymph node metastasis was found in 1 case. Data from a large number of cases of SBA in Japan are needed before the criteria for endoscopic therapy can be established. In Western countries, EMR is widely accepted as treatment for dysplasia and adenocarcinoma in BE, and complete local remission achieved by EMR has been reported in 96.6% to 99% of cases.24-26 However, piecemeal resection and repeated resection are also reported, and recurrent and metachronous lesions occurred in 11% to 21.5% of these cases.24-26 All SBAs included in our study were resected by ESD, which requires a more advanced technique and takes more time than EMR. We think that ESD is preferred over EMR because large esophageal lesions can be resected en bloc, allowing for accurate histological assessment. Neuhaus et al27 reported safe performance of ESD for SBA, but they did not achieve sufficient R0 resection rates to warrant its recommended use over piecemeal EMR. However, in combination with radiofrequency ablation (RFA) and ESD, yielded complete eradication of neoplastic lesions. It has also been reported that intestinal metaplasia and dysplasia in BE can be effectively and safely treated with the combination of EMR and RFA.28 Pathological en bloc resection was achieved in 85% of the lesions in this study, and it was higher rate than any reported previously. We were able to achieve accurate histological assessment of the resected specimens and thus performed additional surgical resection in cases in which ESD was not curative. We did not perform RFA for BE. During follow-up, there was no local or metastatic recurrence and no treatment-related or SBA-related deaths. One metachronous adenocarcinoma (4%) was found. LSBE is reported to be a risk factor for metachronous adenocarcinoma,26 and the metachronous tumor in our patient was associated with LSBE. There were only 3 cases of LSBE in this study; all others were SSBE cases. This might explain the low incidence of metachronous adenocarcinoma without RFA. We think that careful surveillance is necessary after ESD. In Western countries, endoscopic surveillance once every 2 or 3 years is recommended when there is no dysplasia, twice yearly in cases of low-grade dysplasia, and every 3 months in cases of high-grade dysplasia.29,30 The criterion standard is random endoscopic biopsies from 4 directions at 2-cm intervals (1-cm intervals if dysplasia is present).31 After endoscopic therapy in highrisk patients with LSBE who had piecemeal resection of 6 GASTROINTESTINAL ENDOSCOPY Volume
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the neoplasia and/or multifocal neoplasia, endoscopic surveillance every 3 months during the first 2 years and then twice annually is suggested.26 In Japan, targeted biopsy is common for suspected BE-associated dysplasia or adenocarcinoma.32 A recent prospective, randomized, controlled trial that compared standard endoscopy with random biopsies with NBI target biopsies for BE was reported. Dysplasia was detected more frequently with targeted biopsies using NBI.33 On the other hand, there has been a report that neither indigo carmine chromoendoscopy nor NBI improves the sensitivity for detection of high-grade dysplasia and early cancer.34 Thus, further studies are needed to establish a post-ESD surveillance program in Japan and to confirm the clinical usefulness of NBI for detecting dysplasia.
CONCLUSIONS We investigated the outcomes of ESD for SBA in relation to clinicopathological features. ESD for early stage SBA appears to be a safe and effective treatment strategy. However, the histopathological criteria after ESD of SBA have not been established, and it will be necessary to understand the long-term prognosis after ESD for SBA before we can establish such criteria. REFERENCES 1. Cameron AJ. Epidemiology of Barrett’s esophagus and adenocarcinoma. Dis Esophagus 2002;15:106-8. 2. Makuuchi H. The present state of Barrett’s cancer in Japan and views on the future. Jpn J Gastroenterol 2008;105:1299-308. 3. Koike T, Ohara S, Shimosegawa T, et al. Role of gastric acid secretion in the pathogenesis of Barrett’s esophageal cancer in a Japanese population. Clin J Gastroenterol 2009;2:143-8. 4. Oryu M, Mori H, Kobara H, et al. Differences in the characteristics of Barrett’s esophagus and Barrett’s adenocarcinoma between the United States and Japan. ISRN Gastroenterol 2013;840690. 5. Inomata Y, Koike T, Ohara S, et al. Preservation of gastric acid secretion may be important for the development of gastroesophageal junction adenocarcinoma in Japanese people, irrespective of the H. pylori infection status. Am J Gastroenterol 2006;101:926-33. 6. Ikeda K, Isomoto H, Oda H, et al. Endoscopic dissection of a minute intramucosal adenocarcinoma in Barrett’s esophagus. Dig Endosc 2009;21:34-6. 7. Hoteya S, Matsui A, Iizuka T, et al. Comparison of the clinicopathological characteristics and results of endoscopic submucosal dissection for esophagogastric junction and non-junctional cancers. Digestion 2013;87:29-33. 8. Oka S, Tanaka S, Kaneko I, et al. Advantage of endoscopic submucosal dissection compared with EMR for early gastric cancer. Gastrointest Endosc 2006;64:877-83. 9. Urabe Y, Hiyama T, Tanaka S, et al. Advantages of endoscopic submucosal dissection versus endoscopic oblique aspiration mucosectomy for superficial esophageal tumors. J Gastroenterol Hepatol 2011;26: 275-80. 10. Higashimaya M, Oka S, Tanaka S, et al. Outcome of endoscopic submucosal dissection for gastric neoplasm in relationship to endoscopic classification of submucosal fibrosis. Gastric Cancer 2013;16:404-10. 11. Oda I, Saito D, Tada M, et al. A multicenter retrospective study of endoscopic resection for early gastric cancer. Gastric Cancer 2006;9:262-70.
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Kagemoto et al 12. Oyama T, Tomori A, Hotta K, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol 2005;3: S67-70. 13. Fujishiro M, Yahagi N, Kakushima N, et al. Endoscopic submucosal dissection of esophageal squamous cell neoplasms. Clin Gastroenterol Hepatol 2006;4:688-94. 14. Singh M, Bansal A, Curvers WL, et al. Observer agreement in the assessment of narrow-band imaging system surface patterns in Barrett’s esophagus: a multicenter study. Endoscopy 2011;43:745-51. 15. Shimoda T. Japanese classification of esophageal cancer, the 10th edition-pathological part. Nihon Rinsho 2011;69:109-20. 16. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129:1825-31. 17. Westhoff BC, Weston A, Cherian R, et al. Development of Barrett’s esophagus six months after total gastrectomy. Am J Gastroenterol 2004;99:2271-7. 18. Enestvedt BK, Lugo R, Guarner-Argente C, et al. Location, location, location: does early cancer in Barrett’s esophagus have a preference? Gastrointest Endosc 2013;13:382-9. 19. Katsube T, Adachi K, Furuta K, et al. Difference in localization of esophageal mucosal breaks among grades of esophagitis. J Gastroenterol Hepatol 2006;21:1656-9. 20. Goda K, Tajiri H, Ikegami M, et al. Usefulness of magnifying endoscopy with narrow band imaging for the detection of specialized intestinal metaplasia in columnar-lined esophagus and Barrett’s adenocarcinoma. Gastrointest Endosc 2007;65:36-46. 21. Amano Y, Komazawa Y, Ishimura N, et al. Two cases of superficial cancer in Barrett’s esophagus detected by chromoendoscopy with crystal violet. Gastrointest Endosc 2004;59:143-6. 22. Yamashina T, Uedo N, Matsui F, et al. Usefulness of chromoendoscopy and magnifying narrow band imaging endoscopy for diagnosis of demarcation of adenocarcinoma in Barrett’s esophagus. Dig Endosc 2013;25:173-6. 23. Faragalla HF, Marcon NE, Yousef GM, et al. Immunohistochemical staining for smoothelin in the duplicated versus the true muscularis mucosae of Barrett esophagus. Am J Surg Pathol 2011;35:55-9.
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ESD for superficial Barrett’s adenocarcinoma 24. Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 2007;65:3-10. 25. Behrens A, May A, Gossner L, et al. Curative treatment for high-grade intraepithelial neoplasia in Barrett’s esophagus. Endoscopy 2005;37: 999-1005. 26. Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s esophagus. Gut 2008;57:1200-6. 27. Neuhaus H, Terheggen G, Rutz EM, et al. Endoscopic submucosal dissection plus radiofrequency ablation of neoplastic Barrett’s esophagus. Endoscopy 2012;44:1105-13. 28. Pouw RE, Wirths K, Eisendrath P, et al. Efficacy of radiofrequency ablation combined with endoscopic resection for Barrett’s esophagus with early neoplasia. Clin Gastroenterol Hepatol 2010;8:23-9. 29. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 1998;93: 1028-32. 30. Garud SS, Keilin S, Cai Q, et al. Diagnosis and management of Barrett’s esophagus for the endoscopist. Ther Adv Gastroenterol 2010;3:227-38. 31. Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002;97:1888-95. 32. Goda K, Singh R, Oda I, et al. Current status of endoscopic diagnosis and treatment of superficial Barrett’s adenocarcinoma in Asia-Pacific region. Dig Endosc 2013;25:146-50. 33. Sharma P, Hawes RH, Bansal A, et al. Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett’s esophagus: a prospective, international, randomised controlled trial. Gut 2013;62:15-21. 34. Kara MA, Peters FP, Rosmolen WD, et al. High-resolution endoscopy plus chromoendoscopy or narrow-band imaging in Barrett’s esophagus: a prospective randomized crossover study. Endoscopy 2005;37: 929-36.
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