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Endoscopic submucosal dissection for suspected early gastric cancer: absolute versus expanded criteria in a large Western cohort (with video)

      Background and Aims

      Endoscopic submucosal dissection (ESD) is an effective, minimally invasive, surgery-sparing technique for the treatment of early gastric cancer (EGC). It is not well established whether EGC within the Japanese expanded criteria can be safely and effectively treated using ESD in the West. We describe the outcomes of ESD for endoscopically suspected, biopsy specimen–confirmed EGC and its adenomatous precursor lesions (pEGC) using the Vienna classification of dysplasia in a Western cohort.

      Methods

      Prospective data were collected on all pEGCs undergoing ESD at a single expert endoscopy center. Outcomes were compared among pEGC, satisfying the Japanese absolute and expanded criteria, those outside criteria, and those specimens that contained low-grade dysplasia (LGD) only. Specialist GI pathologists reviewed and classified all ESD specimens. Patients were followed up at 6 and 12 months.

      Results

      Over 71 months, 135 pEGCs in 121 patients (mean age, 72.0 years; 61.2% men) underwent ESD. Median pEGC size was 20 mm (interquartile range, 15-30), and 62 (45.9%) satisfied the expanded clinical criteria. Perforation occurred in 1.5% and postprocedural bleeding in 5.2%. Forty-two pEGCs (31.1%) contained LGD only. Rates of en bloc and R0 resection were 94.8% and 86.7%, respectively. One hundred seven pEGCs (79.2%) met the absolute or expanded criteria for endoscopic cure. Two pEGCs recurred during follow-up. Ten of 26 patients with pEGC (38.5%) outside criteria for cure underwent surgery after ESD with residual tumor detected in 3 specimens. Fifteen patients with outside criteria for pEGCs did not undergo surgery because of frailty or their expressed wish. Eleven of 15 patients have so far undergone first surveillance with 1 of 11 experiencing endoscopic and histologic recurrence.

      Conclusions

      ESD is a safe and effective treatment for pEGCs in a Western context. Patients who either decline or are too frail for surgery, with outside criteria resections, may benefit from ESD for local disease control. Large Western studies of ESD for pEGCs are required to define long-term patient outcomes and surveillance guidelines, particularly where pathology shows LGD or high-grade dysplasia only. (Clinical trial registration number: NCT02306707.)

      Abbreviations:

      EGC (early gastric cancer), ESD (endoscopic submucosal dissection), HGD (high-grade dysplasia), IMC (intramucosal carcinoma), IQR (interquartile range), LGD (low-grade dysplasia), pEGC (precursor to early gastric cancer), SE (surveillance endoscopy), SMIC (submucosal invasive cancer)
      Endoscopic submucosal dissection (ESD) was developed and pioneered in Japan to treat early gastric cancer (EGC) and its adenomatous precursors (pEGC). ESD enables the en bloc resection of large GI lesions with curative intent and subsequent accurate histologic assessment. Large studies with long-term outcomes have demonstrated the safety and efficacy of this approach.
      • Tanabe S.
      • Ishido K.
      • Higuchi K.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.
      • Chung I.-K.
      • Lee J.H.
      • Lee S.-H.
      • et al.
      Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study.
      • Ahn J.Y.
      • Jung H.-Y.
      • Choi K.D.
      • et al.
      Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370 cases of absolute and extended indications.
      • Choi M.K.
      • Kim G.H.
      • Park D.Y.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a single-center experience.
      Compared with surgery, ESD for EGC has significantly lower morbidity, length of hospital stay, and mortality with similar long-term efficacy.
      • Shin D.W.
      • Hwang H.Y.
      • Jeon S.W.
      Comparison of endoscopic submucosal dissection and surgery for differentiated type early gastric cancer within the expanded criteria.
      Initially, ESD was indicated for nonulcerated EGCs in the stomach up to 20 mm in size (absolute indication).
      • Gotoda T.
      • Sasako M.
      • Ono H.
      • et al.
      Evaluation of the necessity for gastrectomy with lymph node dissection for patients with submucosal invasive gastric cancer.
      Because of the excellent outcomes of this cohort and the observation that some larger lesions were low risk for lymph node metastases, these criteria were expanded to include nonulcerated, differentiated EGCs of any size, ulcerated differentiated EGCs up to 30 mm, or undifferentiated EGCs up to 20 mm in size (expanded indication).
      • Kodera Y.
      • Sano T.
      Japanese gastric cancer treatment guidelines 2014 (version 4).
      These expanded criteria have been shown to achieve acceptable en bloc resection and R0 resection rates
      • Gotoda T.
      • Iwasaki M.
      • Kusano C.
      • et al.
      Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria.
      with low risks of distant disease at follow-up.
      • Suzuki H.
      • Oda I.
      • Abe S.
      • et al.
      High rate of 5-year survival among patients with early gastric cancer undergoing curative endoscopic submucosal dissection.
      Western centers have been slow to adopt ESD because of the comparatively low frequency of EGC in Western populations, which limits skill acquisition and training opportunities. Some Western centers have published encouraging results using ESD for EGC, satisfying the absolute indication,
      • Dinis-Ribeiro M.
      • Pimentel-Nunes P.
      • Afonso M.
      • et al.
      A European case series of endoscopic submucosal dissection for gastric superficial lesions.
      • Probst A.
      • Pommer B.
      • Golger D.
      • et al.
      Endoscopic submucosal dissection in gastric neoplasia—experience from a European center.
      • Schumacher B.
      • Charton J.P.
      • Nordmann T.
      • et al.
      Endoscopic submucosal dissection of early gastric neoplasia with a water jet-assisted knife: a Western, single-center experience.
      but few data exist that apply the expanded indication to Western cohorts.
      • Probst A.
      • Schneider A.
      • Schaller T.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?.
      Moreover, the internationally accepted Vienna classification
      • Schlemper R.J.
      • Riddell R.H.
      • Kato Y.
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      or the similar World Health Organization

      Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of tumours of the digestive system. World Health Organization. Lyon: France.

      definition of adenomatous dysplasia within the stomach (none, indefinite, low-grade dysplasia [LGD], high-grade dysplasia [HGD], intramucosal carcinoma [IMC], submucosal invasive carcinoma [SMIC]) have not been used in large series, and this makes interpretation of clinical outcomes difficult.
      We present a large prospective Western cohort of patients undergoing ESD for endoscopically suspected, biopsy specimen–confirmed EGC and pEGC. We present outcome, safety, and follow-up data by applying the World Health Organization criteria to the pathologic classification of EGC as judged by specialist GI pathologists.

      Methods

      Data were collected and analyzed among a prospective observational cohort study of all patients referred for ESD of biopsy specimen–proven EGC or adenomatous dysplasia at a single Australian tertiary endoscopy center from January 2013 until November 2018. Institutional review board approval was obtained from Western Sydney Local Heath District Ethics Committee, and all patients provided written informed consent for inclusion in the study.
      Demographic, lesion, and procedural data were collected on all patients prospectively. Ethnicity described the place of birth of participants. Adverse events were assessed 4 weeks after the procedure by structured telephone interview with the patient. Surveillance examinations were scheduled at desired intervals of 4 to 6 months (first surveillance endoscopy [SE1]) and 12 months (second surveillance endoscopy [SE2]).

      Definitions

      Endoscopically or biopsy sample–suspected pEGC refers to a demarcated gastric lesion that was suspected on endoscopic imaging (with confirmatory forceps biopsy histology) to be EGC of any subtype or adenomatous dysplasia and is a pre-ESD entity. pEGCs were categorized into clinical criteria based on size and the presence of ulceration (absolute or expanded) (Table 1).
      Table 1Allowable criteria for endoscopic cure used for the divisions of precursor to EGC removed during the study
      CriteriaLow gradeAbsoluteExpandedOutside
      ClinicalHistologicDefinition
      Columns indicate possibility of endoscopic cure.
      Columns indicate possibility of endoscopic cure.
      Columns indicate possibility of endoscopic cure.
      Columns indicate possibility of endoscopic cure.
      YesYesSizeAny≤20 mm>20 mmAny
      YesYesUlcerationNoneNoneAllowed if ≤3 cmAllowed
      NoYesR1 resectionhm only allowed
      Horizontal margin positive does not indicate endoscopic cure but the possibility of endoscopic surveillance rather than surgery.
      Not allowedhm only allowed,
      Horizontal margin positive does not indicate endoscopic cure but the possibility of endoscopic surveillance rather than surgery.
      if no other high-risk feature
      Allowed
      NoYesDysplasia (World Health Organization criteria)Low grade onlyHGD, IMC onlyAnyAny
      NoYesDifferentiation (if IMC/SMIC)xIMC only wellWell

      Poorly diff allowed if ≤2 cm
      Any
      NoYesSM depthxNot allowedsubmucosal invasion < 500 μm allowed if ≤3 cmAny
      Clinical criteria refers to endoscopic categorization of a lesion before availability of histology (all lesions previously biopsy sample–proven as EGC or adenomatous dysplasia). Histologic criteria refers to categorization of a lesion once ESD specimen histology was available. Based on the Japanese gastric cancer treatment guidelines.
      • Kodera Y.
      • Sano T.
      Japanese gastric cancer treatment guidelines 2014 (version 4).
      Dysplasia grade defined by World Health Organization criteria.

      Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of tumours of the digestive system. World Health Organization. Lyon: France.

      R1 resection describes positive horizontal or deep margin for dysplasia.
      EGC, Early gastric cancer; IMC, intramucosal cancer; SMIC, submucosal invasive cancer; SM, submucosa; hm, horizontal margin; x, not applicable.
      Columns indicate possibility of endoscopic cure.
      Horizontal margin positive does not indicate endoscopic cure but the possibility of endoscopic surveillance rather than surgery.
      The term “early gastric cancer” was reserved for histologically proven gastric adenocarcinoma. The precursors of EGC were classified into LGD and HGD. These are post-ESD entities. These entities were classified according to the histopathology criteria (LGD, absolute, expanded, outside) (Table 1).
      The morphology of pEGC was defined relative to the normal pit pattern of the gastric mucosa as seen under high-definition white-light endoscopy and/or narrow-band imaging (Olympus, Tokyo, Japan). A disrupted area of pit pattern was described as a demarcated area ± ulceration.
      Complete endoscopic resection described removal of all pEGC tissue as determined by endoscopic imaging and was subclassified as en bloc or piecemeal. Duration described the time from first submucosal injection to specimen retrieval. Intraprocedural bleeding was described if bleeding during the procedure necessitated device change. Perforation described an actual hole in the gastric wall. Delayed bleeding was recorded if the patient required hospital admission or intervention for bleeding after they had left the endoscopy room. A severe adverse event described any event requiring hospital admission in the 30 days after the procedure.
      pEGC size was determined after ex vivo measurement of the resected specimen before pinning out on a corkboard. Pathologic assessment was by specialist GI pathologists. R0 resection described vertical and horizontal resection margins clear of dysplasia. The grade of dysplasia present within resected specimens was described according to the Vienna classification
      • Schlemper R.J.
      • Riddell R.H.
      • Kato Y.
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      of adenomatous dysplasia. Carcinoma was divided into IMC (T1a) or SMIC (T1b). Depth of submucosal invasion was described from the muscularis mucosae as submucosal invasion <500 μm or ≥500 μm. Carcinoma was described as well differentiated (papillary adenocarcinoma, well differentiated or moderately differentiated tubular adenocarcinoma) or poorly differentiated (poorly differentiated adenocarcinoma and signet-ring cell carcinoma). Endoscopic cure described lesions that fulfilled the absolute or expanded indication for endoscopic cure as set out by the Japanese gastric cancer treatment guidelines version 3
      Japanese Gastric Cancer Association
      Japanese gastric cancer treatment guidelines 2010 (version 3).
      with modification to include LGD (Table 1). Recurrence of pEGC was described if there was evidence of residual pEGC at the ESD scar at SE as determined using high-definition white-light and narrow-band imaging (Olympus) and confirmed histologically.

      Exclusions

      Lesions removed by ESD that were histologically assessed as non-EGC or its adenomatous precursors were excluded.

      ESD procedures

      ESD procedures were performed by 3 endoscopists (M.J.B. [most experienced operator and trained the other 2 in the technique], E.Y.T.L., D.J.T.). The electrosurgical knives used were the Dual Knife J (Olympus) after June 2016 and the HybridKnife (Erbe Elektromedizin, Tübingen, Germany) earlier driven by an electrosurgical generator (VIO 300D; Erbe Elektromedizin). The submucosal injectate comprised succinylated gelatin (Gelofusine; B. Braun Australia Pty Ltd, Bella Vista, Australia)
      • Moss A.
      • Bourke M.J.
      • Metz A.J.
      A randomized, double-blind trial of succinylated gelatin submucosal injection for endoscopic resection of large sessile polyps of the colon.
      with indigo carmine blue (40 mg/500 mL solution) and 1:100,000 epinephrine. Exposed nonbleeding vessels were coagulated before termination of the procedure. Patients underwent endotracheal intubation and general anesthesia. Pathologic specimens were pinned and submitted for analysis in formalin. Images from representative ESD procedures are presented in Figures 1 and 2 and Video 1 (available online at www.giejournal.org).
      Figure thumbnail gr1ac
      Figure 1Endoscopic submucosal dissection procedures for precursor to early gastric cancer satisfying the expanded histologic criteria. Technique described in Methods. A, 60-mm demarcated area occupying 75% circumference of the gastric antrum. B, 70-mm demarcated area on the lesser curve. C, 15-mm demarcated area with central ulceration in the inferior gastric antrum. D, 35-mm demarcated area at the incisura. E, 40-mm demarcated area with central ulceration in the posterior gastric antrum removed by endoscopic submucosal dissection.
      Figure thumbnail gr1de
      Figure 1Endoscopic submucosal dissection procedures for precursor to early gastric cancer satisfying the expanded histologic criteria. Technique described in Methods. A, 60-mm demarcated area occupying 75% circumference of the gastric antrum. B, 70-mm demarcated area on the lesser curve. C, 15-mm demarcated area with central ulceration in the inferior gastric antrum. D, 35-mm demarcated area at the incisura. E, 40-mm demarcated area with central ulceration in the posterior gastric antrum removed by endoscopic submucosal dissection.
      Figure thumbnail gr2ab
      Figure 2Endoscopic submucosal dissection procedures for precursor to early gastric cancer satisfying the absolute histologic criteria or low-grade dysplasia. Technique described in Methods. A, 10 mm-demarcated area in the distal gastric body, lesser curve side. B, 40-mm demarcated area at the incisura. C, 45-mm demarcated area at the incisura. D, 8-mm nodule in the gastric body. Histopathology showed intramuscosal carcinoma.
      Figure thumbnail gr2cd
      Figure 2Endoscopic submucosal dissection procedures for precursor to early gastric cancer satisfying the absolute histologic criteria or low-grade dysplasia. Technique described in Methods. A, 10 mm-demarcated area in the distal gastric body, lesser curve side. B, 40-mm demarcated area at the incisura. C, 45-mm demarcated area at the incisura. D, 8-mm nodule in the gastric body. Histopathology showed intramuscosal carcinoma.
      After ESD, all patients were observed for 4 hours. Antibiotics were not routinely used periprocedurally. Most patients were fasted in the hospital overnight and were discharged the next day on a clear fluid diet for 24 hours. Selected patients (eg, those with small lesions, patients without discomfort) were discharged the same day with instructions to maintain a clear fluid diet overnight. After ESD, patients were instructed to take proton pump inhibitors (pantoprazole 40 mg twice daily) for 8 weeks.
      Once histopathology was available, if the lesion or pathologic parameters were outside criteria for endoscopic cure, a comprehensive discussion was undertaken with the patient and specialist surgical review carried out. These patients were counseled regarding risk of lymph node metastases and the various treatment options including surgery. The final decision regarding further treatment or endoscopic surveillance was made jointly with the patient.
      At surveillance the ESD scar was located and biopsy specimens taken. Suspected recurrent disease was treated either using further ESD or surgery.

      Outcomes

      The primary outcomes of the study were rates of en bloc and R0 resection at the index ESD. Secondary outcomes included safety (rates of delayed bleeding, perforation, admission, and mortality), rates of surgery, and rates of pEGC recurrence at surveillance procedures.

      Statistical analysis

      Statistical analysis was performed using SPSS version 23 (IBM, Chicago, Ill) with 2-tailed t test used for normally distributed continuous variables, Mann-Whitney U test for skewed continuous variables, and χ2 or Fisher exact test for categorical variables. Significance was regarded at P < .05.

      Results

      One hundred thirty-five pEGCs in 121 patients were referred for ESD over the study period and were included in the analysis (Fig. 3). The mean age of patients was 72.0 years (standard deviation, 10.6), 61.2% were men, and 54.5% were born in Australia.
      Figure thumbnail gr3
      Figure 3Recruitment of patients and lesions to the study. ESD, Endoscopic submucosal dissection; pEGC, a demarcated gastric lesion that was suspected on endoscopic imaging (with confirmatory forceps biopsy histology) to be early gastric cancer of any subtype or adenomatous dysplasia; R0, histologically complete resection with clear margins; R1 resection, involved margin, curative resection (within Japanese gastric cancer guidelines); HM, horizontal margin; LGD, low-grade dysplasia; SE1, surveillance endoscopy 1; SE2, surveillance endoscopy 2. *More than 30 days after ESD, not procedure related.

      Lesion assessment

      Most pEGCs were located in the gastric antrum (60/135, 44.4%) (Table 2). The median size of pEGCs was 20 mm (interquartile range [IQR], 15-30), and this was larger in the expanded criteria (30 mm; IQR, 25-40) and outside criteria groups (30 mm; IQR, 20-50) versus the LGD (15 mm; IQR, 10-30) and absolute criteria (15 mm; IQR, 10-20) groups (P < .001). LGD was commonly located in the antrum (24/42, 57.1%). The most common morphology of pEGC was Paris 0-IIa (54/135, 40.0%). Before ESD 73 of 135 lesions (54.1%) satisfied the absolute clinical criteria and 62 (45.9%) the expanded clinical criteria (Fig. 4).
      Table 2Patient, lesion, and procedural characteristics of early gastric cancer and adenomatous precursors undergoing endoscopic submucosal dissection split by the histologic criteria in Table 1


      Low-grade dysplasiaAbsoluteExpandedOutsideOverallP value
      (n = 34)(n = 33)(n = 29)(n = 25)(n = 121)
      Patient (n = 121)
      Age, mean (standard deviation)67.4 (13.2)72.0 (8.4)75.2 (8.3)74.3 (9.8)72.0 (10.6).013
      Sex, male, n (%)23 (67.6)22 (66.7)17 (58.6)12 (48.0)74 (61.2).429
      Ethnicity, n (%)
       Asian8 (23.5)6 (18.2)1 (3.4)2 (8.0)17 (14.0).321
       European11 (32.4)10 (30.3)9 (31.0)8 (32.0)38 (31.4)
       Australian15 (44.1)17 (51.5)19 (65.5)15 (60.0)66 (54.5)
      Metachronous lesion, n (%)1 (2.9)5 (15.1)2 (6.9)1 (4.0)9 (7.5).159
      Lesion (n = 135)(n = 42)(n = 37)(n = 30)(n = 26)(n = 135)
       Size, median mm (IQR)15.0 (10-30)15.0 (10-20)30.0 (25-40)30.0 (20-50)20.0 (15-30)<.001
      Paris classification, n (%)
       IIa19 (45.2)13 (35.1)14 (46.7)8 (30.8)54 (40.0).156
       Is0 (0)2 (5.4)0 (0)1 (3.8)3 (2.2)
       IIa+c15 (35.7)10 (27.0)10 (33.3)15 (57.7)50 (37.0)
       IIa+Is2 (4.8)5 (13.5)2 (6.7)2 (7.7)11 (8.1)
       IIb6 (14.3)7 (18.9)4 (13.3)0 (0)17 (12.6)
      Location, n (%)
       Antrum24 (57.1)14 (37.8)14 (46.7)8 (30.8)60 (44.4).192
       Incisura5 (11.9)6 (16.2)3 (10.0)1 (3.8)15 (11.1)
       Distal body6 (14.3)4 (10.8)8 (26.7)6 (23.1)24 (17.8)
       Proximal body5 (11.9)5 (13.5)1 (3.3)6 (23.1)17 (12.6)
       Cardia2 (4.8)7 (18.9)3 (10.0)4 (15.4)16 (11.9)
       Remnant stomach0 (0)1 (2.7)1 (3.3)1 (3.8)3 (2.2)
      Ulceration0 (0)0 (0)0 (0)3 (11.5)3 (2.2).006
      Procedure
      Duration, min, median (IQR)81.5 (35-120)75.0 (45-120)110 (85-170)127.5 (60-200)92.5 (55-140).027
      IPB, n (%)10 (23.8)8 (21.6)13 (43.3)12 (46.2)43 (31.9).063
      Deep injury,
      Describes injury to the muscularis propria requiring endoscopic closure methods.
      n (%)
      2 (4.8)3 (8.1)2 (6.7)2 (7.7)7 (5.2).820
      Perforation, n (%)0 (0)1 (3.3)1 (3.8)0 (0)2 (1.5).245
      Adverse events
      Delayed bleeding, n (%)2 (4.8)1 (2.7)2 (6.7)2 (7.7)7 (5.2).789
      Delayed perforation, n (%)0 (0)0 (0)0 (0)0 (0)0 (0)x
      Admission, n (%)32 (76.2)33 (89.2)30 (100.0)24 (92.3)119 (88.1).013
      Any severe adverse event within 30 days, n (%)6 (16.2)1 (3.3)2 (7.7)9 (21.4)18 (13.3).111
      Mortality, n (%)0 (0)0 (0)0 (0)0 (0)0 (0)x
      IQR, Interquartile range; IPB, intraprocedural bleeding; x, not applicable.
      Describes injury to the muscularis propria requiring endoscopic closure methods.
      Figure thumbnail gr4
      Figure 4Important outcomes of lesions in the study stratified by clinical and histopathologic criteria (defined in ). ESD, Endoscopic submucosal dissection; LGD, low-grade dysplasia; pEGC, a demarcated gastric lesion that was suspected on endoscopic imaging (with confirmatory forceps biopsy histology) to be early gastric cancer of any subtype or adenomatous dysplasia; SE1, surveillance endoscopy 1; SE2, surveillance endoscopy 2. *Lesions referred for surgery at index. **Low-grade dysplasia with multiple recurrence, surgical specimen showed high-grade dysplasia. ***Recurrence at second surveillance in a non-R0 resection referred for surgery after second surveillance (first surveillance negative).

      ESD procedures

      Of 135 ESD procedures, the median procedure duration was 92.5 minutes (IQR, 55.0-140.0). It was significantly longer in the expanded (110 minutes; IQR, 85-170) and the outside criteria (127.5 minutes; IQR, 60-200) groups versus the low-grade (81.5 minutes; IQR, 35-120) and absolute criteria (75 minutes; IQR, 45-120) groups (P = .027) (Table 2, Supplementary Table 1, available online at www.giejournal.org).
      Intraprocedural bleeding occurred in 43 cases (31.9%) overall and was not more common among any group (P = .063). Full-thickness perforation occurred in 2 cases (1.5%). The first perforation was early in the experience (2013). The second was more recent (2016) and involved an extremely large lumen-filling pEGC in the proximal gastric corpus. Complete closure was achieved using through-the-endoscope clips in both cases, with no adverse sequelae.
      Delayed bleeding occurred in 7 of 135 patients (5.2%). Admission to the hospital occurred in most patients (119, 88.1%), although admission was less likely in the LGD group (32, 76.2%) versus the outside criteria group (24, 92.3%; P = .013). No factor known before the resection procedure predicted the need for admission at univariate analysis (Supplementary Table 2, available online at www.giejournal.org ). There was no mortality within 30 days of ESD.

      Completeness of resection and lesion categorization

      Complete clearance of pEGC was achieved in 133 of 135 cases (98.5%). Reasons for failure were significant intraprocedural bleeding in 1 case and extensive fibrosis and vasculature raising concern for invasive disease in 1 case. A further 5 cases underwent piecemeal resection (Table 3).
      Table 3Characteristics of precursor to early gastric cancer that underwent endoscopic resection split by the clinical criteria in Table 1 (n = 135)
      Absolute (n = 73)Expanded (n = 62)Total (n = 135)
      En bloc resection72 (98.6)56 (90.3)128 (94.8)
      R0 resection68 (93.2)49 (79.0)117 (86.7)
       R1 vm+2/4 (50)3/7 (42.9)x
       R1 hm+2/4 (50)5/7 (71.4)x
      Histology
       LGD27 (37.0)15 (24.2)42 (31.1)
       HGD21 (28.8)16 (25.8)37 (27.4)
       IMC16 (21.9)14 (22.6)30 (22.2)
       SMIC9 (12.3)17 (27.4)26 (19.3)
      Differentiation (n = 56)
       Well22 (88.0)24 (77.4)46 (82.1)
       Poorly3 (12.0)7 (22.6)10 (17.9)
      SMIC depth (n = 26)
       SM17 (77.8)11 (64.7)18 (69.2)
       >SM12 (22.2)6 (35.3)8 (30.8)
      Lymphovascular invasion, % IMC, SMIC (n = 56)1 (4.0)10 (32.3)11 (19.6)
      Underwent surgery at index1 (1.4)9 (14.5)10 (7.4)
      Underwent surgery during surveillance0 (0)2 (3.2)2 (1.5)
      SE1 recurrence (n = 100)0 (0)1 (2.4)1 (1.0)
      SE2 recurrence (n = 48)0 (0)2 (9.1)2 (4.2)
      Values are n (%). Version split by histologic criteria can be found in Supplementary Table 3 (available online at www.giejournal.org).
      x, Not applicable; LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMC, intramucosal carcinoma; SMIC, submucosal invasive carcinoma; R0, clear horizontal and deep resection margins; vm, vertical margin; hm, horizontal margin; SM1, invasion ≤ 500 μm into the submucosa; SE1, surveillance endoscopy 1; SE2, surveillance endoscopy 2.
      The overall en bloc resection rate was 128 of 135 (94.8%), 72 (98.6%) in the absolute clinical criteria group, and 56 (90.3%) in the expanded clinical criteria group. R0 resection was achieved in 117 cases (86.7%) overall, 68 of 73 (93.2%) in the absolute clinical criteria group and 49 of 62 (79.0%) in the expanded clinical criteria group (Fig. 4). Two patients with R1 resections without other high-risk features entered endoscopic surveillance but were not considered endoscopically cured.
      Histopathology was LGD in 42 cases (31.1%), HGD in 37 (27.4%), IMC in 30 (22.2%), and SMIC in 26 (19.3%). Among 56 EGCs with IMC or SMIC, 46 of 56 (82.1%) were well differentiated and 10 (17.9%) were poorly differentiated. Lymphovascular invasion was present in 11 cases (19.6%). Among the 26 EGCs with SMIC, 18 of 26 (19.6%) had depth of invasion of <500 μm.
      Accounting for histopathologic analysis (Supplementary Table 3, available online at www.giejournal.org), 42 of 135 lesions (31.1%) contained only LGD, 37 of 135 (27.4%) lesions satisfied the absolute criteria, 30 of 135 lesions (22.2%) the expanded criteria, and 26 of 135 lesions (19.3%) were outside criteria for endoscopic cure. Overall, 107 of 135 lesions (79.2%) fulfilled criteria for endoscopic cure at the index procedure.

      Outcomes of patients with LGD and HGD only

      Forty-two pEGCs (31.1%) contained LGD only and 37 (27.4%) HGD only. Of 37 patients with LGD, none underwent surgery after the index ESD with 1 undergoing surgery after SE2 because of recurrence (see below). One patient with HGD underwent surgery because of piecemeal resection, and 1 patient with non-R0 resection experienced recurrence at SE2 after negative SE1 and was referred for surgery.

      Surgical referral outside criteria

      Reasons for noncurative ESD were incomplete resection in 2, piecemeal resection in 4, R1 resection in 9, poor tumor differentiation in 3, submucosal invasive cancer ≥500 μm in 3, and lymphovascular invasion in 5. All pEGCs that fell outside criteria for endoscopic cure were considered for surgery (Supplementary Table 4, available online at www.giejournal.org).
      Fifteen of 26 patients (60.9%) did not undergo surgery after the index procedure, 3 because of their wishes and 12 because of frailty. These patients all also declined radiologic surveillance for extraluminal disease. Eleven of 15 patients (73.3%) have undergone SE1, with 1 of 11 exhibiting endoscopic and histologic evidence of pEGC recurrence.
      Eleven of 26 patients with lesions outside criteria for endoscopic cure were referred for surgery after the index ESD. Of 10 patients who underwent surgery, residual tumor was detected in 3 of 10 surgical specimens, and no surgical specimens contained positive lymph nodes. One patient was awaiting surgery at the time of writing.

      Endoscopic surveillance

      One hundred of 124 patients who did not undergo surgery underwent SE1 at a median of 8 months (IQR, 5-16). Reasons for not undergoing SE1 are shown in Figure 4. A single pEGC (1.0%) demonstrated endoscopic and histologic recurrence at the resection scar. This was a 70-mm Paris 0-IIa demarcated area on the lesser curve with LGD in the resection specimen and failed en bloc resection. The patient elected to undergo further surveillance. At the surveillance procedure (4 months) a small residual at the scar was treated with cold forceps avulsion and adjuvant snare tip soft coagulation.
      • Tate D.J.
      • Bahin F.F.
      • Desomer L.
      • et al.
      Cold-forceps avulsion with adjuvant snare-tip soft coagulation (CAST) is an effective and safe strategy for the management of non-lifting large laterally spreading colonic lesions.
      At second surveillance (10 months) a depressed, demarcated area was detected adjacent to the scar, and the patient was referred for surgery. The surgical specimen demonstrated HGD only.
      Fifty of 100 pEGCs that underwent SE1 also underwent SE2 at a median of 16 months (IQR, 11-25). Reasons for not undergoing SE2 are shown in Figure 4. Including the above second recurrence 2 of 50 EGCs (4.0%) recurred. The other recurrence was in a 68-year-old patient who had previously undergone distal gastrectomy for a metachronous tumor 2 years prior and who had a severely scarred 100-mm proximal body pEGC removed by ESD within an inflamed postsurgical stomach and non-R0 resection. Because of prior experience, the patient declined further surgery. He underwent negative SE1, but at SE2 there was endoscopic and histologic evidence of recurrence at the resection scar, and so he was referred for total gastrectomy. The surgery demonstrated residual T3N0M0 carcinoma.

      Discussion

      ESD is a safe, effective, and surgery-sparing
      • Shin D.W.
      • Hwang H.Y.
      • Jeon S.W.
      Comparison of endoscopic submucosal dissection and surgery for differentiated type early gastric cancer within the expanded criteria.
      procedure for pEGCs larger than 10 to 15 mm.
      • Pimentel-Nunes P.
      • Dinis-Ribeiro M.
      • Ponchon T.
      • et al.
      Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) guideline.
      Eastern centers achieve excellent en bloc resection (86%-97%) and R0 resection rates (88%-93%),
      • Tanabe S.
      • Ishido K.
      • Higuchi K.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.
      • Chung I.-K.
      • Lee J.H.
      • Lee S.-H.
      • et al.
      Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study.
      • Ahn J.Y.
      • Jung H.-Y.
      • Choi K.D.
      • et al.
      Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370 cases of absolute and extended indications.
      • Choi M.K.
      • Kim G.H.
      • Park D.Y.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a single-center experience.
      good adverse event profiles,
      • Gotoda T.
      • Iwasaki M.
      • Kusano C.
      • et al.
      Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria.
      and long-term disease-free survival.
      • Tanabe S.
      • Ishido K.
      • Matsumoto T.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a multicenter collaborative study.
      The situation in Western centers is very different; EGC is much less common, ESD is not widely available, and there are few opportunities to train in the technique.
      • Bourke M.J.
      • Neuhaus H.
      • Bergman J.J.
      Endoscopic submucosal dissection: indications and application in Western endoscopy practice.
      • Ma M.X.
      • Bourke M.J.
      Endoscopic submucosal dissection in the West: current status and future directions.
      In addition, although a growing number of studies now address the application of the absolute criteria to Western patients,
      • Dinis-Ribeiro M.
      • Pimentel-Nunes P.
      • Afonso M.
      • et al.
      A European case series of endoscopic submucosal dissection for gastric superficial lesions.
      • Probst A.
      • Pommer B.
      • Golger D.
      • et al.
      Endoscopic submucosal dissection in gastric neoplasia—experience from a European center.
      • Schumacher B.
      • Charton J.P.
      • Nordmann T.
      • et al.
      Endoscopic submucosal dissection of early gastric neoplasia with a water jet-assisted knife: a Western, single-center experience.
      the expanded criteria for ESD of pEGCs remain relatively untested in this context. In this study, among 135 pEGCs removed by ESD, the R0 resection rate was 93.2% for absolute clinical indication lesions and 79.0% for the expanded clinical indication. The overall curative resection rate was 79.2%, with 46% of the lesions satisfying the expanded criteria.
      The largest published Western experience to date
      • Probst A.
      • Schneider A.
      • Schaller T.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?.
      demonstrates similar results, although it only included histopathologically proven gastric carcinoma. Among 179 EGCs removed by ESD, the en bloc resection rate was 92.1%, the R0 resection rate 75.9%, and the overall curative resection rate 63.9%, with 48.6% of the lesions satisfying the expanded criteria. Together these studies indicate the feasibility of ESD for expanded criteria EGC in the West. However, rates of R0 and en bloc resection are lower than Eastern studies.
      • Tanabe S.
      • Ishido K.
      • Higuchi K.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.
      • Chung I.-K.
      • Lee J.H.
      • Lee S.-H.
      • et al.
      Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study.
      • Ahn J.Y.
      • Jung H.-Y.
      • Choi K.D.
      • et al.
      Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370 cases of absolute and extended indications.
      • Choi M.K.
      • Kim G.H.
      • Park D.Y.
      • et al.
      Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a single-center experience.
      The cause of this is likely multifactorial, including a learning curve. In addition, in both Western studies, most R1 resections involved the lateral margin, suggesting improved lesion delineation or that postresection pathologic processing was required.
      Despite the increasing evidence for the safety and efficacy of endoscopic resection for EGC in a Western cohort, for a Western endoscopist encountering an area of endoscopically demarcated suspected dysplasia (pEGC) in the stomach there is little evidence to guide the selection of treatment options. These could include watchful waiting, endoscopic resection, or surgery. Reasons for this conundrum are the different pathologic reporting systems in use between Japanese and Western centers; the difficulties in differentiating LGD from higher-grade precursors of gastric cancer endoscopically, even in Japan, and the failure to identify separately LGD, HGD, and IMC in most studies addressing outcomes of ESD for EGC.
      Most such studies, including the only large Western cohort,
      • Probst A.
      • Schneider A.
      • Schaller T.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?.
      use the Japanese gastric cancer treatment guidelines
      • Kodera Y.
      • Sano T.
      Japanese gastric cancer treatment guidelines 2014 (version 4).
      Japanese Gastric Cancer Association
      Japanese gastric cancer treatment guidelines 2010 (version 3).
      for assessment of endoscopic cure. However, these guidelines do not use the internationally accepted Vienna criteria
      • Schlemper R.J.
      • Riddell R.H.
      • Kato Y.
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      for the reporting of dysplasia, which are commonly used in Western centers. The Vienna classification for dysplasia demonstrates better interobserver agreement than the Japanese criteria
      • Schlemper R.J.
      • Riddell R.H.
      • Kato Y.
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      and has been adopted by the World Health Organization.

      Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of tumours of the digestive system. World Health Organization. Lyon: France.

      In particular, within the Japanese system, HGD is not differentiated from intramucosal cancer. HGD has been reported to transform to carcinoma in 60% to 85% over 4 to 48 months
      • Sung J.K.
      Diagnosis and management of gastric dysplasia.
      but is not at risk for lymph node metastases. Conversely, intramucosal cancer is at risk of metastasis where the tumor has access to lymphatics. This distinction is irrelevant in the colon because the mucosa has no lymphatics; however, the gastric mucosa is fundamentally different
      • Listrom M.B.
      • Fenoglio-Preiser C.M.
      Lymphatic distribution of the stomach in normal, inflammatory, hyperplastic, and neoplastic tissue.
      and contains lymphatics. Thus, lymph node metastasis from IMC limited to the mucosa is entirely possible. In this study, stratification of these pathologies revealed that 40% of expanded (Japanese criteria) lesions contained HGD only. The grouping of these pathologies therefore risks upstaging lymph node metastasis risk for lesions with HGD and may result in overtreatment and unnecessary distress for patients.
      Low-grade adenomatous dysplasia within the stomach has been shown to regress in 38% to 75%, persist in 19% to 50%, and transform to cancer in 0% to 9% during surveillance.
      • Srivastava A.
      • Lauwers G.Y.
      Gastric epithelial dysplasia: the Western perspective.
      Particular difficulties for Western endoscopists arise because there is no consistently reproducible data to guide the endoscopic discrimination of LGD or HGD from more advanced precursors of gastric cancer within a demarcated area of suspected dysplasia in the stomach, even in Japan. Furthermore, multiple studies have demonstrated that an endoscopically demarcated area biopsy sampled as LGD has a risk of hidden, more advanced precursors of gastric cancer (up to 25% in a meta-analysis
      • Zhao G.
      • Xue M.
      • Hu Y.
      • et al.
      How commonly is the diagnosis of gastric low grade dysplasia upgraded following endoscopic resection? A meta-analysis.
      ). Such areas are therefore recommended for complete resection if detected by a technique that can reliably achieve en bloc excision (ie, ESD).
      • Bourke M.J.
      • Neuhaus H.
      • Bergman J.J.
      Endoscopic submucosal dissection: indications and application in Western endoscopy practice.
      In this study, a demarcated lesion with LGD and a positive lateral margin at histopathology was subjected to endoscopic treatment at a surveillance procedure and eventually required surgery because of persistent recurrence. Taken together, this evidence suggests a clear need for prospective studies that identify long-term outcomes of gastric LGD subjected to endoscopic resection.
      This is the first study to separately identify pEGC containing LGD and HGD in a Western cohort. The group of lesions containing only LGD was differentiated from the standard Japanese absolute and expanded indication groups. At endoscopic assessment 64% of these demarcated areas would otherwise have satisfied the absolute criteria and 46% the expanded criteria. Many previous studies on ESD for EGC have not reliably identified this group, leading to the suspicion that they are either excluded or grouped within the Japanese criteria groups; therefore, long-term outcomes in this subgroup including 5-year survival and recurrence rates are not individually defined. The largest Western study to date on ESD for EGC excluded this group.
      • Probst A.
      • Schneider A.
      • Schaller T.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?.
      Data from the present study suggest the efficacy of endoscopic resection for demarcated LGD; however, there is need for close surveillance after resection and further long-term survival data. This is particularly important given the high risk of metachronous lesions (8% of patients over the study period) in this cohort.
      The above observations lead to difficulties when applying the available literature to the patient in the Western consultation room. The stratification of patient, lesion, and outcome data in this study by endoscopically determinable criteria (lesion size and presence of ulceration) will be useful information for all Western endoscopists, not only those performing ESD. When this information is used, the likelihood of success of resection and likely histopathology (Vienna/World Health Organization criteria but including matching to the Japanese gastric cancer guidelines classification) can be predicted by the detecting endoscopist and an informed discussion scheduled with the patient covering an evidence-based selection of treatment options before intervention. Of particular importance in these discussions, as is evident from Figure 1, is that very few pEGCs judged as absolute by clinical criteria (small and without ulceration) are upstaged to expanded or outside criteria by the addition of histopathology. In addition, because of the use of the Vienna classification and after resection, those pEGCs completely resected (R0) with LGD or HGD can be discussed with the patient in the appropriate (benign) clinical context.
      The outcomes of the 26 pEGCs in this study whose histology were outside the Japanese gastric cancer association criteria for curative resection are of considerable interest. Among those who had surgery, only a few surgical specimens contained residual neoplasia, and none contained positive lymph nodes. Among patients who declined surgery, only 1 has experienced recurrence at a median 6 months of follow-up. This suggests a cohort of patients in whom an outside criteria resection for pEGC may well be if not a cure then sufficient to prevent local disease progression and its associated morbidity. Many of these patients are elderly with significant comorbidity, and local disease control during their remaining years may be all that is required to prevent death or morbidity from gastric cancer. This is supported by a large South Korean retrospective study where such patients had a long-term cancer-specific survival of 86.2%
      • Jeon M.Y.
      • Park J.C.
      • Hahn K.Y.
      • et al.
      Long-term outcomes after noncurative endoscopic resection of early gastric cancer: the optimal time for additional endoscopic treatment.
      and a recent study demonstrating the feasibility of ESD in elderly patients.
      • Watanabe K.
      • Hikichi T.
      • Nakamura J.
      • et al.
      Endoscopic submucosal dissection for early gastric cancer in very elderly patients age 85 or older.
      In addition, the risk and morbidity of recurrent disease must be weighed against the considerable perioperative and quality of life risks of surgery in this cohort.
      This study adds to the growing body of literature suggesting ESD for EGC and its precursors is safe in a Western context. Increasing Western operator experience has led to decreased rates of adverse events comparable with Eastern rates.
      • Barret M.
      • Lepilliez V.
      • Coumaros D.
      • et al.
      The expansion of endoscopic submucosal dissection in France: a prospective nationwide survey.
      In this study, intraprocedural bleeding (31.9%), full-thickness perforation (1.5%), and delayed bleeding (5.2%) occurred at rates consistent with the comparable Eastern literature
      • Chung I.-K.
      • Lee J.H.
      • Lee S.-H.
      • et al.
      Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study.
      • Ahn J.Y.
      • Jung H.-Y.
      • Choi K.D.
      • et al.
      Endoscopic and oncologic outcomes after endoscopic resection for early gastric cancer: 1370 cases of absolute and extended indications.
      • Shin D.W.
      • Hwang H.Y.
      • Jeon S.W.
      Comparison of endoscopic submucosal dissection and surgery for differentiated type early gastric cancer within the expanded criteria.
      and were all treated endoscopically. No patients died as a result of ESD procedures. Admission to the hospital is universally recommended after gastric ESD. Exploratory data from this study suggest that it may not be required; however, larger numbers are required. This is an important aspect in Western healthcare systems where reduction of resource usage is a priority.
      As Western referral pathways for EGC are modified to incorporate ESD, consideration must be given to developing training opportunities for Western endoscopists to master ESD without travel to Japanese centers. The potential Western ESD practitioner should make the procedure their focus and immerse themselves in the procedure for an apprenticeship of at least 12 months at a tertiary referral center. The practitioner should be familiar with the entire pathway of management of pEGC in addition to the surgical and oncologic treatment of more advanced lesions.
      This is a series of prospectively collected, well-characterized cases of gastric ESD from a Western center. We have meticulously described the cohort from which the cases derive and all losses to follow-up. All pathologic specimens underwent review by specialist GI pathologists. The drawbacks of the study design include the single-center recruitment and limited long-term follow-up data. This was an elderly population with substantial comorbidity perhaps because of a negative selection bias for those who could not undergo surgery. Age or comorbidity was the predominant reason for not undergoing surveillance. Further follow-up of this cohort will be required to determine long-term oncologic cure.
      In conclusion, high rates of curative resection for pEGC can be safely achieved in a Western setting. Patients with outside criteria resections, who either decline or are too frail for surgery, may benefit from ESD for local disease control and potential cure. Application of internationally accepted pathologic reporting criteria in large prospective Western studies of ESD for pEGC is required to better define surveillance guidelines and patient outcomes, particularly in the group of patients with isolated LGD or HGD.

      Appendix

      Supplementary Table 1Patient, lesion, and procedural characteristics of precursor to early gastric cancer undergoing endoscopic submucosal dissection classified by the clinical criteria described in Table 1
      AbsoluteExpandedOverallP value
      (n = 61)(n = 60)(n = 121)
      Patient (n = 121)
      Age, mean (standard deviation)71.0 (10.9)73.0 (10.3)72.0 (10.6).297
      Sex, male, n (%)37 (60.7)37 (61.7)74 (61.2).909
      Ethnicity
       Asian11 (18.0)6 (10.0)17 (14.0).426
       European19 (31.1)19 (31.7)38 (31.4)
       Australian31 (50.8)35 (58.3)66 (54.5)
      Metachronous lesion, n (%)6 (9.9)3 (5.0)9 (7.5).667
      Lesion (n = 35)(n = 73)(n = 62)(n = 135)
       Size, mm, median (IQR)15 (10-20)30 (25-40)20 (15-30)<.001
      Paris classification
       IIa25 (34.2)29 (46.8)54 (40.0).415
       Is2 (2.7)1 (1.6)3 (2.2)
       IIa+c29 (39.7)21 (33.9)50 (37.0)
       IIa+Is5 (6.8)6 (9.7)11 (8.1)
       IIb12 (16.4)5 (8.1)17 (12.6)
      Location
       Antrum35 (47.9)25 (40.3)60 (44.4).659
       Incisura8 (11.0)7 (11.3)15 (11.1)
       Distal body10 (13.7)14 (22.6)24 (17.8)
       Proximal body11 (15.1)6 (9.7)17 (12.6)
       Cardia8 (11.0)8 (12.9)16 (11.9)
       Remnant stomach1 (1.4)2 (3.2)3 (2.2)
      Ulceration0 (0)3 (4.8)3 (2.2).094
      Procedure
      Duration, min, median (IQR)69 (35-99)120 (90-170)92.5 (55-140)<.001
      IPB, n (%)16 (21.9)27 (43.5)43 (31.9).007
      Deep injury,
      Describes injury to the muscularis propria requiring endoscopic closure methods.
      n (%)
      3 (4.1)5 (8.1)8 (5.9).369
      Perforation, n(%)0 (0)2 (3.2)2 (1.5).209
      Adverse events
      Delayed bleeding, n (%)3 (4.1)4 (6.5)7 (5.2).703
      Delayed perforation, n (%)0 (0)0 (0)0 (0)x
      Admission, n (%)62 (84.9)57 (91.9)119 (88.1)
      Any severe adverse event within 30 days, n (%)12 (16.4)6 (9.7)18 (13.3).249
      Mortality, n (%)0 (0)0 (0)0 (0)x
      Version classified by histologic criteria found in Table 2.
      IQR, Interquartile range; IPB, intraprocedural bleeding; x, not applicable.
      Describes injury to the muscularis propria requiring endoscopic closure methods.
      Supplementary Table 2Predictors of admission in patients undergoing endoscopic submucosal dissection for precursor to early gastric cancer
      AdmissionP value
      Size <20 mm47 (85.5).422
      Size 20 mm72 (90.0)
      Age <7147 (83.9).202
      Age 7172 (91.1)
      Male76 (87.4).702
      Female43 (89.6)
      Location antrum52 (86.7).634
      Other location67 (89.3)
      Values are n (%). No factor predicted admission at univariate analysis.
      Supplementary Table 3Characteristics of early gastric cancer and adenomatous precursors that underwent endoscopic resection (n = 135)
      LGD (n = 42)Absolute (n = 37)Expanded (n = 30)Outside (n = 26)Total (n = 135)
      En bloc resection41 (97.6)37 (100)30 (100)20 (76.9)128 (94.8)
      R0 resection40 (95.3)37 (100)29 (96.7)11 (42.3)117 (86.7)
       R1 vm+0/1 (0)x0/1 (0)5/9 (55.6)x
       R1 hm+1/1 (100)x1/1 (100)5/9 (55.6)x
      Histology
       LGD42 (100)00042 (31.1)
       HGDx21 (56.8)12 (40.0)4 (15.4)37 (27.4)
       IMCx16 (43.2)10 (33.3)4 (15.4)30 (22.2)
       SMICx08 (26.7)18 (69.2)26 (19.3)
      Differentiation
       Wellx16/16 (100)18/18 (100)12/22 (54.5)46/56 (82.1)
       Poorlyx00/18 (0)10/22 (45.5)10/56 (17.9)
      SMIC depth
       SM1xx8/8 (100)10/18 (55.6)18/26 (69.2)
       >SM1xx08/18 (44.4)8/26 (30.8)
      Lymphovascular invasion, IMC/SMICxx011/22 (50.0)11/56 (19.6)
      Underwent surgery at index0 (0)0 (0)0 (0)10 (38.5)10 (7.4)
      Underwent surgery during surveillance1 (2.4)0 (0)0(0)1 (3.8)2 (1.5)
      SE1 recurrence (n = 100)/1001/36 (3.8)0/28 (0)0/25 (0)0/11 (0)1 (1.0)
      SE2 recurrence (n = 48)/481/22 (4.5)
      Same lesion that recurred at SE1 (version split by clinical criteria found in Table 3).
      0/13 (0)0/11 (0)1/2 (50)2 (4.2)
      Values are n or n/N (%).
      x, Not applicable; LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMC, intramucosal carcinoma; SMIC, submucosal invasive carcinoma; R0, clear horizontal and deep resection margins; vm, vertical margin; hm, horizontal margin; SM1, invasion ≤500 μm into the submucosa; SE1, surveillance endoscopy 1; SE2, surveillance endoscopy 2.
      Same lesion that recurred at SE1 (version split by clinical criteria found in Table 3).
      Supplementary Table 4Detailed characteristics of pEGC with indication for surgery during the study
      PatientLesionSurgery
      Age (y)SexEGC size (mm)LocationOriginal histologyEn blocR0Histological criteriaReason for surgical indicationTiming of surgical indicationUnderwent surgeryIf no surgery, reasonResidual tumorLymph node statusOutcome
      Outside criteria, did not undergo surgery
      87F80CardiaHGDNoNoOutsideIncompleteIndexNoFrailtyxxAwaiting SE1
      86F60Proximal bodyInvasiveNoNoOutsideIncompleteIndexNoPatient wishesxxClear SE1
      87F70Distal bodyHGDNoNoOutsidePiecemealIndexNoFrailtyxxAwaiting SE1
      68++M100Proximal bodyHGDNoNoOutsidePiecemealIndexNo++, see belowPatient wishesxxSurgery at SE2 for persistent recurrence
      77M20CardiaInvasiveYesNoOutsideR1, >SM1IndexNoFrailtyxxClear SE1
      82M40Proximal bodyIMCYesNoOutsideR1, poorly diffIndexNoFrailtyxxClear SE1
      83F20Proximal bodyInvasiveYesNoOutsideR1, poorly diffIndexNoFrailtyxxClear SE1
      88F10Distal bodyInvasiveYesNoOutsideR1, >SM1, poorly diffIndexNoFrailtyxxClear SE1
      71M15AntrumInvasiveYesYesOutsidePoorly diff and ulcerationIndexNoFrailtyxxAwaiting SE1
      76M25CardiaInvasiveYesYesOutsideLVIIndexNoFrailtyxxClear SE1
      82M30Distal bodyInvasiveYesYesOutsideLVIIndexNoFrailtyxxClear SE1
      82M25AngulusInvasiveYesYesOutside>SM1, LVIIndexNoFrailtyxxAwaiting SE1
      79F35antrumIMCYesYesOutsidePoorly diffIndexNoFrailtyxxClear SE1
      83M25AntrumInvasiveYesYesOutsideLVIIndexNoFrailtyxxClear SE1
      78F40AntrumInvasiveYesYesOutsideover size criteria for SM1IndexNoPatient wishesxxClear SE1
      Outside criteria, underwent surgery
      69F15Distal bodyInvasiveNoNoOutsidePiecemeal, Poorly diff, LVIIndexYesxNoNegativex
      66M45AntrumHGDNoNoOutsidePiecemeal,IndexYesxYesNegativex
      53M30CardiaInvasiveYesNoOutsideR1, Poorly diff, >SM1IndexYesxYesNegativex
      63M60Distal bodyInvasiveYesNoOutsideR1, Poorly diff, >SM1, LVIIndexYesxNoNegativex
      65F20Distal bodyInvasiveYesNoOutsideR1, LVIIndexYesxYesNegativex
      69F25Proximal bodyIMCYesNoOutsideR1, Poorly diffIndexYesXNoNegativex
      55F50AntrumInvasiveYesNoOutsideR1, over size criteria for SM1IndexYesXNoNegativex
      68M30Proximal bodyInvasiveYesYesOutside>SM1IndexYesxNoNegativex
      69F30Proximal bodyIMCYesYesOutsidePoorly diffIndexYesxNoNegativex
      69F60Proximal bodyIMCYesYesOutsideLVIIndexYesxNoNegativex
      71M10AntrumInvasiveYesYesOutsideLVIIndexNoAwaiting surgeryxxx
      Surgery for other reason
      59+M70Distal bodyLGDYesNoLGDPersistent recurrence at SE2SurveillanceYesxHGDNegativex
      68++M*100Proximal bodyHGDYesNoOutsideRecurrence at SE2 after negative SE1SurveillanceYesxYesNegativex
      x, Not applicable; +, patient with LGD only who experienced persistent endoscopic recurrence and was therefore referred for surgery; ++, patient with an outside criteria resection who initially declined surgery but later underwent surgery during surveillance and therefore appears twice in the table; pEGC, a demarcated gastric lesion that was suspected on endoscopic imaging (with confirmatory forceps biopsy histology) to be early gastric cancer of any subtype or adenomatous dysplasia; LGD, low-grade dysplasia; HGD, high-grade dysplasia; LVI, lymphovascular invasion; diff, differentiation; R1, either horizontal or deep margin containing tumor or dysplasia; SM1, submucosal invasion < 500 μm; >SM1, submucosal invasion ≥500 μm; SE1, first surveillance endoscopy; SE2, second surveillance endoscopy.

      Supplementary data

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      Linked Article

      • Endoscopic submucosal dissection for early gastric cancer in the West: the absolute but not final word
        Gastrointestinal EndoscopyVol. 90Issue 3
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          Gastric cancer remains one of the most common cancers worldwide and is the third leading cause of cancer-related mortality, trailing only lung and colon cancer.1 Given its historically low survival rates, early detection and resection is the most effective strategy to improve prognosis. Endoscopic submucosal dissection (ESD), a technique developed in Japan, enables en bloc resection of early gastric cancer (EGC) and can be curative for selected lesions, depending on the histologic features, size, and tumor depth.
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