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Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, AustraliaWestmead Clinical School, The University of Sydney, Sydney, New South Wales, AustraliaUniversity Hospital Ghent, Ghent, Belgium
Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, AustraliaWestmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia
Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia
Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, AustraliaWestmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia
Reprint requests: Michael J. Bourke, MBBS, Suite 106a 151-155 Hawkesbury Road, Westmead Hospital, Sydney, New South Wales, Australia 2145.
Affiliations
Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, AustraliaWestmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia
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.)
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.
Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.
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).
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,
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
Horizontal margin positive does not indicate endoscopic cure but the possibility of endoscopic surveillance rather than surgery.
if no other high-risk feature
Allowed
No
Yes
Dysplasia (World Health Organization criteria)
Low grade only
HGD, IMC only
Any
Any
No
Yes
Differentiation (if IMC/SMIC)
x
IMC only well
Well Poorly diff allowed if ≤2 cm
Any
No
Yes
SM depth
x
Not allowed
submucosal invasion < 500 μm allowed if ≤3 cm
Any
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.
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
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
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).
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 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 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 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 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 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.
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
Figure 4Important outcomes of lesions in the study stratified by clinical and histopathologic criteria (defined in Table 1). 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).
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)
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.
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.
Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.
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.
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.
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.
Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center.
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,
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
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
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
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.
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
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.
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%
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.
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
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
Supplementary Table 4Detailed characteristics of pEGC with indication for surgery during the study
Patient
Lesion
Surgery
Age (y)
Sex
EGC size (mm)
Location
Original histology
En bloc
R0
Histological criteria
Reason for surgical indication
Timing of surgical indication
Underwent surgery
If no surgery, reason
Residual tumor
Lymph node status
Outcome
Outside criteria, did not undergo surgery
87
F
80
Cardia
HGD
No
No
Outside
Incomplete
Index
No
Frailty
x
x
Awaiting SE1
86
F
60
Proximal body
Invasive
No
No
Outside
Incomplete
Index
No
Patient wishes
x
x
Clear SE1
87
F
70
Distal body
HGD
No
No
Outside
Piecemeal
Index
No
Frailty
x
x
Awaiting SE1
68++
M
100
Proximal body
HGD
No
No
Outside
Piecemeal
Index
No++, see below
Patient wishes
x
x
Surgery at SE2 for persistent recurrence
77
M
20
Cardia
Invasive
Yes
No
Outside
R1, >SM1
Index
No
Frailty
x
x
Clear SE1
82
M
40
Proximal body
IMC
Yes
No
Outside
R1, poorly diff
Index
No
Frailty
x
x
Clear SE1
83
F
20
Proximal body
Invasive
Yes
No
Outside
R1, poorly diff
Index
No
Frailty
x
x
Clear SE1
88
F
10
Distal body
Invasive
Yes
No
Outside
R1, >SM1, poorly diff
Index
No
Frailty
x
x
Clear SE1
71
M
15
Antrum
Invasive
Yes
Yes
Outside
Poorly diff and ulceration
Index
No
Frailty
x
x
Awaiting SE1
76
M
25
Cardia
Invasive
Yes
Yes
Outside
LVI
Index
No
Frailty
x
x
Clear SE1
82
M
30
Distal body
Invasive
Yes
Yes
Outside
LVI
Index
No
Frailty
x
x
Clear SE1
82
M
25
Angulus
Invasive
Yes
Yes
Outside
>SM1, LVI
Index
No
Frailty
x
x
Awaiting SE1
79
F
35
antrum
IMC
Yes
Yes
Outside
Poorly diff
Index
No
Frailty
x
x
Clear SE1
83
M
25
Antrum
Invasive
Yes
Yes
Outside
LVI
Index
No
Frailty
x
x
Clear SE1
78
F
40
Antrum
Invasive
Yes
Yes
Outside
over size criteria for SM1
Index
No
Patient wishes
x
x
Clear SE1
Outside criteria, underwent surgery
69
F
15
Distal body
Invasive
No
No
Outside
Piecemeal, Poorly diff, LVI
Index
Yes
x
No
Negative
x
66
M
45
Antrum
HGD
No
No
Outside
Piecemeal,
Index
Yes
x
Yes
Negative
x
53
M
30
Cardia
Invasive
Yes
No
Outside
R1, Poorly diff, >SM1
Index
Yes
x
Yes
Negative
x
63
M
60
Distal body
Invasive
Yes
No
Outside
R1, Poorly diff, >SM1, LVI
Index
Yes
x
No
Negative
x
65
F
20
Distal body
Invasive
Yes
No
Outside
R1, LVI
Index
Yes
x
Yes
Negative
x
69
F
25
Proximal body
IMC
Yes
No
Outside
R1, Poorly diff
Index
Yes
X
No
Negative
x
55
F
50
Antrum
Invasive
Yes
No
Outside
R1, over size criteria for SM1
Index
Yes
X
No
Negative
x
68
M
30
Proximal body
Invasive
Yes
Yes
Outside
>SM1
Index
Yes
x
No
Negative
x
69
F
30
Proximal body
IMC
Yes
Yes
Outside
Poorly diff
Index
Yes
x
No
Negative
x
69
F
60
Proximal body
IMC
Yes
Yes
Outside
LVI
Index
Yes
x
No
Negative
x
71
M
10
Antrum
Invasive
Yes
Yes
Outside
LVI
Index
No
Awaiting surgery
x
x
x
Surgery for other reason
59+
M
70
Distal body
LGD
Yes
No
LGD
Persistent recurrence at SE2
Surveillance
Yes
x
HGD
Negative
x
68++
M*
100
Proximal body
HGD
Yes
No
Outside
Recurrence at SE2 after negative SE1
Surveillance
Yes
x
Yes
Negative
x
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.
Technique of endoscopic submucosal dissection in a Western endoscopy center.
References
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.
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.
DISCLOSURE: Dr David Tate received a scholarship from the “Westmead Medical Research Foundation.” These funds were not used for this study. All authors disclosed no financial relationships relevant to this publication. The Cancer Institute New South Wales provided funding for a research nurse and data manager to assist with the administration of the study. There was no influence from the Institution regarding study design or conduct, data collection, management, analysis or interpretation, or preparation, review, or approval of the manuscript.
If you would like to chat with an author of this article, you may contact Dr Bourke at [email protected]
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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