Abstract
Background Endoscopic resection of Barrett’s esophageal neoplasia is commonly performed using either endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR). While submucosal dissection enables en bloc resection, institutional approaches vary. We compared clinical, histopathologic, and oncologic outcomes between a primary submucosal dissection strategy and a mucosal resection-based strategy with selective use of submucosal dissection.
Methods This retrospective cohort study included all patients with Barrett’s esophageal neoplasia treated at two European tertiary referral centers. At Karolinska University Hospital, the primary submucosal dissection strategy was adopted, whereas at Erasmus Medical Center the mucosal resection-based strategy was employed. Patients with prior endoscopic therapy or hematologic disorders were excluded. Primary outcomes were local recurrence, synchronous and metachronous lesions prior to ablation, and cancer- or treatment-related mortality. Secondary outcomes included resection quality, adverse events, and the need for repeated resections. Time-to-event analyses were performed using Kaplan–Meier and Cox regression models.
Results A total of 332 patients were included (132 in the primary submucosal dissection group and 200 in the mucosal resection–based group). En bloc resection was more frequent with the primary submucosal dissection strategy (98.5% vs 40.0%, p < 0.001). Compared with the EMR-based strategy, the pESD strategy was associated with significantly lower local recurrence (3.0% vs 10.0%, p = 0.02) and fewer resection sessions per patient, whereas rates of synchronous and metachronous lesions were similar between groups. Adverse events and cancer- or treatment-related mortality did not differ between strategies.
Conclusions Both strategies are safe. However, the primary submucosal dissection strategy is associated with lower local recurrence and fewer resection sessions.
Keywords: local recurrence, endoscopic resection, metachronous neoplasia, survival analysis, long-term outcome
1. Introduction
Current guidelines recommend treatment of Barrett’s esophageal neoplasia (BEN) through endoscopic resection of neoplastic lesions followed by ablation, due to the high risk of synchronous and metachronous neoplasia. 1 2 Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are the two standard resection techniques. 3 4 5 For lesions >20 mm, EMR is typically performed in a piecemeal fashion (pEMR), potentially compromising histopathologic evaluation. When lesions are suspected of deep submucosal invasion or located in fibrotic areas, ESD is usually preferred. 6 ESD enables en bloc resection regardless of size, thereby providing a more accurate histopathologic evaluation. 4 Compared with EMR, ESD is associated with higher rates of complete resection and lower recurrence. 7 8 Treatment choice is largely guided by institutional protocols and lesion characteristics, making comparison between EMR and ESD difficult. 3 Nevertheless, distinct endoscopic treatment strategies have been implemented in different centers. Some use a primary ESD strategy (pESD), others an EMR-based strategy (EMR-based) in which EMR is generally performed as the main option, with ESD reserved for advanced lesions. This divergence in institutional practice provides a unique opportunity to compare outcomes between these treatment strategies. In this study, we evaluated the clinical and histopathologic outcomes between these strategies in patients with BEN. Prespecified subgroup analyses based on pathologic stage (precancerous and pT1a, including low-grade dysplasia (LGD), high-grade dysplasia (HGD) and intramucosal (M) adenocarcinoma, and pT1b disease) were performed to reflect clinically relevant decision-making strata rather than to enable direct technique-level comparisons.
2. Patients and Methods
2.1. Study Design and Setting
This was a retrospective observational cohort study based on routinely collected clinical data from two tertiary referral centers: Karolinska University Hospital (KUH), Stockholm, Sweden, and Erasmus Medical Center (EMC), Rotterdam, the Netherlands. Data from all BEN ESDs and EMRs performed between 2013 and 2023 were collected. At KUH, where pESD was adopted since 2013, ESD was performed as the primary resection modality for all patients with BEN, with EMR performed only in exceptional cases. At EMC, an EMR-based strategy with selective use of ESD was employed (EMR-based). Ethical approval was obtained (KUH: 2024-02930-02; EMC: MEC-2019-0222).
2.2. Patient Eligibility and Data Collection
Eligible patients had visible lesions on Barrett’s esophagus (BE) with or without neoplasia on previous biopsies, without endoscopic signs of ulceration. In all cases, ESD or EMR was the initial therapeutic modality. Exclusion criteria comprised hematologic disorders, inability to discontinue anticoagulant therapy, and prior esophageal endoscopic or surgical treatment. All cases were discussed in a multidisciplinary setting. Management of antiplatelet and anticoagulant therapy followed international guidelines. 9 10 11
2.3. Endoscopic Assessment
All Barrett’s mucosa was assessed using high-definition endoscopes (GIF-H180, GIF-H180J, GIF-HQ190 and GIF-EZ1500, Olympus, Hamburg, Germany). BE was characterized according to the Prague 12 and Paris classifications. 13 Examinations were conducted using white light (WL) and narrow-band imaging (NBI). Acetic acid was applied when deemed necessary.
2.4. Procedure
All procedures were performed by experienced endoscopists who had each previously performed more than 50 endoscopic BEN resections.
2.4.1. ESD
In the pESD cohort, ESD was performed under general anesthesia, whereas in the EMR-based cohort, ESD was usually carried out under deep sedation. After endoscopic assessment, ESD was performed using a Dual knife (Olympus Co) in the pESD group and a Hybrid knife (Erbe, Tübingen, Germany) in the EMR-based group. 5 Patients were admitted for 1–2 days in the pESD cohort, whereas in the EMR-based cohort, most patients were treated on an outpatient basis.
2.4.2. EMR
At both institutions, EMR was performed using the Duette system (Cook, Limerick, Ireland), under conscious sedation in an outpatient setting. 14 Lesions >20 mm were typically resected in a piecemeal fashion.
2.4.2.1. Stricture Prevention
In resections involving ≥75% of the luminal circumference, stricture-prevention strategies evolved over the study period and differed between centers. In the pESD cohort, oral prednisolone was used from the beginning of the study period, with the steroid lifting method introduced in 2018. 15 In the EMR-based cohort, stricture prevention was implemented from 2018 onward, using oral prednisolone after EMR and orodispersible budesonide (1–3 mg/day for 6–8 weeks) after ESD.
2.5. Outcome of the Study
The primary endpoints included rates of local recurrence, and of synchronous and metachronous lesions following resection and prior to ablation. The secondary endpoints comprised the rates of en bloc, radical (R0), and curative resections, as well as adverse events such as bleeding, perforation, stricture formation, and the need for unplanned medical assistance after discharge.
2.6. Definitions
2.6.1. Recurrence
Recurrence was assessed following resection and prior to ablation. Local recurrence was defined as HGD or esophageal adenocarcinoma (EAC) detected <2 cm from the previous ESD/EMR scar. 16 A synchronous lesion was defined as HGD or EAC located ≥2 cm from the scar and detected within 6 months after resection. A metachronous lesion was defined as HGD or EAC located ≥2 cm from the scar and detected after 6 months. 16 17
2.6.2. Resection Status
Complete resection was defined as the removal of the entire visible target lesion including its markers. En bloc resection referred to removal of the lesion in a single piece. In pEMR, HM are typically not assessed; therefore, R0 was defined as tumor-free VM (VM0) irrespective of HM, according to a previously described definition. 18 The same definition was applied to ESD to ensure comparability. In pEMR, specimen size was defined as the cumulative size of all fragments. Curative resection was defined as an R0 resection with one of the following criteria: M or superficial submucosal (SM1), well- to moderately differentiated EAC without lymphovascular invasion (LVI).
2.6.3. Adverse Events
Bleeding was defined as any hemorrhage requiring blood transfusion during endoscopic treatment, or the need for medical assistance within two weeks post-procedure. Perforation was defined as a full-thickness defect in the esophageal wall. Stricture was defined as the inability to pass a standard 9.9 mm diameter gastroscope through the esophagus, or the presence of dysphagia requiring endoscopic balloon dilation within 1 year prior to ablation. Adverse events were classified as acute (during procedure), early (<48 h), or late (>48 h). In terms of severity, they were characterized as previously described. 19
2.7. Follow-Up Protocol and Recurrence and Survival Analysis
In the pESD group, the first surveillance endoscopy was scheduled 2 weeks after resection if ≥75% of the circumference was removed, or 3 months if <75%. In the EMR-based cohort, follow-up endoscopy was scheduled after 3 months, with earlier evaluation if symptoms occurred. In both centers, radiofrequency ablation (RFA) was planned 3–6 months after resection but deferred if suspicious lesions were identified. In such cases, targeted biopsies or EMR/ESD were performed.
Patients requiring additional surgery or chemoradiotherapy (CRT) due to noncurative resection were censored at the time of intervention. Recurrence analyses therefore reflect outcomes prior to ablation. Time to recurrence was calculated from the date of initial endoscopic resection to the date of histologically confirmed local recurrence. Patients without local recurrence were censored at the time of the last available endoscopic follow-up, irrespective of subsequent ablation therapy. Survival outcomes included cancer- or treatment-related mortality, defined as death attributable to EAC or to complications related to endoscopic treatments.
2.8. Subgroup Analysis
The prespecified subgroup analyses comparing outcomes between pESD and EMR-based strategies were stratified by final pathologic stage (precancerous lesions and pT1a, including LGD, HGD, and M adenocarcinoma, and pT1b). These analyses were conducted to reflect clinically relevant decision-making steps and to reduce biological heterogeneity.
2.9. Statistical Analysis
Data were extracted from institutional records and compiled into a standardized electronic database using Microsoft Excel. Statistical analyses were conducted using R software (version 4.5.0; R Foundation for Statistical Computing, Vienna, Austria). Continuous variables are presented as medians with interquartile ranges (IQR), and categoric variables as counts and percentages. Group comparison used the t -test or Mann–Whitney U test for continuous variables and Fisher’s exact test for categoric variables. The number of endoscopic resections was analyzed as a continuous (Wilcoxon rank-sum test) and as a categoric variable (>2 resections). Multivariable Poisson regression with robust standard errors was used to assess factors associated with the number of resections, adjusting for baseline histology, BE length, and treatment strategy. Time-to-event outcomes were analyzed using Kaplan–Meier curves and log-rank tests. Cox proportional hazards regression was used to evaluate associations between treatment strategy and recurrence and mortality, adjusted for relevant covariates and reported as hazard ratios (HR) and 95% confidence intervals (CI).
3. Results
3.1. Pre-resection
3.1.1. Patient and Lesion Characteristics
In total, 367 patients underwent endoscopic resection for BEN. Thirty-five patients were excluded due to prior endoscopic therapy ( n = 34) or the presence of a hematologic disorder ( n = 1). The final study cohort comprised 132 patients treated in the pESD cohort (132 ESDs, 0 EMRs), and 200 patients treated in the EMR-based cohort (41 ESDs and 159 EMRs) ( Fig. 1 ). There were no significant differences between the two cohorts in baseline patient or lesion characteristics ( Table 1 ).
Fig. 1.
Flowchart of patient inclusion.
Table 1. Patient and lesion characteristics.
| pESD ( n = 132) n (%) | EMR-based ( n = 200) n (%) | p -Value | |
|---|---|---|---|
| Gender (male) | 106 (80.3) | 157 (78.5) | 0.78 |
| Age (years, median, IQR) | 71 (63–75) | 70 (62–76) | 0.38 |
| BMI, kg/m 2 (median, IQR) | 27.1 (25.3–31.0) | 26.8 (24.7–29.8) | 0.24 |
| DM | 22 (16.7) | 40 (20.0) | 0.48 |
| The length of BE | n = 132 | n = 191 | |
| Length of ‘C’ (cm, median, IQR) | 1 (0–5) | 2 (0–6) | 0.49 |
| Length of ‘M’ (cm, median, IQR) | 4 (2–9) | 4 (2–7) | 0.32 |
| SSBE (maximum ≤ 3cm) | 58 (43.9) | 83 (43.5) | 1.00 |
| Preprocedural histology | n = 132 | n = 187 | 0.51 |
| IND | 0 (0.0) | 2 (1.1) | |
| LGD | 17 (12.9) | 31 (16.6) | |
| HGD | 74 (56.1) | 98 (52.4) | |
| EAC | 41 (31.1) | 56 (29.9) | |
| Macroscopic type (Paris classification) | n = 132 | n = 147 | 0.06 |
| Protruding (Is, Isp, Ip) | 14 (10.6) | 28 (19.0) | |
| Flat (IIa, IIb) | 107 (81.1) | 113 (76.9) | |
| Depressed (IIc) | 11 (8.3) | 6 (4.1) |
pESD, primary endoscopic submucosal dissection strategy.
EMR-based strategy, endoscopic mucosal resection–based strategy with selective use of endoscopic submucosal dissection.
IQR, interquartile range; BMI, body mass index; DM, diabetes mellitus; BE, Barrett’s esophagus.
3.2. Post-resection
3.2.1. Procedural and Technical Outcomes
Lesions involving ≥75% of the luminal circumference were observed at similar frequencies in the two groups (pESD: 25.4% vs EMR-based: 25.3%, p = 1.00). Nevertheless, the use of stricture prevention measures was more common in the pESD group ( p < 0.002). In the EMR-based group, the median number of resection fragments was 3 (IQR 2–4). Complete resection was achieved in 98.5% of patients treated in the pESD and in 100% of those treated in the EMR-based group ( p > 0.05). En bloc resection was significantly more frequent in the pESD than in the EMR-based group (98.5% vs 40.0%, p < 0.001). Two incomplete resections occurred in the pESD cohort due to perforation ( n = 1) and advanced cancer ( n = 1) ( Table 2 ).
Table 2. Procedural and technical outcomes.
| pESD ( n = 132) n (%) | EMR-based ( n = 200) n (%) | p -Value | |
|---|---|---|---|
| Extent of luminal circumference involved | n = 130 | n = 75 | <0.001 |
| <25% | 2 (1.5) | 14 (18.7) | |
| 25–49% | 61 (46.9) | 23 (30.7) | |
| 50–74% | 34 (26.2) | 19 (25.3) | |
| 75–99% | 20 (15.4) | 12 (16.0) | |
| 100% | 13 (10.0) | 7 (9.3) | |
| Lumen circumference >75% | 33 (25.4) | 19 (25.3) | 1.00 |
| Stricture prevention | 0.002 | ||
| Any prophylactic measure, n (%) | 41 (31.1) | 32 (16.0) | |
| In case of piecemeal EMR, number of pieces (median, IQR) | — | 3 (2-4) | — |
| Complete resection | 130 (98.5) | 200 (100.0) | 0.16 |
| En bloc | 130 (98.5) | 80 (40.0) | <0.001 |
| Adverse events | |||
| Perforation | 2 (1.5) | 4 (2.0) | 1.00 |
| Bleeding | 6 (4.5) | 10 (5.0) | 1.00 |
| n = 111 | n = 196 | ||
| Stricture (within 1 year prior to ablation) | 10 (9.0) | 18 (9.2) | 1.00 |
3.2.2. Adverse Events
Adverse events occurred at comparable rates between strategies ( p > 0.05). Perforation occurred in 2/132 (1.5%) in the pESD and 4/200 (2.0%) in the EMR-based, of which 3 occurred during EMR and 1 during ESD. All cases were successfully managed endoscopically (3 with stent, 3 with clips). Bleeding (acute: 4, early: 6, late: 6) occurred in 6/132 (4.5%) and 10/200 (5.0%) in the pESD and the EMR-based group, respectively. Fifteen patients with mild or moderate bleeding were successfully managed endoscopically. In the pESD cohort, one patient had a pulmonary embolism diagnosed in another hospital 5 days after the ESD. That patient started anticoagulation that was followed by esophageal bleeding treated with off-label esophageal stent placement (SX-Ella Danis stent, Hradec Kralove, Czech Republic) . The stent was not removed, and the patient died due to a stent-caused perforation 27 days after stent insertion. This case was classified as a fatal adverse event. Esophageal strictures within 1 year prior to ablation occurred in 9.0% of patients in the pESD and 9.2% in the EMR-based ( p = 1.00). All strictures were managed endoscopically ( Table 2 ).
3.2.3. Histologic Results
The median specimen size was larger in the pESD than in EMR-based (50 mm [IQR 40–65] vs 40 mm [IQR 25–60], p < 0.001). Final histopathologic diagnoses differed significantly between the two strategies ( p < 0.001), with EAC more frequently observed in the EMR-based cohort, whereas LGD and HGD were more common in the pESD cohort. Rates of VM0 resection did not differ significantly between the two strategies ( Table 3 ).
Table 3. Histopathologic findings.
| pESD ( n = 132) n (%) | EMR-based ( n = 200) n (%) | p -Value | |
|---|---|---|---|
| The specimen size (mm, median IQR) | 50 (40–65) | 40 (25–60) | <0.001 |
| Final highest histology | n = 130 | n = 200 | <0.001 |
| No dysplasia | 0 (0.0) | 7 (3.5) | |
| LGD | 26 (20.0) | 18 (9.0) | |
| HGD | 44 (33.8) | 36 (18.0) | |
| EAC | 60 (46.2) | 139 (69.5) | |
| Among EAC | |||
| Differentiation (well/moderate) | 56 (93.3) | 103 (74.1) | 0.002 |
| LVI (positive) | 23 (38.3) | 27 (19.4) | 0.007 |
| Depth of invasion | n = 60 | n = 138 | 0.050 |
| Mucosal (pT1a) | 33 (55.0) | 97 (70.3) | |
| Submucosal (pT1b) | 27 (45.0) | 41 (29.7) | |
| Resection margins | |||
| VM0 | 117 (88.6) | 182 (91.0) | 0.57 |
LVI, lymphovascular invasion; VM, Vertical margin.
3.2.4. Noncurative Resection and Additional Therapy
In the pESD cohort, 34 of 132 resections (25.8%) were classified as noncurative, due to positive VM ( n = 12), SM2-3 invasion ( n = 21), positive LVI ( n = 23), and/or poorly differentiated adenocarcinoma ( n = 4). Sixteen patients underwent additional esophagectomy, with residual tumor in 6 and lymph node metastasis in 5 patients. Among patients without any additional therapy, 1 patient died due to metastatic EAC.
In the EMR-based cohort, 31 of 200 patients (15.5%) had noncurative resections due to positive VM ( n = 16), SM2–3 invasion ( n = 27), positive LVI ( n = 27), and/or poorly differentiated adenocarcinoma ( n = 26). In total, 12 patients underwent surgery, of whom 5 had residual tumor and 4 had lymph node metastases in the surgically resected specimen. Four patients received CRT or radiotherapy. Among patients without surgery, 5 patients died of metastatic EAC, 2 of whom received chemotherapy.
3.3. Follow-up
The median overall follow-up period was significantly longer in the pESD than in the EMR-based (40.4 months [IQR 17.9–61.3] vs 20.7 months [IQR 5.5–50.9], p < 0.001). Only 1 patient (0.5%) in the EMR-based group was lost to follow-up. Following endoscopic resection, ablative therapy was performed in 37.9% of patients in the pESD and in 39.5% in the EMR-based group ( p > 0.05). The median time to ablation did not differ significantly between strategies (6.7 months [IQR 4.6–9.2] vs 5.2 months [IQR 3.7–9.7]), respectively ( Table 4 ).
Table 4. Clinical and oncologic outcomes.
| pESD ( n = 132) n (%) | EMR-based ( n = 200) n (%) | p -Value | |
|---|---|---|---|
| Oncologic outcomes | |||
| Noncurative resection (without HM1) | 34 (25.8) | 31 (15.5) | 0.02 |
| Local recurrence | 4 (3.0) | 20 (10.0) | 0.02 |
| Synchronous | 5 (3.8) | 3 (1.5) | 0.27 |
| Metachronous | 8 (6.1) | 6 (3.0) | 0.26 |
| Additional surgery | 16 (12.1) | 12 (6.0) | 0.07 |
| Cancer/treatment-related mortality | 3 (2.3) | 6 (3.0) | 1.00 |
| Follow-up and ablation | |||
| Overall follow-up time, months (median, IQR) | 40.4 | 20.7 | <0.001 |
| (17.9–61.3) | (5.5-50.9) | ||
| Ablation n (%) | 50 (37.9) | 79 (39.5) | 0.82 |
| Time from resection until first ablative treatment, months (median, IQR) | 6.7 (4.6–9.2) | 5.2 (3.7–9.7) | 0.16 |
| Endoscopic resection sessions | n = 130 | n = 200 | |
| Total number of endoscopic resection sessions, median (IQR) | 1 (1–1) | 1 (1–1) | 0.10 |
| >2 resections | 5 (3.8) | 21 (10.5) | 0.04 |
HM, horizontal margin; HM1, a positive horizontal margin.
3.3.1. Recurrence and Need for Repeated Resections
The incidence of local recurrence was significantly higher in the EMR-based cohort than in the pESD cohort (10.0% vs 3.0%; p = 0.02). The rates of synchronous (3.8% vs. 1.5%; p = 0.27) and metachronous lesions (6.1% vs. 3.0%; p = 0.26) and the median time to recurrence were not significantly different between groups (4.1 months [IQR 3.2–6.6] vs. 4.4 months [IQR 2.4–6.1]; p = 0.46). All patients with local recurrence were managed endoscopically with the previous endoscopic resection technique used.
To assess the need for repeated resections, the total number of endoscopic resection sessions per patient was evaluated. Repeated resections (>2 sessions) were more frequently required in the EMR-based cohort than in the pESD cohort (10.5% vs. 3.8%; p = 0.04) ( Table 4 ).
In multivariable Poisson regression analysis with robust standard errors, the EMR-based strategy, long segment BE (LSBE), and advanced histology (HGD/EAC) were independently associated with a higher number of resections ( Table 5 ).
Table 5. Multivariable Poisson regression analysis of factors associated with the number of endoscopic resection sessions.
| Variable | IRR | 95% CI | p- Value |
|---|---|---|---|
| EMR-based vs pESD | 1.17 | 1.02-1.33 | 0.02 |
| LSBE vs SSBE | 1.30 | 1.14-1.48 | <0.001 |
| Histology | |||
| HGD/EAC vs IND/LGD | 1.18 | 1.04-1.33 | 0.008 |
SSBE, short segment BE; LSBE, long segment BE; IRR, incidence rate.
3.3.2. Survival and Recurrence-Free Outcomes
Kaplan–Meier analysis demonstrated higher local recurrence-free survival in patients treated with the pESD strategy compared with the EMR-based strategy (log-rank p = 0.0045; Fig. 2 ), with local recurrence occurring in 3.0% and 10.0% of patients, respectively. Most local recurrences occurred within the first 12 months following resection in both strategies.
Fig. 2.
Local recurrence–free survival according to treatment strategy.
No significant differences were observed between strategies in synchronous or metachronous recurrence-free survival (log-rank p > 0.05 for both outcomes).
Cancer- or treatment-related mortality was low with both strategies, with no significant difference observed between groups (2.3% vs 3.0%; log-rank p = 0.33). Kaplan–Meier analysis also showed no significant difference in overall survival between strategies during 60 months of follow-up.
3.3.3. Multivariable Analysis of Oncologic Outcomes
In Cox proportional hazards models, the EMR-based strategy was associated with an increased risk of local recurrence in both crude and adjusted analyses. After adjustment for age, sex, DM, highest histologic diagnosis (IND/LGD or HGD vs EAC), and BE length (short- vs long-segment), the adjusted hazard ratio for local recurrence was 3.80 (95% CI 1.26–11.45; p = 0.017) ( Table 6 ).
Table 6. Multivariable Cox regression analysis of oncologic outcomes comparing two strategies.
| pESD N (%) | EMR-based N (%) | HR crude (95% CI) | p -Value | HR adjusted* | p -Value | |
|---|---|---|---|---|---|---|
| Local recurrence | 4 (3.0) | 20 (10.0) | 4.22 (1.43–12.42) | 0.009 | 3.80 (1.26–11.45) | 0.017 |
| Cancer- or treatment-related mortality | 3 (2.3) | 6 (3.0) | 1.98 (0.49–7.94) | 0.334 | 1.67 (0.38–7.30) | 0.499 |
HR – Hazard Ratio for comparison between EMR and ESD, 95% CI – 95% confidence interval.
*Adjusted for age, gender, diabetes mellitus, highest histological diagnosis (IND/LGD vs HGD/EAC), and Barrett’s esophagus length (SSBE vs LSBE).
No significant associations were observed between treatment strategy for synchronous, metachronous lesions, and cancer-/treatment-related mortality.
3.4. Subgroup Analysis
Among patients with precancerous and pT1a disease, the pESD group was associated with a lower incidence of local recurrence compared with the EMR-based group (2.9% vs. 9.4%, p = 0.047, Table 7 ). Repeated resections (>2 resections) were less frequent in the pESD than in the EMR-based group (4.9% vs. 11.9%, p = 0.077). Rates of additional surgery and cancer- or treatment-related mortality were low and did not differ significantly between strategies.
Table 7. Outcomes stratified by pathologic stage.
| pESD n (%) | EMR-based n (%) | p -Value | |
|---|---|---|---|
| pT1a | n = 103 | n = 159 | |
| Local recurrence | 3 (2.9) | 15 (9.4) | 0.047 |
| >2 resections | 5 (4.9) | 19 (11.9) | 0.077 |
| Additional surgery | 2 (1.9) | 2 (1.3) | 0.65 |
| Cancer- or treatment-related mortality | 3 (2.9) | 3 (1.9) | 0.68 |
| pT1b | n = 27 | n = 41 | |
| Local recurrence | 1 (3.7) | 5 (12.2) | 0.39 |
| >2 resections | 0 (0) | 2 (4.9) | 0.51 |
| Additional surgery | 13 (48.1) | 10 (24.4) | 0.07 |
| Cancer- or treatment-related mortality | 0 (0) | 3 (7.3) | 0.27 |
In patients with pT1b disease, no statistically significant differences were observed between strategies for local recurrence, repeated resections, additional surgery, or cancer-/treatment-related mortality. Additional surgery tended to be more frequent in the pESD group than in the EMR-based group, although this difference did not reach statistical significance (48.1% vs 24.4%, p = 0.07).
4. Discussion
In this large study comparing two different predefined endoscopic treatment strategies for BEN, the pESD strategy was associated with lower local recurrence and a reduced need for repeated resections. However, cancer- and treatment-related mortality was low and comparable between strategies, and all local recurrences (both in the pESD and EMR-based group) could be treated endoscopically. When analyses were restricted to precancerous and pT1a disease to reduce confounding by advanced pathologic features, the reduction in local recurrence remained statistically significant, while the need for repeated resection sessions (>2 sessions) showed a similar favorable trend.
4.1. Recurrence
Previous studies comparing EMR and ESD for BEN have applied heterogeneous definitions of recurrence. 7 8 18 20 21 22 By distinguishing local recurrence from synchronous and metachronous lesions, the present study allows a more precise assessment of oncologic outcomes following endoscopic resection, including noncurative cases. Our study shows that pESD was associated with a persistently lower overall recurrence rate than the EMR-based group, regardless of adjustment for BE length and final histologic diagnosis. This indicates that the initial resection strategy may contribute to local disease control beyond differences in these variables. The reduced local recurrence rate has practical implications, as patients require less additional resection sessions (3.8% for pESD vs. 10.5% for EMR-based).
However, as all recurrences could be successfully treated endoscopically, both strategies resulted in excellent long-term outcomes. This information may help clinicians and patients in shared decision-making, as the choice of strategy may have less impact on ultimate outcomes than expected.
4.2. Technical and Safety Aspects
Despite larger resection areas and greater technical complexity for the pESD cohort, rates of adverse events—including perforation, bleeding, and stricture—were comparable between both strategies. 23 A single fatal adverse event occurred in the pESD cohort and was associated with postprocedural anticoagulation and subsequent off-label stent placement at a different institution. This case highlights the importance of specialized referral centers and close interhospital collaboration for not only performing endoscopic resection but also for the management of adverse events. 24
4.3. Comparison with Previous Literature
A unique aspect of the present study is the consistent use of two different institutional practices from as early as 2013, which enabled a comparison of endoscopic strategies rather than individual endoscopic techniques. As our research demonstrated lower local recurrence rates and a reduced need for repeated resections when applying the pESD strategy across the full spectrum of BEN (including LGD, HGD, pT1a and pT1b), other recent studies have advocated for use of ESD from different perspectives. One study by Younis et al., evaluating allocation strategies (EMR for cT1a and ESD for cT1b EAC), demonstrated that ESD achieved significantly higher R0 resection rates and more reliable pathologic assessment without compromising safety. They showed that of the pT1a group, 37.0% was overtreated with ESD, and of the pT1b group, 39.5% was undertreated with EMR. Their research highlights the limitations of pre-resection staging and therefore potentially advocates for an “exploratory” ESD approach for all cancer lesions, including T1a. 25 Furthermore, a different recently published study showed that an ESD-first strategy was associated with reduced recurrence rates and improved cancer-free survival, especially in T1b disease. 26 The aforementioned studies, together with the present study, indicate that a pESD strategy might achieve superior local disease control without increasing adverse events. However, both studies were subject to methodologic limitations, including selection bias due to stage-based technique allocation and temporal bias related to period comparisons. In contrast, our study compared two predefined institutional strategies applied during the same timeframe, enabling evaluation of oncologic outcomes in routine clinical practice across the full spectrum of BEN.
4.4. Strengths and Limitations
The major strength of this study is its strategy-based comparison of endoscopic management for BEN across the full BEN spectrum, ranging from LGD to EAC. The use of institutional databases from two high volume referral centers with comparable surveillance protocols enabled a comprehensive assessment of oncologic outcomes, procedural safety, and the need for repeated resections.
However, several limitations should be acknowledged. First, this was a retrospective observational study in which treatment allocation was determined by institutional strategy rather than randomization, introducing potential center-related confounding. Although prespecified subgroup analyses stratified by pathologic stage were performed to address differences in disease severity, residual confounding cannot be fully excluded. For example, differences in referral patterns, patient selection, and local treatment practices between centers may have resulted in systematic baseline differences in disease severity that were not fully captured by the available variables. Consequently, unmeasured confounders may have influenced both treatment allocation and outcomes, and the results should therefore be interpreted with caution. Second, recurrence analyses were intentionally restricted to the period following endoscopic resection and prior to RFA. As RFA is routinely performed after resection in current practice, our Kaplan–Meier estimates do not reflect long-term oncologic outcomes following a complete eradication strategy. Accordingly, outcomes such as complete remission of neoplasia or intestinal metaplasia after ablation, as well as late recurrence occurring beyond the ablation phase, could not be reliably assessed. Additionally, the number of clinically relevant events, particularly cancer-related mortality and events in subgroup analyses, was limited. Therefore, the findings from these analyses should be considered exploratory as they may be affected by limited power and potential model instability. Third, the long inclusion period inevitably encompassed temporal changes in endoscopic devices, techniques, and adjunctive measures such as stricture prevention. To address this, exploratory analyses comparing the first and second halves of the study period were performed, which did not reveal significant differences in ESD-related outcomes. Therefore, firm conclusions regarding the comparative effectiveness of the treatment strategies should be drawn with appropriate caution.
5. Conclusion
The pESD strategy is associated with reduced local recurrence although all recurrences were managed with repeated endoscopic resections. Adverse-event rates were comparable between strategies, despite pESD being applied across a broad spectrum of BEN, suggesting that the pESD strategy is feasible in expert referral centers and may reduce local recurrence and the need for repeated resections.
Footnotes
Conflict of Interest M.O. received consulting fees from Olympus (paid to the institution). M.V. received consulting fees and speaker honoraria from Abbott, Amgen, Viatris, and Nordmark Pharma, outside the submitted work. A.D.K. received educational support from ERBE, Pentax, and Fujifilm (paid to the institution), and consulting fees from Fujifilm. F.B.S. received speaker honoraria from Olympus and Medtronic. The other authors declare no conflicts of interest.
Contributors’ Statement M.O.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Writing—original draft, Writing—review & editing. A.D.I.M.: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Validation, Writing—original draft, Writing—review & editing. H.M.: Project administration, Writing—review & editing. M.V.: Supervision, Writing—review & editing. M.N.: Conceptualization, Funding acquisition, Methodology, Supervision, Writing—review & editing. F.K.: Data curation, Formal analysis, Funding acquisition, Methodology, Writing—review & editing. A.D.K.: Conceptualization, Funding acquisition, Methodology, Visualization, Writing—review & editing. F.B.-S.: Conceptualization, Funding acquisition, Methodology, Supervision, Validation, Writing—review & editing.
Declaration of GenAI Use
During the preparation of this manuscript, ChatGPT (OpenAI) was used solely to assist with English language and grammar editing. The authors subsequently reviewed all AI-assisted revisions and take full responsibility for the final content.
References
- 1.Phoa K N, Pouw R E, Bisschops R, et al. Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II) Gut. 2016;65:555–562. doi: 10.1136/gutjnl-2015-309298. [DOI] [PubMed] [Google Scholar]
- 2.Weusten B, Bisschops R, Dinis-Ribeiro M, et al. Diagnosis and management of Barrett esophagus: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2023;55:1124–1146. doi: 10.1055/a-2176-2440. [DOI] [PubMed] [Google Scholar]
- 3.Pimentel-Nunes P, Libanio D, Bastiaansen B AJ, et al. Endoscopic submucosal dissection for superficial gastrointestinal lesions: European Society of Gastrointestinal Endoscopy (ESGE) guideline - update 2022. Endoscopy. 2022;54:591–622. doi: 10.1055/a-1811-7025. [DOI] [PubMed] [Google Scholar]
- 4.Maan A DI, Sharma P, Koch A D. Curative criteria for endoscopic treatment of oesophageal adenocarcinoma. Best Pract Res Clin Gastroenterol. 2024;68:101886. doi: 10.1016/j.bpg.2024.101886. [DOI] [PubMed] [Google Scholar]
- 5.Omae M, Hagstrom H, Ndegwa N, et al. Wide-field endoscopic submucosal dissection for the treatment of Barrett’s esophagus neoplasia. Endosc Int Open. 2021;9:E727–E734. doi: 10.1055/a-1386-3668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lupu A, Faller J, Oung B, et al. Endoscopic submucosal dissection using countertraction with clips and rubber band allows safe en bloc resection of recurrent duodenal superficial lesions with intense fibrosis. Endoscopy. 2020;52:E398–E399. doi: 10.1055/a-1144-2611. [DOI] [PubMed] [Google Scholar]
- 7.Doumbe-Mandengue P, Pellat A, Belle A, et al. Endoscopic submucosal dissection versus endoscopic mucosal resection for early esophageal adenocarcinoma. Clin Res Hepatol Gastroenterol. 2023;47:102138. doi: 10.1016/j.clinre.2023.102138. [DOI] [PubMed] [Google Scholar]
- 8.Mejia Perez L K, Yang D, Draganov P V, et al. Endoscopic submucosal dissection vs. endoscopic mucosal resection for early Barrett’s neoplasia in the west: a retrospective study. Endoscopy. 2022;54:439–446. doi: 10.1055/a-1541-7659. [DOI] [PubMed] [Google Scholar]
- 9.Veitch A M, Radaelli F, Alikhan R, et al. Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update. Endoscopy. 2021;53:947–969. doi: 10.1055/a-1547-2282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Veitch A M, Vanbiervliet G, Gershlick A H, et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Endoscopy. 2016;48:385–402. doi: 10.1055/s-0042-102652. [DOI] [PubMed] [Google Scholar]
- 11.Veitch A M, Baglin T P, Gershlick A H, et al. Guidelines for the management of anticoagulant and antiplatelet therapy in patients undergoing endoscopic procedures. Gut. 2008;57:1322–1329. doi: 10.1136/gut.2007.142497. [DOI] [PubMed] [Google Scholar]
- 12.Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology. 2006;131:1392–1399. doi: 10.1053/j.gastro.2006.08.032. [DOI] [PubMed] [Google Scholar]
- 13.The Paris endoscopic classification of superficial neoplastic lesions . esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc. 2003;58:S3–S43. doi: 10.1016/s0016-5107(03)02159-x. [DOI] [PubMed] [Google Scholar]
- 14.Belghazi K, Marcon N, Teshima C, et al. Risk factors for serious adverse events associated with multiband mucosectomy in Barrett’s esophagus: an international multicenter analysis of 3827 endoscopic resection procedures. Gastrointest Endosc. 2020;92:259 e2–268 e2. doi: 10.1016/j.gie.2020.03.3842. [DOI] [PubMed] [Google Scholar]
- 15.Omae M, Maltzman H, Vujasinovic M, et al. Steroid lifting method during endoscopic submucosal dissection: a novel strategy for stricture prevention. DEN Open. 2025;5:e403. doi: 10.1002/deo2.403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Subramaniam S, Chedgy F, Longcroft-Wheaton G, et al. Complex early Barrett’s neoplasia at 3 Western centers: European Barrett’s endoscopic submucosal dissection trial (E-BEST) Gastrointest Endosc. 2017;86:608–618. doi: 10.1016/j.gie.2017.01.027. [DOI] [PubMed] [Google Scholar]
- 17.Ikenoyama Y, Namikawa K, Takamatsu M, et al. Risk stratification for synchronous/metachronous recurrence after endoscopic submucosal dissection for Barrett’s esophageal adenocarcinoma using the length of Barrett’s esophagus. Esophagus. 2024;21:357–364. doi: 10.1007/s10388-024-01058-8. [DOI] [PubMed] [Google Scholar]
- 18.Fujiyoshi Y, Khalaf K, Tham D, et al. Recurrence following successful eradication of neoplasia with endoscopic mucosal resection compared with endoscopic submucosal dissection in Barrett’s esophagus: a retrospective comparison. Endoscopy. 2025;57:5–13. doi: 10.1055/a-2382-5891. [DOI] [PubMed] [Google Scholar]
- 19.Pouw R E, Seewald S, Gondrie J J, et al. Stepwise radical endoscopic resection for eradication of Barrett’s oesophagus with early neoplasia in a cohort of 169 patients. Gut. 2010;59:1169–1177. doi: 10.1136/gut.2010.210229. [DOI] [PubMed] [Google Scholar]
- 20.Terheggen G, Horn E M, Vieth M, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017;66:783–793. doi: 10.1136/gutjnl-2015-310126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Podboy A, Kolahi K S, Friedland S, et al. Endoscopic submucosal dissection is associated with less pathologic uncertainty than endoscopic mucosal resection in diagnosing and staging Barrett’s-related neoplasia. Dig Endosc. 2020;32:346–354. doi: 10.1111/den.13487. [DOI] [PubMed] [Google Scholar]
- 22.Codipilly D C, Dhaliwal L, Oberoi M, et al. Comparative outcomes of cap assisted endoscopic resection and endoscopic submucosal dissection in dysplastic Barrett’s Esophagus. Clin Gastroenterol Hepatol. 2022;20:65 e1–73 e1. doi: 10.1016/j.cgh.2020.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Chevaux J B, Piessevaux H, Jouret-Mourin A, et al. Clinical outcome in patients treated with endoscopic submucosal dissection for superficial Barrett’s neoplasia. Endoscopy. 2015;47:103–112. doi: 10.1055/s-0034-1390982. [DOI] [PubMed] [Google Scholar]
- 24.Fleischmann C, Probst A, Ebigbo A, et al. Endoscopic submucosal dissection in Europe: results of 1000 neoplastic lesions from the German endoscopic submucosal dissection registry. Gastroenterology. 2021;161:1168–1178. doi: 10.1053/j.gastro.2021.06.049. [DOI] [PubMed] [Google Scholar]
- 25.Younis F, Rosch T, Anders M, et al. Universal submucosal dissection outperforms selective mucosal resection in early esophageal adenocarcinoma. Endoscopy2026 [DOI] [PubMed]
- 26.Gupta S, Bucalau A M, Mandarino F V, et al. Oncological impact of universal endoscopic submucosal dissection for large Barrett’s cancers. Gut2026 [DOI] [PubMed]