Keywords Endoscopy Upper GI Tract - Barrett's and adenocarcinoma - Endoscopic resection (ESD,
EMRc, ...) - RFA and ablative methods
Introduction
Barrett's esophagus (BE) is defined by replacement of the normal squamous epithelium
of the distal esophagus with metaplastic intestinal-type columnar epithelium. This
condition is associated with development of dysplasia and esophageal adenocarcinoma
(EAC) [1 ]. Endoscopic mucosal resection (EMR) has been one of the main endoscopic approaches
for managing BE, especially in cases involving nodular high-grade dysplasia (HGD)
and early-stage EAC [2 ]
[3 ]. EMR has been shown to have high therapeutic efficacy and low complication rates
and has long been the cornerstone of management of Barrett's neoplasia [4 ]
[5 ]
[6 ].
Current guidelines recommend endoscopic resection of visible nodular lesions in BE,
both for treatment as well as for histopathological staging [7 ]
[8 ]
[9 ]. After EMR, patients are categorized into high- or low-risk groups according to
risk for lymph node metastasis and local recurrence, based on histopathological findings
[9 ]. Low-risk patients are considered to have had successful endoscopic resection and
additional ablation and ongoing surveillance with endoscopy is recommended for them,
whereas high-risk patients are advised to undergo esophagectomy. For patients undergoing
surveillance following successful endoscopic resection, identification of recurrent
neoplasia is critical [10 ]. Also, given that Barrett’s HGD and early-stage EAC are typically not immediately
life-threatening, long-term follow-up is vital.
However, there are relatively few studies that have examined very long-term recurrence
rates following EMR [3 ]. Guidelines recommend performing surveillance endoscopy for 10 years [9 ], but there is no research providing data that extend beyond a 10-year period. Therefore,
this study aimed to investigate the long-term recurrence rate of BE neoplasia following
successful endoscopic resection by EMR.
Patients and methods
Study design and setting
A retrospective cohort study was conducted at a single tertiary referral center in
Toronto, Canada, utilizing a prospectively maintained database of patients diagnosed
with BE. The study covered the period from January 2001 to December 2023. Data collection
included patient demographics, procedure information, histopathological findings,
and follow-up.
Inclusion and exclusion criteria
Inclusion criteria comprised patients with histologically confirmed HGD or esophageal
adenocarcinoma (EAC) based on EMR specimens. Exclusion criteria were patients with
low-grade dysplasia (LGD), those undergoing endoscopic submucosal dissection (ESD)
for treatment of HGD/EAC, and those without follow-up data post-EMR.
Variables and definitions
Baseline characteristics, such as age, gender, and body mass index (BMI), were documented.
During initial endoscopy, the circumferential and maximal length of BE was assessed
and described according to the Prague criteria [11 ]. Successful endoscopic resection was defined as low risk of lymph node metastasis
(i.e. submucosal invasion ≤ 500 μm, no poor differentiation, and no lymphovascular
invasion) and low risk of local recurrence (i.e. tumor-free deep resection margin).
As for adverse events (AEs), delayed bleeding was defined as clinical signs of bleeding
with a drop in hemoglobin > 2 g/dL. Esophageal stricture was defined as a stricture
that could not be passed with a regular gastroscope. Complete remission of neoplasia
(CRN) was defined as complete absence of endoscopic and histological evidence of neoplasia
(HGD and EAC) on follow-up. Complete remission of intestinal metaplasia (CRIM) was
defined as complete absence of endoscopic evidence of BE and histological evidence
of intestinal metaplasia on follow-up. Follow-up outcomes included patients who achieved
successful endoscopic resection. Recurrence of neoplasia was defined as any recurrence
of HGD or EAC after CRN. This recurrence of neoplasia included local recurrence and
metachronous lesions after CRN, which were not differentiated.
Outcomes
The primary outcome was the long-term recurrence rate of neoplasia after CRN, assessed
by Kaplan-Meier analysis. Secondary outcomes were the rate of residual/metachronous
neoplasia at the first follow-up, the rate of CRN, and the long-term rate of patients
who were successfully managed by endoscopy. This reflected the current status of CRN,
regardless of any prior recurrences, among all patients who underwent successful endoscopic
resection.
EMR protocol
A therapeutic gastroscope (GIF1T-160 or GIF 1T-190, Olympus Co., Tokyo, Japan) was
used for the procedure. EMR was conducted using either the cap technique [12 ] or multiband ligation, which involves a band-and-cut method [13 ]
[14 ]. All specimens were sent for histopathological analysis. Patients underwent follow-up
endoscopy approximately every 3 to 6 months post endoscopic treatments until CRN and
CRIM were achieved. Ablation techniques including radiofrequency ablation (RFA), photodynamic
therapy (PDT), and cryotherapy were performed in cases in which residual/metachronous
BE was detected on follow-up. In addition, all patients received once- or twice-daily
proton pump inhibitor therapy during and after endoscopic treatment.
Histological analysis
Histological assessments were performed by at least two gastrointestinal pathologists.
EMR specimens were evaluated based on several criteria, including depth of tumor infiltration,
grade of differentiation, presence of lymphatic or vascular invasion, and completeness
of resection at the deep (vertical) margin. Histological criteria, classification,
and differentiation grading were based on the World Health Organization classification
[15 ].
Biopsies were evaluated for presence of dysplasia and intestinal metaplasia.
Post‑endoscopic treatment surveillance
Follow-up was scheduled every 3 to 6 months during the period aimed at eradication
of intestinal metaplasia, and then annually thereafter. Systematic biopsies were conducted
in all four quadrants of the esophagus at 1-cm intervals along the initial length
of the BE segment, in addition to biopsies at the gastroesophageal junction (GEJ)
in accordance with the Seattle protocol [16 ]. In addition, targeted biopsies were taken from any visually detected abnormalities.
Statistical analysis
Continuous variables were expressed as a mean with standard deviation (SD), or median
with interquartile range (IQR) based on normality of distribution. The long-term recurrence
rate (cumulative incidence of recurrence) was evaluated with a time to event analysis
using Kaplan-Meier curve. Recurrence rates were presented as percentages with their
95% confidence intervals (CIs). Statistical analyses were conducted using JMP Pro
17 software (SAS Institute Inc. Cary, North Carolina, United States).
Ethics considerations
Each patient provided written informed consent for all procedures and participation
in the prospective institutional registry. The study received approval from the Research
Ethics Board (REB 08–265) on December 19, 2008.
Results
Patient characteristics and procedure outcomes
A total of 552 consecutive patients were diagnosed with Barrett’s HGD/EAC and were
treated with EMR between January 2001 and December 2023. The patient cohort was predominantly
male (462 patients, 83.7%), with a mean age of 66.3 ± 11.2 years and a mean BMI of
29.0 ± 6.4 kg/m2 . Median Barrett’s length based on Prague classification was circumferential 1 cm
(0–4) and maximal 4 cm (2–6). Barrett’s types were 199 short-segment BE (36.1%) and
353 long-segment BE (63.9%). Mean lesion size was 3.67 ± 2.37 cm, with a mean circumferential
occupancy of 47.3 ± 20.8 %. Mean procedure time was 58.1 ± 22.0 minutes. AEs included
delayed bleeding in four cases (0.72%) and perforation in two cases (0.36%) ([Table 1 ]).
Table 1 Population data and procedure outcomes.
N = 552
All values are expressed as percentages among both groups.
BMI, body mass index; IQR, interquartile range; LSBE, long-segment Barrett’s esophagus;
SD, standard deviation; SSBE, short-segment Barrett’s esophagus.
Age, mean (SD)
66.3 (11.2)
Male gender
462 (83.7%)
BMI, mean (SD)
29.0 (6.4)
Prague C, cm, median (IQR)
1 (0–4)
Prague M, cm, median (IQR)
4 (2–6)
Barrett’s length
199 (36.1%)
353 (63.9%)
Size of the lesion, cm, mean (SD)
3.67 (2.37)
Circumferential occupancy of the lesion, mean, (SD)
47.3 (20.8)
Operative time, mean (SD)
58.1 (22.0)
Adverse events
4 (0.72%)
2 (0.36%)
Histology
High-grade dysplasia
124 (22.5%)
Adenocarcinoma
428 (77.5%)
Differentiation
N = 428
293 (68.4%)
112 (26.1%)
23 (5.3%)
Invasion depth
N = 428
369 (86.2%)
43 (10.0%)
16 (3.7%)
Lympho-vascular invasion
N = 428
30 (7.0%)
Vertical margin positive
N = 428
32 (7.4%)
Successful endoscopic resection
475 (86.1%)
Additional treatment for high-risk patients
30 (5.4%)
10 (1.8%)
37 (6.7%)
Histopathological findings and identification of successful endoscopic resection
HGD was present in 124 patients (22.5%), and esophageal adenocarcinoma (EAC) in 428
patients (77.5%). Tumor differentiation was well-differentiated in 293 cases (68.4%),
moderately-differentiated in 112 (26.1%), and poorly-differentiated in 23 (5.3%).
Invasion depth was T1a in 369 cases (86.2%), T1b SM1 in 43 (10.0%), and T1b SM2 or
deeper in 16 (3.7%). Based on histopathological results, successful endoscopic resection
was achieved in 475 patients (86.1%). For those considered as having non-curative
or unsuccessful endoscopic resection (high risk for lymph node metastasis or positive
deep margin), additional treatments included esophagectomy in 30 cases (5.4%), chemoradiotherapy
in 10 cases (1.8%), and close follow-up in 37 cases (6.7%).
Short-term follow-up outcomes in patients with successful endoscopic resection
Of 475 patients with successful endoscopic resection, 455 patients underwent follow-up.
At initial follow-up endoscopy, residual/metachronous neoplasia was observed in 95
cases (20.9%) (95/455). After additional EMR, a total of 435 patients (95.6%) achieved
CRN after undergoing a median of two EMR sessions (IQR 1–4). Twenty patients (4.4%)
did not achieve CRN, and of them, 14 underwent esophagectomy, four patients received
chemoradiotherapy, and two patients entered palliative care. CRIM was achieved with
only EMR in 40.2% (183/455). Ablations techniques were performed following EMR in
37.6% (170/455). After undergoing a median of two ablation sessions (IQR 1–3), CRIM
was achieved in an additional 23.9% of patients (109/455). In total, 64.1% (292/455)
of the follow-up cohort achieved CRIM ([Fig. 1 ], [Table 2 ]).
Fig. 1 Flowchart of study patients.
Table 2 Follow-up outcomes for successful endoscopic resection patients.
N = 455
All values are expressed as percentages among both groups.
APC, argon plasma coagulation; CRIM, complete remission of intestinal metaplasia;
CRN, complete remission of neoplasia; IQR, interquartile range; PDT, photodynamic
therapy; RFA, radiofrequency ablation; SD, standard deviation.
Residual neoplasia at first follow-up
95 (20.9%)
Number of EMR sessions until CRN, median (IQR)
2 (1–4)
Complete remission of neoplasia (CRN)
435 (95.6%)
Non-CRD
20 (4.4%)
Treatment for non-CRN
14
4
2
Stricture formation
160 (35.2%)
Number of dilations, median (IQR)
2 (1–5)
Ablation techniques performed
170 (37.6%)
148
1
4
17
Number of ablation sessions until CRIM, median (IQR)
2 (1–3)
Complete remission of intestinal metaplasia (CRIM)
292 (64.1%)
183 (40.2%)
109 (23.9%)
Recurrence of neoplasia after CRN
N = 435
38 (8.7%)
Local recurrence of neoplasia
N = 435
37 (8.5%)
Lymph node recurrence
N = 435
1 (0.2%)
Treatment for recurrence
26
5
4
3
Total follow-up period, months, mean (SD)
50.0 (39.3)
Long-term follow-up outcomes of patients who achieved CRN
During a mean total follow-up period of 50.0 ± 39.3 months, recurrence of neoplasia
occurred in 38 of 435 patients (8.7%) who had achieved CRN. This includes local recurrence
of neoplasia in 37 cases (8.5%) and lymph node recurrence in one case (0.2%). Of the
38 patients with recurrence, 26 (68.4%) were successfully treated endoscopically,
but 12 patients (31.6%) were not: five underwent esophagectomy, four received chemoradiotherapy,
and three entered palliative care.
Among the entire follow-up cohort of 455 patients, 93.0% (423/455) were successfully
managed with endoscopic therapy. In contrast, 32 patients (7%) failed to achieve CRN
or had recurrence of neoplasia leading to esophagectomy, chemoradiotherapy, or palliative
care.
The Kaplan-Meier curve representing cumulative incidence of neoplasia recurrence after
CRN is shown in [Fig. 2 ]. As a primary outcome, the 1-year recurrence rate was 3.1% (95% CI 1.4–4.7), the
3-year recurrence rate was 6.3% (95% CI 3.5–9.0), the 5-year recurrence rate was 10.5%
(95% CI 6.4–14.6), the 10-year recurrence rate was 21.6% (95% CI 13.2–29.9), and the
15-year recurrence rate was 34.9% (95% CI 16.2–53.7) ([Table 3 ]).
Fig. 2 Kaplan-Meier curve of cumulative incidence of neoplasia recurrence.
Table 3 Cumulative incidence of neoplasia recurrence following complete remission of neoplasia.
Recurrence rate
95% CI
CI, confidence interval.
1-year
3.1%
1.4%-4.7%
3-year
6.3%
3.5%-9.0%
5-year
10.5%
6.4%-14.6%
10-year
21.6%
13.2%-29.9%
15-year
34.9%
16.2%-53.7%
The Kapan Meier curve representing cumulative incidence of neoplasia recurrence in
patients who underwent ablations vs. those who did not is shown in [Fig. 3 ]. The 1-year recurrence rate for patients who underwent RFA was 0.6% (95% CI 0–1.8),
the 3-year recurrence rate was 4.5% (95% CI 0.52–8.48), the 5-year recurrence rate
was 12.7% (95% CI 4.7–20.6), and the 10-year recurrence rate was 30.2% (95% CI 12.2–48.2).
The 1-year recurrence rate for patients who did not undergo RFA was 4.8% (95% CI 2.0–7.5),
the 3-year recurrence rate was 7.6% (95% CI 3.7–11.4), the 5-year recurrence rate
was 9.5% (95% CI 4.9–14.1), and the 10-year recurrence rate was 17.5% (95% CI 8.6–26.3).
There was no statistically significant difference in recurrence rate between the two
groups (P = 0.68, log-rank test).
Fig. 3 Kaplan-Meier curve of cumulative incidence of neoplasia recurrence in patients who
underwent ablations vs. those who did not.
Discussion
In this large, single-center, retrospective cohort study, we investigated long-term
outcomes of EMR for Barrett's neoplasia, with a particular focus on recurrence of
neoplasia. Although the overall rate of patients who were successfully managed by
endoscopy was 93%, recurrence rates for neoplasia following CRN were observed to be
considerable over the long term, reaching 10.5% at 5 years, 21.6% at 10 years, and
34.9% at 15 years.
EMR for BE has become one of the standard procedures for treating BE HGD and EAC.
Guidelines recommend histopathological staging based on endoscopic resection of visible
lesions within BE [7 ]
[8 ]
[9 ]. Following endoscopic resection, patients are categorized based on their risk of
lymph node metastasis and local recurrence, as predicted by histopathology. For patients
assessed as low-risk, endoscopic follow-up is recommended [9 ]. Several studies have examined long-term recurrence rates following EMR for Barrett’s
neoplasia. One study reported a 6.2% recurrence rate for neoplasia over a mean follow-up
of 64.8 months post-EMR for lesions including LGD to adenocarcinoma [17 ]. Another study showed that the recurrence rate for HGD or EAC was 14.5% over a mean
follow-up period of 56.6 months post-EMR for intramucosal adenocarcinoma [3 ]. Our study indicated that the 5-year recurrence rate was 10.5%, the 10-year recurrence
rate was 21.6%, and the 15-year recurrence rate was 34.9%. Our findings align with
previous reports, but this is the first report to show long-term recurrence rates
beyond 10 years.
In the current guideline, for patients with a baseline diagnosis of HGD or EAC, surveillance
endoscopy is recommended at 1, 2, 3, 4, 5, 7, and 10 years after last treatment [9 ]. This guideline also indicates that surveillance may be discontinued after 10 years
[9 ]. However, our findings demonstrate that recurrence rates continue to increase over
time, even beyond the 10-year mark. This evidence suggests that continuing surveillance
endoscopy beyond 10 years should be considered, taking into account patient age and
comorbidities.
In our study of 435 patients who underwent successful endoscopic resection and completed
follow-up endoscopy, 93.0% (423/455) were successfully managed with endoscopic treatments.
This confirms the high efficacy of EMR in management of Barrett’s neoplasia. Previous
studies reported a similar rate of successful endoscopic management of 93.8% [3 ], which is consistent with our results.
In contrast, 32 patients in our study (7%) who were initially considered as having
had successful endoscopic treatment ultimately required esophagectomy or chemoradiotherapy,
or entered palliative care. This includes 20 patients who were initially considered
successfully treated by EMR but ultimately failed to achieve CRN due to residual/metachronous
neoplasia and required more invasive therapy. Repeat attempts at EMR on the same area
become increasingly challenging as the neoplastic area becomes fibrotic and scarred
down. Furthermore, 31.6% of patients who had neoplastic recurrence (12/38) had lesions
that were not amenable to endoscopic management. Similar challenges in treating recurrent
lesions are that the lesions become embedded in fibrotic areas. For band ligation
or cap EMR, suction of lesions into the cap is particularly difficult when lesions
are within scarred or fibrotic areas. If endoscopic treatment is not feasible, more
invasive approaches such as esophagectomy, chemoradiotherapy, or palliation were often
necessary, even for lesions that were not advanced cancers.
The current guideline recommends en bloc resection by ESD for lesions suspected of
submucosal invasion, for malignant lesions larger than 20 mm, and for lesions in scarred
or fibrotic areas [9 ]. In addition, recent studies have demonstrated a lower recurrence rate following
ESD compared with EMR [18 ]
[19 ]. Most of our study data come from a period before the widespread availability of
ESD in the West. However, use of ESD for appropriate lesions could potentially reduce
recurrence rates and increase the success rate for treatment of recurrent lesions
in fibrosis. Consequently, judicious selection of resection techniques is likely to
improve the proportion of patients who can be successfully managed with endoscopy.
In this study, ablation techniques were performed in 37.6% of patients (170/455),
resulting in achievement of CRIM in 64.1% (292/455). Adoption of ablation techniques
for BE became common following introduction and validation of RFA [20 ]. The relatively low rate of ablation technique use in our study can be attributed
to our cohort encompassing the period before RFA became common. CRIM was achieved
by EMR alone in only 40.2% (183/455), with ablation techniques performed following
EMR in 37.6% (170/455) and CRIM achieved in an additional 23.9% of patients (109/455).
Interestingly, there was no statistically significant difference in recurrence rate
between the groups of patients who underwent RFA compared with those who did not (P = 0.68), which is potentially explained by the increased tendency to perform widefield
EMR of BE prior to the RFA era. We acknowledge that our lower rate of CRIM is relevant
because some studies have indicated that failure to achieve CRIM is associated with
an increased risk of dysplasia recurrence [21 ].
This study has several limitations. First, its retrospective design and extended follow-up
period inevitably led to some patients being lost to follow-up. To account for this,
we employed the Kaplan-Meier method, which accommodates censoring and provides an
estimate of recurrence probability over time. This approach helps mitigate selection
bias associated with loss to follow-up. The Kaplan-Meier analysis assumes that patients
lost to follow-up have a similar prognosis (i.e., recurrence risk) as those who remain
under observation. To assess this assumption, we conducted a comparative analysis
of patient and lesion characteristics, as well as follow-up outcomes, between individuals
with shorter follow-up durations (< 5 years) and those with longer follow-up durations
(≥ 5 years) (Supplementary Table 1 ). The results demonstrated no significant differences in lesion characteristics between
the two groups. Although patients with longer follow-up had longer BE segments, they
also exhibited a higher rate of CRIM. Furthermore, recurrence rates were comparable
between the short- and long-term follow-up groups. Given that achieving CRIM has been
reported to significantly reduce recurrence risk [21 ], these findings suggest that patients with longer follow-up do not have an increased
risk of recurrence compared to those with shorter follow-up. Nonetheless, our study
observed a high cumulative recurrence rate, with estimated rates of 21.6% at 10 years
and 34.9% at 15 years. However, to more accurately assess recurrence risk, future
studies with more comprehensive and complete follow-up data are warranted to minimize
potential biases associated with loss to follow-up.
Second, endoscopic techniques and tools have evolved over time, particularly devices
used for EMR and ablation. Third, indications for EMR have shifted over time. Prior
to the advent of RFA, EMR was often utilized to completely eradicate the entire Barrett’s
segment. With widespread adoption of RFA, the focus of EMR shifted to resection of
visible lesions. More recently, larger lesions or those suspected to harbor more advanced
pathology are preferentially selected for treatment with ESD, whereas EMR has often
been reserved for smaller, less invasive lesions. This shift in indications is likely
to have influenced outcomes in our study. Fourth, RFA is currently performed following
EMR with the aim of achieving CRIM as standard of care. Therefore, reduction in recurrence
rates due to RFA also affects the recurrence rates following EMR. However, the data
in our study reflect real-world clinical situations, which underscores the importance
of reporting recurrence data that accurately represent actual clinical practice. Finally,
it is possible that AEs may not have been fully captured within our cohort. This is
because patients who experienced post-procedure AEs may have sought care at other
medical centers, which we may have failed to capture. This may have resulted in underestimation
of the AEs in this study. However, given that AE rates were not an outcome of interest,
no additional methodology was employed to ensure comprehensive documentation of all
AEs.
Conclusions
In summary, in this large, single-center, retrospective cohort study, long-term outcomes
following EMR for Barrett's neoplasia were investigated. Although the overall rate
of patients who were successfully managed by endoscopy was excellent, the recurrence
rate over time was notably high. These data imply that surveillance endoscopy beyond
10-year follow-up should be considered.
Bibliographical Record
