Mike Visser

Low-Grade Dysplasia in Barrett's Esophagus: Overdiagnosed and Underestimated

OBJECTIVES:Published data on the natural history of low-grade dysplasia (LGD) in Barretts esophagus (BE) are inconsistent and difficult to interpret. We investigated the natural history of LGD in a large community-based cohort of BE patients after reviewing the original histological diagnosis by an expert panel of pathologists.METHODS:Histopathology reports of all patients diagnosed with LGD between 2000 and 2006 in six non-university hospitals were reviewed by two expert pathologists. This panel diagnosis was subsequently compared with the histological outcome during prospective endoscopic follow-up.RESULTS:A diagnosis of LGD was made in 147 patients. After pathology review, 85% of the patients were downstaged to non-dysplastic BE (NDBE) or to indefinite for dysplasia. In only 15% of the patients was the initial diagnosis LGD. Endoscopic follow-up was carried out in 83.6% of patients, with a mean follow-up of 51.1 months. For patients with a consensus diagnosis of LGD, the cumulative risk of progressing to high-grade dysplasia or carcinoma (HGD or Ca) was 85.0% in 109.1 months compared with 4.6% in 107.4 months for patients downstaged to NDBE (P<0.0001). The incidence rate of HGD or Ca was 13.4% per patient per year for patients in whom the diagnosis of LGD was confirmed. For patients downstaged to NDBE, the corresponding incidence rate was 0.49%.CONCLUSIONS:LGD in BE is an overdiagnosed and yet underestimated entity in general practice. Patients diagnosed with LGD should undergo an expert pathology review to purify this group. In case the diagnosis of LGD is confirmed, patients should undergo strict endoscopic follow-up or should be considered for endoscopic ablation therapy.

Radiofrequency Ablation vs Endoscopic Surveillance for Patients With Barrett Esophagus and Low-Grade Dysplasia: A Randomized Clinical Trial

IMPORTANCE Barrett esophagus containing low-grade dysplasia is associated with an increased risk of developing esophageal adenocarcinoma, a cancer with a rapidly increasing incidence in the western world. OBJECTIVE To investigate whether endoscopic radiofrequency ablation could decrease the rate of neoplastic progression. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial that enrolled 136 patients with a confirmed diagnosis of Barrett esophagus containing low-grade dysplasia at 9 European sites between June 2007 and June 2011. Patient follow-up ended May 2013. INTERVENTIONS Eligible patients were randomly assigned in a 1:1 ratio to either endoscopic treatment with radiofrequency ablation (ablation) or endoscopic surveillance (control). Ablation was performed with the balloon device for circumferential ablation of the esophagus or the focal device for targeted ablation, with a maximum of 5 sessions allowed. MAIN OUTCOMES AND MEASURES The primary outcome was neoplastic progression to high-grade dysplasia or adenocarcinoma during a 3-year follow-up since randomization. Secondary outcomes were complete eradication of dysplasia and intestinal metaplasia and adverse events. RESULTS Sixty-eight patients were randomized to receive ablation and 68 to receive control. Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma by 25.0% (1.5% for ablation vs 26.5% for control; 95% CI, 14.1%-35.9%; P < .001) and the risk of progression to adenocarcinoma by 7.4% (1.5% for ablation vs 8.8% for control; 95% CI, 0%-14.7%; P = .03). Among patients in the ablation group, complete eradication occurred in 92.6% for dysplasia and 88.2% for intestinal metaplasia compared with 27.9% for dysplasia and 0.0% for intestinal metaplasia among patients in the control group (P < .001). Treatment-related adverse events occurred in 19.1% of patients receiving ablation (P < .001). The most common adverse event was stricture, occurring in 8 patients receiving ablation (11.8%), all resolved by endoscopic dilation (median, 1 session). The data and safety monitoring board recommended early termination of the trial due to superiority of ablation for the primary outcome and the potential for patient safety issues if the trial continued. CONCLUSIONS AND RELEVANCE In this randomized trial of patients with Barrett esophagus and a confirmed diagnosis of low-grade dysplasia, radiofrequency ablation resulted in a reduced risk of neoplastic progression over 3 years of follow-up. TRIAL REGISTRATION trialregister.nl Identifier: NTR1198.

Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett's oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial

Objective After focal endoscopic resection (ER) of high-grade dysplasia (HGD) or early cancer (EC) in Barretts oesophagus (BO), eradication of all remaining BO reduces the recurrence risk. The aim of this study was to compare the safety of stepwise radical ER (SRER) versus focal ER followed by radiofrequency ablation (RFA) for complete eradication of BO containing HGD/EC. Methods A multicentre randomised clinical trial was carried out in three tertiary centres. Patients with BO ≤5 cm containing HGD/EC were randomised to SRER or ER/RFA. Patients in the SRER group underwent piecemeal ER of 50% of BO followed by serial ER. Patients in the ER/RFA group underwent focal ER for visible lesions followed by serial RFA. Follow-up endoscopy with biopsies (four-quadrant/2 cm BO) was performed at 6 and 12 months and then annually. The main outcome measures were: stenosis rate; complications; complete histological response for neoplasia (CR-neoplasia); and complete histological response for intestinal metaplasia (CR-IM). Results CR-neoplasia was achieved in 25/25 (100%) SRER and in 21/22 (96%) ER/RFA patients. CR-IM was achieved in 23 (92%) SRER and 21 (96%) ER/RFA patients. The stenosis rate was significantly higher in SRER (88%) versus ER/RFA (14%; p<0.001), resulting in more therapeutic sessions in SRER (6 vs 3; p<0.001) due to dilations. After median 24 months follow-up, one SRER patient had recurrence of EC, requiring ER. Conclusions In patients with BO ≤5 cm containing HGD/EC, SRER and ER/RFA achieved comparably high rates of CR-IM and CR-neoplasia. However, SRER was associated with a higher number of complications and therapeutic sessions. For these patients, a combined endoscopic approach of focal ER followed by RFA may thus be preferred over SRER. Clinical trial number NTR1337.

Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel

Objective Reported malignant progression rates for low-grade dysplasia (LGD) in Barretts oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barretts Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD. Design We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC. Results 293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16–72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively. Conclusions Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.

Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II)

Objective Focal endoscopic resection (ER) followed by radiofrequency ablation (RFA) safely and effectively eradicates Barretts oesophagus (BO) containing high-grade dysplasia (HGD) and/or early cancer (EC) in smaller studies with limited follow-up. Herein, we report long-term outcomes of combined ER and RFA for BO (HGD and/or EC) from a single-arm multicentre interventional study. Design In 13 European centres, patients with BO≤12 cm with HGD and/or EC on 2 separate endoscopies were eligible for inclusion. Visible lesions (<2 cm length; <50% circumference) were removed with ER, followed by serial RFA every 3 months (max 5 sessions). Follow-up endoscopy was scheduled at 6 months after the first negative post-treatment endoscopic control and annually thereafter. Outcomes: complete eradication of neoplasia (CE-neo) and intestinal metaplasia (CE-IM); durability of CE-neo and CE-IM (once achieved) during follow-up. Biopsy and resection specimens underwent centralised pathology review. Results 132 patients with median BO length C3M6 were included. After entry-ER in 119 patients (90%) and a median of 3 RFA (IQR 3–4) treatments, CE-neo was achieved in 121/132 (92%) and CE-IM in 115/132 patients (87%), per intention-to-treat analysis. Per-protocol analysis, CE-neo and CE-IM were achieved in 98% and 93%, respectively. After a median of 27 months following the first negative post-treatment endoscopic control, neoplasia and IM recurred in 4% and 8%, respectively. Mild-to-moderate adverse events occurred in 25 patients (19%); all managed conservatively or endoscopically. Conclusions In patients with early Barretts neoplasia, intensive multimodality endotherapy consisting of ER combined with RFA is safe and highly effective, and the treatment effect appears to be durable during mid-term follow-up. Trial registration number NTR 1211, http://www.trialregister.nl.

Randomized trial on endoscopic resection-cap versus multiband mucosectomy for piecemeal endoscopic resection of early Barrett's neoplasia

BACKGROUND Endoscopic resection (ER) is an important treatment for high-grade intraepithelial neoplasia and early cancer in Barretts esophagus. ER-cap requires submucosal lifting and positioning of a snare in the cap, making it technically demanding and laborious. Multiband mucosectomy (MBM) uses a modified variceal band ligator and requires no submucosal lifting or positioning of a snare. OBJECTIVE To compare ER-cap and MBM for piecemeal ER of early Barretts neoplasia. DESIGN Randomized, controlled trial. SETTING Tertiary-care and community-care centers. PATIENTS This study involved 84 patients (64 men; median age 70 years) undergoing piecemeal ER of Barretts neoplasia. INTERVENTION Piecemeal ER was performed by using ER-cap (n = 42) or MBM (n = 42). MAIN OUTCOME MEASUREMENTS Safety, efficacy, procedure time, costs. RESULTS Procedure time (34 vs 50 minutes; P = .02) and costs (€240 vs €322; P < .01) were significantly less with MBM compared with ER-cap. MBM resulted in smaller resection specimens than ER-cap (18 ×13 mm vs 20 × 15 mm; P < .01). Maximum thicknesses of specimens and resected submucosa were not significantly different. There were no clinically relevant bleeding episodes. Four perforations occurred, 3 with ER-cap, 1 with MBM (P = not significant). LIMITATIONS Potential bias because of different levels of experience among participating endoscopists. CONCLUSION Piecemeal ER with MBM is faster and cheaper than with ER-cap. Despite the lack of submucosal lifting, MBM appears not to be associated with more perforations. Although MBM results in slightly smaller specimens, the clinical relevance of this may be limited because depth of resections does not differ between both techniques. MBM may thus be preferred for piecemeal ER of early Barretts neoplasia. ( CLINICAL TRIAL REGISTRATION NUMBER NTR1435.).

Risk of Lymph Node Metastasis Associated with Deeper Invasion by Early Adenocarcinoma of the Esophagus and Cardia: Study Based on Endoscopic Resection Specimens

BACKGROUND Most risk estimations for lymph node metastasis in adenocarcinoma of the esophagus and cardia (AEC) with invasion into the muscularis mucosae (m3) or submucosa are based on surgical series. This study aimed to correlate the lymph node metastasis rate with m3 and submucosal infiltration depth of AEC in endoscopic resection specimens. METHODS Patients undergoing endoscopic resection for AEC between January 2000 and March 2008 at two centers were included if the endoscopic resection specimen showed m3 or submucosal cancer. Infiltration into the muscularis mucosae was defined as m3. Submucosal invasion was classified as sm1 (≤ 500 µm) or sm2/3 (> 500 µm). Exclusion criteria were chemotherapy or radiotherapy and nonradical endoscopic resection. RESULTS 82 patients included 57 with m3, 12 with sm1, and 13 with sm2/3 cancers. Of the tumors, 13 were poorly differentiated and five showed lymphovascular invasion. After initial endoscopic resection, seven patients underwent surgery and 75 endoscopic therapy. No lymph node metastases were found in 158 lymph nodes of the esophagectomy specimens and none of the endoscopically treated patients were diagnosed with lymph node metastasis during a median follow-up of 26 months (interquartile range [IQR] 14 - 41). CONCLUSION This study suggests that lymph node metastasis risk for m3 and submucosal AEC may be lower than has been assumed on the basis of surgical series, and that current guidelines are valid regarding suitability of m3 AECs for endoscopic therapy. It may also suggest that selected patients with submucosal cancers are also eligible for endoscopic management. Confirmation of these results is needed in larger series with longer follow-up.

Do we still need EUS in the workup of patients with early esophageal neoplasia? A retrospective analysis of 131 cases

BACKGROUND EUS is often used for locoregional staging of early esophageal neoplasia. However, its value compared with that of endoscopic examination and diagnostic endoscopic resection (ER) may be questioned because diagnostic ER allows histological assessment of submucosal invasion and other risk factors for lymph node metastasis, eg, poor differentiation/lymphovascular invasion. OBJECTIVE To evaluate how often patients were excluded from endoscopic treatment of esophageal neoplasia based on EUS findings. DESIGN Retrospective cohort study. SETTING Tertiary care institution. PATIENTS Patients with early esophageal neoplasia. INTERVENTIONS EUS, diagnostic ER. MAIN OUTCOME MEASUREMENTS Number of patients excluded from endoscopic treatment based on EUS results. RESULTS A total of 131 patients were included (98 men, 33 women; age 66 ± 13 years). In 105 of 131 patients (80%), EUS findings were unremarkable. In 25 of 105 patients (24%), diagnostic ER showed submucosal invasion (n = 17), deep resection margins positive for cancer (n = 2, confirmed at surgery), or poor differentiation/lymphovascular invasion (n = 6). In 26 of 131 patients (20%), EUS findings raised the suspicion of submucosal invasion and/or lymph node metastasis. In the 14 of 26 patients (54%) with abnormal EUS findings, endoscopy results were unremarkable. Diagnostic ER showed submucosal invasion in 7 of 14 (50%) patients, whereas no lymph node metastasis risk factors were found in 7 of 14 patients (50%), who subsequently underwent curative endoscopic treatment. In 12 of 26 patients (46%) with abnormal EUS, endoscopy also raised doubts on whether curative endoscopic treatment could be achieved. After diagnostic ER, no risk factors for lymph node metastasis were found in 3 of 12 patients (25%). LIMITATION Retrospective study. CONCLUSIONS This study shows that EUS has virtually no clinical impact on the workup of early esophageal neoplasia and strengthens the role of diagnostic ER as a final diagnostic step.

Safety and efficacy of multiband mucosectomy in 1060 resections in Barrett's esophagus

INTRODUCTION Multiband mucosectomy (MBM) is a relatively new technique for endoscopic resection in Barretts esophagus. This ligate-cut technique uses a modified variceal band ligator allowing for six consecutive resections without prior submucosal lifting. The aim was to evaluate the safety of MBM and its efficacy for complete endoscopic removal of delineated target areas in Barretts esophagus. METHODS Prospective registration of all MBM procedures in Barretts esophagus was carried out between November 2004 and October 2009 in two hospitals. Prior to MBM, the target area was delineated with coagulation markings, followed by endoscopic resection until the delineated area was completely resected. Primary end points were acute (during procedure) plus early complications (<30 days) and the rate of complete endoscopic resection of the delineated target area. RESULTS A total of 243 MBM procedures, with 1060 resections, were performed in 170 patients. MBM was performed for focal lesions (n=113), for Barretts esophagus removal as part of a (stepwise) radical endoscopic resection protocol (n=117), and as escape treatment after radiofrequency ablation (n=13). The only acute complication was bleeding (in 3%, endoscopically managed); no perforations occurred despite absence of submucosal lifting. Early complications consisted of delayed bleeding (in 2%, endoscopically managed) and stenosis, which occurred in 48% of patients treated in a (stepwise) radical resection protocol; patients treated for focal lesions or in escape treatment showed no stenosis. Complete endoscopic resection was achieved in 91% of the focal lesions, in 86% of cases treated under the (stepwise) radical endoscopic resection protocol, and 100% for escape treatment after radiofrequency ablation. CONCLUSION MBM is a safe and effective technique for the removal of delineated target areas in Barretts esophagus.

Learning to perform endoscopic resection of esophageal neoplasia is associated with significant complications even within a structured training program

BACKGROUND AND STUDY AIMS Endoscopic resection is the cornerstone of endoscopic treatment of esophageal high grade dysplasia or early cancer. Endoscopic resection is, however, a technically demanding procedure, which requires training and expertise. The aim of the current study was to prospectively evaluate efficacy and safety of the first 120 endoscopic resection procedures of early esophageal neoplasia performed by six endoscopists (20 endoscopic resections each) who were participating in an endoscopic resection training program. PATIENTS AND METHODS The program consisted of four tri-monthly 1-day courses with lectures, live-demonstrations, hands-on training on anesthetized pigs, and one-on-one hands-on training days. Gastroenterologists from centers with multidisciplinary expertise in upper gastrointestinal oncology participated, together with an endoscopy nurse and a pathologist. Outcome measures were complete endoscopic removal of the target area and acute complications. RESULTS A total of 120 consecutive esophageal endoscopic resection procedures (85 ER-cap, 35 multiband mucosectomy [MBM]) were performed by six endoscopists: 109 in Barretts esophagus, 11 for squamous neoplasia; 85 piecemeal endoscopic resections (median 3 specimens, interquartile range 2 - 4 specimens). Complete endoscopic removal was achieved in 111 /120 cases (92.5 %). Six perforations occurred (5.0 %): five were effectively treated endoscopically (clips, covered stent), and one patient underwent esophagectomy. There were 11 acute mild bleedings (9.2 %), which were managed endoscopically. Perforations occurred in ER-cap procedures performed by four participants (7.1 % ER-cap vs. 0 % MBM; P = 0.18), and in 1.7 % of the first 10 endoscopic resections and 8.3 % of the second 10 endoscopic resections per endoscopist (P = 0.26). CONCLUSION In this intense, structured training program, the first 120 esophageal endoscopic resections performed by six participants were associated with a 5.0 % perforation rate. Although perforations were adequately managed, performing 20 endoscopic resections may not be sufficient to reach the peak of the learning curve in endoscopic resection.