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Low-grade dysplasia in Barrett’s esophagus — a second opinion is important, but then treatment is needed

Thomas Rösch, Hamburg

Gut 2015;64: 700-706

Barrett’s oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel
Lucas C Duits, K Nadine Phoa, Wouter L Curvers, Fiebo J W ten Kate, Gerrit A Meijer, Cees A Seldenrijk, G Johan Offerhaus, Mike Visser, Sybren L Meijer, Kausilia K Krishnadath, Jan G P Tijssen, Rosalie C Mallant-Hent, Jacques J G H M Bergman

Objective

Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett’s 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 valueof an expert pathology panel organised in the Dutch Barrett’s Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after experthistological 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 relatedto 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 followup 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.


JAMA. 2014;311:1209-1217

Radiofrequency Ablation vs Endoscopic Surveillance for Patients With Barrett Esophagus and Low-Grade Dysplasia A Randomized Clinical Trial
K. Nadine Phoa, MD; Frederike G. I. van Vilsteren, MD; Bas L. A. M.Weusten, MD; Raf Bisschops, MD; Erik J. Schoon, MD; Krish Ragunath, MD; Grant Fullarton, MD; Massimiliano Di Pietro, MD; Narayanasamy Ravi, MD; Mike Visser, MD; G. Johan Offerhaus, MD; Cees A. Seldenrijk, MD; Sybren L. Meijer, MD; Fiebo J.W. ten Kate, MD; Jan G. P. Tijssen, PhD; Jacques J. G. H.M. Bergman, MD, PhD

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 Measure

The primary outcomewas 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.


Gastroenterology 2015;online (doi:10.1053/j.gastro.2015.04.013.)

Radiofrequency Ablation is Associated with Decreased Neoplastic Progression in Patients with Barrett’s Esophagus and Confirmed Low-Grade Dysplasia
Aaron J. Small, MD, MSCE, James L. Araujo, MD, Cadman L. Leggett, MD, Aaron H. Mendelson, MD, Anant Agarwalla, MD, Julian A. Abrams, MD, MPH, Charles J. Lightdale, MD, Timothy C. Wang, MD, Prasad G. Iyer, MD, MS, Kenneth K. Wang, MD, Anil K. Rustgi, MD, Gregory G. Ginsberg, MD, Kimberly A. Forde, MD, MHS, Phyllis A. Gimotty, PhD, James D. Lewis, MD, MSCE, Gary W. Falk, MD, MS, Meenakshi Bewtra, MD, MPH, PhD

Background & Aims

Barrett’s esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD following RFA to that with endoscopic surveillance alone in routine clinical practice.

Methods

We performed a retrospective study of patients who either underwent RFA (n=45) or surveillance endoscopy (n=125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the US. Cox regression analysis was used to assess the association between progression and RFA.

Results

Data were collected over median follow-up periods of 889 days (inter-quartile range, 264–1623 days) after RFA and 848 days (inter-quartile range, 322–2355 days) after surveillance endoscopy (P=.32). The annual rates of progression to HGD or EAC was 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio, 0.06; 95% confidence interval, 0.008–0.48).

Conclusions

Among patients with BE and confirmed LGD, rates of progression to a combined endpoint of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.

What you need to know

Low-grade dysplasia (low-grade intraepithelial neoplasia, LGIN) is difficult to distinguish from inflammation histopathologically. The interobserver variance rates usually show kappa values below 0.4 (1–5), representing a poor level of interobserver variance. The research group in Amsterdam already showed in an earlier study that among 147 LGIN diagnoses from pathology practices, reassessment by specialist gastrointestinal pathologists only confirmed the findings in 15% of cases. Among these 15% of the patients, however, 85% developed higher-grade neoplasias (high-grade IN or carcinoma) during the subsequent follow-up (with a mean of 9 years); this was only the case in 4.6% of the remaining 85% of the patients (6).

This multicenter study from Amsterdam shows that histopathologically confirmed LGIN has an annual progression risk of 9.1% (7). A total of 293 LGIN patients whose cases were presented to a panel of expert pathologists received reassessment, and the diagnosis was confirmed in 27%, a slightly larger figure. During the mean follow-up period (36 months, with a 90% follow-up rate), the patients with confirmed diagnosis developed higher-grade neoplasias 10 times more often than the remaining patients (0.6–0.9% per year). However, only rudimentary findings were available for the initial and follow-up endoscopies in each case (date, “endoscopic landmarks,” number of biopsies), so that it is not clear how many patients had endoscopically visible lesions — one of the few weak points in the study. The median number of follow-up endoscopies was 2, and with a mean Barrett’s segment length of 4 cm, eight biopsies were taken, so that there was good compliance with the guidelines.

Whether patients with Barrett’s and LGIN should be treated is thus decisively dependent on whether the histopathological findings are confirmed by a second opinion. In addition, the endoscopic appearance also plays a role (although this is not discussed in the studies from Amsterdam). The results of a randomized study from Amsterdam published a year ago show that radiofrequency ablation of Barrett’s in the presence of confirmed LGIN decisively slows the progression rate (8). Incidentally, patients with endoscopically visible lesions were excluded. The detailed results are as follows:

Ablation group
(n = 68)
Controls
(n = 68)
Risk reduction
Progression to HGIN/carcinoma 1.5% 26.5% 25%
Progression to carcinoma 1.5% 8.8% 7.4%
Both differences are significant
Treatment success in the RFA group (median of three sessions)
Complete eradication Dysplasia initially 92.6%
Dysplasia and Barrett’s initially 88.2%
Dysplasia during the follow-up 98.4%
Dysplasia and Barrett’s during the follow-up 90.0%

To qualify this, however, it should be mentioned that the good results from the Amsterdam group and their research partners have not been confirmed by all groups. In routine work, ablation rates are lower and recurrence rates are higher (9–14), and in the studies with good long-term results, the fine print sometimes shows that 55% of the patients received repeat radiofrequency treatment after the end point had been reached, without histological confirmation in 62% of these cases (15). If constant follow-up treatment is given, the results are of course better.

These results have now been confirmed in a retrospective, nonrandomized study in the USA, although with quite a steep decline in the grade of evidence involved. It is surprising that this relatively small retrospective and nonrandomized multicenter study over a period of 11 years from three U.S. centers was accepted by the journal Gastroenterology. Over a follow-up period of only 2.5 years, the progression rates were 6.6% (LGIN, n = 45) versus 0.8% (controls, n = 123). So far as one can see from the findings, three patients in the ablation group and 13 in the control group had focal nodular lesions on endoscopy, and some also underwent EMR; these patients should really have been excluded. This was thus a methodologically rather weak confirmation of the evidence, although the results point in the same direction.

References

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