Primary Motility  Disorders of the  Esophagus
 The Esophageal
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Volume: Barrett's Esophagus
Chapter: Screening and surveillance

What are the problems related to interpretation of "regression"?

R.E. Sampliner (Tucson)

What is regression?

Regression of Barrett's esophagus has been interpreted in many different ways: decrease in the length of Barrett's esophagus documented at endoscopy, decrease in the surface area, appearance of squamous islands in Barrett's esophagus. All of the above are approximations of what would really be desirable, i.e. the complete elimination of intestinal metaplasia (IM). Many assessments of the length of Barrett's esophagus in patients on standard or high dose proton pump inhibitor therapy over intervals of up to 6 years have shown little change in the length of Barrett's esophagus with the exception of a few patients who reportedly have had their Barrett's esophagus resolve [1-5]. Perhaps the methodologically strongest study evaluated 26 patients on 2 years of omeprazole 40 mg bid [4]. One of the strengths of this study is that it was controlled with 24-hour pH with a mean value of 0.1% of a 24 hour period with a pH less than 4. Even with this rigorous intraesophageal acid control, there was only an 8% decrease in the surface area of Barrett's esophagus. This measurement considered squamous islands as non-Barrett's which is not always accurate (see below). Although the 8% decrease was judged to be significant, this limited amount of regression of Barrett's esophagus from a clinical perspective is not impressive.

One of the caveats of "regression" is that it has been recognized that many patients with squamous islands have IM underlying the squamous epithelium by biopsy [6]. Although these islands have been interpreted as regression, they may represent just surface remodeling as long as there is residual IM underneath. The dilemma of regression of Barrett's as judged by squamous islands is highlighted in a case of a 58 year old man who had high-grade dysplasia and received a fundoplication. He was then subsequently treated with a proton pump inhibitor (PPI) for 4 years. He presented with respiratory failure due to herniation of his stomach into his chest. At esophagogastrectomy, intramucosal cancer was recognized to underly squamous epithelium in the area of his Barrett's esophagus [7].

Many modalities of endoscopic therapy have been used in an effort to ablate Barrett's esophagus [8]. In this context there is a clear functional definition of reversal. Endoscopically, reversal means there is no visual evidence of Barrett's esophagus. The visual sensitivity can be enhanced with Lugol's stain in the setting of a non-inflammatory esophagus [9]. Any area that fails to stain with Lugol's may represent residual IM. Additionally, reversal has to be documented histologically - at a minimum this would require 4-quadrant large capacity biopsies every 2 cm to document the lack of IM. Unfortunately, there is one patient from a multipolar electrocoagulation trial that ended up with an esophagectomy which in fact documented no residual IM in the specimen [10].

Regression with multipolar electrocoagulation

One of the modalities of endoscopic therapy that has been utilized in an effort to reverse Barrett's esophagus is multipolar electrocoagulation. Rather than reviewing all the trials, the focus will be on two large experiences.

Reversal therapy is a combination of acid reduction and endoscopic destruction of Barrett's epithelium. The acid reduction is typically accomplished with PPI therapy but can also be accomplished with fundoplication. In a multicenter trial using electrocautery plus omeprazole 40 mg bid, 58 patients with Barrett's 2-6cm in length were treated for reversal [11]. Six months after the last treatment session 85% of patients had no endoscopic evidence of Barrett's including Lugol's staining and 78% had no endoscopic nor histologic evidence of Barrett's esophagus utilizing large capacity 4-quadrant biopsies every 2 cm. In a larger trial 168 patients with Barrett's esophagus were followed a mean of 37 months after electrocautery therapy [12]. Patients were treated with lansoprazole 60 mg daily. Eightynine percent had short segment Barrett's esophagus and all were non-dysplastic. There was reversal of Barrett's esophagus in all patients. In 11 patients who stopped their PPI, recurrent short tongues of Barrett's were recognized. Only 3 patients in this trial had underlying IM.

In each of the above trials one patient developed a stricture requiring dilation. One patient required overnight hospitalization for chest pain management. This procedure was readily accomplished in a ambulatory setting.

The rate of squamous epithelialization of Barrett's esophagus can be over 70%. There is still a concern about standardization of the endoscopic technique as well as standardization of the documentation of reversal of Barrett's esophagus. The durability of the new epithelium is also a major issue, although in many patients the squamous epithelium is present beyond 3 years [12, 13]. IM can be recognized under squamous epithelium. Whether this represents recurrence or a sampling problem is not clear. The squamous epithelium may have been there all along but just recognized in one biopsy from an extensive biopsy protocol on a particular endoscopy.

Biologic studies have been performed in patients with reversal of Barrett's esophagus. In one trial of 11 patients, 4 with low-grade dysplasia had no residual dysplasia after therapy [14]. Ki-67, a marker of proliferation, was normally located only basally in the new squamous epithelium. By immunohistochemistry, no p53 mutations were recognized in the new Barrett's epithelium. Additionally, ornithine decarboxylase, the rate limiting step in protein metabolism, was at a lower level in the squamous epithelium as expected, in contrast to the usually elevated level in Barrett's esophagus. In contrast to the finding of the new squamous epithelium after endoscopic therapy, squamous islands after prolonged PPI therapy demonstrated multilayer Ki-67 staining in more than half of the tested patients [14].

In summary, the endoscopic and histologic criteria for reversal in the setting of endoscopic ablation can also serve to standardize and objectify the criteria for regression of Barrett's esophagus.


1. Malesci A, Savarino V, Ventilin P, et al. Partial regression of Barrett's esophagus by long-term therapy with high dose omeprazole. Gastrointest Endosc 1996;44:700-705.

2. Sharma P, Sampliner R, Camargo E. Normalization of esophageal pH with high dose proton pump inhibitor therapy does not result in regression of Barrett's esophagus. Am J Gastroenterol 1997;92:582-585.

3. Cooper B, Neumann C, Cox M, Iqbal T. Continuous treatment with oemprazole 20 mg daily for up to 6 years in Barrett's oesophagus. Aliment Pharmacol Ther 1998;12:893-897.

4. Peters F, Ganesh S, Kuipers E, et al. Endoscopic regression of Barrett's oesophagus during omeprazole treatment: a randomized double blind study. Gut 1999;45:489-494.

5. Wilkinson S, Biddlestone L, Gore S, Shepherd N. Regression of columnar lined (Barrett's) oesophagus with omeprazole 40mg daily: results of 5 years of continuous therapy. Aliment Pharmacol Ther 1999;13:1205-1209.

6. Sharma P, Morales T, Bhattacharyya A, Garewal H, Sampliner R. Squamous islands in Barrett's esophagus: what lies underneath? Am J Gasroenterol 1998;93:332-335.

7. Sampliner R, Fass R. Partial regression of Barrett's esophagus: an inadequate endpoint. Am J Gastroeneterol 1993;88:2092-2094.

8. Sampliner R. Ablative therapies for the columnar lined esophagus. Gastroenterol Clin North Am 1997;26:685-694.

9. Woolf G, Riddell R, Irvine E, Hunt R. A study to examine agreement between endoscopy and histology for the diagnosis of columnar lined (Barrett's) esophagus. Gastrointest Endosc 1989;35:541-544.

10. Fennerty M, Corless C, Sheppard B, Faigel D, Lieberman D, Sampliner R. Pathological documentation of complete elimination of Barrett's metaplasia following endoscopic multipolar electrocoagulation therapy. Gut 2001;49:142-144.

11. Sampliner R, Faigel D, Fennerty M, et al. Effective and safe endoscopic reversal of nondysplastic Barrett's esophagus with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter study. Gastrointest Endosc 2001;53:554-558.

12. Guelrud M, Herrera I, Essenfeld H. Long term results of multipolar electrocoagulation therapy for Barrett's esophagus. Gastrointest Endosc 2001;53:AB72.

13. Sharma P, Bhattacharyya A, Garewal H, Sampliner R. Durability of new squamous epithelium following endoscopic reversal of Barrett's esophagus. Gastrointest Endosc 1999;50(2):159-164.

14. Garewal H, Ramsey L, Sharma P, Kraus K, Sampliner R, Fass R. Biomarker studies in reversed Barrett's esophagus. Am J Gastrenterol 1999;94:2829-2833.

Publication date: August 2003 OESO©2015