Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Screening and surveillance
 

How should development of squamous islands on Barrett's mucosa be interpreted?

S. Gore (Yeovil)

The incidence of adenocarcinoma of the esophagus and gastric cardia appears to be increasing more rapidly than any other cancer [1-3]. Barrett's esophagus (columnar lined esophagus - CLE) is the most important predisposing factor for esophageal adenocarcinoma, having an incidence of malignant transformation of approximately one per 100 patient years [4-6].

There has been considerable interest for many years in developing treatment strategies which could reduce the malignant potential of Barrett's esophagus by bringing about regression of the abnormal mucosa. Initial optimism was sparked by a case study reporting complete regression of 16 cm Barrett's mucosa with 18 months proton pump inhibitor (PPI) treatment [7]. These strategies have included medical [8, 9], surgical [10, 11] and photoablative [12-15] therapies and have been subject to recent review [16].

Regression of Barrett's esophagus can be measured endoscopically by reduction in the length of CLE, development of squamous islands [8, 9, 17-19] or reduction in the total area of CLE [20, 21]. The histological evidence for squamous re-epithelialization includes microscopic squamous islands, squamous encroachment at the squamocolumnar junction and apparent squamous metaplasia within Barrett's glandular mucosa [8, 17, 22, 23].

The purpose of this paper is to review the literature on the development of squamous islands within CLE and discuss their significance.

Definition

Squamous islands seen at endoscopy can be defined as patches of white and lighter coloured epithelium surrounded on all sides by columnar appearing mucosa (darker pink coloured) [24].

Microscopic squamous islands have been described in biopsy specimens from Barrett's esophagus [8, 17, 22].

Development of squamous islands

Squamous islands, both macroscopic and microscopic, may occur in untreated Barrett's esophagus [24, 25]. However, there is good evidence that their presence is greatly increased by acid suppression. In fact 50-90% of patients with Barrett's esophagus treated with PPIs develop squamous islands within the CLE. It would appear that the partial regression of Barrett's epithelium as evidenced by the development of squamous islands occurs early on with PPI therapy [8, 19].

Not only do these findings persist over 5-6 years but there appears to be further development of squamous islands with an increase in their number and size [17, 26].

There are practical difficulties in assessing the development of squamous islands endoscopically. Their size varies from 2 mm to 2 cm and with time they may coalesce to form larger islands. Thus counting numbers of squamous islands per se may not accurately reflect the amount of squamous re-epithelialisation within the Barrett's epithelium. Therefore, other methods to determine regression, using area of CLE, have been employed. Such a method has been used in a randomized double blind study comparing omeprazole with ranitidine in the regression of Barrett's esophagus [21]. In this study the development of squamous islands probably accounts for the small but significant partial regression of surface area of CLE (8% over 2 years) with omeprazole compared with no regression in the ranitidine group. There was no significant reduction in length of CLE in either group.

Significance of squamous islands in Barrett's esophagus

The pathological explanations for the development of squamous islands has recently been reviewed [23].

It appears likely that squamous islands both macroscopic and microscopic, derive from esophageal gland ducts [22]. Squamous re-epithelialization is more extensive with photoablative therapies where squamous metaplasia has been noted within the Barrett's glands [13, 22]. Thus, there are perhaps pluripotential cells within the Barrett's glands which may account for squamous re-epithelialization particularly in response to photoablation [12].

The key issue is: does the development of squamous islands lead to a reduction in the malignant potential of Barrett's mucosa? Sharma et al. [24] have found that in 38.5% of biopsies taken from macroscopic squamous islands, microscopic intestinal metaplasia (IM) is detected, concluding that the development of squamous islands does not confer any protection against future development of adenocarcinoma of the esophagus in these patients. An alternative view may be that this buried IM may be protected from the toxic stimuli within the esophageal lumen resulting in a reduced malignant potential [23]. However, an elegant study using tumor biomarkers (Ki-67 and p53 abnormalities), albeit in small numbers, has shown that completely reversed squamous epithelium following a combination of thermal injury and PPI therapy, is biologically similar to normal squamous epithelium and therefore of low cancer risk; whereas, partially reversed squamous epithelium manifest as squamous islands, is accompanied by biomarker abnormalities suggesting a continued cancer risk [27].

Conclusion

The final answer to the question as to whether the development of squamous islands confers any protection against future progression to adenocarcinoma will continue to elude us unless large, long-term, randomized trials are carried out with high-grade dysplasia or adenocarcinoma as the end point. Until then, I believe that the development of squamous islands represents, at best, a partial regression of the columnar lining of Barrett's esophagus and surveillance of these areas should continue with endoscopy and deep biopsies.

References

1. Blot WJ, Devesa S, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the oesophagus and gastric cardia. JAMA 1991:265:1287-1289.

2. Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the oesophagus and oesophagogastric junction. Gastroenterology 1993:104:510-513.

3. Cameron AJ. Epidemiology of columnar-lined oesophagus and adenocarcinoma. Gastroenterol Clin N Am 1997;26:487494.

4. Ifthikar SY, James PD, Steele RJC, Hardcastle JD, Atkinson M. Length of Barrett's oesophagus: an important factor in the development of dysplasia and adenocarcinoma. Gut 1992;33:1155-1158.

5. Hameetman W, Tytgat GNG, Houtnoff HJ, Van den Tweel JG. Barrett's oesophagus. Development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-1256.

6. Wright TA, Gray MR, Morris AI, Gilmore IT, Ellis A, Smart HL, Myskow M, Nash J, Donnelly RJ, Kingsnorth AN. Cost effectiveness of detecting Barrett's cancer. Gut 1996;39:574-579.

7. Deviere J, Buset M, Dumongeau JM, Rickaert F, Cremer M. Regression of Barrett's epithelium with omeprazole. N Engl J Med 1989;320:1497-149

8. . 8. Gore S, Healey CJ, Sutton CJ, Eyre-Brook IA, Gear MWL, Shepherd NA, Wilkinson SP. Regression of columnar line (Barrett's oesophagus) with continuous omeprazole therapy. Aliment Pharmacol Ther 1993;7:623-628.

9. Sampliner RE. Effect up to 3 years of high-dose lansoprazole on Barrett's oesophagus. Am J Gastroenterol 1994;89:1844-1848.

10. Sagar PM, Ackroyd R, Hosie KB, Patterson JE, Stoddard CJ, Kingsnorth AN. Regression and progression of Barrett's oesophagus after antireflux surgery. Br J Surg 1995;82:806-810.

11. Ortiz A, Martinez de Haro LF, Parilla P, Morales G, Molina J, Bermejo J, Liron R, Aguilar J. Conservative treatment versus antireflux surgery in Barrett's oesophagus. Br J Surg 1996;83:274-278.

12. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowitz WS. Restoration of squamous mucosa after ablation of Barrett's oesophageal epithelium. Gastroenterology 1993;104:1686-1691.

13. Barr H, Shepherd NA, Dix A, Roberts DJH, Tan WC, Kransner N. Eradication of high grade dysplasia in columnar lined (Barrett's) oesophagus by photodynamic therapy with endogenously generated protoporphyrin IX. Lancet 1996;348:584-585.

14. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's oesophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49:1-7.

15. Barham CP, Jones RL, Biddlestone LR, Hardwick RH, Shepherd NA, Barr H. Photothermal laser ablation of Barrett's oesophagus: endoscopic and histological evidence of squamous re-epithelialisation. Gut 1997;41:281-284.

16. Haag S, Nandurkar S, Talley NJ. Regression of Barrett's oesophagus: the role of acid suppression, surgery and ablative methods. Gastrointest Endosc 1999;50:229-240.

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

18. Neumann CS, Iqbal TH, Cooper BT. Long term continuous omeprazole treatment of patients with Barrett's oesophagus. Aliment Pharmacol Ther 1995;9:451-454.

19. Malesci A, Savarino V, Zentilin P, Belicchi M, Mela GS, Lapertosa G, Bocchio P, Ronchi G, Franceschi M. Partial regression of Barrett's esophagus by long term therapy with high-dose omeprazole. Gastrointest Endosc 1996;44:700705.

20. Kim R. Baggot BB, Rose S, Shar AO, Mallory DL, Kasky SS. Quantitative endoscopy: precise computerized measurement of metaplastic epithelial surface area in Barrett's oesophagus. Gastroenterology 1995;108:360-366.

21. Peters FTM, Ganesh S, Kuipers EJ, Sluiter WJ, Klinkenberg-knol EC, Lamers CBHW, Kleibenker JH. Endoscopic regression of Barrett's oesophagus during omeprazole treatment; a randomized double blind study. Gut 1999;45:489494.

22. Biddlestone LR, Barham CP, Wilkinson SP, Barr H, Shepherd NA. The histopathology of treated Barrett's oesophagus. Squamous reepithelialisation after acid suppression and laser and photodynamic therapy. Am J Surg Pathol 1998;22:239-245.

23. Shepherd NA. Barrett's oesophagus and proton pump inhibitors: a pathological perspective. Gut 200;46:147-149.

24. Sharma P, Morales TG, Bhattacharyya A, Garewal HS, Sampliner RE. Squamous islands in Barrett's oesophagus: what lies underneath? Am J Gastroenterol 1998;93:332-335.

25. Sampliner RE, Steinbronn K, Garewal HS, Riddell RH. Squamous mucosa overlying columnar epithelium in Barrett's oesophagus in the absence of antireflux surgery. Am J Gastroenterol 1998;83:510-512.

26. Cooper BT, Neumann CS, Cox MA, Iqbal TH. Continuous treatment with omeprazole 20 mgs daily for up to 6 years in Barrett's oesophagus. Aliment Pharmacol Ther 1998;12:893-897.

27. Garewal HS, Ramsey L, Sharma P, Kraus K, Sampliner RE, Fass R. Biomarker studies in reversed Barrett's oesophagus. Am J Gastroenterol 1999;94:2829-2833.


Publication date: August 2003 OESO©2015