Barrett’s oesophagus: preventing progression

teaser

Kenneth K Wang
MD
Director
Barrett’s Esophagus Unit
Mayo Clinic
Rochester
USA
E:[email protected]

Barrett’s oesophagus has become a prevalent and controversial condition that affects at least 1% of adults in Western countries. Its significance lies with its association with adenocarcinoma of the oesophagus, which has been increasing dramatically in frequency over the past two decades.

Therapy for this condition has traditionally focused on early recognition and surveillance. However, should cancer occur, there have been limited treatment options for the sufferer. New therapies have been developed that can actually reverse the metaplastic condition, thereby avoiding the traditional approach of removal of the oesophagus. These treatments offer hope for a condition that has not previously been truly treatable.

Definition
Barrett’s oesophagus is a metaplastic condition of the distal oesophagus that is thought to occur as the result of chronic gastro-oesophageal reflux disease. It is named after the English surgeon Norman Barrett who originally described its association with oesophageal ulcers. Originally, Barrett’s oesophagus was thought to be a rare congenital abnormality. It is now believed that years of chronic inflammation can erode the normal squamous epithelium in the oesophagus and lead to its replacement with a columnar epithelium that histologically has features similar to the small intestine. The term “specialised Barrett’s epithelium” is often used to describe this incomplete intestinal metaplasia. The epithelium has as its hallmark goblet cells, which are found in small intestinal mucosa. However, the specialised mucosa does not have the absorptive potential of actual intestinal mucosa, so it is often termed incomplete intestinal metaplasia.

The Barrett’s epithelium can easily be seen using endoscopy to visualise the lower oesophagus. The normally whitish shiny appearing squamous epithelium is replaced by a reddish velvety Barrett’s mucosa. However, the endoscopic appearance must be confirmed by biopsies that demonstrate specialised Barrett’s epithelium to truly establish the diagnosis.

There has been some controversy over the importance of the length of Barrett’s oesophagus present. The original definition of Barrett’s oesophagus required that the Barrett’s mucosa involved at least 3cm of the distal oesophagus. This definition has persisted, with the term “short-segment Barrett’s oesophagus” referring to Barrett’s oesophagus of less than 3cm in length.(1) However, studies have shown that even short-segment Barrett’s oesophagus has malignant potential, although probably less so than long-segment (>3cm) Barrett’s oesophagus.(2) A recent definition of Barrett’s oesophagus also encompasses Barrett’s mucosa that is not visible to the endoscope but is present on biopsies of a normal appearing squamocolumnar junction. This term is microscopic Barrett’s oesophagus or columnar metaplasia of the squamocolumnar junction.

The difficulty with these definitions is their inability to predict outcomes based on their occurrence. It certainly appears that short-segment Barrett’s oesophagus is more common than long-segment Barrett’s oesophagus. It also has been found that short-segment Barrett’s oesophagus can develop cancer. However, the incidence and prevalence of these cancers has not been defined in large populations, only in smaller series. Controversially, it was recently found that the prevalence of Barrett’s oesophagus in a population without any heartburn symptoms is 25%.(3)

Cancer risk
At the current time, clinical assessment of cancer risk is determined by the degree of dysplasia found on random biopsies of the oesophagus. Dysplasia is a histological finding and is not evident on endoscopy – only when biopsies are examined microscopically can dysplasia be ascertained. There have been some difficulties in standardising the definition of dysplasia. Pathologists do not commonly agree when it is present, although expert pathologists can agree when a standard definition is applied.(4) It is advisable that patients with Barrett’s oesophagus undergo surveillance biopsies, which are taken in four quadrants for every 2cm of the oesophagus involved. If low-grade dysplasia is found, repeat biopsies are warranted to confirm the diagnosis within six months.(5) If persistent low-grade dysplasia is found on biopsies, the patient should be followed on a yearly basis. The incidence of cancer in patients with established low-grade dysplasia is about 4–10%. If no dysplasia is found, the risk of cancer is small, approximately 1 per 250 patient-years of follow-up, and surveillance is usually performed after three years. If high-grade dysplasia is found, intensive surveillance endoscopy is indicated, with biopsies taken from every centimetre of involved oesophagus to exclude the possibility of cancer, which has been found to exist in Barrett’s with high-grade dysplasia in roughly 45% of patients.(6) If no cancer is found, these patients are monitored on a quarterly basis (every three months) or can have their oesophagus removed surgically.

Molecular markers have been investigated to determine which patients will develop cancers.(7) Markers that appear to be of some benefit include p53 status and presence of aneuploidy.(8,9) These are usually associated with the development of cancer. Pathways involved in the development of oesophageal adenocarcinoma include defects in regulation of the cell cycle as well as cell signalling abnormalities. Markers that have gained interest include increased telomerase activity, the mitogen-activated protein kinases, protein kinase C and cyclo-oxygenase II (cox 2).

Treatment for Barrett’s oesophagus

Low-risk Barrett’s oesophagus
Patients that are at low risk for development of cancer, such as those with nondysplastic Barrett’s oesophagus or low-grade dysplasia, are usually simply observed with periodic surveillance. There is no standard treatment for Barrett’s oesophagus in these patients since the benefit of cancer risk reduction is not very high given the low incidence of disease. It is advocated that these patients have their reflux disease treated aggressively with proton pump inhibitors. It has been demonstrated that patients with Barrett’s oesophagus have increased reflux compared with those with simple heartburn and often require larger dosages of medications to maintain acid suppression. Patients with Barrett’s oesophagus also have more nocturnal reflux and may require dosages of medications in the evening as well as in the morning to maintain control of reflux. Chemoprevention in this population has been postulated to be of benefit, although the evidence for this has primarily been based on epidemiological studies that have shown a benefit for oesophageal cancer risk reduction with aspirin.(10)

High-risk Barrett’s oesophagus
Patients with high-grade dysplasia have a significant chance (>25%) of developing cancer within two years of diagnosis. Oesophagectomy or removal of the oesophagus was the traditional treatment approach for these patients. Since a large number may already have occult cancer at the time of diagnosis, surgical treatment seemed reasonable. Recent studies examining the role of careful surveillance biopsies in the management of these patients have shown that the risk of cancer is highest in the first year following initial diagnosis. The majority do not appear to develop cancer, and a significant number of patients (25–30%) actually seem to lose their high-grade dysplasia. In addition, in patients who have lesser amounts of dysplasia (focal high-grade dysplasia), the incidence of cancer has been found to be less than those with more diffuse high-grade dysplasia.(11) These findings have led to some changes in the management of patients with high-grade dysplasia.(12) Patients with focal high-grade dysplasia can be offered the possibility of continued surveillance or treatment with endoscopic therapies such as photodynamic therapy. Photodynamic therapy has recently been approved in the USA for the treatment of Barrett’s oesophagus with high-grade dysplasia. A photosensitising drug (Photofrin II; Axcan Pharma) is intravenously administered at a dosage of 2mg/kg followed by photoradiation of the involved Barrett’s oesophagus segment 48 hours afterwards. This treatment has been shown to significantly decrease cancer risk by about 40% for at least 24 months following therapy. The primary drawbacks to photodynamic therapy are the cutaneous photosensitivity that can persist for 30–90 days after drug administration, the formation of oesophageal strictures in over a third of treated patients, and the possibility of not completely treating the Barrett’s oesophagus. In patients who are good surgical candidates and have a very strong suspicion of harbouring cancer, oesophagectomy is still the preferred approach. Observation can be done but must be performed by a vigilant endoscopist with a compliant patient who is willing to undergo multiple endoscopies. Other therapies that are under investigation have been the use of cautery devices to destroy the Barrett’s mucosa. These devices include the argon plasma coagulator, which was developed to treat bleeding lesions in the mucosa. This cautery device generally has been reported to have good initial success but requires multiple therapies and can leave behind areas of Barrett’s mucosa. Mucosal resection techniques that can remove large area of mucosa have been applied to Barrett’s oesophagus.(13) These have roles in the evaluation of Barrett’s oesophagus, but their role in definitive therapy has yet to be determined.

The most recent therapy that has been advocated for the treatment of Barrett’s oesophagus has been cox-2 inhibitors. Cox 2 has been shown to be expressed more in
Barrett’s oesophagus and in Barrett’s oesophagus- associated adenocarcinoma.(14) Epidemiological studies have found that aspirin users have a significantly reduced incidence of oesophageal cancer. Animal studies have found that cox-2 inhibitors have reduced the incidence of cancer in a rat model of Barrett’s oesophagus.(15) However, prospective clinical data are lacking, and the use of cox-2 inhibitors has been investigational.

Future avenues of treatment of Barrett’s oesophagus are the development of new chemopreventive medications and development of devices that can remove the Barrett’s mucosa in a comprehensive manner. It will also be necessary to develop molecular markers that determine which patients are at the greatest risk of developing adenocarcinoma, especially since it appears that most will not develop cancer.

References

1. Spechler SJ. Short and ultrashort Barrett’s esophagus – what does it mean? Semin Gastrointest Dis 1997;8:59-67.
2. Sharma P, Weston AP, Morales T, et al. Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia. Gut 2000;46:9-13.
3. Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett’s esophagus in asymptomatic individuals [comment]. Gastroenterology 2002;123:461-7.
4. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol 2001;32:368-78.
5. Sampliner RE. Diagnosing and managing Barrett’s esophagus. Am J Managed Care 2000;6:S886-90.
6. Pellegrini CA, Pohl D. High-grade dysplasia in Barrett’s esophagus: surveillance or operation? J Gastrointest Surg 2000;4:131-4.
7. Krishnadath KK, Reid BJ, Wang KK. Biomarkers in Barrett esophagus. Mayo Clin Proc 2001;76:438-46.
8. Reid BJ, Prevo LJ, Galipeau PC, et al. Predictors of progression in Barrett’s esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am J Gastroenterol 2001;96:2839-48.
9. Rabinovitch PS, Longton G, Blount PL, et al. Predictors of progression in Barrett’s esophagus III: baseline flow cytometric variables. Am J Gastroenterol 2001;96:3071-83.
10. Morgan G, Vainio H. Barrett’s oesophagus, oesophageal cancer and colon cancer: an explanation of the association and cancer chemopreventive potential of nonsteroidal anit-inflammatory drugs. Eur J Cancer Prev 1998;7:195-9.
11. Buttar NS, Wang KK, Sebo TJ, et al. Extent of high-grade dysplasia in Barrett’s esophagus correlates with risk of adenocarcinoma. Comment. Gastroenterology 2001;120:1630-9.
12. Pacifico RJ, Deschamps C, Wang KK. Management of Barrett’s esophagus with high-grade dysplasia. Surg Clin North Am 2002;82:683-95.
13. Nijhawan PK, Wang KK. Endoscopic mucosal resection for lesions with endoscopic features suggestive of malignancy and high-grade dysplasia within Barrett’s esophagus. Gastrointest Endosc 2000;52:328-32.
14. Morris CD, Armstrong GR,Bigley G, et al. Cyclooxygenase-2 expression in the Barrett’s metaplasia-dyplasia-adenocarcinoma sequence. Am J Gastroenterol 2001;96:990-6.
15. Buttar NS, Wang KK, Anderson MA, et al. The effect of selective cyclooxygenase-2 inhibition in Barrett’s esophagus epithelium: an in vitro study [comment]. J Natl Cancer Inst 2002;94:422-9.

Websites
National Institutes of Health
Definition and description of Barrett’s oesophagus
W:http://digestive.niddk.nih.gov/ddiseases/pubs/barretts
Barrettsinfo.com Comprehensive updated site on Barrett’s oesophagus
W:http://www.barrettsinfo.com/content/1_what_is_barretts.htm