[Postgraduate Medicine]
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[SYMPOSIUM]

Another look at Barrett's esophagus

Current thinking on screening and surveillance strategies

Deepak V. Gopal, MD, FRCP(C)

VOL 110 / NO 3 / SEPTEMBER 2001 / POSTGRADUATE MEDICINE

CME learning objectives

  • To become familiar with risk factors and symptoms associated with Barrett's esophagus
  • To learn the indications and recommendations for endoscopic screening and surveillance in patients with Barrett's esophagus
  • To understand the benefits and limitations of various therapeutic options for management of Barrett's esophagus

The authors disclose no financial interest in this article.

This is the second of four articles on acid peptic disease.

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Preview: When British surgeon Norman Barrett first identified the metaplastic columnar epithelium of the esophagus that bears his name, the condition was considered an oddity that was probably of little significance. Now, half a century later, Barrett's esophagus is recognized as the most serious complication of gastroesophageal reflux disease (GERD) and a precursor of esophageal adenocarcinoma. Primary care physicians often face concerns about how to manage patients with long-standing GERD who could be at risk for cancer. In this article, Dr Gopal reviews the incidence of Barrett's esophagus, current screening recommendations, surveillance guidelines, prevention strategies, and management options for patients found to have the condition.
Gopal DV. Another look at Barrett's esophagus: current thinking on screening and surveillance strategies. Postgrad Med 2001:110(3):57-68

Barrett's esophagus is a complication that develops in a minority of patients who have chronic GERD. The disorder can be identified endoscopically (figure 1: not shown) and is well established as predisposing to esophageal adenocarcinoma. Diagnosis is confirmed by biopsy of the esophageal lesion that shows intestinal metaplasia (1).

Development of adenocarcinoma of the esophagus is a multistep process that starts with intestinal metaplasia in which columnar epithelium with goblet cells replaces normal squamous epithelium. This can be followed first by low-grade dysplasia, then by high-grade dysplasia, and finally by adenocarcinoma (2).

Periodic endoscopic surveillance of Barrett's epithelium is recommended to identify patients at risk for adenocarcinoma (3). However, while our understanding of Barrett's esophagus has improved considerably, many issues relating to screening and surveillance remain controversial (3,4). No randomized prospective trials have been undertaken to evaluate whether or not endoscopic surveillance leads to improvement in survival rates.

Epidemiology

Barrett's esophagus is predominantly a disease of white males, with prevalence increasing until it plateaus between the seventh and eighth decades of life (5). The mean age of development of Barrett's esophagus is estimated to be 40 years, yet the mean age at diagnosis is 63 years. This suggests that a premalignant disorder may be present for up to 20 years before it is clinically recognized.

Barrett's esophagus is found in about 12% of patients undergoing endoscopy for symptoms of GERD. A Mayo Clinic study of autopsy data from Olmsted County, Minnesota, suggests that the majority of cases of Barrett's esophagus in the general population are never detected (5). Other studies indicate that in patients undergoing upper endoscopy for a variety of indications, the prevalence of Barrett's esophagus is between 0.41% and 0.89% (3-6).

GERD affects about 20% of the adult population in the United States. The typical symptoms are heartburn and regurgitation, but some patients have atypical supraesophageal symptoms, including persistent cough, hoarseness, substernal chest pain with negative cardiac workup, and asthmalike illness (5). Thus, when atypical symptoms are included, the true incidence of GERD is likely to be higher than 20%.

Although between 10% and 15% of GERD patients have Barrett's esophagus, neither the frequency nor the severity of symptoms correlates with the presence of Barrett's epithelium (5). Age, male sex, white race, and obesity have been implicated in some studies (5,7). However, the only clinical factor identified to date that indicates a propensity to Barrett's esophagus is chronicity of symptoms. Patients who have had GERD symptoms for 5 years or longer have a markedly increased incidence of Barrett's esophagus and esophageal adenocarcinoma.

When to use endoscopy

The aim of endoscopic screening and surveillance is to both identify Barrett's esophagus and detect early neoplastic changes, defined as dysplasia. The goal of such monitoring is to improve early recognition of invasive esophageal cancer, presumably at a curable stage (1,5,8).

Before endoscopic and biopsy screening is undertaken in a patient with GERD, symptoms should be treated and the patient should be in symptomatic remission (8). The three main reasons for this approach are as follows:

  • Endoscopic examination is a screening tool for detection of Barrett's esophagus and not GERD.
  • One third to one half of patients who have untreated symptoms of GERD have erosive esophagitis, which makes diagnosis of underlying Barrett's epithelium challenging. Often these patients need to be treated with high-dose proton pump inhibitor therapy for 8 weeks, followed by repeat endoscopy.
  • If Barrett's esophagus is suspected in patients who have active esophagitis, biopsies may be inaccurate because of uncertainty about whether the cause of reactive cellular changes is inflammation or true dysplasia (1,8).

Surveillance techniques

Once inflammation related to GERD is controlled and endoscopic diagnosis of Barrett's esophagus is established, current guidelines recommend obtaining four-quadrant jumbo biopsies at 2-cm intervals (3). The rationale for comprehensive surveillance stems from observations that dysplasia may be focal and that high-grade dysplasia and early carcinoma in Barrett's esophagus can occur in the absence of endoscopic abnormalities.

Dysplasia is a pathologic diagnosis and is graded as negative, indefinite, positive for low-grade or high-grade changes, or characteristic of intramucosal carcinoma (2). If a biopsy specimen is labeled negative for dysplasia, the glandular architecture is intact and shows a normal cellular nuclear-to-cytoplasmic ratio. Biopsy samples labeled indefinite for dysplasia include those in which the architecture is moderately distorted but nuclear abnormalities are less marked than with dysplasia. Features such as nuclear stratification, diminished mucus production, or increased cytoplasmic basophilia may be present. The indefinite category is reserved for cases in which changes are too marked to be classified as negative but insufficient for diagnosis of dysplasia (2).

The histologic diagnosis of low- or high-grade dysplasia is based on the severity of architectural distortion and cytologic criteria that reflect neoplastic transformation of the columnar epithelium. Abnormalities include branched, crowded, and irregularly shaped glands with marked variation in nuclear features, increased nuclear-to-cytoplasmic ratio, increased mitoses, and hyperchromatism (2).

Intramucosal adenocarcinoma is defined histologically as carcinoma that has moved through the basement membrane into the lamina propria mucosae but has not invaded the submucosa (2). Generally, biopsies--even jumbo biopsies--are not deep enough to rule out submucosal invasion, and further staging, usually with endoscopic ultrasound, is required.

The direct costs of surveillance can be substantial (9). Moreover, the appropriate interval of surveillance is still controversial. Generally, surveillance every 2 to 3 years is considered adequate for patients who have no evidence of dysplasia (3). When low-grade dysplasia is present, the interval is shortened to every 6 months for 1 year, followed by annual surveillance. If high-grade dysplasia is detected on biopsy, the findings should be confirmed by an expert histopathologist. When the confirmation is consistent with high-grade dysplasia, surveillance every 3 months is appropriate if esophageal resection is declined by the patient or is not performed because of other medical considerations (table 1).

Table 1. Guidelines for endoscopic surveillance of Barrett's esophagus (1998)
Dysplasia Endoscopic surveillance interval
None Every 2-3 yr after two negative endoscopic examinations
Low grade Every 6 mo for 1 yr, then every yr
High grade Confirmation by expert histopathologist. If high-grade dysplasia is found, options are:
  • Esophageal resection
  • Continued surveillance every 3 mo

Adapted from Sampliner (3).

Recently Provenzale and associates (9) reported on a cost-utility analysis model with estimated cancer incidence risks ranging from 1 in 251 to 1 in 208 patient-years. This study included a combined series of patients with long- and short-segment Barrett's esophagus. Findings suggested that surveillance every 5 years was the most viable strategy, with a cost-utility ratio of $98,000 per quality-adjusted year of life gained. However, the current practice of most physicians is to perform endoscopic surveillance every 2 to 3 years in patients with Barrett's esophagus, with increased frequency if dysplasia is detected. It remains unclear whether or not this is the ideal surveillance strategy, and there is a lack of agreement as to which clinical factors should be used to determine who should be screened (4).

Estimates of the annual cancer incidence in patients with Barrett's esophagus have ranged from 0.2% to 2.0% (4,9). Data from several prospective studies on development of cancer in Barrett's esophagus (4,8,9) show that the mean annual incidence of esophageal cancer associated with this condition may be as high as 1%. Evidence supporting surveillance suggests that the four-quadrant jumbo biopsy technique does, in fact, detect cancer at earlier stages and results in improved survival rates. With surveillance, improved quality-adjusted life expectancy occurs in patients in whom the risk of cancer exceeds 0.2%. However, despite the fact that patients with Barrett's esophagus are at least 30 times more likely to have esophageal cancer than persons in the general population, this form of cancer continues to be a rare cause of death.

Risk stratification

At this time, no adequate clinical or biologic markers identify which patients with Barrett's esophagus are at increased risk for development of adenocarcinoma. Smoking, alcohol consumption, increased length of Barrett's esophagus, and possibly age may be risk factors, but data remain unclear.

In a retrospective study of patients with Barrett's esophagus (7), my coinvestigators and I looked at age and length of Barrett's epithelium in development of dysplasia and adenocarcinoma. The prevalence of Barrett's esophagus increased with age and reached a plateau by the seventh decade, so it may be intuitive that this expectation should also apply to the development of dysplasia.

In our patients with Barrett's esophagus, there was a steady increase in the prevalence of dysplasia with age; half of the maximum prevalence was reached during the sixth decade. Statistical multivariate analysis showed a 3.3% increase in the risk of dysplasia each year after age 40. The issue of how the length of Barrett's esophagus relates to development of dysplasia raises interesting questions. At present, the implications of short-segment Barrett's esophagus are largely unknown.

Traditionally, short-segment Barrett's esophagus measures less than 3 cm and long-segment involvement is 3 cm or longer. We have found an increased prevalence of dysplasia in long-segment Barrett's esophagus, compared with short-segment involvement (figure 2: not shown) (7,10). Nonetheless, patients with short-segment Barrett's esophagus should still undergo endoscopy and biopsy surveillance for dysplasia (table 2).

Table 2. Proposed classification of intestinal metaplasia
Terminology Length of Barrett's epithelium Adenocarcinoma risk Surveillance
Long-segment Barrett's esophagus >3 cm Yes Yes
Short-segment Barrett's esophagus <3 cm Yes Yes
Intestinal metaplasia of cardia ? No

Adapted from Falk (4).

Recently the p53 tumor suppressor gene has been identified as a promising marker to predict the development of adenocarcinoma. Studies have reported p53-positive biopsy results in patients whose samples initially showed low- or indefinite-grade dysplasia but later progressed to high-grade dysplasia or adenocarcinoma (11). Similarly, patients whose biopsy samples were p53-negative did not develop high-grade dysplasia. Emerging molecular biologic techniques and flow cytometry studies may aid in predicting which Barrett's esophagus patients are at risk, thus allowing more focused endoscopic surveillance programs (11).

Treatment options

Proton pump inhibitors are now considered the cornerstone of therapy for symptomatic GERD. However, there is little data to support the theory that use of proton pump inhibitors, even in high doses, causes clinically significant regression of Barrett's epithelium (12). Moreover, it is less clear whether asymptomatic patients should be treated with proton pump inhibitors if Barrett's esophagus is diagnosed incidentally. Currently, there is a paucity of data to suggest that normalization of acid exposure decreases the risk of dysplasia and adenocarcinoma (12,13).

Antireflux surgery also alleviates the symptoms of GERD, but long-term follow-up studies have not demonstrated a significant regression of Barrett's esophagus after surgery. Certainly, complete regression is uncommon, and even "partial" regression, referring to a decrease in the length of the Barrett's esophagus segment, may be misleading (13-15). Other studies have suggested that antireflux surgery was associated with a reduced risk of dysplasia. However, this may have been due to sampling error and the transient nature of dysplasia, especially low-grade dysplasia (16).

Other experimental strategies for eliminating Barrett's esophagus, such as thermal ablation (17,18) and photodynamic therapy (19), are based on the principle that long-term regression may require reinjury of the metaplastic epithelium, followed by regeneration of normal squamous epithelium. Thermal ablation using multipolar electrocoagulation (17), argon plasma coagulation (18), and laser therapy ablation are all feasible in the sense that they are minimally invasive and cause less morbidity and mortality than surgery. Nevertheless, although these techniques may initially eliminate much or all of the Barrett's epithelium, it appears that residual intestinal metaplasia may remain under the new squamous epithelium. Moreover, the value of these procedures in patients who have low- or high-grade dysplasia is unclear.

Finally, there has been recent interest in the use of cyclooxygenase-2 (COX-2) inhibitors (ie, celecoxib [Celebrex] and rofecoxib [Vioxx]) to decrease or delay progression of Barrett's esophagus to high-grade dysplasia and adenocarcinoma. COX-2 drugs are potent inhibitors of epithelial apoptosis, a crucial step in tumorigenesis. They have received attention because they bring about regression of colorectal polyps, thus decreasing the risk of colon cancer. This cancer follows a dysplasia-to-carcinoma sequence similar to that seen with Barrett's esophagus (20).

Preliminary studies have suggested that use of aspirin or nonsteroidal anti-inflammatory drugs decreases the risk of esophageal adenocarcinoma (21). Other recent studies (20,22) showed that there is increased expression of COX-2 in intestinal metaplasia, dysplasia, and adenocarcinoma in patients with Barrett's esophagus. It is hypothesized that treatment with COX-2 antagonists could interfere with the metaplasia-dysplasia-carcinoma sequence by increasing apoptosis and causing regression of dysplasia (20,22). Future multicenter trials are needed to study this theory.

Summary

Barrett's esophagus remains a major health problem and a risk factor for the development of esophageal adenocarcinoma. Given the low incidence of this disorder, efforts should be made to identify risk factors that target patients with GERD or known Barrett's esophagus who would most benefit from screening and surveillance strategies. It is clear that identifying esophageal adenocarcinoma at an early and treatable stage reduces morbidity and mortality. However, currently available screening tools (endoscopy with surveillance biopsies every 2 years) are expensive and not easily applied.

Identification of tumor markers and other specific risk factors may be helpful in predicting who is at risk for dysplasia. Current therapeutic strategies are successful in the treatment of GERD symptoms, but further research and longer follow-up studies are needed to determine if these strategies bring about regression of Barrett's esophagus, reversal of dysplasia, or prevention of cancer.

References

  1. Falk GW. Endoscopic surveillance of Barrett's esophagus: risk stratification and cancer risk. Gastrointest Endosc 1999;49(3 Pt 2):S29-34
  2. Reid BJ, Weinstein WM, Lewin KJ, et al. Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions. Gastroenterology 1988;94(1):81-90
  3. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93:1028-32
  4. Falk G. Unresolved issues in Barrett's esophagus in the new millennium. Dig Dis 2000;18(1):27-42
  5. Cameron AJ, Lomboy CT. Barrett's esophagus: age, prevalence, and extent of columnar epithelium. Gastroenterology 1992;103(4):1241-5
  6. Falk GW, Chittajallu R, Goldblum JR, et al. Surveillance of patients with Barrett's esophagus for dysplasia and cancer with balloon cytology. Gastroenterology 1997;112(6):1787-97
  7. Gopal DV, Faigel DO, Magaret N, et al. Risk factors for dysplasia in patients with Barrett's esophagus (BE): results from a multicenter consortium. (Abstr) Gastroenterology 1999;116(4 Pt 2):A175
  8. Katz D, Rothstein R, Schned A, et al. The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett's esophagus. Am J Gastroenterol 1998;93(4):536-41
  9. Provenzale D, Schmitt C, Wong JB. Barrett's esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol 1999;94(8):2043-53
  10. Rudolph RE, Vaughan TL, Storer BE, et al. Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med 2000;132(8):612-20
  11. Younes M, Lebovitz RM, Lechago LV, et al. p53 protein accumulation in Barrett's metaplasia, dysplasia, and carcinoma: a follow-up study. Gastroenterology 1993;105(6):1637-42
  12. Sharma P, Sampliner RE, 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(4):582-5
  13. Haag S, Nandurkar S, Talley NJ. Regression of Barrett's esophagus: the role of acid suppression, surgery, and ablative methods. Gastrointest Endosc 1999;50(2):229-40
  14. Williamson WA, Ellis FH Jr, Gibb SP, et al. Effect of antireflux operation on Barrett's mucosa. Ann Thorac Surg 1990;49(4):537-42
  15. Low DE, Levine DS, Dail DH, et al. Histological and anatomic changes in Barrett's esophagus after antireflux surgery. Am J Gastroenterol 1999;94(1):80-5
  16. Brand DL, Ylvisaker JT, Gelfand M, et al. Regression of columnar esophageal (Barrett's) epithelium after anti-reflux surgery. N Engl J Med 1980;302(15):844-6
  17. Sampliner RE, Fennerty B, Garewal HS. Reversal of Barrett's esophagus with acid suppression and multipolar electrocoagulation: preliminary results. Gastrointest Endosc 1996;44(5):523-5
  18. Byrne JP, Armstrong GR, Attwood SE. Restoration of the normal squamous lining in Barrett's esophagus by argon beam plasma coagulation. Am J Gastroenterol 1998;93(10):1810-5
  19. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's esophagus: follow-up in 100 patients. Gastrointest Endosc 1999;49(1):1-7
  20. Morgan G, Vainio H. Barrett's oesophagus, oesophageal cancer and colon cancer: an explanation of the association and cancer chemopreventive potential of non-steroidal anti-inflammatory drugs. Eur J Cancer Prevent 1998;7(3):195-9
  21. Farrow DC, Vaughan TL, Hansten PD, et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 1998;7(2):97-102
  22. Wilson KT, Fu S, Ramanujam KS, et al. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res 1998;58(14):2929-34

Dr Gopal is assistant professor of medicine, division of gastroenterology, Oregon Health and Science University School of Medicine, Portland. Correspondence: Deepak V. Gopal, MD, FRCP(C), Division of Gastroenterology, Oregon Health and Science University School of Medicine, Mail Code PV-310, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098. E-mail: gopalde@ohsu.edu.

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