Barrett’s esophagus is a well-known risk factor for the development of esophageal adenocarcinoma. Current practice guidelines recommend endoscopic surveillance of patients with Barrett’s esophagus in an attempt to detect cancer at an early and potentially curable stage. This review addresses the rationale behind surveillance and criteria for inclusion of patients in surveillance programs as well as the appropriate technique and intervals that should be used. This work addresses other key topics in Barrett’s esophagus surveillance, including the efficacy of surveillance programs, physician compliance with surveillance guidelines, cost-effectiveness of surveillance programs, and areas for future research.
The clinical problem of esophageal adenocarcinoma
Barrett’s esophagus is a recognized risk factor for the development of esophageal adenocarcinoma. The incidence of this cancer has increased approximately 6-fold between 1975 and 2001, a rate greater than that of any other cancer in the United States during that time. This increase has been accompanied by an increase in mortality rates from 2 to 15 deaths per million during that same time period. Despite these alarming findings, the overall burden of esophageal adenocarcinoma remains low. It is estimated that there will be 16,640 new cases of esophageal cancer in the United States (of which more than half will be adenocarcinoma) accompanied by approximately 14,500 deaths in 2010. Survival in esophageal adenocarcinoma is inversely related to the depth of invasion as well as lymph node metastases. Patients with T1-stage disease have a survival rate of greater than 90% at 5 years, but this group represents less than 10% of patients undergoing esophagectomy in the United States. Therefore, detection of adenocarcinoma at earlier stages has the potential to dramatically improve survival in these patients.
The association of Barrett’s esophagus with the development of adenocarcinoma, the often years-long stepwise progression of columnar metaplasia to adenocarcinoma, and the poor prognosis of advanced adenocarcinoma all make endoscopic surveillance an attractive option for Barrett’s esophagus patients. As such, regular endoscopic surveillance is recommended by all of the major American professional societies as well as other international gastroenterology organizations in an attempt to detect cancer at an early and potentially curable stage.
Who should undergo surveillance?
Only patients with a clear diagnosis of Barrett’s esophagus are candidates for surveillance. The diagnosis of Barrett’s esophagus is established if the squamocolumnar junction is displaced proximal to the gastroesophageal junction and intestinal metaplasia is detected by biopsy, although the need for intestinal metaplasia for the diagnosis has recently been questioned. Recent evidence suggests that nongoblet columnar metaplasia demonstrates DNA content abnormalities indicative of neoplastic risk similar to those encountered in intestinal metaplasia, and the risk of developing esophageal adenocarcinoma is similar among patients with and without intestinal metaplasia. The professional societies of North America all require intestinal metaplasia for the diagnosis of Barret esophagus whereas the British Society of Gastroenterology and a global consensus group do not require the presence of intestinal metaplasia for the diagnosis. Currently, the issue of intestinal metaplasia versus columnar metaplasia as a diagnostic criterion for Barrett’s esophagus remains unsettled.
Before entering into a surveillance program, patients should be advised about risks and benefits, including the limitations of surveillance endoscopy as well as the importance of adhering to appropriate surveillance intervals. Other considerations include age less than 80 years, likelihood of survival over the next 5 years, and ability to tolerate either endoscopic or surgical interventions for early esophageal adenocarcinoma. Patients without documented Barrett’s esophagus or in poor overall health will likely not benefit from endoscopic surveillance programs. Recent advances in endoscopic therapy with techniques, such as radiofrequency ablation and endoscopic mucosal resection, have the potential to change the inclusion criteria for Barrett’s esophagus surveillance in the future. This may ultimately lead to application of surveillance programs to a wider population.
The number of individuals with Barrett’s esophagus is sizable. It is estimated that Barrett’s esophagus is found in approximately 5% to 15% of patients undergoing endoscopy for symptoms of gastroesophageal reflux disease. Population-based studies suggest that the prevalence of Barrett’s esophagus is approximately 1.3% to 1.6%. A recent simulation model using the Surveillance, Epidemiology and End Result cancer registry estimated that the prevalence of Barrett’s esophagus was 5.6% in the general population of the United States. Using these data, the number of eligible patients for surveillance in the United States could range from 4 to 20 million individuals. The economic consequences of surveillance for this large a population are considerable, emphasizing the importance of developing more effective and selective surveillance programs than are currently in use.
Who should undergo surveillance?
Only patients with a clear diagnosis of Barrett’s esophagus are candidates for surveillance. The diagnosis of Barrett’s esophagus is established if the squamocolumnar junction is displaced proximal to the gastroesophageal junction and intestinal metaplasia is detected by biopsy, although the need for intestinal metaplasia for the diagnosis has recently been questioned. Recent evidence suggests that nongoblet columnar metaplasia demonstrates DNA content abnormalities indicative of neoplastic risk similar to those encountered in intestinal metaplasia, and the risk of developing esophageal adenocarcinoma is similar among patients with and without intestinal metaplasia. The professional societies of North America all require intestinal metaplasia for the diagnosis of Barret esophagus whereas the British Society of Gastroenterology and a global consensus group do not require the presence of intestinal metaplasia for the diagnosis. Currently, the issue of intestinal metaplasia versus columnar metaplasia as a diagnostic criterion for Barrett’s esophagus remains unsettled.
Before entering into a surveillance program, patients should be advised about risks and benefits, including the limitations of surveillance endoscopy as well as the importance of adhering to appropriate surveillance intervals. Other considerations include age less than 80 years, likelihood of survival over the next 5 years, and ability to tolerate either endoscopic or surgical interventions for early esophageal adenocarcinoma. Patients without documented Barrett’s esophagus or in poor overall health will likely not benefit from endoscopic surveillance programs. Recent advances in endoscopic therapy with techniques, such as radiofrequency ablation and endoscopic mucosal resection, have the potential to change the inclusion criteria for Barrett’s esophagus surveillance in the future. This may ultimately lead to application of surveillance programs to a wider population.
The number of individuals with Barrett’s esophagus is sizable. It is estimated that Barrett’s esophagus is found in approximately 5% to 15% of patients undergoing endoscopy for symptoms of gastroesophageal reflux disease. Population-based studies suggest that the prevalence of Barrett’s esophagus is approximately 1.3% to 1.6%. A recent simulation model using the Surveillance, Epidemiology and End Result cancer registry estimated that the prevalence of Barrett’s esophagus was 5.6% in the general population of the United States. Using these data, the number of eligible patients for surveillance in the United States could range from 4 to 20 million individuals. The economic consequences of surveillance for this large a population are considerable, emphasizing the importance of developing more effective and selective surveillance programs than are currently in use.
How should surveillance be done?
The aim of surveillance is the detection of dysplasia or early cancer. Active inflammation makes it more difficult to distinguish dysplasia from reparative changes. As such, it is essential that surveillance endoscopy is only performed after any active inflammation related to gastroesophageal reflux disease is controlled with antisecretory therapy. The presence of ongoing erosive esophagitis is a contraindication to performing surveillance biopsies.
At the time of endoscopy, the esophagus should first be carefully examined with high-resolution white light endoscopy, with definition of appropriate landmarks, including the diaphragmatic hiatus, esophagogastric junction, and squamocolumnar junction before commencing biopsies. It is still unclear how much enhanced imaging techniques add to careful inspection with high-resolution or high-definition white light endoscopy. Because the distribution of dysplastic mucosa and cancer is patchy in Barrett’s esophagus, current guidelines suggest obtaining systematic four-quadrant biopsies at 2-cm intervals along the entire length of the Barrett segment commencing at the proximal margin of the gastric folds and continuing to the transition zone at the squamocolumnar junction. The rationale for such a comprehensive biopsy program comes from the focal nature of dysplasia and the observation that high-grade dysplasia and early carcinoma in Barrett’s esophagus often occur in the absence of endoscopic abnormalities.
A systematic biopsy protocol detects more dysplasia and early cancer compared with ad hoc random biopsies. Furthermore, the safety of systematic endoscopic biopsy protocols has been well demonstrated. Subtle mucosal abnormalities, no matter how trivial, such as ulceration, erosion, plaque, nodule, stricture, or other luminal irregularity in the Barrett segment, should also be extensively biopsied, because there is an association of such lesions with underlying cancer. Current guidelines recommend that mucosal abnormalities, especially in the setting of high-grade dysplasia, should undergo endoscopic mucosal resection. Endoscopic mucosal resection changes the diagnosis in approximately 50% of patients compared with endoscopic biopsies, given the larger tissue sample available for review by a pathologist. Interobserver agreement among pathologists is improved as well.
There has been considerable debate over the years regarding the need for large particle (jumbo) forceps to obtain biopsies, a technique that requires passage of a therapeutic larger-caliber endoscope. Current guidelines suggest, however, that best available evidence does not support the routine use of the jumbo biopsy forceps. New large-capacity forceps that can be passed through the biopsy channel of standard-diameter endoscopes provides larger samples than standard large-capacity forceps and may increase the yield of dysplasia, thus providing a reasonable alternative approach. The increasing importance of appropriately applied endoscopic mucosal resection, however, has changed biopsy sampling considerably and makes much of this debate of historical interest only.
There is some evidence that a smaller biopsy interval of 1 cm in addition to biopsies of visible lesions is more effective at detection of adenocarcinoma in patients with high-grade dysplasia, a method known as the Seattle protocol. Although this protocol was considered ideal for patients with high-grade dysplasia, a recent comparison of the Seattle protocol with standard four-quadrant biopsies every 2 cm in a group of patients with high-grade dysplasia found that the detection of unsuspected cancer at the time of esophagectomy was no different between the two groups. This intensive biopsy protocol has yet to be adopted into official surveillance guidelines. Furthermore, the widespread use of endoscopic mucosal resection in patients with high-grade dysplasia or early adenocarcinoma has changed the paradigm for these patients considerably.
Another available surveillance method is brush cytology. Brush cytology is simpler and less expensive than endoscopic biopsy protocols and has the ability to sample more of the mucosal surface. One study found a 72% concordance rate between brush cytology specimens and simultaneous biopsies with cytology often demonstrating higher grades of dysplasia. More recent work from the Cleveland Clinic demonstrated 95% specificity for brush cytology with 82% sensitivity for the detection of high-grade dysplasia or adenocarcinoma, but the sensitivity for low-grade dysplasia was only 31%. Currently, cytology is not recommended as an appropriate surveillance technique. Cytology does have considerable potential as a platform for molecular biomarker techniques, however, such as fluorescence in situ hybridization, should they become validated.
Once biopsy specimens are obtained, the samples are classified with a standard five-tier system as (1) negative for dysplasia, (2) indefinite for dysplasia, (3) low-grade dysplasia, (4) high-grade dysplasia, or (5) carcinoma. Any diagnosis of dysplasia should be confirmed by an expert gastrointestinal pathologist. One report found that when low-grade dysplasia was a consensus diagnosis between two expert pathologists, there was a subsequent increased risk of further neoplastic transformation. Furthermore, confirmation by expert pathologists often leads to downgrading of biopsies graded as low-grade dysplasia or high-grade dysplasia by general pathologists. In one study, 64 of 71 (90%) samples of low-grade dysplasia were downgraded as were 11 of 23 (48%) samples of high-grade dysplasia. Reasons for downgrading biopsies include ulceration, ongoing inflammation, and tangential sectioning of specimens.
How often should surveillance be performed?
Surveillance intervals, determined by the presence and grade of dysplasia, are based on the limited understanding of the biology of esophageal adenocarcinoma. These intervals, however, are arbitrary, have never been subject to a clinical trial, and likely never will be. Guidelines from the various professional societies are not in agreement on surveillance intervals. Surveillance every 3 years is recommended as adequate in patients without dysplasia after two negative examinations by both the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy ( Table 1 ). The American Gastroenterological Association recommends extending the surveillance interval up to 5 years whereas the British Society of Gastroenterology recommends continued surveillance at 2-year intervals in this setting. Alternatively, the French Society of Digestive Endoscopy recommends intervals in patients without dysplasia based on the Barrett segment length (see Table 1 ). A recent meta-analysis, however, showed that the risk of cancer was no different between short- and long-segment Barrett’s esophagus.
| Organization | Surveillance Interval |
|---|---|
| American College of Gastroenterology | Two EGDs in first year If negative for dysplasia, then every 3 years |
| American Gastroenterological Association | Two EGDs in first year If negative for dysplasia, then every 5 years |
| American Society for Gastrointestinal Endoscopy | Two EGDs in first year If negative for dysplasia, then every 3 years |
| British Society of Gastroenterology | Every 2 years |
| French Society of Digestive Endoscopy | Short-segment Barrett’s esophagus (<3 cm)—every 5 years Long-segment Barrett’s esophagus (3–6 cm)—every 3 years Long-segment Barrett’s esophagus (>6 cm)—every 2 years |
If low-grade dysplasia is found, the diagnosis should first be confirmed by an expert gastrointestinal pathologist due to the marked interobserver variability in interpretation of these biopsies. These patients should also receive aggressive antisecretory therapy for reflux disease with a proton pump inhibitor to decrease the changes of regeneration that make pathologic interpretation of this category so difficult. Patients with confirmed low-grade dysplasia warrant shorter surveillance intervals and, therefore, more intensive monitoring. There is minor discord between the American organizations, with all three requiring at least one repeat endoscopy within 6 to 12 months after the initial diagnostic endoscopy ( Table 2 ). Subsequent recommendations for follow-up intervals also vary between the American organizations (outlined in Table 2 ). Both the British and French guidelines recommend a trial of aggressive acid suppression therapy for 1 to 2 months followed by repeat endoscopy (see Table 2 ). If low-grade dysplasia persists after intensive acid suppression therapy, then the European guidelines suggest that follow-up endoscopies be performed every 6 months until two consecutive endoscopies demonstrate no dysplasia. There is no agreement on the biopsy protocol to use, although a protocol of four-quadrant biopsies at 1-cm intervals as used for high-grade dysplasia makes sense to the authors. Endoscopic mucosal resection should be performed if any mucosal abnormality is present in these patients.
| Organization | Surveillance Interval |
|---|---|
| American College of Gastroenterology | Repeat EGD in 6 months Then yearly EGD until no dysplasia for 2 years |
| American Gastroenterological Association | Repeat EGD within 1 year If LGD confirmed by two expert pathologists, then yearly EGD Otherwise, if disagreement, then every 2 years |
| American Society for Gastrointestinal Endoscopy | Repeat EGD in 6 months Additional EGD in 6 months, then yearly |
| British Society of Gastroenterology | Acid suppression for 8–12 weeks, then repeat EGD If LGD persists, EGDs every 6 months After two EGDs with no dysplasia, increase to every 2–3 years |
| French Society of Digestive Endoscopy | Double-dose PPI for 2 months, then repeat EGD If LGD persists, EGD at 6 months, 1 year and then yearly |
If high-grade dysplasia is found, the diagnosis should be confirmed by an experienced gastrointestinal pathologist. High-grade dysplasia is considered a threshold for intervention by both the American College of Gastroenterology and the French Society of Digestive Endoscopy after confirmation by repeat endoscopy within 2 to 3 months ( Table 3 ). A strategy of continued endoscopic surveillance in these patients may well be eclipsed by endoscopic intervention, and current guidelines may be out of date given the rapid evolution of endoscopic approaches. If continued surveillance is chosen, one proposed option is surveillance at 3-month intervals for 1 year. If there is no high-grade dysplasia on two consecutive endoscopies for the first year, endoscopy frequency is lengthened to every 6 months for the second year then to annually thereafter as long as high-grade dysplasia is not encountered again. If high-grade dysplasia persists, then continued short-interval endoscopy is warranted.
| Organization | Surveillance Interval |
|---|---|
| American College of Gastroenterology | Repeat EGD in 3 months If HGD present, needs additional intervention |
| American Gastroenterological Association | Repeat EGD every 3 months 8 biopsies every 2 cm |
| American Society for Gastrointestinal Endoscopy | Repeat EGD every 3 months After 1 year, if two EGDs with no dysplasia, can lengthen interval |
| British Society of Gastroenterology | EGDs every 6 months if no additional interventions |
| French Society of Digestive Endoscopy | Double-dose PPI for 1–2 months, then repeat EGD If HGD persists, needs additional intervention |
Extent of high-grade dysplasia is thought by some investigators to be a risk factor for the subsequent development of adenocarcinoma. There are currently no uniform criteria for defining the extent of high-grade dysplasia and there are conflicting data on the clinical significance of extent of high-grade dysplasia in biopsy specimens and risk for unsuspected carcinoma. Mucosal abnormalities in patients with multifocal high-grade dysplasia may also be a risk factor for adenocarcinoma.
Does surveillance endoscopy work?
Several observational studies suggest that patients with Barrett’s esophagus in whom adenocarcinoma was detected in a surveillance program have their cancers detected at an earlier stage ( Fig. 1 ), with markedly improved 5-year survival compared with similar patients not undergoing routine endoscopic surveillance ( Fig. 2 ). Furthermore, nodal involvement is far less likely in surveyed patients compared with nonsurveyed patients. Because esophageal cancer survival is stage dependent, these studies suggest that survival may be enhanced by endoscopic surveillance. Several decision-analysis models support the concept of endoscopic surveillance. The model of Provenzale and colleagues suggests that surveillance every 5 years is the most effective strategy to increase both length and quality of life, whereas the model of Inadomi and colleagues suggests that surveillance should be limited only to individuals with dysplasia at the time of initial endoscopy. Because most patients with Barrett’s esophagus do not die from esophageal cancer, however, the entire concept of surveillance remains of uncertain benefit. Design flaws, such as selection bias, healthy volunteer bias, lead time bias, and length time bias, are inherent in the observational studies that support endoscopic surveillance. Despite the concern regarding the esophageal cancer “epidemic,” the overall burden of disease is limited in the Western world in comparison with other malignancies, such as colon cancer.
Related posts:
Barrett’s Esophagus: Clinical Issues
Biology of Barrett’s Esophagus and Esophageal Adenocarcinoma
Endoscopic Evaluation and Advanced Imaging of Barrett’s Esophagus
The Role of Radiofrequency Ablation in the Management of Barrett’s Esophagus
Endotherapy for Barrett’s Esophagus: Which, How, When, and Who?
Role of Minimally Invasive Surgery in the Modern Treatment of Barrett’s Esophagus
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