The Role o f E s o p h a g o g a s t ro d u o denoscopy Surveillance for P a t i e n t s wi t h B a r ret t E s o p h a g u s Kerri Palamara,
MD
KEYWORDS Barrett esophagus Surveillance Esophagogastroduodenoscopy GERD Esophageal adenocarcinoma KEY POINTS Barrett esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but malignant transformation of dysplastic epithelium is rare. Patients with BE should be managed with proton pump inhibitors (PPIs) to control symptoms. Elderly white men with chronic gastroesophageal reflux disease (GERD) are at highest risk of BE and progression to EAC. Patients with BE and evidence of dysplasia on endoscopy should undergo routine surveillance according to the major gastroenterological society guidelines.
INTRODUCTION
GERD affects 40% of the general population at some point in their lives, and up to 20% of US adults report symptoms on a weekly basis.1–3 Patients with GERD are at risk for barrett esophagus. BE is a metaplastic change in the lining of the esophageal mucosa from its normal squamous epithelium to specialized, columnar intestinal epithelium.2–5 BE affects 5% to 6% of the average population (approximately 3 million people diagnosed annually in the United States) and up to 25% of the elderly population.6,7 Although the overall risk for esophageal adenocarcinoma is low (26 cases per 1 million in general US population), its incidence is on the rise in Western populations, with a 300% increase since the 1970s.4,8 Most patients with EAC present symptomatically at a stage associated with few curative interventions available and a poor prognosis. The 5-year survival rate of EAC is less than 10% and this number has not been affected by current screening and surveillance efforts.2,8 BE is diagnosed and monitored through endoscopy, using visual and histologic criteria, and then characterized by length and severity. First, visualization of salmon-colored 55 Fruit Street, Gray 7-730, Boston, MA 02114, USA E-mail address: [emailprotected] Med Clin N Am 100 (2016) 1057–1064 http://dx.doi.org/10.1016/j.mcna.2016.04.014 medical.theclinics.com 0025-7125/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
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columnar epithelium in the normally white to light pink-colored tubular esophagus suggests proximal displacement of the squamocolumnar junction.2 Second, biopsy of the tubular esophagus confirms the presence of columnar intestinal epithelium, typically containing goblet cells. If the length of the displaced squamocolumnar junction is longer than 3 cm, it is considered long-segment BE (LSBE) and shorter than 3 cm is considered shortsegment BE (SSBE).4 EAC is thought to arise from BE through progressive dysplasia. This association raises concern for the need for screening and surveillance of patients with chronic GERD and BE to identify those at risk for progression to EAC. Although at first glance this seems logical, the utility, efficacy, and cost of such an approach must be considered. Patients with BE have a decreased quality of life compared with the general population due to inappropriately high level of fear for their risk of progression to cancer, unnecessary testing and visits, and increased life insurance premiums. In 1 study, patients diagnosed with BE experienced a 100% increase in life-insurance premiums compared with their age-matched and gender-matched controls, and some were unable to obtain insurance at all after diagnosis with BE.9,10 DEVELOPMENT OF BARRETT ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA
GERD is thought to progress to BE through frequent, severe, and/or long-term exposure to acid and bile reflux. This reflux alters the normal squamous epithelium of the esophagus, which is replaced with columnar epithelium.1,2,5 Although BE is a precursor to EAC, most patients with BE do not progress past nondysplastic or low-dysplastic disease.2,11 The yearly esophageal cancer risk for patients with GERD who are 50 years or older is only 0.04%, and the risk of progression from BE to EAC is only 0.5% per patient year.2,4,6 Risk factors for the development and progression of BE and EAC include onset of symptoms before age 30, history of severe GERD symptoms, and greater than 20 cumulative years of exposure (Fig. 1).1,4 The use of the term, alarm symptoms, describes the symptoms a patient may experience as this progression occurs. These alarm symptoms include dysphagia, anemia, weight loss, bleeding, and recurrent vomiting. Chronic acid exposure increases the risk for BE and the subsequent segment length and severity of BE. For reasons that are not understood, men are in the highest risk group, accounting for 80% of cases of EAC. To give some perspective, rates of EAC in women are equivalent to the prevalence of breast cancer diagnoses in men.3 In particular, elderly white men seem at the highest risk. Elderly patients are at high risk due to increased time for symptom exposure as well as a high frequency of atypical symptoms, thought to be due to less sensation to the typical heartburn symptoms of reflux.12 Obesity is associated with increased GERD symptoms and erosive esophagitis, due to the increased risk of reflux and hiatal hernia in patients with an elevated body mass index (BMI). Patients with central obesity in particular are at an increased risk of BE due to elevated intragastric pressure.2–4 Alcohol use and smoking have also been suggested risk factors for development of esophageal adenocarcinoma, but more recent data have been conflicting.1,2,6,13,14 In summary, elderly white men with chronic GERD symptoms, hiatal hernia, and elevated BMI are at greatest risk for developing severe BE and progression to EAC. Although having ever used a PPI is thought to be a risk factor for BE, one group excluded from this risk are those on a PPI due to history of Helicobacter pylori. Several studies have found a protective effect of prior H pylori infection and BE, which is not thought to be linked solely to adequate treatment of H pylori infection.1,2
EGD Surveillance for Patients with Barrett Esophagus
Fig. 1. Risk factors for BE and EAC. GI, gastrointestinal. (Data from Refs.1–4)
Endoscopic and histologic factors associated with increased risk for progression from BE to EAC include LSBE and high-grade dysplasia. Patients with LSBE are 3 times more likely to show evidence of dysplasia on biopsy than SSBE and are at higher risk of having undetected dysplasia on endoscopy.8,15 Even more predictive is highgrade dysplasia, the presence of which increases risk of EAC greater than 25% compared with those with no dysplasia.4 MANAGEMENT OF BARRETT ESOPHAGUS
The recommended treatment of BE is PPIs taken once to twice daily, 30 to 60 minutes before a meal. There is no preferred PPI based on prior studies; all have equally efficacious symptom control.16,17 PPIs do not prevent progression to EAC in patients with BE or regress metaplastic tissue at time of treatment, but they prevent further injury and the symptoms associated with tissue injury.2,4,18–20 Knowing which patients with GERD will benefit from endoscopy referral is an important means to reduce overutilization. Patients with GERD who exhibit any alarm symptoms should be referred immediately for screening endoscopy. Patients with chronic reflux symptoms despite 4 to 8 weeks of maximum acid-suppression therapy should
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also be screened for BE. Endoscopy should not be pursued prior to 4 weeks of treatment due to the possibility of mucosal inflammation from erosive esophagitis obscuring BE.21 In 1 study, up to 12% of SSBE was missed due to severe EE.11,22 If symptoms persist despite initial negative endoscopy, it is reasonable to pursue a follow-up endoscopy given high possibility for sampling error. More than 20% of patients without BE on initial endoscopy have BE on subsequent endoscopy23 (Box 1). For patients diagnosed with BE with no dysplasia seen on initial endoscopy, the 3 major gastroenterological societies in the United States (American College of Gastroenterology, American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy) recommend a repeat endoscopy within a year because dysplasia can be missed.15 Confirmation of dysplasia should prompt enrollment into a surveillance protocol based on the findings. Patients with nondysplastic or low-dysplastic disease should be managed symptomatically with acid-reducing treatments at the lowest effective dose. Antireflux surgery could be considered in patients who are intolerant or unresponsive to acidsuppression therapy. Although treatment typically leads to return of squamous epithelium on repeat endoscopy, risk for progression to EAC persists due to concern that small islands of metaplastic tissue may remain.4,24–26 Therefore, these patients should undergo surveillance endoscopy based on the algorithm agreed on by the gastroenterological societies and highlighted in Fig. 2. Those with high-grade dysplasia should be managed with high-dose PPI twice daily, frequent surveillance, and consideration of endoscopic or surgical intervention at earliest evidence of disease progression. SURVEILLANCE CHALLENGES AND STRATEGIES
Patients with reflux who are older than 50 years have an annual esophageal cancer incidence rate of 6500 cases for every 10 million patients.4 No study has yet shown that screening and surveillance endoscopy programs promote early detection and decrease death from EAC, and those that have suggested benefit are limited by lead-time and length-time biases.27,28 This is not surprising given the lack of conformity with typical disease and screening characteristics professional societies adhere to when making recommendations, as illustrated in Fig. 3. Despite screening and surveillance guidelines, the most common indication for upper endoscopy remains GERD, and up to 40% of the endoscopies performed in the United States are not within the recommended guidelines.3 Fear of litigation and patient disproportionate fear of malignancy may drive this overuse.10 Outpatient endoscopies cost $800 per Box 1 Who to screen for Barrett esophagus Endoscopy referral criteria GERD symptoms 1 alarm symptoms Persistent symptoms despite 4 to 8 weeks of maximum acid reduction therapy (twice daily PPI) Severe erosive esophagitis (after 2 months of treatment with PPI) History of esophageal stricture 1 recurrent dysphagia Consider endoscopy Men 501 with chronic GERD (>5 years) 1 additional risk factors Data from Shaheen N, Richter J. Barretts oesophagus. Lancet 2009;373:850–61; and Allen Jl. Endoscopy for gastroesophageal reflux disease: choose wisely. Ann Intern Med 2012;157(11):827–8.
EGD Surveillance for Patients with Barrett Esophagus
Fig. 2. Recommended BE and EAC surveillance program.
examination — $8500 if pathology and anesthesia are included — and account for more than $32 billion in health care spending annually.29,30 The cost of loss of productivity for the patient and companion is not factored into those dollars nor is the cost of managing potential complications. Although overuse is an issue, several studies have
Fig. 3. Features of BE and endoscopic surveillance of EAC that limit its efficacy, cost effectiveness, and impact. (Data from Refs.3,4,8)
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found low rates of surveillance endoscopy in patients with BE, suggesting that underutilization is a problem as well.10,31 Although the surveillance algorithm outlined in this article is a reasonable approach, caution must be taken when applying this to entire populations. One study found that only 50% of patients with frequent reflux sought care with their internist, suggesting that studies looking at rates of BE and EAC in patients referred for testing may overestimate the risks in the general population.32 Choosing which patients to screen based on patient and symptoms risk factors greatly reduces the risk and burden of screening while ensuring patients who warrant screening are appropriately referred. RECOMMENDATIONS
Despite concerns that chronic reflux is a precursor of esophageal cancer, if the clinical scenario is consistent with uncomplicated GERD and there are no alarm symptoms, there is no need for a screening or diagnostic upper endoscopy. Patients with GERD should be treated with a PPI at the lowest effective dose. If symptoms persist after 8 weeks of adhering to treatment and lifestyle modifications, or if alarm symptoms develop, patients should be referred for upper endoscopy. If there is no evidence of BE on endoscopy, no further endoscopies are warranted. If erosive esophagitis is seen on a negative BE endoscopy a repeat endoscopy should be considered in 2 months. For those patients diagnosed with BE, only a small number progress to EAC. In these patients, surveillance endoscopy should be done based on an assessment of a patient’s individual risks and clinical presentation. Patients with BE and dysplasia should be monitored according to the surveillance strategies outlined by the major gastroenterological societies in the United States. FUTURE CONSIDERATIONS
Patients with EAC are more likely to have first-degree relatives with symptoms of reflux.5 There has been an effort to identify genetic factors associated with increased GERD symptoms and the dysplastic progression to BE and adenocarcinoma. This information could be incorporated into a more targeted screening and surveillance algorithm for better risk stratification. Identification of biomarkers for dysplastic progression is another area of focus. Research to identify noninvasive or less invasive screening techniques has not shown improved early detection of BE, death from EAC, or reduced costs associated with screening and surveillance.27,28,33,34 Advances in technology may serve to improve detection but may be limited by cost as well as the overall high mortality of EAC. REFERENCES
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24. Macey N, Le Dreau G, Volant A, et al. Adenocarcinoma of the esophagogastric junction arising after endoscopic laser photocoagulation ablation of the short segment of Barretts esophagus. Gastroenterol Clin Biol 2001;25:204–6. 25. Shand A, Dallal H, Palmer K, et al. Adenocarcinoma arising in columnar lined oesophagus following treatment with argon plasma coagulation. Gut 2001;48: 580–1. 26. Van Laethem JL, Peny MO, Salmon I, et al. Intramucosal adenocarcinoma arising un- der squamous re-epithelialisation of Barretts oesophagus. Gut 2000;46: 574–7. 27. Rubenstein JH, Sonnenberg A, Davis J, et al. Effect of a prior endoscopy on outcomes of esophageal adenocarcinoma among United States veterans. Gastrointest Endosc 2008;68(5):849–55. 28. Rubenstein JH, Inadomi JM, Brill JV, et al. Cost utility of screening for Barretts esophagus with esophageal capsule endoscopy versus conventional upper endoscopy. Clin Gastroenterol Hepatol 2007;5(3):312–8. 29. Allen J. Endoscopy for gastroesophageal reflux disease: choose wisely. Ann Intern Med 2012;157(11):827–8. 30. Zamosky L. GERD: rising healthcare costs spark new debate, guidelines. Revised standards designed to save system money, prevent overuse of diagnostics. Med Econ 2013;90(1):48–54. 31. El-Serag HB, Duan Z, Hinojosa-Lindsey M, et al. Practice patterns of surveillance endoscopy in a Veterans Affairs database of 29,504 patients with Barretts esophagus. Gastrointest Endosc 2012;76(4):743–55. 32. Nandurkar S, Locke GR, Murray JA, et al. Rates of endoscopy and endoscopic findings among people with frequent symptoms of gastroesophageal reflux in the community. Am J Gastroenterol 2005;100(7):1459–65. 33. Atkinson M, Das A, Faulx A, et al. Ultrathin esophagoscopy in screening for Barretts esophagus at a Veterans Administration Hospital: easy access does not lead to referrals. Am J Gastroenterol 2008;103(1):92–7. 34. Lin OS, Schembre DB, Mergener K, et al. Blinded comparison of esophageal capsule endoscopy versus conventional endoscopy for a diagnosis of Barretts esophagus in patients with chronic gastroesophageal reflux. Gastrointest Endosc 2007;65(4):577–83.
