It has been estimated that 5.6% of adults in the United States have Barrett’s esophagus (BE). The metaplastic columnar mucosa of BE can silently evolve into adenocarcinoma and thus the clinical importance. The American Gastroenterological Association defines BE as “the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus.”
In this chapter, we examine the current guidelines for BE screening, in at-risk patients, and current surveillance approaches for patients with and without dysplasia. We also discuss future novel approaches to Barrett’s screening and surveillance.
KeywordsBarrett’s esophagus, screening, surveillance, metaplasia, intestinal metaplasia, low-grade dysplasia, high-grade dysplasia, esophageal, adenocarcinoma
Five decades after the British surgeon Norman Barrett first described the condition that bears his name, the true incidence of Barrett’s esophagus (BE) in the general population and the risk of progression to cancer continue to be areas of uncertainty, debate, and controversy . While the pathologic definition of BE has evolved over time, our current screening and surveillance recommendations are based in large on data derived from recent treatment trials, where clear endoscopic definitions of landmarks are recorded and expert pathologists performed biopsy analysis .
In this chapter, we will examine the rational behind screening and surveillance of BE. This will include the epidemiology, risk factors for developing Barrett’s, risk stratification for screening, and how the presence of dysplasia affects surveillance strategies, cost-effectiveness of screening and surveillance as well as potential technological advances which may affect screening/surveillance approaches in the future.
While the defining features of BE have been covered in detail in earlier chapters, its definition is key to understanding the approach to screening and surveillance in BE. The American Gastroenterological Association defines BE as “the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus.” Presently in the United States, intestinal metaplasia (the presence of columnar epithelium with goblet cells) is required for the diagnosis of BE because intestinal metaplasia is the predominant, while not the only, type of esophageal columnar epithelium that has malignant potential . An international agreement was achieved for the first time on a definition of Barrett’s in 2015 by the BOB CAT (Benign Barrett’s and CAncer Taskforce) consensus group which broadens the description as “Barrett’s is defined by the presence of columnar mucosa in the esophagus and it should be stated whether intestinal metaplasia is present above the gastroesophageal junction” .
It has been estimated that 5.6% of adults in the United States have BE . The metaplastic columnar mucosa of BE can silently evolve into adenocarcinoma . The prognosis of adenocarcinoma remains extremely poor, with a 5-year survival rate of 16% in the United States, highlighting the importance of screening and surveillance in BE .
Pathogenesis of Barrett’s Esophagus
One of the many challenges BE presents is that it is not entirely clear which precursor cells are responsible for metaplastic change. Metaplasia, the process wherein one mature cell type replaces another, can be the result of chronic tissue injury . In patients with chronic esophageal injury from gastroesophageal reflux disease (GERD), Barrett’s metaplasia develops when mucus-secreting columnar cells replace reflux-damaged esophageal squamous cells. While the mechanism of this process is not fully understood, it has been proposed that GERD might induce alterations in the expression of key developmental transcription factors, causing mature esophageal squamous cells to change into columnar cells, a process known as transdifferentiation or causing immature esophageal progenitor cells to undergo columnar rather than squamous differentiation a process known as transcommitment . Interestingly, when rat models of reflux esophagitis have been studied, it has been observed that the metaplasia develops from bone marrow stem cells that enter the circulation and settle in the reflux-damaged esophagus . Studies in mouse models have suggested that metaplasia might result from upward migration of stem cells from the gastric cardia or from the proximal expansion of embryonic-type cells at the gastroesophageal junction . It is not clear which of these processes contribute to the pathogenesis of BE in humans.
Risk Factors for Barrett’s Esophagus
There are multiple risk factors that can predispose an individual to BE. One of the most common conditions that can propagate BE is gastroesophageal reflux disease or GERD. In individual patients, the extent of Barrett’s metaplasia may be related to the severity of underlying GERD . Untreated patients with long-segment BE typically have severe GERD with erosive esophagitis, whereas short-segment BE may not be associated with GERD symptoms or endoscopic signs of reflux esophagitis . Presumably, short-segment BE develops as a consequence of protracted acid reflux involving only the most distal portion of the esophagus, a phenomenon that can be documented in apparently healthy persons . Short-segment BE was not widely recognized until 1994 , and earlier studies generally involved patients with long-segment disease exclusively. More recent studies have involved varying proportions of patients with long-segment and short-segment BE, and the proportion can profoundly influence the frequency of associated GERD symptoms and complications.
Proposed risk factors for BE are listed in Table 6.1 . BE is believed to be more common in Caucasian patients 50 years of age or older. BE is two to three times as common in men as in women, it is uncommon in blacks and Asians and is rare in children . Other important risk factors include obesity (with a predominantly intraabdominal fat distribution) and cigarette smoking, and there is a familial form of BE, which accounts for 7–11% of all cases . Most conditions associated with Barrett’s metaplasia are also risk factors for esophageal adenocarcinoma (EAC) . Conversely, factors that might provide protection against BE include the use of nonsteroidal anti-inflammatory drugs, Helicobacter pylori , and consumption of a diet high in fruits and vegetables.
|Factors||Risk Factor for Barrett’s Esophagus||Risk Factor for Esophageal Adenocarcinoma|
|Age <30 years at onset of GERD symptoms||Yes||–|
|Obesity with intraabdominal fat distribution||Yes||Yes|
|Family history of GERD, Barrett’s esophagus, or esophageal adenocarcinoma||Yes||Yes|
|Obstructive sleep apnea||Yes||–|
|Low birth weight for gestational age||Yes||No|
|Consumption of red meat and processed meat||Yes||Yes|
|Human papillomavirus infection||No||Yes|
|Protective Factor for Barrett’s Esophagus||Protective Factor for Esophageal Adenocarcinoma|
|Use of nonsteroidal anti-inflammatory drugs||Yes||Yes|
|Use of statins||Yes||Yes|
|Helicobacter pylori infection||Yes||Yes|
|Diet high in fruits and vegetables||Yes||Yes|
|Exposure to ambient ultraviolet radiation||–||Yes|
|Breast feeding for parous women||–||Yes|
a A dash indicates that studies have not addressed the question of whether the specified factor is associated with an increased risk or has a protective effect. Citations for the information in this table are provided in the Supplementary Appendix, available at NEJM.org . GERD denotes gastroesophageal reflux disease.
No single risk factor yet identified can account for the profound increase in the incidence of EAC in Western countries during the past 40 years, a period when GERD and BE appear to have increased only modestly in frequency . There has been a steep rise in the frequency of central obesity, which might contribute to Barrett’s carcinogenesis by promoting GERD and by increasing the production of hormones that promote cell proliferation such as leptin and insulin-like growth factors . H. pylori infection, which may protect the esophagus from GERD by causing a gastritis that reduced gastric acid production, has declined in frequency during the same period when EAC has risen in developed countries . Another hypothesis links the rising incidence of EAC with increased dietary intake of nitrates, which has resulted from the widespread use of nitrate-based fertilizers .
Estimates of the annual incidence of EAC among patients with nondysplastic Barrett’s esophagus (NDBE) have ranged from 0.1% to 2.9%, with the highest estimates in studies with evidence of publication bias . Recent better-quality studies suggest that the risk of EAC in the general populations of patients with NDBE is only 0.1–0.3% per year . However, a number of factors influence the risk of cancer for individual patients. For example, cancer risk among men with BE is approximately twice that among women , the risk is greater with longer segment of Barrett’s metaplasia , and the risk is especially high among persons with certain familial forms of BE . In addition, the risk appears to decrease with follow-up endoscopies showing no progression to dysplasia . While the incidence and epidemiology are still being elucidated for Barrett’s, it is a key component to establishing screening and surveillance guidelines. Refer to Chapter 2 : “Fluctuating Risk Factors and Epidemiology” for additional environmental and genetic risk factors in BE.
Screening for Barrett’s Esophagus
For the past few decades, the primary strategy for preventing mortality from EAC has been to screen patients with GERD symptoms for BE with the use of upper endoscopy and, for patients with established Barrett’s, to perform regular endoscopic surveillance to detect curable dysplasia and neoplasia . With an annual cancer incidence of only 0.1–0.3%, there have been no randomized trials to prove that screening and surveillance is an effective strategy. There is data, however, from observational studies suggesting that for patients with BE, cancers diagnosed by means of surveillance endoscopy are more likely to be earlier stage tumors with higher survival rates than tumors discovered secondary to symptoms such as weight loss and dysphagia .
Despite the lack of high-quality evidence to support the practice, medical societies currently recommend endoscopic screening for BE in patients with chronic GERD symptoms who have at least one additional risk factor for EAC ( Table 6.1 ). These risk factors include age of 50 years or older, male sex, white race, hiatal hernia, elevated body mass index, intraabdominal body fat distribution, or tobacco use . If the screening examination does not reveal BE, no further endoscopic screening is recommended .
Nevertheless, there are a number of reasons to question this approach to screening for BE. The screening prerequisite of GERD symptoms limits the usefulness of the practice, because patients with short-segment BE often have no GERD symptoms, and approximately 40% of patients with EAC report no history of GERD . Studies have shown that less than 10% of patients with EAC have a prior diagnosis of BE, suggesting that current screening practices may be ineffective .
Surveillance of Barrett’s Esophagus
Surveillance of Nondysplastic Barrett’s Esophagus
Endoscopic surveillance of BE is used to identify patients at earlier curable stages of esophageal cancer and is endorsed by major gastroenterology societies including those in the United States and in the United Kingdom despite fairly limited evidence that it confers a survival advantage . Because the risk of EAC varies based on the grade of dysplasia, surveillance guidelines also vary depending on histology.
The rate of progression from NDBE to EAC is estimated to be as high as 0.6% per year or as low as 0.21% per year . A recent multicenter study showed a rate of progression to EAC of 0.27% per year and a rate of progression to HGD (high-grade dysplasia) of 0.48% per year . In this study, 97.1% of patients with NDBE were cancer free at 10 years. A recent population-based study showed the incidence of HGD and EAC in patients with BE to be 0.38% per year . Sharma et al. found that half of patients who developed HGD or EAC demonstrated only NDBE on a previous biopsy, suggesting that not all cases of EAC develop in a stepwise fashion from NDBE to LGD (low-grade dysplasia) to HGD and then finally to EAC. Nevertheless, studies of patients whose EAC was detected through surveillance have consistently demonstrated improved survival over patients whose EAC was not detected through surveillance, although this observation likely represents lead time bias .
Systematic biopsy protocols for NDBE surveillance have been evaluated in patients with NDBE and four-quadrant biopsies obtained every 2 cm appear to be more sensitive for detection of dysplasia than random biopsies . A recent study demonstrated similar rates of adequate specimens with large capacity forceps (2.8 mm) compared with jumbo forceps (3.2 mm) . The standard approach to NDBE has been outlined in Fig. 6.1 .