Barrett’s Esophagus

Introduction

In Barrett’s esophagus, the normal cellular lining of the esophagus (called squamous epithelium) is replaced by an abnormal lining (called specialized intestinal metaplasia), that is predisposed to develop cancer.  Barrett’s esophagus develops as a consequence of gastroesophageal reflux disease (GERD), a disorder in which acid and other noxious materials in stomach juice reflux (backwash) into the esophagus.  GERD and Barrett’s esophagus are the major risk factors for a type of cancer of the esophagus called esophageal adenocarcinoma. In the United States, the frequency of this cancer has increased more than 6-fold over the past several decades, for reasons that are not clear. 

Barrett’s esophagus is named for Norman Rupert Barrett, an Australian surgeon who drew attention to the condition in a report published in 1950.  Early controversies about Barrett’s esophagus focused on whether the condition was congenital or acquired, and on whether the abnormal lining in the esophagus resembled the lining of the stomach or the intestine.  Today, it is widely accepted that Barrett’s esophagus is acquired as a consequence of chronic GERD.  Although gastric types of epithelia (cellular linings) can be found in Barrett’s esophagus, specialized intestinal metaplasia, which resembles the lining of the intestines, is the most distinctive and important type of Barrett’s epithelium.  Most modern authorities require the presence of specialized intestinal metaplasia for a diagnosis of Barrett’s esophagus.  Endoscopy, a test in which a lighted tube is passed into the esophagus to visualize its lining and to take biopsy samples, usually is required to establish the diagnosis.

Before the 1990s, Barrett’s esophagus was not recognized unless specialized intestinal metaplasia was seen to extend at least several centimeters up the distal esophagus.  In 1994, Spechler and his colleagues demonstrated that short segments of specialized intestinal metaplasia are present frequently in the distal esophagus.  Since then, Barrett’s esophagus has been categorized as “long-segment” when the abnormal lining involves more than 3 cm of the distal esophagus, and as “short-segment” when there are less than 3 cm of abnormal lining.  The cutoff value of 3 cm is arbitrary, however, and the long/short classification presently has no clear implications regarding either how the condition developed or how to manage affected patients.

Epidemiology

Barrett's esophagus can be found in children, although it is rare in children under the age of 10, and is almost non-existent in children under 5 years of age.  The condition usually is found in adults, for whom the average age at the time of diagnosis is approximately 55 years.  White men predominate in most series and, for unknown reasons, Barrett's esophagus is uncommon in blacks and Asians.  In most cases, Barrett’s esophagus is discovered during endoscopic examinations performed for the evaluation of GERD symptoms such as heartburn, regurgitation, and dysphagia (difficulty swallowing).  Long-segment Barrett’s esophagus is found in fewer than 5% of such patients, whereas 10% to 15% have short-segment Barrett’s esophagus. 

The precise frequency of Barrett’s esophagus in the general population is not clear, but recent studies suggest that it is between 1.6% to 6.8%.  Long-segment Barrett’s esophagus is found most often in patients with longstanding GERD symptoms, but the frequency of short-segment Barrett’s esophagus appears to be similar for individuals with and without GERD symptoms (approximately 5%).  Some recent reports suggest that the frequency of Barrett’s esophagus is increasing.  In a large study from the Netherlands, for example, the incidence of Barrett’s esophagus in the general population was found to have increased from 14.3 cases per 100,000 persons in 1997 to 23.1 cases per 100,000 in 2002.

The endoscopist who finds a Barrett's esophagus has no way to determine precisely when the condition developed, but a study from the Mayo Clinic has shed some light on this issue.  In that study, the investigators reviewed the records of 51,311 patients who had endoscopic examinations between 1976 and 1989, and found 377 cases of long-segment Barrett's esophagus.  The frequency of the disorder was found to increase from 0% in patients 0-9 years of age to a maximum of 0.928% in patients 80-89 years old.  Unlike the age-related rise in frequency, however, the length of esophagus lined by Barrett's epithelium did not appear to increase significantly with age.  Twenty-year-old patients had a segment of columnar-lined esophagus similar in length to that of the octogenarians.  Furthermore, no progression of Barrett's esophagus was found among 101 patients who had follow-up endoscopic examinations performed after a mean interval of 3.2 years.  These data suggested that the average age for developing Barrett's esophagus was approximately 40 years, whereas the average age of patients at the time of diagnosis was 63 years, an observation implying that Barrett's epithelium often develops more than 20 years before it is discovered.  This report also suggests that Barrett's esophagus usually develops to its full extent all at once, many years before it is discovered, and does not progress substantially with time.

Published estimates on the annual risk of cancer in patients with Barrett’s esophagus have ranged from 0.2% to 2.9%.  However, there is compelling evidence that the cancer risk in Barrett’s esophagus had been overestimated for years because of the practice of publication bias, which is the selective reporting of studies that have positive or extreme results.  Modern studies suggest that patients with Barrett’s esophagus develop esophageal cancer at the rate of approximately 0.5% per year (i.e., 1 cancer per 200 patients per year).  Regular endoscopic surveillance is proposed to identify these tumors when they are in an early, curable stage.  Although it is not clear that long- and short-segment Barrett’s esophagus have the same risk for malignancy, the 2 conditions presently are managed similarly.

In addition to GERD and Barrett’s esophagus, obesity is a strong risk factor for esophageal adenocarcinoma.  Although cigarette smoking and alcohol consumption are very strong risk factors for another type of esophageal cancer, called squamous cell carcinoma of the esophagus, cigarette smoking only modestly increases the risk of esophageal adenocarcinoma and alcohol does not appear to affect the risk at all.  The use of aspirin and similar medications called non-steroidal anti-inflammatory drugs (NSAIDs) has been found to protect against esophageal cancer, as does a diet high in fruits and vegetables. 

Pathogenesis (Development) of Barrett’s Esophagus

Barrett’s esophagus develops through a process called metaplasia in which one type of adult cell replaces another.  Metaplasia usually develops as a response to chronic injury and inflammation.  Metaplasia can be considered a protective response, because the metaplastic lining typically is more resistant to the agents causing the chronic injury and inflammation than the native tissues.  For reasons that are not clear, however, metaplasia also can predispose to cancer development.  For patients who develop Barrett’s esophagus, GERD injures the normal squamous lining of the esophagus, and ongoing GERD provides an abnormal environment in the esophagus so that the injury heals, not with the regeneration of more squamous cells, but with the development of specialized intestinal metaplasia.  The specialized intestinal metaplasia appears to be more resistant to GERD-induced injury than the native squamous epithelium of the esophagus.  Unfortunately, specialized intestinal metaplasia also is predisposed to malignancy.

A number of abnormalities that predispose to severe GERD have been described in patients with long-segment Barrett’s esophagus.  For example, some patients have been found to have abnormally large amounts of acid secretion in their stomachs, and abnormally high concentrations of bile in their stomach juice.  In those patients, reflux episodes may be exceptionally damaging to the esophagus because the refluxed stomach juice contains such high concentrations of acid and bile.  Some studies have shown that the lower esophageal sphincter, a group of muscles that wrap around the lower esophagus to prevent reflux, is very weak in patients with long-segment Barrett’s esophagus.  This abnormality results in a strong propensity for stomach material to reflux into the esophagus.  Some patients have been found to have poor function of the muscles that normally push swallowed material through the esophagus, an abnormality that may delay the clearance of refluxed material out of the esophagus.  Diminished esophageal pain sensitivity has been demonstrated in some patients, and so the reflux of caustic material may not cause heartburn.  Such patients may be unlikely to seek medical attention for GERD or to take medications that could prevent injury to the esophagus.  Individual patients with Barrett’s esophagus may exhibit all or none of these abnormalities, and their frequency and importance in the development of the condition are disputed. 

The frequency of the aforementioned abnormalities that predispose to GERD is especially unclear in patients who have short-segment Barrett’s esophagus.  Many such patients have no GERD symptoms and no endoscopic signs of reflux damage to the esophagus.  Some studies suggest that the length of specialized intestinal metaplasia in Barrett’s esophagus is related to the length of time that the esophagus is exposed to acid.  Thus, patients with long-segment disease may have protracted acid exposure of the esophagus, whereas patients with short-segment Barrett’s esophagus may have acid exposure values that are normal or only minimally increased.

Even in patients who have no signs or symptoms of GERD, recent studies have shown that the region where the esophagus joins the stomach, called the gastroesophageal junction (GEJ), is exposed frequently to concentrated acid and other noxious materials that might cause inflammation and metaplasia.  After meals, there is a pocket of acid at the GEJ that escapes the acid-buffering effects of ingested food.  One recent study has shown that the very end of the esophagus of normal individuals is exposed to acid for more than 10% of the day.  Potential consequences of such persistent acid exposure at the GEJ include not only acid injury, but also exposure to high concentrations of nitric oxide (NO), a toxic molecule that is generated from dietary nitrate (NO3-), which is found in green, leafy vegetables.  After nitrate ingestion, high levels of NO have been demonstrated at the GEJ.  NO in these concentrations can cause mutations (DNA damage) that might predispose to metaplasia and malignancy. 

Diagnosis

Endoscopic examination generally is required to identify Barrett’s esophagus, and the endoscopic impression that there is Barrett’s esophagus must be confirmed by the examination of esophageal biopsy specimens.  Specifically, 2 diagnostic criteria must be fulfilled to establish a diagnosis of Barrett’s esophagus: 1) The endoscopist must identify an abnormal lining (epithelium) in the esophagus, and 2) Biopsy specimens of the abnormal lining must show specialized intestinal metaplasia.  To document that an abnormal, columnar epithelium lines the esophagus, the endoscopist must identify both the squamo-columnar junction (SCJ) and the GEJ (Figure 1).   

 Figure 1.  Endoscopic landmarks for identifying Barrett’s esophagus.  The squamo-columnar junction (SCJ or Z-line) is the visible line formed by the juxtaposition of the normal squamous epithelium of the esophagus and a columnar-type epithelium.  The gastroesophageal junction (GEJ) is the imaginary line at which the esophagus ends and the stomach begins.  When the SCJ is located above the GEJ, there is a columnar-lined segment of esophagus.  (From Spechler SJ.  The role of gastric carditis in metaplasia and neoplasia at the gastroesophageal junction.  Gastroenterology 1999; 117:218-28.).

Barrett’s epithelium has a reddish color and coarse texture on endoscopic examination, whereas squamous epithelium has a pale, glossy appearance.  The juxtaposition of these linings at the SCJ forms a visible line called the Z-line.  The GEJ is identified endoscopically as the level of the most proximal extent of the stomach folds.  When the SCJ and GEJ coincide, then there is no columnar-lined esophagus.  When the SCJ is located proximal to the GEJ (Figure 1), then there is a columnar-lined segment of esophagus.  If the endoscopist takes biopsy specimens from that columnar-lined segment and those specimens show specialized intestinal metaplasia, then the patient has Barrett’s esophagus.  There is long-segment Barrett’s esophagus if the distance between the Z-line and the GEJ is 3 cm or more, and short-segment Barrett’s esophagus if that distance is less than 3 cm.

Intestinal Metaplasia at the GEJ

Intestinal metaplasia can develop as a result of chronic inflammation in the stomach, the esophagus, or both.  Under the microscope, biopsy specimens of intestinal metaplasia from the stomach can appear to be identical to biopsy specimens of intestinal metaplasia from the esophagus.  During endoscopic examination, the GEJ is a dynamic structure whose position can vary by several centimeters from moment to moment.  Along with the difficulty of localizing the GEJ with great precision, it can also be difficult to determine whether short segments of intestinal metaplasia found in the GEJ region are lining the distal esophagus (short-segment Barrett’s esophagus) or the most proximal (top) portion of the stomach, which is called the gastric cardia.  The term “intestinal metaplasia at the GEJ” has been used to describe the condition in which intestinal metaplasia is found at a Z-line that appears to coincide precisely with the GEJ.  Rather than constituting an independent condition, however, intestinal metaplasia at the GEJ almost certainly represents either short-segment Barrett’s esophagus or intestinal metaplasia of the cardia.

Intestinal metaplasia in the stomach often results from the chronic inflammation caused by infection with a bacterium called Helicobacter  pylori, whereas GERD causes the chronic inflammation that results in intestinal metaplasia in the esophagus.  For some patients, therefore, intestinal metaplasia at the GEJ is due to H. pylori infection of the stomach whereas, for others, the condition results from GERD that causes intestinal metaplasia in segments of esophagus so short that they cannot be distinguished from the serrations of a normal Z-line.  Chronic H. pylori infection may even protect against the development of Barrett’s esophagus and other complications of GERD, because the organisms can cause stomach inflammation that decreases the secretion of acid. 

For patients with intestinal metaplasia at the GEJ, the distinction between short-segment Barrett’s esophagus and intestinal metaplasia of the gastric cardia may have clinical importance because circumstantial evidence suggests that short-segment Barrett’s esophagus has a substantially higher cancer risk.  In 1 study, for example, investigators found dysplasia (the precursor of cancer) in 20 of 177 patients (11.3%) with short-segment Barrett’s esophagus, but in only 1 of 76 patients (1.3%) with intestinal metaplasia in the gastric cardia.  Medical societies recommend regular endoscopic cancer surveillance for patients with Barrett’s esophagus, but not for patients with intestinal metaplasia in the stomach.  Therefore, the distinction between these 2 conditions has important implications for patient management. 

Dysplasia in Barrett’s Esophagus

Cancers in Barrett’s esophagus evolve through a series of mutations (DNA damage) that give the affected cell growth advantages over its normal, neighboring cells.  Those same mutations cause changes in the appearance of the cells that can be recognized as a finding in biopsy specimens called dysplasia.  Pathologists diagnose dysplasia when they see changes in the size, appearance and location of the cell nuclei, and abnormalities in the microscopic structure of the tissue.  The finding of dysplasia suggests that cells have sustained DNA damage that renders them especially likely to become cancerous.  Dysplasia is categorized as low-grade or high-grade depending on the degree of abnormalities seen by the pathologist.  High-grade dysplasia is believed to reflect severe genetic damage, with high potential for cancer development.

An esophageal epithelium that is regenerating in response to GERD-induced injury can exhibit microscopic changes that are very similar to those of low-grade dysplasia.   Consequently, it can be difficult for pathologists to distinguish low-grade dysplasia in Barrett’s esophagus from reactive changes caused by GERD.  Inter-observer agreement among experienced pathologists for the diagnosis of low-grade dysplasia may be less than 50%, whereas inter-observer agreement for distinguishing high-grade dysplasia from lesser lesions is approximately 85%.

Dysplasia is a diagnosis that requires the examination of biopsy specimens under the microscope.  There is no endoscopic feature that reliably identifies dysplastic epithelium.  Therefore, endoscopists traditionally have relied on random biopsy sampling techniques to identify dysplasia.  As a result, dysplasia can easily be missed due to biopsy sampling error.  For patients found to have dysplasia, furthermore, higher grade lesions (including cancer) elsewhere in the esophagus can be missed.  In series of patients who had the esophagus surgically removed because endoscopic examination revealed high‑grade dysplasia in Barrett's esophagus, with no apparent tumors, invasive cancer (missed because of biopsy sampling error) has been found in 30% to 40% of the surgical specimens.  Extensive biopsy sampling of the Barrett esophagus can reduce biopsy sampling error, but cannot eliminate the problem entirely.

A number of molecular tests for cancer risk and endoscopic techniques for recognizing dysplasia have been studied as alternatives to random biopsy sampling for dysplasia in Barrett’s esophagus.  Promising molecular markers include abnormalities in certain proteins (e.g., p53, cyclin D1), and abnormal cellular DNA content that can be demonstrated by a technique called flow cytometry.  A number of endoscopic techniques to identify dysplastic areas for biopsy sampling have been proposed (e.g., chromoendoscopy, endosonography, optical coherence tomography, spectroscopy).  Although some early results have been promising, none of these tests and techniques yet has been shown to provide sufficient clinical information to justify its routine use for cancer surveillance in patients with Barrett’s esophagus.

Natural History of Dysplasia

Few studies have documented the natural history of dysplasia in Barrett’s esophagus; the rates at which low-grade dysplasia progresses to high-grade dysplasia and then to cancer are not clear.  Furthermore, the fact that low-grade dysplasia in Barrett’s esophagus is not diagnosed reliably is a major problem that confounds the interpretation of all studies on this condition.  Diagnostic difficulties undoubtedly underlie some of the disparities among published series regarding the prevalence and incidence of low-grade dysplasia in Barrett’s esophagus.  For example, low-grade dysplasia was described in approximately 70% of patients in 1 large series from a Veterans Administration hospital, whereas another study that reviewed the pathology archives of 3 large university hospitals identified low-grade dysplasia in only 37 (4.7%) of 790 cases of Barrett’s esophagus.  One recent report suggests that patients who have Barrett’s esophagus develop low-grade dysplasia at the rate of 4.3% per year, and high-grade dysplasia at the rate of 0.9% per year.  In 1 recent study that included 156 patients with low-grade dysplasia, the rate of progression to cancer was 0.6% per year.

There are substantial variations among reported estimates of the rate at which high-grade dysplasia in Barrett’s esophagus progresses to cancer.  For example, a study from Seattle that included 76 patients with high-grade dysplasia in Barrett’s esophagus found that 59% developed cancer within a 5-year period of follow-up.  In contrast, a study from the Chicago area found that only 16% of 75 patients with high-grade dysplasia developed cancer during an average follow-up period of 7.3 years.  The reasons underlying the large disparities in the results of these studies are not clear, but may involve differences among pathologists in their grading of dysplasia and differences regarding whether patients found to have cancer within 1 year of the initial diagnosis of high-grade dysplasia were included or excluded from the outcome analyses.  In a recent report that reviewed all of these data, Spechler estimated that patients with high-grade dysplasia in Barrett’s esophagus develop cancers at the rate of 4% to 6% per year.

Screening and Surveillance for Barrett’s Esophagus

Authorities dispute whether patients with GERD symptoms should have a screening endoscopy to look for the Barrett’s esophagus, and whether patients found to have Barrett’s esophagus should have regular surveillance endoscopies to look for dysplasia.  The rationale for these practices includes the following assumptions: 1) Screening will reliably identify those individuals at highest risk for developing cancer, 2) Without intervention, patients with Barrett’s esophagus will have decreased survival because of deaths from esophageal adenocarcinoma, 3) Surveillance will reliably detect dysplasia in Barrett’s esophagus, and 4) Treatment of the dysplasia found by surveillance will prolong survival and improve the quality of life by preventing death and debility from esophageal cancer.  Unfortunately, all of these assumptions are unproved and questionable.

It has not been established that screening patients with GERD symptoms reliably identifies those individuals at high risk for esophageal adenocarcinoma.  Indeed, available studies suggest that approximately 40% of patients with esophageal adenocarcinomas have no history of GERD symptoms.  Therefore, screening programs that target only patients with heartburn can have only limited impact on cancer mortality rates, and there is little evidence that these programs have prevented deaths from esophageal adenocarcinomas.  In published series of patients found to have these tumors, fewer than 5% were known to have had Barrett's esophagus before they sought medical attention for the cancer.

Studies have shown that, compared with the general population, patients with Barrett’s esophagus have a significantly increased frequency of developing esophageal adenocarcinoma.  Despite this increase in esophageal cancer development, however, esophageal cancer is an uncommon cause of death for patients with Barrett’s esophagus.  Esophageal adenocarcinoma is such an uncommon cancer in the general population that even a 100-fold increase in its frequency in Barrett’s esophagus remains a small risk.  Older patients with Barrett’s esophagus succumb far more often to common illnesses like heart disease than to esophageal adenocarcinoma.  Thus, overall mortality in patients with Barrett’s esophagus appears to be affected only slightly by their higher frequency of esophageal cancer.

Investigators have reported that endoscopic surveillance can detect curable tumors in Barrett’s esophagus, and that asymptomatic cancers discovered during surveillance usually are less advanced than those found in patients who have cancer symptoms like dysphagia (difficulty swallowing) and weight loss.  However, those reports are highly susceptible to a number of biases that can exaggerate the benefits of surveillance programs.   No study has established the reliability of surveillance in detecting curable dysplasia, and a number of reports have documented the development of incurable cancers in patients who had regular endoscopic surveillance.  Computer model studies have found that endoscopic screening and surveillance for Barrett’s esophagus can be beneficial under certain circumstances.  None of the computer models can be considered definitive, however, because all incorporate numerous layers of soft data and questionable assumptions.

The dilemma regarding screening and surveillance for Barrett’s esophagus can be summarized as follows:  1) Endoscopy is expensive.  2) There is no proof that endoscopic screening of patients with GERD for Barrett’s esophagus has any impact on survival.  3) No “proof” in the form of a definitive study is likely to become available in the near future.  4) Available observational studies, which are subject to numerous forms of bias, suggest that screening and surveillance are beneficial.  5) Available computer models, which are based on some soft data and questionable assumptions, suggest that screening can be beneficial.  6) Although endoscopic screening clearly can be associated with risks (i.e., complications resulting both from endoscopy and from the invasive procedures used to treat conditions found by endoscopy), no study has shown an overall survival disadvantage for patients in screening and surveillance programs.  In this murky situation, where the indirect evidence available suggests that screening and surveillance are beneficial and the major objection is cost, it seems better to err by performing unnecessary endoscopy rather than by missing curable esophageal tumors.

Treatment of Barrett’s Esophagus

Treatment of GERD in Barrett’s Esophagus.  Most patients with Barrett’s esophagus have GERD, and the principles of GERD treatment in patients with Barrett’s esophagus are similar to those for patients who have GERD without Barrett’s esophagus.  The major difference is in the routine use of proton pump inhibitors (PPIs), which are the most powerful medications for the treatment of GERD in patients with Barrett’s esophagus.  PPIs are potent blockers of stomach acid secretion.  For patients who have GERD without Barrett’s esophagus, PPIs often are used only after other, less potent medications have been tried (e.g., antacids, histamine H2-receptor antagonists) and, for patients whose symptoms resolve, medications may be withdrawn entirely.  In contrast, many authorities recommend that patients with Barrett’s esophagus should be treated with PPIs indefinitely, even in the absence of GERD symptoms.  This recommendation is based primarily on circumstantial evidence suggesting that control of acid reflux may prevent the development of cancer.  For example, a recent study of 236 veteran patients with Barrett’s esophagus found that the use of PPIs was associated with a reduced frequency of dysplasia.  The 10-year cumulative incidence of dysplasia was 21% for the 155 patients on PPI therapy, compared with 58% for the 81 patients treated with either a histamine H2-receptor antagonist or no antisecretory therapy.

Surgeons have proposed that fundoplication, an operation designed to prevent reflux, might be more effective than medical therapy for GERD in preventing cancer in Barrett’s esophagus.  A number of flawed studies have found fewer cases of dysplasia and cancer among patients with Barrett’s esophagus who had fundoplications than among those who had received medical treatment.  However, all of the high-quality studies on this issue have found no significant difference in cancer development between medically- and surgically-treated GERD patients.  For example, in a study of 247 veteran patients with GERD who were randomly assigned to receive either medical or surgical treatment, only 4 of 165 patients (2.4%) in the medical group and 1 of 82 (1.2%) in the surgical group developed an esophageal adenocarcinoma during 10 to 13 years of follow-up.  The difference between the treatment groups in the frequency of this tumor was not statistically significant.  The bulk of evidence suggests that antireflux surgery should not be advised with the expectation that the procedure will prolong life by preventing esophageal cancer.  Presently, no GERD therapy, medical or surgical, has been proved to decrease the risk of esophageal adenocarcinoma for patients with Barrett’s esophagus. 

The role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDS).  Epidemiological studies suggest that aspirin and similar drugs called non-steroidal anti-inflammatory medications (NSAIDs) may protect against cancer in Barrett’s esophagus.  Aspirin and other NSAIDs inhibit an enzyme called cyclo-oxygenase-2 (COX-2) that may promote cancer formation.  The specialized intestinal metaplasia of Barrett’s esophagus has high levels of COX-2.  Inhibition of COX-2 with NSAIDs has been found to prevent the development of esophageal adenocarcinoma in an animal model of Barrett’s esophagus.  Nevertheless, clinical studies are needed before NSAIDs can be recommended routinely for cancer prevention in patients with Barrett’s esophagus.  Even if efficacy in cancer prevention could be demonstrated, it is not clear that the cost and potential risks of NSAIDs in causing ulcers, heart disease, strokes, and kidney problems would be justified for routine clinical use in patients with Barrett’s esophagus.  Aspirin, an inexpensive NSAID that can prevent heart attacks as well as esophageal cancer, might be a useful drug if its protective effects can be shown to outweigh its risk of gastrointestinal complications like ulcers in the stomach and duodenum.   Presently, a large study of aspirin for the prevention of cancer in Barrett’s esophagus is underway in the United Kingdom.

Treatment of Dysplasia in Barrett’s Esophagus.  Patients treated for cancers traditionally are deemed cured when they have no evidence of recurrence at 5 years, because it is assumed that any cancer stem cells that survived the treatment would have proliferated and become clinically manifest within that time period.  Studies on the natural history of dysplasia in Barrett’s esophagus suggest that, without invasive therapy, only 20% to 30% of patients with high-grade dysplasia will develop a demonstrable cancer within 5 years.  In theory, if a treatment for dysplasia leaves even 1 dysplastic stem cell behind, that cell can proliferate and eventually become malignant.  Consequently, it is not appropriate to conclude that the cancer risk has been eliminated for a patient who has survived 5 years after treatment of dysplasia in Barrett’s esophagus.  Indeed, 5 years might be considered the absolute minimum for a meaningful follow-up of this condition, and many more years would be required before one could reasonably consider that the risk of dysplasia-associated cancer has been eradicated.  Unfortunately, the follow-up duration in most studies on treatments for dysplasia in Barrett’s esophagus is considerably less than 5 years.

For patients with verified high-grade dysplasia in Barrett’s esophagus, there are generally 4 proposed management options: 1) Esophagectomy (surgical removal of the esophagus), 2) Endoscopic therapies that ablate the Barrett’s epithelium, 3) Endoscopic mucosal resection (EMR), and 3) Intensive endoscopic surveillance in which invasive therapies are withheld until biopsy specimens reveal adenocarcinoma.  Each of these options is associated with substantial risks and unclear benefits.

Esophagectomy.  Esophagectomy has been considered the most definitive treatment for high-grade dysplasia, but this definitive therapy has the highest rates of short-term mortality and long-term health problems of all the treatment options.  Studies on esophagectomy for high-grade dysplasia in Barrett’s esophagus typically have involved small numbers of patients from a single institution, and such reports are of limited value for estimating the complication rates of esophagectomy for patients with dysplasia.  Much larger series are available on the results of esophagectomy for esophageal cancer, but it may not be appropriate to extrapolate the results of surgery performed on debilitated patients with esophageal cancer to those for otherwise healthy patients with dysplasia.  Nevertheless, there are some important lessons to be learned from the large series that may be applicable to patients with dysplasia in Barrett’s esophagus.

One lesson is that the mortality rate for esophagectomy depends on the frequency with which the operation is performed at any given institution.  In 1 study of 340 esophagectomies performed at 25 different hospitals, the mortality rate was 3.0% for patients who had the operation at institutions that did 5 or more esophagectomies per year, compared with 12.2% for patients treated at institutions where the operation was performed less frequently.  In a study of data from the Netherlands, the mortality rates for esophagectomy were 12.1%, 7.5%, and 4.9% at centers performing 1-10, 11-20, and >50 esophagectomies per year, respectively. 

The average hospital stay for open esophagectomy is approximately 2 weeks, and 30% to 50% of patients develop at least 1 serious complication of the operation such as pneumonia, myocardial infarction (heart attack), and wound infection.  Esophagectomy also can cause long-term medical problems like dysphagia and weight loss.  Nevertheless, the limited quantitative data available suggest that the impact of these problems on quality of life may be surprisingly small.  One group of investigators asked patients who had an esophagectomy at least 1 year earlier to rate their quality of life on a scale of 0 to 1 (where 0=death and 1=perfect health), and found that patients rated their quality of life at approximately 0.97.  In another study of 53 patients who had an esophagectomy for high-grade dysplasia in Barrett’s esophagus and who completed a standardized health status questionnaire, there appeared to be few important differences between the patients and a normal control population. 

Endoscopic Ablative Therapies.  Endoscopic ablative therapies use heat or photochemical energy to ablate the abnormal epithelium in Barrett’s esophagus.  Heat can be delivered with a laser or with an electrical device that is passed through the endoscope.  After ablation, patients are treated with PPIs and the injured epithelium heals with the growth of new squamous epithelium.  One major concern regarding endoscopic ablative therapies for dysplasia is that the procedures will not eradicate all of the dysplastic cells.  Partially-ablated Barrett’s esophagus can heal with an overlying layer of squamous epithelium that buries the abnormal tissue and hides it from the endoscopist.  There are reports of adenocarcinoma developing from this buried metaplastic tissue. 

Presently, photodynamic therapy (PDT) is the most extensively studied of the ablative techniques.  For PDT, patients are treated with a chemical called porfimer sodium that is taken up by esophageal cells and that can be activated by exposure to light.  Using a low-power laser that is passed through the endoscope, the esophagus is irradiated with laser light.  This activates the chemical to form a toxic molecule that destroys the abnormal cells and their blood supply. 

In 1 study, 138 patients with high-grade dysplasia in Barrett’s esophagus were randomly assigned to receive treatment with PDT plus a PPI, whereas 70 were randomly assigned to treatment with a PPI alone (without PDT).  No dysplasia was seen on repeat endoscopy in 77% of the patients treated with PDT, compared with 39% of the patients who received PPI alone.  During up to 5 years of follow-up, 15% of the PDT patients developed cancer, compared with 29% of those treated with PPI alone.  There were no procedure-related deaths, but 69% of the patients who received PDT developed photosensitivity reactions (sunburns) and 36% developed esophageal strictures that had to be treated with a device that stretches the esophagus.  Although these results show that PDT clearly is superior to PPI alone for eradicating dysplasia and preventing cancer in Barrett’s esophagus, the frequency of serious complications is disturbing, as is the fact that 15% of the patients who received PDT nevertheless developed cancer.

Endoscopic Mucosal Resection.  In endoscopic mucosal resection (EMR), a large segment of the lining of the esophagus is removed using a cutting device that is passed through the endoscope.  Unlike the endoscopic ablative techniques, EMR provides large tissue specimens that can be examined by the pathologist to determine whether there is invasive cancer that may require further treatment.  Presently, data on the efficacy of EMR for the treatment of dysplasia and early cancers in Barrett’s esophagus are limited, but impressive nevertheless.  For example, 1 group of investigators performed EMR on 100 patients with early cancers in Barrett’s esophagus.  There were no serious complications, and the calculated 5–year survival rate was an extraordinary 98%.  However, recurrent cancers were found in 11% of the patients during a mean follow-up period of 37 months.  The recurrent tumors were treated successfully with more endoscopic therapy, but this high rate of recurrence shows that EMR often leaves behind cells that can turn into cancers.  Another recent study from the Mayo Clinic has confirmed this observation.  The investigators compared long-term survivals in patients with high-grade dysplasia who were treated either with esophagectomy or with a combination of EMR and PDT.  There was no statistically significant difference in overall, long-term survival for patients treated with either of the therapies, even though 6.2% of the patients treated with PDT and EMR developed esophageal cancer during the follow-up period. 

EMR for dysplasia and early cancers in Barrett’s esophagus appears to be safe in experienced hands, and the limited data available suggest that 5-year survival rates are excellent.  However, recurrent cancers develop frequently.  Although the results so far are impressive, it is important to appreciate that the data are still limited in duration and in scope.  Most of the studies on EMR have come from only a handful of highly specialized centers, and it is not clear that these results can be duplicated in a community hospital setting.

Intensive Endoscopic Surveillance.  Some authorities have recommended a program of intensive endoscopic surveillance (i.e., endoscopic examinations every 3 to 6 months) for patients with high-grade dysplasia.  With this approach, invasive treatments like esophagectomy are withheld until biopsy specimens reveal cancer.  This practice has been endorsed as a management option by the American College of Gastroenterology, but few published data directly support the safety and efficacy of intensive surveillance for high-grade dysplasia.

One report described 12 patients who developed adenocarcinomas during intensive endoscopic surveillance for high-grade dysplasia in Barrett’s esophagus.  The cancers were deemed potentially curable at the time of detection in all 11 patients who were compliant with the surveillance program, but 1 patient who was lost to follow-up returned 10 years later with an unresectable tumor.  In another series of 32 patients with high-grade dysplasia who developed adenocarcinoma during intensive endoscopic surveillance, only 1 patient (3%) had incurable disease when the cancer was first detected on surveillance endoscopy.  Another group of investigators performed intensive endoscopic surveillance in 15 patients with high-grade dysplasia for an average duration of 36.8 months, during which 4 developed adenocarcinoma.  The cancer was incurable in 1 of those 4 patients.

Management Recommendations

No management strategy for patients with Barrett’s esophagus has been proved to prolong life or to prevent death from esophageal adenocarcinoma.  The management strategy that has been endorsed by the American College of Gastroenterology is arguably the most complete and widely followed of the published guidelines for the management of patients with Barrett’s esophagus.  Their guidelines, with minor modifications, are as follows:

Patients with Barrett’s esophagus should have regular surveillance endoscopy.

For patients who have had 2 consecutive endoscopies that show no dysplasia, surveillance endoscopy is recommended at an interval of every 3 years.  The American Gastroenterological Association suggests that the interval could be 5 years in this same situation.

If dysplasia is noted, another endoscopy should be performed with extensive biopsy sampling to look for invasive cancer, and the biopsy specimens should be evaluated by a pathologist with expertise in this condition.

For patients with verified low-grade dysplasia after extensive biopsy sampling, yearly surveillance endoscopy is recommended.

For patients with verified high-grade dysplasia, intervention (e.g., esophagectomy) may be considered.  Intensive endoscopic surveillance is another consideration.  As a result of the recent intensive interest in and promising results of studies on EMR and ablative therapies for dysplasia in Barrett’s esophagus, guidelines may soon include these treatments as options as well.