Barrett’s Esophagus

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CHAPTER 44 Barrett’s Esophagus

Stuart Jon Spechler, Rhonda F. Souza

CHAPTER OUTLINE

Diagnosis 727
Epidemiology 727
Pathogenesis 728
Molecular Biology of Neoplasia 729
Dysplasia 729
Management 730

Treatment of Gastroesophageal Reflux Disease 730
Endoscopic Surveillance for Dysplasia 730
Treatment of Dysplasia 731
Recommendations 732

Barrett’s esophagus is the condition in which an abnormal columnar epithelium that is predisposed to malignancy replaces the stratified squamous epithelium that normally lines the distal esophagus.1 The condition is named for Norman Barrett, an Australian surgeon who drew attention to the columnar-lined esophagus in 1950.2 Barrett’s esophagus is a consequence of chronic gastroesophageal reflux disease (GERD), which damages the esophageal squamous epithelium and causes it to heal through a metaplastic process in which columnar cells replace reflux-damaged squamous cells. The columnar-lined esophagus causes no symptoms, and the condition has clinical importance only because it is a risk factor for esophageal adenocarcinoma, a tumor whose frequency has increased more than six-fold over the past several decades.3

DIAGNOSIS

Barrett’s esophagus is diagnosed by endoscopic examination, and two criteria must be fulfilled. First, the endoscopist must ascertain that columnar-appearing epithelium lines the distal esophagus. Second, biopsy specimens of that columnar-appearing epithelium must show evidence of metaplasia, which is a change from one adult cell type to another. To ascertain that columnar-appearing epithelium lines the distal esophagus, the endoscopist first must locate the gastroesophageal junction (GEJ, which is recognized as the most proximal extent of the gastric folds), and then determine that columnar-appearing epithelium extends above the GEJ into the esophagus (Fig. 44-1). Endoscopically, columnar epithelium has a reddish color and velvet-like texture that can be distinguished readily from normal esophageal squamous epithelium, which is pale and glossy. There is disagreement among experts regarding the histologic type of epithelium required to confirm that there is evidence of metaplasia in the esophagus.4 Virtually all would agree that the finding of an intestinal-type epithelium with goblet cells (which has been called intestinal metaplasia, specialized intestinal metaplasia, or specialized columnar epithelium) is clear evidence of metaplasia. Most published studies on Barrett’s esophagus have used intestinal metaplasia as a requisite diagnostic criterion. However, some authorities argue that gastric cardiac-type epithelium, which is composed almost exclusively of mucus-secreting cells, also is metaplastic, has malignant predisposition, and can be considered diagnostic of Barrett’s esophagus.5,6 This debate remains unresolved.

image

Figure 44-1. Endoscopic photograph of Barrett’s esophagus. The arrows mark the gastroesophageal junction (GEJ), which is identified endoscopically as the most proximal extent of the gastric folds. The reddish color and velvet-like texture of the Barrett’s epithelium contrast sharply with the pale and glossy appearance of the esophageal squamous epithelium. Note that Barrett’s columnar epithelium extends well above the GEJ to line the distal esophagus.

Barrett’s esophagus can be further categorized as long-segment (when the metaplastic epithelium extends at least 3 cm above the GEJ) or short-segment (when <3 cm of metaplastic epithelium lines the esophagus).7 Another more recently proposed system for categorizing Barrett’s esophagus, the Prague C and M criteria, identifies the circumferential (C) and the maximum extent (M) of Barrett’s metaplasia.8 Data suggest that the cancer risk in Barrett’s esophagus may vary with the extent of the metaplastic lining. However, the clinical value of the proposed classification systems has not been established and presently patients with any extent of Barrett’s metaplasia are managed similarly.

EPIDEMIOLOGY

Barrett’s esophagus typically is discovered during endoscopic examinations performed for the evaluation of GERD symptoms in middle-aged and older adults.9 The average age at the time of diagnosis is approximately 55 years. The condition is rare in children younger than age 10 and virtually nonexistent in children younger than age 5.10 White men predominate in most series and, for unknown reasons, Barrett’s esophagus is uncommon in black and Asian populations. Among adult patients who have endoscopic examinations because of GERD symptoms, long-segment Barrett’s esophagus is found in 3% to 5%, whereas 10% to 20% have short-segment Barrett’s esophagus.1 In the general adult population of Western countries, the prevalence of Barrett’s esophagus (predominantly short-segment) is between 1.6% and 6.8%.11,12

Published estimates on the annual incidence of cancer in patients with long-segment Barrett’s esophagus have ranged from 0.2% to 2.9%, but it has been shown that many of those estimates were based on older, small studies that suffered from publication bias. Modern, larger studies, which are less susceptible to such bias, suggest that the risk of cancer in the general population of patients with Barrett’s esophagus is approximately 0.5% per year.13

The epidemiology of esophageal adenocarcinoma is similar to that of Barrett’s esophagus. GERD is strongly associated with both conditions and, like Barrett’s esophagus, esophageal adenocarcinoma affects white men predominantly.9,14 Obesity, especially with central adiposity, predisposes to both Barrett’s esophagus and esophageal adenocarcinoma,14,15 and the dramatic rise in the frequency of obesity in the United States has paralleled a similar rise in the prevalence of Barrett’s cancer. The mechanisms underlying these associations with obesity are not clear, but may relate to the fact that central adiposity predisposes to GERD, perhaps by increasing intra-abdominal pressure16 (see also Chapters 43 and 46). Obesity also is associated with elevated serum levels of pro-proliferative hormones such as insulin-like growth factor I (IGF I) and leptin, and with decreased levels of the antiproliferative hormone adiponectin, factors that may contribute to carcinogenesis in Barrett’s esophagus.

It has been proposed that the declining frequency of infection with Helicobacter pylori in Western populations also may be contributing to the rising frequency of esophageal adenocarcinoma (see Chapter 46). A number of studies have suggested that H. pylori infection may protect against the development and neoplastic progression of Barrett’s esophagus, perhaps because, in a subset of patients, this infection may prevent GERD by decreasing gastric acid secretion.17 Other factors that appear to protect against the development of esophageal adenocarcinoma include the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs),18,19 and the consumption of a diet high in fruits and vegetables.18 Although cigarette smoking and alcohol consumption are very strong risk factors for squamous cell carcinoma of the esophagus, cigarette smoking only modestly increases the risk for esophageal adenocarcinoma and alcohol does not appear to affect that risk at all.18

PATHOGENESIS

Patients with long-segment Barrett’s esophagus often have severe GERD (see Chapter 43). Table 44-1 lists some physiologic abnormalities that have been reported in Barrett’s patients, and suggests how those abnormalities might contribute to GERD severity. Individual patients may exhibit any, all, or none of those abnormalities, and their prevalence in Barrett’s esophagus is disputed. For example, some investigators have described normal gastric acid secretion in patients with long-segment Barrett’s esophagus.20 In addition, many patients with short-segment Barrett’s esophagus have no GERD symptoms and no endoscopic signs of esophagitis. Indeed, one large study has suggested that short-segment Barrett’s esophagus may affect approximately 5% of adults, irrespective of the presence of GERD symptoms.11 Studies have shown that even in healthy volunteers, the very distal esophagus can be exposed to acid for more than 10% of the day.21 Such acid exposure can damage the esophagus directly and indirectly when nitrite (generated from dietary nitrate) reacts with acid to produce nitric oxide. High concentrations of nitric oxide in the distal esophagus have been observed in patients with GERD who have ingested nitrate.22

Table 44-1 Proposed Physiologic Abnormalities Contributing to Gastroesophageal Reflux Disease in Patients with Barrett’s Esophagus*

ABNORMALITY POTENTIAL CONSEQUENCES
Extreme LES hypotension Gastroesophageal reflux
Ineffective esophageal motility Defective clearance of refluxed material
Gastric acid hypersecretion Reflux of highly acidic gastric juice
Duodenogastric reflux Esophageal injury caused by reflux of bile acids and pancreatic enzymes
Decreased salivary secretion of epidermal growth factor Delayed healing of reflux-damaged esophageal mucosa
Decreased esophageal pain sensitivity Loss of sensation to refluxed caustic material and resulting failure to initiate therapy

LES, lower esophageal sphincter.

* See Chapter 43 for detailed discussion of these abnormalities.

The progenitor cells that give rise to Barrett’s metaplasia are not known. The prevailing hypothesis is that metaplasia results when GERD damages the esophageal squamous epithelium, thereby exposing multipotential stem cells in the basal layers to gastric juice, which stimulates their abnormal differentiation into columnar cells. Two other candidates for Barrett’s progenitor cells include stem cells in the ducts of the esophageal submucosal glands and circulating bone marrow stem cells.23 Genes that appear to play a key role in the squamous-to-columnar metaplasia of Barrett’s esophagus include certain Cdx genes, which are known to mediate the differentiation of intestinal epithelial cells, and the gene encoding bone morphogenetic protein (BMP)-4, which also is involved in columnar cell differentiation.24 Reflux esophagitis appears to up-regulate the expression of these genes by the squamous epithelium.

Barrett’s epithelial cells appear to be more capable of resisting reflux-induced esophageal injury than the native squamous epithelial cells. Unlike squamous cells, for example, Barrett’s cells secrete mucins and express the tight-junction protein claudin 18, features that render the epithelium more resistant to acid-peptic attack.25,26 Unfortunately, Barrett’s epithelium also is predisposed to neoplasia.

MOLECULAR BIOLOGY OF NEOPLASIA

During carcinogenesis, Barrett’s epithelial cells accumulate a series of genetic and epigenetic alterations that endow the cells with the physiological attributes of malignancy (see Chapter 3). Those include self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and the abilities to invade adjacent structures and to metastasize (Fig. 44-2).27 Numerous genetic alterations have been described during the neoplastic progression of Barrett’s esophagus. Although a single such alteration may have multiple disparate effects, conceptually it can be useful to classify the alteration according to the major physiologic cancer attributes that it endows (see Fig. 44-2).27 For example, the expression of oncogenes (e.g., cyclin D1, K-ras), growth factors (e.g., transforming growth factor-α [TGF-α]), and growth factor receptors (e.g., epidermal growth factor receptor [EGFR]) enable Barrett’s cells to acquire self-sufficiency in growth signals. Insensitivity to antigrowth signals occurs primarily through the inactivation of tumor suppressor genes (e.g., TP53 and p16). Inactivation of TP53 also enables cells to evade apoptosis. Reactivation of the enzyme telomerase, which enables the cells to replace telomeres needed for cell division, can endow the cells with limitless replicative potential.18 Neoplasms can increase their vascular supply by secreting angiogenic factors such as vascular endothelial growth factor (VEGF).18 Finally, for neoplastic cells to invade and metastasize, they must dissociate themselves from surrounding cells by disrupting cell adhesion proteins such as the cadherins and catenins, and by degrading the extracellular matrix through the secretion of enzymes such as matrix metalloproteases (MMPs).18

image

Figure 44-2. Molecular biology of neoplasia in Barrett’s esophagus. Some of the major genetic alterations that have been identified during carcinogenesis in Barrett’s esophagus are shown. The histologic stage at which each genetic change has been recognized is also depicted. These DNA alterations allow the cells to acquire the physiologic attributes of malignancy. EGFR, epidermal growth factor receptor; MMP, matrix metalloprotease; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

During carcinogenesis, Barrett’s epithelial cells display genetic instability manifested as gains or losses in segments of chromosomes, which alter the cells’ deoxyribonucleic acid (DNA) content. Aneuploidy is the condition in which there is abnormal cellular DNA content, and aneuploid cells are at increased risk for neoplastic progression.28 Aneuploidy can be detected by flow cytometry and by fluorescence in situ hybridization (FISH), and has been proposed as a biomarker for neoplastic progression in Barrett’s esophagus, as have a number of the genetic alterations discussed in the preceding paragraph.29 Although there have been some promising preliminary studies, molecular biomarkers are not yet ready for routine clinical use in patients with Barrett’s esophagus.

DYSPLASIA

Before neoplastic Barrett’s cells become malignant, some of the same genetic alterations that endow the physiologic attributes of malignancy also cause morphologic changes in the tissue that the pathologist recognizes as dysplasia (Fig. 44-3). Dysplasia (also called intraepithelial neoplasia) can be viewed as the histologic expression of genetic alterations that favor unregulated cell growth.30 Dysplasia is recognized by cytologic and architectural abnormalities in esophageal biopsy specimens that include (1) nuclear changes such as enlargement, pleomorphism, hyperchromatism, stratification, and atypical mitoses; (2) loss of cytoplasmic maturation; and (3) crowding of tubules and villiform surfaces. Dysplasia is categorized as low-grade or high-grade depending on the degree of histologic abnormalities, with more pronounced abnormalities assumed to reflect more severe genetic damage and greater potential for carcinogenesis. Pathologists have difficulty distinguishing low-grade dysplasia in Barrett’s esophagus from reactive changes caused by reflux esophagitis, and inter-observer agreement for the diagnosis of low-grade dysplasia may be less than 50%. Interobserver agreement is better (approximately 85%) for high-grade dysplasia, but there is substantial disagreement among pathologists in distinguishing high-grade dysplasia from intramucosal carcinoma (see Chapter 46).

image

Figure 44-3. Dysplasia in Barrett’s esophagus. This biopsy specimen taken during endoscopic surveillance shows low-grade dysplasia in the gland at 11 o’clock and high-grade dysplasia in the gland in the center of the photomicrograph.

Dysplasia in Barrett’s esophagus often causes no endoscopically apparent abnormalities, and dysplasia can be patchy in its extent and severity. These factors contribute to the substantial problem of biopsy sampling error in identifying dysplasia. Although endoscopists traditionally have used a four-quadrant biopsy sampling system (essentially a random sampling technique) to find dysplasia in Barrett’s esophagus, this system can miss areas of dysplasia and even cancer. In series of patients who had esophagectomies because endoscopic examination with biopsies revealed high-grade dysplasia in Barrett’s esophagus, for example, a number of studies have found that invasive cancer is present in 30% to 40% of the resected esophagi.31 However, a critical review of those studies suggests that 13% is a more accurate estimate of the frequency of invasive cancer in this situation.32

Researchers have tried to develop endoscopic techniques for recognizing dysplasia and early cancer in Barrett’s esophagus including chromoendoscopy, autofluorescence endoscopy, magnification endoscopy, narrow band imaging, optical coherence tomography, Raman detection methods, and confocal laser endomicroscopy.33 There have been some promising preliminary results (see Chapter 46) but presently none of the techniques has provided sufficient clinical information to justify its routine application in clinical practice.

The overall incidence of cancer development in patients with Barrett’s esophagus is approximately 0.5% per year. A recent study suggests that patients who have non-neoplastic 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.34 Few meaningful data are available on the natural history of low-grade dysplasia in Barrett’s esophagus, but a recent study that included 156 patients with low-grade dysplasia found that they developed cancer at an incidence of 0.6% per year.35 For patients with high-grade dysplasia, however, the cancer risk is substantially higher. A recent critical review estimates that the rate of cancer development for patients with high-grade dysplasia in Barrett’s esophagus is 4% to 6% per year.30

MANAGEMENT

TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE

The general approach to the treatment of GERD for patients with Barrett’s esophagus is very similar to that recommended for patients who have GERD without Barrett’s esophagus (see Chapter 43). One important difference, however, is that modern authorities generally advocate initial and maintenance therapy with a proton pump inhibitor (PPI) for patients with Barrett’s esophagus, irrespective of symptoms and signs of esophagitis. This practice is based on indirect evidence suggesting that acid reflux promotes carcinogenesis in Barrett’s metaplasia, and that aggressive control of acid reflux may interfere with carcinogenesis.35

For patients with Barrett’s esophagus, the elimination of heartburn by antisecretory therapy should not be construed as evidence that acid reflux has normalized. Studies using esophageal pH monitoring have shown that Barrett’s patients may be rendered asymptomatic by PPIs given in dosages that fail to normalize esophageal acid exposure. In one such study of 48 patients with Barrett’s esophagus, for example, 24 of them had persistently abnormal acid reflux during PPI therapy that had abolished their GERD symptoms.36 It has been proposed that patients with long-segment Barrett’s esophagus might be unusually resistant to PPIs, but another study has suggested that this problem is not due to gastric resistance to the antisecretory effects of PPIs.37 In that study, patients with long-segment Barrett’s esophagus treated with high doses of esomeprazole exhibited normal degrees of gastric acid suppression, but up to 23% still had abnormal esophageal acid exposure. This suggests that the so-called PPI resistance of patients with Barrett’s esophagus is a consequence of their profound reflux diathesis.

Some surgeons have proposed that fundoplication might be more effective than antisecretory therapy for preventing cancer in Barrett’s esophagus, but a number of high quality studies on this issue refute that contention. These studies include one randomized controlled trial of medical and surgical GERD therapies, studies using large patient databases, and some meta-analyses.38–40 Available data suggest that antireflux surgery should not be performed solely for cancer prevention in patients with Barrett’s esophagus.

ENDOSCOPIC SURVEILLANCE FOR DYSPLASIA

Although a number of medical societies recommend regular endoscopic surveillance for patients with Barrett’s esophagus, some authorities have questioned the wisdom of these surveillance programs with arguments that can be summarized as follows: (1) Endoscopy is expensive, (2) endoscopy has risks and adverse emotional and financial consequences, (3) the absolute risk of cancer for patients with Barrett’s esophagus (0.5% per year) is small and therefore the large majority of patients derive no benefit from endoscopic surveillance, and (4) there is no proof, in the form of a randomized controlled trial, that endoscopic surveillance for Barrett’s esophagus has any effect on patient survival.

Proponents of endoscopic surveillance counter the aforementioned arguments as follows41: (1) the concept that surveillance for Barrett’s esophagus can prevent deaths from esophageal adenocarcinoma seems reasonable, (2) no proof of efficacy in the form of a randomized controlled trial is likely to become available in the foreseeable future, (3) a number of observational studies suggest that surveillance is beneficial, (4) virtually all of the published computer models on this issue suggest that surveillance can be beneficial, and (5) the risks of endoscopy for otherwise healthy individuals with Barrett’s esophagus are very small, and no study has shown an overall survival disadvantage for patients in surveillance programs. The potentially adverse emotional and financial consequences of establishing a diagnosis of Barrett’s esophagus are regrettable, but less so than the failure to prevent an esophageal cancer. Therefore, the proponents argue, it is ethically wrong for physicians to forgo the potentially life-saving practice of performing endoscopic surveillance for Barrett’s esophagus while awaiting the results of a definitive study that may never appear.

There have been numerous debates at medical meetings and in medical journals regarding the utility of surveillance for Barrett’s esophagus, with no clear winners. This issue is likely to remain contentious for the foreseeable future. Likewise, whether certain individuals should be screened for Barrett’s esophagus is also controversial (see Chapter 46).

Some authorities also recommend a program of expectant management with intensive endoscopic surveillance (i.e., endoscopic examinations every three to six months) for patients with high-grade dysplasia in Barrett’s esophagus, withholding more invasive treatments (discussed following) until biopsy specimens reveal adenocarcinoma.30,42 Although this practice has been endorsed as a management option by the American College of Gastroenterology, few published data directly support the safety and efficacy of intensive surveillance for high-grade dysplasia. Available studies show that intensive endoscopic surveillance generally is safe, but even patients who are compliant with intensive surveillance programs can develop incurable cancers.30

TREATMENT OF DYSPLASIA

Because of difficulties in verifying the diagnosis of low-grade dysplasia and its low rate of progression to cancer, invasive therapies generally are not recommended for patients with low-grade dysplasia in Barrett’s esophagus. For patients found to have high-grade dysplasia, there are several proposed management options, as discussed following. All of these options are associated with substantial risks and uncertain benefits.

Esophagectomy

Esophagectomy is the most definitive and most hazardous of the treatments for dysplasia in Barrett’s esophagus. The average hospital stay for open esophagectomy is approximately two weeks, and 30% to 50% of patients develop at least one serious postoperative complication such as pneumonia, myocardial infarction, and wound infection.43 A number of series describe high operative mortality rates that in some series can exceed 20%. In addition to death and short-term complications, esophagectomy can be accompanied by substantial long-term morbidity including profound weight loss and dysphagia.

Interest in endoscopic therapies for dysplasia has been driven largely by the perception that esophagectomy has unacceptably high rates of mortality and morbidity. However, recent data suggest that for patients with Barrett’s esophagus those rates have been exaggerated. For example, mortality rates for esophagectomy are inversely related to the frequency with which the operation is performed. In a study of data from the Dutch National Medical Registry, the mortality rates for esophagectomy were 12.1%, 7.5%, and 4.9% at centers performing 1 to 10, 11 to 20, and more than 50 esophagectomies per year, respectively.44 Furthermore, estimates of mortality rates for esophagectomy generally have been based on series of patients with esophageal cancer who are often older adults and debilitated. Mortality rates for younger and otherwise healthy patients with dysplasia in Barrett’s esophagus may be substantially lower, especially when the operation is performed by experienced surgeons in a high-volume center. Finally, published data do not confirm the perception that most patients have an unacceptable quality of life after esophagectomy. In a study in which quality of life questionnaires were administered to 199 patients before and after esophagectomy, for example, quality of life was found to decline substantially immediately after the operation, but to return to baseline values within 2 years.45 Thus, the esophagectomy option still warrants serious consideration, especially for young and fit patients.

Endoscopic Therapies (see also Chapter 46)

There are two general types of endoscopic therapies available for the treatment of Barrett’s esophagus: (1) endoscopic ablative therapy, which uses thermal energy (e.g., delivered by laser, electrocoagulation, argon plasma coagulation, the HALO360 System, BÂRRX Medical, Sunnyvale, Calif., cold nitrogen gas) or photochemical energy (photodynamic therapy) to ablate the Barrett’s epithelium; and (2) endoscopic mucosal resection (EMR), in which a diathermic snare or endoscopic knife is used to remove a segment of Barrett’s epithelium, usually down to the submucosa. After these endoscopic treatments, patients are given potent antireflux therapy (usually PPIs) so that the ablated mucosa can heal with the regrowth of normal esophageal squamous epithelium rather than with the regeneration of more Barrett’s epithelium. The ablative therapies destroy metaplastic tissue, but do not provide a pathology specimen by which to judge the depth of neoplastic invasion and the completeness of the ablation. In contrast, EMR provides large tissue specimens that can be examined by the pathologist to determine the character and extent of the mucosal abnormality and, for neoplastic lesions, the depth of involvement and the adequacy of resection.

When reviewing literature on endoscopic therapies for dysplasia, it is important to consider the issue of follow-up duration. Patients treated for carcinomas traditionally have been deemed cured if they have no evidence of the cancer at five years, because it is assumed that any cancer stem cells that survived the treatment would have become clinically manifest within that time. It often takes considerably longer than five years for dysplasia to progress to invasive cancer, however. Five years after the treatment of dysplasia, therefore, it is not appropriate to conclude that a patient who has not developed cancer has been “cured.” Unfortunately, many studies on endoscopic treatments for dysplasia in Barrett’s esophagus include considerably less than five years of follow-up, a factor that severely limits the conclusions that can be drawn regarding efficacy.

Endoscopic Ablative Therapies (see also Chapter 46 and Fig. 46-14)

An ideal ablative technique would inflict an injury deep enough to destroy all of the abnormal epithelium, but not so deep as to cause serious complications like esophageal hemorrhage, perforation, and stricture formation. So far, none of the ablative therapies has achieved this ideal, and all have been associated with serious complications. In addition, the procedures often leave behind residual foci of metaplastic epithelium.46 Partially ablated Barrett’s epithelium can heal with an overlying layer of squamous epithelium that “buries” metaplastic tissue (with its neoplastic potential) and hides it from the endoscopist. Even after apparent complete ablation, furthermore, Barrett’s metaplasia may recur over time.

To date, photodynamic therapy (PDT) has been the most extensively studied of the endoscopic ablative treatments for dysplasia in Barrett’s esophagus (see also Chapter 46 and Fig. 46-14). For PDT, patients are given a systemic dose of a light-activated chemical that is taken up by the esophageal cells. The esophagus is then irradiated using a low-power laser that activates the chemical, which transfers that acquired energy to molecular oxygen. This results in the formation of singlet oxygen, a toxic molecule that destroys the abnormal cells and their vasculature.

In a multicenter randomized trial of PDT using porfimer sodium for high-grade dysplasia in Barrett’s esophagus, 138 patients were treated with PDT plus omeprazole 20 mg twice daily, and 70 received omeprazole 20 mg twice daily alone.47,48 No dysplasia was found on repeat endoscopy with biopsy in 77% of the patients treated with PDT as compared with 39% of the patients who received omeprazole alone (P < 0.0001). During up to 5 years of follow-up, 15% of the PDT patients developed cancer, compared with 29% of those treated with omeprazole alone (P = 0.027). There was no procedure-related mortality, but 69% of the patients who received PDT developed photosensitivity reactions and 36% developed esophageal strictures. Although this study documents the superiority of PDT over PPI alone for eradicating dysplasia and preventing cancer in Barrett’s esophagus, the frequency of serious complications is disconcerting, as is the fact that 15% of the patients who received PDT developed cancer nevertheless.

There has been much recent interest in the HALO360 system (BÂRRX Medical, Sunnyvale, Calif), which uses a balloon-based array of closely spaced electrodes to deliver radiofrequency energy to ablate the esophageal mucosa. This system was designed with the intent of inflicting a uniform, circumferential thermal injury whose depth is controlled by a generator, which can vary the power, density, and duration of the energy applied. There is also a smaller, endoscope-mounted radiofrequency catheter ablation device (the HALO90 ablation catheter) that can be used for the focal ablation of metaplasia that remains behind after treatment with the HALO360 system.

In an uncontrolled study, 142 patients with high-grade dysplasia in Barrett’s esophagus were treated with the HALO360 system.49 There were no serious adverse events reported during 229 total ablation sessions, although 1 patient was found to have developed an asymptomatic esophageal stricture on follow-up endoscopic examination. At least one postablation endoscopy was performed during a median follow-up period of 12 months in 92 patients, only 9 of whom (10%) had high-grade dysplasia found in follow-up esophageal biopsy specimens. However, persistent low-grade dysplasia was found in another 9 patients (10%), and 42 patients (46%) had residual foci of nondysplastic intestinal metaplasia in the esophagus.

The preliminary results of a randomized sham-controlled trial of radiofrequency ablation for patients with dysplasia in Barrett’s esophagus have been presented in abstract form.50 The trial included 64 patients with low-grade dysplasia and 63 with high-grade dysplasia who were randomized to receive either radiofrequency ablation with the HALO360 system or sham ablation. Twelve months after the procedure, no dysplasia was found in esophageal biopsy specimens for 80% of the HALO-treated patients who had high-grade dysplasia at baseline, and for 11% of the patients who received sham treatment (P < 0.001). Among the patients with low-grade dysplasia at baseline, 90% of the HALO-treated patients had no dysplasia at 12 months, compared with 37% of the sham-treated patients (P < 0.001). Complications were few and easily managed. Five patients developed esophageal strictures that resolved with dilation. One patient experienced upper gastrointestinal bleeding, and 2 developed chest pain following the procedure that resulted in overnight hospitalizations.

These reports document the feasibility of eradicating neoplastic Barrett’s epithelium with endoscopic ablation, but none has established the long-term benefit of the techniques for cancer prevention. Endoscopic ablation is expensive, and all of the treatments entail inconvenience and risks. Without histologic examination of the resected esophagus or durations of follow-up well beyond five years, it is not yet possible to verify claims that dysplasia and cancer indeed are “eliminated” by endoscopic ablation.

Endoscopic Mucosal Resection (see also Chapter 46)

EMR commonly is performed using a “suck and cut” method in which the endoscopist elevates the dysplastic area by injecting fluid into the submucosa, after which the elevated mucosa is suctioned into a cap that fits over the tip of the endoscope.51 A polypectomy snare is then deployed around the suctioned area to remove it. A recent variation on this technique is the “band and snare” method that uses a ligating device, similar to that used for endoscopic variceal ligation, which deploys elastic bands around the suctioned mucosal segment without the requirement for prior submucosal fluid injection.52 The banded segment is removed using a polypectomy snare (see Fig. 46-11).

Available reports on limited (noncircumferential) EMR describe few serious complications and virtually no procedure-related mortality. However, esophageal stricturing occurs frequently if EMR is used to remove the entire circumferential extent of Barrett’s epithelium in a single endoscopic session.53 If the EMR specimen shows that there is no submucosal invasion and the margins of the specimen are free of neoplastic cells, then the patient may be cured and an esophagectomy is unlikely to show residual tumor.54 However, limited data suggest that a single cap-assisted EMR leaves neoplastic cells behind in the large majority of cases.

The long-term data that are available on the efficacy of EMR are limited but impressive (see also Chapter 46). Ell and colleagues performed EMR on 100 patients with early adenocarcinomas in Barrett’s esophagus (tumor diameter <20 mm, well-differentiated histology, no invasion of lymphatics or blood vessels, and no evidence of metastases, submucosal invasion, or lymph node involvement).55 There were no serious complications, and the calculated five-year survival rate was an extraordinary 98%. However, recurrent or metachronous 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 recurrence rate shows that EMR often leaves behind cells with neoplastic potential.

A study from the Mayo Clinic compared long-term survivals in patients with high-grade dysplasia who were treated either with esophagectomy or with a combination of EMR and PDT.56 There was no statistically significant difference in survival for patients treated with either of the therapies, even though 6.2% of the patients treated with PDT and EMR were found to have a metachronous esophageal cancer during the follow-up period.

Another recent report describes the long-term results of endoscopic therapies in 349 patients who had high-grade dysplasia or mucosal adenocarcinoma in Barrett’s esophagus.57 Endoscopic treatments included EMR alone for 279 patients, PDT alone for 55, EMR and PDT combined for 13, and argon plasma coagulation alone for 2 patients. Serious complications of endoscopic therapy occurred in 5% of cases (important bleeding in 2 patients, esophageal stricture in 15 patients). During a mean follow-up of 64 months, a complete remission (defined as complete elimination of the neoplastic lesion and at least one follow-up endoscopy showing no neoplasia) was achieved in 97%. However, metachronous neoplasms were found during the follow-up period in 21%. The calculated five-year survival rate was 84%, and none of the deaths were from esophageal cancer.

Available data show that EMR for dysplasia and early cancers in Barrett’s esophagus is safe in experienced hands, and five-year survival rates are excellent. However, most reports have come from only a handful of highly specialized centers, and it is not clear that those results can be duplicated in community practice settings. Furthermore, recurrent neoplasms develop frequently after endoscopic therapy, especially if the residual Barrett’s epithelium is not eradicated, mandating close surveillance.

RECOMMENDATIONS

No management strategy for patients with Barrett’s esophagus has been verified by studies demonstrating that the strategy prolongs life by preventing deaths from esophageal cancer. The bulk of the indirect evidence available suggests that acid suppression with PPIs may reduce the cancer risk in Barrett’s esophagus, and we recommend that Barrett’s patients should be treated with a PPI using whatever dose is needed to control GERD symptoms and to maintain the healing of esophagitis. We do not routinely recommend esophageal pH monitoring to verify that esophageal acid exposure has been normalized by PPI therapy. We also feel that antireflux surgery should not be prescribed solely as a cancer preventive strategy. Finally, we feel that it is appropriate to consider the prescription of low-dose aspirin for its cancer-preventive and cardioprotective effects, especially for patients who are not at high risk for complications of NSAID treatment. Because these patients should already be taking a PPI, the risks of aspirin causing serious gastrointestinal toxicity in average risk individuals should be minimal.

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 to date for the management of patients with Barrett’s esophagus.58 Their guidelines are as follows:

• Patients with Barrett’s esophagus should have regular surveillance endoscopy to obtain esophageal biopsy specimens. GERD should be treated prior to surveillance to minimize confusion in the interpretation of dysplasia caused by inflammation.
• For patients who have had two consecutive endoscopies that show no dysplasia, surveillance endoscopy is recommended at an interval of every three years.
• If dysplasia is noted, another endoscopy should be performed with extensive biopsy sampling (especially from areas with mucosal irregularity) to look for invasive cancer, and the histology slides should be interpreted by an expert pathologist.
• For patients with verified low-grade dysplasia after extensive biopsy sampling, yearly surveillance endoscopy is recommended.
• For patients with verified high-grade dysplasia, treatment should be individualized. If there is accompanying mucosal irregularity, the area should be evaluated by EMR, primarily to determine if there is submucosal invasion (for more details, see Chapter 46).

Individualization of treatments for high-grade dysplasia is based initially on considerations of age, comorbidities, and life expectancy. For example, endoscopic therapy (ablative or EMR), or even no therapy, may be preferable to esophagectomy for an older and infirm patient who has a very limited life expectancy. The extent of the Barrett’s metaplasia is also an important factor when considering endoscopic therapy. Is there short-segment Barrett’s esophagus with a single focus of dysplasia that can easily be removed endoscopically, or is there a long-segment of Barrett’s epithelium with multiple neoplastic areas that make endoscopic treatments difficult and less effective? In the latter situation, a young and otherwise healthy patient may be better served by esophagectomy than by endoscopic therapy. It is also important to consider the patient’s preferences. Is the patient willing to accept the need for long-term endoscopic surveillance and the possibility of recurrence that accompanies the endoscopic treatments for neoplasia in Barrett’s esophagus?

Available data suggest that following EMR, residual, non-neoplastic Barrett’s epithelium should be eradicated to prevent the recurrence of neoplasia. It is not yet clear whether that eradication should be effected by extended EMR or by endoscopic ablation. If all of the Barrett’s epithelium is to be removed by EMR, it seems prudent not to perform circumferential EMR in a single endoscopic session because this practice has been associated with esophageal stricture formation. For endoscopic treatment of long-segment Barrett’s esophagus, the combination of using EMR for the initial staging or treatment of dysplasia along with an ablation procedure to eradicate the remaining Barrett’s epithelium seems most reasonable. Ablation should be delayed for approximately two months (the ideal interval is not known) after the initial EMR to allow the mucosal wound to heal. The preferred ablation procedure is disputed. PDT with porfimer sodium is the most extensively studied of the ablation techniques to date, but this procedure is associated with substantial inconvenience and frequent serious side effects. Preliminary data on radiofrequency ablation with the HALO system suggest that this technique may have similar efficacy to PDT but with less patient inconvenience and fewer side effects. Far more data are needed before dogmatic recommendations can be made regarding the choice of ablation procedure for the eradication of Barrett’s epithelium.

KEY REFERENCES

Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc. 2007;65:3-10. (Ref 55.)

Iijima K, Henry E, Moriya A, et al. Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology. 2002;122:1248-57. (Ref 22.)

Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825-31. (Ref 14.)

Overholt BF, Wang KK, Burdick JS, et al. on behalf of the International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc. 2007;66:460-8. (Ref 48.)

Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut. 2008;57:1200-6. (Ref 57.)

Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142-6. (Ref 3.)

Prasad GA, Wang KK, Buttar NS, et al. Long-term survival following endoscopic and surgical treatment of high-grade dysplasia in Barrett’s esophagus. Gastroenterology. 2007;132:1226-33. (Ref 56.)

Rex DK, Cummings OW, Shaw M, et al. Screening for Barrett’s esophagus in colonoscopy patients with and without heartburn. Gastroenterology. 2003;125:1670-7. (Ref 11.)

Shaheen NJ, Crosby MA, Bozymski EM, Sandler RS. Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology. 2000;119:333-8. (Ref 13.)

Souza RF, Krishnan K, Spechler SJ. Acid, bile and CDX: The ABCs of making Barrett’s metaplasia. Am J Physiol Gastrointest Liver Physiol. 2008;295:G211-18. (Ref 24.)

Souza RF, Morales CP, Spechler SJ. Review article: A conceptual approach to understanding the molecular mechanisms of cancer development in Barrett’s oesophagus. Aliment Pharmacol Ther. 2001;15:1087-100. (Ref 28.)

Souza RF, Spechler SJ. Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach. CA Cancer J Clin. 2005;55:334-51. (Ref 18.)

Spechler SJ. Barrett’s esophagus. N Engl J Med. 2002;346:836-42. (Ref 1.)

Spechler SJ. Dysplasia in Barrett’s esophagus: Limitations of current management strategies. Am J Gastroenterol. 2005;100:927-35. (Ref 30.)

Wang KK, Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol. 2008;103:788-97. (Ref 58.)

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