Gastroenterology
Volume 138, Issue 3 , Pages 854-869, March 2010

History, Molecular Mechanisms, and Endoscopic Treatment of Barrett's Esophagus

  • Stuart Jon Spechler

      Affiliations

    • VA North Texas Healthcare System and The University of Texas Southwestern Medical Center, Dallas, Texas
    • Corresponding Author InformationReprint requests Address requests for reprints to: Stuart Jon Spechler, MD, Division of Gastroenterology, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, Texas 75216. fax: (214) 857-1571
    • ,
  • Rebecca C. Fitzgerald

      Affiliations

    • MRC Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, England
    • ,
  • Ganapathy A. Prasad

      Affiliations

    • Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
    • ,
  • Kenneth K. Wang

      Affiliations

    • Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota

Received 3 December 2009; accepted 11 January 2010. published online 18 January 2010.

John P. Lynch and David C. Metz, Section Editors

Article Outline

This report is an adjunct to the American Gastroenterological Association Institute's medical position statement and technical review on the management of Barrett's esophagus, which will be published in the near future. Those documents will consider a number of broad questions on the diagnosis, clinical features, and management of patients with Barrett's esophagus, and the reader is referred to the technical review for an in-depth discussion of those topics. In this report, we review historical, molecular, and endoscopic therapeutic aspects of Barrett's esophagus that are of interest to clinicians and researchers.

Keywords: Gastroesophageal Reflux, Esophageal Neoplasms, Gene Expression Regulation

Abbreviations used in this paper: BMP, bone morphogenetic protein, EMR, endoscopic mucosal resection, GERD, gastroesophageal reflux disease, LOH, loss of heterozygosity, PDT, photodynamic therapy, RFA, radiofrequency ablation

 

Barrett's esophagus is a condition named for the late Norman Rupert Barrett, an influential esophageal surgeon who was born in Adelaide, Australia, in 1903.1 Barrett worked for most of his career as a consultant surgeon at St. Thomas' Hospital in London. He was a pioneer in the field of thoracic surgery and a charismatic academic leader who served for more than 25 years as editor of Thorax. By all accounts, Norman Barrett was an outstanding surgeon, scholar, and teacher. However, Norman Barrett was not the first to describe the condition that now bears his name; in fact, his original contentions about the nature and pathogenesis of the condition were incorrect. The eponym “Barrett's esophagus” continues to evoke confusion and controversy, and authorities still dispute the definition of the disorder.2 To appreciate these controversies, it is helpful to consider some key events in the relatively brief history of Barrett's esophagus.

In 1950, Barrett published a treatise proposing that the esophagus should be defined as “that part of the foregut, distal to the cricopharyngeal sphincter, which is lined by squamous epithelium.”3 He commented on earlier reports describing patients with ulcerations in a tubular organ that grossly appeared to be the esophagus but had a distal, ulcerated portion lined by columnar epithelium. Because Barrett had defined the esophagus by its squamous lining, he argued that the ulcerated, columnar-lined viscus described in those reports was a tubular segment of stomach that had been tethered within the chest by a congenitally short esophagus. To support that contention, Barrett noted that the ulcerated columnar lining always was identified as “histologically gastric in type.”

Barrett himself claimed that peptic ulcer of the esophagus was first reported in 1839 by the German pathologist Albers.3 However, credit for describing the columnar-lined esophagus probably should go to Wilder Tileston, a pathologist who, while working in Boston in 1906, described 3 cases of “peptic ulcer of the oesophagus” and noted “the close resemblance of the mucous membrane about the ulcer to that normally found in the stomach.”4 Tileston wrote that “the first requisite for the formation of the peptic ulcer of the oesophagus is an insufficiency of the cardia” (ie, gastroesophageal reflux). Thus, almost a half-century before Barrett, Tileston described the columnar-lined esophagus and correctly attributed the pathogenesis of the associated ulceration to gastroesophageal reflux.

In 1953, Allison and Johnstone described 7 patients who had reflux esophagitis involving an “oesophagus lined with gastric mucous membrane.”5 In this report, they refuted Barrett's contention that the tubular, intrathoracic, columnar-lined viscus was stomach. They noted that, unlike the stomach, the columnar-lined organ lacked a peritoneal covering, harbored islands of squamous epithelium, and had submucosal glands and a muscularis propria typical of the esophagus. In deference to Barrett, the editor of the journal to which they had submitted their report, Allison and Johnstone suggested that ulcerations in the columnar-lined esophagus should be called “Barrett's ulcers.” Barrett eventually accepted Allison and Johnstone's arguments and, in a report published in 1957, suggested that the condition should be called “lower oesophagus lined by columnar epithelium.”6 Whether justified or not, the eponym “Barrett's esophagus” has been retained.

In another influential report published in Thorax in 1961, an Australian surgeon named John Hayward elaborated his opinions on the histologic features of the distal esophagus.7 He contended that the distal 1 to 2 cm of the esophagus is normally lined by a mucus-secreting, junctional epithelium (also called gastric cardia-type epithelium). Hayward argued that “…if squamous epithelium joined gastric epithelium of fundal [acid-secreting] type directly, it would be liable to digestion at the junction. The buffer zone of junctional epithelium, which does not secrete acid or pepsin but is resistant to them, has to be interposed.” Hayward provided no data to support his contentions, and Barrett remarked that Hayward's report contained “a lot of nonsense.”1 Nevertheless, Barrett published the report essentially unaltered, and it has had substantial influence on the course of studies on Barrett's esophagus.

The histology of the columnar-lined esophagus remains a controversial issue to this day. Barrett, and virtually all of the investigators who wrote about the condition before he did, described an acid-secreting, gastric type of columnar epithelium lining the esophagus.3 In 1951, Bosher and Taylor were the first to describe intestinal-type goblet cells in the columnar-lined esophagus.8 In 1952, Morson and Belcher reported a patient who had an adenocarcinoma in an esophageal mucosa that had “atrophic changes with a tendency towards intestinal type containing many goblet cells.”9 Still other investigators described cardia-type epithelium in Barrett's esophagus.10

This confusing situation was clarified somewhat in 1976, when Paull et al reported a systematic study of 11 patients with Barrett's esophagus who had esophageal biopsy specimens taken above the lower esophageal sphincter using manometric guidance.11 Those patients were found to have as many as 3 types of columnar epithelia lining the distal esophagus: (1) a junctional (cardia-type) epithelium that comprised mucus-secreting cells, (2) a gastric fundic-type epithelium with parietal and chief cells, and (3) intestinal-type metaplasia, which the authors called specialized columnar epithelium, with prominent goblet cells. The 3 epithelial types occupied different zones in the columnar-lined esophagus, with intestinal-type metaplasia adjacent to squamous epithelium in the most proximal segment, followed by cardia-type epithelium, with gastric fundic-type epithelium lining the most distal esophageal segment.

By the 1970s, it was well established that Barrett's esophagus was associated with severe gastroesophageal reflux disease (GERD) and hiatal hernia,12, 13, 14 conditions that can obscure the endoscopic landmarks used to identify the gastroesophageal junction. Endoscopists intent on collecting biopsy samples from the distal esophagus of patients with these disorders could mistakenly take those specimens from the proximal stomach, resulting in a spurious diagnosis of Barrett's esophagus lined by gastric-type epithelium. Further complicating diagnostic issues, Hayward had contended that even the normal esophagus could be lined by up to 2 cm of cardia-type epithelium.7 Therefore, analysis of biopsy samples from this “normal” columnar mucosa also might result in a spurious diagnosis of Barrett's esophagus. These factors created major problems for investigators, because accurate diagnostic criteria are a prerequisite for a meaningful study of a disease.

In the early 1980s, investigators intent on avoiding the problem of spurious diagnoses established diagnostic criteria for Barrett's esophagus based on an arbitrary extent of esophageal columnar lining above the gastroesophageal junction. For example, Skinner et al chose 3 cm as the extent of esophageal columnar lining required for patients to be enrolled in studies of Barrett's esophagus.15 These arbitrary, investigative criteria were eventually used by clinicians as diagnostic criteria. As a result, endoscopists often dismissed columnar epithelium limited to the distal few centimeters of the esophagus as normal and obtained biopsy specimens to confirm a diagnosis of Barrett's esophagus only when columnar lining extended some arbitrary distance (eg, >3 cm) above the gastroesophageal junction. Furthermore, endoscopists sought to identify Barrett's esophagus almost exclusively in patients who had symptoms and endoscopic signs of severe GERD. By adhering to such diagnostic guidelines, physicians minimized the problem of misdiagnosis but failed to identify short segments of metaplastic epithelium in the distal esophagus.

By the 1980s, it was well established that adenocarcinoma was associated with Barrett's esophagus.16, 17, 18 When reports of esophageal adenocarcinomas in patients with Barrett's esophagus provided a description of the associated Barrett's epithelium, they almost invariably identified that epithelium as intestinal-type metaplasia, usually with dysplastic features.19 By the late 1980s, intestinal metaplasia was widely regarded as both the most common type of Barrett's epithelium and the epithelial type associated with cancer development.20, 21 Barrett's esophagus had little clinical importance outside of its malignant predisposition, and intestinal metaplasia was distinct in its histologic appearance (and, unlike the gastric types of Barrett's epithelia, clearly abnormal when located at the gastroesophageal junction). Consequently, some researchers chose to define Barrett's esophagus by the presence of intestinal metaplasia.22, 23 This diagnostic criterion, arguably based more on convenience than on science, also was adopted into clinical practice.

An esophageal biopsy specimen showing intestinal-type metaplasia had become virtually a sine qua non for the diagnosis of Barrett's esophagus by the early 1990s.22 Nevertheless, in the early 1990s, most endoscopists would not take esophageal biopsy specimens to seek a diagnosis of Barrett's esophagus unless their patients had GERD with some minimal extent of esophageal columnar lining (eg, at least 3 cm). That practice was challenged in 1994, when Spechler et al showed that 18% of consecutive patients in a general endoscopy unit who had columnar epithelium that involved <3 cm of the distal esophagus also had intestinal metaplasia.24 Furthermore, they showed that symptoms and endoscopic signs of GERD were not reliable markers for intestinal metaplasia in the distal esophagus. Numerous subsequent studies confirmed that short segments of intestinal metaplasia frequently line the distal esophagus of individuals with no signs or symptoms of GERD.25, 26, 27 Since the late 1990s, therefore, Barrett's esophagus has been categorized as long segment (when the metaplastic epithelium extends at least 3 cm above the gastroesophageal junction) or short segment (when there is <3 cm of metaplastic epithelium lining the esophagus).28 Thus, 5 decades after the publication of Norman Barrett's treatise, the diagnostic criteria for Barrett's esophagus had evolved from an esophagus lined extensively by gastric epithelium in patients with severe GERD to an esophagus lined by any extent of intestinal epithelium in patients who might not have GERD.

A recent issue of contention is whether the presence of gastric cardia-type epithelium in the distal esophagus warrants a diagnosis of Barrett's esophagus.29 Recent guidelines from the British Society of Gastroenterology specifically state that only “columnar lined oesophagus on histology” (ie, cardia- or intestinal-type epithelium) is needed for the diagnosis of Barrett's esophagus.30 Data indicate that cardia-type epithelium is not normal, as Hayward had contended, but rather a metaplastic lining that develops as a consequence of GERD.31 Histochemical and genetic studies of cardia-type epithelium have revealed molecular abnormalities, similar to those found in intestinal metaplasia, that could predispose patients to carcinogenesis,32, 33 and recent clinical studies support the concept that cardia-type epithelium has malignant potential.34, 35, 36 This issue and others related to diagnostic criteria for Barrett's esophagus are discussed in detail in the AGA Institute's technical review on Barrett's esophagus, which recommends that Barrett's esophagus should now be defined 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.”

Physicians should consider how and when the diagnostic criteria for Barrett's esophagus changed when evaluating reports on the disorder. Short-segment Barrett's esophagus was not widely recognized until 1994,24 and the vast majority of studies reported before that year included patients with only long-segment disease. More recent studies, however, include a substantial proportion of patients with short-segment Barrett's esophagus. Patients with short- and long-segment Barrett's esophagus can differ considerably in the severity of their associated GERD and risk of developing esophageal adenocarcinoma. It is therefore not appropriate to extrapolate the results of older studies on the epidemiology and natural history of Barrett's esophagus to patients with short-segment disease.

Back to Article Outline

Molecular Events That Underlie Metaplasia and Cancer in Barrett's Esophagus 

GERD and Metaplasia 

Long-segment Barrett's esophagus is associated with GERD, and the epithelial metaplasia characteristic of Barrett's esophagus is widely regarded as a consequence of GERD (Figure 1A and B). Early investigators proposed that Barrett's esophagus developed from gastric columnar cells that migrated from the stomach into the esophagus to reconstitute GERD-damaged squamous epithelium.5 This hypothesis did not account for the intestinal metaplasia typical of Barrett's esophagus, however. The prevailing hypothesis now is that Barrett's esophagus forms when GERD damages the esophageal squamous epithelium, thereby exposing multipotential stem cells in the basal layers to refluxed gastric juice that stimulates abnormal differentiation.37, 38, 39 These progenitor cells may also be present in the ducts of esophageal mucosal glands.40 One recent study has suggested that circulating stem cells of bone marrow origin might contribute to the development of Barrett's esophagus.41 Although the progenitor cell for Barrett's esophagus remains unknown, metaplasias must arise from changes in cellular gene expression and, in Barrett's esophagus, those changes appear to be induced by GERD.

  • View full-size image.
  • Figure 1. 

    A schematic illustrating the sequential somatic genetic changes in the progression from the squamous esophagus to Barrett's esophagus to adenocarcinoma. (A) The normal squamous esophagus undergoes a metaplastic transformation with the oxidative damage and chronic inflammation that accompanies chronic gastroesophageal reflux. (B) The initial metaplastic change is followed early on by the loss of one p16 allele; this clone may then expand (pink area, C), followed by loss of the second p16 allele and the formation of some p16 null clones (blue area, C). (D) The subsequent loss of p53 may be associated with morphologic changes of low-grade dysplasia (LGD). (E) Genetic instability may lead to aneuploidy, which is commonly seen with high-grade dysplasia (HGD). (F) Numerous clones may develop, and there may be heterogeneity within clones, especially as the degree of genetic instability increases and invasive adenocarcinoma develops.

Recent studies have reported molecular events in esophageal squamous epithelium that might be triggered by gastroesophageal reflux to cause Barrett's metaplasia. In esophageal squamous cell lines, for example, acid and bile induce the expression of caudal homeobox genes such as CDX1 and CDX2.42, 43, 44, 45 The word homeobox originates from the Greek homeosis, meaning a shift in structural development; homeobox genes encode transcription factors that regulate cell differentiation during embryogenesis. In adult cells, alterations in homeobox genes might alter cellular phenotypic features.46, 47 Homeobox gene expression in adult cells can be regulated epigenetically, such as through alterations in gene promoter methylation, or via cell signaling pathways regulated by factors such as bone morphogenetic proteins (BMPs) or fibroblast growth factors.45, 48

Compared with normal esophageal squamous epithelium, BMP4 expression is increased in Barrett's metaplasia; in a rat model of reflux-induced Barrett's esophagus, BMP4 expression is increased in the stroma that underlies the Barrett's metaplasia.49 Cultures of human esophageal squamous cells treated with BMP4 express cytokeratins that are characteristic of columnar cells.49 Bile acids, at neutral and acidic pH levels, cause a cancer cell line to express CDX2 through ligand-dependent transactivation of the epidermal growth factor receptor.50 It was therefore proposed that GERD induces the expression of Cdx genes through BMP4 and, perhaps, epidermal growth factor receptor activation and that GERD-induced Cdx expression might partially mediate the development of Barrett's metaplasia.47

GERD and Carcinogenesis in Barrett's Esophagus 

Tumor initiation is the process in which cells are changed so that they are able to form tumors. Although GERD clearly plays a role in the pathogenesis of Barrett's metaplasia, it is not clear whether gastroesophageal reflux can initiate tumor formation in the metaplastic cells. Studies have shown that esophageal cells exposed to acid develop DNA double-strand breaks that might contribute to tumor initiation.51, 52 In addition, deoxycholic acid (a bile acid) induces DNA damage in a dose-dependent but nonlinear fashion.53, 54 These DNA injuries appear to be mediated by reactive oxygen species, so antioxidants could have chemopreventive effects in patients with Barrett's esophagus.

In addition to its potential role in initiating tumor development, GERD might also promote the growth of established neoplasms in Barrett's esophagus (a process called tumor promotion). Acid and bile exposure alter Barrett's cell kinetics55, 56, 57, 58 so as to enable cells that have sustained DNA damage to resist apoptosis via activation of the nuclear factor κB pathway.59 Other studies have shown that acid and bile salts increase nuclear factor κB activity60 and have effects on molecules involved in inflammation and proliferation.61, 62, 63 For example, the farnesoid X receptor, a nuclear receptor that regulates inflammation, is up-regulated by deoxycholic acid in vitro.64 Tuberous sclerosis complex 1 is a tumor suppressor that regulates the mammalian target of rapamycin pathway; in neoplastic Barrett's cells, bile acids deregulate the tuberous sclerosis complex/mammalian target of rapamycin pathway.65 There are therefore several potential mechanisms by which gastroesophageal reflux of acid and bile might initiate and promote tumors in Barrett's esophagus.

Obesity, Metabolic Syndrome, and Barrett's Esophagus 

Obesity is a risk factor for Barrett's esophagus and Barrett's adenocarcinoma,66, 67 especially an abdominal pattern of obesity, which has been associated both with GERD and Barrett's esophagus.68 The mechanical effects of intra-abdominal fat might adversely affect the anatomic antireflux barrier.69 The metabolic syndrome is also frequently observed in patients with Barrett's esophagus70; the adipocytokines associated with the metabolic syndrome and central adiposity have been proposed to contribute to the development of GERD, Barrett's esophagus, and cancer.71 For example, adipose tissues secrete inflammatory cytokines such as tumor necrosis factor α and interleukin-6, as well as pro-proliferative hormones such as leptin and insulin-like growth factor 1 that might promote carcinogenesis. Obesity is also associated with low levels of the antiproliferative hormone adiponectin, and low plasma levels of adiponectin have been described in patients with Barrett's esophagus.72 Nevertheless, the precise nature of the relationships among the metabolic syndrome, GERD, Barrett's esophagus, and cancer remains to be established.

Diet and Barrett's Esophagus 

The role of specific dietary factors in the pathogenesis of Barrett's esophagus is not clear. In patients with GERD, the distal esophagus can be exposed to high concentrations of nitric oxide and other nitrosating species, which are generated from the nitrate in green leafy vegetables in the diet.73 Those nitrosating species are capable of causing DNA double-strand breaks, which are potentially carcinogenic.51 These types of oxidative injuries to DNA might be prevented by dietary antioxidant compounds such as polyphenols. Modest wine intake has been associated with a lower risk of Barrett's esophagus and esophageal adenocarcinoma, possibly from the reduction in oxidative stress provided by polyphenols in wine.74

Iron also might have a role in the development of esophageal cancer. After the surgical induction of reflux in rats, the rate of development of esophageal adenocarcinoma is substantially higher in animals that receive iron supplementation.75 One study described overexpression of iron transport proteins in the progression of Barrett's metaplasia to adenocarcinoma, and cultured cancer cells loaded with iron increased proliferation.76 Reduced iron levels in premenopausal women might underlie the delayed onset of adenocarcinoma in women with Barrett's esophagus.77 However, no link has been found between hemochromatosis (excess iron storage) genes and Barrett's esophagus, so the relationship between iron metabolism and this condition is complex.78

Genetics, Carcinogenesis, and Barrett's Esophagus 

Unlike the well-characterized sequence of genetic alterations that lead to some forms of colon cancer, no well-defined pathway has been shown to mediate the pathogenesis of adenocarcinoma in Barrett's esophagus. There is considerable genetic heterogeneity among the adenocarcinomas that develop in patients with Barrett's esophagus, which frequently involve alterations in tumor suppressor genes.79, 80 A number of the many molecular changes that have been described in Barrett's-associated cancers are so-called “hitchhiker mutations” that do not directly contribute to carcinogenesis but are retained in the cancer cell genome because they are linked to oncogenic mutations.81 It is not clear which of the many genetic changes described in Barrett's esophagus are required for oncogenesis; when these are identified, they might be used in diagnosis and as therapeutic targets.

In general, both alleles of a tumor suppressor gene must be silenced to contribute to carcinogenesis. The first silencing event (allele 1) usually involves a DNA nucleotide sequence change mutation (eg, a nucleotide base excision or deletion). The second silencing event (allele 2) can also be a sequence change mutation but more commonly involves loss of a chromosome segment after a faulty cell division (so-called loss of heterozygosity [LOH]). Methylation of DNA cytosine residues in the gene promoter region is another common gene silencing mechanism.

Alterations in genes that encode the tumor suppressors p16 (CDKN2A) and TP53 are frequently found in cells from Barrett's esophagus samples. Loss of expression of a CDKN2A allele, usually through methylation of its promoter, is found in nondysplastic Barrett's metaplasia in 85% of cases (Figure 1B).82, 83, 84 The CDKN2A mutations found in Barrett's metaplasia appear to have been caused by oxidative damage in areas of chronic inflammation.85 LOH has been observed in CDKN2A in dysplastic regions of Barrett's esophagus (Figure 1B and C).82, 83, 86, 87 CDKN2A abnormalities do not always alter esophageal cell proliferation and the affected cells can remain diploid, so these defects might not cause histologic abnormalities.85, 88 However, there is little point in testing for loss of p16 expression to predict adenocarcinoma risk because it occurs with such high frequency that it is not a useful biomarker.81

In addition to being part of the coding sequence of p16, exon 2 of CDKN2A is also part of the region that encodes p14ARF (alternate reading frame). P14ARF is a tumor suppressor that prevents degradation of TP53. Because p16 expression is down-regulated so frequently in Barrett's metaplasia, there has been interest in whether p14ARF expression is also lost. p14ARF expression appears to be lost in approximately 30% of Barrett's cancers. Data indicate that p14ARF loss is a relatively late event that is independent of the loss of p16 expression in Barrett's metaplasia. The loss of p14ARF expression appears to occur primarily as the result of CpG or histone methylation, rather than LOH.89

The appearance of low-grade dysplasia in Barrett's esophagus often coincides with the loss of TP53 expression through methylation of the gene promoter, mutations, or LOH in cells that have already lost p16 expression (Figure 1D). LOH at TP53 is associated with a 16-fold increase in the rate of progression to cancer.90 Certain mutations in TP53 result in nuclear accumulation of the resulting nonfunctional p53 protein that can be detected by immunohistochemistry. A large, nested, case-control study found that TP53 staining was increased in biopsy specimens from patients who developed esophageal adenocarcinoma compared with controls, with an odds ratio of 11.7 91, 92

Cells that lose TP53 expression often acquire an abnormal content of DNA (tetraploidy or aneuploidy) that can be detected by flow cytometry. These DNA changes correlate with increased proliferation and expansion of the proliferative compartment toward the mucosal surface.93, 94, 95 The increased proliferation is associated with an increase in the proportion of cells in the S phase of the cell cycle and increased expression of cell cycle–related proteins such as cyclins.85, 92, 96 These molecular changes and the associated proliferative abnormalities are often accompanied by histologic changes in tissues recognized as high-grade dysplasia (Figure 1E). Widespread LOH at TP53 and cytogenetic abnormalities are associated with an increased risk of cancer, perhaps because these changes increase sensitivity to mutagens.96, 97, 98, 99

Aneuploidy has diverse effects on cell metabolism, proliferation, and immortalization.100 Chromosomal copy number changes (a manifestation of aneuploidy) do not appear to be random events in Barrett's cells. Aneuploidy at chromosomes 4 and 7 usually occurs early in carcinogenesis, followed by aneuploidy at chromosomes 8 and 17 and then by the loss of the Y chromosome in cells from male patients.101, 102 The presence of ploidy abnormalities in esophageal cells increases the risk of cancer among patients with Barrett's esophagus (relative risks of 4.4 and 11 for tetraploidy and aneuploidy, respectively, and 20 when both are present).103

At advanced stages of neoplastic progression, the Barrett's esophagus often harbors multiple distinct clones that exhibit variable degrees of expansion (Figure 1F),104 and the level of clonal diversity correlates with the risk of adenocarcinoma development.97, 105 One study found that samples of adenocarcinoma in Barrett's esophagus had such high levels of genomic heterogeneity that even neighboring crypts had distinct genetic profiles.106 This genomic heterogeneity results from local variations in the microenvironment of different regions of the esophagus (so-called microenvironmental niches) or from genetic instability.105 However, microsatellite instability, which often underlies colorectal carcinomas, does not seem to contribute importantly to carcinogenesis in Barrett's esophagus.107

The number of molecular abnormalities identified in Barrett's esophagus has greatly increased with advances in high-throughput screening techniques for genomic and epigenetic alterations. Unfortunately, our understanding of the functional implications of these abnormalities and how they might be used to improve patient care lags behind. Application of concepts from other disciplines, such as evolutionary biology and bioinformatics, should facilitate progress in understanding causality. This information might be used to develop noninvasive tests for determining which patients will benefit most from the exciting new endoscopic techniques available for treatment of patients with Barrett's esophagus.

Back to Article Outline

Endoscopic Therapy for Barrett's Esophagus 

Endoscopic ablative therapy for Barrett's esophagus is based on the principle that, when gastroesophageal acid reflux is controlled by medical or surgical means, squamous epithelium replaces ablated metaplastic epithelium. This principle was first validated more than 20 years ago in subjects whose Barrett's epithelium was ablated by endoscopic laser treatment.108, 109 Since then, endoscopic ablation has advanced from an experimental approach to a valid therapeutic option that is endorsed by professional societies.110, 111 Large cohort studies with long durations of follow-up have documented the durability of endoscopic therapies and the comparability of their outcomes to those of traditional surgical treatment for neoplasia in Barrett's esophagus.112, 113, 114 The efficacy of endoscopic ablation has been confirmed in multicenter, randomized, controlled trials.115, 116, 117 Nevertheless, many questions remain regarding which patients are appropriate candidates for endoscopic therapy and which endoscopic eradication technique is most effective in preventing cancer.118, 119

Techniques of endoscopic therapy for Barrett's esophagus can be categorized broadly into those that provide tissue for histologic examination (endoscopic mucosal resection [EMR] and endoscopic submucosal dissection) and those that do not (ablative therapies). The ablative therapies can be further classified as heat-generating thermal techniques (radiofrequency ablation [RFA], multipolar electrocoagulation, and argon plasma coagulation), photochemical techniques (photodynamic therapy [PDT]), and cryotherapy. Multimodal endoscopic therapy, which uses a resection technique to remove visible abnormalities followed by an ablation technique to eradicate the remaining Barrett's epithelium, is considered to be the most comprehensive endoscopic management of neoplasia in Barrett's esophagus. Table 1 summarizes the evidence for efficacy, advantages, and limitations of each technique.

Table 1. Studies on Endoscopic Therapies for Barrett's Esophagus: Outcomes, Advantages, and Limitations
TechniqueStudyStudy designDysplasia grade included (sample size)OutcomesAdvantagesLimitations
Endoscopic resection techniques
Focal endoscopic resectionPech et al113aSingle-center cohort
HGD (61)

IMCA (288)

Median follow-up, 63 mo


CR-D, 97%

Recurrence of HGD/IMCA, 21.5%

Overall 5-year survival, 84%


Allows precise determination of depth of invasion and assessment of margins

Less variability in pathologic assessment


May need multiple sessions to achieve remission

Focal EMR alone may be associated with higher recurrence rates and positive margins

Bleeding (0.6%–6%)

Perforation (0%)

Stricture (4%)

Prasad et al114bSingle-center cohort study (endoscopic: PDT/EMR and surgical cohorts)
IMCA (178)

Median follow-up:

Surgery, 64 mo

Endoscopy, 43 mo


CR-D, 94%

Recurrent cancer, 12%

Overall 5-year survival: 83% in the endoscopy group and 95% in the surgery group

Circumferential endoscopic resectionGondrie et al162Multicenter cohort study
HGD/IMCA (149)

Median follow-up, 18 mo


CR-IM, 97%

Recurrent neoplasia, 3%

2–3 sessions needed to achieve CR


Low rate of recurrence by removing all at-risk mucosa

With availability of EMR ligation easier to perform


Perforation, 1%

High stricture rate, 52%

Bleeding, 1%–4%

Ridges of tissue persist between EMR sites, which may contribute to recurrence

Buried metaplasia (8%)

Larghi et al123
Multicenter cohort study


HGD/IMCA (26)

Median follow-up, 28 mo


CR-IM, 88%

Recurrent neoplasia, 4% (IMCA)

Submucosal dissectionYoshinaga et al163Single-center cohort study
Gastroesophageal junction adenocarcinoma (24)

Median follow-up, 30 mo


CR, 72%

No recurrence in those with CR


En bloc resection allows clear margins to be obtained

May be more suitable in lesions >2 cm in diameter


Long procedure times

Strictures

Endoscopic ablation techniques
Thermal
Multipolar electrocoagulationSampliner et al135Multicenter cohort study
No dysplasia (58)

Median follow-up, 6 mo

CR-IM, 78%
Technically easy

Relatively inexpensive

Well tolerated (1/58 developed stricture, 1/58 hospitalized for chest pain)

Persistent reversal of IM at 24 mo in 68%


Difficult to treat longer segments (study used 10F probe via therapeutic endoscope)

Not used for treatment of HGD

Short follow-up

Sharma at al164Multicenter RCT (comparing MEPC and APC)
No dysplasia and LGD (35)

Median follow-up, 24 mo


CR-IM, 83% (75% MPEC, 63% APC)

CR-IM at 24 mo, 68%

Argon plasma coagulationAttwood et al165Single-center cohort study
HGD (29)

Median follow-up, 37 mo


CR-D, 86%

CR-IM, 76%

4 patients progressed to EAC

1 esophageal perforation

Technically easy to perform
Dosimetry variable across studies

Superficial effect leads to high prevalence of buried metaplasia

Perforation reported

Limited evidence in HGD

Ferraris et al166Multicenter cohort study
No dysplasia (96)

Median follow-up, 36 mo


CR-IM 96%

Recurrence 18%

RFAShaheen et al147Multicenter, sham-controlled, RCT
HGD (64)

LGD (63)


CR-IM (12 mo), 77% vs 2.3%

CR-D (12 mo):
HGD, 81% vs 19%

LGD, 90% vs 23%

Progression to cancer, 19% vs 2%



Well tolerated by most patients

Low stricture rate (6%)

Low rate of subsquamous Barrett's esophagus (5%)


Ablation requires multiple steps

Long-term data on durability of ablation and recurrence not available

Fleischer et al116Multicenter cohort studyNo dysplasia (100)
CR-IM (12 mo), 70%

CR-IM (30 mo), 96%

Photochemical
Porfimer PDTOverholt et al115Multicenter, partially blinded, controlled RCTHGD (208)
CR-HGD (24 mo), 77% vs 38%

CR-IM (24 mo), 52% vs 7%

CR-D (24 mo, 59% vs 14%


Easy to administer

Results of RCT durable at 5 years33


Photosensitivity (60%)

Strictures (27%–39%)5

Significant postprocedure morbidity

Prasad et al141Single-center cohort study (endoscopic: PDT/EMR and surgical cohorts)HGD (199)
Overall survival comparable at 5 years between endoscopic and surgical cohorts

No death from esophageal carcinoma in both groups

Compares favorably to esophagectomy36
ALA PDTPech et al167Single-center cohort study
HGD (35)

IMCA (31)


CR-D, 100%

CR-D, 97%

Median follow-up, 37 mo


Oral administration of 5-ALA

Limited photosensitivity


Minor adverse effects, 40%

No strictures reported

29% recurrent carcinoma

Peters et al144Single-center cohort studyResidual HGD or IMCA after EMR (23)
CR-D, 75%

CR-IM, 0%

Median follow-up, 30 mo

Recurrent HGD, 27%

Oral administration of 5-ALA
Major adverse effects: arrhythmia, hypotension, hematemesis

Buried metaplasia in 33%

High recurrence rate

Death has been reported

Cryotherapy
Liquid N2 sprayGreenwald et al150Multicenter cohort studyIMCA, HGD, nondysplastic Barrett's esophagus, severe squamous dysplasia (77)
CR-D, 88% (in HGD)

CR-IM: 53%

1 perforation (in patient with Marfan syndrome)

3 esophageal strictures

Adverse effects: chest pain (17%), dysphagia (13%)


No mucosal contact required

Well tolerated by most patients


Dosimetry not well established

No controlled data available

Technically challenging: need for accompanying decompression tube, visibility impaired due to freezing

CO2 sprayCanto et al151Single-center cohort study
HGD/IMCA (44)

Median follow-up, 12 mo

CR-IM 86% (after median of 6 procedures)Initial promising results in patients who failed other forms of ablation (n = 25), including EMRAdditional decompression tube not needed; may be option for patients who fail RFA, PDT

HGD, high-grade dysplasia; IMCA, intramucosal carcinoma; CR-D, complete remission–dysplasia; CR-IM, complete remission–intestinal metaplasia; RCT, randomized controlled trial; MEPC, multipolar electrocoagulation; APC, argon plasma coagulation; LGD, low-grade dysplasia; 5-ALA, 5-aminolevulinic acid.

aAdditional ablative therapy used: PDT used in 64 patients, APC in 136 patients.

bAdditional ablative therapy used PDT used in 43 patients.

EMR 

EMR involves the removal of mucosal and submucosal tissue, usually after the targeted mucosal segment is elevated by the submucosal injection of fluid.120, 121 The most commonly used EMR technique is the “suck and cut” method, wherein the mucosal lesion is sucked into a cap on the tip of the endoscope and then resected using a diathermic snare. There is also a “band and snare” method that uses a band ligating device, similar to that used for endoscopic variceal ligation, which deploys elastic bands around the suctioned mucosal segment. The banded segments are then removed with a snare. The band ligation method allows multiple resections to be completed in a single intubation and does not always require submucosal fluid injection before banding. The 2 EMR techniques have been compared; the suck and cut method provides larger tissue samples, whereas the band ligation technique is faster and less expensive for multiple resections.122 EMR can be applied focally (to resect only a visible lesion) or circumferentially (to remove the entire segment of Barrett's metaplasia).113, 114, 123

Compared with conventional endoscopic biopsy methods, EMR allows for more precise characterization of neoplasia, less interobserver variation among pathologists, and more accurate assessments of dysplasia grades and the depths of invasion.124, 125 In addition, the pathologist can provide information about neoplastic involvement in the margins of the resection specimens.126 All of this information is invaluable in determining whether endoscopic therapy is adequate or whether surgical resection is required to cure neoplasias in patients with Barrett's esophagus. Results of the 2 approaches are summarized in Table 1.

Accurate T staging of the depth of neoplastic involvement is required to determine whether endoscopic therapy can be considered definitive. Esophageal resections performed on patients with intramucosal carcinomas, which do not penetrate the muscularis mucosae, have revealed a low rate of metastases to lymph nodes (<5%).127, 128, 129, 130 Thus, endoscopic therapy might be curative for most patients with neoplasms confined to the mucosa. For tumors that involve the submucosa, however, the rate of metastasis to the lymph nodes exceeds 20%.126, 131 Therefore, endoscopic therapy is generally not considered definitive for patients with submucosal neoplasia, despite reports documenting successful endoscopic therapy for some patients with tumors that invaded only the upper third of the submucosa.132 Noninvasive procedures such as endoscopic ultrasonography have relatively poor accuracy for staging early esophageal neoplasia.133 Consequently, EMR has a major role in staging early esophageal neoplasms and determining whether endoscopic therapy is feasible.

Endoscopic Submucosal Dissection 

Endoscopic submucosal dissection has been used primarily in Japan, predominantly for the treatment of gastric neoplasia. Endoscopic submucosal dissection starts with injection of fluid into the submucosa, followed by incision around the mucosal segment to be removed using a cutting device (eg, ceramic tip knife, triangle tip knife, flex knife, hook knife, standard needle knife) and, finally, submucosal dissection of the segment.121 This technique requires meticulous endoscopic control and the use of a cap to help with the submucosal dissection.

The major proposed advantage of endoscopic submucosal dissection over EMR is the ability to remove a neoplastic lesion en bloc, which provides more precise determination of its vertical and lateral margins and, perhaps, greater potential for the complete removal of all neoplastic cells. However, endoscopic submucosal dissection is a technically challenging and lengthy procedure that sometimes requires hours to complete, and serious complications such as perforation are frequent. In the esophagus, furthermore, GERD-induced inflammation and fibrosis in the submucosa can make endoscopic submucosal dissection difficult and even more hazardous. These concerns have limited the use of endoscopic submucosal dissection in the treatment of Barrett's esophagus.

Multipolar Electrocoagulation 

Multipolar electrocoagulation involves the application of thermal energy to the mucosa using an electrode-tipped 7F or 10F catheter that is advanced through the working channel of the endoscope.134, 135 The technique is time consuming and not practical for ablating large mucosal areas; there are no published data on the efficacy of multipolar electrocoagulation for treating neoplasia in Barrett's esophagus. Because multipolar electrocoagulation is a bipolar device, however, it might be used to eradicate residual areas of intestinal metaplasia for patients who have implanted cardiac devices.

Argon Plasma Coagulation 

Unlike multipolar electrocoagulation, argon plasma coagulation is a noncontact technique in which monopolar energy is delivered to tissue using ionized argon gas. Energy settings from 40 to 90 W have been used to ablate Barrett's metaplasia and dysplasia, with short-term success rates ranging from 70% to 90%. However, some studies have reported recurrence rates as high as 66% and frequently found metaplastic glands underlying squamous epithelium (so-called “buried metaplasia”). This might reflect the relatively superficial injury inflicted by argon plasma coagulation.136 In addition, reports of serious complications such as perforation, pneumomediastinum, and major bleeding have reduced endoscopists' enthusiasm for argon plasma coagulation ablation of Barrett's esophagus.137, 138 Newer ablation techniques (see the following text) have rendered both argon plasma coagulation and multipolar electrocoagulation largely obsolete for the eradication of Barrett's esophagus, although argon plasma coagulation and multipolar electrocoagulation could still be used to eliminate small islands of Barrett's metaplasia.

PDT 

PDT is an ablation technique that destroys Barrett's epithelium using photochemical energy generated through the interaction between endoscopically delivered light and a photosensitizer that is concentrated in the tissue. This interaction leads to the generation of toxic, singlet oxygen molecules that damage tissue. The photosensitizers used for PDT include porfimer sodium, which is administered intravenously, and 5-aminolevulinic acid, which can be administered orally.139 The most data on efficacy, durability, and long-term outcome are available for the use of PDT with porfimer sodium.115, 140, 141 Common side effects of PDT using porfimer sodium include photosensitivity reactions in more than 60% of patients, a high rate of esophageal stricture formation (as much as 36%), and substantial short-term morbidity.115, 142 PDT with 5-aminolevulinic acid is associated with a shorter duration of photosensitivity and less esophageal stricturing than with porfimer sodium, but 5-aminolevulinic acid appears to be less efficacious and has been associated with vascular instability and at least 1 death.143, 144

RFA 

RFA uses radiofrequency energy, which is delivered by an endoscopic balloon catheter (Halo 360 system, BÂRRX Medical, Sunnyvale, CA) or a focal ablation device (Halo 90 system), to destroy Barrett's epithelium. To perform RFA, the endoscopist first determines the esophageal diameter using a balloon measuring device. The mucosa is sprayed with 1% N-acetyl cysteine solution to remove mucus that might interfere with energy delivery to the mucosa, and a 3-cm-long ablation balloon (with a diameter determined by the aforementioned measurement) that is lined by circumferential electrodes is positioned in the esophageal segment to be ablated. If there is evidence of fibrosis in the wall of the esophagus, an ablation balloon with a diameter smaller than that determined by the measuring balloon is used to prevent esophageal tears; RFA is not recommended for patients with esophageal strictures because inflation of the treatment balloons (typical diameters of 28 to 31 mm) could cause perforations. Radiofrequency energy is delivered through the electrodes to produce heat that destroys the metaplastic tissue. Patients return 2 to 3 months after initial RFA treatment for endoscopic evaluation, and any residual metaplastic tissue is ablated using the focal ablation device (which measures 20 mm in its longest dimension).

Initial dose-finding and phase 2 studies showed the efficacy and safety of RFA for ablating nondysplastic Barrett's epithelium.145, 146 By using a combination of the balloon-based and focal RFA devices, an uncontrolled study has described complete eradication of Barrett's epithelium in 60 of 61 patients (98%) during a follow-up period of 30 months.116 A recent multicenter, randomized, sham-controlled study showed the ability of RFA to eradicate dysplasia and intestinal metaplasia in patients with Barrett's esophagus.147 Adverse events included esophageal stricture formation (6%), gastrointestinal bleeding (1%), and chest pain requiring hospitalization (2%); these rates of serious complications were substantially lower than those reported for PDT with porfimer sodium. Esophageal mucosal tears and perforations with RFA have been reported infrequently to the Food and Drug Administration MAUDE database (www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/search.CFM). Although these results are encouraging, the long-term durability of RFA remains to be determined. Furthermore, the randomized controlled trial enrolled patients who had high-grade dysplasia without associated nodularity, so only a small proportion had undergone EMR before RFA (7 of 84 patients in the ablation arm of the study). Moreover, the EMR was performed by endoscopists with substantial expertise, so it is not clear whether the results could be reproduced by community endoscopists.

Cryotherapy 

Cryotherapy involves the use of an endoscopically delivered cryogen (liquid nitrogen or carbon dioxide) to inflict tissue injury. One of the 2 cryotherapy systems available (CryoSpray Ablation System, CSA Medical, Inc, Baltimore, MD) uses a 7F catheter passed through the working channel of the endoscope to spray liquid nitrogen onto the metaplastic epithelium. The other system (Polar Wand, GI Supply, Camp Hill, PA) delivers cold carbon dioxide gas to the mucosa through a spray catheter. Tissue destruction from cryotherapy occurs in 2 phases: an immediate phase, caused by freezing of the cell and its organelles, followed by a delayed phase, in which cells undergo apoptosis.148 Cryotherapy is delivered by spraying without the need for mucosal contact with the catheter, which might be useful for application to uneven surfaces. Problems encountered with cryotherapy include overdistention with perforation (in a patient with Marfan syndrome) and fogging of the endoscope lens (with the liquid nitrogen device). Although initial results with cryotherapy are promising and its adverse event profile seems reasonable, long-term data are lacking.149, 150, 151 Initial results are summarized in Table 1.

Buried Metaplasia 

A major concern for all of the endoscopic ablative procedures is that partially ablated Barrett's epithelium might heal with an overlying layer of squamous epithelium that “buries” metaplastic tissue (with neoplastic potential) and hides it from the endoscopist. Although some studies suggest that buried metaplasia has a low risk of malignant transformation,152 case reports of dysplasia and adenocarcinoma in buried metaplastic glands continue to cause concern.153, 154

A recent study that explored the prevalence of buried metaplasia in a large randomized trial of PDT for patients with high-grade dysplasia in Barrett's esophagus has allayed some concerns about buried metaplasia.155 A systematic review of more than 33,000 esophageal biopsy specimens revealed that the frequency of buried metaplasia increased after PDT (from 5.8% to 30%). However, a similar increase in the frequency of buried metaplasia was noted for patients treated with proton pump inhibitors alone (from 2.9% to 33%). In addition, the highest grade of dysplasia detected during any given endoscopic examination was not found exclusively in the buried metaplasia in any patient.

In the aforementioned sham-controlled trial of RFA for dysplasia in Barrett's esophagus, the frequency of buried metaplasia decreased in the group treated with RFA and proton pump inhibitors (from 25% to 5%) and increased in the control group that received sham therapy and proton pump inhibitors (from 25% to 40%).147 Another study of 22 patients treated with RFA found no buried metaplasia 2 months after the procedure in biopsy specimens of neosquamous epithelium taken using a “keyhole” technique designed to obtain deep specimens.156 Nevertheless, the importance of buried metaplasia remains controversial, and large, well done, long-term studies are needed to determine its risk of malignancy.

Factors That Influence Choice of Endoscopic Therapy 

The choice among treatment options for patients with dysplasia in Barrett's esophagus requires consideration of patient, esophageal, and institutional factors. Patient factors include age, fitness for therapy, and personal preferences.157 The risks of esophagectomy might be prohibitive for older patients with substantial comorbidities. Before endoscopic therapy is chosen, patients should be informed of the failure rates of the procedure and of the need for careful endoscopic follow-up.158 Patients who choose endoscopic therapy should be willing to comply with follow-up requirements and be aware of the uncertainty regarding the long-term efficacy of endoscopy in preventing cancer. Esophageal factors include the length of the Barrett's segment, the presence of visible lesions such as nodules that can be targeted for EMR, and the presence of multifocal lesions.142, 159, 160 Extensive metaplasia involving long segments of the esophagus can be difficult to eradicate with ablative therapies. The absence of a visible lesion to target by EMR makes it difficult to stage the depth of the neoplasia or determine whether endoscopic therapy can be successful. Dysplasia that is focal might be easily resected or ablated, whereas multifocal dysplasia can be much harder to eradicate with a reasonable degree of certainty. Institutional factors include the levels of expertise of the surgeons and endoscopists. Surgical volume has been repeatedly shown to be an important determinant of esophagectomy outcome.161 Undoubtedly, an endoscopist's level of experience will affect results as well. An approach to choosing endoscopic therapy for neoplasia in patients with Barrett's esophagus is illustrated in Figure 2.

  • View full-size image.
  • Figure 2. 

    Algorithm for the endoscopic management of dysplasia in Barrett's esophagus. LGD, low-grade dysplasia; HGD, high-grade dysplasia; IMCA, intramucosal cancer; HRE, high-resolution endoscopy; NBI, narrow band imaging; BE, Barrett's esophagus.

There are a number of unresolved issues in the endoscopic treatment of Barrett's esophagus. Dysplasia is an imperfect marker for cancer risk, and the identification of biomarkers to select patients who would benefit most from endoscopic or surgical treatments would represent a major advance. Although data from retrospective studies have shown that complete elimination of all metaplasia decreases the recurrence rate, prospective studies on this issue are needed. Predictors of recurrent dysplasia following ablation need to be defined to design interventions to limit that recurrence. New imaging techniques such as narrow band imaging, laser confocal endomicroscopy, and endocytoscopy have the potential to improve the detection of neoplasia in Barrett's esophagus and to direct endoscopic therapies. Finally, long-term data on the recurrence of metaplasia and dysplasia following ablation are required to determine the need for postablation surveillance and select appropriate surveillance intervals.

Back to Article Outline

References 

  1. Lord RV. Norman Barrett, “doyen of esophageal surgery”. Ann Surg. 1999;229:428–439
  2. Vakil N, van Zanten SV, Kahrilas P, et al. Global Consensus Group The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–1920
  3. Barrett NR. Chronic peptic ulcer of the oesophagus and “oesophagitis”. Br J Surg. 1950;38:175–182
  4. Tileston W. Peptic ulcer of the oesophagus. Am J Med Sci. 1906;132:240–265
  5. Allison PR, Johnstone AS. The oesophagus lined with gastric mucous membrane. Thorax. 1953;8:87–101
  6. Barrett NR. The lower esophagus lined by columnar epithelium. Surgery. 1957;41:881–894
  7. Hayward J. The lower end of the oesophagus. Thorax. 1961;16:36–41
  8. Bosher LH, Taylor FH. Heterotopic gastric mucosa in the esophagus with ulceration and stricture formation. J Thorac Surg. 1951;21:306–312
  9. Morson BC, Belcher JR. Adenocarcinoma of the esophagus and ectopic gastric mucosa. Br J Cancer. 1952;6:127–130
  10. Pedersen SA, Hage E, Nielsen PA, et al. Barrett's syndrome: morphological and physiological characteristics. Scand J Thorac Cardiovasc Surg. 1971;6:191–205
  11. Paull A, Trier JS, Dalton MD, et al. The histologic spectrum of Barrett's esophagus. N Engl J Med. 1976;295:476–480
  12. Burgess JN, Payne WS, Andersen HA, et al. Barrett esophagus: the columnar-epithelial-lined lower esophagus. Mayo Clin Proc. 1971;46:728–734
  13. Naef AP, Savary M, Ozzello L. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition: report on 140 cases of Barrett's esophagus with 12 adenocarcinomas. J Thorac Cardiovasc Surg. 1975;70:826–834
  14. Borrie J, Goldwater L. Columnar cell-lined esophagus: assessment of etiology and treatment: a 22 year experience. J Thorac Cardiovasc Surg. 1976;71:825–834
  15. Skinner DB, Walther BC, Riddell RH, et al. Barrett's esophagus: comparison of benign and malignant cases. Ann Surg. 1983;198:554–565
  16. Adler RH. The lower esophagus lined by columnar epithelium: its association with hiatal hernia, ulcer, stricture, and tumor. J Thorac Cardiovasc Surg. 1963;45:13–32
  17. Hawe A, Payne WS, Weiland LH. Adenocarcinoma in the columnar epithelial lined lower (Barrett) esophagus. Thorax. 1973;28:511–514
  18. Haggitt RC, Tryzelaar J, Ellis FH, et al. Adenocarcinoma complicating columnar epithelium-lined (Barrett's) esophagus. Am J Clin Pathol. 1978;70:1–5
  19. Haggitt RC, Dean PJ. Adenocarcinoma in Barrett's epithelium. In:  Spechler SJ,  Goyal RK editor. Barrett's esophagus: pathophysiology, diagnosis, and management. New York: Elsevier; 1985;p. 153–166
  20. Reid BJ, Weinstein WM. Barrett's esophagus and adenocarcinoma. Annu Rev Med. 1987;38:477–492
  21. Reid BJ, Weinstein WM, Lewin KJ, et al. Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions. Gastroenterology. 1988;94:81–90
  22. Reid BJ. Barrett's esophagus and esophageal adenocarcinoma. Gastroenterol Clin North Am. 1991;20:817–834
  23. Weinstein WM, Ippoliti AF. The diagnosis of Barrett's esophagus: goblets, goblets, goblets. Gastrointest Endosc. 1996;44:91–95
  24. Spechler SJ, Zeroogian JM, Antonioli DA, et al. Prevalence of metaplasia at the gastro-oesophageal junction. Lancet. 1994;344:1533–1536
  25. Spechler SJ. The columnar lined oesophagus: a riddle wrapped in a mystery inside an enigma. Gut. 1997;41:710–711
  26. Rex DK, Cummings OW, Shaw M, et al. Screening for Barrett's esophagus in colonoscopy patients with and without heartburn. Gastroenterology. 2003;125:1670–1677
  27. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett's esophagus in the general population: an endoscopic study. Gastroenterology. 2005;129:1825–1831
  28. Sharma P, Morales TG, Sampliner RE. Short segment Barrett's esophagus (The need for standardization of the definition and of endoscopic criteria). Am J Gastroenterol. 1998;93:1033–1036
  29. Riddell RH, Odze RD. Definition of Barrett's esophagus: time for a rethink—is intestinal metaplasia dead?. Am J Gastroenterol. 2009;104:2588–2594
  30. Playford RJ. New British Society of Gastroenterology (BSG) guidelines for the diagnosis and management of Barrett's oesophagus. Gut. 2006;55:442
  31. Chandrasoma P. Pathophysiology of Barrett's esophagus. Semin Thorac Cardiovasc Surg. 1997;9:270–278
  32. Liu W, Hahn H, Odze RD, et al. Metaplastic esophageal columnar epithelium without goblet cells shows DNA content abnormalities similar to goblet cell-containing epithelium. Am J Gastroenterol. 2009;104:816–824
  33. Hahn HP, Blount PL, Ayub K, et al. Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus. Am J Surg Pathol. 2009 Apr 9;[Epub ahead of print]
  34. Takubo K, Aida J, Naomoto Y, et al. Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma. Hum Pathol. 2009;40:65–74
  35. Kelty CJ, Gough MD, Van Wyk Q, et al. Barrett's oesophagus: intestinal metaplasia is not essential for cancer risk. Scand J Gastroenterol. 2007;42:1271–1274
  36. Gatenby PA, Ramus JR, Caygill CP, et al. Relevance of the detection of intestinal metaplasia in non-dysplastic columnar-lined oesophagus. Scand J Gastroenterol. 2008;43:524–530
  37. Jankowski JA, Wright NA, Meltzer SJ, et al. Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Pathol. 1999;154:965–973
  38. Pera M, Pera M. Experimental Barrett's esophagus and the origin of intestinal metaplasia. Chest Surg Clin North Am. 2002;12:25–37
  39. Seery JP. Stem cells of the oesophageal epithelium. J Cell Sci. 2002;115:1783–1789
  40. Glickman JN, Chen YY, Wang HH, et al. Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett's esophagus. Am J Surg Pathol. 2001;25:569–578
  41. Sarosi G, Brown G, Jaiswal K, et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus. Dis Esophagus. 2008;21:43–50
  42. Hu Y, Williams VA, Gellersen O, et al. The pathogenesis of Barrett's esophagus: secondary bile acids upregulate intestinal differentiation factor CDX2 expression in esophageal cells. J Gastrointest Surg. 2007;11:827–834
  43. Kazumori H, Ishihara S, Kinoshita Y. Roles of caudal-related homeobox gene Cdx1 in oesophageal epithelial cells in Barrett's epithelium development. Gut. 2009;58:620–628
  44. Pera M, Pera M, de Bolos C, et al. Duodenal-content reflux into the esophagus leads to expression of Cdx2 and Muc2 in areas of squamous epithelium in rats. J Gastrointest Surg. 2007;11:869–874
  45. Wong NA, Wilding J, Bartlett S, et al. CDX1 is an important molecular mediator of Barrett's metaplasia. Proc Natl Acad Sci U S A. 2005;102:7565–7570
  46. Beck F. The role of Cdx genes in the mammalian gut. Gut. 2004;53:1394–1396
  47. 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–G218
  48. Liu T, Zhang X, So CK, et al. Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis. 2007;28:488–496
  49. Milano F, van Baal JW, Buttar NS, et al. Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells. Gastroenterology. 2007;132:2412–2421
  50. Avissar NE, Toia L, Hu Y, et al. Bile acid alone, or in combination with acid, induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR). J Gastrointest Surg. 2009;13:212–222
  51. Clemons NJ, McColl KE, Fitzgerald RC. Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms. Gastroenterology. 2007;133:1198–1209
  52. Zhang HY, Hormi-Carver K, Zhang X, et al. In benign Barrett's epithelial cells, acid exposure generates reactive oxygen species that cause DNA double strand breaks. Cancer Res. 2009;69:9083–9089
  53. Jenkins GJ, D'Souza FR, Suzen SH, et al. Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett's oesophagus. Carcinogenesis. 2007;28:136–142
  54. Jenkins GJ, Cronin J, Alhamdani A, et al. The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS. Mutagenesis. 2008;23:399–405
  55. Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett's esophagus (An ex vivo proliferation and differentiation model). J Clin Invest. 1996;98:2120–2128
  56. Fitzgerald R, Omary M, Triadafilopoulos G. Altered sodium-hydrogen exchange activity is a mechanism for acid-induced hyperproliferation in Barrett's esophagus. Am J Physiol. 1998;275:G47–G55
  57. Kaur BS, Triadafilopoulos G. Acid- and bile-induced PGE(2) release and hyperproliferation in Barrett's esophagus are COX-2 and PKC-epsilon dependent. Am J Physiol Gastrointest Liver Physiol. 2002;283:G327–G334
  58. Souza RF, Shewmake K, Pearson S, et al. Acid increases proliferation via ERK and p38 MAPK-mediated increases in cyclooxygenase-2 in Barrett's adenocarcinoma cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G743–G748
  59. Hormi-Carver K, Zhang X, Zhang HY, et al. Unlike esophageal squamous cells, Barrett's epithelial cells resist apoptosis by activating the nuclear factor-kappaB pathway. Cancer Res. 2009;69:672–677
  60. Konturek PC, Nikiforuk A, Kania J, et al. Activation of NFkappaB represents the central event in the neoplastic progression associated with Barrett's esophagus: a possible link to the inflammation and overexpression of COX-2, PPARgamma and growth factors. Dig Dis Sci. 2004;49:1075–1083
  61. Abdalla SI, Lao-Sirieix P, Novelli MR, et al. Gastrin-induced cyclooxygenase-2 expression in Barrett's carcinogenesis. Clin Cancer Res. 2004;10:4784–4792
  62. Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, et al. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut. 2002;50:451–459
  63. Shirvani V, Ouatu-Luscar R, Kaur B, et al. Cyclo-oxygenase 2 expression in Barrett's esophagus and adenocarcinoma (ex vivo induction by bile salts and acid exposure). Gastroenterology. 2000;118:487–496
  64. Capello A, Moons LM, Van de Winkel A, et al. Bile acid-stimulated expression of the farnesoid X receptor enhances the immune response in Barrett esophagus. Am J Gastroenterol. 2008;103:1510–1516
  65. Yen CJ, Izzo JG, Lee DF, et al. Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett's-associated esophageal adenocarcinoma. Cancer Res. 2008;68:2632–2640
  66. Kamat P, Wen S, Morris J, et al. Exploring the association between elevated body mass index and Barrett's esophagus: a systematic review and meta-analysis. Ann Thorac Surg. 2009;87:655–662
  67. Lagergren J, Bergström R, Nyrén O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med. 1999;130:883–890
  68. El-Serag H. The association between obesity and GERD: a review of the epidemiological evidence. Dig Dis Sci. 2008;53:2307–2312
  69. Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006;130:639–649
  70. Ryan AM, Healy LA, Power DG, et al. Barrett esophagus: prevalence of central adiposity, metabolic syndrome, and a proinflammatory state. Ann Surg. 2008;247:909–915
  71. Watanabe S, Hojo M, Nagahara A. Metabolic syndrome and gastrointestinal diseases. J Gastroenterol. 2007;42:267–274
  72. Rubenstein JH, Dahlkemper A, Kao JY, et al. A pilot study of the association of low plasma adiponectin and Barrett's esophagus. Am J Gastroenterol. 2008;103:1358–1364
  73. Suzuki H, Iijima K, Scobie G, et al. Nitrate and nitrosative chemistry within Barrett's oesophagus during acid reflux. Gut. 2005;54:1527–1535
  74. El-Serag HB, Lagergren J. Alcohol drinking and the risk of Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology. 2009;136:1155–1157
  75. Chen X, Yang G, Ding WY, et al. An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload. Carcinogenesis. 1999;20:1801–1808
  76. Boult J, Roberts K, Brookes MJ, et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res. 2008;14:379–387
  77. Derakhshan MH, Liptrot S, Paul J, et al. Oesophageal and gastric intestinal-type adenocarcinomas show the same male predominance due to a 17 year delayed development in females. Gut. 2009;58:16–23
  78. Corley DA, Kubo A, Levin TR, et al. Hemochromatosis gene status as a risk factor for Barrett's esophagus. Dig Dis Sci. 2008;53:3095–3102
  79. Fitzgerald RC. Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma. Gut. 2006;55:1810–1820
  80. Wild CP, Hardie LJ. Reflux, Barrett's oesophagus and adenocarcinoma: burning questions. Nat Rev Cancer. 2003;3:676–684
  81. Maley CC, Galipeau PC, Li X, et al. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus. Cancer Res. 2004;64:3414–3427
  82. Barrett MT, Sanchez CA, Neshat K, et al. Allelic loss of 9p21 and mutations of the CDKN2/p16 gene develop as early events in neoplastic progression in Barrett's esophagus. (abstr) Gastroenterology. 1996;110:A489
  83. Barrett MT, Sanchez CA, Prevo LJ, et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet. 1999;22:106–109
  84. Hardie LJ, Darnton SJ, Wallis YL, et al. p16 expression in Barrett's esophagus and esophageal adenocarcinoma: association with genetic and epigenetic alterations. Cancer Lett. 2005;217:221–230
  85. Chao DL, Sanchez CA, Galipeau PC, et al. Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett's esophagus: a long-term prospective study. Clin Cancer Res. 2008;14:6988–6995
  86. Galipeau PC, Li X, Longton G, et al. A panel of molecular and cytometric markers in Barrett's Oesophagus predicts progression to oesophageal adenocarcinoma. Gastroenterology. 2004;126:A114
  87. Wong DJ, Paulson TG, Prevo LJ, et al. p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. Cancer Res. 2001;61:8284–8289
  88. Lai LA, Paulson TG, Li X, et al. Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH. Genes Chromosomes Cancer. 2007;46:532–542
  89. Huang Y, Peters CJ, Fitzgerald RC, et al. Progressive silencing of p14ARF in oesophageal adenocarcinoma. J Cell Mol Med. 2009;13:398–409
  90. Reid BJ, Prevo LJ, Galipeau PC, et al. Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am J Gastroenterol. 2001;96:2839–2848
  91. Murray L, Sedo A, Scott M, et al. TP53 and progression from Barrett's metaplasia to oesophageal adenocarcinoma in a UK population cohort. Gut. 2006;55:1390–1397
  92. Bani-Hani K, Martin IG, Hardie LJ, et al. Prospective study of cyclin D1 overexpression in Barrett's esophagus: association with increased risk of adenocarcinoma. J Natl Cancer Inst. 2000;92:1316–1321
  93. Hong MK, Laskin WB, Herman BE, et al. Expansion of the Ki-67 proliferative compartment correlates with degree of dysplasia in Barrett's esophagus. Cancer. 1995;72:423–429
  94. Sirieix P, O'Donovan M, Brown J, et al. Surface expression of mini-chromosome maintenance proteins provides a novel method for detecting patients at risk for developing adeocarcinoma in Barrett's oesophagus. Clin Cancer Res. 2003;9:2560–2566
  95. Williams GH, Swinn R, Prevost AT, et al. Diagnosis of oesophageal cancer by detection of minichromosome maintenance 5 protein in gastric aspirates. Br J Cancer. 2004;91:714–719
  96. Lao-Sirieix PS, Brais RJ, Lovat LB, et al. Cell cycle phase abnormalities do not account for disordered proliferation in Barrett's carcinogenesis. Neoplasia. 2004;6:751–760
  97. Maley CC, Galipeau PC, Li X, et al. The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res. 2004;64:7629–7633
  98. Vaughan TL, Dong LM, Blount PL, et al. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett's oesophagus: a prospective study. Lancet Oncol. 2005;6:945–952
  99. Chao DL, Maley CC, Wu X, et al. Mutagen sensitivity and neoplastic progression in patients with Barrett's esophagus: a prospective analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:1935–1940
  100. Williams BR, Prabhu VR, Hunter KE, et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008;322:703–709
  101. Cestari R, Villanacci V, Rossi E, et al. Fluorescence in situ hybridization to evaluate dysplasia in Barrett's esophagus: a pilot study. Cancer Lett. 2007;251:278–287
  102. Chaves P, Crespo M, Ribeiro C, et al. Chromosomal analysis of Barrett's cells: demonstration of instability and detection of the metaplastic lineage involved. Mod Pathol. 2007;20:788–796
  103. Rabinovitch PS, Longton G, Blount PL, et al. Predictors of progression in Barrett's esophagus III: baseline flow cytometric variables. Am J Gastroenterol. 2001;96:3071–3083
  104. Galipeau PC, Prevo LJ, Sanchez CA, et al. Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in premalignant esophageal (Barrett's) tissue. J Natl Cancer Inst. 1999;91:2087–2095
  105. Maley CC, Galipeau PC, Finley JC, et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet. 2006;38:468–473
  106. Leedham SJ, Preston SL, McDonald SA, et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus. Gut. 2008;57:1041–1048
  107. Muzeau F, Flejou JF, Belghiti J, et al. Infrequent microsatellite instability in oesophageal cancers. Br J Cancer. 1997;75:1336–1339
  108. Brandt LJ, Kauvar DR. Laser-induced transient regression of Barrett's epithelium. Gastrointest Endosc. 1992;38:619–622
  109. Berenson MM, Johnson TD, Markowitz NR, et al. Restoration of squamous mucosa after ablation of Barrett's esophageal epithelium. Gastroenterology. 1993;104:1686–1691
  110. Curvers WL, Singh R, Song LM, et al. Endoscopic tri-modal imaging for detection of early neoplasia in Barrett's oesophagus: a multi-centre feasibility study using high-resolution endoscopy, autofluorescence imaging and narrow band imaging incorporated in one endoscopy system. Gut. 2008;57:167–172
  111. Fernando HC, Murthy SC, Hofstetter W, et al. The Society of Thoracic Surgeons practice guideline series: guidelines for the management of Barrett's esophagus with high-grade dysplasia. Ann Thorac Surg. 2009;87:1993–2002
  112. Das A, Singh V, Fleischer DE, et al. A comparison of endoscopic treatment and surgery in early esophageal cancer: an analysis of surveillance epidemiology and end results data. Am J Gastroenterol. 2008;103:1340–1345
  113. 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;57:1200–1206
  114. Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus. Gastroenterology. 2009;137:815–823
  115. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc. 2005;62:488–498
  116. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic ablation of Barrett's esophagus: a multicenter study with 2.5-year follow-up. Gastrointest Endosc. 2008;68:867–876
  117. Inadomi JM, Somsouk M, Madanick RD, et al. A cost-utility analysis of ablative therapy for Barrett's esophagus. Gastroenterology. 2009;136:2101–2114e1–6
  118. Sampliner RE. Endoscopic therapy for Barrett's esophagus. Clin Gastroenterol Hepatol. 2009;7:716–720
  119. Falk GW. Radiofrequency ablation of Barrett's esophagus: should everybody get it?. Gastroenterology. 2009;136:2399–2401
  120. Prasad G, Wang KK. Endoscopic mucosal resection: esophageal applications. Curr Treat Options Gastroenterol. 2005;8:41–49
  121. Seewald S, Ang TL, Gotoda T, et al. Total endoscopic resection of Barrett esophagus. Endoscopy. 2008;40:1016–1020
  122. Peters FP, Kara MA, Curvers WL, et al. Multiband mucosectomy for endoscopic resection of Barrett's esophagus: feasibility study with matched historical controls. Eur J Gastroenterol Hepatol. 2007;19:311–315
  123. Larghi A, Lightdale CJ, Ross AS, et al. Long-term follow-up of complete Barrett's eradication endoscopic mucosal resection (CBE-EMR) for the treatment of high grade dysplasia and intramucosal carcinoma. Endoscopy. 2007;39:1086–1091
  124. Mino-Kenudson M, Hull MJ, Brown I, et al. EMR for Barrett's esophagus-related superficial neoplasms offers better diagnostic reproducibility than mucosal biopsy. Gastrointest Endosc. 2007;66:660–666quiz 767, 769
  125. Peters FP, Brakenhoff KP, Curvers WL, et al. Histologic evaluation of resection specimens obtained at 293 endoscopic resections in Barrett's esophagus. Gastrointest Endosc. 2008;67:604–609
  126. Prasad GA, Buttar NS, Wongkeesong LM, et al. Significance of neoplastic involvement of margins obtained by endoscopic mucosal resection in Barrett's esophagus. Am J Gastroenterol. 2007;102:2380–2386
  127. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol. 2001;32:368–378
  128. Montgomery E, Goldblum JR, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett esophagus: a follow-up study based on 138 cases from a diagnostic variability study. Hum Pathol. 2001;32:379–388
  129. Lewis JT, Wang KK, Abraham SC. Muscularis mucosae duplication and the musculo-fibrous anomaly in endoscopic mucosal resections for Barrett esophagus: implications for staging of adenocarcinoma. Am J Surg Pathol. 2008;32:566–571
  130. Stein HJ, Feith M, Bruecher BL, et al. Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg. 2005;242:566–573discussion 573–575
  131. Buskens CJ, Westerterp M, Lagarde SM, et al. Prediction of appropriateness of local endoscopic treatment for high-grade dysplasia and early adenocarcinoma by EUS and histopathologic features. Gastrointest Endosc. 2004;60:703–710
  132. Manner H, May A, Pech O, et al. Early Barrett's carcinoma with “low-risk” submucosal invasion: long-term results of endoscopic resection with a curative intent. Am J Gastroenterol. 2008;103:2589–2597
  133. Larghi A, Lightdale CJ, Memeo L, et al. EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett's esophagus. Gastrointest Endosc. 2005;62:16–23
  134. Dulai GS, Jensen DM, Cortina G, et al. Randomized trial of argon plasma coagulation vs. multipolar electrocoagulation for ablation of Barrett's esophagus. Gastrointest Endosc. 2005;61:232–240
  135. Sampliner RE, Faigel D, Fennerty MB, et al. Effective and safe endoscopic reversal of nondysplastic Barrett's esophagus with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter study. Gastrointest Endosc. 2001;53:554–558
  136. Mork H, Al-Taie O, Berlin F, et al. High recurrence rate of Barrett's epithelium during long-term follow-up after argon plasma coagulation. Scand J Gastroenterol. 2007;42:23–27
  137. Ragunath K, Krasner N, Raman VS, et al. Endoscopic ablation of dysplastic Barrett's oesophagus comparing argon plasma coagulation and photodynamic therapy: a randomized prospective trial assessing efficacy and cost-effectiveness. Scand J Gastroenterol. 2005;40:750–758
  138. Pereira-Lima JC, Busnello JV, Saul C, et al. High power setting argon plasma coagulation for the eradication of Barrett's esophagus. Am J Gastroenterol. 2000;95:1661–1668
  139. Wang KK, Lutzke L, Borkenhagen L, et al. Photodynamic therapy for Barrett's esophagus: does light still have a role?. Endoscopy. 2008;40:1021–1025
  140. Overholt BF, Wang KK, Burdick JS, et al. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia. Gastrointest Endosc. 2007;66:460–468
  141. 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;132:1226–1233
  142. Prasad GA, Wang KK, Buttar NS, et al. Predictors of stricture formation after photodynamic therapy for high-grade dysplasia in Barrett's esophagus. Gastrointest Endosc. 2007;65:60–66
  143. Hage M, Siersema PD, van Dekken H, et al. 5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett's oesophagus: a randomised trial. Gut. 2004;53:785–790
  144. Peters F, Kara M, Rosmolen W, et al. Poor results of 5-aminolevulinic acid-photodynamic therapy for residual high-grade dysplasia and early cancer in Barrett esophagus after endoscopic resection. Endoscopy. 2005;37:418–424
  145. Sharma VK, Wang KK, Overholt BF, et al. Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett's esophagus: 1-year follow-up of 100 patients. Gastrointest Endosc. 2007;65:185–195
  146. Dunkin BJ, Martinez J, Bejarano PA, et al. Thin-layer ablation of human esophageal epithelium using a bipolar radiofrequency balloon device. Surg Endosc. 2006;20:125–130
  147. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med. 2009;360:2277–2288
  148. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37:171–186
  149. Dumot JA, Greenwald BD. Argon plasma coagulation, bipolar cautery, and cryotherapy: ABC's of ablative techniques. Endoscopy. 2008;40:1026–1032
  150. Greenwald BD, Dumot JA, Horwhat JD, et al. Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus. Dis Esophagus. 2009 Jun 9;[Epub ahead of print]
  151. Canto MI, Gorospe EC, Shin EJ, et al. Carbon dioxide (CO2) cryotherapy is a safe and effective treatment of Barrett's esophagus (BE) with HGD/intramucosal carcinoma. Gastrointest Endosc. 2009;69:AB341
  152. Hornick JL, Mino-Kenudson M, Lauwers GY, et al. Buried Barrett's epithelium following photodynamic therapy shows reduced crypt proliferation and absence of DNA content abnormalities. Am J Gastroenterol. 2008;103:38–47
  153. Mino-Kenudson M, Ban S, Ohana M, et al. Buried dysplasia and early adenocarcinoma arising in Barrett esophagus after porfimer-photodynamic therapy. Am J Surg Pathol. 2007;31:403–409
  154. Van Laethem JL, Peny MO, Salmon I, et al. Intramucosal adenocarcinoma arising under squamous re-epithelialisation of Barrett's oesophagus. Gut. 2000;46:574–577
  155. Bronner MP, Overholt BF, Taylor SL, et al. ; International Photodynamic Therapy Group for High-Grade Dysplasia in Barrett's Esophagus (Squamous overgrowth is not a safety concern for photodynamic therapy for Barrett's esophagus with high-grade dysplasia). Gastroenterology. 2009;136:56–64
  156. Pouw RE, Gondrie JJ, Rygiel AM, et al. Properties of the neosquamous epithelium after radiofrequency ablation of Barrett's esophagus containing neoplasia. Am J Gastroenterol. 2009;104:1366–1373
  157. Wang KK. Selecting treatment for Barrett's esophagus: no second chances to make a first impression. Clin Gastroenterol Hepatol. 2008;6:1181–1182
  158. Yachimski P, Nishioka NS, Richards E, et al. Treatment of Barrett's esophagus with high-grade dysplasia or cancer: predictors of surgical versus endoscopic therapy. Clin Gastroenterol Hepatol. 2008;6:1206–1211
  159. Yachimski P, Puricelli WP, Nishioka NS. Patient predictors of histopathologic response after photodynamic therapy of Barrett's esophagus with high-grade dysplasia or intramucosal carcinoma. Gastrointest Endosc. 2009;69:205–212
  160. Yachimski P, Puricelli WP, Nishioka NS. Patient predictors of esophageal stricture development after photodynamic therapy. Clin Gastroenterol Hepatol. 2008;6:302–308
  161. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002;346:1128–1137
  162. Gondrie JJ, Seewald S, Pouw RE, et al. Stepwise radical endoscopic resection for complete removal of Barrett's esophagus with early neoplasia: an international multicenter study. Gastrointestinal Endoscopy. 2008;67:AB175
  163. Yoshinaga S, Gotoda T, Kusano C, et al. Clinical impact of endoscopic submucosal dissection for superficial adenocarcinoma located at the esophagogastric junction. Gastrointest Endosc. 2008;67:202–209
  164. Sharma P, Wani S, Weston AP, et al. A randomised controlled trial of ablation of Barrett's oesophagus with multipolar electrocoagulation versus argon plasma coagulation in combination with acid suppression: long term results. Gut. 2006;55:1233–1239
  165. Attwood SE, Lewis CJ, Caplin S, et al. Argon beam plasma coagulation as therapy for high-grade dysplasia in Barrett's esophagus. Clin Gastroenterol Hepatol. 2003;1:258–263
  166. Ferraris R, Fracchia M, Foti M, et al. Barrett's oesophagus: long-term follow-up after complete ablation with argon plasma coagulation and the factors that determine its recurrence. Aliment Pharmacol Ther. 2007;25:835–840
  167. Pech O, Gossner L, May A, et al. Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett's cancer and high-grade intraepithelial neoplasia. Gastrointest Endosc. 2005;62:24–30

 Conflicts of interest The authors disclose no conflicts.

 Funding This work was supported by the Office of Medical Research, Department of Veterans Affairs and the National Institutes of Health (R01-CA134571). Dr Spechler receives research support from AstraZeneca, Takeda Pharmaceuticals, Inc, and BARRX Medical, Inc. Dr Spechler is a consultant for Procter & Gamble and Xenoport. Dr Wang received NIH grants R01CA097048, R01CA111603, and R21CA122426. In addition, Dr Wang receives research support from Mayo Foundation, BARRX Medical, Inc, Axcan Pharma, Olympus and Fujinon. Dr Prasad receives research support from AstraZeneca, Takeda, and the Mayo Foundation. Dr Fitzgerald receives research support from the Medical Research Council (MRC).

PII: S0016-5085(10)00018-1

doi:10.1053/j.gastro.2010.01.002

Gastroenterology
Volume 138, Issue 3 , Pages 854-869, March 2010

Article Tools

* Image Usage & Resolution