Barrett's esophagus: observations on diagnosis and management.

Barrett's esophagus is a premalignant condition that may often pass unrecognized in clinical practice. In adults, this condition is generally believed to be caused by chronic gastroesophageal reflux resulting in a metaplastic change in the epithelium of the esophagus. Diagnosis of Barrett's esophagus is established by careful biopsy of the involved esophageal mucosa. Periodic surveillance is recommended because of the risk of carcinoma. Antireflux surgery has not been shown to result consistently in the regression of the metaplastic epithelium, but potent acid suppression offers a new therapeutic approach that leads to healing of esophagitis and the potential regression of Barrett's epithelium.     

Barrett's esophagus and esophageal adenocarcinoma: pathogenesis,diagnosis, and therapy

Gastric juice that refluxes into the esophagus can injure esophageal squamous epithelium. When the injury heals through a metaplastic process in which an abnormal columnar epithelium replaces the injured squamous one, the resulting condition is called Barrett's esophagus. Gastroesophageal reflux disease and Barrett's esophagus are the most important risk factors for esophageal adenocarcinoma. This article examines such issues as the treatment, endoscopic surveillance, and chemoprevention of Barrett's esophagus. Also included are published guidelines and recommendations.     

Gastroesophageal reflux disease and Barrett's esophagus

Gastroesophageal reflux disease (GERD) is a common clinical problem. Circumstantial evidence continues to suggest that infection with Helicobacter pylori may protect some patients from developing GERD and its complications. An empirical trial of a proton-pump inhibitor may now be a reasonable alternative to endoscopy or 24-hour pH testing for the diagnosis of GERD. Long-term follow-up data covering more than over a decade indicate that proton-pump inhibitors are effective and safe agents for the treatment of GERD. Furthermore, a strategy of proton-pump inhibitors first may be the most cost-effective approach to GERD. It remains unclear why some patients with GERD develop Barrett's esophagus, whereas others do not. Recent studies demonstrate the importance of pulses of acid or bile in increasing cell proliferation and cyclooxygenase-2 expression in Barrett's epithelium cell cultures. Short-segment Barrett's esophagus is now clearly associated with an increased risk of dysplasia or cancer compared to intestinal metaplasia of the cardia, and the cancer risk in this condition is similar to that with long-segment Barrett's esophagus. However, the overall cancer risk in patients with Barrett's esophagus is lower than previously estimated, at approximately 0.5% annually. Ablation techniques continue to show promise, but are not yet ready for routine clinical use. Endoscopic mucosal resection is a new treatment option for selected patients with high-grade dysplasia or superficial esophageal adenocarcinoma.     

Circumferential endoscopic mucosal resection in Barrett's esophagus with high-grade intraepithelial neoplasia or mucosal cancer. Preliminary results in 21 patients

BACKGROUND AND STUDY AIMS: Treatment by endoscopic mucosal resection (EMR) has been established for early lesions in Barrett's esophagus. However, the remaining Barrett's esophagus epithelium remains at risk of developing further lesions. The aim of this study was to evaluate the efficacy of circumferential endoscopic mucosectomy (circumferential EMR)s in removing not only the index lesion (high-grade intraepithelial neoplasia (HGIN) or mucosal cancer), but also the remaining Barrett's esophagus epithelium. PATIENTS AND METHODS: A total of 21 patients were included in the study (11 men, 10 women), who had Barrett's esophagus and either HGIN (n = 12) or mucosal cancer (n = 9). Of the patients, 17/21 were at high surgical risk and five had refused surgery. On the basis of preprocedure endosonography their lesions were classified as T1N0 (n = 19) or T0N0 (n = 2). The lesions and the Barrett's esophagus epithelium were removed by polypectomy after submucosal injection of 10-15 ml of saline; a double-channel endoscope was used in 15/21 cases. Circumferential EMR was performed in two sessions, the lesion and the surrounding half of the circumferential Barrett's esophagus mucosa being removed in the first session. In order to prevent the formation of esophageal stenosis, the second half of the Barrett's esophagus mucosa was resected 1 month later. RESULTS: Complications occurred in 4/21 patients (19 %), consisting of bleeding which was successfully managed by endoscopic hemostasis in all cases. No strictures were observed during follow-up (mean duration 18 months) and endoscopic resection was considered complete in 18/21 patients (86 %). For three patients, histological examination showed incomplete removal of tumor: one of these underwent surgery; two received chemoradiotherapy, and showed no evidence of residual tumor at 18 months' and 24 months' follow-up, respectively. Two patients in whom resection was initially classified as complete later presented with local recurrence and were treated again by EMR. Barrett's esophagus mucosa was completely replaced by squamous cell epithelium in 15/20 patients (75 %). CONCLUSIONS: Circumferential EMR is a noninvasive treatment of Barrett's esophagus with HGIN or mucosal cancer, with a low complication rate and good short-term clinical efficacy. Further studies should focus on long-term results and on technical improvements.     

Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus: an in vivo and ex vivo study

BACKGROUND AND STUDY AIMS: Methylene blue selectively stains specialized columnar epithelium in Barrett's esophagus with high accuracy. We prospectively evaluated the methylene blue staining properties of dysplastic and nondysplastic Barrett's esophagus and the association of these properties with the risk for dysplasia and cancer. PATIENTS AND METHODS: In a ex vivo study, we mapped, photographed, and sampled esophagectomy specimens with high grade dysplasia and/or early adenocarcinoma before and after methylene blue staining. In a concurrent in vivo study, we performed methylene blue staining and characterized methylene blue stain characteristics. Pathologists estimated the proportion of specialized columnar epithelium in each specimen and graded dysplasia. RESULTS: We examined 551 biopsies from 47 patients with biopsy-proven Barrett's esophagus and 48 sections from five surgical specimens with Barrett's esophagus and dysplasia and early adenocarcinoma. The accuracy of ex vivo and in vivo methylene blue staining for specialized columnar epithelium was 87% and 90%, respectively. It was influenced by the length of Barrett's esophagus, biopsy location, and the presence of esophagitis and/or dysplasia. Light to absent staining (p = 0.01) and moderate to marked heterogeneity (p = 0.01) were significantly associated with high grade dysplasia or cancer in the univariate analysis and in a multivariate model that adjusted for the length of Barrett's esophagus and the presence of a lesion. These staining characteristics were present in all patients with severe dysplasia and/or adenocarcinoma. CONCLUSIONS: Highly dysplastic or malignant Barrett's esophagus stains differently with methylene blue. Increased heterogeneity and decreased methylene blue stain intensity are significant independent predictors of high grade dysplasia and/or cancer. These features may help to direct biopsies in patients without a lesion.     

Reflux disease and Barrett's esophagus

Gastroesophageal reflux disease (GERD) is still an important clinical problem. Continuing efforts are being made to establish a classification of the condition that would allow improved communications for both clinical and research purposes. In medical treatment, the trends are toward proton-pump inhibitor therapy at all stages of GERD, calling into question the role of endoscopy for tailoring individual therapy. Arguments against the use of H. pylori eradication therapy in GERD have gained importance. Surgeons are continuing to report excellent results with fundoplication, but careful studies are needed to prove whether antireflux surgery is really capable of saving costs, as its proponents claim. Barrett's esophagus is still a topic of lively interest. Since there is no method of primary prevention, endoscopy has a crucial role in detecting affected patients and guiding them toward one of the various surveillance strategies--which are not yet clearly established. The debate over short-segment Barrett's esophagus, and especially over "microscopic" Barrett's esophagus (at the squamocolumnar junction), has not yet been resolved. However, there is now less doubt that GERD is a condition associated with a substantially higher risk for the development of esophageal adenocarcinoma. Given this risk of malignant transformation, there is continuing competition between different ablation techniques; however, careful data from much larger populations will be needed before ablation reaches the stage of broad clinical application. Until specific guidelines become available, patients with Barrett's esophagus should receive endoscopic follow-up until it can be ascertained which individuals are at risk for cancer and require ablation of Barrett's mucosa.     

Endoscopic diagnosis of Barrett's esophagus

In Japan Barrett's mucosa is defined as columnar lined esophagus (CLE). The prevalence of Barrett's esophagus and Barrett's adenocarcinoma is very low. But in Western countries Barrett's mucosa is defined as CLE with intestinal metaplasia, and many cases of Barrett's esophagus and Barrett's adenocarcinoma are reported. The definite endoscopic diagnosis of Barrett's mucosa cannot be so easy. We investigated the positional relationship between the esophageal hiatus, squamo-columnar junction, and longitudinal vessels in persons who underwent esophagogastroduodenoscopy. Subepithelial longitudinal vessels were found at the lower esophagus in all cases. In no cases were the longitudinal vessels observed under the gastric mucosa beyond the esophageal hiatus. It is peculiar to the esophagus to be able to observe subepithelial longitudinal vessels in the vicinity of the esophago-gastric junction. When longitudinal vessels are found only under the columnar epithelium at the oral side over the esophageal hiatus from the stomach, this indicates Barrett's epithelium. Thus the definite diagnosis of Barrett's epithelium can be made by endoscopy.     

Barrett食管的临床及病理研究

目的:探讨Barrett食管的临床及病理特点。方法:回顾性分析32例经胃镜及病理确诊的Barrett食管的临床表现、内镜及病理特点。结果:32例Barrett食管患者中临床出现反酸25例(78.1%)、胸骨后疼痛22例(68.8%)、烧心感18例(56.3%),无症状者6例(18.8%),胃镜检查伴有反流性食管炎表现者27例(84.4%),胆汁反流者10例(31.3%),病理检查结果全部病例食管下段均有柱状上皮化生。结论:Barrett食管多见于老年人,是反流性食管炎发展的结果,具有恶变为食管癌的潜在危险,其确诊须组织病理检查,内科治疗只能缓解及改善症状,发现恶变及早手术。     

Argon plasma coagulation in Barrett's esophagus

Argon plasma coagulation (APC) is noncontact electrocoagulation technique that creates tissue damage. Recently, it has been reported that Barrett's esophagus and Barrett's adenocarcinoma in situ could be successfully managed by APC. The aims of this treatment are to prevent the developing of adenocarcinoma and to promote the restitution of normal squamous epithelium. Combined antireflux surgery or proton pump inhibitor therapy are indispensable to this treatment. Shorter length of Barrett's epithelium and normalization in pH with PPI treatment were the independent predictors of sustained long-term restitution of squamous epithelium. In patient with Barrett's esophagus, APC offers an effective, minimally invasive alternative to other treatments previously performed.     

Diagnosis of Barrett's esophagus by pertechnetate radionuclide.

In Barrett's esophagus the normal stratified squamous epithelium of esophagus is replaced by columnar epithelium and other charcteristics of gastric mucosa. Barrett's esophagus has an increased tendency to bleed and is more prone to undergo malignant change. There are many procedures used to diagnose this entity, but only by serial and multiple esophageal mucosal biopsies can the diagnosis be confirmed. Harper et al (2) demonstrated an early and intense uptake of 99m Tc pertechnetate by the stomach in animals. Since the Barrett's esophagus is lined by gastric mucosa, pertechnetate scintigraphy was used as a screening procedure. The criteria for a postive scan was an area of increased uptake of technetium extending above the normal dense uptake of stomach configuration. Pertechnetate scintigraphy was performed in 4 patients with Barrett's esophagus and 6 controls with only one false negative result. Thus pertechnetate scintigraphy is a rapid, safe, and atraumatic screening procedure.     

Carcinogenesis of Barrett's esophagus

Barrett's esophagus is a premalignant condition and remains the number one risk factor for developing adenocarcinoma. Gastro-esophageal reflux disease is a strong risk factor for both esophageal adenocarcinoma and the precancerous lesion Barrett's esophagus. Both of these conditions are related to the reflux of acid and bile into the esophagus. This results in inflammation and cell damage which initiates a sequence of events termed the metaplasia-dysplasia sequence in which the squamous epithelium is replaced by columnar epithelium exhibiting increasing degrees of dysplasia and overt malignancy. The underlying disease mechanisms remain unclear, but tumor suppression genes (p53, p16, APC) and, oncogenes (K-ras, cyclin D1, c-erb-2) seem to cause the malignant transformation of Barrett's esophagus, and the genetic or epigenetic alterations of these genes have been reported.     

Histology of Barrett's esophagus and dysplasia

This article explores issues related to the diagnosis of Barrett's esophagus (BE) in endoscopic biopsies and dysplasia in Barrett's epithelium. The definitions of BE, including long- and short-segment BE, are reviewed, with an emphasis on the significance of intestinal metaplasia (IM). IM of the gastroesophageal junction and cardia is reviewed and problems in its distinction from short-segment BE are discussed. In addition, the article reviews the classification of dysplasia in Barrett's mucosa, with reference to problematic areas, such as sampling error and interobserver variability. Biomarkers and their role in the diagnosis of dysplasia and stratification of risk are summarized.     

Detection of Barrett's epithelium by acoustic microscopy

Barrett's esophagus is associated with increased risk of adenocarcinoma of the gastroesophageal junctional region. The presence of goblet cells (intestinal metaplasia) in columnar cell-lined esophageal mucosa defines Barrett's change. The diagnosis of Barrett's esophagus is based on the presence of intestinal metaplasia in a biopsy from an endoscopically visualized abnormal columnar epithelium. In this pilot study, acoustic microscopy was used to identify the mucosal structure of 10 distal esophageal biopsies. Sections cut at 5 microm of archival paraffin blocks on glass slides were used for this study. Acoustic microscopy permitted the identification of low- and high-power images of epithelial architecture and cellular detail, including Barrett's epithelium. This modality of visualization has the potential to detect lesions such as Barrett's metaplasia, low- and high-grade dysplasia and early carcinoma. If it can be applied to in vivo endoscopy, acoustic microscopy has the potential to increase the accuracy of the diagnosis of Barrett's esophagus, dysplasia and malignancy by providing a method of accurately directing biopsies at endoscopy.     

Epidemiology of Barrett's esophagus--comparison of Japan and the West

We compared the epidemiology of Barrett's esophagus in Japan and the West. Japan GERD Society Study Committee conducted the epidemiological survey in 2,595 patients who underwent endoscopy the first time, confirming that Barrett's mucosa was observed in 536 patients (20.8%) out of 2,577. But Barrett's esophagus (>3 cm of columnar lined epithelium) was detected only 5 (0.2%). The prevalence of typical Barrett's esophagus was markedly low in Japanese compared with Westerners. In Western, the incidence of Barrett's esophagus has increased markedly since the 1970s. It is estimated that Barrett's esophagus is found in approximately 6-12% of patients undergoing endoscopy for symptoms of GERD and in 1% or less of unselected patient populations undergoing endoscopy.     

Argon plasma coagulation in Barrett's esophagus

Despite the availability of many clinical trials, there is no evidence that APC has any role in the management of Barrett's esophagus. Ablation therapy is not indicated for nondysplastic Barrett's esophagus (and this is true, whatever the technique used), and it should not be performed outside of a carefully designed and approved clinical trial. Indeed, these patients have a low risk of cancer, and there is no evidence that Barrett's esophagus ablation will be of any benefit for these patients. In some cases, APC could be of some help, especially for treating short segments of dysplastic Barrett's esophagus. In this field, however, it competes with the growing indication of mucosectomy, which clearly offers advantages in terms of treatment's quality control assessment.     

Reflux disease and Barrett's esophagus

Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal disorders. The key feature of GERD is reflux of gastric contents into the esophagus. Medical treatment with proton-pump inhibitors (PPIs) is well established and is considered the standard treatment. Given the high prevalence of the condition and the excellent response to medical therapy, antireflux surgery is an option for patients with volume reflux that is not properly controlled by medical therapy. Adenocarcinoma is a rare but life-threatening complication of GERD. The only known precursor lesion for esophageal adenocarcinoma is Barrett's esophagus. In recent years, a clearer understanding of the development of Barrett's and of its progression toward invasive cancer has developed. Genetic factors almost certainly determine the individual risk. The length of the Barrett's esophagus segment and the size of a hiatal hernia are associated with the risk of developing high-grade dysplasia and esophageal adenocarcinoma.With regard to the clinical management of GERD patients with Barrett's, endoscopic surveillance at 3-year intervals is now considered appropriate in the absence of dysplasia. In patients with high-grade dyspepsia, the situation is more difficult. While a considerable proportion of these patients may already have invasive cancers, there is also the possibility that there is only focal dysplasia. For this reason, it is justifiable to carry out curative endoscopic resection. Mucosal ablation procedures may also be appropriate, but these still need to be properly investigated in clinical trials.     

Pathogenesis of Barrett's esophagus--new findings in the experimental studies of duodenal reflux models

Duodeno-gastro-esophageal reflux has been thought to induce Barrett's esophagus. Recently, we designed a new duodenal reflux model using rats, and studied sequential morphological changes of esophageal mucosa leading to Barrett's esophagus. A specialized columnar epithelium (SCE) developed 20 weeks after operation. Barrett's epithelium originated from pyloric-foveolar metaplasia of stem cells in the basal layer of the esophageal squamous epithelium. The pyloric-foveolar metaplasia was then followed by the appearance of goblet cells, becoming a typical SCE. The expression of homeobox gene Cdx2 was seen in this process, thereby suggesting a role of Cdx2 in intestinal differentiation of Barrett's esophagus. We noticed the pyloric-foveolar metaplasia followed by the appearance of goblet cells is common to entire gut in regenerative process, and proposed a concept of GRCL (gut regenerative cell lineage), and an implication of GRCL in digestive tract carcinogenesis was discussed.     

The clinical strategy for the Barrett's esophagus

The treatment of Barrett's esophagus is controversial. Current treatments include endoscopic therapy, surgical procedures, gastric acid-suppressive therapy with proton pump inhibitors (PPIs), and cancer chemoprevention such as nonsteroidal anti-inflammatory drugs. Endoscopic therapy combined with gastric acid suppressive therapy can result in squamous reepithelialization of the Barrett's mucosa. Antireflux surgery and PPIs therapy are potential options for the treatment of gastroesophageal reflux symptoms in patients with Barrett's esophagus. But there are no prospective studies that support any alternative approach to treatment. Although chemoprevention therapy may reduce cancer risk in Barrett's esophagus, no randomized controlled trials that prove its efficacy have been reported.     

Expression of transcription factor in Barrett's esophagus

Barrett's esophagus is the result of chronic injury which is usually caused by gastroesophageal reflux. NF-kappaB is expressed in the reflux esophagitis. Specialized columnar epithelium (SCE) is characteristic of Barrett's esophagus and has a malignant predisposition. SCE expresses Cdx1 and Cdx2. Adenocarcinoma in Barrett's esophagus is believed to develop through the metaplasia-dysplasia-carcinoma sequence. P53, beta-catenin, PPARgamma, and estrogen receptor beta are closely related to the development of esophageal carcinogenesis.     

Diagnosis of Barrett's esophagus and Barrett's carcinoma using magnifying endoscopy

Specialized columnar epithelium (SCE) in Barrett's esophagus has been detected by random or four quadrant biopsy using conventional endoscopy; however little is known about the fine mucosal structure of SCE. The fine mucosal pattern (pit pattern) was classified into five categories. Tubular or villous pit patterns were not only characteristics of both SCE and methylene blue absorption but also possessed intestinal mucin phenotype. Targeted biopsy under the magnifying chromo-endoscopy might contribute to the early detection of Barrett's cancer.