Endoscopic therapy for Barrett's esophagus

With the increase in the rate of esophageal adenocarcinoma in the United States and the Western world matched with the high morbidity and mortality of esophagectomy, there is an increasing need for new and effective techniques to treat and prevent esophageal adenocarcinoma. A wide variety of endoscopic mucosal ablative techniques have been developed for early esophageal neoplasia. However, long-term control of neoplasic risk has not been demonstrated. Most studies show that specialized intestinal metaplasia may persist underneath neo-squamous mucosa, posing a risk for subsequent neoplastic progression. In this article we review current published literature on endoscopic therapies for the management of Barrett's esophagus.     

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.     

Endoluminal therapy for Barrett's esophagus

This article reviews methods to minimize the complications associated with endoscopic therapy for patients with Barrett's esophagus. To place this discussion in context, the natural history of Barrett's esophagus and the risks associated with progression to dysplasia and invasive carcinoma are reviewed. Operative esophageal resection traditionally is recommended for patients with Barrett's high-grade dysplasia and early carcinoma, and these surgical risks also are reviewed. Finally, all currently approved and commercially available methods for endoscopic ablation and resection of Barrett's disease are categorized according to their application methods of ablation: focal ablation, field ablation, and mucosal resection. The clinical experience with these devices is reviewed with their associated adverse events and complications. Caveats, concerns, and recommendations are discussed to help minimize the complications associated with the use of these important technologies that hold the promise of removing or destroying Barrett's disease to prevent the development of invasive carcinoma.     

Endoscopic diagnosis and surveillance of Barrett's esophagus

There are many questions regarding the screening and surveiliance of BE for which there are currently no answers. Despite the use of models and extrapolations by some authors to suggest that screening and surveiliance for a cancer of such low incidence will never be justified, others argue just as vociferously that given the continued epidemic rise in incidence of this cancer, the uniformly fatal outcome of these cancers if dianosed after symptoms occur, and the enormous pool of patients remaining at risk for future cancer development, a focused and prudent screening and surveillance strategy for Barrett's-related esophageal adenocarcinoma is justified. The data also show that a single screening examination is probably as effective as almost all subsequent surveilance examinations in detecting advanced neoplasia, and much of the current resource use and energy for screening and surveillance in BE should be directed toward screening. Whether screening should be offered or recommended to only older patients (> 50-55 years), whites, and men is unknown, but it is premature to adopt this strategy until better evidence exist supporting a restricted screening policy. Regarding the optimal surveilance frequency and technique, examinations more frequent than every 3 to 5 years are not justifiable, and until proven otherwise, biopsy specimens should be obtained with the largest forceps that can be used with the endoscopic instrument and "saturation" biopsies from the Barrett's obtained. It is unlikely that too many biopsy specimens can be taken. Furthermore, the safety of this approach has been, proven. It is quite likely that the inverse is not true; clinicians likely can do much more harm by taking too few biopsy specimens. It is hoped that the current intense interest in Barrett's neoplasia allows clinicians to address these critical issues in the years to come and resolve this clinical conundrum.     

Photodynamic therapy of Barrett's esophagus

Photodynamic therapy seems to be able to control high-grade dysplasia within Barrett's esophagus about 80% of the time. Long-term results are not available, but the treatment is promising. Given the success with surgical intervention, however, use of photodynamic therapy should be reserved for nonsurgical candidates at the current time. The complications that occur with photodynamic therapy are not trivial and must be weighed against the potential benefits.     

Photodynamic therapy in Barrett's esophagus

Photodynamic therapy (PDT) was one of the earliest ablative techniques applied to Barrett's esophagus. The rationale for this use was the ability to treat large amounts of esophageal mucosa in a single rapid application. Additionally, PDT has the ability to treat early carcinoma and dysplastic tissue. Because a small carcinoma in dysplastic Barrett's esophagus cannot not be excluded, PDT therapy is a reasonable treatment in this setting. The treatment involves the use of a light and drug combination that must be administered with close attention to dosimetry, since tissue effects of the therapy are delayed and cannot be observed at the time of treatment. Drug administration of sodium porfimer should precede photoradiation by 48 hours. Overall results with this treatment have been good. Case series have established a success rate of 88% to 100% in elimination of high-grade dysplasia. The only randomized multi-center prospective trial in the treatment of Barrett's esophagus with high-grade dysplasia has established that the treatment eliminates high-grade dysplasia better than administration of proton pump inhibitors alone. Unfortunately, there are significant adverse events, including cutaneous photosensitivity, odynophagia, stricture formation, and lack of response.     

Endoscopic evaluation and advanced imaging of Barrett's esophagus

Enhanced visualization techniques are available for Barrett's esophagus and have promise in the detection of dysplasia and cancer. Several of these techniques, such as narrow band imaging and chromoendoscopy, are being applied clinically. These techniques will allow the endoscopist to screen the surface of the Barrett's esophagus to detect areas of neoplasia. Once detected, it is hoped that either magnification techniques, such as confocal laser endomicroscopy, or spectroscopic techniques can be of value in allowing in vivo real-time diagnostic capabilities.     

Barrett's esophagus

The Barrett's esophagus showing columnar metaplasia upward to the esophagus from the esophago-gastric junction is one of the final appearance of reflux esophagitis and important as a precancerous state of esophageal adenocarcinoma. Especially the Barrett's mucosa with intestinal metaplasia has high potential risk for adenocarcinoma. Although the clinical definition of the esophago-gastric junction is not easy, the criteria of the esophago-gastric junction and the Barrett's mucosa proposed by the Japanese Society for Esophageal Diseases is useful. The gastro-esophageal reflux is important in the development of Barrett's mucosa not only in the classical Barrett's esophagus but also in the short-segment Barrett's.     

Barrett's esophagus

Gastroesophageal reflux disease (GERD) is a condition commonly managed in the primary care setting. Patients with GERD may develop reflux esophagitis as the esophagus repeatedly is exposed to acidic gastric contents. Over time, untreated reflux esophagitis may lead to chronic complications such as esophageal stricture or the development of Barrett's esophagus. Barrett's esophagus is a premalignant metaplastic process that typically involves the distal esophagus. Its presence is suspected by endoscopic evaluation of the esophagus, but the diagnosis is confirmed by histologic analysis of endoscopically biopsied tissue. Risk factors for Barrett's esophagus include GERD, white or Hispanic race, male sex, advancing age, smoking, and obesity. Although Barrett's esophagus rarely progresses to adenocarcinoma, optimal management is a matter of debate. Current treatment guidelines include relieving GERD symptoms with medical or surgical measures (similar to the treatment of GERD that is not associated with Barrett's esophagus) and surveillance endoscopy. Guidelines for surveillance endoscopy have been published; however, no studies have verified that any specific treatment or management strategy has decreased the rate of mortality from adenocarcinoma.     

Barrett's esophagus

Esophageal cancer staging is a widely accepted indication for endoscopic ultrasonography (EUS). The evaluation of Barrett's esophagus (BE) with EUS is indicated only when there is high-grade dysplasia or a concern for malignancy in an endoscopic lesion. Because the options for the management of BE and early adenocarcinoma are diverse, proper selection of patients by accurate staging with EUS is critical, particularly when nonoperative management is considered. For example, patients with BE with high-grade dysplasia may be offered esophagectomy in some medical centers, but nonoperative therapies such as endoscopic ablative therapy or mucosal resection may be the preferred treatment options in other gastroenterology practices. This article discusses the scientific evidence for the use of EUS in BE or early esophageal adenocarcinoma.     

Barrett's esophagus: treatment with 5-aminolevulinic acid photodynamic therapy

Barrett's esophagus has been identified as the premalignant precursor of esophageal adenocarcinoma. The eradication of metaplastic or dysplastic columnar-lined (Barrett's) esophagus may prevent progression to esophageal adenocarcinoma. 5-Aminolevulinic acid photodynamic therapy is a simple method for the mucosal ablation of the abnormal segment. Areas of metaplastic epithelium may remain buried after treatment and continued surveillance is necessary. Repeated treatments often are necessary but are very well tolerated with few complications.     

Biomarkers in Barrett's esophagus

This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.     

Barrett's esophagus: chemoprevention

The clinical applicability of the experimental data discussed previously remains questionable, and results of clinical studies on chemoprevention in Barrett's esophagus are needed. The utility of selectively targeting acid exposure, ODC, and COX-2 is not clear, and elucidation of that role will be facilitated by a better understanding of the contribution of these factors in the development of Barrett's cancers. The insights already gained into the basic mechanisms of acid exposure, ODC, and COX-2 in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma hold promise for the development of future therapies aimed at these molecular targets and their signaling pathways. In preclinical studies, the ability of COX-2 selective NSAIDs and DFMO to inhibit carcinogenesis is encouraging. Results of well-designed, prospective clinical studies, however, are still needed to establish the efficacy of potent acid suppression, COX-2 inhibitors, and DFMO in the prevention of this malignancy.     

Barrett's esophagus in children

Barrett's esophagus (BE) is a condition of esophageal dysplasia in which the tubular esophagus is lined with columnar instead of squamous mucosa--not with just any type of columnar mucosa, but with a specialized type with goblet cells. It is considered to be an acquired phenomenon secondary to acid exposure from gastro-esophageal reflux (GER). This report shows a review of BE of children and our data about BE from the study of 19 handicapped children with GER. 3 had intestinal dysplasia with goblet cells (BE). The % time of pH under 4 on 24-hour pH monitoring was significantly lower in the patients with esophagitis including BE than in them with normal esophagus. BE of our study seemed to be reversible after the surgery and anti-acid therapy. It is suggested that BE is not a rare condition even in children and biopsy specimens should be taken to establish the diagnosis.     

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.