Barrett's esophagus: screening and prognosis

The diagnostic criteria for Barrett's disease have changed very considerably during the last 10 years. Classically, the definition asked for columnar epithelium in the lower esophagus extending for at least 3 cm proximally. Now, the diagnosis rests on the finding of specialised intestinal metaplasia, i.e. columnar epithelium with goblet cells, in the esophagus, regardless of the extension. This is important because it is this type of metaplasia that is associated with an increased risk for the development of esophageal adenocarcinoma and esophageal adenocarcinoma is the tumor with the fastest rising incidence in the western world in recent years. The criteria of the current definition of Barrett's esophagus are described in detail and the implications this change in definition carries for screening and surveillance of patients is discussed.     

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.     

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食道和Barrett食道腺癌的临床病理学研究

本文报告Ｂａｒｒｅｔｔ食道４２例，其中８例具有腺癌结构。内镜观察：食道粘膜上皮粗糙、糜烂、颗粒状增生、斑块状隆起、溃疡、粘膜充血或苍白。组织学观察：Ｂａｒｒｅｔｔ食道上皮有三种不同形态，其中胃底型上皮８例，交界型上皮１４例，特殊型上皮２０例，８例具有腺癌结构，特殊型上皮与腺癌结构间可见过渡形态。粘液组化染色观察：２０例特殊型上皮，ＨＩＤ（＋）１８例，８例具有腺癌结构的病例，ＡＢ、ＨＩＤ均呈不同程度的阳性。ＡｇＮＯＲ染色观察，Ｂａｒｒｅｔｔ食道三种上皮与食道腺癌平均每核含ＡｇＮＯＲ颗粒数相比均有非常显著的统计学差异（Ｐ＜０．０１）；观察结果提示：Ｂａｒｒｅｔｔ食道与食道腺癌关系密切，特殊上皮型Ｂａｒｒｅｔｔ食道可能是食道腺癌的癌前病变。     

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.     

Controversies in Barrett Esophagus

Barrett esophagus develops when metaplastic columnar epithelium predisposed to develop adenocarcinoma replaces esophageal squamous epithelium damaged by gastroesophageal reflux disease. Although several types of columnar metaplasia have been described in Barrett esophagus, intestinal metaplasia with goblet cells currently is required for a definitive diagnosis in the United States. Studies indicate that the risk of adenocarcinoma for patients with nondysplastic Barrett esophagus is only 0.12% to 0.38% per year, which is substantially lower than previous studies had suggested. Nevertheless, the incidence of esophageal adenocarcinoma continues to rise at an alarming rate. Regular endoscopic surveillance for dysplasia is the currently recommended cancer prevention strategy for Barrett esophagus, but a high-quality study has found no benefit of surveillance in preventing deaths from esophageal cancer. Medical societies currently recommend endoscopic screening for Barrett esophagus in patients with multiple risk factors for esophageal adenocarcinoma, including chronic gastroesophageal reflux disease, age of 50 years or older, male sex, white race, hiatal hernia, and intra-abdominal body fat distribution. However, because the goal of screening is to identify patients with Barrett esophagus who will benefit from endoscopic surveillance and because such surveillance may not be beneficial, the rationale for screening might be made on the basis of faulty assumptions. Endoscopic ablation of dysplastic Barrett metaplasia has been reported to prevent its progression to cancer, but the efficacy of endoscopic eradication of nondysplastic Barrett metaplasia as a cancer preventive procedure is highly questionable. This review discusses some of these controversies that affect the physicians and surgeons who treat patients with Barrett esophagus. Studies relevant to controversial issues in Barrett esophagus were identified using PubMed and relevant search terms, including Barrett esophagus, ablation, dysplasia, radiofrequency ablation, and endoscopic mucosal resection.     

Histochemical diagnosis of short segment Barrett's esophagus

Recently, we have many chances of findings of Barrett's esophagus in routine endoscopic examination. It is also reported that we have few frequent findings of typical Barrett's esophagus, long segment Barrett's esophagus (LSBE) which is seen predominantly in Europe and United States, however the frequency of finding of short segment Barrett's esophagus (SSBE) and adenocarcinoma derived from SSBE is gradually increasing in Japan. So it is thought that precise diagnosis of SSBE and the evaluation of potential malignancy of SSBE are needed in the present medical management. The present study has shown the differences of characteristics of mucinous contents and malignant potentials between in SSBE and LSBE by use of biopsy specimen taken by endoscopic procedure. It is well known that Barrett's epithelium is categorized gastric fundic type, junctional type and specialized columnar epithelium, especially Barrett's mucosa is characterized by specialized columnar epithelium, e. g. incomplete epithelial type of intestinal metaplasia. We have set up two characteristic groups, gastric mucin dominant and intestinal mucin dominant by using specific mucin staining for MUC2, MUC5AC, Con A and CD10. In results, we confirmed that 80% of specialized columnar epithelia revealed intestinal mucin dominant in LSBE and 77% revealed gastric mucin dominant as compared with 23%, intestinal mucin dominant. Moreover, we have examined the ability of cell proliferation using Ki67-immunostaining in Barrett's epithelia. It was demonstrated that positive immunoactivity of Ki67 in proliferative zone was shown in 37.5% of gastric mucin dominant and 76.5% of intestinal mucin dominant. The results described above suggested that specialized columnar epithelia with intestinal mucin dominant have a higher potential of malignant transformation. We concluded that the evaluation of characteristics of mucinous contents in specialized columnar epithelia plays an important role in determination of high risk group of carcinogenesis in the case of SSBE.     

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食管的病理本质及其与返流性食管炎,食管腺癌关系的研究

从１０００例食管粘膜咬检及１５８０例食管贲门癌切除标本中交界处癌１６５例的形态学、粘液组化及ＦＣＭ分析，探讨ＢＥ病理本质及其与返流性食管炎、食管腺癌的关系。结果：１０００例咬检中２２７例有不同程度的返流性食管炎，其中３例符合ＢＥ。１５８０例食管贲门癌中，交界处癌２３例（１．５％）为食管腺癌，１３例（５６．５％）根据部位、形态、粘液组化分析证明为ＢＥ来源的腺癌。本文认为慢性胃液返流使食管粘膜鳞状上皮长期受损，修复中，部分病例食管鳞状上皮由邻接耐酸性较强、增殖更活跃的胃贲门上皮向上异位生长而代替。长期非特异性刺激附加致癌因素刺激下，修复性增生转变为渐进性异型增生，最终导致癌变，形成ＢＥ来源的腺癌。     

Role of minimally invasive surgery in the modern treatment of Barrett's esophagus

Gastroesophageal reflux disease (GERD) is a highly prevalent disease. Population studies have demonstrated that a significant proportion of individuals weekly experience GERD symptoms. Barrett's esophagus (BE), defined by the presence of intestinal metaplasia (columnar epithelium with goblet cells), is considered a consequence of chronic reflux. This review defines the role of surgery in the modern treatment of BE, taking into consideration the pathophysiology of the disease and the new endoscopic procedures available at present.     

Barrett Esophagus

Barrett esophagus is a metaplastic change in the lining of the distal esophageal epithelium, characterized by replacement of the normal squamous epithelium by specialized intestinal metaplasia. The presence of Barrett esophagus increases the risk of esophageal adenocarcinoma several-fold. Esophageal adenocarcinoma is a malignancy with rapidly rising incidence and persistently poor outcomes when diagnosed after the onset of symptoms. Risk factors for Barrett esophagus include chronic gastroesophageal reflux, central obesity, white race, male gender, older age, smoking, and a family history of Barrett esophagus or esophageal adenocarcinoma. Screening for Barrett esophagus in those with several risk factors followed by endoscopic surveillance to detect dysplasia or adenocarcinoma is currently recommended by society guidelines. Minimally invasive nonendoscopic tools for the early detection of Barrett esophagus are currently being developed. Multimodality endoscopic therapy—using a combination of endoscopic resection and ablation techniques—for the treatment of dysplasia and early adenocarcinoma is successful in eliminating intestinal metaplasia and preventing progression to adenocarcinoma, with outcomes comparable to those after esophagectomy. Risk stratification of those diagnosed with Barrett esophagus is a challenge at present, with active research focused on identifying clinical and biomarker panels to identify those with low and high risk of progression. This narrative review highlights some of the challenges and recent progress in this field.     

Short segment Barrett esophagus and specialized columnar mucosa at the gastroesophageal junction

The rising incidence of adenocarcinoma of the esophagus and the gastric cardia has generated interest in the finding of intestinal metaplasia or specialized columnar mucosa in this location. Short segment Barrett esophagus is defined by the presence of columnar-appearing mucosa in the distal esophagus (<3 cm in length) with intestinal metaplasia on biopsy. In contrast, intestinal metaplasia may also be present if biopsy specimens are obtained from a normal-appearing squamocolumnar junction or from the gastric cardia (ie, immediately below the gastroesophageal junction) in the absence of columnar lining of the distal esophagus. This has been termed cardia intestinal metaplasia, gastroesophageal junction intestinal metaplasia, or specialized columnar mucosa at the gastroesophageal junction. This article reviews the currently available data on these rapidly evolving entities of short segment Barrett esophagus and specialized columnar mucosa at the gastroesophageal junction.     

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.     

Reflux of duodenal or gastroduodenal contents induces esophageal carcinoma in rats

We observed the sequential development of columnar lined epithelium associated with adenocarcinoma, squamous dysplasia related with squamous cell carcinoma and adenosquamous carcinoma which were induced by duodeno-esophageal or gastro-duodeno-esophageal reflux in rats. Wistar male rats, weighing approximately 250 g were employed. Animals received total gastrectomy and were reconstructed with esophago-jejunostomy, which causes unavoidable duodeno-esophageal reflux. The animals were sacrificed every 10 weeks after surgery until 50 weeks. Erosions and basal cell hyperplasia were observed in the lower esophageal squamous epithelium at 10 weeks after surgery. At 20 weeks, glandular structures featured with galactose oxidase-Schiff-positive staining (foveolar metaplasia) appeared in the basal layer of esophageal squamous epithelium. At 30 weeks, the glands developed and formed cysts which were stained with concanavalin A (pyloric glandular metaplasia) or/and high iron diamine and alcian blue (intestinal metaplasia). Since 40 weeks after surgery, esophageal carcinomas were found. As adenocarcinomas were surrounded by the columnar-lined epithelium, squamous cell carcinoma and adenosquamous carcinoma were accompanied by squamous dysplasia. Persistent duodeno-esophageal reflux can change the stem cells of squamous epithelium to make columnar-lined cells. As part of the sequence of events leading to the development of columnar-lined epithelium, foveolar metaplasia was observed followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia. Chronic duodenal reflux induces the development of esophageal carcinoma not only adenocarcinoma also squamous cell carcinoma and adenosquamous carcinoma. These pathways of carcinogenesis were different dual patterns.     

Glycoconjugate expression in normal, metaplastic, and neoplastic human upper gastrointestinal mucosa.

Glycoconjugate structure in upper gastrointestinal epithelium was studied using five lectins to determine the relationship between aberrant differentiation and glycoconjugate expression. Specimens of normal esophagus, stomach, and duodenum were examined and compared with specimens of columnar metaplasia in the esophagus (Barrett's esophagus) and specimens of adenocarcinoma of the esophagus and stomach. Specific terminal glycoconjugate structures were found for the esophagus, stomach, and duodenum. Minor differences were found between the antral and fundic gland mucosae, reflecting their respective cell populations. In biopsies of Barrett's esophagus, gastric-type columnar metaplasia expressed glycoconjugates indistinguishable from those in the normal stomach. In specialized-type columnar metaplasia, a more restricted expression of glycoconjugates was seen resembling the normal duodenum. The presence of low grade dysplasia in Barrett's esophagus associated with adenocarcinoma had no impact on glycoconjugate expression. However, a distinctive difference in glycosylation was seen in high grade dysplasia of the columnar-lined esophagus and in adenocarcinoma of the esophagus and stomach. Barrett's esophagus is a morphological mosaic in which the glycoconjugate expression resembles that seen in the normal stomach and duodenum. However, in high grade dysplasia and carcinoma, variable deletion of glycoconjugate expression can be found.     

Barrett食管与胃食管反流病及食管腺癌的关系

胃食管反流(gastroesophageal reflux,GER)在人群中普遍存在,Barrett食管(Barrett’s esophagus,BE)及食管腺癌(esophageal adenocarcinoma,EA)的发病率也在逐年升高。为了解BE与胃食管反流病(gastroesophageal reflux dis-ease,GERD)、EA的关系,本文复习近年相关文献,从病理生理基础及诊断、治疗方法入手进行探讨,结果发现三者的病情进展过程为正常食管黏膜-GERD-BE化生-BE低度和高度异型增生-EA。故BE的治疗应以减轻GER症状为主,并定期筛检和评价预后,以早期发现EA。     

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.     

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.