食管胃结合部癌前病变和早期癌的研究进展

Siewert将在食管胃连接部上下5 cm范围内发生的肿瘤定义为食管胃结合部肿瘤,包括远端食管腺癌、真正意义上的贲门癌和近端胃癌。传统上认为远端食管腺癌起源于Barrett食管黏膜,与反流相关疾病关系密切;贲门腺癌起源于贲门黏膜,与幽门螺杆菌感染关系密切;而近端胃癌则与幽门螺杆菌和肠化具有较强的关联性。反流相关疾病、Barrett食管和肠上皮化生、幽门螺杆菌感染等与食管胃结合部肿瘤的关系一直是该部位肿瘤的研究热点,但是也存在强烈的争议。随着食管胃结合部解剖学和组织学发展成熟,结合早期发现该部位癌变倾向,使得关于食管胃结合部癌变的病因、分子机制、解剖学及组织学上的探讨越来越深入明朗。因此在早期发现该部位病变并加以干预可以有效地帮助临床和科研工作者解决困扰,同时显著提高肿瘤患者的生存率。     

The definition of Barrett's esophagus

Recently, according to increasing gastroesophageal reflux disease (GERD), the patients with Barrett's esophagus (BE) are increasing. Since Barrett have reported cases of esophageal ulcers surrounding by columnar epithelium, the various criteria of the BE have been proposed. In 1998, practice guidelines for BE were developed under the auspices of the American College of Gastroenterology. They proposed that BE was a chance in the esophageal epithelium of any length that can be recognized at endoscopy, and confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia. Endoscopically, BE is determined, when 'gastric-appearing mucosa' or apparent 'columnar lined esophagus' is evident proximal to the esophagogastric junction. Histologically, BE has double muscularis mucosae, and contains a mixture cell types; gastric-fundic type epithelium, junctional type epithelium, and specialized columnar epithelium (SCE). Especially SCE is distinctive features of BE, available for diagnosis. On the other hand, BE is premalignant condition for the adenocarcinoma of the esophagus, therefore the features of the BE are researched to prevent and find out earlier development of adenocarcinoma. In this review, we referred to the definition of BE with some topics.     

Videoendoscopy and histopathology of the esophagogastric junction in patients with gastroesophageal reflux disease

BACKGROUND AND AIMS: During endoscopy the stomach is considered to rise at the level of the 'gastric' folds; however, anatomical studies have demonstrated that the proximal gastric folds may in fact be esophageal. This prospective study was designed to assess the histopathology of endoscopically visible proximal gastric folds in patients with gastroesophageal reflux disease. METHODS: 35 consecutive patients (20 males) with gastroesophageal reflux disease underwent video endoscopy, including biopsy sampling from the endoscopically visible esophagogastric junction (0 cm, 0.5 cm and 1.0 cm distal to the rise of gastric folds and 0.5 cm and 1.0 cm proximal to it). Endoscopy was digitally recorded and reviewed for assignment of biopsy level. Columnar-lined esophagus and esophagitis were cataloged according to the Paull-Chandrasoma histopathologic classification and the Los Angeles endoscopic classification. RESULTS: Endoscopy: Normal endoscopic esophagogastric junction was seen in 11 (31%) patients and visible columnar-lined esophagus < or = 0.5 cm in 24 (69%). Histology: Columnar-lined esophagus extended 1.0 cm in 22.8% of patients and 0.5 cm in 51.4%, distal to the rise of the gastric folds. In all patients columnar-lined esophagus was interposed between squamous epithelium and gastric oxyntic mucosa. Thus, so-called gastric folds contained mucosa of esophageal origin in all patients. Intestinal metaplasia (Barrett esophagus) was detected in eight (22.9%) patients. CONCLUSIONS: Endoscopy cannot exclude histopathologic columnar-lined esophagus within gastric rugae. Thus, visible 'gastric' folds should not be used for definition of the esophagogastric junction but as a reference landmark for biopsy sampling during endoscopy.     

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.     

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.     

Histopathology of columnar-lined esophagus in patients with gastroesophageal reflux disease

BACKGROUND AND AIMS: The question of whether an endoscopically normal-appearing esophagogastric junction should be biopsied in patients with gastroesophageal reflux disease is controversial. We have addressed this issue using endoscopy and histopathology. METHODS: A total of 114 consecutive patients (58 males) with symptoms of gastroesophageal reflux disease prospectively underwent endoscopy, including biopsy sampling from the esophagogastric junction. Endoscopically visible columnar-lined esophagus was defined by the presence of gastric-type mucosa above the level of the rise of the gastric folds. Histopathology was conducted using the Paull-Chandrasoma classification. RESULTS: Of the 114 patients, 85 (74.6%) had endoscopically visible columnar-lined esophagus of length < or =0.5 cm (n = 82), 1 cm (n = 2) and 7 cm (n = 1); 29 patients (25.4%) had a normal endoscopic junction. All patients had histopathologic columnar-lined esophagus. Intestinal metaplasia and low-grade dysplasia was identified in 26 (22.8%) and 5 (4.4%) individuals, respectively, and was not statistically different in endoscopically normal vs. abnormal junction (P = 0.408 for intestinal metaplasia, P = 0.775 for low grade dysplasia). Intestinal metaplasia was independent from endoscopic esophagitis (P = 0.398) and hiatal hernia (P = 0.405). CONCLUSIONS: Columnar-lined esophagus cannot be excluded by endoscopy. In patients with gastroesophageal reflux disease, biopsy sampling of normal-appearing junction is recommended for histopathologic exclusion of intestinal metaplasia and low-grade dysplasia.     

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.     

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.     

The history of Barrett esophagus

The term Barrett esophagus has become well established in the medical literature to indicate columnar metaplasia of the distal esophagus associated with chronic gastroesophageal reflux disease. However, the historical events that led to the use of this term have become obscured. Here, the historical aspects of Barrett esophagus are reviewed, providing insight not only to this condition but also to the evolution of medical thought in general.     

Endoscopic and histologic diagnosis of Barrett esophagus

Endoscopy plays an important role in the identification, diagnosis, and treatment of Barrett esophagus. Short-segment (<2-3 cm) and traditional long-segment (>2-3 cm) Barrett esophagus are distinguished solely on the length of metaplastic tissue above the esophagogastric junction. The histologic hallmark of intestinal metaplasia is required to confirm diagnosis. Biopsy specimens obtained from tissue of presumed Barrett esophagus or an irregular Z line confirm metaplastic glandular mucosa and permit evaluation of dysplastic or neoplastic changes. In the appropriate clinical setting, the use of adjunctive diagnostic techniques may facilitate the diagnosis of Barrett esophagus and sequelae such as dysplasia. Chromoendoscopy with high-resolution or magnified endoscopy is simple, safe, and desirable for surveillance but requires additional procedural time. The use of light-induced fluorescence endoscopy and light-scattering spectroscopy (i.e., optical biopsy) is appealing for the diagnosis and characterization of suspicious lesions. Adjunctive endoscopic techniques and adherence to a protocol for performing biopsies facilitate the early detection and subsequent surveillance of Barrett 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.     

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.     

Pathogenesis of gastroesophageal reflux and Barrett esophagus

Barrett esophagus is a metaplastic condition that affects the lower esophagus and is a complication of gastroesophageal reflux disease (GERD). Under normal circumstances, the reflux of gastric contents into the esophagus is prevented by a complex barrier at the esophagogastric junction. Dysfunction of the lower esophageal sphincter and the presence of a hiatal hernia lead to failure of this barrier. Esophageal mucosal damage results from the chronic exposure of the esophageal mucosa to gastroduodenal contents and the lack of an effective mucosal defense. This article is an overview of the dysfunction of the esophagogastric junction that leads to GERD. The role of the contents of the reflux and that of Helicobacter pylori infection in the pathogenesis of Barrett esophagus are also summarized.     

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.     

Diagnosis of esophagogastric tumors

Esophagogastric tumors occur in three sectors: the esophagus, the EG junction and the non-cardia stomach. Neoplasia develops in the squamous stratified epithelium of the esophagus and in the columnar epithelium of the Barrett's esophagus or in the stomach. At the junction, tumors arise either in a very short Barrett's esophagus or in the gastric epithelium of the cardia. The prognosis of tumors detected at the advanced stage is poor. Secondary prevention requires detection at the early stage. Most superficial neoplastic lesions in the esophagus and in the stomach have a non-protruding appearance, which is similar for premalignant and malignant lesions. Improved accuracy in endoscopic diagnosis and prediction of histology prior to biopsy and treatment decision is based upon magnification with a optical zoom and electronic processing of the captured image with structure enhancement, enhancement of the color of hemoglobin and narrow band imaging. This applies particularly to the exploration of the Barrett's esophagus for identification of the areas with intestinal metaplasia and of flat neoplastic areas. In spite of the predictive value of endoscopy for histology, biopsy samples are still required for pathology and eventually studies with biological markers. Spectroscopic techniques provide a new perspective, up to the level of molecular endoscopy, but they are unlikely to be cost/effective. The classification in the sub-types 0 of neoplastic lesions has some relevance to prediction of depth of invasion. In the esophagus, EUS staging with high frequency miniprobes is a useful complement.     

Barrett esophagus: update for radiologists

Barrett esophagus is a well-recognized entity in which there is progressive columnar metaplasia of the lower esophagus due to longstanding gastroesophageal reflux and reflux esophagitis [1]. This condition is important because it is associated with an increased risk of developing esophageal adenocarcinoma by a well-established sequence from dysplasia to carcinoma [2]. During the past decade, however, an explosion of new data has dramatically affected our understanding of Barrett esophagus. Not only have revised histopathologic criteria been developed for this condition, but it is currently believed that patients with Barrett esophagus should be classified as having short-segment or long-segment disease based on the extent of columnar metaplasia in the distal esophagus. This distinction has important implications for the risk of developing esophageal adenocarcinoma and subsequent need for endoscopic surveillance. The purpose of this article is to present these new concepts about Barrett esophagus and provide radiologists with a more current framework for diagnosing this condition.     

P物质在BARRETT食管黏膜组织中的表达

目的研究P物质在BARRETT食管（BE）黏膜组织中的表达,探讨其在BE发病中的作用。方法应用免疫组织化学方法测定P物质在正常对照组（n=25）及BE组（n=58）中的表达,并比较P物质在不同化生程度、伴或不伴胆汁反流BE组中表达的差异。结果 P物质在BE中的表达低于对照组,且胃化生（＋）BE组P物质表达高于肠化生（＋）BE组,差异均有显著性（t=9.98、3.25,P〈0.05）;伴胆汁反流BE组P物质表达明显低于不伴胆汁反流BE组（t=3.04,P〈0.05）,而伴胆汁反流BE组肠化生阳性率高于不伴胆汁反流BE组,差异有显著性（χ2=4.99,P〈0.05）。结论 BE组存在P物质分泌失调,其可能在BE的发生发展中起着一定作用;胆汁反流可能影响BE黏膜P物质的分泌,而与肠化生的发生可能有关。     

Biopsy methods and pathology of Barrett's esophagus

We reviewed the definition of the esophagogastric junction and the biopsy sites and histologic findings of biopsy specimens from Barrett's esophagus. The borderline between the esophagus and stomach has been defined as the distal limit of the longitudinal vessels by the Japan Esophageal Society, because the longitudinal vessels are always located within the esophagus. As squamous islands in Barrett's mucosa are usually the orifices of esophageal glands proper, biopsy specimens from the squamous islands show esophageal glands proper or their ducts. The identification of esophageal glands proper is a definite histological indicator that a piece of biopsy tissue is of esophageal origin. Therefore, a diagnosis of Barrett's esophagus can be made purely on the basis of the histologic findings in these biopsy specimens of squamous islands. Since columnar mucosa is usually recognizable at endoscopy, a diagnosis of Barrett's esophagus can be made solely on the basis of endoscopic examination, without any need for histologic confirmation, if squamous islands are recognized in columnar-lined mucosa.     

Mucosal ablation therapy of barrett esophagus

Barrett esophagus is defined by the metaplasia of existing squamous mucosa into a specialized intestinal-type mucosa. The importance of this metaplasia is the association of this condition with the development of adenocarcinoma of the esophagus. Elimination of the metaplastic mucosa may decrease the cancer risk. Currently, several forms of therapy have evolved with the goal of replacing the specialized mucosa with normal squamous mucosa. These proposed treatments include photodynamic therapy and thermal techniques. The effectiveness of photodynamic therapy varies depending on the pharmaceutical photosensitizer used and the wavelength of light applied to activate the drug. Thermal techniques include multipolar coagulation, argon plasma coagulation, KTP:YAG laser therapy, Nd:YAG laser therapy, and argon laser therapy. Finally, mucosal resection has been attempted through the endoscope to remove large areas of the Barrett mucosa. All of these ablative strategies attempt to destroy the metaplastic mucosa and promote the regrowth of squamous epithelium. These therapies have demonstrated the ability to "reverse" the metaplasia to varying degrees, but a decrease in cancer risk has not been demonstrated conclusively with any of these treatment methods.