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.     

Risk factors for gastroesophageal reflux disease and analysis of genetic contributors

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including: (1) motor abnormalities, such as impaired lower esophageal sphincter (LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and (2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD- related disorders development such Barrett’s esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett’s esophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis, specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease.     

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.     

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.     

难治性胃食管反流病的反流危险因素调查

目的：收集胃食管反流病（gastroesophageaf reflux disease,GERD）患者的临床信息、胃镜表现以及24 h食管pH-阻抗监测结果,比较难治性GERD和非难治性GERD的反流特点,探讨难治性GERD的预测因素,为临床处理提供依据.方法：入选2008年10月-2012年12月因反酸、烧心、非心源性胸痛、咽痛等症状在复旦大学附属中山医院消化科疑诊为GERD的74例患者.记录患者的年龄、性别、身高、体质量、胃镜结果等.监测患者的食管下段pH和食管阻抗变化.难治性GERD诊断：符合GERD诊断标准,同时经过质子泵抑制剂（PPI）治疗4周（每天至少1次）无效或者deMeester评分下降少于50％;非难治性GERD诊断：符合GERD诊断标准,同时经过PPI治疗4周（每天至少1次）症状改善明显;非GERD诊断：内镜检查未见食管黏膜损害,且24 h食管pH-阻抗监测反流次数和deMeester评分不足以诊断GERD.计数资料正态分布者用r±s表示,菲正态分布者用中位数和百分位数（25th,75th）表示.采用SPSS 17.0软件进行统计学处理.按是否为GERD、是否为难治性GERD分组,比较患者的一般资料和反流特征性因素.结果：（1）难治性GERD患者与非难治性GERD患者的酸反流次数、总反流次数差异无统计学意义;难治性GERD患者的deMeester评分较非难活性GERD患者高,长酸反流次数较非难治GERD患者多（P=0.032,P=0.008）;（2）经Logistic多因素分析发现,难治性GERD与长酸反流次数、非糜烂性胃食管反流病（NERD）呈正相关（P值分别为0.01和0.045）.长酸反流次数增加1次,发生难治性GERD的危险增加36％;NERD患者发生难治性GERD的危险是反流性食管炎患者的4.54倍;（3）不同类型GERD的反流特征：NERD患者的近端反流次数大于反流性食管炎和Barrett食管患者,而近端反流百分比显著大于反流性食管炎患者和Barrett食管患者（P=0.006）.结论：（1）长酸反流次数多和NERD是难治性GERD的独立危险因素;（2）NERD患者比糜烂食管炎患者更容易发展为难治性GERD.NERD患者的近端反流百分比的升高可能与其对PPI的反应差有关.     

GERD and tight junction proteins of the esophageal mucosa

Recent advancement in the research of GERD has revealed that endoscopy negative GERD may not be a milder form of erosive GERD and may have different pathogenesis. We have previously proven that hypersensitivity to the acid of the esophageal mucosa plays an important role in its pathogenesis. Regarding the mechanisms for the esophageal hypersensitivity, we hypothesized that the tight junction proteins of the esophageal mucosa are fully or partially impaired in GERD patients. Accordingly, we immunohistologically studied the expression of various tight junction proteins using the rat reflux esophagitis model. The results demonstrated that the several kinds of tight junction proteins are expressed differently in the various parts of esophagus and their expression altered according to the development of reflux esophagitis.     

Gastroesophageal reflux patients' defective antioxidative capacity in the proximal esophageal mucosa before antireflux surgery and also after 4-year follow-up

BACKGROUND: Oxidative stress has a role in the pathogenesis of gastroesophageal reflux disease (GERD). AIM: To investigate the redox balance in proximal esophagus before and 6 and 48 months after antireflux surgery. METHODS: In 20 GERD patients and 9 controls oxidative stress by myeloperoxidase activity (MPO activity) and antioxidative capacity of esophageal mucosa by superoxide dismutase activity (SOD), and glutathione content (GSH) was measured from proximal esophageal samples. RESULTS: In proximal esophagus of GERD patients compared to controls', antioxidative capacity appearing as GSH level was significantly decreased (P < 0.001) at all time points and as SOD levels preoperatively (P < 0.001) and 4 years postoperatively (P = 0.01). MPO activity of patients was significantly lower than controls' preoperatively, and 6 months and 4 years postoperatively (P < 0.05). MPO activity remained lower than that of the distal esophagus at 6 months and 4 years (P < 0.01 for both). CONCLUSIONS: In GERD patients, proximal esophageal mucosal antioxidative defense is defective before and after antireflux surgery. Antireflux surgery seems not to change the level of oxidative stress in proximal esophagus, suggesting that defective mucosal antioxidative capacity plays a role in development of oxidative damage to the esophageal mucosa in GERD.     

Esophagogastric ring: why and when we see it, and what it implies: a radiologic-pathologic correlation.

Schatzki first reported a ring-like structure at the esophagogastric mucosal junction in 1953. There is still no uniform agreement as to its exact location, etiology, or clinical importance. We found an esophagogastric ring in 15% to 18% of 22,368 patients having routine upper gastrointestinal examinations. It was present only in patients with cephalad displacement of the esophagogastric junction and only in those who had sharply and circumferentially marginated transition of esophagogastric mucosal junction. It is postulated that the esophagus shortens on vagal stimulation by contracture of the longitudinal esophageal muscle, which causes a mucosal infolding at the esophagogastric junction. In a small group of these patients, fibrosis apparently develops in this region and results in a fixed organic circumferential diaphragm, which may cause obstructive symptoms. These concepts affect therapeutic alternatives.     

Natural progression of the lower esophageal mucosal ring

Among 390 patients with endoscopically verified lower esophageal mucosal ring (LEMR), 22 cases were identified with previous or subsequent radiologic examinations of the esophagogastric region. Among these, it was found that 2 cases of LEMR had developed from a normal esophagus. In 3 patients, there was increasing stenosis of the LEMR. In 8 cases, the LEMR was transformed into an esophageal stricture. In 10 of the 13 cases, esophagitis of varying degree was present endoscopically. In the 9 patients exhibiting no change in the LEMR, only 1 patient had esophagitis. The data suggest that there is a potential progression from normal esophagus to lower esophageal ring to esophageal stricture that occurs in association with reflux esophagitis.     

Schatzki环研究进展

Schatzki环(SR)是一种食管贲门交界处的黏膜环,可引起食管狭窄,是间歇性固体食物吞咽困难、食物嵌顿最常见原因之一。其病因尚不明确,可能与胃食管反流有关。SR可与食管裂孔疝、Barrett食管及嗜酸细胞性食管炎等一些食管疾病并存。其最主要的诊断方法是上消化道钡剂造影。有症状的SR可以使用抑酸药物治疗、内镜下治疗及外科手术。     

Inflammation and oxidative stress in gastroesophageal reflux disease

The etiology of esophageal mucosal injury is complex, since it may involve the reflux of gastric acid, bile acid, and pancreatic juice, external factors such as drugs and alcohol, or functional factors such as esophagogastric motility. The mechanism of esophageal mucosal injury has gradually been understood at the molecular biological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines (interleukin-6 and -8), leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). In addition, nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with anti-inflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.     

Endoscopic examination including magnifying endoscopy for diagnosis of GERD

Symptoms of heartburn and regurgitation are the most important for diagnosis of gastroesophageal reflux disease (GERD) in the clinical field. Endoscopic examination is also widely used modality for Los Angeles classification of GERD according to endoscopic severity of esophageal mucosal breaks. However, about half of GERD patients reveal no abnormality under conventional endoscopy. These endoscopic negative GERD is called as non-erosive reflux disease (NERD). There is the possibility to underestimate a minute mucosal change of GERD by conventional endoscopy that has the limitation of visual ability. Magnifying endoscopic examination is able to get clear visualization of intrapapillary capillary loops(IPCL), which are usually shown as dot-like structures in esophageal mucosa by a conventional endoscopy. The changing of IPCLs is associated with inflammation and neoplasia of esophagus. Minute change of IPCLs such as a dilation and elongation with regular intervals were reported to be suggestive of inflammatory change in esophagus. Magnifying endoscopic observation of IPCLs is useful for diagnosis of NERD which cannot be visualized by conventional endoscopy.     

从心身角度认识胃食管反流病

胃食管反流病(GERD)为一组疾病症候群,包括典型症状如反酸和烧心,以及不典型症状如胸痛、嗳气,还有食管外症状如咳嗽、哮喘等。其定义不断进行更新,最新定义为胃内容物反流入食管或口腔、咽喉、肺部引起的症状和并发症。GERD发病机制包括滑动性食管裂孔疝、一过性食管下括约肌松弛、酸囊、食管清除能力下降、胃排空延迟、十二指肠胃食管反流等。焦虑、抑郁等心理因素可导致食管的敏感性增高,而后者可产生GERD相关症状。心理应激对食管敏感性的影响主要通过外周及中枢机制,即外周致敏和中枢致敏,而后者起主要作用。对GERD患者的治疗中应根据每位患者的具体情况采取个体化原则,应重视心理因素。     

Laparoscopic surgery for an esophageal duplication cyst using a near‐infrared indocyanine green fluorescence system: A case report

We herein describe a case of laparoscopic surgery for an esophageal duplication cyst using a near‐infrared indocyanine green fluorescence system. A 64‐year‐old woman with a cystic tumor adjacent to the esophagogastric junction was referred to our hospital for treatment. Esophagogastroduodenoscopy and abdominal CT revealed a 70‐mm submucosal tumor derived from the abdominal esophagus. We performed laparoscopic resection and then evaluated the tissue perfusion of the abdominal esophagus by using a near‐infrared indocyanine green fluorescence system. A Dor fundoplication was performed to prevent postoperative gastroesophageal reflux disease and reinforce the mucosal layer defect. The postoperative course was uneventful, and pathological evaluation confirmed that the tumor was an esophageal duplication cyst. The patient did not develop recurrence in the 24 months after surgery. We have demonstrated that laparoscopic resection of an esophageal duplication cyst may be performed effectively with intraoperative assessment of tissue perfusion using a near‐infrared indocyanine green fluorescence system.     

Lansoprazole-induced improvement of esophageal submucosal injury

The proton pumpvinhibitor, lansoprazole, is reported to have acid secretion inhibiting effect as well as anti-inflammatory effects such as inhibition of cytokine secretion from inflammatory cells. Clinically, excellent efficacy of lansoprazole is reported for not only gastric ulcer but also gastroesophageal reflux disease (GERD). Since GERD is categorized endoscopically into erosive esophagitis and non-erosive reflux disease, it is important to make accurate assessment of any improvement in the inflammatory process when using endoscopic ultrasonography (EUS) capable of visualizing the submucosal structure. We report here our experience in assessing the effect of treatment with lansoprazole on esophageal wall structure using EUS in patients with GERD. At baseline (before treatment), EUS showed abnormalities in the mucosa, submucosa and muscularis propria caused by inflammation, thickening of the entire esophageal wall and changes in the contractile properties of esophageal smooth muscles reflecting the effects of inflammation on the entire wall of the lower esophagus in reflux esophagitis regardless of whether it is erosive or endoscopically-negative. Treatment with lansoprazole resulted in normalization of esophageal wall structure and improvement of motility, suggesting that lansoprazole improves not only mucosal inflammation but also submucosal inflammation in GERD.     

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 occurring as a complication of scleroderma

Two patients had both scleroderma and a columnar epithelium-lined lower esophagus (Barrett esophagus). Features of Barrett's esophagus included high esophageal strictures in both patients and ulcer craters in the columnar area of one. Biopsy confirmed columnar epithelium in the lower esophagus of each patient. In these patients, the Barrett esophagus probably was a complication of scleroderma and resulted from long-standing gastroesophageal reflux.     

Gastroesophageal reflux patients' defective antioxidative capacity in the proximal esophageal mucosa before antireflux surgery and also after 4‐year follow‐up

Background. Oxidative stress has a role in the pathogenesis of gastroesophageal reflux disease (GERD).

Aim. To investigate the redox balance in proximal esophagus before and 6 and 48 months after antireflux surgery.

Methods. In 20 GERD patients and 9 controls oxidative stress by myeloperoxidase activity (MPO activity) and antioxidative capacity of esophageal mucosa by superoxide dismutase activity (SOD), and glutathione content (GSH) was measured from proximal esophageal samples.

Results. In proximal esophagus of GERD patients compared to controls', antioxidative capacity appearing as GSH level was significantly decreased (P<0.001) at all time points and as SOD levels preoperatively (P<0.001) and 4 years postoperatively (P = 0.01). MPO activity of patients was significantly lower than controls' preoperatively, and 6 months and 4 years postoperatively (P<0.05). MPO activity remained lower than that of the distal esophagus at 6 months and 4 years (P<0.01 for both).

Conclusions. In GERD patients, proximal esophageal mucosal antioxidative defense is defective before and after antireflux surgery. Antireflux surgery seems not to change the level of oxidative stress in proximal esophagus, suggesting that defective mucosal antioxidative capacity plays a role in development of oxidative damage to the esophageal mucosa in GERD.