Cardia-type metaplasia arising in the remnant esophagus after cardia resection

BACKGROUND: Specialized intestinalized metaplasia in the distal esophagus (Barrett's esophagus) is a recognized precursor of esophageal adenocarcinoma, but its pathogenesis is incompletely understood. The aim of this study was to investigate the mucosal effects of esophagogastrostomy, an artificial interface between esophageal squamous and gastric oxyntic epithelium. METHODS: EGD was performed in 14 consecutive patients (median age 63 years, range 26-71 years) who had undergone esophagogastrostomy from 3 to 88 months earlier. Biopsy specimens were obtained in 13 patients from the anastomosis and, when present, columnar epithelium in the remnant esophagus. RESULTS: In 10 patients, EGD demonstrated tongue-shaped segments of columnar epithelium extending from 0.3 to 7 cm into the remnant esophagus. Biopsy specimens revealed cardia-type mucosa in all patients, whether at the anastomosis or proximally in esophageal segments of columnar epithelium. Magnification endoscopy of cardia-type mucosa visualized a long-oval, tubular, or ridged surface pattern. In 3 cases, complete intestinal metaplasia was observed within the cardia-type mucosa. CONCLUSIONS: The frequent transformation of squamous epithelium into cardia-type mucosa in the distal remnant esophagus after esophagogastrostomy supports the concept that cardia-type mucosa is a reflux-induced metaplasia that may give rise to the subsequent development of specialized intestinalized metaplasia.     

Barrett食管黏膜微细形态改变和CDX2蛋白的表达

目的 研究食管黏膜微细形态的改变和CDX2蛋白表达在Barrett食管（BE）诊断中的意义。方法 采用高清晰内镜观察BE及非BE的胃食管反流疾病（GERD）患者的齿状线附近黏膜的小凹及微细血管形态变化，并采用免疫组化方法检测CDX2蛋白的表达。结果 48例BE中，40例可观察到食管下段的栅状血管末端有不同程度的下移现象，而60例非BE的GERD患者均未发现有血管下移现象；放大内镜下BE黏膜可分为绒毛型、条纹型和小点型，绒毛型肠上皮化生（肠化）检出率显著高于条纹型及点状（P〈0.01）；CDX2蛋白不但在肠化的杯状细胞表达，而且在BE和非BE的柱状上皮中亦有表达，绒毛状上皮CDX2表达的阳性率显著高于条纹状（P〈0.01）和点状上皮（P〈0．05）。结论 观察食管黏膜微细形态有助于对BE的诊断、分型及了解其相关病理背景，CDX2蛋白是一种具有较高敏感性的肠上皮特异标志物，有助于判断早期肠化的发生，对BE的早期诊断可能有重要价值。     

CDX2 MUC2在胃黏膜肠上皮化生组织中的表达情况及其临床意义研究

目的 探讨尾型同源盒转录因子2(CDX2)、黏蛋白2(MUC2)在胃黏膜肠上皮化生组织中的表达情况及其临床意义.方法 选择2011年1月至2014年5月于宁夏医科大学总医院消化内科就诊并行内镜活检的152例患者,根据病理检查结果将其分为非萎缩性胃炎组(32例)、萎缩性胃炎组(31例)、低级别上皮内瘤变组(24例)、高级...     

Comparison of clinical, endoscopic and functional findings in patients with intestinal metaplasia at the cardia, carditis and short-segment columnar epithelium of the distal esophagus with and without intestinal metaplasia

In recent years, the diagnosis of short segments of intestinal metaplasia lining the distal esophagus has increased. The aim of the present study was to determine the clinical, endoscopic, histologic and functional results in patients with intestinal metaplasia at the cardia (IMC), carditis and short-segment columnar epithelium (CE) lining the distal esophagus with and without intestinal metaplasia. Four groups were studied: 48 patients with carditis, 105 patients with IMC, 78 patients with short-segment CE (SSCE) without IM and 69 patients with short-segment CE with IM. All had clinical questionnaire, endoscopic and histological evaluation, manometric studies and measurements of acid and bilirubin exposition of the distal esophagus over 24 h. Patients without IM were found to be younger than those with IM. Erosive esophagitis was observed in similar proportions, but hiatal hernia was present in patients with SSCE with or without IM. Patients without IM had mainly cardial mucosa more than fundic mucosa. However, patients with IM had almost exclusively cardial mucosa. Low-grade dysplasia was observed only in patients with IM. Manometric evaluation demonstrated a structural defective lower esophageal sphincter in all groups. Acid and duodenal exposures of the distal esophagus over 24 h were significantly greater in patients with SSCE with IM. In the presence of pathologic gastroesophageal reflux (GER), there are several histological changes at the mucosa distal to the squamous columnar junction. The first metaplastic change is one from fundic to cardial mucosa and, when duodenal reflux occurs, a second metaplastic change to intestinal metaplasia from cardial mucosa occurs. Therefore, in all patients with symptoms of GER, biopsies specimens distal to the squamous columnar junction should be taken routinely.     

Evaluation of Barrett's esophagus with CK7, CK20, p53, Ki67, and COX2 expressions using chromoendoscopical examination

Barrett's esophagus (BE) is a complication of chronic gastroesophageal reflux disease and can be diagnosed when there is an endoscopically irregular Z‐line and intestinal metaplasia (IM) in a biopsy obtained lower esophagus. It is still not clear whether IM in the gastric cardia or columnar mucosa without IM in the lower esophagus have any significance as BE, which is considered as preneoplastic. The aim of the study was to determine the immunohistochemical features of BE and columnar mucosa in the distal esophagus and also to evaluate the value of chromoendoscopy in the diagnosis of BE in a prospective manner. A total of 12 chromoendoscopic biopsies (six from normal‐looking unstained esophagus and six from esophageal mucosa stained with methyl blue suspicious of BE) were taken from 111 cases who underwent endoscopy because of a variety of upper gastrointestinal symptoms. Immunohistochemical analysis was performed using CK7, CK20, p53, Ki67, and cyclooxygenase 2 (COX2). Of the 111 cases, 19 cases with carcinoma (nine adeno, six squamous, four undifferentiated carcinomas) and 17 cases with normal squamous epithelium were excluded, while 75 cases showing columnar epithelium, including 46 (61.3%) with IM and 29 (38,7%) without IM, were further evaluated immunohistochemically. CK7 was observed in surface, crypt, and glandular epithelium, whereas CK20 was expressed in surface and superficial crypt epithelium. No significant difference was observed between the Barrett and non‐Barrett type of CK7/20 staining pattern (P > 0,05). Expression of p53 did not show any difference between BE and columnar mucosa without IM, whereas COX2 expression was significantly increased in BE (P < 0.05) in comparison with columnar mucosa without IM. Ki67 expression was significiantly higher both in upper and lower crypts in BE (P < 0.05). The present study showed that a Barrett pattern does not seem to exist; however, the analysis of COX2 expression and the Ki67 proliferation fraction by immunohistochemistry can be used to separate BE from non‐Barrett's metaplasia of the distal esophagus. In our point of view, the immunohistochemical detection of p53 expression in Barrett's metaplasia stage is useless as a marker for early detection of high‐risk patients.     

CDX1/2在人Barrett's食管中的表达以及胆酸对CDX2表达的影响

目的: 观察Barrett's食管黏膜组织中CDX mRNA和蛋白表达,观察不同胆汁酸对人食管细胞株Eca-109 CDX2 mRNA表达水平的影响.方法: 收集内镜下正常食管组织( n = 5),反流性食管炎( n = 7),Barrett's食管( n = 8)标本. 采用RT-PCR测定CDX1和CDX2 mRNA表达;实时荧光定量PCR测定CDX2 mRNA表达. 用免疫组织化学染色法对CDX2蛋白进行定位. 人食管癌细胞株Eca-109分别在100、400、1000μmol/L胆酸(CA),脱氧胆酸(DCA),甘胆酸(GC)中培养,分别在0-24 h收取细胞,荧光定量PCR测定CDX2 mRNA表达.结果: CDX2 mRNA在正常食管组织中无表达,在Barrett's食管组、反流性食管炎组表达增高(9.6411±6.6823,3.9156±3.6700),与正常食管组之间比较均存在显著性差异( P = 0.006,0.025),但2组之间没有显著性差异( P = 0.133),CDX1在所有食管组织中均无表达. 免疫组织化学染色在Barrett's食管有CDX2蛋白胞核呈特异性染色阳性反应,反流性食管炎组织CDX2胞质显示细颗粒性染色(假阳性),正常的食管组织未发现特异性染色. CDX2 mRNA在未加药物处理的Ec a-109细胞株中没有表达,其表达量对DCA、GC、CA显示出时间和剂量依赖性.结论: CDX2基因异常表达在食管黏膜肠化生过程中可能具有较重要作用,CDX2基因的表达可能是Barrett's食管发生过程的早期事件.胆汁酸在体外实验上调CDX2基因表达,通过调节其表达在Barrett's食管发生中起重要作用.     

Unraveling the mystery of the gastroesophageal junction: a pathologist's perspective

The gastroesophageal junction (GEJ), which is defined as the point where the distal esophagus joins the proximal stomach (cardia), is a short anatomic area that is commonly exposed to the injurious effects of GERD and/or Helicobacter pylori infection. These disorders often lead to inflammation and intestinal metaplasia (IM) of this anatomic region. The true gastric cardia is an extremely short segment (<0.4 mm) of mucosa that is typically composed of pure mucous glands, or mixed mucous/oxyntic glands that are histologically indistinguishable from metaplastic mucinous columnar epithelium of the distal esophagus. In patients with GERD, whether physiologic or pathologic, the length of cardia-type epithelium increases and extends proximally above the level of the anatomic GEJ into the distal esophagus. Columnar metaplasia of the distal esophagus represents a squamous to columnar metaplastic reaction that develops from an esophageal stem cell and may pass through an intermediate phase characterized by the presence of a type of epithelium that possesses a mixture of squamous and columnar features, termed multilayered epithelium. In contrast, IM of the gastric cardia represents a columnar to columnar cell metaplastic reaction that develops from a gastric stem cell located in the deep foveolar compartment of the gastric mucosa. Intestinal metaplasia, particularly the incomplete type, is widely believed to represent the precursor lesion upon which dysplasia and cancer arises. The frequency of IM is probably greater in metaplastic columnar epithelium in the esophagus secondary to GERD, than in cases of true gastric carditis secondary to H. pylori, and may be a reason why there is a higher risk of carcinoma in the former compared to the latter. A variety of clinical, endoscopic, histologic, and histochemical methods can be used to distinguish GERD-induced columnar metaplasia of the distal esophagus from H. pylori-induced inflammation of true gastric cardia, and these are outlined in this review, but further controlled studies are needed to critically evaluate these techniques. Further prospective trials are needed to adequately evaluate the different etiologic and pathogenetic mechanisms and, most importantly, the risk of malignancy in these two conditions.     

Expression of sulfated carbohydrate chain and core peptides of mucin detected by monoclonal antibodies in Barrett's esophagus and esophageal adenocarcinoma

Columnar epithelium-lined esophagus (Barrett's esophagus) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Columnar epithelium resembling intestinal metaplasia (IM) is especially important, since it is considered to be a premalignant condition. The aim of this study was to define the sulfated carbohydrate chain of mucin and its core peptide profile in Barrett's esophagus (BE) and to compare it with the profile in Barrett's adenocarcinoma and lower esophageal adenocarcinoma. The sulfated carbohydrate chain was not expressed in 16 specimens of normal esophageal epithelium, but in BE, it was expressed in 50% (8/16) of the specimens. This chain was detected in 100% (7/7) of esophageal adenocarcinoma specimens, including four cases of Barrett's adenocarcinoma. These data suggest that the sulfated carbohydrate chain may be associated with malignant phenotype of the esophagus. MUC1 core peptide was positive in 87% (13/15) of BE specimens and in 29% (2/7) of the esophageal adenocarcinoma specimens. MUC2 core peptide was present in 57% (8/14) and 43% (3/7) of these specimens, respectively. These data suggest that Barrett's epithelium, which is similar to IM, but not normal esophageal epithelium, expresses the sulfated sugar chain which is known to be present in gastric IM and colonic mucosa. However, there was no significant correlation between the expression of the sulfated sugar chain and the expression of either mucin core peptide MUC1 or MUC2. Thus, this carbohydrate chain may be expressed on as yet unidentified core proteins, other than MUC1 or MUC2 core peptide, in BE and esophageal adenocarcinoma. Identification of these proteins may be very important in helping to detect premalignant status in BE. (Received Jan. 26, 1998; accepted May 22, 1998)     

Small-bowel metaplasia arising in the remnant esophagus after esophagojejunostomy--a [corrected] prospective study in patients with a history of total gastrectomy

OBJECTIVES: The pathogenesis of Barrett's mucosa is incompletely understood. Acidic gastro-esophageal reflux is considered an essential causative factor. The aim of this study was to detect esophageal columnar metaplasia after total gastrectomy with esophagojejunostomy, a condition of enteric, but nonacidic reflux. METHODS: In a prospective study, patients with a history of total gastrectomy and esophagojejunostomy were investigated for the presence of columnar metaplasia in the remnant esophagus. Patients with such history, who were now referred for esophagogastroduodenoscopy, were included during a 2-yr period. Biopsies for histopathology were taken from the anastomosis and any columnar metaplasia of the esophagus. RESULTS: In 8 of 25 patients (32%) with a history of gastrectomy, columnar metaplasia was found in the remnant esophagus, mostly in shape of tongues, partly associated with erosive reflux esophagitis. Histopathology showed a typical small-bowel mucosa, but with some villous atrophy. In a resection specimen, a double-layered muscularis mucosa was present, which proved the metaplastic nature of the intestinal mucosa. Length of the columnar metaplasia correlated with the time interval since surgery. CONCLUSIONS: Esophageal mucosa, if exposed long term to an enteric, but nongastric refluxate, can evolve into a highly differentiated intestinal metaplasia, which resembles small-bowel mucosa. This proves that complete-type intestinal metaplasia may arise not only in the stomach, but also in the esophagus. Esophageal intestinalization seems to reflect adaptation to enteric reflux.     

Expression of homeodomain protein CDX2 in gallbladder carcinomas

Purpose Caudal-related homeobox protein CDX2 plays an important role in the regulation of cell proliferation and differentiation of the intestinal epithelium. CDX2 is associated with intestinal metaplasia and carcinomas of the stomach, but the role of CDX2 in gallbladder carcinogenesis remains unknown.Methods We analyzed the expression of CDX2 and intestinal apomucin MUC2 in gallbladder cancer cell lines at the mRNA level by the RT-PCR method. We also investigated the expression of CDX2 and MUC2 in 68 primary gallbladder carcinomas by the immunohistochemical staining method and compared the expression of CDX2 with the clinicopathological factors in the gallbladder carcinoma cases.Results Expression of CDX2 and MUC2 was found in three of four gallbladder cancer cell lines at the mRNA level. In addition, we found that CDX2 was absent in the normal gallbladder epithelium, but the CDX2 protein was expressed in 25 of the 68 (36.8%) gallbladder carcinomas. Interestingly, in the tubular type gallbladder carcinomas, the frequency of CDX2 expression was much higher in the well-differentiated type than the moderately and poorly differentiated types, the difference being statistically significant (P<0.01). CDX2 expression showed a relationship with expression of MUC2 (P<0.04) in the gallbladder carcinomas. CDX2 was expressed in intestinal metaplasia and dysplasia, which are hypothesized to be premalignant conditions.Conclusion These results imply that CDX2 plays an important role in gallbladder carcinogenesis with intestinal differentiation.     

The role of mucin in GERD and its complications

Acid, pepsin and other noxious material reach the esophageal mucosa and interact with the luminal aspect of the squamous epithelium. The first protective barrier to these potentially injurious substances is the mucus buffer layer that covers the mucosa. In healthy people, the esophagus has a protective surface adherent mucus gel barrier. Levels of mucin glycoprotein are considerably increased in response to acid and pepsin. A wide spectrum of mucin genes are expressed in normal esophageal mucosa, squamous cell carcinoma of the esophagus, Barrett epithelium and esophageal adenocarcinoma. The mucins MUC5AC and MUC6 are expressed to a similar degree in Barrett metaplasia and gastric mucosa, as is MUC2 in Barrett intestinal metaplasia and small bowel mucosa. Increased expression of MUC1 is associated with progression from dysplasia to adenocarcinoma of the esophagus. Thus, mucins have an important role in the defense of esophageal mucosa against the acid, pepsin and bile that are present in the refluxate. Changes in the expression of mucins occur in patients with GERD, and might lead to the development of new drugs.     

Mucin gene expression in Barrett's oesophagus: an in situ hybridisation and immunohistochemical study

BACKGROUND AND AIMS: Mucin genes are expressed in a site specific manner throughout the gastrointestinal tract. Little is known about the expression pattern in the oesophagus. In this study we have investigated MUC gene expression in both the normal oesophagus and specialised intestinal metaplasia (Barrett's oesophagus). PATIENTS: Archived paraffin embedded material from eight specimens of normal oesophagus, 18 Barrett's oesophagus, eight gastric metaplasia, six high grade dysplasia, and six cases of adenocarcinoma were examined for expression of the mucin genes MUC1-6. METHODS: Mucin mRNA was detected by in situ hybridisation using [(35)S] dATP labelled oligonucleotide probes. Mucin core protein was detected by immunohistochemistry. RESULTS: Normal oesophagus expressed MUC5B in the submucosal glands and MUC1 and MUC4 in the stratified squamous epithelium. Barrett's oesophagus strongly expressed MUC5AC and MUC3 in the superficial columnar epithelium, MUC2 in the goblet cells, and MUC6 in the glands. In high grade dysplasia and adenocarcinoma there was downregulation of MUC2, MUC3, MUC5AC, and MUC6, but upregulation of MUC1 and MUC4 in half of the specimens examined. CONCLUSIONS: Normal oesophagus and Barrett's oesophagus have a novel pattern of mucin gene expression. Barrett's oesophagus expressed the mucins associated with normal gastric epithelium and normal intestinal epithelium. While most mucin genes were downregulated in severely dysplastic and neoplastic tissues, there was upregulation of the membrane bound mucins MUC1 and MUC4. This may prove useful in detecting early signs of progression to adenocarcinoma of the oesophagus.     

PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas

BACKGROUND AND AIMS: Although it has been reported that intestinal metaplasia implicated in gastric carcinogenesis is induced by the ParaHox gene CDX2, it is unclear which genes are responsible for the formation of pseudopyloric glands and whether they play a role in gastric carcinogenesis. Pancreatic-duodenal homeobox 1 (PDX1) is also a ParaHox gene which contributes to the genesis and development of the pancreas, duodenum, and antrum. To clarify its significance for the formation of pseudopyloric glands and gastric carcinogenesis, we investigated expression of PDX1 and mucin in gastric carcinomas and surrounding mucosa. METHODS: Gastric carcinoma tissues from 95 patients were used for immunohistochemical analyses of PDX1, and mucins MUC6 and MUC5AC. RESULTS: PDX1 was found to be frequently expressed in pseudopyloric glands and intestinal metaplasia. MUC6 was more abundant than MUC5AC in pseudopyloric glands while higher levels of MUC5AC than MUC6 were evident in intestinal metaplasia. The frequency of PDX1 positive reactivity was higher in differentiated type carcinomas (39/43, 90.7%) and T1 carcinomas (42/43, 97.7%) than in undifferentiated type (33/52, 63.5%) and T2-4 (30/52, 57.7%) carcinomas. PDX1 and MUC6 double positive expression was observed in carcinomas, respectively, including the corpus, and also correlated with histological type and depth of invasion. In contrast, no link was apparent between PDX1 and MUC5AC double positive reactivity and histological type. CONCLUSION: Our study suggests that PDX1 plays an important role in the development of pseudopyloric glands, and that pseudopyloric glands may reflect a condition associated with gastric carcinogenesis.