Association of Metallothionein Expression and Lack of Apoptosis with Progression of Carcinogenesis in Barrett's Esophagus
Yan LiJohn M. WoLu CaiZhanxiang ZhouDavid RosenbaumChristian MéndezMukunda B. RayWhitney F. JonesY. James Kang
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Abstract:
Barrett's esophagus is the transformation of normal esophageal squamous epithelium to specialized intestinal metaplasia (SIM). Among the Barrett's specialized cells, those that can develop protective mechanisms against apoptosis may have potential to become malignant. Studies have shown that overexpression of metallothionein (MT), low molecular protein that protects cells from apoptotic stimuli, appears to be associated with more advanced, highly malignant tumors. We thus investigated the relationship between MT expression and apoptosis in different stages of Barrett's carcinogenesis. Terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling and immunohistochemical dual-staining assay were performed in human biopsy samples of normal, SIM, dysplasia, and adenocarcinoma. Apoptotic index and MT expression were quantified by using an image system to analyze the converted digital data. A negative correlation between MT expression and apoptotic index was found. MT expression was significantly increased along with the histologic progression towards adenocarcinoma. This study thus suggests that MT may contribute to cytoprotection, thereby inhibiting apoptosis and leading to carcinogenesis of Barrett's esophageal cells.Keywords:
Barrett's esophagus
Intestinal metaplasia
Metallothionein
Malignant Transformation
Metaplasia
To determine whether there is a relationship between the presence of H pylori and the various subtypes of intestinal metaplasia in the gastric antrum, 2274 antral gastroscopic biopsies from 533 patients were examined. H pylori was found in 289 patients. Intestinal metaplasia in general was found in 135 patients. Type I intestinal metaplasia was found in 133 patients (98.5%), type II in 106 patients (78.5%) and type III in 21 patients (15.6%). Ninety eight of these 135 patients (72.6%) were H pylori positive and 37 patients (27.4%) were H pylori negative. No statistically significant difference was found in the prevalence of type I and II intestinal metaplasia between the intestinal metaplasia positive and H pylori positive and intestinal metaplasia negative and H pylori negative patients. Type III intestinal metaplasia was found less often in the intestinal metaplasia positive and H pylori positive patients (11.2%) as compared with intestinal metaplasia positive and H pylori negative patients (27%) (p less than 0.05). In contrast with type I and II intestinal metaplasia type III intestinal metaplasia was found more often in moderate/severe intestinal metaplasia than in mild intestinal metaplasia (p less than 0.02). Within the group of patients with moderate/severe intestinal metaplasia, type III was found less often in the H pylori positive patients (p less than 0.05). We suggest that the gastric milieu for H pylori is less appropriate in type III intestinal metaplasia positive patients. As type III intestinal metaplasia might be regarded as a marker of possibly increased gastric cancer risk, the lower prevalence of H pylori in these type III intestinal metaplasia positive patients might be the result of severe changes in mucosal architecture.
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To explore the roles of the microstructural changes and the expression of the intestinal marker CDX2 served in diagnosing Barrett＇s esophagus. Methods Microstructural changes of esophageal mucosa were observed with high-resolution magnification endoscopy and expression of CDX2 was detected by immunohistochemical staining. Results Of 48 patients with Barrett＇s mucosa, 40 showed a down-shift of palisade veins overstepped the Z-line, but 60 gastroesophageal reflux disease （GERD） patients without Barrett＇s mucosa did not. Three distinct mucosal patterns observed under magnification endoscopy： villus-like,line-like and dot-like mucosa. Villus-like mucosa only occurred in Barrett＇s esophagus and showed a significantly higher frequency of intestinal metaplasia than in line-like and dot-like mucosa （ P 〈 0.01 ）. CDX2 expression was not only found in Barrett＇s mucosa with globlet cells, but also detected in columnar mucosa without globlet cells. Positive rate of CDX2 staining in villus-like mucosa was significantly higher than that in line-like mucosa（P 〈 0. 01 ）and in dot-like mucosa（P 〈 0. 05）. Conclusion Results suggest that observation of esophageal mucosal microstructure is useful in diagnosing and classifying Barrett＇s esophagus, while CDX2 immunoassaying could be a valuable marker for discovery of early intestinal metaplasia, and for early diagnosis of Barrett＇s esophagus.
Key words:
Barrett＇s esophagus ; Intestinal metaplasia; Palisade veins ; CDX2 protein
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Abstract Context.—Dysplasia is thought to be a precursor of invasive gallbladder carcinoma, but it is unsettled whether dysplasia arises from other precursor lesions. Objective.—To ascertain the presence and nature of precursors of dysplasia in the gallbladder. Design.—Four hundred consecutive cholecystectomy specimens were processed and stained routinely for diagnosis. We retrospectively reviewed these cases to look for the presence of epithelial changes, including antral-type metaplasia, intestinal metaplasia, and dysplasia. Results.—Antral-type metaplasia, intestinal metaplasia, and dysplasia were found in 238 (59.5%), 39 (9.8%), and 20 (5.0%) cases, respectively. The mean patient age was 47.7 years (range, 15–93 years). The mean ages for patients with antral-type metaplasia, intestinal metaplasia, and dysplasia were 49.4, 50.9, and 52.6 years, respectively. Statistically significant associations were found between antral-type metaplasia and intestinal metaplasia (P = .007, χ2 test) and between intestinal metaplasia and dysplasia (P < .001, χ2 test). Conclusion.—These associations, along with the age gradient from antral-type metaplasia to dysplasia, suggest a progression from antral-type metaplasia to dysplasia via intestinal metaplasia.
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Short segment Barrett's esophagus (SSBE) is defined by the presence of intestinal metaplasia in biopsies obtained from mucosa with an appearance suggestive of Barrett's that extends <3 cm into the esophagus. It has been suggested that this lesion may represent a stage in an ongoing process of Barrett's esophagus progression. If so, then the prevalence of SSBE would be expected to decrease with advancing age, and patients followed over time should exhibit an increase in the extent of columnar-lined esophagus. The aim of this study was to determine whether SSBE length progresses or regresses over time by following a prospective cohort and by assessing the relationship between age and the length, as well as prevalence of SSBE.The study included consecutive patients who were evaluated prospectively by an upper endoscopy and were found to have SSBE between October, 1983, and December, 1999, at the Southern Arizona VA Health Care System. All patients underwent a systematic biopsy protocol, and a designated pathologist who reviewed all specimens confirmed the diagnosis of Barrett's esophagus. Patients were subsequently interviewed for demographic information. In those patients who were enrolled into our surveillance program, SSBE length was remeasured and intestinal metaplasia reconfirmed on follow-up endoscopies.Of 343 patients with endoscopically proven Barrett's esophagus, 116 (33.8%) were found to have SSBE. Almost all were male (97.4%) and white (85.3%), with a mean age of 60.1+/-1.0 yr. The prevalence of SSBE increased with age and reached a plateau during the seventh decade of life. One-way analysis of variance showed that there was no significant difference in the mean length of SSBE among the various age groups (p = 0.84). This trend was maintained when only the white group was assessed. Follow-up endoscopies were performed in 57 patients, revealing a mean interval of 64 months to the latest endoscopy, with no significant difference in SSBE length between the first and last endoscopy (p = 0.16).The prevalence of SSBE increases with age until the seventh decade of life. Finding that SSBE length does not change across the various age groups and during a 64-month mean follow-up, suggests that SSBE does not progress over time.
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Abstract This study evaluated the prevalence of intestinal metaplasia (IM) in patients with varying lengths of columnar-lined esophagus (CLE) during long-term endoscopic and histopathologic surveillance. A total of 177 patients were followed for a median surveillance period of 5.1 yr and a median four endoscopies per patient. Fifty-two percent of the patients had IM at first surveillance endoscopy. The prevalence of IM increased with increasing number of endoscopies, and after six endoscopies the IM prevalence had increased from ≈30% to ≈64% in patients with a 1–2 cm CLE length, and from ≈45% to ≈89% in those with a 3–4 cm length. IM was found in longer CLE segments early in the surveillance period, whereas detection of IM was evenly spread out over the surveillance period in the short segment patients. A second aim of this study was to compare the effectiveness of antireflux surgery with acid suppressant therapy in preventing the development of IM. Studying patients without IM at the first two endoscopies, the investigators found that IM developed significantly less frequently among the 20 surgically treated patients compared with the 49 medically treated patients (PPI therapy in 45 out of 49). The time to development of IM was shorter in the medically treated group (p = 0.001, log-rank test) and in a multivariable logistic analysis, prior antireflux surgery was the only significant factor associated with a reduced risk of intestinalization (10.3-fold decreased risk).
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It has been postulated that the endoscopic ablation of Barrett's esophagus can lead to complete eradication of the disease. This study was undertaken to evaluate the efficacy of endoscopic eradication therapy for Barrett's esophagus and the rates of recurrence of intestinal metaplasia.As part of an initial randomized controlled trial, patients with nondysplastic or low grade dysplastic Barrett's esophagus underwent mucosal ablation. Following ablation, the patients had annual surveillance endoscopies. Recurrence was defined as the presence of intestinal metaplasia after initial complete eradication had been achieved.A total of 28 patients with Barrett's esophagus were followed for a mean of 6.4 years after ablation therapy. At baseline, the majority of the patients had nondysplastic Barrett's esophagus (79 %). Initial complete eradication of intestinal metaplasia was achieved at a mean of 4.1 months. During long-term follow-up, initial recurrence of intestinal metaplasia was seen in 14 of the 28 of patients (50 %) at a mean of 40 months, and further maintenance ablation therapy was applied. At the final follow-up, 36 % of the patients had complete eradication of intestinal metaplasia, 18 % of the patients had intestinal metaplasia, and 21 % had died of unrelated causes; invasive esophageal adenocarcinoma had developed in 1 patient.The long-term results of this study demonstrate a recurrence rate of 50 % after complete eradication of Barrett's esophagus with endoscopic eradication therapy. In addition, re-recurrence (in 36 %), even after further maintenance endoscopic eradication therapy, and deaths unrelated to the disease (21 %) occurred. Complete remission of Barrett's esophagus appears to be a difficult goal to achieve. These results call into question the role of ablation in patients with low risk Barrett's esophagus.
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Objective To investigate the similarities and differences of endoscopic and pathological char- acteristics between long and short segment Barrett's esophagus.Methods One hundred and twenty-eight cases of Barrett's esophagus identified both by endoscopy and pathology were enrolled in this retrospective study. Among them,40 cases were long segment Barrett's esophagus (LSBE) and 88 were short segment Barrett's esophagus (SSBE).The age distribution,sex distinction,endoscopic manifestations and pathological changes were assessed.Data were statistically analyzed by t-test or u-test.Results There were no differences in age distribution and sex distinction between LSBE and SSBE groups (P＞0.05).The ring pattern was the most prominent type accounting for 62.5% in LSBE group.The island pattern was the most prominent type accounting for 85.2% in SSBE group.There were significant differences in the rates of specialized intestinal metaplasia between LSBE and SSBE groups(47.5% vs 14.8%,P＜0.01).Moreover,among the special- ized intestinal metaplasia,low grade (15.0% vs 4.5%),medium grade (12.5% vs 3.4%) and high grade dysplasia (5.0% vs 0.0%) between LSBE and SSBE groups also had statistical differences (all P＜0.05).Conclusions LSBE may have more tendency in dysplasia than that of SSBE.We should pay attention to the importance of endoscopic manifestations and pathological diagnosis.
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