Methylene blue chromoendoscopy for the detection of Barrett's esophagus in a Greek cohort

BACKGROUND AND STUDY AIMS: Specialized columnar epithelium of Barrett's esophagus is a precursor of dysplasia and adenocarcinoma, and methylene blue selectively stains this type of epithelium. The present prospective study examined the detection of short-segment and long-segment Barrett's esophagus using methylene blue chromoendoscopy-directed biopsies, in comparison with biopsies directed using conventional endoscopic criteria. PATIENTS AND METHODS: Biopsies were obtained from macroscopically conspicous areas in the distal esophagus observed during conventional endoscopy in a total of 975 patients. Immediately after conventional biopsies, the distal esophagus was sprayed with methylene blue and directed biopsies were then obtained from the stained regions. All patients with a histologically established Barrett's esophagus underwent a second upper gastrointestinal endoscopy within 1 year in order to assess the reproducibility of the method. RESULTS: In a total of 3,900 conventional biopsy specimens (without staining), 54 specimens (1.4%) were found to show Barrett's esophagus and were confined to 16 of the 975 patients (1.6%). Of the total 130 directed biopsy specimens obtained during chromoendoscopy, 114 (87.7%) revealed Barrett's esophagus (P<0.00001) and were confined to 35 of the 975 patients (3.5%; P < or = 0.001). The findings were confirmed within 1 year in all dye-positive patients. CONCLUSIONS: Chromoendoscopy with methylene blue appears to be an accurate, simple, safe, inexpensive, and reproducible method of detecting specialized columnar epithelium in Barrett's esophagus.     

A randomized, prospective cross-over trial comparing methylene blue-directed biopsy and conventional random biopsy for detecting intestinal metaplasia and dysplasia in Barrett's esophagus

BACKGROUND AND STUDY AIMS: The value of methylene blue-directed biopsies (MBDB) in detecting specialized intestinal metaplasia and dysplasia in Barrett's esophagus remains unclear. The aim of this study was to compare the accuracy of MBDB with random biopsy in detecting intestinal metaplasia and dysplasia in patients with Barrett's esophagus. PATIENTS AND METHODS: A prospective, randomized, cross-over trial was undertaken to compare MBDB with random biopsy in patients with Barrett's esophagus segments 3 cm or more in length without macroscopic evidence of dysplasia or cancer. Dysplasia was graded as: indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or carcinoma, and was reported in a blinded fashion. RESULTS: Fifty-seven patients were recruited, 44 of whom were male. A total of 1,269 biopsies were taken (MBDB-651, random biopsie-618). Analysis of the results by per-biopsy protocol showed that the MBDB technique diagnosed significantly more specialized intestinal metaplasia (75 %) compared to the random biopsy technique (68 %; P = 0.032). The sensitivity and specificity rates of MBDB for diagnosing specialized intestinal metaplasia were 91 % (95 % CI, 88 - 93 %) and 43 % (95 % CI, 36 - 51 %), respectively. The sensitivity and specificity rates of MBDB for diagnosing dysplasia or carcinoma were 49 % (95 % CI, 38 - 61 %) and 85 % (95 % CI, 82 - 88 %), respectively. There were no significant differences in the diagnosis of dysplasia and carcinoma - MBDB 12 %, random biopsy 10 %. The methylene blue staining pattern appeared to have an influence on the detection of specialized intestinal metaplasia and dysplasia/carcinoma. Dark blue staining was associated with increased detection of specialized intestinal metaplasia (P < 0.0001), and heterogeneous staining (P = 0.137) or no staining (P = 0.005) were associated with dysplasia and/or carcinoma detection. The MBDB technique prolonged the endoscopy examination by an average of 6 min. CONCLUSION: The diagnostic accuracy of the MBDB technique was superior to that of the random biopsy technique for identifying specialized intestinal metaplasia, but not dysplasia or carcinoma. The intensity of methylene blue staining has an influence on the detection of specialized intestinal metaplasia and dysplasia or carcinoma, which may help in targeting the biopsies. Although MBDB prolongs the endoscopy procedure slightly, it is a safe and well-tolerated procedure. Further clinical studies on the MBDB technique exclusively in endoscopically normal dysplastic Barrett's esophagus are needed.     

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.     

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.     

Endoscopic ultraviolet-induced autofluorescence spectroscopy of the esophagus: tissue characterization and potential for early cancer diagnosis

BACKGROUND AND STUDY AIMS: Endoscopic identification of dysplasia and early carcinoma of the esophagus is difficult and is currently done through random pinch biopsies. This study assesses the potential of ultraviolet-induced autofluorescence spectroscopy for early diagnosis with special focus on Barrett's esophagus. PATIENTS AND METHODS: Measurements were performed on 24 patients using 330 nm light excitation. The determination of the spectral distribution typical of each histological tissue type was done using three fluorescence intensity ratios: RI = I390nm/I450nm; R2 = I550nm/I450nm; R3 - I390nm/I550nm. RESULTS: The spectral distribution of normal esophageal mucosa and specialized columnar Barrett's mucosa were similar. A strong modification of the spectral distribution was observed for high grade dysplasia and intramucosal carcinoma. Statistical analysis indicated that the spectral shape modification associated with neoplastic transformation was greater than intra- and interpatient spectral variations. These results allow the determination of discriminating criteria based on ratios R1 and R3. Using ratio R3, the spectroscopy-based diagnosis differentiated neoplastic tissue from normal esophageal mucosa and specialized columnar Barrett's mucosa with a sensitivity and specificity of 86% and 95 %, respectively. CONCLUSIONS: The use of ultraviolet autofluorescence spectroscopy should improve the diagnostic yield of standard endoscopy in patients with Barrett's esophagus.     

Diagnosis of Barrett's esophagus and Barrett's carcinoma using magnifying endoscopy

Specialized columnar epithelium (SCE) in Barrett's esophagus has been detected by random or four quadrant biopsy using conventional endoscopy; however little is known about the fine mucosal structure of SCE. The fine mucosal pattern (pit pattern) was classified into five categories. Tubular or villous pit patterns were not only characteristics of both SCE and methylene blue absorption but also possessed intestinal mucin phenotype. Targeted biopsy under the magnifying chromo-endoscopy might contribute to the early detection of Barrett's cancer.     

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.     

Chromoendoscopy and magnification endoscopy in Barrett's esophagus

Chromoendoscopy and magnification endoscopy appear to be a valuable adjuncts for the detection and classification of BE. These techniques may also prove to be useful aids in surveillance protocols for identifying dysplastic epithelium or early cancer within a segment of BE. Ideally, the use of these techniques would enable the endoscopist to rule in or out the presence of IM and of dysplastic or cancerous epithelium by obtaining only a minimal number of targeted biopsy specimens, or potentially performing no biopsies at all. This could transform upper endoscopy into a much more effective screening and surveillance tool for BE. Several problems currently exist for the use of chromoendoscopy for BE. Results of studies reporting the accuracy of chromoendoscopy remain mixed,and are likely explained by the wide range of techniques and materials used in the investigations. Staining adds several steps, and likely several minutes, to an upper endoscopy. Staining within the esophagus is often patchy and uneven. In addition, poor spraying technique exaggerates the irregular uptake by the mucosa. There is a high false-positive rate when staining gastric-type epithelium and denuded epithelium. Areas of dysplasia or cancer may take up stain in an irregular manner, or may not stain at all. Chromoendoscopy is a relatively new technique in the management of BE and depends on the skill and experience of the endoscopist. Magnification, however, only allows the endoscopist to observe small areas of mucosa at a time, increasing the overall complexity and length of the procedure. The learning curve for this procedure is relatively short, however, and endoscopists can usually become proficient in the technique quickly. Currently, the greatest body of literature exists concerning the use of methylene blue for diagnosing BE. At the present time, chromoendoscopy and magnification endoscopy appear to be most beneficial in detecting IM in short segments of esophageal columnar-appearing mucosa. If used consistently by practicing physicians, the accuracy of biopsies for IM could be improved. If endoscopic ablative therapy for HGD and early adenocarcinoma becomes accepted, sensitive methods of detecting residual BE after ablation will be needed to help guide additional endoscopic therapy. Chromoendoscopy and magnification endoscopy could prove helpful in this setting. Further research in this field remains to be performed. As a first step, a uniform classification system for staining and magnification patterns should be devised. If investigators can reach a consensus, and validate classification, terminology, and pattern-types, future studies could be performed using "common and similar language." More controlled investigations with larger numbers of patients must be performed before tissue staining and magnification endoscopy become a part of the practicing endoscopist's armamentarium. The ultimate aims of chromoendoscopy and magnification endoscopy in the setting of BE are to show improved outcomes--namely, early detection of cancer and improved survival rates. These goals have not yet been realized and meeting them will require well-designed studies in the future.     

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。     

Another look at Barrett's esophagus. Current thinking on screening and surveillance strategies

Barrett's esophagus remains a major health problem and a risk factor for the development of esophageal adenocarcinoma. Given the low incidence of this disorder, efforts should be made to identify risk factors that target patients with GERD or known Barrett's esophagus who would most benefit from screening and surveillance strategies. It is clear that identifying esophageal adenocarcinoma at an early and treatable stage reduces morbidity and mortality. However, currently available screening tools (endoscopy with surveillance biopsies every 2 years) are expensive and not easily applied. Identification of tumor markers and other specific risk factors may be helpful in predicting who is at risk for dysplasia. Current therapeutic strategies are successful in the treatment of GERD symptoms, but further research and longer follow-up studies are needed to determine if these strategies bring about regression of Barrett's esophagus, reversal of dysplasia, or prevention of cancer.     

Eradication of dysplastic Barrett's oesophagus using photodynamic therapy: long-term follow-up

BACKGROUND AND STUDY AIMS: Barrett's oesophagus is a major risk factor for oesophageal adenocarcinoma, a condition which is rapidly increasing in incidence. Photodynamic therapy (PDT) is a developing treatment in which tissue damage is caused by the action of light on a previously administered photosensitizing agent. We present the results of long-term follow-up of its efficacy in patients with dysplastic Barrett's oesophagus. PATIENTS AND METHODS: A total of 40 patients with low-grade dysplasia in Barrett's oesophagus were treated with oral 5-aminolaevulinic acid (ALA) at a dose of 30 mg/kg, followed by laser endoscopy 4 hours later. Patients were treated between December 1995 and December 1998, and all were followed up regularly with endoscopy and biopsies in our surveillance programme. RESULTS: Among the patients, 35 (88%) showed a macroscopic reduction in the area of the columnar epithelium, and in all 40 patients dysplasia was found to be eradicated at 1 month. The effect has been maintained for a median follow-up of 53 months (range 18-68 months), although one patient developed a late carcinoma in an untreated area of Barrett's oesophagus 3 years after the intervention. CONCLUSIONS: Safe and effective ablation of low-grade dysplastic Barrett's oesophagus can be achieved with the use of ALA-induced PDT, and the effects are maintained in the long term.     

Barrett's esophagus. A continuing conundrum

Barrett's esophagus, a condition in which the distal esophagus is lined by columnar epithelium, is almost always caused by gastroesophageal reflux and often occurs in conjunction with a sliding hiatal hernia. Patients are typically white men in their 50s who smoke and drink, and they present with complaints of regurgitation, heartburn, and/or dysphagia. Endoscopic biopsies are required to confirm the diagnosis. Complications, such as stricture, ulcer, dysplasia, and malignant degeneration, occur in many cases. Adenocarcinoma is the most serious complication. Medical treatment, including life-style changes as well as pharmacologic therapy, usually relieves symptoms and heals esophagitis, but when it fails, antireflux surgery is indicated. Patients without evidence of dysplasia should undergo endoscopy yearly; those with mild dysplasia require more frequent surveillance. If biopsies disclose severe dysplasia, esophagogastrectomy should be performed.     

Barrett's esophagus: treatment with 5-aminolevulinic acid photodynamic therapy

Barrett's esophagus has been identified as the premalignant precursor of esophageal adenocarcinoma. The eradication of metaplastic or dysplastic columnar-lined (Barrett's) esophagus may prevent progression to esophageal adenocarcinoma. 5-Aminolevulinic acid photodynamic therapy is a simple method for the mucosal ablation of the abnormal segment. Areas of metaplastic epithelium may remain buried after treatment and continued surveillance is necessary. Repeated treatments often are necessary but are very well tolerated with few complications.     

Barrett's esophagus and esophageal adenocarcinoma: pathogenesis,diagnosis, and therapy

Gastric juice that refluxes into the esophagus can injure esophageal squamous epithelium. When the injury heals through a metaplastic process in which an abnormal columnar epithelium replaces the injured squamous one, the resulting condition is called Barrett's esophagus. Gastroesophageal reflux disease and Barrett's esophagus are the most important risk factors for esophageal adenocarcinoma. This article examines such issues as the treatment, endoscopic surveillance, and chemoprevention of Barrett's esophagus. Also included are published guidelines and recommendations.     

Chromoendoscopic diagnosis of Barrett's esophagus

Some kinds of chromoendoscopy have been reported to survey the cases with Barrett's esophagus more effectively, since random biopsy as a gold standard is not an ideal method from the viewpoint of safety, labor or cost effectiveness. Methylene blue (MB) chromoendoscopy has been reported that a targeted biopsy is possible to limit because MB only stains non-dysplastic Barrett's mucosa but not dysplastic one. However, many of supplementary studies have not agreed this recommendation. Crystal violet (CV) chromoendoscopy clearly stains Barrett's mucosa and makes a detailed observation of pit pattern possible. The availability of this method is required a further mass survey although CV chromoendoscopy has been reported to be effective in Barrett's screening. Other chromoendoscopic methods using indigo carmine or fluorescence dye also have been reported to be effective for discovering a dysplastic lesion by some investigator, but the efficacy has not been sufficiently evidenced. Conclusively, chromoendoscopic diagnosis of Barrett's esophagus has not yet got a consensus in the availability for Barrett's surveillance at present in Barrett's Esophagus Chicago Workshop 2003 of AGA.     

Gastroesophageal reflux disease and Barrett's esophagus

Gastroesophageal reflux disease (GERD) is a common clinical problem. Circumstantial evidence continues to suggest that infection with Helicobacter pylori may protect some patients from developing GERD and its complications. An empirical trial of a proton-pump inhibitor may now be a reasonable alternative to endoscopy or 24-hour pH testing for the diagnosis of GERD. Long-term follow-up data covering more than over a decade indicate that proton-pump inhibitors are effective and safe agents for the treatment of GERD. Furthermore, a strategy of proton-pump inhibitors first may be the most cost-effective approach to GERD. It remains unclear why some patients with GERD develop Barrett's esophagus, whereas others do not. Recent studies demonstrate the importance of pulses of acid or bile in increasing cell proliferation and cyclooxygenase-2 expression in Barrett's epithelium cell cultures. Short-segment Barrett's esophagus is now clearly associated with an increased risk of dysplasia or cancer compared to intestinal metaplasia of the cardia, and the cancer risk in this condition is similar to that with long-segment Barrett's esophagus. However, the overall cancer risk in patients with Barrett's esophagus is lower than previously estimated, at approximately 0.5% annually. Ablation techniques continue to show promise, but are not yet ready for routine clinical use. Endoscopic mucosal resection is a new treatment option for selected patients with high-grade dysplasia or superficial esophageal adenocarcinoma.