Esophageal chromoendoscopy in Barrett's esophagus: “cons”

Abstract

At present, the classification of mucosal patterns of BE on magnification endoscopy has not yet been standardized or validated sufficiently to recommend its use in ordinary clinical practice. At present, the classification of mucosal patterns of BE on magnification endoscopy has not yet been standardized or validated sufficiently to recommend its use in ordinary clinical practice. “What is the most difficult of all? For your eyes to see what is under your nose.”JW GoetheBarrett's esophagus (BE) is a precancerous condition in which the normal squamous epithelium is replaced by a metaplastic columnar one. The specialized intestinal metaplasia (SIM) is genetically unstable, and these patients have an increased risk of developing an esophageal adenocarcinoma.1Conio M. Blanchi S. Lapertosa G. et al.Long term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study.Am J Gastroenterol. 2003; 98: 1931-1939Crossref PubMed Scopus (211) Google Scholar, 2Shaheen N.J. Advances in Barrett's esophagus and esophageal adenocarcinoma.Gastroenterology. 2005; 128: 1554-1566Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar The diagnosis of BE relies on endoscopy with biopsy and histologic assessment of the specimens. The anatomic landmarks are easily recognized by an experienced endoscopist, helped by differences in color between the squamous epithelium and the columnar one. Upward displacement of the squamocolumnar junction is concealed if severe esophagitis is present. So, at present, the correct diagnosis of BE is still a problem, especially in patients with short segments of BE (SSBE). An even more difficult task is identification of small areas of dysplasia, especially high-grade dysplasia (HGD). This is still impossible, in spite of technologic progress. The available endoscopes with a high-resolution charged-coupled device provide excellent image quality. Better morphologic details of the mucosa are obtainable with magnification endoscopy. Ideally, an accurate diagnosis should avoid discomfort to the patient, should be done in a short time, and the procedure used should give the highest diagnostic yield. Chromoendoscopy (CE) has been proposed to help in identifying both SIM and dysplasia. This could lead to performing target biopsies of suspicious areas, which would be preferable to random biopsies of all the BE. In spite of this desirable aim, there are still doubts and difficulties in the detection of SIM. Methylene blue (MB) is the dye most often used in BE. It is a vital stain absorbed by small intestinal and colonic cells. MB allows identification of BE, areas of dysplasia, and carcinoma.3Canto M.I. Setrakian S. Willis J. et al.Methylene blue-directed biopsies improve detection of intestinal metaplasia and dysplasia in Barrett's esophagus.Gastrointest Endosc. 2000; 51: 560-568Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Concerns about its safety have been reported, because MB binds to deoxyribonucleic acid (DNA) and when exposed to white light can induce oxidative damage to DNA. It is still unknown whether this affects the risk of cancer.4Olliver J.R. Wild C.P. Sahay P. et al.Chromoendoscopy with methylene blue and associated DNA damage in Barrett's esophagus.Lancet. 2003; 362: 373-374Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Indigo carmine is a contrast stain that is not taken up by cells. It highlights mucosal irregularities and can help in the identification of BE when combined with magnification endoscopy.5Stevens P.D. Lightdale C.J. Green P.H. et al.Combined magnification endoscopy with chromoendoscopy for the valuation of Barrett's esophagus.Gastrointest Endosc. 1994; 40: 747-749Abstract Full Text Full Text PDF PubMed Google Scholar It should also be remembered that the diagnostic accuracy of dyes is reduced in patients with esophagitis.6Kiesslich R. Hahn M. Herrmann G. et al.Screening for specialized columnar epithelium with methylene blue: chromoendoscopy in patients with Barrett's esophagus and a normal control group.Gastrointest Endosc. 2001; 53: 47-52Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 7Canto M.I. Setrakian S. Willis J.E. et al.Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus: an in vivo and ex vivo study.Endoscopy. 2001; 33: 391-400Crossref PubMed Scopus (134) Google Scholar In spite of the large number of publications devoted to this topic, the results are still debatable. The use of CE in the routine clinical setting has been recommended, but a large number of centers do not follow this advice. Adding CE to accurate sampling is regarded as an overload by the majority of endoscopists, because it considerably lengthens procedure time. In 1996, Canto et al8Canto M.I. Setrakian S. Petras R.E. et al.Methylene blue selectively stains intestinal metaplasia in Barrett's esophagus.Gastrointest Endosc. 1996; 44: 1-7Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar studied the effects of MB in 26 patients with proven BE and 12 patients without proven BE. The sensitivity and the specificity of MB-positive staining for a histologic detection of SIM was 95% and 97%, respectively. The investigators concluded that MB staining was highly accurate in the diagnosis of SIM.8Canto M.I. Setrakian S. Petras R.E. et al.Methylene blue selectively stains intestinal metaplasia in Barrett's esophagus.Gastrointest Endosc. 1996; 44: 1-7Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar This degree of accuracy has often not been confirmed by other groups. Dave et al9Dave U. Shousha S. Westaby D. Methylene blue staining: is it really useful in Barrett's esophagus?.Gastrointest Endosc. 2001; 53: 333-335Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar examined 9 patients with BE and reported a sensitivity of 57% and a specificity of 32%. They did not recommend MB staining for BE surveillance. Similar results were reported by Gangarosa et al,10Gangarosa L.M. Halter S. Mertz H. Methylene blue staining and endoscopic ultrasound evaluation of Barrett's esophagus with low-grade dysplasia.Dig Dis Sci. 2000; 45: 225-229Crossref PubMed Scopus (45) Google Scholar who evaluated the utility of MB in BE with low-grade dysplasia (LGD). The sensitivity and the specificity of deep blue MB staining was 68% and 85%, respectively. BE with LGD stained deep blue less often than BE without dysplasia (52% vs 74%, P < .05), but the positive predictive value for poor staining was 41%. They concluded that the utility of MB has to be proven. Kiesslich et al6Kiesslich R. Hahn M. Herrmann G. et al.Screening for specialized columnar epithelium with methylene blue: chromoendoscopy in patients with Barrett's esophagus and a normal control group.Gastrointest Endosc. 2001; 53: 47-52Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar examined 51 BE patients and 22 controls. MB stained and unstained areas were biopsied. SIM was found in stained areas, with a 98% sensitivity and 61% specificity. Surprisingly, SIM was found in 75% of patients with visible BE vs 73% of controls, so the value of finding SIM may be questioned here. It is interesting to note that 3 of 4 patients with HGD were identified by endoscopy alone, without staining. Similarly, Wo et al11Wo J.M. Ray M.B. Mayfield-Stokes S. et al.Comparison of methylene blue-directed biopsies and conventional biopsies in the detection of intestinal metaplasia and dysplasia in Barrett's esophagus: a preliminary study.Gastrointest Endosc. 2001; 54: 294-301Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar reported that MB-directed biopsy results were similar to conventional biopsy in detecting SIM, indefinite, and LGD. The procedure took on average 7 minutes longer than standard endoscopy and biopsy. MB has also been evaluated as a screening tool in patients with GERD, but the results were disappointing.12Duncan M.B. Horwhat J.D. Maydonovitch C.L. et al.Use of methylene blue for detection of specialized intestinal metaplasia in GERD patients presenting for screening upper endoscopy.Dig Dis Sci. 2005; 50: 389-393Crossref PubMed Scopus (12) Google Scholar Other investigators reported that MB would not help reduce the number of routine biopsies taken in BE.13Egger K. Werner M. Meining A. et al.Biopsy surveillance is still necessary in patients with Barrett's esophagus despite new endoscopic imaging techniques.Gut. 2003; 52: 18-23Crossref PubMed Scopus (141) Google Scholar The problem becomes more complicated if we evaluate the role of CE in the detection of SSBE (<3 cm). In this subgroup of patients, random biopsies allow the detection of SIM in 30% to 50% of patients. This could be because of an erroneous endoscopic diagnosis or to a patchy distribution of SIM.14Johnston M.H. Hammond A.S. Laskin W. et al.The prevalence and clinical characteristics of short segments of specialized intestinal metaplasia in the distal esophagus on routine endoscopy.Am J Gastroenterol. 1996; 91: 1507-1511PubMed Google Scholar, 15Chalasani N. Wo J.M. Hunter J.G. et al.Significance of intestinal metaplasia in different areas of esophagus including esophagogastric junction.Dig Dis Sci. 1997; 42: 603-607Crossref PubMed Scopus (103) Google Scholar Sharma et al16Sharma P. Topalovski M. Mayo M.S. et al.Methylene blue chromoendoscopy for detection of short-segment Barrett's esophagus.Gastrointest Endosc. 2001; 54: 289-293Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar evaluated the usefulness of MB in the identification of SIM in 75 patients with SSBE. They were compared with an historical control group of 83 patients in whom biopsies were performed randomly, without staining. SIM was detected in 61% of cases in the MB group and 42% in the random biopsy group. MB was of no use in patients with short (<1 cm) irregularities of the Z-line.16Sharma P. Topalovski M. Mayo M.S. et al.Methylene blue chromoendoscopy for detection of short-segment Barrett's esophagus.Gastrointest Endosc. 2001; 54: 289-293Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar A new dye, crystal violet, has been tested in BE. With MB, the sensitivity and the specificity for SIM was rather low, 65% and 53%, respectively. By using 0.05% of crystal violet, the mucosal surface pit pattern was visible without magnification endoscopy, with a sensitivity and a specificity of 89% and 86%, respectively.17Amano Y. Kushiyama Y. Ishihara S. et al.Crystal violet chromoendoscopy with mucosal pit pattern diagnosis is useful for surveillance of short-segments Barrett's esophagus.Am J Gastroenterol. 2005; 100: 21-26Crossref PubMed Scopus (57) Google Scholar In 2001, Canto,18Canto M.I. Methylene blue chromoendoscopy for Barrett's esophagus: coming soon to your GI unit?.Gastrointest Endosc. 2001; 54: 403-409Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar a proponent of the procedure, stated that more work was needed before vital stains become a standard part of the endoscopic practice. This conclusion is still true in 2005. The main drawback of MB is the lack of certitude in the identification of areas of HGD. So, an unstained area in a BE could be either benign cardiac or fundic (non-SIM) or it could be HGD. When facing this dilemma, the endoscopist is obliged to biopsy the metaplastic epithelium extensively.19Wong R.K. Horwhat J.D. Maydonovitch C.L. Sky blue or murky waters: the diagnostic utility of methylene blue.Gastrointest Endosc. 2001; 54: 409-413Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Most of the available studies have been performed with conventional and not high-resolution video endoscopes. The introduction of the latter fuelled the enthusiasm toward CE, because a more detailed morphologic analysis of the mucosa is possible. Stevens et al5Stevens P.D. Lightdale C.J. Green P.H. et al.Combined magnification endoscopy with chromoendoscopy for the valuation of Barrett's esophagus.Gastrointest Endosc. 1994; 40: 747-749Abstract Full Text Full Text PDF PubMed Google Scholar were able to detect BE by using in combination indigo carmine and magnification endoscopy. However, they did not try to identify dysplastic areas.5Stevens P.D. Lightdale C.J. Green P.H. et al.Combined magnification endoscopy with chromoendoscopy for the valuation of Barrett's esophagus.Gastrointest Endosc. 1994; 40: 747-749Abstract Full Text Full Text PDF PubMed Google Scholar Endo et al20Endo T. Awakawa T. Takahashi H. et al.Classification of Barrett's epithelium by magnifying endoscopy.Gastrointest Endosc. 2002; 55: 641-647Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar suggested a classification of the mucosal structure of SIM that encompasses 5 distinct types. The tubular and villous pit patterns are associated with 100% in the presence of BE. They found discrepancies between histologic results and MB staining with regard to the presence of SIM.20Endo T. Awakawa T. Takahashi H. et al.Classification of Barrett's epithelium by magnifying endoscopy.Gastrointest Endosc. 2002; 55: 641-647Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Sharma et al21Sharma P. Weston A.P. Topalovski M. et al.Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett's esophagus.Gut. 2003; 52: 24-27Crossref PubMed Scopus (303) Google Scholar used indigo carmine combined with high-magnification endoscopy (×115) for the surveillance of BE patients. They identified 3 patterns within BE: ridged/villous, circular, and distorted. The ridged/villous pattern had a high sensitivity (97%) and specificity (76%) to identify SIM. The presence of the distorted pattern was associated with HGD. This observation needs to be confirmed by further studies.21Sharma P. Weston A.P. Topalovski M. et al.Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett's esophagus.Gut. 2003; 52: 24-27Crossref PubMed Scopus (303) Google Scholar By applying the method of gynecologists, Guelrud et al,22Guelrud M. Herrera I. Essenfeld H. et al.Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett's esophagus.Gastrointest Endosc. 2001; 53: 559-565Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar at this point, used the instillation of acetic acid, which produces reversible intracellular cytoplasmic protein denaturation and allows identification of areas of SIM. After spraying acetic acid, the epithelial surface becomes transiently more opaque and looks whiter. This group classified 4 types of mucosal surface patterns, and 2 of them (III, villous pattern; IV, ridged pattern) were highly predictive of the presence of SIM. However, this study did not use randomization and blind controls.22Guelrud M. Herrera I. Essenfeld H. et al.Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett's esophagus.Gastrointest Endosc. 2001; 53: 559-565Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar A big issue is represented by the interobserver and intra-observer variability, which was evaluated by Meining et al.23Meining A. Rösch T. Kiesslich R. et al.Inter- and intra-observer variability of magnification chromoendoscopy for detecting specialized intestinal metaplasia at the gastroesophageal junction.Endoscopy. 2004; 36: 160-164Crossref PubMed Scopus (117) Google Scholar They took 51 patients with reflux symptoms and no known BE. They looked at the gastroesophageal junction with magnification endoscopy, either unstained or randomly stained with MB dye or acetic acid. Biopsy specimens were taken at the Z-line, and the videos of the procedure were shown to 4 experienced endoscopists, who had no knowledge of the clinical or biopsy data. They looked for the pit pattern as classified by Endo20Endo T. Awakawa T. Takahashi H. et al.Classification of Barrett's epithelium by magnifying endoscopy.Gastrointest Endosc. 2002; 55: 641-647Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar and Guelrud.22Guelrud M. Herrera I. Essenfeld H. et al.Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett's esophagus.Gastrointest Endosc. 2001; 53: 559-565Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Interobserver agreement was poor (kappa < 0.4) for pit pattern, MB staining, presence of villous/ridged structures, or SIM. For predicting SIM, sensitivity was 69% (unstained), 77% (acetic acid), 68% (MB); specificity was 33% (unstained), 15% (acetic acid), 23% (MB). More simply, the accuracy rate for diagnosing SIM was similar, 54% (unstained), 52% (acetic acid), and 53% (MB). Thus, accuracy was low, according to this paper, adding MB or acetic acid did not make magnification endoscopy any more accurate. The negative results in this well-controlled study are impressive. However, this article did not investigate patients with BE or with dysplasia. The fact that the value of magnifying endoscopy and tissue staining still needs to be supported by further studies has been claimed by authoritative groups in the field of BE.24Kiesslich R. Neurath M.F. Galle P.R. Chromoendoscopy and magnifying endoscopy in patients with gastroesophageal reflux disease.Dig Dis. 2004; 22: 142-147Crossref PubMed Scopus (21) Google Scholar It has been noted that in 6 previous reports of magnification endoscopy, different criteria were used for mucosal pattern features of SIM without dysplasia.25Sharma P. Magnification endoscopy.Gastrointest Endosc. 2005; 61: 435-443Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar At present, the classification of mucosal patterns on magnification endoscopy has not yet been standardized or validated sufficiently to recommend its use in ordinary clinical practice. In this issue of Gastrointestinal Endoscopy, a well-known group in the field of CE presents its well-done prospective randomized trial with a crossover design, aimed at evaluating the diagnostic yield of magnifying endoscopy with targeted biopsies compared with random biopsies.26Hoffman A. Kiesslich R. Bender A. et al.Acetic acid–guided biopsies after magnifying endoscopy compared with random biopsies in the detection of Barrett's esophagus: a prospective randomized trial with crossover design.Gastrointest Endosc. 2006; 64: 1-8Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Thirty-one patients with BE longer than 2 cm were included in the study. Acetic acid was instilled into the esophagus, and the surface was classified according to a simplified Guelrud's classification: type 1-2 (gastric epithelium), and 3-4 (BE) were gathered. Magnifying endoscopy predicted BE with a sensitivity and specificity of 100% and 66%, respectively. Acetic acid–guided biopsies allowed a diagnosis of SIM in 78% of patients, while, in the random biopsy group, it was 57%. Furthermore, the number of biopsies needed to confirm BE was half when acetic acid was used. They also confirmed that type III and IV patterns were predictors of BE with a sensitivity of 100%, specificity of 64%, and accuracy rate of 83%. In this study, identification of dysplastic areas was not attempted. It is interesting to note that 2 patients were identified with LGD and 2 with HGD. In the 2 latter patients, mucosal abnormalities were visibile at endoscopy.26Hoffman A. Kiesslich R. Bender A. et al.Acetic acid–guided biopsies after magnifying endoscopy compared with random biopsies in the detection of Barrett's esophagus: a prospective randomized trial with crossover design.Gastrointest Endosc. 2006; 64: 1-8Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar This paper represents a further improvement in the identification of SIM.26Hoffman A. Kiesslich R. Bender A. et al.Acetic acid–guided biopsies after magnifying endoscopy compared with random biopsies in the detection of Barrett's esophagus: a prospective randomized trial with crossover design.Gastrointest Endosc. 2006; 64: 1-8Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar However, the investigators stated that, at present, the combined approach cannot be recommended in daily clinical practice. Skill, training, cost, and refinement of the technology still represent drawbacks that must be eliminated. It is clear that such sophisticated techniques cannot be applied indiscriminately in all endoscopy units. The Hoffman paper raises points of concern that are a matter of speculation.26Hoffman A. Kiesslich R. Bender A. et al.Acetic acid–guided biopsies after magnifying endoscopy compared with random biopsies in the detection of Barrett's esophagus: a prospective randomized trial with crossover design.Gastrointest Endosc. 2006; 64: 1-8Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Only patients with BE >2 cm were recruited.26Hoffman A. Kiesslich R. Bender A. et al.Acetic acid–guided biopsies after magnifying endoscopy compared with random biopsies in the detection of Barrett's esophagus: a prospective randomized trial with crossover design.Gastrointest Endosc. 2006; 64: 1-8Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar If detection of SIM in this group of patients is still a challenge, what about those with shorter extensions? What about the identification of dysplastic areas in BE? Furthermore, all patients received proton pump inhibitors (PPI) at least 14 days before endoscopic examination. The logical consequence is that every patient with GERD symptoms should receive PPI therapy before undergoing endoscopy, because inflammation could prevent an adequate inspection of the lower esophagus. The unquestionable advantage of CE is that it obliges the endoscopist to spend more time in evaluating the esophagus and carefully analyzing the possible presence of tiny mucosal abnormalities. We have learned from our Japanese colleagues how important it is to pay great attention when performing endoscopy. They have taught us to predict when a lesion harbors an invasive cancer and how to detect small, nonpolypoid colorectal lesions.27Kudo S. Kashida H. Tamura T. et al.Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer.World J Surg. 2000; 24: 1081-1090Crossref PubMed Scopus (374) Google Scholar CE is a simple procedure, but it requires careful execution of all the necessary steps, and, as in many other medical procedures, it is strictly dependent on the operator. Is magnifying endoscopy with or without CE set to dominate our diagnostic approach to patients with suspected BE? Probably yes but not yet. It would be interesting to evaluate the efficacy of CE and magnifying endoscopy when not performed in the referral centers where interested and skilled endoscopists are involved in research protocols. Efforts should be aimed at identifying BE patients at high risk of cancer progression to know who to screen and survey. The hope is that the improvement of technology will enable recognition of early neoplastic changes, amenable to endotherapy.28Kwon R.S. Sahani D.V. Brugge W.R. Gastrointestinal cancer imaging: deeper than the eye can see.Gastroenterology. 2005; 128: 1538-1553Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 29Conio M. Cameron A.J. Chak A. et al.Endoscopic treatment of high-grade dysplasia and early cancer in Barrett's esophagus.Lancet Oncol. 2005; 6: 311-321Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar By looking to the future, in our daily work, we have to be scrupulous in performing more biopsies, always keeping Goethe's advice in mind.