“Red flag” techniques in Barrett’s esophagus: minor additional benefit or a waste of time?

Barrett’s esophagus is associated with an increased risk of adenocarcinoma developing in the distal esophagus [1]; the incidence of this type of tumor is dramatically increasing in Western countries [2]. The multi-step process of malignant transformation of Barrett’s metaplasia means that surveillance should be recommended in patients who have been diagnosed with the condition. However, the value of surveillance programs of this type is still a matter of controversy, as they have little impact on life expectancy and a poor degree of cost-effectiveness [3]. A major reason for this is that since Barrett’s esophagus is often asymptomatic, a large proportion of the patients remain undiagnosed [4]. A surveillance policy is therefore unlikely to have a major impact on deaths related to esophageal adenocarcinoma, except with mass screening programs; however, the costs of the latter may easily be prohibitive. Another issue is the relatively low incidence of high-grade dysplasia and early cancer (HGD/EC), currently estimated at 0.5 % per year, which implies that a large majority of Barrett’s patients will never develop esophageal cancer. Finally, early neoplastic lesions are difficult to identify, and the current “gold standard”, the Seattle protocol, has a poor degree of accuracy, particularly in long-segment Barrett’s esophagus without visible lesions [5]. Moreover, besides being time-consuming and uncomfortable for the patient, this surveillance technique (based on taking random four-quadrant biopsies every 2 cm in the esophagus) is associated with sampling errors and is far from being widely applied in everyday practice.

However, the numbers of patients being followed up, and to whom potentially curative therapy can be offered, have dramatically increased. The first reason for this is the increasing use of endoscopy, leading to more and more patients being diagnosed with Barrett’s esophagus and offered surveillance. The second reason is the development of endoscopic treatment methods. These are associated with low morbidity rates and can be used with curative intent in older patients who are not candidates for surgery.

The development of new approaches aimed at improving the efficacy of Barrett’s surveillance is therefore of crucial importance. These new approaches have mainly focused on two areas: finding molecular markers in order to identify patients who are at high risk for malignant degeneration, and improving the endoscopic detection of early neoplastic lesions. In addition to improvements in the resolution of endoscopic images, the development of high-quality charge-coupled devices (CCDs) with a “red flag” imaging technique that could identify areas of long-segment Barrett’s esophagus that are more susceptible to HGD/EC would be of major interest.

“Red flag” methods involve special techniques that are added to standard white-light endoscopy in order to increase the sensitivity for detecting early neoplasia in a broad-field imaging examination. In Barrett’s esophagus, these techniques can be divided into three groups: chromoendoscopy, electronic chromoendoscopy, and fluorescence imaging.

Methylene blue is a staining agent that improves the detection of intestinal metaplasia, among other types [6]. In a randomized study, Canto et al. showed that methylene blue improved the biopsy-based detection of dysplasia in Barrett’s esophagus [7]. Even though fewer biopsies need to be taken per patient, the use of a methylene blue-directed biopsy technique allows dysplasia or cancer to be diagnosed in significantly larger numbers of patients (44 % vs. 28 %; P = 0.03) than with the random biopsy technique. It is unclear whether this was associated with an increased recognition of dysplasia or intestinal metaplasia. Other reports have described this technique as disappointing [8]. One possible reason for discrepancies in the rates of detection of Barrett’s esophagus with methylene blue staining is wide variation in the preparation technique used and in the interpretation of the staining patterns.

During the past 5 years, several groups of authors have described the use of contrast agents such as acetic acid, indigo carmine and methylene blue in association with magnifying endoscopy in the diagnosis of intestinal metaplasia, and even for early detection of neoplastic changes in Barrett’s esophagus [9] [10] [11]. Although they are undoubtedly interesting for recognizing the architecture and predicting the histological findings, these techniques are time-consuming and cannot be regarded as “red flag” techniques, since a prerequisite for them is that a suspicious area has already been identified.

These procedures rely on the assumption that the neoplastic process is associated with early visible changes in the superficial mucosal architecture. The endoscopist’s perception of these small mucosal alterations may be improved by using recently developed narrow-band imaging (NBI) techniques, involving filtering of blue light and illumination of very superficial tissue. In Barrett’s esophagus, NBI has been shown to identify specific morphological characteristics of HGD on the basis of irregular mucosal and vascular patterns and abnormal blood vessels. In a prospective and randomized cross-over trial using high-resolution endoscopes, Kara et al. [12] demonstrated that the increase in the sensitivity of targeted biopsies for HGD/EC was similar with narrow-band imaging (93 %) and indigo carmine chromoendoscopy (86 %) in comparison with high-resolution endoscopy alone (79 %). Interestingly, however, one of 14 patients with HGD/EC was diagnosed by random biopsies alone, and it is therefore unclear whether this technique can make surveillance easier.

Autofluorescence endoscopy is based on blue-light excitation of receptive tissue molecules called fluorophores, and it can be carried out without the use of any drugs. Dysplastic tissue and normal metaplastic tissue have different autofluorescence spectra, due to morphological differences and different fluorophore content. This difference led to the development of a technique in which the mucosa is excited with blue light and a real-time autofluorescence endoscopic image is produced based on the ratio of red to green autofluorescence; dysplastic tissue is displayed with a different color from that of the “normal” background. This is a typical example of a “red flag” technique.

In this issue of Endoscopy, Borovicka et al. present a multicenter randomized cross-over trial comparing an autofluorescence-targeted biopsy technique with conventional endoscopic examination. Both protocols included four-quadrant biopsies. The major finding of the study is that autofluorescence surveillance in patients with Barrett’s esophagus requires fewer endoscopic examinations in order to diagnose one HGD/EC lesion than conventional white-light endoscopy, both in a randomized population (n = 23 vs. 93) and after cross-over (n = 34 vs. 62). However, the sensitivity was only 42 %, and 43 % of the 35 pathological specimens identified were diagnosed with four-quadrant biopsies alone. One possible reason for this low sensitivity is that in this study, the autofluorescence examinations were carried out with fiber endoscopes.

A recent advance with this technique is the development of a third-generation fluorescence endoscope that uses two switchable CCD chips for standard video and autofluorescence imaging. A nonrandomized trial was presented in 2005 by the Amsterdam group, comparing HGD/EC diagnosis with a standard video endoscope with this latest generation of autofluorescence endoscopes [13]. In a per-patient analysis, autofluorescence identified six more patients out of 22 with HGD/EC. Again, however, one patient with HGD/EC was identified only with the random biopsy protocol. In a per-lesion analysis, the negative predictive value for HGD/EC of autofluorescence was 89 % (31 of 35).

All of these studies suggest that while autofluorescence may increase the chances of finding pathological lesions, it is still not capable of replacing the four-quadrant biopsy protocol.

At present, these “red flag” techniques offer some additional benefit to the Seattle protocol for detecting HGD/EC, but with additional costs both in time and money. However, there are still many limitations on the use of these techniques. The materials and instruments are expensive and have been used so far only in study conditions. The limited diagnostic gain suggests that most surveillance endoscopies should only be carried out at referral centers - an aspect that has little prospect of success from a public-health policy perspective. Further technical developments will be needed in order to determine whether a single, fast technique is capable of identifying neoplastic tissue in Barrett’s esophagus, avoiding the need to take numerous biopsies while at the same time providing accurate detection of early neoplasia.

Competing interests: None

References

• 1 Spechler S J. Clinical practice. Barrett’s esophagus.  N Engl J Med. 2002;  346 836-842
• 2 Devesa S S, Blot W J, Fraumeni J F. Changing patterns in the incidence of oesophageal and gastric carcinoma in the United States.  Cancer. 1998;  83 2049-2053
• 3 Inadomi J M, Sampliner R, Lagergren J. et al . Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis.  Ann Intern Med. 2003;  138 176-186
• 4 Cameron A J, Zinsmeister A R, Ballard D J. et al . Prevalence of columnar-lined (Barrett’s) esophagus: comparison of population-based clinical and autopsy findings.  Gastroenterology. 1990;  99 918-922
• 5 Reid B J, Blount P, Feng Z. et al . Optimizing endoscopic biopsy detection of early cancers in Barrett’s high grade dysplasia.  Am J Gastroenterol. 2000;  95 3089-3096
• 6 Canto M I, Setrakian S, Petras R E. et al . Methylene blue selectively stains intestinal metaplasia in Barrett’s esophagus.  Gastrointest Endosc. 1996;  44 1-7
• 7 Canto 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;  51 560-568
• 8 Ragunath K, Krasner N, Raman V S. et al . 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.  Endoscopy. 2003;  35 998-1003
• 9 Sharma P, Weston A P, Topalovski M. et al . Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett’s oesophagus.  Gut. 2003;  52 24-27
• 10 Guelrud 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;  53 559-565
• 11 Endo T, Awakawa T, Takahashi H. et al . Classification of Barrett’s epithelium by magnifying endoscopy.  Gastrointest Endosc. 2002;  55 641-647
• 12 Kara M A, Peters F P, Rosmolen W D. et al . High-resolution endoscopy plus chromoendoscopy or narrow-band imaging in Barrett’s esophagus: a prospective randomized crossover study.  Endoscopy. 2005;  37 929-936
• 13 Kara M A, Peters F P, Ten Kate F J. et al . Endoscopic video autofluorescence imaging may improve the detection of early neoplasia in patients with Barrett’s esophagus.  Gastrointest Endosc. 2005;  61 679-685