Clinical Gastroenterology and Hepatology
Volume 7, Issue 6 , Pages 610-612, June 2009

Declaration of Bankruptcy for Four-Quadrant Biopsies in Barrett's Esophagus?

published online 25 February 2009.

Article Outline

 

See more, biopsy less! This should be the ultimate goal for every endoscopist treating patients with Barrett's esophagus. But how can this goal be achieved? Four-quadrant biopsy protocols were introduced for surveillance and mapping purposes in patients with Barrett's esophagus more than 15 years ago, and they are still the standard of care in most countries.1, 2, 3 At that time, however, endoscopists still were using fiberoptic endoscopes with poor image quality. It was not possible to detect subtle changes in the mucosal pattern with such instruments, and it was therefore almost impossible to identify early neoplastic lesions.1 However, 85% of high-grade dysplasias and mucosal Barrett's cancers appear as very discrete changes in the mucosal and vascular pattern (type II lesions in the Paris classification). Only 13% of these early neoplastic lesions appear as nodules (type I).4 It is hardly surprising, therefore, that a systematic biopsy protocol was at that time able to identify significantly more neoplastic lesions than targeted biopsies did. Dramatic developments have taken place in endoscope technology since the early 1990s—but despite this, we are still continuing to cling to the 4-quadrant biopsy protocol, which is now senescent and even starting to look rather antiquated, in view of the technical facilities available today.

In this issue of Clinical Gastroenterology and Hepatology, Kariv et al5 report on their experience with the Seattle biopsy protocol in comparison with a standard biopsy protocol for detecting occult cancers in Barrett's mucosa. In their retrospective analysis, the investigators found that both the Seattle protocol and the less rigorous clinical protocol missed intramucosal cancers in 40% and 30% of cases, respectively. However, it is important to emphasize that no submucosal cancers were missed in the study.

This surprisingly large number of overlooked mucosal cancers raises several questions. Are we really as bad as this at detecting clinically relevant neoplasia in patients with Barrett's esophagus? Were the biopsy-detected high-grade dysplasias (HGDs) only the tip of the iceberg, representing mucosal carcinomas in the immediate vicinity (ie, are HGDs and mucosal cancer one and the same lesion)? Would the use of advanced imaging techniques significantly have improved the detection rate?

Dr. Falk's research group certainly can be described as one of the leading ones in the field of Barrett's esophagus, and in contrast to numerous earlier studies with similarly poor results, high-resolution video endoscopes were used in the study.5 The miss rate for mucosal cancer was high despite this. This might perhaps be explained by the fact that HGD very often is located next to cancer lesions, and that a previously detected HGD and the mucosal cancer diagnosed in the resected specimen after surgery often represent the same lesion. In an era in which diagnostic and therapeutic endoscopic resection (ER) is available, however, what is the clinical impact of these missed cancers? The strategy in the presence of HGD nowadays always should be to perform ER of the lesion. In addition to providing a definitive treatment approach, this procedure also is able to precisely define the extent and depth of infiltration of a neoplastic lesion. Outstanding long-term data on endoscopic therapy and on ER in particular now are available, so that this treatment method now can be described as the standard.6, 7, 8 The large number of missed cancers in this study, as well as in numerous other studies, also makes it clear that simply destroying the lesions by ablating localizable HGDs, either thermally or with photodynamic therapy, is not the ideal solution. Although no submucosal cancers were overlooked in the study by Kariv et al,5 it is inevitable that when ablative techniques such as photodynamic therapy, cryotherapy, and radiofrequency therapy are overused, particularly in less-experienced centers, patients with underestimated submucosal cancers will receive inadequate endoscopic treatment when they actually need to undergo surgery. In addition, important risk factors such as lymphatic and vascular infiltration can be identified only using ER.

More than 15 years ago, our own research group also used ablative procedures such as photodynamic therapy in particular, but in view of the uncertainties mentioned earlier we switched to ER almost completely at a relatively early stage. Only ER allows precise risk stratification (infiltration depth, grade of differentiation, vascular infiltration, tumor cell dissociation), and it is only in this way that adequate treatment can be recommended to the patient.

Another question that arises on reading the article by Kariv et al5 is whether the use of advanced imaging techniques might not have reduced the rate of missed mucosal cancers markedly. For most of the advanced imaging techniques, numerous studies have confirmed that their use significantly improved the detection rate for neoplasia. Numerous studies are available on classic methylene blue chromoendoscopy, although with highly contradictory results.9, 10, 11 For this reason, because of the technique's questionable potential to induce DNA damage, and above all because of the time-consuming and examiner-dependent quality of the method's application, methylene blue staining has not found its way into everyday clinical practice. For other chromoendoscopic procedures, such as the use of indigo carmine in patients with Barrett's esophagus, very few data are available, so that here again it is not possible to make a general recommendation.

Applying acetic acid to improve the surface structure is easy and quick, and the results are easy to interpret. Here again, however, there have been only a few studies including small numbers of patients, and this method therefore also has not yet been adopted widely.12, 13 In our own department, we routinely use acetic acid 1.5% to screen for neoplastic areas and for surveillance in every patient with Barrett's esophagus.14 The effectiveness of acetic acid currently is being investigated in an ongoing prospective study at our institution. The patients initially underwent acetic acid–targeted biopsies, followed by 4-quadrant biopsies as the gold standard to detect any neoplastic lesions that might have been overlooked. An interim analysis of the data showed that using acetic acid allowed detection of nearly all neoplastic areas in 500 patients.15 Sixty-five patients with 97 lesions had HGD or early cancer, and the neoplasia was detected using the acetic acid–guided biopsies in 62 patients (95.5%). A neoplastic lesion was detected using 4-quadrant biopsies alone in only 3 patients. These figures are extremely promising, but publication of the completed study still needs to be awaited before conclusions can be drawn.

There are also attractive new techniques in virtual chromoendoscopy, such as narrow-band imaging (NBI) and Fujinon Intelligent Color Enhancement (FICE) (Fujinon, Saitama, Japan), in which pressing a button on the endoscope can provide markedly improved visualization of the surface structure and vascular pattern. Because of the method's ease of use and the now widespread availability of the technology, virtual chromoendoscopy is certainly the most frequently used advanced imaging technique at present. Almost all publications on the topic have reported an improvement in the neoplasia detection rate, with sensitivities of between 86% and 100%.16, 17 NBI also can be combined with autofluorescence endoscopy. The use of NBI to evaluate lesions that were suspicious on autofluorescence imaging reduced the high false-positive rate of autofluorescence imaging from 81% to 26%.

Confocal laser endomicroscopy (CLE) is a revolutionary new technique that has been introduced into endoscopy in recent years.18, 19, 20, 21 The CLE technique, which uses a specially designed confocal endoscope, provides images at the cellular level and has shown promising results in the diagnosis of high-grade intraepithelial neoplasia and early adenocarcinoma in patients with Barrett's esophagus, with a sensitivity of 93% and a specificity of 98%.18 However, these figures mainly included visible neoplastic lesions. A recently published study investigated the value of a CLE miniprobe for detecting nonvisible neoplasia in Barrett's esophagus. Here, however, CLE only achieved an examiner-dependent sensitivity of 75% to 88.8%. The added value provided by CLE needs to be compared with normal high-resolution endoscopy with targeted biopsies plus 4-quadrant biopsies in a prospective, randomized, and multicenter study; only then will it be possible to assess the value of the procedure.

Common to all of the advanced imaging techniques mentioned is the fact that the published studies on them mostly represent small, single-center investigations with selected groups of patients. There are as yet no published data from studies including sufficiently large numbers of patients to make it possible to dispense with 4-quadrant biopsy and move to using biopsies guided by advanced imaging techniques alone. As endoscopists, do we have to continue with the time-consuming, antiquated, 4-quadrant biopsy method, even though we have high-technology, high-definition, high-resolution video endoscopy with NBI/FICE among the fleet of techniques available to us? It is like driving a Porsche using only first gear.

But not quite. What we need to do is put our foot down on the gas pedal, move up a gear, and exploit all of the technological features that modern endoscopy makes available to us. We should take our time and inspect the Barrett's esophagus precisely and carefully. A precise examination of the quadrants at the 12-o'clock and 3-o'clock positions is helpful because more than 50% of HGDs and early cancers are located there.4 This certainly would make it possible to achieve a substantial increase in the detection rate for neoplastic lesions in Barrett's esophagus. However, 4-quadrant biopsies of the rest of the Barrett's esophagus segment still always should be performed at the end of the examination—whether this is performed using the Seattle protocol with jumbo biopsy forceps or with the conventional less invasive biopsy protocol—to minimize the likelihood of overlooking relevant neoplasia. HGD and mucosal cancers that are detected then should be resected endoscopically. After ER, close follow-up endoscopies are mandatory—this is a major drawback of endoscopic therapy, but it is the price that has to be paid for preserving the esophagus and thereby maintaining the patient's quality of life, avoiding relevant rates of complications and mortality. Ablation of the remaining nondysplastic Barrett's mucosa, either with radiofrequency therapy or argon plasma coagulation after successful ER, seems to reduce the rate of recurrences and metachronous neoplasia. In addition, follow-up endoscopies have the advantage that any cancers that have been missed initially can be detected later.

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References 

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 Conflicts of interest The author discloses no conflicts.

PII: S1542-3565(09)00135-9

doi:10.1016/j.cgh.2009.02.012

Clinical Gastroenterology and Hepatology
Volume 7, Issue 6 , Pages 610-612, June 2009