Diagnosis
As noted previously, the diagnosis of Barrett’s esophagus requires the demonstration of intestinal metaplasia on targeted biopsy sampling of endoscopically abnormal appearing esophageal mucosa [7]. The definition and diagnosis of Barrett’s is difficult for several reasons. First, there are no symptoms specific for this condition. For the most part, the symptoms are essentially identical to those of GERD and most patients are asymptomatic [27]. In addition, accurate identification of the location of the gastroesophageal junction is required in order to determine if the squamo-colum-nar junction is displaced proximal to this location, since this displacement is what alerts the endoscopist to the possibility of the diagnosis of Barrett’s and thus leads to biopsy of the mucosa. The former junction can at times be very difficult to determine endoscopically because of the presence of a hiatal hernia, esophagitis, and the constant movement of the area. This is highlighted by a multicenter study in which only 72% of the endoscopists correctly recorded endoscopic landmarks in the diagnosis of Barrett’s esophagus [86]. SSBE can thus be particularly difficult to identify and distinguish from an irregular Z line (a normal anatomical finding). This is very important because intestinal metaplasia in the gastric cardia does not seem to have the same implications as intestinal metaplasia of the esophagus and, indeed, may be a normal histological finding in this location. Erythema or erosive esophagitis can also impair the visual recognition of Barrett’s esophagus, and repeat endoscopy after treatment with acid suppression may be necessary to make the diagnosis of Barrett’s in this situation [87].
Currently, intestinal metaplasia is a prerequisite in order to make the diagnosis of Barrett’s esophagus. This fact, however, seems not to be fully understood as some pathol-ogists continue to classify patients without intestinal metaplasia as Barrett’s esophagus. In one study, correct identification of intestinal metaplasia without dysplasia occurred in only 35% of 20 community-based pathologists [88]. The hematoxylin and eosin stain combined with alcian blue at pH 2.5 can be used to facilitate the recognition of the acid mucin-containing goblet cells characteristic of intestinal metaplasia [5].
A further difficulty with diagnosis is sampling error. When obtaining biopsies for Barrett’s esophagus, samples may miss the area with metaplasia and hence fail to lead to the diagnosis. This addresses the important issue of the number of biopsies required; intuitively, the more endoscopic biopsies taken, the more accurate the diagnosis of Barrett’s. It has also been suggested that endoscopic adjuncts such as chromoendoscopy and/or narrow band imaging (NBI) may help in targeting biopsies and thus increase the diagnostic yield. Methylene blue, toluene blue, indigo carmine, and Lugol’s iodine have all been used as chromoendoscopic agents to identify specialized intestinal metaplasia as well as the characteristic surface patterns suggestive of neoplasia [89–92]. These contrast agents are sprayed over the esophageal mucosa at the time of endoscopy, with areas of intestinal metaplasia and dysplasia demonstrating a variety of characteristic staining patterns. However, interpretation of the staining process may be tedious, and the results are not necessarily reproducible [93]. More recently, the pairing of magnification endoscopy [94] with narrow-band imaging (NBI) has emerged as a new modality that may obviate the need for staining altogether.
Dysplasia is only detectable histologically. Dysplasia, the next step in the neoplastic process, represents a change in architecture of the metaplastic glands and is associated with individual cellular nuclear abnormalities. Dysplasia is felt to progress along a continuum from no dysplasia to low-grade dysplasia, high-grade dysplasia and finally adenocarcinoma, although the time course of this progression is highly variable and not inevitable. Furthermore, it is likely reversible in the stages leading up to adenocarci-noma. Dysplasia is often focal and not easily detectable endoscopically without the aid of stains, magnification and narrow-band imaging, rendering the targeting of biopsy sampling difficult. It has been established that random biopsies taken every 2 cm detect 50% fewer cancers than four-quadrant biopsies taken every 1cm [95]. The latter approach has yet to be recommended in formal guidelines because of the effort involved in following such an intensive biopsy protocol. In addition, there is significant inter-observer variation in the diagnosis and grading of dysplasia by both academic and non-academic pathologists [12]. Reactive change due to esophagitis is difficult to distinguish from dysplasia and further compounds the problem. However, recent data from a randomized controlled trial demonstrated that roughly half the biopsies are required to detect dysplasia with methylene blue-targeting compared with four-quadrant biopsies every 2 cm within Barrett’s metaplasia [96]. Furthermore, the combination of NBI and high-magnification endoscopy reportedly identifies microstructural changes suggestive of dysplasia with a sensitivity and specificity of 90% and 100% respectively [97]. Although not formally recommended yet, such advances in endoscopic imaging are likely to be incorporated into endoscopic practice if confirmed and reproducible.
Although the diagnosis of Barrett’s esophagus can be difficult, if the endoscopist suspects that the level of the squamo-columnar junction is above the esophagogastric junction (the proximal margin of the gastric folds), biopsies are required. If intestinal metaplasia is present, then the diagnosis of Barrett’s esophagus has been established.
Treatment
The goals of treatment for Barrett’s esophagus are the same as for GERD; the control of symptoms and maintenance of healed mucosa [6].
Acid suppression
Lifestyle modifications (including dietary adjustment) may help control GERD symptoms somewhat, but these measures are unlikely to have an effect on the regression of Barrett’s metaplasia. In fact, some individuals with Barrett’s esophagus are asymptomatic, possibly due to the replacement of the normal squamous epithelium with the acid insensitive Barrett’s epithelium. Nevertheless, these patients may still benefit from acid suppression given the potential regression of Barrett’s metaplasia as discussed below [6].
Histamine H2-receptor antagonists (H2-RA) often improve GERD symptoms but they do not effect regression of Barrett’s metaplasia [98, 99]. Proton pump inhibitors (PPI) are the most potent antisecretory agents, superior to H2-RA in the treatment of symptoms and the healing of esophagitis [100]. In Barrett’s esophagus, these same end-points are effectively achieved with PPIs [101–103]. Some studies have also suggested a modest endoscopic regression of Barrett’s esophagus with use of PPIs, although these usually utilized a high dose PPI [99, 101, 104–106]. In a randomized controlled trial, Peters et al. [99] demonstrated that omeprazole 40 mg bid resulted in an 8% reduction of surface area of Barrett’s esophagus and a 6% decrease in length, superior to the comparator, ranitidine 150mg bid (Table 3.1). There is also evidence that normalization of intra-esophageal acid exposure decreases cellular proliferation rates and use of PPIs has been associated with a decreased incidence of dysplasia [107, 108]. It is noteworthy that, despite adequate symptom control, even high dose PPI therapy often does not normalize esophageal acid exposure in patients with Barrett’s metaplasia [109–112]. However, there is no evidence that normalization of pH leads to a decreased incidence of adenocarcinoma and, therefore, it is not rational to routinely perform pH-metry to determine the level of acid suppression. What is often seen with acid suppression is an increase in islands of squamous epithelium within the Barrett’s segment. Biopsies of such islands have often shown underlying intestinal metaplasia, indicating that complete regression of Barrett’s does not occur with pharmacological acid inhibition [113]. At this point, no study has shown a reduction of esophageal adenocarcinoma or mortality, although a large randomized control trial examining PPIs and/or aspirin as a chemopreventive agent is underway [114]. Nevertheless, PPIs remain the best pharmacological treatment for Barrett’s presently available. B2
Given that even high dose PPI may fail to normalize esophageal pH [109–112, 115–117], some have considered anti-reflux surgery as an alternative to decreasing cancer risk with the consideration that continued reflux is the promoting agent. Surgery does provide excellent control of symptoms, and the development of squamous islands after surgery suggests possible regression. One randomized trial comparing medical therapy with anti-reflux surgery with follow up for one to eleven years (Table 3.1) demonstrated a 25% rate of some regression in the surgically treated group (9% progression, 3/32) compared to 7% regression (41% progression, 11/27) in the medical group [118]. However, complete regression of Barrett’s metaplasia with surgery is very uncommon and may, in fact, reflect “pseudoregression” due to surgical repositioning of the esophagus [12]. Some studies have also reported a reduced risk of progression of low grade dysplasia [119]. However, both dysplasia and cancer continue to occur after surgery [120–124]. Csendes et al. [123] found that dysplasia developed in 17 (10.5%) and adenocarcinoma in 4 (2.5%) of 161 patients who had undergone surgery at late (7–21 years) follow-up. In a small randomized controlled trial comparing medical to surgical anti-reflux therapy, there was no significant difference between groups in incidence of esophageal cancer (Table 3.1) [124], although this study probably lacked power to demonstrate a true difference should one exist. A more recent retrospective observational study of Barrett’s patients who underwent Rosetti-Nissen fundoplication for medically-refractory reflux demonstrated regression of LGD to nondysplastic Barrett’s esophagus in six of eight patients, and complete regression of metaplasia to normal mucosa in eight of fifty-seven patients (14%). However, six of fifty-seven (11%) demonstrated an increase in length of involvement with Barrett’s postoperatively, and two patients went on to develop adenocarcinoma after surgery [125]. Hence, surgery does not reliably prevent dysplasia or cancer and, therefore, does not obviate the need for surveillance and should not be promoted as a cancer prevention therapy.
Table 3.1 Summary of randomized controlled trials for the treatment of Barrett’s esophagus discussed in this chaptera.
aThis list is not meant to be an exhaustive list of all randomized clinical trials in the literature.
bThis includes all GERD patients, not just those with Barrett’s esophagus.
Abbreviations: PDT: Photodynamic therapy.
Chemoprevention of esophageal adenocarcinoma with anti-inflammatory agents
The use of aspirin (ASA) or nonsteroidal anti-inflammatory drugs (NSAID) has been demonstrated to be associated with a significantly reduced risk of developing esophageal adenocarcinoma [126, 127]. Cycooxygenase-2 (COX-2) expression is increased in Barrett’s epithelium [128] and COX-2 inhibition has been shown to reduce cell growth in esophageal adenocarcinoma cell lines, as well as inhibit cancer formation in animal models of Barrett’s [129, 130]. Modeling the use of aspirin in patients with HGD suggests that this may be a very cost-effective intervention [131]. As such, it has been suggested that using NSAIDs and ASA as chemoprevention agents in Barrett’s esophagus may be a viable management option. In a randomized controlled trial reported in 2007 in which 100 patients with low or high-grade dysplasia were randomized to receive celecoxib 200mg twice daily or placebo, no significant differences were demonstrated in progression of either extent of Barrett’s, dysplasia, or cancer at 48 weeks [132]. The possibility of a type II error exists in this study. Despite significant biological plausibility and epidemiological evidence of an ASA/NSAID chemoprevention effect in Barrett’s, at this time no recommendation for the use of NSAIDs as chemopreventive agents in patients with Barrett’s can be made. Studies involving larger populations and follow-up periods are in progress and may provide a definitive answer in the future [12,133,134].
Ablative therapies
Given the theory that Barrett’s esophagus develops in the predisposed individual as a consequence of a perturbation in healing of the injured esophageal epithelium in an abnormal esophageal acidic environment, it was further hypothesized that reversal of Barrett’s would require re-injuring of the metaplastic epithelium with ablative therapy in an acid normalized esophageal environment, resulting in re-epithelialization with a native normal squamous epithelium. This effect could eliminate or decrease the risk for dysplasia and esophageal adenocarcinoma. Endoscopic injury or ablation of Barrett’s has been demonstrated with a variety of endoscopic techniques, including thermal techniques (radiofrequency energy, electrocoagulation, heater probe, argon plasma coagulation, or laser), cryotherapy, chemical induced injury with photodynamic therapy, or resection via endoscopic mucosal resection.
Reports using a wide variety of different thermal techniques have suggested both complete and incomplete histologicalregressioninBarrett’sesophagus,butcomplications are not uncommon [12]. Multipolar electrocoagulation (MPEC) has resulted in a fibrotic and friable esophagus with adhesions to the pleura in one patient [135]. Argon plasma coagulation (APC) has had significant complications including chest pain and odynophagia (58%), fever and pleural effusion (15%), strictures (9%), pneumomedi-astinum (3%) and perforation [136, 137]. In addition, one study using heater probe reported buried islands of intestinal metaplasia in 23% of patients [138].
Photodynamic therapy (PDT) is a process in which a light-sensitive agent, which concentrates in neoplastic tissue, is administered and subsequently activated by light of an appropriate wavelength. This results in selective damage of the neoplastic tissue. The sensitizing agents used include porfimer sodium, a hematoporphyrin derivative, or 5-aminolaevulinic acid (5-ALA). Reports describe elimination and regression of dysplasia and early cancers, but complete regression of Barrett’s was not achieved in the majority of patients [139]. A randomized trial compared PDT using sodium porfimer to medical therapy with omeprazole in 208 patients (Table 3.1) with high grade dysplasia [140]. At 12-month follow-up, 9% of the PDT group developed cancer compared to 19% of the omeprazole group (NS), but strictures developed in 38% of the patients who underwent PDT. The same authors reported five-year follow-up data on an incomplete subset of these patients in 2007. They demonstrated twice the rate of HGD elimination (77% versus 39%) and nearly half the progression to cancer (15% versus 29%) for the PDT group. The reported strictures were limited to the first phase of the trial in the PDT group, and all had resolved at five-year follow-up [141]. Another randomized study compared PDT with 5-ALA to placebo in low-grade dysplasia patients and achieved regression of dysplasia in 89% (16/18) versus 11% (2/18) of patients in the placebo group (Table 3.1), but only 30% of the surface area was eliminated in the 5-ALA group [142]. Hence, some risk of progression for residual neoplastic and non-neoplastic tissue still remains with this intervention. In fact, a case of adenocarcinoma developing underneath new squamous epithelium after treatment for high grade dysplasia with PDT using sodium porfimer has been reported [12]. A1d
Radiofrequency ablation (RFA) is a relatively new technique that involves the application of high-frequency energy through an endoscopic balloon probe or contact device. The device, comprised of a radiofrequency energy generator and ablation catheter, is usually mounted on a balloon to ensure circumferential ablation. Early uncontrolled trials demonstrate considerable success with this technique. Sharma et al. demonstrated elimination of Barrett’s with RFA of 70% at one year of follow-up, in addition to a complete absence of buried IM (or squamous overgrowth) [143]. Recent studies have also examined the use of RFA for the treatment of low-grade and high-grade dysplasia, demonstrating elimination rates for both non-dysplastic IM and dysplasia in excess of 90% after one to two years of follow-up [144,145]. Furthermore, stricturing and buried islands of IM rarely (if ever) occurred in these studies, suggesting potential for this Barrett’s ablation modality as a safer (versus PDT) and/or more efficacious (versus MPE or APC) therapy. B4
Endoscopic mucosal resection (EMR) has also been performed in patients with and without visible lesions within Barrett’s esophagus. In one study, EMR resulted in complete local remission of 97% (34/35) of patients with low-risk lesions characterized by diameter of less than 20 mm, well or moderately differentiated histology, lesions limited to mucosa, or non-ulcerated lesions, compared to 59% (13/22) of patients with high-risk lesions characterized by diameter of greater than 20 mm, poorly differentiated histology, lesions extending into sub-mucosa, or ulcerated lesions [146]. However, metachronous lesions or recurrent high-grade dysplasia or cancer were detected in the subsequent year in 17% of the low risk and 14% of the high risk group. Larger studies with longer follow-up are required, but EMR also appears to be relatively safe and promising as an effective non-surgical alternative for management of neoplastic Barrett’s metaplasia. B4
With all endoscopic Barrett’s ablative therapies, even if all of the Barrett’s epithelium is thought to be eliminated, some residual intestinal metaplasia may be present underneath the neosquamous epithelium, along with the continued risk of cancer development. Thus, these patients have a continued need for surveillance which may be more difficult given that the endoscopic landmarks may be less easily identifiable after ablative therapy [12]. In addition, most of these techniques are associated with a small but significant risk of stricture and perforation. They are (for the most part) costly, the methods have not yet been standardized, and the results are likely very operator dependent. At this time, endoscopic ablative therapy is a reasonable option in the Barrett’s patient with high grade dysplasia or superficial adenocarcinoma. A1d There are no data allowing one to recommend these therapies in the Barrett’s patient without neoplasia, since continued surveillance will still be required, and the risk/benefit ratio is not firmly established.
Screening and surveillance
Screening for the detection of Barrett’s esophagus is currently recommended in patients with chronic GERD symptoms, especially in those over age 50 [7, 147]. This recommendation is based in part on the observation that patients with a longer duration of symptoms have a higher prevalence of Barrett’s esophagus [39, 60]. GERD patients who are white, male or have more severe acid reflux also have a higher prevalence of Barrett’s esophagus [6, 79, 80]; hence the emphasis on screening this population. Most authors have recommended that a “once in a lifetime” endoscopy should be performed in all GERD patients (based on the premise that Barrett’s occurs early on in a GERD patient and thus repeat screening endoscopy is not required), although the optimal timing and utility of such a recommendation is unknown [148]. This approach seems to be favored by Canadian gastroenterologists, of whom 76% agreed that all patients with chronic GERD should have a “once in a lifetime” endoscopy [149]. Although the asymptomatic Barrett’s esophagus patient would not be picked up with this screening method, a generalized screening endoscopy in the general population is not recommended.
The aim of the “once in a lifetime” gastroscopy in GERD patients is to detect Barrett’s esophagus, as this entity increases the risk of developing esophageal adenocarcinoma. Some have argued that cancer surveillance once non-neoplastic Barrett’s is discovered is too costly and/or may be ineffective in improving outcomes. In Barrett’s patients with dysplasia there is little controversy that either heightened surveillance or an intervention should be recommended, as it is the only method currently available to identify the high risk patients with dysplasia who may benefit from treatment, including new ablative therapies.
Arguments in support of a screening and surveillance strategy
The rationale for screening for and carrying out surveillance of patients with Barrett’s esophagus is based on the fact that GERD is a risk factor for esophageal adenocarcinoma (EAC) [60], that Barrett’s esophagus represents an intermediate step between esophagitis and adenocarcinoma (and is also the only known precursor of esophageal adenocarcinoma) [6], that the rate of esophageal adenocarcinoma is steadily increasing in Western societies [150] and the prognosis for esophageal adenocarcinoma is very poor unless detected early [151]. Over 50% of all esophageal tumors on the National Cancer database for 1988 were stage III or IV at the time of detection with five-year disease specific survivals of 15% and 3% respectively [152]. It is argued that surveillance programs will detect dysplasia or cancers at an earlier stage when the prognosis is much better. In stage I or II EAC cases the five-year disease specific survival rates were 42% and 29% respectively [152]. In addition, small retrospective observational studies suggest that Barrett’s surveillance improves survival. A comparison was made between patients who initially presented with esophageal adenocarcinoma (n = 54) versus those in whom the cancer had been detected during surveillance (n = 16) of Barrett’s esophagus [153]. Surveyed patients had significantly earlier stages than non-surveyed patients (75% had stage 0 or I, 25% stage II, and 0% stage III compared to 26%, 25% and 56% respectively, for non-surveyed patients). Survival was also significantly better in the surveyed group, with a two-year survival of 86% versus 43%. Similar results were also demonstrated in an earlier retrospective study comparing 17 adenocarcinoma patients found from surveillance programs versus 35 patients who had not been in a program [154]. Again, the cancers were at an earlier stage and survival was significantly greater in the surveyed group than in the non-surveyed group prior to diagnosis. A third study obtained similar results, with a five-year survival of 62% in those who underwent surveillance, compared to 20% in those that did not [155]. In addition, a prospective study from the UK reported on the results of a surveillance program involving 126 patients and spanning more than nine years; although there was no non-surveillance comparator group, 4% of all patients with Barrett’s developed adenocarcinoma, half of which were cured by esophagectomy [156]. These data lead to the recommendation by many experts to advocate for a Barrett’s screening and surveillance program in higher risk GERD patients. B3
Arguments against a surveillance strategy
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