Barrett’s esophagus (BE) is the partial replacement, from the gastro-esophageal junction (GEJ) proximally, of esophageal squamous epithelium with metaplastic columnar epithelium. It develops in patients with gastroesophageal reflux disease (GERD) because of chronic injury and inflammation of the esophageal epithelium. Many other factors have also significance. BE is the only known precursor to esophageal adenocarcinoma (EAC), the incidence of which has been increased faster in Western world in the past four decades [1, 2]. In the United States, the incidence of EAC increased from 3.6 cases per 1,000,000 in 1973 to 25.6 per 1,000,000 in 2006 . Since EAC is frequently detected at an advanced stage, the prognosis remains poor. The 5-year survival rate of patients with locally advanced EAC undergoing curative resection is around 15–20% . So detection at an early stage of neoplastic progression may be important in improving survival. The risk of developing EAC is 30–40-fold higher in patients with BE compared with the general population [4, 5]. The development of EAC in BE has been shown to occur through a multistep process of increasing grades of epithelial dysplasia, from no dysplasia to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and finally EAC . In two studies of 136 and 170 patients with nondysplastic Barrett's esophagus (NDBE), followed for approximately 4 years, the rate of progression to EAC was 0.5% per patient-year [7, 8]. The risk additionally increases if Barrett’s dysplasia is present. The annual incidence of EAC in patients with LGD and HGD is about 1.7% and 6.6% respectively . In another study of 75 BE patients with HGD, 16% developed EAC over a mean follow-up period of 7.3 years . In last years, there are many new data for the pathogenesis and the natural history of BE, which raise many points regarding surveillance of BE and risk stratification for EAC, and current role of anti-reflux therapy. Many enhanced imaging technologies and new endoscopic modalities for detection or management of any grade dysplasia and early cancer have been developed.
2. Definitions and diagnosis of BE
2.1. Definitions of BE
There is universal agreement that the underlying component of the definitions of Barrett’s esophagus is the partial replacement, from the GEJ proximally, of esophageal squamous epithelium with metaplastic columnar epithelium. A mosaic of several histologic types of columnar metaplasia can be seen on biopsies from BE, including cardia type metaplasia, gastric fundus type metaplasia and specialized intestinal metaplasia (IM) type, containing goblet cells. The term BE is currently confusing because of varying definitions used for the diagnosis of BE [11, 12]. There is a lack of consensus among various professional organizations whether goblet metaplasia should be a requirement for the diagnosis of BE. According to the British Society of Gastroenterology (BSG), BE represents an endoscopically apparent area of columnar mucosa proximal to the GEJ, proven on histologic examination . The American College of Gastroenterology(ACG) and the American Gastroenterological Association (AGA) recommend documentation of IM for the diagnosis of BE [14, 15]. Several arguments can be made in favor of requiring IM for the diagnosis of BE. This definition is related with the concept of more malignant potential of IM compared to the risk of neoplastic progression in patients with metaplastic nongoblet columnar epithelium . Some studies have also suggest that a diagnosis of BE may have a negative impact on overall quality of life of the patients. Patients with BE tend to overestimate their risk of EAC, and this leads to higher utilization of healthcare resources. A diagnosis of BE can result in higher health insurance premium and difficulty in obtaining health insurance [16, 17]. The varying definitions of BE lead to difficulties in the interpretation of know ledges for BE, because of the selection and follow-up of different cohorts of cases . The “only IM type” definition of BE dominates the literature, but in many publications the diagnosis is made on the basis of varying endoscopic criteria unsupported by histopathology or on the presence of any type of columnar metaplasia. In 2006 the definition of BE was considered by the Global Evidence-Based Consensus Workshop on the Definition and Classification of Reflux Disease (the Montréal workshop) . The experts reached consensus that the label BE should be used when any type of columnar metaplasia (CM) is confirmed by histology, with description of presence or absence of IM. There are different evidence –based considerations which support this non-restrictive definition of BE. The density of goblet cells in any segment of CM is dependent on a variety of factors, such as patient age, length of the columnar-lined segment, and number or location in which biopsies are obtained [19-22]. The most endoscopists in routine practice do not take enough biopsies to screen adequately for IM so many patients are being incorrectly assigned to diagnosis “not BE” on the basis of a technically inadequate diagnostic process. The analysis of 1646 biopsies from 125 consecutive patients with suspected endoscopic CM showed that goblet cells were identified in 68% of patients when a mean of 8 biopsies were obtained but only in 34.7%, when a mean of 4 biopsies were evaluated . The goblet cell density is greater near the proximal neo-squamocolumnar compared to the distal area of CM . The findings that the nongoblet columnar epithelium possess “intestinal” features and exhibit molecular and genetic abnormalities similar to those seen in BE with IM are other data supporting the use of non-restrictive definition of BE [23, 24]. The immunohistochemical study of the expression of different markers of intestinal differentiation as DAS-1, villin, and CDX-2 showed reactivity in both types of metaplastic (goblet and nongoblet) epithelium . Abnormal DNA has been found recently to be present to similar degrees in esophageal CM of all types, making the malignant potential of “negative for IM-type” BE also probable . In confirmation of Montreal definition of BE are the data that dysplasia and cancer may arise in nongoblet CM [25, 26]. It was found that there is no statistical difference in the risk of dysplasia or EAC in patients either without (
All these data confirm that the more correct definition of BE is that of Montreal definition.
2.2. Diagnosis of BE
BE is diagnosed by both endoscopy and histology. On endoscopy, it is suspected by the presence of ‘‘tongues’’ as extensions of salmon-colored mucosa above the GEJ. According to Montreal classification endoscopically suspected esophageal metaplasia (ESEM) describes the endoscopic findings consistent with BE that await histological evaluation . The term BE should not be used before histological confirmation. Multiple, closely spaced biopsies are necessary to characterize ESEM. Standard protocol includes four quadrant biopsies performed at every 1 or 2 cm intervals from the proximal GEJ extending to the squamocolumnar junction. It was decided that all types of histologically proven oesophageal CM, including gastric or specialized IM should be included in the diagnosis of BE. The presence or absence of dysplasia should be evaluated. Morphologically, dysplasia is defined as “unequivocal neoplastic epithelium confined to the basement membrane, classified as LGD and HGD. Because of significant interobserver variations, the diagnosis of dysplasia should be confirmed by at least one additional pathologist, preferably one who is an expert in gastrointestinal (GI) pathology.
2.2.1. Endoscopy in BE
Endoscopy is the only practical option for the routine diagnosis and surveillance of esophageal CM. The first steps of endoscopic assessment are the recognition of BE and the grading of it’s extent. BE has been divided into long-segment (>3 cm), short-segment (1-3 cm), and ultra-short-segment (< 1cm) categories . The first systematic and standardized method for description of the extent of BE, which was carried out by the International Working Group for the Classification of Oesophagitis (IWGCO), resulted in the Prague C & M Criteria . They were developed on the base of interpretations of purpose-recorded and standardized endoscopic video recordings. The
The most misdiagnoses of BE are related with the endoscopic features in patients with a hiatus hernia. This is due to failure to spend enough time in observing the region of the diaphragmatic hiatus and the upper end of the gastric mucosal folds at a relatively low level of distension . Accurate location of the GEJ is of diagnostic importance, since mucosa of columnar appearance above this level has to be concluded to be metaplastic. The histological examination cannot reliably differentiate between metaplastic esophageal mucosa and the mucosa of the extreme upper stomach. Correct interpretation of biopsies around the GEJ depends on the accuracy of their location by endoscopy. Current guidelines recommend use of the Seattle protocol as the primary approach to assessment of the mucosa in BE with and without dysplasia [14, 15]. It was found that the protocol, with biopsies from all visible abnormalities and random four-quadrant biopsies every 1cm starting from the top of the gastric folds up to the GEJ, is superior to random biopsies or 2-cm biopsies in detecting early cancers arising in BE with HGD. In a study of 45 patients with BE with HGD, the 2-cm protocol (four-quadrant biopsies every 2 cm) missed 50% of cancers that were detected by a 1-cm protocol in Barrett's segments of 2 cm or more length without visible lesions . In last years, with the improvement of image resolution of endoscopes, there is convincing evidence that guided biopsy is more sensitive for detection of dysplasia and EAC than blind biopsies [31-33].
The significant increase in image resolution by high-resolution endoscopy and high definition monitors (HDTV) is the most important recent improvement in endoscopic imaging in general, and particularly with regard to detection of early neoplastic lesions .
These require updating to place greater emphasis on visually guided biopsy with a high-resolution endoscopic system . Given that general endoscopists are currently inadequately skilled and equipped for recognition of mucosal areas of concern, it is probably best that blind biopsies are also taken at least for the present . Many imaging modalities as chromoendoscopy/magnifying chromoendoscopy, narrow band imaging (NBI) with/without magnification, autofluorescence imaging (AFI), and confocal microendoscopy can improve identification of abnormal areas and their targeting biopsy, and finally increase identifying HGD and early neoplasia [32, 34, 35].
2.2.2. Histology in BE
The normal squamous epithelium in BE is replaced by a mixture of cell types resembling gastric and or intestinal mucosa. The cardiac type BE contains mucus-secreting columnar cells; the fundic type BE is characterized with the parietal cells and chief cells; and the specialized intestinal epithelium is indicated by the presence of goblet cells. Morphologically, goblet cells can be identified by their large, cytoplasmic vacuole filled with abundant mucin on routine hematoxylin-eosin stain. The so called ‘pseudogoblet cells” represent injured foveolar epithelial cells by concomitant GERD and resemble goblet cells with their abundant accumulation of cytoplasmic mucin . But compared with true goblet cells, the mucin in pseudogoblet cells is neutral and stains slightly eosinophilic on hematoxylin-eosin stain. The biopsies specimens may also show a multilayered epithelium, which is characterized basally located squamous epithelium overlaid by superficial columnar epithelium. It is thought that this epithelium represents an early stage in the development of esophageal CM . The cases with BE also exhibit stromal alterations as duplication and fragmentation of the muscularis mucosae (MM), increase in the number of blood vessels and lymphatics, and changes in the inflammatory cells [56, 57]. As already mentioned, the histological diagnosis of BE cannot be made when the exact site of biopsy is not known. Beside this, the IM of the distal esophagus and upper stomach are histologically indistinguishable. IM in a biopsy taken near the EGJ could be a part of a multifocal atrophic gastritis secondary to Helicobacter pylori. The etiology and significance of cardiac IM has become a topic of interest, because of rapidly rising incidence of gastric cardiac adenocarcinoma . One study showed that the dysplasia risk of BE patients is significantly greater than in IM from the cardia, indicating two potentially different clinical processes . Because of the difficulty in determining the precise site of a biopsy specimen in some cases and the inability to distinguish IM of the esophagus from gastric origin (cardiac IM) by routine methods, various immunohistochemical markers have been studied to be useful for this distinction. For example, cytokeratin (CK)7 and CK20 immunohistochemical staining has been used to differentiate IM of the esophagus versus gastric cardia . It was found that Barrett’s mucosa displays CK20 expression in the surface epithelium and superficial glands with no staining in the deep glands, but CK7 shows strong diffuse positivity in superficial and deep glands. On the other hand, gastric IM displays focal CK20 staining of both the superficial and deep glands, but only weak and variable CK7 labeling in the deep glands. Our results showed similar results . Unfortunately, other studies have been unable to show the reliability of CK7 and CK20 immunoreactivity in distinguishing short-segment BE from IM in gastric cardia and corpus [62-64].
Barrett’s dysplasia is recognized histologically and graded into LGD or HGD by a combination of architectural and cytologic abnormalities. When no features of dysplasia are found, the diagnosis is negative for dysplasia. When the findings are uncertain, the category indefinite for dysplasia is applied. The grading in BE dysplasia is analogous to that of dysplasia complicating inflammatory bowel disease .
In last years, with the wide use of ablative and nonablative endoscopic therapy for BE with and without dysplasia, the role of histology increased. Because of ablation, patients develop islands of re-epithelialized squamous mucosa as it is called “neosquamous epithelium” (NSE). The last may also develop in patients treated with high-dose proton pump inhibitors (PPIs), but without ablation [78, 79]. The findings of various studies strongly suggest that NSE has no malignant potential and represents a successful outcome of ablation [19, 80]. A problem with NSE is that a residual Barrett’s epithelium or dysplasia may persist underneath NSE, because they remain invisible on endoscopy. The prevalence rate of buried Barrett’s or buried dysplasia is variable and dependent on the type of ablative therapy. The buried dysplasia is difficult to interpret because the maturation to the mucosal surface cannot be evaluated in the presence of NSE. The biologic potential of buried BE is the subject of many investigations [19, 81, 82]. The available data suggest that residual buried dysplasia, continues to be at risk for malignant progression. In contrast to non-tissue acquiring ablative therapies, endoscopic mucosal resection (EMR) is a modality designed to remove mucosa and superficial submucosal tissue . In this way, it allows more accurate histologic evaluation and grading of dysplasia and determination of location and depth of invasion by adenocarcinoma when present. EMR is a valuable diagnostic tool which allows change of diagnosis of BE dysplasia when compared with mucosal biopsies. One study repoted that 37% of cases of BE with dysplasia showed a change of dysplasia grade in pre-EMR biopsies compared with EMR specimens. Of them, 21% of biopsies were with under-reported grade of neoplasia and 16% of biopsies were with over-reported grade . In another study it was found that 24% of cases with HGD in biopsy specimens showed an increase in grade to IMC, and 40% of patients with IMC had their stage increased to submucosal invasive carcinoma by evaluation of EMR specimens . There is also a greatly improved diagnostic agreement between pathologists when evaluating dysplasia in EMR specimens compared with biopsies . This results is related to the larger tissue sampling compared with biopsy specimens and the ability to evaluate mucosal landmarks, such as double muscularis mucosae. Evaluation of depth of invasion in EMR specimens is important because the rate of lymph node metastasis has been shown to correlate with depth of invasion [19, 70]. The evaluations of the presence or absence of lymphovascular invasion and the status of the lateral and deep tissue margins are also of prognostic significance [85-88]. In this aspect, the method of processing EMR specimens and their orientation is very important. In summary, the problems in the diagnosis of dysplasia included difficulties relating to sampling errors, the distinction of reactive changes versus dysplastic ones, differences in observer interprepation of the diagnosis of dysplasia and in the differentiation of HGD from invasive carcinoma. Requiring confirmation of a diagnosis by a second pathologist is important in taking the decision for management.
The utility of many immunohistochemical and molecular markers has been studied as adjunctive tool for the diagnosis of dysplasia and also for identifying the cases of risk for malignant progression. Unfortunately, only a few markers show such a potential, including studies of DNA ploidy by computerized morphometric analysis, the expression of proliferation antigen Ki-67 (MIB-1) and of tumor suppressor proteins p53 and p16. By flow cytometry, it was found that patients with diploid baseline biopsies showed a significantly lower rate of cancer progression compared with patients with either aneuploidy or an increased 4N fraction (tetraploidy) . Immunohistochemical staining for MIB-1 showed increased expression from normal squamous epithelium to CM to dysplasia and to invasive carcinoma [90, 91]. There are also alterations in the pattern of localization of staining. In NDBE the expression of MIB-1 is limited to the bases of the crypts, whereas in dysplasia it extends upward the mucosal surface. A recent study suggests that the combined use of MIB-1 and p53 staining reduces variations in the diagnosis of BE dysplasia . Immunostaining for p53 has been widely studied, but the results have been controversial [19, 91, 92]. The frequency of positive immunostaining for p53 has been shown to correlate with higher grades of dysplasia, and, in some cases, is associated with an increased risk of cancer. Allelic loss of p16 (p16 LOH), which results in block of cell cycle in the G1-S phase and provides survival advantage of the cells, is common in EAC and appears to be an early event in the BE-dysplasia-adenocarcinoma sequences [94, 95]. It is well-known that the carcinogenesis is a multi-step process that occurs as a result of alterations in many different genes. Because of that, it is clear that there is no single molecular marker that will allow with high sensitivity to predict the neoplastic risk in BE.
3. Screening for BE
The most appropriate method for both diagnosis and surveillance of BE is upper GI endoscopy. There are no concrete guidelines for selecting patients who should undergo screening for BE, and this decision is currently made case by case.
The cost-effectiveness of upper GI endoscopy in patients with reflux symptoms, most of whom will never develop cancer is discussed. Approximately 40% of adults in the US experience symptoms of heart burn at least once a month and about 20% report these symptoms once a week . So a large proportion of adult US population would be eligible for screening for BE based on this screening criteria. A study from Sweden estimated that BE was present in 1.6% of the general population . BE patients are usually white, middle-aged males, often overweight . The male-to-female ratio is 2:1 . According to a retrospective study of 2100 patients undergoing upper GI endoscopy, the prevalence is higher among Whites (6.1%) as compared with Hispanics (1.7%) and African Americans (1.6%) . The relationship between BE and gastroesophageal reflux symptoms is well known, but many patients with biopsy-proven BE do not report such symptoms. In one study, BE was identified in 50 of 300 consecutive patients (16.7%) undergoing screening or surveillance colonoscopies who also received upper GI endoscopy . Among them, 19.8% reported GERD symptoms, whereas 14.9% were asymptomatic and the symptom questionnaires were unable to predict the presence of BE. It has been shown that 40% of patients with EAC also do not report heartburn or regurgitation . By the other hand, even when BE is diagnosed, a vast majority of these patients will not develop EAC during their lifetime . Studies have shown that the overall mortality rate in patients with BE is closely similar to that of the general population and EAC mortality is an uncommon cause of death in these patients [103, 104]. The most patients with BE die due to causes other than EAC. From this point of view, the current position of the AGA is that inadequate evidence exists to endorse endoscopic screening for BE based solely on the presence of GERD symptoms . The decision regarding screening should be individualized after discussion about the benefits and limitations of screening with the patient. Other professional organizations also do not recommend routine screening for BE [13, 15, 105, 106]. The American Society of Gastrointestinal Endoscopy (ASGE) guidelines proposed that an initial screening endoscopy is appropriate in select patients with frequent, chronic, long-standing GERD (
According to the current data, there are no evidence that routine screening for BE will increase the rate of diagnosed cases of BE with or without dysplasia, or EAC.
4. Surveillance of patients with BE
Surveillance endoscopy is intended to detect neoplastic progression at an early stage and prevent cancer-related death. As pointed above, the histologic diagnosis and grading
The effectiveness of surveillance of patients with BE is also discussed. By one hand, it has been demonstrated that patients with surveillance-detected EAC are diagnosed at an earlier stage and have a better prognosis than those who present with symptomatic tumours [114, 115]. These data support the effectiveness of endoscopic biopsy surveillance for early detection of EAC. However, there are no prospective data showing survival advantage with surveillance. As noted above, the majority of patients diagnosed with EAC have not a prior diagnosis of BE. A study reported that only 3.9% of the patients had a BE diagnosed before their EAC . A review of reports on mortality in BE patients undergoing surveillance found that their risk of malignant progression is low and most of them die of other causes, especially cardiovascular, without development of HGD or EAC . This undermines the cost-effectiveness of BE surveillance and supports the search for valid risk stratification tools to identify the minority of patients that are likely to benefit from surveillance. The majority of patients with LGD regressed and had a cancer incidence similar to all BE patients . HGD is highly heterogeneous with regard to progression to EAC and rates of progression vary substantially in different studies. The reported 5-year cumulative incidences of EAC range from less than 10% to 59% [10, 89]. It may be concluded that even if current surveillance techniques are effective, they are unlikely to substantially impact the population's mortality from EAC and better methods are needed to identify at risk patients .
5. Therapy of BE
The management of patients with BE includes following major aims: treatment of the associated GERD, endoscopic surveillance to detect HGD or EAC, and treatment of dysplasia or IMC, as well as prevention of cancer.
5.1. Antireflux therapy
If one goal of this treatment is the control of GERD symptoms and heal esophagitis, anothers should be the regression of BE, and prevention of progression to EAC.
Several observational and prospective studies have assessed
Some studies suggest that acid reflux plays a key role in the
It has been discussed that
5.2. Chemoprevention therapy
Except of antireflux medication and surgery, non-steroid anti-inflammatory drugs (NSAIDs) and acetyl-salicylic acid (ASA) as well as other drugs have been evaluated to be able to prevent cancer development in BE patients. It is well known that chronic inflammation has been associated with neoplasia formation in many organs, as well as esophagus. Chronic inflammation is characterised by production of cyclooxygenase (COX) and prostaglandins. COX-2 enzyme participates in several important tissue processes, for example cell proliferation, migration, apoptosis and angiogenesis. Overexpression of COX-2 has been found in patients with reflux esophagitis, BE, dysplasia, and EAC. NSAIDs and ASA as inhibitors of COX-1 and COX-2 enzymes attenuate cell growth and proliferation, inhibits angiogenesis, and restores apoptosis . In addition to these findings, epidemiological studies suggest that ASA and other NSAID use may protect against cancers of several sites, especially colorectal cancer. Various studies suggest that NSAIDs and ASA use may reduce the risk of EAC but the other studies do not confirm these results [156-159]. Patients with exposure to NSAIDs or ASA had a 55% reduction of development of EAC [160-162]. A systematic review of 9 studies and meta-analysis assessed more than 1800 patients has been showed that NSAIDs or ASA had a 33% odds reduction of development of cancer . Any use of ASA or NSAIDs was associated with a 43% reduced risk of cancer. Frequent use of ASA or NSAIDs decreased cancer risk with 46%, but intermittent use was associated with 18% risk reduction. Both ASA and NSAIDs use was associated separately with reduced risk of cancer. The associations were seen for both EAC and squamous cell carcinoma. In a recent study from Netherlands, 570 BE patients were prospectively followed for a median of 4.5 years. Use of NSAIDs (median duration 2 months) was associated with 53% lower risk of progression to HGD/EAC . A cohort of 350 Barrett’s patients from 20770 persons was followed up (median 65.5 months) . The data showed that current NSAID and ASA users had 68% reduced risk of EAC, the past use decreased the risk with 30% compared with never-users of NSAIDs. The 5-year incidence of EAC was observed in 6.6% versus 14.3% in current versus never-users. It is discussed that NSAIDs and ASA may protect against EAC by reducing the risk of development of BE or by preventing progression from BE to EAC . In a retrospective study, NSAIDs use was not found to be higher in BE patients when compare to EAC. However, ASA and NSAID use was lower in both of these groups compared with controls . If there is a true protective effect of NSAIDs, this study suggests it may occur prior to the development of BE. A recent retrospective large population-based case-control study failed to find any benefit of aspirin use . This study collected information of intake for ASA and NSAIDs during the past 5 years and other exposures from 285 patients with NDBE, 108 patients with dysplastic BE, and two separate control groups, including 313 endoscopy patients with acute inflammatory changes ('inflammation controls') and 644 population controls. Use of ASA was not associated with NDBE when compared with population or inflammation controls, but significant risk reductions for users of NSAIDs were found when compared with population controls. No dose-response effects were observed. These data showed little consistent evidence of an inverse association between use of ASA or NSAIDs and risk of BE. Authors concluded that the question of whether or not these medications prevent the onset of BE remains open. PPIs are usual concomitant medication in NSAID or ASA users with GERD. From this point of view, one study evaluated patients who take prescripted NSAIDs/ASA as well as PPIs. A decreased risk of EAC was demonstrated . This protective effect may be due to the combination of each medication. On the other hand, the concomitant use of PPI in BE patients, should decrease the risk of serious GI complications associated with NSAIDs or ASA . COX-2 inhibitors may be of benefit because of more specific inhibition of COX-2 receptors and fewer side effects on GI tract. In a multicenter, randomized trial of celecoxib versus placebo in 222 patients with BE and LGD or HGD, at 48 week follow up, no significant difference was observed in dysplasia or cancer between the groups . Authors suggest that celecoxib does not prevents progression of BE, although further studies are needed. However the majority of these studies are associations and observations, because there are significant barriers in conducting a large clinical trial evaluating NSAIDs/ASA as potential chemoprotective agents . Current evidence shows that NSAIDs may reduce the risk of EAC. Despite of this, most experts agree it is not clear that potential benefit overweighs the GI risks of this group of medication. On the other hand, there is also evidence that cardiovascular deaths became more common than deaths from EAC among BE patients. Because of that it is appropriate to screen these patients for cardiovascular risk. In addition, the proportion of cases that take low dose aspirin or statins for cardiovascular risk factors or events will be increase in the near future.
Possible chemopreventive properties of
According to all current data, in the last version of AGA guidelines for the management of BE, AGA’s experts strongly recommend: 1) Elimination of esophageal acid exposure by PPIs more than once daily. Esophageal pH monitoring is needed to define PPI dosing. Antireflux surgery is also recommended as a method to control esophageal acid exposure; 2) Screening of BE patients to assess cardiovascular risk and prescribe an ASA therapy is indicated. On the other hand using ASA solely to prevent EAC in the absence of other cardiovascular indications is not recommended .
5.3. Endoscopic treatment of BE
In recent years, endoscopic techniques used to eradicate BE with presence or absence of dysplasia or IMC include endoscopic resection and/ or ablations. The most commonly used technologies currently are EMR and RFA, applied alone or in combination. Evidence for their efficacy has emerged rapidly over the past decade [151, 169-171). The goal of endoscopic eradication therapy (EET) for BE patients, especially those with HGD or IMC is to complitelly eliminate all dysplastic and non-dysplastic Barrett’s epithelium to get a complete reversion to normal squamous epithelium without islands of buried IM.
5.3.1. Non ablative modalities (endoscopic resection–EMR)
EMR has been provided both a diagnostic/ staging and therapeutic tool for Barrett’s neoplasia. At now, EMR should be performed in BE patients who have dysplasia as macroscopically visible mucosal irregularities to determine the T stage of the neoplasia (151, 169-175). A large number of different techniques with or without suction or submucosal injection that raise the lesions can be used. EMR can be performed by the lift and snare technique, cap-assisted endoscopic resection, multiband mucosectomy, and Euroligator technique [169, 170, 172-175]. Endoscopic submucosal dissection (ESD) is also used. No data confirmed that one of these endoscopic techniques has proven to be superior to another. In a prospective randomized trial, both “cap-and-snare” and “band-and-snare” technique can provide adequate depth and histological staging and have similar safety profies [176, 177]. Studies have demonstrated that EMR is safe and effective for the treatment of superficial lesions for successful eradication of BE with varied degree of dysplasia and IMC [169, 178, 179]. Five-year follow-up data for 231 BE patients with IMC demonstrated a 95.7% complete response rate . Focal EMR is associated with high recurrence rate up to 47%, and increased with longer observation times, may be due to multifocal synchronous lesions previously missed by biopsy, as well as the metachronous development of new lesions [169-172, 181-184]. Recent data suggests that the presence of submucosal invasion of occult adenocarcinoma in the setting of HGD was 6.7% - 12%, which was much lower than previously reported [171, 185]. One small, prospective study demonstrated an eradication rate of focal HGD or IMC more than 90% for small (< 2 cm) or low-risk lesions at a mean of 12 months follow-up . On the opposite, a remission rate of only 59% and recurrence rates of 11% to 14% were observed for larger lesions (> 2 cm). Therefore, EMR has been accepted method for BE with small and/or raised lesions of HGD or IMC . Independently of endoscopic techniques, the most common complications of EMR are bleeding and esophageal stricture formation, but most of them can be treated successfully by endoscopy [186-199]. Perforation has been reported in 1–2.6% of the patients, but seems to decrease with more experience. Despite known efficacy and a relatively good safety profile for small segments of neoplasia and raised lesions, the potential role of EMR in longer segments of BE remains limited because of several factors: piecemeal resections are needed a long time to complete; repeat sessions are often necessary; the risk of possible bleeding and perforation can be increased. EMR for long-segment BE appears to be associated with a relatively high stricture rates of 26% to 37% [196, 198].
Regarding all current data, EMR remains one of the preferred first-line endoscopic treatment for selected patients with early HGD and/or IMC because of its diagnostic/staging value and its established therapeutic role.EMR is characterized with high eradication rate of Barrett’s dysplasia, but also with high rate of complications and recurrence. Because of that additional ablation is used to reach complite eliminate all dysplastic and non-dysplastic Barrett’s epithelium, as well as complete reversion to normal squamous epithelium.
5.3.2. Endoscopic ablative therapies
Endoscopic ablative modalities used to eradicate BE include thermal energy application, argon plasma coagulation (APC), photodynamic therapy (PDT), radiofrequency ablation (RFA), and cryotherapy. In these modalities ablated epithelium is replaced by a neosquamous epithelium. Ablative therapies have an increasing role in the management of BE. In general, they are well tolerated. There are two major limitations related to ablative methods. First there is no possibility for histologic examination. The second problem is associated with the squamous overgrowth and risk of development of EAC beneath regenerated squamous epithelium after ablation, which may be due on the progression of buried Barrett's metaplasia or dysplasia . Most of thermal energy application methods, as well as APC are unsuitable to treat BE with HGD or IMC alone. Despite that, they can be useful as an adjunct to EMR in the treatment of selected BE patients. Our data on 50 BE patients with LGD, treated by APC plus PPIs showed that de novo Barrett’s metaplasia was observed in 23 patients, with islands of LGD in 12 cases at 10 years follow up. All of them were treated successfully by new endoscopy. No progression to HGD or EAC was found [210, 211]. No serious adverse events or strictures were observed.
For a long time of period
Several smaller trials have shown the possibility of combination of EMR of visible lesions with subsequent RFA for the treatment patients with dysplastic BE or EAC. The results of these studies showed that eradication rate of IM, any dysplasia, including also HGD was in 46%-100%, and 71%-100% respectively. [230, 232, 234-240]. In one study 44 patients with LGD, HGD, or IMC treated with RFA (31 patients had prior EMR for visible lesions before RFA) were evaluated . Complete eradication of all dysplasia and IM was achieved in 98%. Post-ablation complications (all with prior EMR) included mucosal laceration and transient dysphagia (
RFA is characterized with very good control of the depth of ablative penetration . Because of that many side effects are reduced. Now, RFA is seem to be the most efficacious modality to treats any stage of BE with a better safety profile than other ablation techniques (PDT) and EMR. RFA is also safely when combined with EMR for visible lesions. This combined endoscopic method is quickly integrated in routine clinical practice. RFA therapy for patients with NDBE and LGD seems to be capable to reverse to normal squamous epithelium for a long time (5 year) after procedure. In addition, RFA treatment reduces progression to EAC in patients with HGD. Because of that RFA has became one of the preferable method for the EET of BE with HGD and/or IMC.
In summary, cryotherapy has become now as a potential alternative to the other endoscopic ablative modalities. According to present data, cryotherapy appears to be safe, well tolerated, and capable to ablate IM, dysplasia and early EAC. On the other hand, there is no evidence that cryotherapy leads to sustained reversion to normal squamous epithelium.The efficacy of this ablation method is lower when compared with RFA or PDT. There are no randomized trials comparing CSA with other endoscopic or nonendoscopic modalities. Further studies are needed also to assess long-term efficacy of cryotherapy, as well as its real clinical significance.
Two recent studies evaluated the cost-effectiveness of ablative therapy for BE [249, 250].One of them reported endoscopic ablation with continued surveillance is significantly more cost-effective than surveillance only . A separate cost-effective analysis concluded that endoscopic ablation could be the preferred strategy for management of BE with HGD . If ablation permanently eradicates ≥ 28% of LGD or 40% of NDBE, endoscopic ablation would be preferred to surveillance alone.
5.4. Surgical treatment
Until the past decade, esophagectomy for BE with HGD and IMC had been the traditional standard, because of the high rate of suspected risk of occult invasive carcinoma or recurrence [132, 184, 185, 251-253]. Surgery ensures accurate staging and adequate therapy including negative margins and lymph nodes extraction. Complete resection of the entire Barrett’s segment is done in cases of unsuspected multifocal disease and to minimize the risk of metachronous lesion development in residual Barrett’s . Some studies reported significant morbidity and mortality associated with esophagectomy, with overall morbidity rates as high as 50% and mortality as high as 10% . The immediate postoperative complications include pulmonary events, hemorrhage, anastomotic leak, infections, postoperative arrythmias and heart failure, and nerve palsy [132, 224]. The long-term complications are dysphagia, weight loss, GERD, esophageal strictures, cough and dumping which may impair health-related quality of life . Reported mortality rates for esophagectomy usually were based on outcomes after surgery for cancer and not HGD. It is well known that patients with cancers are older, more morbid, and have more comorbidities than patients with HGD alone . On the other hands the results from high-volume centers with greater surgical expertise have shown better outcomes . The mortality rate from esophagectomy for cancer of 2%–3% was reported [258, 259]. In a Dutch study, based on the number of esophagectomies a year, hospitals were classified as low-volume centers (<10 resections a year), medium-volume centers (11–20 resections a year) and high-volume centers (>50 resections a year). Hospital mortality at these centers was 12.1%, 7.5% and 4.9%, respectively . In another study a mortality rate of 1% after esophagectomy for HGD was found. Others data also confirmed that surgical resection of patients with HGD is associated with operative mortality of 0-2% and overall 5-year survival of 83%-88% (91% for HGD without invasion and 68% for those with invasion), and 10-year survival of 86% [261-264]. This result showed that regarding HGD and surgical experience, esophagectomy is a lower-risk surgery . Recurrence rates of BE or EAC after esophagectomy have been assessed in a limited number of trials. In one study on BE patients with HGD or EAC, the 2-year surveillance of 85% was reported . The cure rate for dysplasia or localized EAC was reported to be lower that 78% in another study . These data raise questions about the need for continued endoscopic surveillance following surgical resection. Conventional approaches for esophagectomy are transhiatal and transthoracic resection. A randomized trial comparing of patients undergoing transhiatal esophagectomy (n=106) or transthoracic esophagectomy with lymphadenectomy (n=114) demonstrated a significantly lower rate of postoperative respiratory complications with the transhiatal approach (27% versus 57%), but greater survival was shown for the transthoracic approach at 5 years (39% versus 27%) . One potential limitation of the transhiatal approach is the inability to retrieve lymph nodes required for nodal staging . Minimally invasive esophagectomy avoids the thoracotomy and laparotomy has potential advantages over open esophagectomy because of a lower incidence of pulmonary complications, faster postoperative recovery, and decreased length of hospital stay [268, 269]. However, lymph node retrieval is largely inferior to the standards of open surgery. The morbidity and mortality of minimally invasive esophagectomy is not proven to be lower when compared with open esophagectomy at experienced centers . Recommendations favoring minimally invasive esophagectomy over open esophagectomy cannot be made due to a lack of randomized trials comparing the two approaches. In patients with few comorbidities and an otherwise long life expectancy, a vagal-sparing esophagectomy can be considered to improve outcomes and quality of life. It was demonstrated lower infectious, respiratory, and anastomotic complications in patients with HGD or IMC undergoing this procedure compared with transhiatal esophagectomy. Quality of life advantages were also demonstrated because of the reduction of postvagotomy dumping and diarrhea, as well as a shorter hospital stay . However, lymphadenectomy is not performed with this procedure. Regarding early cancer (IMC), esophagectomy with therapeutic lymphadenectomy is today reserved for more selected cases with evidence of submucosal invasion, lymph node metastasis, or unsuccessful endoscopic therapy, National Comprehensive Cancer Network (NCCN) recommended all modalities –EMR or ablation or esophagectomy , but European Society for Medical Oncology (ESMO)  pointed that surgery is the treatment of choice in early cancer. On the contrary, esophagectomy can be discussed in patients with high-risk features of HGD or IMC . A patient’s age, comorbidities, and willingness to undergo surgery should also be taken into account. According to the current AGA’s guidelines for BE management ”Esophagectomy in patients with HGD is an alternative; however, current evidence suggests that there is less morbidity with ablative therapy” The experts also enhance that patients with HGD or IMC “should be referred for evaluation by surgical centers that specialize in the treatment of foregut cancers and HGD” .
There are no prospective head-to-head randomized trials to compare EET versus surgery. However, when compared with esophagectomy, EET is less invasive, associated with low morbidity and mortality, and is more cost-effective in treating all types of BE. The reported outcomes of EET are superior to those of esophagectomy. Endoscopic procedures related mortality versus death from postoperative complications was 0% v/s 2.1% and the percent of patients free of carcinoma after EET v/s free of carcinoma after esophagectomy was 88% v/s 86% [191, 275]. Recurrence rates of EAC after EET were 12% and all were cured by further endoscopic therapy. In a long-term follow-up of 132 patients treated with EMR and 46 who underwent surgery, there was no difference in the 5-year survival rate between the surgically or endoscopically treated groups .
Now, EET with EMR, RFA or PDT is became a first chois of treatment for BE patients with confirmed HGD [151,169-172]. The key point to successful EET is appropriate selection of each patients. EET is also associated with complete reversion to normal squamous epithelium in NDBE or LGD. Despite that, there is no evidence EET is more cost-effective to reduce cancer risk than long-term endoscopic surveillance [14, 151, 234]. Regardless EET can be used for select BE patients with LGD who have high risk for progression to HGD and EAC .
All types of histologically proven esophageal columnar metaplasia, including gastric or specialized intestinal metaplasia should be included in the diagnosis of BE. But various definitions of BE still exist. Diagnosis and grading of dysplasia rely on careful endoscopic and histological examinations in a Barrett’s segment, cofirmed by expert. There is different management strategy in BE with or without LGD and HGD because of the different prognostic profiles between them. There are no evidence regarding outcome of endoscopic surveillance but all professional organizations recommend this approach for all types of BE. When BE without evidence of dysplasia or cancer is found on biopsy, the management focuses on reflux control and risk of cancer development (periodic endoscopic surveillance, PPIs or fundoplication, and ASA for cardiovascular risk/disease). Patients with LGD might be managed similar to NDBE. Antireflux therapy (medical or surgical) and endoscopic surveillance to exclude HGD missed on prior biopsy or progression to EAC are recommended. There is a greater discrepancy regarding the management of BE with HGD. The options for management of these patients include intensive surveillance until EAC, EET with EMR, RFA, or PDT, and surgery. The EET and surveillance are both equal recommended as a first choice of treatment for patients with confirmed HGD on BE. An individualized approach based on risk startification and patient preference is also recommended, especially for LGD or HGD.