Barrett’s esophagus (BE) is a precancerous state with a field defect, and is the first step in the metaplasia-dysplasia-cancer sequence, in which molecular aberrations precede neoplasia; Radiofrequency ablation (RFA) can eliminate such mutations. A wait and watch policy might be inadequate to reliably detect early changes. Here we discuss BE risk factors, diagnosis and management, and present an update on the use of RFA in the management of BE.
Amaninder S. Dhaliwal, MBBS, Resident in Internal Medicine, Department of Medicine, NYU School of Medicine/Brooklyn Campus, NY, Benjamin Tharian, MD, MRCP (Med, Gastro), FRACP, Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, Mohit Girotra, MD, FACP, Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR
AcknowledgementsThe authors are grateful to Dr. Lauren G. Khanna (Assistant Professor, Division of Gastroenterology, NYU Langone Medical Center, New York) and Dr. Farshad Aduli (Former Associate Professor, University of Arkansas for Medical Sciences, Little Rock, AR) for allowing us to utilize Barrett’s and RFA pictures from their patients. We also thank Mr. Jared Pittman from Medtronic, for providing us the consolidated image of all available RFA catheters.
BACKGROUND
Barrett’s esophagus (BE), first described in 1950 by Dr. Norman Barrett, a British thoracic surgeon, refers to replacement of normal squamous epithelium of the esophagus by columnar epithelium, at least 1cm above the gastro-esophageal junction (GEJ).1 It is considered a precursor lesion of esophageal adenocarcinoma (EAC). The incidence of BE is increasing in the western world has paralleled the increase in endoscopic procedures worldwide. The risk of EAC in patients with BE, which was earlier projected to be significantly higher, is now estimated at least 10 fold higher when compared to the general population.2 The reason for this decline in risk as compared to the previous studies may be due to the earlier recognition of dysplastic changes and improved endoscopic ablative therapies.3 In the United States, the overall mortality with EAC is high, and 5-year survival rate is under 20% per SEER cancer statistics review (1975-2011). Since transformation of BE into EAC involves progression of dysplasia, surveillance is important at an early stage, for the reduction in the overall mortality in EAC.3
Risk Factors for BE
Gastro-esophageal reflux disease (GERD) is considered an independent risk factor for BE and has been on a rise in the western world with a prevalence of 10-20%.5 About 15% patients with chronic GERD can develop BE, as compared to 1-2% of general population.6 Males are more predisposed to develop BE/EAC than females with ratio of 2:1. Caucasian males over the age of 60 years with chronic GERD symptoms are at higher risk for developing BE/EAC than males under the age of 50 years or women.7
While cigarette smoking is strongly associated with both BE and GERD,8,9 the relationship of alcohol consumption and BE is conflicting.10 Classically, alcohol has been considered as a risk factor, especially in combination with smoking. A recent study proposed that wine consumption was associated with reduced risk of BE, although no consistent dose-response relationship could be established for this protective effect.10 Central obesity is another significant risk factor for BE, independent of overall body fat (measured by body mass index, BMI), in both men and women.11 Metabolic syndrome, obstructive sleep apnea, and some germ-line mutations have also been implicated as additional risk factors for BE.
Diagnosis of BE
BE is traditionally classified based on endoscopic length of salmon colored mucosa, as long segment (LSBE > 3cm) or short segment (SSBE < 3 cm).12 However, diagnosis of BE needs histological correlation in addition to endoscopic appearance, which takes into account replacement of esophageal squamous epithelium by columnar epithelium (CE) along with presence of goblet cells, a marker of intestinal metaplasia (IM).15,16 The significance of these two histological features can be appraised by considering the debate around insufficient diagnosis of BE in presence of CE in distal esophagus (1cm above GEJ) but without IM.13 Moreover, epidemiological evidence suggests that patients with CE without IM are at low risk of developing EAC as compared to patients with CE and IM (0.07% vs 0.38%.14 Hence, the current American College of Gastroenterology (ACG) clinical guideline recommends obtaining at least 8 biopsies in patients with suspected BE < 2cm and four quadrant 2-cm biopsies in segments > 2cm, whereas it recommends against endoscopic biopsy of normal or irregular Z-line of less than 1 cm from GEJ.15,18
In cases of suspected BE, documentation of endoscopic landmarks (GEJ, diaphragmatic hiatus: DH) along with measurement of maximal (M) and circumferential (C) length of visible segment of BE should be mandatorily performed using the Prague classification (Figure 1). Sharma et al. have demonstrated that reliability coefficient (RC) for endoscopic landmarks (GEJ: RC 0.88; DH: RC 0.85) and of BE segment >1 cm (RC 0.72) is high when Prague classification is used.17
Screening Methods for BE
Currently, screening for BE is limited to patients with recognized high-risk factors like chronic GERD, caucasian race, male gender, age > 60 years, smoking, central obesity and confirmed family history of BE, but not extended to the general population. While this can be achieved using various techniques like conventional endoscopy (CEGD), unsedated transnasal endoscopy (TNE), esophageal video capsule endoscopy (VCE) and cytosponge, CEGD remains the gold standard because of its ability to achieve histological correlation. While limited evidence may support TNE for its comparable efficacy to CEGD (sensitivity and specificity 91% and 100% respectively) for diagnosing BE, especially given its ease of performance with minimal complications,19 it still needs multi-centric validation. VCE appeals as a non-invasive screening method, but should be reserved for patients who refuse CEGD, given its lower sensitivity and specificity (78% and 73% respectively), no cost advantage and inability of histological sampling.20 Contrarily, cytosponge is an emerging non-invasive yet cost effective screening tool, which if followed by dysplasia and intra-mucosal cancer treatment, may reduce the incidence of symptomatic EAC in high-risk patients by 19%.21
High-definition white light endoscopy (HD-WLE) is superior for both screening and surveillance of BE, over standard-definition endoscopy, for detecting dysplastic lesions.22 Since standard protocol biopsies have high miss rate of dysplasia, advance imaging, including chromoendoscopy, narrow band imaging (NBI) and confocal laser endomicroscopy (CLE), are increasingly being employed to further increase the rate of detection of dysplastic lesions as well as EAC. Chromoendoscopy utilizes a special dye (methylene blue, acetic acid or indigo carmine) to enhance the dysplastic lesions, which helps in better visualization during the endoscopy. NBI also referred to as virtual chromoendoscopy, works on the same principle as above, except that it utilizes narrow band filters instead of spraying dyes.23 Sharma et al. compared NBI to HD-WLE using Seattle protocol and found that fewer biopsies were required using NBI when compared to HD-WLE, with similar overall IM detection rates.24 Although NBI is considered superior to HD-WLE, it’s yield of detecting early neoplasia is controversial, but is still being suggested as the diagnostic modality of choice for surveillance in BE.23 CLE magnifies the mucosal patterns of dysplastic lesions by thousand folds enabling to visualize them to the cellular level.25 However, its use is limited as evidence from the prospective studies suggests that CLE does not help in increasing the overall detection rates of IM.25 Increased time to examine during endoscopy is associated with higher detection rates of dysplasia and EAC.26
Management of BE
The strong argument for endoscopic eradication of BE rather than a permissive surveillance approach arises from several facts, as elucidated. BE is a precancerous state with a “field defect”, and is the first step in the “metaplasia-dysplasia-cancer” sequence, in which molecular aberrations precede neoplasia and radiofrequency ablation (RFA) can eliminate such mutations.27,28 Furthermore, a multicenter study found that over 50% of those who developed high- grade dysplasia (HGD) or cancer while undergoing surveillance did not have prior findings of dysplasia, suggesting that the “wait and watch” policy might be inadequate to reliably detect early changes.29,30
The incidence of EAC in the general population (0.003%) goes up by 200 (0.6%), 560 (1.7%) and 2,200 (6.6%) folds once an individual develops BE, low-grade dysplasia (LGD) and HGD respectively,31 per SEER cancer statistics review (1975-2011). This is in sharp contrast to the incidence of colon cancer (0.048%), which increases 12 folds (0.58%) with development of a polyp.32 Like colonic polyps are actively managed with polypectomy followed by surveillance, experts endorse similar philosophy in BE management, to steer the paradigm from surveillance only to dysplasia treatment followed by surveillance.33 It is noteworthy that less than 50% endoscopists adhere to the Seattle Protocol for BE biopsies. Even if adherence is sustained, it still leaves behind a large unsampled segment of esophagus. Lastly, there still remains a high interobserver variation between pathologists, especially in the diagnosis of indefinite or indeterminate dysplasia (ID) and low-grade dysplasia (LGD). All these facts must be deliberated to maintain a perspective during management of BE.
The treatment modalities for BE can be categorized as endoscopic, surgical and chemoprophylaxis.
Endoscopic Management
Per Seattle protocol, targeted biopsies of suspicious dysplastic lesions should be performed along with random 4-quadrant biopsies every 1 cm versus every 2 cm in patients with and without prior history of dysplasia respectively.34 (Figure 2). Subsequent management depends on whether the BE is smooth or nodular. Most of the ablation treatments like RFA and cryotherapy are effective only on a smooth non-nodular esophagus. Hence any nodularity or mucosal / vascular abnormality visualized on endoscopy should be managed by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for histopathological staging of the lesion (Figure 3). A study on 293 consecutive endoscopic resections demonstrated that use of EMR alone changed the diagnosis and treatment policy in 49% and 30% of the lesions respectively.35 The subsequent management after EMR depends upon the histological staging of the endoscopic resections.
Patients with non-dysplastic BE (NDBE) should be engaged in endoscopic surveillance every 3-5 years and do not need endoscopic ablative techniques (EAT), given the low incidence of dysplasia and EAC in this population. Recent data estimates that 98.6% and 97.1% NDBE patients remain cancer free after 5-year and 10-year follow-up respectively.36 On the other hand, presence of indefinite/indeterminate dysplasia (ID) is a trickier situation, and such patients should undergo repeat endoscopic evaluation after aggressive PPI treatment in 3-6 months. It is now proposed that patients with ID may carry a significant risk of harboring prevalent dysplasia, although the risk of incident dysplasia is similar to the general BE population.37 Hence, ACG guideline suggests surveillance for these patients like those with LGD, especially because the risk of progression to cancer or dysplasia (LGD/HGD) is highest during the first year. Skacel et al. showed that LGD progressed to HGD over a median of 11 months, in 41% and 80% respectively, depending on whether two or three independent pathologists concurred with the initial diagnosis of LGD.38
The confirmed cases of BE with LGD (BE-LGD) should be reviewed by a second pathologist for adequate staging of dysplasia and risk stratification39 followed by aggressive acid suppression aimed at downgrading the dysplasia. If dysplasia resolves, these patients can be surveyed annually for 2 years after which this interval may be increased. If LGD persists, the current ACG guideline endorses endoscopic treatment, although acknowledges yearly endoscopic surveillance as an acceptable alternative. However, there is emerging data favoring endoscopic therapy over surveillance by demonstrating decreased risk of neoplastic progression after 3 years.40 Similarly, patients with HGD require histological confirmation by a second expert pathologist, concomitant acid suppression, but are candidates for endoscopic interventions. Currently, EAT is preferred over esophagectomy as the treatment choice for patients with BE-HGD for its proven efficacy, cost effectiveness and better adverse event profile.41
EAC is staged depending upon the depth of invasion as T1a (limited to mucosa), T1b sm1 (extension into upper one-third of submucosa), T1b sm2 (extension into middle one-third of submucosa) and T1b sm3 (extension into deep one-third of submucosa). The risk of lymph node (LN) metastases in patients with BE-HGD and IMC is estimated at 0% and <2% respectively,42 hence EAT makes sense as the preferred treatment strategy. However, situation gets murkier with EAC. Surgical literature estimates up to 7% and 27% LN metastases risk in patients with EAC T1a and T1b respectively43, therefore making this distinction of paramount importance. However, data on accuracy of EUS for staging of superficial esophageal cancers (T1a, T1b sm1) is limited, and hence EMR remains the gold standard.44-46
EAT remains the treatment of choice for BE patients with dysplasia, T1a EAC and well-differentiated T1b sm1 EAC with no lympho-vascular spread.47 The various EAT include radiofrequency ablation (RFA), photodynamic therapy (PDT) and cryotherapy. For limited surface areas, argon plasma coagulation and bipolar probes are a less expensive alternative, although they may have higher recurrence rates, and hence rarely preferred. RFA is the preferred modality for most patients as it is cost effective and has better adverse event profile than PDT or cryotherapy, and would be the main focus of discussion in this article.
Surgical Management
Endoscopic therapy for HGD/IMC has similar survival (94% at 3 years both groups) but lower morbidity (0% vs. 39%; P<0.0001) compared to esophagectomy.48 Esophagectomy in combination with chemo-radiation is the treatment of choice for patients with advanced EAC (T1b sm2-3) or high-risk superficial EAC (poor differentiation or lymphovascular invasion).49 While robust acid suppression is an accepted strategy to decrease neoplastic progression of BE, anti-reflux surgeries have no proven efficacy and hence not recommended.50 The SAGES guideline also endorses endoscopic treatment modalities.51 Reflux surgery should be considered in individuals with objective evidence of reflux that fails to respond to PPI, especially those with hiatus hernia, before, during or after ablation treatment.
Chemoprophylaxis
In addition to symptomatic control of GERD, PPIs also serve an additional role as chemoprophylactic agents, given their effect on decrease dysplasia/EAC in patients with BE.52 Additionally, data exists describing beneficial effects of NSAID’S, aspirin and statins in reducing incidence of EAC in BE patients, but none are currently endorsed exclusively for their anti-neoplastic effects.53-54
An Update on Radiofrequency Ablation (RFA)
a. Types of RFA catheters and Biophysiology
RFA combined with EMR has become the standard treatment for BE because of increased efficacy, cost effectiveness and better side effect profile. The biophysical principle of RFA ablation therapy is using electricity in the radiofrequency range of 450- 500 kHz for small vessel and tissue destruction.55 Barrett’s epithelium is approximately 500 µm thick, and RFA is designed to achieve a uniform, superficial depth of ablation between ∼ 500 µm and ∼ 1,000 µm in short bursts of ∼ 1 sec, thus achieving optimal removal of esophageal epithelium with minimal risk for complications like buried glands or stricture formation. The ablative energy ranges between 12J/ cm2 to 15J/cm2; the use of N-acetyl cysteine sprayed over esophageal mucosa is encouraged for effective contact between RFA catheter and the mucosa.56 There are different RFA catheters available for circumferential and focal therapies, as depicted in Figure 4. (BarrxTM ablation system, Covidien-Medtronic, Sunnyvale, CA). The Barrx360 3cm catheter is used for ablation of circumferential dysplastic mucosa, whereas Barrx90 focal/ultra-long, Barrx60 and channel catheters are employed for focal ablation of small isolated areas/ islands of dysplasia and possibly for short segment BE. Smaller and channel catheters have added advantage of being useful in patients with difficult anatomy and strictures.57
b. Efficacy and Safety of RFA
In a sham-controlled trial performed on patients with dysplastic BE, RFA was associated with a high rate of complete eradication of both dysplasia (CED = 90.5% vs. 22.7%; p<0.001) and intestinal metaplasia (CEIM = 77.4% vs. 2.3%; p<0.001) and a reduced risk of disease progression (3.6% versus 16.3%; p=0.03).58 at 12 months. A subsequent multi-centric study reported eradication of dysplasia and CEIM in 98% and 91% patients respectively, thus establishing durability of this therapy.59 In addition to the proven role of RFA in BE with dysplasia, its utility in patients with NDBE is often discussed. In a multi-centric trial from 8 centers in the US, Fleischer et al. reported 98% complete eradication of intestinal metaplasia (CEIM) in NDBE patients with ablative therapies over 2.5 years follow-up.60 The same authors later obtained biopsies from previous known length of BE at 5 years to demonstrate 92% (46/50) CEIM and the remaining 8% had easy conversion to CEIM with single session of focal RFA.61 Although RFA is efficacious and durable in NDBE patients, however, given the low risk of its progression to cancer, the current ACG guideline recommends against routine application of endoscopic therapies in these patients.
Although these studies established RFA as the cornerstone treatment for dysplastic BE, our understanding regarding indications is still evolving and we are constantly striving to improve in this area. The major RFA studies have been tabulated in Table 1. We also know that RFA is associated with improved quality of life (QoL) in dysplastic BE. Ablation alters the natural history of BE.62 Wani et al. in their meta analysis showed that the progression risk to cancer went down to 0.16%, 0.16% and 1.7% for NDBE, LGD and HGD respectively with ablation, with the number needed to treat (to avoid one cancer over 5 years) being 45, 13 and 4 respectively.31 Das et al. concluded from his economic analysis study that radiofrequency ablation was more cost-effective than surveillance even for non- dysplastic BE.63
c. Efficacy of RFA+EMR over RFA
In patients with dysplastic BE (both HGD and LGD), EMR+RFA is superior to RFA alone, based on higher efficacy (18% vs. 10%).64 Also, EMR prior to RFA was found to be as safe in patients with BE/EAC as was RFA alone with no higher stricture formation rates.65 Furthermore, a comparison of outcomes in BE patients between 2011-2013 and 2008-2010 from the UK demonstrated significantly higher CEIM (83% vs. 56%) and CED (92% vs. 77%) in recent time period, most of which was attributable to improved lesion recognition and aggressive resection of visible lesions prior to RFA (with EMR), though progression to EAC was not statistically different (2.1% vs 3.4%)66. Most importantly, EMR provides the most accurate staging, and helps plan further management of patients with BE/EAC.
Extensive EMR alone may be an alternative strategy for management of dysplastic BE. However, a multicenter trial established that in patients with ≤ 5cm segment BE/HGD, stepwise radical EMR (SEMR) and RFA+EMR achieved high rates of CED (100% vs. 96%), but SEMR group had more stenosis (88% vs. 14%; p<0.001) requiring subsequent endoscopic treatments.67
Hence, EMR+RFA is now recognized to be efficacious, safe and superior to RFA or EMR alone, in management of dysplastic BE.
d. Association of Acid Control and RFA Outcomes
Concurrent anti-reflux therapy is an important concept in patients with BE, especially in those who undergo therapy. A retrospective study of RFA outcomes in patients with BE suggested better CEIM rates in BE patients with normal-mild esophageal acid exposure as compared to patients with moderate-severe acid exposure (44% vs. 15%),68 thus endorsing effective intra- esophageal pH control for improved RFA outcomes.68,69 Moreover, inadequate control of reflux post ablation may result in recurrence.69,70 The ACG endorses use of PPI in daily doses in BE patients, unless warranted in twice-daily doses because of reflux symptoms or esophagitis.15 Although not a recommendation, most experts use PPI in twice daily dose after RFA to minimize complications, especially stricture formation.
e. Recurrence of IM after RFA
In a recent retrospective cohort of patients with BE and dysplasia/IMC who achieved CEIM, the post-RFA recurrence rates for IM and EAC progression were ascertained to be 5.2%/year and 1.9%/year respectively.71 Subsequently using the much larger US RFA registry, it was demonstrated that after CEIM, BE recurrence may occur in upto 20% patients, and is usually very short (0.6 cm average length) and non-dysplastic/indefinite for dysplasia in 86%.72 The study identified older age, non-Caucasian race, increasing length of BE length and advanced pre-treatment histology as risk factors for recurrence, and these are now taken into account while planning post-RFA surveillance intervals.73 Subsequent studies revealed area around GEJ as most vulnerable for IM recurrence.74
Since no specific characteristics are currently established which accurately predict recurrence, it is important for subjects undergoing RFA for dysplastic BE to be retained in endoscopic surveillance programs. Modalities like laser assisted Optical coherence tomography (OCT) and Confocal laser endomicroscopy (CLE) have been used to assist the endoscopist in the post RFA surveillance phase to pick up “buried glands” and early recurrence, and to target treatment.
CONCLUSIONS
In summary, while cryotherapy and PDT are available alternatives, RFA in conjunction with EMR is the most robustly studied and practiced endoscopic technique for management of dysplastic BE, with high success, cost effectiveness and very few limitations. The modality and equipment are a work-in-evolution, and have plenty of areas requiring continued research. However, the bottom line remains that endoscopists should carefully inspect the Barrett’s mucosa, both pre and post ablation as part of surveillance. We endorse that the modality of choice for endoscopic eradication of Barrett’s esophagus must be in accordance with endoscopist’s training and preference, institutional availability and patient characteristics.