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doi:10.1111/jgh.12696

GASTROENTEROLOGY

Risk for esophageal neoplasia in Barrett’s esophagus patients with mucosal changes indefinite for dysplasia Bela Horvath,* Prabhdeep Singh,† Hao Xie,* Prashanthi N Thota,† Daniela S Allende,* Rish K Pai,* Deepa T Patil,* Thomas P Plesec,* John R Goldblum* and Xiuli Liu* *Department of Anatomic Pathology, and †Department of Gastroenterology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA

Key words Barrett’s esophagus, dysplasia, esophageal adenocarcinoma. Accepted for publication 21 June 2014. Correspondence Dr Xiuli Liu, Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Avenue/L25, Cleveland, OH 44195, USA. Email: [email protected] Potential conflicts of interest: None.

Abstract Background and Aim: Patients with Barrett’s esophagus (BE) are at increased risk for esophageal adenocarcinoma (EAC) and therefore require surveillance. Biopsies are classified as indefinite for dysplasia (IND) when the significance of epithelial abnormalities is uncertain due to inflammation or sampling. Our aim was to characterize the neoplastic risk of IND in BE patients and to identify predictors of neoplastic risk. Methods: Our pathology database from 1992 to 2007 was searched for BE and IND. Progression rates were calculated and univariate analysis was performed to identify predictors for neoplasia progression in BE-IND patients. Results: Among 85 patients who had a follow-up (FU) biopsy within 1 year, 11 (12.9%) patients had prevalent neoplasia (seven low-grade dysplasia [LGD], two high-grade dysplasia [HGD], and two EAC). Among 82 patients who did not have prevalent neoplasia but had ≥ 1 year FU, 17 progressed to dysplasia (14 LGD, 3 HGD) and 2 developed EAC during a mean FU period of 59 months. The incidence of neoplasia (LGD, HGD, or EAC) and advanced neoplasia (HGD + EAC) was 4.5 and 1.2 cases per 100 patient-years, respectively. Longer length of BE and multi-focal IND on index biopsy were associated with progression to neoplasia. Conclusion: Patients with BE-IND carry a significant risk of harboring prevalent dysplasia, but the risk of incident dysplasia is similar to the general BE population. The length of BE and the multifocal IND might tentatively help to identify a patient subpopulation at higher risk of neoplastic progression before more definitive data becomes available.

Introduction Barrett’s esophagus (BE) is a complication of chronic gastroesophageal reflux disease and is defined as “the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus. Presently, intestinal metaplasia is required for the diagnosis of Barrett’s esophagus because intestinal metaplasia is the only type of esophageal columnar epithelium that clearly predisposes to malignancy.”1 Patients with BE are at increased risk of esophageal adenocarcinoma (EAC)2–4 and, as such, undergo endoscopic surveillance and biopsy with the goal of detecting dysplasia or early adenocarcinoma.5,6 Dysplasia in the endoscopic biopsy is the best risk marker for prevalent or incident cancer;7,8 hence, surveillance intervals are based on the degree of dysplasia. Dysplasia is defined as the presence of neoplastic epithelium that is confined within the basement membrane of the gland from which it arises.9 Histologic 262

criteria for dysplasia in BE were well described in 1988 by Reid et al.10 and classified as BE with low-grade dysplasia (LGD), BE with high-grade dysplasia (HGD), and BE with changes indefinite for dysplasia (IND). Biopsies are classified as IND when the epithelial abnormalities are not sufficient to diagnose dysplasia or the nature of the epithelial abnormalities is uncertain due to inflammation or sampling.11 However, specific diagnostic criteria for IND are not well established. Few studies have investigated the risk of EAC in patients with BE-IND.7,12 The reported EAC risk was 14%7 and was associated with ulceration7 or multi-focal IND.12 Because of the lack of uniform criteria for IND, poor interobserver agreement, and a paucity of published outcome data, the management of patients with BE-IND is not clearly defined. This study aimed to assess (i) the prevalence of neoplasia in patients with BE-IND, (ii) risk of neoplastic progression in this patient group, and (iii) to identify predictors of neoplastic progression in this patient group by assessing their demographic, clinical, and endoscopic parameters at the time of diagnosis of IND.

Journal of Gastroenterology and Hepatology 30 (2015) 262–267 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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Methods

the last surveillance endoscopy. Progression probability was estimated using Kaplan–Meier method and compared using log-rank test. Univariate analysis was performed using Cox proportional hazards regression. Categorical variables were summarized as count and proportion and compared using Fisher’s exact test. Continuous variables were summarized as median and interquartile range and compared using Wilcox rank-sum test. Fleiss’ kappa was used to assess the interobserver agreement on BE-IND. A kappa value < 0, 0.01–0.20, 0.21–0.40, 0.41–0.60, 0.61–0.80, and 0.81−1.0 is considered poor, slight, fair, moderate, substantial, and almost perfect agreement, respectively.13 A P-value < 0.05 was considered statistically significant. Statistical analysis was performed using R 2.15.2 (R Development Core Team, Vienna, Austria).

Study population. The pathology database from 1992 to 2007 in the Department of Anatomic Pathology at Cleveland Clinic was searched for BE and IND. Patients who had LGD, HGD, or EAC diagnosed previously or synchronously at the time of IND diagnosis, had missing medical charts or slides, or were lost to follow-up (FU) were excluded. The biopsy protocol for BE surveillance consisted of four quadrant biopsies taken every 2 cm intervals within the Barrett’s segment. In cases with known or suspected dysplasia, biopsies were taken every 1 cm interval. In addition, nodules and ulcers, if any, were biopsied and placed in separate bottles. Demographic and clinical variables. Data were collected on demographic and clinicopathologic variables using medical charts, including age, gender, body mass index (BMI), duration and extent of BE, length of hiatal hernia, endoscopic presence of BE mucosal irregularities or esophagitis, proton-pump inhibitor (PPI) use, non-steroidal anti-inflammatory drug (NSAID), or aspirin use, present or past alcohol abuse or smoking and family history of EAC. Multifocal involvement referred to the presence of IND in biopsies from different levels in the esophagus submitted in different containers. Persistence of IND is defined as the presence of IND in at least one FU biopsy. Outcome measurement. The primary end-points of this study were prevalent neoplasia (defined as the presence of LGD, HGD, or EAC in a surveillance biopsy or resection within 12 months following IND diagnosis) and incident neoplasia (defined as the presence of LGD, HGD, or EAC in a surveillance biopsy or resection identified 12 months or more after IND diagnosis). Pathology review. Histology slides from patients with IND were retrieved. All slides carrying a diagnosis of IND were reviewed by five Gastrointestinal (GI) pathologists (X.L., R.K.P., T.P.P., D.T.P., and D.A., with a median practicing experience of 5 years [range: 3–7]) in a blinded fashion. Slides were reviewed and classified according to the criteria and definitions of Vienna classification11 adapted by Reid et al.10 Each slide was scored as negative, positive (LGD, HGD, or EAC), or IND. Slides containing prevalent or incident neoplasia in the study group were reviewed by one GI pathologist (X.L.). Statistical analysis. Patients with an index diagnosis of IND were included in this study. The patients were divided into two subgroups: one that underwent surveillance biopsy or resection within 12 months and one that was followed by surveillance biopsies or had resection at least 12 months after their index biopsies. While the presence of prevalent neoplasia was assessed in the first subgroup, the progression rate to neoplasia (incident neoplasia, including LGD, HGD, or EAC) and advanced neoplasia (HGD or EAC) was determined in the second subgroup. Time to progression was measured in months. Patients who did not develop LGD, HGD, or EAC during FU were censored at the moment of

Results A total of 225 BE patients with a diagnosis of IND on biopsy were identified from our pathology database from 1992 to 2007. One hundred eighteen patients were excluded due to a prior or concurrent diagnosis of neoplasia (n = 70), lack of FU (n = 37), and missing slides or lack of BE (n = 11). A total of 107 patients with an index diagnosis of IND were included in this study. Prevalent neoplasia in patients with BE-IND. Eighty-five of 107 IND patients (79.4%) had a surveillance biopsy within 12 months of the IND diagnosis; 11 (12.9%) had dysplasia (seven LGD and two HGD and two EAC) in their biopsies. The prevalence of HGD or EAC was 4.7%. Statistical analysis revealed that patient age, gender, BMI, duration and extent of BE, length of hiatal hernia, endoscopic presence of BE mucosal irregularities or esophagitis, PPI, NSAID, or aspirin use, present or past alcohol abuse or smoking, and family history of EAC were not associated with prevalent neoplasia in the surveillance biopsy specimen (Table 1). Incident dysplasia in patients with BE-IND. Among 107 IND patients, 82 patients did not have prevalent dysplasia but had more than 1 year follow up (mean FU duration of 59 months [range: 13–182]). During the FU, 19 patients (23.2%) developed dysplasia or EAC with a median interval of 54 months (range: 13–115). Fourteen patients progressed to LGD with a median interval of 62 months (range: 13–115), three progressed to HGD at 30, 71, and 114 months, respectively, after the diagnosis of IND, and two patients developed EAC at 37 and 50 months. Those who progressed has a significantly longer BE segment length (P = 0.01) (Table 2). The Kaplan–Meier curve of progression to LGD, HGD, or EAC in patients with BE-IND is shown in Figure 1. The calculated incidence rate of neoplasia (LGD, HGD, and EAC) was 4.5 cases/ 100 person-years at risk and the incidence rate of advanced neoplasia (HGD or EAC) was 1.2 cases/100 person-years at risk. On univariate analysis longer BE was associated with higher rate of neoplastic progression (hazard ratio 1.2; 95% confidence interval [CI] 1.03–1.3; P = 0.03) (Table 3) (Fig. 2a). Furthermore, multifocal IND at the time of index biopsy was also associated with higher risk of neoplastic progression (hazard ratio 2.9; 95% CI 1.09–7.6; P = 0.03) (Table 3) (Fig. 2b). PPI use was slightly

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Table 1

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Demographic and clinicopathologic factors in relation with the presence of prevalent neoplasia

Parameter

Prevalent neoplasia (n = 11)

No prevalent neoplasia (n = 74)

P-value

Age (years) Number of index biopsies Length of BE (cm) Length of hiatal hernia (cm) BMI (kg/m2) Gender (female/male) Multiple IND (yes/no) Family History of EAD (yes/no) Duration of BE (< 10 year/ ≥ 10 year) BE mucosal irregularity (yes/no) Esophagitis (yes/no) PPI use (yes/no) NSAID use (yes/no) Aspirin use (yes/no) Smoking (current/former/never) Alcohol abuse (current/former/never)

69 (54–86) 1 (1–4) 3.5 (1–5) 3 (2–5) 29 (24–31) 3/8 1/10 1/9 4/6 2/9 1/9 8/3 0/11 3/8 1/4/6 6/0/5

63 (33–85) 2 (1–9) 4 (1–15) 3 (0–12) 28 (18–49) 19/55 15/59 1/68 25/44 14/51 11/55 55/14 6/64 12/57 8/35/27 31/3/36

0.4 0.08 0.4 0.8 0.8 1.0 0.7 0.2 1.0 1.0 1.0 0.7 0.6 0.4 0.6 0.7

Categorical variables were summarized as count and proportion and compared using Fisher’s exact test. Continuous variables were summarized as median and interquartile range and compared using Wilcox rank-sum test. BE, Barrett’s esophagus; BMI, body mass index; EAC, esophageal adenocarcinoma; IND, indefinite for dysplasia; NSAID, non-steroidal antiinflammatory drug; PPI, proton-pump inhibitor.

Table 2

Demographic and clinicopathologic factors associated with the development of incident neoplasia

Parameter

Progressors (n = 19)

Non-progressors (n = 63)

P-value

Age (years) Number of index biopsies Number of interval scopes Number of interval biopsies Follow-up duration (months) Length of BE (cm) Length of hiatal hernia (cm) BMI (kg/m2) Gender (female/male) Multifocal IND (yes/no) Persistent IND (yes/no) Family History of EAD (yes/no) Duration of BE (< 10 year/ ≥ 10 year) BE mucosal irregularity (yes/no) Esophagitis (yes/no) PPI use (yes/no) NSAID use (yes/no) Aspirin use (yes/no) Smoking (current/former/never) Alcohol abuse (yes/no)

65 (40–77) 3 (1–10) 3 (0–7) 6 (0–48) 54 (13–115) 6 (2–15) 3 (0–8) 28 (18.5–34) 2/17 7/12 6/13 0/18 3/15 4/13 2/15 17/1 2/16 5/13 1/13/5 10/1/8

60 (30–85) 2 (1–12) 2 (0–9) 5 (0–56) 63 (15–182) 3 (0–13) 3 (0–12) 29 (19–47) 16/47 11/52 11/52 3/55 23/35 10/45 9/47 40/16 6/51 10/46 7/22/27 27/1/28

0.2 0.3 0.9 0.8 0.7 0.01 0.7 0.2 0.2 0.1 0.2 1.0 0.09 0.7 1.0 0.055 1.0 0.5 0.1 0.5

Categorical variables were summarized as count and proportion and compared using Fisher’s exact test. Continuous variables were summarized as median and interquartile range and compared using Wilcox rank-sum test. BE, Barrett’s esophagus; BMI, body mass index; EAC, esophageal adenocarcinoma; IND, indefinite for dysplasia; NSAID, non-steroidal antiinflammatory drug; PPI, proton-pump inhibitor.

more common in patients who developed dysplasia (94.4% vs 71.4%, P = 0.055). Patient age, gender, BMI, length of hiatal hernia, endoscopic presence of BE mucosal irregularities or esophagitis, NSAID, or aspirin use, present or past alcohol abuse, and family history of esophageal cancer was not associated with neoplastic progression (Table 3). 264

Interobserver agreement on IND diagnosis in patients with BE. Slides with a diagnosis of BE-IND were reviewed by five GI pathologists in a blinded fashion. When categories were simplified into negative versus non-negative, the kappa value was 0.33, indicating fair interobserver agreement among five GI pathologists.

Journal of Gastroenterology and Hepatology 30 (2015) 262–267 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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Figure 1 Neoplastic progression in Barrett’s esophagus patients with mucosal changes indefinite for dysplasia. (a) Progression to neoplasia (low-grade dysplasia [LGD], high-grade dysplasia [HGD], or esophageal adenocarcinoma [EAC]; 4.5 cases/100 person-years at risk). (b) Progression to advanced neoplasia (HGD or EAC; 1.2 cases/100 person-years at risk).

Discussion In our study, we showed that patients with BE-IND have a considerable risk of harboring prevalent neoplasia (12.9%), with 4.7% developing either HGD or EAC within 1 year. We did not identify any significant risk factor for prevalent dysplasia, although previous study suggested that ulceration at the time of IND diagnosis was associated with prevalent invasive cancer.7 This discrepancy may be due to the relatively large size of our cohort (85 cases) compared with this prior study (seven cases). The natural history of patients with BE-IND is largely unknown. In one cohort of 22 cases with an initial diagnosis of IND, four (18%) patients progressed to LGD at a median of 20 months.7 Likewise in our study, 17.1% of 82 BE patients with IND progressed to LGD (median interval of 62 months). The incidence rates for advanced neoplasia were 1.68 cases/100 patient-years in BE with IND in our study, including 1.2 cases/100 patient-years for HGD and 0.48 cases/100 patient-years for EAC. The incidence rate for advanced neoplasia in our study is slightly higher than a previously reported overall progression rate of 3.6% to advanced neoplasia with a mean FU of 41 months,12 but is less than the 2.7 cases per 100 patient-years progression rate for BE with LGD from our institution during a study period of 2002 to 2012 (our unpublished data). The incidence rate of advanced neoplasia in our study is also lower than that reported by Montgomery et al. where 4 (18%) of 22 cases with the diagnosis of IND developed EAC with a median FU of 36 months;7 these EACs were diagnosed at 19, 55, 60, and 62 months after the diagnosis of IND. These differences might be due to the known interobserver variability of this diagnosis,8 different study size, and inclusion crite-

Indefinite for dysplasia in Barrett’s

ria. For example, Younes et al.12 included cases with dysplastic changes involving the crypts but involvement of the surface epithelial could not be documented and cases with so called “crypt dysplasia with surface maturation.” In our study, most cases belonged to the former group. Cases showing “crypt dysplasia with surface maturation” would be classified as negative for dysplasia. Nonetheless, our data, along with those of Montgomery et al.,7 imply that the diagnosis of BE-IND carries a significant risk of neoplastic progression. Unlike previous studies, our study attempted to identify factors associated with neoplastic progression in patients with BE-IND patients. Indeed, univariate analysis confirmed longer length of BE at the diagnosis of index IND was associated with higher rates of neoplastic progression (hazard ratio 1.2; 95% CI 1.03–1.3; P = 0.03), which is in line with many previous reports showing a relationship between BE length and risk of EAC.14 Furthermore, multifocality of IND was also associated with higher risk of neoplastic progression (hazard ratio 2.9; 95% CI 1.09–7.6; P = 0.03), similar to the findings of a previous study.12 Interestingly, there was a trend towards higher risk in patients using PPIs, which might imply more severe acid reflux prompting PPI use. BE patients who developed HGD or EAC have been found to have more severe acid reflux than those with non-dysplastic BE.14 The study by Montgomery et al.7 revealed that epithelial alterations which are near an ulcer indicates significant cancer risk. For example, of 21 cases with ulceration, EAC developed in 15 (71%) cases on FU, including the one case of IND diagnosed by the majority of reviewing pathologists. However, the presence of endoscopic abnormalities at the diagnosis of index BE-IND was not associated with prevalent or incident neoplasia in our study. The discrepancy may be due to different study size between these two studies or different definition of mucosal abnormalities used (mucosal abnormalities in current study vs ulceration). We also examined the association of other parameters including patient age, gender, BMI, length of hiatal hernia, esophagitis, NSAID, or aspirin use, present or past alcohol abuse, and family history of esophageal cancer with neoplastic progression in our cohort of patients with BE-IND; however, none were associated with neoplastic progression. The lack of association between age, gender, ethanol consumption, and smoking history with neoplastic progression is in line with previous observations.14 The use of NSAID or aspirin was not protective against neoplastic progression in our study, which is in concert with a previous study which noted a higher rate of NSAIDs use in patients with EAC.15 Although BMI, markers of obesity, and central adiposity have been shown to be risk factors for EAC,15–17 they were not associated with neoplastic progression in patients with BE-IND. We observed a fair agreement among our pathologists (κ = 0.33). These inter-observer agreement data are consistent with those in the literature.7,18 There are several reasons for this repeatedly reported variability on the category of IND in BE. Small and maloriented biopsy specimen or those with inflammation can cause diagnostic dilemmas. It has also been shown that the presence of ulcers and even the specific type of fixative used can be a source of misinterpretation.7 In some cases, it is due to biology, such as when biopsy is taken when the epithelium is at the transitional stage from negative to dysplasia, the so called “basal dysplasia with surface maturation.”19 These difficulties in diagnosing IND in BE patients further justify the need for risk stratifica-

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Table 3

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Univariate analysis of risk factors for the development of incident neoplasia

Age Number of index biopsies Number of interval scopes Number of interval biopsies BE length Hiatal length BMI (kg/m2) Gender (male/ female) Multifocal IND (yes/no) Persist IND (yes/no) BE duration (> = 10 year/ < 10 year) BE mucosal irregularity (yes/no) Grade of esophagitis (1/0) PPI (yes/no) NSAID (yes/no) Aspirin (yes/no) Smoking (former + current/never) Alcohol (former + current/never)

Incidence rate (95% CI)

HR (95% CI)

P-value

— — — — — — — 5.3 (3.3–8.6)/2.0 (0.5–7.8) 8.5 (4–17.8)/3.5 (2–6.2) 6.9 (3.1–15)/3.9 (2.3–6.7) 5.5 (3.3–9.2)/2.6 (0.8–8.1) 5.7 (2.1–15)/4.2 (2.4–7.2) 3.8 (0.9–15)/4.6 (2.7–7.6) 5.7 (3.5–9.1)/1.1 (0.2–7.7) 4.4 (1.1–17.8)/4.6 (2.8–7.5) 7.8 (3.3–19)/4 (2.3–6.8) 6.1 (3.6–10)/3 (1.2–7.2) 5.1 (2.8–9.2)/4.4 (2.2–8.9)

1.03 (0.99–1.07) 1.2 (0.98–1.4) 0.8 (0.7–1.04) 0.99 (0.95–1.03) 1.2 (1.03–1.3) 1.04 (0.8–1.3) 0.96 (0.9–1.04) 3.3 (0.8–14) 2.9 (1.09–7.6) 2.2 (0.8–5.8) 1.5 (0.4–5.4) 1.4 (0.5–4.4) 0.8 (0.2–3.7) 6.5 (0.8–49) 0.9 (0.2–3.8) 2.0 (0.7–5.8) 2 (0.7–5.5) 1.1 (0.4–2.7)

0.1 0.09 0.1 0.6 0.02 0.8 0.3 0.1 0.03 0.1 0.5 0.5 0.8 0.07 0.9 0.2 0.2 0.8

Categorical variables were summarized as count and proportion and compared using Fisher’s exact test. Continuous variables were summarized as median and interquartile range and compared using Wilcox rank-sum test. BE, Barrett’s esophagus; BMI, body mass index; CI, confidence interval; HR, hazard ratio; IND, indefinite for dysplasia; NSAID, non-steroidal anti-inflammatory drug; PPI, proton-pump inhibitor.

Figure 2 Long segment of Barrett’s esophagus (BE) (a, P = 0.02; , , BE < 3 cm) and multifocal mucosal changes indefinite BE ≥ 3 cm; for dysplasia (IND) (b, P = 0.03; , Presence of multifocal IND; , Absence of multifocal IND) were associated with neoplastic progression in BE patients with IND.

tion (as attempted in this manuscript) and for additional biomarkers in this heterogeneous patient population. One of the main strengths of this study is that it includes one of the largest cohorts of patients with BE-IND. We studied two sub266

groups of IND patients: one underwent repeat endoscopy examination within 12 months and the other group was followed by surveillance endoscopy. The first subgroup allowed us to estimate the prevalence of neoplasia associated with an index diagnosis of IND to be at least 25.4%. None of the clinical, demographic, or endoscopic findings predicted prevalent dysplasia. The second subgroup allowed us to determine factors associated with neoplastic progression in patients with BE-IND. There are limitations to our study. The rate of prevalent neoplasia in our study may represent an overestimate because of referral bias and we could not completely rule out an outside diagnosis of dysplasia prior to the IND diagnosis at our institute, although the patients’ previous biopsies are routinely reviewed in our institute. Similarly, the study population was based on a highly specialized tertiary center, and conclusions from this study may not be applicable to other practice settings. The retrospective nature of our study limited the quality of our data, despite our best effort to collect all data. Furthermore, even though our study has the largest number of cases with IND so far, the relatively small number of outcomes precluded a multivariate analysis of the data. In summary, our study reaffirms the value of IND as a diagnostic category for BE esophageal biopsies. The diagnosis of IND in BE patients carries significant risk of prevalent neoplasia. Patients with BE-IND should be followed by repeat endoscopic examination after a short interval (within months) and then managed based on the findings at repeat biopsy. Length of BE and multifocal IND might tentatively help to identify a subset of patients at higher risk, who might benefit from closer surveillance, similar to patients with LGD (6–12 months). Further studies with larger sample size and multivariable analyses are needed to make definitive conclusions and universal recommendations.

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Acknowledgment None.

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Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.

Patients with Barrett's esophagus (BE) are at increased risk for esophageal adenocarcinoma (EAC) and therefore require surveillance. Biopsies are clas...
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