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Introduction: Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS 3D ) has been shown to increase the detection rate of dysplasia (and intestinal metaplasia) in patients with Barrett's esophagus (BE). The purpose of this study was to evaluate the interobserver variability and accuracy of diagnosing BE-associated dysplasia in WATS 3D specimens among gastrointestinal (GI) pathologists without prior experience with this technology., Methods: Five GI pathologists underwent a 4-hour in-person (at microscope) and virtual training session and then evaluated digital images of discrete cellular foci from 60 WATS 3D cases with BE (20 nondysplastic BE [NDBE], 20 low-grade dysplasia [LGD], and 20 high-grade dysplasia/esophageal adenocarcinoma [HGD/EAC]). Each case consisted of 1 hematoxylin and eosin-stained image (cell block), and 1 liquid cytology or papanicolaou-stained smear image (120 images in total)., Results: The overall kappa value among the 5 study pathologists was excellent (overall kappa = 0.93; kappa = 0.93 and 0.97 for cell block and smear specimens, respectively). There were no significant differences noted in kappa values in interpretation of the cell block vs smear specimens or in any of the individual diagnostic categories when the latter were evaluated separately. Furthermore, agreement was perfect (100%) regarding detection of neoplasia (either LGD, HGD, or EAC). Diagnoses were made with complete confidence in 91% of instances., Discussion: We conclude that GI pathologists, without any prior experience in interpretation of WATS 3D specimens, can undergo a short training session and then diagnose these specimens with a very high level of accuracy and reproducibility., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Introduction: Objective risk stratification is needed for patients with Barrett's esophagus (BE) to enable risk-aligned management to improve health outcomes. This study evaluated the predictive performance of a tissue systems pathology [TSP-9] test (TissueCypher) vs current clinicopathologic variables in a multicenter cohort of patients with BE., Methods: Data from 699 patients with BE from 5 published studies on the TSP-9 test were evaluated. Five hundred nine patients did not progress during surveillance, 40 were diagnosed with high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) within 12 months, and 150 progressed to HGD/EAC after 12 months. Age, sex, segment length, hiatal hernia, original and expert pathology review diagnoses, and TSP-9 risk classes were collected. The predictive performance of clinicopathologic variables and the TSP-9 test was compared, and the TSP-9 test was evaluated in clinically relevant patient subsets., Results: The sensitivity of the TSP-9 test in detecting progressors was 62.3% compared with 28.3% for expert-confirmed low-grade dysplasia (LGD), while the original diagnosis abstracted from medical records did not provide any significant risk stratification. The TSP-9 test identified 57% of progressors with nondysplastic Barrett's esophagus (NDBE) ( P < 0.0001). Patients with NDBE who scored TSP-9 high risk progressed at a similar rate (3.2%/yr) to patients with expert-confirmed LGD (3.7%/yr). The TSP-9 test provided significant risk stratification in clinically low-risk patients (NDBE, female, short-segment BE) and clinically high-risk patients (IND/LGD, male, long-segment BE) ( P < 0.0001 for comparison of high-risk classes vs low-risk classes)., Discussion: The TSP-9 test predicts risk of progression to HGD/EAC independently of current clinicopathologic variables in patients with BE. The test provides objective risk stratification results that may guide management decisions to improve health outcomes for patients with BE., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Aims: Seattle protocol forceps biopsy sampling (FB) is currently recommended for surveillance in Barrett's esophagus (BE) but limited by sampling error and lack of compliance. Wide-area transepithelial sampling with 3-dimensional analysis (WATS3D; CDx Diagnostics, Suffern, NY, USA) is reported to increase BE dysplasia detection. We assessed the incremental yield and clinical significance of WATS3D for dysplasia detection over FB in a systematic review and meta-analysis., Methods: We queried major scientific databases for studies using WATS3D and FB from 2000 to 2020. The primary outcome was the incremental yield of WATS3D-detected dysplasia (defined as a composite of indefinite for dysplasia, low- and high-grade dysplasia [HGD] and esophageal adenocarcinoma [EAC]) over FB. Secondary outcomes were incremental yields of HGD/EAC and rate of reconfirmation of WATS3D dysplasia on subsequent FB., Results: Meta-analysis of 7 eligible studies demonstrated that FB diagnosed dysplasia in 15.9% of cases, whereas the incremental yield with WATS3D was 7.2% (95% confidence interval, 3.9%-11.5%; I 2 = 92.1%). Meta-analysis of 6 studies demonstrated that FB diagnosed HGD/EAC in 2.3% of patients, whereas the incremental yield with WATS3D was 2.1% (95% confidence interval, .4%-5.3%; I 2 = 92.7%). Notably, WATS3D was negative in 62.5% of cases where FB identified dysplasia. Two studies reported reconfirmation of WATS3D dysplasia with FB histology in only 20 patients., Conclusions: WATS3D increases dysplasia detection; however, the clinical significance of this increased dysplasia detection remains uncertain. Data from endoscopic follow-up to ascertain FB histology in patients with dysplasia based solely on WATS3D are needed to determine the optimal clinical application and significance of WATS3D-only dysplasia., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Subsquamous intestinal metaplasia (SSIM) in the setting of Barrett's esophagus (BE) is a technically challenging diagnosis. While the risk for progression of BE involving the surface mucosa is well documented, the potential risk for development of advanced neoplasia associated with SSIM has been controversial. This study aimed to determine the effects of specimen adequacy, presence of dysplasia, and interobserver agreement for SSIM interpretation. Adult patients (n = 28) who underwent endoscopic therapy for BE with high-grade dysplasia or intramucosal carcinoma (HGD/IMC) between October 2005 and June 2013 were included. Initial evaluation (n = 140 slides) by an experienced gastrointestinal pathologist was followed by an interobserver study by 8 pathologists. Forty-seven (34%) slides had insufficient subsquamous tissue to assess for SSIM. SSIM was found in 19% of all slides and 29% of slides with sufficient subsquamous tissue. At least one slide had SSIM in 54% to 64% of patients. Subsquamous low grade dysplasia (LGD) was found in 4 (15%) slides with SSIM and subsquamous HGD/IMC was found in 5 (19%) slides with SSIM. At the patient level, 8 (53%) had no dysplasia, 4 (27%) had LGD and 3 (20%) had HGD/IMC. Overall agreement for SSIM by slide was 92% to 94% (κ = 0.73 to κ = 0.82, moderate to strong agreement), and by patient was 82% to 94% (κ = 0.65 to κ = 0.87, moderate to strong agreement). This study confirms the need for assessing specimen adequacy and assessing the prevalence of SSIM and is the first to assess interobserver agreement for SSIM and dysplasia within SSIM., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Goals: Visible lesions (VLs) in Barrett's esophagus (BE) are seen in 70% to 90% of patients presenting for endoscopic eradication therapy (EET). It is not known if there are any differences in outcomes of patients with flat dysplasia versus patients with VL. Our aim was to assess outcomes of EET in BE patients with VL and BE patients with flat dysplasia., Study: This is a single center study with data drawn from a prospective registry of patients referred for EET of BE between 2011 and 2015. Demographic data, endoscopic findings, histologic findings, and response to EET were analyzed., Results: There were 264 patients of which 34 had flat dysplasia, 180 had VL before initiating EET (prevalent lesions) and 50 who developed VL during EET (incident lesions). Compared with patients with flat dysplasia, patients with VL had longer segments of BE (5 vs. 4 cm, P=0.002) and greater prevalence of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) (63.6% vs. 29.4%, P<0.001). Incident lesions are less likely to harbor HGD/EAC compared with prevalent lesions (28.1% vs. 61.8%, P<0.001). There were no significant differences in eradication of metaplasia/dysplasia between the groups. No progression or recurrences were observed in flat dysplasia group. In VL group, 14 patients progressed (prevalent VL=11, incident VL=3) and 15 had recurrences (prevalent VL=11, incident VL=4)., Conclusions: About 19% of BE patients developed VL during EET. There is higher prevalence of HGD/EAC in prevalent VL compared with incident VL. However, the outcomes did not differ.

Background and Aims: Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells., Methods: We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS., Results: One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure., Conclusion: Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.)., (Copyright © 2018. Published by Elsevier Inc.)

Background: Patients with Barrett's esophagus (BE) and high-grade dysplasia (HGD) or intramucosal cancer (IMC) on endoscopic forceps biopsies are referred to endoscopic therapy even though forceps biopsies do not reflect the disease extent accurately. Endoscopic mucosal resection (EMR) and endoscopic ultrasound (EUS) are frequently used for staging prior to endoscopic therapy. Our aims were to evaluate: (1) if endoscopic forceps biopsies correlated with EMR histology in these patients; (2) the utility of EUS compared to EMR; and (3) if accuracy of EUS varied based on grade of differentiation of tumor., Methods: This is a retrospective review of patients referred to endoscopic therapy of BE with HGD or early esophageal adenocarcinoma (EAC) who underwent EMR from 2006 to 2011. Age, race, sex, length of Barrett's segment, hiatal hernia size, number of endoscopies and biopsy results and EUS findings were abstracted., Results: A total of 151 patients underwent EMR. In 50 % (75/151) of patients, EMR histology was consistent with endoscopic forceps biopsy findings. EMR resulted in change in diagnosis with upstaging in 21 % (32/151) and downstaging in 29 % (44/151). In patients with HGD on EMR, EUS staging was T0 in 74.1 % (23/31) but upstaged in 25.8 % (8/31). In patients with IMC on EMR, EUS findings were T1a in 23.6 % (9/38), upstaged in 18.4 % (7/38) and downstaged in 57.8 % (22/38). EUS accurately identified EMR histology in all submucosal cancers. Grade of differentiation was reported in 24 cancers on EMR histology. There was no correlation between grade and EUS staging., Conclusions: EUS is of limited utility in accurate staging of BE patients with HGD or early EAC. Endoscopic forceps biopsy correlated with EMR findings in only 50 % of patients. Irrespective of the endoscopic forceps biopsy results, all BE patients with visible lesions should be referred to EMR.

Background & Aims: There is suboptimal inter-observer agreement, even among expert gastrointestinal pathologists, in the diagnosis of low-grade dysplasia (LGD) in patients with Barrett's esophagus (BE). We analyzed histopathologic criteria required for a diagnosis of LGD using the new subcategories of LGD with inflammatory and dysplastic features. We categorized each diagnosis based on the level of confidence and assessed inter-observer agreement among gastrointestinal pathologists from 5 tertiary centers in the United States and Europe., Methods: In the first phase of the study, 3 pathologists held a consensus conference at which they discussed the diagnostic criteria for LGD. In the second phase, 79 slides from patients with BE (23 samples of non-dysplastic BE, 22 samples of LGD, and 34 samples of high-grade dysplasia) were identified, randomly assigned to 7 pathologists (4 from the United States and 3 from Europe), and interpreted in a blinded fashion. κ Values were calculated for inter-observer agreement. We performed multinomial logistic regression analysis to assess the weighting of histologic features with the diagnosis., Results: The overall κ value for diagnosis was 0.43 (95% confidence interval [CI], 0.42-0.48). When categorized based on degree of dysplasia, the κ value was 0.22 (95% CI, 0.11-0.29) for non-dysplastic BE, 0.11 (95% CI, 0.004-0.15) for LGD, and 0.43 (95% CI, 0.36-0.46) for high-grade dysplasia. When all pathologists made a diagnosis with high confidence, the inter-observer agreement was substantial among the US pathologists (κ, 0.63; 95% CI, 0.61-0.66) and European pathologists (κ, 0.80; 95% CI, 0.74-0.97). The κ values for all diagnoses made by European pathologists were higher than those made by US pathologists., Conclusions: In an analysis of criteria used in histopathologic diagnosis of LGD, we did not observe improvement in level of agreement among experienced pathologists, even after accounting for inflammation. The level of inter-observer agreement increased with level of pathologist confidence. There was also a difference in reading of histopathology samples of BE tissues between US and European pathologists., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Although several classification systems have been proposed for characterization of Barrett's esophagus (BE) surface patterns based on narrow-band imaging (NBI), none have been widely accepted. The Barrett's International NBI Group (BING) aimed to develop and validate an NBI classification system for identification of dysplasia and cancer in patients with BE., Methods: The BING working group, composed of NBI experts from the United States, Europe, and Japan, met to develop a validated, consensus-driven NBI classification system for identifying dysplasia and cancer in BE. The group reviewed 60 NBI images of nondysplastic BE, high-grade dysplasia, and esophageal adenocarcinoma to characterize mucosal and vascular patterns visible by NBI; these features were used to develop the BING criteria. We then recruited adult patients undergoing surveillance or endoscopic treatment for BE at 4 institutions in the United States and Europe, obtaining high-quality NBI images and performing histologic analysis of biopsies. Experts individually reviewed 50 NBI images to validate the BING criteria, and then evaluated 120 additional NBI images (not previously viewed) to determine whether the criteria accurately predicted the histology results., Results: The BING criteria identified patients with dysplasia with 85% overall accuracy, 80% sensitivity, 88% specificity, 81% positive predictive value, and 88% negative predictive value. When dysplasia was identified with a high level of confidence, these values were 92%, 91%, 93%, 89%, and 95%, respectively. The overall strength of inter-observer agreement was substantial (κ = 0.681)., Conclusions: The BING working group developed a simple, internally validated system to identify dysplasia and EAC in patients with BE based on NBI results. When images are assessed with a high degree of confidence, the system can classify BE with >90% accuracy and a high level of inter-observer agreement., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients with non-dysplastic Barrett's esophagus (ND-BE) and low-grade dysplasia (LGD) are typically monitored by periodic endoscopic surveillance, while those with high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) are usually treated by more aggressive interventions like endoscopic mucosal resection, ablation or surgery. Therefore, the accurate grading of dysplasia in Barrett's esophagus (BE) is essential for proper patient care. However, there is significant interobserver and intraobserver variability in the histologic grading of BE dysplasia. The objective of this study was to create an immunohistochemical (IHC) panel that facilitates the grading of BE dysplasia and can be used as an adjunct to histology in challenging cases., Methods: 100 BE biopsies were re-graded for dysplasia independently by 3 subspecialized gastrointestinal pathologists. IHC staining for CDX2, p120ctn, c-Myc and Jagged1 proteins was then performed and assessed by two separate methods of semi-quantitative scoring. Scores were integrated using a principal component analysis (PCA) and receiver operating characteristic (ROC) curve., Results: Principal component analysis demonstrated the ability of this panel of proteins to segregate ND-BE/LGD and HGD/EAC, as the expression of the four proteins is significantly altered between the two subsets. Analysis of the receiver operating characteristic curve showed that this panel has the potential to aid in the grading of dysplasia in these two subcategories with both high sensitivity and specificity. While not able to discriminate between ND-BE and LGD, this panel of four proteins may be used as an adjunct to help discriminate subsets of ND-BE/LGD from HGD/EAC., Conclusions: We propose that the maximum utility of this IHC panel of CDX2, p120ctn, c-Myc, and Jagged1 proteins would be to distinguish between LGD and HGD in histologically challenging cases, given the aggressive interventions still used for HGD in many institutions, and hence may aid in the optimal patient management. The results of this initial study are promising, though further validation is needed before this panel can be used clinically, including future randomized prospective studies with larger patient cohorts from diverse locations.

Background & Aims: In patients with Barrett's esophagus (BE), low-grade dysplasia (LGD) is a risk factor for esophageal adenocarcinoma (EAC), progressing at variable rates. Patients at higher risk for progression could benefit from intervention. We assessed rates of progression of LGD and indefinite for dysplasia (IND) and risk factors for progression to high-grade dysplasia (HGD) and EAC., Methods: We analyzed data from Cleveland Clinic Barrett's Registry on patients with BE and LGD or IND at least 1 year of follow-up from January 1, 2002 through December 31, 2012. Prevalent cases were those diagnosed at or within 1 year of the first endoscopy, and the rest were incident cases., Results: Among 299 patients with BE and LGD or IND, there were 32 cases of HGD and 10 cases of EAC during a follow-up period of 1577.4 patient-years. The annual incidence rates were 2.4% (95% confidence interval [CI], 1.7%-3.3%) for HGD, 0.6% (95% CI, 0.3%-1.2%) for EAC, and 2.7% (95% CI, 1.9%-3.6%) for HGD or EAC. The rates were higher in men than in women with BE and LGD or IND. Prevalent cases were 3-fold more likely to progress than incident cases. Multifocality and nodules were associated with higher risk of progression to HGD or EAC. None of the patients with IND at index biopsy developed EAC. For every 5-year increase in age, chance of regression increased by 7% (P = .04). Also, for every 1-cm increase in BE length, probability of regression decreased by 6% (P = .016). LGD at index biopsy was associated with 56% lower chance of regression compared with IND (P < .001)., Conclusions: On the basis of a database analysis of patients with BE, prevalent LGD, male sex, multifocality, and nodules were associated with higher risk for progression to EAC. Older age at LGD diagnosis, IND at index biopsy, and shorter BE length were associated with regression. These findings help in risk stratification of patients with BE and LGD or IND., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Surgical pathologists frequently encounter biopsies in patients with Barrett's esophagus (BE), defined as replacement of the normal stratified squamous epithelium of the distal esophagus by metaplastic columnar epithelium containing goblet cells. Thus, one of the primary roles of the pathologist is to definitively identify goblet cells, best done on routine stained sections. It has recently been questioned as to whether goblet cells should be absolutely necessary to render a diagnosis of BE, given immunohistochemical and flow cytometric similarities between columnar-lined esophagus with and without goblet cells. Once a diagnosis of BE is rendered, the pathologist must state, using a simple classification, whether the biopsy is negative for dysplasia or shows dysplasia (low-grade dysplasia or high-grade dysplasia). However, there are a number of known pitfalls in distinguishing dysplasia from reactive epithelium, and it can be similarly difficult to distinguish low-grade dysplasia from high-grade dysplasia. In addition, there are some cases in which the distinction of high-grade dysplasia from intramucosal adenocarcinoma can be challenging. All of these issues are summarized in this paper.

High-grade dysplasia in Barrett esophagus is a marker for future development of cancer and for the existence of synchronous cancer. A significant problem in management is intraobserver and interobserver variation in the diagnosis of high-grade dysplasia in Barrett esophagus, the natural history of which is poorly understood; thus, treatment decisions are problematic. The ability to preserve the esophagus with endoscopic mucosal ablation or resection and reduce morbidity of treatment has made endoscopic treatment the mainstay of therapy. Esophagectomy is reserved for treatment failures and for high-grade dysplasia not amenable to less aggressive therapies. This article outlines the data supporting current management strategies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: After endoscopic eradication therapy (EET) for Barrett's esophagus (BE), surveillance of residual/recurrent intestinal metaplasia/dysplasia including subsquamous tissue is performed by using biopsy forceps., Objective: The goal of this study was to compare the adequacy of biopsy specimens obtained from neo-squamous (post-EET patients) and native (non-BE patients) squamous mucosa., Design: A case-control study using squamous biopsy specimens obtained at 2 tertiary referral centers was conducted., Interventions: Two experienced GI pathologists reviewed specimens from patients with neo- (post-EET patients) and native (non-BE patients) squamous mucosa in a blinded fashion after developing standardized criteria to assess tissue depth., Main Outcome Measurements: The primary outcome was the proportion of biopsy specimens that contained any amount of lamina propria., Results: A total of 193 biopsy specimens (1692 tissue pieces) from 104 patients were reviewed: 163 neo- and 30 native squamous. Of all biopsy specimens, only 37% contained any amount of lamina propria, and, furthermore, fewer than 4% of specimens had sufficient lamina propria (ie, more than two thirds of the entire squamous tissue present). When examining individual squamous tissue pieces, fewer than 11% contained lamina propria. No statistically significant differences in the presence of lamina propria were detected between neo- and native squamous mucosa., Conclusion: The majority of esophageal squamous biopsy specimens obtained during endoscopy do not demonstrate lamina propria and subepithelial structures. This is true for both neo- and native squamous mucosa. Biopsy specimens of neo-squamous mucosa obtained after EET appear to be inadequate to exclude subsquamous intestinal metaplasia/dysplasia because lamina propria is not present in more than 60% of specimens. This has larger implications in the clinical management of BE patients after EET., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Distinguishing Barrett esophagus with high-grade dysplasia (BE-HGD) from intramucosal and submucosal adenocarcinomas on biopsies is challenging, yet important, in the choice of therapy. The current study evaluates preresection biopsies from patients who underwent esophagectomy for at least BE-HGD, to compare the recently published histologic categories by the University of Michigan (UM) and Cleveland Clinic (CC), correlate preresection and final resection diagnosis, and identify histologic features in biopsies that might be predictive of adenocarcinoma on esophagectomy. A total of 112 cases with a consensus biopsy diagnosis (agreement by ≥4 of 7 gastrointestinal pathologists) were statistically analyzed to identify histologic features that predicted adenocarcinoma on resection. Applying the UM criteria to the biopsy series showed excellent agreement with the CC system (κ=0.86) and significant correlation between preoperative and esophagectomy diagnoses (P<0.001). The likelihood of finding carcinoma on resection was significantly higher with the category of HGD with marked glandular distortion cannot exclude intramucosal adenocarcinoma [CC; odd ratio (OR), 2.8; P=0.046] or HGD suspicious for adenocarcinoma (UM; OR, 4.3; P=0.008), compared to HGD alone. The presence of "never-ending" glands (OR, 3.7; P=0.008), sheet-like growth (P<0.001), angulated glands (OR, 8.5; P<0.001), ≥3 dilated glands with intraluminal debris (OR, 2.6; P=0.05), and >1 focus of single-cell infiltration into the lamina propria (OR, 8.9; P<0.001) increased the odds of finding carcinoma on resection. The latter 2 variables remained independent predictors of adenocarcinoma in multivariable analysis. In conclusion, the CC and UM systems show excellent agreement and define histologic categories that can improve prediction of adenocarcinoma on resection.

Background & Aims: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE., Methods: We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events., Results: After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years)., Conclusions: In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the relationship between the depth of invasion within the mucosal compartment, with particular attention to the duplicated muscularis mucosae, and survival after esophagectomy performed as treatment for Barrett esophagus-related superficial adenocarcinoma., Methods: A total of 185 patients with pT1 esophageal adenocarcinoma treated by esophagectomy without induction therapy were identified. Depth of invasion was subdivided into invasion into the lamina propria (LP), into the inner muscularis mucosae, between the inner and outer muscularis mucosae, and into the outer muscularis mucosae (OMM), with comparison with tumors invading the inner one third of the submucosa (SM-1). Patient and tumor characteristics were compared among the 5 groups using the χ test or the Kruskal-Wallis test. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. The prognostic effect of depth of invasion on survival was assessed with Cox proportional hazards analysis., Results: Depth of invasion was LP (n=68), inner muscularis mucosae (n=38), BMM (n=11), OMM (n=33), and SM-1 (n=35). There was no significant difference in sex or age among groups. One of 150 patients with intramucosal adenocarcinoma (0.7%; LP, pN2) and 3 of 35 patients with SM-1 (8.6%; all pN1) had nodal disease. There were no significant differences in survival among the groups., Conclusions: Depth of invasion relative to the duplicated muscularis mucosae for tumors restricted to the mucosal compartment does not affect survival in Barrett esophagus-related superficial adenocarcinoma. Patients with SM-1 tumor had survival similar to those patients with tumor invasion into the OMM.

Recent morphologic and molecular evidence suggests that dysplasia in Barrett esophagus (BE) begins in the bases of the crypts [crypt dysplasia (CD)] and progresses with time to involve the upper portions of the crypts and surface epithelium. The aim of this study was to evaluate the criteria and reproducibility of diagnosing CD among 6 gastrointestinal pathologists, all with research interest in BE. Six gastrointestinal pathologists evaluated 2 clinical study sets, the first consisting of 40 BE cases [BE: 10, CD: 9, low-grade dysplasia (LGD): 10, high-grade dysplasia (HGD); 9, and intramucosal adenocarcinoma; 2] and the second consisting of 63 cases (BE: 16, CD: 15, LGD: 15, HGD: 15, and intramucosal adenocarcinoma: 2), at least 4 months apart. In between evaluations, all of the pathologists met at 1 hospital (consensus conference) to review the areas of disagreement and establish more objective criteria. Overall, the level of agreement for all cases was moderate (κ=0.44), and the level of agreement did not change significantly after evaluation of the second study set. The highest levels of agreement were obtained for lesions at the low and high end of the spectrum (BE without dysplasia and HGD). Overall, the degree of agreement for CD was moderate after both the first and second study set review (κ=0.44 and 0.46, respectively). However, the degree of agreement for CD was higher than that obtained for LGD in both study sets. In the first study set, 4 or more pathologists agreed with the original CD diagnosis in 78% of cases, and this value did not change significantly after review of the second study set. The observers agreed that characteristic features of CD include the presence of unequivocal dysplastic cells, similar in appearance to traditional LGD, involving any part, or all of the length, of the crypt in the absence of intercrypt surface epithelial involvement. Rare cases of CD may show high-grade cytologic features composed of markedly enlarged nuclei with increased nuclear/cytoplasmic ratio, eosinophilic cytoplasm, irregular nuclear membranes, and loss of polarity. The findings in this study suggest that CD can be diagnosed reliably with a moderate level of interobserver agreement. Long-term and multi-institutional studies should be carried out to further determine the biological and clinical significance and natural history of CD in patients with BE.

Background & Aims: Patients with Barrett's esophagus (BE) show increased risk of developing esophageal adenocarcinoma and are routinely examined using upper endoscopy with biopsy to detect neoplastic changes. Angle-resolved low coherence interferometry (a/LCI) uses in vivo depth-resolved nuclear morphology measurements to detect dysplasia. We assessed the clinical utility of a/LCI in the endoscopic surveillance of patients with BE., Methods: Consecutive patients undergoing routine surveillance upper endoscopy for BE were recruited at 2 endoscopy centers. A novel, endoscope-compatible a/LCI system measured the mean diameter and refractive index of cell nuclei in esophageal epithelium at 172 biopsy sites in 46 patients. At each site, an a/LCI measurement was correlated with a concurrent endoscopic biopsy specimen. Each biopsy specimen was assessed histologically and classified as normal, nondysplastic BE, indeterminate for dysplasia, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). The a/LCI data from multiple depths were analyzed to evaluate its ability to differentiate dysplastic from nondysplastic tissue., Results: Pathology characterized 5 of the scanned sites as HGD, 8 as LGD, 75 as nondysplastic BE, 70 as normal tissue types, and 14 as indeterminate for dysplasia. The a/LCI nuclear size measurements separated dysplastic from nondysplastic tissue at a statistically significant (P < .001) level for the tissue segment 200 to 300 μm beneath the surface with an accuracy of 86% (147/172). A receiver operator characteristic analysis indicated an area under the curve of 0.91, and an optimized decision point gave 100% (13/13) sensitivity and 84% (134/159) specificity., Conclusions: These preliminary data suggest a/LCI is accurate in detecting dysplasia in vivo in patients with BE., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Context: athologists frequently assess esophageal biopsy specimens to “rule out Barrett esophagus,” as well as to assess for the presence or absence of dysplasia., Objective: To review some of the recent controversies in the diagnosis of Barrett esophagus and Barrett-related dysplasia., Data Sources: Sources were the author's experience and review of the English literature from 1978 to 2009., Conclusions: Although goblet cells are required by the American College of Gastroenterology to confirm a diagnosis of Barrett esophagus, this definition might expand to include columnar-lined esophagus without goblet cells. The recognition of dysplasia in Barrett esophagus remains a difficult task for the surgical pathologist, with difficulties in distinguishing reactive epithelium from dysplasia, low-grade dysplasia from high-grade dysplasia, and even high-grade dysplasia from intramucosal adenocarcinoma.

Background: After endoscopic radiofrequency ablation (RFA) of dysplastic Barrett's esophagus (BE), endoscopic biopsy samples are obtained to assess response to therapy. Whether these biopsies are of adequate depth to assess efficacy is unknown., Objective: To compare the depth of endoscopic biopsy samples after RFA with those of untreated controls and to determine the prevalence of subepithelial structures in endoscopic biopsy fragments., Design: Secondary analysis of the AIM Dysplasia Trial, a multicenter, randomized, sham-controlled study., Setting: Nineteen treatment centers., Patients: Subjects with dysplastic BE, either status post RFA or ablation naïve (sham)., Main Outcome Measurements: The proportion of biopsy samples demonstrating subepithelial structures, stratified by tissue type (columnar vs squamous) in sham- and RFA-treated subjects., Results: A total of 5648 biopsy fragments were analyzed from 113 subjects (78 RFA, 35 sham; mean 50.0 fragments per subject). Most fragments (4653, 82.4%) contained subepithelium. Squamous biopsy samples from RFA and sham subjects demonstrated subepithelium at similar rates (78.4% vs 79.1%, respectively, P = not significant [NS]). Columnar biopsy samples from RFA and sham subjects also included subepithelium at similar rates (99.0% vs 98.8%, respectively, P = NS). Regardless of treatment assignment, more columnar than squamous biopsy samples demonstrated subepithelium (98.8% vs 78.5%, P < .001)., Limitations: Biopsy samples were not individually mounted., Conclusions: In both squamous and columnar tissue, endoscopic biopsy samples after RFA were as likely to demonstrate subepithelium as untreated controls. Almost 80% of all biopsy samples were adequate to evaluate for subsquamous intestinal metaplasia. The primary determinant of biopsy depth is the type of epithelium that underwent biopsy, with squamous less likely to yield subepithelium than columnar. Biopsy samples after RFA appear to be of adequate depth to assess response to therapy. (Clinical trial registration number NCT00282672.)., (Copyright 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background & Aims: The optimal management of high-grade dysplasia in Barrett's esophagus remains controversial. A biopsy protocol consisting of 4 quadrant jumbo biopsies (every 1 cm) with biopsies of mucosal abnormalities (the Seattle protocol) is considered to be the optimal method for detecting early cancers in patients with high-grade dysplasia, although it has never been validated. This study aimed to determine the frequency of unsuspected carcinoma at esophagectomy in Barrett's esophagus patients with high-grade dysplasia who underwent the Seattle protocol and to compare the findings with those of a less rigorous biopsy protocol., Methods: Thirty-three patients with high-grade dysplasia underwent esophagectomy. None had obvious mass lesions at preoperative endoscopy. Patients were divided into group 1 (preoperative surveillance biopsies according to Seattle protocol) and group 2 (4 quadrant biopsies every 2 cm). Preoperative and postoperative diagnoses were confirmed by 2 expert gastrointestinal pathologists., Results: Unsuspected intramucosal cancer was found in 8 of 20 (40%) patients in group 1 versus 4 of 13 (30%) in group 2 (P = .6). Preoperative mucosal nodularity was observed in 4 of 8 (50%) postoperative intramucosal cancers from group 1 versus 3 of 4 (75%) from group 2. Multifocal high-grade dysplasia was seen preoperatively in 7 of 8 (87.5%) postoperative intramucosal cancers in group 1 versus 2 of 4 (50%) in group 2. No patient had submucosal cancer or lymph node metastases at surgery., Conclusions: Intense preoperative biopsy sampling by the Seattle protocol does not more reliably predict the detection of cancer at the time of esophagectomy than a less intensive surveillance protocol. This calls into question the concept that extensive sampling with the Seattle protocol consistently detects early cancers arising in Barrett's esophagus patients with high-grade dysplasia.

Background: Barrett's esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barrett's esophagus and decrease the rate of neoplastic progression., Methods: In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barrett's esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barrett's esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia., Results: In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture., Conclusions: In patients with dysplastic Barrett's esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.), (2009 Massachusetts Medical Society)

Objective: Grading Barrett's dysplasia at the lower end of the metaplasia-dysplasia spectrum (negative, indefinite, and low-grade dysplasia) suffers from poor interobserver agreement, even among gastrointestinal pathologists. Data evaluating interobserver agreement in Barrett's mucosal biopsies with changes at the upper end of the dysplasia spectrum (high-grade dysplasia, intramucosal, and submucosal adenocarcinoma) have not been published. The accurate categorization of pretreatment biopsies drives therapeutic decision making, but if the diagnostic distinction between cancer and high-grade dysplasia in Barrett's biopsies is inconsistent, then the use of these diagnoses to make management decisions is suspect. To this end, our aim was to assess interobserver reproducibility among a group of gastrointestinal pathologists in the interpretation of preresection biopsies., Methods: All study pathologists agreed upon the histologic criteria distinguishing four diagnostic categories, including high-grade dysplasia; high-grade dysplasia with marked distortion of glandular architecture, cannot exclude intramucosal adenocarcinoma; intramucosal adenocarcinoma; and submucosally invasive adenocarcinoma. The histologic criteria were used to independently review preresection biopsies from 163 consecutive Barrett's esophagus patients with at least high-grade dysplasia who ultimately underwent esophagectomy. Reviewers recorded the specific histologic criteria used to categorize each case and Kappa statistics were calculated to assess interobserver agreement., Results: Using kappa statistics, the overall agreement was only fair (kappa= 0.30). Agreement for high-grade dysplasia was moderate (kappa= 0.47), while agreement for high-grade dysplasia with marked architectural distortion, cannot exclude intramucosal adenocarcinoma and intramucosal adenocarcinoma were only fair (kappa= 0.21 and 0.30, respectively) and agreement for submucosal adenocarcinoma was poor (kappa= 0.14)., Conclusions: The overall poor interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barrett's cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma, and submucosal adenocarcinoma can reliably be distinguished in biopsy specimens.

Barrett's esophagus (BE) is a complication of chronic reflux that results in the replacement of esophageal squamous epithelium with columnar epithelium. BE is endoscopically recognized and pathologically confirmed. The presence of goblet cells is diagnostic. The pathologist must also determine if dysplasia or invasive cancer is present. Acceptable terms for dysplasia are no dysplasia, indefinite for dysplasia, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). It can be difficult to differentiate HGD from intramucosal cancer (IMC) in an endoscopic biopsy specimen. Treatment based on this differentiation is problematic. Indications for treatment of BE are similar to those of patients without BE. Treatment will not cause clinically significant regression of BE or prevent progression to cancer. Cancer development following successful antireflux surgery is uncommon.

Our aim was to determine whether p53 and Rab11a immunoreactivity enhance diagnostic assessment of esophageal dysplasia. Histologic sections from 68 cases of Barrett esophagus obtained as part of a 12-institution study were stained with antibodies to p53 and Rab11a, randomized, and coded. The mucosal surface layer and deeper glands were scored blindly on a semiquantitative scale. The correlations between p53 and Rab11a scoring with the consensus diagnosis of dysplasia were analyzed. The histologic scale was as follows: no dysplasia, indefinite, low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma, and invasive carcinoma. Rab11a staining was most prominent in epithelia negative for dysplasia but with regenerative features. There was an inverse relationship between Rab11a staining and findings of surface dysplasia (P < .02, chi(2)). However, statistical significance largely reflected loss of Rab11a immunoreactivity in intramucosal and invasive carcinoma, which was not a diagnostic dilemma. There was a strong positive correlation of p53 immunoreactivity with an increasing degree of epithelial dysplasia and carcinoma (P < .03, chi(2)). Rab11a immunoreactivity did not enhance the diagnostic assessment of dysplasia in Barrett esophagus. The previously reported positive correlation of p53 immunoreactivity with the presence of dysplasia in Barrett esophagus was confirmed.

A unique pattern of cytokeratin (CK) 7/20 immunostaining (diffuse staining with CK7 and surface and superficial crypt staining with CK20) has been reported to be useful in differentiating Barrett esophagus (BE) from intestinal metaplasia of the stomach. However, there are conflicting results regarding the prevalence of a BE CK7/20 staining pattern in BE between different studies. Therefore, this study was performed to determine the degree of variability in interpretation of a BE CK7/20 pattern and to determine the reasons for variability when present. Esophageal and gastric mucosal biopsies from 67 patients with BE and antral intestinal metaplasia at 2 institutions were immunostained for CK7/20. All cases were evaluated for the presence of a BE CK7/20 pattern by 2 gastrointestinal pathologists from each institution, and the degree of agreement between institutions was determined. To determine the effect of tissue fixation and staining methods on the pattern of CK7/20 staining, unstained slides were exchanged between institutions, stained separately by each institution, and reexamined by all pathologists. There was excellent agreement on the presence of a BE CK7/20 staining pattern between pathologists at the same institution but only moderate agreement between pathologists at different institutions (71% overall, kappa = 0.58). Among BE cases, a BE CK7/20 staining pattern was identified in 50 (96%) of 52 cases by Cleveland Clinic Foundation pathologists but only 35 (67%) of 52 cases by Brigham and Women's Hospital pathologists. The major source of disagreement related to the interpretation of weak or variable CK7 staining of deep intestinalized mucosa in BE biopsies that were fixed in Hollande, but not those that were fixed in formalin. After the creation of a new set of criteria for a positive BE CK7/20 staining pattern, which took into account the effects of Hollande's fixative, the degree of agreement between pathologists at each of the 2 institutions was excellent (100%, kappa value = 1.0). Therefore, the CK7/20 staining pattern is influenced by the type of fixative used. Only a moderate level of interobserver agreement among pathologists regarding a BE CK7/20 pattern can be achieved if one is not aware of these effects. Nevertheless, specific criteria for interpretation of CK7/20 staining can be successfully applied between institutions and need to be developed before use of this technique in clinical practice.

Background: Endoscopic brush cytology is a promising surveillance technique for Barrett's esophagus. However, there is a need for ancillary biomarkers to increase the sensitivity of cytology and to allow identification of patients at increased risk for disease progression. The aims of this study were to evaluate the feasibility of fluorescence in situ hybridization of endoscopic brush cytology specimens and to determine if there are specific chromosomal changes in cytologic specimens from patients with cancer that are not present in patients without dysplasia., Methods: Archival cytology slides from 16 patients with Barrett's esophagus were studied: 8 negative for dysplasia and 8 positive for adenocarcinoma. Fluorescence in situ hybridization was used to detect two alterations: HER-2 gene (17q11.2-q12) and 20q13.2 region amplification., Observations: For 7 of 8 adenocarcinoma cases, there was amplification/aneusomy of at least one of the two analyzed regions by fluorescence in situ hybridization. None of the samples negative for dysplasia were abnormal for either of the two genomic regions studied., Conclusions: Fluorescence in situ hybridization is feasible by using routine Barrett's esophagus cytologic specimens. Differences in genomic makeup can be detected in cells from patients negative for dysplasia and in those with adenocarcinoma.

Endoscopic brush cytology is a promising surveillance technique for Barrett's esophagus. Ancillary markers are sought to increase the sensitivity of cytology and allow identification of patients at increased risk for disease progression. To determine if there are specific genetic changes in Barrett's esophagus with associated high-grade dysplasia/intramucosal adenocarcinoma compared to those without dysplasia, we performed fluorescence in situ hybridization (FISH) on cytologic specimens using probes to chromosomes and genomic regions previously described as altered in this disease. We studied archival brush cytology slides from 40 Barrett's esophagus patients: 21 with biopsy-proven high-grade dysplasia/carcinoma and 19 with no dysplasia and a minimum 5 years of negative follow-up. Centromeric enumeration probes (CEP) for chromosomes 6, 7, 11, and 12, and locus-specific probes (LSI) for 9p21 (p16 gene), and 17p13.1 (p53 gene) loci along with their corresponding CEP (9 and 17, respectively) were used in this study. A positive FISH result was defined as the presence of cells with >2 CEP signals or with a loss of the LSI signals relative to their corresponding CEP. p53 locus loss and/or aneusomy of chromosomes 6, 7, 11, and 12 abnormalities could be detected by FISH in routinely processed endoscopic brush cytology specimens from 95% of biopsy-positive cases with a specificity of 100%. Interestingly, all five cases with cytologic changes classified as indefinite for dysplasia from patients with a positive biopsy showed changes by FISH. Loss of the p16 locus was seen commonly in patients both with and without dysplasia/carcinoma. Selected biomarkers from this study merit further investigation to determine their potential to detect genetic changes in patients with Barrett's esophagus prior to the development of high-grade dysplasia.

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease and can be diagnosed when there is an endoscopic abnormality in which a biopsy shows evidence of specialized columnar epithelium, characterized by the presence of acid mucin-containing goblet cells. Much of the controversy in this body of literature relates to the complex anatomy of the esophagogastric junction and the difficulty in precisely identifying this landmark at endoscopy. By definition, in Barrett's esophagus, the squamocolumnar junction is proximal to the esophagogastric junction. Although fundic-type or cardiac-type (junctional) columnar epithelium may be present in Barrett's esophagus, it is only the presence of specialized columnar epithelium that is diagnostic of this condition. Patients with Barrett's esophagus are at risk of progressing to esophageal dysplasia and adenocarcinoma. There are several problems with using dysplasia as a marker for increased cancer risk in these patients, including problems with sampling error and intra- and interobserver variation in the recognition of dysplasia. It may be difficult to distinguish regenerative epithelial changes from dysplasia, low-grade from high-grade dysplasia, and high-grade dysplasia from intramucosal adenocarcinoma. Finally, there are relatively few prospective data evaluating the natural history of high-grade dysplasia. The management of patients with Barrett's-related dysplasia is controversial and varies from institution to institution. Future emphasis should be on cost-effective techniques for sampling as much of the esophageal mucosa as possible in patients who are at the highest risk of progressing to dysplasia and adenocarcinoma. Identification of biomarkers that identify such patients before the histologic recognition of dysplasia will be an area of intensive research.

Objectives: The frequency of progression from low grade dysplasia (LGD) to high grade dysplasia/carcinoma (HGD/ CA) in Barrett's esophagus (BE) varies among studies. Current assessment is made more difficult because of pathologists' interobserver variability in diagnosing LGD. We recently conducted an interobserver study on LGD and reported a positive correlation between the extent of agreement among GI pathologists and progression of LGD. In the current study, we analyzed the immunohistochemical staining for p53 in patients diagnosed with LGD with known clinical outcome and interobserver agreement data., Methods: Fixed, paraffin-embedded endoscopic biopsy specimens from 16 patients diagnosed with LGD in BE were immunostained for p53 (DO-7, Dako, Carpinteria, CA). Hematoxylin and eosin-stained and immunostained sections were examined in tandem to determine whether the LGD areas in question stained for p53. The p53 immunoreactivity was correlated with clinical progression and with the interobserver agreement among three GI pathologists., Results: The overall mean follow-up was 23 months (range 2-84 months). LGD areas in seven of eight patients (88%) who progressed to HGD/CA stained positively for p53 compared to only two of eight nonprogressors (25%). A correlation with clinical progression was seen for p53 positivity (p = 0.017; log-rank test), and for either p53 positivity or complete agreement among three GI pathologists on LGD diagnosis (p = 0.014; log-rank test). The p53 staining demonstrated 88% sensitivity and 75% specificity for progression of LGD to HGD/CA. Adding complete interobserver agreement on LGD among three experienced GI pathologists to p53 positivity resulted in improved sensitivity with no change in specificity (100% and 75%, respectively)., Conclusions: In conjunction with histological evaluation by GI pathologists for a diagnosis of LGD, immunohistochemical staining for p53 can be used as an adjunctive test, as it correlated with progression to HGD/CA in this series.

Objectives: Several previous studies have shown that malignant progression in Barrett's metaplasia (BM) occurs even in patients treated with fundoplication or acid suppression therapy (AST). The aim of this study was to test the hypothesis that AST may not alter malignant progression in BM if key genes involved in DNA repair and cell cycle control, particularly p53, are defective., Methods: Initial and follow-up biopsies from 21 patients with BM treated with AST and observed for 1-13 yr were entered in the study. All biopsies were graded for dysplasia and evaluated for p53 protein accumulation and oxidative DNA damage by immunohiostochemistry, using antibodies to p53 and to 8-hydroxydeoxyguanosine, respectively. DNA ploidy was determined using image analysis. Statistical analysis was performed using Kaplan-Meier curves, log rank test, and multivariate regression., Results: Patients with p53 positive initial biopsies were more likely to have progression in dysplasia grade (p = 0.022) and DNA ploidy status (p = 0.023) than those with p53 negative biopsies. In eight patients AST resulted in significant reduction in oxidative DNA damage in the five patients with p53-negative initial biopsies, but not the three with p53 positive ones (p = 0.0007)., Conclusions: We conclude that failure of AST to alter malignant progression in BM may be due, at least in part, to defects in DNA repair and cell cycle control resulting from p53 gene mutation, present before AST treatment. Although AST may be effective in preventing further DNA damage, it is unlikely to alter progression in genetically unstable cells.

Biopsies from the vicinity of the esophagogastric junction occasionally show foci of intestinal metaplasia. Whether these biopsies represent Barrett's esophagus in all cases is controversial and of clinical importance because patients with Barrett's esophagus are at significantly increased risk for developing esophageal adenocarcinoma. Recent evidence suggests that intestinal metaplasia of the gastric cardia is also quite common. Although prospective data are relatively sparse, it has been suggested that the risk of progressing to dysplasia and adenocarcinoma is significantly lower for intestinal metaplasia of the gastric cardia when compared with esophageal intestinal metaplasia (Barrett's esophagus). Immunohistochemical stains for cytokeratins 7 and 20 may be useful in more precisely localizing the site of intestinal metaplasia in biopsy specimens taken from the vicinity of the esophagogastric junction. Correlation of all clinical, endoscopic, histologic, and immunohistochemical data may be used by the gastroenterologist to determine the likely source of the intestinal metaplasia and whether the patient should be followed by endoscopic surveillance., (Copyright 2002 by W.B. Saunders Company)

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease and is defined as a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy. Esophageal ulcerations and stricture are rarely seen, and the major complications of this disease are epithelial dysplasia and esophageal adenocarcinoma. Dysplasia is felt to represent the best currently available marker of increased cancer risk in these patients. However, there are many pitfalls in the histologic recognition of dysplasia, a particularly difficult problem in the face of active inflammation in patients with ongoing reflux disease. The recognition and grading of dysplasia is subject to significant interobserver variability, particularly at the lower end of the histologic spectrum (negative v indefinite for dysplasia v low-grade dysplasia). High-grade dysplasia and to a lesser degree low-grade dysplasia are markers of increased cancer risk, although their natural history are difficult to determine. Up to 40% of patients with a preoperative diagnosis of high-grade dysplasia have an adenocarcinoma in their esophagectomy specimen. Despite this observation, there is still debate as to whether esophagectomy or close endoscopic surveillance with biopsy is the most appropriate and cost-effective way to manage these patients. The search for more objective surrogate biomarkers that recognize patients who are truly at risk of progressing along the dysplasia-carcinoma sequence is underway. However, no biomarker has yet proven to be superior to the histologic recognition of dysplasia in identifying these high-risk patients.

Objectives: We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers., Methods: A group of pathologist participants were asked to contribute patients' initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients., Results: There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients., Conclusion: If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.

Background & aimsThe goal of treatment for Barrett's esophagus (BE) with dysplasia is complete eradication of intestinal metaplasia (CEIM). The long-term durability of CEIM has not been well characterized, so the frequency and duration of surveillance are unclear. We report results from a 5-year follow-up analysis of patients with BE and dysplasia treated by radiofrequency ablation (RFA) in the randomized controlled Ablation of Intestinal Metaplasia Containing Dysplasia (AIM) trial.MethodsParticipants for the AIM Dysplasia trial (18-80 years old) were recruited from 19 sites in the United States and had endoscopic evidence of non-nodular dysplastic BE ≤8 cm in length. Subjects (n = 127) were randomly assigned (2:1 ratio) to receive either RFA (entire BE segment ablated circumferentially) or a sham endoscopic procedure; patients in the sham group were offered RFA treatment 1 year later, and all patients were followed for 5 years. We collected data on BE recurrence (defined as intestinal metaplasia in the tubular esophagus) and dysplastic BE recurrence among patients who achieved CEIM. We constructed Kaplan-Meier estimates and applied parametric survival analysis to examine proportions of patients without any recurrence and without dysplastic recurrence.ResultsOf 127 patients in the AIM Dysplasia trial, 119 received RFA and met inclusion criteria. Of those 119, 110 (92%) achieved CEIM. Over 401 person-years of follow-up (mean, 3.6 years per patient; range, 0.2-5.8 years), 35 of 110 (32%) patients had recurrence of BE or dysplasia, and 19 (17%) had dysplasia recurrence. The incidence rate of BE recurrence was 10.8 per 100 person-years overall (95% CI, 7.8-15.0); 8.3 per 100 person-years among patients with baseline low-grade dysplasia (95% CI, 4.9-14.0), and 13.5 per 100 person-years among patients with baseline high-grade dysplasia (95% CI 8.8-20.7). The incidence rate of dysplasia recurrence was 5.2 per 100 person-years overall (95% CI 3.3-8.2); 3.3 per 100 person-years among patients with baseline low-grade dysplasia (95% CI 1.5-7.2), and 7.3 per 100 person-years among patients with baseline high-grade dysplasia (95% CI 4.2-12.5). Neither BE nor dysplasia recurred at a constant rate. There was a greater probability of recurrence in the first year following CEIM than in the following 4 years combined.ConclusionsIn this analysis of prospective cohort data from the AIM Dysplasia trial, we found BE to recur after CEIM by RFA in almost one third of patients with baseline dysplastic disease; most recurrences occurred during the first year after CEIM. However, patients who achieved CEIM and remained BE free at 1 year after RFA had a low risk of BE recurrence. Studies are needed to determine when surveillance can be decreased or discontinued; our study did not identify any BE or dysplasia recurrence after 4 years of surveillance.