High-grade Dysplasia In Barrett's Esophagus Research Articles

Clinical significance and management of Barrett's esophagus with epithelial changes indefinite for dysplasia.

Barrett's esophagus (BE) is defined as the extension of salmon-colored mucosa into the tubular esophagus ≥ 1 cm proximal to the gastroesophageal junction with biopsy confirmation of intestinal metaplasia. Patients with BE are at increased risk of esophageal adenocarcinoma (EAC), and undergo endoscopic surveillance biopsies to detect dysplasia or early EAC. Dysplasia in BE is classified as no dysplasia, indefinite for dysplasia (IND), low grade dysplasia (LGD) or high grade dysplasia (HGD). Biopsies are diagnosed 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 technical issues. Specific diagnostic criteria for IND are not well established and its clinical significance and management has not been well studied. Previous studies have focused on HGD in BE and led to changes and improvement in the management of BE with HGD and early EAC. Only recently, IND and LGD in BE have become focus of intense study. This review summarizes the definition, neoplastic risk and clinical management of BE IND.

Long-term outcomes of a primary complete endoscopic resection strategy for short-segment Barrett’s esophagus with high-grade dysplasia and/or early esophageal adenocarcinoma

Complete endoscopic resection (CER) of Barrett's esophagus (BE) with high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EEA) is a comprehensive and precise staging tool and may produce a sustained treatment response, preventing metachronous disease. There are limited data on long-term clinical outcomes and the sustainability of dysplasia eradication after CER. We aimed to describe long-term outcomes of a primary CER strategy of BE with HGD/EEA. Patients with biopsy-proven HGD and EEA in short-segment BE (≤ 3 cm in circumferential length and ≤ 5 cm in maximal length) underwent staged CER by multiband mucosectomy or the cap method. The primary endpoint was remission of HGD or EEA (complete resection of HGD/EEA), dysplasia (complete resection of any dysplasia), and complete resection of intestinal metaplasia. Of 153 patients (126 HGD, 27 EEA; 83.7% male, median age of 66 years) considered suitable for CER, 138 met all inclusion criteria. CER was technically successful in all patients and was established after a median of 2 sessions. Covert synchronous EEA was found in 1 patient. At a mean follow-up of 40.7 months by intention-to-treat analysis, complete remission of HGD/EEA, dysplasia, and intestinal metaplasia was achieved in 98.5%, 89.1%, and 71.0%, respectively. In 47.1% of patients, CER changed the histological grade compared with pretreatment biopsies (28.1% downstaged and 19.0% upstaged). Esophageal dilation was performed in 36.8% in a mean of 2.5 sessions. At the end of follow-up, 96.4% of patients had no or minimal dysphagia and 90.6% of patients found CER an acceptable treatment. On long-term follow-up, a primary CER strategy was a highly effective, safe, and durable treatment for HGD and EEA. Despite the need for post-CER dilation in one-third of patients, the majority found it an acceptable treatment on long-term follow-up.

Comparison of endoscopic treatment modalities for Barrett’s neoplasia

There are few data comparing endoscopic treatment outcomes for Barrett's esophagus (BE). To compare treatment outcomes in BE patients treated with radiofrequency ablation (RFA), RFA after EMR, and porfimer sodium photodynamic therapy (Ps-PDT). Retrospective, observational study. Single tertiary center between 2001 and2013. A total of 342 BE patients treated with RFA (n= 119), EMR+RFA (n= 98), and Ps-PDT (n= 125). Rates of complete remission of intestinal metaplasia (CRIM), BE recurrence, and adverse events. Baseline BE high-grade dysplasia (HGD) and adenocarcinoma were more common in the Ps-PDT group (89%) compared with the EMR-RFA (70%) and RFA (37%) groups. At a median follow-up of 14.2 months, 173 patients (50.6%) achieved CRIM. CRIM was significantly more common in Ps-PDT patients compared with RFA (P< .001) and EMR-RFA (P< .001) patients on multivariable analysis. In patients who achieved CRIM, the rates of subsequent BE recurrence were relatively similar among the 3 groups. Although the rates of bleeding were similar, strictures were less common in RFA patients (2.4%) compared with EMR-RFA (13.3%, P= .001) and Ps-PDT (10.4%, P=.043) patients. This study of endoscopic treatment for Barrett's dysplasia and neoplasia found that complete remission was achieved more often and more rapidly after Ps-PDT with similar disease recurrence rates compared with EMR or RFA. Adverse events were more common after EMR and Ps-PDT. Further studies are required to determine which ablation and resection techniques are ideally suited for each BE patient.

Endoscopic mucosal resection or ablation for Barrett’s esophagus containing high grade dysplasia: agreement strongest among expert gastroenterologists

Background and study aims: Endoscopic mucosal resection (EMR) plays an important role in the staging of Barrett’s esophagus (BE) and the evaluation of high grade dysplasia (HGD). The study aim is to assess the interobserver agreement among gastroenterologists expert in BE endotherapy, gastroenterologists without specified expertise in BE endotherapy, and gastroenterology trainees in recommending EMR vs ablation for BE HGD lesions, and to assess the effect of a one-time educational intervention on the interobserver agreement among non-experts and trainees. Patients and methods: An electronic survey containing 30 still endoscopic images of BE HGD was sent to three groups of respondents: experts, non-experts, and trainees. Respondents were asked to select “Endoscopic Mucosal Resection” or “Ablation” as the most appropriate next step in management. Non-experts and trainees were then invited to repeat the survey following an educational intervention. The main outcome measure was interobserver agreement measured by Fleiss’ Kappa statistic and percent agreement. Results: In selecting between EMR and ablation, on the pre-intervention survey there was the highest amount of agreement among experts (kappa = 0.437), followed by agreement among trainees (kappa = 0.281), and non-experts (kappa = 0.107). Experts demonstrated significantly higher agreement compared to either trainees (P < 0.001) or non-experts (P < 0.001). On the post-intervention survey, interobserver agreement remained low among both trainees (kappa = 0.20) and non-experts (kappa = 0.14). Comparing the results of the surveys, there was no evidence that agreement differed for either trainees or non-experts. Conclusions: Future efforts are needed to enable endoscopist recognition of BE HGD lesions. Consensus guidelines alone are insufficient in directing preferred endoscopic management of BE HGD.

Incidence and Predictors of Adenocarcinoma Following Endoscopic Ablation of Barrett’s Esophagus

The rate and risk factors of recurrent or metachronous adenocarcinoma following endoscopic ablation therapy in patients with Barrett's esophagus (BE) have not been specifically reported. The aim of this study was to determine the incidence and predictors of adenocarcinoma after ablation therapy for BE high-grade dysplasia (HGD) or intramucosal carcinoma (IMC). This is a single center, retrospective review of prospectively collected data on consecutive cases of endoscopic ablation for BE. A total of 223 patients with BE (HGD or IMC) were treated by ablation between 1996 and 2011. Primary outcome measures were recurrence and new development of adenocarcinoma after ablation. Recurrence was defined as the presence of adenocarcinoma following the absence of adenocarcinoma in biopsy samples from two consecutive surveillance endoscopies. Logistic regression analysis was performed to assess predictors of adenocarcinoma after ablation. One hundred and eighty-three patients were included in the final analysis, and 40 patients were excluded: 22 for palliative ablation, eight lost to follow-up, five for residual carcinoma and five for postoperative state. Median follow-up was 39 months. Recurrence or new development of adenocarcinoma was found in 20 patients (11 %) and the median time to recurrence/development of adenocarcinoma was 11.5 months. Independent predictors of recurrent or metachronous adenocarcinoma were hiatal hernia size ≥ 4 cm (odds ratio 3.649, P = 0.0233) and histology (HGD/adenocarcinoma) after first ablation (odds ratio 4.141, P = 0.0065). Adenocarcinoma after endoscopic therapy for HGD or IMC in BE is associated with large hiatal hernia and histology status after initial ablation therapy.

Su1449 Can Volumetric LASER Endomicroscopy Detect Dysplasia in Barrett's Esophagus?

Volumetric laser endomicroscopy (VLE) is a novel second-generation optical coherence tomography (OCT) device that is capable of generating in-vivo three-dimensional views of the human esophagus. This technology has not been validated in Barrett's esophagus (BE) for the detection of dysplasia. We used a scoring index based on surface maturation and glandular architecture that has been validated for high-grade dysplasia in BE using traditional OCT.

Evaluating Mutation Load in Low- and High-Grade Dysplasia in Barrett Esophagus

Evaluating Mutation Load in Low- and High-Grade Dysplasia in Barrett Esophagus

High Prevalence of Overdiagnosis of High-Grade Dysplasia in Barrett Esophagus: A Multicenter International Phase 3 Trial in 485 Patients

High Prevalence of Overdiagnosis of High-Grade Dysplasia in Barrett Esophagus: A Multicenter International Phase 3 Trial in 485 Patients

319 Recurrence of Intestinal Metaplasia After Eradication of Barrett's Esophagus With Radio Frequency Ablation - Results From a BETRNet Consortium

Background: Although the incidence of esophageal adenocarcinoma (EAC) has increased by 500% over the past 40 years, the management of Barrett's esophagus (BE), a precursor to EAC, has remained largely ineffective and controversial. Current strategies employ endoscopic surveillance with biopsy to detect early cancer or high-grade dysplasia (HGD). The eradication of BE HGD with radiofrequency ablation (RFA) has demonstrated short-term efficacy in reducing the risk of progression to EAC. However, RFA for patients with non-dysplastic BE is controversial as a relatively small percentage of these patients progress to EAC. Recently published data demonstrated: 1) the need for multiple follow-up RFA treatments; and 2) lower progression rates from non-dysplastic BE to EAC than those previously published; these findings could significantly impact the decision to treat BE with no dysplasia (ND). The aim of our study was to analyze the effectiveness and cost-effectiveness of RFA for the management of BE, both with HGD and ND. Methods: A decision analytic Markov model was constructed. Separate analyses were conducted for cohorts consisting of HGD or ND BE patients. For the HGD analysis, we compared initial RFA to endoscopic surveillance with surgery when cancer was detected. For the ND analysis, we compared three strategies (S1,S2,S3): S1) endoscopic surveillance with surgery when cancer detected; S2) endoscopic surveillance with RFA when HGD detected; S3) initial RFA for ND followed by endoscopic surveillance. The simulation began with a hypothetical cohort of 50-year-old men with BE (HGD or ND) who were followed until age 80 or death. Age-related mortality, surgical mortality, EAC mortality and complications were modeled. In sensitivity analysis, three different rates of progression from BE ND to EAC were examined. Results: HGD ANALYSIS: Endoscopic surveillance was dominated by the Initial RFA strategy. ND ANALYSIS: S1 (Surveillance, Surgery for Ca) was dominated by the S2 (Surveillance, RFA HGD). When comparing S3 (Initial RFA) to S2 (Surveillance, RFA HGD), the incremental cost-effectiveness ratios (ICER) were $277,000, $140,000, and $109,000/Quality-Adjusted-Life-Year (QALY) using overall annual progression rates from ND to EAC of 0.12%, 0.33%, or 0.5% per year, respectively (Table 1). Sensitivity analysis on the progression rate from BE ND to EAC found that S3 (Initial RFA) could be cost-effective (assuming willingness to pay threshold=$100,000 per QALY) if EAC progression rates were greater than 0.6% per year. Conclusions: Using updated rates of cancer progression, our analysis found that for HGD the initial RFA strategy is both more effective and less costly than endoscopic surveillance. For BE ND, initial RFA is not cost-effective within the range of plausible progression rates of BE ND to EAC. Table 1

Surveillance and Follow-Up Strategies in Patients With High-Grade Dysplasia in Barrett's Esophagus: A Dutch Population-Based Study

In patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE), it is incompletely known which factors are associated with developing esophageal adenocarcinoma (EAC). We analyzed prior biopsy and follow-up strategies in a large nationwide population-based cohort of patients with HGD in BE, and identified predictors of EAC progression. Prior biopsy records and follow-up evaluations were studied in patients with HGD in BE diagnosed between 1999 and 2008, using PALGA, a nationwide network and registry of histopathology and cytopathology in the Netherlands. Multivariate Cox proportional hazards regression analysis was performed to identify predictors for prevalent (≤ 6 months) and incident (> 6 months) EAC. In total, 827 patients with HGD in BE were included. Follow-up data after HGD diagnosis were available in 699 (85%) patients. In 249 (36%) of these patients, an EAC was detected (14.1 EACs per 100 person-years). The risk of prevalent EAC (n=177) was lower with previous surveillance (hazards ratio 0.7; 95% confidence interval 0.5-0.9), unifocal HGD (0.3;0.2-0.6), diagnosis in a university hospital (0.5;0.3-0.9), endoscopic resection (0.5;0.3-0.7), or ablation (0.0;0.0-0.3); and higher when patients were 65-75 years (1.5;1.04-2.04). After exclusion of prevalent EACs, the progression rate was 4.2 EACs per 100 person-years. The risk of progression to incident EAC (n = 72) was lower with previous surveillance (0.6;0.3-0.9) and ablation (0.2;0.0-0.8), and higher when > 75 years (3.8;2.0-7.2) or with an interval > 6 months between HGD diagnosis and first follow-up (e.g., 7-12 months 2.9;1.3-6.3). In this cohort of patients with HGD in BE, the EAC detection rate was 14.1 per 100 person-years and 4.2 per 100 person-years after excluding prevalent cases. The risk of both prevalent and incident EAC was reduced with previous surveillance and endoscopic treatment, while it was increased with older age.

Predictors for Neoplastic Progression in Patients With Barrett's Esophagus: A Prospective Cohort Study

Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Hybrid Therapy with EMR and RFA Throughout Treatment Sessions for Barrettʼs Neoplasia

Purpose: Patients with high grade dysplasia (HGD) and intramucosal carcinoma (IMC) in the setting of Barrett's esophagus (BE) may undergo a combination of modalities to achieve total Barrett's eradication (TBE). Initial EMR of any visible lesions followed by a radiofrequency ablation (RFA) in repeated sessions is emerging as a method to achieve TBE. Our aim is to report our initial experience with a combined approach of EMR and RFA to treat both initial and follow up lesions in the management of HGD and IMC in BE. Methods: Patients referred to our institution for the treatment of BE with HGD and IMC were enrolled in a protocol for treating long segment BE with EMR of any suspicious abnormalities in initial or follow up visits and ablation of remaining epithelium with RFA. Detailed white light exams and exams with narrow band imaging and acetic acid were performed to look for suspicious abnormalities. Follow-up sessions were performed at 3-6 month intervals. Results: Sixteen patients entered the hybrid protocol between February 2007 and May 2009 (mean age 66.9 y; 3 F: 13 M). The average length of BE was 7.8 cm. Ten patients had visible lesions. Two patients were referred with a biopsy diagnosis of IMC, and the rest had HGD. A total of 61 treatment sessions were performed with 40 EMR sessions, 20 circumferential RFA sessions, and 21 focal RFA applications. 16 sessions employed a combination of EMR and RFA. An average of 7 EMRs were performed per patient with total of 111 EMR specimens. The 2 patients with IMC had only HGD on their first EMR, whereas 3 patients with a pretreatment diagnosis of HGD were upstaged to IMC after initial EMR. Thirty-five EMR sessions were performed after an RFA session to diagnose and treat the residual BE, and 16 of these yielded pathology of HGD. Eradication of dysplasia has been achieved in 4 patients, 3 of whom also have eradication of BE. The remaining patients were still undergoing treatment sessions. Six patients have experience esophageal stenoses, managed with endoscopic dilations (median 1.5). One patient required multiple dilations and steroid injection. Conclusion: The accurate histopathologic diagnosis and deliberate treatment of neoplasia in BE may require a combination of EMR and RFA not only at the initial sessions, but also in the treatment of follow-up sessions. The most effective way to manage residual areas of neoplasia needs to be addressed.

An open-label, prospective trial of cryospray ablation for Barrett's esophagus high-grade dysplasia and early esophageal cancer in high-risk patients

Endoscopic ablation of Barrett's esophagus (BE) is a treatment option for patients with high-grade dysplasia (HGD) and intramucosal carcinoma (IMCA). To assess the safety and efficacy of a unique noncontact method of liquid nitrogen cryoablation as measured by histologic response rate and cancer-free survival. Single-center, nonrandomized cohort study. Referral center, conducted between September 2005 and September 2008. Patients with BE and HGD or IMCA who were deemed inoperable or who refused esophagectomy. Age, length of BE, and previous ablation were not exclusion criteria. Cryoablation every 6 weeks until endoscopic resolution. EMR was used for pathologic staging of nodular areas before cryoablation and focal residual areas during the follow-up period. Histologic response was defined by the worst pathology obtained at any level of the esophagus or gastric cardia in 1 of 3 categories: (1) incremental = absence of HGD and IMCA in all biopsy specimens, (2) partial = residual IMCA with absence of any dysplasia, and (3) complete = absence of any intestinal metaplasia or dysplasia. Thirty patients underwent ablation; 9 had undergone previous ablation or mucosectomy. Twenty-seven of 30 patients (90%) had downgrading of pathology stage after treatment. Elimination of cancer or downgrading of HGD at last follow-up was 68% for HGD and 80.0% for IMCA, with a median follow-up period of 12 months (25th percentile, 6; 75th percentile, 24). Minor adverse events included mild pain (n = 7), a low incidence of mild strictures (n = 3), and lip ulcer (n = 1). One major adverse event (perforation) in a patient with Marfan syndrome occurred with the prototype system. During follow-up, 3 of 6 patients with complete response had recurrence of dysplasia or cancer in the gastric cardia. A nonrandomized, single-center study with a heterogeneous cohort of patients. Patients with BE and HGD or IMCA have a positive response to endoscopic cryotherapy at 1-year follow-up.

Endoscopic and Endosonographic Predictors of Cancer in Patients with Barrett's Esophagus and High Grade Dysplasia

Background: Barrett's esophagus (BE) with high grade dysplasia (HGD) may have co-existent esophageal carcinoma and as a result traditional treatment has been esophagectomy. There has been increasing interest in endoscopic therapy as a viable alternative to esophagectomy in the management of HGD but little data exists to correctly guide patients between these treatment options. Aim: We studied patients referred for Endoscopic Ultrasound (EUS)/EGD who had BE with HGD to evaluate the ability of EGD and EUS to determine the presence of co-existing malignancy in HGD before therapy is instituted. Methods: All patients referred for evaluation of HGD in BE from October 2001 to November 2008 for EUS were included. Patients with prior biopsy proven carcinoma were excluded. A total of 53 patients met the above entry criteria. Analysis was performed to see if the findings of endoscopic nodularity, ulcer, stricture, length of BE, focal vs. multifocal HGD, or lesion seen on EUS staging predicted the presence of cancer. Cancer diagnosis was determined by histologic specimen and/or follow-up without evidence of cancer development. Mortality was confirmed for all patients as of November 2008. Results: A total of 30 out of 53 (57%) underwent esophagectomy. 5 patients had continued surveillance, 6 underwent photodynamic therapy, 6 endoscopic mucosal resection, 5 radiofrequency ablation, and 1 chemotherapy and radiation. The average length of follow-up for patients was 43 months (range 1 month to 84 months) with no new cases of adenocarcinoma. 11 patients out of 53 (20%) with HGD had proven esophageal cancer by histology. The mortality rate for the cohort was 2/53 (3.77%), both patients with proven carcinoma. Endoscopic findings of nodularity (p=0.004) and ulceration (p=0.01) predicted the presence of carcinoma. Other findings on endoscopy did not predict carcinoma including stricture (p=0.79), length of BE (p=0.11) or multifocal HGD (p=0.36). EUS stage greater than T0N0 significantly predicted cancer with an odds ratio of 49.4 and p value <0.0000001. One patient with flat HGD and a normal EUS exam was found to have intramucosal carcinoma. Conclusion: 1. The findings of nodularity and ulceration in patients with BE and HGD significantly predicts a co-existent cancer diagnosis. 2. EUS stage is the greatest independent predictor of carcinoma in patients with BE/HGD 3. Patients with flat HGD and negative EUS exam are very unlikely to have invasive cancer present and are thus are the best candidates for endoscopic therapy.

Endoscopic Cryoablation of Barrett's with High Grade Dysplasia: A Single Center Case Series

Background: Endoscopic ablation of Barrett's esophagus (BE) with high grade dysplasia (HGD) is a potential alternative to surgery in poor surgical candidates. Currently, there are multiple ablative modalities demonstrating various levels of safety and efficacy. Spray cryotherapy is considered a safe, and well tolerated procedure. Given its potential to treat both flat and nodular lesions, cryotherapy is emerging as an attractive endoscopic ablation option. Aim: Review the efficacy and safety of spray cryoablation in patients with BE with HGD at a tertiary care center. Methods: A retrospective review of records of patients undergoing spray cryotherapy for HGD in BE was done. All procedures were performed by the authors. Spray cryotherapy with low pressure liquid nitrogen was performed using the CryoSpray Ablation System (CSA Medical, Baltimore, MD). A dual lumen CryoDecompression tube was placed in the gastric antrum to evacuate the nitrogen gas when suction was activated during the procedure. The abdomen was monitored by a nurse for any signs of gastric distention. Freezing and thawing techniques were monitored by direct visualization. Dosimetry used was 10 or 20 seconds for 4 or 3 cycles respectively, followed by 60 seconds interim thaws. Results: Five male patients were treated. The BE appeared flat, ranging from 25- 100% circumferential. Two patients had short segment HGD (1cm). One patient had failed radiofrequency ablation and photodynamic therapy (PDT) with resultant post PDT stricture. Complete reversal of the intestinal metaplasia (CR-IM) and dysplasia (CR-D) was seen in all patients after an average of 1.5 treatments. Follow-up duration is 10 months and 1.5 months respectively. The other 3 patients had longer segments Barrett's with HGD (3-6 cm), one had failed radiofrequency ablation. Although still in treatment, 30-50% reduction was observed endoscopically in all patients after 2 treatment sessions (Table 1). There were no adverse events or complications including perforations, strictures, bleeding, or chest pain. Conclusions: Our early experience with endoscopic spray cryotherapy indicates that it is a safe and well-tolerated procedure. These results suggest that this technology may be an attractive alternative to other endoscopic ablative modalities.

Endoscopic Therapy for Barrett's Esophagus

Recent retrospective cohort data and a prospective randomized sham controlled trial have clearly documented the impact of endoscopic ablation therapy on dysplasia and Barrett's esophagus (BE). The clinical indications for ablation of BE includes high-grade dysplasia and intramucosal adenocarcinoma. The techniques of resection of mucosal irregularities and of ablation are reviewed, primarily thermal and photodynamic ablation. Ablation of BE with neoplasia has appropriately entered the clinical arena.

Immunohistochemical Evaluation of a Panel of Tumor Cell Markers During Malignant Progression in Barrett Esophagus

Histopathologic grading of dysplasia in Barrett esophagus (BE) shows substantial interobserver and intraobserver variation. We used immunohistochemical analysis with a set of tumor cell markers, ie, epidermal growth factor receptor (EGFR), ERBB2 (HER2/neu), MYC, CDKN2A (p16), SMAD4, MET, CCND1 (cyclin D1), CTNNB1 (beta-catenin), and TP53 (p53), in histologic sections of endoscopic biopsies of 86 patients with BE in various stages of neoplastic progression. The markers, except SMAD4, were scored as 0 (<1% of cells stained), 1 (1%-25%), 2 (26%-50%), or 3 (>50%). All markers, except EGFR, showed a significant trend for immunohistochemical protein overexpression during malignant progression in BE (P <.01). When the successive stages along the metaplasia-low-grade dysplasia (LGD)-high-grade dysplasia (HGD)-adenocarcinoma axis were compared, protein overexpression of beta-catenin separated LGD from metaplasia, whereas protein overexpression of cyclin D1 and p53 discriminated HGD from LGD (all P <.001). beta-Catenin can be helpful for a diagnosis of LGD in BE, although it stains positively in a subset only, whereas p53 remains an appropriate marker to define HGD. In case of doubt, cyclin D1 can be added to separate LGD from HGD in BE.

Paget Cells in the Esophagus: Assessment of Their Histopathologic Features and Near-universal Association With Underlying Esophageal Adenocarcinoma

Pagetoid spread of primary esophageal melanomas and several cases of pagetoid esophageal squamous cell carcinoma are known. However, true esophageal Paget disease (intraepithelial growth of neoplastic cells with glandular differentiation) has only rarely been reported. We encountered 3 endoscopic biopsy specimens containing Paget cells in squamous epithelium associated with adenocarcinomas in Barrett esophagus (BE) and in the esophagogastric junction. To determine the prevalence of Paget cells in the esophagus, we studied 81 endoscopic mucosal resections and 27 esophagectomies from patients with invasive or intramucosal adenocarcinoma, and compared the findings to a control group of 47 endoscopic mucosal resections and 25 esophagectomies from patients with high-grade dysplasia in BE. Paget cells were present in squamous epithelium overlying 5 (4.9%) of 108 adenocarcinomas but in none (0%) of 72 BE with high-grade dysplasia (P=0.16). A computerized search for primary Paget disease using the terms "Paget's and esophagus" or "pagetoid and esophagus" from 1994 to 2007 did not yield any additional cases. Among the 8 patients with Paget cells (including the 2 index biopsies) there were no differences in either sex distribution (7M:1F) or age (mean 62.4 y) as compared with 103 adenocarcinomas without Paget cells (93M:10F, P=0.58; mean age 69.2 y, P=0.78). Morphologically, all adenocarcinomas with Paget cells contained at least a component of diffuse, poorly differentiated adenocarcinoma, and 1 was a signet ring cell carcinoma. Paget cells involved only squamous epithelium directly above the poorly differentiated tumor foci. Histochemistry for periodic acid-Schiff with diastase (PAS-D) and mucicarmine, and immunohistochemistry for CK7, CK20, p53, and E-cadherin, were performed on 7 Paget cases with the following results: PAS-D+ (7 of 7, 100%), mucicarmine+ (6 of 7, 86%), CK7+ (7 of 7, 100%), CK20+ (5 of 7, 71%), p53 overexpression (3 of 7, 43%), and E-cadherin loss (complete loss in 1 and faint expression in 3, 57%). Overall, PAS-D was the most efficacious stain for highlighting Paget cells. A control group of 19 adenocarcinomas without Paget cells were also stained for E-cadherin; only 1 showed faint expression (5%) and none showed complete loss (P=0.01). These results demonstrate a low but significant prevalence (4.9%) of Paget cells in esophageal and esophagogastric junction adenocarcinomas. Unlike previously described cases of mammary, vulvar, and perianal Paget disease, esophageal Paget cells are almost universally associated with underlying adenocarcinoma and not with high grade dysplasia ("in situ" disease) or primary Paget disease. A commonality among cases with Paget cells is the presence of focal or diffuse, poorly differentiated adenocarcinoma with discohesive cells. E-cadherin alterations seem to play a less significant role.

Management of Barrett's Esophagus in the UK: Overtreated and Underbiopsied but Improved by the Introduction of a National Randomized Trial

To assess the variation in practice of Barrett's esophagus (BE) management in comparison with accepted international guidelines before and after the introduction of a large BE randomized controlled trial (RCT) with protocols including those of tissue sampling. A validated anonymized questionnaire was sent to 401 senior attending gastroenterologists asking for details of their current management of BE, especially histological sampling. Of the 228 respondents, 57 individuals (each from a different center) were in the first group to enter the ASPirin Esomeprazole (BE) Chemoprevention Trial (AspECT), and we assessed change in practice in these centers. Ninety percent of specialists did not take adequate biopsies for histological diagnosis. Furthermore, 74% would consider aggressive surgical resection for prevalent cases of high-grade dysplasia in BE as their first-line choice despite the associated perioperative mortality. Ninety-two percent claim their lack of adherence to guidelines is because there is a need for stronger evidence for surveillance and medical interventions. Effect of the AspECT trial: Those clinicians in centers where the AspECT trial has started have improved adherence to ACG guidelines compared with their previous practice (P < 0.05). BE patients now get 18.8% more biopsies compared with previous practice, and 37.7% if the patient is entered into the AspECT trial (P < 0.01). This large study indicates both wide variation in practice and poor compliance with guidelines. Because optimal histology is arguably the most important facet of BE management, the improvement in practice in centers taking part in the AspECT trial indicates an additional value of large international RCTs.

Stepwise Radical Endoscopic Resection for Complete Removal of Barrett's Esophagus with Early Neoplasia: An International Multicenter Study

Objectives: Endoscopic resection (ER) of high-grade dysplasia (HGD) or intramucosal cancer (IMC) in Barrett's esophagus (BE) is an effective and safe alternative to surgical treatment. After ER as monotherapy, recurrent lesions may develop elsewhere in the residual BE during follow-up (FU). Stepwise radical endoscopic resection (SRER) allows for removal of the whole BE by subsequent ERs with histological correlation and has been shown effective and safe in small-sized single-center studies. The aim of this study was to evaluate the efficacy and safety of SRER for BE-HGD/IMC in 4 European tertiary referral centres that used a prospective SRER protocol in the past years. Methods: Patients with HGD or IMC in BE ≤5 cm, without signs of submucosal infiltration or lymph node metastases on endoscopy or endosonography, were included. Patients underwent ER sessions (cap, multiband mucosectomy or simple snare technique) with intervals of 4-8 weeks until complete eradication of BE. Results: 151 BE patients with HGD or IMC, treated between Jan 2000 and Sept 2006 were included. Two patients discontinued treatment due to unrelated comorbidity. Complete eradication of early neoplasia was achieved in 148/149 patients (99%) after a median number of two ER sessions (IQR 2-3). One patient with persisting IMC after 6 therapeutic sessions was referred for esophagectomy. Complete removal of all intestinal metaplasia (IM) was achieved in 145/149 (97%) patients. Complications occurred in 1% of ER procedures: 2 perforations treated conservatively and 2 delayed bleedings treated with endoscopic hemostatic techniques. Symptomatic stenosis occurred in 79 patients (52%) and was effectively treated by endoscopic dilatations. There was a significant trend in stenosis rate with increasing BE length (Chi square for trend; p = 0.04). Two patients had a perforation during endoscopic dilatation that was treated by stenting and esophagoectomy. During a median FU of 18 mo (IQR 7-31), 4 (3%) patients had recurrence of neoplasia, treated with repeat ER in 3 and curative surgery in one. Seven patients (5%) had recurrence of visible BE mucosa (generally small islands) and 12 (8%) patients had IM detected distal to neo-z-line. Subsquamous IM was found in 9 patients (6%), all had undergone additional APC. Discussion: SRER for BE-HGD/IMC <5 cm allows for removal of the whole BE with histological correlation and is associated with a low recurrence rate during FU. Severe complications are rare but about 50% of patients develop an esophageal stenosis.