Clarisse Bohmer

Low-Grade Dysplasia in Barrett's Esophagus: Overdiagnosed and Underestimated

OBJECTIVES:Published data on the natural history of low-grade dysplasia (LGD) in Barretts esophagus (BE) are inconsistent and difficult to interpret. We investigated the natural history of LGD in a large community-based cohort of BE patients after reviewing the original histological diagnosis by an expert panel of pathologists.METHODS:Histopathology reports of all patients diagnosed with LGD between 2000 and 2006 in six non-university hospitals were reviewed by two expert pathologists. This panel diagnosis was subsequently compared with the histological outcome during prospective endoscopic follow-up.RESULTS:A diagnosis of LGD was made in 147 patients. After pathology review, 85% of the patients were downstaged to non-dysplastic BE (NDBE) or to indefinite for dysplasia. In only 15% of the patients was the initial diagnosis LGD. Endoscopic follow-up was carried out in 83.6% of patients, with a mean follow-up of 51.1 months. For patients with a consensus diagnosis of LGD, the cumulative risk of progressing to high-grade dysplasia or carcinoma (HGD or Ca) was 85.0% in 109.1 months compared with 4.6% in 107.4 months for patients downstaged to NDBE (P<0.0001). The incidence rate of HGD or Ca was 13.4% per patient per year for patients in whom the diagnosis of LGD was confirmed. For patients downstaged to NDBE, the corresponding incidence rate was 0.49%.CONCLUSIONS:LGD in BE is an overdiagnosed and yet underestimated entity in general practice. Patients diagnosed with LGD should undergo an expert pathology review to purify this group. In case the diagnosis of LGD is confirmed, patients should undergo strict endoscopic follow-up or should be considered for endoscopic ablation therapy.

Endoscopic trimodal imaging versus standard video endoscopy for detection of early Barrett's neoplasia: a multicenter, randomized, crossover study in general practice

BACKGROUND Endoscopic trimodal imaging (ETMI) may improve detection of early neoplasia in Barretts esophagus (BE). Studies with ETMI so far have been performed in tertiary referral settings only. OBJECTIVE To compare ETMI with standard video endoscopy (SVE) for the detection of neoplasia in BE patients with an intermediate-risk profile. DESIGN Multicenter, randomized, crossover study. SETTING Community practice. PATIENTS AND METHODS BE patients with confirmed low-grade intraepithelial neoplasia (LGIN) underwent both ETMI and SVE in random order (interval 6-16 weeks). During ETMI, BE was inspected with high-resolution endoscopy followed by autofluorescence imaging (AFI). All visible lesions were then inspected with narrow-band imaging. During ETMI and SVE, visible lesions were sampled followed by 4-quadrant random biopsies every 2 cm. MAIN OUTCOME MEASUREMENTS Overall histological yield of ETMI and SVE and targeted histological yield of ETMI and SVE. RESULTS A total of 99 patients (79 men, 63±10 years) underwent both procedures. ETMI had a significantly higher targeted histological yield because of additional detection of 22 lesions with LGIN/high-grade intraepithelial neoplasia (HGIN)/carcinoma (Ca) by AFI. There was no significant difference in the overall histological yield (targeted+random) between ETMI and SVE. HGIN/Ca was diagnosed only by random biopsies in 6 of 24 patients and 7 of 24 patients, with ETMI and SVE, respectively. LIMITATIONS Inspection, with high-resolution endoscopy and AFI, was performed sequentially. CONCLUSION ETMI performed in a community-based setting did not improve the overall detection of dysplasia compared with SVE. The diagnosis of dysplasia is still being made in a significant number of patients by random biopsies. Patients with a confirmed diagnosis of LGIN have a significant risk of HGIN/Ca. ( CLINICAL TRIAL REGISTRATION NUMBER ISRCTN91816824; NTR867.).

Combining Autofluorescence Imaging and Narrow-Band Imaging for the Differentiation of Adenomas from Non-Neoplastic Colonic Polyps Among Experienced and Non-Experienced Endoscopists

OBJECTIVES:Endoscopic tri-modal imaging incorporates high-resolution white-light endoscopy (HR-WLE), narrow-band imaging (NBI), and autofluorescence imaging (AFI). Combining these advanced techniques may improve endoscopic differentiation between adenomas and non-neoplastic polyps. In this study, we aimed to assess the interobserver variability and accuracy of HR-WLE, NBI, and AFI for polyp differentiation and to evaluate the combined use of AFI and NBI.METHODS:First, still images of 50 polyps (22 adenomas; median 3 mm) were randomly displayed to three experienced and four non-experienced endoscopists. All HR-WLE and NBI images were scored for Kudo classification and AFI images for color. Second, the combined AFI and NBI images were assessed using a newly developed algorithm by six additional non-experienced endoscopists.RESULTS:The outcomes measured were interobserver agreement and diagnostic accuracy using histopathology as reference standard. Experienced endoscopists had better interobserver agreement for NBI (κ=0.77) than for AFI (κ=0.33), whereas non-experienced endoscopists had better agreement for AFI (κ=0.58) than for NBI (κ=0.33). The accuracies of HR-WLE, NBI, and AFI among experienced endoscopists were 65, 70, and 74, respectively. Figures among non-experienced endoscopists were 57, 63, and 77. The algorithm was associated with a significantly higher accuracy of 85% among all observers (P<0.023). These figures were confirmed in the second evaluation study.CONCLUSIONS:Non-experienced endoscopists have better interobserver agreement and accuracy for AFI than for HR-WLE or NBI, indicating that AFI is easier to use for polyp differentiation in non-experienced setting. The newly developed algorithm, combining information of AFI and NBI together, had the highest accuracy and obtained equal results between experienced and non-experienced endoscopists.

Derivation of genetic biomarkers for cancer risk stratification in Barrett’s oesophagus: a prospective cohort study

Objective The risk of developing adenocarcinoma in non-dysplastic Barretts oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barretts oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barretts length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an ‘Abnormal Marker Count’ that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barretts length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). Conclusions A prediction model based on age, Barretts length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barretts oesophagus.

Su1181 A Diagnostic DNA FISH Biomarker Assay Identifies HGD or EAC in Barrett Esophagus

examine the effect of acid on Wnt/β-catenin signaling activation and on regulating the expression of Dickkopf1 (DKK1), an inhibitor of the Wnt. Methods: Normal esophageal squamous cells lines (EPC1-hTERT, EPC2-hTERT), a non-dysplastic Barretts esophageal cell line (CP-A) and an esophageal adenocarcinoma cell line (OE33) were exposed to acidic media (pH 4.0) in a pulsive manner. Human esophageal mucosal biopsies in triplicate from healthy (n=1), NERD (n=1), GERD (n=1) and Barretts (n=1) patients were obtained and cultured in acidic (pH 4.0) or non acidic media. Localization and levels of β-catenin were determined by Immunofluorescence staining and Western blot. Wnt-activity was assessed by Luciferase assay following transfection with β-catenin-LEF/TCF-sensitive (TOP) or βcatenin-LEF/TCF insensitive (FOP) reporter vector. Immunofluorescence was used for βcatenin and E-Cadherin co-localization. DKK1 and β-catenin gene expression was resolved by qRT-PCR. DKK1 secretion in cells culture media and organ culture media was quantified by ELISA assay.Results: Acid destabilized E-cadherin/β-catenin complex in cell-cell junctions and resulted in β-catenin translocation to nucleus. Wnt-activity correlated with nuclear translocation of β-catenin. Cytosolic shuttling of β-catenin occurred in a rapid and transient manner after acid withdrawal. Chronic pulsed acid exposure increased DKK1 expression in normal squamous cells but not in metaplastic columnar cells. DKK1 overexpression correlated with a significant degradation of β-catenin. Mucosal biopsies from patients with NERD/ GERD secreted significantly higher levels of Dkk1 than healthy and metaplastic mucosa biopsies. Conclusions: These findings suggest that acid reflux induces the activation of Wnt-signaling pathway and that the overexpression of DKK1 is the long term response in the normal squamous esophageal tissue but not in the Barretts esophagus. These findings also suggest a homeostatic role for DKK1 in GERD and its dysfunction to be a potential mechanism for progression to Barretts metaplasia.