Sharad C. Mathur

Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett's oesophagus: a prospective, international, randomised controlled trial

Background White light endoscopy with random biopsies is the standard for detection of intestinal metaplasia (IM) and neoplasia in patients with Barretts oesophagus (BO). Narrow band imaging (NBI) highlights surface patterns that correlate with IM and neoplasia in BO. Objective To compare high-definition white light (HD-WLE) and NBI for detection of IM and neoplasia in BO. Design International, randomised, crossover trial comparing HD-WLE and NBI. Patients referred for BO screening/surveillance at three tertiary referral centres were prospectively enrolled and randomised to HD-WLE or NBI followed by other procedures in 3–8 weeks. During HD-WLE, four quadrant biopsies every 2 cm, together with targeted biopsies of visible lesions (Seattle protocol), were obtained. During NBI examination, mucosal and vascular patterns were noted and targeted biopsies were obtained. All biopsies were read by a single expert gastrointestinal pathologist in a blinded fashion. Results 123 patients with BO (mean age 61; 93% male; 97% Caucasian) with mean circumferential and maximal extents of 1.8 and 3.6 cm, respectively, were enrolled. Both HD-WLE and NBI detected 104/113 (92%) patients with IM, but NBI required fewer biopsies per patient (3.6 vs 7.6, p<0.0001). NBI detected a higher proportion of areas with dysplasia (30% vs 21%, p=0.01). During examination with NBI, all areas of high-grade dysplasia and cancer had an irregular mucosal or vascular pattern. Conclusions NBI targeted biopsies can have the same IM detection rate as an HD-WLE examination with the Seattle protocol while requiring fewer biopsies. In addition, NBI targeted biopsies can detect more areas with dysplasia. Regular appearing NBI surface patterns did not harbour high-grade dysplasia/cancer, suggesting that biopsies could be avoided in these areas.

Risk Factors for Progression of Low-Grade Dysplasia in Patients With Barrett's Esophagus

BACKGROUND & AIMS Data vary on the progression of low-grade dysplasia (LGD) in patients with Barretts esophagus (BE); in patients with LGD, we investigated the incidence of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) and compared progression in patients with different forms of LGD (prevalent vs incident and multifocal vs unifocal). We assessed the effects of consensus diagnosis of LGD on progression rates to HGD and EAC among expert pathologists. METHODS In a multicenter outcomes project, 210 patients with BE and LGD (classified as incident, prevalent, or persistent) were included. Patients were followed up for an average of 6.2 years (959.6 patient-years). Persistent LGD was defined as detection of LGD on ≥2 consecutive occasions during the follow-up period and extent as either unifocal (LGD at one level of BE segment) or multifocal (>1 level). Histology specimens were reviewed by 2 blinded pathologists. RESULTS Six patients developed EAC (incidence of 0.44%/year), and 21 developed HGD (incidence of 1.6%/year). The incidence of the combination of HGD and EAC was 1.83%/year. There were no associations between presence of prevalent, incident, or persistent LGD and the extent of LGD with progression rates. Based on consensus diagnosis of 88 reviewed specimens, there was no difference in the progression of LGD to either EAC (the incidence based on analyses by the local pathologist was 0.18%/year, the incidence when there was agreement between the local and one central pathologist was 0.21%/year, and the incidence when all 3 pathologists were in agreement was 0.39%/year) or combined HGD and EAC (0.94%/year, 0.87%/year, and 0.84%/year, respectively). CONCLUSIONS Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.

Patients With Nondysplastic Barrett's Esophagus Have Low Risks for Developing Dysplasia or Esophageal Adenocarcinoma

BACKGROUND & AIMS The risks of dysplasia and esophageal adenocarcinoma (EAC) are not clear for patients with nondysplastic Barretts esophagus (NDBE); the rate of progression has been overestimated in previous studies. We studied the incidences of dysplasia and EAC and investigated factors associated with progression of BE. METHODS The BE study is a multicenter outcomes project of a large cohort of patients with BE. Neoplasia was graded as low-grade dysplasia, high-grade dysplasia (HGD), or EAC. Patients followed up for at least 1 year after the index endoscopy examination were included, whereas those diagnosed with dysplasia and EAC within 1 year of diagnosis with BE (prevalent cases) were excluded. Of 3334 patients with BE, 1204 met the inclusion criteria (93.7% Caucasian; 88% male; mean age, 59.3 y) and were followed up for a mean of 5.52 years (6644.5 patient-years). RESULTS Eighteen patients developed EAC (incidence, 0.27%/y; 95% confidence interval [CI], 0.17-0.43) and 32 developed HGD (incidence, 0.48%/y; 95% CI, 0.34-0.68). The incidence of HGD and EAC was 0.63%/y (95% CI, 0.47-0.86). There were 217 cases of low-grade dysplasia (incidence, 3.6%/y; 95% CI, 3.2-4.1). Five and 10 years after diagnosis, 98.6% (n = 540) and 97.1% (n = 155) of patients with NDBE were cancer free, respectively. The length of the BE was associated significantly with progression (EAC <6 cm, 0.09%/y vs EAC ≥ 6 cm, 0.65%/y; P = 0.001). CONCLUSIONS There is a lower incidence of dysplasia and EAC among patients with NDBE than previously reported. Because most patients are cancer free after a long-term follow-up period, surveillance intervals might be lengthened, especially for patients with shorter segments of BE.

Risk Stratification of Barrett's Esophagus: Updated Prospective Multivariate Analysis

OBJECTIVES:Prospective evaluation of Barretts esophagus (BE) in order to determine what demographic, endoscopic, and histologic features are predictive of the prevalence and incidence of Barretts high-grade dysplasia (HGD) and adenocarcinoma (Ca).METHODS:Newly diagnosed BE patients were entered into and followed in a standardized surveillance protocol. The following features were examined using either forward, stepwise multiple regression analysis, or Cox proportional hazards to determine their ability to predict the presence of HGD or Ca at index BE diagnosis as well as their ability to predict progression of BE during follow-up: age, race, gender, length of BE in cm, size of a hiatal hernia, severity of dysplasia at index diagnosis as well as during surveillance, gastric Helicobacter pylori infection status, and type of medical acid-reflux treatment.RESULTS:A total of 550 patients were diagnosed with BE over the study period. Stepwise multiple regression analysis showed three factors significantly associated with index diagnosis of HGD or Ca: hiatal hernia (larger size), Barretts length (longer length), and absence of H. pylori infection. Three hundred and twenty-four BE entered the surveillance protocol. Cox proportional hazards models revealed a significant and independent association for five factors predictive of the time to progression of BE: presence of dysplasia at index diagnosis (p < 0.001), severity of dysplasia during surveillance (p < 0.001), length of Barretts epithelium (p = 0.012), size of hiatal hernia (p = 0.006), and gastric H. pylori infection status (p = 0.023).CONCLUSIONS:Endoscopic and histologic features of BE at initial diagnosis are predictive of index HGD and cancer as well as with risk of BE progression.

Detection of Barrett's esophagus after endoscopic healing of erosive esophagitis

BACKGROUND:The presence of erosive esophagitis (EE) in patients presenting for upper endoscopy may prevent the detection of underlying Barretts esophagus (BE) in the distal esophagus.AIM:To prospectively determine the proportion of patients detected with BE upon repeat endoscopy after healing of EE.METHODS:Patients with endoscopically confirmed EE without BE were treated with standard doses of acid suppression therapy and a repeat endoscopy was performed to assess the presence of BE. If columnar mucosa was visualized in the distal esophagus, targeted biopsies were obtained and all biopsies were evaluated for the presence of intestinal metaplasia. BE was defined as columnar mucosa in the distal esophagus with intestinal metaplasia on biopsy.RESULTS:A total of 172 patients with reflux symptoms were diagnosed with EE without BE on initial endoscopy. They were treated with standard doses of proton pump inhibitor therapy, and after a mean duration of 11 wk (range 8–16 wk), a repeat endoscopy was performed to confirm healing of EE and to document the presence of BE. On repeat endoscopy, EE was completely healed in 116 patients (67%), and of those, BE was suspected in 32 patients (i.e., columnar-lined distal esophagus) and was confirmed in 16 patients (13.8%). In the 56 patients with persistent EE on repeat endoscopy, columnar mucosa in areas of previously healed esophagitis was visualized in 8 and confirmed in 5 patients (8.9% of nonhealed cases). Overall, 21 (12%) patients were confirmed with BE on repeat endoscopy; all men, mean age 61 yr with a median BE length of 0.5 cm (range 0.5–5 cm, interquartile range 0.5 cm). The majority of these patients (N = 19) had short segment Barretts esophagus (SSBE) (i.e., length <3 cm).CONCLUSIONS:In patients with EE undergoing treatment with acid suppressive therapy, BE (mainly SSBE) is detected in approximately 12% of patients on repeat endoscopy. Patients with reflux symptoms undergoing endoscopy for the detection of BE (i.e., screening) should be treated with acid suppressive therapy prior to endoscopy to enhance the yield of BE. Alternatively, if the goal is to document BE and if EE is found at the initial endoscopy, then repeat endoscopy may be considered after acid suppressive therapy.

The diagnostic accuracy of esophageal capsule endoscopy in patients with gastroesophageal reflux disease and Barrett's esophagus: a blinded, prospective study.

BACKGROUND:Esophageal capsule endoscopy (ECE) is a novel technique that offers noninvasive evaluation of esophageal pathology in gastroesophageal reflux disease (GERD) patients.OBJECTIVE:To assess the diagnostic accuracy of ECE for Barretts esophagus (BE), erosive esophagitis, and hiatal hernia and to assess the safety profile of ECE.METHODS:Patients with GERD symptoms and those undergoing BE surveillance were prospectively enrolled. All patients underwent ECE followed by standard upper endoscopy. ECE findings were interpreted by examiners blinded to endoscopy results. The gold standard was the findings at endoscopy and ECE results were compared with those at endoscopy.RESULTS:One hundred patients were enrolled of which 94 completed the study. At upper endoscopy, BE was suspected in 53 (mean length 3.1 cm) and confirmed in 45 patients. Erosive esophagitis and hiatal hernia were identified in 18 and 70 patients, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ECE for BE in GERD patients were 67%, 87%, 60%, and 90%, respectively. The sensitivity, specificity, PPV, and NPV of ECE for BE patients undergoing surveillance were 79%, 78%, 94%, and 44%, respectively. The sensitivity, specificity, PPV, and NPV for erosive esophagitis were 50%, 90%, 56%, and 88% and for hiatal hernia were 54%, 67%, 83%, and 33%, respectively.CONCLUSIONS:Current diagnostic rates of ECE for BE are not yet accurate enough for application in clinical practice. An improvement in technology and learning curve assessments are required, until then standard upper endoscopy remains the gold standard.

Feasibility of MicroRNAs as Biomarkers for Barrett's Esophagus Progression: A Pilot Cross-Sectional, Phase 2 Biomarker Study

OBJECTIVES:Risk stratification of Barretts esophagus (BE) using biomarkers remains an important goal. We evaluated feasibility and clinical accuracy of novel microRNA (miRNA) biomarkers for prediction of BE dysplasia.METHODS:Paired fresh-frozen and hematoxylin/eosin specimens from a prospective tissue repository where only biopsies with the lesion of interest (i.e., intestinal metaplasia (IM) or high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC)) occupying >50% of biopsy area were included. Tissue miRNA expression was determined by microarrays and validated by quantitative reverse transcription-PCR (qRT-PCR). Three groups were compared—group A, IM tissues from BE patients without dysplasia; group B, IM tissues from group C patients; and group C, dysplastic tissues from BE patients with HGD/EAC.RESULTS:Overall, 22 BE patients, 11 with and without dysplasia (mean age 64±8.2 and 63±11.6 years, respectively, all Caucasian males) were evaluated. Nine miRNAs were identified by high-throughout analysis (miR-15b, -21, -192, -205, 486-5p, -584, -1246, let-7a, and -7d) and qRT-PCR confirmed expression of miR-15b, -21, 486-5p, and let-7a. Two of 4 miRNAs (miR-145 and -203, but not -196a and -375) previously described in BE patients also exhibited differential expression. Sensitivity and specificity of miRNAs for HGD/EAC were miR-15b: 87 and 80%, miR-21: 93 and 70%, miR-203: 87 and 90%, miR-486-5p: 82 and 55%, and miR-let-7a: 88 and 70%. MiRNA-15b, -21, and -203 exhibited field effects (i.e., groups A and B tissues while histologically similar yet exhibited different miRNA expression).CONCLUSIONS:This pilot study demonstrates feasibility of miRNAs to discriminate BE patients with and without dysplasia with reasonable clinical accuracy. However, the specific miRNAs need to be evaluated further in future prospective trials.

Correlation between narrow band imaging and nonneoplastic gastric pathology: a pilot feasibility trial.

BACKGROUND A novel narrow band imaging (NBI) system is able to visualize the mucosal and vascular network in the GI tract. OBJECTIVE The aim of the current study was to test the feasibility of NBI to predict gastric histologic diagnosis. DESIGN A pilot feasibility study. SETTING Veterans Affairs Medical Center. PATIENTS Forty-seven patients undergoing upper endoscopy for various indications were prospectively enrolled. METHODS The gastric body and antrum were systematically examined by NBI before targeted biopsies. Images were graded according to the mucosal (ridge/villous and circular) and vascular patterns and correlated with histologic findings in a blinded manner. MAIN OUTCOME MEASUREMENTS Final histologic diagnosis based on updated Sydney classification system. RESULTS Overall, 25 patients (53.1%) had a normal biopsy specimen, 13 (27.6%) had non-Helicobacter pylori gastritis, 4 (8.5%) had H pylori gastritis, and 5 (10.6%) had intestinal metaplasia. The sensitivity, specificity, and positive predictive value of a regular mucosal and vascular pattern for the diagnosis of normal mucosa/mild gastritis were 89%, 78%, and 94%, respectively. The sensitivity and specificity of an irregular pattern with decreased density of vessels for the diagnosis of H pylori were 75% and 88%, and that of the ridge/villous pattern for the diagnosis of intestinal metaplasia were 80% and 100%, respectively. LIMITATION The small number of patients with H pylori and intestinal metaplasia was the main limitation. CONCLUSIONS This is the first U.S. study of NBI for gastric lesions. NBI may help predict in vivo histologic diagnosis of gastric pathologic conditions with a good degree of accuracy. Future larger studies are needed.

Adequacy of esophageal squamous mucosa specimens obtained during endoscopy: are standard biopsies sufficient for postablation surveillance in Barrett's esophagus?

BACKGROUND After endoscopic eradication therapy (EET) for Barretts 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.

Visible endoscopic and histologic changes in the cardia, before and after complete Barrett's esophagus ablation

BACKGROUND Adverse events associated with the thermal ablation of Barretts esophagus (BE) include the generation of gastric mucosa buried beneath the neosquamous regrowth, and unrecognized development and growth of adenocarcinomas. No reports exist regarding the endoscopic appearance and histology of the cardia before and after BE ablation. The aim of our study was to assess the relative frequency of the occurrence of visible endoscopic and histologic changes in the cardia, before and after complete BE ablation. METHODS A subset analysis of patients with uncomplicated BE, BE with dysplasia, or early carcinoma, who had been enrolled into one of 4 ongoing prospective studies of mucosal ablation, was examined. Eighty-two patients were identified who entered a BE ablation study, with 75 of these completing BE mucosal ablation. Cardia biopsy specimens were taken in all patients before ablation and serially after BE ablation. Cardia histology was graded by using the modified Sydney System for gastritis. RESULTS Before ablation, cardia nodules were noted in 3, cardia intestinal metaplasia (IM) in 7 (8.5%), and none harbored cardia dysplasia. Postablation surveillance ranged from 3 to 75 months (mean 31.1 months [19.5]). Six subjects (8%) developed cardia nodules during surveillance; cardia IM was found in 21(28%), with 17 of these being a new finding (incidence of 25%). Cardia low-grade dysplasia incidence was 1.3% and high-grade dysplasia was 4% after BE ablation. CONCLUSIONS The pathophysiology of the abnormal cardia histology and the endoscopic lesions (nodules) is unclear, but endoscopic surveillance of not only the neosquamous epithelium but also the cardia should be considered after ablation, especially in those high-grade dysplasia and early adenocarcinoma BE patients.