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Objectives: Previous studies that evaluated extent of high-grade dysplasia (HGD) as a risk factor for esophageal adenocarcinoma (EA) in Barrett's esophagus (BE) were conflicting, and no prior study has evaluated extent of low-grade dysplasia (LGD) as a risk factor. The aim of this discovery study was to evaluate the hypothesis that extent of LGD and HGD are risk factors for progression to EA., Methods: We evaluated baseline biopsies from 77 BE patients with dysplasia including 44 who progressed to EA and 33 who did not progress during follow-up. The total numbers of LGD and HGD crypts were determined separately by counting all crypts and the extent of LGD, HGD, and total dysplasia were correlated with EA outcome., Results: Thirty-one and 46 patients had a maximum diagnosis of LGD and HGD, respectively. When the crypts were stratified by dysplasia grade, the mean number of LGD crypts per patient was borderline higher in progressors (93.9) compared with nonprogressors (41.2, P= 0.07), and the mean proportion of LGD crypts per patient was significantly higher in progressors (46.4%vs 26.0%, P= 0.037). Neither the mean number of HGD crypts per patient (P= 0.14) nor the mean proportion of HGD crypts per patient (P= 0.20) was significantly associated with EA outcome., Conclusions: The extent of LGD is a significant risk factor for the development of EA in BE in this study. Although the presence of HGD is significantly associated with a greater relative risk for development of EA, the extent of HGD was not an independent risk factor for progression.

Objectives: Barrett's esophagus develops in 5-10% of patients with gastroesophageal reflux disease and predisposes to esophageal adenocarcinoma. We have previously shown that a systematic baseline endoscopic biopsy protocol using flow cytometry with histology identifies subsets of patients with Barrett's esophagus at low and high risk for progression to cancer. In this report, we further examined cytometric variables to better define the characteristics that best enable DNA cytometry to help predict cancer outcome., Methods: Patients were prospectively evaluated using a systematic endoscopic biopsy protocol, with baseline histological and flow cytometric measurements as predictors and with cancer as the outcome., Results: A receiver operating curve analysis demonstrated that a 4N fraction cut point of 6% was optimal to discriminate cancer risk (relative risk [RR] = 11.7, 95% CI = 6.2-22). The 4N fractions of 6-15% were just as predictive of cancer as were fractions of >15%. We found that only aneuploid DNA contents of >2.7N were predictive of cancer (RR = 9.5, CI = 4.9-18), whereas those patients whose sole abnormality was an aneuploid population with DNA content of < or =2.7 had a low risk for progression. The presence of both 4N fraction of >6% and aneuploid DNA content of >2.7N was highly predictive of cancer (RR = 23, CI = 10-50). S phase was a predictor of cancer risk (RR = 2.3, CI = 1.2-4.4) but was not significant when high-grade dysplasia was accounted for., Conclusions: Flow cytometry is a useful adjunct to histology in assessing cancer risk in patients with Barrett's esophagus. Careful examination of cytometric variables revealed a better definition of those parameters that are most closely associated with increased cancer risk.

Objectives: Most patients with Barrett's esophagus do not progress to cancer, but those who do seem to have markedly increased survival when cancers are detected at an early stage. Most surveillance programs are based on histological assessment of dysplasia, but dysplasia is subject to observer variation and transient diagnoses of dysplasia increase the cost of medical care. We have previously validated flow cytometric increased 4N fractions and aneuploidy as predictors of progression to cancer in Barrett's esophagus. However, multiple somatic genetic lesions develop during neoplastic progression in Barrett's esophagus, and it is likely that a panel of objective biomarkers will be required to manage the cancer risk optimally., Methods: We prospectively evaluated endoscopic biopsies from 325 patients with Barrett's esophagus, 269 of whom had one or more follow-up endoscopies, by a robust platform for loss of heterozygosity (LOH) analysis, using baseline 17p (p53) LOH as a predictor and increased 4N, aneuploidy, high-grade dysplasia, and esophageal adenocarcinoma as outcomes., Results: The prevalence of 17p (p53) LOH at baseline increased from 6% in negative for dysplasia to 57% in high-grade dysplasia (p < 0.001). Patients with 17p (p53) LOH had increased rates of progression to cancer (relative risk [RR] = 16, p < 0.001), high-grade dysplasia (RR = 3.6, p = 0.02), increased 4N (RR = 6.1, p < 0.001), and aneuploidy (RR = 7.5, p < 0.001)., Conclusions: Patients with 17p (p53) LOH are at increased risk for progression to esophageal adenocarcinoma as well as high-grade dysplasia, increased 4N, and aneuploidy. 17p (p53) LOH is a predictor of progression in Barrett's esophagus that can be combined with a panel of other validated biomarkers for risk assessment as well as intermediate endpoints in prevention trials.

Objective: The of high-grade dysplasia management (HGD) in Barrett's esophagus remains controversial, in part, because of uncertainty about the ability of endoscopic biopsies to consistently detect early, curable cancers., Methods: Here we report cancers we have diagnosed in 45 patients with Barrett's HGD using a protocol involving serial endoscopies with four-quadrant biopsies taken at 1-cm intervals. We compare these results to a modeled endoscopic biopsy protocol in which four-quadrant biopsies are taken every 2 cm in the Barrett's segment., Results: Thirteen cancers were detected at the baseline endoscopy and 32 in surveillance. In 82% of patients, cancer was detected at a single 1-cm level of the esophagus, and in 69% the cancer was detected in a single endoscopic biopsy specimen. A 2-cm protocol missed 50% of cancers that were detected by a 1-cm protocol in Barrett's segments 2 cm or more without visible lesions. The maximum depth of cancer invasion was intramucosal in 96% of patients. Only 39% of patients who had endoscopic biopsy cancer diagnoses had cancer detected in the esophagectomy specimen. Adverse outcomes included the development of regional metastatic disease during surveillance (1 of 32), operative mortality (3 of 36), including two patients who had their primary surgeries at other institutions, and death from metastatic disease after endoscopic ablation performed at another institution (1 of 3)., Conclusions: A four-quadrant, 1-cm endoscopic biopsy protocol performed at closely timed intervals consistently detects early cancers arising in HGD in Barrett's esophagus and should be used in patients with HGD who do not undergo surgical resection.

Objective: Barrett's esophagus develops in 5-20% of patients with gastroesophageal reflux disease and predisposes to esophageal adenocarcinoma. The value of endoscopic biopsy surveillance is questioned because most patients do not develop cancer. Furthermore, observer variation in histological diagnosis makes validation of surveillance guidelines difficult because varying histological interpretations may lead to different estimated rates of progression. Thus, objective biomarkers need to be validated for use with histology to stratify patients according to their risk for progression to cancer., Methods: We prospectively evaluated patients using a systematic endoscopic biopsy protocol with baseline histological and flow cytometric abnormalities as predictors and cancer as the outcome., Results: Among patients with negative, indefinite, or low-grade dysplasia, those with neither aneuploidy nor increased 4N fractions had a 0% 5-yr cumulative cancer incidence compared with 28% for those with either aneuploidy or increased 4N. Patients with baseline increased 4N, aneuploidy, and high-grade dysplasia had 5-yr cancer incidences of 56%, 43%, and 59%, respectively. Aneuploidy, increased 4N, or HGD were detected at baseline in all 35 patients who developed cancer within 5 yr., Conclusions: A systematic baseline endoscopic biopsy protocol using histology and flow cytometry identifies subsets of patients with Barrett's esophagus at low and high risk for progression to cancer. Patients whose baseline biopsies are negative, indefinite, or low-grade displasia without increased 4N or aneuploidy may have surveillance deferred for up to 5 yr. Patients with cytometric abnormalities merit more frequent surveillance, and management of high-grade dysplasia can be individualized.

Objective: Widespread implementation of rigorous, systematic endoscopic biopsy protocols for patients with Barrett's esophagus may be hindered by concerns about their safety. This report describes the safety experience of a large series of patients with gastroesophageal reflux disease and Barrett's esophagus who underwent such procedures., Methods: Patients in the Seattle Barrett's Esophagus Project undergo biopsy surveillance in a research-based clinical setting, using large channel endoscopes and "jumbo" biopsy forceps. After visual inspection, multiple biopsies are obtained from lesions and at 1- to 2-cm intervals throughout the Barrett's esophageal segment., Results: From 1983 to 1997, 1,458 consecutive endoscopies were performed on 705 patients and 50,833 biopsies (average, 35; maximum, 120 per procedure) were taken. Procedures lasted from 15 to 90 min during which one to two biopsies were obtained per minute. Eleven patients experienced 18 significant adverse events, five of which led to overnight hospitalizations: two for bleeding attributed to concomitant esophageal stricture dilation; two for cardiac dysrhythmias; and one for respiratory arrest. Events managed in outpatient settings included chest pain during seven endoscopies (all accounted for by two patients), chest or epigastric pain developing after five endoscopies, and one tonsillar abrasion. All patients recovered completely, and no deaths, perforations, aspiration, or esophageal stricturing resulted from the procedures., Conclusions: A rigorous, systematic endoscopic biopsy protocol in patients with Barrett's esophagus does not produce esophageal perforation or bleeding when performed by an experienced team of physicians, nurses, and technicians.