Rachel Cherian

Long-term follow-up of Barrett's high-grade dysplasia

OBJECTIVE:The management of Barretts high-grade dysplasia (HGD) remains controversial. The aims of this study were to evaluate prospectively the outcome of unifocal HGD (uHGD) in patients with Barretts esophagus, and to determine demographic and endoscopic features predictive of progression to multifocal HGD (mHGD) and/or adenocarcinoma.METHODS:Consecutive Barretts patients in whom uHGD was found at initial endoscopy or during surveillance underwent intensification of medical treatment and repeat endoscopy. The study endpoint was progression to mHGD or adenocarcinoma or HGD in conjunction with a dysplasia-associated lesion or mass (DALM). HGD diagnosis was confirmed by a second, blinded pathologist.RESULTS:A total of 15 Barretts patients with uHGD met inclusion criteria and have been prospectively followed for a mean ± SD of 36.8 ± 23.2 months. All were white and male, with a mean age ± SD of 61.4 ± 14.9 yr. Barretts length varied from 1 to 13 cm (mean, ± SD, 6.8 ± 4 cm). Overall, eight (53.3%) uHGD progressed: four of 15 (26.7%) to frank cancer between 17 and 35 months of follow-up, two of 15 (13.3%) to mHGD with DALM in conjunction with one or more foci of possible intramucosal cancer after 12–91 months of follow-up, one of 15 (6.7%) to mHGD with a focus of possible intramucosal cancer after 14 months, and one of 15 (6.7%) to mHGD after 29 months. Seven of 15 (46.7%) uHGD have regressed, five to no dysplasia and two to LGD, over the course of follow-up ranging from 24 to 73 months (mean ± SD, 43.3 ± 19.9). All three patients with short-segment Barretts esophagus with uHGD regressed. Fishers exact test revealed that Barretts length ≥3 cm and presence of hiatal hernia approached significance (p < 0.08) in predicting uHGD progression to mHGD/DALM/cancer. However, use of the log-rank test to account for differences in length of follow-up show no significance for hiatal hernia or Barretts length.CONCLUSIONS:Barretts uHGD has a high risk for progressing to mHGD or cancer. Justification of an observational approach to uHGD should be discouraged. Markers of uHGD progression, as well as regression, are needed.

p53 protein overexpression in low grade dysplasia (LGD) in barrett’s esophagus: Immunohistochemical marker predictive of progression ☆

OBJECTIVES:The presence of low grade dysplasia (LGD) within Barretts esophagus (BE) has a multitude of ramifications. Identification of markers that could risk stratify LGD would be of great clinical benefit. We aimed to prospectively evaluate the prognosis of the immunohistochemical overexpression of p53 protein in BE colocalized to LGD.METHODS:Consecutive BE patients in whom LGD was found had a repeat esophagogastroduodenoscopy within 8–12 wk per an ongoing prospective study. At each esophagogastroduodenoscopy, a therapeutic scope was used in conjunction with the Seattle Biopsy Protocol. Patients were observed until development of multifocal high grade dysplasia (mHGD), presence of an HGD dysplasia-associated lesion or mass (DALM) lesion, or frank adenocarcinoma. p53 protein overexpression was determined by computerized immunoquantitation using image analysis software on step serial-sectioned specimens of BE segment(s) harboring LGD. Kaplan-Meier survival curves were made on the ability of p53 staining colocalized to areas of LGD to predict progression to mHGD, HGD DALM, or cancer during prospective follow-up.RESULTS:Forty-eight BE patients with LGD were observed for a mean of 41.2 ± 22.5 months. During this period, five of 48 patients progressed to mHGD with a focus in which intramucosal cancer could not be excluded (one), mHGD/DALM with one or more foci in which intramucosal cancer could not be excluded (two), cancer (one), or mHGD (one). Twelve had persistent LGD and 31 had regressed to no dysplasia. p53 staining was positive and colocalized to areas of LGD in 4/31 of patients that regressed, 3/12 that persisted, and 3/5 that progressed. Kaplan-Meier curves differed significantly between p53 positive and negative patients for outcome defined as progression of LGD.CONCLUSIONS:p53 colocalization with LGD at index LGD diagnosis is a risk factor for progression of LGD. This can potentially be used to risk stratify BE LGD patients in terms of surveillance intervals or enrollment into secondary prevention studies.

Prospective evaluation of the prevalence of gastric Helicobacter pylori infection in patients with GERD, Barrett's esophagus, Barrett's dysplasia, and Barrett's adenocarcinoma

OBJECTIVE:This study was undertaken to prospectively determine the prevalence of gastric H. pylori infection in Barretts esophagus and Barretts complicated by dysplasia or adenocarcinoma.METHODS:The prevalence of H. pylori was determined in Barretts esophagus patients compared to a control population of patients with gastroesophageal reflux disease (GERD) only. All patients had a minimum of 10 gastric surveillance biopsies obtained. H. pylori colonization was determined upon the basis of hematoxylin and eosin and use of a modified Giemsa and or Steiners silver stain of all gastric biopsy specimens.RESULTS:Two hundred and eighty-nine Barretts patients and 217 GERD control patients were included in the study. H. pylori was found in 95/289 (32.9%) of the Barretts patients, compared with 96/217 (44.2%) of the GERD controls (NS). Forty-seven of the Barretts patients had low-grade dysplasia/indefinite dysplasia, 14 high-grade dysplasia, and 20 Barretts adenocarcinoma. When Barretts was subgrouped according to absence of dysplasia, and presence of low-grade dysplasia, high-grade dysplasia, or adenocarcinoma, H. pylori prevalence was found to be significantly less for patients with Barretts high-grade dyslpasia (14.3%) and adenocarcinoma (15.0%) versus patients with GERD alone (44.2%), Barretts alone (35.1%), or Barretts with low-grade dysplasia (36.2%) (p = 0.016). This difference could not be explained by differences between Barretts esophagus patients infected with H. pylori and those who were not with respect to gender, smoking history, alcohol consumption, use of proton pump inhibitor, or length of Barretts mucosa.CONCLUSIONS:Barretts high-grade dysplasia and adenocarcinoma are significantly more prevalent in patients who are not infected with H. pylori. H. pylori appears to have a protective effect against the development of Barretts adenocarcinoma.

Interphase Cytogenetics of Esophageal Adenocarcinoma and Precursor Lesions

Limited information is currently available on chromosomal abnormalities in esophageal adenocarcinoma and associated premalignant lesions. In this study, numeric changes affecting chromosomes 4, 6, 7, 8, 9, 10, 11, 12, 17, 18, X, and Y were analyzed by using fluorescence in situ hybridization (FISH) with chromosome-specific centromere DNA probes in 12 esophageal adenocarcinomas. In addition, TP53 overexpression, measured by immunohistochemistry, and amplification of HER-2/neu and C-MYC, detected by FISH, were analyzed within the same tumors. The most common numeric abnormalities detected were gains of chromosomes 12 (8 cases), 6 (7 cases), 7 (7 cases), and 11 (6 cases). The total number of abnormal chromosomes varied from 0 to 10, with an average of 4.6 per case. Overexpression of TP53 was present in 9 of 12 cases. No correlation was noted between the degree of aneusomy and TP53 overexpression. In contrast, HER-2/neu amplification was present in two cases, both with large numbers of aneusomic chromosomes. Amplification of C-MYC was detected in only one case that had a moderate number of numeric abnormalities. In a subset of cases in which premalignant lesions were examined, aneusomy was found to be an early change, frequently present in both Barretts esophagus and dysplastic regions. In contrast, gene amplification and TP53 overexpression were restricted to more advanced areas of dysplasia and malignancy. Screening larger cohorts of patients with Barretts esophagus or dysplasia for numeric abnormalities of chromosomes 6, 7, 11, and 12 may determine whether any of these abnormalities are predictive markers of progression to malignancy.

p53 Expression in Incidental Prostatic Cancer

Incidental prostate cancer is an indolent disease typically characterized by a benign clinical course. This is not clearly established, however, as recent reports suggest that up to 27% of cases progress with long-term follow-up. The indolent history of this disease led initially to the hypothesis that mutations of the p53 gene would be an infrequent event in this patient population. Archival specimens from 24 patients with Stage A1 carcinomas were evaluated for abnormal p53 expression. In 23 patients the disease was diagnosed after transurethral resection for bladder outlet obstructive symptoms, and in one patient after a radical prostatectomy. Using a monoclonal antibody (PAb 240) and an immunohistochemical technique, a total of 36 microfoci of tumor were evaluated. Thirteen (36%) microfoci were positive with an intense nuclear staining pattern (2+), and eight (22%) microfoci had an intermediate staining pattern. Four areas of prostatic intraepithelial neoplasia also stained positively with a 2+ staining pattern. These results suggest that abnormal p53 expression is a feature of a significant number of incidental prostatic carcinomas and that this occurrence is an early event in the development of the malignant phenotype.