Expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and p53 tumor suppressor in dysplastic progression and adenocarcinoma in Barrett esophagus

Abstract

BACKGROUND Barrett esophagus predisposes individuals to esophageal carcinoma, which develops from intermediate stages of tissue dysplasia primarily in the vicinity of the gastroesophageal junction. Understanding the cellular and molecular events in the progression of Barrett esophagus to adenocarcinoma may contribute to its early diagnosis and treatment. Mutation and overexpression of the tumor suppressor p53 have previously been observed in Barrett high grade dysplasia and adenocarcinoma. The expression of the cyclin‐dependent kinase (CdK) inhibitor p21 can be up‐regulated by p53, resulting in the down‐regulation of cell division at the G1/S‐phase transition. The current study examined the correlation between the expression of p21 and p53 by quantifying their levels during the progression of dysplasia and adenocarcinoma in Barrett esophageal tissues. METHODS Barrett esophageal tissue samples that were negative or indefinite for dysplasia, contained dysplasia, and contained adenocarcinoma were examined by immunohistochemistry. Paraffin embedded sections of lining and glandular epithelia were adsorbed with primary murine antibodies against human p21 or p53 followed by horseradish peroxidase secondary antibody. An immunoreactivity score for each primary antibody and section was obtained by multiplying a staining intensity factor by the percent of positively stained cells. RESULTS Nuclear p21 expression was detectable immunohistochemically in Barrett esophagus that was negative for dysplasia, but it was significantly elevated (P ≤ 0.05) in tissues scored as indefinite for dysplasia, positive for low grade or high grade dysplasia, and positive for adenocarcinoma. Importantly, p53 expression did not parallel p21 expression. p53 levels were low in the early stages of Barrett dysplasia and were increased in high grade dysplasia and adenocarcinoma. There were no differences in p21 or p53 levels between glandular and lining epithelia in Barrett tissue throughout the histologic stages of neoplastic progression evaluated in this study. CONCLUSIONS p21 expression in Barrett tissue scored as indefinite for dysplasia or low grade dysplasia was significantly elevated relative to p53 expression. Elevated levels of p21 were also observed in high grade dysplasia and adenocarcinoma, in which they do not appear to be effective in down‐regulating cell division. Analysis of p21 and p53 expression may aid in the evaluation of tissue abnormalities in Barrett esophagus. Cancer 1999;86:756–63. © 1999 American Cancer Society.

Prevalence of p21 immunohistochemical expression in esophageal adenocarcinoma

“…The comparison of the same tumor areas with p53 and p21 expression showed discrepant results in most cases; therefore, it is believed that p21 expression is independent of p53 protein (23) . According to HANAS et al (13) , an overexpression of p21 was observed in a small series of three patients with adenocarcinoma. And to CHATELAIN et al (8) , in another small series, p21 was overexpressed in 2 superfi cial adenocarcinomas, and in most cases, p21 expression was not related to p53 expression.…”

“…In human cells, p21 is considered a major factor in the up-regulation of the nuclear expression of p53 (10) . p21 has been expressed in several malignant neoplasms, including esophageal adenocarcinomas (8,13,23) . p21 expression also varies considerably in adenocarcinoma and epidermoid carcinoma of the esophagus (Table 2).…”

“…p21 expression was assessed at the margin of the infi ltrative lesion, only in cancer cells, as a nuclear pattern, using the Immunoreactive Scoring System (IRS), used by REMMELE and SCHICKETANZ (28) and cited by HANAS et al (13) IRS is obtained by multiplying the staining intensity (0 = negative, 1 = weak, 2 = moderate, and 3 = strong) by the percentage of positive cells (0 = negative, 1 = 10% positive, 2 = 11%-50% positive, 3 = 51%-80% positive, and 4 = >80%). A total of 10 highpower fi elds are used for each IRS assessment.…”

“…Barrett's esophagus is a condition in which the normal squamous epithelium of the esophagus is replaced by a columnar epithelium as a result of long-established gastroesophageal refl ux, which predisposes the affected individual to the development of adenocarcinoma (8,13,16,21,23,29,39) . Barrett's esophagus is the preliminary step towards esophageal adenocarcinoma.…”

“…Early-stage esophageal carcinoma is often asymptomatic and detection is uncommon. Diagnosis is usually established at advanced stages, which results in remarkable mortality (2,13) . The large number of patients with advanced disease, combined with poor response to treatment, stresses the necessity to find better tools for early diagnosis and intervention, which may increase the chances of treatment success (9) .…”