Published in Cancer Detection and Prevention 2000; 24(1):13-23.

Integrated P53 Histopathologic/Genetic Analysis of Premalignant Lesions of the Esophagus

Adriana V Safatle-Ribeiro2,4, M.D., Ulysses Ribeiro, Jr. 1,4, M.D., Paulo Sakai4, M.D., Martha R. Clarke 3, M.D., Sônia N. Fylyk4,M.D., Shinichi lshioka4, M.D., Joaquim Gama-Rodrigue M.D., Sidney D. Finkelstein3, M.D., James C. Reynolds2, M.D.

Departments of Surgery1, Gastroenterology2 and Pathology3, University ot Pittsburgh Medical Center, Piitsburgh,PA. U.S.A.; Department of Gastroenterology4, University of São Paulo, Brazil

Address all correspondence to: Adriana Vaz Safatle-Ribeiro, MD, Rua Treze de Majo, 1954, Cj. 54, São Paulo SP, CEP 01327-002Brazil. Tel: +55-11-2893541. Fax: +55-11-2843998.

ABSTRACT Esophageal carcinoma frequently occurs in patients with long-standing achalasia. Aim: To examinethe role of p53 alterations and PCNA in patients with megaesophagus. Methods: Sections of four tumors, and corresponding adjacent areas, from patients with achalasia due to Chagas’ disease were examined by immunohisto-chemistry for p53 and PCNA proteins. Furthermore, 128 biopsies from 16 advanced achalasic patients wereprospectively collected and evaluated for grades of inflammation, hyperplasia, dysplasia and also for p53 andPCNA proteins. All specimens showing p53 immunoreactivity were topographically genotyped using microdissection, PCR amplitication and direct sequencing of p53 exons 5-8. Results: Diffuse strong immunoreactivity of p53was observed in 2/4 tumors. In one patient, the adjacent mucosa also showed strong p53. In the adjacent mucosa,the same areas showing p53 averexpression also had PCNA positive cells. In the prospective group, 7/16 (43.7%)patients cr 53/128 (41.4%) biopsies expressed p53. The grade of inflammation was significantly correlated with thepresence of positive p53, in patients, p = 0.004 and in biopsies, p <0.00001. PCNA expression was found in thebasal layer of the mucosa, and increased PCNA was associated with p53 overexpression, p = 0.00018. Genotypingdetected mutation in excn 6, codon 213 RG, in one patient (1/16, 6.2%). Conclusions . (I.) p53 alterations, overexpression and mutational change, are an early event in patients with achalasia; (2.) The intlammation frequently seenin these patients appears to be associated with altetations of the p53 protein; (3.) Expression of the tumor suppressor gene is increased in areas showing proliferation.

KEY WORDS: p53, megaesophagus, esophageal tumor, achalasia, Chagas' disease.

For more information, contact