p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lun g cancer. Several atypical epithelial lesions are frequently observed in th e fibrotic area in IPF patients, and they have been suspected to be related to lung cargingenesis. Several studies have suggested that p53 protein acc umulation and mutation occur in the early pathogenesis of squamous cell car cinoma of the lung, suggesting some abnormality of the p53 tumor-suppressor gene in interstitial lung diseases. To examine the cause of the high frequ ency of lung cancer in IPF, we examined the p53 changes in atypical epithel ial lesions and carcinoma in patients with IPF by immunohistochemistry and mutational analysis. We examined 19 lung cancer patients with IPF who under went surgical resection for lung cancer in our institute. Paraffin-embedded tissues were treated by microwave and stained with an anti-p53 antibody (R SP53) by the avidin-biotin-peroxidase complex method. Mutations in exons 5 through 8 of the p53 gene were also examined by polymerase chain reaction m ediated single-strand conformation polymorphism (polymerase chain reaction- single-strand conformation polymorphism) analysis and DNA sequencing. p53 p rotein was immunohistochemically detected in 13 (62%) of 21 squamous cell c arcinomas, 3 (60%) of 5 squamous metaplasia with atypia, 16 (54%) of 30 squ amous metaplasia, and 1 (4%) of 26 other hyperplastic lesions. p53 mutation was detected in 12 (57%) of 21 squamous cell carcinomas, 2 (40%) of 5 squa mous metaplasia with atypia, 7 (23%) of 30 squamous metaplasia, and 0 (0%) of 26 other hyperplastic lesions. In conclusion, there are frequent p53 gen e alterations in squamous metaplasia, which is distributed in the periphera l zone of the fibrotic area in patients with IPF. The present findings migh t provide a clue to the molecular mechanisms underlying the high incidence of lung cancer, especially peripheral-type squamous cell carcinoma in WIT p atients, and suggest that p53 gene alterations play an important role in th e early stages of lung carcinogenesis in patients with IPF. HUM PATHOL 32:1 043-1049. Copyright (C) 2001 by W.B. Saunders Company.