LKB1 protein expression in the evolution of glandular neoplasia of the lung

Purpose: About one-third of sporadic lung adenocarcinomas demonstrates biallelic inactivation of the LKB1 gene, but the timing of this event is not known. Design: We performed LKB1 immunohistochemistry on 35 primary lung adenocarcinomas and 96 atypical adenomatous hyperplasias (AAH), a form of early glandular neoplasia from which some lung adenocarcinomas arise. Results: In all cases, strong cytoplasmic staining was noted in the non-neoplastic epithelium lining the airways from the bronchi to the terminal bronchioles. There was a marked reduction in LKB1 staining in 9 of 35 (26%) adenocarcinomas and in 10 of 96 (10%) AAHs. When the AAHs were subclassified on the basis of cytoarchitectural atypia, loss of LKB1 expression was more frequent in the highgrade lesions (7 of 33, 21%) than low-grade lesions (3 of 63, 5%; P = 0.021). For the 21 adenocarcinomas where the genetic status was known, immunohistochemistry staining reliably reflected the activational state of the LKB1 gene (95% concordancy). Conclusions: In AAH, loss of LKB1 expression is strongly associated with severe dysplasia, suggesting that LKB1 inactivation may play a role in the critical transition from premalignant to malignant tumor growth.