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

About one-third of sporadic lung adenocarcinomas demonstrates biallelic inactivation of the LKB1 gene, but the timing of this event is not known. 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. 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 high-grade 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). 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.