Atypical Adenomatous Hyperplasia of the Lung: Implications for the Pathogenesis of Peripheral Lung Adenocarcinoma

Abstract

Bronchioloalveolar lung carcinoma (BAC) exhibits many features that distinguish it from bronchogenic carcinomas. For early detection, therapy, and prevention of BAC, it is essential to understand its pathogenesis. Development of BAC appears to be stepwise, and the earliest lesion to be recognized is atypical adenomatous hyperplasia (AAH), the proliferative lesion of atypical epithelial cells along the alveolar septa. Our review of the studies of AAH revealed that certain populations of AAH cells exhibit active proliferation, aneuploidy, 3p and 9p deletions, K-ras codon 12 mutation, and disruption of the cell cycle control, but p53 gene aberrations are rare and telomerase activation is absent. We emphasize that AAH is an alveolar intraepithelial neoplasia. This allows more precise analyses of the process and mechanism of the development of BAC. Furthermore, AAH could serve as a surrogate end-point biomarker in future chemoprevention trials. The criteria for the diagnosis of AAH and related lesions should be established as early as possible.

Innovative molecular and imaging approaches for the detection of lung cancer and its precursor lesions

“…Laboratory investigations demonstrate that AAH cells have the ultrastructural features of Clara cells or Type II pneumocytes (Mori et al, 1998) and that many of the molecular changes present in lung adenocarcinomas are present in these lesions. AAH cells exhibit active proliferation, aneuploidy, 3p and 9p deletions, K-ras codon 12 mutation, and disruption of cell cycle control, but p53 gene aberrations are rare and telomerase activation is absent (Kitamura et al, 1999). These findings support the concept that AAH lesions are precursor lesions of peripheral adenocarcinoma.…”

The association between atypical adenomatous hyperplasia and primary lung cancer

“…These data underpin the proposed AAH/adenoma-carcinoma sequence in the lung, a concept further strengthened by various immunohistochemical and molecular biological studies (Kitamura et al, 1999;Kerr, 2000). The finding of multiple AAH lesions in patients with multiple lung cancers, together with the report of AAH in a patient with multiple synchronous lung cancers in Li-Fraumeni syndrome (Nadav et al, 1998) and multiple AAH lesions associated with tumours which have deletions in the tuberous sclerosis complex (TSC-1) region on 9 q (Suzuki et al, 1998b), raises interesting questions about possible underlying genetic abnormalities in this disease.…”

Relationships between EGFR Mutation Status of Lung Cancer and Preoperative Factors - Are they Predictive?

“…It is generally accepted that BAC, at least in part, develops from its precursor AAH in the fashion of the adenoma-carcinoma sequence (Kitamura et al, 1999). The peripheral lung progenitor cell (Clara type 2, or other specified cell) is considered the origin of AAH and BAC (Kitamura et al, 1999).…”