Multistep Progression from Atypical Adenomatous Hyperplasia to Lung Adenocarcinoma: Clinico-Pathologic, Epigenetic and Genetic Aspects

Detection of small peripheral ground-glass opacity nodules has increased due to the advances in imaging modalities and the widespread use of computed tomography screening. Pathologic examination of these nodules revealed that they have a pure lepidic or replacement growth pattern such as atypical adenomatous hyperplasia or adenocarcinoma in situ (formerly known as bronchioloalveolar carcinoma). When untreated, ground-glass opacity nodules gradually develop a solid component. The greater the solid component or the invasive component, the less favorable outcomes after treatment for patients with ground-glass opacity nodules. Based on the clinical, radiologic and pathologic findings, the concept of multistep progression from preinvasive atypical adenomatous hyperplasia through noninvasive adenocarcinoma in situ to invasive adenocarcinoma has been postulated. Recently, evidence has accumulated explaining this putative concept by molecular alterations, including activating mutation of oncogenes and inactivation of tumor suppressor genes by epigenetic changes or loss of heterozygosity. This review 1) comprehensively outlines the accumulated knowledge regarding radiologic and pathologic features of adenocarcinoma and its precursor which presents as ground-glass opacity and 2) summarizes the molecular basis of the multistep progression to lung adenocarcinoma. As a result, we believe identification of undiscovered molecular markers involved in the progression of lung adenocarcinoma is critical for early detection of lung cancer and the development of targeted therapeutic and chemoprevention strategies.