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Abstract

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. IntroductionLung cancer is the leading cause of cancer deaths in the United States and worldwide with over 1.3 million deaths in 2008 [1][2][3]. Despite the fact that enormous resources have been spent on research involving molecular and therapeutic aspects of lung adenocarcinoma (ADC), there has been no significant improvement in the mortality associated with lung cancer for the past 25 years. This can be attributed in part to untimely diagnosis at advanced stages or recurrence occurring even after optimal treatment at early stages. About 70% of patients are diagnosed with lung cancer at advanced stages when there is little chance to cure [4]. Although patients diagnosed at early stages receive curative-intent complete resection by surgery, about 20% of them will not survive due to recurrence within 5 years [5][6][7][8][9][10][11][12]. One cause may be that patients already have microscopic systemic metastases in other distant organs at the time of surgery. In order to reduce the mortality and eventually to overcome lung cancer, understanding carcinogenesis and tumor progression is paramount.ADC is the most common histologic type of non-small cell lung cancer (NSCLC) in the United States, accounting for almost half of all lung cancers [13,14]. ADC tends to develop distant organ metastases easily even in early stage compared to squamous cell carcinoma, underscoring the need for early detection methods. A multistep...