Current concepts in bronchioloalveolar carcinoma biology.

Bronchioloalveolar carcinoma (BAC) has a unique clinical and radiological presentation and a different response to systemic treatments compared with conventional lung adenocarcinoma. Although tobacco-related, BAC is found disproportionately in never-smokers, women, and Japanese patients (1). The molecular basis for these predispositions is unknown. The WHO defines BAC as a subtype of adenocarcinoma with growth along the alveolar septa and without evidence of stromal, vascular, or pleural invasion. Although only f4% of lung cancers meet this definition, up to 20% of lung cancers comprise a heterogeneous group of tumors with BAC histology mixed with a varying population of invasive cells, ranging from predominant BAC histology with a small focus of invasion, to invasive adenocarcinoma with an isolated group of cells with BAC features at the periphery (2–4). Tumors with BAC histology are associated with improved survival rates compared with pure adenocarcinoma. A subset of BAC, mucinous BAC, has poorer outcomes than nonmucinous BAC and accounts for f20% of BACs. In contrast to nonmucinous BACs, which most commonly present as small peripheral nodules, mucinous BACs frequently masquerade as pneumonia often resulting in a delay in diagnosis (5). The proportion of tumors with BAC features may have increased in incidence over the past 50 years (6). A populationbased study using the Surveillance, Epidemiology, and End Results database found that BAC accounted for only 4% of non–small cell lung carcinomas (NSCLC), a percentage that did not significantly change during the last 25 years (2). However, several single institution series report that BAC accounts for >20% of NSCLC, with some series reporting numbers as high as 40% (6–8). This discrepancy is likely due to the inclusion of BAC tumors mixed with adenocarcinoma in most single institution series, which would have been classified as adenocarcinoma in the Surveillance, Epidemiology, and End Results registry. Moreover, most institutional series of BAC have studied patients with surgically resected lung cancer. BAC seems to be more common in early stage lung cancer, and there may be misclassification of BAC as adenocarcinoma in patients with surgically unresectable lung cancer because these patients typically are diagnosed by cytologic means, which has poor sensitivity for BAC (9). Because two-thirds of patients with NSCLC present with metastatic or surgically unresectable disease, a large number of patients with advanced stage lung adenocarcinoma in the Surveillance, Epidemiology, and End Results registry may in fact have BAC histology. The reasons for the apparent increase in incidence in BAC reported by several groups may include increased detection of small lung cancers with increased thoracic imaging, increased reporting of BAC features by pathologists, or an actual increase in incidence due to a viral etiology or other environmental factor (10).