Systemic Approaches for Multifocal Bronchioloalveolar Carcinoma: Is There an Appropriate Target?

Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma characterized by distinct and unique pathological, molecular, radiographic, and clinical features. While the incidence of pure BAC is rare, comprising only 1% to 4% of non–small-cell lung cancer (NSCLC), mixed subtypes (including BAC with focal invasion and adenocarcinoma with BAC features) represent as much as 20% of adenocarcinomas-and that figure may be increasing. Despite the longstanding recognition of this entity, there is no established treatment paradigm for patients with multifocal BAC, resulting in competing approaches and treatment controversies. Current options for multifocal BAC include both surgery and systemic therapies. Unfortunately, prospective data on systemic approaches are limited by study design and small patient numbers; there are only seven phase II studies involving four therapies. This article evaluates key characteristics of BAC, including the current understanding of histopathology and tumor biology. In addition, it comprehensively reviews the systemic phase II studies in an attempt to clarify the therapeutic challenges in this disease. It also includes the first proposed treatment paradigm that integrates both EGFR mutational status and the sub-histologies, mucinous and nonmucinous BAC.

Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma characterized by distinct and unique pathological, molecular, radiographic, and clinical features. BAC was initially described by Malassez in 1876.[1] The term “bronchioloalveolar carcinoma” was coined by Liebow in 1960 and identifies a well-differentiated tumor (adenocarcinoma) with neoplastic cells that spreads along alveoli without stromal reaction or invasion, and with preservation of alveolar architecture.[2] Although the pathological assessment of this tumor is still evolving, the current (1999) definition of BAC by the World Health Organization (WHO) is restricted to lesions with a pure bronchioloalveolar growth pattern in which there is no evidence of invasion of stroma, pleura, or lymphatic spaces.[3] The clinical applicability of this definition remains in question, considering that BAC most often presents as admixed adenocarcinoma, with the clinical course of these tumors often differing from that of both pure BAC and adenocarcinoma. The incidence of pure BAC is rare, comprising only 1% to 4% of non–small-cell lung cancer (NSCLC); however, these mixed subtypes, including BAC with focal invasion and adenocarcinoma with BAC features, represent as much as 20% of adenocarcinomas-and their frequency may be increasing.[4]

As BAC becomes a more recognized entity within the pathological continuum of adenocarcinoma, several controversies have emerged regarding the appropriate management of these tumors, especially those that represent multifocal or unresectable disease. First, while BAC features may be prognostic of improved survival, it remains unclear whether the percentage of BAC admixed within a tumor is prognostic of outcome or predictive of therapy efficacy. For example, should those adenocarcinomas with greater BAC features be more conservatively managed than those with less BAC? Second, there is an increasing awareness that two subtypes of BAC lesions exist: mucinous and nonmucinous.[5] Whether this pathological distinction is clinically relevant and whether it should guide management decisions remain unclear; these questions will be addressed in the discussion section of this review. Finally, it has been demonstrated consistently that patients with advanced-stage BAC have a disproportionately high response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Recent phase III data in patients with advanced NSCLC have demonstrated the EGFR mutation to be a reliable predictor of response to TKIs in the front-line setting.[8] However, whether response to TKIs in BAC is exclusively mediated by the EGFR mutation that is more frequently found in this subtype of tumor has yet to be prospectively evaluated. In this review, we attempt to evaluate these controversies as we discuss the key characteristics and current management of multifocal/unresectable BAC.

Histopathology of BAC

The definition of BAC has evolved significantly over the years. In 1960, when Averill Liebow gave the tumor its current name, BAC was defined as a subtype of adenocarcinoma with four features: well-differentiated cytology, an origin distal to recognizable bronchi, a proclivity for lymphatic and aerogenous spread, and a tendency to grow across intact alveolar septa.[2] Liebow asserted, however, that this last feature was probably “imaginary,” implying that despite seemingly preserved architecture, invasion was a likely feature. In 1999, a major shift occurred in the WHO classification: BAC was redefined as a neoplasm that demonstrated pure lepidic growth with a lack of invasion of stroma, blood vessels, or pleura.[3] The modification essentially restricted BAC to carcinoma in situ and was maintained in the 2004 revision of the criteria.[5] Currently, tumors that are predominantly BAC and that have areas of invasion are classified as “mixed subtype adenocarcinomas.”

FIGURE 1

Histopathology of Mucinous vs Nonmucinous Bronchioloalveolar Carcinomas (BACs) (Hematoxylin and Eosin Stain, High-Power Magnification)

The WHO decision to reclassify BAC as a distinct pathological entity was largely based on seminal work by Noguchi and colleagues, who examined 236 cases of small (less than 2 cm), surgically resected peripheral adenocarcinomas with mediastinal and pulmonary hilar lymph node dissection.[9] Samples were separated into groups by histology, and patients were monitored longitudinally for survival. In patients with Noguchi type A histology (localized bronchioloalveolar carcinoma [LBAC]) and type B histology (LBAC with foci of alveolar collapse), 0% showed lymph node metastasis, and survival was 100% at 5 years. However, among patients with Noguchi type C histology (LBAC with active fibroblastic proliferation), 28% had lymph node metastasis, and 5-year survival was 75%. Furthermore, patients with poorly differentiated adenocarcinoma (Noguchi type D histology) had a 52% 5-year survival rate. These results demonstrated that BAC had a distinct clinical course differing from that of adenocarcinoma and suggesting that this type of tumor warranted its own classification.

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