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

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

ABSTRACT: 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.”

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.

Two major subtypes of BAC are recognized by the WHO—mucinous BAC and nonmucinous BAC—along with a third category that represents a combination of the two (Figure 1).[5] Increasing evidence suggests that the major subtypes represent biologically distinct entities and underscores the necessity of distinguishing between the two in pathology specimens.[10]

The nonmucinous variant is the clinically predominant subtype, occurring in 40% to 60% of cases.[11] Nonmucinous BAC tumors tend to present grossly as solitary peripheral nodules and are histologically composed of cuboidal or columnar cells with eosinophilic or clear cytoplasm, with or without vacuolization.[12,13] Nonmucinous BAC is recognized as comprising two cell types: Clara cells, with apical snouts and PAS+ granules; and type 2 pneumocytes, often with eosinophilic nuclear inclusions. No clinical or prognostic difference has been ascribed to a predominance of either cell type.[13] Immunohistochemically, the nonmucinous variant of BAC exhibits a pattern similar to that of conventional adenocarcinoma, with cytokeratin 7 (CK7) and thyroid transcription factor 1 (TTF1) positivity and cytokeratin 20 (CK20) negativity.[5] BAC with nonmucinous histology is more often dependent on EGFR pathway mutations and is consequently more sensitive to EGFR-targeted therapy.[10]

Mucinous BAC occurs in anywhere from 25% to 50% of patients.[11,13] In contrast to nonmucinous tumors, mucinous BAC more commonly presents with extensive disease, manifested as multiple nodules or diffuse consolidation (pneumonic pattern). Because of the more advanced stage at diagnosis, overall prognosis is poorer. Histologically, cells are tall and columnar with basal nuclei and abundant mucin.[12,13] The tumor is thought to arise from metaplastic goblet cells. In mucinous BAC, immunohistochemistry (IHC) results tend to be more variable: CK7 is usually positive, as in nonmucinous BAC; however, CK20 is positive, and TTF1 is usually negative—or weak and patchy if positive. K-ras mutations are more commonly detected in mucinous BAC, likely accounting for the relative insensitivity of this subclass to EGFR-based treatments.[14]

In patients with mixed subtype adenocarcinoma, the exact contribution of a bronchioloalveolar component to prognosis has been the subject of debate. In the only Western study to address this question, Ebright and colleagues reported no significant difference in survival between groups with pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features.[15] The study did include patients with pure BAC who had multifocal disease and pneumonic-type presentations; these patients had poorer expected outcomes. In contrast to the Ebright data, multiple previous Japanese studies have provided evidence—in addition to that of Noguchi’s work—to support a favorable prognosis for specimens with large proportions of BAC and minimal invasion.[16-19] Terasaki and colleagues grouped specimens according to increasing proportions of BAC and reported that groups with either pure BAC or BAC with minimal areas of invasion were less likely to have pleural invasion or metastatic spread to lymph nodes or vasculature.[20] These studies suggest that tumors with higher proportions of BAC may be prognostically more favorable.

In light of the possible differences in clinical behavior between BAC with minimal invasion and tumors with larger invasive components, some authors have proposed that a category called “minimally invasive adenocarcinoma” be established in future classifications.[21] Sakurai and colleagues demonstrated that the prognosis of BAC with stromal invasion limited to the area of tumor growth or the periphery of the tumor scar was equal to that seen in pure BAC.[18] Similarly, Yim and colleagues reported that the prognosis of patients with BAC and invasion of less than 5 mm was equivalent to that of patients with BAC and no evidence of invasion.[19] In 2004, however, a consensus definition of “minimally invasive” BAC was not recommended by the WHO panel on the basis of lack of sufficient evidence.[22] As further data become available, it is possible that this category may be formally separated, considering its increased incidence and clinical relevance.


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