c omprehensive review Bronchioloalveolar Carcinoma: The Case for Two Diseases David H. Garfield,1 Jacques Cadranel,2 Howard L. West3 Abstract By current criteria, bronchioloalveolar carcinoma (BAC) is a subtype of pulmonary adenocarcinoma, developing from terminal bronchiolar and acinar epithelia and progressing in a lepidic and/or aerogenous manner on intact alveolar walls but without stromal, vascular, or pleural invasion. Evidence suggests that the 2 main cytologic types of BAC, ie, nonmucinous and mucinous, have some differing characteristics. The more frequent nonmucinous BAC directly evolves from the terminal respiratory unit cells, the type II pneumocyte, and Clara cells. This form predominates in smokers, presents more frequently as a ground-glass opacity, and frequently harbors epidermal growth factor receptor (EGFR) polysomy/mutations, believed to be the driver of its malignant process. The less frequent mucinous BAC, on the other hand, derived from metaplasia of bronchiolar epithelia, presents more frequently as a pneumonic-type infiltrate, rarely demonstrates EGFR polysomy/mutations, and much more frequently harbors and is driven by a K-ras mutation. These mutational oncogenic differences could lead to different therapeutic responses: nonmucinous BAC has been found to be sensitive to EGFR tyrosine kinase inhibitors, while mucinous BAC might be more responsive to taxane-based chemotherapy. In fact, there might be more differences than similarities, suggesting 2 distinct phenotypes that might need to be treated differently in order to optimize our management of the range of clinical disease that is often currently broadly classified as BAC. Clinical Lung Cancer, Vol. 9, No. 1, 24-29, 2008
Key words: Adenocarcinoma, Histologic subtype, K-ras, Mucinous, Non–small-cell lung cancer, Nonmucinous
ing various amounts of BAC features. However, it is unknown what percentage of BAC becomes peripheral adenocarcinoma or how many such adenocarcinoma evolve from BAC. Bronchioloalveolar carcinoma is categorized as having distinct histologic and cytologic subtypes. With the former, there is pure BAC and mixed adenocarcinoma with bronchioloalveolar features. With the latter, there is nonmucinous BAC, the most common, with mucinous as uncommon, and the rare mixed type containing elements of the first 2. Earlier literature often distinguished among the first 2, calling the mucinous form type I and the nonmucinous form type II.5 It was believed that mucinous was associated with aerogenous spread, advanced disease, bronchorrhea, and a more rapid course. Nonmucinous BAC, on the other hand, was considered to be more often asymptomatic, localized, slow growing, presenting as resectable, and having a better prognosis. It is now recognized, however, that mucinous tumors might be localized and grow slowly and that nonmucinous tumors might present with more advanced disease and produce bronchorrhea. Also, there appear to be no differences in stage presentation and, at least for resected disease, no difference
Bronchioloalveolar carcinoma (BAC) has long been recognized as a discrete clinical as well as pathologic entity1-3 which, until recently, has generally been considered an “orphan” among lung cancers. It was not studied separately but rather had usually been pooled in the broad range of subtypes of non–small-cell lung cancer (NSCLC), where its unique clinical behavior and response to therapy remained unclear. More recently, however, it has been recognized as a putative precursor of the increasingly prevalent peripheral lung adenocarcinoma,4 with many such tumors show1Department
of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado 2Université de Médecine Pierre et Marie Curie, Paris, France 3Swedish Cancer Institute, Seattle, Washington Submitted: Jun 28, 2007; Revised: Nov 3, 2007; Accepted: Jan 2, 2008 Address for correspondence: David Garfield, MD, Department of Medicine, University of Colorado Health Sciences Center, 57 Hyde Park Circle, Denver, CO 80209 Fax: 303-744-8868; e-mail: [email protected]
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in prognosis, although these conclusions await the results of further epidemiologic studies. Although there is clinical overlap between these 2 cytologic types, there are also many immunohistochemical, genetic, molecular, and, in particular, therapeutic differences, some perhaps significant, making this distinction more than of purely academic interest. However, it is important to note that not only is the accuracy of fine-needle aspirates for adenocarcinoma only 35%6 but also specifically that a diagnosis of BAC cannot be made solely on a cytology specimen.7
Histopathology of the Bronchioloalveolar Carcinomas
Pathology Histologically, the nonmucinous form (Figure 1A) is derived mainly from secretory bronchiolar (Clara) cells and/or, less often, from terminal alveolar (type II pneumocyte) cells, while the mucinous form (Figure 1B) is derived from metaplastic goblet cells. A rare third subtype, perhaps under-recognized, is a mixture of nonmucinous and mucinous types, designated as “mixed” BAC. Clara cells are columnar and eosinophilic, with frequent apical extensions (“snouts”), and type II cells are low columnar to cuboidal, with a clear-to-foamy, occasionally vacuolated cytoplasm and infrequent nuclear inclusions. Nuclei of both types are centralto-apical, are frequently vesicular, might have prominent nucleoli and eosinophilic inclusions, and are sometimes pleomorphic, but they might be low grade with infrequent mitoses. Mitotic rate of nonmucinous cells tends to be higher than their mucinous counterparts. Clara cells have characteristically small, apical, periodic acid-Schiff (PAS)–positive granules, and most Clara cell tumors have PAS-positive vacuoles in the cytoplasm and between tumor cells.7-11 Mucinous cells are tall, columnar, well differentiated, nonpleomorphic, and evenly distributed in single layers along alveoli, the pattern being almost always lepidic. The cytoplasm contains abundant pale, large, apical, mucin-containing vacuoles compressing nuclei, making the latter difficult to visualize. Mucinous cells, by definition, contain intra- and extracellular12 mucins that nonmucinous cells do not. Exfoliated tumor cells are not infrequent (Table 1).7-11 Immunohistochemistry (IHC) might help to distinguish the 2 types. Nonmucinous tumors are usually thyroid transcription factor-1 (TTF-1)– and cytokeratin (CK)-7–positive but CK-20–negative. However, in mucinous disease, IHC studies give variable results. TTF-1, if positive, is weak and patchy, while CK-7 is usually somewhat positive, CK-20 even less so.13-21 They also express most of the mucins. Based on these significant IHC differences, it appears that nonmucinous tumors are derived from the terminal respiratory unit, while mucinous BAC are derived from less peripheral airways and thus should not be considered a terminal respiratory unit type of adenocarcinoma (Table 2).13-22 Nonmucinous tumors are often associated with a putative precursor lesion, atypical adenomatous hyperplasia (AAH). These have Clara cell and type II pneumocyte features,23 but the cells and nuclei are smaller in AAH than in BAC.24 Cells of AAH also express TTF-1 and surfactant proprotein B.20 Atypical adenomatous hyperplasia has been divided into low- and high-grade categories and is usually < 3 mm. High-grade lesions > 5 mm
(A) Nonmucinous BAC. (B) Mucinous BAC.
are considered to be nonmucinous BAC.24 This morphologic progression from AAH to nonmucinous BAC is associated with concurrent and progressive accumulation of genetic and molecular abnormalities.25,26 In contrast, the only known precursor lesion for mucinous tumors is the rare congenital pulmonary airway malformation, type I.27 Nonmucinous tumors are frequently associated with scarring and sclerosis, believed to represent presumed invasion and progression over time to invasive adenocarcinoma.24,28 In contrast, pure mucinous tumors tend to demonstrate neither scarring nor invasion,5 although mixed types can show invasion.29 Both tumor types are associated cellular infiltrates. Langerhans cells have been described only with nonmucinous tumors,30-32 while neutrophils have been significantly more frequent with mucinous tumors5,33,34 and might contribute to alveolar progression.34
Imaging Although computed tomodensitometry had been thought to be helpful in determining cell type,5,35 more recent studies do not find this to be the case.36,37 The pneumonic form of ad-
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Mucinous and Nonmucinous BAC Table 1 Histopathologic Differences Between Nonmucinous and Mucinous Bronchioloalveolar Carcinoma Cell of Origin
Eosinophilic apical “snouts”
Central or apical; usually low grade; pleomorphic; mitoses infrequent; prominent nucleoli; eosinophilic inclusions
Few PAS-positive granules
Low columnar, cuboidal
Might have foamy vacuoles
Same as Clara cell
Columnar; single layered and lepidic; cells exfoliated
PAS-positive mucous vacuoles
Basal, compressed by apical mucous vacuoles; low grade; nonpleomorphic; mitoses rare
Abundant PAS-positive mucin deposits
Nonmucinous Clara cells Type II pneumocytes Mucinous Bronchiolar cells
enocarcinoma, which might contain mucinous or nonmucinous BAC elements, correlates with mucinous disease.38,39 The correlation between nonmucinous and mucinous types and patterns of pulmonary spread was evaluated in 20 surgical specimens of BAC. Eleven out of 12 mucinous versus 0 out of 8 nonmucinous BAC developed parenchymal opacification (P < .028).40 On contrast-enhanced computed tomodensitometry, consolidation, a result most often of mucin, allows visualization of normally enhancing pulmonary vessels within the consolidation, termed the computed tomodensitometry “angiogram sign.”41,42 Most recently, by high-resolution computed tomography, mucinous disease was correlated with ill-defined margins, consolidation, and pseudocavitation in 49 tumors < 3 cm (P < .01). Such lesions consisted mainly of consolidation, with ground-glass opacity comprising < 25%. Nonmucinous disease, on the other hand, demonstrated mainly ground-glass opacity.43 The literature varies as to whether mucinous or nonmucinous tumors are more often positron emission tomography–positive.44-46 Heavily T2-weighted magnetic resonance images with high signal intensity (“white lung sign”) have been seen only in mucinous disease.47,48
Molecular Biologic Differences In contrast with these previously noted clinical, pathologic, and radiographic differences, data on the molecular characteristics of the distinct BAC subtypes have only just begun to emerge. From
clinical and molecular standpoints, it has been suggested that mucinous cell spread along alveolar septae, resulting in intrapulmonary spread rather than invasion as seen in nonmucinous disease. In mucinous BAC, there has been no bone marrow (BM) disruption, normal type IV collagen and laminin, and no evidence of neovascularization,49 while an increased expression of type IV collagenase50 and a decreased expression of alpha-2 integrin and CD44v6 molecules (thought to anchor epithelial cells to the BM)40,51 have been described in comparison with nonmucinous BAC.49-51 Although this might allow for greater ease of detachment from the BM by mucinous cells, no definitive conclusions can be drawn from these studies, based on comparisons between so few cases of mucinous and nonmucinous specimens. Epidermal growth factor receptor (EGFR) mutation and polysomy/amplification determined by fluorescence in situ hybridization (FISH) are almost entirely associated with nonmucinous disease. Such mutations are frequent but vary widely (32%88%) (Table 3).52-56 Polysomy/amplification, determined by FISH, in advanced nonmucinous disease was positive in 11 of 35 cases but only in 1 of 14 cases in mucinous diseases.57 These differences might be related to geography, ie, East Asia versus all others, as it has been shown that EGFR tumor mutation rates in non–East Asians are 8%, while East Asians have a rate of 30% (P = .001).58 In both groups this is often associated with nonmucinous BAC-containing adenocarcinoma, female sex,
Table 2 Immunohistochemical Differences Between Nonmucinous and Mucinous Bronchioloalveolar Carcinoma CK-7
Goldstein et al15
Marson et al16
Simsir et al17
Shah et al19
Tsuta et al21 Yatabe et
Total Positive (%)
*Seen but weak.
Lau et al13 Sarantopoulos et
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David H. Garfield et al Table 3 Frequency of EGFR Mutations in Nonmucinous and Mucinous Bronchioloalveolar Carcinoma Study Marchetti et al52 Tam et
Table 4 Frequency of K-ras ras Mutations in Nonmucinous and Mucinous Bronchioloalveolar Carcinoma Nonmucinous
Study Marchetti et al52
Finberg et al54
Sakuma et al55
Total Positive (%)
Wislez et al56*
Total Positive (%)
*A total of 20/25 nonmucinous and 20/25 mucinous BAC were sequenced for EGFR. Abbreviation: ND = not determined
and minimal-to-nonsmoking status. Results of EGFR protein expression by IHC are more heterogeneous, perhaps reflecting the types of antibodies used, techniques applied, and the scoring of positivity in the different studies. EGFR expression has been felt to be more frequent in nonmucinous than in mucinous tumors.59 K-ras mutations, on exon 1, codon 12, on the other hand, are significantly more frequent in mucinous than in nonmucinous disease in most studies (Table 4).52,54,55 Interestingly, the types of mutations vary.27,29,52-55 The type of K-ras mutation might be of particular importance as mucinous tumors are, surprisingly, significantly less frequently observed in smokers than nonmucinous tumors. In a study of 54 surgically resected BAC tumors, 29 of 35 nonmucinous tumors (83%) were observed in smokers, while only 5 of 10 mucinous tumors (50%) occurred in smokers (P < .05).36 In a second study based on 67 BAC tumors, 31 of 43 patients with nonmucinous tumors (72%; P = .019) but only 6 of 15 patients with mucinous tumors (40%; P = .074) were smokers, respectively.60 However, at the present time, no data exist on the type of K-ras mutations seen in mucinous tumors from smokers versus nonsmokers. Other molecular abnormalities have been less well described in comparing nonmucinous with mucinous BAC. Abnormalities of p53, although infrequent in BAC, are seen almost exclusively with nonmucinous tumors (respectively, 10% to 48% in nonmucinous BAC and 0 to 20% in mucinous BAC).61-65 Moderate to high Akt activation, evaluated by IHC, was observed in 63% of 46 BAC tumors and was associated with nonmucinous histology (P = .026).66 Similarly, the ratio of the putative oncogene cdk4 to its inhibitor, p16INK4, tended to be higher in nonmucinous than in mucinous tumors (P = .06) in a series of 38 resected BACs.67
Systemic Treatment Some of the molecular differences observed between nonmucinous and mucinous BAC might be of importance in selecting medical treatment in the setting of nonresectable disease. Among 58 patients receiving 96-hour paclitaxel infusions in the SWOG (Southwest Oncology Group) 9714 trial for advanced BAC,68 37 had sufficient tissue available for central review and an assignment of subhistology, including 3 reclassified as invasive adenocarcinoma, 5 as adenocarcinoma with BAC features, 16 with mucinous, and 19 with nonmucinous BAC. Within the
Abbreviation: ND = not determined
subset with tissue available to confirm a pure BAC subtype, 19% (3 of 16) with mucinous BAC, compared with none (0 of 13) with nonmucinous BAC demonstrated an objective response. Although any interpretation is limited by the small numbers, one might surmise that this clinical distinction might be related to the preclinical finding that some EGFR mutant human lung cancer cell lines, as seen in nonmucinous but not mucinous tumors, have marked cisplatin and taxane resistance.69 These differences might also have significant implications in anticipated results of BAC subtypes in trials of EGFR inhibitor–based therapy. Accordingly, tissue from 81 of 136 patients with advanced BAC receiving the EGFR tyrosine kinase inhibitor (TKI) gefitinib in the SWOG 0126 trial was reviewed centrally for histologic confirmation and FISH testing for EGFR and other molecular analysis.57 Of these, 7 were invasive adenocarcinoma (9%), 24 were adenocarcinoma with BAC features (30%), 14 were mucinous BAC (18%), and 35 were nonmucinous BAC (44%), although response rate (RR) correlation is reported for only a subset of these and not defined in the manuscript. For nonmucinous BAC, the RR was 30% (6 of 20), with an additional 40% (8 of 20) demonstrating stable disease (SD), for a disease control rate of 70%. In contrast, none with mucinous BAC tumors (0 of 11; P = .0004) had a partial response or SD, with all patients demonstrating disease progression. Nonmucinous BAC was also associated with significantly longer overall survival (hazard ratio, 2.86; P = .0030). In another study of patients with advanced BAC disease with pneumonia-like presentation treated with gefitinib,56 66 of 90 enrolled patients had histology evaluable for central pathology review, among which 50 were found to be BAC variants, evenly divided between mucinous or mixedtype and nonmucinous BAC. Disease control was achieved in 10 patients with nonmucinous BAC (40%) compared with only 2 patients with mucinous or mixed type (8%), a difference that was significant (P = .006). Median survivals were 11.3 months and 2.6 months for nonmucinous and mucinous/mixed BAC, respectively (P = .002). Thus, while limited in numbers, the data consistently demonstrate a dramatic disparity in outcomes for EGFR TKI therapy between recipients with nonmucinous and mucinous BAC, with far more favorable outcomes among patients with the nonmucinous subtype.
Prognosis Although 2 older surgical studies had suggested that patients with mucinous disease had a worse prognosis,70,71 most surgi-
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Mucinous and Nonmucinous BAC cal studies have not shown a survival difference according to cell type in series before5,35-37,39,60,72-75 and after 1999 World Health Organization criteria (“an in situ lesion, with no evidence of stromal, pleural, or vascular involvement, totally removed, and not metastatic”).76,77 Finally, results from the Surveillance, Epidemiology, and End Results database of patients with stage IIIB/IV ipsilateral disease also show no survival differences between the 2 subtypes.78 However, all of these studies were performed before 2001-2002 and therefore likely do not reflect EGFR TKI (gefitinib, erlotinib) treatments commercially available in the United States since 2003. In contrast, in advanced disease studies in which gefitinib was administered, there was significantly superior disease control56 and survival56,57 among patients with nonmucinous BAC. Thus, surgical series mainly indicate no significant differences between types, while patients with advanced disease with nonmucinous disease seemed to do better, especially if treated with an EGFR TKI.
Conclusion The study of BAC has grown dramatically in recent years, coincident with this entity having been recognized as distinct from other forms of NSCLC and having a unique natural history and treatment responsiveness.79 The first prospective trials of BAC with chemotherapy and EGFR inhibitors have been completed and reported in just the past few years. In that short time, these studies have dramatically raised awareness of BAC and have led to broad changes in how patients with BAC are managed. Just as the study of EGFR mutations might be further developed by an emerging recognition of distinct differences in how the common subtypes respond, a critical next step in BAC research now involves carefully reviewing BAC pathology specimens and correlating these results with molecular features and clinical outcomes. While the clinical entity of BAC might not be common enough to conduct trials of specific BAC subtypes, the relevance of the emerging differences underscores the need to continue the line of questioning as to whether BAC actually represents 2 separate diseases,14,29,70 with only the nonmucinous type harboring p53 abnormalities and being predominantly EGFR driven, while K-ras mutations preferentially drive the mucinous type. Answers to these questions will likely further refine our management of patients with BAC tumors. At the present time, the converging evidence of clinically relevant differences among BAC subhistologies has several practical implications. While we do not feel the limited data at this time warrant changes in how such patients are managed, it will be helpful to focus on obtaining better answers to BAC subhistology questions in ongoing and future clinical research. Histologic diagnosis rather than cytology should be strongly encouraged and arguably mandated for clinical trials that focus on BAC, as well as advocated in general clinical practice. Central review of tumor tissue by expert pathologists should be incorporated as standard practice for clinical trials of BAC. While EGFR TKI therapy would not be considered contraindicated for patients with mucinous BAC, it is very appropriate to favor EGFR TKI–based therapy as often administered early in treatment for advanced BAC, primarily if not exclusively in
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patients with nonmucinous BAC. Future trials of BAC should consistently provide information on subhistology and differences in outcomes on treatment in patients with mucinous versus nonmucinous histology. On the basis of these refinements in our research questions, treatment approaches for distinct BAC subsets might be optimized by managing these groups differently in the future.
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