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Lung Adenocarcinoma With Mixed Bronchioloalveolar and Invasive Components: Clinicopathological Features, Subclassification by Extent of Invasive Foci, and Immunohistochemical Characterization

Terasaki, Hiroshi M.D.; Niki, Toshiro M.D.; Matsuno, Yoshihiro M.D.; Yamada, Tesshi M.D.; Maeshima, Arafumi M.D.; Asamura, Hisao M.D.; Hayabuchi, Naofumi M.D.; Hirohashi, Setsuo M.D.

American Journal of Surgical Pathology: July 2003 - Volume 27 - Issue 7 - pp 937-951
Original Articles

A significant proportion of small lung adenocarcinomas consists of two components: bronchioloalveolar carcinoma (BAC) and invasive carcinoma. The purpose of this study was to compare their clinicopathologic features with those of BAC and those of invasive cancer without BAC, and to define “early invasive” lesions based on the extent of invasive foci. We reviewed 484 lesions of resected lung adenocarcinoma and classified them into three groups according to tumor growth pattern: group 1 (n = 102, BAC), group 2 (n = 216, adenocarcinoma consisting of BAC and invasive carcinoma), and group 3 (n = 166, invasive adenocarcinoma without BAC component). Group 2 was further subdivided according to the extent of the invasive area: group 2a (n = 54), BAC with invasive foci ≤5 mm; group 2b (n = 162), BAC with invasive foci >5 mm. These groups were compared with regard to their clinicopathologic features, expression of Ki-67 and p53, and expression of laminin-5, a putative marker for tumor invasion. The positivity rates of vascular, lymphatic, and pleural invasion in each group were as follows: 0%, 0%, and 0% in group 1; 5.5%, 14.8%, and 1.9% in group 2a; 45.7%, 41.4%, and 25.9% in group 2b; and 84.9%, 61.4%, and 60.8% in group 3. Notably, no lymph node metastasis occurred in either group 2a or group 1, but it was observed in 24.1% of group 2b and 47.0% of group 3. The mean Ki-67 labeling index, the frequency of p53 overexpression, and the frequency of laminin-5 overexpression increased from group 1 (11%, 4%, and 0%) to group 2a (16%, 20%, and 7%) to group 2b (24%, 41%, and 23%) to group 3 (35%, 38%, and 38%). In contrast, no clear differences were observed when lesions were subdivided according to size. Based on the distribution pattern of Ki-67-positive tumor cells, lesions were classified into two groups: marginal type (63%) and nonmarginal type (37%). The latter showed a significantly higher labeling index than the former. Moreover, the proportion of the marginal type clearly decreased from group 1 (85%) and group 2a (87%) to group 2b (55%) to group 3 (19%). Group 2 lesions showed characteristics intermediate between the BAC and invasive adenocarcinoma. According to the extent of the invasive area, we were able to define a subgroup of mixed-type adenocarcinomas (group 2a) that could be regarded as early invasive cancer because they showed low rates of vascular, lymphatic, and pleural invasion, and no nodal involvement.

Adenocarcinoma that arises in the peripheral lung parenchyma is the most representative type of lung cancer. 34 Unlike the case of squamous cell carcinoma, precursor lesions for lung adenocarcinoma are not clear. A possible precursor for lung adenocarcinoma is atypical adenomatous hyperplasia (AAH), 16,25 which is a focal lesion, often ≤5 mm in diameter, in which the involved alveoli and respiratory bronchioles are lined by monotonous, slightly atypical, cuboidal to low columnar epithelial cells. 16,25,44 In AAH, areas of varying degrees of atypia are frequently observed. Some lesions may exhibit foci of increased atypia that may warrant a diagnosis of bronchioloalveolar carcinoma (BAC). Moreover, AAH lesions are occasionally seen in the periphery of indisputable adenocarcinoma. 16,25 Thus, it has been proposed that AAH and BAC represent a spectrum of bronchioloalveolar neoplasias analogous to the adenoma–carcinoma sequence in colon cancer. 16,22,25

Although AAH and a proportion of BAC show only modest thickening of alveolar walls, a subset of BAC lesions may form characteristic central or subpleural fibrotic foci with anthracosis, often accompanied by pleural indentation (so-called “sclerosing BAC”2). Tumor cells within the fibrotic foci may show increased nuclear atypia, a distorted acinar structure, and increased mitotic activity. Stromal invasion, as suggested by foci of fibroblastic proliferation, may be present. Shimosato et al. 34,35 and Suzuki 41 postulated that the central scar formed along with tumor progression in most cases of peripheral adenocarcinoma rather than the “scar-cancer” concept.

Several investigators classified lung adenocarcinomas according to the growth pattern of tumor cells and studied their prognostic significance. Yamashiro et al. 50 classified surgically resected lung adenocarcinomas into four groups according to the growth pattern of cancer cells and the extent of their invasion. The histologic criteria were based on the recognition of three qualitatively different structures: 1) alveoli replaced by cancer cells, 2) a central area of fibrosis, and 3) invasion of central fibrotic tissue by cancer cells. Eto et al. 4 evaluated peripheral lung adenocarcinoma focusing on changes of the stromal elastic framework. The tumors were classified into two types: those with a preserved elastic framework and uniformly thickened stroma and those with a disrupted framework and collagenized stroma. The authors postulated that in the early stage of tumor development, the elastic framework is preserved, as in the former type, but as the tumors grow, the framework becomes disrupted, as in the latter type. Noguchi et al. 24 proposed a new histologic classification for small peripheral lung adenocarcinomas measuring ≤2 cm in greatest dimension. Tumors are first classified into two groups: those with a replacement growth pattern (BAC component) and those without such a pattern. The former group was further classified into three groups, according to the presence or absence of collapse and “active” fibroblastic proliferation. BACs with foci of active fibroblastic proliferation showed a worse prognosis than those without them. Furthermore, localized BAC without active fibroblast proliferation showed no lymph node involvement and had an excellent prognosis (100% 5-year survival). 24 These results suggest that BACs without foci of active fibroblastic proliferation may represent in situ adenocarcinomas, whereas those with foci are adenocarcinomas with components of BAC and invasive adenocarcinoma. More recently, Suzuki et al. 42 and Yokose et al. 51 examined the prognostic value of various histologic parameters in small lung adenocarcinomas ≤3 cm in diameter. They found that no patient death occurred in tumors with any of the following: 1) a >75% of lepidic growth component, 2) central focus of fibrosis ≤5 mm in maximum diameter, or 3) no elastic fiber framework destruction.

In the new World Health Organization (WHO) classification, adenocarcinomas with components of BAC and invasive carcinoma are now classified as “adenocarcinoma with mixed subtypes.”44 However, their clinicopathologic characteristics are yet to be compared with those of BAC and invasive cancer. Another problem is that these tumors account for most small lung adenocarcinomas, representing a heterogeneous group ranging from minimal to overtly invasive cancer. Therefore, it is necessary to further subclassify this heterogeneous group by using histologic criteria that define a biologically distinct subgroup. These issues are important because the number of small-sized lung cancers detected at early stage is going to rise because of recent developments in radiographic techniques, such as spiral CT scan, and the introduction of CT screening. 9,12,13,40

In this study, we classified lung adenocarcinomas into three groups: BAC, adenocarcinoma with components of BAC and invasive cancer, and invasive adenocarcinoma without BAC component. Adenocarcinomas with components of BAC and invasive cancer were subdivided into two groups according to the extent of the invasive area. We then compared their clinicopathologic features, such as patient age, patient gender, tumor size, vascular invasion, pleural invasion, lymph node involvement, and stage. We also evaluated their proliferative potential and p53 abnormalities by immunohistochemical analysis. These parameters have previously been used to characterize AAH, BAC, and early-stage lung adenocarcinomas. 14,17,18,38 We further evaluated the expression of laminin-5, a possible indicator of tumor invasion, 29,30,37 in the different subgroups.

From the Clinical Laboratory Division (H.T., Y.M.), and Thoracic Surgery Division (H.A.), National Cancer Center Hospital, Tokyo; Pathology Division (T.N., T.Y., A.M., S.H.), National Cancer Center Research Institute, Tokyo; and Department of Radiology (H.T., N.H.), Kurume University School of Medicine, Fukuoka, Japan.

Supported by Grants-in-Aid for Cancer Research (12-5) and for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan.

Address correspondence and reprint requests to Yoshihiro Matsuno, MD, Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail:

© 2003 Lippincott Williams & Wilkins, Inc.