Journal of Thoracic Oncology:
Bronchioloalveolar Carcinoma (Lepidic Growth) Component Is a More Useful Prognostic Factor than Lymph Node Metastasis
Anami, Yoichi MD*†; Iijima, Tatsuo MD‡; Suzuki, Kenji MD†§; Yokota, Jun MD∥; Minami, Yuko MD*; Kobayashi, Hiromi MD*; Satomi, Kaishi MD*; Nakazato, Yoshimasa MD*; Okada, Masafumi MD¶; Noguchi, Masayuki MD*
*Department of Pathology, Institute of Basic Medical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; †Department of Thoracic Surgery, Juntendo University, Tokyo, Japan; ‡Pathology Division, Ibaraki Prefectural Central Hospital, Ibaraki, Japan; §Thoracic Surgery Division, National Cancer Center Hospital, Tokyo, Japan; ∥Biology Division, National Cancer Center Research Institute, Tokyo, Japan; and ¶Department of Epidemiology, Institute of Social Medical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Masayuki Noguchi, MD, PhD, Department of Pathology, Institute of Basic Medical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan. E-mail: firstname.lastname@example.org
Introduction: Although many factors predictive of patient survival have been reported for lung cancer, no comparative studies have attempted to determine those that are most significant for practical medicine.
Methods: We conducted a retrospective review of 139 patients who underwent complete resection of adenocarcinomas less than 2 cm in diameter between 1993 and 2000 at the National Cancer Center Hospital (Tokyo, Japan). The MIB-1 labeling index (LI), immunohistochemical staining for carcinoembryonic antigen (CEA), p53, p27, epidermal growth factor receptor (EGFR), phosphorylated-EGFR (pEGFR), Cox-2, neuronatin, γH2AX, and thyroid transcription factor-1 (TTF-1), the prevalence of a micropapillary pattern, and the ratio of the bronchioloalveolar cell carcinoma (BAC) or lepidic growth (LG) component were determined, and their significance as prognostic factors for lung adenocarcinoma was compared.
Results: Univariate analysis showed that lymph node metastasis (p-N status), BAC/LG component, vascular invasion (p-V status), MIB-1 LI, pEGFR, and CEA were prognostically significant (p-N status: p < 0.0001, BAC/LG: p = 0.0005, p-V status: 0.002, MIB-1 LI: p = 0.005, pEGFR: p = 0.024, and CEA: p = 0.049). Multivariate analysis showed that only p-N status (p = 0.013) was of prognostic significance. However, BAC/LG component (p = 0.051) was a more reliable prognostic factor than p-N status in mixed adenocarcinoma with a BAC/LG component.
Conclusion: In comparison with other immunohistochemical and histopathologic factors, BAC/LG component is independently and reliably prognostic for small adenocarcinoma of the lung, and, in particular, for the major histologic subtype (adenocarcinoma mixed subtype with BAC/LG), BAC/LG component is more reliably prognostic than lymph node metastasis.
Lung adenocarcinoma is one of the most common causes of death due to cancer worldwide. Until now, many immunohistochemical prognostic factors of lung adenocarcinoma such as carcinoembryonic antigen (CEA), p53, Ki-67, MIB-1 labeling index (LI), epidermal growth factor receptor (EGFR), and phosphorylated-EGFR (pEGFR) have been reported.1–6 Although a few reports have compared the prognostic significance of multiple immunohistochemical markers in non-small cell lung carcinoma,7–9 no study has yet investigated adenocarcinoma. Similar to immunohistochemical factors, histologic factors such as micropapillary pattern and bronchioloalveolar cell carcinoma (BAC) component/lepidic growth (LG) pattern have been recently reported to be significantly associated with the prognosis of adenocarcinoma. However, this has not been verified by multivariate analysis.10–12
With the recent advances in computed tomography (CT) imaging techniques, such as high-resolution CT and helical CT, the number of patients with small adenocarcinomas detected by CT screening has been increasing. Cases detected by CT screening include various kinds of adenocarcinomas that can have favorable or unfavorable prognosis.13–16 To select cases with a more favorable prognosis that are eligible for reduction surgery or cases with unfavorable prognosis that require additional adjuvant chemotherapy or radiotherapy after surgical resection, it is very important to evaluate appropriate biologic markers. We have extensively examined the histologic patterns of small-sized adenocarcinoma and reported a working histologic classification (Noguchi Classification).17 Small adenocarcinomas show two types of growth pattern: replacement (lepidic) growth and nonreplacement (nonlepidic) growth along preexisting alveolar structures. The former type is the predominant one and includes cases with various prognoses. Patients with type A (localized bronchioloalveolar carcinoma [LBAC]) and type B (LBAC with focal collapse) have a 5-year survival rate of 100%, whereas type C (LBAC with foci of fibroblastic proliferation) is invasive and the prognosis is variable.
In this study, we selected 10 immunohistochemical markers (CEA, p53, MIB-1 LI, EGFR, pEGFR, Cox-2, neuronatin, γH2AX, p27, and thyroid transcription factor-1 (TTF-1)) and two histopathologic markers (BAC/LG component and micropapillary pattern) that have been reported to be significantly associated with the prognosis of lung carcinoma and tested their significance using 139 cases of small adenocarcinoma, with the aim of finding the best marker for practical medicine.1–6,10–12,18–22 Our findings indicated that BAC/LG component is more prognostically reliable than lymph node metastasis in adenocarcinoma mixed subtype with a BAC/LG component, which is the major histologic subtype of small adenocarcinoma.
PATIENTS AND METHODS
Patient Selection and Tissue Sample Collection
Primary tumors were obtained from 139 patients with small adenocarcinomas <2 cm in maximum diameter who were treated surgically at the National Cancer Center Hospital (Tokyo, Japan) between December 1993 and December 2000. Informed consent was obtained from all patients for specimen collection. None of the patients had received neoadjuvant or adjuvant chemotherapy and radiotherapy before or after surgery. Six patients subsequently died of causes other than lung carcinoma. The average patient age was 61.0 years (range, 38–82 years), and the group included 68 men and 71 women. The median follow-up period was 83.5 months (range, 4.6–150.7 months). The tumors were diagnosed pathologically according to the recent 1999 WHO classification23 and the International System for Staging of Lung Cancer.24 In addition, all the tumors were classified histologically into six subtypes (types A–F) according to the histologic classification for small-sized adenocarcinoma of the lung reported previously by Noguchi et al.17 (the Noguchi classification). Furthermore, they were divided into three groups according to BAC/LG component status. The first group was pure BAC/LG, comprising only the BAC/LG component, and corresponding to types A and B. The second was mixed adenocarcinoma with various proportions of BAC/LG component, corresponding to type C, and the third was adenocarcinoma without a BAC/LG component, corresponding to types D–F.
All surgically resected samples were immediately fixed in 10% neutral buffered formalin and embedded in paraffin. For immunohistochemistry, consecutive 3-μm-thick sections were cut from each tumor. The WHO classification and Noguchi classification of each sample were confirmed by three pathologists (YA, TI, and MN) using hematoxylin and eosin (HE)-stained sections.
Among many immunohistochemical prognostic factors reported previously, we selected CEA and neuronatin as embryonal protein markers and p53 as an apoptosis-related marker.2,4,5,21 p27, MIB-1 LI, EGFR, pEGFR, and Cox-2 were selected as cell growth markers.1,3,6,18,22 TTF-1 was examined as a cell differentiation marker and γH2AX as a DNA damage marker.19,20,25 Antibodies used for immunohistochemistry in this study are summarized in Table 1. The ENVISION+ detection system using a DAKO Autostainer Plus (DAKO Glostrup, Denmark) was used for immunohistochemical staining with monoclonal antibodies. Microwave treatment in citrate buffer (pH 6.8) was used for antigen retrieval. Using specific antibodies against these 10 antigens, the expression of each marker protein was examined and evaluated by immunohistochemistry according to the original protocol reported previously.3–6,18–22 In brief, CEA was judged as positive when more than 60% of the tumor cells were stained in the cytoplasm and membrane. p53 was judged as positive when more than 30% of tumor nuclei were stained. The number of nuclei showing positive staining with MIB-1 antibody/1000 total tumor nuclei was counted, and the MIB-1 LI was calculated. A case was judged as positive when more than 10% of the tumor cells showed nuclear expression. p27 was judged as positive when more than 30% of tumor cells were stained. For EGFR, pEGFR, Cox-2, and neuronatin, cases were judged as positive when more than 30% of the tumor cells were stained. For γH2AX and TTF-1, cases were judged as positive when more than 1 and 50% of the tumor cells were stained, respectively.
The presence of a micropapillary pattern was determined and calculated according to the criteria of Miyoshi et al.12 A BAC/LG component was defined as LG of cancer cells without stromal invasion and destruction of elastic fibers based on the WHO classification of bronchioloalveolar carcinoma. The ratio of a micropapillary pattern and BAC/LG component was confirmed by a review of HE- and elastica van Gieson-stained sections at the maximum cut surface of each sample. Cases in which a micropapillary pattern covered more than 5% of the area were judged as positive.12 The ratio of BAC/LG component was calculated as the area of the BAC/LG component/maximum cut surface area of the tumor. Patients were divided into two groups according to the ratio of BAC/LG component: 50% or more (BAC/LG >50%) and less than 50% (BAC/LG <50%).11 All histologic sections were independently reviewed by three pathologists (YA, TI, and MN), and the average ratio for each case was obtained. In cases where there was an occasional discrepancy in the interpretation (<5%), consensus was achieved after discussion with the aid of a multiheaded microscope. The interobserver variability in diagnosing the ratio of BAC/LG ratio was 10–20%, even with reference to information about the preservation of the preexisting elastic fiber frame network.
Fisher’s exact test was used to examine correlations between two groups. The cumulative survival rates for patient groups were estimated using the Kaplan-Meier method, and statistical analysis was carried out with the log-rank test. For univariate and multivariate analyses, the influence of each variable on survival was assessed using the Cox proportional hazards regression model. The multivariate technique was carried out by forced entry. The level of statistical significance was defined as p ≤ 0.05. All analyses were carried out with SPSS II for Windows (SPSS Inc., Chicago, IL).
Clinicopathologic findings in these 139 patients are summarized in Table 2: 89 patients, stage IA; three patients, stage IB; 16 patients, stage IIA; four patients, stage IIB; 17 patients, stage IIIA; nine patients, stage IIIB; and one patient, stage IV. All 27 patients with a WHO BAC classification corresponding to types A and B of the Noguchi classification were stage IA (100%). Among 70 patients diagnosed as type C, 43 patients (61.7%) were stage IA, and 24 patients (34.3%) showed lymph node metastasis (p-N1-3). Among 42 patients diagnosed as types D to F, 19 patients (45.2%) were stage I, and 23 patients (54.8%) showed lymph node metastasis (p-N1-3).
Immunohistochemical Positivity and Histopathologic Features
Representative examples of immunohistochemical staining and histologic features are shown in Figures 1A–L. The positivity rates for the various factors, shown in Table 3, were compared between BAC/LG (types A and B) and mixed adenocarcinoma with a BAC/LG component (type C). Fisher’s exact test showed that the positivity rates for p53, MIB-1 LI, γH2AX, and a micropapillary pattern were significantly associated with the presence of a BAC/LG component (p < 0.05).
Relationship of Various Factors to Survival Rate
Kaplan-Meier analysis indicated that patients who were positive for BAC/LG (>50%) had a significantly more favorable prognosis than the others (p < 0.001) (Figure 2A). On the other hand, patients who were positive for pEGFR, MIB-1 LI, and CEA had significantly worse survival rates than those who were negative for these factors, respectively (pEGFR: p = 0.018, MIB-1 index: p = 0.019, and CEA: p = 0.044) (Figures 2B–D). None of the other factors were correlated with prognosis.
As indicated by various reports, pure BAC/LG has an extremely favorable prognosis, whereas adenocarcinoma without BAC/LG (solid, acinar, and papillary) has an unfavorable prognosis. We focused on the 70 patients with adenocarcinoma mixed subtypes with a BAC/LG component (type C) in this study. Kaplan-Meier analysis indicated that patients with BAC/LG (>50%) and positivity for TTF-1 had markedly more favorable prognoses than the others. None of the other factors was correlated with prognosis.
Determination of Independent Factors Affecting Prognosis
To find practically useful prognostic factors, we carried out univariate analysis for 17 factors: 10 immunohistochemical, two histologic, and five clinicopathological (Table 4). The five clinicopathological factors included sex, age, lymph node metastasis (p-N status), vascular invasion (p-V status), and pleural invasion (p-p status). p-N status, BAC/LG component, p-V factor, MIB-1 LI, pEGFR, and CEA were significant prognostic factors (p-N status: p < 0.0001, BAC/LG component: p = 0.0005, p-V status: p = 0.002, MIB-1 LI: p = 0.005, pEGFR: p = 0.024, and CEA: p = 0.049).
We then performed multivariate analysis for these six factors whose presence significantly affected prognosis and for demographic factors, such as age and sex (Table 5). This showed that only p-N status was significantly related to prognosis (p-N status: p = 0.013). Because the prognosis of pure BAC/LG and non-BAC/LG is already known to be markedly favorable and unfavorable, respectively, we focused on mixed adenocarcinoma with a BAC/LG component, which is the major histologic subtype and includes cases showing various prognoses. Surprisingly, BAC/LG component was selected as the most reliable prognostic factor (p = 0.051) (Table 6).
Numerous studies have examined the biologic significance of various proteins in lung carcinoma and concluded that the expression of several of them could be useful for prognostication. However, few multiinstitutional confirmation studies have been performed, except for factors such as CEA and p53. The purpose of this study was to compare these factors in small-sized lung adenocarcinoma and to select any that could be useful in practical medicine.
In terms of histopathology, we have previously reported that the growth pattern of small adenocarcinomas, as categorized by the Noguchi classification, is very important for prognostication.17 According to this classification, BAC/LG (types A and B) is thought to progress to mixed adenocarcinoma with a BAC/LG component (type C), and adenocarcinomas without a BAC/LG component (types D–F) have a worse prognosis than those with a BAC/LG component.26 These characteristic findings have been confirmed by various pathologic studies.10,11,27–29 On the basis of this classification, we first divided the cases examined into three groups: BAC/LG, mixed adenocarcinoma with a BAC/LG component, and adenocarcinoma without BAC/LG. Four factors—p53, MIB-1 LI, γH2AX, and a micropapillary pattern—were significantly associated with the amount of the BAC/LG component (BAC/LG versus mixed adenocarcinoma with a BAC/LG component) (Table 3). In the early stage of adenocarcinogenesis, DNA damage to important cancer-related genes such as those responsible for double-strand break repair (γH2AX), the proliferation markers such as MIB-1 LI, and apoptosis-related markers such as p53 increases during the course of tumor progression. With regard to the presence of a micropapillary pattern, there was a significant difference between pure BAC/LG and adenocarcinoma with a BAC/LG component. Thus, a micropapillary pattern may be a more characteristic feature of adenocarcinoma with a BAC/LG component.
The present univariate analysis showed that, as expected, lymph node metastasis (p-N status) and vascular invasion (p-V status) were significant prognostic markers. Other than these important histologic markers, BAC/LG component, MIB-1 LI, pEGFR, and CEA were shown to have prognostic significance (Table 4, Figure 2). This result seems reasonable because MIB-1 LI and CEA are already well-known prognostic markers in various cancers. Several contradictory reports have stressed a relationship between EGFR and/or pEGFR expression and prognosis.1,6,30,31 For example, Kanematsu et al.30 reported that EGFR overexpression was related to good performance status but not correlated with a short time to progression in patients with non-small cell lung carcinoma. However, in another study of patients with non-small cell lung carcinoma, Selvaggi et al.,31 reported a significant relationship between EGFR expression and prognosis. In the present study of small-sized adenocarcinoma, pEGFR but not EGFR was associated with poor prognosis. These previous reports and our results suggest that pEGFR overexpression is correlated with tumor progression at least in small adenocarcinomas.
We next performed multivariate analysis to determine independent prognostic factors that can be used for practical medicine. As shown in Table 5, multivariate analysis indicated that only p-N status was an independent prognostic factor. None of the remaining immunohistochemical and histologic factors showed a significant relationship to prognosis. Although the presence of a BAC/LG component was not proved to be as strong a prognostic factor as p-N factor in small-sized adenocarcinomas, it was, however, prognostically reliable.
Although many reports have indicated an extremely favorable prognosis of BAC/LG and a poor prognosis of adenocarcinoma without a BAC/LG component, mixed adenocarcinoma with a BAC/LG component represents a heterogeneous group showing favorable and unfavorable prognoses.10,11,17,27,28 We examined 70 cases of this adenocarcinoma type using Kaplan-Meier analysis and showed that BAC/LG component and TTF-1 were significantly prognostic (Figure 3). In multivariate analysis, as Table 6 indicates, although there were no significant prognostic markers, BAC/LG component was most reliable (p = 0.051) among those examined.
In this study, we have stressed that tumors including a BAC/LG pattern show an extremely favorable prognosis and that small-sized adenocarcinoma comprising pure BAC/LG corresponds to in situ adenocarcinoma. However, the biologic concept of BAC/LG is still controversial because an LG pattern is also widely observed in various invasive pulmonary adenocarcinomas and even several types of metastatic pulmonary carcinoma. The LG pattern itself is not necessarily indicative of the biologic nature of the tumor cells. Its morphologic characteristics involving expansion along the preexisting alveolar structure resemble the intraepithelial spread that is usually observed at the periphery of invasive squamous cell carcinoma.
BAC/LG is known to correspond to ground glass opacity (GGO) revealed by diagnostic radiology.32 Several reports have indicated that the outcome of adenocarcinoma cases can be evaluated by the appearance of GGO.11,13–16,33,34 Most of these papers have stressed that GGO area is a very important parameter in this respect. The findings of the present study are considered to confirm this conclusion pathologically. To determine the disease stage before treatment, forecasting of lymph node metastasis is very important, and radiologists usually pay much attention to lymph node swelling in the mediastinal and hilar regions. However, the accuracy of estimation is not high because many cases have lymph nodes showing reactive swelling. However, because GGO area can be evaluated precisely by high-resolution CT before surgery, clinicians should pay more attention to the GGO (BAC/LG) component than to lymph node swelling when diagnosing small nodules using this imaging modality.
Supported in part by a Grant-in-Aid for Cancer Research (16-1) from the Ministry of Health, Labor and Welfare of Japan.
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