Ann Thorac Surg 2003;75:1113-1117
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Clinicopathological analysis of prognostic factors in clinical IA peripheral adenocarcinoma of the lung
Yukinori Sakao, MD, PhDa*,
Toru Sakuragi, MDa,
Masafumi Natsuaki, MD, PhDa,
Tsuyoshi Itoh, MD, PhDa
a Department of Thoracic and Cardiovascular Surgery, Saga Medical School, Saga, Japan
Accepted for publication November 1, 2002.
* Address reprint requests to Dr Sakao, Department of Thoracic and Cardiovascular Surgery, Saga Medical School, Nabesima, 5-1-1, Saga 849-8501, Japan
e-mail: sakao{at}post.saga-med.ac.jp
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Abstract
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BACKGROUND: The clinical IA (C-IA) lung cancer patient shows a 5-year survival rate of approximately 70% after surgical therapy alone. We have tried to clarify the prognostic factors in C-IA adenocarcinoma of the lung to identify those candidates who might benefit from preoperative or postoperative adjuvant therapy.
METHODS: Between 1994 and June 2001, 54 patients were diagnosed with C-IA adenocarcinoma of the lung and underwent lobectomy and hilar and mediastinal node dissection. The clinicopathological records of the patients were examined for age, gender, nodal status, tumor size, serum CEA level, and histologic subtype (replacing vs nonreplacing type). Localized bronchioloalveolar carcinoma (LBAC; noninvasive cancer) was excluded from this study.
RESULTS: Nodal involvement, high serum CEA level (
4.0 ng/mL), and nonreplacing type were significant (p < 0.05) prognostic factors for poor outcome in univariate analyses. Nodal involvement, larger tumor size ( 20 mm), and nonreplacing type were significant (p < 0.05) prognostic factors for poor outcome in multivariate analyses. High serum CEA level and nonreplacing type were significant (p < 0.01) risk factors for lymph node involvement both in univariate and multivariate analyses. Up to 71.5% of patients with both factors showed lymph node metastases. Furthermore, based on histologic subtype and tumor size, the 4-year survival rate was 33% for patients with both of these factors, and 34.3% even if they were pN0.
CONCLUSIONS: C-IA patients, both with the larger tumor size ( 20 mm) and nonreplacing type, show poor outcome after surgery, and patients with both high serum CEA level and nonreplacing type are at high risk for lymph node metastases.
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Introduction
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Non–small cell lung cancer (NSCLC) is the leading cause of cancer death in the US and Japan, and the death rate from lung cancer is increasing [1, 2]. Furthermore, adenocarcinoma is the predominant histologic type of lung cancer [3, 4].
Surgical resection, the standard treatment for clinical IA (C-IA), the earliest stage of lung cancer, results in a 5-year survival rate of approximately 67% to 77% [5, 6]. Recently, improvements in diagnostic radiology have led to earlier detection of lung cancer. Efforts to improve survival for early-stage NSCLC patients have focused on the use of chemotherapy administered postoperatively (adjuvant) or preoperatively (induction) to eradicate micrometastatic disease. Wada and associates reported that adjuvant chemotherapy after surgery improved the prognosis in pT1N0M0-IA patients, with a 5-year survival rate of 90.7% in patients with adjuvant chemotherapy and 75.3% after surgery alone (p = 0.03) [7]. The patients showed a beneficial effect of adjuvant chemotherapy after surgery in the early stage of lung cancer. On the other hand, preoperative chemotherapy (induction therapy) for locally advanced NSCLC has been suggested to have possible advantages [8, 9], and a combined modality approach is being applied to patients in the early stage [10].
Although many clinical and pathologic prognostic factors have been reported [5, 11], the important prognostic factors in C-IA patients remain unclear.
In this retrospective study, we have tried to clarify the preoperative and postoperative prognostic factors in patients diagnosed with C-IA adenocarcinoma (bronchioloalveolar carcinoma is excluded) of the lung in order to identify those individuals who might benefit from preoperative or postoperative adjuvant therapy.
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Material and methods
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Between 1994 and June 2001, 386 patients underwent surgical resection of primary lung cancer within our department. Of those, 54 patients were classified clinically with stage IA adenocarcinoma of the lung, and standard surgical procedures (lobectomy and hilar and mediastinal node dissection) were performed. The group comprised 33 women and 21 men, with ages ranging from 42 to 82 years (median, 64 years). Preoperative staging was assessed according to the TNM classification of the International Union Against Cancer [12] using chest computed tomography (CT), abdominal CT, ultrasonography, brain CT or magnetic resonance imaging, and bone scanning in all patients. Clinical mediastinal and hilar lymph node status were assessed as positive if the results of the chest CT showed the shorter axis was larger than 1.0 cm. The follow-up period ranged from 12 to 84 months (median, 48 months).
Methods
The clinicopathological records of the patients were examined for age (
70 years vs > 70 years), gender, nodal status (p-N0 vs p-N1 or p-N2), tumor size (< 20 mm vs 20 mm), serum CEA level ( 4.0 vs > 4.0 ng/mL), and histologic typing (replacing type vs nonreplacing type). Histologic type was assessed according to Noguchi’s classification of small adenocarcinomas, in which the tumor shows the following features: replacing type, replacement growth of the pulmonary alveolar structure; and nonreplacing type, compressive or destructive growth against the pulmonary alveolar structure. Replacing type includes types: A, localized bronchioloalveolar carcinoma (LBAC); B, LBAC with foci of collapse of alveolar structure; and C, LBAC with foci of active fibroblastic proliferation. Nonreplacing type includes types: D, poorly differentiated adenocarcinoma; E, tubular adenocarcinoma; and F, papillary adenocarcinoma with compressive and destructive growth [11, 13]. Type A adenocarcinoma (localized bronchioloalveolar carcinoma [LBAC]) was excluded from this examination because the newly revised third edition of WHO concerning histologic typing of lung tumor classified it as noninvasive cancer [14].
Statistical analysis
The length of survival was defined as the interval between the day of surgery and the day of death from tumor or last follow-up date. The survival rates were calculated using the Kaplan-Meier method, and univariate analyses were performed using the log-rank test or 
2 test. Multivariate analyses were performed by means of the Cox proportional hazard model on Stat View J 5.0 (SAS Institute Inc, Cary, NC).
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Results
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Overall survival
The overall 5-year survival rate for the 54 patients with C-IA adenocarcinoma of the lung was 70.5%.
Univariate analysis of clinicopathological factors
The survival rates according to the various clinicopathological variables of C-IA lung adenocarcinoma patients are shown in Table 1.
Three variables are significant for a poor prognostic outcome of these six variables: nodal involvement, high serum CEA level, and nonreplacing type in the histologic subtype. Patients with nodal involvements (N1 [n = 2], N2 [n = 9]) had a 5-year survival rate of 26.2% versus 78.1% in patients without nodal involvement (p < 0.001). The 5-year survival rate for patients with high serum CEA levels (n = 12) was 51.6%, and was 73.7% for patients with normal CEA (n = 42) levels (p = 0.045). The 5-year survival for patients with nonreplacing type (n = 25) was 49.1%, and was 82.4% for patients with replacing type (n = 29) (p = 0.011).
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Table 1. Relationship Between Clinical Variables and Survival for Patients With Surgically Resected Clinical Stage IA Adenocarcinoma of the Lung
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Men had a tendency toward a poorer 5-year survival than women (56.8% and 79.3%, respectively; p = 0.07).
Multivariate analysis of clinicopathological factors
Five variables (with p values less than 0.2 from univariate analysis) were analyzed using the Cox proportional hazard model, and the results are summarized in Table 2.
Larger tumor size (p = 0.012, hazard ratio = 7.50), nonreplacing type in histologic examination (p = 0.011, hazard ratio = 6.50), and nodal involvement (p < 0.01, hazard ratio = 9.01) were significant indicators for a poor prognostic outcome. The 4-year survival rate was 33.2% for patients with large tumor size and nonreplacing type, 93.4% for patients with neither, and 66.8% for patients with either of the factors (p < 0.01) (Fig 1).
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Table 2. Multivariate Analysis of Prognostic Factors in Surgically Resected Clinical Stage IA Adenocarcinoma of the Lung
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Fig 1. The 4-year survival rates in patients diagnosed with clinical IA adenocarcinoma of the lung depend on tumor size and histologic subtype. Both factors: the tumor size was greater than or equal to 20 mm and was nonreplacing in histologic subtype. Either factor: the tumor size was greater than or equal to 20 mm or was nonreplacing in histologic subtype. Neither factor: the tumor size was less than 20 mm and was replacing in histologic subtype. *p less than 0.01, versus with either or neither factor.
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Gender and CEA serum level were not significant prognostic factors in multivariate analyses.
Risk for lymph node involvement
The five variables were examined with respect to risk for lymph node involvement. Results of univariate analyses are summarized in Table 3.
High serum CEA concentrations and nonreplacing type were significantly associated with lymph node involvement (p = 0.013, p < 0.01, respectively). Furthermore, both of the factors were significant risk factors for lymph node involvement in multivariate analysis (p = 0.014, hazard ratio = 7.10; p < 0.01, hazard ratio = 8.54, respectively) (Table 4).
Table 5 shows the rate of lymph node involvement based on serum CEA concentration and histologic subtype. The rate of lymph node positivity was 71.5% for patients with both of the factors, and was much higher than for the patients with either (20.8%, p = 0.02) or with neither
(4.3%, p < 0.01) of the two factors. Tumor size, age, and gender were not significant risk factors for lymph node involvement.
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Table 3. Relationship Between Clinical Variables and Lymph Node Involvement for Patients With Surgically Resected Clinical Stage IA Adenocarcinoma of the Lung
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Table 4. Multivariate Analysis of Risk Factors for Lymph Node Involvement in Surgically Resected Clinical Stage IA Adenocarcinoma of the Lung
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Table 5. Risk for Lymph Node Involvement Based on Serum Carcinoembryonic Antigen (CEA) Level and Histological Subtype in Surgically Resected Clinical Stage IA Adenocarcinoma of the Lung
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Prognosis in C-IA-pN0 (p-IA) patients
Figures 2 and 3
show survival rates in C-IA-pN0 patients based on histologic subtype and tumor size, respectively. The 5-year survival rates were 88.4% in replacing type and 62.5% in nonreplacing type (p = 0.034).
The 5-year survival rates were 65.5% in tumor size greater than or equal to 20 mm and 89.0% in tumors less than 20 mm (p = 0.04). Furthermore, the 4-year survival rate was 34.3% for patients with both nonreplacing type and tumors larger than 20 mm, and was significantly lower than the 92.3% for patients with neither or 81.6% for individuals with either of these criteria (p < 0.01) (Fig 4).
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Fig 2. The 5-year survival rate depends on the histologic subtype in those patients with clinical IA and pN0 adenocarcinoma.
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Fig 3. The 5-year survival rate depends on tumor size in those patients with clinical IA and pN0 adenocarcinoma.
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Fig 4. The 4-year survival rate in patients diagnosed as clinical IA and pN0 adenocarcinoma of the lung depend on tumor size and histologic subtype. Both factors: the tumor size was greater than or equal to 20 mm and was nonreplacing in histologic subtype. Either factor: the tumor size was greater than or equal to 20 mm, or was nonreplacing in histologic subtype. Neither factor: the tumor size was less than 20 mm and was replacing in histologic subtype. *p less than 0.01, versus with either or neither factor.
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Comment
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In this study, we revealed the prognostic factors for poor outcome in C-IA peripheral adenocarcinoma of the lung, such as nonreplacing histologic subtype and tumor size greater than or equal to 20 mm together with lymph node involvement. In particular, when two of the factors, such as nonreplacing type in histologic subtype and larger tumor size ( 20 mm), were positive, the 4-year survival rate was only 33%, and 34.3% even if the individual was assessed as pN0. Patients with a high serum CEA concentration had a poor prognosis in univariate analysis. Similarly, Suzuki and associates reported that preoperative high serum CEA concentration and clinical T2 disease were significant factors for poor prognosis in clinical stage I lung cancer [5]. In the present study, we showed that a high serum CEA concentration was associated with the risk for lymph node metastasis, and that a high serum CEA concentration was not an independent factor for poor outcome in C-IA patients. Furthermore, not only a high serum CEA concentration but also a nonreplacing histologic subtype were highly associated with risk for lymph node involvement, and when both of the two factors were positive, the incidence of lymph node metastasis was 71.5%, even in C-IA patients. Thus, histologic subtype was a very important prognostic factor not only as a risk factor for lymph node involvement but also as a prognostic factor for poor outcome after surgery, independent from lymph node metastases.
Noguchi and associates classified the peripheral small adenocarcinoma into two subgroups: replacing type, the tumor shows replacement growth of the pulmonary alveolar structure; and nonreplacing type, the tumor does not show replacement growth but shows compressive or destructive growth against alveolar structure [11]. Noguchi and associates reported that lymph node involvements were seen 22.4% of the time in replacing type (excluding type A: LBAC) and 41.1% of the time in nonreplacing type, and that mitotic figures were more often observed in nonreplacing type than in replacing type (excluding type A: LBAC) [11, 13]. Thus, the nonreplacing type may have more malignant biological characters than the replacing type. They also suggested that the replacing type could be distinguished from the nonreplacing type by cytopathological features. These features include nuclear chromatin pattern, shape, size, atypia, and variation in nuclear size using a sputum, bronchial brushing, or fine needle aspiration specimen obtained on preoperative examination [11, 13]. On the other hand, Aoki and associates reported that CT findings in peripheral lung adenocarcinoma were correlated with histologic classification, such as replacing or nonreplacing type adenocarcinoma. The CT findings, such as airbronchogram or ground glass opacity with slow growth, were features of replacing type adenocarcinoma; however solid attenuation with rapid growth were features of the nonreplacing type [15, 16]. Thus, recent histopathological and radiologic studies may make it possible to detect histologic subtypes preoperatively. In summary, patients both with the larger tumor size ( 20 mm) and nonreplacing type show poor outcome after surgery even if they are diagnosed with C-IA-pN0 lung cancer, and patients with both high serum CEA levels and nonreplacing type are at high risk for lymph node metastases even if they are diagnosed with C-IA lung cancer. According to recent studies [7–10], such groups may be candidates for adjuvant or induction therapy. In particular, patients with both high serum CEA levels and nonreplacing type may be candidates for induction therapy even if they are diagnosed with C-IA lung cancer.
Further investigation will be needed to determine the beneficial effect of adjuvant or induction therapy for such patients with nonreplacing type adenocarcinoma.
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Acknowledgments
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We thank Dr Edmund J. Miller, Chief, Surgical Research, North Shore University Hospital, for critical reviews.
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Abstract
Introduction
