Ann Thorac Surg 2004;77:1157-1161
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Predictive factors for survival in surgically resected clinical IA peripheral adenocarcinoma of the lung
Yukinori Sakao, MD, PhDa*,
Takahiko Nakazono, MDb,
Toru Sakuragi, MD, PhDa,
Masafumi Natsuaki, MD, PhDa,
Tsuyoshi Itoh, MD, PhDa
a Department of Thoracic and Cardiovascular Surgery, Saga Medical School of University, Nabesima, Saga, Japan
b Department of Radiology, Saga Medical School, Nabesima, Saga, Japan
Accepted for publication September 11, 2003.
* 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: Patients with clinical IA (C-IA) lung cancer have a 5-year survival rate of approximately 70% after surgical therapy alone. We attempted to clarify preoperative factors that are predictive for poor prognosis after surgery among patients diagnosed with C-IA adenocarcinoma of the lung.
METHODS: Between 1994 and April 2002, 65 patients with C-IA adenocarcinoma of the lung underwent lobectomy + hilar and mediastinal node dissection. The chest computed tomography (CT) imaging and clinicopathologic records of the patients were examined. Tumors were subtyped into solid type or nonsolid type categories according to the component of ground glass opacity assessed by CT. Age, sex, serum carcinoembryonic antigen (CEA) level, histologic subtype (replacing versus nonreplacing), and tumor size were also analyzed.
RESULTS: Solid type on CT and high serum CEA level (
4.0 ng/mL) were prognostic factors for poor outcome in univariate analyses (p < 0.05). Solid type on CT, high serum CEA level, and larger tumor size (> 20 mm) were significant (p < 0.05) prognostic factors for poor outcome in multivariate analyses. Solid type on CT and high serum CEA level were significant (p < 0.01) risk factors for lymph node involvement in both univariate and multivariate analyses. Furthermore, based on the factors of CT subtype, tumor size, and serum CEA level, the 5-year disease-free survival rate was 20.1% for patients with two of the three factors, and 21.2% even if they were assessed as pN0. Computed tomography subtype was strongly associated with histologic subtype (p < 0.0001).
CONCLUSIONS: Solid type on CT (associated with histologic subtype such as nonreplacing type), tumor size larger than 20 mm, and high serum CEA concentration are important preoperative predictive factors for poor outcome after surgery for patients with C-IA lung adenocarcinoma.
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Introduction
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Clinical IA (C-IA) lung cancer results in a 5-year survival rate of approximately 67% to 77% after surgery [1, 2]. Although many clinical and pathologic prognostic factors have been reported [1, 3–6], preoperative factors that can predict the prognosis after surgery in C-IA lung adenocarcinoma have not been previously defined.
We have already reported that histologic subtype of adenocarcinoma (such as nonreplacing type), high serum CEA concentration, and larger tumor size (> 20 mm) are important prognostic factors for poor outcome among patients with C-IA adenocarcinoma of the lung [6]. In particular, a patient with both large tumor size (> 20 mm) and nonreplacing histologic subtype shows a poor outcome after surgery. This group showed a 4-year survival rate of less than 40% even when diagnosed with C-IA-pN0 lung adenocarcinoma [6].
Recently, improvements in diagnostic radiology have revealed the association between computed tomography (CT) findings such as ground glass opacity (GGO) and replacement growth of adenocarcinoma [4, 5]. Further, such developments in diagnostic radiology may enable us to preoperatively predict the prognosis after surgery using histologic features.
In this retrospective study, we tried to identify preoperative predictive factors for poor prognosis after surgery in patients diagnosed with C-IA adenocarcinoma of the lung. This strategy will allow us to identify those individuals who might benefit from preoperative multimodal therapy.
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Material and methods
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Patients
Between 1994 and April 2002, 431 patients underwent surgical resection of primary lung cancer within our department. Of those, 65 patients were classified clinically as having stage IA adenocarcinoma of the lung and standard surgical procedures (lobectomy + hilar and mediastinal node dissection) were performed. The group comprised 24 women and 41 men with a median age of 66 years (range 42 to 81 years). Preoperative staging was assessed according to the TNM classification of the International Union Against Cancer [7] using chest CT, abdominal CT or ultrasonography, brain CT or magnetic resonance imaging, and bone scanning in all patients. Clinical mediastinal and hilar lymph node status was assessed as positive if the results of the chest CT showed that the shorter axis was larger than 1.0 cm. The follow-up period ranged from 12 to 102 months (median 48 months).
Methods
The clinicopathologic records of the patients were examined and the following potential preoperative prognostic factors were compiled: age ( 70 versus < 70 years), sex, tumor size measured by CT (
20 mm versus > 20 mm), preoperative serum CEA level (4.0 versus > 4.0 ng/mL), and thin-section chest CT images (CT with 2.0- or 3.0-mm section thickness to image the tumor, window level −500 HU and width 1,500 HU). The findings on thin-section CT were analyzed with respect to size of the GGO component. Ground glass opacity was defined as hazy and amorphous increased lung attenuation without obscuration of the underlying vascular markings and bronchial walls. The tumor was defined as solid type when the size of the GGO component was less than 10% in thin-section CT; the percentage of the GGO component was calculated using the ratio of the non-GGO area to the greatest diameter of the tumor (including the GGO area) [5] (Fig 1).
Furthermore, the associations between nodal status, histologic typing (replacing type or nonreplacing type) [3, 8] and thin-section chest CT images were analyzed. Histologic type was assessed according to Noguchi's classification of small adenocarcinomas [3] in which the tumor is of the replacing or nonreplacing type, the replacing type being defined as having replacement growth of the pulmonary alveolar structure and the nonreplacing type being defined as having compressive or destructive growth against the pulmonary alveolar structure. When the two components were both present in the largest cut surface with an area of less than 20%, the tumor was defined as heterogeneous. Localized bronchoalveolar carcinoma was excluded from this examination because the newly revised World Health Organization guidelines, concerning histologic typing of lung tumors, classified this cancer as noninvasive [9]. Further, we excluded the 100% GGO type tumors from this study because they were believed to be noninvasive or precancerous lesions on microscopic examination.
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Fig 1. Transverse thin-section computed tomography scan of the lung adenocarcinoma. (A) Nonsolid type: Peripheral ground glass opacity (GGO) (arrow) and an area of increased attenuation. The greatest diameter of the tumor (a) and the diameter without GGO (b) were determined for calculation. (B) Solid type: Bronchogram showing solid attenuation without GGO or air.
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Statistical analysis
The length of survival was defined as the interval in months between the day of surgery and the date of death or last follow-up date. Nine patients with recurrences have survived (13 to 28 months), and all of the patients with recurrence have received chemotherapy after detection of relapse in combination with various new agents. Disease-free survival rate was used in this study to exclude the effect of the chemotherapy. The disease-free survival rates were calculated using the Kaplan–Meier method, and univariate analyses were performed using the log-rank test or 
-square 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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Survival rate
The postoperative prognosis for 65 patients with C-IA adenocarcinoma of the lung is shown in Figure 2.
Overall survival rate at 5 years was 80.9%, and disease-free survival rate at 5 years was 62.2%.
Univariate analysis of preoperative factors
The disease-free survival rates according to the various preoperative variables of C-IA lung adenocarcinoma patients are shown in Table 1.
Two of the five variables were significant for a poor prognostic outcome: high serum CEA concentration and solid CT subtype. The 5-year disease-free survival rate for the patients with high serum CEA level (n = 9) was 22.2% compared with 75.0% for the patients with normal CEA level (n = 48) (p < 0.001). The 5-year disease-free survival for the patients with solid type (n = 27) was 48.1% compared with 78.9% for the patients with nonsolid type (n = 38) (p = 0.004). Larger tumor size had a tendency toward a poorer 5-year disease-free survival than did the other variables (p = 0.10).
Multivariate analysis of preoperative factors
Three variables (p < 0.15 in univariate analysis) were analyzed using the Cox proportional hazard model; the results are summarized in Table 2.
High CEA concentration (p = 0.003, hazard ratio = 6.27), larger tumor size (p = 0.03, hazard ratio = 3.11), and solid type in CT examination (p = 0.005, hazard ratio = 4.56) were significant indicators for a poor prognostic outcome. The 5-year disease-free survival rate was 20.1% for patients with two of the three factors (n = 19); however, the 5-year disease-free survival rate for patients with one factor (n = 23) and no factors (n = 14) were 68.6% and 100%, respectively (Fig 2). Because there was only one patient with all three factors, we excluded that patient from this analysis; that patient died from the tumor within 6 months after surgery. The 5-year overall survival rate was 35.5% for patients with two of the three factors (n = 19).
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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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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 solid type in CT were significantly associated with lymph node involvement (p = 0.005 and p = 0.005, respectively). Furthermore, both of the factors were significant risk factors for lymph node involvement in multivariate analysis (p = 0.013, hazard ratio = 10.92; p = 0.022, hazard ratio = 14.7, respectively) (Table 4).
Tumor size, age, and sex were not significant risk factors for lymph node involvement.
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Table 3. 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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Prognosis in C-IA-pN0 (p-IA) patients
Even when patients with nodal involvement (n = 11) were excluded from the analyses, the 5-year disease-free survival rates were 21.2% in patients with the two of the three factors and 69.3% in patients with one of the three factors. The results were almost the same when including the patients with lymph node metastases (Fig 3).
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Fig 3. The 5-year survival rate in patients diagnosed with clinical IA adenocarcinoma of the lung depending on three factors: computed tomography subtype (solid type), high carcinoembryonic antigen concentration (> 4.0 ng/mL), and large tumor size (> 20 mm). 2 factors: any two of the three factors are positive. 1 factor: any of one of the three factors is positive. 0 factors: none of the three factors is positive.
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Correlation of computed tomography subtype and histologic findings
Computed tomography findings were highly correlated with histologic subtype (Table 5,
p < 0.0001). When CT findings indicated the tumor was solid, histologic subtyping revealed 77.8% to be of the nonreplacing type. Although they were of the replacing type in histologic examination, three cases were defined as solid type by CT. Two of the three tumors were associated with large fibrous scars and the third with a quantity of mucin that filled the alveolar spaces. When CT findings indicated tumors to be of the nonsolid type, 84.2% were of the replacing type. Three cases indicated as nonsolid type by CT were found to be of the nonreplacing type on histologic examination. Two of the three were tubular adenocarcinoma and the other was a poorly differentiated adenocarcinoma spreading mainly into the alveolar septa.
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Comment
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In this study, we found three preoperative factors were predictive for poor outcome after surgery in C-IA adenocarcinoma of the lung, namely solid type in CT findings (which is highly associated with histologic subtype), a tumor size larger than 20 mm, and high serum CEA concentration. Furthermore, we revealed that two of the three predictive factors, namely solid type and high serum CEA concentration, were also strongly associated with the risk of lymph node metastases. When any two of the three predictive factors were positive, the 5-year disease free survival rate was only 20.1%, and 21.2% even if the individual was assessed as pN0. When the three factors were analyzed together with the factor of lymph node involvement (the presence or absence of which can be recognized after surgery) using the Cox proportional hazard model, serum CEA and CT subtype were revealed to be independent of lymph node involvement for poor outcome after surgery (p = 0.0013, p = 0.049, respectively; tumor size, p = 0.06). In particular, the CT subtype was an 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 of lymph node metastasis.
Noguchi and colleagues [3] classified the peripheral small adenocarcinoma into two subgroups: replacing type and nonreplacing type. The tumor was considered to be of the replacing type when it showed replacement growth of the pulmonary alveolar structure, and considered to be of the nonreplacing type if it showed not replacement growth but compressive or destructive growth against alveolar structure [3]. Noguchi and colleagues [3] suggested that the nonreplacing type has more malignant biological characteristics than the replacing type [3, 8].
Recently, many studies concerning the correlation between CT findings and pathologic subtype classified by Noguchi have been reported [4, 5, 10, 11]. They subtyped the small adenocarcinoma of the lung into such criteria as GGO predominant or not, according to the size of the GGO component calculated by various techniques using CT. The patients with GGO predominant type adenocarcinoma (approximately 50% or more) showed very good outcome after surgery—almost a 100% 5-year survival rate—which suggests noninvasive or microinvasive cancer, and that they may be candidates for limited surgery [4, 5, 10, 11]. However, few reports have focused on patients who have a poor outcome even after undergoing standard radical operation for C-IA lung cancer. In this study, however, we focused on such patients even if they were diagnosed as having C-IA. We showed that the poor outcome of solid type adenocarcinoma as diagnosed by preoperative CT correlated with histologic subtype. Small GGO areas detected by CT in adenocarcinoma of the lung are highly suggestive of a nonreplacing type adenocarcinoma, with poor results to be expected [3, 6, 8]. Six of the 27 solid cases were not the nonreplacing type during histologic analysis. Five of the six showed a large fibrous scar in the tumors, and the other contained a substantial amount of mucin (mucinous bronchioloalveolar carcinoma [BAC]). Lesions with nonreplacing type growth, a large component of fibrous scar tissue, and pooling of mucin were recognized as solid (little GGO area) lesions on CT. The two factors on microscopic examination—nonreplacing type growth and large component of fibrous scar—have been recognized as adverse prognostic factors [3, 8, 12]. Recently, Maeshima and associates [12] reported that the density and the extent of desmoplasia (scar) was strongly associated with a poor prognosis after surgery in small (maximum dimension 30 mm or less) peripheral adenocarcinoma. However, mucinous BAC is thought to be a preinvasive lesion [9], and it should be excluded from the solid type grouping when dealing with the solid type as an adverse prognostic type. Because mucinous BAC consists of goblet-like cells, a diagnosis may not be difficult to make, according to the cytopathologic features obtained from the specimens preoperatively.
In summary, solid type in CT findings, tumor size larger than 20 mm, and high serum CEA concentration are important preoperative predictive factors for poor outcome after surgery in C-IA adenocarcinoma. We suggest that for patients for whom at least two of the three factors are positive, a new strategy for therapy should be investigated, ie, neoadjuvant chemotherapy, even when they are diagnosed as having C-IA lung adenocarcinoma.
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Acknowledgments
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We thank Dr Edmund J. Miller, Chief, Surgical Immunology, North Shore University Hospital, for critical reviews.
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Abstract
Introduction
