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Ann Thorac Surg 2003;75:1727-1732
© 2003 The Society of Thoracic Surgeons

Original article: general thoracic

Ki-67 expression and prognosis for smokers with resected stage i Non–Small cell lung cancer

Yukiko Haga, MDa*, Kenzo Hiroshima, MDa, Akira Iyoda, MDb, Kiyoshi Shibuya, MDa, Fumihiko Shimamura, MDa, Toshihiko Iizasa, MDb, Takehiko Fujisawa, MDb, Hidemi Ohwada, MDa

a DEPARTMENT OFBasic Pathology, Chiba, Japan
b DEPARTMENT OFThoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

Accepted for publication January 7, 2003.

* Address reprint requests to Dr Haga, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
e-mail: yukiko30{at}lapis.plala.or.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The cigarette smoking status of patients before surgery is an important prognostic factor in evaluation of stage I non–small cell lung cancer, and the proliferative activity of lung tumors is also related to the patient’s prognosis. This study evaluates relationships between various clinicopathologic factors, including tumor proliferative activity and smoking status, and the patient’s prognosis in stage I non–small cell lung cancer.

METHODS: One hundred eighty-seven stage I adenocarcinoma and squamous cell carcinoma cases were evaluated. The patients underwent complete resection between 1988 and 1993 at Chiba University Hospital. Expression levels of Ki-67 nuclear antigen, p53 protein, and retinoblastoma protein were determined immunohistochemically, and postoperative survival rates for patients in the categories of clinicopathologic factors were estimated.

RESULTS: The mean Ki-67 labeling index (LI) for all cases was 19.3%. Labeling index values were significantly higher in squamous cell carcinoma than in adenocarcinoma (p < 0.0001). Postoperative survival of adenocarcinoma patients was significantly related to the LI values and to the patient’s smoking status (p = 0.0164 and 0.0268, respectively). The LI values were also related to smoking status and the extent of histologic differentiation (p = 0.0112 and p < 0.0001, respectively). For nonsmoking adenocarcinoma patients, higher LI values were associated with abnormalities in p53 expression (p = 0.0048). Retinoblastoma protein abnormalities were not related to LI values.

CONCLUSIONS: In smokers with stage I pulmonary adenocarcinoma, tumor proliferative activity and smoking status before surgery were important prognostic determinants. The LI values were related to several clinicopathologic factors.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Lung cancer is one of the most difficult cancers to cure, and the prognosis for patients with non–small cell lung cancer (NSCLC) is closely correlated to their disease stage. The prognosis for stage I NSCLC patients who have undergone complete resection, ie, complete lobectomy or complete segmentectomy with standard lymph node dissection, is better than that for patients who are in later stages of the disease [1, 2]. However, some deaths occur among patients with stage I NSCLC as a result of recurrence. We previously reported that the cigarette smoking status before surgery was one of the most important clinical prognostic factors in stage I NSCLC [3].

A large number of biologic prognostic factors for lung cancers have been described [4, 5]. Altered regulation of the cell cycle, which is related to tumor proliferative activity, is a hallmark of human cancers [6, 7]. The expression of Ki-67 antigen can be used as a simple histologic marker for cell proliferation. A monoclonal antibody against Ki-67 antigen detects a human nuclear antigen that is present only in proliferating cells, but is absent in quiescent cells [8–11]. This antibody has been used to assess tumor cell proliferation in breast cancers, lung tumors, nervous system tumors, and non-Hodgkin’s lymphomas [12–16]. The relationship between Ki-67 antigen expression and the cigarette smoking status of patients has also been reported [13].

It is important to identify additional risk factors for development of lung cancers, and Ki-67 antigen expression may be useful for this purpose. Ki-67 antigen expression of resected stage I NSCLC is analyzed here. The expression of p53 and retinoblastoma (RB) proteins is analyzed as well, because abnormalities of p53 and inactivation of the RB protein pathway may well be necessary for tumor development [7]. Finally, the relationship between prognosis and several clinicopathologic factors, including Ki-67 antigen expression and smoking status, is evaluated. Stage I lung cancer was chosen for study to minimize the confounding effects of prognostic factors such as lymph node and distant metastases or direct invasion of adjacent structures.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Tissue samples
One hundred eighty-seven patients (120 men and 67 women) were enrolled. The group included 122 patients with adenocarcinoma and 65 with squamous cell carcinoma. All of the patients had undergone complete resection, involving complete lobectomy or complete segmentectomy with standard lymph node dissection, at the Department of Thoracic Surgery, Chiba University Hospital, between 1988 and 1993. Patients were followed there for at least 5 years after their operations, and informed consents were obtained. These patients were confirmed by pathologic examination to have stage I lung cancer according to international TNM staging criteria. All of the squamous cell carcinoma patients were smokers, and among the adenocarcinoma patients there were 64 nonsmokers and 58 smokers. We defined "smokers" as patients who had smoked before surgery and "nonsmokers" as patients who had never smoked. The "smoker" classification thus included ex-smokers as well as current smokers.

Immunohistochemical staining
Immunohistochemical staining was performed on the 187 lung tumor specimens. Four-micrometer-thick sections were cut from formalin-fixed, paraffin-embedded tumor tissues and placed on silanized slides (Dako, Glostrup, Denmark). For staining of Ki-67 nuclear antigen, p53 protein, and RB protein, the following monoclonal antibodies were used: MIB-1 (Immunotech SA, Marseilles, France) diluted 1:100, DO-7 (Dako) diluted 1:1600, and anti-RB antibody (PharMingen, San Diego, CA) diluted 1:200. These antibodies were used as primary antibodies, with a streptavidin-biotin staining technique (Histofine kit; Nichirei, Tokyo, Japan) used for detection. Deparaffinized sections were boiled in 10 mmol/L citrate buffer, pH 6.0, for antigen retrieval before immunohistochemical staining.

Two independent observers (Y.H., K.H.) who had no knowledge of clinical information regarding the patients evaluated all specimens. Discordant independent readings were resolved by simultaneous review performed by the two readers.

The Ki-67 labeling index (LI) was defined as the number of Ki-67–positive tumor cells divided by the sum of Ki-67–positive and Ki-67–negative tumor cells after counting at least 1,000 tumor nuclei per specimen. p53 overexpression was defined as more than 10% positive tumor nuclei in the specimen, and the absence of RB protein staining was categorized as abnormal. Figure 1 shows a representative photograph of Ki-67 expression in a tumor removed from an adenocarcinoma patient.



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  		Fig 1. Micrograph of Ki-67 expression in adenocarcinoma.

 
Statistical analysis
Associations between Ki-67 protein expression and other clinicopathologic factors were analyzed using the Student’s t test for unpaired data and the {chi}2 test. The Kruskal-Wallis test was used to analyze nonparametric data [17]. Postoperative survival rates for patients in the various categories were estimated using the method of Kaplan and Meier [18], and survival distributions were compared using the log rank test [19]. Among the listed categories, those having continuous variables were subdivided into several groups, eg, age (<65, ≥65), smoking status (nonsmoker, 1 to 29 pack-years, 30 to 49 pack-years, ≥50 pack-years), and LI (LI<10%, 10%≤LI< 35%, LI≥35%). The ranges for the LI classifications were chosen to bracket the mean LI values for adenocarcinoma and squamous cell carcinoma cases. Using these factors as explanatory variables, the Cox proportional hazards model [20] was applied to evaluate joint influences on postoperative survival. Statistical analyses were performed using the StatView statistical software package (Abacus Concepts, Inc, Berkeley, CA). The level of significance was set at 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Clinicopathologic features and prognosis
According to the Kaplan-Meier method the postoperative overall 5-year survival rate for patients with adenocarcinoma was 81.7% and that for squamous cell carcinoma patients was 68.4%.

Table 1 shows the postoperative overall 5-year survival rates for the patients and their relationships to several clinicopathologic factors, as calculated using the Kaplan-Meier method. In the group of smokers with adenocarcinoma, the following factors affected survival rates: smoking status (p < 0.0001), tumor size (p = 0.0025), and LI (p = 0.0014). Figure 2 shows the relationship between LI values and the prognoses for these patients. Nonsmokers with adenocarcinoma showed no association of these factors with survival rates. In the squamous cell carcinoma group, the prognosis for the patients aged 65 or older was poorer than that for patients younger than 65 years (p = 0.0300). There were no significant relationships between the prognosis and p53 or RB expressions.


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  		Table 1. Overall 5-Year Survival Rates and the Clinicopathologic Factors in Adenocarcinoma and Squamous Cell Carcinoma (n = 187)a

 


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  		Fig 2. Overall postoperative survival rates stratified by Ki-67 labeling index (LI) for smokers with adenocarcinoma (n = 58).

 
The Cox proportional hazards model was applied to carry out multivariate analysis of the significant prognostic factors in the group of smokers with adenocarcinoma (Table 2). The LI values and smoking status emerged as statistically significant prognostic factors (p = 0.0164 and 0.0268, respectively).


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  		Table 2. Multivariate Analysis of Factors for Overall Survival Using the Cox Proportional Hazards Regression Model in Smokers With Adenocarcinoma (n = 58)

 
Labeling index and other clinicopathologic features
Because it was found that LI was one of the important prognostic factors in evaluating smokers with adenocarcinoma, the relationships between LI and other clinicopathologic features were analyzed next. The mean LI values were 19.3% for all cases, 10.7% for all adenocarcinomas, and 35.4% for all squamous cell carcinomas. The difference in LI between adenocarcinoma and squamous cell carcinoma cases was statistically significant (p < 0.0001, Student’s t test for unpaired data). Among the cases of adenocarcinoma the mean LI for nonsmokers was 8.5% and that of smokers was 13.1%, and this difference was significant (p = 0.0112, Student’s t test for unpaired data).

Table 3 shows the relationships between LI values and several pathologic factors in the group of nonsmokers with adenocarcinoma, the smokers with adenocarcinoma, and in the squamous cell cancer group. For the nonsmokers with adenocarcinoma, the LI was significantly related to histologic differentiation (p = 0.0001) and p53 expression (p = 0.0048). For the smokers with adenocarcinoma, the LI was significantly related to tumor size (p = 0.0231) and histologic differentiation (p = 0.0303). There was no significant relationship between LI values and the other pathologic factors evaluated for the squamous cell carcinoma group.


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  		Table 3. Ki-67 Labeling Index and Other Pathologic Factors (n = 187)a

 
P53 and retinoblastoma protein expressions
p53 protein expression was detected for positive in 33.9% cases of adenocarcinoma and in 52.3% of squamous cell carcinoma cases, and the difference between these groups was significant (p = 0.0214, {chi}2 test). The prevalence of p53 protein expression in adenocarcinoma did not differ between smokers and nonsmokers. Abnormal RB protein expression was not related to histologic types, LI values, or smoking habits of the patients. p53 abnormalities were related to LI values for nonsmokers with adenocarcinoma (p = 0.0048; Table 3), but this relationship did not hold for smokers.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Since we reported that the cigarette smoking status before surgery was one of the most important clinical prognostic factors in stage I NSCLC [3], we have tried to find the specific factors that can explain this result. In the current study, we elucidate the fact that smoking status before surgery is a prognostic factor for patients with stage I pulmonary adenocarcinoma, but not for patients with stage I squamous cell carcinoma. We also found that the Ki-67 LI was a significant pathologic prognostic factor for smokers with stage I pulmonary adenocarcinoma, although this relationship was not observed in nonsmokers or in patients with squamous cell carcinoma. We previously reported that the LI was related to the patient’s prognosis [13], but the difference between smokers and nonsmokers was not evaluated in the earlier report. The current study shows that LI values are related to the patient’s prognosis in the group of smokers with adenocarcinoma but not in nonsmokers with adenocarcinoma.

D’Amico and associates [21] analyzed relationships between survival and molecular marker expression, but found no correlation between Ki-67 expression and survival. We suggest that their results differ from ours because they did not evaluate Ki-67 expression specifically with respect to smoking status. Interestingly, the LI for the group of smokers with adenocarcinoma was higher than that for nonsmokers with adenocarcinoma. These results suggest that smoking causes the proliferative activity of tumors to increase, and consequently smoking worsens the prognosis for smokers with adenocarcinoma.

Tumor proliferative activity has some relationship to an altered cell cycle [6, 7]. Oncogenic processes exert their greatest effects when particular regulators of the G1 phase in progression of the cell cycle are targeted [6, 22]. G1 progression normally relies on stimulation by mitogenesis, and can thus be blocked by antiproliferative cytokines [7]. On the other hand, abnormalities of the p53 protein and inactivation of the RB protein pathway may well be necessary for tumor development [7]. It has been reported that the tumor suppressor p53 gene seems to be affected by exposure to carcinogens in tobacco [23]. Therefore, we investigated whether there were relationships between LI values and alterations of p53 and RB proteins that could regulate the proliferative activity of lung carcinomas (subdivided accorded to patients’ smoking status). We found that LI and abnormalities of the p53 protein were significantly related in nonsmokers with adenocarcinoma, but not in smokers with adenocarcinoma. This result suggests that alterations of the p53 protein play an important role in the proliferative activity of tumor cells in nonsmokers with adenocarcinoma, but not in smokers. There must therefore be some other mechanisms besides alteration of the p53 protein that can explain the relationship between the proliferative activity of tumor cells and the smoking status of the patient. No relationship was found between RB abnormalities and proliferative activity of tumor cells. The reason for this may be that the number of patients with RB abnormalities was too small in this study.

Tumor proliferative activity in smokers was related to tumor size (Table 3). Tumor size also had some association with prognosis for smokers with adenocarcinoma, according to the Kaplan-Meier method (Table 1), although multivariate analysis did not indicate that this relationship was significant. This result was comparable to previous studies reporting that the prognosis in lung cancer cases correlates well with the doubling time [24, 25]. A tumor diameter greater than 3.0 cm was an independent factor predicting a poor survival outcome [26, 27].

In addition, histologic types were not related to patients’ prognoses. A previous report also showed that histologic type did not correlate with survival significantly for patients with resected T3 NSCLC [28]. However, as described previously, we found that there were adenocarcinoma patients who had good prognoses. Some members of this group had a better prognosis than did squamous cell carcinoma patients, and this result is in agreement with previous studies [2]. Some reports have commented on the relationship between tumor proliferative activity and histologic differentiation [2]. Histologically poorly differentiated adenocarcinoma grows rapidly in smokers [29]. Well-differentiated tumors tend to have longer tumor doubling times [30–32]. One report showed that patients with poorly differentiated adenocarcinomas had a higher risk of death than did patients with well or moderately differentiated adenocarcinomas [2], and patients with localized bronchioloalveolar carcinomas showed the most favorable prognosis [33]. The current study could suggest that a small, peripheral, well-differentiated adenocarcinoma usually has a low LI and grows slowly.

In conclusion, tumor proliferative activity, smoking status before surgery, and tumor size were important prognostic factors in smokers with stage I pulmonary adenocarcinoma, and detecting the Ki-67 antigen expression was useful to evaluate the prognosis for these patients.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The authors thank Tamiyo Taniguchi, Michiko Hanazono, Ayaka Sato, and Kazuko Abe for their technical assistance.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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