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Ann Thorac Surg 2006;82:1198-1204
© 2006 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Combined Analysis of Cyclooxygenase-2 Expression With p53 and Ki-67 in Nonsmall Cell Lung Cancer

Hiroyoshi Tsubochi, MDa,*, Nobuyuki Sato, MDb, Misae Hiyama, MDc, Mitsuomi Kaimori, MDc, Shunsuke Endo, MDa, Yasunori Sohara, MDa, Tadashi Imai, MDb

a Department of General Thoracic Surgery, Omiya Medical Center, Jichi Medical School, Omiya, Saitama, Japan
b Department of General Thoracic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan
c Department of Pathology, Aomori Prefectural Central Hospital, Aomori, Japan

Accepted for publication April 19, 2006.

* Address correspondence to Dr Tsubochi, Department of General Thoracic Surgery, Omiya Medical Center, Jichi Medical School, Amanuma-cho 1-847, Omiya, Saitama, 330-8503 Japan (Email: h-tsubochi{at}omiya.jichi.ac.jp).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: Cyclooxygenase-2 (COX-2) is known to play a role in carcinogenesis and tumor progression. The aim of this study was to evaluate the relationship between COX-2 expression and clinicopathologic features, and to define the importance of COX-2 expression alone and in combination with p53 and Ki-67 expression in the clinical outcome of NSCLC.

METHODS: A total of 219 patients with stage I-IIIB nonsmall cell lung cancer (NSCLC) who previously underwent surgery were analyzed in this study. The COX-2 expression was evaluated by means of immunohistochemistry; p53 and Ki-67 immunoreactivity were also studied.

RESULTS: The COX-2 expression was observed in 137 patients (63%) and was significantly associated with lymph node metastasis and the histological grade of those with adenocarcinoma (p = 0.02 and 0.04, respectively). Kaplan-Meier analyses revealed that COX-2 expression was correlated with poor survival (p = 0.005), whereas multivariate survival analysis did not reveal COX-2 expression to be an independent prognostic factor. When the patients were stratified according to gender, age, tumor histology, and disease stage, COX-2 expression was significantly associated with unfavorable prognosis in males, younger patients (≤ 65 years), and those with adenocarcinoma and stage I tumors. The prognosis of patients with tumors negative for both COX-2 and p53 expression was significantly favorable, whereas those with tumors positive for COX-2 expression and with a high Ki-67 labeling index had a significantly unfavorable prognosis.

CONCLUSIONS: These findings indicate that combined immunohistochemical analysis of COX-2 with p53 and Ki-67 can be useful for identifying the prognosis of NSCLC patients.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Lung cancer is the leading cause of cancer death in most industrialized countries. Although surgical resection is the preferred treatment for nonsmall cell lung cancer (NSCLC) when the tumor is localized, the postoperative long-term survival rate remains unsatisfactory due to the high percentage of recurrence. Because patients with a similar stage of disease show different probabilities of survival, identification of specific prognostic markers is important for avoiding overtreatment of low-risk groups and identifying patients at high risk of recurrence who may benefit from adjuvant therapy.

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme involved in the synthesis of prostaglandins (PGs) and other eicosanoids derived from arachidonic acid and expressed in various human malignancies. COX-2 is known to mediate the progression of malignancies through several mechanisms: apoptosis, angiogenesis, tumor invasion, metastasis, and suppression of the immune system [1–5], and recently, COX-2 inhibitors have been investigated as a novel agent for treatment of malignant tumors [6–11]. Although expression of COX-2 in NSCLC has been reported [12–14], the clinical or prognostic significance of COX-2 expression has yet to be established.

Various markers of possible prognostic importance in lung cancer patients have been described. For example, p53 and Ki-67 have potential value in defining populations at high or low risk of recurrence [15–19]. The tumor suppressor p53 is known to play a central role in controlling carcinogenesis and tumor development, and Ki-67 is expressed in actively cycling cells, and has been used as a measure of proliferation. In addition, a close relationship between these markers and COX-2 expression has been reported in some malignant tumors [20, 21]. Therefore, combined analysis of these prognostic markers may give more valuable information than a study of just one. The purpose of the present study is to define the importance of COX-2 expression alone and in combination with p53 and Ki-67 expression in the clinical outcome of NSCLC, and to identify patients at low and high risk of disease recurrence after surgery.


   Material and Methods
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 Material and Methods
Results
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Patients
We analyzed 232 consecutive patients with NSCLC who underwent complete resection either by lobectomy or pneumonectomy with mediastinal lymph node dissection at Aomori Prefectural Central Hospital between November 1988 and June 1998. Fifteen patients who received induction chemotherapy or radiation therapy and 1 patient who suffered an operation-related death were excluded. Specimens of 12 patients were not available. A total of 219 patients (150 men, 69 women) were therefore evaluated. This study was approved by the Institutional Review Board of Aomori Prefectural Central Hospital. The need for individual informed consent was waived.

The age of the patients ranged from 34 to 81 years, and the mean age at the time of surgery was 62.5 years. The tumor specimens were histologically classified according to the criteria of the World Health Organization. Postsurgical pathologic stage was determined by the current tumor-node-metastasis classification [22]. Histologically, 116 patients had adenocarcinoma, 97 had squamous cell carcinoma, 5 had adenosquamous cell carcinoma, and 1 had large cell carcinoma. Of the total patients, 150, 34, 30, and 5 had stage I, II, IIIA, and IIIB tumors, respectively. As postoperative adjuvant therapies, cisplatin-based chemotherapy, radiation, and chemoradiation were administered to 46, 14, and 2 patients, respectively. The postoperative clinical course was assessed by analyzing outpatient medical records and by making telephone inquiries. The day of surgery was considered the starting day for counting postoperative survival. The follow-up duration ranged from 5 to 172 months (mean, 79 months).

Immunohistochemistry
Expression of COX-2, p53, and Ki-67 was analyzed immunohistochemically. Three-micrometer-thick, formalin fixed paraffin-embedded sections were deparaffinized in xylene. For antigen retrieval, sections were microwaved for 20 minutes in 10 mM citrate-phosphate buffer (pH 6.0). The primary antibodies used in this study included mouse monoclonal antihuman COX-2 antibody (Transduction Laboratories, Lexington, KY) (diluted 1:50), mouse monoclonal antihuman p53 (DO-7) (DAKO Corp, Carpinteria, CA) (diluted 1:100), and mouse monoclonal antihuman Ki-67 antibody (Ventana Medical Systems, Inc, Tucson, AZ) (undiluted). After antigen retrieval, the sections were incubated with the primary antibodies and stained using the Basic DAB Detection Kit (Ventana Medical Systems, Inc) with an autoimmunostaining system (NexES IHC, Ventana Medical Systems, Inc).

The COX-2 expression in smooth muscles and vascular endothelial cells were used as internal controls, as described in a previous study [12]. Those cases with tumor cells showing more intense staining than the internal control cells were recorded as positive.

To assess positive staining of p53 and Ki-67, the number of nuclear-stained tumor cells among the 500–1,000 cells in each section was counted under 400-fold magnification. With regard to p53, the median percentage of positively stained cells was 11.5; therefore 10% was used as the cutoff value. The median percentage of Ki-67 positive cells (Ki-67 labeling index [LI]) was 18%. Based on this value, the tumors were divided into two groups: (1) Ki-67 LI < 20% and (2) Ki-67 LI ≥ 20%, and the former was considered to have low Ki-67 expression, whereas the latter was considered to have high Ki-67 expression, respectively. All immunohistochemical studies were carried out by two of the authors (HT and NS) without knowledge of the clinical data.

Statistical Analysis
Associations between COX-2 expression and clinicopathologic features were determined using the {chi}2 test. Survival was examined using the Kaplan-Meier method and survival differences were analyzed using the log-rank test. Variable effects of survival time were investigated using Cox's regression model. Comparisons between COX-2 positive and negative tumors on the basis of Ki-67 LI were analyzed using the Mann-Whitney U test. The value for p ≤ 0.05 was considered statistically significant. All statistical analyses were performed using Stat View (version 5.0) (Abacus Concepts, Inc, Berkeley, CA).


   Results
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 Material and Methods
 Results
Comment
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The COX-2 Expression and Clinicopathologic Measurements
Expression of COX-2 was observed in 63, 67, and 56% of all carcinomas, adenocarcinomas, and squamous cell carcinomas, respectively. No significant association was found between COX-2 immunoreactivity and tumor histology.

The relationships between COX-2 expression and the various clinicopathologic measurements of NSCLC are shown in Table 1. In adenocarcinoma, COX-2 expression was significantly associated with lymph node involvement and histological grade (p = 0.02 and 0.04, respectively). In squamous cell carcinoma, no significant associations were found between COX-2 expression and any of the studied clinicopathologic measurements.


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  		Table 1. Association Between COX-2 Expression and the Clinicopathologic Measurements
 
COX-2 Expression and Disease Outcome
Of the 219 patients included in the survival analysis, relapse of cancer and death occurred in 65 and 73 patients, respectively. Of the deceased patients, 59 died because of cancer relapse and 14 of the other causes were without cancer recurrence. The 5-year disease-free and cancer-related survival rates were 71.8 and 75.9%, respectively. The reason why the prognosis of patients in this study was relatively good is believed to be due to the large number of patients with stage I and relatively small number with advanced stage disease included in this study.

Table 2 shows the 5-year cancer-specific survival rate according to Kaplan-Meier survival analysis. The cancer-specific survival rate of patients with COX-2 positive tumors was significantly poorer than that of patients with COX-2 negative tumors (70.4 % vs 85.0 %; p = 0.005). The influence of COX-2 expression on prognosis after stratification by patient age, gender, histological subtype, and disease stage is also shown in Table 2. The COX-2 expression was associated with an unfavorable prognosis in males (p = 0.018), but was not in females (p = 0.135). Moreover, when patients were divided into two groups by age (≤ 65 years and > 65 years), the COX-2 expression was shown to be significantly associated with the cancer-specific survival rate in patients belonging to the younger age group (p = 0.004), but not those in the older age group (p = 0.470). Regarding histological subtypes, COX-2 expression was significantly correlated with an unfavorable prognosis in those with adenocarcinoma (p = 0.028) and tended to be correlated with an unfavorable prognosis in those with squamous cell carcinoma (p = 0.061). When separately analyzed according to disease stage, a significant association between COX-2 expression and a decreased survival rate was observed in patients with stage I disease (p = 0.047), but not those with stage II/III disease (p = 0.314).


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  		Table 2. Five-Year Cancer-Specific Survival According to COX-2 Expression
 
Univariate analysis showed that gender, tumor size, lymph node metastasis, COX-2 expression, p53 expression, and Ki-67 LI were significant prognostic factors (Table 3). The prognostic importance of these significant factors in univariate analysis was further assessed with Cox's multivariate analysis (Table 3). As a result, lymph node metastasis, Ki-67 LI, and p53 expression were shown to be independent prognostic factors, but COX-2 expression was not significant in the multivariate analysis.


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  		Table 3. Univariate and Multivariate Analysis of Prognostic Factors
 
COX-2 and p53 Aberrant Expression
Aberrant expression of p53 was observed in 112 of the 219 patients (51.1%) studied. Kaplan-Meier analysis demonstrated that 5-year cancer-specific survival significantly decreased in patients with p53 positive tumors in compared with those with p53 negative tumors (68.1% vs 83.8%; p = 0.016). Combined immunohistochemical analysis of COX-2 and p53 expression divided patients into different prognostic groups. Prognosis of patients with tumors negative for both COX-2 and p53 was shown to be the best among those with different COX-2 and p53 features (Fig 1). Furthermore, when the cancer-specific survival rate was separately analyzed according to disease stage (stage I and stage II/III), the prognosis of patients with tumors negative for both COX-2 and p53 was significantly favorable regardless of disease stage (data not shown).


Figure 1
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  		Fig 1. Postoperative survival rates of patients with pathologic stages I–IIIB nonsmall cell lung cancer (NSCLC). Comparisons of postoperative survival rates were based on cyclooxygenase-2 (COX-2) expression in combination with p53 status. The survival rate of COX-2-/p53- patients was significantly higher than that of COX-2+/p53-, COX-2-/p53+, and COX-2+/p53+ patients (p = 0.0099).

 
COX-2 and Ki-67 Expression
The cellular proliferation activity of tumors was evaluated along with Ki-67 immunoreactivity. The mean value of Ki-67 LI was 18.9% for all cases, 12.0% for adenocarcinoma, and 26.1% for squamous cell carcinoma. The Ki-67 LI value for squamous cell carcinoma was significantly higher than that of adenocarcinoma (p < 0.0001). Using the Mann-Whitney U test, COX-2 expression tended to be correlated with increasing Ki-67 LI in adenocarcinoma (p = 0.098); however, no relationship was found in squamous cell carcinoma (p = 0.528). Kaplan-Meier analysis demonstrated that 5-year cancer-specific survival of patients with high Ki-67 LI (≥ 20) tumors significantly decreased in comparison with those with low Ki-67 LI (< 20) tumors (64.2% vs 85.1%; p = 0.0005). Furthermore, we also analyzed the significance of COX-2 expression on clinical outcome in combination with Ki-67 status. It was demonstrated that patients with COX-2 positive and high Ki-67 LI tumors had a significantly unfavorable prognosis compared with those in the other 3 groups (Fig 2). Moreover, when patients were stratified according to disease stage, prognosis of patients with COX-2 positive high Ki-67 LI tumors had a significantly poorer prognosis than those in the other groups regardless of stage (data not shown).


Figure 2
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  		Fig 2. Postoperative survival rates of patients with pathologic stages I-IIIB nonsmall cell lung cancer (NSCLC). Comparisons of postoperative survival rates were based on cyclooxygenase-2 (COX-2) expression in combination with Ki-67 status. The survival rate of COX-2+/high Ki-67 labeling index (LI) patients was significantly worse than that of COX-2-/high Ki-67 LI, COX-2 +/low Ki-67 LI, and COX-2-/low Ki-67 LI patients (p = 0.0093).

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
In the present study, we analyzed COX-2 expression in NSCLC and demonstrated that combined analysis of COX-2 with p53 and Ki-67 can give more valuable information than a study of just 1 marker. Several previous reports have shown the prognostic significance of elevated COX-2 expression in NSCLC [12–14]; however, the associations between COX-2 and its clinicopathologic or prognostic significance in NSCLC has not been sufficiently determined. In this study, we found that COX-2 expression is significantly associated with lymph node metastasis and histological grade in adenocarcinoma, but not in squamous cell carcinoma. The correlation between elevated COX-2 expression and unfavorable prognosis was first shown immunohistochemically by Achiwa and colleagues [12] in stage I adenocarcinoma. Using in situ hybridization, another report demonstrated that high COX-2 expression helps predict cases with a poor survival probability in stage I NSCLC [13]. In addition, using a quantitative real-time polymerase chain reaction, it was demonstrated that the high COX-2 mRNA expression in NSCLC is associated with inferior survival [14]. In contrast, it has also been reported immunohistochemically that COX-2 expression is not correlated with the outcome of NSCLC patients [23].

Cyclooxygenase is the target for nonsteroidal anti-inflammatory drugs, such as aspirin, which have epidemiologically been shown to reduce the risk of gastric, colorectal, lung, and breast cancers [24]. In experimental animal models, COX-2 inhibitors were shown to suppress the formation, growth, and metastasis of tumors [6–8], and further, to enhance the cytotoxic activity of anticancer agents and radiation [9, 10]. Moreover, a clinical trial revealed that celecoxib, a selective COX-2 inhibitor, can reduce levels of PGE2 in tumors and enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC [11]. However, the efficacy of COX-2 inhibitors on NSCLC has not yet been established.

Previous reports indicated a reciprocal relationship between p53 and COX-2. For example, Subbaramaiah and colleagues [20] demonstrated that COX-2 expression is markedly suppressed by p53. Moreover, the possibility that COX-2 can regulate p53 activity has also been demonstrated [25]. Although nuclear localization of p53 is essential for its tumor suppressing activity [26], electrophilic prostaglandins produced by COX-2 cause an accumulation of p53 in the cytoplasm in a deranged conformation, resulting in impaired normal translocation to the nucleus and subsequent inhibition of p53 activity [25]. Indeed, several types of malignant tissue have been shown to contain genetically wild-type p53, which is transcriptionally inactive because it localizes in the cytoplasm [27, 28]. In addition, it has also been demonstrated that inhibition of COX-2 with celecoxib increases the nuclear localization of active p53 in colon cancer cell lines [29]. Therefore, it is possible that prostaglandins produced by COX-2 inhibit p53 tumor-suppressing activity by inhibiting nuclear localization of p53 in NSCLC, even in the absence of p53 mutations. The p53 gene mutations reportedly occur in 40% to 50% of NSCLCs, and immunohistochemically detected aberrant p53 expression is reportedly correlated with worsened prognosis in NSCLC patients [15–17]. The presence of p53 gene mutations is indicated by immunohistochemically detected nuclear accumulation of p53, because altered p53 protein has a longer half-life than wild-type p53 [30]. A significant relationship between COX-2 and p53 expression was previously reported in lung adenocarcinoma [31]; however, in our study, no statistically significant correlation between COX-2 expression and p53 immunostaining was shown in either adenocarcinoma or squamous cell carcinoma. The present study also demonstrated that the status of COX-2 and p53 expression in combination provides additional information compared with the use of single markers alone in NSCLC patients.

In the present study, the relationship between COX-2 and Ki-67 expression as a marker for tumor proliferation was also investigated, since recent reports have suggested that COX-2 may regulate tumor proliferation [21, 32, 33]. A previous report demonstrated that COX-2 inhibition by celecoxib decreases the percentage of Ki-67-positive tumor cells in human cervical cancer [21]. Rofecoxib, a COX-2 inhibitor, was also shown to reduce cell proliferation in Barrett's esophagus [32]. Moreover, a recent report demonstrated that celecoxib significantly reduces Ki-67 LI of bronchial epithelial cells in bronchial biopsy samples obtained from active smokers [33]. These reports indicate that COX-2 may increase cell proliferation of malignant and pre-malignant tissues, possibly modulating the tumor proliferative potential of NSCLC. However, in regard to NSCLCs, few studies have demonstrated the correlation between COX-2 and Ki-67. In our study, COX-2 expression showed a strong tendency toward increased Ki-67 LI in adenocarcinoma; however, no association was found in squamous cell carcinomas. We also analyzed the impact of COX-2 and Ki-67 on prognosis of NSCLC patients. The present study revealed that high Ki-67 LI is associated with an unfavorable prognosis, which is consistent with previous studies conducted on Ki-67 in NSCLC [18]. In addition, patients in whom the tumor revealed COX-2 expression and high Ki-67 LI had a particularly poor prognosis as shown in Figure 2.

Another finding of this study was the association between COX-2 expression and survival and age group. When survival rates were compared between patients in two groups (ie, ≤ 65 and > 65 years of age, respectively), COX-2 expression was found to be significantly associated with poor prognosis in younger patients, but not older patients. It is therefore possible that the efficacy of COX-2 expression in NSCLC may vary according to patient age. A few previous reports have also demonstrated that the prognostic value of COX-2 expression in malignancies varies depending on patient age. In ovarian cancer, for example, COX-2 expression has a significant prognostic value in patients who are younger than or equal to 60 years of age, but not in those who are older than 60 years of age [34]. In contrast, in breast cancer, COX-2 expression was shown to be significantly associated with unfavorable prognosis of older patients compared with younger patients [35]. In these malignancies, hormonal regulation in addition to COX-2 may have a possible influence on tumor cells [36]. However, the mechanism governing lung cancer remains unclear, and therefore, further investigation is required.

In conclusion, evaluation of the status of COX-2 expression provides additional information to disease stage for prognosis of NSCLC patients. Furthermore, COX-2 expression in combination with the status of p53 and Ki-67 may give more valuable information for stratifying patients with NSCLC into more accurate prognostic groups and for selecting those at high risk of recurrence who may benefit from intensive adjuvant therapy.


   References
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 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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