Ann Thorac Surg 2003;76:909-914
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Clinicopathologic significance of cyclooxygenase-2 overexpression in esophageal squamous cell carcinoma
Kuang-Tai Kuo, MDa,
Kuan-Chih Chow, PhDa,
Yu-Chung Wu, MDa,
Chen-Sung Lin, MDa,
Hao-Wei Wang, MDa,
Wing-Yin Li, MDb,
Liang-Shun Wang, MD*a
a Division of Thoracic Surgery, Departments of Surgery and Pathology, Taipei-Veterans General Hospital, Taipei, Taiwan
b National Yang-Ming University, Taipei, Taiwan
Accepted for publication April 22, 2003.
* Address reprint requests to Dr Liang-Shun Wang, Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital, No. 201, 2nd Section, Shih-Pai Rd, Taipei 11217, Taiwan
e-mail: lswang{at}vghtpe.gov.tw
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Abstract
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BACKGROUND: Esophageal cancer is one of the most aggressive malignancies in the world, and whether multiple therapeutic modalities could improve long-term survival remains controversial. Recent studies have shown an increase of cyclooxygenase-2 (COX-2) expression in various malignancies, but its clinicopathologic role in esophageal squamous cell carcinoma (ESCC) remains unclear.
METHODS: From 1993 to 1997, tissue samples from 96 patients with ESCC who underwent esophagectomy at our institution were collected for analysis. Cyclooxygenase-2 expression was examined by immunohistochemical staining, and further confirmed by Western blot analysis on six frozen tissues. Clinicopathologic data were analyzed to verify the significance.
RESULTS: Cyclooxygenase-2 immunoreactivity was detected in 59 of 96 ESCC specimens (61%), and COX-2 overexpression (COX-2 high) was observed in 49% (47 of 96) of ESCCs. Statistical differences between COX-2 high and COX-2 low were found with respect to the status of distant metastasis (M factor) (p = 0.035) and tumor stage (p = 0.04). The survival was not significantly different between patients with and without COX-2 overexpression (p = 0.43). Using the Cox regression analysis, only the N factor (p = 0.0034) and M factor (p = 0.0325) were independent prognostic factors.
CONCLUSIONS: Our results showed that in patients with ESCC, COX-2 overexpression was significantly correlated with fewer metastases and less advanced stage, but had no impact on survival. The status of local or distant lymph node metastasis was the most important prognostic factor. The biological role and pathophysiologic regulation of COX-2 overexpression in ESCC deserve further investigation.
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Introduction
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Esophageal cancer is one of the most aggressive human malignancies in the world, with dismal prognosis having changed little over the past 2 decades. Its overall 5-year survival rate remains below 15% [1]. Recent epidemiologic studies have shown that chronic intake of nonsteroidal anti-inflammatory drugs reduced the incidence of many digestive tract cancers, including esophageal cancer [2]. As we know, the main target of nonsteroidal anti-inflammatory drugs is cyclooxygenase (COX), the rate-limiting enzyme involved in the conversion of arachidonic acid to eicosanoids. Two COX genes (COX-1 and COX-2) have been identified, which share more than 60% identity at the amino acid level [3]. Cyclooxygenase-1 is constitutively expressed in many tissues and is responsible for various physiologic functions. Conversely, COX-2 is an inducible gene found to be induced by inflammation or a variety of stimuli.
Histologically, increased COX-2 expression can be detected in various malignancies including head and neck cancer [4], breast cancer [5], lung cancer [5, 6], gastric cancer [7], pancreatic cancer [8], and colorectal cancer [9, 10]. Nevertheless, the clinicopathologic role of COX-2 overexpression in cancers is still to be clarified, and only some preliminary results in specific cancers have been reported so far [11–13].
There have been couples of studies investigating COX-2 expression in human esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAD) [14–16]. In one study [15], COX-2 expression was observed in 91% of the ESCCs and 78% of the EADs, but the clinical significance of COX-2 expression in esophageal cancer was not addressed in that article. Recently, Buskens and colleagues [13] reported that elevated expression of COX-2 protein is associated with significantly reduced survival of patients undergoing surgery for EAD. Therefore, elucidating the prognostic significance of COX-2 overexpression in ESCC elicited our interests.
In the present study, we evaluated the COX-2 expression in surgical specimens of ESCCs by immunohistochemistry (IHC), we confirmed the results by Western blot analysis, and we correlated the elevated expression of COX-2 with clinicopathologic data to verify its significance.
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Patients and methods
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Patients
Tumor parts of surgical specimens from 96 patients with ESCCs who underwent esophagectomy at our institution from 1993 to 1997 were collected for analysis. Of these patients, 87 underwent en-bloc resections and 9 underwent palliative resections. None of them received neoadjuvant radiotherapy or chemotherapy, nor did they have distant organ metastasis in preoperative assessment. Stage of disease progression was classified according to the Union Internationale Contre le Cancer staging system. All stage IV patients in the present series were due to distant lymph node metastasis (M1a disease). Postoperative chemoradiotherapy was administered to the patients with locally advanced disease (T4), regional lymph node metastasis (N1), or tumor recurrence. The irradiation dose was 60 Gy (10 Gy/5 fractions/wk), with a combined chemotherapy regimen of choice, which consisted of cisplatin (20 mg/m2/d), 5-fluorouracil (600 mg/m2/d), and leucovorin (120 mg/m2/d) administered by 24-hour infusion for 4 days. After treatment all patients were followed up with systemic examinations of biochemical tests, chest radiography, sonogram of abdomen and neck, and whole body bone radioisotope scans every 3 to 6 months. A computed tomographic scan of the chest and abdomen was also performed if indicated. There were 12 patients lost to follow-up, and the follow-up rate was 87.5%.
Immunohistochemical staining
An immunoperoxidase procedure [17] was used to detect the expression of COX-2 in the pathologic sections. All of the samples were routinely fixed in 4% buffered formalin, embedded in paraffin, and cut into 4 µm sections. The sections were deparaffinized and incubated with 3% hydrogen peroxide to inactivate endogenous peroxides. Specific polyclonal rabbit antibodies against COX-2 (PG-27; Oxford Biomedical Research Inc, MI) were used at a dilution of 1:100 and applied to tissue sections. They were then washed and incubated with secondary antibody (LSAB kit; DAKO, Glostrup, Denmark). Finally, the sections were counterstained with hematoxylin.
Evaluation of COX-2 immunostaining
All immunostained sections were evaluated in a coded manner without knowledge of the clinical and pathologic background of the patients. Each stained specimen was evaluated semiquantitatively according to the gross percentage of cells demonstrating a cytoplasmic immunoreactivity on the whole tumor section; the assessment was accomplished independently by two examiners (KCC and WYL). The following criteria for scoring of the tumor cells were agreed on before the analysis: 0 = no staining; 1+ = weak diffuse cytoplasmic staining (may contain stronger intensity in less than 10% of the cancer cells); 2+ = heterogeneous granular cytoplasmic staining in 10% to 90% of the cancer cells; 3+ = more than 90% of the cancer cells stained with strong intensity. We used this scoring system to select the extreme cases of immunostaining (< 10% and > 90%), and we tried to find out if there were any special clinicopathologic features. In fact, this scoring system had been applied by other investigators [13], and 10% of immunostained cells as a cutoff point for positivity had also been used before [18]. For fitness of statistical analyses, 2+ or 3+ cytoplasmic granular COX-2 immunoreactivity was defined as elevated expression of COX-2 protein or COX-2 high, whereas 0 or 1+ cytoplasmic granular COX-2 immunoreactivity was defined as COX-2 low. There were no differences in overall interpretation of IHC results between the two examiners.
Western blot analysis
Procedures for immunoblotting have been described previously [19]. Frozen tissue samples from 6 patients (scoring for IHC stain: one 0, one 1+, two 2+, and two 3+) were examined first by microscope to ensure that at least 90% of each sample was composed of tumor. The samples were thawed in ice-cold homogenization buffer and the lysates were sonicated and centrifuged at 10,000 x g for 10 minutes to sediment the particulate material. The protein content was measured and 100 µg of proteins were separated by sodium dodecyl sulfate (10%)-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. The membrane was then probed with COX-2 specific antibodies (PG-27, 1:500). The signal was amplified by biotin-labeled goat anti-rabbit IgG (1:3000) and peroxidase-conjugated streptavidin (1:5000). Cyclooxygenase-2 protein was visualized by exposing the membrane to an X-Omat film (Eastman Kodak, Rochester, NY) with enhanced chemiluminescent regent.
Clinicopathologic variables and statistical analysis
Age, sex, history of smoking or habitual alcohol consumption, differentiation of tumor, lymphovascular invasion, tumor location, length of tumor, depth of tumor invasion (T factor), status of lymph node metastasis (N factor), status of distant metastasis (M factor), and tumor stage in the database were reviewed.
The relationships between clinicopathologic factors and COX-2 expression were analyzed by 
2 test (or two-tailed Fischer’s exact test when the expected number in any cell was smaller than 5 cases). Survival was plotted, and median survival was estimated by the Kaplan-Meier method. Survival and the strength of associations between categories within a variable were compared with the log-rank test. Variable effects on survival were investigated with a stepwise Cox regression analysis. Twelve variables were analyzed: sex, age, smoking, alcohol consumption, COX-2 overexpression, tumor location, length of tumor, differentiation of tumor, lymphovascular invasion, T factor, N factor, and M factor. Statistical significance was defined as a probability value of less than 0.05.
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Results
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There were 89 males and 7 females, and the mean age was 65 years (range, 39 to 88). Seventy-nine patients (82.3%) were smokers and 62 patients (64.6%) habitually consumed alcohol; of these patients, 55 (57.3%) had both habits of smoking and alcohol consumption. The rates of surgical morbidity and mortality were 26.0% (25 patients) and 5.2% (5 patients), respectively. The most frequent surgical complication was cervical anastomotic leakage (19.8%), followed by pulmonary complications (15.6%). The causes of surgical mortality in 5 patients included pulmonary complications (4 patients) and myocardial infarction (1 patient). The median follow-up period for the remaining 91 patients was 19.2 months, ranging from 2.3 to 99.8 months.
Immunohistochemically, COX-2 expression was mainly localized in the tumor cells. Esophageal squamous epithelium, smooth muscle cells, and endothelial cells exhibited only weak immunoreactivity for COX-2. In the current series, COX-2 immunoreactivity (1+ to 3+) was detected in 59 of 96 ESCC specimens (61%). Elevated COX-2 expression (2+ and 3+) (Fig 1A)
was observed in 47 patients (49%), whereas negative (Fig 1B) or only weak COX-2 expression (1+) was observed in 49 patients (51%). The results of the immunohistochemical investigations were confirmed by Western blot analysis (Fig 2). The CA-4 was a tumor with 1+ IHC stain, and both CA-1 and CA-5 were tumors with 2+ IHC stains. The CA-6 was a tumor with negative IHC stain, and the remaining two were tumors with 3+ IHC stains. The results of the Western blot analysis correlated well with their respective immunohistochemical stains.
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Fig 1. Representative examples of cyclooxygenase (COX)-2 immunohistochemical stains. (A) Negative (0) immunoreactivity in the tumor cells (Tu). The stroma (Str) is also negative. This tumor was categorized as COX-2 low (original magnification, x200). (B) Strong (3+) immunoreactivity in the Tu. The nontumorous Str is either negative or weakly positive. This tumor was categorized as COX-2 high (original magnification, x200).
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Fig 2. Western blot analysis demonstrating cyclooxygenase-2 (COX-2) protein expression in six esophageal squamous cell carcinoma samples (CA-1 to CA-6). The CA-4 corresponded to a 1+ tumor, and the CA-6 corresponded to a 0 tumor. The T denotes tumor and the N denotes normal esophageal squamous epithelium. The M means markers for 58kD and 82kD, and the C means control for COX-2 protein.
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The overall median survival time was 22.7 months; the cumulative 5-year survival rate was 17.7%. At various stages of disease, the cumulative 2-year survival rates were 100% (stage I), 57.1% (stage II), 34.3% (stage III), and 15% (stage IV), and the cumulative 5-year survival rates were 55.6% (stage I), 42.4% (stage II), 22.4% (stage III), and 0% (stage IV) (Fig 3).
The cumulative 5-year survival rate for N0 patients (n = 34) was 29.4%, and for N1 patients (n = 62) was 9.7%.
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Fig 3. Survival curves of patients at various tumor stages (p < 0.00001). The numbers in parentheses are the patients at risk yearly.
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As shown in Table 1,
no significant difference was observed between tumors with and without COX-2 overexpression except the status of distant nodal metastasis (M factor) (p = 0.035) and tumor stage (p = 0.04). Patients with M1a lesion or advanced stages had less COX-2 overexpression on tumors. We also found that in the current study, tumors with different scorings did not have different clinicopathologic features statistically (data not shown).
The survival was not significantly different between patients with and without COX-2 overexpression (p = 0.43) (Fig 4).
In the univariate analysis, T factor (p = 0.0011), N factor (p = 0.0000), M factor (p = 0.0000), and differentiation of tumor (p = 0.025) were significant factors for survival. When we used the backward stepwise (Wald) method for multivariate analysis, only N factor (p = 0.0034) and M factor (p = 0.0325) were present after step 11, indicating that they were independent factors.
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Fig 4. Survival curves of patients with or without cyclooxygenase-2 (COX-2) expression (p = 0.43). The numbers in parentheses are the patients at risk yearly.
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Comment
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Our results showed that in patients with ESCC, COX-2 overexpression was significantly correlated with earlier tumor stage and less M1a lesion. Other factors such as sex, age, smoking, alcohol consumption, differentiation of tumor, lymphovascular invasion, tumor location, length of tumor, T factor, and N factor were not correlated with COX-2 overexpression. This interesting finding suggests that COX-2 overexpression may play more a loco-regional role in ESCC. Of course, patients with early-stage cancer usually have better prognosis and longer survival. Nevertheless, the current study showed no statistical difference in the overall survival between patients with and without COX-2 overexpression. In fact, the median survival of COX-2 high stage IV patients (5.1 months; n = 6) was somehow shorter than that of COX-2 low stage IV patients (6.7 months; n = 15) (Fig 5),
although the difference did not reach its statistical significance (p = 0.17). These evidences may reflect the pathophysiologic complexity of disease progression in ESCC, and we propose that COX-2 overexpression may be related to a poorer response to adjuvant therapy in these patients. A recent study [20] demonstrated the association between elevated COX-2 expression and chemotherapy resistance in cervical cancer patients, but more pioneer studies are still warranted to investigate this type of relationship with ESCC.
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Fig 5. Survival curves of stage IV patients with or without cyclooxygenase-2 (COX-2) overexpression (p = 0.17). The numbers in parentheses are the patients at risk yearly.
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In this study, prognosis of ESCC was correlated to T, N, and M factors, and differentiation of tumor on univariate analysis. However, Cox regression analysis showed only N and M factors to be independent prognostic factors. As this result was in accordance with several other studies previously reported [21, 22], we believe that patient selection in the current study was adequate.
It has been stated that COX-2 overexpression was more common in well-differentiated tumors than in poorly differentiated tumors [23, 24], although results counter to this have also been reported [18]. In the current study, COX-2 overexpression was not correlated to differentiation of tumor. It is a pity that our number of poorly differentiated tumors was relatively small and may detract from the statistical significance. However, our result was similar to a recent report on EADs [13], which had sufficient numbers of poorly differentiated tumors.
Recent studies have shown the association of COX-2 overexpression with a poor prognosis in early-stage adenocarcinomas of lung [25], human gliomas [26], breast cancer [27], and EADs [13]. However, we failed to confirm such a relationship in this study. Perhaps the prognostic significance of COX-2 overexpression varied in different cancers. Indeed, a recent study [28] on laryngeal squamous cell carcinoma has documented a different relationship of COX-2 overexpression and prognosis in which COX-2 is overexpressed in less aggressive, low grade laryngeal squamous cell carcinoma, and is negative in tumors with a worse clinical outcome as compared with those bearing a COX-2 positive neoplasia. Moreover, another study of squamous carcinogenesis of the esophagus [29] also failed to identify the relationship of COX-2 expression with various clinicopathologic variables including prognosis. Both studies support our point of view, but more survival analyses are needed to clarify the fact.
Several studies about lung cancer have demonstrated that adenocarcinomas had a significant increase in COX-2 expression than squamous cell carcinomas [5, 6]. In regard to esophageal cancer, the COX-2 expression was identified in 61% of ESCC in our series. As compared with the result reported by Buskens and colleagues [13], which detected COX-2 immunoreactivity in 98.6% of EADs, our study certainly showed a marked decrease in COX-2 expression in ESCC. However, in another series reported by Zimmermann and colleagues [15], they found COX-2 expression in 91% (156 of 172) of the ESCCs and 78% (21 of 27) of the EADs. There are some possible reasons for this controversy. First, the inexact and subjective nature of immunostaining may influence the result. Second, the number of ESCCs and EADs in the Zimmermann series was quite unequal and may not exhibit the true difference. Third, the biological behavior of ESCCs may be different when they happen in patients from different areas. It is well known that esophageal cancer has a striking geographic variation in incidence because of various etiologic factors including diet, nutrition, alcohol and tobacco use, infectious causes and so forth. Different causes may result in various biological behaviors of cancer cells and consequently exhibit different levels of COX-2 expression. This may also help to unravel why our COX-2 expression of ESCC is relatively lower than series from other areas.
In conclusion, our results demonstrated COX-2 overexpression in 49% (47 of 96) of ESCC and its association with earlier tumor stage. However, the survival made no difference whether the patients had COX-2 overexpression or not. These results suggest that COX-2 overexpression in ESCC may influence the disease progression or resistance of chemotherapy. Nevertheless, this point of view remains undetermined and deserves further investigation.
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Acknowledgments
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This study was supported by a grant from Taipei-Veterans General Hospital (VGH90–350) and partly by the Lite-on Culture Foundation (LCF-R-90–1). We are indebted to Li-Ling Yang and Yi-Hsiu Kuo for their excellent technical assistance and Hwa-Ping Kao for her manuscript preparation. We especially thank Dr Chin-Chen Pan for his great assistance with photography.
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Abstract
Introduction
