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Ann Thorac Surg 2012;93:398-403. doi:10.1016/j.athoracsur.2011.10.033
© 2012 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Maximal Standardized Uptake Value on FDG-PET Is Correlated With Cyclooxygenase-2 Expression in Patients With Lung Adenocarcinoma

Katsuhiko Shimizu, MD, PhD*, Yuji Hirami, MD, PhD, Shinsuke Saisho, MD, Takuro Yukawa, MD, Ai Maeda, MD, Koichiro Yasuda, MD, Masao Nakata, MD, PhD

Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan

Accepted for publication October 14, 2011.

* Address correspondence to Dr Shimizu, Department of General Thoracic Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki Okayama 701-0192, Japan (Email: kshimizu{at}med.kawasaki-m.ac.jp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Cyclooxygenase-2 (COX-2) is constitutively overexpressed in a variety of epithelial malignancies and is usually associated with a poor prognosis. Fluorodeoxyglucose positron emission tomography (FDG-PET) has become an important tool for the diagnosis and staging of non–small-cell lung cancer. The maximal standardized uptake values (SUVmax) of primary tumors on FDG-PET have been shown to be correlated with some clinicopathologic factors. In this study, we investigated the prediction of intratumoral COX-2 expression by FDG-PET in cases of lung adenocarcinoma.

Methods: We conducted a retrospective review of the data of 60 patients with lung adenocarcinoma measuring less than 3 cm in diameter. Immunohistochemical staining for COX-2 and other biological factors that might influence cancer progression was performed, and the correlations of the selective tumor marker expression with the SUVmax were evaluated.

Results: A significant correlation was observed between the SUVmax and the expressions of COX-2, Ki-67, and vascular endothelial growth factor (VEGF). Multiple stepwise regression analysis revealed significant relationships between the SUVmax and the expression of COX-2 (p < 0.001) and Ki-67 (p = 0.016). Of the 2, COX-2 expression was the stronger determinant of the SUVmax, which increased in proportion to the score for COX-2 expression. The recurrence-free survival of patients with elevated COX-2 expression was significantly worse than that of patients not showing COX-2 expression.

Conclusions: The expression of COX-2 in primary tumors is as strongly correlated with a worse clinical outcome as is increased FDG uptake in cases of lung adenocarcinoma. These findings indicate that the SUVmax of primary tumors might reflect the biological malignant potential in lung adenocarcinomas.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cyclooxygenase (COX) is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified and are referred to as constitutive COX (COX-1) and inducible COX (COX-2) [1]. COX-1 is constitutively expressed in many tissues and plays important roles in the control of homeostasis. In contrast, COX-2 is an inducible enzyme that is activated in response to extracellular stimuli, such as growth factors and proinflammatory cytokines [2]. Some investigators have demonstrated that COX-2 is constitutively overexpressed in a variety of epithelial malignancies—such as lung, breast, pancreas, colon, esophagus, and head and neck cancers— and COX-2 overexpression is usually associated with a poor prognosis [3–5].

Fluorodeoxyglucose positron emission tomography (FDG-PET) has become an important tool for the diagnosis and staging of non–small-cell lung cancer (NSCLC) [6]. The maximal standardized uptake values (SUVmax) on FDG-PET is the ratio of the activity in the tissue per unit volume to the injected dose by body weight, and is widely used because of its simplicity [7]. The SUVmax of primary tumors have been shown to be correlated with the stage, nodal status, histologic type, differentiation, and progression of tumors in patients with NSCLC [8–10]. In addition, high SUVmax has been reported as 1 of the prognostic factors in patients with NSCLC [10–12].

Recently, several studies have reported the existence of a relationship between the FDG uptake and the expression of some biomarkers. Previous studies have demonstrated a correlation between FDG uptake in lung cancer and tumor expression of the glucose transporter (Glut) 1 [13, 14]. Several studies have investigated the correlation of FDG uptake with the expressions of other biological markers of lung cancer, such as Ki-67, p53, and vascular endothelial growth factor (VEGF) [15–18].

In the present study, the 6 biological markers were selected as cell growth markers: COX-2, Ki-67, VEGF, and 3 growth factor receptors—phosphorylated epidermal growth factor receptor (pEGFR) (an activated form of EGFR), insulin-like growth factor 1 receptor (IGF-1R), and platelet-derived growth factor receptor α (PDGFRα). These markers have been implicated in previously published literature in the development and progression of lung cancer [19–26]. In addition, we restricted the tumor histologic type and tumor size to adenocarcinomas measuring less than 3 cm in diameter because SUVmax is known to be higher in large tumors and other histologic types of tumors [9]. The purpose of this study was to investigate the correlation between the expression of selective tumor markers, especially that of COX-2 and the SUVmax, on FDG-PET to examine whether the SUVmax might reflect tumor proliferation and angiogenesis.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Population
Sixty patients with lung adenocarcinomas measuring less than 3 cm in diameter who underwent surgical resection (lobectomy or segmentectomy) with systematic lymph node dissection at Kawasaki Medical School Hospital between 2007 and 2009 were enrolled in this study. None of the patients had received either radiotherapy or chemotherapy before the surgery. The histologic diagnosis of the tumors was based on the criteria of the World Health Organization, and the TNM stage was determined according to the criteria in 2009. Written informed consent was obtained from each patient for the study of the excised tissue samples from the surgical specimens. This study was conducted with the approval of the institutional Ethics Committee of Kawasaki Medical School.

FDG-PET
All PET/computed tomography (CT) examinations were performed with a dedicated PET/CT scanner (Discovery ST Elite; GE Healthcare, Kyoto, Japan). The axes of the multidetector CT and PET systems were mechanically aligned so that the patient could be moved from the CT to the PET scanner gantry by simply changing the position of the examination table. The resultant PET and CT scans were coregistered with hardware. PET/CT scanning was performed at 115 minutes after the intravenous injection of 150 to 220 MBq of 18-fluorodeoxyglucose (FDGscan, Universal Giken, Nihon Medi-Physics, Tokyo, Japan). The regions of interest were placed 3-dimensionally over the lung cancer nodules. Semiquantitative analysis of the images was performed by measuring the SUVmax of the lesions. SUV was calculated on the basis of the following equation: tumor activity concentration/(injected dose/body weight).

Immunohistochemical Staining
Immunohistochemical analyses were performed on resected paraffin-embedded lung cancer tissues. After microtome sectioning (4 μm slices), the slides were processed for staining using an automated immunostainer (Nexes, Ventana Medical Systems, Tucson, AZ). The streptavidin-biotin-peroxidase detection technique using diaminobenzidine as the chromogen was applied.

The primary antibodies were used according to the manufacturer's instructions. The antibodies used are summarized in Table 1. The slides were examined by 2 investigators who had no knowledge of the corresponding clinicopathologic data. The expression of each marker protein was examined and evaluated according to the original protocol reported previously. For COX-2, the slides were scored for intensity of staining (0 to 3) and the percentages of cells with scores of 0 (0%), 1 (1% to 9%), 2 (10% to 49%), and 3 (50% to 100%) were determined. The immunohistochemistry (IHC) score (0 to 9) was defined as the product of the intensity and percentage of cells. We categorized the patients according to IHC score as follows: group 1, 0; group 2, 1 to 3; group 3, 4 to 6; group 4, 7 to 9. COX-2 expression was judged as positive when the IHC score was greater than or equal to 4 (groups 3 and 4) [20] (Fig 1 A). VEGF expression was judged as positive when more than 20% of cancer cell cytoplasm showed positive staining [21] (Fig 1B). The labeling index of Ki-67 was measured by determining the percentage of cells with positively stained nuclei. Ki-67 expression was judged as positive when more than 10% of the cancer cell nuclei showed positive staining [22] (Fig 1C). There are at present no validated scoring systems for interpreting immunohistochemical staining for pEGFR, IGF-1R, and PDGFRα. We used a system that was based on the staining intensity and percentage of stained cells, as previously described for EGFR [23]. pEGFR and IGF-1R protein expressions were judged as positive when more than 10% of the cancer cells showed distinct cell membrane staining [24, 25]. PDGFRα protein expression was judged as positive when more than 10% of cancer cells showed positive cytoplasmic staining [26].


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  		Table 1 Antibodies Used for Immunohistochemical Analysis
 

Figure 1
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  		Fig 1. Immunohistochemical staining for (A) cyclooxygenase-2 (COX-2), (B) vascular endothelial growth factor (VEGF), and (C) Ki-67 (magnification, x400).

 
Statistical Analysis
Continuous variables were analyzed by the Student's t test, and the results were expressed as mean ± standard deviation. Dichotomous variables were analyzed by Fisher's exact test or the {chi}2 test, as appropriate. Discontinuous variables were coded as dummy variables. To determine the final parameters related to the SUVmax, multiple stepwise regression analyses was performed. To explore the association between recurrence-free survival and COX-2 expression, a Kaplan-Meier survival analysis was performed by stratifying significant predictor variables identified from the Cox proportional hazards model. Two-sided p values of less than 0.05 were considered to be statistically significant. All analyses were performed using SPSS software, version 17.0 (SPSS Inc, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Clinical Characteristics
The characteristics of the patients are summarized in Table 2. The patients ranged in age from 46 to 83 years (mean, 66.8 years). There were 29 men and 31 women. The median value of the SUVmax of all the tumors was 5.9 ± 5.2 (range, 0 to 18.1). No statistically significant association was observed between the SUVmax of primary tumors and the age, sex, or smoking status of the patients. A statistically significant correlation was observed between the SUVmax and the degree of tumor differentiation (p = 0.001), pleural invasion (p = 0.001), vascular invasion (p < 0.001), and nodal status (p = 0.004) (Table 2).


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  		Table 2 Characteristics of the Patients With SUVmax
 
Relationship Between the FDG-PET and Immunohistochemical Findings
The COX-2–, Ki-67–, and VEGF-positive cases showed significantly higher SUVmax than did the cases negative for these markers (p < 0.001). The mean value of SUVmax was 8.4 ± 5.1 in the COX-2–positive cases and 2.2 ± 2.4 in the COX-2–negative cases. The mean value of SUVmax was 8.7 ± 5.7 in the Ki-67–positive cases and 3.6 ± 3.3 in the Ki-67–negative cases. The mean value of SUVmax was 7.7 ± 5.1 in the VEGF-positive cases and 3.0 ± 3.8 in the VEGF-negative cases. The cases showing positive growth factor receptor (pEGFR, IGF-1R, or PDGFRα) expression tended to show higher SUVmax than did the growth factor receptor expression–negative cases; however the differences were not significant (Table 3).


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  		Table 3 Correlation Between Biological Factors With SUVmax
 
For the significant factors shown in Table 3, we performed multiple stepwise regression analyses (Table 4). COX-2 expression (p < 0.001) and Ki-67 expression (p = 0.016) remained significant factors independently related to the SUVmax. Of the 2, COX-2 expression was the stronger determinant of the SUVmax. In addition, the SUVmax increased in proportion to the IHC score for COX-2 expression (Fig 2). The mean value of SUVmax was 1.7 ± 1.7 in group 1 (n = 10), 2.6 ± 2.7 in group 2 (n = 14), 7.1 ± 4.1 in group 3 (n = 29), and 13.4 ± 6.0 in group 4 (n = 7). Group 4 showed a significantly higher SUVmax than did group 3 (p = 0.032), and group 3 showed a significantly higher SUVmax than did group 2 (p < 0.001).


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  		Table 4 Multiple Stepwise Regression Analysis for Factors Associated With SUVmax in Lung Adenocarcinoma
 

Figure 2
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  		Fig 2. Relationship between the immunohistochemistry (IHC) score for cyclooxygenase-2 (COX-2) expression and the maximal standardized uptake values (SUVmax); *p = 0.032, **p < 0.001.

 
Prognostic Value of COX-2 Expression
The recurrence-free survival of patients with elevated COX-2 expression in the tumors was significantly worse than that of patients not showing COX-2 expression in the tumors (p = 0.047 according to the log-rank test; Fig 3).


Figure 3
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  		Fig 3. Kaplan-Meier recurrence-free survival curve according to cyclooxygenase-2 (COX-2) expression, log-rank, p = 0.047.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
The SUV measured on FDG-PET is a semiquantitative value that indicates the degree of glucose uptake in a lesion. The SUVmax of primary lung nodules has been reported to be helpful in distinguishing between malignant and benign tumors, based on the relatively higher values in malignant tumors [27]. We speculated that tumors showing higher SUVmax might be more aggressive and have a higher proliferation potential. We examined this hypothesis by studying the correlation between the SUVmax and the expression of some molecular biomarkers, because overexpression of these markers is known to accelerate the tumor progression in patients with NSCLC. In particular, the biomarkers such as pEGFR, IGF-1R and PDGFRα selected by us are targets of new biological agents of the small-molecule receptor tyrosine-kinase inhibitor family.

To the best of our knowledge, the present study provides the first evidence showing a positive association between COX-2 expression in the tumor and the SUVmax on FDG-PET in patients with lung adenocarcinoma. Furthermore, in this study we found that the FDG accumulation increased in proportion to the IHC score for COX-2 expression. The important findings of this present study were as follows: (1) the SUVmax was correlated with the expressions of COX-2, Ki67, and VEGF and (2) among the markers, the strongest determinant of the SUVmax was the expression of COX-2.

First, this present study demonstrated significant correlations between the expression of COX-2, Ki67, and VEGF and the SUVmax on FDG-PET. Immunostaining with the Ki-67 antibody is a widely accepted method for evaluating the proliferative activity in a variety of human tumors. Tumors showing a high expression index of Ki-67 are frequently more aggressive than tumors showing a low Ki-67 expression index. Vesselle and associates [11] reported the existence of a relationship between the Ki-67 expression index and the degree of FDG uptake in NSCLC. In this study, too, the expression of Ki-67 was significantly related to the SUVmax of the primary tumors. These findings were therefore consistent with previously reported observations [17, 18, 28].

Conversely, the VEGF family of proteins modulates angiogenesis, which is essential for tumor growth and metastasis. The expression of VEGF has been shown to be associated with tumor angiogenesis, metastasis, and prognosis in several cancers, including NSCLC. To date, 2 reports have shown a correlation between the expression of VEGF and the SUV on PET-CT. Kaira and colleagues [18] demonstrated a significant correlation between VEGF expression and 18-fluorodeoxyglucose uptake in NSCLC. Takenaka and colleagues [28] demonstrated that the SUVmax was associated with the expression of VEGF in NSCLC.

Our results using tissues from patients with lung adenocarcinomas measuring less than 3 cm in diameter were similar to this previous report in cases of NSCLC and represents, to our knowledge, the first report of these phenomena, particularly in patients with lung adenocarcinoma. However, to the best of our knowledge, no reports have shown a correlation between the expression of COX-2 and the SUV on FDG-PET.

We speculated that the reason that the strongest determinant of the SUVmax was the COX-2 expression was that COX-2 expression is highly correlated with tumor angiogenesis and also regulates other angiogenic factors. To date, some articles have investigated the association between COX-2 expression and tumor angiogenesis [29–31]. Recent evidence suggests that COX-2 plays an important role in tumor-induced angiogenesis through the synthesis of angiogenic prostaglandins, such as prostaglandin E2, which induce VEGF, and that COX-2 contributes to neovascularization and may support vasculature-dependent growth of solid tumors [29, 32]. Our results using resected tissues indicated that the SUVmax of primary tumors might reflect a biological malignant potential such as tumor angiogenesis in lung adenocarcinomas measuring less than 3 cm in diameter.

The defining feature of the present study was that the examination was restricted to adenocarcinomas measuring less than 3 cm in diameter. In addition, the cases were also restricted to patients who underwent lobectomy or segmentectomy with systematic lymph node dissection as the surgical procedure. The reason for such restriction was that SUVmax is known to be higher in larger tumors and other histologic types, such as squamous cell carcinoma or large cell carcinoma, and lower in cases of bronchioloalveolar carcinomas and well-differentiated adenocarcinomas in which the surgical procedure was adjusted to wedge resection [33]. The unification of the backgrounds was attempted by this selection.

Lobectomy with lymph node dissection is the standard surgical treatment for NSCLC [34]. Recently, patients with small adenocarcinomas showing dominance of ground-glass opacity on high-resolution CT have been reported as good candidates for limited resection [35, 36]. However for patients with small adenocarcinomas showing solid tumor dominance, limited resection is a controversial surgical option [37].

The present study results might suggest that the SUVmax could assist in deciding the appropriate surgical procedure because SUVmax was associated with some biomarkers that were known to accelerate the tumor progression. Cancer treatment targeting the control of COX-2 might become feasible in the future. In fact, a recent clinical trial by the Cancer and Leukemia Group B demonstrated that among patients with increased COX-2 expression, survival was better in those who received COX-2 inhibitor treatment than among those who did not receive this treatment [20]. We have proposed to conduct a clinical trial of a COX-2 inhibitor for the treatment of tumors that are strongly PET-positive.

In conclusion, the expressions of COX-2, Ki-67, and VEGF in primary lung adenocarcinomas measuring less than 3 cm in diameter were associated with the SUVmax on FDG-PET. This is the first report, to our knowledge, to describe a significant correlation between the intratumoral expression of COX-2 and the SUVmax in cases of lung adenocarcinoma. The expression of COX-2 in the primary tumors is as strongly correlated with a worse clinical outcome as is increased FDG uptake. Based on the relationship between the SUVmax and the biological factors that influence cancer progression, these findings indicate that the SUVmax of primary tumors might reflect the biological malignant potential in lung adenocarcinomas. Further study is needed to investigate other factors that might influence the SUVmax on FDG-PET.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
The authors thank Keiko Isoda for technical assistance.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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