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10.1245/ASO.2005.09.018
Annals of Surgical Oncology 12:817-824 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Prognostic Significance of Reversion-Inducing Cysteine-Rich Protein With Kazal Motifs Expression in Resected Pathologic Stage IIIA N2 Non–Small-Cell Lung Cancer

Kazumasa Takenaka, MD1, Shinya Ishikawa, MD1, Kazuhiro Yanagihara, MD1, Ryo Miyahara, MD1, Seiki Hasegawa, MD1, Yosuke Otake, MD2, Yoko Morioka, MMed Sci3, Chiaki Takahashi, PhD3, Makoto Noda, PhD3, Harumi Ito, MD4, Hiromi Wada, MD1 and Fumihiro Tanaka, MD1

1 Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawahara-cho 54, Sakyo-ku, Kyoto, 606-8507, Japan
2 Department of Thoracic Surgery, Seishin-Iryo Center Hospital, Kobe, 651-2273, Japan
3 Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
4 Department of Radiology, Faculty of Medicine, University of Fukui, Fukui, 910-1193, Japan

Correspondence: Address correspondence and reprint requests to: Fumihiro Tanaka, MD; E-mail: ftanaka{at}kuhp.kyoto-u.ac.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a novel membrane-anchored matrix metalloproteinase inhibitor, and experimental studies have shown that RECK can suppress tumor progression through angiogenesis inhibition. We have already revealed that enhanced RECK expression is significantly correlated with a favorable prognosis in non–small-cell lung cancer (NSCLC). In this study, further analyses focused on pN2 disease were conducted to assess the clinical significance of RECK expression.

Methods: A total of 118 patients with completely resected pathologic stage IIIA N2 NSCLC were retrospectively examined. RECK expression in the primary tumor, along with involved N2 nodes, was examined immunohistochemically.

Results: RECK expression in the primary tumor was strong in 53 patients (44.9%) and was weak in the other 65 patients. The 5-year survival rate of patients with RECK-strong tumor (42.9%) was significantly higher than that of patients with RECK-weak tumor (23.1%; P = .017). Reduced RECK expression significantly correlated with a poor prognosis for patients with a single N2 node involved (P = .019), but not for patients with multiple N2 nodes involved (P = .440). A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (P = .031). RECK expression in involved N2 nodes was significantly higher than in primary tumors (P < .001).

Conclusions: RECK status was a novel prognostic factor in pathologic stage IIIA N2 NSCLC.

Key Words: Non–small-cell lung cancer • Stage IIIA • N2 • Prognosis • RECK


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Non–small cell lung cancer (NSCLC), which accounts for approximately 80% of primary lung cancers, is a malignant tumor with a poor prognosis. Complete resection is the most effective therapeutic modality for cure, but the postoperative survival remains unsatisfactory.1,2 In fact, the 5-year survival rate after surgery for N2 disease in which the mediastinal node is involved is only 20%.1,3–5 To improve the prognosis, it is important to reveal and establish prognostic factors other than the tumor-node-metastasis system, and many clinical studies have demonstrated possible prognostic values of a variety of biological factors, such as p53 status, in early-stage NSCLC.6–8 However, little has been reported on the prognostic values of biological markers in pN2 NSCLC,9–11 and significant factors that influence the prognosis for pN2 disease remain unclear.

The RECK (reversion-inducing cysteine-rich protein with Kazal motifs) gene was originally isolated by an expression-cloning strategy designated to find transformation-suppressor genes against an activated RAS oncogene.12 The RECK gene is widely expressed in many normal organs, including the lung, and the expression is low or undetectable in many tumor-derived cell lines.13,14 The RECK-encoded protein acts as a membrane-anchored regulator of matrix metalloproteinases (MMPs), including MMP-2, MMP-9, and MT1-MMP. Previous experimental studies revealed that RECK can inhibit tumor invasion and metastasis.12–15 These experimental data suggest a potential importance of RECK in the diagnosis and therapy of malignant tumors. Nevertheless, only a few studies have demonstrated that RECK expression at the messenger RNA or protein level can be a useful prognostic indicator in cancer patients with hepatocellular carcinoma,16 breast cancer,17 and pancreatic cancer.18 We conducted a preliminary study on RECK expression in resected pathologic stage I to IIIA NSCLC and found that enhanced RECK expression was correlated with a favorable prognosis. It is interesting to note that a subset analysis suggested that the prognostic significance is not evident in early-stage disease but is evident in advanced-stage disease.19 Thus, in this study, we focused on homogeneous patients—that is, pathologic stage IIIA N2 patients—and assessed the prognostic significance of RECK status, along with differences in RECK expression between primary tumors and involved nodes.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Preparation
This study was approved by our institutional review board. A total of 118 patients with pathologic stage IIIA N2 NSCLC who underwent complete tumor resection at Kyoto University Hospital between January 1985 and December 1998 and whose histological specimens were available for immunohistochemical staining (IHS) were retrospectively reviewed (Table 1Go). In 40 patients, paired primary tumors and involved mediastinal nodes were available for IHS. The operation with lymph node dissection was performed according to the general rules for clinical and pathologic recording of lung cancer by the Japan Lung Cancer Society. Brain computed tomography (CT) for preoperative staging in all patients was performed. Pathologic stage was reevaluated according to the current tumor-node-metastasis classification (revised in 1997).1 The clinical nodal status (cN factor) was determined with CT as described previously20; briefly, CT scans were performed with a 10-mm slice thickness, and nodal status was evaluated by a thoracic radiologist (H.I.) as follows: mediastinal lymph nodes were considered to be enlarged (cN2) when the short-axis diameter exceeded 1.5 cm for the subcarinal node or 1.0 cm for other nodes. The histological type and tumor cell differentiation were also reevaluated according to the current classification by World Health Organization (revised in 1999).21 In analyses of RECK expression stratified by grade of tumor cell differentiation, well-differentiated squamous cell carcinoma and adenocarcinoma were classified into well-differentiated tumor; moderately differentiated squamous cell carcinoma and adenocarcinoma were classified into moderately differentiated tumor; and large-cell carcinoma, poorly differentiated squamous cell carcinoma, and adenocarcinoma were classified into poorly differentiated tumor. Other histological types were excluded in the analyses stratified by cell differentiation. The inpatient and outpatient medical records, chest x-ray films, whole-body CT films, bone and gallium scanning data, and operation records were reviewed without knowledge of the results of IHS. Follow-up of the postoperative clinical course was conducted by outpatient medical records and by inquiries by telephone or letter.


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  		TABLE 1. Characteristics of patients with pathologic stage IIIA N2 non–small-cell lung cancer and RECK expression
 
As preoperative induction therapy, 8 patients received intravenous chemotherapy (cisplatin-based regimens in 5 patients and other regimens in 3 patients), and 13 patients received radiation; among them, 3 patients received both radiation and chemotherapy. No intraoperative therapy was performed for any patient. As postoperative adjuvant therapy, 25 patients received intravenous chemotherapy (cisplatin-based regimens in 22 patients and other regimens in 3 patients), and 33 patients received radiation; among them, 5 patients received radiation followed by chemotherapy. Fifty-four patients received oral administration of 5-fluorouracil derivatives (tegafur in 4 patients and a combination drug of tegafur and uracil in the other 50 patients).

All tumors and lymph node specimens were immediately fixed in 10% (v/v) formalin and then embedded in paraffin. Serial 4-µm sections were prepared from each sample and used for hematoxylin and eosin staining, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, and IHS for evaluation of RECK, proliferative cell nuclear antigen (PCNA), and aberrant p53. Slides were reviewed independently by two investigators (K.T. and F.T.) without knowledge of clinical data.

Immunohistochemistry
The procedure of IHS for evaluation of RECK expression by using a streptavidin-biotinylated horseradish peroxidase detection system (LSAB+ kit/HRP; DAKO, Kyoto, Japan) was described previously.19 In brief, after retrieval of the antigen with heating in a microwave oven for 5 minutes three times, sections were incubated overnight at 4°C with an anti-RECK monoclonal antibody (mAb; clone 5B11D12; a gift from Amgen, Thousand Oaks, CA) 12,14 diluted 1/50. RECK expression was estimated from the staining intensity and graded as follows: grade 0, no staining; grade 1, faint staining; grade 2, moderate staining; and grade 3, strong staining comparable to the staining intensity documented in the positive control slide. Finally, the RECK status of each patient was classified according to the grade of staining intensity of the primary tumor as follows: RECK-weak tumor when the staining grade was 0 or 1 and RECK-strong tumor when the staining grade was 2 or 3.

IHS for CD34 to highlight endothelial cells was performed with a sensitive streptavidin-biotinylated horseradish peroxidase complex system (TSA-Indirect Kit; NEN Life Science Products, Boston, MA) as described previously.22 Briefly, an anti-CD34 mAb, QBEnd10 (mouse immunoglobulin [Ig]G1, {kappa}, 50 µg/mL; DAKO), diluted 1/50 was used as the primary antibody. The 10 most vascular areas within a section were selected for evaluation of angiogenesis, and vessels highlighted with the anti-CD34 mAb were counted under light microscopy at 200-fold magnification. The average counts were defined as the CD34 intratumoral microvessel density (IMVD) for each case.

The proliferative activity of tumor cells and aberrant p53 expression was evaluated with IHS as described previously23 by using an anti-PCNA mAb, PC-10 (mouse IgG2a, {kappa}, 400 µg/mL; DAKO), diluted 1:50 and a mouse anti-human p53 mAb, DO-7 (mouse IgG2b, {kappa}, 250 µg/mL; DAKO), diluted 1:50. The proliferative index was defined as the percentage of PCNA-positive cells. The p53 expression was judged to be aberrant when the percentage of cancer cells with nuclear positive staining exceeded 5%.

Detection of Apoptosis (Apoptotic Index)
Apoptotic cells were detected with TUNEL staining by using an In Situ Death Detection Kit (Boehringer Manheim, Manheim, Germany) as described previously.23 The specificity of the assay was confirmed by including a negative control (terminal deoxynucleotidyl transferase omitted) and a positive control (sections treated with deoxyribonuclease I) every time. Apoptotic cells were determined with careful comparison of TUNEL sections and serial hematoxylin and eosin–stained sections, because some necrotic cells also give rise to TUNEL signals. In each case, a total of 10,000 tumor cells (in 10 microscopic fields; 1000 cells per field) were observed, and the apoptotic index was defined as the number of apoptotic cells per 1000 tumor cells.

Statistical Analysis
Counts were compared by the {chi}2 test. Continuous data were compared by using Student’s t-test if the sample distribution was normal or by using the Mann-Whitney U-test if the sample distribution was asymmetrical. The postoperative survival rate was analyzed by the Kaplan-Meier method, and the differences in survival rates were assessed by the log-rank test. Multivariate analysis of prognostic factors was performed with Cox’s regression model. Differences were considered significant when P was <.05. All statistical manipulations were performed with SPSS for Windows (SPSS Inc., Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
RECK Expression and Clinical Characteristics
RECK immunoreactivity was found in the cytoplasm of NSCLC tumor cells in both primary tumors and involved nodes and was homogeneously distributed in all cases (Fig. 1Go). The mean RECK score of the primary tumor was significantly lower than that of the involved nodes (1.51 vs. 2.00; P < .001; Fig. 2Go).



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  		FIG. 1. Immunohistochemical staining for reversion-inducing cysteine-rich protein with Kazal motifs in lung squamous cell carcinoma [(A) primary tumor; (B) involved node] and adenocarcinoma [(C) primary tumor; (D) involved node]. Intense staining was found in the cytoplasm of the tumor cells in both primary tumors and involved nodes.

 


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  		FIG. 2. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) intensity scores of the primary tumors and involved nodes. The mean RECK intensity score of involved nodes was significantly higher than that of primary tumors.

 
On the basis of the staining intensity of RECK in the primary tumors, 65 patients (55.1%) were classified as RECK-weak patients and 53 patients (44.9%) as RECK-strong patients. RECK-strong expression seemed to be more frequent in patients with squamous cell carcinoma than in those with adenocarcinoma, but the difference did not reach statistical significance (P = .090). No correlation was revealed between the RECK status and age, sex, performance status, grade of tumor differentiation, histological type, clinical N factor, pathologic T factor, or number of N2 nodes involved (Table 1Go). There was no difference in the mean RECK intensity scores between patients who received preoperative intravenous chemotherapy and those who did not (1.27 vs 1.38; P = .670) or between patients who received preoperative radiation and those who did not (1.19 vs 1.40; P = .330).

Furthermore, correlations between RECK expression and other biomarkers were also examined. There was no significant difference in the mean IMVD, proliferative activity (proliferative index), incidence of apoptotic cells (apoptotic index), or p53 status between RECK-weak patients and RECK-strong patients (Table 2Go).


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  		TABLE 2. Correlation between RECK expression and other biomarkers of tumor in pathologic stage IIIA N2 non–small-cell lung cancer
 
Prognostic Factors and Postoperative Survival
Univariate analyses of prognostic factors demonstrated that the preoperative N2 status (cN factor) and the number of involved N2 stations were significant prognostic factors; patients with cN2 disease had a significantly poorer prognosis than those with cN0/1 disease (P = .039), and patients with multiple N2 station involvement had a significantly poorer prognosis than those with single N2 station involvement (P = .012; Table 3Go). Any preoperative therapy or any postoperative therapy did not improve the postoperative survival (Table 3Go). Preoperative or postoperative cisplatin-based chemotherapy, which was conducted in most patients who received intravenous chemotherapy, did not improve the postoperative survival (data not shown).


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  		TABLE 3. Univariate analyses of prognostic factors in pathologic stage IIIA N2 non–small-cell lung cancer
 
The 5-year survival rate of RECK-strong patients was 42.9%, which was significantly higher than that of RECK-weak patients (23.1%; P = .017; Table 4Go and Fig. 3Go). When patients were stratified by histological types, reduced RECK expression proved to be a significant factor to predict a poor prognosis in patients with squamous cell carcinoma (Table 4Go). Reduced RECK expression was also a significant factor to predict a poor prognosis in patients with poorly differentiated tumors, but not in patients with well-differentiated to moderately differentiated tumors (Table 4Go). In addition, reduced RECK expression was a significant predictor of prognosis in the subset of patients with cN0/1 disease and in patients with single N2 station involvement (Table 4Go).


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  		TABLE 4. RECK expression and postoperative survival in pathologic stage IIIA N2 non–small-cell lung cancer
 


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  		FIG. 3. Postoperative survival of patients with completely resected pathologic stage IIIA N2 non–small-cell lung cancer. The postoperative survival of reversion-inducing cysteine-rich protein with Kazal motifs (RECK)-strong patients was compared with that of RECK-weak patients.

 
Multivariate Analysis of Prognostic Factors
A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (P = .031; hazard ratio, .588; 95% confidence interval, .357–.966; Table 5Go). The clinical N factor and the number of involved pN2 stations were also significant prognostic factors.


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  		TABLE 5. Multivariate analysis of prognostic factors in pathologic stage IIIA N2 non–small-cell lung cancer
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We focused on RECK expression and its prognostic significance in resected pathologic stage IIIA N2 NSCLC and demonstrated that reduced RECK expression was a significant factor to predict a poor prognosis. We also demonstrated that the preoperative clinical N2 status and multiple involved pN2 stations were significant negative prognostic factors in stage IIIA N2 patients. This finding was consistent with results documented in other clinical studies.3,5,24–26 Only a few clinical studies have been reported on the prognostic significance of RECK status in malignant tumors such as hepatocellular carcinoma,16 breast cancer,17 and pancreas cancer18; all these studies showed that enhanced RECK expression was a significant factor to predict a favorable prognosis, but this finding was inconsistent with the results documented in our previous study in NSCLC.19 The present study on a homogeneous population—pathologic stage IIIA N2 patients—has confirmed the prognostic value of RECK status, and prospective studies should be conducted to establish the prognostic value in clinical practice.

Experimental studies have revealed that RECK can inhibit tumor progression through inhibiting tumor angiogenesis, as well as tumor invasion and metastasis, because RECK can regulate a variety of MMPs.12–15 Thus, a favorable prognosis in a tumor with enhanced RECK expression may be explained by the biological roles of RECK demonstrated in these experimental studies. However, this study failed to reveal a significant correlation between RECK status and IMVD, a measurement of tumor angiogenesis. The underlying mechanism of RECK action is still unclear, and our results may suggest minimal effects of RECK expression on IMVD (regarding only N2 disease of NSCLC). To clarify a correlation between tumor angiogenesis and RECK status in clinical specimens, methods to estimate RECK status other than IHS, i.e., quantitative evaluation of gene expression and immunoblotting, should be also examined in future studies, although we confirmed the positive correlation between RECK protein expression and messenger RNA expression in other patients.27 In addition, correlations between RECK status and MMPs in clinical specimens should be examined. In fact, Masui et al.18 revealed an inverse correlation between RECK expression and MMP-2 activation in pancreas cancer, and this finding was consistent with experimental results.14 The present study revealed enhanced RECK expression in involved nodes as compared with that in primary tumors. However, large-scale prospective studies should confirm our result, because this study was small. Moreover, the mechanism and the biological significance should be revealed in future studies.

In conclusion, reduced expression of RECK in pathologic stage IIIA N2 NSCLC correlated with a worse postoperative prognosis. The prognosis of IIIA N2 disease is generally considered poor, but reduced RECK expression results in an even worse postoperative prognosis.


   ACKNOWLEDGMENTS
 
The authors thank Tomoko Yamada for preparation of histological sections. We also thank Seiko Sakai for manuscript preparation. Supported by Grants-in-Aid 14370410 (F.T.) and 15390411 (S.H., F.T., and H.W.) for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was also supported by a grant from the Japanese Foundation for Multidisciplinary Treatment of Cancer.


   FOOTNOTES
 
Presented in part at the 40th Annual Meeting of the Society of Thoracic Surgeons, San Antonio, Texas, January 26–28, 2004.

Received for publication September 17, 2004. Accepted for publication April 28, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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