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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.07.013 on May 18, 2004

Annals of Surgical Oncology 11:612-618 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Prognostic Factors in Resected Pathologic (p-) Stage IIIA-N2, Non-Small-Cell Lung Cancer

Fumihiro Tanaka, MD, Kazuhiro Yanagihara, MD, Yosuke Otake, MD, Yozo Kawano, MD, Ryo Miyahara, MD, Kazumasa Takenaka, MD, Hiromichi Katakura, MD, Shinya Ishikawa, MD, Harumi Ito, MD and Hiromi Wada, MD

From the Department of Thoracic Surgery, Kyoto University (FT, KY, YK, RM, KT, HK, SI, HW), Kyoto; Department of Thoracic Surgery, Seishin-iryo Center Hospital (YO), Kobe; and Department of Radiology, Fukui Medical University (HI), Fukui, Japan.

Correspondence: Address correspondence and reprint requests to: Fumihiro Tanaka, MD, Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan; Fax: 81-075-751-4974; e-mail: ftanaka{at}kuhp.kyoto-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Postoperative prognosis for patients with pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) is poor, and significant factors that influence the prognosis remain unclear.

Methods: A total of 99 patients who underwent complete resection for p-stage IIIA-N2 NSCLC without any preoperative therapy were retrospectively reviewed. Biological features such as tumor angiogenesis (intratumoral microvessel density [IMVD]), proliferative activity (proliferative index [PI]), and p53 status were also evaluated immunohistochemically.

Results: Univariate analysis revealed that the number of involved N2 stations was a significant prognostic factor; 5-year survival rates for a tumor with metastases in single N2 stations, tumor with metastases in two N2 stations, and tumor with metastases in 3 or more N2 stations were 41.6%, 35.3%, and 0.0%, respectively (P = .041) In addition, the 5-year survival rate for cN0-1 disease was significantly higher than that for cN2 disease (41.9% and 25.5%, respectively; P = .048) Tumor angiogenesis and proliferative activity were the most significant prognostic factors; 5-year survival rates for lower-IMDV tumor and higher-IMVD tumor were 53.6% and 15.9%, respectively (P = .002), and those for lower-PI tumor and higher-PI tumor were 47.0% and 20.4%, respectively (P = .019) There was no difference in the postoperative survival between tumor showing aberrant p53 expression and tumor showing no aberrant p53 expression. These results were confirmed by a multivariate analysis.

Conclusions: P-stage IIIA-N2 NSCLC cases represented a mixture of heterogeneous prognostic subgroups, and the number of involved N2 stations, cN status, PI, and IMVD were significant predictors of the survival.

Key Words: Angiogenesis • N2 • Non-small-cell lung cancer • Proliferative activity • Stage IIIA • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Postoperative survival of patients with non-small-cell lung cancer (NSCLC), which accounts for approximately three-quarters of all primary lung cancers, is poor.1,2 One of the most critical factors to determine the postoperative survival is a status of pathologic nodal involvement (pN-factor); when mediastinal lymph nodes are involved (pN2), the 5-year survival rate after surgery is only 20%.1,3–5 To improve the prognosis, significant prognostic factors other than the tumor-nodes-metastases (TNM) system should be clarified, and many clinical studies have suggested that a variety of biological factors such as tumor angiogenesis, proliferative activity, and p53 status can be significant prognostic factors in resected p-stage I NSCLC.6 However, only a few clinical studies have focused on the prognostic significance of biological features in pN2 disease.7

Among a variety of biomarkers that have been examined in NSCLC, abnormality of the p53 gene, a tumor suppressor gene, is the most common and most important disorder. Many clinical studies have revealed that p53 status can be not only a significant prognostic factor8 but also a predictive factor of therapeutic efficacy in NSCLC.9 In addition, proliferative activity of tumor cells and tumor angiogenesis10 can be prognostic factors in resected NSCLC. However, the clinical significance of such biomarkers has not been established in NSCLC, and decision-making about therapy for NSCLC on the basis of these biomarkers is not recommended.11

In the present study, therefore, we reviewed several prognostic factors, including biomarkers (angiogenesis, proliferative activity, and p53 status) in completely resected pathologic (p-) stage IIIA-N2 NSCLC. In evaluation of angiogenesis, panendothelial (pan-EC) markers such as CD34 are generally used, but pan-EC antibodies react with not only newly forming vessels but also "inactivated" vessels just trapped within tumor tissues. It has been recently reported that anti-CD105 antibodies preferentially react with "activated" endothelial cells in angiogenic tissues, and superiority of anti-CD105 antibodies in evaluation of angiogenesis has been suggested.12 Thus, in the present study, we used both an anti-CD34 antibody and an anti-CD105 antibody and compared the usefulness of these antibodies in evaluation of angiogenesis in N2 disease.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A total of 99 consecutive patients with p-stage IIIA-N2 NSCLC who underwent complete resection without any preoperative therapy at the Department of Thoracic Surgery, Kyoto University, from 1985 through 1995 were retrospectively reviewed (Table 1). Preoperative clinical staging (c-stage) and postoperative p-stage were reevaluated and determined by the current TNM classification, as revised in 1997.1 Clinical nodal status (cN factor) was determined with computed tomography (CT), as described previously.13 In brief, CT scans were performed with a 10-mm slice thickness, and nodal status was evaluated by a thoracic radiologist (HI) as follows: mediastinal lymph nodes were considered to be enlarged (cN2) when the short-axis diameter exceeded 1.5 cm for subcarinal node or 1.0 cm for other nodes.


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  		TABLE 1. Characteristics of patients and postoperative survival (univariate analysis)
 
Histological type and tumor-cell differentiation were determined with use of the classification of the World Health Organization (WHO).14 With regard to tumor differentiation, well-differentiated squamous cell carcinoma and adenocarcinoma were classified as well-differentiated tumors. Moderately differentiated squamous cell carcinoma and adenocarcinoma were classified as moderately differentiated tumors. Large-cell carcinoma and poorly differentiated squamous cell carcinoma and adenocarcinoma were classified as poorly differentiated tumors. The other histologic types were excluded in analysis according to cell differentiation.

Performance status (PS) was determined according to the ECOG scale, as follows: grade 0, fully active and able to carry on all predisease activities without restriction; grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework or office work; grade 2, ambulatory, capable of all self-care, unable to carry out work activities, and up and about >50% of waking hours; grade 3, capable of only limited self-care and confined to bed or chair >=50% of waking hours; grade 4, completely disabled, incapable of any self-care, and totally confined to bed or chair.13 For all these patients, the inpatient medical records, chest x-ray films, whole-body CT films, bone and gallium scanning data, and surgical records were reviewed. As postoperative adjuvant therapy, 26 patients received intravenous chemotherapy and 33 received radiation; among them, 5 patients received radiation followed by chemotherapy. Forty-four patients received oral 5-fluorouracil derivatives; 4 patients had tegafur (FT); and 44 had tegafur and uracil (UFT)15,16 (Table 1). This study was approved by the Ethics Committee, Faculty of Medicine, Kyoto University.

Immunohistochemistry
The biological features of histological sections from the primary tumor were evaluated, and results of immunohistochemical staining (IHS) were evaluated by two authors independently (FT and YO) without knowledge of clinical data. All tumor specimens were immediately fixed in 10% (v/v) formalin and then embedded in paraffin. Serial 4-µm sections were prepared from each sample and were used for routine staining with hematoxylin and eosin (HE) and IHS. The IHS procedure with use of streptoavidin-biotinylated horseradish peroxidase complex method (LSAB kit; DAKO JAPAN, Kyoto, Japan) was described previously.17 In brief, dewaxed sections were heated in a microwave oven for 5 minutes three times each to retrieve their antigeneities. Mouse anti-human p53 monoclonal antibody (MoAb) DO-7 (mouse IgG2b, kappa, 250 µg/ml; DAKO Japan) diluted at 1:50 and mouse anti-human PCNA MoAb PC-10 (mouse IgG2a, kappa, 400 µg/ml; DAKO Japan) diluted at 1:50 were used as the primary antibodies. Aberrant p53 expression was noted when the percentage of cancer cells with nuclear positive staining exceeded 5%. Proliferative activity was represented as the percentage of PCNA-positive cancer cells (proliferative index = PI) The mean PI value was used as the cutoff value for differentiating lower-PI tumors from higher-PI tumors.

IHS for CD34 and CD105 to highlight ECs was performed with use of a sensitive streptoavidin-biotinylated horseradish peroxidase complex system (TSATM-Indirect Kit; NENTM Life Science Products, Boston, MA), as described previously.10 An anti-CD34 MoAb (QBEnd10, mouse immunoglobulin G [IgG] 1, kappa; 50 µg/ml; DAKO Japan) diluted at 1:50 and an anti-CD105 MoAb (SN6h, mouse IgG1, kappa; 366 µg/ml; DAKO, Japan) diluted at 1:100 were used. The 10 most vascular areas within a section were selected for evaluation of angiogenesis, and vessels labeled with the anti-CD34 or the anti-CD105 MoAb were counted under light microscopy with 200-fold magnification. The average counts were recorded as the CD34-IMVD or CD105-IMVD for each case. The mean value of CD34-IMVD or CD105-IMVD was used as the cutoff value for differentiating lower-IMVD from higher-IMVD tumors.

Statistical Methods
Counts were compared by the {chi}2 test, and trends in counts were analyzed by the {chi}2 test for trends. Continuous data were compared with use of Student’s t-test if the distribution of samples was normal or with the Wilcoxon 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 the Cox regression model. Differences were considered significant when the P value was less than .05. All statistical manipulations were performed with the SPSS for Windows software system (SPSS, Inc., Chicago, IL, USA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics and Survival
Characteristics of patients and postoperative survival are detailed in Table 1. Univariate analysis demonstrated that preoperative N2 status was a significant prognostic factor; the 5-year survival rate for cN2 disease was 25.5%, which was significantly lower than that for cN0-1-disease (5-year survival rate, 41.9%; P = .048) (Fig. 1). The number of involved N2 stations was also a significant factor (P = .041); the 5-year survival rate was 0.0% when three or more N2 stations were involved, 41.6% when only one station was involved, and 35.2% when two stations were involved (Fig. 2) The 5-year survival rate for pT3N2 disease (27.5%) seemed worse than that for pT1N2 disease (42.6%) or pT2N2 disease (42.5%), but the difference did not reach statistical significance (P = .232) Age, sex, PS, smoking history, site of the primary tumor, histologic type, or grade of tumor differentiation did not influence the survival. Postoperative intravenous chemotherapy, radiation, or oral chemotherapy did not improve the postoperative survival.



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  		FIG. 1. Postoperative survival of completely resected pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) Comparison according to clinical nodal status, evaluated with computed tomography.

 


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  		FIG. 2. Postoperative survival of completely resected pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) Comparison according to the number of mediastinal nodal stations involved.

 
Biomarkers and Postoperative Survival
The 5-year survival rate with tumors showing lower CD105-IMVD values (CD105-IMVD <34, the mean value) was 53.6%, which was significantly higher than that with tumors showing higher CD105-IMVD values (15.9%; P = .002) (Fig. 3B). When CD34 was used as a marker in evaluation of angiogenesis, there was no difference in the postoperative survival between the lower-CD34-IMVD tumors and the higher-CD34-IMVD tumors (Fig. 3A).



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  		FIG. 3. A, Postoperative survival of completely resected pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) Comparison according to intratumoral microvessel density, determined with an anti-CD34 antibody (CD34-IMVD). B, Postoperative survival of completely resected pathologic (p-) stage IIIA-N2, non-small-cell lung cancer (NSCLC) Comparison according to intratumoral microvessel density, determined with an anti-CD105 antibody (CD105-IMVD).

 
The 5-year survival rates with tumors showing lower PI values (PI < 50, the mean value) and tumors with higher PI values were 47.0% and 20.4%, respectively, showing that lower PI was a significant factor for prediction of a favorable postoperative survival rate (P = .019) (Fig. 4). In contrast, there was no difference in the postoperative survival for tumors showing no aberrant p53 expression and tumors with an aberrant p53 status (Fig. 5).



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  		FIG. 4. Postoperative survival of completely resected pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) Comparison according to proliferative index (PI), determined immunohistochemically.

 


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  		FIG. 5. Postoperative survival of completely resected pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC). Comparison according to p53 status, determined immunohistochemically.

 
Multivariate Analysis of Prognostic Factors
A multivariate analysis of prognostic factors in the Cox proportional hazard model confirmed that preoperative N2 enlargement (cN2), increased number of involved N2 stations, increased CD105-IMVD, and increased PI were significant factors for prediction of a poor prognosis (Table 2). When CD34-IMVD was used instead of CD105-IMVD as a marker of angiogenesis, IMVD failed to be a significant prognostic factor (data not shown).


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  		TABLE 2. Multivariate analysis of prognostic factors in p-stage IIIA–N2, non-small cell lung cancer
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we clearly demonstrated that angiogenesis evaluated with an anti-CD105 MoAb (CD105-IMVD) was the most important prognostic factor in resected p-stage IIIA-N2 NSCLC. Angiogenesis is an essential process in progression of malignant tumors,18 and many clinical studies have suggested that angiogenesis could be a significant prognostic factor in p-stage I NSCLC.19,20,21 With respect to p-stage IIIA-N2 disease, only one clinical study documented a prognostic value of angiogenesis; 96 patients were retrospectively reviewed, and a higher IMVD as determined with antibody to factor VIII, a pan-EC marker, was correlated with a poor prognosis.7 In the present study, IMVD as determined with a pan-EC MoAb, CD34-IMVD, was not a significant prognostic factor, whereas CD105-IMVD was a significant prognostic factor. We had demonstrated previously that CD105-IMVD is superior to CD34-IMVD in evaluation of angiogenesis in p-stage I-IIIA NSCLC.10 In the present study we focused on prognostic significance of angiogenesis in p-stage IIIA-N2 disease and again demonstrated the superiority of CD105-IMVD. In fact, several clinical studies failed to find that IMVD determined with pan-EC antibodies was a significant prognostic factor in NSCLC.6,22 These results may suggest that tumor angiogenesis should be evaluated with use of proliferation-related EC antibodies rather than pan-EC antibodies, a speculation which should be confirmed in future prospective studies. In addition, we differentiated lower-IMVD tumors and higher-IMVD tumors according to the mean IMVD as the cut-off value, but the validity of use of the mean value also should be assessed in a future study.

We also demonstrated in the present study that PI was another prognostic factor in pN2 disease. However, we failed to show that p53 status is a significant prognostic factor in pN2 disease, although we had demonstrated in previous studies that aberrant p53 status is a significant factor for prediction of a poor prognosis in p-stage I disease9 and p-stage II-N1 disease.23 Many clinical studies of the prognostic significance of p53 status in NSCLC have been conducted, but its clinical significance has not been established11; however, its prognostic significance was demonstrated in a meta-analysis.8 These results may suggest that abnormality of p53 is an early event in the development and progression of NSCLC and that an aberrant p53 status can be a significant prognostic factor in relatively early disease, such as stages I and II, but not in advanced disease such as IIIA-N2.

We demonstrated that preoperative N2 enlargement (cN2) and an increased number of involved N2 stations were significant factors for prediction of a poor prognosis, findings consistent with results documented in many clinical study reports. Ichinose and coworkers5 analyzed postoperative survival of 406 patients with p-stage IIIA-N2 NSCLC who underwent surgery at institutes of the Japanese Oncology Group and demonstrated that involvement of multiple N2 stations was the most significant factor predictive of a poor prognosis. Andre and coworkers24 demonstrated that preoperative nodal status was the most significant prognostic factor in 686 patients with pN2 disease, which was followed by involvement of multiple N2 stations. To improve the prognosis for such patients, accurate preoperative evaluation of N2 status is essential, for which purpose positron emission tomography followed by mediastinoscopy may be useful.25

In the present study, a variety of postoperative adjuvant therapies were performed, principally based on patients’ decisions. Such therapies may influence the prognostic significance of the number of involved N2 stations, cN-status, IMVD, or PI, which proved to be independent and significant prognostic factors in the present study. To establish the clinical significance, such prognostic significance should be assessed in prospective clinical studies. In previous studies, we had demonstrated that oral administration of UFT, a 5-fluorouracil-derivative chemotherapeutic agent, was effective in completely resected NSCLC, especially p-stage I disease.15,16 In the present study, postoperative survival of patients who received postoperative UFT was higher than for patients who did not, but the difference did not reach statistical significance. A multi-institutional prospective randomized study should be conducted to examine the efficacy of postoperative UFT.

In conclusion, p-stage IIIA-N2 disease cases were a prognostically heterogeneous group showing different N2 status as well as different biological features. When any prospective study to examine the efficacy of preoperative induction and/or postoperative adjuvant therapy for pN2 patients is planned, such heterogeneity should be taken into consideration.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.

Part of this article was presented at the 16th Annual Meeting of The European Association for Cardiothoracic Surgery, held in Monte Carlo, Monaco, on September 25th, 2002. This work was supported by grants-in-aid 14370410 (to FT) for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Part of this work was also supported by The Japanese Foundation For Multidisciplinary Treatment of Cancer. The authors thank Miss Seiko Sakai for helpful assistance in preparation of the manuscript.


   FOOTNOTES
 
Preoperative nodal status and the number of nodal stations involved were significant prognostic factors in resected pathologic stage IIIA-N2 non-small-cell lung cancer. In addition, increased proliferative activity and active angiogenesis were significant factors predictive of a poor survival rate.

Received for publication July 21, 2003. Accepted for publication February 25, 2004.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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